ISSN 1883-9606

2012

Vol.125

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2011 ---- March 2012

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2011-March 2012

Introduction
This is volume 125 (the edition of year 2012) of the annual report by the University of Tokyo’s
Graduate School of Medicine and Faculty of Medicine.
In it are recorded the past year’s research, educational, clinical, and other activities of the
Graduate School of Medicine and Faculty of Medicine, the International Research Center for
Medical Education, and the Tokyo Society of Medical Sciences.
It reports our accomplishments, and each year we make such a document freely available bypublishing it on compact disk and on the Internet, expecting it to be used for internal and external
evaluations.
The University of Tokyo’s Faculty of Medicine was founded 150 years ago. Since then we haveconsistently driven Japan’s progress in medical research, medical education, and clinical care, andin some fields we have become world leaders.
We have more than 1000 students in the Graduate School of Medicine, and with as many as 150
foreign researchers and students we are an international center for medical research and education.
Pursuing excellence in our research, educational, and clinical activities, we will continue meetingthe needs for tomorrow’s pioneers in medical sciences and clinical care.

Kohei Miyazono, Dean
Graduate School of Medicine and Faculty of Medicine
The University of Tokyo
October, 2012

i

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

1

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

2

Department of Structural Biology ···············································································

4

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

6

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

8

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

9

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

12

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

15

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

18

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

19

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

22

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

25

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

28

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

29

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

53

ii

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

55

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

56

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

60

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

61

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

69

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

70

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

72

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

76

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

77

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

80

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

85

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

87

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

88

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

90

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

92

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

93

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

96

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

102

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

107

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

108

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

110

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

113

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

114

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

117

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

120

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

121

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

126

iii

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

130

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

137

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

138

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

143

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

149

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

153

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

157

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

160

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

162

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.433] )Department of Transfusion Medicine ·········································································

163

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

166

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

167

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

169

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

174

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

176

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

177

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

181

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

185

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

186

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

189

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

190

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

193

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

197

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

202

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

204

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

207

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

211

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

214

iv

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

216

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

217

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

221

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

225

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

230

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

236

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

241

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 ·······················

265

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

269

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

270

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

273

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

275

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

279

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

280

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

295

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

296

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

299

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

302

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

303

v

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

306

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

309

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

313

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

315

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

316

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

319

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.265] )3. Health Services Sciences ·························································································

329

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.110] )Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.117] )Department of Clinical Information Engineering ····························································

330

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.114] )Endowed Department ···································································································

332

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

333

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

335

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 Central Clinical Facilities Division of Tissue Engineering [P.474] )Department of Clinical Epidemiology and Systems ·························································

338

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

341

Science for joint reconstruction ( See Department of Orthopaedic Surgery [P.230] )vi

Department of Molecular Neuroscience on Neurodegeneration(See Department of Neurology [P.96] )Department of Chronic Kidney Disease (CKD) ·····························································

344

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

346

Department of Molecular Vascular Endocrinology ··························································

348

Department of Continence Medicine ··········································································

351

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

353

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

356

Department of Life Support Technology (Molten) ··························································

358

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

361

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

363

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

364

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

367

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

371

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

373

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

376

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

380

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

383

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

385

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

388

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

391

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

394

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

396

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

399

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

401

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

403

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

406

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

408

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

411

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

414

Department of Quality Assessment and Control of Medical Device Sterilization ······················

418

Department of Molecular Medicinal Sciences on Metabolic Regulation ·································

420

Social Cooperation Program ···························································································

422

Department of Lipidomics ······················································································

423

Functional Regulation of Adipocytes ··········································································

425

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

427

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

428

vii

University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.121] )Respiratory Medicine (See Department of Respiratory Medicine [P.126] )Gastroenterology (See Department of Gastroenterology [P.130] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.138] )Diabetes and Metabolic Diseases (See Department of Metabolic Diseases [P.143] )Hematology and Oncology (See Department of Hematology and Oncology [P.149] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.153] )Infectious Diseases (See Department of Infectious Diseases [P.157] )Neurology (See Department of Neurology [P.96] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.186] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.160] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.197] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.207] )Hepatobiliary Pancreatic Surgery(See Department of Hepatobiliary Pancreatic Surgery [P.202] )Vascular Surgery (See Department of Vascular Surgery [P.211] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.214] )Artificial Organ and Transplantation Surgery(See Department of Artificial Organ and Transplantation Surgery [P.202] )Cardiovascular Surgery (See Department of Cardiothoracic Surgery [P.193] )Thoracic Surgery (See Department of Thoracic Surgery [P.190] )Neurosurgery (See Department of Neurosurgery [P.102] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.248] )Urology and Andrology (See Department of Urology [P.204] )Gynecologic Surgery (See Obstetrics and Gynecology [P.166] )Sensory and Motor System Medicine
Dermatology and Photolaser Medicine (See Department of Dermatology [P.217] )Ophthalmology and Vision Correction (See Department of Ophthalmology [P.236] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.230] )

431

viii

Otorhinolaryngology, and Auditory and Voice Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.241] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.245] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.221] )Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.225] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.177] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.181] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.167, 169, 174] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.93] )Radiology
Radiology (See Department of Radiology [P.61] )Central Clinical Facilities ···························································································

432

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

433

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

436

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

440

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

443

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.163] )Delivery Unit ·····································································································

447

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

448

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

450

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

452

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

454

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

457

Department of Hemodialysis & Apheresis(See Department of Nephrology and Endocrinology[P.138]
Clinical Research Support Center ··············································································

461

ix

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.53] )Department of Planning, Information, and Management(See Department of Medical Informatics and Economics [P.117] )University Hospital Medical Information Network (UMIN) Center ······································

464

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

467

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

469

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

474

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

479

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

482

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

485

Cancer Resource Center ·························································································

489

Center for Genome Medicine
Genome Informatics ··························································································

490

Clinical Genomics Department ·············································································

492

Genomic Analysis Department ··············································································

495

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

497

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

505

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

506

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

507

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

511

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

514

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

516

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

520

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

523

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

525

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

527

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

530

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

532

x

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

History
1858

May

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

Nov.

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

1859

Sep.

Shutojo was reconstructed at Shitaya Izumibashi Dohri.

1860

Oct.

Shutojo became an official medical institution of the Shogunate Government.

1861

Oct.

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

1863

Feb.

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

1868

Jul.

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

1869

1871

Feb.

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

Dec.

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

Jul.

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

1872

Aug.

A School System was established. Toko was renamed as Daiichi-Daigaku-Ku- Igakko (The First
University District Medical School).

1874

May

Daiichi-Daigaku-Ku-Igakko was renamed as Tokyo-Igakko (Tokyo Medical School).

1876

Nov.

Tokyo-Igakko was moved to Hongo.

1877

Apr.

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

1886

Mar.

The University of Tokyo was renamed as Imperial University, and The University of Tokyo
Faculty of Medicine was renamed as the Imperial University Medical College. A Graduate
School was established.

1897

Jun.

The Imperial University was renamed as Tokyo Imperial University.

1917

Aug.

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

1919

Apr.

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

1931

Feb.

The first building of the Faculty of Medicine was constructed.

1936

Jan.

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

Nov.

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

1947

Oct.

Tokyo Imperial University was renamed as The University of Tokyo.

1950

Apr.

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

1953

Apr.

The School of Health Care and Nursing was founded.

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

Jul.

xi

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

1956

Apr.

The Midwives School was established.

1958

Apr.

The Division of Pharmaceutical Sciences became an independent faculty.

May

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

Mar.

The Medical Library was built in commemoration of the centenary.

Apr.

The Institute of Medical Electronics was established.

Apr.

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

1961

1965

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

Sep.

The third building of the Faculty of Medicine was constructed.

1971

Apr.

The Laboratory of Animal Experiments was established.

1973

Mar.

The Animal Center for Biomedical Research was constructed.

1983

Jan.

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

1985

Sep.

The office of International Academic Affairs was established.

1987

Apr.

Specialized courses were introduced to the Graduate School of Medicine.

1992

Apr.

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

1995

Jul.

The Radiation Research Institute was established.

Apr.

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

1996

Apr.

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

1997

Apr.

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

1999

Apr.

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

xii

2000

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

Apr.

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

2001

Apr.

The University Branch Hospital was united with the University Hospital.

2003

Apr.

The Center for Disease Biology and Integrative Medicine was established.

2004

Apr.

All

the

National

Universities owned

by

the

Japanese

Government

becameNational University Corporations. and the University of Corporation.
2007

Apr.

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

2008

May.

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

2010

Apr.

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

2011

Jan.

The Museum of Health and Medicine was established.

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

xiii

Organization Chart
Cell Biology
Cell Biology and Anatomy

Structural Biology
Structural Cell Biology

Molecular Cell Biology

Cellular Neurobiology
Molecular Biology
Biochemistry and Molecular Biology

Cellular Signaling
Physiological Chemistry andMetabolism
Integrative Physiology

Physiology
Functional Biology

Cellular and Molecular Physiology
Neurophysiology

Pharmacology

Cellular and Molecular Pharmacology
Molecular Neurobiology
Human Pathology and Diagnostic Pathology

Pathology

Molecular Pathology
Surgical Pathology

Pathology, Immunology
and Microbiology

Microbiology

Microbiology
Infection Control and Prevention

Immunology

Molecular Immunology
Clinical Immunology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

System Physiology
Biomedical Engineering

Chemical Biology and Molecular Imaging
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology
Developmental Neuroscience

Neuroscience

Integrativ Medical Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience

Graduate School of
Medicine

Child Neuropsychiatry
Neuropsychiatry
Clinical Neuroscience

Neurology
Neurosurgery
Molecular Preventive Medicine

Occupational, Environmental andPreventive Medicine

Public HealthRadiological HealthSocial Medicine

Forensic Medicine, and Medical
Informatics and Economics

Forensic Medicine
Medical Informatics and Economics

xiv

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

Cardiovascular Medicine
Vascular Biology
Medicine I

Respiratory Medicine
Gastroenterology
Nephrology
Endocrinology

Internal Medicine

Diabetes and Metabolic Diseases
Medicine II

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

Clinical Laboratory Medicine
and Pathology

Clinical Laboratory Medicine
Transfusion Medicine

Reproductive Endocrinology
Obstetrics and Gynecology

Gynecological Oncology
Perinatal Medicine
Molecular Reproductive Endocrinology
Pediatrics

Reproductive,
Developmental andAging Sciences

Pediatric Sciences

Developmental Pediatrics
Pediatric Surgery
Pediatric Oncology

Aging Sciences

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

Surgery

Urology
Artificial Organ and Transplantation
Division
Surgical Oncology

Surgical Sciences

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

Orthopaedic Surgery
Ophthalmology
Otorhinolaryngology and Head & Neck
Surgery
Rehabilitation Medicine

Vital Care Medicine

Anesthesiology
Emergency and Critical Care Medicine

xv

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012
Health Sociology
Mental Health
Epidemiology and Preventive Health
Sciences
Health Sciences

Social Gerontology
Health Promotion Sciences
Biostatistics
Biomedical Ethics

Health Sciences andNursing

Advanced Clinical Nursing
Nursing Administration
Preventive and Administrative
Nursing

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

Clinical Nursing

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

International Social Medicine

Global Health Policy
Community and Global HealthInternational Health

Human Genetics
International Biomedical
Sciences

Developmental Medical Sciences
Human Ecology
Biomedical Chemistry

Medical Science (Master’s Program)

Biostatistics
Social and Preventive Epidemiology
Epidemiology and Health Sciences

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
Healthcare Informatics

Health Services Sciences

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. 125, October 2012
Office of International Academic Affairs
Institution

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

Endowed Department

Clinical Motor System Medicine
Health Care Safety Management(Tokio Marine & Nichido)
Molecular Cardiovascular Metabolism
Healthcare Quality Assessment
Anti-Aging Medicine
Nutriproteomics
Clinical Epidemiology and Systems
Clinical Trial Data Management
Pharmacology and Pharmacokinetics
Ubiquitous Preventive Medicine
Science for Joint Reconstruction
Therapeutic Strategy for Heart Failure
Molecular Neuroscience on Neurodegeneration
Chronic Kidney Disease
Molecular Structure and Dynamics(JEOL/Zeiss)
Molecular Vascular Endocrinology
Medical Genomics
Molecular Psychiatry
Continence Medicine
Department of Life Support Technology (Molten)
Quality Assessment and Control of Medical Device Sterilization
Youth Mental HealthMolecular Medicinal Sciences on
Metabolc Regulation
Clinical Renal Regeneration

Social Cooperation Program

General Affairs Office
Personnel Office
Research Liaison

Ubiquitous Health Informatics

Educational Affairs

Lipidomics

Graduate Student Affairs

Functional Regulation of Adipocytes

Buget Office

Administrative office

Purchasing Office

xvii

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

Faculty of Medicine
Graduate School of
Medicine

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

Administrative Office

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

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

Faculty of
Medicine

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

Midwifery and Women’s Health
Adult Health and Nursing
Mental Health and Nursing
Health Sociology
Health Administration
Epidemiology and Biostatistics
Human Ecology
Biochemistry and Nutrition
Maternal and Child HealthxviiiThe Tokyo Journal of Medical Sciences. Vol. 125, October 2012

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

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

ClinicalDivisions

Neurology
Geriatric Medicine
Psychosomatic Medicine
General Surgery
Stomach and Esophagus Surgery

University
Hospital

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

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

Sensory and Motor System
Medicine

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

Pediatrics, Perinatal and
Women's Medicine

Pediatric Surgery

Neuropsychiatry

NeuropsychiatryRadiology

Obstetrics and Gynecology

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

Central Clinical Facilities

Emergency Services
Blood Transfusion
Perinatal Center
Rehabilitation Service
Medial Engineering

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

xix

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

Central Supply Service
Intensive Care Unit
Pathology
Corneal Transplantation
Department of Cell a Therapy and Transplantation Medicine
Department of Endoscopy and Endoscopic Surgery
Department of Hemodialysis and Apheresis
Department of Medical Community Network
Clinical Research Center
Infection Control and Prevention Service
Department of Planning, Information, and Management
University Hospital Medical Information Network Center
Organ Transplantation Service
Department of Nutrition
Labor Safety and Health Management Office
Department of Child Psychiatry
Tissue Bank
Epidemiology and Preventive Medicine
Cancer Resource Center
Center for Liaison and Public Relations
Database Center of the National University Hospitals
Outpatient Chemotherapy Department
Neonatal and Pediatric Intensive Care Unit
Department of Health Record Management
Critical Care Center
Clinical Research Support Center
22nd Century Medical and Research Center
Tissue Engineering
Clinical Research Division

Cooperative Unit of Medicine and Engineering Research
Translation Research Center
Center for Genome Medicine
Unite for Early and Exploratory Clinical Department

Organization of ClinicalManagement Support

Personnel Administration and
Human Resource Management

Hospitality Center

Performance Monitoring,
Risk Management, and Staff
Development

Education andResearch support

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

Inpatient Services
Administration

Cancer Board

Hospital Planning andManagement

Organization of ClinicalManagement

Outpatient Services
Administration
Central Clinical Services
Administration

Medical Specialists
Training Center

Pediatric Medical Center

Vascular Board

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012xx

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

Kohei Miyazono(Dean, Faculty of Medicine)
Chairman, School of Health Sciences and Nursing

Yasuo Ohashi

Director, Medical LibraryKazuhiko Ohe

Director General, University Hospital

Takashi Kadowaki

Director, Center for Disease Biology and Integrative Medicine

Masamitsu Iino

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. 125, October 2012

xxi

Department of Integrative Medical Neuroscience
Department of Clinical Neuroscience

professor

Kiyoto Kasai

professor

Shoji Tsuji

professor

Nobuhito Saito

Department of Occupational, Environmental and Preventive

professor

Koji Matsushima

Medicine

professor

Yasuki Kobayashi

Department of Forensic Medicine, and Medical Informatics

professor

Kenichi Yoshida

and Economics

professor

Kazuhiko Ohe

professor

Ryozo Nagai

professor

Takahide Nagase

professor

Kazuhiko koike

professor

Toshiro Fujita

professor

Takashi Kadowaki

professor

Mineo Kurokawa

professor

Kazuhiko Yamamoto

professor

Akira Akabayashi

professor

Yutaka Yatomi

professor

Koki Takahashi

professor

Yuji Taketani

professor

Shiro Kozuma

professor

Takashi Igarashi

professor

Tadashi Iwanaka

professor

Yasuyoshi Ouchi

professor

Jun Nakajima

professor

Minoru Ono

professor

Yasuyuki Seto

professor

Norihiro Kokudo

professor

Yukio Homma

professor

Shinichi Sato

professor

Isao Koshima

professor

Tsuyoshi Takato

Professor

Sakae Tanaka

professor

Shiro Amano

professor

Tatsuya Yamasoba

professor

Nobuhiko Haga

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II

Department of Clinical Laboratory Medicine and Pathology

Reproductive, Developmental and Aging Science
Department of Obstetrics and Gynecology

Department of Pediatric Science

Department of Aging Science
Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

xxii

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

Department of Vital Care Medicine

Professor

Yoshitsugu Yamada

professor

Naoki Yahagi

professor

Norito Kawakami

professor

Yasuo Ohashi

professor

Ichiro Kai

professor

Akira Akabayashi

professor

Katsuya Kanda

professor

Sachiyo Murashima

professor

Noriko Yamamoto

professor

Norito Kawakami

professor

Hiromi Sanada

professor

Sachiyo Murashima

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

Norito 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. 125, October 2012

xxiii

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

professor

Toru Miyazaki

Laboratory of Structural Physiology

professor

Haruo Kasai

Laboratory of Regenerative Medical Engineering

professor

Takashi Ushida

Laboratory of Clinical Biotechnology

professor

Kazunori Kataoka

Laboratory of Environmental Health Sciences

professor

Chiharu Tohyama

Laboratory of Animal Resources

professor

Atsu Aiba

Laboratory of Molecular Radiology

professor

Kiyoshi Miyakawa

International Academic Affairs

professor

Yasuyuki Seto

Medical LibraryProfessor

Kazuhiko Ohe

Medical Scientist Training Program

Professor

Masahide Kikkawa

Museum of Health and Medicine

Professor

Kazuhiko Ohe

professor

Kiyoshi Kubota

Associate professor

Soko Setoguchi

Department of Integrated Traditional Medicine(Tsumura)

Associate professor

Tetsuro Okabe

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

Associate professor

Hiroyuki Koyama

Department of Bone & Cartilage Regenerative Medicine

Associate professor

Taku Saito

Department of

Associate professor

Kazuto Hoshi

Associate professor

Keiichi Hishikawa

Division of Research Resources and Support

Faculty of Medicine
Endowed Departments
Department of Pharmacoepidemiology

Cartilage & Bone Regeneration(Fujisoft)

Department of Clinical Renal Regeneration

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

Takanari Gotoda

Immunotherapeutics (Medinet)

Associate professor

Kazuhiro Kakimi

Total Renal Care Medicine

Associate professor

Akira Ishikawa

Integrated Molecular Science on Metabolic Diseases

Associate professor

Hara Kazuo

Department of Advanced Clinical Science and Therapeutics

Associate professor

Junichi Suzuki

Associate professor

Yasunobu Hirata

Ischemic Circulatory Physiology, Kaatsu Training

Associate professor

Toshiaki Nakajima

Translational Research for Healthcare and Clinical Science

Associate professor

Hiroyuki Morita

Department of Joint Disease Research

Associate professor

Noriko Yoshimura

Health Management and Policy

Associate professor

Hideo Yasunaga

Computational Diagnostic Radiology and Preventive Medicine

Associate professor

Naoto Hayashi

Associate professor

Kansei Uno

Clinical Motor System Medicine

Associate professor

Toru Akune

Medical Safety Management (Tokio Marine & Nichido)

Professor

Yasushi Kodama

Associate professor

Katsuyuki Ando

Molecular Cardiovascular Metabolism (Daiich-Sankyo Company, Limited)xxiv

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

The Department of Healthcare Quality Assessment

Associate professor

Hiroaki Miyata

Anti-Aging Medicine

professor

Satoshi Inoue

Integrated Imaging Informatics

Associate professor

Naoki Yoshioka

The Department of Nutriproteomics

professor

Kazumi Yagasaki

Clinical Epidemiology and Systems

professor

Tsutomu Yamazaki

Associate professor

Daisuke Koide

Clinical Trial Data Manegement

Associate professor

Takuhiro Yamaguchi

Pharmacology and Pharmacokinetics

Associate professor

Akihiro Hisaka

Ubiquitous Preventive Medicine

Associate professor

Toru Suzuki

Science for joint reconstruction

professor

Yoshio Takatori

Associate professor

Toru Moroprofessor

Shunei Kyo

Associate professor

Takashi Nishimura

Department of Molecular Neuroscience on Neurodegeneration

Associate professor

Atsushi Iwata

Department of Chronic Kidney Disease

Associate professor

Miki Nagase

Department of Molecular Structure and Dynamics (JEOL/Zeiss)

professor

Nobutaka Hirokawa

Department of Molecular Vascular Endocrinology

Associate professor

Masashi Isshiki

Department of Medical Genomics

professor

Hiroyuki Mano

Associate professor

Young Lim Choi

Department of Molecular Psychiatry

Associate Professor

Kazuya Iwamoto

Continence medicine

Professor

Yasuhiko Igawa

Department of Life Support Technology (Molten)

Associate Professor

Taketoshi Mori

Quality assessment and control of medical device sterilization

Associate Professor

Yushi Uetera

Department of Youth Mental Health

Associate Professor

Tsuyoshi Araki

Department of Molecular Medicinal Sciences on Metabolic Regulation

Professor

Hiroaki Okazaki

Department of Ubiquitous Health Informatics

Associate Professor

Hideo Fujita

Department of Lipidomics

Professor

Takao Shimizu

Associate Professor

Yoshihiro Kita

Associate Professor

Hironori Waki

Director

Kazuhiko Yamamoto

professor

Kiyoshi Kitamura

General Medicine

Head

Takahide Nagase

Cardiovascular Medicine

Head

Ryozo Nagai

Respiratory Medicine

Head

Takahide Nagase

Department of Therapeutic Strategy for Heart Failure

Social Cooperation Program

Functional Regulation of Adipocytes

International Research Center for Medical Education

University Hospital
Clinical Divisions

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012xxv

Gastroenterology

Head

Kazuhiko Koike

Nephrology and Endocrinology

HeadToshiro Fujita

Diabetes and Metabolic Medicine

Head

Takashi Kadowaki

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Kazuhiko Yamamoto

Infectious Diseases

Head

Hiroshi Yotsuyanagi

Neurology

Head

Shoji Tsuji

Geriatric Medicine

Head

Yasuyosi Ouchi

Psychosomatic Medicine

Head

Akira Akabayashi

General Surgery

Head

Norihiro Kokudo

Stomach and Esophagus Surgery

Head

Yasuyuki Seto

Colon and Rectal Surgery

HeadJoji Kitayama

Hepatobiliary Pancreatic Surgery

Head

Norihiro Kokudo

Vascular Surgery

Head

Tetsuro Miyata

Breast and Endocrine Surgery

HeadToshihisa Ogawa

Artificial organ and Transplantation Surgery

Head

Norihiro Kokudo

Cardiovascular Surgery

HeadMinoru Ono

Thoracic Surgery

Head

Jun Nakajima

Neurosurgery

Head

Nobuhito Saito

Anesthesiology and Pain Relief Center

Head

Yoshitsugu Yamada

Urology and Andrology

Head

Yukio Honma

Gynecologic Surgery

Head

Tetsu Yano

Dermatology and Photolaser Medicine

Head

Shinichi Sato

Ophthalmology and Vision Collection

Head

Shiro Amano

Orthopaedic Surgery and Spinal Surgery

Head

Sakae Tanaka

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

Yuji Taketani

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

Central Clinical Facilites

xxvi

The Tokyo Journal of Medical Sciences. Vol. 125, October 2012

Blood Transfusion

Head

Koki Takahashi

Perinatal Center

Head

Shiro Kozuma

Rehabilitation Service

Head

Nobuhiko Haga

Central Supply Service

Head

Hisayoshi Tamai

Department of Medical Engineering

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoki Yahagi

Division of Diagnostic Pathology

Head

Masashi Fukayama

Corneal Transplantation

Head

Shiro Amano

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Department of Endoscopy and Endoscopic Surgery

Head

Mitsuhiro FujisiroCenter for Hemodialysis and Apheresis

Head

Toshiro Fujita

Medical Community Network

Head

Yasuyoshi Ouchi

Clinical Research Support Center

Head

Nobuhito Saito

Infection Control and Prevention Service

Head

Kyoji Moriya

Department of Planning, Information and Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Organ Transplantation Service

Head

Norihiro Kokudo

Department of Child Psychiatry

Head

Yukiko Kano

Tissue Bank

Head

Noboru Motomura

Cancer Resource Center

Head

Sachiyo Nomura

Center for Liaison and Public Relations

Head

Kazuhiko Ohe

Outpatient Chemotherapy Department

Head

Norihiro Kokudo

Neonatal and Pediatric Intensive Care Unit

Head

Arata Murakami

Department of Health Record Management

Head

Yasuyoshi Ouchi

Critical Care Center

Head

Susumu Nakajima

Division of Tissue Engineering

Head

Tsuyoshi Takato

Department of Clinical and Genetic Informatics

Head

Ryozo Nagai

Department of Palliative Medicine

Head

Keiichi Nakagawa

Department of Clinical Genomics

Head

Shoji Tsuji

Cooperative Unit of Medicine and Engineering Research

Head

Tetsuro Miyata

Translational Research Center

Head

Ryozo Nagai

22nd Century Medical and Research Center

Head

Tuyoshi Takato

Pharmaceutical Department

Head

Hiroshi Suzuki

Epidemiology and Preventive Medicine

The University of Tokyo,
Graduate School of Medicine

Molecular Cell Biology
1. Cell Biology and Anatomy

2

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

Associate
Yasushi Okada, M. D.,

Yosuke Tanaka, M. D.,

Noriko Homma, Ph. D.,

Harukata Miki, Ph. D.,

Homepage

Ryo Nitta, M. D.,

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

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

Research activities
Our research field covers the molecular cell biologyof the cytoskeleton. We focus on the molecularmechanisms of cell morphogenesis and intracellulartransports.
Our laboratory studies molecular architecture,dynamics and function of the neuronal cytoskeleton
using various new molecular cell 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
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 new3molecular cell biological approaches including
electron microscopy of molecular resolution,
biochemistry, biophysics, molecular biology andmolecular genetics and X-ray crystallography.

References
1. Yin, X,. Y. Takei, M. Kido and N. Hirokawa.
Molecular motor KIF17 is fundamental for
memory and learning via differential support ofsynaptic NR2A.2B levels. Neuron 70; 310-325,
2011
2. Nakata, T., S. Niwa, Y. Okada, F. Perez, and N.
Hirokawa. Preferential binding of a kinesin-1
motor to GTP-tubulin–rich microtubules underlies polarized vesicle transport. J Cell Biol 194:245-255, 2011.
3. Hirokawa, N. From electron microscopy tomolecular cell biology, molecular genetics andstructural biology: intracellular transport andkinesin superfamily proteins, KIFs: genes,
structure, dynamics and functions.
J Electron Microscopy 60 (Supplement 1) (60thAnniversary Issue: Biological): S63–S92, 2011.
4. Noda Y., S.Niwa, N.Homma, H. Fukuda, S.
Imajo-Ohmib, and N. Hirokawa. Phosphatidylinositol 4-phosphate 5-kinase alpha (PIPKα)regulates neuronal microtubule depolymerasekinesin, KIF2A and suppresses elongation ofaxon branches. Proc Natl Acad Sci, U.S.A
109:1725-1730, 2012.
5. Hirokawa N., Y. Tanaka, and Y. Okada. Cilia,
KIF3 Molecular Motor and Nodal Flow. Curr
Opi Cell Biol 24:31-39, 2012.
6. Kondo, M., Y. Takei, and N. Hirokawa. Motorprotein KIF1A is essential for hippocampal
synaptogenesis and learning enhancement in anenriched environment. Neuron 73: 743-757,
2012.
7. Yin, X., X. Feng, Y. Takei, and N. Hirokawa.
Regulation of NMDA Receptor Transport: A
KIF17-cargo
Binding/Releasing
Underlies
Synaptic Plasticity and Memory in vivo.
J Neurosci 32: 5486-5499, 2012.
8. Yajima, H., T. Ogura, R. Nitta. Y. Okada, C.Sato,and N. Hirokawa.
Conformational changes in tubulin in GMPCPP

and GDP-taxol microtubules observed bycryoelectron microscopy. J Cell Biol 198: 315322, 2012
9. Nakajima, K., X. Yin, Y. Takei, D-H. Seog, N.
Homma, and N. Hirokawa.
Molecular motor KIF5A is essential for GABA A
receptor transport to neuronal surface and is
involoved in inhibitory transmission. Neuron inpress, 2012

4

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

Lecturer
Toshiki Yagi, Ph.D.

Associate
Toshiyuki Oda, Ph. D., Haruaki Yanagisawa, Ph. D.

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

Research activities

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.

Our lab focuses on the structure and function of
eukaryotic flagella/cilia. Flagella/cilia is both“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.

Currently the lab members includes: Masahide
Kikkawa (Professor), Toshiki Yagi (Lecturer),
Toshiyuki Oda (Jokyo), Haruaki Yanagisawa (Jokyo),Toshiharu Sano, Yuma Tani, and Shohei Fujita(student), Oosakaya (Technician) and Yuka Kimura(secretary).

To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope in combination with genetic manipulations.

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

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 to obtain sub-nanometer resolution of macromolecular complexes such as axonemes. We havebeen developing new techniques, such as asymmetrichelical reconstruction and Ruby-Helix software.
By using these new techniques, we are currently
studying dynein-microtubule complex, dynein stalkmicrotubule complex to elucidate the mechanism of

5dynein’s motor functions.
Model Organism
Our lab currently uses Chlamydomonas as a modelorganism for studying flagella. To identify moleculesthat are involved in regulating dynein, we use various
genetic tools, including classical mutagenesis, siRNA.
In addition, we are also developing 3D-tracking
microscopy in collaboration with Dr. Oku in
Department of Engineering. We are trying to track
Chlamydomonas cells and simultaneously record
flagella movement to elucidate the mechanism offlagella regulation.

References

6

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

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

Homepage

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

Introduction and Organization
The Department of Cellular Neurobiolgy was
initially established as Neuroanatomy department offormer Brain Institute of Medical School of Imperial
University of Tokyo in 1936. Since the structural
reconstruction of School of Medicine in 1997 thisdepartment became one of the departments of Cell
Biology and Anatomy of Graduate School of Medicine.
This department is currently organized by Professor
Shigeo Okabe since September in 2007. The
department is constituted of other 21 members.

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

Research activities
Brain functions, which are dependent on mutualcommunication of a tremendous number of neuronalcells, regulate the behavior of animals and humans.
The main structure specifically differentiated for
information exchange between neurons is called"synapse". Long-term maintenance of synaptic
properties underlies stability and reproducibility of
behavior in responses to external stimuli. In turn,
alterations of synaptic properties are thought to be thebasis of behavioral change in the course of animal
development and also after learning. Therefore,
synapses should be stabilized for a long term to realize
fidelity of various animal behaviors, but also shouldbe altered rapidly when animals adapt to a newenvironment. Molecular basis of this dichotomy,
which is unique to synapses, is the main interest of ourlaboratory.
Synapse formation during development
Synapse is one of the major elements to transduce
information from neuron to neuron. Most of thesynapses are formed during the early development andthereafter they become stable after the intensive
pruning. We are interested in how synapse is formed
and maintained.
The postsynaptic densities (PSDs) are protein dense
structures which are located closely to postsynaptic
membranes. PSDs include a variety of receptors,
scaffolding proteins and signaling molecules. We
focus on some PSD proteins and examine their roles
in synapse formation and maintenance.
Two-photon excitation microscopy allows imagingof living brain. We examine synapse remodeling invivo by observing the postsynaptic structures and7some PSD proteins tagged by fluorescent proteins. We
are also investigating abnormality of synapse
remodeling in developmental disorders by using somemouse models. Our laboratory is investing theproperties and molecular basis of synapses in vitro
and in vivo by various imaging techniques.

Publications
1. Kondo, S., Kohsaka, S., and S. Okabe.
Long-term changes of spine dynamics andmicroglia after transient peripheral immune
response triggered by LPS in vivo.
Molecular Brain 4, 27, 2011.
2. Kusano K, Enomoto M, Hirai T, Wakabayashi Y,
Itoh S, Ichinose S, Okabe S, Shinomiya K, and A.
Okawa. Enhancement of sciatic nerve regeneration
by adenovirus-mediated expression of dominantnegative RhoA and Rac1. Neuroscience Letter 492,
64-69, 2011.

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/※ The following information is the same as that of the previous year for certain reasons.

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

10

ABO blood type antigens.
Professor Masami Muramatsu graduated The
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 intra-cellular pathways
mediating signals for cellular anchorage to
extra-cellularmatrices–theTSC1/TSC2-Rheb-mTORC1 pathway
A key to understand the molecular basis formalignant transformation is elucidation of signal
pathways that mediate anchorage signals andcontrol expression and activity of cell cycle startfactors including Cdc6 and cyclin A. We haveidentified that the TSC1/2-Rheb-mTORC1
pathway mediates an anchorage signal andcontrols Cdk4/Cdk6 activity.
Integrins bound to the extracellular matrix
allow GTP-bound Rho A to activate ROCK.
Activated ROCK controls assembly of the actin
filaments, thereby regulating cell shape andmotility. In addition, activated ROCK activates
mTORC1 via inactivating Tsc2 by directly
phosphorylating Thr1203. Activated mTORC1
activates Cdk4/Cdk6, which in turn inactivates Rb,
and therefore activates E2F, resulting in inductionof Emi1 as well as Cdc6 and Cyclin A. Induced
Emi1 inactivates the APC/CCDH1 ubiquitin ligase,
thereby suppressing degradation of Cdc6 andCyclin A. This finding strongly suggests that the
Tsc1/2-Rheb-mTOR cascade serves a majortransduction pathway for the anchorage signal tocontrol the G1-S transition. How does mTORC1
control Cdk4/Cdk6 activity? We still do notknow the mechanism, but it seems to involve anever anticipated mechanism independent of CKI
and cyclin availability.
2. Identification of the intra-cellular pathways
mediating signals for cellular anchorage to
extra-cellular matrices – the anchorage signal
pathway to activate Cdk2
One remaining question regarding the anchorage
signal cascade to control the G1-S transition in thecell cycle is: how does anchorage signal regulate
Cdk2 activity. When cells traverse G1 phase,
Cdk2 is inactivated mainly by p27 until S phase
onset. We solved this question. We initially foundthat when CKI-resistant Cdk6/cyclin D3 complex
is overexpressed in anchorage-deprived rat
embryonic fibroblasts, Cdk2 remains active atleast for initial 36 hr. Detailed analysis revealed
the following cascade reactions. Overexpressionof Cdk6/cyclin D3 stabilizes Pim1, an oncogene
product inactivated by proviral insertion of mouse
leukemia virus, and activates ROCK in theabsence of anchorage. Activated Pim1 and ROCK
phosphorylate the C-terminus of free orCdk2-bound p27. Cdc6 then activates the Cdk2 byutilizing ATP hydrolysis energy.
Thus, ROCK-mediated C-terminal p27
phosphorylation and subsequent activation of the
p27-bound Cdk2 by Cdc6 are the rest of theanchorage signal cascade that regulates the G1-Stransition. Consequently, overexpression of
Cdk6/cyclin D3, Cdc6 and active Rheb to activate
mTORC1 conferred on rat embryonic fibroblasts
the ability to proliferate in anchorage-free soft

11

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

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

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

12Department of Cellular Signaling
Professor
Takao Shimizu, M,D., Ph.D.

Associate Professor
Motonao Nakamura, Ph.D.

Research Associate
Hideo Shindou, Ph.D., Keisuke Yanagida, Ph.D.

Homepage

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

Introduction and Organization

Research

In addition to the above 4 faculty members, wehave 4 graduate students (3 doctor course students and1 master course student), and 7 undergraduate medical
students (Free Quarter and others). Three postdoc
scientists and several clinical researchers are also ourmembers. We have a foreign scientist (postdoc) from
Germany. Ms. Toshie Takahashi (Assistant belongs
to the Dean of the Faculty), Ms. Fumie Hamano(Research associate) and Mr. Shinji Ichihara(Technical staff) are in charge of maintenance andeducation of various instruments for common use.
Professor Takao Shimizu was awarded Japan
Academy Prize in June 2009.

1. Lipid mediator and lipid metabolism.
Oxygenated products of arachidonic acid (prostaglandins, leukotrienes, and hydroxyeicosatetraenoic
acids) as well as bioactive phospholipids (plateletactivating factor and other related phospholipids)
activate cellular signaling pathways in various cells.
These lipid mediators, working together with otherbioactive substances such as neurotransmitters andcytokines, are now considered to play significant roles
in neuronal plasticity and self-defense systems. To
identify the roles of lipid mediators in the living
systems, principally three approaches are ongoingwith different strategies; (1) isolation of enzymes
involved in syntheses and degradation of lipid
mediators, cloning of cDNAs and genes, elucidationof enzyme regulation at transcriptional and posttranscriptional levels; (2) cloning of G-protein
coupled receptors for lipid mediators and clarificationof intracellular trafficking and signaling mechanisms;
and (3) target disruption or overexpression of the geneof interest in mice, and identification of the in vivorole of each molecule by examining phenotypes ofthese mice. In the last several years we have cloned
several key enzymes of phospholipid metabolism andreceptors for lipid mediators. Recently, we havesuccessfully identified several lysophospholipid acyltransferases involved in Lands’ cycle. Thus, we areable to explain the molecular mechanism and

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 2011 is over
30. For graduate course students, we have threemonth lecture series and one-week practical training(Lecture on receptor and signal transduction), and aneight-week laboratory course for clinical scientists
from the University Hospital.

13

biological significance of diversity and asymmetry ofmembrane glycerophospholipids. Several lines oftransgenic mice and knock-out mice were establishedand their phenotypes were analyzed. We found thatthese mediators are involved in inflammation, allergy,
and neuronal functions.
2. Simultaneous quantitation of lipid mediators(lipidomics).
Lipid mediators are produced through a cascade
pathway. In the cascade known as “arachidonate
cascade”, several key enzymes such as cytosolic
phospholipase A2, cyclooxygenases (Cox-1, Cox-2),
and lipoxygenases function as common regulators incombination with various terminal synthases that
produce specific molecular species of lipid mediators.
For a comprehensive analysis of lipid mediators, asimultaneous quantitation method with high sensitivity and reliability is necessary. Thus, we haverecently developed a quantitation system for multiplex
lipid mediators by column-switching HPLC–tandem
mass spectrometry (LC-MS/MS). When optimized,
the system enables the rapid analysis of 14 lipid
mediators with a throughput of 96 samples/24 h, lower
limits of quantitation of 5 pg on column, and dynamic
calibration ranges up to 2,000–5,000 pg. Indeed, we
successfully detected dynamic changes in a series oflipid mediators in some pathologic tissues of rodents.
3. Various instrumental analyses.
The Faculty of Medicine has various analyticaland preparative instruments for the common use,which include mass spectrometers (LCMS-IT-TOF,
AXIMA, Performance [Shimadzu], Exactive, TSQ
7000, TSQ Quantum Ultra, LCQ [Thermo Fischer],
Q-TOF micro [Waters], Q-TOF micro [JASCO], and4000 Q TRAP [AB Sciex]) equipped with gas
chromatographs or HPLC, PerkinElmer peptide
sequencers, FUJI BAS 2000 image analyzer, BD
FACScan, and Beckman capillary electrophoresis
system (P/ACE 2000). Ms. Takahashi is in charge ofthe maintenance of these machines and instruction forthe beginners.
As her own projects, she isidentifying peptide sequences of various proteins by
HPLC-MS, and identification of small-molecularweight compounds by GC-MS and HPLC-MS.

4. Internet Web site
To see our research activities in more detail,please refer to our web site (http://biochem2.umin.jp/
index_j.html). In 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 Lipidomics
Department of Metabolome (2003-2011) and
Department of Lipidomics (2011-present) have been
established by the donation of Shimadzu Co., Ltd, and
Ono Pharmaceutical Co. In collaboration with thisdepartment, we are searching for novel lipid mediatorsthat 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 anovel 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 pumonary
surfactant.
These research are supported by
Grant-in-Aids from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan, theMinistry of Health, Labour, and Welfare of Japan(Health and Labour Sciences Research Grants),
Nanobio Integration Program of the University ofTokyo, and a global COE program.

Publications
1.

2.

3.

Taniguchi, M., Masuda, T., Mikami, Y., Kimura,M., Yoshida, T., Mishina, M., and Shimizu, T.
Identification and characterization of a novel
zebrafish semaphorin. Neurosci. Lett., 2011; 488:
215-220
Jonson, F., Mancardi, DA., Kita, Y., Karasuyama,
H., Iannascoli, B., Rooijen, NV., Shimizu, T.,
Daeron, M., and Bruhns, P. Mouse and humanneutrophils induce anaphylaxis. J. Clin. Invest.,
2011; 121: 1484-1496
Doi,K., Hamasaki, Y., Noiri, E., Nosaka, K.,
Suzuki, T., Toda, A., Shimizu, T., Fujita, T.,
Nakao, A. Role of leukotriene B4 in accelerated
hyperlipidaemic renal injury. Nephrology, 2011;14

16: 304-309
4. Tanaka, K., Yamamoto, Y., Ogino, K., Tsujimoto,S., Saito, M., Uozumi, N., Shimizu, T., Hisatome,
I.
CytosolicPhospholipase
A2{alpha}
Contributes to Blood Pressure Increases andEndothelial Dysfunction Under Chronic NO
Inhibition. Arterioscler. Thromb. Vasc. Biol.,2011; 31: 1133-1138
5. Soontrapa, K., Honda, T., Sakata, D., Yao, C.,
Hirata, T., Hori, S., Matsuoka, T., Kita, Y.,
Shimizu, T., Kabashima, K., Narumiya, S.
Prostaglandin E2-prostoglandin E receptor
subtype 4 (EP4) signaling mediates UV
irradiation-induced systemic immunosuppression.
Proc. Natl. Acad. Sci. U. S. A., 2011; 108: 66686673
6. Nakamura, M., and Shimizu, T. Leukotriene
Receptors. Chem. Rev., 2011; 111: 6231-6298
7. Koeberle, A., Shindou, H., Harayama, T., Yuki,
K., Shimizu, T. Polyunsaturated fatty acids areincorporated into maturating male mouse germ
cells by lysophosphatidic acid acyltransferase 3.
FASEB J. 2011; 26: 169-180
8. Ueno, N., Taketomi, Y., Yamamoto, K.,
Hirabayashi, T., Kamei, D., Kita, Y., Shimizu, T.,
Shinzawa, K., Tsujimoto, Y., Ikeda, K., Taguchi,R., Murakami, M. Analysis of two major
intracellular phospholipase A2s in mast cells
reveals crucial contribution of cPLA2alpha, not
iPLA2beta, to lipid mobilization in proximal
mast cells and distal fibroblasts. J. Biol. Chem.
2011; 286: 37249-37263
9. Lopez-Vales, R., Ghasemlou, N., Redensek, A.,
Kerr, BJ., Barbayianni, E., Antonopoulou, G.,
Baskakis, C., Rathore, KI., ConstantinouKokotou, V., Stephens, D., Shimizu, T., Dennis,
EA., Kokotos, G., David, S. Phospholipase A2
superfamily members play divergent roles after
spinal cord injury. FASEB J. 2011; 25:
4240-4252
10. Jonsson, F., Mancardi, DA., Zhao, W., Kita, Y.,
Iannascoli, B., Khun, H., van Rooijen, N.,
Shimizu, T., Schwartz, LB., Daeron, M., Bruhns,
P. Human FcγRIIA induces anaphylactic andallergic reactions. Blood 2012; 119: 2533-2544
11. Saito, Y., Watanabe, K., Fujioka, D., Nakamura,T., Obata, J., Kawabata, K., Watanabe, Y.,

12.

13.

14.

15.

Mishina, H., Tamaru, S., Kita, Y., Shimizu, T.,
Kugiyama, K. Disruption of group IVA cytosolic
phospholipase
A2
attenuates
myocardialischemia-reperfusion injury partly throughinhibition of TNFa-mediated pathway. Heart Circ.
Physiol., 2012; 302: H2018-H2030
Sasaki, F., Okuno, T., Saeki, K, Min, L., Onohara,N., Kato, H., Shimizu, T., Yokomizo, T. A
high-affinity monoclonal antibody against the
FLAG tag useful for G-protein-coupled receptor
family. Anal. Biochem., 2012; 425: 157-165
Ishihara, K., Miyazaki, A., Nabe, T., Fushimi, H.,
Iriyama, N., Kanai, S., Sato, T., Uozumi, N,
Shimizu, T. Beneficial effects of Group IVA
phospholipase A2 deficiency on the progressionof hepatic fibrosis. FASEB J., 2012, in press
Echigo, R., Shimohata, N., Karatsu, K., Yano, F.,
Kayasuga-Kariya, Y., Fujisawa, A., Ohto, T., Kita,
Y., Nakamura, M., Suzuki, S., Mochizuki, M.,
Shimizu, T., Chung, U-i., and Sasaki, N.
Trehalose treatment suppresses inflammation,oxidative stress, and vasospasm induced byexperimental subarachnoid hemorrhage. J.
Translational Medicine, 2012 in press
Koeberle, A., Shindou, H., Harayama, T.,
Shimizu, T. Palmitoleate is a mitogen, formed
upon stimulation with growth factors, andconverted to palmitoleoyl-phosphatidylinositol., J.
Biol. Chem., 2012 , in press

15

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

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kouichi Nishiyama, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html※ The following information is the same as that of the previous year for certain reasons.

Introduction and Organization

scientific discussion.

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.

Research Activities

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

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 and16cell motility. We further identified TAZ as a proteinthat binds to and coactivates Pax3, a key transcription factor in neural crest development and its rolein the organogenesis of the kidney and lung as
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 stressduring preimplantation development. Sirt3 inactivation increased mitochondrial ROS production,
leading to the upregulation of p53 and changes indownstream gene expression. p53 inactivation
improved developmental outcome of Sirt3knockdown embryos, indicating that the ROS-p53
pathway is responsible for the developmental
defects. These findings may contribute to theunderstanding of preimplantation biology and give aclue to the better outcome of assisted 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)

(3)

(4)

(5)

(6)

2. Mouse Genetics
Collaborative works as follows are going on byusing gene manipulation approach in mice.
(1) Physiological roles of vasoactive peptides(2) Pathophysiological roles of defensin(3) Developmental roles of non-coding RNA

References(1)

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. 120: 28172828, 2010.

(7)

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

17

(8)

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

Functional Biology
1. Physiology

19

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

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

Research Associate
Toshiyuki Hirabayashi, Ph.D.,

Homepage

Masaki Takeda, Ph.D.,

Takahiro Osada, Ph.D.

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

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

Teaching activities
The staff members as well as experts from otheruniversities (Drs. A. Nambu, S. Kaname, S. Sugiuraand A. Mori) 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 new electrocardiogram experiment in humans was introduced to thelaboratory course, in which students learned humanphysiology of electrocardiogram, its practicalprocedure in clinical settings and its cellularphysiological origins. This practice gained popularity
and interest among students. We accept Free-Quarter
students every year. Usually these students' activities
are not limited to one Quarter, and 2 students
continued to enjoy their researches from 2010 through2012. Some of these students completed their own
projects, and gave oral presentations in international
meetings and published original papers in top-rankinternational journals. It is not rare that students who
enjoyed his/her Free-Quarter decided to get into the
Ph-D. course after the completion of the 2-year
clinical training and started to study neurophysiology
in our laboratory. Furthermore, we accepted a
Ph-D.-M.D course student who enjoyed his FreeQuarter and decided to get into the Ph-D.-M.D course.
Thus the Free-Quarter system has proved to provide
an excellent basis for bringing up M.D. researchers for
future Japanese basic medicine.
To facilitate communication among research groups
in our laboratory, a weekly conference is held for
discussing current research activities. We also have amonthly joint seminar with Department of Pharmacology, Department of Psychology in Faculty of
Letters and Department of Biophysics in Faculty of
Science. As part of a teaching activity for the graduate
students, we have another weekly English seminar, in20

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

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

References
1

2

3

4

5

Takeuchi, D., Hirabayashi, T., Tamura, K. andMiyashita, Y. : Reversal of interlaminar signal
between sensory and memory processing inmonkey temporal cortex.
Science 331, 1443-1447, 2011.
Koyano, K.W., Machino, A., Takeda, M., Matsui,T., Fujimichi, R., Ohashi, Y. and Miyashita, Y. :In vivo visualization of single-unit recording sites
using MRI-detectable elgiloy deposit marking.
J. Neurophysiol. 105, 1380-1392, 2011.
Matsui, T., Tamura, K., Koyano, K.W., Takeuchi,D., Adachi, Y., Osada, T. and Miyashita, Y. :Direct comparison of spontaneous functional
connectivity and effective connectivity measured
by intracortical microstimulation: an fMRI study
in macaque monkeys. Cereb. Cortex 21, 23482356, 2011.
Konishi, S., Watanabe, T., Jimura, K., Chikazoe,J., Hirose, S., Kimura, H.M. and Miyashita, Y. :Role for presupplementary motor area ininhibition of cognitive set interference.
J. Cogn. Neurosci. 23, 737-745, 2011.
Ohashi, Y., Tsubota, T., Sato, A., Koyano, K.W.,
Tamura, K. and Miyashita, Y. : A bicistronic
lentiviral vector-based method for differential

21

6

7

8

9

10

11

12

13

transsynaptic tracing of neural circuits.
Mol. Cell. Neurosci. 46, 136-147, 2011.
Watanabe, T., Hirose, S., Wada, H., Katsura, M.,
Chikazoe J., Jimura, K., Imai, Y., Machida, T.,
Shirouzu, I., Y. Miyashita and Konishi, S. :Prediction of Subsequent Recognition Performance Using Brain Activity in the Medial
Temporal Lobe. NeuroImage 54, 3085-3092,
2011.
Tsubota, T., Ohashi, Y., Tamura, K., Sato, A., andMiyashita, Y. : Optogenetic manipulation of
cerebellar Purkinje cell activity in vivo.
PLoS One 6, e22400, 2011.
Kamigaki, T., Fukushima, T. and Miyashita, Y. :Neuronal signal dynamics during preparation andexecution for behavioral shifting in Macaqueposterior parietal cortex. J. Cogn. Neurosci. 23,
2503-2520, 2011.
Yamane, T., Hanaoka, K., Muramatsu, Y., Tamura,K., Adachi, Y., Miyashita, Y., Hirata, Y. andNagano,T. : Method for Enhancing Cell
Penetration of Gd3+-based MRI Contrast Agentsby Conjugation with Hydrophobic FluorescentDyes. Bioconjug. Chem. 22, 2227-2236, 2011.
Watanabe, T., Kimura, H. M., Hirose, S., Wada,
H., Imai, Y., Machida, T., Shirouzu, I., Miyashita,
Y. and Konishi, K.: Functional Dissociation
between Anterior and Posterior Temporal
Cortical Regions during Retrieval of Remote
Memory. J. Neurosci. 32, 9659-9670, 2012.
Tsubota, T., Ohashi, Y., Tamura, K. andMiyashita, Y. : Optogenetic inhibition of Purkinje
cell activity reveals cerebellar control of bloodpressure during postural alterations in anesthetized rats. Neuroscience 210, 137-144, 2012.
Hirose, S., Watanabe, T., Jimura, K., Katsura, M.,
Kunimatsu, A., Abe, O., Ohtomo, K., Miyashita,
Y. and Konishi, S. : Local Signal Time-Series
during Rest Used for Areal Boundary Mapping in
Individual Human Brains. PLoS One 7, e36496,
2012.
Adachi, Y., Osada, T., Sporns, O., Watanabe, T.,
Matsui, T., Miyamoto, K. and Miyashita, Y. :Functional Connectivity between AnatomicallyUnconnected Areas Is Shaped by Collective
Network-level Effects in the Macaque Cortex.
Cereb. Cortex 22, 1586-1592, 2012.

14 Hirose, S., Chikazoe, J., Watanabe, T., Jimura, K.,
Kunimatsu, A., Abe, O., Ohtomo, K., Miyashita,
Y. and Konishi, S. : Efficiency of Go/No-Go Task
Performance
Implemented
in
the
Left
Hemisphere. J. Neurosci. 32, 9059-9065, 2012.
15 Watanabe, T., Yahata, N., Abe, O., Kuwabara,
H., Inoue, H., Takano, Y.,
Iwashiro, N.,
Natsubori, T., Aoki, Y., Takao, H., Sasaki, H.,
Gonoi, W.,
Murakami, M.,
Katsura, M.,
Kunimatsu, A., Kawakubo, Y., Matsuzaki, H.,
Tsuchiya, K.J., Kato, N., Kano, Y., Miyashita, Y.,
Kasai, K. and Yamasue, H. : Diminished medial
prefrontal activity behind autistic social
judgments of incongruent information.
PloS One 7, e39561, 201216 Iwai, L., Ohashi, Y., van der List, D., Usrey,
W.M., Miyashita, Y. and Kawasaki, H.: FoxP2 isa parvocellular-specific transcription factor in thevisual thalamus of monkeys and ferrets. Cereb.
Cortex, in press, 2012.
17 Tamura, K., Ohashi, Y., Tsubota, T., Takeuchi, D.,
Hirabayashi, T., Yaguchi, M., Matsuyama, M.,
Sekine, T. and Miyashita, Y. : A glass-coatedtungsten microelectrode enclosing optical fibers
for optogenetic exploration in primate deep brain
structures. J. Neurosci. Methods, in press,
2012.
18 Hirose, S., Watanabe, T., Wada, H., Imai, Y.,
Machida, T., Shirouzu, I., Miyashita, Y. andKonishi, S. : Functional Relevance of MicroModules in Human Association Cortex
Delineated with High-Resolution fMRI.
Cereb. Cortex, in press, 2012.
19 Miyamoto, K., Hirabayashi, T. and Miyashita,
Y. : To bet, or not to bet: that is the question of
SEF spikes Neuron in press, 2012.
20 Kamigaki, T., Fukushima, T., Tamura, K. andMiyashita, Y. : Neurodynamics of Cognitive Set
Shifting in Monkey Frontal Cortex and Its Causal
Impact on Behavioral Flexibility.
J. Cogn. Neurosci. in press, 2012.

22

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

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

Research Associate
Hideki Kashiwadani, Ph.D.,

Homepage

Hiroyuki Manabe, 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 belongs 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, 6
graduate students and 1 secretary stuff.

Using multidisciplinary approaches including
electrophysiology, optical imaging, molecular andcellular biology and molecular genetics, we at the
Department of Cellular and Molecular Physiology aim
at understanding neuronal circuit mechanisms for thetranslation of olfactory sensory information to avariety of behavioral and emotional responses in the
mammalian brain. Our recent focus includes thefunctional and spatial organization of the odor maps in
the olfactory bulb, axonal projection pattern ofolfactory bulb neurons to various areas of theolfactory cortex, and olfactory cortical mechanisms
for the recognition of objects. We study also
behavioral state-dependent change in the information
processing mode in the olfactory bulb and olfactorycortex, focusing on the experience-dependent
reorganization of neuronal circuitry in the olfactorycortex and bulb during postprandial slow-wave sleep.

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

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

23

elimination of adult-born granule cells into or fromthe pre-existing neuronal circuit in the olfactory bulb.
Currently we are focusing on the following topics.
(1) Parallel mitral and tufted cell pathways to theolfactory cortex.
Odor signals are conveyed from the olfactory
bulb to the olfactory cortex by mitral cells andtufted cells. Whether and how the two types ofprojection neurons differ in function and axonal
connectivity is still poorly understood. Odor
responses and axonal projection patterns werecompared between mitral cells and tufted cells inmice by visualizing axons of electrophysiologically identified single neurons. Tufted
cells demonstrated shorter onset latency forreliable responses than mitral cells. The shorter
latency response of tufted cells was maintained ina wide range of odor concentrations, whereas
mitral cells responded only to strong signals.
Furthermore, individual tufted cells projected
densely to focal targets only in anterior areas ofthe olfactory cortex, whereas individual mitralcells dispersedly projected to all olfactory cortex
areas. In the anterior areas of the olfactory cortex,
the two cell types projected to segregated subareas.
These results suggest that mitral cells and tufted
cells transmit temporally distinct odor information
to different olfactory cortex targets.
(2) Olfactory cortex generates synchronized top-down
inputs to the olfactory bulb during slow-wave
sleep.
The olfactory cortex is functionally isolated
from the external odor world during slow-wave
sleep. However, the neuronal activity pattern inthe olfactory cortex and its functional roles duringslow-wave sleep are not well understood. Here,
we demonstrate in freely behaving rats that theanterior piriform cortex, a major area of theolfactory cortex, repeatedly generates sharp waves
that are accompanied by synchronized discharges
of numerous cortical neurons. Olfactory cortex
sharp waves occurred relatively independently ofhippocampal sharp waves. Current source density
analysis showed that sharp wave generation
involved the participation of recurrent association
fiber synapses to pyramidal cells in the olfactorycortex. During slow wave sleep, the olfactory bulb
showed sharp waves that were in synchrony witholfactory cortex sharp waves, indicating that theolfactory cortex sharp waves drove synchronized
top-down inputs to the olfactory bulb. Based onthese results, we speculate that the olfactorycortex sharp waves play a role in the
reorganization of bulbar neuronal circuits duringslow-wave sleep.
(3) Elimination of adult-born neurons in the olfactory
bulb is promoted during the postprandial period.
Granule cells in the mouse olfactory bulb
continue to be generated in adulthood, with nearly
half incorporated and the remainder eliminated.
We showed that elimination of adult-born granulecells is promoted during a short time window inthe postprandial period. Under restricted feeding,the number of apoptotic granule cells increased
within a few hours after the start of feeding. Thisenhanced granule cell apoptosis occurred inassociation with postprandial behaviors that
included grooming, resting, and sleeping, and wasparticularly correlated with the length of
postprandial sleep. Deprivation of olfactory
sensory experience in the local olfactory bulb area
potentiated the extent of granule cell eliminationin that area during the postprandial period. These
results suggest that extensive structural
reorganization of bulbar circuitry occurs during
the postprandial period, reflecting sensory
experience during preceding waking period.
(4) Compensation of depleted subsets by new neurons
in a local area of the adult olfactory bulb
In the olfactory bulb, loss of preexisting
granule cells and incorporation of adult-born new
granule cells continues throughout life. Granulecells consist of distinct subsets. We examined
whether the loss and incorporation of granule cell

24subsets are coordinated in the olfactory bulb. We
selectively ablated mGluR2-expressing subsets of
granule cells in a local area of the olfactory bulb
using immunotoxin-mediated cell ablation method.
During recovery, an mGluR2-expressing new
granule cell subset was preferentially incorporated
over an mGluR2-negative new granule cell subset
in the area of ablation, whereas the preferential
incorporation was not observed in the intact area.
These results indicate that local areas of theolfactory bulb have a mechanism to coordinate theloss and incorporation of granule cell subsets bycompensatory incorporation of new granule cellsubsets, which involves subset-specific cellularincorporation and subset-specific regulation ofspine size.

Publications (2010~)
1. Tsuboi, A., Imai, T., Kato, H.K., Matsumoto, H.,
Igarashi, K.M., Suzuki, M., Mori, K. and Sakano,H.

Two highly homologous mouse odorant

receptors encoded by tandemly-linked MOR29A
and MOR29B genes differently respond to phenyl
ethers.

European Journal of Neuroscience

33(2): 205-213 (2011)
2. Mitsui, S., Igarashi, K.M., Mori, K. and Yoshihara,
Y.
Genetic visualization of the secondary
olfactory pathway in Tbx21 transgenic mice.
Neural Systems and Circuits 1: 5 (2011)
3. Mori, K. and Sakano, H. How is the olfactory
map formed and interpreted in the mammalianbrain?
Annu. Rev. Neurosci. 34: 467-499(2011)
4. Sakamoto, M., Imayoshi, I., Ohtsuka, T.,
Yamaguchi, M, Mori, K. and Kageyama, R.
Continuous neurogenesis in the adult forebrain isrequired for innate olfactory responses Proc.
Natl. Acad. Sci. USA 108(20): 8479-8484 (2011)
5. Manabe, H., Kusumoto-Yoshida, I., Ota, M. andMori, K.
Olfactory cortex generates
synchronized top-down inputs to the olfactory
bulb during slow-wave sleep.
J. Neurosci.
31(22): 8123-8133 (2011)
6. Murata, M., Imai, M., Nakanishi S., Watanabe, D.,
Pastan I., Kobayashi, K., Nihira T., Mochizuki, H.,
Yamada, S., Mori, K. and Yamaguchi, M.

Compensation of depleted neuronal subsets by
new neurons in a local area of the adult olfactorybulb. J. Neurosci. 31(29):10540-10557 (2011)
7. Yokoyama, T.K., Mochimaru, D., Murata, K.,
Manabe H, Kobayakawa, K., Kobayakawa, R.,
Sakano, H., Mori, K., and Yamaguchi M.
Elimination of adult-born neurons in the olfactory
bulb is promoted during the postprandial period.
Neuron 71:883-897 (2011).
8. Matsumoto, T., Saito, K., Nakamura, A., Saito, T.,
Nammoku T., Ishikawa, M., and Mori, K.
Dried-bonito aroma components enhance salivary
hemodynamic responses to broth tastes detectedby near-infrared spectroscopy. J. Agric Food
Chemistry 60(3):805-811 (2012).
9. Yoshihara, S., Takahashi, H., Nishimura, N.,
Naritsuka, H., Shirao, T., Hirai, H., Yoshihara, Y.,
Mori, K., Stern P.L., and Tsuboi, A.
5T4
glycoprotein regulates the sensory inputdependent development of a specific subtype ofnewborn interneurons in the mouse olfactory bulb.
J. Neurosci. 32(6):2217-2226 (2012).
10. Igarashi, K., Ieki, N., An, M., Yamaguchi, Y.,
Nagayama, S., Kobayakawa, K., Kobayakawa, R.,
Tanifuji, M., Sakano, H., Chen, W., and Mori, K.
Parallel mitral and tufted cell pathways routedistinct odor information to different targets in theolfactory cortex. J. Neurosci. 32(23):7970-7985(2012).
11. Muzuguchi, R., Naritsuka, H., Mori, K, andYoshihara, Y. Tbr2 deficiency in mitral andtufted cells disrupts excitatory-inhibitory balanceof neural circuitry in the mouse olfactory bulb. J.
Neurosci. 32(26):8831-8844 (2012).

25

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

Associate Professor
Kazuo Kitamura, Ph.D.

Research Associate
Naofumi Uesaka, Ph.D.

Homepage

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

Introduction and Organization
This laboratory was founded in 1953 as Departmentof Neurophysiology, Institute for Brain Research. In
1996, it was integrated into Graduate School of
Medicine. The current members of this laboratory are
5 faculty members (professor, associate professor,
project lecturer, research associate, project research
associate), 7 postdoctoral fellows, 10 graduate students,
2 undergraduate students and 5 technicians. We teachneurophysiology for medical undergraduates and forstudents in the Master and Ph.D. courses. Our researchaims at elucidating cellular and molecular mechanisms
underlying regulation of synaptic transmission andpostnatal development of neuronal circuits.

Teaching activities
We teach neurophysiology for medical undergraduates in lectures and practical courses. Lectures
are designed for students to learn basic mechanisms
underlying the generation of electrical signals,
synaptic transmission and their regulations in the
nervous system. Students also learn how functional
neural circuits in the brain are formed and matured
during postnatal development. In the practical courses,
students perform two types of classical experiments ofneurophysiology. First, students make intracellular
recording from frog skeletal muscle fibers andexamine the endplate potential for understanding basic

properties of synaptic transmission. Second, students
record electromyogram (EMG) from humangastrocnemius muscles and learn how the stretch
reflex works.
We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in dissociatedculture, or to experience recordings of neuronal
activities from living animals.
For the training of Master and Ph.D. course
students, we have a weekly conference for discussing
current research activities. A laboratory member
summarizes his/her recent experimental data orpresents papers closely related to his/her research.
Moreover, for mutual communication between thelaboratories with similar interests in neuroscience, wehave a weekly joint seminar with Department of
Cellular Neurobiology, Division of Structural
Physiology and Division of Animal Resources.

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

26

cology, morphology, and genetic engineering ofmouse. We particularly focus on observing neuronal
activities in real time in intact neurons. We use
whole-cell patch clamp recording, calcium imaging,two-photon imaging and their combinations in various
preparations (cultured neurons, brain slices and intact
animals) and investigate molecular mechanisms ofsynaptic transmission and plasticity.
The main subjects of our research are as follows(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminatedeventually with the progress of postnatal development,
and most Purkinje cells become innervated by single
climbing fibers by the end of the third postnatal weekin mice. We investigate the mechanisms how single
climbing fibers are selected and how the surplus
climbing fibers are eliminated.
(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an
activity-dependent manner, act retrogradely onto
presynaptic cannabinoid receptors and suppress
transmitter release. Since then, we have been
investigating the mechanisms of this retrograde
modulation. We are also interested in elucidating thephysiological significance of this phenomenon
including learning and memory, addiction, andanxiety.
(3) Synaptic integration in intact animals:
To understand the physiological function ofsynapses in vivo, we analyze synaptic transmission
and integration in single neurons in the intact brain byusing in vivo two-photon imaging and whole-cellrecording. We also develop new methods toimplement these experiments.

References(1) Miyazaki T, Yamasaki M, Hashimoto K, Yamazaki
M, Abe M, Usui H, Kano M, Sakimura K,
Watanabe M: Cav2.1 in cerebellar Purkinje cells
regulates competitive excitatory synaptic wiring,cell survival, and cerebellar biochemicalcompartmentalization. J. Neurosci. 32: 1311-28(2012).
(2) Takahashi N, Kitamura K, Matsuo N, Mayford M,
Kano M, Matsuki N & Ikegaya Y: Locallysynchronized synaptic inputs. Science 335:
353-356 (2012).
(3) Ohno-Shosaku T, Tanimura A, Hashimotodani Y,
Kano M:
Endocannabinoids and retrograde
modulation of synaptic transmission. Neuroscientist 18:119-32 (2012).
(4) Kano M, Hashimoto K: Activity-Dependent
Maturation of Climbing Fiber to Purkinje Cell
Synapses during Postnatal Cerebellar Development. Cerebellum 11: 449-50 (2011).
(5) Watanabe M & Kano M: Climbing fiber synapse
elimination in cerebellar Purkinje cells. Eur. J.
Neurosci. 34: 1697-1710 (2011).
(6) Ichikawa R, Yamasaki M, Miyazaki T, Konno K,
Hashimoto K, Tatsumi H, Inoue Y, Kano M &Watanabe M: Developmental Switching ofPerisomatic Innervation from Climbing Fibers to
Basket Cell Fibers in Cerebellar Purkinje Cells. J.
Neurosci. 31: 16916 –16927 (2011).
(7) Kano M & Watanabe M:
Synaptogenesis andSynaptic elimination.
In: Handbook of
Cerebellum and Cerebellar Disorders, Mario
Manto, Donna Gruol, Jeremy Schmahmann, Nori
Koibuchi, Ferdinando Rossi, (eds), Springer, inpress.
(8) Kitamura K & Häusser M: Dendritic Calcium
Signaling Triggered by Spontaneous andSensory-Evoked Climbing Fiber Input toCerebellar Purkinje Cells In Vivo. J. Neurosci.
31: 10847-10858 (2011).
(9) Hashimoto K, Tsujita M, Miyazaki T, Kitamura
K, Yamazaki M, Shin H-S, Watanabe M,
Sakimura K, Kano M: Postsynaptic P/Q-type
Ca2+ channel in Purkinje cell mediates synaptic
competition and elimination in developing
cerebellum. Proc Natl Acad Sci USA 108:9987-9992, (2011).
(10) Uchigashima M, Yamazaki M, Yamasaki M,
Tanimura A, Sakimura K, Kano M, Watanabe
M: Molecular and morphological configurationfor 2-arachidonoylglycerol-mediated retrogradesignaling at mossy cell-granule cell synapses in27

the dentate gyrus. J. Neurosci. 31: 7700-7714(2011).
(11) Noguchi J, Nagaoka A, Watanabe S, Ellis-Davies
GC, Kitamura K, Kano M, Matsuzaki M, Kasai
H: In vivo two-photon uncaging of glutamate
revealing the structure-function relationships ofdendritic spines in the neocortex of adult mice.
J. Physiol. 589: 2447-2457 (2011).
(12) Miyata M, Kishimoto Y, Tanaka M, Hashimoto K,
Hirashima N, Murata Y, Kano M, Takagishi Y:
A role for myosin Va in cerebellar plasticity andmotor learning: a possible mechanism underlying
neurological disorder in myosin Va disease. J
Neurosci 31: 6067-6078 (2011).

Functional Biology
2. Pharmacology

29

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

Lecturer
Yohei Okubo, Ph. D.,

Research Associate
Kazunori Kanemaru, Ph. D.,

Homepage

Hiroshi Sekiya, M.D.

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

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, we studied inositol 1,4,5trisphosphate (IP3)-induced Ca2+ release mechanism, 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 of mobilized Ca2+.
We identified the Ca2+ sensor region of the IP3R

30

and showed that the positive feedback regulationof IP3R via the Ca2+ sensor of 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 of
Ca2+ oscillation, dephosphorylated NFAT accumulates in the cytoplasm to enhance its nuclear
translocation. This is the molecular basis of themechanism 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 indicatorsof signalling molecules upstream and downstream
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 the phosphorylation of myosin regulatory light chain. The
indicator allowed us to image phosphorylation
state of myosin light chain in living cells.
Furthermore, we generated a nitric oxide (NO)indicator based on the heme-binding domain ofsoluble guanylyl cyclase. This indicator was
successfully used in cerebellar slice preparations
to image NO signals in response to parallel fiber(PF) stimulation. We found that the NO signal
intensity decreases steeply with distance form theactivated synapse and generate synapse-specificlong-term potentiation (LTP) of PF-Purkinje cell
synapses. We also showed that the NO signal
intensity depends biphasically on the frequency of
PF stimulation. Importantly, the LTP depends
similarly on the frequency of PF stimulation. Thus,
our NO indicator provided us with valuable
information regarding the role of NO signals in thecentral nervous system.
Glutamate is the most important excitatory
synaptic transmitter in the brain. We havegenerated a glutamate indicator based on theglutamate-binding domain of the AMPA-typeglutamate receptor. Using this fluorescentglutamate indicator, we have succeeded in imaging
spatiotemporal dynamics of glutamate in theextrasynaptic space in brain slices. This study
demonstrated that bursting synaptic activities
cause glutamate spillover from the synaptic cleft
to activate perisynaptic metabotropic glutamate
receptors, and will provide a basis for the researchof extrasynaptic glutamate transmission that is
involved in many important brain functions.
3) Exploration of new cellular functions that are
regulated by Ca2+ signals
Although many important cell functions havebeen found to be regulated by Ca2+ signals, not all
the Ca2+-dependent cell functions have been
identified. We are now searching for new cellfunctions that are regulated by Ca2+ signals.
Cells communicate with each other to form
organized structures by cell-cell adhesion andcell-cell repulsion, but it remains to be clarified
how cell-cell contact information is converted to31intracellular signals. We found that cells in contact
with neighbouring cells generate local transient
intracellular Ca2+ signals (Ca2+ lightning). Ca2+
lightning was exclusively observed near cell-cell
contact regions and was not observed in the central
regions of cells, nor was it found in solitary cells
that are not in contact with other cells. We also
show that Ca2+ lightning is capable of 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
downstream of metabotropic glutamate receptormediated IP3-Ca2+ signaling in Purkinje cells,
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 maintenance mechanism.
We have studied the role of IP3-Ca2+ signaling
in astrocytes (the most abundant glial cells) andfound that it regulates the expression of moleculeson the surface of astrocytes that regulate thegrowth of neurons. Our results indicate thatN-cadherin is involved in the regulation of neural
growth. We are now studying the molecularmechanism that links between Ca2+ signals andN-cadherin expression. Furthermore, we recently
showed that IP3-Ca2+ signaling in cerebellar
astrocytes (Bergmann glia) regulates glutamate
transporter levels in Bergman glial cells tomaintain glutamate clearance in the mature
cerebellum.
We recently identified a new NO-dependent
Ca2+ signaling mechanism in central neurons. We
found that synaptically released NO S-nitrosylates
the ryanodine receptor (RyR) to activate Ca2+
release through the Ca2+ release channel, which werefer to as NO-induced Ca2+ release (NICR).
NICR is required for the NO-dependent LTP at theparallel fiber-Purkinje cell synapse describedabove. Furthermore, NICR has a pathophysiological role, and seems to play an importantrole in NO-dependent neuronal cell death after
brain ischemia. This finding suggests that NICR
can be a therapeutic target in certain forms ofischemic brain diseases.
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+ imaging and mathematical modeling, we analyzing the basis of thecell-to-cell variability. We found that the balance
between Ca2+ release and uptake is enhanced by
the positive feedback property of the Ca2+ relase to
generate the all-or-none propety of the Ca2+ relase.
Furthermore, individual cells switched between
the caffeine-sensitive and caffeine-insensitive
states with an average transition time of
approximately 65 h, suggestive of temporalfluctuation in endogenous protein expression
levels associated with caffeine response. Thus, thestudy provides a conceptual basis of the cellto-cell phenotypic variability in mammalian cells.

References
1. Kakizawa, S., Yamazawa, T., Chen, Y., Ito, A.,
Murayama, T., Oyamada, H., Kurebayashi, N.,
Sato, O., Watanabe, M., Mori, N., Oguchi, K.,
Sakurai, T., Takeshima, H., Saito, N. and Iino, M.
Nitric oxide-induced calcium release via ryanodine
receptors regulates neuronal function. EMBO J.
31, 417-428, 2012.
2. Okubo, Y., Kanemaru, K. and Iino, M. Imaging
of Ca2+ and related signaling molecules andinvestigation of their functions in the brain.
Antioxid Redox Signal. 14, 1303-1314, 2011.
3. Iino, M. Spatiotemporal dynamics of Ca2+
signaling and its physiological roles. Proc. Jpn.
Acad. Ser. B-Phys. Biol. Sci. 86: 244, 2010.
4. Okubo, Y., Sekiya, H, Namiki, S, Sakamoto, H.,

32

Iinuma, S., Yamasaki, M., Watanabe, M., Hirose, K.
and Iino, M. Imaging extrasynaptic glutamate
dynamics in the brain. Proc. Natl. Acad. Sci.
U.S.A. 107: 6526, 2010.
5. Mashimo, M., Okubo, Y., Yamazawa, T., Yamasaki,M., Watanabe, M., Murayama, T. and Iino, M.
Inositol 1,4,5-trisphosphate signaling maintains theactivity of glutamate uptake in Bergmann glia.
Eur. J. Neurosci. 32: 1668, 2010.

33

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

LecturerTomoyuki Yoshida, Ph.D.

Research Associate
Takeshi Uemura, Ph.D.,

Misato Yasumura, Ph.D.

Takashi Hayashi, Ph.D.

Homepage

http://www.pharmacol2.m.u-tokyo.ac.jp/※ The following information is the same as that of the previous year for certain reasons.

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

34

form of associate learning, implying a systemic
regulation of learning and memory.
To investigate the regulation of learning andmemory, we established an inducible andneuron-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 the35adult 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
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.

36

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

upstream signals to induce axon terminal
differentiation during synapse formation.
Synapse formation is the key step in thedevelopment of neuronal networks. Precise synaptic
connections between nerve cells in the brain provide
the basis of perception, learning, memory, andcognition. Thus, elucidation of molecular mechanismsthat regulate the formation and modulation of central
synapses will be essential for the understanding ofneural wiring, brain functions and mental disorders
such as schizophrenia, autism and mental retardation.

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

37e13722.
(6) Miyazaki, T., Yamasaki, M., Takeuchi, T.,
Sakimura, K., Mishina, M. and Watanabe, M.
Ablation of glutamate receptor GluRδ2 in adult
Purkinje cells causes multiple innervation ofclimbing fibers by inducing aberrant invasion toparallel fiber innervation territory. J. Neurosci.
2010; 30, 15196-15209.
(7) Mozhui, K., Karlsson, R-M., Kash, T., Ihne, J.,
Norcross, M., Patel, S., Farrell, M., Hill, E.,
Martin, K., Camp, M., Fitzgerald, P., Ciobanu, D.,
Sprengel, R., Mishina, M., Wellman, C., Winder,D., Williams, R. W., and Holmes, A. Strain
differences in stress responsivity are associatedwith divergent amygdala gene expression andglutamate-mediated neuronal excitability. J.
Neurosci. 2010; 30, 5357-5367.
(8) Hayashi, R., Nakazato, Y., Takamori, S., Ebihara,
S., Uematsu, M., Mishina, M., Miyazaki, J.,
Yokoyama, M., Konishi, S., Inoue, K., Fukuda,A., Fukumoto, M., Nakamura, K., Obata, K., andYanagawa, Y. The physiological roles ofvesicular GABA transporter during embryonicdevelopment: a study using knockout mice. Mol.
Brain 2010; 3, 40.
(9) Taniguchi, M. Masuda, T., Mikami, Y., Kimura,M., Yoshida, T., Mishina, M. and Shimizu, T.
Identification and characterization of a novel
zebrafish semaphorin. Neurosci. Lett. 2011; 488,
215-220.
(10) Larsen, R. S., Corlew, R. J., Henson, M. A.,
Roberts, A. C., Mishina, M., Watanabe, M.,
Lipton, S. A., Nakanishi, N., Pérez-Otaño, I.,
Weinberg, R. J., and Philpot, B. D.
NR3A-containing NMDA receptors promote
neurotransmitter release and spike timingependent plasticity. Nature Neurosci. 2011; 14,338-344.
(11) Yamasaki, M., Miyazaki, T., Azechi, H., Abe, M.,
Natsume, R., Hagiwara, T., Aiba, A., Mishina, M.,
Sakimura, K. and Watanabe, M. Glutamate
receptor δ2 is essential for input pathwayependent regulation of synaptic AMPAR contents
in cerebellar Purkinje cells. J. Neurosci. 2011; 31,
3362-3374.
(12) Joo, J., Lee, S., Uemura, T., Yoshida, T.,
Yasumura, M., Watanabe, M. and Mishina, M.

Differential interactions of cerebellin precursor
protein (Cbln) subtypes and neurexin variants forsynapse formation of cortical neurons. Biochem.
Biophys. Res. Commun. 2011; 406, 627-632.
(13) Kaneko, M., Yamaguchi, K., Eiraku, M., Sato, M.,
Takata, N., Kiyohara, Y., Mishina, M., Hirase, H.,
Hashikawa, T. and Kengaku, M. Remodeling ofmonoplanar Purkinje cell dendrites during
cerebellar circuit formation. PLoS ONE 2011; 6,e20108.
(14) Biase, L. D., Kang, S., Potter, E., Fukaya, F.,
Pucak, M., Mishina, M., Calabresi, P. and Bergles,
D. NMDA receptor signaling in oligodendrocyte
progenitorsisnotrequiredforoligodendrogenesis and myelination. J. Neurosci.
2011.
(15) Chen, X., Yoshida, T., Sagara, H., Mikami, Y. andMishina, M. Protein tyrosine phosphatase regulates the synapse number of zebrafish
olfactory sensory neurons. j. Neurochem. 2011;
E-pub (29 August).
(16) Yoshida, T., Yasumura, M., Uemura, T., Lee, S.,
Ra, M., Taguchi, R., Iwakura, Y. and Mishina, M.
IL1RAPL1 associated with mental retardation
and autism mediates synapse formation bytrans-synaptic interaction with PTPδ. J. Neurosci.
2011; 31, 13485-13499.

Pathology, Immunology andMicrobiology
1. Pathology

39

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

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

Lecturer
Yutaka Takazawa, M.D., Ph.D.*
Junji Shibahara, M.D., Ph.D. (visiting researcher, USA)

Lecturer (Hospital)
Tetsuo Ushiku, M.D., Ph.D.*

Associate
Rumi Hino, M.D., Ph.D.,

Aya Shinozaki, M.D., Ph.D.,

Yukako Shintani, M.D., Ph.D.,

Akiko Kunita, M.D., Ph.D.

Masako Ikemura, M.D., Ph.D.*,

Daichi Maeda, M.D., Ph.D.*,

Keisuke Matsusaka, M.D., Ph.D.*
Teppei Morikawa, M.D., Ph.D.* (visiting researcher, USA)
Naoko Yamauchi, M.D., Ph.D. (Global COE Program)Technical Support Specialist
Yasuyuki Morishita, M.T.,

Homepage

Shinichi Harada, Kei Sakuma

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. Shibahara and Dr. Morikawa were working as
a visiting researcher in Mayo and Harvard University,
USA, respectively.Dr. Nakaya moved to Tokyo

Medical College. Dr. Kunita moved here from
University of Basel, and Dr. Matsusaka from
Metropolitan Cancer and Infectious Disease Center,
Komagome Hospital.
Four postgraduate students (Hibiya, Tanaka, Sung,
Yoshida) finished the course and received Ph.D. In the
new fiscal year, 2011, five new students will enter the
postgraduate course, and there will be 16
postgraduates (including one foreign student).
We are responsible for the pathology practice of
the University Hospital, and carrying forward themorphology-based research targeting human diseases.

40

As for the education of Pathology, we take charge ofthe following courses for the medical students;
General Pathology course for the 1st grade students incollaboration with Department of Molecular Pathology,
Systemic Pathology for the 2nd grade, ClinicalClerkship for the 3rd grade, and Bedside-learning(BSL) for the 4th grade students, respectively.
Programs for postgraduates and junior residents arealso included in our education activities.
We held 100th Annual Meeting of JapaneseSociety of Pathology from April, 28-30, 2011 at
Yokohama Pacifico (President Fukayama, Vice
President: Dr. Miyazono), with wish to recover fromthe Great East Japan Earthquake of March, 11, 2011,
although we had to reduce the number of programs.
The memorial ceremony was held on April 29, tocelebrate the 100th Anniversary of the JapaneseSociety of Pathology in the very presence of Price
Hitachinomiya Masahito.
We had to postpone the Extension Lecture for
Citizens “Autopsy and Medical Safety” on May 1, but
could hold it on September 23 at Sanjo Kaikan, theUniversity of Tokyo. The contents were included in
the book, “Autopsy in Medical Practice”.

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 thoracic organs, liver and pancreatobiliary tract, urology, gynecology, breast, andorthopedics, as well as biopsy cases of kidney, skin
and GI tract 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. Digest
version of CPC slides is now open in the hospital, and
we also started e-learning program for interns tofacilitate the understanding of the CPC contents.
A model project for the survey analysis of deaths

related to medical treatment (DRMT) has been in
operation since September 2005, and we continue tobe a member of the autopsy inspection of the project.

Teaching activities
We take on General Pathology Course for the 1st gradeof undergraduate students, especially in its
morphological field. The course program and lecturenotes are open to the public and available in UT OpenCourse Ware（http://ocw.u-tokyo.ac.jp/）.
Each class of Systemic Pathology Course andexercises are held in parallel with that of Systemic
Medicine Course. Handouts are available in every halfcourse of the pathological exercises, and all slides
used in the course are accessible on our website as
virtual slides (digital images of the slides).
Clinical clerkship for the 3rd grade, and BSL for
the 4th grade are carried out. In BSL, following
courses are included; autopsy pathologic practices
with a case presentation for paired students, surgicalpathologic practices using various tumor sections, anda tour of the pathology laboratory. The past
examinations for graduation and Systemic Pathology
for the second grade students and are referred to thewebsite.
We also have charge of the lecture series of tumor
pathology for the Cancer Profession Training Programin postgraduate school.

Research activities
The first major theme is “chronic inflammation andneoplasms”, especially Epstein-Barr virus (EBV)
associated gastric carcinoma (GC) (Drs. Uozaki,
Ushiku, Hino, Shinozaki, Matsusaka, and Kunita). We
are focusing on mechanisms of abnormalties in CpG
island methylation and microRNA molecules in thedevelopment and progression of EBV-associated GC(Matsusaka el al. ref.16)
The second major theme is ‘traslational researchpathology’. We are engaged in search of target
molecules for cancer therapy by global analysis ofexpression profiles of various cancers, in collaboration
with Research Center for Advanced Science andTechnology (RCAST), the University of Tokyo. In
addition, we take part in a global COE program,

41“Comprehensive Center of Education and research
for Chemical Biology of the Diseases”, in which weare investigating the morphological analysis of gene
expression abnormalities of the key molecules forseveral diseases (Dr. Yamauchi). We discovered
expression of gastric type claudin 18 in intraepithelial
neioplasms of biliary and pancreatic ducts during thescreening of cancer specific molecules (Drs. Shibahara,
Shinozaki) and pointed out the importance of gastricmetaplasia for the development of cancer (Shinozaki
et al. ref. 25, Tanaka et al. ref. 29).
Dr. Ishikawa’s group is developing the methods
analyzing genome information precisely to establish afield of pathology.
The third theme is to re-evaluate the disease
entities and tumor entities from the standpoint ofclassical histopathology. Dr. Ushiku reported a
micro-papillary subtype of gastric carcinoma, withhigh frequency of lymph node metastasis (ref. 32) . Dr.
Maeda discovered a subtype of ovarian tumor,
microcystic stromal tumor of ovary, which wascharacterized by beta catenin mutation (ref. 16).
The research works closely related withpathology practice will be described in Diagnostic
Pathology Division.

References(including those of Diagnostic Pathology Division)(1) Abe H, Morikawa T, Araki A, Shima T, Nakatsu
H, Fukayama M, Suzuki Y.
IgG4-related
periureteral fibrosis presenting as a unilateral
ureteral mass. Pathol Res Pract. 2011; 207(11):712-4.
(2) Fujiwara M, Kashima TG, Kunita A, Kii I,
Komura D, Grigoriadis AE, Kudo A, Aburatani H,
Fukayama M. Stable knockdown of S100A4
suppresses cell migration and metastasis ofosteosarcoma, Tumour Biol. 2011; 32(3): 611-22.
(3) Goto A, Li CP, Ota S, Niki T, Ohtsuki Y, Kitajima
S, Yonezawa S, Koriyama C, Akiba S, Uchima H,
Lin YM, Yeh KT, Koh JS, Kim CW, Kwon KY,
Nga ME, Fukayama M. Human papillomavirus
infection in lung and esophageal cancers: analysisof 485 Asian cases. J Med Virol. 2011; 83(8):1383-90.
(4) Guan B, Mao TL, Panuganti PK, Kuhn E, Kurman

RJ, Maeda D, Chen E, Jeng YM, Wang TL, Shih
IeM. Mutation and loss of expression of ARID1A
in uterine low-grade endometrioid carcinoma. Am
J Surg Pathol. 2011; 35(5): 625-32.
(5) Hanamura K, Tojo A, Kinugasa S, Asaba K,
Onozato ML, Uozaki H, Fukayama M, Fujita T.
Detection of myeloperoxidase in membranous
nephropathy-like deposits in patients with
anti-neutrophil cytoplasmic antibody-associatedglomerulonephritis. Hum Pathol. 2011; 42(5):649-58.
(6) Inoue H, Yamazaki S, Shimizu M, Uozaki H,
Goto T, Ohnishi S, Koike K. Liver injury inducedby the Japanese herbal drug kamishoyosan.
Gastroenterol Hepatol (N Y). 2011; 7: 692-5.
(7) Ishida M, Gonoi W, Hagiwara K, Takazawa Y,
Akahane M, Fukayama M, Ohtomo K. Hypostasis
in the heart and great vessels of non-traumatic
in-hospital death cases on postmortem computed
tomography: relationship to antemortem blood
tests. Leg Med (Tokyo). 2011; 13(6): 280-5.
(8) Ishida M, Gonoi W, Hagiwara K, Takazawa Y,
Akahane M, Fukayama M, Ohtomo K.
Postmortem changes of the thyroid on computed
tomography. Leg Med (Tokyo). 2011; 13(6):318-22.
(9) Isagawa T, Nagae G, Shiraki N, Fujita T, Sato N,
Ishikawa S, Kume S, Aburatani H. DNA
methylation profiling of embryonic stem celldifferentiation into the three germ layers. PLoS
One. 2011; 6(10):e26052.
(10) Kitano K, Watanabe K, Emoto N, Kage H,
Hamano E, Nagase T, Sano A, Murakawa T,
Nakajima J, Goto A, Fukayama M, Yatomi Y,
Ohishi N, Takai D. CpG island methylation of
microRNAs is associated with tumor size andrecurrence of non-small-cell lung cancer. Cancer
Sci. 2011; 102(12): 2126-31.
(11) Kagoya Y, Takahashi T, Nannya Y, Shinozaki A,
Ota S, Fukayama M, Kurokawa M.
Hyperbilirubinemia after hematopoietic stem celltransplantation: comparison of clinical andpathologic findings in 41 autopsied cases. Clin
Transplant. 2011; 25(5): E552-7.
(12) Kozu Y, Tsuta K, Kohno T, Sekine I, Yoshida A,
Watanabe S, Tamura T, Yokota J, Suzuki K,
Asamura H, Furuta K, Tsuda H. The usefulness42

of mutation-specific antibodies in detecting
epidermal growth factor receptor mutations and in
predicting response to tyrosine kinase inhibitor
therapy in lung adenocarcinoma. Lung Cancer.
2011;73(1): 45-50.
(13) Kubota D, Orita H, Yoshida A, Gotoh M, Kanda T,
Tsuda H, Hasegawa T, Katai H, Shimada Y,
Kaneko K, Kawai A, Kondo T. Pfetin as aprognostic biomarker for gastrointestinal stromal
tumor: validation study in multiple clinicalfacilities. Jpn J Clin Oncol. 2011; 41(10):1194-202.
(14) Kunita A, Kashima TG, Ohazama A, Grigoriadis
AE, Fukayama M. Podoplanin is regulated byAP-1 and promotes platelet aggregation and cell
migration in osteosarcoma. Am J Pathol. 2011;
179(2): 1041-9.
(15) Maeda D, Shibahara J, Sakuma T, Isobe M,
Teshima S, Mori M, Oda K, Nakagawa S,
Taketani Y, Ishikawa S, Fukayama M.
β-catenin (CTNNB1) S33C mutation in ovarian
microcystic stromal tumors. Am J Surg Pathol.
2011; 35(10): 1429-40.
(16) Matsusaka K, Kaneda A, Nagae G, Ushiku T,
Kikuchi Y, Hino R, Uozaki H, Seto Y, Takada K,
Aburatani H, Fukayama M. Classification of
Epstein-Barr virus positive gastric cancers bydefinition of DNA methylation Epigenotypes.
Cancer Res. 2011; 71(23):7187-97.
(17) Mimae T, Tsuta K, Takahashi F, Yoshida A,
Kondo T, Murakami Y, Okada M, Takeuchi M,
Asamura H, Tsuda H. Steroid receptor expression
in thymomas and thymic carcinomas. Cancer.
2011; 117(19): 4396-405.
(18) Miyazaki H, Goto A, Hino R, Ota S, Okudaira R,
Murakawa T, Nakajima J, Fukayama M. Pleuralcavity angiosarcoma arising in chronic expanding
hematoma after pneumonectomy. Hum Pathol.
2011; 42(10): 1576-9.
(19) Morikawa T, Kuchiba A, Yamauchi M,
Meyerhardt JA, Shima K, Nosho K, Chan AT,
Giovannucci E, Fuchs CS, Ogino S. Associationof CTNNB1 (beta-catenin) alterations, body massindex, and physical activity with survival inpatients with colorectal cancer. JAMA. 2011;
305(16): 1685-94.
(20) Morita S, Goto A, Sakatani T, Ota S, Murakawa T,

Nakajima J, Maeda E, Fukayama M. Multicystic
mesothelioma of the pericardium. Pathol Int.
2011; 61(5):319-21.
(21) Nagae G, Isagawa T, Shiraki N, Fujita T,
Yamamoto S, Tsutsumi S, Nonaka A, Yoshiba S,
Matsusaka K, Midorikawa Y, Ishikawa S, Soejima
H, Fukayama M, Suemori H, Nakatsuji N, Kume
S, Aburatani H. Tissue-specific demethylation in
CpG-poor
promoters
duringcellulardifferentiation. Hum Mol Genet. 2011;20(14):2710-21.
(22) Nishiyama T, Kii I, Kashima TG, Kikuchi Y,
Ohazama A, Shimazaki M, Fukayama M, Kudo A.
Delayed re-epithelialization in periostin-deficient
mice during cutaneous wound healing. PLoS One.
2011; 6(4): e18410.
(23) Ogura K, Hosono A, Yoshida A, Beppu Y, Kawai
A. A retroperitoneal mass, systemic lymphadenopathy, and pulmonary nodules in a pregnant
woman. Skeletal Radiol. 2011; 40(5): 631-2,
657-8.
(24) Shima K, Morikawa T, Yamauchi M, Kuchiba A,
Imamura Y, Liao X, Meyerhardt JA, Fuchs CS,
Ogino S. TGFBR2 and BAX mononucleotide tract
mutations, microsatellite instability, and prognosis
in 1072 colorectal cancers. PLoS One. 2011; 6(9):e25062.
(25) Shinozaki A, Shibahara J, Noda N, Tanaka M,
Aoki T, Kokudo N, Fukayama M. Claudin-18 inbiliary neoplasms.
Its significance in theclassification of intrahepatic cholangiocarcinoma.
Virchows Arch. 2011; 459(1): 73-80.
(26) Shoji K. Oda K. Nakagawa S. Kawana K. Yasugi
T. Ikeda Y. Takazawa Y. Kozuma S. Taketani Y.
Aromatase inhibitor anastrozole as a second-line
hormonal treatment to a recurrent low-grade
endometrial stromal sarcoma: a case report. Med
Oncol 2011; 28(3):771-4.
(27) Sugaya M. Fujita H. Izutsu K. Oshima K.
Takazawa Y. Ohmatsu H. Yoshimi A. Takahashi T.
Kanda Y. Kurokawa M. Tamaki K. Sato S.
Primary cutaneous anaplastic large cell lymphomawith leg involvement: a case report and review of
11 cases. J Dermatol 2011; 38(10):1009-12.
(28) Suehara Y, Tochigi N, Kubota D, Kikuta K,
Nakayama R, Seki K, Yoshida A, Ichikawa H,
Hasegawa T, Kaneko K, Chuman H, Beppu Y,43Kawai A, Kondo T. Secernin-1 as a novel
prognostic biomarker candidate of synovial
sarcoma revealed by proteomics. J Proteomics.
2011; 74(6): 829-42.
(29) Tanaka M, Shibahara J, Fukushima N, Shinozaki
A, Umeda M, Ishikawa S, Kokudo N, Fukayama
M. Claudin-18 is an early-stage marker ofpancreatic carcinogenesis. J Histochem Cytochem.
2011; 59(10): 942-52.
(30) Tsuta K, Tanabe Y, Yoshida A, Takahashi F,
Maeshima AM, Asamura H, Tsuda H. Utility of 10
Immunohistochemical Markers Including Novel
Markers (Desmocollin-3, Glypican 3, S100A2,
S100A7, and Sox-2) for Differential Diagnosis ofSquamous Cell Carcinoma from Adenocarcinomaof the Lung. J Thorac Oncol. 2011; 6(7): 1190-9.
(31) Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda
F, Ishikawa S, Tsutsumi S, Sonoda K, Totsuka H,
Shirakihara T, Sakamoto H, Wang L, Ojima H,
Shimada K, Kosuge T, Okusaka T, Kato K,
Kusuda J, Yoshida T, Aburatani H, Shibata T.
High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet. 2011;
43(5):464-9.
(32) Ushiku T, Matsusaka K, Iwasaki Y, Tateishi Y,
Funata N, Seto Y, Fukayama M.
Gastric
carcinoma with invasive micropapillary pattern
and its association with lymph node metastasis.
Histopathology. 2011; 59(6): 1081-9.
(33) Hanamura K, Tojo A, Kinugasa S, Asaba K,
Onozato ML, Uozaki H, Fukayama M, Fujita T:
Detection of myeloperoxidase in membranous
nephropathy-like deposits in patients with
anti-neutrophil cytoplasmic antibody-associatedglomerulonephritis. Hum Pathol. 2011; 42(5):649-58.
(34) Watanabe A, Ogiwara H, Ehata S, Mukasa A,
Ishikawa S, Maeda D, Ueki K, Ino Y, Todo T,
Yamada Y, Fukayama M, Saito N, Miyazono K,
Aburatani H. Homozygously deleted gene
DACH1 regulates tumor-initiating activity ofglioma cells. Proc Natl Acad Sci U S A. 2011;
108(30): 12384-9.
(35) Yamauchi C, Fujii S, Kimura T, Kuwata T, WadaN, Mukai H, Matsumoto N, Fukayama M, Ochiai
A. E-cadherin expression on human carcinoma
cell affects trastuzumab-mediated antibody-dependent cellular cytotoxicity through killer cell
lectin-like receptor G1 on natural killer cells. Int J
Cancer. 2011; 128(9): 2125-37.
(36) Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Yoshida H, Aoki T, Hasegawa K, Akahane M,
Ohtomo K, Fukayama M, Koike K, Kokudo N.
Diagnostic accuracy of α-fetoprotein anddes-γ-carboxy prothrombin in screening forhepatocellular carcinoma in liver transplantcandidates. Hepatol Res. 2011; 41(12): 1199207.
(37) Yamazaki S, Fujioka Y, Nakamura F, Ota S,
Shinozaki A, Yamamoto G, Kamikubo Y, Nannya
Y, Ichikawa M, Fukayama M, Kurokawa M.
Composite diffuse large B-cell lymphoma andCD20-positive peripheral T-cell lymphoma.
Pathol Int. 2011; 61(11): 662-6.
(38) Yoshida A, Tsuta K, Watanabe S, Sekine I,
Fukayama M, Tsuda H, Furuta K, Shibata T.
Frequent ALK rearrangement and TTF-1/p63
co-expression of lung adenocarcinoma withsignet-ring cell component. Lung Cancer. 2011;
72(3): 309-15.
(39) Yoshida A, Tsuta K, Nakamura H, Kohno T,
Tkahashi F, Asamura H, Sekine I, Fukayama M,
Shibata T, Furuta K, Tsuda H. Comprehensive
histologic analysis of ALK-rearranged lungcarcinomas. Am J Surg Pathol. 2011; 35(8):1226-34.
(40) Yoshida A, Tsuta K, Nitta H, Hatanaka Y,
Asamura H, Sekine I, Grogan TM, Fukayama M,
Shibata T, Furuta K, Kohno T, Tsuda H.
Bright-field dual-color chromogenic in situ
hybridizationfordiagnosing
echinoderm
microtubule -associated protein-like 4-anaplastic
lymphoma kinase-positive lung adenocarcinomas.
J Thorac Oncol. 2011; 6(10): 1677-86.
(41) Yoshida Y, Inoh S, Murakawa T, Ota S, Fukayama
M, Nakajima J. Preoperative localization of small
peripheral pulmonary nodules by percutaneous
marking under computed tomography guidance.
Interact Cardiovasc Thorac Surg. 2011; 13(1):
25-8.

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 the professor of the Department of
Molecular Pathology from August 2000. Now, theDepartment consists of a professor, an associate
professor, two lecturers, two assistant professors, twoproject assistant professors, technical assistants, andsome research fellows, including 11 graduate students
and 8 post-doctoral fellows.

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

students of the Department. Our laboratory is locatedat the 11th floor at the Research Building of Graduate
School of Medicine. The laboratory is very convenientfor doing research, since most of the experiments canbe done at this floor. We have “Progress Meeting”
twice a month and “Monday Seminar” once a month.
Our research projects are supported by KAKENHI(Innovative Area on “Integrative research on cancer
microenvironment network”) from the Ministry of
Education, Culture, Science, Sports and Technology(MEXT) (http://cancer- microenvironment.jp) since2010, and we are studying the effects of TGF-betafamily proteins on cancer microenvironment.
We have been doing collaboration with the Ludwig
Institute for Cancer Research, Uppsala, Sweden for
more than 15 years, and the collaborations between
Sweden, the Netherlands, and Japan are currently
supported by the Core-to-Core Program “Cooperative
International Framework in TGF-beta Family
Signaling” of Japan Society for the Promotion of
Science (JSPS) (http://c2ctgfb. umin.jp/). We haveannual TGF-beta meeting in Sweden or in the
Netherlands every autumn, and six graduate students
participated in the TGF-beta meeting in Uppsala in2011. At the 1st international core-to-core symposium
held at the Koshiba hall, Graduate School of Science,

45

a graduate student presented her data by oralpresentation, and six students presented their data at
the poster session.
We have been supported by the Global Center of
Excellence (GCOE) Program for "Integrative Life
Science Based on the Study of Biosignaling
Mechanisms" from the MEXT. This program
stimulates interaction with students and scientists inthe program as well as those from other laboratories(http://www.coe.s.u-tokyo.ac.jp/integr-life/index.html).

Research activities
Our major research interest is to elucidate how
members of the TGF-beta (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.
Stem cells in normal tissues and cancer- initiating
cells are enriched in side population (SP) cells, whenseparated by FACS (fluorescence- activated cell
sorter). However, factors responsible for the regulationof expression of ABCG2, which is involved in effluxof dyes and typically expressed in SP cells, have notbeen fully elucidated. Ehata and colleagues isolated
SP cells in diffuse-type gastric carcinoma, and studied
the effects of TGF-beta on the SP cells. Diffuse-type
gastric carcinoma cells established from four patientscontained SP cells less than 4% of total cells. SP cells
from the diffuse-type gastric carcinoma cells had
higher tumorigenic activity than non-SP cells.
TGF-beta down-regulated the expression of ABCG2
through direct binding of Smad3 to its promoter and/or
enhancer. TGF-beta reduced the number of SP cells
and inhibited the tumor-forming ability of cancer cells,
but ABCG2 turned out to be not directly involved in
the tumor-forming ability of SP cells. SP cells thus
play a critical role in the progression of diffuse-type
gastric carcinoma, and TGF-beta functions as anegative regulator for maintenance of the diffuse-type
gastric carcinoma-initiating cells (Ehata et al.,Oncogene, 2011).
Bone morphogenetic proteins (BMPs), members of

the TGF-beta family, exhibit pleiotropic functions invarious tissues and organs. Shirai and colleagues
studied the functions of BMPs in human diffuse-type
gastric carcinoma. Exogenous expression of thedominant-negative form of ALK-3, a type I receptor
for BMP-2 and BMP-4, in diffuse- type gastriccarcinoma cells resulted in stimulation of the tumor
growth in vivo. BMP-4 induced cell cycle arrest inthese cells through induction of CDK inhibitor p21 ina Smad-dependent manner. Moreover, exogenous
expression of the constitutively active form of ALK-3
in diffuse-type gastric carcinoma cells inhibited their
growth in vitro and in vivo. These findings suggestthat BMP-2 and BMP-4 serve as tumor suppressors in
diffuse-type gastric carcinoma (Shirai et al., Am. J.
Pathol., 2011).
Perturbations of BMP signaling in vascularendothelial cells (ECs) and pulmonary arterial smoothmuscle cells (PASMCs) are responsible forpathogenesis of certain human vascular disorders,
including hereditary hemorrhagic telangiectasia andpulmonary arterial hypertension. Morikawa andcolleagues generated genome-wide maps of bindingsites of Smad1 and Smad5, BMP-specific receptor
regulated Smads, in ECs and PASMCs. Smad1/5
preferentially interacted with the region outside thepromoter of known target genes, and the Smad1/5
binding was linked to up-regulation of target genes. A
Smad1/5 binding motif was identified and termed
GC-rich Smad binding element (GC-SBE), which isdifferent from the canonical SBE. GC-SBE sequences
had relatively low affinity for Smad binding, and both
GC-SBE and the canonical SBE affect binding affinity
for the Smad complex. Analyses of EC-specificSmad1/5 target genes revealed that some Notch
signaling pathway-related genes were regulated by
BMPs in ECs. Notably, a Notch ligand, JAG1, wasregulated directly by BMP-Smad1/5 pathway, leading
to transactivation of Notch signaling in neighboring
cells. These findings provide new insights into themolecular mechanisms of BMP signaling in vascular
cells and the pathogenesis of some genetic vasculardisorders (Morikawa et al., Nucleic Acids Res., 2011).
MicroRNAs (miRNAs), critical regulators of gene
expression, are known to undergo complex maturation
processes. However, the mechanisms regulating themiRNA maturation have not been fully investigated.

46

H.I Suzuki and colleagues identified the MCPIP1
ribonuclease (also known as Zc3h12a) as a suppressorof miRNA activity and biogenesis. MCPIP1
counteracted Dicer, a central ribonuclease in miRNAprocessing and biogenesis. MCPIP1 suppressed
miRNA synthesis through cleavage of the terminal
loops of precursor miRNAs (pre-miRNAs). Potential
antagonism between the functions of MCPIP1 andDicer has been found in human cancer. A role of
MCPIP1 in regulation of the signaling axis comprising
miR-155 and its target c-Maf has also been observed.
These findings suggest that the balance between Dicer
and MCPIP1, processing and destroying ribonucleases,
respectively, modulates biogenesis of miRNAs underphysiological and pathological conditions (Suzuki HI
et al., Mol. Cell, 2011).
Prox1 is a master gene for lymphangiogenesis,
which plays important roles during embryonicdevelopment and in adult tissues. However, themolecular mechanisms through which Prox1 regulates
its target genes have not been fully elucidated.
Yoshimatsu and colleagues have identified Ets-2 as amolecule that regulates the functions of Prox1.
Endogenous Ets-2 interacted with Prox1 in lymphatic
endothelial cells (LECs). In an in vivo model ofchronic
aseptic
peritonitis,
Ets-2
enhancedinflammatory lymphangiogenesis. In contrast, adominant-negative mutant of Ets-1 suppressed
lymphangiogenesis in vivo. Ets-2 also enhanced
endothelial migration towards vascular endothelial
growth factor (VEGF)-C through induction of theexpression of VEGF receptor-3 (VEGFR3) in thepresence of Prox1. Both Prox1 and Ets-2 bound to the
VEGFR3 promoter. Ets family proteins thus functionastranscriptional
co-factors
thatenhancelymphangiogenesis induced by Prox1 (Yoshimatsu etal., J. Cell Sci., 2010).

References
1. Hoshino, Y., Katsuno, Y., Ehata, S., Miyazono, K.
(2011) Autocrine TGF-beta protects breast cancer
cells from apoptosis through reduction of BH3only protein, Bim. J Biochem. 149 (1), 55-65.

2. Ehata, S., Johansson, E., Katayama, R., Koike, S.,
Watanabe, A., Hoshino, Y., Katsuno, Y., Komuro,A., Koinuma, D., Kano, M.R., Yashiro, M.,
Hirakawa, K., Aburatani, H., Fujita, N., Miyazono,
K. (2011) Transforming growth factor-beta
decreases the cancer-initiating cell population
within diffuse-type gastric carcinoma cells.
Oncogene 30 (14), 1693-1705.
3. Shirakihara, T., Horiguchi, K., Miyazawa, K.,
Ehata, S., Shibata, T., Morita, I., Miyazono, K.,
Saitoh, M. (2011) TGF-beta regulates isoform
switching of FGF receptors and epithelialmesenchymal transition. EMBO J. 30 (4), 783795
4. Mizutani, A., Koinuma, D., Tsutsumi, S.,
Kamimura, N., Morikawa, M., Suzuki, H.I.,
Imamura, T., Miyazono, K., Aburatani, H. (2011)
Cell type-specific target selection by combinatorial binding of Smad2/3 proteins and hepatocyte
nuclear factor 4alpha in HepG2 cells. J Biol Chem.
286 (34), 29848-29860.
5. Watanabe, A., Ogiwara, H., Ehata, S., Mukasa, A.,
Ishikawa, S., Maeda, D., Ueki, K., Ino, Y., Todo,
T., Yamada, Y., Fukayama, M., Saito, N.,
Miyazono, K., Aburatani, H. (2011) Homozygously deleted gene DACH1 regulates tumorinitiating activity of glioma cells. Proc Natl Acad
Sci USA. 108 (30), 12384-12389.
6. Morikawa, M., Koinuma, D., Tsutsumi, S.,
Vasilaki, E., Kanki, Y., Heldin, C.H., Aburatani,
H., Miyazono, K. (2011) ChIP-seq reveals cell
type-specific binding patterns of BMP-specificSmads and a novel binding motif. Nucleic Acids
Res. 39 (20), 8712-8727.
7. Koinuma, D., Shinozaki, M., Nagano, Y.,
Ikushima, H., Horiguchi, K., Goto, K., Chano, T.,
Saitoh, M., Imamura, T., Miyazono, K., Miyazawa,K. (2011) RB1CC1 protein positively regulates
transforming growth factor- beta signaling
through the modulation of Arkadia E3 ubiquitin
ligase activity. J Biol Chem. 286 (37), 3250232512.

47

8. Yoshimatsu, Y., Yamazaki, T., Mihira, H., Itoh, T.,
Suehiro, J., Yuki, K., Harada, K., Morikawa, M.,
Iwata, C., Minami, T., Morishita, Y., Kodama, T.,
Miyazono, K., Watabe, T. (2011) Ets family
members induce lymphangiogenesis throughphysical and functional interaction with Prox1. J
Cell Sci. 124 (16), 2753-2762.
9. Ikushima, H., Todo, T., Ino, Y., Takahashi, M.,
Saito, N., Miyazawa, K., Miyazono, K. (2011)
Glioma-initiating cells retain their tumorigenicity
through integration of the Sox axis and Oct4
protein. J Biol Chem. 286 (48), 41434-41441.
10. Shirai, Y.T., Ehata, S., Yashiro, M., Yanagihara, K.,
Hirakawa, K., Miyazono, K. (2011) Bonemorphogenetic protein-2 and -4 play tumor
suppressive roles in human diffuse-type gastriccarcinoma. Am J Pathol. 179 (6), 2920-2930.
11. Cabral, H., Matsumoto, Y., Mizuno, K., Chen, Q.,
Murakami, M., Kimura, M., Terada, Y., Kano,
M.R., Miyazono, K., Uesaka, M., Nishiyama, N.,
Kataoka, K. (2011) Accumulation of sub-100 nm
polymeric micelles in poorly permeable tumours
depends on size. Nat Nanotechnol. 6 (12),815-823.
12. Matsuyama, H., Suzuki, H.I., Nishimori, H.,
Noguchi, M., Yao, T., Komatsu, N., Mano, H.,
Sugimoto, K., Miyazono, K. (2011) miR-135b
mediates NPM-ALK-driven oncogenicity andrenders IL-17-producing immunophenotype toanaplastic large cell lymphoma. Blood. 118 (26),6881-6892.
13. Suzuki, H.I., Arase, M., Matsuyama, H., Choi,
Y.L., Ueno, T., Mano, H., Sugimoto, K.,
Miyazono, K. (2011) MCPIP1 ribonucleaseantagonizes Dicer and terminates microRNAbiogenesis
throughprecursor
microRNAdegradation. Mol Cell. 44 (3), 424-436.
14. Ikushima, H., Miyazono, K. (2011) Biology oftransforming growth factor-beta signaling. Curr
Pharm Biotechnol. 12 (12), 2099-2107.
15. Yoshimatsu, Y., Watabe, T. (2011) Roles of
TGF-beta signals in endothelial-mesenchymaltransition during cardiac fibrosis. Int J Inflam.
2011: 724080.

Pathology, Immunology andMicrobiology
2. Microbiology

49

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

Lecturer
Naoko Kamiya, Ph.D.

Associate
Ryohei Tsutsumi, Ph.D., Yasuhiro Saito, Ph.D.

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

Introduction and Organization

Research activities

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 23 members; 1 professor (Dr. Hatakeyama),
1 lecturer (Dr. Kamiya), 2 associates (Drs. Tsutsumi
and Saito), 3 Post-doc (Drs. Zhang, Takahashi,
Takeda), 5 technical staffs (Ms. Sekiguchi, Morohashi,
Yoshihashi, Kashiba, Goto), 11 Graduate School
students (Ms. and Mrs. Fujii, Yamahashi, Hayashi,
Safari, Suzuki, Yanagiya, Kikuchi, Nagase, Hashi,
Bingo, Noda).

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 andChina, are known to show the highest incidence ofgastric cancer in the world. In Japan, for instance,
50,000 peoples are killed by gastric cancer each year.
Thus, establishment of new strategies for prevention
and treatment 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.

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

50

1. Identification of parafibromin/Cdc73 as a key
substrate of SHP2 tyrosine phosphatase toderegulate Wnt signaling.
H. pylori CagA undergoes tyrosine phosphorylation by
host cell kinases. Tyrosine-phosphorylated CagA
acquires the ability to specifically bind to andaberrantly activate SHP2 tyrosine phosphatase. SHP2
is expressed in a wide range of cell types, and exists inboth the cytoplasm and nucleus. Whereas SHP2
functions as a positive regulator of RAS-ERK
signaling pathway in the cytoplasm, potential roles of
SHP2 in the nucleus are not completely understood.
In order to elucidate the functions of SHP2 in the
nucleus, we investigated SHP2 substrates bycombining a substrate-trapping technique and mass
spectrometry. We found that SHP2 dephosphorylates
parafibromin/Cdc73, a component of the nuclear RNA
polymerase II-associated factor (PAF) complex.
parafibromin has been reported to interact with
β-catenin and thereby activate nuclear Wnt signaling.
We found that, on tyrosine dephosphorylation by
SHP2, parafibromin acquires the ability to stably bindto β-catenin. Furthermore, parafibromin induced theexpression of Wnt target genes, including c-myc andcyclin D1 in a tyrosine dephosphorylation-dependent
manner. Hence, on tyrosine dephosphorylation by
SHP2, parafibromin acquires the ability to activate
Wnt signaling, which plays a key role in cell growthand differentiation.
Whereas parafibromin is strictly localized in the
nucleus, β-catenin shuttles between the cytoplasm andnucleus. On tyrosine dephosphorylation by SHP2,
parafibromin tethered β-catenin to the nucleus. The
finding indicates that nuclear translocation of SHP2 isa key event to activate Wnt signaling. We found thatgrowth-stimulating signals such as Ras signal promote
nuclear accumulation of SHP2, which in turn activates
nuclear Wnt signaling.
Our findings indicate that aberrantly activated SHP2
promotes malignant transformation of cells not only
via deregulation of the Ras-ERK signal but also
through aberrant activation of Wnt signaling.
Furthermore, RAS-ERK signal and Wnt signal arecooperatively activated through nuclear translocationof SHP2.

2. Stimulation of H. pylori CagA virulence throughhomodimerization.
CagA-deregulated
SHP2
activates
RAS-ERKsignaling pathway, which stimulates cell proliferation.
CagA-deregulated SHP2 also inhibits focal adhesion
kinase (FAK), a tyrosine kinase that regulates theturnover of focal adhesion spots. As a result, CagA
induces an elongated cell shape known as thehummingbird phenotype.
CagA specifically interacts with partitioningdefective 1(PAR1)/microtubule affinity-regulating
kinase (MARK) in a tyrosine phosphorylationindependent manner and inhibits the kinase activity,
resulting in disruption of the tight junction and loss ofepithelial polarity. The PAR1-binding region of CagA
is the 16-amino-acid CagA multimerization (CM)sequence that mediates CagA dimerization. Because
PAR1 is thought to exist as a dimer within the cells,
two CagA proteins appear to passively dimerizethrough binding with a PAR1 dimer. Upon tyrosine
phosphorylation, the dimerized CagA binds
specifically to two SH2 domains of SHP2.
To investigate the role of CagA dimerization in
induction of the hummingbird phenotype, we
generated a CagA mutant that is conditionally homodimerized by a chemical dimerizer, coumermycin. We
found that CagA dimerization markedly stabilizes the
CagA-SHP2 complex and thereby induces thehummingbird phenotype. Hummingbird cells inducedby chemical dimerization of CagA developed longer
protrusions
when
PAR1
expression
wassimultaneously inhibited. This study revealed that fullinduction of the hummingbird phenotype by CagA
requires two independent functions of the CM
sequence: 1) dimerization of CagA that potentiates
SHP2 deregulation and 2) inhibition of PAR1 activity.
Furthermore, the results indicate that inhibition of
CagA dimerization has therapeutic value in preventing
gastric carcinoma.
3. Inhibition of Pragmin-Csk interaction by H. pylori
CagA through EPIYA-mediated competitive
binding to Csk for successful infection.
Upon delivery into gastric epithelial cells via type IV
secretion, CagA is tyrosine-phosphorylated by Src
family kinases (SFKs) or c-Abl kinase at the EPIYA
motif. Recent studies revealed that several pathogenic

51bacteria, such as Anaplasma phagocytophilum,
enteropathogenic Escherichia coli, and Chlamydia
trachomatis, possess effector proteins that undergotyrosine phosphorylation at the EPIYA or EPIYA-like
motif by host kinases. As is the case with CagA,
tyrosine-phosphorylated effectors may bind to SH2
domain-containing proteins and thereby deregulate
host-signaling pathways. Whereas bacterial EPIYA
effectors have important roles in exerting virulence,
functions of mammalian EPIYA-containing protein
remain unknown.
A search of the human proteome with the National
Center for Biotechnology Information BLAST
program identified six proteins that possess a perfect
EPIYA motif. Of these, Pragmin (also known as
SgK223) is a cytoplasmic pseudokinase reported as adownstream effector of Rnd2, a Rho family GTPase
predominantly expressed in neurons. Notably,
expression of Pragmin is not limited to neurons, whichindicates that the protein has more functions. The
EPIYA motif is perfectly conserved among
mammalian Pragmin orthologs, indicating that the
motif has an important role in the function of Pragmin.
We found that Pragmin undergoes tyrosine
phosphorylation at the EPIYA motif by SFKs andthereby acquires the ability to interact with the SH2
domain of C-terminal Src kinase (Csk) that is anegative regulator of SFKs. Csk is localized
predominantly in the cytoplasm. Because SFKs areanchord to the plasma membrane via myristoylation/
palmitoylation, Csk needs to translocate to themembrane to inhibit SFKs. The Pragmin-Csk
interaction prevented translocation of Csk from thecytoplasm to the membrane and thereby potentiatedkinase activity of SFKs. Notably, EPIYA motif of
Pragmin was phosphorylated by SFKs. The findings
indicate that the Pragmin-Csk interaction establishes apositive feedback regulation of SFKs.
We have previously reported that H. pylori CagA
interacts with the SH2 domain of Csk in an EPIYA
tyrosine phosphorylation-dependent manner andstimulates the kinase activity. Furthermore, CagA
recruits Csk to the plasma membrane and thereby
inactivates the SFKs. We revealed that CagA inhibits
Pragmin-Csk interaction via complex formation with
Csk. In epithelial cells, SFKs are required for the
induction of antibacterial peptides such as defensins

and are involved in the activation of NF-κB in
response to bacterial infection. Our findings indicatethat CagA targets Pragmin to inhibit SFKs for
successful bacterial infection.
4. Regulation of RhoA-dependent actin cytoskeletal
reorganization by polarity-regulating kinase
PAR1b.
In mammals, PAR1 kinases were originally identified
as MARKs, which phosphorylate microtubuleassociated proteins (MAPs) and thereby regulate thestability of microtubules. Mammalian PAR1/MARK
comprises four isoforms, PAR1a/MARK3, PAR1b/
MARK2, PAR1c/MARK1, and PAR1d/MARK4. In
particular, PAR1b plays a key role in the establishment
and maintenance of the epithelial cell polarity. PAR1b
also influences actin cytoskeleton organization, butlittle is known about how it works. Recent study
showed that PAR1b forms a physical complex with a
RhoA-specific guanine nucleotide exchange factor H1(GEF-H1). This observation suggests that PAR1b
influences actin cytoskeleton organization throughGEF-H1.
We found that PAR1b induces phosphorylation of
RhoA activator GEF-H1 on serine 885 and serine 959.
This PAR1b-induced phosphorylation inhibited the
RhoA-specific nucleotide exchange activity of
GEF-H1, resulting in suppression of actin stress fiber
formation by RhoA. Our findings indicate that PAR1b
not only regulates microtubule stability throughphosphorylation of MAPs but also influences actin
stress fiber formation through phosphorylation of
GEF-H1.

References
1.

2.

Yamahashi Y, Saito Y, Murata-Kamiya N,
Hatakeyama M. Polarity-regulating kinase
partitioning-defentive 1b (PAR1b) phosphorylates
guanine nucleotide exchange factor H1 (GEF-H1)
to regulate RhoA-dependent actin cytoskeletal
reorganization. J Biol Chem 2011:286:4457644584.
Safari F, Murata-Kamiya N, Saito Y, Hatakeyama
M. Mammalian Pragmin regulates Src family
kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif

52

3.

4.

5.

6.

that is exploited by bacterial effectors. Proc Natl
Acad Sci USA 2011:108:14938-14943.
Furuta Y, Yahara K, Hatakeyama M, Kobayashi I.
Evolution of cagA oncogene of Helicobacter
pylori through recombination. PLoS One 2011:6:
e23499.
Nagase L, Murata-Kamiya N, Hatakeyama M.
Potentiation of Helicobacter pylori CagA protein
virulence through homodimerization. J Biol Chem
2011:286: 33622-33631.
Takahashi A, Tsutsumi R, Kikuchi I, Obuse C,
Saito Y, Seidi A, Karisch R, Fernandez M, Cho T,
Ohnishi N, Rozenblatt-Rosen O, Meyerson M,
Neel BG, Hatakeyama M. SHP2 tyrosine
phosphatase converts parafibromin/Cdc73 from atumor suppressor to an oncogenic driver. Mol Cell
2011:43:45-56.
Hatakeyama M. Anthropological and clinicalimplications for the structural diversity of the
Helicobacter pylori CagA oncoprotein. Cancer Sci
2011:102:36-43.

53

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

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

Homepage http://www.cc.h.u-tokyo.ac.jp/mulins/kansen/index.html(inside the hospital only)※ The following information is the same as that of the previous year for certain reasons.

Introduction and Organization
The Department of Infection Control and Prevention
started at first as the Division of Hospital Infection
Control Services on January 23, 1991. This divisiondeveloped into the Division of Infection Control andPrevention on September l, 1993 and the present
department on June 4, 1994. Currently, our faculty
consists of one professor, five guest lecturers, four
research associates, 11 laboratory technicians, and two
office assistants. For isolation and identification of
microorganisms from clinical specimens, we
amalgamated the microbiology unit from the
Department of Clinical Laboratory in 2001.

Clinical activities
Our daily activities are as follows:
1) Surveillance and control of hospital-acquired
infection, such as infection or colonization ofmethicillin-resistant Staphylococcus aureus andother drug-resistant microbes.
2) Investigation of trends in weekly bases andmonthly reports to all departments; Screening ofcolonization; monitoring of appropriate use ofantibiotics such as mupirocin and vancomycin.
3) Microbiological investigation of wards andenvironment (at request or need).
4) Detection, investigation, intervention and controlof the hospital infection outbreak.
5) Offering of information and advice on HIVinfected patients’ management.
6) Direct inquiries and advises on management ofpatients with various infections through ward
rounds every week.

Teaching activities
We have been charged for education of undergraduate
students on the course of medicine (lectures andpractical exercises on the infection control for the 4th
grade students). These lectures and exercises contain
subjects not only on the hospital infection but also on
clinical microbiology. We are also engaged in the
education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed
to the guidance for new postgraduates and residents

54

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) Lipid metabolism and liver disease in hepatitis C
viral infection.Koike K, Tsutsumi T, Yotsuyanagi
H, Moriya K.Oncology. 2010 Jul;78 Suppl
1:24-30. Epub 2010 Jul 8.
(2) Hepatitis C virus core protein compromises
iron-induced activation of antioxidants in miceand HepG2 cells.Moriya K, Miyoshi H,
Shinzawa S, Tsutsumi T, Fujie H, Goto K,
Shintani Y, Yotsuyanagi H, Koike K.J Med Virol.
2010 May;82(5):776-92.
(3) Animal models for hepatitis C and related liverdisease.Koike K, Moriya K, Matsuura Y. Hepatol
Res. 2010 Jan;40(1):69-82.

(4) Inflammasome sensor Nlrp1b-dependent resistance to anthrax is mediated by caspase-1, IL-1
signaling and neutrophil recruitment. Moayeri M,
Crown D, Newman ZL, Okugawa S, Eckhaus M,
Cataisson C, Liu S, Sastalla I, Leppla SH.PLoS
Pathog. 2010 Dec 9;6(12):e1001222.
(5) Anthrax toxin targeting of myeloid cells throughthe CMG2 receptor is essential for establishment
of Bacillus anthracis infections in mice.Liu S,
Miller-Randolph S, Crown D, Moayeri M,
Sastalla I, Okugawa S, Leppla SH.Cell Host
Microbe. 2010 Nov 18;8(5):455-62.
(6) MyD88-dependent signaling protects against
anthrax lethal toxin-induced impairment ofintestinal barrier function.Okugawa S, Moayeri
M, Eckhaus MA, Crown D, Miller-Randolph S,
Liu S, Akira S, Leppla SH.Infect Immun. 2011
Jan;79(1):118-24. Epub 2010 Oct 25.
(7) Cryptococcus gattii genotype VGIIa infection inman, Japan, 2007.Okamoto K, Hatakeyama S,
Itoyama S, Nukui Y, Yoshino Y, Kitazawa T,
Yotsuyanagi H, Ikeda R, Sugita T, Koike
KEmerg Infect Dis. 2010 Jul;16(7):1155-7.
(8) Cryptococcal pleuritis containing a high level ofadenosine deaminase in a patient with AIDS: acase report.Yoshino Y, Kitazawa T, Tatsuno K,
Ota Y, Koike K.Respiration. 2010;79(2):153-6.
Epub 2009 Apr 29.
(9) Defective membrane expression of the
Na(+)-HCO(3)(-) cotransporter NBCe1 is
associated with familial migraine.Suzuki M, Van
Paesschen W, Stalmans I, Horita S, Yamada H,
Bergmans BA, Legius E, Riant F, De Jonghe P,
Li Y, Sekine T, Igarashi T, Fujimoto I, Mikoshiba
K, Shimadzu M, Shiohara M, Braverman N,
Al-Gazali L, Fujita T, Seki G.Proc Natl Acad Sci
U S A. 2010 Sep 7;107(36):15963-8. Epub 2010
Aug

Pathology, Immunology andMicrobiology
3. Immunology

56

Department of Immunology
Professor
Tadatsugu Taniguchi, Ph.D.

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

Assistant Professor
Hideyuki Yanai, Ph.D.;

Hideo Negishi, Ph.D.;

Koji Atarashi, Ph.D.;

Junko Nishio, M.D., Ph.D.

Homepage

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

Introduction and Organization
The history of the Department of Immunology,
formerly the Department of Serology, dates back to1918. The department’s adopted its present namewhen 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 a worldrenowned 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57

world, such as Jeffrey V. Ravetch (Professor of The
Rockefeller University) and Shimon Sakaguchi(Professor of Osaka University).

Research activities
Our research interests within the fields of cellularand molecular immunology involve the extensive
analysis of the mechanisms that underlie theregulation of gene expression and signal transduction
in host defense systems, with a focus on the molecularmechanisms of the host defense against viral andbacterial infections. Among these mechanisms, theinterferon (IFN) system is one of the most importantin the control of such infections. During the course of
our studies, we have identified members of theinterferon regulatory factor (IRF) family to play anumber of critical roles in immunity. In total, ourstudies on IRFs have revealed a remarkable functional
diversity and serve as key regulators in the control of
innate immune responses. For example, we haveshown that the transcription factor IRF-7 is essential
for type I IFN production upon virus- and TLRactivated signaling pathways. Furthermore, IRF-5 wasdemonstrated by us to be critical for the induction of
pro-inflammatory cytokines and chemokine genes,
which are typically activated by TLRs in response toinfections.
Recently, attention has been focused on the role ofinnate immune receptors including Toll-like receptors(TLRs) in the evocation of immune responses. So far,several cytosolic nucleic acid-sensing receptors
including TLRs (TLR3, 7, 9) and RIG-I-like receptors(RLRs; RIG-I and MDA5) have been identified.
Although much attention has been focused on howeach of these innate receptors enhances adaptive
immune responses, whether and how the signaling
events from one class of receptors affect the activityof another in modulating adaptive immunity remains
unknown. We demonstrated that the cytosolic RLRs
activation by viruses or viral mimetics results inselective suppression of the gene transcription ofinterleukin (IL)-12p40, the common subunit of IL-12
and IL-23, effectively induced by TLRs activation bybacteria or bacterial mimetics. This suppression
mechanism is unique in that the RLR-activated IRF3
transcription factor, best known to robustly activate

type I IFN genes, predominantly binds to the
IL-12p40 promoter where it interferes with the
productive assembly of transcription factors that isotherwise induced by TLR signaling. Consequently,
RLR activation attenuates Th1- and Th17-type T cell
responses, which are otherwise robustly induced by
TLR activation. Consistent with this, viral infection
markedly suppresses bacteria-induced Th1/Th17
responses, causing lethality at sub-lethal doses ofbacterial infection. This newly identified facet of
innate immune receptor cross-interference, which
modulate adaptive immune responses, may have
implications for infection-associated clinical episodes.
Based on this, we are currently trying to address
further the relation between pathogen infection andpathogenesis of autoimmune diseases.
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 the

58promiscuous sensing by high-mobility group box
proteins (HMGBs).
From the above new finding, we reasoned that
nonimmunogenic nucleotides with high-affinity
HMGB binding may function as suppressing agentsfor HMGB-mediated diseases, particularly thoseinitiated and/or exacerbated by nucleic acids. We
characterized
an
array
of
HMGB-binding,nonimmunogenic oligodeoxynucleotides (ni-ODNs).
Interestingly, we fund that binding affinity is for themost part independent of nucleotide sequence, but isinstead dependent on length and the secondary
structure of the deoxyribose backbone. We further
showed that these ni-ODNs can strongly suppress theactivation of innate immune responses induced byboth classes of nucleic acid-sensing receptors. We
also provided evidence for the suppressive effect of an
ni-ODN, termed ISM ODN, on the induction ofadaptive immune responses and in mouse models of
sepsis and autoimmunity. Thus, our study suggests
the possible use of these ni-ODNs in therapeuticinterventions.
We also conducted applied research projects, inwhich we discovered several unique compounds thatinterfere with innate immune receptor signaling. Oneof these compounds turned out to be quite unique inthat it activated stress-induced MAK kinases, JNK and
p38 while inhibiting the activation of NF-κB
transcription factor. We have promising results,
indicating the usefulness of this compound for thetreatment of inflammatory autoimmune diseases andcancers. We aim at improving the efficacy of thiscompound by modifying its structure for clinicalpurposes and, at the same time, try to elucidate its
mechanism of action.
Finally, we have also been conducting a newresearch project focusing on the intestinal immune
system and their relationship with the intestinal
microbiota. The intestinal mucosa has a unique andcomplicated immune system composed of a variety ofadaptive immune cell populations. In particular,
CD4+ T cells in the intestinal mucosa comprisesignificant numbers of interleukin (IL)-17-producing
cells (‘Th17 cells’) and IL-10-producing regulatory T
cells (‘Treg cells’). These cells are particularly
abundant at the intestine and are present even at thesteady state. Employing gnotobiotic techniques, wehave demonstrated that components of the intestinalcommensal microbiota, particularly segmented
filamentous bacteria (SFB), strongly induce small
intestinal Th17 cells, whereas the accumulation of
Foxp3+ Treg cells in the colon of mice is promoted by
the presence of the spore-forming component ofindigenous intestinal microbiota—particularly thegenus Clostridium belonging to clusters XIVa and IV.
By extending our results, we are currently trying todevelop new therapeutic strategies by intervention of
the microbiota for various diseases including Crohn’sdisease and ulcerative colitis.

References(1) Taniguchi, T.; Aimez-vous Brahms? A story
capriccioso from the discovery of a cytokine family
and its regulators. (2009) Nat. Immunol., 10,447-449(2) Yanai, H., Savitsky, D., Tamura, T. and Taniguchi,T.; Regulation of the cytosolic DNA-sensing
system in innate immunity: a current view. (2009)
Curr. Opin. Immunol., 1, 17-22(3) Suzuki, S., Nakasato, M., Shibue, T., Koshima, I.
and Taniguchi, T.; Therapeutic potential ofproapoptotic molecule Noxa in the selective
elimination of tumor cells. (2009) Cancer Sci., 100,759-769(4) Chen, H.M., Tanaka, N., Mitani, Y., Oda, E.,
Nozawa, H., Chen, J.Z., Yanai, H., Negishi, H.,
Choi, M.K., Iwasaki, T., Yamamoto, H., Taniguchi,
T. and Takaoka, A.; Critical role for constitutive
type I interferon signaling in the prevention ofcellular transformation. (2009) Cancer Sci., 100,
449-456(5) Yanai, H., Savitsky, D., Tamura, T. and Taniguchi,T.; Regulation of the cytosolic DNA-sensing
system in innate immunity: a current view. (2009)
Curr. Opin. Immunol., 1, 17-22(6) Taniguchi, T.; Aimez-vous Brahms? A story
capriccioso from the discovery of a cytokine family
and its regulators. (2009) Nat. Immunol., 10,447-449(7) Nakajima A, Nishimura K, Nakaima Y, Oh T,
Noguchi S, Taniguchi T, Tamura T. Cell typedependent proapoptotic role of Bcl2L12 revealed
by a mutation concomitant with the disruption of

59

the juxtaposed Irf3 gene. Proc. Natl. Acad. Sci.
USA 106, 12448-12452 (2009).
(8) Choi MK, Wang Z, Ban T, Yanai H, Lu Y, Koshiba
R, Nakaima Y, Hangai S, Savitsky D, Nakasato M,
Negishi H, Takeuchi O, Honda K, Akira S, Tamura
T, and Taniguchi T. A selective contribution of the
RIG-I-like receptor pathway to type I interferon
responses activated by cytosolic DNA. Proc. Natl.
Acad. Sci. USA 106, 17870-17875 (2009).
(9) Yanai H, Ban T, Wang Z, Choi MK, Kawamura T,
Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba
R, Savitsky D, Ronfani R, Akira S, Bianchi ME,
Honda K, Tamura T, Kodama T, and Taniguchi
T.(HMGB proteins function as universal sentinels
for nucleic acid-mediated innate immune
responses. Nature 462, 99-103 (2009).
(10) Savitsky D, Tamura T, Yanai H, and Taniguchi
T. Regulation of immunity and oncogenesis by the
IRF transcription factor family. Cancer Immunol.
Immunother. 59, 489-510 (2010).
(11) Savitsky D, Yanai H, Tamura T, Taniguchi T and
Honda K. Contribution of IRF5 in B cells to thedevelopment of murine SLE-like disease through its
transcriptional control of the IgG2a locus. Proc.
Natl. Acad. Sci. USA 107, 10154-10159 (2010).
(12) Yanai, H., Chiba, S., Ban, T., Nakaima, Y.,
Onoe, T., Honda, K., Ohdan, H. and Taniguchi, T.
Suppression of immune responses by nonimmunogenic oligodeoxynucleotides with highaffinity for high-mobility group box proteins(HMGBs). Proc. Batl. Acad. Sci. USA. 108,
11542-11547 (2011)(13) Atarashi K, Tanoue T, Shima T, Imaoka A,
Kuwahara T, Momose Y, Cheng G, Yamasaki S,
Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S,
Ivanov II, Umesaki Y, Itoh K and Honda K.
Induction of colonic regulatory T cells byindigenous Clostridium species. Science 331,
337-341 (2011)(14) Matsuda A., Ogawa M., Yanai H., Naka D., Goto
A., Ao T., Tanno Y., Takeda K., Watanabe Y.,
Honda K. and Taniguchi T. Generation of mice
deficient in RNA-binding motif protein 3(RBM3) and characterization of its role in innate
immune responses and cell growth. Biochem.
Biophys. Res. Commun. 411, 7-13 (2011)(15) Yanai H., Ban T. and Taniguchi T. Essential roleof high-mobility group box proteins in nucleic
acid-mediated innate immune responses. J. Intern.
Med. 270, 301-308 (2011)(16) Tsushima K., Osawa T., Yanai H., Nakajima A.,
Takaoka A., Manabe I., Imai Y., Taniguchi T. andNagai R. IRF3 regulates cardiac fibrosis but not
hypertrophy in mice during angiotensin IIinduced hypertension. FASEB J. 25, 1531-1543(2011)(17) Negishi H., Yanai H., Nakajima A., Koshiba R.,
Atarashi K., Matsuda A., Matsuki K., Miki S.,
Doi T., Aderem A., Nishio J., Smale ST., Honda
K and Taniguchi T. Cross-interference of RLR
and TLR signaling pathways modulates
antibacterial T cell responses. Nat. Immunol. 13,
659-666 (2012)

Radiology and Biomedical
Engineering
1. Radiology

61

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

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

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

Masaaki Akahane, M.D.,

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

Lecturer
Yoshitaka Masutani, Ph.D.,

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

Harushi Mori, M.D.

Assistant Professor
Tsuyoshi Nojo, M.D., Ph.D.,

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

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

Jiro Sato, M.D.,

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

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

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

Hiroyuki Akai, M.D., Ph.D.

Homepage

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

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

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

In the section of Diagnostic Radiology, all CT and
MRI examinations are monitored and reported bydiagnostic radiologists. Diagnostic radiologists,
gastroenterologists and cardiologists mainly perform
interventional procedures.
In the section of Nuclear Medicine, there are two
SPECT rooms and three PET rooms. These nuclear
imaging procedures are chiefly performed andreported by radiologists and cardiologists.
Each year, over 700 new patients receive radiation
therapy in the Radiation Oncology section. Highly
accurate 3D radiation therapy is the most outstanding
feature. Stereotactic radiation therapy for small lungor liver tumors has been carried out.
In the 9th floor of the new inpatient building, there
are 12 beds in the Radiology ward, which are usuallyused for oncology patients receiving radiation therapy
and chemotherapy. Some of them are sometimes used
for patients receiving invasive diagnostic procedures
such as interventional radiology (IVR), angiography
and myelography. There are two special beds for62radionuclide (RN) therapy in the same floor. In
addition, four beds are allotted to terminal care ward
located in the 14th floor.

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

Research activities
Research activities in our department include
clinicalresearch,
animalexperiments
anddevelopment of instruments as well as computer-based
new technology. Diagnostic Radiology group in thedepartment promotes research activities aiming at
efficacy improvement of diagnostic imaging andexpansion of its application. Multi-row detector
helical computed tomography (MDCT) enables us totake tomographic images in a three-dimensional (3D)fashion. Using the data acquired by MDCT, various
kinds of diseases in almost all parts of the body, from
cerebral diseases to musculoskeletal diseases, can bedisplayed in 3D images. New 3D software developedin our departments is now widely used in the field of
the gastrointestinal tract, lung, and central nervous
system. In addition, we have opened a new laboratory
section named Image Computing and Analysis
Laboratory with invitation of a new staff from theFaculty of Engineering, the University of Tokyo. Thissection will contribute to development of novelsoftware to abstract clinically useful information fromthe 3D imaging data more sophisticatedly. In the fieldof magnetic resonance (MR) imaging, MR digital
subtraction angiography, perfusion imaging, anddiffusion tensor imaging are the foci of research.
These techniques are aggressively applied to theinvestigation of vascular and neoplastic diseases ofthe brain.
Radiation oncology group promotes research
projects in two major fields, one is physicalengineering aspect of radiotherapy and the other isreduction of injuries due to radiation exposure. With
the purpose of achieving precise external irradiation, a
new linear accelerator with C-arm and multileaf
collimator systems was developed and installed,which is utilized mainly for non-coplanar radiation
therapy in many patients especially with brain tumor
or head and neck tumor. Dynamic conical conformal
radiotherapy (Dyconic therapy) for metastatic brain
tumors using the accelerator is under evaluation. In
addition to gamma knife radiosurgery, this new
accelerator based stereotactic radiotherapy for brain
diseases has been undergone, and stereotactic
radiotherapy for body tumors, such as lung and liver
tumors, has been investigated. A new technology to
track mobile tumors, represented by lung tumors isunder investigation in collaboration with accelerator
makers. Novel approach to terminal care of patientswith various cancers has been investigated andimplemented as the palliative care team in cooperation
with expert nurses. The relationship between terminal
condition and cytokines, and newly developed scoring
system of quality of life are being evaluated. The
gustatory injury due to radiotherapy has been
investigated through animal experiments incombination with the laboratory of biological function,
Graduate School of Agricultural and Life Sciences,
University of Tokyo, and through taste tests in clinicalsetting. Radiation injuries in many tissues in thecritically accident in Tokai-mura were also
investigated.
Nuclear Medicine group promote clinical researchon images of function by the application ofradioisotope-labeled tracer technology. In particular,emission tomography (PET and SPECT) is applied for63

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

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HPB (Oxford) 14(1): 32-41, 2012
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Soma T, Momose T, Takahashi M, Koyama K,
Kawai K, Murase K, Ohtomo K.
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Ann Nucl Med: Epub ahead of print, 2012
Takao H, Hayashi N, Inano S, Ohtomo K.
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Takao H, Hayashi N, Ohtomo K.
Effect of scanner in longitudinal studies of brain
volume changes.
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Takahashi W, Yamashita H, Saotome N, Iwai Y,
Sakumi A, Haga A, Nakagawa K.
Evaluation of heterogeneity dose distributions for
Stereotactic Radiotherapy (SRT): comparison ofcommercially available Monte Carlo dose
calculation with other algorithms.
Radiat Oncol 7(1): 20, 2012
Takao H, Hayashi N, Kabasawa H, Ohtomo K.
Effect of scanner in longitudinal diffusion tensor
imaging studies.
Hum Brain Mapp 33(2): 466-77, 2012
Takao H, Abe O, Yamasue H, Aoki S, Sasaki H,
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Tomizawa N, Komatsu S, Akahane M, Torigoe R,
Kiryu S, Ohtomo K.
Relationship between beat to beat coronary artery
motion and image quality in prospectively
ECG-gated two heart beat 320-detector row
coronary CT angiography.
Int J Cardiovasc Imaging 28(1): 139-46, 2012
Tomizawa N, Komatsu S, Akahane M, Torigoe R,
Kiryu S, Ohtomo K.
Influence of hemodynamic parameters on coronary
artery attenuation with 320-dete ctor coronary CT
angiography.
Eur J Radiol 81(2): 230-3, 2012
Tomizawa N, Nojo T, Akahane M, Torigoe R, Kiryu
S, Ohtomo K.
Prediction of the attenuation of the ascending aorta
using bolus-tracking parame ters and heart rate incoronary computed tomography angiography.
Eur J Radiol: Epub ahead of print, 2012
Ueta T, Mori H, Kunimatsu A, Yamaguchi T,
Tamaki Y, Yanagi Y.
Stroke and Anti-VEGF Therapy.
Ophthalmology 118(10): 2093, 2011
Watanabe T, Hirose S, Wada H, Katsura M,
Chikazoe J, Jimura K, Imai Y, Machida T, Shirouzu
I, Miyashita Y, Konishi S.
Prediction of subsequent recognition performanceusing brain activity in the medial temporal lobe.
Neuroimage 54(4): 3085-92, 2011
Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Yoshida H, Aoki T, Hasegawa K, Akahane M,
Ohtomo K, Fukayama M, Koike K, Kokudo N.
Diagnostic accuracy of α-fetoprotein and des-γcarboxy prothrombin in screening for hepatocellular
carcinoma in liver transplant candidates.
Hepatol Res 41(12): 1199-207, 2011
Yamashita H, Nakagawa K, Okuma K, Sakumi A,
Haga A, Kobayashi R, Ohtomo K.
Correlation between bladder volume and irradiateddose of small bowel in CT-based planning of
intracavitary brachytherapy for cervical cancer.
Jpn J Clin Oncol 42(4): 302-8, 2012
Yamasue H, Suga M, Yahata N, Inoue H, Tochigi M,
Abe O, Liu X, Kawamura Y, Rogers MA, Takei K,

68

Yamada H, Aoki S, Sasaki T, Kasai K.
Reply to: Neurogenetic effects of OXTR rs2254298
in the extended limbic system of healthy caucasian
adults.
Biol Psychiatry 70(9): e41-2, 2011
73. Yoda K, Nakagawa K.
Extension of Van Herk's treatment margin model foranisotropic systematic positioning errors incartesian coordinate systema.
Med Phys 38(7): 3913-4, 2011

Radiology and Biomedical
Engineering
2. Biomedical Engineering

70

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

Assistant Professor
Mako Kamiya, Ph.D.

Homepage

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

Introduction and Organization

Research activities

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

1. Development of novel fluorescence probes
By the end of March 2011, various instruments forchemical syntheses, purification, and characterization
were settled in our department, i.e., four chemical
hoods, four evaporators, two instruments for the
purification of compounds based on different
chromatographical mechanisms, two HPLC systems,
400 MHz NMR, ESI-TOF mass, and so on. Further,another room for organic syntheses has been set up
equipped with two chemical hoods, two evaporators,
and one HPLC system in FY2011. UV-Vis
spectrometers and fluorometers were also settled in
our laboratory. So now, molecular design, chemical
syntheses, purification, characterization of novel
probes can be done in our department.
By using above instruments, we are now conducting
various projects of establishing novel bioimaging
techniques based on the development of new
fluorescence probes. So far, we have succeeded inestablishing rational design strategies of fluorescenceprobes based on photoinduced electron transfer
mechanism. Further in 2011, we have succeeded toestablish another versatile design strategy by utilizing
the concept of intramolecular spirocyclization.

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

2. Live imaging of cellular functions and in vivo
tumors by precisely designed fluorescence probes
Various instruments for live imaging of cells andanimals were already settled in our laboratory, i.e.,

71

confocal fluorescence microscope equipped with awhite-light laser, two wide field fluorescencemicroscopes, FACS, two in vivo fluorescent imagers,
in vivo bioluminescent imager, fluorescent endoscope,
etc. Also, instruments for cell culture and DNA work
were also settled in our laboratory.
By using these instruments, we are doing live imaging
of cancer cells and model mice extensively, forelucidating characteristic features of live cancer cells.
Based on the acquired data, we are developing novel
fluorescence probes for detecting tiny tumor sites invivo. In 2011, comparison of various hydrolase
activities in cancer and normal cells were extensively
examined by utilizing novel probes, and we found thatthe activity of γ-glutamyltranspeptidase is upregulated
in cancer cells.
Based on this finding, we havesucceeded to detect tiny tumor sites in cancer bearing
model mice within several tens of seconds to minutesby spraying our new fluorescence probes for GGT.
This achievement was published in Science
Translational Medicine, and was introduced in many
televisions, newspapers and magazines. Now, we start
to apply these probes to real human resected tumor
samples, and examine the efficiency of our probes.

References
1. Sasaki H, Hanaoka K, Urano Y, Terai T, Nagano
T: Design and synthesis of a novel fluorescenceprobe for Zn2+ based on the spirolactam
ring-opening process of rhodamine derivatives.
Bioorg. Med. Chem., 19(3): 1072-1078, Feb,2011.
2. Koide Y, Urano Y, Hanaoka K, Terai T, Nagano
T: Development of an Si-rhodamine-based far-red
to near-infrared fluorescence probe selective for
hypochlorous acid and applications for biologicalimaging. J. Am. Chem. Soc., 133(15): 5680-5682,
Apr, 2011.
3. Matsumoto T, Urano Y, Takahashi Y, Mori Y,
Terai T, Nagano T: In situ evaluation of kinetic
resolution catalysts for nitroaldol by using arationally designed fluorescence probe. J. Org.
Chem., 76(10): 3616-3625, May, 2011.
4. Komatsu T, Johnsson K, Okuno H, Bito H, Inoue
T, Nagano T, Urano Y: Real-time measurements
of protein dynamics using fluorescence

activation-coupled protein labeling method. J. Am.
Chem. Soc., 133(17): 6745-6751, May, 2011.
5. Koide Y, Urano Y, Hanaoka K, Terai T, Nagano
T: Evolution of group 14 rhodamines as platforms
for near-infrared fluorescence probes utilizing
photoinduced electron transfer. ACS Chem. Biol.,
6(6): 600-608, Jun, 2011.
6. Takakura H, Kojima R, Urano Y, Terai T,
Hanaoka K, Nagano T: Aminoluciferins asfunctional bioluminogenic substrates of firefly
luciferase. Chem. Asian J., 6(7): 1800-1810, Jul,2011.
7. Abo M, Urano Y, Hanaoka K, Terai T, Komatsu
T, Nagano T: Development of a Highly Sensitive
Fluorescence Probe for Hydrogen Peroxide. J. Am.
Chem. Soc., 133(27): 10629-10637, Jul, 2011.
8. Kamiya M, Asanuma D, Kuranaga E, Takeishi A,
Sakabe M, Miura M, Nagano T, Urano Y:
β-Galactosidase Fluorescence Probe with
Improved Cellular Accumulation Based on
Spirocyclized Rhodol Scaffold. J. Am. Chem. Soc.,
133(33):12960-12963, Aug, 2011.
9. Komatsu T, Oushiki D, Takeda A, Miyamura M,
Ueno T, Terai T, Hanaoka K, Urano Y, Mineno T,
Nagano T: Rational Design of Boron
Dipyrromethene(BODIPY)based
Photobleaching-resistant Fluorophore Applicableto Protein Dynamics Study. Chem. Comm., 47:
10055-10057, Sep, 2011.
10. Urano Y, Sakabe M, Kosaka N, Ogawa M,
Mitsunaga M, Asanuma D, Kamiya M, Young
MR, Nagano T, Choyke PL, Kobayashi H: Rapid
Cancer Detection by Topically Spraying a
Gamma-glutamyltranspeptidaseactivatedFluorescent Probe. Sci. Transl. Med., 3:110ra119,
Nov, 2011.
11. McCann TE, Kosaka N, Koide Y, Mitsunaga M,
Choyke PL, Nagano T, Urano Y, Kobayashi H:
Activatable Optical Imaging with a SilicaRhodamine Based Near Infrared (SiR700)
Fluorophore: A comparison with cyanine baseddyes. Bioconjugate Chem., 22(12): 2531-2538,
Dec, 2011.

72

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

Lecturer
Takashi Isoyama, Ph.D.

Homepage

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

Introduction and Organization

Teaching activities

Institute of Medical Electronics was established in
1963 as the first research institute for medical
engineering in Japan. Department of Clinical
Medicine in the Institute of Medical Electronics wasstarted in 1964 for research and development of theadvanced diagnostic and therapeutic medical
engineering technologies for clinical medicine. To
date, medical engineering has grown up not only to avery important academic discipline but also to a very
important means for clinical medicine. With thestructural reformation of the Faculty of Medicine,
Institute of Medical Electronics has been shifted to the
Graduate School of Medicine, and the name of thedepartment has been changed as shown above sinceApril 1, 1997.
The current members include 1 associate professor, 1lecturer, 3 graduate students, 1 professor emeritus, 2
research fellows, 16 visiting researchers, 1 technicalstaff, and 1 secretary.
Our research covers wide area of interdisciplinary andcomprehensive research fields based on the advanced
medical and engineering technologies. We arecooperating with various laboratories. Our doctor
course students have the opportunity to performresearch works under the guidance of Prof. Mabuchi
at Department of Information Physics and Computing,
Graduate School of Information Science andTechnology.

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

73

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

Research activities
Our research field covers advanced diagnostic andtherapeutic medical engineering technologies forclinical medicine. The main subjects are artificialorgans (artificial hearts, assist circulations, artificial
lungs, artificial valves, tissue engineered artificialorgans, regenerative artificial organs, etc). Especially,
the artificial heart is our world famous research
project having a long history since 1959. Almost all
the researches and developments for driving
mechanisms, energy converters, blood pumps,
artificial valves, biomaterials, power transmissions,
measurement techniques, control methods, anatomicalcompatibility, hemocompatibility, tissue compatibility,
computer fluid dynamics, physiology, pathology, andso on, have been studied. All the stuffs and students
are in part participating in the artificial heart project.
In 1995, we succeeded to survive a goat for 532 days
with the paracorporeal total artificial heart (TAH) withno anticoagulant, which is still the longest surviving
record of TAH animals in the world.
Our artificial heart research at present is to develop an
implantable TAH using continuous flow pumps. We
have developed an undulation pump total artificial
heart (UPTAH) using undulation pumps. The
undulation pump, which was invented in ourlaboratory in 1992, is a small continuous-flow bloodpump with high performance. The original UPTAH
was designed to generate a pulsatile flow by changing
motor speed periodically. The recent model of the
UPTAH can switch a pulsatile flow to a nonpulsatile
flow for the purpose of studying physiology with a
nonpulsatile TAH. We succeeded to survive a goat for
153 days with the UPTAH.
For the next generation TAH, a new blood pump,
named the helical flow pump (HFP) was invented in

our laboratory in 2005. The HFP is a novel bloodpump having a hydrodynamic levitating impeller,
which promises high durability. The first model of thehelical flow TAH (HFTAH) is under the developmentusing HFPs. The animal experiment of the HFTAH
had started. We are expecting to develop an ideal TAH
that surpass the outcome of the heart transplantation
with combination of the technologies of the 1/R
control and hybrid materials described later.
How to control the output of a TAH is another big
interest. We have developed our original control
method, named 1/R control. The 1/R control is aphysiological flow control method of TAH developedwith a conductance (1/R: reciprocal of a resistance)
parallel circuit model. At the present time, the 1/R
control is the only reported method to achieve
physiological control of a TAH. With the 1/R control,
the particular problems of a TAH such as venous
hypertension, slight anemia, low thyroid hormone
level, and so on, were not observed and the output
changed in accordance with a metabolic demand of
the animal.
The 1/R control was applied to the UPTAH and thepathophysiological study has been performed with a
nonpulsatile TAH. The result showed that the 1/R
control could be possible not only with a pulsatile
TAH, but also with a nonpulsatile TAH. The generalconditions and organ functions were not changed by
the application of the nonpulsatile mode. The cardiac
output and the arterial pressure changed with thecondition of the goat in the pulsatile mode and also in
the nonpulsatile modes, which seemed almost
identical. However, under the physiological atrial
pressure, the sucking effect of atria was moresignificant in the nonpulsatile mode than the pulsatilemode. Therefore, the nonpulsatile TAH with the 1/R
control was considered to be inadequate, unless somepulsatility would be introduced to avoid the sucking
effect for ensuring sufficient inflow condition.
Concerning the biomaterials, we have beendeveloping a new method to develop hybrid materials.
In general, it is not easy to develop mechanical partsfor implantable artificial organs from the componentsof living tissue because these components haveinsufficient strength and durability, even though they
have excellent tissue compatibility. To overcome these
problems, an insert molding method, which is

74

commonly used for the molding of resin in theindustrial field, was introduced. In this method, themold, in which an artificial material was inserted, was
implanted in the animal, and the tissue grew into themold to make a hybrid material. The method was first
applied to the Jellyfish valve that was originally apolymer valve for the artificial hearts. The hybrid
Jellyfish valve demonstrated a good possibility. This
year, with this insert molding technique, we started todevelop the tip of the inflow conduit for theventricular assist device. The tip of the conduit isinserted into the apex of the left ventricle where thethrombus often formed. In this method, the mold inwhich the core of the tip was inserted was implanted
under the skin of a goat. The experiments are going on.
This hybrid technique will be important technology
for developing the next generation artificial organs.
Concerning the measuring technique, an implantablevideo camera for observation of angiogenesis has beendeveloped using a CMOS chip. This device is an
evolved version of our implantable video camera forobservation of microcirculation using a CCD image
sensor. In the new devices, a scaffold was attached tothe camera and was implanted in the animal. The
camera having a polyglycolic acid fabric sheet as a
scaffold was implanted in goats and succeeded toobserve the real-time growth of tissue and micro
blood vessels in the scaffold. The influence of cellseeding in the scaffold was studied. The subcutaneous
tissue of a goat was cultured to obtain the seeding
cells. These cells were seeded in the scaffold attachedto the camera. The camera was implanted under theskin of the same goat. Another camera without cellseeding was also implanted in the same goat as acontrol study. The results showed that the growth
speed of tissue and micro blood vessels in the scaffold
was faster in the cell-seeding scaffold thannon-seeding one. The technique of the observation of
microcirculation and angiogenesis will give important
information for the studies of tissue engineering andregenerative medicine as well as the implantableartificial organs.
A project of the emergency life support system(ELSS) that is a compact and transportablepercutaneous cardiopulmonary support (PCPS) device
for emergency use, which can be used as an
extracorporeal membrane oxygenator (ECMO), hasbeen started in 2004. The device consists of a blood
pump, an oxygenator, a drive and control unit, and abattery unit. A new membrane oxygenator and a new
blood pump were designed and integrated into one
piece. An experimental model exhibited good
performance. The improved model of the ELSS isunder the development to realize one-month support.
The whole system components will be packed in acase having 180 mm in diameter and 390 mm inlength. The whole weight will be 20 kg.
Our research of the IT (information technology)
medicine is focused to the home medical care. The
research and development of the IT infrastructures formonitoring the condition of the patients living at homeis being performed. The miniaturized wireless ECG(electro cardiogram) unit is attached on the patient’s
chest at home. The ECG data is transmitted to thelaptop computer set in the patient’s home. The data isthen transmitted to the data server set at our laboratory
through the mobile Internet communication. The
client computers in the clinic or doctor’s mobile
computer receive the real-time data through theInternet lines from the data server. This system has
been tested experimentally in a clinic and theoperating records revealed that the system was very
useful for the remote real-time monitoring of thepatients at home. The system is being improved forgeneral use in Japan.
Nerve interface will be very important technology fordeveloping control mechanism of artificial organs.
The basic study to develop a multiple interface arrayfor brain machine interface is being studied at Prof.
Mabuchi’s laboratory, Department of Information
Physics and Computing, Graduate School ofInformation Science and Technology.

References
1. Abe Y, Isoyama T, Saito I, Shi W, Inoue Y, Ishii K,
Nakagawa H, Ono T, Ono M, Imachi K. Resultsof animal experiments with the fourth model ofthe undulation pump total artificial heart in goat.
Artif Organs 2011;35(8):781-90
2. Shi W, Saito I, Isoyama T, Nakagawa H, Inoue Y,
Ono T, Kouno A, Imachi K, Abe Y. Automatic
calibration of the inlet pressure sensor for the
implantable continuous-flow ventricular assist

75

device. J Artif Organs 2011;14: 81-8
3. Hoshino T, Saito I, Kometani R, Samejima K,
Matsui S, Suzuki T, Mabuchi K, Kato YX.
Improvement of neuronal cell adhesiveness on
parylene with oxygen plasma treatment. J
Bioscience and Bioengineering 2011; 113(3):395-98Neuroscience
1. Basic Neuroscience

77

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

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

Homepage

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

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

ADNI project, in which Dr. Iwatsubo serves as the PI
of Japanese ADNI.
1. Research on β-amyloid and presenilins
Using C-terminal specific monoclonal antibodies
that discriminate amyloid β peptides (Aβ) ending at
40th or 42nd residues (Aβ40 and Aβ42, respectively),
Dr. Iwatsubo has performed 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 andpredominantly 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 afirm basis for the currently prevailing β-amyloid
hypothesis. They then focused on the mechanisms ofγ-secretase complex that cleaves the C terminus of Aβ,

78

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

Using cortical Lewy bodies purified frompostmortem brains of patients with dementia with
Lewy bodies (DLB) by his original method (Iwatsubo
et al. Am J Pathol 1996) as immunogens, Dr.
Iwatsubo’s group, in collaboration with Drs. Virginia
Lee and John Trojanowski at Univ. Penn, performed
an extensive immunochemical search for componentsof Lewy bodies. They have demonstrated by raising a
specific monoclonal antibody that α-synuclein, thatproved to be a product of pathogenic gene for familial
form of Parkinson’s disease, is one of the major
constituent of Lewy bodies in sporadic Parkinson’s
disease and DLB (Baba et al. Am J Pathol 1998). His
group then purified aggregated α-synuclein from DLB
cortices using fine biochemical techniques, purified it
to near homogeneity, and demonstrated using mass
spectrometry and specific antibodies that α-synuclein
deposited in synucleinopathy lesions is highly
phosphorylated at a specific serine residue (Fujiwara
et al. Nature Cell Biol 2002). This finding led to arange of studies focusing on the role of synuclein
phosphorylation in neurodegeneration. Also, thephospho-specific α-synuclein antibody is widely usedas the most sensitive marker for α-synucleinopathy
lesions, and they have characterized a wide spectrumof α-synuclein pathologies in neurodegenerative
disorders.
3. Identification of a non-Aβ Alzheimer amyloid plaquecomponent CLAC, and its precursor CLAC-P
The major component of Alzheimer’s amyloid
plaques is Aβ, although there are a number of non-Aβ
components that potentially affect fibrillization anddegradation of amyloid deposits. Among these, there
has been an enigmatic “missing piece” protein ofmolecular masses of 50/100 kDa. Dr. Iwatsubo’sgroup raised a monoclonal antibody against amyloid
fraction that recognizes this protein, and using thisantibody as a probe, they conducted a thoroughbiochemical purification of these antigens and finallycloned a cDNA coding for the precursor of this protein.
This protein turned out to be a novel class ofmembrane-bound collagen, which was named CLAC
(collagen-like Alzheimer amyloid plaque component)
and its precursor CLAC-P (Hashimoto et al. EMBO J
2002). This finding had an immense impact both on
fields of AD research as well as on general biology as

79

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

References
1) Takasugi N, Sasaki T, Suzuki K, Osawa S, Isshiki
H, Hori Y, Shimada N, Higo T, Yokoshima S,
Fukuyama T, Lee VM, Trojanowski JQ, Tomita T,
Iwatsubo T: BACE1 activity is modulated by cellassociated sphingosine-1-phosphate. J Neurosci
31: 6850-6857, 20112) Sperling RA, Aisen PS, Beckett LA, Bennett DA,
Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J,
Montine TJ, Park DC, Reiman EM, Rowe CC,
Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B,
Morrison-Bogorad M, Wagster MV, Phelps CH:
Toward defining the preclinical stages of
Alzheimer's disease: Recommendations from the

National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for
Alzheimer's disease. Alzheimers Dement 7:280292, 2011
3) Fujiyoshi M, Tachikawa M, Ohtsuki S, Ito S,
Uchida Y, Akanuma S-i, Kamiie J, Hashimoto T,
Hosoya K-i, Iwatsubo T, Terasaki T: Amyloid-β
peptide(1-40) elimination from cerebrospinal fluid
involves low-density lipoprotein receptor-related
protein 1 at the blood-cerebrospinal fluid barrier. J
Neurochem 118:407-415, 2011
4) Miyashita H, Maruyama Y, Isshiki H, Ogura T,
Mio K, Sato C, Tomita T, Iwatsubo T: Threedimensional structure of the signal peptide
peptidase. J Biol Chem 286: 26188-26197, 20115) Ohki Y, Higo T, Uemura K, Shimada N, Osawa S,
Berezovska O, Yokoshima S, Fukuyama T, Tomita
T, Iwatsubo T: Phenylpiperidine-type γ-secretasemodulators target the transmembrane domain 1 ofpresenilin 1. EMBO J 30:4815-4824, 2011
6) Tamura T, Sone M, Iwatsubo T, Tagawa K, Wanker
EE, Okazawa H: Ku70 alleviates neurodegeneration in Drosophila models of Huntington's disease.
PLoS One 6:e27408, 2011
7) Yonemura Y, Futai E, Yagishita S, Suo S, Tomita T,
Iwatsubo T, Ishiura S: Comparison of preselinin1
and presenilin 2 γ-secretase activities using a yeast
reconstitution system. J Biol Chem 286:4456944575, 2011

80

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

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

Homepage

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

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

spectrum of the molecular changes in the neurons that
undergo heavy or patterned electrical activity? What
are the molecular rules that govern these local andglobal changes, both electrical and chemical? How arethese events, in turn, converted into more profoundmodifications of the synaptic wiring mechanisms?
And finally do these alterations genuinely underlie
certain kinds of information processing and storage?
To address these issues, this Department
currently focuses its resources into two basic aims:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfrom synapse-to-nucleus, and back from nucleusto-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, four assistant professors, three81

postdoctoral scholars, one technical staff member, six
Ph.D. graduate students, three rotating medical
students, three technical assistants and one administrative assistant.

Teaching activities
The Department’s teaching activities include:
1) Introductory Neuroscience coursework provided to
pre-medical students in the Komaba campus (onehour);
2) Neurochemistry lectures to medical students 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” (Molecular and Cellular Neuroscience) (alecture series with fifteen lectures from outstanding
neuroscientists from all over Japan).
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 dedicated tosynaptic 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 importanceof a CaMKK/CaMKIV cascade in triggering
synaptically-stimulated nuclear CREB phosphorylation in hippocampal neurons. The extreme
biochemical efficacy and the relative poor frequencydependence of this signaling cascade, in combination
with the robust correlation between prolonged pCREB
response and downstream gene expression led us topropose that CaMKK/CaMKIV/pCREB cascade was
likely to act as a critical temporal integrator for
activity-dependent gene expression in excitatoryneurons (Bito et al., Cell, 1996; Bito et al., Curr. Opin.
Neurobiol., 1997; Bito, Cell Calcium, 1998). Thishypothesis has now been critically tested in various
brain systems and indeed pCREB immunofluorescence is now considered as a universal marker
for integrated synaptic activity that is more sensitive
than that of c-Fos (Nonaka, J. Neurosci. 2009). The
critical function of CaMKK/CaMKIV/pCREB cascadein the expression of long-term synaptic plasticity was

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also validated in long-term potentiation in the
hippocampus (Redondo et al., J Neurosci. 2010).
Furthermore,
CaMKIV-KO,
CaMKK-KO
and
CaMKIV-dominant negative transgenic studies bymany laboratories have confirmed the critical role for
CaMKIV as synaptic activity-triggered CREB kinase.
We subsequently also showed that CaMKIV inthe cerebellar granule cells played a critical role intuning the pCREB response necessary for
depolarization-mediated neuronal survival, and that infact CaMKIV stability was actively maintained bydepolarization. Loss of depolarizing signal led to a
caspase-mediated proteolytic degradation of CaMKIV.
This in turn severely impaired CREB phosphorylation,
facilitating apoptosis, and conversely rescuing pCREB
by overexpressing an active form of CaMKIV was
sufficient to prevent apoptosis (See et al., FASEB J.,
2001). Consistent with our observation that subtle
CREB regulation may underlie the neuronal cell
survival, CREB-dependent gene expression mechanisms, especially CBP regulation, have actually been
proposed to be affected in one way or another in manyneurodegenerative disorders such as hereditary
polyglutamine diseases. We thus speculated that if
CREB-opathies (or various defects in CREB-mediatedgene activation mechanisms) were critical determinants in exacerbating neurodegeneration, certain
disease forms may actually accompany deficit in
CaMKIV / pCREB signaling (Bito and TakemotoKimura, Cell Calcium 2003).
To elucidate the significance of the genes
regulated downstream of CREB during learning andmemory, we set out to uncover the most elementary
regulatory element required and sufficient to trigger
robust activity-dependent gene induction of theimmediate early gene Arc, whose expression in many
brain areas have been invariably associated with key
cognitive activities mediated by these areas. We
discovered a fundamentally novel synaptic activityresponsive element (SARE) which was present as a
distal regulatory promoter element and was conserved
across most mammalian species (Kawashima et al.
PNAS 2009; Kim et al. Nature 2010; Inoue et al.
Commun. Integr. Biol. 2010). Surprisingly, SARE
contained juxtaposed binding elements for all three
activity-regulated transcription factors, CREB, MEF2
and SRF. Currently, experiments are ongoing tocapitalize on this knowledge in order to build reporter
virus and mouse lines that are expected to be useful to
map the extent of neuronal circuit activation during
various kinds of cognitive activities.
One parallel branch of CaMK signaling that has
not been widely studied is the CaMKK/CaMKI
pathway. During the search for potential CaMKIV-like
CREB regulatory kinases (CLICKs) (Ohmae et al., J.
Biol. Chem. 2006), we identified a novel CaMKI
isoform that contained a C-terminal CAAX lipid
modification motif (Takemoto-Kimura, Ageta-Ishihara
et al., J. Biol. Chem., 2003; Takemoto-Kimura et al.
Neuron 2007). This novel membrane-bound CaMK
(CLICK-III/CaMKIγ) is most expressed in the central
nucleus of the amygdala and in the ventral medial
hypothalamus, while also being present at a much
weaker amount in most central neurons. Biochemical
and cell biological studies indicated a critical role forlipidification of this kinase to be properly sorted into
specific lipid-restricted membrane microdomains. The
function played by this lipidified, membrane-inserted
CaMK in circuitry formation and maturation was
scrutinized using RNA interference. Along with theidentification of the critical lipid-modifying enzymethat controls lipid-anchoring of this kinase, we
discovered a novel activity-regulated mechanism
whererby CLICK-III/CaMKIγ is actively sorted into
dendritic lipid rafts, where it specifically regulates
Rac-mediated actin remodeling that is required for
BDNF-stimulated dendritogenesis (Takemoto- Kimura
et al., Neuron, 2007; Takemoto-Kimura et al. Eur. J.
Neurosci. 2010). Similar studies in axonal growth alsosuggest the active contribution of CaMKK cascade inthis process (Ageta-Ishihara et al., J. Neurosci. 2009;
Takemoto-Kimura et al. Eur. J. Neurosci. 2010).
One further important topic that we have been
focusing for a number of years is the role of gene
expression in prolongation / consolidation of synapsespecific local changes. Neurons undergoing various
stimulus patterns have been followed up in time andthe amount of newly synthesized proteins and the
local distribution of induced gene products have beenmonitored. Using state-of-the-art multi-wavelength
fluorescence imaging techniques, we are now
quantitatively assessing how local distribution of these
newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature

83

Mol. Pages, 2006).
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Both synaptic maturation and synaptic plasticity
have been shown to include a morphologicalcomponent that is directed by the dynamics of actin
cytoskeleton, a major cytoskeletal component both in
the dendritic spines and at the very proximity ofboutons in the axon terminals. Few studies in the past,
however, had directly addressed what moleculardeterminants regulate actin dynamics in living central
neurons undergoing synaptic activity. This was in part
because actin filament assembly and disassembly wereclassically studied mostly at the moving edges oflamellipodia of large growth cones in large-size
neurons from either mollusc or peripheral nerve cells.
Such visualization turned out to be much moredifficult in seemingly far less mobile spine structures
tightly apposed to presynaptic active zones.
We (and others) used GFP-actin imaging to try tounderstand how neuronal actin cytoskeleton in
hippocampal neurons was organized and reorganizedby exposure to synaptic activity. In our dissociatedculture system, virtually all spines contained a highamount of GFP-actin and most of them with few
exceptions were apposed to FM4-64-positive active
presynaptic termini. In these cultures, increases insynaptic glutamatergic transmission by repeated burstsof high-frequency synaptic activity clearly induced
several distinct kinds of activity-dependent actin
mobilization, including a slow but sustained synaptic
delivery of GFP-actin in a non-negligible number ofactivated spines and a massive but transientenhancement in cortical actin at the somatic periphery.
The former was entirely dependent on NMDAdependent Ca2+-influx while the latter was likely to be
mediated at least in part by L-type voltage-gated Ca2+
channel activity. Thus distinct patterns and sources of
Ca2+ influx were likely to trigger a complex spatiallysegretated patterns of actin cytoskeletal reorganization,with variable impact on either neuronal morphology
and/or synaptic protein assembly (Furuyashiki et al.,
PNAS, 2002).
Similar studies are now ongoing in cerebellar

Purkinje neurons, where spinogenesis is also subject
to complex regulation during development, and where
calcium dynamics is key to pre- and postsynaptic
plasticity.
What are the key signaling pathways controlling
actin dynamics in central neurons? We were especiallykeen to resolve the contribution of the small GTPase
Rho and its downstream effectors, initially in thecontext of developmentally regulated neuronalmorphogenesis. We first established in a model cellline N1E-115 that neurite retraction was directly
linked to Rho/ROCK activity (Hirose et al., J. Cell
Biol., 1998). We subsequently revealed that in central
neurons, in addition to its essential role in regulating
growth cone motility, Rho/ROCK activity in fact acted
as a negative gate that tightly controls the timing withwhich the first processes are initiated out from theround cell soma (Bito et al., Neuron, 2000).
Disruption of Rho/ROCK activity was sufficient toimmediately initiate neuritogenesis. This indicatedthat endogenous Rho activators, by titrating ROCK
activity, continuously antagonized process/ branchformation and that local gradient of Rho activators
might play a crucial role in shaping the timing and theextent of process formation (Bito, J. Biochem., 2003).
Consistent with this idea, we found that in cerebellar
granule cells, a chemokine SDF-1α released from thepia mater was likely to be a predominant Rho
activator via stimulation of a cognate and specific
GPCR CXCR4 (Arakawa et al., J. Cell Biol., 2003).
While a true gradient in SDF-1α still remains to be
demonstrated in vivo, it is intriguing to note that mostactive axonal process formation and elongation
actually occur in the inner zone of EGL that is
opposite and most distant from the interface with the
pia mater (Bito, J. Biochem., 2003). Most strikingly,
we demonstrated that axon elongation could actively
occur in an intermediate Rho activity range thatenables ROCK to be weakened enough while allowing
another Rho effector mDia1 to actively mediate its
effect on actin nucleation and polymerization(Arakawa et al., J. Cell Biol., 2003).
Whether similar or distinct mechanisms also
operate during spinogenesis and spine maturation
remains to be determined, though a role for Rho andROCK has already been postulated in control of spinecomplexity and spine stability. However, multiple

84

small GTPase signaling cascades clearly seem tocontribute together, in a tightly coordinated manner, tospine regulation, since many distinct classes of GEFs
and GAPs have now been shown to be localized in thedendritic spines. We ourselves initially reported thefirst two direct examples for PSD localization for such
Rho small GTPases interacting proteins, Citron(Furuyashiki et al., J. Neurosci., 1999) and Cupidin/
Homer2 (Shiraishi et al., J. Neurosci., 1999).
In an attempt to pin down molecular mechanismsthat link PSD complexes and spine formation, wequantitatively examined the effect of deleting thebinding capacity of single PDZ domains of PSD-95,
one by one, and in combination, by structure-based
amino acid replacements rather than domain deletion.
Such a second-generation structure-function relation
study surprisingly revealed that a quantitative binding
between PSD-95 and synGAP tighly controlled thedegree of PSD protein clustering in a manner that was
inversely correlated with the distance from the spine
head to the shaft. Thus, these results suggest theexistence of a tight coordination between the state of
PSD complex and the morphogenetic activity of eachspine (Nonaka et al. J. Neurosci., 2006).
In parallel with this work, we and others
determined that protein-protein interaction was key todetermining the physical distance between thesynaptic vesicles in the active zone and thevoltage-gated calcium channels in its vicinity, theopening of which triggers their release (Kiyonaka etal., Nature Neurosci., 2007).

Publications by lab members(January 2011- December 2011)
1. Komatsu T, Johnsson K, Okuno H, Bito H, Inoue
T, Nagano T, Urano Y. Real-time measuremens ofprotein dynamics using fluorescence activationcoupled protein labeling method. J Am Chem
Soc.,133:6745-6751, 2011.
2. Tse D, Takeuchi T, Kakeyama M, Kajii Y, Okuno
H, Tohyama C, Bito H, Morris RG. Schemadependent gene activation and memory encoding
in neocortex. Science. 333:891-895, 2011
3. Negishi-Koga T, Shinohara M, Komatsu N, Bito
H, Kodama T, Friedel RH, Takayanagi H.
Suppression of bone formation by osteoclastic

expression of semaphorin 4D. Nat Med., 17:1473-1480, 2011.
4. Yoshida K, Ono M, Bito H, Mikami T, Sawada H.
Plasmodium induced by SU6656, an Src family
kinase inhibitor, is accompanied by a contractile
ring defect. Cell Biochem Funct., 30: 33–40,
2011.

85

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

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

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

Research activities
A goal of our research is to elucidate regulation
mechanisms of cell function through newdevelopment of novel technologies. The main subjectsof our research are as follows
1) Development of novel strategy for generating
fluorescent probes for live cell imaging
Imagingtechniques
whichvisualizesignaling
molecules in living cells is apowerful 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 toclarifyexocytosis 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, whichfunction as molecular switches in many signalingcascades. These indicators revealed spatial-temporal

86

dynamicsof 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 hairpin RNAexpressing vectors (shRNA vectors) is a powerful maneuver for functional genomics. We have previously
reportedamethodcalledEPRIL(enzymatic

production of RNAi library) by which shRNA vectors
are produced from a cDNA fragment through multiple
enzyme reactions. Recently, we have tried to improve
the original EPRIL method to enable constructing agenome-wide RNAi library. The improved EPRIL
method was successfully adapted to 96-well plate
format which allows high-throughput production ofshRNA vectors. Using EPRIL technology and imaging
techniques, we explore physiologically functional
molecules by a high-throughput screening system.

References
1. Sugao K, Hirose K. Enzymatic production ofRNAi libraries from cDNAs and high-throughput
selection of effective shRNA expression
constructs.
Methods Mol Biol. 729, 123-39(2011)

Neuroscience
2. Integrative Medical Neuroscience88

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

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

Homepage

http://square.umin.ac.jp/dcntky/English/Etop.html※ The following information is the same as that of the previous year for certain reasons.

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

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

Research activities
We all know that our perception, action, emotion,
thought and consciousness depend on the activity ofneurons in the brain. But we know very little about
how the neurons do these jobs. The aim of cognitive
neuroscience is to clarify the neural mechanisms ofour mental activity. Conventional and still very
powerful approach is to devise a task paradigm that
represents the psychological phenomenon in question
and measure the brain activity while the experimental
subjects perform the task. Studies to date haveidentified neural correlates for varieties of mental
activities.
Here in this lab, we attempt to go beyond the simple
correlation between brain activity and behavior. The
key questions are the following. .
- Behavioral significance: You've got nice activation
in some parts of the brain. Is the activity truly
associated with the behavior? Is it necessary for the
behavior? In other words we are interested in thecausality of the brain activity to behavior.
- Temporal dynamics: The temporal order of theevents in the brain is not enough to understand theneural mechanisms. Let's clarify the causal
relationships between the activations in different brain
regions.
- System dynamics: Do not be satisfied with pretty
brain images with blobs. Neurons are useless unlessthey transmit impulses to other neurons. It is thebi-directional interactions between multiple brain
areas that make us perceive, feel, and think. I am nowinterested in the dynamics in the transition between
symmetric and asymmetric impulse transmission
between brain areas.

89- 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.
To answer these questions we are using various
behavioral paradigms such as selective attention, task
switching, perceptual decision making, masked
priming and so on. We are interested in themechanistic explanation of brain function. Students
and younger researchers are free to choose any kind of
behavioral paradigms if we agree that the paradigm isthe best one to answer the questions about the brain.

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

90

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

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

Homepage

http://childpsy.umin.jp/

Introduction and Organization

Neuropsychiatry.

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

Research activities

Teaching activities
In the year of 2011, we had 4 graduate students
including one who moved from Department ofMain subjects of our research are ASD including
autism and Asperger syndrome, ADHD, Tourette
syndrome which is a severe and chronic tic disorder,and child & adolescent obsessive-compulsive disorder(OCD). We are trying to combine scientific analysis ofobjective mental and behavioral indicators withneuropsychological, brain-imaging, and genetic
studies into comprehensive and multidimensional
approach to problems in development of brain andmind. We are applying this comprehensive approach
to intervention studies including pharmacotherapy.
Major research projects with full or preliminary
performance in 2011 are as follows:
・ Behavior phenotype, neuropsychological, genetic
and treatment study of Tourette syndrome and child& adolescent OCD
・Brain-imaging study of ASD, ADHD and Tourette
syndrome by structural-MRI, functional-MRI andnear-infrared spectroscopy (NIRS)
・Genomic and epigenomic analysis of ASD
・Development of predictor of pharmacotherapy andparent training for ADHD
・Effectiveness study of early intervention for autisticpreschoolers and group cognitive behavior therapy for
adults with high-functioning ASD

91

References
1. Kawakubo Y, Suga M, Tochigi M, Yumoto M,
Itoh K, Sasaki T, Kano Y, Kasai K: Effects ofmetabotropic glutamate receptor 3 genotype onphonetic mismatch negativity. PLoS ONE. 6(10):e24929, 2011.
2. Kawakubo Y, Kono T, Takizawa R, Kuwabara H,
Ishii-Takahashi A, Kasai K: Developmental
changes of prefrontal activation in humans: anear-infrared spectroscopy study of preschool
children and adults. PLoS ONE 6(10): e25944,
2011.
3. Marui T, Funatogawa I, Koishi S, Yamamoto K,
Matsumoto H, Hashimoto O, Jinde S, Nishida H,
Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato
N: The NADH-ubiquinone oxidoreductase 1 alphasubcomplex 5 (NDUFA5) gene variants areassociated with autism. Acta Psychiatr Scand.
123(2):118-124, 2011.
4. Sumiyoshi C, Kawakubo Y, Suga M, Sumiyoshi T,
Kasai K: Impaired ability to organize information
in individuals with autism spectrum disorders andtheir siblings. Neurosci Res. 69:252-257, 2011.
5. Iwanami A, Okajima Y, Ota H, Tani M, Yamada
T, Hashimoto R, Kanai C, Watanabe H, Yamasue
H, Kawakubo Y, Kato N: Task dependent
prefrontal dysfunction in persons with Asperger’s
disorder investigated with multi-channel nearinfrared spectroscopy. Research in Autism
Spectrum Disorders, 5(3): 1187-1193, 2011.
6. Kuroda M, Wakabayashi A, Uchiyama T, Yoshida
Y, Koyama T, Kamio Y: Determining differencesin social cognition between high-functioning
autistic disorder and other pervasive developmental disorders using new advanced “mindreading” tasks. Research in Autism Spectrum
Disorders 5, 554-561, 2011.

Neuroscience
3. Clinical Neuroscience93

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

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

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

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

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

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

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

Takuji Nishida, M.D.

Junichi Terai, M.D.

Shinya Fujikawa, M.D.

Youhei Kabaya, M.D.

Takafumi Makino, M.D.

Tatsuya Nagai, M.D.

Wataru Kanata, M.D.

Homepage

http://npsy.umin.jp/

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

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

psychiatrists, 4 clinical psychologists and 1
psychiatric social worker. Approximately 1000 new
patients visited yearly (2011), and the total visits per
day was about 150.
The secluded ward has 29 beds including 3
seclusion rooms. We also have 31 beds for the open
general ward. Approximately 550 patients withvarious psychiatric disorders were admitted in a year.
Recently, the number of patients who were referredfrom the emergency unit is increasing. The age ofpatients is variable from teenager to senior. The
majority of the patients are schizophrenia, mooddisorder and psychosis based on the somatic disease.
Mean hospitalization is 30 day long, and modified
electro-convulsive therapy was performed for over
400 patients.
We established day care unit for outpatients withschizophrenia in 1974, and the patients are engaged inrehabilitation and re-work programs. We also haveJapan's first child psychiatry day care unit in national
university hospitals since 1967, and mainly patientswith pervasive developmental disorders are engaged

94

in clinical and educational activities.

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 18 neuropsychiatry Ph.D. students are
studying.

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

the studies is exploration of susceptibility genes of thedisorders including schizophrenia, autism, theirspectrum disorders and anxiety disorder (mainly panic
disorder).

References(1) Arai M, Koike S, Oshima N, Takizawa R, Araki
T, Miyashita M, Nishida A, Miyata T, Kasai K,
Itokawa M: Idiopathic carbonyl stress in a
drug-naive case of at risk mental state. Psychiatry
Clin Neurosci 65: 606-607, 2011 Oct (letter tothe editor).
(2) Suga M, Uetsuki M, Takizawa R, Araki T, Kasai
K: Phonological fluency is uniquely impaired inJapanese-speaking schizophrenia: a confirmation
study. Psychiatry Clin Neurosci 65: 672-675,
2011 Oct.
(3) Otowa T, Tochigi M, Umekage T, Ebisawa T,
Kasai K, Kato N, Sasaki T: No association
between CLOCK gene 3111C/T polymorphismand personality traits in Japanese healthy subjects.
Psychiatry Clin Neurosci 65: 604, 2011.
(4) Kawakubo Y, Kono T, Takizawa R, Kuwabara H,
Ishii A, Kasai K: Developmental changes ofprefrontal activation in humans: a near-infrared
spectroscopy study of preschool children andadults. PLoS ONE 6: e25944, 2011 Oct.
(5) Kawakubo Y, Suga M, Tochigi M, Yumoto M,
Itoh K, Sasaki T, Kano Y, Kasai K: Effects ofmetabotropic glutamate receptor 3 genotype onphonetic mismatch negativity. PLoS ONE 6:
e24929, 2011 Oct.
(6) Orikabe L, Yamasue H, Inoue H, Takayanagi Y,
Mozue Y, Sudo Y, Ishii T, Itokawa M, Suzuki M,
Kurachi M, Okazaki Y, Kasai K: Reduced
amygdala and hippocampal volumes in patientswith methamphetamine psychosis. Schizophr Res
132: 183-189, 2011 Nov.
(7) Ohi K, Hashimoto R, Yasuda Y, Fukumoto M,
Yamamori H, Umeda-Yano S, Kamino K,
Ikezawa K, Azechi M, Iwase M, Kazui H, Kasai
K, Takeda M: The SIGMAR1 gene is associatedwith a risk of schizophrenia and activation of theprefrontal cortex. Prog Neuropsychopharmacol
Biol Psychiatry 35: 1309-1315, 2011 Jul 1.
(8) Otowa T, Shimada T, Kawamura Y, Sugaya N,

95

Yoshida E, Inoue K, Yasuda S, Liu X, Minato T,
Tochigi M, Umekage T, Kasai K, Tanii H,
Okazaki Y, Kaiya H, Sasaki T: Association
analysis of RGS2 variants with panic disorder ina Japanese population. Am J Med Genet B
Neuropsychiatr Genet 156B: 430-434, 2011.
(9) Murakami M, Takao H, Abe O, Yamasue H,
Sasaki H, Gonoi W, Takano Y, Takei K, Kasai K,
Ohtomo K: Cortical thickness, gray mattervolume, and white matter anisotropy anddiffusivity in schizophrenia. Neuroradiology 53:
859-866, 2011 Nov.
(10) Yamasue H, Suga M, Yahata N, Inoue H, Tochigi
M, Abe O, Xiaoxi Liu, Kawamura Y, Mark A
Rogers, Takei K, Yamada H, Aoki S, Sasaki T,
Kasai K: Reply to "Neurogenetic effects of
OXTR rs2254298 in the extended limbic systemof healthy Caucasian adults". Biol Psychiatry 70:
e41-42, 2011. (correspondence).
(11) Takayanagi Y, Takahashi T, Orikabe L, Mozue Y,
Kawasaki Y, Nakamura K, Sato Y, Itokawa M,
Yamasue H, Kasai K, Kurachi M, Okazaki Y,
Suzuki M: Classification of first-episodeschizophrenia patients and healthy subjects byautomated MRI measures of regional brain
volume and cortical thickness. PLoS One 6:
e21047, 2011.
(12) Koike S, Takizawa R, Nishimura Y, Takano Y,
Takayanagi Y, Kinou M, Araki T, Harima H,
Fukuda M, Okazaki Y, Kasai K: Different
hemodynamic response patterns in the prefrontal
cortical sub-regions according to the clinicalstages of psychosis. Schizophr Res 132: 54-61,
2011.
(13) Koike S, Nishida A, Yamasaki S, Ichihashi K,
Maegawa S, Natsubori T, Harima H, Fujita I,
Harada M, Okazaki Y, Kasai K: Conprehensive
early intervention for patients with first-episodepsychosis in Japan (J-CAP), study protocol for arandomized controlled trial. Trials 12: 156, 2011.
(14) Tamiya H, Okamura T, Iwashiro N, Ishiki K,
Yamasue H, Kasai K: Case of alfacalcidolinduced hypercalcemia presenting as bipolar
disorder. Psychiatry Clin Neruosci 65: 536-537,
2011. (letter)(15) Yoshida T, Suga M, Arima K, Muranaka Y,
Tanaka T, Eguchi S, Lin C, Yoshida S, Ishikawa

M, Higuch Y, Seo T, Ueoka Y, Tomotake M,
Kaneda Y, Darby D, Maruff P, Iyo M, Kasai K,
Higuchi T, Sumiyoshi T, Ohmori T, Takahashi K,
Hashimoto K: Criterion and construct validity of
the CogState schizophrenia battery in Japanesepatients with schizophrenia. PLoS ONE 6:e20469, 2011.
(16) Nishimura Y, Takizawa R, Muroi M, Marumo K,
Kinou M, Kasai K: Prefrontal cortex activity
during response inhibition associated withexcitement symptoms in schizophrenia. Brain
Res 1370: 194-203, 2011 Jan 25.
(17) Sumiyoshi C, Kawakubo Y, Suga M, Sumiyoshi
T, Kasai K: Impaired ability to organize
information in individuals with autism spectrum
disorders and their siblings. Neurosci Res 69:
252-257, 2011 Mar.
(18) Takao H, Abe O, Yamasue H, Aoki S, Sasaki H,
Kasai K, Yoshioka N, Ohtomo K: Gray and whitematter asymmetries in healthy individuals aged
21-29 years: A voxel-based morphometry anddiffusion tensor imaging study. Hum Brain Mapp
32: 1762-1773, 2011.
(19) Koike S, Takizawa R, Nishimura Y, Marumo K,
Kinou M, Kawakubo Y, Rogers M, Kasai K:
Association between severer dorsolateralprefrontal dysfunction during random number
generation and earlier onset in schizophrenia.
Clin Neurophysiol 122: 1533-1540, 2011.
(20) Marui T, Funatogawa I, Koishi S, Yamamoto K,
Matsumoto H, Hashimoto O, Jinde S, Nishida H,
Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato
N: The NADH-ubiquinone oxidoreductase 1
alpha subcomplex 5 (NDUFA5) gene variants areassociated with autism. Acta Psychiatr Scand
123: 118-124, 2011.

96

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

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

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

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

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

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

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

Yuji Takahashi, M.D.,PhD.

Homepage

http://square.umin.ac.jp/neurotky/

Introduction and Organization
The Department of Neurology was establishedby the founder Professor Yasuo Toyokura in 1964 as
one Department in the Brain Research Institute. The
Department of Neurology was succeeded byProfessors Toru Mannen and Ichiro Kanazawa. The
organization of the Brain Research Institute wasreorganized as the Division of Neuroscience of the
Graduate School of Medicine in 1997. We celebrated
40th Anniversary of the Department of Neurology in
2004.

Clinical activities
We offer clinical services in the field of
Neurology. We are putting our effort to provide thepatients with highly advanced clinical practice as wellas on clinical activities connected to postgraduate
education of Neurology.
We have outpatient clinics covering the broad
fields of Neurology. Furthermore, we also provide
clinics specialized to movement disorders andheadaches.
In the in patient ward, we offer programs forpostgraduate education including the program for the
first stage postgraduate education. We also offer the
excellent training program with the goal to get theboard of Neurologist. In 2005, we initiated deep brain
stimulation for the treatment of movement disorders incooperation with Department of Neurosurgery.
Clinical trials including that for polyglutamine disease
and that based on vestibular nerve stimulation arebeing conducted.

Teaching activities
As for under-graduate education, our Department takes a part in lectures of Neurology for the 4th
and 5th grade medical students, and bed-side learning
for the 5th grade medical students, and clinicalclerkship for the 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 weoffer various opportunities for medical students to be
involved in research activities, and 2-3 medical
students are conducting their research activities in the97laboratories.
In postgraduate education we offer the
integrated program including Neurology as the part ofthe program of Internal Medicine.
For training of board-certified Neurologists, weoffer the excellent program including patients’care,training in Neurophysiology and Neuropathology,
consultation for Neurology, and supervising of juniortrainees. This program is integrated with clinicalpractice at the affiliated hospitals where richexperience is obtained for numerous cases in Clinical
Neurology.
In Graduate School, we offer highly advanced
research activities based on the interest of graduate
students. In 2003, 21st Century COE program started
in the Neuroscience Division, and we havesuccessfully completed the program. Following the
21st Century COE program, we started “Global Centerof Education and Research for Chemical Biology of
the Diseases” as a Global COE program, in 2008.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and toeventually develop new therapeutic strategies. Our
research activities include molecular genetics,
developmental biology, cell biology, pharmacology,
pathology, and physiology. We aim to integrate thesebroad research fields to better contribute to clinicalneurology.
In the filed of molecular genetics, we havedevelop Medical Genome Center, and introduced
next-generation sequencers to conduct comprehensive
genome analyses to elucidate molecular bases ofneurological diseases. Applying massively parallel
sequencing technologies, we have discovered thecausative gene, TFG, for hereditary motor andsensory
neuropathy withproximaldominant
involvement (HMSN-P). We have initiatedmulticenter-based consortium for multiple system
atrophy. A large-scale genome-wide analyses are being
conducted to identify disease susceptibility genes. We
have established excellent animal models fordentatorubral-pallidoluysian atrophy, and conducting
studies for development of therapeutics. As the newprotein degradation pathway, the role of autophagy
was investigated. (Tsuji, S., Goto, J., Takahashi, Y.,
Ichikawa, Y., Date, H., Suzuki, K., Mitsui, J., Ishiura,
H., Matsukawa, T., Taira, M., Hahimoto, A)
Development of pathomechanism-based therapy
for amyotrophic lateral sclerosis (ALS) is a mission ofneurologist. In motor neurons of sporadic ALS
patients, naturally occurring RNA editing of glutamate
receptor subunit GluR2 is inefficient in a neuronalclass-selective and disease-specific manner. Because
RNA editing at the GluR2 Q/R site is specificallycatalyzed by an RNA editing enzyme called adenosine
deaminase acting on RNA 2 (ADAR2), we developed
mice in which the ADAR2 gene was conditionallytargeted. By analyzing these mice, we demonstratethat failure to edit the GluR2 Q/R site is the primarycause of death of motor neurons. Based on thesefindings, we are currently involved in the developmentof specific therapy for ALS. (Kwak, S., Hideyama, T.,
Yamashita, T., Teramoto, S., Hachiga K., Kaneko, S.,
Chai, H.)The human neurophysiology section has been
studying normal function of the human brain andpathophysiology for neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and EOG. Our final
goal is to develop a new therapeutic method for
intractable disorders. One of them is deep brain
stimulation (DBS) which has been partly established.
We began a physiological approach to elucidate thetherapeutic mechanisms for DBS in the patients. We
have also recently developed a new, highly effective
TMS method to induce long-term effects on thehuman brain using repetitive, monophasic magnetic
stimuli. We have just stared a project to treat patientswith movement disorders, intractable pain, epilepsy
and so on using that new treatment. (Terao, Y.,
Hanajima, R., Okabe, S., Terada, S. Higashihara, M.,
Shirota, Y, Ohminami, S., Tsutumi, R., Matsuda, S.)
In the field of neuromuscular diseases, we
provide pathological diagnosis of biopsied materials
from patients with myopathy or neuropathy. We also
provide autoantibody testing for anti-gangliosideantibodies, muscle specific antibodies and paraneoplastic neurological antibodies. In research field,
using biopsied muscles and collected serum samples,
we have been studying the mechanisms of

98

inflammatory myopathies especially in polymyositis,
cancer associated myositis, dermatomyositis, collagendisease associated myositis and myositis withautoantibodies. We have also been studying themechanism of muscle fiber regeneration in various
myopathies including inclusion body myositis. We aim
to increase understanding of the etiology andpathogenesis of neuromuscular diseases. (Shimizu, J.,
Hashimoto, H., Kubota, A.,Tokimura, N., Sagishima,M., Tokimura, N., Nishizawa, M.).
Department of Molecular Neuroscience on
Neurodegenerationisfundedby
JanssenPharmaceuticals. Several projects are ongoing/ We
found new ubiquitin ligase UHRF-2 and new
ubiquitin-like modulator FAT10 related to thepathogenesis of polyglutamine diseases. Studies on
epigenetics of Parkinson’s disease revealed abnormal
epigenetic changes in the disease. We also reported anovel mutation of aceruloplasminemia (Iwata, A.,
Hyashi, H.).

Publication
1. Bomprezzi R, Powers JM, Shimizu J, Tsuji S,
Weinshenker BG, Wingerchuk DM. IFNβ-1b may
severely exacerbate Japanese opticspinal MS inneuromyelitis optica spectrum: Japanese opticspinal MS: Is it MS or neuromyelitis optica anddoes the answer dictate treatment? Neurol. 77:
195-6, 2011.
2. Doi H, Yoshida, K, Yasuda T, Fukuda M, Fukuda
Y, Morita H, Ikeda S, Kato R, Tsurusaki Y,
Miyake N, Saitsu H, Sakai H, Miyatake S, ShiinaM, Nukina N, Koyano S, Tsuji S, Kuroiwa Y,
Matsumoto N. Exome Sequencing Reveals a
Homozygous SYT14 Mutation in Adult-Onset,
Autosomal-Recessive Spinocerebellar Ataxia with
Psychomotor Retardation. Am. J. Hum. Genet.
89: 320-327, 2011
3. Hanajima R, Terao Y, Nakatani-Enomoto S,
Okabe S, Shirota Y, Oominami S, Matsumoto H,
Tsuji S, and Ugawa Y. Triad stimulation frequency
for cortical facilitation in cortical myoclonus. Mov.
Disord. 26: 685-90, 2011.
4. Hideyama T, Kwak S: When does ALS start?
ADAR2-GluA2 hypothesis for the etiology ofsporadic ALS. Fron.t Mol. Neurosci. 4:33, 2011.

5. Higashihara M, Sonoo M, Yamamoto T,
Nagashima Y, Uesugi H, Terao Y, Ugawa Y,Stålberg E, Tsuji S. Evaluation of spinal andbulbar muscular atrophy by the Clustering Index
method. Muscle Nerve 44:539-46, 2011
6. Iida A, Takahashi A, Kubo M, Saito S, Hosono N,
Ohnishi Y, Kiyotani K, Mushiroda T, Nakajima M,
Ozaki K, Tanaka T, Tsunoda T, Oshima S, Sano M,
Kamei T, Tokuda T, Aoki M, Hasegawa K,
Mizoguchi K, Morita M, Takahashi Y, Katsuno M,
Atsuta N, Watanabe H, Tanaka F, Kaji R, Nakano
I, Kamatani N, Tsuji S, Sobue G, Nakamura Y,
Ikegawa S. A functional variant in ZNF512B is
associated with susceptibility to amyotrophic
lateral sclerosis in Japanese. Hum. Mol. Genet.
20:3684-3692, 2011
7. Ishiura H, Fukuda Y, Mitsui J, Nakahara Y,
Ahsan B, Takahashi Y, Ichikawa Y, Goto J, Sakai
T, Tsuji S. Posterior column ataxia with retinitis
pigmentosa in a Japanese family with a novel
mutation in FLVCR1. Neurogenet. 12:117-21,
2011.
8. Kagoya R, Iwasaki S, Chihara Y, Ushio M,
Murofushi T, Tsuji S, and Yamasoba T. Cephalictetanus presenting as acute vertigo with bilateral
vestibulopathy. Acta Oto-Laryngologica 131:334-336, 2011.
9. Matsukawa T, Asheuer M, Takahashi Y, Goto J,
Suzuki Y, Shimozawa N, Takano H, Onodera O,
Nishizawa M, Aubourg P and Tsuji S.
Identification of novel SNPs of ABCD1, ABCD2,
ABCD3 and ABCD4 genes in patients with
X-linked adrenoleukodystrophy (ALD) based oncomprehensive resequencing and association
studies with ALD phenotypes. Neurogenet. 12:
41-50, 2011.
10. Matsukawa T, Wang X, Liu R, Onuki Y, Kubota A,
Hida A, Kowa H, Fukuda Y, Ishiura H, Mitsui J,
Takahashi Y, Aoki S, Takizawa T, Shimizu J, Goto
J, Proud CG and Tsuji S. Adult-onset
leukoencephalopathies with vanishing whitematter with novel missense mutations in EIF2B2,
EIF2B3, and EIF2B5. Neurogenet. 12:259-61,
2011
11. Nagashima Y, Suzuki T, Terada S, Tsuji S and
Misawa K. In-vivo molecular labeling of
halogenated volatile anesthetics via intrinsic

99

molecular vibrations using nonlinear Raman
spectroscopy. J. Chem. Physics 134: 024525,
2011.
12. Nagashima Y, Kowa H, Tsuji S, Iwata A. FAT10
binds to polyglutamine proteins and modulates
their solubility. J. Biol. Chem. 286: 29594-29600
13. Ogawa N, Imai Y, Takahashi Y, Nawata K, Hara K,
Nishimura H, Kato M, Takeda N, Kohro T, Morita
H, Taketani T, Morota T, Yamazaki T, Goto J,
Tsuji S, Takamoto S, Nagai R, Hirata Y.
Evaluating Japanese patients with the Marfan
syndrome using high-throughput microarraybased mutational analysis of fibrillin-1 gene. Am.
J. Cardiol. 108:1801-1807,2011
14. Pan W, Kwak S, Lu Y, Fang Z, Zhu X, Yamamoto
Y: Traditional Chinese medicine improvesnocturnal activity with nighttime in Parkinson's
disease. Sleep Med. 12:307-308，2011.
15. Pan W, Yamamoto Y, Kwak S: Objective
evaluation of the severity of parkinsonism using
power-law temporal autocorrelation of activity. In
Diagnostics and Rehabilitation of Parkinson's
Disease, Ed Dushanova J, InTech, Croatia. ISBN979-953-307-247-9. pp. 225-238, 2011.
16. Saigoh K, Izumikawa T, Koike T, Shimizu J,
Kitagawa H, Kusunoki S. Chondroitin beta-1,
4-N-acetylgalactosaminyltransferase-1 missense
mutations are associated with neuropathies. J.
Hum. Genet. 56:143-6, 2011.
17. Seki N, Takahashi Y, Tomiyama H, Rogaeva E,
Murayama S, Mizuno Y, Hattori N, Marras C,
Lang AE, St George-Hyslop P, Goto J and STsuji
S. Comprehensive mutational analysis of LRRK2
reveals variants supporting association with
autosomal dominant Parkinson's disease. J. Hum.
Genet. 56:671-675, 201118. Shirota Y, Hanajima R, Hamada M, Terao Y,
Matsumoto H, Tsutsumi R, Ohminami S,
Furubayashi T, Ugawa Y. Inter-individual
variation in the efficient stimulation site formagnetic
brainstem
stimulation.
Clin
Neurophysiol. 122:2044-8, 2011.
19. Soga T, Sugimoto M, Honma M, Mori M, Igarashi
K, Kashikura K, Ikeda S, Hirayama A, Yamamoto
T, Yoshida H, Otsuka M, Tsuji S, Yatomi Y,
Sakuragawa T, Watanabe H, Nihei K, Saito T,
Kawata S, Suzuki H, Tomita M, and Suematsu M.

Serum
Metabolomics
Reveals-Glutamyl
Dipeptides as Biomarkers for Discrimination
among Different Forms of Liver Disease. J.
Hepatol. 896-905, 2011
20. Terao Y, Fukuda H, Yugeta A, Hikosaka O,
Nomura Y, Segawa M, Hanajima R, Tsuji S,
Ugawa Y. Initiation and inhibitory control ofsaccades with the progression of Parkinson's
disease - changes in three major drives converging
on the superior colliculus. Neuropsychologia.
49:1794-806, 2011.
21. Yokoseki A, Ishihara T, Koyama A, Shiga A,
Yamada M, Suzuki C, Sekijima Y, Maruta K,
Tsuchiya M, Date H, Sato T, Tada M, Ikeuchi T,
Tsuji S, Nishizawa M and Onodera O. Genotypephenotype correlations in early onset ataxia withocular motor apraxia and hypoalbuminaemia.
Brain 134:1387-99, 2011.
22. Yoshikado T, Takada T, Yamamoto T, Yamaji H,
Ito K, Santa T, Yokota H, Yatomi Y, Yoshida H,
Goto J, Tsuji S and Suzuki H. Itraconazoleinduced cholestasis: involvement of the inhibitionof bile canalicular phospholipid translocator
MDR3/ABCB4. Mol. Pharmacol. 79: 241-250,
2011.
23. Fujisawa T, Homma K, Yamaguchi N, Kadowaki
H, Tsuburaya N, Naguro I, Matsuzawa A, Takeda
K, Takahashi Y, Goto J, Tsuji S, Nishitoh H, andIchijo H. A novel monoclonal antibody reveals a
conformational alteration shared by amyotrophic
lateral sclerosis-linked SOD1 mutants. Ann.
Neurol. (in press)
24. Hashimoto Maeda M, Mitsui J, Soong B-W,
Takahashi Y, Ishiura H, Hayashi S, Shirota Y,
Ichikawa Y, Matsumoto H, Arai M, Okamoto T,
Miyama S, Shimizu J, Inazawa J, Goto J and Tsuji
S. Increased gene dosage of myelin protein zero
causes Charcot-Marie-Tooth disease. Ann Neurol.
71:84-92, 2012
25. Hashimoto Maeda M, Tsuji S. and Shimizu J.
Inflammatory myopathies associated with antimitochondrial antibodies. Brain 135: 1767-1777,
2012
26. Hida A, Ishiura H, Arai N, Fukuoka H, Kurono H,
Hasuo K, Shimizu K, Goto J, Uesaka Y, Tsuji S
and Takeuchi S. Title: Adult-onset Alexander
disease with a novel R66Q mutation of GFAP

100

gene presenting severe vocal cord paralysis during
sleep. J. Neurol. (in press)
27. Hideyama T, Yamashita T, Aizawa H, Tsuji S,
Kakita A, Takahashi H, Kwak S: Profounddownregulation of the RNA editing enzyme
ADAR2 in ALS spinal motor neurons. Neurobiol.
Dis. 45：1121-28, 2012.
28. Iizuka T, Takahashi Y, Sato M, Yonekura J,
Miyakawa S, Endo M, Hamada J, Kan S,
Mochizuki H, Momose Y, Tsuji S, Sakai F.
Neurovascular changes in prolonged migraine
aura in FHM with a novel ATP1A2 gene mutation.
J. Neurol. Neurosurg. Psych. 83: 205-212, 2012
29. Ishiura H, Takahashi Y, Mitsui J, Yoshida S,
Kihira T, Kokubo Y, Kuzuhara S, Ranum LPW,
Tamaoki T, Ichikawa Y, Date H, Goto J, and Tsuji
S. C9ORF72 repeat expansion in amyotrophic
lateral sclerosis in the Kii peninsula of Japan.
Arch. Neurol. (in press)
30. Kiyono K, Hoyano J, Kwak S, Watanabe E,
Yamamoto Y: Non-Gaussianity of low frequency
heart rate variability and sympathetic activation:lack of increases in multiple system atrophy andParkinson disease. Front. Compu. Physiol. Med.
(in press).
31. Kubota A, Shimizu J, Iwata A, Tsuji S. Aberrant
expression of myogenin in inclusion body
myositis: Immunohistochemical studies of transcription factors regulating myogenesis in inflammatory myopathies. Clin. Exp. Neuroimmunol.
(in press)
32. Lee Y-C, Durr A, Majczenko K, Huang Y-H, Liu
Y-C, Lien C-C, Ichikawa Y, Goto J, Monin M-L,
Li JZ, Chung M-Y, Mundwiller E, Dell' Orco J,
Shakkottai V, Liu T-T, Tesson C, Lu Y-C, Tsai P-C,
Brice A, Tsuji S, Burmeister A, Stevanin G, Soong
B-W. Mutations in KCND3 cause spinocerebellar
ataxia type 22. Ann. Neurol. (in press)
33. Majounie E, Renton AE, Mok K, Dopper EGP,
Waite A, Rollinson S, Chi? A, Restagno G,
Nicolaou N, Simon-Sanchez J, van Swieten JC,
Abramzon Y, Johnson JO, Sendtner M, Pamphlett
R, Orrell RW, Mead S, Sidle KC, Houlden H,
Rohrer JD, Morrison KE, Pall H, Talbot K,
Ansorge O, The Chromosome 9-ALS/FTD
Consortium, The French research network on
FTLD/FTLD/ALS, The ITALSGEN Consortium,

Hernandez DG, Arepalli S, Sabatelli M, Mora G,
Corbo M, Giannini F, Calvo A, Englund E,
Borghero G, Floris GL, Remes AM, Laaksovirta
H, McCluskey L, Trojanowski JQ, Van Deerlin
VM, Schellenberg GD, Nalls MA, Drory VE, Lu
C-S, Yeh T-H, Ishiura H, Takahashi Y, Tsuji S, Ber
IL, Brice A, Drepper C, Williams N, Kirby J,
Shaw P, Hardy J, Tienari PJ, Heutink P, Morris
HR, Pickering-Brown S, *Traynor BJ. C9ORF72
hexanucleotide repeat expansion in sporadic ALS
and FTD around the world. Lancet Neurol. 11:
323-30, 2012
34. Martins S, Soong, B-W. Wong VCN, Giunti P,
Brice A, Ranum LPW, Sasaki H, Riess O, Tsuji S,
Coutinho P, Amorim A, Sequeiros J, Nicholson
GA. Mutational Origin of Machado-Joseph
Disease in the Australian Aboriginal Communities
of Groote Eylandt and Yirrkala. Arch. Neurol. 69:
746-751, 2012.
35. Mitsui J, Matsukawa T, Ishiura H, Higasa K,
Yoshimura J, Saito TL, Ahsan B, Takahashi Y,
Goto J, Iwata A, Niimi Y, Riku Y, Goto Y, Mano K,
Yoshida M, Morishita M, and Tsuji S. CSF1R
mutations identified in three families with
autosomal
dominantly
inheritedleukoencephalopathy. Amer. J. Med. Genet. Neuropsych.
Genet. (in press)
36. Montenegrob G, Rebelo AP, Connell J, Allison R,
Babalini C, D'Aloia M, Montieri P, Sch?le-Freyer
R, Ishiura H, Price J, Strickland A, Gonzalez MA,
Baumbach-Reardon L, Deconinck T, Huang J,
Bernardi G, Vance JM, Rogers MT, Tsuji S, deJonghe P, Pericak-Vance MA, Schöls L, Orlacchio
A, Reid E, and Züchner S. Mutations in human
Reticulon2 cause axonal degeneration in
Hereditary Spastic Paraplegia type 12. J. Clin.
Invest. 122: 538-544, 2012
37. Naruse H, Takahashi Y, Kihira T, Yoshida S,
Kokubo Y, Kuzuhara S, Ishiura H, Amagasa M,
Murayama S, Tsuji S and Goto J. Mutational
Analysis of Familial and Sporadic Amyotrophic
Lateral Sclerosis with OPTN Mutations inJapanese Population. Amyotrophic Lateral
Sclerosis 13: 562-566, 2012.
38. Saito N, Hida A, Koide Y, Ooka T, Ichikawa Y,
Shimizu J, Mukasa A, Nakatomi H, Hatakeyama S,
Hayashi and Tsuji S. Culture-negative brain

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abscess with Streptococcus intermedius infection
whose diagnosis was established by direct
nucleotide sequence analysis of the 16S ribosomal
RNA gene. Int. Med. 51: 211-216, 2012
39. Suzuki K, Zhou J, Sato T, Takao K, Miyagawa T,
Oyake M, Yamada M, Takahashi H, Takahashi Y,
Goto J, and Tsuji S. DRPLA transgenic mouse
substrains carrying single copy of full-lengthmutant human DRPLA gene with variable sizes of
expanded CAG repeats exhibit CAG repeat
length- and age-dependent changes in behavioral
abnormalities and gene expression profiles.
Neurobiol. Dis. 46: 336-350, 2012
40. Tsuji S. Neurogenomics view of neurologicaldiseases. Arch. Neurol. (in press)
41. Yamashita T, Hideyama T, Teramoto S, Kwak S:
Abnormal processing of TDP-43 does not regulate
ADAR2 activity in cultured cell lines. Neurosci.
Res. 73:153-160, 2012.
42. Yamashita T, Tadami C, Nishimoto Y, Hideyama T,
Kimura D, Suzuki T, Kwak S: RNA editing of the
Q/R site of GluA2 in different cultured cell linesthat constitutively express different levels of RNA
editing enzyme ADAR2. Neurosci. Res. 73:42-48,
2012.

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

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

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

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

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

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

Associate
Kazuhiko Ishii, M.D.,

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

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

Yasutaka Suzuki, M.D.,

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

Takashi Ochi, M.D.

Kuniaki Saito, M.D.,

Hanakita shunya, M.D.

Homepage

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

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

Clinical activities
General and specialized outpatient clinics are open

three days a week (Monday, Wednesday and Friday).
New patient are accepted two days a week (Tuesday
and Thursday). Specialized outpatient clinics are open
for patient with brain tumors, pituitary disease, spinal
disease, cerebrovascular disease, endovascularintervention, epilepsy, and gamma knife treatment.
From April 2011 to March 2012, 15,791 patients weretreated at the outpatient clinics.
The Neurosurgery Ward has about 40 beds on theseventh floor of the new hospital building opened in
Sept. 2001. In 2010 and 2011, 874 and 854 patientswere admitted to the Neurosurgical Ward, respectively.
Four hundred and twenty six and 482 surgicalprocedures were performed with 138 and 126 gamma
knife precedures in each year. Our practice covers awide variety of neurosurgical diseases including
malignant and benign brain tumors, hemorrhagic andocclusive cerebrovascular diseases, spinal disorders,
epilepsy, pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional
mapping in epilepsy surgery are frequently used to103preserve brain function as much as possible.
State-of-the-art techniques including intraoperative
computer-aided
navigation
andintravascular
procedures help our continuous effort to increase thesafety of surgical treatment.
Our department is affiliated with 30 neurosurgicalinstitutions in and around the city of Tokyo including
5 university medical centers, where our residents andstudents are exposed to various clinical experiences.
Surgical case volume in all hospitals exceeds 9000
cases.

Teaching activities
Medical students take lectures of clinicalneurosurgery in their second year. Clinical casestudies and bedside teaching are scheduled in the thirdand fourth years. The lecturers introduce general
Neurosurgery as well as the state-of-art Neurosurgicalpractice to the students. At the bedside teaching andclinical clerkship, they are offered opportunities tolearn clinical management of Neurosurgical patients in
the hands-on style, and also are exposed to practice invarious subspecialties in neurosurgery through special
seminars given by experts in the fields.
We accepted 6 residents in 2010 as a neurosurgicalresidency program. These residents are trained in theuniversity hospital and affiliated hospitals toexperience every aspects of neurosurgical practice forfive years in average. Our residency training is
finalized after the sixth year, when the finishingresidents serve as senior resident at the university
hospital for 6 months. Academic training is provided
through numerous intramural clinical and research
conference, journal clubs seminars as well as quarterly
regional meeting of Japan Neurosurgical Society.
After the residents finish their training, or during
training, they can choose to be admitted into the Ph.D.
course at the graduate school of Medicine, Universityof Tokyo, to be involved in advanced basic research
activities for 4 year. After complete training, our
graduates stay in the department to be an associate in
our or other university hospitals or become clinicalstaff in our affiliated hospitals.

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

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BTICs.
We also practice optimized therapy based on the
results of genetic analyses routinely performed ontumor specimens obtained from glioma patients.
3) Development and evaluation of functionpreserving and less invasive treatment of
intractable epilepsy
We have been promoting the research on
development, evaluation and standardization of thenovel treatment for intractable epilepsy. Since ourfacility was the first in Japan to provide vagus nerve
stimulation therapy, we evaluated its efficacy andsafety in epilepsy treatment. We are now establishinga new intraoperative monitoring method of vagusnerve evoked potential. Efficacy evaluation anddevelopment of surgical instruments were promoted
for novel function-preserving techniques, multiple
subpial transection and multiple hippocampal
transection. Basic and clinical research on gamma
knife treatment of epilepsy has been performed as well.
For the purpose of more precise localization of
epileptic foci and elucidation of epileptogenesis, weare now developing novel types of intracranial
eletrodes.
4) Research on brain function using non-invasive andinvasive techniques
We have been studying human brain function using
not only non-invasive techniques such as fMRI, MEG,NIRS but also electrocorticography (ECoG) obtainedby intracranial electrodes implanted in epilepsy
patients. The latter is our markedly advantageous
feature that enables us to extract brain information
with much higher spatial resolution and SN ratio. We
aim to understand brain mechanisms as complicatednetwork systems and to improve the reliability of
non-invasive techniques. Since ECoG is a strong
candidate for a decoding source of brain-computerinterface (BCI), we are planning to expand theresearch on this field to clinical implementation of
BCI for communication and motor control incooperation with other brain research laboratories andengineering laboratories.
5) Gamma knife radiosurgery
Gamma knife is a kind of devices for stereotactic

radiosurgery in which high doses of radiation aredelivered at one session and has been widely accepted
as one of treatment options for various intracranial
disorders such as brain tumors, vascular disorders andfunctional disorders. The first gamma knife in Japanwas introduced at our department and diverse clinicalresults have been published. Recently, less invasive
treatment has taking on an added significance in thefield of neurosurgery as well. Therefore, appropriate
combination of radical surgery and radiosurgery isnecessary to manage difficult-to-treat lesions such as
skull base tumors and deeply seated cerebral
arteriovenous malformations, and thus gamma knife
radiosurgery would play a more important role inneurosurgery. Further, technological progress has
refined treatment as an example of integration ofdiffusion tensor tractography which was firstly
attempted at our department. Such technologicalprogresses might contribute to better outcomes ofgamma knife radiosurgery in the future.
6) Clinical applications of the functional brain
imaging and operative simulation using threedimensional computer graphics for neurosurgery
Our department intensively utilizes various kinds offunctional and metabolic imaging modalities including
magnetoencephalography, functional MRI, and diffusion tensor imaging-based tractography for presurgicalbrain mapping. Combining the results of themulti-modalities enables to visualize all cortical andsubcortical networks of the motor, language and othercognitive functions in each patient. Furthermore, we
succeeded to import the combined information into a
neuronavigation system (functional neuronavigation),
which quickly and accurately indicates the eloquent
brain areas. We could develop virtual reality operative
simulation using multi-modal fusion threedimensional computer graphics. Then, it was possible
to precisely examine surgical strategy.

References (2011)1.

Hanakita S, Ishikawa O, Iijima A, Kamada K,
Saito N: Treatment of Cervical Carotid
Pseudoaneurysm that Occurred Years After
Laryngectomy and Irradiation of a Neck Tumor:
A Case Report. Neurol Med Chir (Tokyo) 51:

105

588-591, 2011
2. Hoya K, Yoshimoto Y, Shin M: Rupture of aninternal carotid artery aneurysm within aclinoidal meningioma following stereotactic
radiosurgery. Acta Neurochir (Wien) 153:
1995–1996, 2011
3. Ikushima H, Todo T, Ino Y, Takahashi M, Saito N,
Miyazawa K, Miyazono K: Glioma-initiating
cells retain their tumorigenicity throughintegration of the Sox axis and Oct4 protein. J
Biol Chem 286: 41434-41441, 2011
4. Indo M, Tsutsumi K, Shin M: The practice ofknots untying technique using a 10-0 nylon
suture and gauze to cope with technicaldifficulties of microvascular anastomosis. World
Neurosurg 75: 87-89, 2011
5. Ishii Y, Harada K, Kuroda R, Nagai H, Nakajima
M, Saito N, Ogata K, Yoshida KI: Bilateralthalamic hemorrhage and intracranial injuries
related to alcohol-induced thrombocytopenia. J
Clin Pathol 64: 1034-1035, 2011
6. Kakizawa S, Yamazawa T, Chen Y, Ito A,
Murayama T, Oyamada H, Kurebayashi N, SatoO, Watanabe M, Mori N, Oguchi K, Sakurai T,
Takeshima H, Saito N, Iino M: Nitricoxide-induced calcium release via ryanodine
receptors regulates neuronal function. EMBO J
31: 417-428, 2011
7. Kin T, Shin M, Oyama H, Kmada K, Kunimatsu
A, Momose T, Saito N: Impact of multiorgan
fusion imaging and interactive three-dimensional
visualization for intraventricular neuroendoscopic surgery. Neurosurgery 69: 40-48, 2011
8. Kobayashi K, Nakao K, Kawai K, Ito K,
Hukumoto S, Asakage T, Oota S, Motoi R:
Tumor-induced osteomalacia originating fromthe temporal bone: A case report. Head Neck 33:
1072-5. 2011
9. Koga T, Shin M, Maruyama K, Kurita H,
Kawamoto S, Saito N: Contribution oftechnological progress, inter-operator difference
and experience of operators in gamma knife
radiosurgery for arteriovenous malformation.
Acta Neurochir (Wien) 153: 879-882, 2011
10. Koga T, Shin M, Terahara A, Saito N: Outcomesof radiosurgery for brain stem arteriovenous
malformations. Neurosurgery 6: 45-52, 2011

11. Koizumi S, Kawai K, Asano S, Ueki K, Suzuki I,
Saito N: Familial lateral temporal lobe epilepsy
confirmed
withintracranialelectroencephalography and successfully treated bysurgery. Neurol Med Chir (Tokyo) 51: 604-610,
2011
12. Kunii N, Kamada K, Ota T, Kawai K, Saito N: A
detailed analysis of functional magnetic
resonance imaging in the frontal language area: acomparative study with extraoperative electrocortical stimulation. Neurosurgery 69: 590-596.
2011
13. Kunii N, Ota T, Kin T, Kamada K, Morita A,
Kawahara N, Saito N: Angiographic classification of tumor attachment of meningiomas at
the cerebellopontine angle. World Neurosurg 75:
114-121, 2011
14. Li M, Mukasa A, Inda MM, Zhang J, Chin L,
Cavenee WK, Furnari F: Guanylate binding
protein-1 is a novel effector of EGFR-driven
invasion in glioblastoma. J Exp Med 208:
2657-73, 2011
15. Matsuo T, Kawasaki K, Osada T, Sawahata H,
Suzuki T, Shibata M, Miyakawa N, Nakahara K,
Sato N, Kawai K, Saito N, Hasegawa I:
Intrasulcal electrocorticography in macaquemonkeys with minimally invasive neurosurgicalprotocols. Front Syst Neurosci 5: 1-9, 2011
16. Nakagawa D, Ota T, Iijima A, Saito N: Diagnosis
of Eagle Syndrome with 3-Dimensional
angiography and near-infrared spectroscopy.
Neurosurgery 68: 837-838, 2011
17. Nakamizo A, Suzuki SO, Saito N, Shono T,
Matsumoto K, Onaka S, Mizoguchi M, Sasaki T:
Clinicopathologicalstudy
onchronic
encapsulated expanding hematoma associatedwith incompletely obliterated AVM after
stereotactic radiosurgery. Acta Neurochir (Wien)
153: 883-893, 2011
18. Nakatomi H, Saito N: Current concept of
cerebral aneurysms arising at nonbranching sites.
World Neurosurg 74: 441-443, 2011
19. Nomura M, Shin M, Ohta M, Nukui Y, Ohkusu K,
Saito N: Atypical osteomyelitis of the skull baseand craniovertebral junction caused by
Actinomyces infection-- case report. Neurol Med
Chir (Tokyo) 51: 64-66, 2011

106

20. Ono H, Shin M, Takai K, Oya S, Mukasa A,
Saito N: Spontaneous regression of germinoma
in the pineal region before endoscopic surgery: A
pitfall of modern strategy for pineal germ celltumors. J Neurooncol 103: 755-758, 2011
21. Ota T, Kamada K, Kawai K, Yumoto M, Aoki S,
Saito N: Refined analysis of complex language
representation by non-invasive neuroimaging
techniques. Br J Neurosurg 25: 197-202, 2011
22. Saito N, Imai H: Insights on the revascularization
mechanism for treatment of Moyamoya disease
based on the histopathologic concept of angiogenesis and arteriogenesis. World Neurosurg 75:
204-205, 201123. Saito N: Great hospitals of asia: The university of
tokyo hospital. World Neurosurg 75: 364-368,
2011
24. Saito N: keiji SANO, MD, PhD, 1920-2011.
Neurol Med Chir (Tokyo) 51: 335-336, 2011
25. Saito N: Treatment of complex internal carotid
artery aneurysms. World Neurosurg 75: 412-413,
2011
26. Shin M, Jan C, Jacquard C, Jarraya B, Callebert J,
Launay JM, Palfi S, Brouillet E: Chronicsystemic treatment with high dose proteasome
inhibitor in mice produces akinesia unrelated tonigro-striatal degeneration. Neurobiol of Aging
32: 2100-2102, 2011
27. Shinoura N, Yamada R, Tabei Y, Saito K, Suzuki
Y, Yagi K: Advantages and disadvantages of
awake surgery for brain tumours in the primary
motor cortex : institutional experience andreview of literature. Br J Neurosurg. 25: 218-24,
2011.
28. Shinozaki M, Takahashi Y, Mukaino M, Saito N,
Toyama Y, Okano H, Nakamura M: Novel
concept of motor functional analysis for spinal
cord injury in adult mice. J Biomed Biotechnol
2011: 157458, 2011
29. Shojima M, Saito N: Has the introduction ofcoiling improved therapeutic outcomes forsubarachnoid hemorrhage? A report from theJapanese PRESAT Group. World Neurosurg 76:
394-395, 2011
30. Takai K, Kin T, Oyama H, Iijima A, Shojima M,
Nishido H, Saito N: The use of 3D computer
graphics in the diagnosis and treatment of spinal

vascular malformations. J Neurosurg Spine 15:654-659, 2011
31. Tanaka S, Kabayama H, Enomoto M, Saito N,
Mikoshiba K: Inositol 1, 4, 5-trisphosphate
receptor interacts with the SNARE domain ofsyntaxin 1B. J Physiol Sci 61: 221-229, 2011
32. Uno T, Kawai K, Kunii N, Fukumoto S,
Shibahara J, Motoi T, Saito N: Osteomalacia
caused by skull base tumors: report of 2 cases.
Neurosurgery 69: E239-244, 2011
33. Usami K, Saito N: Prophylactic anticonvulsants
after subarachnoid hemorrhage. World Neurosurg
75: 214, 2011
34. Watanabe A, Ogiwara H, Ehata S, Mukasa A,
Ishikawa S, Maeda D, Ueki K, Ino Y, Todo T,
Yamada Y, Fukayama M, Saito N, Miyazono M,
Aburatani H: A homozygously deleted gene
DACH1 regulates tumor-initiating activity ofglioma cells. Proc Natl Acad Sci U S A 108:
12384-12389, 2011.
35. Yamaguchi R, Hosaka M, Torii S, Hou N, Saito
N, Yoshimoto Y, Imai H, Takeuchi T: Cyclophilinc-associated protein regulation of phagocytic
functions via nfat activation in macrophages.
Brain Res 1397: 55-65, 2011
36. Yamaguchi T, Shojima M, Delashaw JB, Jr.,
Watanabe E: Wada test using secobarbital
sodium (Ional) to determine language dominance.
Br J Neurosurg 25:203-209, 2011.
37. Yoshida K, Saito N, Iriki A, Isoda M:
Representation of others' action by neurons inmonkey medial frontal cortex. Curr Biol 21:249-53, 2011

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

108

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

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

Research Associate
Satoshi Ueha, Ph. D.,

Homepage

Takeshi Shimaoka, Ph.D.

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) Elucidation of the cellular and molecularmechanisms that leads to organ fibrosis
3) Molecular analysis of chemokine receptor
signaling pathway.
4) Genome-wide transcriptome and epigenetic
signature of various types of cells and tissues innormal as well as disease state5) Development of vaccines against pathogenic
microorganisms and cancer
6) Establishment of a novel bio-monitoring systemfor environmental chemicals.

109

References(1) Esaki K, Terashima Y, Toda E, Yoshinaga S, Araki
N, Matsushima K, Terasawa H. Expression andpurification of human FROUNT, a common cytosolic regulator of CCR2 and CCR5. Protein Expr
Purif. 2011; 77(1):86-91.
(2) Ueha S, Shand FH, Matsushima K. Myeloid cell
population dynamics in healthy and tumor-bearing
mice. Int Immunopharmacol. 2011; 11(7):783-8.
(3) Toda M, Wang L, Ogura S, Torii M, Kurachi M,
Kakimi K, Nishikawa H, Matsushima K, Shiku H,
Kuribayashi K, Kato T. UV irradiation of immunized mice induces type 1 regulatory T cells thatsuppress tumor antigen specific cytotoxic T lymphocyte responses. Int J Cancer. 2011; 129(5):1126-36.
(4) Kurachi M, Kurachi J, Suenaga F, Tsukui T, Abe J,
Ueha S, Tomura M, Sugihara K, Takamura S, Kakimi K, Matsushima K. Chemokine receptor
CXCR3 facilitates CD8(+) T cell differentiation
into short-lived effector cells leading to memory
degeneration. J Exp Med. 2011; 208(8):1605-20.
(5) Ogoshi K, Hashimoto S, Nakatani Y, Qu W,
Oshima K, Tokunaga K, Sugano S, Hattori M,
Morishita S, Matsushima K. Genome-wide profiling of DNA methylation in human cancer cells.
Genomics. 2011; 98(4):280-7.
(6) Kaneko K, Miyabe Y, Takayasu A, Fukuda S,
Miyabe C, Ebisawa M, Yokoyama W, Watanabe K,
Imai T, Muramoto K, Terashima Y, Sugihara T,
Matsushima K, Miyasaka N, Nanki T. Chemerin
activates fibroblast-like synoviocytes in patientswith rheumatoid arthritis. Arthritis Res Ther. 2011;13(5):R158.
(7) Matsushima K, Nagai S. Unraveling the mysteryof the hygiene hypothesis through Helicobacter
pylori infection. J Clin Invest. 2012; 122(3):801-4.
(8) Abe J, Ueha S, Yoneyama H, Shono Y, Kurachi M,
Goto A, Fukayama M, Tomura M, Kakimi K,
Matsushima K. B cells regulate antibody responses
through the medullary remodeling of inflamed
lymph nodes. Int Immunol. 2012; 24(1):17-27.
(9) Furuichi K, Shintani H, Sakai Y, Ochiya T,
Matsushima K, Kaneko S, Wada T. Effects of adipose-derived mesenchymal cells on ische-mia-reperfusion injury in kidney. Clin Exp Nephrol. 2012 (in press)

110

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

Associate Professor
Takahiro Higashi, M.D., Ph.D.

Lecturer
Satoshi Toyokawa, M.S., Ph.D.

Associate
Jun Tomio, M.D., 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.
In the academic year of 2011, the Department
consists of four faculty members above listed, one
project researcher, three supporting staffs, 12 graduate
students (eight in PhD program and four in MPH
program), one research students, 16 part-time lecturers,
and 13 visiting fellows.

Teaching activities
1) Undergraduate Program (Medical School)

111

In the winter term of the fourth grade in the Schoolof Medicine (M2), students are provided with thefollowing lectures; current issues of public health,preventive services, epidemiology, health economics,
community health and medicine, infection andtuberculosis control, mental health, human ecology,international health, current health policy andadministration in Japan, quality of care, and so on.
Similarly, in the sixth grade (M4), a concentration
course of public health (e.g., health care systems,
current health policy, occupational medicine andenvironmental health, nutritional epidemiology, andevidence-based medicine) is provided. All the above
lectures are given by faculty members and part-time
lectures including governmental officials and healthpractitioners.
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, and the School of Integrated Health
Sciences.
2) MPH Program
The Department offers two lectures and one fieldpractice;“HealthPolicy,”“Public
HealthPreparedness,” and “Public Health Practice.” The
Department also provides a research course forindividual students.
3) PhD Program
The Department offers special lectures, seminars,
field practice, and laboratory work on public healthand occupational medicine to graduate students. In
these training, special emphasis has been placed on
the following points: (1) how to conduct

epidemiologicalstudies,
(2)
how
to
use
epidemiological and statistical methods, (3) how to
use economic concepts and methods in the healthfields, (4) how to establish the collaboration withhealth professionals in the various fields, and (5) how
to read and write original papers.

Research activities
1) Health policy and economics
Our research activities focus on the topics of healthcare system and economics in general. We have
performed and published those studies related tosupply and demand sides of health services in Japan;such as supply and distribution of physicians, accessto health care, 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 also conduct research on qualityof care (cancer, diabetes, and osteoporosis). Thesestudies have been published in health policy andhealth services research journals. We have continued acollaborative study on a system of HIV/AIDS carewith the introduction of highly active anti-retroviraltherapy (HAART) in developing countries, since sucha system involves medical, behavioral, social, andeconomic factors, and would inevitably become an
important health policy issue.
2) Occupational health
We have carried on a longitudinal study on life-style,occupational stress, and health status of workers invarious occupational settings for the purpose of
preventing occupational and life-style diseases.
3) Others
Other research activities includes, (1) assessment of
disclosure risk of privacy in cancer registry database,(2) evaluation of newspaper reporting on hospitalcancer survival, (3) evaluation of disaster
preparedness in local communities and healthcare
facilities, (4) evaluation of the effectiveness of the
Safe Communities model for safety promotion, (5)development of the effective risk communication for
public health emergencies, (6) evaluation of theemergency treatments for out-of-hospital cardiac

112

arrest patients, (7) assessment of health care access in
Afghanistan, and (8) epidemiological study on
incidence and survival rate of children with cerebral
palsy.
4) Academic meeting
In collaboration with all the departments affiliatedwith School of Public Health, we hosted The Third
PeSeTo Conference on Public Health at Tetsumon
Memorial Hall, Graduate School of Medicine, The
University of Tokyo, on December 22, 2011.
“PeSeTo” is the abbreviation for Peking University,
Seoul National University, and The University ofTokyo.

References
1. Araki Y, Matsuyama Y, Kobayashi Y, Toyokawa S,
Inoue K, Suzuki S, Makimoto A: Secondary
neoplasms after retinoblastoma treatment: retrospective cohort study of 754 patients in Japan. Japanese
Journal of Clinical Oncology 41(3): 373-379, 2011.
2. You X, Kobayashi Y: Determinants of out-of-pocket
health expenditure in China: analysis using China
Health and Nutrition Survey data. Applied Health
Economics & Health Policy 9(1): 39-49, 2011.
3. Shakubo M, Takegami M, Shibata A, Kuzumaki M,
Higashi T, Hayashino Y, Suzukamo Y, Motira S,
Katsuki M, Fukuhara S: Effect of feedback inpromoting adherence to an exercise programme: arandomized controlled trial. Journal of Evaluation in
Clinical Practice 17 (1): 7-11, 2011.
4. Ohura T, Ishizaki T, Higashi T, Konishi K, Ishiguro
R, Nakanishi K, Shah S, Nakayama T: Reliability andvalidity tests of an evaluation tool based on themodified Barthel Index. International Journal of
Therapy and Rehabilitaion 18(8): 422-428, 2011.
5. Higashi T, Hasegawa K, Kokudo N, Makuuchi M,
Izumi N, Ichida T, Kudo M, Ku Y, Sakamoto M,
Nakashima O, Matsui O, Matsuyama Y, Sobue T:
Demonstration of quality of care measurement using
the Japanese liver cancer registry. Hepatology
Research 41(12): 1208-1215, 2011.
6. Ono R, Higashi T, Takahashi O, Tokuda Y, Shimbo T,
Endo H, Hinohara S, Fukui T, Fukuhara S: Sex
differences in the change in health-related quality oflife associated with low back pain. Quality of Life

Research 2011 Dec 20. (Epub ahead of print)
7. Sabawoon W, Sato H, Kobayashi Y, Pardis A:
Regional differences in delay to tuberculosis
treatment in Afghanistan: a cross-sectional study.
Applied Geography 31 (3): 1123-1131, 2011.
8. Tanihara S, Kobayashi Y, Une H, Kawachi I:
Urbanization and physician maldistribution: alongitudinal study in Japan. BMC Health Services
Research 11 (260): doi: 10.1186/ 1427-6963-11-260,
2011.
9. Ikegami N, Yoo BK, Hashimoto H, Matsumoto M,
Ogata H, Babazono A, Watanabe R, Shibuya K, Yang
BM, Reich MR, Kobayashi Y: Japan: Universal
Health Care at 50 Years 2: Japanese universal healthcoverage: evolution, achievements, and challenges.
Lancet 378 (9796) : 1106-1115, 2011.
10. Tomio J, Sato H, Mizumura H: Desparity in disaster
preparedness among rheumatoid arthritis patientswith various general health, functional, and disability
conditions. Environmental Health and Preventiv
Medicine 2011 Dec 21. (Epub ahead of print).
11. Tomio J, Sato H, Mizumura H: Impact of natural
disasters on the functional and health status ofpatients with rheumatoid arthritis. Modern
Rheumatology 21(4): 381-390, 2011.
12. Nishi A, Kondo K, Hirai H, Kawachi I: Cohort
profile: the AGES 2003 cohort study in Aichi, Japan.
Journal of Epidemiology 21 (2): 151-157, 2011.

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

114

Department of Forensic Medicine
Professor
Ken-ichi Yoshida, M.D., Ph.D.
Lecturer
Kaori Shintani, Ph.D.
Assistant Professor
Hisashi Nagai, M.D.,
Takako Tsujimura, 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 acomplex componet. He helped foundation of national
police academy for death investigators.
The 5th Professor Toshiyuki Miki could not perform
autopsy for four years due to the University of Tokyo
strike. However, he left many achievements in 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, one
lecturer, two assistant professor, one associate, 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 the mostimportant mission of our department. We autopsy about
120 criminal cases in eastern part of Tokyo every year.
We have already autopsied more than 11,240 cases
since 1897. Some of these cases are very famous incriminology in Japan.
In forensic autopsy, we examine the pathological,

115

alcohol, toxicological, and blood type testing of eachcase, too. Finally, forensic pathologists in our
department diagnose the cause of death. Expert
opinions expresses the cause of death and forensic
judgment for each case. We have kept them since first
autopsy case in 1897. We have serious responsibility 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
lead the pilot study on the investigation and analysis of
MPAD (supported by government). We also contributeto evolve new way of presenting expert opinions for thejury courts that has been enacted in 2009.

Education
As for under-graduate education, our department
provides lectures for the 4th year medical students, Free
Quarter training course for the 3-4th year medical
students, and Clinical Clerkship learning for the 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. We
have provided opportunity for PhD students of Schoolof Hearth Science, and master course of Medical
Science.

Research
Our mission is to determine the cause of death inunnatural deaths through autopsy and various
examinations. We have also tried to find problems inlegal-social systems related to death investigation, court
procedure, and patient safety. To improve deathinvestigation and related legal-social systems, we

conducted variety of researches including cardiovascular basic sciences, legal-social medicine, forensic
pathology, toxicology, and DNA polymorphism as
described below.
1. Molecular mechanism of myocardial lesions and cell
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. We study the mechanism of these
phenomena in the models of coronary occlusion,
isolated perfused heart, or cultured cardiomyocytes
through circulatory physiology, biochemistry,
histology, and molecular biology.
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）,
derangement of sarcoplasmic (SR) calcium
handling, and contribution of mitochondria to thedevelopment of myocardial infarction Additionally,
we found that calpain (calcium-dependent protease)
contributes to the myocardial injury, contractile
dysfunction and development of infarction inreperfusion. 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 themodel of heart diseases and amphetamine treatedanimals. Yoshida has published 100 papers on
experimental research with about 2900 citations.

116

3. Research on cardiovascular risk and sudden death insleep 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 theinvestigation on the molecular mechanism of
cardiachypertrophy,
hypertension,andarrhythmias. We have organized multi-facility
research groups to promote the project, after the
Ministry of Education, Culture and Sport has
accepted our proposal as the class A grant.
4. Lesion propagation in rat model of brain contusion.
We study the mechanism underlying the propagation of neural death through the cortical layer VI
through GJ, activation of calpain and astrocyte.
5. Investigation on the law and social system related todeath investigation, medical safety, and lawsuit.
We found that the disclosure of the information andbereavement service related to medicolegal autopsy
are limited. Additionally, the information related to
medicolegal autopsy cannot be used for accident
prevention. Moreover, ethical problems are to beaddressed for the research or educational purpose.
The Department of Health, Welfare, Labor, andSports has promoted the model project on theinvestigation of medical practice-associated deaths(MPADs), and been trying to establish the newinvestigative system for MPADs. We havecontributed to the review of the model project, andsubmitted reports on review and recommendations.
With corroboration with the society ofemergency medicine, we have conducted aquestionnaire study on the usefulness of feedbackof autopsy information to the frontline of medical
practices. On the basis of the results, a group of ER
doctors and forensic pathologists have conductedmonthly case conference, addressing whether
clinical information helps autopsy diagnosis,
autopsy information improves clinical practice, andimage diagnosis is confirmed by autopsy eytc.
6. 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. In the field of 5&6, wehave published 21 papers with 131 citations
including 2 lancet (letters) papers.
7. 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. We
have published 8 papers in clinical & pathology
journals and 18 forensic papers (85 citations).

Publications
1.

2.

3.

4.

5.

Shintani-Ishida K, Yoshida K. Ischemia induces
phospholamban dephosphorylation via activationof calcineurin, PKC-α, and protein phosphatase 1,
thereby inducing calcium overload in reperfusion.
Biochim. Biophys. Acta. 2011;1812:743-751.
Ishii Y, Harada K, Kuroda R, Nagai H, Nakajima
M, Saito N, Ogata K, Yoshida K. Bilateralthalamic haemorrhage and intracranial injuries
related to alchol-induced thrombocytopenia. J.
Clin. Pathol. 2011;64(11):1034-1035.
Kuroda R, Harada K, Kobayashi T, Nagai H,
Unuma K, Saka K, Shintani-Ishida K, Yoshida K.
Sudden cardhiac death caused by theadministration of a β2-agonist for asthma attack.
Int. J. Cardiol. 2011;153:e56-e58.
Ueyama T, Yamamoto T, Ueda K, Kawabe T,
Hano T, Ito T, Tsuruo Y, Ichinose M, Yoshida K.
Cardiac and vascular gene profiles in an animalmodel of takotsubo cardiomyopathy. Heart Vessels.
2011;26:321-337.
Unuma K, Harada K, Furutani M, Furutani Y,
Nakajima M, Nakanishi T, Matsuoka R, Yoshida K.
Multiple stenotic arteriopathy in a 72-year-old
female with Williams syndrome. J. Clin. Pathol.
2011;64:368-370.

117

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
medical and clinical information systems, nextgeneration electronic health record systems, virtual
health care environment, computer representations
and standardization of medical concepts, ontology,
medicalknowledge
engineering,
hospital
epidemiology, quality assessment of healthcare,clinical and bioinformatics engineering, privacy
protection and encryption, analysis of hospitalmanagement, safety management in healthcare.
The professor of the department also holds the
position of director of the department planning,
information and management (DPIM) in the
University of Tokyo Hospital. DPIM is the departmentthat deals with information analyses and futureplanning for the University of Tokyo Hospital byusing information systems as well as the planning,
design, development, and operation of information
systems for the whole hospital. The DPIM was newly

established on April 1, 2003, after integration of the
Hospital Computer Center and the project team for
hospital development, which separately existed until
the end of March, 2003.
Since the professor runs the Department of Medical
Informatics and Economics with staffs of DPIM, they
are practically the same organization. Therefore,
educations and researches in the graduate course arepromoted together with DPIM activities. Only one
professor is the dedicated faculty member of the
Department of Medical Informatics and Economics,
however, faculty outside the department participatesas teaching staffs of the graduate course: Assoc. prof.
S. Koike and Lecturer. K. Miyo from DPIM, Assoc.
Prof. H. Yasunaga from the Department of HealthManagement and Policy, Assoc. Prof. H. Fujita fromthe Department of Ubiquitous Health Informatics,
Assoc. Prof. R. Yamamoto from Interfaculty Initiativein Information Studies, Graduate School ofInterdisciplinary Information Studies.
The origin of the Department of Medical
Informatics and Economics dates back to 1983 when
the hospital computer center was officially approved
as one of the central clinical service facilities in thehospital. At the same time, the doctor’s course for
medical informatics was established. The first
professor was Dr. Shigekoto Kaihara, who is thefounder of medical informatics in Japan, and he is
now a emeritus professor of the University of Tokyo.
In accordance with the reform to the university with
graduate school curriculum in the university of Tokyo,
the Department of Medical Informatics and economics
was established in present division of social medicine

118

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

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

Health Sciences with completion of required units
and passing a master’s thesis. In the doctoral course,
students will acquire Doctor of Health
Sciences(Ph.D.) with completion of required units
and passing a doctoral thesis.
3). 2-year M.P.H and 1-year M.P.H in the Department
of Health Informatics in the Shool of Public Health:
We offer 2-year Master of Publics Health (M.P.H)
course and the 1-year M.P.H program in the Schoolof Publics Health. See the homepage of the Shool of
Publics Health.
4). 2-year M.M.S in the Department of Health
Medical Informatics in the Medical Science
Graduate Program: Graduate School of Medicine,the University of Tokyo, offers the master course in
Medical Sciences. The course was established forstudents who graduate from faculties other than a
6-year program at Faculty of Medicine andeventually wish to advance to the Medical Sciences
doctoral course of the University of Tokyo. It
enables students to enroll in the department theyplan to carry out their research for Doctor of
Medical Science. (the entrance examination
required for enrollment in Medical Sciences
doctoral course) In this Master’s course, all students
entering the course spend the first four months
taking formal coursework for students of alldivisions, and then will decide which department
they wish to affiliate with. At the department
students are expected to conduct their research for
the Master and complete a master’s thesis in the last
one and an half year. They will acquire the Master’s
degree (in Medical Sciences) with completion ofrequired units and passing a master’s thesis. Our
department also accepts students in this course.
The enrolled students in FY2011 are one in doctor’scourse for Medical Informatics and Economics, one inmaster’s course for Health Informatics.
The students’ researches cover various topics;
development of self medication management systemusing smart-phone devices, medical ontology, etc.

Research activities
The research domains are 1) application studies ondevelopments of clinical information systems, hospital

119

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

References
1. Ogawa T, Akahane M, Koike S, Tanabe S,
Mizoguchi T, Imamura T, Outcomes of chest
compression-only CPR versus conventional CPR: anationwide, population-based, observational study

of bystander-witnessed out-of-hospital cardiopulmonary arrest cases. British Medical Journal,
342, c7106,2011.
2. Akahane M, Ogawa T, Koike S, Tanabe S,
Horiguchi H, Mizoguchi T, Yasunaga H, Imamura
T, The effects of sex on out-of-hospital cardiac
arrest outcomes., American Journal of Medicine,
124(4), 325-333,2011.
3. Koike S, Tanabe S, Ogawa T, Akahane M,
Yasunaga H, Horiguchi H, Matsumoto S, Imamura
T, Effect of time and day of admission on 1-monthsurvival and neurologically favourable 1-monthoutcome in out-of-hospital cardiopulmonary arrest
patients, Resuscitation ,82(7) ,863-868 ,2011.
4. Koike S, Tanabe S, Ogawa T, Akahane M, Yasunaga
H, Horiguchi H, Matsumoto S, Imamura
T,.Immediate defibrillation or defibrillation after
cardiopulmonary
resuscitation,
Prehospital
Emergency Care 15(3), 393-400, 2011.
5. Yasunaga H, Miyata H, Horiguchi H, Tanabe S,
Akahane M, Ogawa T, Koike S, Imamura T ,Population density, call-response interval, andsurvival of out-of-hospital cardiac arrest,
International Journal of Health Geographics, 10,26,
2011.
6. Koike S, Ogawa T, Tanabe S, Matsumoto S,
Akahane M, Yasunaga H, Horiguchi H, Imamura T,
Collapse-to-emergency medical service cardiopulmonary resuscitation interval and outcomes ofout-of-hospital cardiopulmonary arrest: a nationwide observational study, Critical Care,15(3), R120,
2011.
7. Tanaka K, Atarashi H, Yamaguchi I, Watanabe H,
Yamamoto R, Ohe K. Wireless LAN Security
Management with Location Detection Capability in
Hospitals. Methods Inf Med,50(3), 2011.
8. Otake H, Yasunaga H, Horiguchi H, Matsutani N,
Matsuda S, Ohe K. Impact of hospital volume onchest tube duration, length of stay, and mortality
after lobectomy. Ann Thorac Surg, 92(3): 1069-74,
2011.

Internal Medicine
1. Medicine Ⅰ

121

Department of Cardiovascular
Medicine
Professor
Ryozo Nagai, M.D., Ph.D. (- March 31, 2012)
Issei Komuro, M.D., Ph.D. (August 1, 2012 -)Associate Professor
Yasunobu Hirata, M.D., Ph.D.

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

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

Masafumi Watanabe, M.D., Ph.D.

Ichiro Manabe, M.D., Ph.D.

Hospital Lecturer
Yasushi Imai, M.D., Ph.D.

Homepage

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

Introduction and Organization

important for the future of cardiovascular medicine.

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 is

Outline of department
Staff: one professor (Issei Komuro), 2 associate
professor, 3 assistant professors, 17 research
associates, 8 staff members, 35 graduate school
students, and 2 members studying abroad.

Clinical activities
In 2011, 1,423 patients were newly admitted to our
hospital ward of approximately 50 beds. Of thesepatients, approximately 70% were due to ischemic
heart disease. Cardiovascular angiograms wereconducted in 2,236 patients, of which 627 cases wereinterventional procedures. CT coronary angiography
was examined in 360 patients and cardiovascular MRI
in 49. For arrhythmias, there were 99 cases of
implantation of a pacemaker, 68 cases of catheter
ablation, and other specialized pacemaker devices
such as 23 cases of implantation of a cardioverterdefibrillator, and 30 cases of implantation of a cardiac

122

resynchronization device.
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 6 cases also in 2011 (total 21
cases). Duration of hospitalization is on average 14.1
days.
Out-patient clinics are available as part of the
Department of Medicine or as a specialized
department. The profile of diseases includes ischemic
heart disease in main and heart failure and arrhythmia
in addition to hypertension and peripheral arterydisease. Out-patient clinics are open both mornings
andafternoonsfrom
Mondayto
Friday.
Approximately 220 patients visit each day. Acutecases of coronary heart disease and aortic disease arealso a focus of the department, as emergent
catheterization is available on a 24-hours basis.

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

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

References
1)

2)

3)

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

4)

5)

Fujita H, Nagai R. Glycemic control is anothertarget of PCI in diabetic patients. Circ J. 2011;
75:773-4.
Fujiu K, Manabe I, Nagai R. Renal collecting ductepithelial cells regulate inflammation in
tubulointerstitial damage in mice. J Clin Invest.
2011;121: 3425-41.
Hasumi E, Iwata H, Saito K, Fujiu K, Ando J,
Imai Y, Fujita H, Hirata Y, Nagai R. Diagnostic
efficacy of coronary CT angiography as afollow-up modality for procedure-related coronary
dissection. Int Heart J. 2011;52:240-2.
Hatano M, Kinugawa K, Shiga T, Kato N, Endo M,
Hisagi M, Nishimura T, Yao A, Hirata Y, Kyo S,
Ono M, Nagai R. Less frequent opening of theaortic valve and a continuous flow pump are risk
factors for postoperative onset of aortic
insufficiency in patients with a left ventricularassist device. Circ J. 2011;75:1147-55.
Hatano M, Yao A, Kinugawa K, Hirata Y, Nagai
R. Acute effect of sildenafil is maintained in123

pulmonaryarterial
hypertension
patients
chronically treated with bosentan. Int Heart J.
2011;52:233-9.
6) Ikutomi M, Matsumura T, Iwata H, Nishimura G,
Ishizaka N, Hirata Y, Ono M, Nagai R. Gianttumorous legions surrounding the right coronary
artery associated with immunoglobulin-G4-related
systemic disease. Cardiology. 2011;120:22-6.
7) Ishizaka N, Sakamoto A, Fujishiro M, Nagai R,
Koike K. Gastrointestinal malignancies andcardiovascular diseases-non-negligible comorbidity in an era of multi-antithrombotic drug use. J
Cardiol. 2011;58:199-207.
8) Kamo T, Matsumura T, Hirata Y, Nagai R.
Multiple pulmonary artery fistulas causing partial
lung edema. Intern Med. 2011;50:1259-60.
9) Kato N, Kinugawa K, Seki S, Shiga T, Hatano M,
Yao A, Hirata Y, Kazuma K, Nagai R. Quality oflife as an independent predictor for cardiac eventsand death in patients with heart failure. Circ J.
2011;75:1661-9.
10) Kimura K, Takenaka K, Pan XF, Ebihara A, Uno
K, Fukuda N, Kohro T, Morita H, Yatomi Y,
Nagai R. Prediction of coronary artery stenosis
using strain imaging diastolic index at rest in
patients with preserved ejection fraction. J Cardiol.
2011;57: 311-5.
11) Kimura K, Takenaka K, Ebihara A, Uno K, Iwata
H, Sata M, Kohro T, Morita H, Yatomi Y, Nagai
R. Reproducibility and diagnostic accuracy of
three-layer speckle tracking echocardiography in aswine chronic ischemia model. Echocardiography.
2011;28:1148-55.
12) Kinugawa K. How to treat stage D heart failure? When to implant left ventricular assist devices inthe era of continuous flow pumps? Circ J. 2011;
75:2038-45.
13) Kiyosue A, Nagata D, Myojo M, Sato T,
Takahashi M, Satonaka H, Nagai R, Hirata Y.
Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves
glucocorticoid response element. Hypertens Res.
2011;34:1283-7.
14) Kobayashi N, Ueki K, Okazaki Y, Iwane A,
Kubota N, Ohsugi M, Awazawa M, Kobayashi M,
Sasako T, Kaneko K, Suzuki M, Nishikawa Y,
Hara K, Yoshimura K, Koshima I, Goyama S,

Murakami K, Sasaki J, Nagai R, Kurokawa M,
Sasaki T, Kadowaki T. Blockade of class IB
phosphoinositide-3 kinase ameliorates obesityinduced inflammation and insulin resistance. Proc
Natl Acad Sci USA. 2011;108:5753-8.
15) Kohro T, Yamazaki T, Izumi T, Daida H,
Kurabayashi M, Miyauchi K, Tojo T, Nagai R, on
behalf of the JCAD II Investigators. Intensively
lowering both low-density lipoprotein cholesteroland blood pressure does not reduce cardiovascularrisk in Japanese coronary artery disease patients.
Circ J. 2011;75:2062-70.
16) Maki H, Yao A, Inaba T, Shiga T, Hatano M,
Kinugawa K, Yamashita T, Aizawa T, Nagai R.
Initial and programmed combination therapy withoral drugs for severe idiopathic pulmonary arterial
hypertension. Int Heart J. 2011;52:323-6.
17) Matsubara TJ, Iwata H, Shiga T, Hatano M, Yao
A, Ono M, Kinugawa K, Hirata Y, Nagai R.
Progressive coronary artery-pulmonary artery
fistula after size-mismatch cardiac transplantation.
Asaio J. 2011;57:346-7.
18) Matsumoto K, Ogawa M, Suzuki J, Hirata Y,
Nagai R, Isobe M. Regulatory T lymphocytes
attenuate myocardial infarction-induced ventricular remodeling in mice. Int Heart J. 2011;52:
382-7.
19) Morita H, Nagai R. Vemurafenib in melanoma
with BRAF V600E mutation. N Engl J Med.
2011;365:1448; author reply 1450.
20) Ngoc PB, Suzuki J, Ogawa M, Hishikari K,
Takayama K, Hirata Y, Nagai R, Isobe M. The
anti-inflammatory mechanism of prostaglandin E2
receptor 4 activation in rat experimental
autoimmune myocarditis. J Cardiovasc Pharm.
2011;57:365-72.
21) Ochiai R, Yao A, Kinugawa K, Nagai R, Shiraishi
I, Niwa K. Status and future needs of regional
adult congenital heart disease centers in Japan.
Circ J. 2011;75:2220-7.
22) Ogawa M, Suzuki J, Yamaguchi Y, Muto S, Itai A,
Hirata Y, Isobe M, Nagai R. The effects ofpharmacologic plasminogen activator inhibitor-1
inhibition in acute and chronic rejection in murine
cardiac allografts. Transplantation. 2011;91:21-6.
23) Ogawa N, Imai Y, Takahashi Y, Nawata K, HaraK, Nishimura H, Kato M, Takeda N, Kohro T,

124

Morita H, Taketani T, Morota T, Yamazaki T,
Goto J, Tsuji S, Takamoto S, Nagai R, Hirata Y.
Evaluating Japanese patients with the Marfan
syndrome using high-throughput microarray-based
mutational analysis of fibrillin-1 gene. Am J
Cardiol. 2011;108:1801-7.
24) Saito T, Watanabe M, Kojima T, Matsumura T,
Fujita H, Kiyosue A, Takahashi M, Takeda N,
Maemura K, Yamashita H, Hirata Y, Komatsu S,
Ohtomo K, Nagai R. Successful blood samplingthrough azygos continuation with interrupted
inferior vena cava. Int Heart J. 2011;52:327-30.
25) Shiga T, Kinugawa T, Hatano M, Yao A,
Nishimura T, Endo M, Kato N, Hirata Y, Kyo S,
Ono M, Nagai R. Age and preoperative total
bilirubin level can stratify prognosis after
TOYOBO left ventricular assist device
implantation. Circ J. 2011; 75: 121-8.
26) Suzuki J, Ogawa M, Muto S, Itai A, Hirata Y,
Isobe M, Nagai R. Effects of specific chemical
suppressors of plasminogen activator inhibitor-1
in cardiovascular diseases. Expert Opin Inv Drug.
2011;20:255-64.
27) Suzuki J, Ogawa M, Watanabe R, Morishita R,
Hirata Y, Nagai R, Isobe M. Autoimmune giant
cell
myocarditisclinicalcharacteristics,
experimental models and future treatments-.
Expert Opin Ther Targets. 2011;15:1163-72.
28) Suzuki J, Ogawa M, Muto S, Itai A, Isobe M,
Hirata Y, Nagai R. Novel IκB kinase inhibitors
for treatment of nuclear factor- κ B-relateddiseases.
ExpertOpin
Investig
Drugs.
2011;20:395-405.
29) Suzuki J, Ogawa M, Watanabe R, Takayama K,
Hirata Y, Nagai R, Isobe M.
Roles ofprostaglandin E2 in cardiovascular diseases: focus
on the potential use of a novel selective EP4
receptor agonist. Int Heart J. 2011;52:266-9.
30) Suzuki T, Yamazaki T, Ogawa S, Nagai R,
Yamashita T, and the J-RHYTHM II investigators.
Echocardiographic predictors of frequency ofparoxysmal atrial fibrillation (AF) and its
progression to persistent AF in hypertensive
patients with paroxysmal AF: Results from theJapaneserhythmmanagement
trial
II(J-RHYTHM II) for atrial fibrillation study. Heart
Rhythm. 2011;8:1831-6.

31) Takahashi M, Shimizu T, Inajima T, Hosoya Y,
Takeda N, Ishizaka N, Yamashita H, Hirata Y,
Nagai R. A case of localized IgG4-related thoracic
periarteritis and recurrent nerve palsy. Am J Med
Sci. 2011;341:166-9.
32) Takeda N, Maemura K. Circadian clock andcardiovascular disease. J Cardiol. 2011;57:249-56.
33) Tamaki Z, Asano Y, Hatano M, Yao A,
Kawashima T, Tomita M, Kinugawa K, Nagai R,
Sato S. Efficacy of low-dose imatinib mesylate forcutaneous involvement in systemic sclerosis: apreliminary report of three cases. Mod Rheumatol.
2011;22:94-9.
34) Tanaka T, Ikeda K, Yamamoto Y, Iida H, Kikuchi
H, Morita T, Yamasoba T, Nagai R, Nakajima T.
Effects of serum amyloid A and lysophosphatidylchoilne on intracellular calcium
concentration in human coronary smooth muscle
cells. Int Heart J. 2011;52:185-93.
35) Tanaka K, Nagata D, Hirata Y, Tabata Y, Nagai R,
Sata M. Augmented angiogenesis in adventitia
promotes growth of atherosclerotic plaque inapolipoprotein E-deficient mice. Atherosclerosis.
2011;215:366-73.
36) Tsushima K, Osawa T, Yanai H, Nakajima A,
Takaoka A, Manabe I, Ohba Y, Imai Y, Taniguchi
T, Nagai R. IRF3 regulates cardiac fibrosis but not
hypertrophy in mice during angiotensin II-induced
hypertension. FASEB. J. 2011;25:1531-43.
37) Watanabe R, Nakajima T, Ogawa M, Suzuki J,
Muto S, Itai A, Hirata Y, Nagai R, Isobe M.
Effects of pharmacological suppression ofplasminogen activator inhibitor-1 in myocardial
remodeling after ischemia reperfusion injury. Int
Heart J. 2011;52:388-92.
38) Watanabe R, Nakajima T, Ogawa M, Suzuki J,
Muto S, Itai A, Hirata Y, Nagai R, Isobe M.
Ikutomi M, Matsumura T, Iwata H, Nishimura G,
Ishizaka N, Hirata Y, Ono M, Nagai R. Gianttumorous legions surrounding the right coronary
artery associated with immunoglobulin-G4-related
systemic disease. Cardiology. 2011;120:22-6.
39) Yamazaki T, Kishimoto J, Ito C, Noda M,
Odawara M, Terauchi Y, Shiba T, Kitazato H,
Iwamoto Y, Akanuma Y, Kadowaki T, for the
J-PREDICT study investigators. Japan prevention
trial of diabetes by pitavastatin in patients with

125

impaired glucose tolerance (the J-PREDICT
study): rationale, study design, and clinicalcharacteristics of 1269 patients. Dia

126

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

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

Associate
Masashi Desaki, M.D.,Ph.D.,

Shin Kawasaki, M.D.,Ph.D.,

Kazutaka Takami, M.D.,Ph.D.,

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

Taisuke Jo M.D.,Ph.D.,

Reiko Okudaira M.D.,Ph.D.,

Yasushi Goto 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 7 associates. In
the University of Tokyo, affiliated hospitals andforeign institutions, approximately 55 members
belong to the Department. In the University of Tokyo
Hospital, about 15 respiratory physicians are doingclinical works.
Based on the fact that the number of patients withrespiratory diseases such as primary lung cancer and
COPD is tremendously increasing, advancement andfruitful results of researches on respiratory medicine
are more and more expected in the 21st century. In thisera, we are conducting basic and clinical researches
for wide variety of respiratory disorders including
lung cancer, COPD, asthma and interstitial lungdiseases. Especially, we have been intensively
studying the molecular mechanisms underlying thepathogenesis of lung disorders. Our research goal is todevelop novel diagnostic and therapeutic tools tomanage these pulmonary diseases.

The Department of Respiratory Medicine is
responsible for the out-patient care as well as care of
in-patients (40 cases on average), which is taken at the13th floor of the hospital ward A of the University ofTokyo Hospital. Our practice is performed by thethree-member system of a junior resident, a seniorresident and an experienced associate.
Main diseases of in-patients are bronchogenic
carcinoma,
respiratory
infections,interstitial
pneumonia, COPD, pneumothorax and asthma. There
are many 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 sincelate 1990s, where staff of our department, departmentof thoracic surgery and department of radiology join
and discuss together to make best diagnostic andtherapeutic approach to individual patients. Thisconference is appreciated as prototype of Cancer

127

Board of the University of Tokyo Hospital, which
launched five 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 2011
1. Primary lung cancer
2. Respiratory infection
3. Interstitial pneumonia
4. COPD
5. Pneumothorax
5. Asthma

372
76
71
33
26
18

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 the Universityof Tokyo Hospital and at one of the affiliated hospitals
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.

128

Under these processes, residents are able to acquire
the knowledge and skills required for diagnosis andtreatment of respiratory diseases. Seminars on
important themes such as medical treatment of lungcancer, chest imaging, pneumonia, COPD and so on
are held at regular interval.

Chair of Central Congress Committee; andProgram Officer, Research Center for Science
Systems, JSPS.

References
1.

Research Activities
Our department is conducting basic and clinicalresearches for many respiratory disorders including
lung cancer, COPD, asthma, interstitial pneumonia,
respiratory infections and others. Epidemiological,
clinical, cellular and molecular biological techniques
are utilized for the elucidation of pathogenetic
mechanisms and for the development of novel
diagnostic and therapeutic modalities in respiratory
medicine. Postgraduate students as well as the Faculty
members make considerable studies about genetic
alterations in lung cancer in collaboration with theFaculty of the Department of Thoracic Surgery, cellbiological analysis using airway epithelial cells,
fibroblast and smooth muscle cells, analysis ofgenetically-engineered mice as disease-models and soon. These results have been presented and/or
published in the Scientific Meeting and/or peer-review
Journals. Our main research projects are as follows.
Exploration of diseases-susceptibility genes in
respiratory diseases.
Analysis of disease-models using geneticallyengineered mice.
Analysis of DNA methylation and miRNA in lungcancer and its clinical application.
Exprolation of previously unidentified oncogenic
fusion kinases in lung cancer
Analysis of functional alterations of airway epithelial
cells and fibloblasts in relation to tissue repair andremodeling,
especiallyepithelial-mesenchymaltransition, in asthma and COPD.
Studies on pathogenesis of tobacco-smoke induced
respiratory diseases using mouse model of long-term
tobacco exposure.
Search for predictive factors for responses tochemotherapy in maligancy including lung cancer.
Takahide Nagase is GOLD National Leader; APSR,

2.

3.

4.

5.

6.

7.

Hijikata M, Matsushita I, Tanaka G, Tsuchiya T,
Ito H, Tokunaga K, Ohashi J, Homma S, Kobashi
Y, Taguchi Y, Azuma A, Kudoh S, Keicho N.
Molecular cloning of two novel mucin-like genes
in the disease-susceptibility locus for diffuse
panbronchiolitis. Hum Genet 2011; 129: 117-128.
Horie M, Saito A, Mikami Y, Ohshima M,
Morishita Y, Nakajima J, Kohyama T, Nagase T.
Characterization of human lung cancerassociated fibroblasts in three-dimensional in
vitro co-culture model. Biochem Biophys Res
Commun 2012; 423: 158-63.
Kage H, Sugimoto K, Sano A, Kitagawa H,
Nagase T, Ohishi N, Takai D. Suppression ofTgfβ1 in lung alveolar epithelium-derived cells
using adeno-associated virus type 2/5 vectors tocarry short hairpin RNA. Exp Lung Res 2011;
37: 175-85.
Kamitani S, Yamauchi Y, Kawasaki S, Takami K,
Takizawa H, Nagase T, Kohyama T.
Simultaneous stimulation with TGF-β1 andTNF-α induces epithelial mesenchymal transitionin bronchial epithelial cells. Int Arch Allergy
Immunol 2011; 155: 119-28.
Kawakami M, Narumoto O, Matsuo Y, Horiguchi
K, Horiguchi S, Yamashita N, Sakaguchi M,
Lipp M, Nagase T, Yamashita N. The role of
CCR7 in allergic airway inflammation inducedby house dust mite exposur. .Cell Immunol 2012;
275: 24-32.
Kitagawa H., Watanabe K., Kage H., Inoh S.,
Goto A., Fukayama M., Nagase T., Ohishi N. andTakai D. Pulmonary venous invasion, determinedby chest computed tomographic scan, as apotential early indicator of zygomycosis
infection: a case series. J Thorac Imaging, 2011;
Sep 9, Epub ahead of print.
Kitano K, Watanabe K, Emoto N, Kage H,
Hamano E, Nagase T, Sano A, Murakawa T,
Nakajima J, Goto A, Fukayama M, Yatomi Y,
Ohishi N, Takai D. CpG island methylation of

129

8.

9.

10.

11.

12.

13.

14.

microRNAs is associated with tumor size and therecurrence of non-small cell lung cancer. Cancer
Sci 2011; 102: 2126-31.
Narumoto O, Matsuo Y, Sakaguchi M, Shoji S,
Yamashita N, Schubert D, Abe K, Horiguchi K,
Nagase T, Yamashita N. Suppressive effects of apyrazole derivative of curcumin on airway
inflammation and remodeling. Exp Mol Pathol.
2012; 93: 18-25.
Risse PA, Jo T, Suarez F, Hirota N, Tolloczko B,
Ferraro P, Grutter P, Martin JG. Interleukin-13
inhibits proliferation and enhances contractilityof human airway smooth muscle cells withoutchange in contractile phenotype. Am J Physiol
Lung Cell Mol Physiol 2011; 300: L958-66.
Sunohara M, Kawakami M, Kage H, Watanabe K,
Emoto N, Nagase T, Ohishi N, Takai D.
Polymerase reaction without primers throughout
for the reconstruction of full-length cDNA fromproducts of rapid amplification of cDNA ends
(RACE). Biotechnol Lett 2011; 33: 1301-7.
Tanaka G, Aminuddin F, Akhabir L, He JQ,
Shumansky K, Connett JE, Anthonisen NR,
Abboud RT, Pare PD, Sandford AJ. Effect ofheme oxygenase-1 polymorphisms on lungfunction and gene expression. BMC Med Genet
2011; 12: 117.
Tanioka M, Nokihara H, Yamamoto N, Yamada Y,
Yamada K, Goto Y, Fujimoto T, Sekiguchi R,
Uenaka K, Callies S, Tamura T. Phase I study of
LY2181308, an antisense oligonucleotide against
survivin, in patients with advanced solid tumors.
Cancer Chemother Pharmacol 2011; 68: 505-11.
Venkatesan N, Siddiqui S, Jo T, Martin JG,
LudwigMS.
Allergen-induced
airwayremodeling in brown norway rats: structural andmetabolic changes in glycosaminoglycans. Am J
Respir Cell Mol Biol 2012; 46: 96-105.
Watanabe K., Emoto N., Hamano E., Sunohara
M., Kawakami M., Kage H., Kitano K., NakajimaJ., Goto A., Fukayama M., Nagase T., Yatomi Y.,
Ohishi N. and Takai D. Genome structure-based
screening identified epigenetically silenced
microRNA associated with invasiveness in
non-small-cell lung cancer. Int J Cancer 2012;
130: 2580-90.

15. Yamauchi Y, Kohyama T, Jo T, Nagase T.
Dynamic change in respiratory resistance duringinspiratory and expiratory phases of tidal
breathing in patients with chronic obstructive
pulmonary disease. Int J Chron Obstruct Pulmon
Dis 2012; 7: 259-6.

130Department of Gastroenterology
Professor
Kazuhiko Koike, M.D., Ph.D.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Takashi Sasaki, M.D., Ph.D.

Atsuo Yamada, 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, 21
associates, 15 fellows, 54 graduates and 5 othervisiting researchers including students from abroad(March, 2012). 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 98 inpatients on average, which are about
3,000 in total per year. We receive about 110 new
patients in and out of the hospital each week, with an

131average hospital stay of 12.3 days. Resident, juniorand senior staff members bear the responsibility for a
medical management of each inpatient, in
collaboration with subspecialty groups concerned. The
staff members examine about 5,500 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(1000 cases in 2011). 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 (50 casesin 2011). In addition, we are making efforts to develop
an innovation for daily clinical activities. For example,
fibrosis progression in chronic liver disease isconventionally assessed by liver biopsy. Recently we
can evaluate the stage of liver fibrosis by Fibroscan®,newly developed equipment that measures liver
stiffness by ultrasound.
In the pancreato-biliary field, ERCP is performed
for more than 1000 cases each year. The number ofpatients treated for choledocholithiasis withendoscopic papillary balloon dilation method exceeds
1,000, which is possibly the largest in the world.
Endoscpic metallic stenting is an effective palliative
care for malignant obstructive jaundice (60 patients ayear). Covered metallic stent placement has been
performed in a total of 800 cases, which may be theworld’s largest number. Pancreatic interventions suchas pancreatic stenting, cystic drainage, endoscopic
stone extraction and lithotripsy using ESWL
(extracorporeal shock-wave lithotripsy) are performed
for many challenging cases. Also we have applied the
EUS-guided techniques to various clinical treatments.
In the gastrointestinal field, ESD (endoscopic
submucosal dissection) is performed as a curativeendoscopic treatment for neoplasms in esophagus,
stomach or colon (200 patients a year). Endoscopic
variceal ligations for esophageal varices (80 patients ayear) are also frequently done. As a big breakthroughin this field, double-balloon endoscopy and capsuleendoscopy have been introduced recently, whichenabled the examination of whole small intestines. All
those interventions are performed by the members ofthe department, specially trained for each technique.
In addition, for the management strategy against
inoperative malignancies, we effectively combine theinterventional treatments with various chemotherapy
regimens using new molecular-targeting drugs.
On outpatient basis, ultrasonography is
performed on 15,000 patients, gastroduodenalendoscopy on 8,200, and colonoscopy on 4,200
patients each year, leading the detection of about 240
cases of gastric cancer and 250 cases of colorectal
cancer annually. About 40 % 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

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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.

2.

Research Activities
Both basic and clinical researchers are equallyencouraged, on condition that the results may
eventually contribute to the cure of gastroenterological disorders. The themes of our recent basic
researches include molecular elucidation ofcarcinogenesis 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 for evidencebased medicine are highly appreciated. Recent studies
include radiofrequency ablation for liver metastasis ofcolorectal cancer, impact of metabolic factors inhepatocarcinogenesis. We have also 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 pancreaticand bile duct cancers, gemcitabine alone or combinedwith cisplatin, additional mosapride in therapy ofgastro-esophageal reflux disease, and investigationand treatment trial of the small intestinal lesions in
NSAID users by capsule endoscopy.
The department is dedicated to pursuing bettermedical services from all facets of the subspecialty ofgastroenterology, which is brought about by bothbasic and clinical researches.

3.

4.

5.

6.

7.

References
8.
1.

Goto T, Yoshida H, Tateishi R, Enooku K, Goto E,
Sato T, Ohki T, Masuzaki R, Imamura J, Shiina S,
Koike K, Omata M. Influence of serum HBVDNA load on recurrence of hepatocellular
carcinoma after treatment with percutaneousradiofrequency ablation. Hepatol Int 2011;5(3):767-773.

Yamamichi N, Shimamoto T, Minatsuki C,
Yoshida Y, Fujishiro M, Kodashima S, Kato J,
Goto O, Ono S, Niimi K, Takahashi Y,
Konno-Shimizu M, Ichinose M, Koike K.
Postprandial fullness correlates with rapid inflow
of gastric content into duodenum but not withchronic gastritis. BMC Gastroenterol 2011 Dec
21;11(1):140.
Kogure H, Tsujino T, Yamamoto K, Mizuno S,
Yashima Y, Yagioka H, Kawakubo K, Sasaki T,
Nakai Y, Hirano K, Sasahira N, Isayama H, Tada
M, Kawabe T, Omata M, Harada S, Ota Y, Koike
K. Fever-based antibiotic therapy for acutecholangitis following successful endoscopic
biliary drainage. J Gastroenterol 2011;46(12):1411-1417.
Tsujino T, Ito Y, Yoshida H, Ikushima S,
Takemura T, Nakata R, Koike K. Duodenal massin a patient with weight loss and liver
dysfunction. Gut 2011;60(12):1659-1660.
Hirano K, Tada M, Mizuno S, Isayama H,
Takahara N, Nagano R, Hamada T, Miyabayashi
K, Ito Y, Mohri D, Kawakubo K, Sasaki T,
Kogure H, Yamamoto N, Sasahira N, Yamashiki
N, Sugawara Y, Kokudo N, Toda N, Koike K.
Lower incidence of biliary carcinoma in patientswith primary sclerosing cholangitis and highserum levels of immunoglobulin E. Clin
Gastroenterol Hepatol 2012;10(1):79-83.
Ishizaka N, Sakamoto A, Fujishiro M, Nagai R,
Koike K. Gastrointestinal malignancies andcardiovascular diseases-Non-negligible comorbidity in an era of multi-antithrombotic drug use.
J Cardiol 2011;58:199-207.
Taguwa S, Kambara H, Fujita N, Noda T,
Yoshimori T, Koike K, Moriishi K, Matsuura Y.
Dysfunction of autophagy participates in vacuole
formation and cell death in cells replicating
hepatitis C virus. J Virol 2011;85:13185-13194.
Kudo Y, Tanaka Y, Tateishi K, Yamamoto K,
Yamamoto S, Mohri D, Isomura Y, Seto M,
Nakagawa H, Asaoka Y, Tada M, Ohta M, Ijichi
H, Hirata Y, Otsuka M, Ikenoue T, Maeda S,
Shiina S, Yoshida H, Nakajima O, Kanai F,
Omata M, Koike K. Altered composition of fatty
acids exacerbates hepatotumorigenesis during
activation of the phosphatidylinositol 3-kinase

133

9.

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pathway. J Hepatol 2011;55(6):1400-1408.
Ishizaka N, Hongo M, Sakamoto A, Saito K,
Furuta K, Koike K. Liver lipid content is reduced
in rat given 7-day administration of angiotensin
II. J Renin Angiotensin Aldosterone Syst
2011;12(4):462-468.
Bertot LC, Sato M, Tateishi R, Yoshida H, Koike
K. Mortality and complication rates of
percutaneous ablative techniques for thetreatment of liver tumors: a systematic review.
Eur Radiol 2011;21(12):2584-2596.
Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Yoshida H, Aoki T, Hasegawa K, Akahane M,
Ohtomo K, Fukayama M, Koike K, Kokudo N.
Diagnostic accuracy of α-fetoprotein anddes-γ-carboxy prothrombin in screening forhepatocellular carcinoma in liver transplantcandidates. Hepatol Res 2011;41(12):1199-1207.
Fujinaga H, Tsutsumi T, Yotsuyanagi H, Moriya
K, Koike K. Hepatocarcinogenesis in hepatitis C:
HCV shrewdly exacerbates oxidative stress bymodulating both production and scavenging ofreactive oxygen species. Oncology 2011;81
Suppl 1:11-7. Epub 2011 Dec 22.
Yashima Y, Isayama H, Tsujino T, Nagano R,
Yamamoto K, Mizuno S, Yagioka H, Kawakubo
K, Sasaki T, Kogure H, Nakai Y, Hirano K,
Sasahira N, Tada M, Kawabe T, Koike K, Omata
M. A large volume of visceral adipose tissue
leads to severe acute pancreatitis. J Gastroenterol
2011;46(10):1213-1218.
Ikeda H, Tateishi R, Enooku K, Yoshida H,
Nakagawa H, Masuzaki R, Kondo Y, Goto T,
Shiina S, Kume Y, Tomiya T, Inoue Y, Nishikawa
T, Ohtomo N, Tanoue Y, Ono T, Koike K, Yatomi
Y. Prediction of hepatocellular carcinoma
development by plasma ADAMTS13 in chronic
hepatitis B and C. Cancer Epidemiol Biomarkers
Prev 2011; 20(10):2204-2211.
Sasaki T, Isayama H, Nakai Y, Mizuno S,
Yamamoto K, Yagioka H, Yashima Y, Kawakubo
K, Kogure H, Togawa O, Matsubara S, Sasahira
N, Hirano K, Tsujino T, Tada M, Omata M, Koike
K. Feasibility study of gemcitabine and cisplatin
combination chemotherapy for patients withrefractory biliary tract cancer. Invest New Drugs
2011;29(6):1488-93.

16. Nakata W, Hayakawa Y, Nakagawa H, Sakamoto
K, Kinoshita H, Takahashi R, Hirata Y, Maeda S,
Koike K. Anti-tumor activity of the proteasome
inhibitor bortezomib in gastric cancer. Int J Oncol
2011;39(6):1529-1536.
17. Ijichi H, Chytil A, Gorska AE, Aakre ME, Bierie
B, Tada M, Mohri D, Miyabayashi K, Asaoka Y,
Maeda S, Ikenoue T, Tateishi K, Wright CV,
Koike K, Omata M, Moses HL. Inhibiting Cxcr2
disrupts tumor-stromal interactions and improves
survival in a mouse model of pancreatic ductal
adenocarcinoma. J Clin Invest 2011;121(10):4106-4117.
18. Nakai Y, Isayama H, Tsujino T, Sasahira N,
Hirano K, Kogure H, Sasaki T, Kawakubo K,
Yagioka H, Yashima Y, Mizuno S, Yamamto K,
Arizumi T, Togawa O, Matsubara S, Yamamoto N,
Tada M, Omata M, Koike K. Impact ofIntroduction of Wire-guided Cannulation in
Therapeutic Biliary ERCP. J Gastroenterol
Hepatol 2011;26(10):1552-1558.
19. Sakitani K, Hirata Y, Watabe H, Yamada A,
Sugimoto T, Yamaji Y, Yoshida H, Maeda S,
Omata M, Koike K. Gastric cancer risk according
to the distribution of intestinal metaplasia andneutrophil infiltration. J Gastroenterol Hepatol
2011;26(10):1570-1575.
20. Watanabe S, Enomoto N, Koike K, Izumi N,
Takikawa H, Hashimoto E, Moriyasu F, Kumada
H, Imawari M; PERFECT Study Group. Cancer
preventive effect of pegylated interferon α-2b
plus ribavirin in a real-life clinical setting inJapan: PERFECT interim analysis. Hepatol Res
2011;41(10):955-964.
21. Otsuka M, Takata A, Yoshikawa T, Kojima K,
Kishikawa T, Shibata C, Takekawa M, Yoshida H,
Omata M, Koike K. Receptor for ActivatedProtein Kinase C: Requirement for Efficient
MicroRNA Function and Reduced Expression in
Hepatocellular Carcinoma. PLoS One. 2011;
6(9):e24359. Epub 2011 Sep 15. PubMed PMID:
21935400.
22. Hamada T, Tsujino T, Sasahira N, Kogure H,
Isayama H, Hirano K, Yamamoto N, Tada M,
Koike K. Percutaneous transhepatic cholangioscopy with an ultraslim video upper
endoscope with CO(2) insufflation: a feasibility

134

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study. Gastrointest Endosc 2011;74(3):696-699.
Ono S, Fujishiro M, Kanzaki H, Uedo N, Yokoi C,
Akiyama J, Sugawara M, Oda I, Suzuki S, Fujita
Y, Tsubata S, Hirano M, Fukuzawa M, Kataoka
M, Kamoshida T, Hirai S, Sumiyoshi T, Kondo H,
Yamamoto Y, Okada K, Morita Y, Fujiwara S,
Morishita S, Matsumoto M, Koike K. Conflicting
clinical environment about the management ofantithrombotic agents during the periendoscopic
period in Japan. J Gastroenterol Hepatol 2011;26(9):1434-1440.
Kawakubo K, Isayama H, Nakai Y, Togawa O,
Sasahira N, Kogure H, Sasaki T, Matsubara S,
Yamamoto N, Hirano K, Tsujino T, Toda N, Tada
M, Omata M, Koike K. Efficacy and safety ofcovered self-expandable metal stents for
management of distal malignant biliary
obstruction due to lymph node metastases. Surg
Endosc 2011;25(9):3094-3100.
Uchino K, Tateishi R, Shiina S, Kanda M,
Masuzaki R, Kondo Y, Goto T, Omata M,
Yoshida H, Koike K. Hepatocellular carcinoma
with extrahepatic metastasis: Clinical featuresand prognostic factors. Cancer 2011;117(19):4475-4483.
Hamada T, Isayama H, Nakai Y, Togawa O,
Kogure H, Kawakubo K, Tsujino T, Sasahira N,
Hirano K, Yamamoto N, Arizumi T, Ito Y,
Matsubara S, Sasaki T, Yagioka H, Yashima Y,
Mohri D, Miyabayashi K, Mizuno S, Nagano R,
Takahara N, Toda N, Tada M, Omata M, Koike K.
Duodenal invasion is a risk factor for the earlydysfunction of biliary metal stents in unresectablepancreatic cancer. Gastrointest Endosc 2011;
74(3):696-699.
Miyamoto H, Miura T, Isayama H, Masuzaki R,
Koike K, Ohe T. Stiffness of the first annularpulley in normal and trigger fingers. J Hand Surg
Am 2011:36;1486-1491.
Hamada T, Nakai Y, Matsubara S, Isayama H,
Narita A, Watanabe K, Koike Y, Matsukawa S,
Kawase T, Koike K. Anchor-wire technique formultiple plastic biliary stents to prevent stentdislocation. World J Gastroenterol. 2011;17(28):3366-3368. PubMed PMID: 21876627.
Takata A, Otsuka M, Kojima K, Yoshikawa T,
Kishikawa T, Yoshida H, Koike K. MicroRNA-22

30.

31.

32.

33.

34.

35.

36.

and microRNA-140 suppress NF-κB activity by
regulating the expression of NF-κB coactivators.
Biochem Biophys Res Commun 2011;411(4):826-831.
Kurano M, Iso-O N, Hara M, Ishizaka N, Moriya
K, Koike K, Tsukamoto K. LXR agonist
increases apoE secretion from HepG2 spheroid,
together with an increased production of VLDL
and apoE-rich large HDL. Lipids Health Dis
2011;10(1):134.
Kawakubo K, Tada M, Isayama H, Sasahira N,
Nakai Y, Yamamoto K, Kogure H, Sasaki T,
Hirano K, Ijichi H, Tateishi K, Yoshida H, Koike
K. Incidence of extrapancreatic malignancies inpatients with intraductal papillary mucinous
neoplasms of the pancreas. Gut 2011;60(9):1249-1253.
Gonoi W, Akai H, Hagiwara K, Akahane M,
Hayashi N, Maeda E, Yoshikawa T, Tada M, Uno
K, Ohtsu H, Koike K, Ohtomo K. Pancreas
divisum as a predisposing factor for chronic andrecurrent idiopathic pancreatitis: initial in vivo
survey. Gut 2011;60(8):1103-1108.
Goto O, Mitsui T, Fujishiro M, Wada I, Shimizu
N, Seto Y, Koike K. New method of endoscopic
full-thickness resection: a pilot study of
non-exposed endoscopic wall-inversion surgery
in an ex vivo porcine model. Gastric Cancer
2011;14(2):183-187.
Wakita T, Suzuki T, Evans MJ, Shimotohno K,
Chayama K, Matsuura Y, Hijikata M, Moriishi K,
Seya T, Enomoto N, Koike K, Kato N, Kanto T,
Hotta H. Will There Be an HCV Meeting in
2020? Summary of the 17th International
Meeting on Hepatitis C Virus and Related Viruses.
Gastroenterology 2011 Jul;141(1):e1-5.
Isayama H, Nakai Y, Kawakubo K, Kogure H,
Togawa O, Hamada T, Ito Y, Sasaki T, Yamamoto
N, Sasahira N, Hirano K, Tsujino T, Tada M,
Koike K. Covered metallic stenting for malignant
distal biliary obstruction: clinical results
according to stent type. J Hepatobiliary Pancreat
Sci 2011;18(5):673-677.
Kojima K, Takata A, Vadnais C, Otsuka M,
Yoshikawa T, Akanuma M, Kondo Y, Kang YJ,
Kishikawa T, Kato N, Xie Z, Zhang WJ, Yoshida
H, Omata M, Nepveu A, Koike K. MicroRNA122

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is a key regulator of α-fetoprotein expression andbiologically aggressive behavior of hepatocellular carcinoma. Nat Commun 2011 Jun 7;2:
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21654638.
Isayama H, Nakai Y, Yamamoto K, Sasaki T,
Mizuno S, Yagioka H, Yashima Y, Kawakubo K,
Kogure H, Arizumi T, Togawa O, Ito Y,
Matsubara S, Yamamoto N, Sasahira N, Hirano K,
Tsujino T, Tada M, Omata M, Koike K.
Gemcitabine and oxaliplatin combination chemotherapy for patients with refractory pancreaticcancer. Oncology 2011;80(1-2):97-101.
Hirano K, Tada M, Isayama H, Sasahira N, Koike
K. Significance of measuring igg and igg4 duringfollow-up of autoimmune pancreatitis. Pancreas
2011;40(5):788-791.
Isayama H, Nakai Y, Tsujino T, Togawa O,
Kogure H, Koike K. Covered biliary metal stent:
which are worse-the concepts, current models, orinsertion methods? Gastrointest Endosc 2011;
73(6):1329-1330.
Tsukada K, Sugawara Y, Kaneko J, Tamura S,
Tachikawa N, Morisawa Y, Okugawa S, Kikuchi
Y, Oka S, Kimura S, Yatomi Y, Makuuchi M,
Kokudo N, Koike K. Living donor livertransplantations in HIV- and hepatitis C viruscoinfected hemophiliacs: Experience in a Single
Center. Transplantation 2011;91(11):1261-1264.
Koshiyama A, Ichibangase T, Moriya K, Koike K,
Yazawa I, Imai K. Liquid chromatographic
separation of proteins derivatized with afluorogenic reagent at cysteinyl residues on a
non-porous column for differential proteomics
analysis. J Chromatogr A 2011;1218(22):34473452.
Nakai Y, Ikeda H, Nakamura K, Kume Y,
Fujishiro M, Sasahira N, Hirano K, Isayama H,
Tada M, Kawabe T, Komatsu Y, Omata M, Aoki J,
Koike K, Yatomi Y. Specific increase in serum
autotaxin activity in patients with pancreaticcancer. Clin Biochem 2011;44(8-9):576-581.
Kumar V, Kato N, Urabe Y, Takahashi A,
Muroyama R, Hosono N, Otuska M, Tateishi R,
Omata M, Nakagawa H, Koike K, Kamatani N,
Kubo M, Nakamura Y, Matsuda K. Genome-wide
association study identifies a susceptibility locus

44.

45.

46.

47.

48.

49.

for HCV-induced hepatocellular carcinoma. Nat
Genet 2011;43(5):455-458.
Tada M, Nakai Y, Sasaki T, Hamada T, Nagano R,
Mohri D, Miyabayashi K, Yamamoto K, Kogure
H, Kawakubo K, Ito Y, Yamamoto N, Sasahira N,
Hirano K, Ijichi H, Tateishi K, Isayama H, Omata
M, Koike K. Recent progress and limitations ofchemotherapy for pancreatic and biliary tract
cancers. World J Clin Oncol 2011;2(3):158-163.
Nakagawa H, Ikeda H, Nakamura K, Ohkawa R,
Masuzaki R, Tateishi R, Yoshida H, Watanabe N,
Tejima K, Kume Y, Iwai T, Suzuki A, Tomiya T,
Inoue Y, Nishikawa T, Ohtomo N, Tanoue Y,
Omata M, Igarashi K, Aoki J, Koike K, Yatomi Y.
Autotaxin as a novel serum marker of liver
fibrosis. Clin Chim Acta 2011;412(13-14):
1201-1206.
Kershenobich K, Razavi HA, Cooper CL, Alberti
A, Dusheiko GM, Pol S, Zuckerman E, Koike K,
Han K-H, Wallace CM, Zeuzem S, Negro F. The
global health burden of hepatitis C virus infection.
Liver Int 31(S2):4-17, 2011.
Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed
EA, AlOmair A, Amarapurkar D, Chen C-H, Dou
X, El Khayat H, elShazly M, Esmat G, Guan R,
Han K-H, Koike K, Largen A, McCaughan G,
Mogawer S, Monis A, Nawaz A, Piratvisuth T,
Sanai FM, Sharara AI, Sibbel S, Sood A, Suh DJ,
Wallace C, Young K, Negro F. A systematic
review of hepatitis C virus epidemiology in Asia,
Australia and Egypt. Liver Int 31(S2):61-80,
2011.
Yasui K, Hashimoto E, Komorizono Y, Koike K,
Arii S, Imai Y, Shima T, Kanbara Y, Saibara T,
Mori T, Kawata S, Uto H, Takami S, Sumida Y,
Takamura T, Kawanaka M, Okanoue T; The
Japan NASH Study Group, The Ministry of
Health, Labour and Welfare of Japan.
Characteristics of patients with nonalcoholicsteatohepatitis who develop hepatocellular
carcinoma. Clin Gastroenterol Hepatol 2011;
9(5):428-433.
Sasaki T, Isayama H, Nakai Y, Togawa O, Kogure
H, Ito Y, Yamamoto K, Mizuno S, Yagioka H,
Yashima Y, Kawakubo K, Arizumi T, Matsubara
S, Sasahira N, Hirano K, Tsujino T, Toda N, Tada
M, Omata M, Koike K. Prognostic factors in

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50.

51.

52.

53.

54.

55.

56.

patients with advanced biliary tract cancer
receiving chemotherapy. Cancer ChemotherPharmacol 2011;67(4):847-853.
Masuzaki R, Shiina S, Tateishi R, Yoshida H,
Goto E, Sugioka Y, Kondo Y, Goto T, Ikeda H,
Omata M, Koike K. Utility of contrast enhanced
ultrasonography with sonazoid in radiofrequency
ablation for hepatocellular carcinoma. J
Gastroenterol Hepatol 2011;26(4):759-764.
Kawakubo K, Isayama H, Sasahira N, Nakai Y,
Kogure H, Sasaki T, Hirano K, Tada M, Koike K.
Endoscopic transpapillary gallbladder drainage
with replacement of a covered self-expandable
metal stent. World J Gastrointest Endosc
2011;3:46-48.
Miyoshi H, Moriya K, Tsutsumi T, Shinzawa S,
Fujie H, Shintani Y, Fujinaga H, Goto K,
Todoroki T, Suzuki T, Miyamura T, Matsuura Y,
Yotsuyanagi H, Koike K. Pathogenesis of lipid
metabolism disorder in hepatitis C: polyunsaturated fatty acids counteract lipid alterations
induced by the core protein. J Hepatol 2011;
54:432-438.
Hayakawa Y, Hirata Y, Nakagawa H, Sakamoto K,
Hikiba Y, Kinoshita H, Nakata W, Takahashi R,
Tateishi K, Tada M, Akanuma M, Yoshida H,
Takeda K, Ichijo H, Omata M, Maeda S, Koike K.
Apoptosis signal-regulating kinase 1 and cyclin
D1 compose a positive feedback loop
contributing to tumor growth in gastric cancer.
Proc Natl Acad Sci USA 2011;108:780-785.
Kondo Y, Shiina S, Tateishi R, Arano T, Uchino
K, Enooku K, Goto E, Nakagawa H, Masuzaki R,
Asaoka Y, Fujie H, Goto T, Omata M, Yoshida H,
Koike K. Intrahepatic bile duct dilatation after
percutaneous radiofrequency ablation forhepatocellular carcinoma: impact on patient's
prognosis. Liver Int 2011;31:197-205.
Kogure H, Isayama H, Nakai Y, Tsujino T, Ito Y,
Yamamoto K, Mizuno S, Yagioka H, Kawakubo
K, Sasaki T, Hirano K, Sasahira N, Tada M,
Omata M, Koike K. Newly designed large cell
Niti-S stent for malignant hilar biliary
obstruction: a pilot study. Surg Endosc 2011;25:
463-467.
Isayama H, Kogure H, Koike K. Endoscopictransgastric pure NOTES cholecystectomy withnaso-gallbladder drainage tube placement andinjection of a hyaluronic acid mixture (withVideo). J Hepatobiliary Pancreat Sci 2011;18:
106-111.
57. Nakai Y, Isayama H, Togawa O, Kogure H,
Tsujino T, Yagioka H, Yashima Y, Sasaki T, Ito Y,
Matsubara S, Hirano K, Sasahira N, Toda N, Tada
M, Kawabe T, Omata M, Koike K. New methodof covered wallstents for distal malignant biliary
obstruction to reduce early stent-related
complications based on characteristics. Dig
Endosc 2011;23:49-55.
58. Ono S, Fujishiro M, Kodashima S, Minatsuki C,
Hirano K, Niimi K, Goto O, Yamamichi N, Koike
K. Controversy on the management of
anticoagulants and antiplatelet agents forscheduled endoscopy. Dig Endosc 2011;23:1-4.

Internal Medicine
2. Medicine Ⅱ138

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

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

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

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

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

Norio Hanafusa, M.D., Ph.D.

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

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

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

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

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

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

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

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

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

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

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

Homepage

http://www.todai-jinnai.com

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

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. We have a clinical conference to discuss thediagnosis and treatment of our patients with all
members of the staff. Particularly difficult cases arefurther discussed with guest specialists from outside.
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

139

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 mineral metabolism.

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. Our department also
participates in Metabolism Research Course foreducating young clinical researchers and fellows incollaboration with Department of Diabetes andMetabolic Diseases, Department of Cardiology, andDepartment of Geriatric Medicine.

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.
1. Investigation of mechanism and development oftreatment of chronic kidney diseases: from theviewpoints of hypoxia, oxidative stress,

epigenetics, carbonyl stress and endoplasmic
reticulum stress.
2. Epigenetic mechanism for progression of renal
impairment.
3. Development of new treatment for anti-neutrophil
cytoplasmic antibody-related vasculitis.
4. Epigenetic mechanism of salt-sensitive hypertension.
5. Rac1 GTPase and mineralocorticoid receptor insalt-sensitive hypertension.
6. Roles of renal proximal tubule transport in theregulation of plasma volume and blood pressure.
7. Physiological and pathological significance of
Na-HCO3 cotransporter NBCe1.
8. Investigation on pathogenesis of disorders ofmineral and bone metabolism
9. Molecular mechanism of G protein-coupled
receptor-mediated signal transduction
10. Development of a new drug and strategy targeting
G protein-coupled receptor.

Department of Hemodialysis &Apheresis
Introduction and Organization
Hemodialysis and related blood purification
therapy had been individually performed in theirrespective 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 and started operations in Fall of
2006.
This new Center for Hemodialysis is equipped with
one pressure control unit in addition to 12 hemodialysis machines under a state-of-the-art hemodialysis control system. Our concept of a hemodialysis
controlling system is a hub to transfer all digital andanalog data from patients and to monitor machines,
including blood purification machines, to the hostcomputer in our hospital, centralizing all data andadministering 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 se-140cure patients’ safety while avoiding human error
and increasing the overall educational quality ofstaff members.

2.
3.

Clinical activities
1.
2.

3.
4.

5.
6.
7.

Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasma exchange for neurodegenerative diseases, SLE, TTP, TMA, and pre/post-livertransplant patients.
DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
LDL apheresis for nephrotic syndrome and
ASO patients.
White blood cell elimination therapy for ulcerative colitis and rheumatological arthritis.

Education
1.

2.
3.
4.
5.

6.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course
to second year residents on request.
Our
state-of-the-art
blood
purification
protocols are summarized in Japanese
handbook in 2010 [Apheresis Pocket Manual]and 2011 [CRRT Pocket Manual].
Our department takes main part in Critical Care
Nephrology Course for educating young
clinical researchers and fellows in collaboration with Department of Critical Care
Medicine.

Research
1.

Prognostic analysis for post-liver transplant

4.
5.
6.
7.
8.

patients received plasma exchange therapy.
Development and application of a non-invasive
pulse hemoglobin meter.
Genome wide association study for Nephrotic
syndrome and those functional analyses.
Elucidation of basic mechanisms in cardio-renal syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
AKI biomarkers and those clinical significancein ICU/CCU.
Renal biomarker to determine clinical action
ability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country [JICA-JST: Science andTechnology Research Partnership for Sustainable Development; SATREPS].

Publications(1) Shibata S, Mu S, Kawarazaki H, Muraoka K,
Ishizawa K, Yoshida S, Kawarazaki W, Takeuchi
M, Ayuzawa N, Miyoshi J, Takai Y, Ishikawa A,
Shimosawa T, Ando K, Nagase M, Fujita T.Rac1
GTPase in rodent kidneys is essential for saltsensitive hypertension via a mineralocorticoid
receptor-dependent pathway. J Clin Invest. 2011;
121(8):3233-43.
(2) Mu S, Shimosawa T, Ogura S, Wang H, Uetake
Y, Kawakami-Mori F, Marumo T, Yatomi Y,
Geller DS, Tanaka H, Fujita T Epigenetic
modulation of the renal β-adrenergic-WNK4
pathway in salt-sensitive hypertension. Nat Med.
2011 May;17(5):573-80.
(3) Hanamura K, Tojo A, Kinugasa S, Asaba K,
Onozato ML, Uozaki H, Fukayama M, Fujita T.
Detection of myeloperoxidase in membranous
nephropathy-like deposits in patients with
anti-neutrophil cytoplasmic antibody-associatedglomerulonephritis. Human Pathology 2011;
42:649-58.
(4) Kinugasa S, Tojo A, Sakai T, Tsumura H,
Takahashi M, Hirata Y. Fujita T. Selective
albuminuria via podocyte albumin transport inpuromycin nephrotic rats is attenuated by an
inhibitor of NADPH oxidase. Kidney Int 2011;
80: 1328–38.

141(5) Lo Y, BS, Yang S, Seki G, Yamada H, Horita S,
Yamazaki O, Fujita T, MD, Usui T, Tsai J, Yu I,
PhD6, Lin S, Lin S: Severe Metabolic Acidosis
Causes Early Lethality in NBC1 W516X
Knock-in Mice as a Model of Human Isolated
Proximal Renal Tubular Acidosis. Kidney Int
2011;79:730–41(6) Yamada H, Horita S, Suzuki M, Fujita F, Seki G:
Functional role of a putative carbonic anhydrase
II-binding
domainintheelectrogenic
Na+-HCO3− cotransporter NBCe1 expressed in
Xenopus oocytes. Channels 2011;5:2:1-4(7) Yamazaki O, Yamada H, Suzuki M, Horita S,
Shirai A, Nakamura M, Seki G, Fujita T:
Functional characterization of nonsynonymous
single nucleotide polymorphisms in theelectrogenic Na+-HCO3- cotransporter NBCe1A.
Pflugers Arch 2011;461: 249-59(8) YongD, Li Q, So I, Huang CL, Ando H, Mizutani
A, Seki G, Mikoshiba K, Thomas PJ, Muallem S:
IRBIT governs murine epithelial secretion byantagonizing the function of the WNK/SPAK
kinases pathway. J Clin Invest 2011;121: 956-65(9) Tanaka M, Seki G, Someya T, Nagata M, Fujita
T: Aberrantly glycosylated IgA1 as a factor in thepathogenesis of IgA nephropathy. Clin Dev
Immunol 2011;2011:470803.
(10) Horita S, Seki G, Yamada H, Suzuki M, Koike K,
Fujita T: Insulin resistance, obesity, hypertension
and renal sodium transport. Int J Hypertension
Volume 2011; 2011:391762(11) Endo Y, Suzuki M, Yamada H, Horita S, Kunimi
M, Yamazaki O, Shirai A, Nakamura M, Iso-O N,
Li Y, Hara M, Tsukamoto K, Moriyama N, Kudo
A, Kawakami H, Yamauchi T, Kubota N,
Kadowaki T, Kume H, Enomoto Y, Homma Y,
Seki G, Fujita T: Thiazolidinediones enhancesodium-coupled bicarbonate absorption fromrenal proximal tubules via PPARγ-dependent
non-genomic signaling. Cell Metab 2011;13:
550-61(12) Seki G, Yamada H, Horita S, Suzuki M,
Yamazaki O, Van Paesschen W, Yang S, Lin S:
Physiological and pathophysiological roles of theelectrogenic Na+-HCO3- cotransporter NBCe1.
Open Journal of Molecular and Integrative
Physiology 2011; 1: 9-16

(13) Ikeda Y, Inagi R, Miyata T, Nagai R, Arai M,
Miyashita M, Itokawa M, Fujita T, Nangaku M.
Glyoxalase I retards renal senescence. Am J
Pathol 2011;179: 2810-21(14) Chiang CK, Tanaka T, Inagi R, Fujita T, Nangaku
M. Indoxyl sulfate, a representative uremic toxin,
suppresses erythropoietin production in a
HIF-dependent manner. Lab Invest 2011;91:
1564-71(15) Nishi H, Inagi R, Kawada N, Yoshizato K,
Mimura I, Fujita T, Nangaku M. Cytoglobin, anovel member of the globin family, protects
kidney fibroblasts against oxidative stress underischemic conditions. Am J Pathol 2011;178:
128-39(16) Tanaka T, Nangaku M, Nishiyama A: The role ofincretins and salt-sensitive hypertension; apotential role for DPP-IV inhibitors. Curr Opin
Nephrol Hypretens 2011;20: 476-81(17) Mimura I, Tanaka T, Wada Y, Kodama T,
Nangaku M. Epigenetic regulation for hypoxic
response via HIF and histone demethylase. J
Pharmacol Sci 2011;115: 453-8(18) Tanaka T, Nangaku M: Pathogenesis of tubularinterstitial nephritis. Contrib Nephrol 2011;169:
297-310(19) Nangaku M, Akizawa T: Diary of a Japanesenephrologist during the present disaster: Part II.
Kidney Int 2011;80:3-5(20) Nangaku M, Akizawa T: Diary of a Japanesenephrologist during the present disaster. Kidney
Int 2011;79:1037-39(21) Nangaku M, Nishiyama A: Frontiers in Research:
Chronic Kidney Disease Introduction: hearing
footsteps of the future. Clin Exp Pharmacol
Physiol 2011;38:388-90(22) Edited by Toshio Miyata, Kai-Uwe Eckardt, andMasaomi Nangaku：Oxidative Stress in Applied
Basic Research and Clinical Practice: Studies on
Renal Disorders. The Humana Press / Springer
Science 2011(23) Aono Y, Hasegawa H, Yamazaki Y, Shimada T,
Fujita T, Yamashita T, Fukumoto S: Anti-FGF23
neutralizing antibodies ameliorate muscle
weakness and decreased spontaneous movementof Hyp mice. J Bone Miner Res 2011;26:803-10(24) Kawarazaki H, Shibagaki Y, Fukumoto S, Kido R,

142

Ando K, Nakajima I, Fuchinoue S, Fujita T,
Fukagawa M, Teraoka S: Natural history ofmineral and bone disorders after living-donor
kidney transplantation: a one-year prospective
observational
study.
Ther
Apher
Dial
2011;15:481-87(25) Kawarazaki H, Shibagaki Y, Fukumoto S, Kido R,
Nakajima I, Fuchinoue S, Fujita T, Fukagawa M,
Teraoka S: The relative role of fibroblast growth
factor 23 and parathyroid hormone in predicting
future hypophosphatemia and hypercalcemia
after living donor kidney transplantation: a
1-year prospective observational study. Nephrol
Dial Transplant 2011;26:2691-95(26) Saito T, Shimizu Y, Hori M, Taguchi M, IgarashiT, Fukumoto S, Fujita T: A patient withhypophosphatemic rickets and ossification ofposterior longitudinal ligament caused by a novel
homozygous mutation in ENPP1 gene. Bone
2011;49:913-16(27) Fukumoto S, Shimizu Y: Fibroblast growth factor
23 as a phosphotropic hormone and beyond. J
Bone Miner Metab 2011;29:507-14(28) Hori M, Shimizu Y, Fukumoto S: Minireview:
Fibroblast growth factor 23 in phosphatehomeostasis
andbonemetabolism.
Endocrinology 2011;152:4-10(29) Makita N, Isojima T, Hiwatari M, Kitanaka S, Ida
K and Iiri T. Painful Thyroiditis and Subacute
Atrophic Hypothyroidism after Cord Blood
Transfusion. Thyroid. 2011;21:1157-58(30) Honda K, Okamoto K, Mochida Y, Ishioka K,
Oka M, Maesato K, Ikee R, Moriya H, Hidaka S,
Ohtake T, Doi K, Fujita T, Kobayashi S, Noiri E:
A novel mechanism in maggot debridement
therapy: protease in excretion/secretion promotes
hepatocyte growth factor production. Am J
Physiol Cell Physiol 2011;301:C1423-30(31) Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki
H, Katoh T, Watanabe T, Nishida N, Mabuchi A,
Takahashi A, Kubo M, Maeda S, Nakamura E,
Noiri E: Common variation in GPC5 is
associated with acquired nephrotic syndrome.
Nat Genet 2011;43:459-63(32) Doi K, Negishi K, Ishizu T, Katagiri D, Fujita T,
Matsubara T, Yahagi N, Sugaya T, Noiri E:
Evaluation of new acute kidney injury

biomarkers in mixed ICU. Crit Care Med ,2011;39: 2464-9(33) Doi K, Hamasaki Y, Noiri E, Nosaka K, Suzuki T,
Toda A, Shimizu T, Fujita T, Nakao A: Role ofleukotriene B4 in accelerated hyperlipidaemic
renal injury. Nephrology 2011;16:304-9(34) Ishii T, Ohtake T, Okamoto K, Mochida Y,
Ishioka K, Oka M, Maesato K, Ikee R, Moriya H,
Hidaka S, Doi K, Noiri E, Fujita T, Kobayashi S:
Serum biological antioxidant potential predicts
the prognosis of hemodialysis patients. Nephron
Clin Pract 117:c230-6, 2011(35) Doi K, Ishizu T, Fujita T, Noiri E: Lung injury
following acute kidney injury: kidney-lungcrosstalk. Clin Exp Nephrol 2011;15:464-70(36) Yamamoto T, Yasuno N, Katada S, Hisaka A,
Hanafusa N, Noiri E, Yahagi N, Fujita T, Suzuki
H: Proposal of a pharmacokinetically optimized
dosage regimen of antibiotics in patients
receiving
continuous
hemodiafiltration.
Antimicrob Agents Chemother 2011;55:5804-12

143

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

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

Lecturer
Toshimasa Yamauchi, M.D., Ph.D.

Specially Appointed Lecturer
Yoshihiko Takahashi, M.D., Ph.D.

Assistant Professor
Ryo Suzuki, M.D., Ph.D.,

Hideyuki Sakoda, M.D., PhD.,

Midori Fujishiro, M.D., Ph.D.,

Yoko Iizuka, M.D., Ph.D.,

Nobuhiro Shojima, M.D., Ph.D.,

Yukiko Okazaki, M.D., Ph.D.,

Yusuke Hada, M.D., Ph.D.,

Motoharu Awazawa, M.D., Ph.D.,

Yoshihiko Izumida, M.D., Ph.D.

URL 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 diabetes and metabolic
diseases from 3 former departments of Internal
Medicine were unified to the Department of Metabolic
Diseases. The Department of Diabetes and Metabolic
Diseases is one of the major divisions in the
Department of Internal Medicine at the University ofTokyo, and covers diabetes mellitus and metabolic
diseases including obesity and dyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003) and Dr.
Toshiro Fujita (2003) and current professor Dr.
Takashi Kadowaki (2003-present), we have been

providing a wide-ranged clinical, teaching andresearch activities. Currently, we hold 33 beds
mainly on the 12th floor of the North Wing Ward A
and the 4th floor of the Ward B of the University ofTokyo 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. Kazuo
Hara and Assistant Professor, Dr. Masato Iwabu),
Department of Translational Systems Biology andMedicine Initiative (Associate Professor, Dr. Naoto
Kubota and Assistant Professors, Dr. Iseki Takamoto
and Dr. Takayoshi Sasako), Functional Regulation of
Adipocytes (Associate Professor, Dr. Hironori Waki
and Assistant Professor, Dr. Nozomu Kamei),
Molecular Medicinal Sciences on Metabolic

144

Regulation (Associate Professor, Dr. Hiroaki Okazaki
and Assistant Professor, Dr. Miki Okada-Iwabu),
Department of Patient Safety & Risk Management(Assistant Professor, Dr. Kenji Harada), Division ofBiophysics, Center for Disease Biology andIntegrative Medicine (Lecturer, Dr. Noriko Takahashi),and Division for Health Service Promotion, The
University of Tokyo (Assistant Professor, Dr. Mikio
Takanashi). With all these staffs, we actively instruct
and teach the residents and medical school students;
annual evaluation of the teaching skill by the students
always rates our department within the three places of
the top. In addition, there are more than 20 students ofGraduate School in our division. With all these 70
members, we enthusiastically work on the research
activities, which lead to the outstanding contributionsin 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 6,500 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 more prevalent inJapan, and lead to complications including nephropathy, retinopathy, neuropathy and cardiovasculardiseases. Thus, in collaboration with other departments, we optimize the treatment of each patient.
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 thenovel therapeutics.
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

145

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 parallelwith information obtained by whole-genome analysis
of human patients. In particular, we are interested in
the physiological and pathophysiological functions ofadipokines secreted by adipocytes, including
adiponectin, and the signal transduction pathway of
adiponectin through the receptors, AdipoR1 andAdipoR2, that we discovered and characterized. In
addition, we have been successfully unraveling themolecular mechanisms of β cell proliferation. We
believe that these findings will lead to novel
therapeutic strategies for diabetes and the metabolic
syndrome.

4.

5.
2) 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. Utilizing theanimal models of lipid disorders and molecularbiological technique, we are analyzing the roles oflipid 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.

6.

References7.
1. Kadowaki, T. and Yamauchi, T. Adiponectin
receptor signaling: a new layer to the current model.
Cell Metab. 13, 123-124, 2011.
2. Ueki, K. and Kadowaki, T. The other sweet face of
XBP-1. Nat. Med. 17, 563-572, 2011.
3. Kubota, T., Kubota, N., Kumagai, H., Yamaguchi,
S., Kozono, H., Takahashi, T., Inoue, M., Itoh, S.,
Takamoto, I., Sasako, T, Kumagai, K., Kawai, T.,
Hashimoto, S., Kobayashi, T., Sato, M.,

Tokuyama, K., Nishimura, S., Tsunoda, M., Ide,
T., Murakami, K., Yamazaki, T., Ezaki, O.,
Kawamura, K., Masuda, H., Moroi, M., Sugi, K.,
Oike, Y., Shimokawa, H., Yanagihara, N., Tsutsui,M., Terauchi, Y., Tobe, K., Nagai, R., Kamata, K.,
Inoue, K., Kodama, T., Ueki, K., and Kadowaki,
T. Impaired insulin signaling in endothelial cells
reduces insulin-induced glucose uptake byskeletal muscle. Cell Metab. 13, 294-307, 2011.
Awazawa, M., Ueki, K., Inabe, K., Yamauchi, T.,
Kubota, N., Kaneko, K., Kobayashi, M., Iwane,
A., Sasako, T., Okazaki, Y., Ohsugi, M.,
Takamoto, I., Yamashita, S., Asahara, H., Akira,S., Kasuga, M., and Kadowaki, T. Adiponectinenhances insulin sensitivity by increasing hepatic
IRS-2 expression via a macrophage-derived
IL-6-dependent pathway. Cell Metab. 13, 401-412,
2011.
Kobayashi, N., Ueki, K., Okazaki, Y., Iwane, A.,
Kubota, N., Ohsugi, M., Awazawa, M.,
Kobayashi, M., Sasako, T., Kaneko, K., Suzuki,
M., Nishikawa, Y., Hara, K., Yoshimura, K.,
Koshima, I., Goyama, S., Murakami, K., Sasaki,J., Nagai, R., Kurokawa, M., Sasaki, T., andKadowaki,T.
Blockade
of
class
IB
phosphoinositide-3 kinase ameliorates obesityinduced inflammation and insulin resistance. Proc.
Natl. Acad. Sci. U. S. A. 108, 5753-5758, 2011.
Waki, H., Nakamura, M., Yamauchi, T.,
Wakabayashi, K., Yu, J., Hirose-Yotsuya, L.,
Take, K., Sun, W., Iwabu, M., Okada-Iwabu, M.,
Fujita, T., Aoyama, T., Tsutsumi, S., Ueki, K.,
Kodama, T., Sakai, J., Aburatani, H., andKadowaki, T. Global mapping of cell typespecific open chromatin by FAIRE-seq reveals theregulatory role of the NFI family in adipocyte
differentiation. PLoS Genet. 7, e1002311, 2011.
Cho, Y.S., Chen, C.H., Hu, C., Long, J, Ong, R.T.,
Sim, X., Takeuchi, F., Wu, Y., Go, M.J.,
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R.C., Yamamoto, K., Adair, L.S., Aung, T., Cai,
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Kim, H.L., Kim, S., Kim, Y.J., Lee, J.J., Lee,
N.R., Li, Y., Liu, J.J., Lu, W., Nakamura, J.,
Nakashima, E., Ng, D.P., Tay, W.T., Tsai, F.J.,
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Hara, K., Cho, Y.M., Cho, N.H., Chang, T.J., Bao,Y., Hedman, Å.K., Morris, A.P., McCarthy, M.I.;
DIAGRAM Consortium; MuTHER Consortium,
Takayanagi, R., Park, K.S., Jia, W., Chuang, L.M.,
Chan, J.C., Maeda, S., Kadowaki, T., Lee, J.Y.,
Wu, J.Y., Teo, Y.Y., Tai, E.S., Shu, X.O., Mohlke,
K.L., Kato, N., Han, B.G., and Seielstad, M.
Meta-analysis of genome-wide association studies
identifies eight new loci for type 2 diabetes in east
Asians. Nat. Genet. 44, 67-72, 2011.
8. Endo, Y., Suzuki, M., Yamada, H., Horita, S.,
Kunimi, M., Yamazaki, O., Shirai, A., Nakamura,M., Iso-O, N., Li, Y., Hara, M., Tsukamoto, K.,
Moriyama, N., Kudo, A., Kawakami, H.,
Yamauchi, T., Kubota, N., Kadowaki, T., Kume,
H., Enomoto, Y., Homma, Y., Seki, G., and Fujita,
T. Thiazolidinediones enhance sodium-coupledbicarbonate absorption from renal proximal
tubules via PPARγ-dependent nongenomic
signaling. Cell Metab. 13, 550-561, 2011.
9. Mutoh, M., Teraoka, N., Takasu, S., Takahashi,M., Onuma, K., Yamamoto, M., Kubota, N., Iseki,T., Kadowaki, T., Sugimura, T., and Wakabayashi,
K. Loss of adiponectin promotes intestinal
carcinogenesis in Min and wild-type mice.
Gastroenterology 140, 2000-2008, 2011.
10. Nishimura, S., Manabe, I., Nagasaki, M., Kakuta,
S., Iwakura, Y., Takayama, N., Ooehara, J., Otsu,
M., Kamiya, A., Petrich, B.G., Urano, T., Kadono,T., Sato, S., Aiba, A., Yamashita, H., Sugiura, S.,
Kadowaki, T., Nakauchi, H., Eto, K., and Nagai,
R. In vivo imaging visualizes discoid platelet
aggregations without endothelium disruption andimplicates contribution of inflammatory cytokine
and integrin signaling. Blood 119, e45-56, 2011.
11. Kurokawa, J., Nagano, H., Ohara, O., Kubota, N.,
Kadowaki, T., Arai, S., and Miyazaki, T.
Apoptosis inhibitor of macrophage (AIM) is
required for obesity-associated recruitment ofinflammatory macrophages into adipose tissue.
Proc. Natl. Acad. Sci. U. S. A. 108, 12072-12077,
2011.
12. Grarup, N., Overvad, M., Sparsø, T., Witte, D.R.,
Pisinger, C., Jørgensen, T., Yamauchi, T., Hara,
K., Maeda, S., Kadowaki, T., Hansen, T., andPedersen, O. The diabetogenic VPS13C/
C2CD4A/C2CD4B rs7172432 variant impairs

glucose-stimulated insulin response in 5,722
non-diabetic Danish individuals. Diabetologia 54,
789-794, 2011.
13. Muraoka, T., Aoki, K., Iwasaki, T., Shinoda, K.,
Nakamura, A., Aburatani, H., Mori, S., Tokuyama,K., Kubota, N., Kadowaki, T., and Terauchi, Y.
Ezetimibe decreases SREBP-1c expression inliver and reverses hepatic insulin resistance inmice fed a high-fat diet. Metabolism 60, 617-628,
2011.
14. Sakoda, H., Ito, S., Kanda, H., Fujishiro, M.,
Osuga, J., Tsukamoto, K., Ueki, K., andKadowaki, T. Association between type 1
diabetes mellitus and remitting seronegative
symmetrical synovitis with pitting edema: a casereport. Diabetes Res. Clin. Pract. 91, e43-44,
2011.
15. Ohta, K., Sekiya, M., Uozaki, H., Igarashi, M.,
Takase, S., Kumagai, M., Takanashi, M.,
Takeuchi, Y., Izumida, Y., Kubota, M., Nishi, M.,
Okazaki, H., Iizuka, Y., Yahagi, N., Yagyu, H.,
Fukayama, M., Kadowaki, T., Ohashi, K.,
Ishibashi, S., and Osuga, J. Abrogation of neutralcholesterol ester hydrolytic activity causes
adrenal enlargement. Biochem. Biophys. Res.
Commun. 404, 254-260, 2011.
16. Kumagai, K., Kubota, N., Saito, T.I., Sasako, T.,
Takizawa, R., Sudo, K., Kurokawa, M., andKadowaki, T. Generation of transgenic mice on an
NOD/SCID background using the conventional
microinjection technique. Biol. Reprod. 84,
682-688, 2011.
17. Kawashima, D., Ohno, T., Kinoshita, O.,
Motomura, N., Kiyosue, A., Fujita, H., Ando, J.,
Ohtomo, K., Shigeeda, T., Kato, S., Kadowaki, T.,
Nagai, R., Takamoto, S., and Ono, M. Prevalenceof vitreous hemorrhage following coronary
revascularization in patients with diabetic
retinopathy. Circ. J. 75, 329-335, 2011.
18. Waki, K., Sugawara, Y., Mizuta, K., Fujita, H.,
Kadowaki, T., and Kokudo, N. Living-donor livertransplantation at the University of Tokyo,
1996-2011: the impact of HLA matching and apositive crossmatch on long-term survival andtolerance. Clin. Transpl. 223-235, 2011.
19. Nagase, T., Sanada, H., Takehara, K., Oe, M.,
Iizaka, S., Ohashi, Y., Oba, M., Kadowaki, T.,

147

and Nakagami, G. Variations of plantar
thermographic patterns in normal controls andnon-ulcer diabetic patients: novel classification
using angiosome concept. J. Plast. Reconstr.
Aesthet. Surg. 64, 860-866, 2011.
20. Kurano, M., Iso-O, N., Hara, M., Noiri, E., Koike,
K., Kadowaki, T., and Tsukamoto, K. Plant
sterols increased IL-6 and TNF-α secretion frommacrophages, but to a lesser extent thancholesterol. J. Atheroscler. Thromb. 18, 373-383,
2011.
21. Takehara, K., Oe, M., Tsunemi, Y., Nagase, T.,
Ohashi, Y., Iizaka, S., Ueki, K., Tsukamoto, K.,
Kadowaki, T., and Sanada, H. Factors associatedwith presence and severity of toenail
onychomycosis in patients with diabetes: a crosssectional study. Int. J. Nurs. Stud. 48, 1101-1108,
2011.
22. Takamoto, I. and Kadowaki, T. [Treatment ofdiabetes mellitus with oral hypoglycemic agents].
Nihon Rinsho 69, 563-572, 2011.
23. Waki, K., Hayashi, A., Ikeda, S., Ikeda, S.,
Nagatsuka, K., Honma, Y., Kadowaki, T., andYoshinoya, S. Measuring platelet aggregation in
dialysis patients with a whole blood aggregometerby the screen filtration pressure method. Ther.
Apher. Dial. 15, 203-206, 2011.
24. Kukimoto-Niino M, Yoshikawa S, Takagi T,
Ohsawa N, Tomabechi Y, Terada T, Shirouzu M,
Suzuki A, Lee S, Yamauchi T, Okada-Iwabu M,
Iwabu M, Kadowaki T, Minokoshi Y, andYokoyama S. Crystal structure of theCa²⁺ /calmodulin-dependent protein kinase kinase
in complex with the inhibitor STO-609. J. Biol.
Chem. 286, 22570-22579, 2011.
25. Waki, H., Yamauchi, T., and Kadowaki, T.
[Adipocytes and bone metabolism]. Clin. Calcium
21, 703-708, 2011.
26. Handa, N., Takagi, T., Saijo, S., Kishishita, S.,
Takaya, D., Toyama, M., Terada, T., Shirouzu,
M., Suzuki, A., Lee, S., Yamauchi, T.,
Okada-Iwabu, M., Iwabu, M., Kadowaki, T.,
Minokoshi, Y., and Yokoyama, S. Structural basis
for compound C inhibition of the human
AMP-activated protein kinase α2 subunit kinasedomain. Acta Crystallogr. D Biol. Crystallogr. 67(Pt 5), 480-487, 2011.

27. Iizuka, Y., Ohashi, K., Tsukamoto, K., andKadowaki, T. Education and management ofdiaetes at The University of Tokyo Hospital. J.
Diabetes 3, 104-108, 2011.
28. Kadowaki, T. [Obesity: Progress in diagnosis andtreatment; Topics, III. Obesity and its
complications; 1. Obesity and diabetes]. Nihon
Naika Gakkai Zasshi 100, 939-944, 2011.
29. Kitajima, K., Miura, S., Yamauchi, T., Uehara, Y.,
Kiya, Y., Rye, K.A., Kadowaki, T., and Saku, K.
Possibility of increasing cholesterol efflux by
adiponectin and its receptors through the ATPbinding cassette transporter A1 in HEK293T cells.
Biochem. Biophys. Res. Commun. 411, 305-311,
2011.
30. Cheng, C., Nakamura, A., Minamimoto, R.,
Shinoda, K., Tateishi, U., Goto, A., Kadowaki, T.,
Terauchi, Y., and Inoue, T. Evaluation oforgan-specific glucose metabolism by 18F-FDG ininsulin receptor substrate-1 (IRS-1) knockout
mice as a model of insulin resistance. Ann. Nucl.
Med. 25, 755-761, 2011.
31. Waki, K., Sugawara, Y., Tamura, S., Mieno, M.N.,
Yamashiki, N., Kadowaki, T., and Kokudo, N.
Outcome of liver transplantation for recipientswith hepatitis B and hepatitis C virus coinfection:
analysis of the UNOS data. Transplantation 15,809-814, 2011.
32. Hakuno, F., Yamauchi, Y., Kaneko, G.,
Yoneyama, Y., Nakae, J., Chida, K., Kadowaki,T., Yamanouchi, K., Nishihara, M., andTakahashi, S. Constitutive expression of insulin
receptor substrate (IRS)-1 inhibits myogenic
differentiation through nuclear exclusion of
Foxo1 in L6 myoblasts. PLoS One 6, e25655,
2011.
33. Ohshige, T., Iwata, M., Omori, S., Tanaka, Y.,
Hirose, H., Kaku, K., Maegawa, H., Watada, H.,
Kashiwagi, A., Kawamori, R., Tobe, K.,
Kadowaki, T., Nakamura, Y., and Maeda, S.
Association of new loci identified in European
genome-wide
association
studieswithsusceptibility to type 2 diabetes in the Japanese.
PLoS One 6, e26911, 2011.
34. Mita, T., Azuma, K., Goto, H., Jin, W.L.,
Arakawa, M., Nomiyama, T., Suzuki, R., Kubota,N., Tobe, K., Kadowaki, T., Fujitani, Y., Hirose,

148T., Kawamori, R., Watada, H. IRS-2 deficiency inmacrophages promotes their accumulation in thevascular wall. Biochem. Biophys. Res. Commun.
415, 545-550, 2011.
35. Kataoka, K., Sato, T., Yoshimi, A., Goyama, S.,
Tsuruta, T., Kobayashi, H., Shimabe, M., Arai, S.,
Nakagawa, M., Imai, Y., Kumano, K., Kumagai,
K., Kubota, N., Kadowaki, T., and Kurokawa, M.
Evi1 is essential for hematopoietic stem cell selfrenewal, and its expression marks hematopoietic
cells with long-term multilineage repopulating
activity. J. Exp. Med. 208, 2403-2416, 2011.
36. Kadowaki, T. [108th Scientific Meeting of theJapanese Society of Internal Medicine: invitedlecture: 4. Molecular mechanism and treatment
strategy of type 2 diabetes]. Nihon Naika Gakkai
Zasshi 100, 2437-2446, 2011.
37. Kadowaki, T., Yamauchi, T., Waki, H., Iwabu,
M., Okada-Iwabu, M., and Nakamura, M.
Adiponectin, adiponectin receptors, and epigenetic regulation of adipogenesis. Cold Spring
Harb. Symp. Quant. Biol. 76, 257-265, 2011.
38. Waki, K. and Kadowaki, T. [Intensive glucose
control and cardiovascular outcomes in diabetes
and impaired glucose tolerance]. Nihon Rinsho 69
Suppl. 7, 573-578, 2011.
39. Wan, M., Easton, R.M., Gleason, C.E., Monks,
B.R., Ueki, K., Kahn, C.R., and Birnbaum, M.J.
Loss of Akt1 in mice increases energy
expenditure and protects against diet-induced
obesity. Mol. Cell. Biol. epub. 2011 Oct 28.
40. Ueki, K. [Development of the treatment of
metabolic syndrome by targeting modification of
signaling molecules]. Nihon Rinsho 69 Suppl. 1,
700-704, 2011.
41. Ueki, K. [A compounding agent of alogliptin andpioglitazone]. Nihon Rinsho 69, 877-882, 2011.
42. Bezy, O., Tran, T.T., Pihlajamäki, J., Suzuki, R.,
Emanuelli, B., Winnay, J., Mori, M.A., Haas, J.,
Biddinger, S.B., Leitges, M., Goldfine, A.B., Patti,
M.E., King, G.L., and Kahn, C.R. PKCδ regulates
hepatic insulin sensitivity and hepatosteatosis inmice and humans. J. Clin. Invest. 121, 2504-2517,
2011.
43. Villanueva, C.J., Waki, H., Godio, C., Nielsen, R.,
Chou, W.L., Vargas, L., Wroblewski, K.,
Schmedt, C., Chao, L.C., Boyadjian, R., Mandrup,

S., Hevener, A., Saez, E., and Tontonoz, P. TLE3
is a dual-function transcriptional coregulator of
adipogenesis. Cell Metab. 13, 413-427, 2011.
44. Amemiya-Kudo, M., Oka, J., Takeuchi, Y.,
Okazaki, H., Yamamoto, T., Yahagi, N.,
Matsuzaka, K., Okazaki, S., Osuga, J., Yamada,N., Murase, T., and Shimano, H. Suppression of
the pancreatic duodenal homeodomain transcription factor-1 (Pdx-1) promoter by sterol
regulatory element-binding protein-1c (SREBP1c). J. Biol. Chem. 286, 27902-27914, 2011.

149

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

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

Motoshi Ichikawa, M.D., Ph.D.

Special Lecturer (Hospital)
Yasuhito Nannya, M.D., Ph.D.

Associate
Fumihiko Nakamura, M.D., Ph.D.,

Masahiro Nakagawa, M.D., Ph.D.,

Akihito Shinohara, M.D., Ph. D.,

Nahoko Nishimoto, M.D., Ph.D.

Shunya Arai, M.D., Ph. D.,

Yumiko Yoshiki, M.D., Ph.D.

Kouki Ueda, M.D., Ph. D.,

Masataka Hosoi, M.D., Ph.D.

Homepage

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

Introduction and Organization

Clinical activities

Department of Hematology and Oncology is
responsible for clinical activities in out-patient as wellas in-patient clinics of hematological disorders,
conducting research activities for hematology andoncology, and are also in charge of teaching activities
for undergraduate medical students, graduate students.
We are also engaged in post-graduate, continued
education to develop many hematologists of eminent
distinction. These activities are performed by theunited efforts of all members who belong to thedepartment. Mineo Kurokawa, M.D., Ph.D. wasinstalled as Professor of Department of Hematology
and Oncology in 2005. The staff of Department of
Hematology and Oncology consists of about twenty
members including one professor, 2 lecturers, one
special lecturer (hospital), and 7 associates.

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

150cases 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
myelogenous leukemia, 20 with multiple myeloma, 80
with myelodysplastic syndrome are annually admitted
to our ward. Out-patient clinical services are provided
daily in the morning and afternoon using three booths.
Approximately 1200 patients are monthly consulted
by our out-patient clinic. One of our final goals in theclinical activities is to cure all patients withhematological malignancies.
We perform various kinds of genetic or molecularanalyses to detect, characterize, and monitor
malignant cells and make use of them for diagnosis
and planning of treatments.
Here are some technical aspects on the treatment
strategy:
1. High-dose chemotherapy with or without
autologous stem cell support: Adequate high-dose
chemotherapy is administered for the treatment ofmalignant disease. For the autologous stem cell
support, peripheral blood stem cell is usually
selected as a source of stem cells.
2. Allogeneic hematopoietic stem cell transplantation: Bone marrow cells are operatively
harvested and infused without preservation. For
peripheral blood stem cell transplantation,
leukapheresis is performed with the use of an
automated continuous flow blood cell separator,and harvested cells are preserved in cooperation
with Department of Transfusion Medicine.
Recently, transplantation after pre-conditioning of
reduced intensity (RIST for reduced-intensity stem
cell transplantation) is commonly performed forthe elderly patients and patients with organ
damages. The development of this strategy is
expanding the eligibility of transplant recipients.
Allogeneic hematopoietic stem cell transplantations for the elderly are performed under theadmission of ethical committee of the Faculty of
Medicine. Cord blood cells are also used as thesources 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 and techniques necessary for hematologists in our hospital and encouraged to present
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 is151also performed. Every effort has been made to achieve
the highest quality in both clinical and basic medical
research. The ultimate aims of our research are theapplication of epoch-making discoveries in research
fields to the clinical hematology and oncology.
Representative publications from our departments
published in the past year are listed in the reference.

References(1) Arai S, Yoshimi A, Shimabe M, Ichikawa M,
Nakagawa M, Imai Y, Goyama S, Kurokawa M.
Evi-1 is a transcriptional target of mixed-lineage
leukemia oncoproteins in hematopoietic stem
cells. Blood. 2011 Jun;117(23):6304-14.
(2) Kagoya Y, Kataoka K, Nannya Y, Kurokawa M.
Pretransplant predictors and posttransplantsequels of acute kidney injury after allogeneic
stem cell transplantation. Biol Blood Marrow
Transplant. 2011 Mar;17(3):394-400.
(3) Kagoya Y, Takahashi T, Yoshimoto T, Ichikawa
M, Hangaishi A, Fukayama M, Kurokawa M.
Recurrent pericardial effusion after treatment for
primary effusion lymphoma-like lymphoma: an
autopsied case. Ann Hematol. 2011 Feb;90(2):219-20.
(4) Kagoya Y, Takahashi T, Nannya Y, Shinozaki A,
Ota S, Fukayama M, Kurokawa M. Hyperbilirubinemia after hematopoietic stem celltransplantation: comparison of clinical andpathologic findings in 41 autopsied cases. Clin
Transplant. 2011 Sep-Oct;25(5):E552-7.
(5) Kataoka K, Sato T, Yoshimi A, Goyama S,
Tsuruta T, Kobayashi H, Shimabe M, Arai S,
Nakagawa M, Imai Y, Kumano K, Kumagai K,
Kubota N, Kadowaki T, Kurokawa M. Evi1 isessential for hematopoietic stem cell self-renewal,
and its expression marks hematopoietic cells withlong-term multilineage repopulating activity. J
Exp Med. 2011 Nov 21;208(12):2403-16.
(6) Kobayashi CI, Yamamoto G, Hayashi A, Ota S,
Imai Y, Fukayama M, Kurokawa M. Fatal
amebic colitis after high-dose dexamethasone
therapy for newly diagnosed multiple myeloma.
Ann Hematol. 2011 Feb;90(2):225-6.
(7) Kobayashi H, Ichikawa M, Hangaishi A, Imai Y,
Kurokawa M. Concurrent development of"Burkitt-like" lymphoma and BCL-2-rearranged
low-grade B cell lymphoma sharing the same
germinal center origin. Int J Hematol. 2011 Jan;
93(1):112-7.
(8) Koya J, Nannya Y, Yoshizato T, Ono K, Seo S,
Nakagawa M, Ichikawa M, Kurokawa M.
Disseminated tuberculosis following unrelated
cord blood transplantation for refractory
peripheral T-cell lymphoma: Clinical role ofserum procalcitonin levels. J Infect. 2011 Mar;62(3):237-40.
(9) Masamoto Y, Nannya Y, Kurokawa M.
Voriconazole is effective as secondary antifungal
prophylaxis in leukemia patients with priorpulmonary fungal disease: case series and review
of literature. J Chemother. 2011 Feb;23(1):17-23.
(10) Nakagawa M, Shimabe M, Watanabe-Okochi N,
Arai S, Yoshimi A, Shinohara A, Nishimoto N,
Kataoka K, Sato T, Kumano K, Nannya Y,
Ichikawa M, Imai Y, Kurokawa M. AML1/
RUNX1 functions as a cytoplasmic attenuator of
NF-κB signaling in the repression of myeloid
tumors. Blood. 2011 Dec 15;118(25):6626-37.
(11) Nannya Y, Kataoka K, Hangaishi A, Imai Y,
Takahashi T, Kurokawa M. The negative impact
of female donor/male recipient combination inallogeneic hematopoietic stem cell transplantation depends on disease risk. Transpl Int.
2011 May;24(5):469-76.
(12) Nishimoto N, Arai S, Ichikawa M, Nakagawa M,
Goyama S, Kumano K, Takahashi T, Kamikubo
Y, Imai Y, Kurokawa M. Loss of AML1/Runx1
accelerates the development of MLL-ENL
leukemia through down-regulation of p19ARF.
Blood. 2011 Sep;118(9):2541-50.
(13) Ogura M, Todo T, Tanaka M, Nannya Y,
Ichikawa M, Nakamura F, Kurokawa M.
Temozolomide may induce therapy-related acutelymphoblastic leukaemia. Br J Haematol. 2011
Sep;154(5):663-5.
(14) Sakata-Yanagimoto M, Sakai T, Miyake Y, Saito
TI, Maruyama H, Morishita Y, NakagamiYamaguchi E, Kumano K, Yagita H, Fukayama
M, Ogawa S, Kurokawa M, Yasutomo K, Chiba
S. Notch2 signaling is required for proper mastcell distribution and mucosal immunity in theintestine. Blood. 2011 Jan;117(1):128-34.

152(15) Seo S, Nakamoto T, Takeshita M, Lu J, Sato T,
Suzuki T, Kamikubo Y, Ichikawa M, Noda M,
Ogawa S, Honda H, Oda H, Kurokawa M.
Crk-associated substrate lymphocyte type
regulates myeloid cell motility and suppresses
the progression of leukemia induced by
p210Bcr/Abl. Cancer Sci. 2011 Dec;102(12):2109-17.
(16) Yamamoto G, Maki H, Ichikawa M, Kurokawa
M. Pure red cell aplasia with follicular lymphoma
showing regression and progression parallel tolymphoma. Int J Hematol. 2011 Dec;94(6):576-7.
(17) Yamazaki S, Nakamura F, Nasu R, Nannya Y,
Ichikawa M, Kurokawa M. Haemophagocytic
lymphohistiocytosis is a recurrent and specificcomplication of acute erythroid leukaemia. Br J
Haematol. 2011 Jun;153(5):669-72.
(18) Yamazaki S, Fujioka Y, Nakamura F, Ota S,
Shinozaki A, Yamamoto G, Kamikubo Y,
Nannya Y, Ichikawa M, Fukayama M, Kurokawa
M. Composite diffuse large B-cell lymphoma andCD20-positive peripheral T-cell lymphoma.
Pathol Int. 2011 Nov;61(11):662-6.
(19) Yoshimi A, Goyama S, Watanabe-Okochi N,
Yoshiki Y, Nannya Y, Nitta E, Arai S, Sato T,
Shimabe M, Nakagawa M, Imai Y, Kitamura T,
Kurokawa M. Evi1 represses PTEN expression
and activates PI3K/AKT/mTOR via interactions
with polycomb proteins. Blood. 2011 Mar;
117(13):3617-28.
(20) Yoshimi A, Kurokawa M. Key roles of histone
methyltransferase and demethylase in leukemogenesis. J Cell Biochem. 2011 Feb;112(2):415-24.
(21) Yoshimi A, Kurokawa M. Evi1 forms a bridge
between the epigenetic machinery and signaling
pathways. Oncotarget. 2011 Jul;2(7):575-86.
(22) Yoshizato T, Nannya Y, Yoshiki Y, Nakamura F,
Imai Y, Ichikawa M, Kurokawa M. Nilotinibinduced hypothyroidism in a patient with chronic
myeloid leukemia. Int J Hematol. 2011 Mar;93(3):400-2.17.

153

Department of Allergy andRheumatology
Professor
Kazuhiko Yamamoto, M.D., Ph.D. (Rheumatology, Allergology)

Lecturer
Fujio Takeuchi, M.D., Ph.D. (Rheumatology)
Makoto Dohi, M.D., Ph.D. (Allergology)
Zen-ichiro Honda, M.D., Ph.D. (Rheumatology)

Lecturer (Hospital)
Kimito Kawahata, M.D., Ph.D. (Rheumatology)

Research Associate
Hiroko Kanda, M.D., Ph.D. (Rheumatology)
Keishi Fujio, M.D., Ph.D. (Rheumatology)
Kanae Kubo, M.D., Ph.D. (Rheumatology)
Hirofumi Syoda、M.D., Ph.D. (Rheumatology)
Syuji Sumitomo，M.D., Ph.D. (Rheumatology)
Mitsuru Imamura，M.D., Ph.D. (Allergology)

Project Research Associate
Tomohisa Okamura，M.D., Ph.D. (Rheumatology)

The Department of Allergy and Rheumatology
presently consists of 12 staff mentioned above, who
preside over 6 medical staff, 13 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.

EducationIn

regardtoundergraduate

education,

theDepartment is in charge of internal medicine
diagnosis and systemic lectures for M2 students andclinical lectures and bedside education for M3 and M4
students in cooperation with other departments ofinternal medicine. The systemic lectures and clinicallectures covers clinical immunology, connective tissue
diseases and allergy. Bedside education provides
students with a good opportunity to learn about
patients as well as practical knowledge throughnumerous seminars.
For postgraduate education, internal medicine
trainees are accepted on rotation basis and trained asinternist. Our department accepts students for "Doctorof Medical Science". Our 4-year education covers
clinicalimmunology,
molecular
immunology,

154

rheumatology and allergology.

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

Research
The Department has 10 research laboratories in whichclinical and basic studies are carried out concerning
mainly rheumatology and allergology. Recently themainstream of research has employed various techniques of molecular biology and cellular immunology.
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

2011
1. Kochi Y, Thabet MM, Suzuki A, Okada Y, Daha
NA, Toes REM, Huizinga TWJ, Myouzen K,
Kubo M, Yamada R, Nakamura Y, Yamamoto K.
PADI4 polymorphism predisposes male smokers
to rheumatoid arthritis. Ann Rheum Dis, 70:
512-5, 2011.
2. Chihara Y, Egawa H, Tsuboi T, Oga T, Handa T,
Yamamoto K, Mishima M, Tanaka K, Uemoto S,
Chin K. Immediate noninvasive ventilation may
improve mortality in patients with hepatopulmonary syndrome after liver transplantation.
Liver Transpl. 17:144-82011, 2011
3. Kawai S, Takeuchi T, Yamamoto K, Tanaka Y,
Miyasaka N. Efficacy and safety of additionaluse of tacrolimus in patients with earlyrheumatoid arthritis with inadequate response to
DMARDs-a multicenter, double-blind, parallelgroup trial. Mod Rheumatol. 2011
4. Tamiya, Hiroyuki; Hagino, Noboru; Okamoto,
Akiko; Yamamoto, Kazuhiko. Morning granulocytopenia in two patients with connective-tissue
disease treated with oral corticosteroids. BMJ
Case Reports 2011
5. Okada Y, Hirota T, Kamatani Y, Takahashi A,
Ohmiya H, Kumasaka N, Higasa K,
Yamaguchi-Kabata Y, Hosono N, Nalls MA,
Chen MH, van Rooij FJ, Smith AV, Tanaka T,
Couper DJ, Zakai NA, Ferrucci L, Longo DL,
Hernandez DG, Witteman JC, Harris TB,
O'Donnell CJ, Ganesh SK, Matsuda K, Tsunoda
T, Tanaka T, Kubo M, Nakamura Y, Tamari M,
Yamamoto K, Kamatani N. Identification of nine
novel Loci associated with white blood cell
subtypes in a Japanese population. PLoS Genet.
7:e1002067, 2011
6. Yukinori Okada, Keiko Yamazaki, Junji Umeno,
Atsushi Takahashi, Natsuhiko Kumasaka, Kyota
Ashikawa, Tomomi Aoi, Masakazu Takazoe,
Toshiyuki Matsui, Atsushi Hirano, Takayuki
Matsumoto,
Naoyuki
Kamatani,
Yusuke155

Nakamura, Kazuhiko Yamamoto, and Michiaki
Kubo. The HLA-Cw*1202-B*5201-DRB1*1502
Haplotype Increases Risk for Ulcerative Colitis
but Reduces Risk for Crohn's Disease.
Gastroenterology,141(3):864-871.e1-5. 2011
7. Okada Y, Takahashi A, Ohmiya H, Kumasaka N,
Kamatani Y, Hosono N, Tsunoda T, Matsuda K,
Tanaka T, Kubo M, Nakamura Y, Yamamoto K,
Kamatani N. Genome-wide association study for
C-reactive protein levels identified pleiotropic
associations in the IL6 locus.. Hum Mol Genet.
2011 Mar 15;20(6):1224-31. Epub 2010 Dec
31.PMID:21196492
8. Nalls MA, Couper DJ, Tanaka T, van Rooij FJ,
Chen MH, Smith AV, Toniolo D, Zakai NA, Yang
Q, Greinacher A, Wood AR, Garcia M, Gasparini
P, Liu Y, Lumley T, Folsom AR, Reiner AP,
Gieger C, Lagou V, Felix JF, Völzke H,
Gouskova NA, Biffi A, Döring A, Völker U,
Chong S, Wiggins KL, Rendon A, Dehghan A,
Moore M, Taylor K, Wilson JG, Lettre G, Hofman
A, Bis JC, Pirastu N, Fox CS, Meisinger C,
Sambrook J, Arepalli S, Nauck M, Prokisch H,
Stephens J, Glazer NL, Cupples LA, Okada Y,
Takahashi A, Kamatani Y, Matsuda K, Tsunoda T,
Tanaka T, Kubo M, Nakamura Y, Yamamoto K,
Kamatani N, Stumvoll M, Tönjes A, Prokopenko
I, Illig T, Patel KV, Garner SF, Kuhnel B,
Mangino M, Oostra BA, Thein SL, Coresh J,
Wichmann HE, Menzel S, Lin J, Pistis G,
Uitterlinden AG, Spector TD, Teumer A,
Eiriksdottir G, Gudnason V, Bandinelli S,
Frayling TM, Chakravarti A, van Duijn CM,
Melzer D, Ouwehand WH, Levy D, Boerwinkle
E, Singleton AB, Hernandez DG, Longo DL,
Soranzo N, Witteman JC, Psaty BM, Ferrucci L,
Harris TB, O'Donnell CJ, Ganesh SK. Multiple
Loci are associated with white blood cell
phenotypes. PLoS Genet. 7:e1002113, 2011
9. Chihara Y, Egawa H, Tsuboi T, Oga T, Handa T,
Yamamoto K, Mishima M, Tanaka K, Uemoto S,
Chin K. Immediate noninvasive ventilation may
improve mortality in patients with hepatopulmonary syndrome after liver transplantation.
LiverTranspl. 17:144-8, 2011
10. Tanaka Y, Harigai M, Takeuchi T, Yamanaka H,
Ishiguro N, Yamamoto K, Miyasaka N, Koike T,

11.

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Kanazawa M, Oba T, Yoshinari T, Baker D; theGO-FORTH Study Group. Golimumab in
combination with methotrexate in Japanesepatients with active rheumatoid arthritis: resultsof the GO-FORTH study. Ann Rheum Dis. 2011
Iwagami M, Kubo K, Tanaka R, Kawahata K,
Okamoto A, Hagino N, Yamamoto K.
Thrombotic thrombocytopenic purpura withsevere hypertension in a patient with systemicsclerosis sine scleroderma and polymyositis.
Intern Med. 2011;50:2413-6. Epub 2011
Nakagome K, Imamura M, Kawahata K, Harada
H, Okunishi K, Matsumoto T, Sasaki O, Tanaka
R, Kano MR, Chang H, Hanawa H, Miyazaki J,
Yamamoto K, Dohi M. High expression of IL-22
suppresses antigen-induced immune responses
and eosinophilic airway inflammation via an
IL-10-associated mechanism. J Immunol. 2011;
187:5077-5089
Iwasaki Y, Okamoto A, Shoda H, Takahashi Y,
Fujio K, Kawahata K, Yamamoto K. Subacutecerebellar ataxia and atrophy developed in ayoung woman with systemic lupus erythematosus
whose cerebrospinal fluid was positive forantineuronal cell antibody. Lupus. 2011;0:1-5.
Nakagome K, Imamura M, Okada H, Kawahata
K, Inoue T, Hashimoto K, Harada H, Higashi T,
Takagi R, Nakano K, Hagiwara K, Kanazawa M,
Dohi M, Nagata M, Matsushita S. Dopamine
D1-like receptor antagonist attenuates Th17mediated immune response and ovalbumin
antigen-induced neutrophilic airway inflammation. J Immunol. 2011;186:5975-5982.
Shoda H, Fujio K*, Shibuya M, Okamura T,
Sumitomo S, Okamoto A, Sawada T, Yamamoto
K. Detection of autoantibody to citrullinated BiP
in rheumatoid arthritis patients and proinflammatory roles of citrullinated BiP incollagen-induced arthritis. Arthritis Res Ther
13:R191,2011 *corresponding author
Okamoto A, Fujio K*, Okamura T, Yamamoto K.
Regulatory T cell-associated cytokines insystemic lupus erythematosus. JBiomedBiotech
2011:463412,2011*corresponding author
Kameda H, Tokuda H, Sakai F, Johkoh T, Mori S,
Yoshida Y, Takayanagi N, Taki H, Hasegawa Y,
Hatta K, Yamanaka H, Dohi M, Hashimoto S,

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Yamada H, Kawai S, Takeuchi T, Tateda K, Goto
H. Clinical and radiological features of acuteonset diffuse interstitial lung diseases in patientswith rheumatoid arthritis receiving treatment
with biological agents: importance of Pneumocystis pneumonia in Japan revealed by a multicenter study. Intern Med. 2011;50(4):305-13.
Epub 2011 Feb 15. PMID: 21325762

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Department of Infectious
Diseases (Internal Medicine)
Associate Professor
Hiroshi Yotsuyanagi, M.D., Ph.D.

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

Homepage

http://infect.umin.jp/

Introduction and Organization
The Department of Infectious Diseases has been oneof the leading academic organizations specialized forinternal medicine, in particular, infectious disease
medicine in Japan since 1998, when the Departments ofInternal Medicine, established in 1890, were rearranged
into new ones according to subspecialty of internal
medicine. Our department has been chiefly engaged inclinical, educational and research activities for
infectious diseases including bacterial, fungal and viral
infections of all organs including HIV infection,
tuberculosis and viral hepatitis. Our department islocated on 11th floor of the University of Tokyo
Hospital Building, and has well-furnished researchlaboratories including P-2 class laboratory, adepartmental library and a computer room as own
properties. In clinical and research activities, we arecollaborating with the Department of Infection Control
and Prevention. An associate professor, 6 guest
lecturers, an associate, 2 graduate students and full-time
staff members are all performing their own duties inclinical, educational and research activities.

Clinical activities
We have hospital beds on the 11th floor of the Ward Aof University of Tokyo Hospital. Diseases include HIV
infection, viral hepatitis, pneumonia, resistant bacteria
infections such as MRSA, BLNAR or VRE,
tuberculosis, EBV infection, CMV infection, parasite

infection, etc. Every effort is made to give patients thebest care and best quality of life. Clinical associates,
full-time staff and residents take care of inpatients. The
case presentation by residents is held on a weekly basis.
Weekly clinical conference is held for discussing about
all cases, in particular, those with problems difficult tobe solved. Consultations are very frequent from otherdepartments on the management of infectious diseases.
The general diagnostic, therapeutic plans and decisions
for each patient are given at the Professor’s round.
Our department offers out-patient care everyday on
infectious diseases and general medicine. We are also
engaged in infection control and prevention of
emerging infectious diseases such SARS or avian
influenza virus, which appeared recently.

Teaching activities
Our department takes a part in clinical lectures andbed-side learning of the internal medicine forundergraduate medical students according to theeducational programs of the University of Tokyo. For
the fourth year medical students, six lectures ofinfectious diseases are given. In addition, principles of
medical diagnosis are taught at the bedside. During the
bed-side teaching for fifth and sixth year students, ourassociates teach them on man-to man basis the basic
way of thinking for correct diagnosis and therapy, thetechniques of interrogation and physical examination,
the way for interpretations of laboratory tests and othermedical examinations, and the basic medical

158

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) Elucidation of the mechanism of hepatocarcinogenesis 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) Establishment of new methods for practical
diagnosis and treatment of respiratory infection
including avian influenza.

Members
Hiroshi Yotsuyanagi, Takeya Tsutsumi, Shuji
Hatakeyama, Shu Okugawa, Shintaro Yanagimoto,
Yohko Nukui, Atsuhito Fukishima, Keita Tatsuno,
Sohei Harada, Koji Goto, Mahoko Ikeda, Koh Okamoto,
Yoshitaka Wakabayashi, Tetsuro Kobayashi, Haruka
Nakamura, Makoto Saito, Hideki Hashimoto, Kohei
Harada.

References
1) Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi
N, Tanaka E, Chayama K, Sakisaka S, Takehara T,
Oketani M, Suzuki F, Toyota J, Nomura H, Yoshioka
K, Seike M, Yotsuyanagi H, Ueno Y; The Study
Group for the Standardization of Treatment of Viral
Hepatitis Including Cirrhosis, Ministry of Health,
Labor and Welfare of Japan. Guidelines for thetreatment of chronic hepatitis and cirrhosis due tohepatitis B virus infection for the fiscal year 2008 in
Japan. Hepatol Res. 2010;40:1-7.
2) Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi
N, Tanaka E, Chayama K, Sakisaka S, Takehara T,
Oketani M, Suzuki F, Toyota J, Nomura H, Yoshioka
K, Seike M, Yotsuyanagi H, Ueno Y; The Study
Group for the Standardization of Treatment of Viral
Hepatitis Including Cirrhosis, Ministry of Health,Labour and Welfare of Japan. Guidelines for thetreatment of chronic hepatitis and cirrhosis due tohepatitis C virus infection for the fiscal year 2008 in
Japan. Hepatol Res. 2010;40:8-13.
3) Nakahara K, Takahashi H, Okuse C, Shigefuku R,
Yamada N, Murao M, Matsunaga K, Koike J,
Yotsuyanagi H, Suzuki M, Kimura K, Itoh F.
Membranous nephropathy associated with chronic
hepatitis B occurring in a short period after acutehepatitis B virus infection. Intern Med. 2010;49:
383-8.
4) Moriya K, Miyoshi H, Shinzawa S, Tsutsumi T, Fujie
H, Goto K, Shintani Y, Yotsuyanagi H, Koike K.

159

Hepatitis C virus core protein compromises
iron-induced activation of antioxidants in mice and
HepG2 cells. J Med Virol. 2010;82:776-92.
5) 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. Effect of nucleosideanalog-interferon sequential therapy on patients withacute exacerbation of chronic hepatitis B. Hepatol Res.
2010;40:461-9.
6) 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.
7) Okamoto K, Hatakeyama S, Itoyama S, Nukui Y,
Yoshino Y, Kitazawa T, Yotsuyanagi H, Ikeda R,
Sugita T, Koike K. Cryptococcus gattii genotype
VGIIa infection in man, Japan, 2007. Emerg InfectDis. 2010;16:1155-7.
8) Koike K, Tsutsumi T, Yotsuyanagi H, Moriya K. Lipid
metabolism and liver disease in hepatitis C viral
infection. Oncology. 2010;78:24-30.
9) Yoshino Y, Kitazawa T, Kamimura M, Tatsuno K, Ota
Y, Yotsuyanagi H. Pseudomonas putida bacteremia in
adult patients: five case reports and a review of theliterature. J Infect Chemother. 2011;17:278-82.
10) Chayama K, Hayes CN, Yoshioka K, Moriwaki H,
Okanoue T, Sakisaka S, Takehara T, Oketani M,
Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H,
Seike M, Ueno Y, Yotsuyanagi H, Kumada H.
Accumulation of refractory factors for pegylated
interferon plus ribavirin therapy in older female
patients with chronic hepatitis C. Hepatol Res.
2010;40:1155-1167.
11) Miyoshi H, Moriya K, Tsutsumi T, Shinzawa S, Fujie
H, Shintani Y, Fujinaga H, Goto K, Todoroki T,
Suzuki T, Miyamura T, Matsuura Y, Yotsuyanagi H,
Koike K. Pathogenesis of lipid metabolism disorder inhepatitis C: polyunsaturated fatty acids counteract
lipid alterations induced by the core protein. J Hepatol.
2011;54:432-8.
12) Chayama K, Hayes CN, Yoshioka K, Moriwaki H,
Okanoue T, Sakisaka S, Takehara T, Oketani M,
Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H,
Seike M, Ueno Y, Yotsuyanagi H, Kumada H. Factors
predictive of sustained virological response following
72 weeks of combination therapy for genotype 1b

hepatitis C. J Gastroenterol. 2011;46:545-55.
13) Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K,
Yanagimoto S, Okugawa S, Ota Y, Yotsuyanagi H.
Clinical features of Bacteroides bacteremia and theirassociation with colorectal carcinoma. Infection.
2011;40:63-7.
14) Hatakeyama S, Iwatsuki-Horimoto K, Okamoto K,
Nukui Y, Yata N, Fujita A, Inaba S, Yotsuyanagi H,
Kawaoka Y. Unadjuvanted pandemic H1N1 influenza
vaccine in HIV-1-infected adults. Vaccine. 2011;29:9224-8.
15) Fujinaga H, Tsutsumi T, Yotsuyanagi H, Moriya K,
Koike K. Hepatocarcinogenesis in hepatitis C: HCVshrewdly exacerbates oxidative stress by modulating
both production and scavenging of reactive oxygen
species. Oncology. 2011;81 Suppl 1:11-7.
16) Fukase H, Furuie H, Yasuda Y, Komatsu R,
Matsushita K, Minami T, Suehiro Y, Yotsuyanagi H,
Kusadokoro H, Sawata H, Nakura N, Lattanzi M.
Assessment of the immunogenicity and safety ofvarying doses of an MF59-adjuvanted cell culturederived A/H1N1 pandemic influenza vaccine inJapanese paediatric, adult and elderly subjects.
Vaccine. 2012 Apr 1. [Epub ahead of print]17) Goto K, Hatakeyama S, Okamoto K, Kitazawa T, Abe
K, Moriya K, Koike K, Yotsuyanagi H. Dengue
hemorrhagic fever in an adult traveler returning toJapan: Case report. Intern Med. 2012 [Epub ahead ofprint]
18) Yanagimoto S, Yotsuyanagi H, Kikuchi Y, Tsukada K,
Kato M, Takamatsu J, Hige S, Chayama K, Moriya K,
Koike K. Chronic hepatitis B in patients coinfectedwith human immunodeficiency virus in Japan: A
retrospective multicenter analysis. J Infect Chemother2012 [Epub ahead of print]

160

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

Tetsuro Ishizawa, M.D., Ph.D.

http://psmut.umin.ac.jp/

Introduction and Organization
The Department of Stress Science andPsychosomatic Medicine is one of 11 divisions of the
Department of Internal Medicine, the University ofTokyo. It covers eating disorder, panic disorder, andvarious psychosomatic diseases such as chronicheadache, irritable bowel syndrome, functional
dyspepsia, hypertension, diabetes mellitus, andhyperthyroidism. Our teaching staff consists of one
professor, one associate professor, two associates, and5 adjunct professors, and other members are 2 seniorresidents, 6 graduate students, and 1 researchers.

Clinical activities
Our department is responsible for both outpatient
clinic and inpatient ward. The ward is managed as apart of the Division of General Internal Medicine, andsenior residents, an associate, and the associate
professor attend it every day and provide close sideby-side instruction to junior residents. The weekly
professor’s round is scheduled on Thursday morning.
During 2011 January to 2011 December, 54 patientswere admitted to the ward, many of whom were eating
disorder patients. Outpatient clinic is attended on
every morning and afternoon in three consultation
rooms by approximately fifteen physicians. During

2011 January to 2011 December, the numbers of the
new outpatients and of the overall outpatients in our
department were 147 and 3143, respectively.

Teaching activities
We are giving 6 methodical lectures on
psychosomatic medicine for fourth grade medical
students, ‘problem-based learning’ lasting 12 weeks(net 24 hours) for 6 or 7 fourth grade students,‘bed-side learning’ for fifth grade students lasting two
weeks, ‘clinical clerkship’ for 3 to 4 fifth gradestudents lasting 4 weeks each, and clinical lectures on
psychosomatic diseases in cardiology for fifth gradestudents and on eating disorders for sixth gradestudents. We are trying to teach them not only basic
knowledge of specific diseases, ways of physicalexamination, or interpretation of laboratory data, butalso relevant ways of clinical interview, doctor-patient
relationship building, and behavior modification.
As for education for junior residents, our seniorresidents and an associate provide man-to-man
instruction. In addition, they can learn how to present
the history of newly-admitted patients at the weekly
professor’s round from our teaching staff.

161

Research activities
Targeting stress-related diseases such as not only
those covered by our department but also otherlifestyle-related disease, and cancers, we areinvestigating their pathophysiology and psychopathology through assessing bio-psycho-behavioral
time-series data, various questionnaire data, andautonomic nervous function. We are also actively
conducting basic as well as clinical research on
eating-related substances.
Some representative research methods are as
follows:
1) Ecological momentary assessment (EMA):
Investigation on neurobehavioral basis of stressrelated diseases such as tension-type headache,eating disorders, insomnia, and panic disorderusing portable computers for real-time assessmentof subjective symptoms in combination withambulatory monitors such as electrocardiogramand actigraphy.
2) Neuroendocrinological and neuroimmunologicalstudies in anorexia nervosa patients: multidisciplinary investigation on energy metabolism
during a refeeding phase; changes in various
substances such as neuropeptides before and after
treatment; relationship between bone metabolism
and various makers; and exploration of biomarkers
for evaluating treatment efficacy.
3) Psycho-oncology: Development of a new questionnaire for evaluating depressive mood in cancer
patients.
Six graduate students and 5 researchers actively
conducted their researches along with our teaching
staff. We have been also collaborating with many
scientists belonging to other departments either inJapan or abroad. Research conferences are held once amonth, where one of the graduate students presents
his/her research for open discussion by all themembers of our department.

References
1.

Sano W, Nakamura T, Yoshiuchi K, Kitajima T,
Tsuchiya A, Esaki Y, Yamamoto Y, Iwata N. Enhanced persistency of resting and active periods of

2.

3.

4.

5.

6.

7.

locomotor activity in schizophrenia. PLoS ONE (inpress)
Fukui S, Yoshiuchi K. Associations with the Japanese population’s preferences for the place of endof-life care and their need for receiving healthcare
services. J Palliat Med (in press)
Fukui M, Iwase S, Sakata N, Kuroda Y, Yoshiuchi
K, Nakagawa K, Quinn K, Hudson PL. Effectiveness of using clinical guidelines for conducting
palliative care family meetings in Japan. Support
Care Cancer (in press)
Fukui S, Yoshiuchi K, Fujita J, Sawai M, Watanabe
M. Japanese people’s preference for place of
end-of-life care and death: a population-based nationwide survey. J Pain Symptom Manage
42:886-892, 2011.
Yoshiuchi K, Akabayashi A. Japan’s nuclear crisis.
Lancet Oncology 12:724-725, 2011. (correspondence)
Kikuchi H, Yoshiuchi K, Yamamoto Y, Komaki G,
Akabayashi A. Does sleep aggravate tension-type
headache?: An investigation using computerized
ecological momentary assessment and actigraphy.
BioPsychoSoc Med 5:10, 2011.
Otani M, Takimoto Y, Moriya J, Yoshiuchi K,
Akabayashi A. Plasma intact fibroblast growth
factor 23 levels in women with bulimia nervosa: A
cross-sectional pilot study. BioPsychoSoc Med 5:7,
2011.

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

163

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

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

Associate
Minoru Tanaka, M.D., Ph.D.,
Naoko Okochi, M.D., Ph.D.

Homepage http://172.27.30.16/yuketsu/s-index.html
Introduction and Organization

Clinical activities

The Transfusion Medicine service was established in1949, as an internal provisional measure, andofficially established in 1966. In 1984, Professor
Hiroshi Toyama assumed as the first Professor of thedepartment. Professor Toyama greatly contributed to
the field of transfusion medicine, especially by
publishing “Transfusion Medicine” (actually in its 3rd.
edition), which is the bible of transfusion medicine inJapan. Other great contributions from the department
are as follows. Dr. Kazuo Okochi, ex-lecturer of thedepartment, is the pioneer in the field of transfusionassociated hepatitis research, ex-Professor Takeo Jujiclarified the mechanisms of transfusion-associatedgraft-versus-host disease (TA-GVHD), a serious posttransfusional complication, and the previous professor,
Professor Yoichi Shibata contributed enourmously tothe field of platelet immunology. In 1997, theDepartment of Transfusion Medicine was established
as a chair of the Division of Internal Medicine of the
Graduate School of Medical Sciences, the Universityof Tokyo.
Actually, the department is composed of 6 medical
doctors (4 full-time, and 2 partial-time), 10 laboratory
technicians, 1 nurse and 1 office assistant.

The main activity of the department of Transfusion
Medicine is the control, preservation, and provision ofsafe blood products and their derivatives. The control
of all blood products in the hospital is centralized tothe department, which, in addition, provides information and orientation related to blood transfusion.
Transfusion-related laboratory tests and tests fortransfusion-transmitted infectious diseases are routine
practices of the department, which also actively takes
part in the diagnosis, prevention and treatment ofadverse reactions and post-transfusion complications.
Collection, preservation and provision of autologous
blood are also important functions of the department,
where the outpatient clinic for autologous blood wasestablished in January 2006. At the outpatient clinic,
the first established in Japan, the transfusionist gives
consultation to the patients, prepares the adequate
blood collection schedule, takes the informed consent,
and performs the blood collection, according to thesurgeons’ needs. Additionally, immunotherapy ofcancer patients and collection and preservation of
peripheral blood stem cells are also performed. The
main activities are as follows:
I. Control and preservation of blood products andits derivatives;;

164

II.

Laboratory tests
1) Blood typing and histocompatibility testing;2) Detection of anti-erythrocyte, anti-leukocyte
and anti-platelet antibodies;3) Detection of HBV antigens and antibodies, HCV,
HAB, ATLA and HIV antibodies;
4) HLA typing for Hematopoietic stem celltransplantation and organ transplantation;
III. Clinical work
1) Pre-operative autologous blood collection andpreservation;2) Collection and preservation of peripheral blood
stem cells for transplantation;3) Dendritic cell-based cancer immunotherapy.
4) 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 “Blood Law”, and therecently 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 of blood
cells is performed by serological and DNA-based
methods. The HLA typing, which was introduced by
ex-Professor Takeo Juji, one of the pioneers of thisfield, is an essential test for hematopoietic 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 is also an
important subject. Also, the role of pre-storage
leukocyte reduction of autologous blood products,
especially focusing on cytokine/chemokines andbioactive lipids, and the improvements of thepreservation methods of autologous blood are being
investigated. Recently, development of new materials
for medical use is also 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, and the improvement of the preservation
methods.
4. Study on the effect of pre-storage leukoreductionof autologous blood for the prevention of possible
adverse effects.
5. Study on the mechanisms of transfusionassociated GVHD and its prevention.
6. Development of a new methodology for plateletcross-match.
7. HLA and HPA genotyping.
8. Development of a new methodology for evaluation

165

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

References
1.

2.

3.

4.

Tanaka M, Tsuno NH, Mitsudo K, Kadota K,
Tatami R, Kato M, Kato K, Nogami A, Ishikawa
O, Takahashi K. First human trial of KW39
slotted-tube stents: for percutaneous coronary
intervention. Tex Heart Inst J. 2011; 38(5):502-7.
Yasuda K, Nirei T, Tsuno NH, Nagawa H,
Kitayama
J.
Intratumoral
injectionofinterleukin-2 augments the local and abscopal
effects of radiotherapy in murine rectal cancer.
Cancer Sci. 2011; 102(7):1257-63.
Kawai K, Tsuno NH, Kitayama J, Sunami E,
Takahashi K, Nagawa H. Catechin inhibits
adhesion and migration of peripheral blood B
cells by blocking CD11b. Immunopharmacol
Immunotoxicol. 2011; 33(2):391-7.
Kawai K, Kitayama J, Tsuno NH, Sunami E,
Nagawa H. Hyperfibrinogenemia after preoperative chemoradiotherapy predicts poor
response and poor prognosis in rectal cancer. Int
J Colorectal Dis. 2011; 26(1):45-51.

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

167

Department of
Reproductive Endocrinology
Associate Professor
Tetsu Yano

Yutaka Osuga

Lecturer
Akihisa Fujimoto

Homepage http://plaza.umin.ac.jp/ivf/index.html
http://square.umin.ac.jp/tkyobgyn/
Organization
The Department of Reproductive Endocrinology isorganized by two associate professors and one lecturer.
All the staff members are taking part in both clinicaland research activities. For the clinical aspect, we areengaged with in-patient and out-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 hysterectomy or laparoscopically assisted vaginal hysterectomy, laparoscopic
or laparoscopically assisted myomectomy, diagnostic
laparoscopy for infertility , laparoscopic surgery forectopic pregnancy, hysteroscopic surgery and so on,which make a total of about 400 cases per year.
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 already168

yielded 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 2011
(1) Wang B, et al. Toll-like receptor-3 ligation-induced
indoleamine 2, 3-dioxygenase expression in humantrophoblasts. Endocrinology 152:4984-4992, 2011
(2) Yoshino O, et al. Activin-A is induced byinterleukin-1beta and tumor necrosis factor-alphaand enhances the mRNA expression ofinterleukin-6 and protease-activated receptor-2 andproliferation of stromal cells from endometrioma.
Fertil Steril 96:118-121, 2011(3) Hirata T, et al. Interleukin-17F increases thesecretion of interleukin-8 and the expression of
cyclooxygenase 2 in endometriosis. Fertil Steril
96:113-117, 2011(4) Saito A, et al. TGF-beta1 induces proteinaseactivated receptor 2 (PAR2) expression in
endometriotic stromal cells and stimulates PAR2
activation-induced secretion of IL-6. Hum Reprod
26:1892-1898, 2011
(5) Yoshino O, et al. Myomectomy reduces
endometrial T2 relaxation times. Fertil Steril 95:
2781-2783, 2011(6) Harada M, et al. Dienogest, a new conservative
strategy for extragenital endometriosis: a pilot study.
Gynecol Endocrinol 27:717-720, 2011(7) Shi J, et al. Bone morphogenetic protein-2 (BMP-2)
increases gene expression of FSH receptor andaromatase and decreases gene expression of LH
receptor and StAR in human granulosa cells. Am J
Reprod Immunol 65:421-427, 2011(8) Osuga Y, et al. Lymphocytes in endometriosis. Am
J Reprod Immunol 65:1-10, 2011(9) Taguchi A, et al. Successful management of aruptured endometrial cyst in acute leukemia. Fertil
Steril 95:292.e1-293, 2011(10) Wada-Hiraike O, et al. Sessile polyps andpedunculated polyps respond differently to oral
contraceptives. Gynecol Endocrinol 27:351-355,

2011

169

Department of
Gynecologic Oncology
Associate Professor
Tetsu Yano

Lecturer
Kei Kawana

Homepage http://go.umin.jp/index.html
http://square.umin.ac.jp/tkyobgyn/
Organization
The Department of Gynecologic Oncology isorganized by one associate professor and one lecturer,
being directed practically by Professor Shiro Kozuma,
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
1. Human Papillomavirus (HPV) and HPV-related
proteins
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

170

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

decrease in the expression of hScrib with theprogression of disease from normal uterine cervicaltissues to invasive cervical cancers through theprecursor lesions. In contrast, the expression of hScrib
was retained in the throughout epithelial layer of the
HPV-negative
cervicalhigh-grade
squamous
intraepithelial lesions (H-SIL). Although quantitative
RT-PCR revealed no significant downregulation of
hScrib mRNA expression in the H-SIL, it revealed aclear downregulation in the invasive cancers. These
results suggest the possibility that degradation by
HPV E6 is one of the causal roles for the progressive
decrease of hScrib expression during the disease progression 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 development.
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 ahuman 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.

171

Furthermore, hDlg was targeted for in vitro
ubiquitination in the presence of both E6 and E6AP.
These data revealed that E6AP is extensively involvedin the ubiquitin-mediated degradation of E6dependent substrates as a cellular E3 ubiquitin-protein
ligase. hScrib, human homologue of Drosophila
neoplastic tumor suppressor, was identified as a targetof human papillomavirus E6 oncoprotein for theubiquitin-mediated degradation. Here, we report that
hScrib is a novel death substrate targeted by caspase.
Full-length hScrib was cleaved by caspase during
death ligands-induced apoptosis, which generates ap170 C-terminal fragments in Hela cells. In vitro
cleavage assay using recombinant caspases showedthat hScrib is cleaved by the executioner caspases.
DNA damage-induced apoptosis caused loss ofexpression of full-length hScrib, which was recoveredby 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 dependentcleavage site of hScrib at the position of Asp-504.
While MDCK cells transfected with GFP-fused wild
type hScrib showed loss of E-cadherin expression andshrinkage of cytoplasm by UV irradiation, cells
transfected with hScrib with Ala substitution of
Asp-504 showed resistance to caspase dependentcleavage of hScrib and intact expression of E-cadherin.
These results indicate that caspase dependent cleavageof hScrib is a critical step for detachment of cell
contact during process of apoptosis.
We also found that hScrib is a direct regulator of
extracellular signal-regulated kinase (ERK). In humankeratinocytes, loss of hScrib results in elevatedphospho-ERK levels and concomitant increased
nuclear translocation of phospho-ERK. We revealed
that hScrib interacts with ERK through twowell-conserved kinase interaction motif (KIM)
docking sites, both of which are also required for
ERK-induced phosphorylation of hScrib on two
distinct residues. Although wild-type hScrib candownregulate activation of ERK and oncogenic Ras
co-transforming activity, an hScrib mutant that lacks
the carboxy terminal KIM docking site has no such
effects. These results provide a clear mechanistic
explanation of how hScrib can regulate ERK

signalling and begin to explain how loss of hScribduring cancer development can contribute to diseaseprogression.
CD1d and CD1d-restricted natural killer T (NKT)
cells serve as a natural bridge between innate andadaptive immune responses to microbes. CD1d
downregulation is utilized by a variety of microbes toevade immune detection. We demonstrated that CD1d
isdownregulatedin
human
papillomavirus(HPV)-positive cells in vivo and in vitro. CD1d
immunoreactivity was strong in HPV-negative normal
cervical epithelium but absent in HPV16-positive
CIN1 and HPV6-positive condyloma lesions. Flowcytometry revealed that cell surface CD1d was
downregulated in both C33A/CD1d and Vag cells
stably transfected with HPV6 E5 and HPV16 E5.
Confocal microscopy demonstrated that residualCD1d was not trafficked to the E5-expressing cellsurface but colocalized with E5 near the endoplasmic
reticulum (ER). In the ER, E5 interacted with calnexin,
an ER chaperone known to mediate folding of CD1d.
CD1d protein levels were rescued by the proteasome
inhibitor, MG132, indicating a role for proteasomemediated degradation in HPV-associated CD1d
downregulation. Finally, CD1d-mediated productionof interleukin-12 from the C33A/CD1d cells wasabrogated in both E5-expressing cell lines. Decreased
CD1d expression in the presence of HPV E5 may help
HPV-infected cells evade protective immunologicalsurveillance.
2. Detection of genetic alterations and oncogenomic
analyses in endometrial cancer
The phosphatidylinositol 3'-kinase (PI3K) pathway
is activated in many human cancers. In addition toinactivation of the PTEN tumor suppressor gene,mutations or amplifications of the catalytic subunit
alpha of PI3K (PIK3CA) have been reported. We
screened 66 primary endometrial carcinomas formutations in the helical and catalytic domains of
PIK3CA. We identified a total of 24 (36%) mutationsin this gene and coexistence of PIK3CA/PTEN
mutations at high frequency (26%). PIK3CA
mutations were more common in tumors with PTEN
mutations (17 of 37, 46%) compared with those
without PTEN mutations (7 of 29, 24%). Arraycomparative genomic hybridization detected 3q24-

172

qter amplification, which covers the PIK3CA gene
(3q26.3), in one of nine tumors. Knocking down
PTEN expression in the HEC-1B cell line, which
possesses both K-Ras and PIK3CA mutations, further
enhances phosphorylation of Akt (Ser473), indicatingthat double mutation of PIK3CA and PTEN has anadditive effect on PI3K activation.
We also reported that PIK3CA mutations occur
almost exclusively in invasive tumors, whereas
upstream mutations occur as frequently in early-stage
and late-stage tumors, suggesting that PIK3CA
mutation is a late-stage event that may augment earlier
activation of the PI3K pathway. Consistent with this,
we found that levels of p-AKT (Ser473) induced bymutant Ras or knockdown of PTEN were dramaticallyincreased by addition of mutant PIK3CA. Soft agar
assays revealed that anchorage-independent growth
induced by mutant Ras was greatly increased in thepresence of mutant PIK3CA. Thus, our data suggestthat PIK3CA mutations cooperate with otherphosphatidylinositol 3'-kinase pathway mutations toeffect oncogenic transformation.
We first reported that AKT1 mutations are observedin endometrial cancer. We detected two AKT1 (E17K)
mutations in the tissue samples (2 out of 89). These
two AKT1 mutant tumors do not possess any
mutations in PIK3CA, PTEN and K-Ras. Our results
and earlier reports suggest that AKT1 mutations might
be mutually exclusive with other PI3K-AKTactivating alterations, although PIK3CA mutations
frequently coexist with other alterations (such as
HER2, K-Ras and PTEN) in several types of tumors.
Endometrial cancer is one of the tumor types inwhich either chromosomal instability (CIN) or
microsatellite instability (MSI) may occur. It is known
to possess mutations frequently in the Ras-PI3K(phosphatidylinositol
3'-kinase)pathway.
We
performed a comprehensive genomic survey in 31
endometrial carcinomas with paired DNA for
chromosomal imbalances (25 by the 50K and 6 by the
250K single-nucleotide polymorphism (SNP) array),and screened 25 of the 31 samples for MSI status andmutational status in the Ras-PI3K pathway genes. We
detected five or more copy number changes (classified
as CIN-extensive) in 9 (29%), 1 to 4 changes(CIN-intermediate) in 17 (55%) and no changes(CIN-negative) in 5 (16%) tumors. Positive MSI wasless common in CIN-extensive tumors (14%),compared with CIN-intermediate/negative tumors(50%), and multivariate analysis showed that CINextensive is an independent poor prognostic factor.
SNP array analysis unveiled copy number neutral
LOH at 54 loci in 13 tumors (42%), including four atthe locus of PTEN. In addition to eight (26%) tumors
with PTEN deletions, we detected chromosomal
imbalances of NF1, K-Ras and PIK3CA in four (13%),four (13%) and six (19%) tumors, respectively. In all,
7 of the 9 CIN-extensive tumors harbor deletions in
the loci of PTEN and/or NF1, whereas all the 10
MSI-positive tumors possess PTEN, PIK3CA and/or
K-Ras mutations. Our results showed that genomic
alterations in the Ras-PI3K pathway are remarkably
widespread in endometrial carcinomas, regardless ofthe type of genomic instability, and suggest that thedegree of CIN is a useful biomarker for prognosis inendometrial carcinomas.
3 Molecular targeted therapies in gynecologic
malignancies
The PI3K/mTOR (mammalian target of rapamycin)
pathway is frequently activated in endometrial cancer
through various
PI3K/AKT-activating genetic
alterations. We examined the antitumor effect of
NVP-BEZ235-a dual PI3K/mTOR inhibitor--andRAD001-an mTOR inhibitor--in 13 endometrial
cancer cell lines, all of which possess one or morealterations in PTEN, PIK3CA, and K-Ras. We also
combined these compounds with a MAPK pathway
inhibitor (PD98059 or UO126) in cell lines with
K-Ras alterations (mutations or amplification). PTEN
mutant cell lines without K-Ras alterations (n = 9)
were more sensitive to both RAD001 and NVPBEZ235 than were cell lines with K-Ras alterations(n = 4). Dose-dependent growth suppression was more
drastically induced by NVP-BEZ235 than by RAD001
in the sensitive cell lines. G1 arrest was induced by
NVP-BEZ235 in a dose-dependent manner. We
observed in vivo antitumor activity of both RAD001
and NVP-BEZ235 in nude mice. The presence of a
MEK inhibitor, PD98059 or UO126, sensitized the
K-Ras mutant cells to NVP-BEZ235. Robust growth
suppression by NVP-BEZ235 suggests that a dual
PI3K/mTOR inhibitor is a promising therapeutic forendometrial carcinomas. Our data suggest that

173

mutational statuses of PTEN and K-Ras might beuseful predictors of sensitivity to NVP-BEZ235 incertain endometrial carcinomas.
(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
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 2011
(1) Kojima S, et al. Characterization of gut-derived
intraepithelial lymphocyte (IEL) residing inhuman papillomavirus (HPV)-infected intraepithelial neoplastic lesions. Am J Reprod
Immunol 66:435-443, 2011(2) Shoji K, et al. Aromatase inhibitor anastrozole asa second-line hormonal treatment to a recurrent
low-grade endometrial stromal sarcoma: a casereport. Med Oncol 28:771-774, 2011

(3) Tanikawa M, et al. Multifunctional transcription
factor TFII-I is an activator of BRCA1 function.
Br J Cancer 104:1349-1355, 2011

174

Department of Perinatal Medicine
Professor
Shiro Kozuma

Tomoyuki Fujii

Lecturer
Yoshimasa Kamei

Takahiro Yamashita

Homepage http://www.iiosan.umin.jp/index.htm
http://square.umin.ac.jp/tkyobgyn/
Organization
The Department of Perinatal Medicine is organizedby two professors and two lecturers, being directed
practically by Professor Shiro Kozuma, the chairmanof the Department of Obstetrics and Gynecology. All
the staff members are taking part in both the clinicaland research activities, as well as the teachingactivities, with 15 associates of the University ofTokyo Hospital. For the clinical aspect, they are
engaged with in-patient and out-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%.

References published in 2011(1) Isono W, et al. Prediction model for the incidence of
emergent cesarean section during induction of labor
specialized in nulliparous low-risk women. J Obstet

175

Gynaecol Res 37:1784-1791, 2011
(2) Wang B, et al. High mobility group box 1(HMGB1) levels in the placenta and in serum in
preeclampsia.. Am J Reprod Immunol 66:143-148,
2011

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

177

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

Associate Professor
Sachiko Kitanaka, M.D., Ph.D. Kohmei Ida, M.D., Ph.D.
Naoto Takahashi, M.D., Ph.D. (Department of Maternal, Fetal and Neonatal Medicine)

Lecturer
Tatsuo Katori, M.D., Ph.D., Shinya Tsuchida, M.D., Ph.D., Masakazu Mimaki, M.D., Ph.D.,
Yutaka Harita, M.D., Ph.D., Junko Takita, M.D., Ph.D. (Department of Cell Therapy andTransplantation Medicine)

Associate
Nobutaka Shimizu, M.D., Ph.D., Mitsuteru Hiwatari, M.D., Ph.D., Masato Takeuchi, M.D.,
Hiroyuki Iwasaki, M.D., Ken-ichirou Miura, M.D., Tsuyoshi Isojima, M.D., Ryo Inuzuka,
M.D., Ayaka Ishii,M.D., Takahiro Shindo,M.D., Koujirou Yasui, M.D., Taiyu Hayashi, M.D.,
Ai Motomura, M.D., Kouhei Kashima, M.D., Yuki Kimura, M.D., Nagahisa Takahashi,
M.D., Shunpei Uchimo, M.D., Ryosuke Shiozawa, M.D.
(As of March 31, 2012)

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, 3 associate
professors, 5 lecturers, 17 associate professors, 11senior residents, 1 research fellow, and 21 graduate
students on March 31, 2012.
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

178

beds in the neonatal intensive care unit (NICU), 15
beds in the growing 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 4,000g often associated withcongenital disorders requiring invasive interventions.
A variety of patients with diseases, such ashematological/oncological disorders (acute leukemia,
neuroblastoma, Ewing sarcoma, osteosarcoma, brain
tumors, etc.), cardiac disorders (congenital heartdiseases and Kawasaki disease), neuromusculardisorders, immunological/allergic disorders (common
variable immunodeficiency, chronic granulomatous
disease and bronchial asthma), renal and urinary tract
diseases (nephrotic syndrome, chronic glomeluronephritis, purpura nephritis and renal and/or urinary
tract
anomalies),
endocrinologicaldisorders,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.

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/metabolism, immunology/
allergy,andneonatology.
We
also
have
multidisciplinary 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: To assess theinvolvements of MYEOV and NEGR1 in thepathogenesis of neuroblastoma, we analyzed thesegenes in 55 neuroblastomas, and revealed that boththese genes are functional gene targets in a subsetof neuroblastoma. Moreover, we undertook wholeexome re-sequencing in advanced neuroblastoma
genomes using next-generation sequencer, anddetected several novel somatic mutations in ourseries. In addition, we found novel splicesome
pathway mutations in 2/27 of JMML cases, andfurther illustrate the large differences in thefrequencies of genetic aberrations found inpediatric MDS/JMML and adult MDS/CMML.
② Nephrology group: We analyzed molecularmechanism of TRPC6 channel activation, anddiscovered role of calcium signaling in podocyte
in the pathogenesis of nephrotic syndrome. We
also found the association of nephrotic syndromeand cord blood stem cell transplantation. Analysesof obstructive renal dysplasia and nephrogenic
diabetes insipidus were performed and the novel

179

insights in the pathogenesis of these diseases were
unraveled.
③ Endocrinology and Metabolism group: Molecularanalyses of genes involved in hereditary rickets
and a novel insight in their functional
consequences are studied. Genetic factors forvitamin D deficiency are analyzed.
④ Cardiology group: We have started constructing agenomic library for genome-wide association
study for congenital heart disease.
⑤ Neurology Group: The pathogenetic mechanismof acute encephalopathy as well as genetic basis ofcongenital CNS anomalies is investigated.
Molecular and clinical analyses of mitochondrial
disorders and the neuropathological studies ofperinatal brain damage are also performed.
⑥ Neonatology group: We conducted a research on
the establishment of the methods of newborn
screening system about the patients of congenital
cytomegalovirus infection. Also a trial of making
new artificial milk contains less protein equivalentof human milk.
⑦ Immunology group: Research area of interest
includes refractory Kawasaki disease andepidemiology of childhood infectious disease.

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Horie H, Kondo S, Watanabe K, Oue T, Tajiri T,
Kamimatsuse A, Ohnuma N, Hiyama E: Outcomeof hepatoblastomas treated using the JapaneseStudy Group for Pediatirc Liver Tumor (JPLT)
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27:1-8, 2011
Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike
M, Nishio C, Higashida M, Mikasa H, Nakaya Y,
Takanashi S, Igarashi T, Kitagawa T, Sata M:
Coronary atherosclerosis is associated withmacrophage polarization in epicardial adipose
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Hirata Y, Kurobe H, Akaike M, Chikugo F, Hori T,
Bando Y, Nishio C, Higashida M, Nakaya Y,

Kitagawa T, Sata M: Enhanced inflammation in
epicardial fat in patients with coronary arterydisease. Int Heart J 52: 139-142, 2011
5. Hirata Y, Soekia T, Yamadaa H, Shiotac A,
Shimabukuroc M, Sakaid Y, Nakayamae M,
Matsumotoe K, Igarashi T, Sata M: A synthetic
prostacyclin agonist, ONO-1301, ameliorates
ventricular remodeling after acute myocardial
infarction via upregulation of HGF in rat.
Biomedicine & Aging Pathology 1: 90–96, 2011
6. Ichioka M, Suganami T, Tsuda N, Shirakawa I,
Hirata Y, Satoh-Asahara N, Shimoda Y, Tanaka M,
Kim-Saijo M, Miyamoto Y, Kamei Y, Sata M,
Ogawa Y: Increased expression of macrophageinducible C-type lectin in adipose tissue of obese
mice and humans. Diabetes 60: 819-826, 2011
7. Ikeda H, Shiojima I, Oka T, Yoshida M, Maemura
K, Walsh K, Igarashi T, Komuro I: Increased
Akt-mTOR signaling in lung epithelium isassociated with respiratory distress syndrome inmice. Mol Cell Biol 31: 1054-1065, 2011
8. Kanda S, Harita Y, Shibagaki Y, Sekine T,
Igarashi T, Inoue T, Hattori S. Tyrosine
phosphorylation-dependent activation of TRPC6
regulated by PLC-γ1 and nephrin: effect ofmutations associated with focal segmental
glomerulosclerosis. Mol Biol Cell 22:1824-1835,
2011
9. Kurobe H, Aihara KI, Higashida M, Hirata Y,
Nishiya M, Matsuoka Y, Kanbara T, Nakayama T,
Kinoshita H, Sugano M, Fujimoto E, Kurobe A,
Sugasawa N, Kitaichi T, Akaike M, Sata M,
Matsumoto T, Kitagawa T:
Ezetimibemonotherapy ameliorates vascular function inpatients with hypercholesterolemia throughdecreasing oxidative stress. J Atheroscler Thromb
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10. Makita N, Isojima T, Hiwatari M, Kitanaka S, Ida
K, Iiri T： Painful thyroiditis and subsequent
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11. Miura K, Sekine T, Nishimura R, Kanamori Y,
Yanagisawa A, Sakai K, Nagata M, Igarashi T:
Morphological and functional analyses of two
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180

Furuya A, Koh K, Takita J, Ida K, Igarashi T:
Early occurrence of nephrotic syndrome
associated with cord blood stem celltransplantation. Clin Exp Nephrol 2011 Oct 12.
[Epub ahead of print]
13. Mizuno Y, Takahashi K, Igarashi T, Saito M,
Mizuguchi
M:
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infection-like
syndrome with intaracranial calcification. Brain& Develop 33: 530-533, 2011
14. Nakamura Y, Awa S, Kato H, Ito YM, Kamiya A,
Igarashi T: Model combining hydrodynamics andfractal theory for analysis of in vivo peropheral
pulmonary and systemic resistance of shuntcardiac defects. J Theoret Biology 287: 64-73,
2011
15. Ogawa S, Takita J, Sanada M, Hayashi Y:
Oncogenic mutations of ALK in neuroblastoma.
Cancer Sci 102: 302-308, 2011
16. Oki K, Takita J, Hiwatari M, Nishimura R,
Sanada M, Okubo J, Adachi M, Sotomatsu M,
Kikuchi A, Igarashi T, Hayashi Y, Ogawa S:
IDH1 and IDH2 mutations are rare in pediatricmyeloid malignancies. Leukemia 25: 1-3, 201117. Shiba N, Taki T, Park MJ, Nagasawa M,
Kanazawa T, Takita J, Ohnishi H, Sotomatsu M,
Arakawa H, Hayashi Y: CBL mutation inchildhood therapy-related leukemia. Leukemia
25: 1356-1358, 201118. Soeki T, Niki T, Kusunose K, Bando S, Hirata Y,
Tomita N, Yamaguchi K, Koshiba K, Yagi S,
Taketani Y, Iwase T, Yamada H, Wakatsuki T,
Akaike M, Sata M: Elevated concentrations ofpentraxin 3 are associated with coronary plaquevulnerability. J Cardiol 58: 151-157, 2011
19. Takahashi K, Oka A, Mizuguchi M, Saitoh M,
Takita J, Sato A, Mimaki M, Kato M, Ogawa S,
Igarashi T: Interstitial deletion of 13q14.13-q32.3
presenting with Arima syndrome and bilateralretinoblastoma. Brain & Develop 33: 353-356,
2011
20. Takita J, Chen Y, Sanada M, Adachi M, Ohki K,
Nishimura R, Hanada R, Igarashi T, Hayashi Y,
Ogawa S: Aberrations of NEGR1 on 1p31 and
MYEOV on 11q13 in neuroblastoma. Cancer
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21. Tay EL, Papaphylactou M, Diller GP,
Alonso-Gonzalez R, Inuzuka R, Giannakoulas G,

Harries C, Wort SJ, Swan L, Dimopoulos K,
Gatzoulis MA: Quality of life and functional
capacity can be improved in patients with
Eisenmenger syndrome with oral sildenafil
therapy. Int J Cardiol 149: 372-376, 2011
22. Tay EL, Peset A, Papaphylactou M, Inuzuka R,
Alonso-Gonzalez R, Giannakoulas G, Tzifa A,
Goletto S, Broberg C, Dimopoulos K, Gatzoulis
MA: Replacement therapy for iron deficiency
improves exercise capacity and quality of life inpatients with cyanotic congenital heart disease
and/or the Eisenmenger syndrome. Int J Cardiol
151: 307-312, 2011
23. Tonoki H, Harada N, Shimokawa O, Yosozumi A,
Monzaki K, Satoh K, Kosaki R, Sato A,
Matsumoto N, Iizuka S: Axenfeld–Rieger
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Clinical, molecular-cytogenetic, and DNA array
analyses of three patients with chromosomal
defects at 6p25. Am J Med Genet A 155:2925-2932, 201124. Yoshida K, Sanada M, Kato M, Kawahata R,
Matsubara A, Takita J, Shih LY, Mori H, Koeffler
HP, Ogawa S: A nonsense mutation of IDH1 inmyelodysplastic syndromes and related disorders.
Leukemia 25: 184-186, 2011
25. Yoshimatsu Y, Yamazaki T, Mihira H, Itoh T,
Suehiro J, Yuki K, Harada K, Morikawa M, Iwata
C, Minami T, Morishita Y, Kodama T, Miyazono
K, Watabe T: Ets family members induce
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throughphysicalandfunctional interaction with Prox1. J Cell Sci
124(Pt 16): 2753-2762, 2011

181

Department of Pediatric Surgery
Professor
Tadashi Iwanaka, M.D., Ph.D.

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

Hiroaki Komuro, M.D., Ph.D.

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

Research Associate
Masahiko Sugiyama, M.D.,

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

Hiroshi Kawashima, M.D.,

Kan Suzuki., M.D., Ph.D.

Homepage

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

History and organization
In 1951, a pediatric surgical team was established in
the Department of Second Surgery. Subsequently, in
1961, a pediatric surgical research team, which would
eventually research diaphragmatic hernia, wasestablished with a chief, Dr. Ishida, by Professor
Kimoto.
In 1971, it was authorized as the first clinicaldepartment of Pediatric Surgery in a National
University.
A pediatric intensive care unit was founded with Prof.
Ishida in 1973, and a ward which could accommodate
mainly pediatric surgical patients was completed.
Assistant Prof. Saito assumed office as the first
Director of this Pediatric Surgery clinical department.
Dr. Sumio Saito became Professor of PediatricSurgery in 1983. Professor Saito had enthusiastically
performed clinical studies such as operation
techniques and the use of biliary atresia.
Dr. Nakajo took office as a professor in 1985. Prof.
Nakajo had developed original operative procedures
such as a radical operation for umbilical hernia and ananti-reflex valve for biliary atresia. These original
operative procedures have been inherited by pediatricsurgeons as Nakajo methods.
Our department was authorized as the Department ofPediatric Surgery in 1989 after Kyusyu University by
the Ministry of Education.
Dr. Yoshiaki Tsuchida assumed the role of Professor in1990 and published many highly regarded articles,
mainly concerning neuroblastoma and Wilm’s tumor
from research and clinical work.
In 1995, the department was reorganized as the
Reproductive, Developmental and Aging Science,
Pediatric Science and Pediatric Surgery, due to the
University policy for the Graduate School.
In 1997, Dr Hashizume became Professor in the
Department of Pediatric Surgery. He started livingrelated partial liver transplantation (LRPLT) for
children with Professor Makuuchi in the Department
of Second Surgery.
Dr. Tadashi Iwanaka became the sixth Professor in
August 2006. The present staffs are the chief professor,
one associate professor, one lecturer, four research
associates, two senior residents, and three graduate
students. More than 20 members of our department
shoulder the clinical work as pediatric surgeons.

Clinical activities
Staffs higher than research associate level take chargeof the out-patient clinic from Monday through Friday.
The pediatric surgical outpatient clinic takes place in

182

the same location as the pediatric outpatient clinic andwe closely cooperate with pediatricians to diagnose
and treat patients. We also have specialized outpatient
clinics, liver and biliary tract clinics and a tumor clinic.
Recently, a second-opinion clinic has opened withcareful detailed explanations and this has received afavorable reception.
Our ward is on the second floor south of the hospital A
wing. Other pediatric surgical patients are also
admitted to this ward. We have 16 beds in the ward
and about 400 patients a year are hospitalized. Most
operation cases are inguinal hernia, but we have othercases such as respiratory surgery disease, neonatal
digestive organ obstructions, infant malignant tumors
such as Wilms' tumor and neuroblastoma, biliary tract
diseases such as biliary tract dilatation and biliaryatresia, respiratory anomalies such as trachea stenosis
and lung cysts, gastrointestinal anomalies, andurological disorders including hydronephrosis andvesicoureteral reflux.
We compare positively with Pediatric Surgery at otherinstitutions that perform endoscopic surgery(laparoscopic surgery/thorascopic surgery). We havedeveloped an endoscopic surgery technique forpediatric diseases not covered by insurance to apply toadvanced medical care. Furthermore, we surgicallymanage seriously ill mentally and physicallyhandicapped infants and nervous system intractabledisease patients to improve their quality of life, andwe cooperate with pediatricians (neonatologists) totreat patients with prenatal diagnosis

Education
We expose 1st and 2nd year students to our dailyclinical work as well as research work during “Free
Quarter” and “Research Lab Visit” courses. Thesestudents are guided to be concerned with clinical areas
and are in charge of part of the research project. The
students hold a results announcement party at the endof training. For M2 students, general pediatric surgery
and neonatal surgery instruction is given by theprofessor and the lecturer.
An education program is also provided for M3 and M4
students for 5 days.
The bedside education of pediatric surgery consists ofparticipation in clinical conferences, attendance at

operations, and small group lectures concerning
neonatal surgery, pediatric surgical oncology, pediatrichepatobiliary surgery, and pediatric emergency
medicine which include the practice of cardiac
massage and intra-tracheal intubation using
mannequins for practice.
We take charge of the core surgical curriculum in the“super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge about pediatric surgical disease andsurgery, and hemodynamic and respiratory evaluation
as well as basic surgical techniques and patientmanagement.

Research activities
Professor Iwanaka has established a low invasive
operation study group and developed experiments forendscopic surgery using white rabbits in the animal
resources research facilities. This study group tries todevelop endoscopic surgery for infants. Prof. Iwanaka
also provides a training program for infant endscopic
surgery for members of our department. In addition,
he has started the project of robotic surgery to perform
radical operation with laparoscopic surgery techniquefor biliary atresia. This group creates multiple
functional forceps 3 mm in a diameter for robotic
surgery system at first. And they are developing
radical operation for long gap esophageal atresia byusing the latest technique of NOTES (Natural OrificeTransluminal Endoscopic Surgery).
The intestinal tract immunity study group was thefirst to start infant digestive organ function activation
medical treatment using a probiotic, Shinbiotic, withgood clinical effects. Further more inspection is
performed in order to do randomized control study inclinical course.
The regenerative medicine study group focused on
the research on regeneration of trachea. A newlaboratory in the Department of Tissue Engineering
was founded to perform not only conventional animal
experiments but also human experiments to fabricate a
trachea in the clinical course.
The researches on development of animal models
for congenital anomalies and their fetal treatments arein progress.
The tumor study group analyzes the genes related to183tumor development and suppression. Further more,
new tumor marker is studying by using tumor tissues
and blood samples.

References(1) Kanazawa S, Fujihara Y, Sakamoto T, Asawa Y,
Komura M, Nagata S, Takato T, Hoshi K. Tissue
responses against tissue-engineered cartilage
consisting of chondrocytes encapsulated within
non-absorbable hydrogel. J Tissue Eng Regen
Med. 2011 Sep 13. doi: 10.1002/term.458.
(2) Komura M, Kim J, Atala A, Yoo J, Lee SJ The
Digit, Engineering of phalanges snd small joints.
Princeple of Regenerative Medicine. 2011; 2ndedition, Edited by Atala A et al, pp1091-1101
Academic Press, Burlington, MA,USA(3) Iwanaka T, Morikawa Y, Yamataka A, Nio M,
Segawa O, Kawashima H, Sato M, Terakura H,
Take H, Hirose R, Yagi M Skill qualifications inpediatric minimally invasive surgery. Pediatr
Surg Int. 2011; 27: 727-731(4) Iwanaka T, Kawashima H, Tanabe Y, Aoki T
Laparoscopic gastric pull-up and thoracoscopic
esophago-esophagostomy
combinedwithintrathoracic fundoplication for long-gap pureesophageal atresia. J Laparoendosc Adv Surg
Tech A. 2011;21:973-978.
(5) Yoshida M, Tanaka M, Gomi K, Ohama Y,
Kigasawa H, Iwanaka T, Tanaka Y Malignant
steroidogenic tumor arising from sacrococcygeal
mature teratoma. Hum Pathol. 2011; 42:
1568-1572(6) Ishimaru T, Iwanaka T, Kawashima H, Terawaki
K, Kodaka T, Suzuki K, Takahashi M : A pilot
study of laparoscopic gastric pull-up by using thenatural orifice translumenal endoscopic surgery
technique: a novel procedure for treating longgap esophageal atresia (type a). J Laparoendosc
Adv Surg Tech A. 2011;21:851-857.
(7) Kanamori Y, Iwanaka T, Sugiyama M, Komura M,
Shibahara J Congenital anterior neck cysts
classified as “thyroglossal anomalies” Pediatr Int
2011; 53: 591-594.
(8) Kanamori Y, Terawaki K, Takayasu H, Sugiyama
M, Komura M, Kodaka T, Suzuki K, Kitano Y,
Kuroda T, Iwanaka T
Interleukin 6 andinterleukin 8 play important roles in systemic
inflammatory response syndrome of meconium
peritonitis. Surg Today 2011 Epub 2010;45:
2386-2389.
(9) Usui N, Kitano Y, Okuyama H, Saito M, Morikawa
N, Takayasu H, Nakamura T, Hayashi S, Kawataki
M, Ishikawa H, Nose K, Inamura N, Masumoto K,
Sago H. Reliability of the lung to thorax transverse
area ratio as a predictive parameter in fetuses withcongenital diaphragmatic hernia. Pediatr Surg Int.
2011;27:39-45(10) Sato K, Gotoh C, Uchida H, Kawashima H,
Yoshida M, Kitano Y, Kishimoto H. Sialolipoma of
the submandibular gland in a child. J Pediatr Surg.
2011;46:408-410.
(11) Sakamoto S, Shigeta T, Hamano I, Fukuda A,
Kakiuchi T, Matsuno N, Tanaka H, Nakagawa A,
Kasahara M. Graft outflow venoplasty on reduced
left lateral segments in living donor livertransplantation for small babies. Transplantation.
2011;91:e38-40.
(12) Udagawa T, Kamei K, Ogura M, Tsutsumi A,
Noda S, Kasahara M, Fukuda A, Sakamoto S,
Shigeta S, Tanaka H, Kuroda T, Matsuoka K,
Nakazawa A, Nagai T, Uemura O, Ito S
Sequential liver-kidney transplantation in a boy
with congenital hepatic fibrosis and nephronophthisis from a living donor. Pediatr Transplant.
2011 Nov 30. doi: 10.1111/j.1399-3046. 2011.
01611.x.
(13) Fukuda A, Sakamoto S, Shigeta T, Kakiuchi T,
Matsuno N, Tanaka H, Kitamura M, Nosaka S,
Nakazawa A, Kasahara M : Hepatobiliary
scintigraphy for the assessment of biliary
stricture after pediatric living donor livertransplantation for hepaticojejunostomy reconstruction: the value of the excretion rate at 60
min.Pediatr Transplant. 2011 Sep;15(6):594-600.
doi: 10.1111/j.1399-3046.2011.01532.x.
(14) Shigeta T, Kasahara M, Sakamoto S, Fukuda A,
Kakiuchi T, Matsuno N, Tanaka H, Miyazaki O,
Isobe Y, Nosaka S, Nakazawa A : Balloonoccluded retrograde transvenous obliteration fora portosystemic shunt after pediatric living-donorliver transplantation.J Pediatr Surg. 2011;46:
e19-22.

184(15) Tanaka H, Honna T, Muto M, Fujino A,
Kasahara M, Kitano Y, Kuroda T :Selective
ligation of portal vein and hepatic artery for
ruptured hepatocellular carcinoma in a
13-year-old boy. J Pediatr Surg. 2011;46:973-977(16) Sasaki K, Kasahara M, Fukuda A, Kimura T,
Shigeta T, Tanaka H, Nakagawa S, Ito S,
Nakagawa A :Living-donor liver transplantation
using hyper-reduced graft for a neonatal
fulminant hepatic failure. Pediatr Int. 2011;53:
247-248(17) Komuro H, Ono K, Hoshino N, Urita Y, Gotoh C,
Fujishiro J, Shinkai T, Ikebukuro K Bile duct
duplication as a cause of distal bowel gas inneonatal duodenal obstruction. J Pediatr Surg.
2011; 46:2301-2304(18) Fujishiro J, Urita Y, Shinkai T, Gotoh C, Hoshino
N, Ono K, Komuro H Clinical characteristics ofliver fibrosis in choledochal cyst. J Pediatr Surg.
2011; 46: 2296-2300(19) Fujishio J, Kaneko M, Urita Y, Hoshino N, Jinbo
T, Sakamoto N, Suzuki H, Komuro H Enteric
duplication cyst of the pancreas with duplicatedpancreatic duct. J Pediatr Surg. 2011;46:e13-6

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

Yasuhiro Yamaguchi, M.D., Ph.D.

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

Research Associate
Kotaro Azuma, M.D., Ph.D.

Hidetaka Ota, M.D., Ph.D.

Taro Kojima, M.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. 359 new
and a total of 19,425 patients visited the out-patient
clinic last 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.

disorderPublications
1.

Research
1) Research on the molecular mechanism of vascular
calcificationi) Molecular biology of vascular calcification invitro using vascular smooth muscle cells andblood vessel sliceii) 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:
Association of vascular and neuronal senescenceand the role of Sirt1
4) Molecular biology and treatment of sarcopenia5) Multicenter-investigation of the optimal treatment
strategy for hypertension or lipid disorder in theelderly6) Clinical study on metabolic syndrome in theelderly7) Biomarkers of dementia, caregiver’s stress andgeriatric syndromes8) Research on appropriate healthcare for the elderly
including pharmacotherapy9) Expression and regulation of nuclear receptors inosteoblast and osteoclast10) Molecular mechanism under the treatment of
osteoporosis11) Genetic analysis of osteoporosis and osteoarthritis
12) Identification and functional analysis of the target
gene networks associated with hormone
responsiveness in prostate and breast cancers13) Role of nuclear receptors in senescence andcarcinogenesis14) Molecular mechanism of vitamin K function andits roles in aging
15) Diagnosis and prevention of aspiration pneumonia
16) Novel roles of antimicrobial peptide, defensin17) Adrenomedullin and airway hyperresponsiveness18) Klotho protein and vitamin D in lung19) Clinical investigation of sleep-related breathing

2.

3.

4.

5.

6.

7.

8.

Arai H, Ouchi Y, Yokode M, Ito H, Uematsu H, Eto
F, Oshima S, Ota K, Saito Y, Sasaki H, Tsubota K,
Fukuyama H, Honda Y, Iguchi A, Toba K, Hosoi T,
Kita T. Members of Subcommittee for Aging.
Toward the realization of a better aged society:messages from gerontology and geriatrics. Geriatr
Gerontol Int. 2012; 12: 16-22.
Azuma K, Urano T, Watabe T, Ouchi Y, Inoue S.
PROX1 suppresses vitamin K-induced transcriptional activity of steroid and xenobiotic receptor.
Genes Cells. 2011; 16: 1063-1070.
Endo H, Ikeda K, Urano U, Horie-Inoue K,
Inoue S. Terf/TRIM17 stimulates degradation of
kinetochore protein ZWINT and regulates cellproliferation. J Biochem. 2012; 151: 139-144.
Fukai S, Akishita M, Yamada S, Ogawa S,
Yamaguchi K, Kozaki K, Toba K, Ouchi Y.
Plasma sex hormone levels and mortality indisabled older men and women. Geriatr
Gerontol Int. 2011. 11; 196-203.
Fujimura T, Takahashi S, Urano T, Tanaka T,
Zhang W, Azuma K, Takayama K, Obinata D,
Murata T, Horie-Inoue K, Kodama T, Ouchi Y,
Homma Y, Inoue S. Clinical significance ofsteroid and xenobiotic receptor (SXR) and its
targeted gene CYP3A4 in human prostate cancer.
Cancer Sci. 2012; 103: 176-180.
Iijima K, Shimokado K, Takahashi T, Morimoto
S, Ouchi Y, Members of JGS Disaster
Supportive Center. Actions of the Japan GeriatricSociety on the 2011 Off the Pacific Coast of
Tohoku Earthquake: First Report. Geriatr
Gerontol Int. 2011; 11: 525-526.
Kojima T, Akishita M, Nakamura T, Nomura K,
Ogawa S, Iijima K, Eto M, Ouchi Y. Associationof polypharmacy with fall risk among geriatricoutpatients. Geriatr Gerontol Int. 2011; 11:438-444.
Kou I, Takahashi A, Urano T, Fukui N, Ito H,
Ozaki K, Tanaka T, Hosoi T, Shiraki M, Inoue S,
Nakamura Y, Kamatani N, Kubo M, Mori S,
Ikegawa S. Common variant s in a novel gene,
FONG on chromosome 2q33.1 confer risk of

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9.

10.

11.

12.

13.

14.

15.

16.

osteoporosis in Japanese. PLoS ONE. 2011; 6:e19641.
Morimoto S, Iijima K, Kuzuya M, Hattori H,
Yokono K, Takahashi T. Guidelines for nonmedical care providers to detect illnesses inelderly evacuees after the 2011 earthquake off
the pacific coast of tohoku. J Am Geriatr Soc.
2011; 59: 2189-2191.
Nagai K, Kozaki K, Sonohara K, Akishita M,
Toba K. Relationship between interleukin-6 andcerebral deep white matter and periventricular
hyperintensity in elderly women. Geriatr
Gerontol Int. 2011; 11: 328-332.
Noda H, Iso H, Yamashita S, Ueno H, Yokode M,
Yamada N, Ouchi Y. Defining Vascular Disease(DVD) Research Group. Risk stratification basedon metabolic syndrome as well as non- metabolicrisk factors in the assessment of carotid atherosclerosis. J Atheroscler Thromb. 2011; 18:504-512.
Obinata D, Takayama K, Urano T, Murata T,
Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K,
Homma Y, Ouchi Y, Takahashi S, Inoue S. Oct1
regulates cell growth of LNCaP cells and is aprognostic factor for prostate cancer. Int J
Cancer. 2012; 130: 1021-1028.
Obinata D, Takayama K, Urano T, Murata T,
Ikeda K, Horie-Inoue K, Ouchi Y, Takahashi S,
Inoue S. ARFGAP3, an androgen target gene,promotes prostate cancer cell proliferation andmigration. Int J Cancer. 2012; 130: 2240-2248.
Ota H, Akishita M, Akiyoshi T, Kahyo T, Setou
M, Ogawa S, Iijima K, Eto M, Ouchi Y.
Testosterone deficiency accelerates neuronal andvascular aging of SAMP8 mice: protective roleof eNOS and SIRT1. PLoS ONE. 2012; 7:e29598.
Takahashi T, Iijima K, Kuzuya M, Hattori H,
Yokono K, Morimoto S. Guidelines fornon-medical care providers to manage the firststeps of emergency triage of elderly evacuees.
Geriatr Gerontol Int. 2011; 11: 383-394.
Takemura A, Iijima K, Ota H, Son BK, Ito Y,
Ogawa S, Eto M, Akishita M, Ouchi Y. Sirtuin1
retards hyperphosphatemia-induced calcificationof vascular smooth muscle cells. Arterioscler
Thromb Vasc Biol. 2011; 31: 2054-2062.

17. Urano T, Narusawa K, Shiraki M, Sasaki N,
Hosoi T, Ouchi Y, Nakamura T, Inoue S. Singlenucleotide polymorphism in the hyaluronan andproteoglycan link protein 1 (HAPLN1) gene isassociated with spinal osteophyte formation anddisc degeneration in Japanese women. Eur Spine
J. 2011; 20: 572-577.
18. Urano T, Shiraki M, Yagi H, Ito M, Sasaki N,
Sato M, Ouchi Y, Inoue S. GPR98/Gpr98 gene isinvolved in the regulation of human and mousebone mineral density. J Clin Endocrinol Metab.
2012; 97: E565-E574.
19. Yamaguchi Y, Hibi S, Ishii M, Hanaoka Y, Kage
H, Yamamoto H,Yamauchi Y, Eto M, Nagase T,
Ouchi Y. Pulmonary features associated withbeing underweight in older men. J Am Geriatr
Soc. 2011; 59: 1558-1560.

Surgical Sciences
1. Surgery

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Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Murakawa, Tomohiro

StaffsNagayama, Kazuhiro 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 Tsuduki, Masao adopted
the modified Coryllos’s thoracoplasty for thetreatment of the pulmonary tuberculosis in 1934. They
initiated thoracoscopy for the treatment of the
tuberculosis in our country. After the successful
application of the antituberculous drugs, surgicaltreatment of the thoracic malignant neoplasms was the
major concern of the thoracic surgery.
The Department of Cardiothoracic Surgery, The
University of Tokyo, was established in December 15,
1964 as the first department of this field along withthe cardiovascular surgery in the Japanese national
universities. Since then it has played an internationallyleading role and contributed to development of the
field in our country.
Professors and Chairs in the history of thedepartment are as follows: Kimoto, Seiji (1964.12.15~ 1968.3.31), Saigusa, Masahiro (1968.4.1 ~ 1981.
3.31), Asano, Ken-ichi (1981.4.1 ~ 1986.3.31), Furuse,
Akira (1986.4.1 ~ 1997.3.31) and Takamoto, Shinichi(1997.6.1 ~ 2009.3.31).
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1997.
The mission of the Department of Thoracic Surgery
is to improve the patients with diseases of the thoracic

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

Clinical activities
Four staffs (Nakajima J, Murakawa T, Nagayama K
and Sano A), who are certificated as members of theJapanese Board of General Thoracic Surgery, are in
charge of the Department of Thoracic Surgery, University of Tokyo Hospital. They specialize in surgicaltreatment of the diseases of the respiratory and the
mediastinal organs and the chest wall, except for diseases of the esophagus and mammary glands. Approximately 300 surgeries are performed in the department in 2011.
Primary lung cancer has been the leading cause ofdeath among the malignant neoplasms in our country.
Basic and clinical investigations for the treatment oflung cancer are very important, because number of thepatients who died of the lung cancer has been increasing. In our department, the staffs are engaging
the clinical works, studies and educations of diagnostics and therapeutics of the lung cancer and 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 accom-

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plished through thoracoscopy. Researches on
less-invasiveness, oncological advantage of the thoracoscopic 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 with paraneoplastic 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.
500
450
400
350
300
250
200
150
100
50
0

Inpatient, total
Surgery, total
Lung cancer
Pulm meta(Figure) Number of inpatient, surgery (total), surgery oflung cancer, and surgery of pulmonary
metastasis by year. Pulm meta, pulmonary
metastasis

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

Current researches
Main subjects of current research at present include
basic and clinical studies on the malignant neoplasmsin the thorax, transplantation of the thoracic organs
and the cryopreserved tissues. Recently we conductedclinical studies on the immunotherapy with adopted
gamma- delta- T-cell for the treatment of the advanced
non-small cell lung cancer and the pulmonoary
metastasis from extrathoracic organs.
We are now preparing clinical lung transplantation
program in this hospital with the usage of lungs frombrain-dead donors.
The following are the major themes under research:(1) Minimally invasive surgeries for thoracic
malignant neoplasms.
(2) Analysis of the factors influencing the prognosis oflung cancer or mediastinal neoplasms.
(3) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(4) Clinical trial and basic research on adoptive
anticancer immunity of the autologous gammadelta-T-cell for the treatment of the recurrent
primary lung cancer or pulmonary metastasis fromcolorectal 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. Sakamoto M, Nakajima J, Murakawa T, Fukami T,
Yoshida Y, Murayama T, Takamoto S, Matsushita
H, Kakimi K. Adoptive immunotherapy foradvanced non-small cell lung cancer using

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zoledronate-expanded γδTcells: a phase I clinicalstudy. J Immunother. 2011;34:202-11.
2. Kakimi K, Isobe M, Uenaka A, Wada H, Sato E,
Doki Y, Nakajima J, Seto Y, Yamatsuji T, Naomoto
Y, Shiraishi K, Takigawa N, Kiura K, Tsuji K,
Iwatsuki K, Oka M, Pan L, Hoffman EW, Old LJ,
Nakayama E. A phase I study of vaccination with
NY-ESO-1f peptide mixed with Picibanil OK-432
and Montanide ISA-51 in patients with cancers
expressing the NY-ESO-1 antigen. Int J Cancer.
2011;129:2836-46.
3. Yoshida Y, Inoh S, Murakawa T, Ota S, Fukayama
M, Nakajima J. Preoperative localization of small
peripheral pulmonary nodules by percutaneous
marking under computed tomography guidance.
Interact Cardiovasc Thorac Surg. 2011;13:25-8.
4. Yoshida Y, Nakajima J, Wada H, Kakimi K. γδ
T-cell immunotherapy for lung cancer. Surg Today.
2011;41:606-11.
5. Sano A, Murakawa T, Morota T, Nakajima J.
Resection of a posterior mediastinal metastasis ofcolon cancer. Ann Thorac Surg. 2011;92:353-4
6. Kitano K, Murayama T, Sakamoto M, Nagayama
K, Ueno K, Murakawa T, Nakajima J. Outcome
and survival analysis of pulmonary metastasectomy for hepatocellular carcinoma. Eur J
Cardiothorac Surg. 2012;41:376-82.
7. Matsuguma H, Yoshino I, Ito H, Goya T, Matsui Y,
Nakajima J, Ikeda N, Okumura S, Shiono S,
Nomori H; Metastatic Lung Tumor Study Groupof Japan. Is there a role for pulmonary metastasectomy with a curative intent in patients withmetastatic urinary transitional cell carcinoma? Ann
Thorac Surg. 2011;92:449-53
8. Murakawa T, Murayama T, Nakajima J, Ono M.
Lung lobectomy in a patient with an implantable
left ventricular assist device. Interact Cardiovasc
Thorac Surg. 2011;13:676-8.
9. Kitano K, Watanabe K, Emoto N, Kage H,
Hamano E, Nagase T, Sano A, Murakawa T,
Nakajima J, Goto A, Fukayama M, Yatomi Y,
Ohishi N, Takai D. CpG island methylation of
microRNAs is associated with tumor size andrecurrence of non-small-cell lung cancer. Cancer
Sci. 2011;102:2126-31.
10. Sakamoto M, Murakawa T, Konoeda C, Inoue Y,
Kitano K, Sano A, Fukayama M, Nakajima J.

Survival after extended thymectomy for thymoma.
Eur J Cardiothorac Surg. 2012;41:623-7
11. Sano A, Takeuchi E, Fukami T, Murakawa T,
Nakajima J. Erosion bleeding as a latecomplication of chest wall reconstruction with a
Dacron mesh silicone prosthesis.
ThoracCardiovasc Surg. 2012;60:170-1

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Department of
Cardiac Surgery
Professor
Minoru Ono, M.D.

Associate Professor
Arata Murakami, M.D.

Lecturer
Noboru Motomura, M.D.,

Tetsuro Morota, M.D.,

Associate
Tetsuhiro Takaoka, M.D.,

Tsuyoshi Taketani, M.D.,

Aya Saito, M.D.,

Osamu Kinoshita, M.D.,

Yoshifumi Fujimoto, M.D.,

Akihide Umeki, M.D.,

Seigo Shimada, M.D.,

Masahiko Ando, M.D.

Homepage

http://ctstokyo.umin.ne.jp/

Introduction and Organization
Cardiac surgery in the Department was initiated by
Dr. Seiji Kimoto, who performed ligation of patentductus arteriosus in June, aortic arch aneurysm
resection in July and first-in-Japan Blalock-Taussig
operation for Tetralogy of Fallot in October in 1951.
He also started implantation of alcohol-preserved
aortic homograft for abdominal aortic aneurysm in
1952, and closed commissurotomy for mitral valve
stenosis in 1954. The first open heart surgery (atrial
septal defect closure) was performed in 1955, using
selective brain perfusion cooling method that wasdeveloped in the Department.
Establishment of Department of Thoracic Surgery
in the University of Tokyo Hospital was approved by
the government first in Japan December 15, 1964.
Under the leadership of Professor Kimoto excellent
research works were created especially on pacemakerand artificial heart, and many opinion leaders were
produced. Dr. Masahiro Saigusa, the second Professor,

endeavored to make open heart surgery safer byintroducing new- generation heart-lung machines tothe Department. Dr. Kenichi Asano, the third
Professor, started posterior-leaflet preserving mitralvalve replacement first in Japan. He also dramatically
improved surgical results of Tetralogy of Fallot. Dr.
Akira Furuse, the fourth Professor, modernizedmanagement of extremely busy clinical works. During
this time, the Department was divided into two
Divisions, Cardiovascular and General thoracic, due
to the University policy of Graduate-school.
Dr. Shinichi Takamoto assumed the fifth Professor
in June 1997. He rearranged clinical teams into threegroups (adult cardiac disease, thoracic aortic diseaseand congenital heart disease) to adapt the rapid
progress of cardiovascular surgery. Dr. Minoru Ono
was elected as the sixth Professor in November 2009.
Additional clinical team of treatment of advanced
heart failure was established to cope with anincreasing number of patients who require ventricularassist device treatment. Present staffs are one Chief

194

Professor, one Associate Professor and two Lecturer
and eight Associates.

Clinical Activities
Clinical conference starts at 7:15 am in weekdays.
Regular surgery is scheduled on Monday, Wednesday,Thursday and Friday. Patient round is on Tuesday.
Adult patients are hospitalized in the South Wing of
5th floor, and pediatric patients in the South Wing of
2nd floor. Clinics are open Monday through Friday forthe follow-up visit as well as for patient referral.
Case volume in recent years has been about 360,
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 offpump coronary artery bypass surgery, mitral valve
plasty, ventricular assist device implantation, aortic
valve sparing root replacement, arch replacement
using retrograde cerebral perfusion, treatment ofextended thoracic aortic aneurysm and repair ofcomplex 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 2012, 21 cases ofheart transplantation and more than 90 cases ofventricular assist device implantation were performedin 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) basic andclinical research on cryopreserved allograft, 3) development of a newly-designed surgical robotic system,4) application of regenerative medicine to end-stage
heart failure, 5) mechanism analysis of right heart

195

failure and development of effective pharmacologicaltherapy, 6) development of versatile suture device, 7)
development of new heart preserving solution .

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Kitahori K, Motomura N, Morota T, Murakami A,
Takamoto S, Kyo S, Ono M: Left ventricularmechanical support with Impella provides more
ventricular unloading in heart failure thanextracorporeal membrane oxygenation. ASAIO J
2011, 57: 169-176(25) Itakura Y, Kimura M, Gojo S, Toyoda M, Kami D,
Motomura N, Umezawa A, Kyo S, Ono M:
Glycan profiling using a lectin microarray is a
novel validation tool for monitoring the damageof freeze-thawed cells. Low Temp Med 2011, 37:
71-77

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※ The following information is the same as that of the previous year for certain reasons.

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.

References
1.

2.

3.

4.

5.

6.

7.

8.

9.

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

200

10.

11.

12.

13.

14.

15.

16.

cooperative surgery for gastrointestinal stromal
tumor dissection. Surg Endosc 22(7):1729-35,
2008
Hiki N, Fukunaga T, Yamaguchi T, Nunobe S,
Tokunaga M, Ohyama S, Seto Y, Yoshiba H,
Nohara K, Inoue H, Muto T. The benefits 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

17.

18.

19.

20.

21.

22.

23.

additional gastrectomy. Dig Liver Dis 40(4):293-7,2008
Raher MJ, Thibault HB, Buys ES, Kuruppu D,
Shimizu N, Brownell AL, Blake SL, Rieusset J,
Kaneki M, Derumeaux G, Picard MH, Bloch KD,
Scherrer-Crosbie M. A short duration of high-fat
diet induces insulin resistance and predisposes toadverse left ventricular remodeling afterpressure overload. Am J Physiol Heart Circ
Physiol 295: H2495 - H2502,2008
Kaneki M, Sakai M, Shimizu N, Chang K. Is
normalized mean blood glucose level goodenough for the intensive care unit?-Glycemic
variability as a new independent predictor ofmortality.Crit Care Med 36: 3104-3106,2008
Seto Y, Chin K, Gomi K, Kozuka T, Fukuda T,
Yamada K, Matsubara T, Tokunaga M, Kato Y,
Yafune A, Yamaguchi T. Treatment of thoracic
esophageal carcinoma invading adjacentstructures. Cancer Sci 98:937-42, 2007
Seto Y, Yamada K, Fukuda T, Hosoi N,
Takebayashi R, Chin K, Kotsuka T, Gomi K,
Yamaguchi T. Esophageal bypass using a gastrictube and a cardiostomy for malignamt
esophagorespiratory fistula. Am J Surg 193:
792-93 2007
Cao L, Mizoshita T, Tsukamoto T, Takenaka Y,
Toyoda T, Cao X, Nozaki K, Tatematsu M.
Development of carcinoid tumors of theglandular stomach and effects of eradication in
Helicobacter pylori-infected Mongolian gerbils.
Cancer Sci 98: 478-483, 2007
Iwata C, Kano MR, Komuro A, Oka M, Kiyono
K, Johansson E, Morishita Y, Yashiro M,
Hirakawa K, Kaminishi M, Miyazono K.
Inhibition of cyclooxygenase-2 suppresses
lymph node metastasis via reduction of
Lymphangiogenesis. Cancer Res 67: 1018110189,2007
Kaneda A, Wang CJ, Cheong R, Timp W,
Onyango P, Wen B, Iacobuzio-Donahue CA,
Ohlsson R, Andraos R, Pearson MA, Sharov AA,
Longo DL, Ko MS, Levchenko A, Feinberg AP.
Enhanced sensitivity to IGF-II signaling links
loss of imprinting of IGF2 to increased cellproliferation and tumor risk. Proc Natl Acad Sci
104: 20926-20931,2007

201

24.

25.

26.

27.

28.

29.

30.

31.
32.

Kaneki M,Shimizu N, Yamada D, Chang K.
Nitrosative stress and pathogenesis of insulin
resistance. Antioxid Redox Signal 9:319-329,
2007
Kodashima S, Fujishiro M, Takubo K, kamimori
M, Nomura S, Kakushima N, Muraki Y, Goto O,
Ono S, Kaminishi M, Omata M. Ex vivo pilot
study using computed analysis of endocytoscopic images to differentiate normal andmalignant squamous cell epithelia in theoesophagus. Dig Liv Dis 39:762-766,2007
Kubota K, Katayama A, Takeshita Y, Nozaki K,
Ueda T, Imamura K, Hiki N, Nomura S,
Kaminishi M, Mafune K. Effect of imatinib
mesylate in a patient with a metastatic
gastrointestinal stromal tumor with a c-kit
mutation in exon 11. Dig Dis Sci 52: 1725-1729,
2007
Kubota K, Kuroda J, Origuchi N, Kaminishi M,
Isayama H, Kawabe T, Omata M, Mafune K.
Stomach-partitioning gastrojejunostomy for
gastroduodenal outlet obstruction. Arch Surg
142: 607-611, 2007
Kuwabara K, Nishishita T, Morishita M, Oyaizu
N, Yamashita S, Kanematsu T, Obara T, Mimura
T, InoueY, Kaminihsi M, Kaga K, Amino N,
Kitaoka M, Ito K, Miyauchi A, Noguchi S,
Uchimaru K, Akagawa E, Watanabe N,
Takahashi T, Sato K, Inazawa T, Nakaoka T,
Yamashita N. Results of a phase i clinical study
using dendritic cell vaccinations for thyroid
cancer. Thyroid 17: 53-58, 2007
Leys CM, Nomura S, Goldenring JR. Expression
and prognostic significance of prothymosinalpha and ERp57 in human gastric cancer
Surgery 141: 41-50, 2007
Mori K, Suzuki T, Uozaki H, Nakanishi H, Ueda
T, Matsuno Y, Kodera Y, Sakamoto H,
Yamamoto N, Kaminishi M. Detection ofminimal gastric cancer cells in peritoneal
washings by focused microarray analysis withmultiple markers: clinical implications. Ann
Surg Oncol 14: 1694-702, 2007
Kaminishi M. Introductory Remarks. Dig Surg
24: 87, 2007
Nomura S, Kaminishi M. Surgical treatment ofearly gastric cancer in Japan. Dig Surg 24:

33.

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35.

36.

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38.

96-100, 2007
Takenaka Y, Tsukamoto T, Mizoshita T,
Ogasawara N, Hirano N, Otsuka T, Ban H,
Nakamura T, Yamamura Y, Kaminishi M,
Tatematsu M. Gastric and intestinal phenotypiccorrelation between exocrine and endocrinecomponents in human stomach tumors. Histol
Histopathol 22: 278-284,2007
Toyoda T, Tsukamoto T, Mizoshita T, Nishibe S,
Deyama T, Takenaka Y, Hirano N, Tanaka H,
Takasu S, Ban H, Kumagai T, Inada K,
Utsunomiya H, Tatematsu M. Inhibitory effectof nordihydroguaiaretic acid, a plant lignan, on
Helicobacter
pylori-associatedgastric
carcinogenesis in Mongolian gerbils. Cancer Sci
98: 1689-1695, 2007
Yoshizawa N, Yamaguchi H, Yamada K, Nozaki
K, Kaminishi M, Mafune K, Nomura S. Early
esophageal cancer in patients with a history ofgastrectomy for gastric cancer. Esophagus 4:
99-102, 2007
Yoshizawa N, Takenaka Y, Yamaguchi H,
Tetsuya T, Tanaka H, Tatematsu M, Nomura S,
Goldenring JR, Kaminishi M. Emergence of
spasmolytic polypeptide-expressing metaplasia
in Mongolian gerbils infected with Helicobacter
pylori. Lab Invest 87: 1265-1276, 2007
Shimoyama S. Angiogenin in gastric cancer andits roles in malignancy Handbook of
immunohistochemistry and in situ hybridizationof human cancers. (Hayat ed) Academic Press
New York: 195-203, 2007
Kaminishi. Digestive Surgery24, SurgicalTreatment for Digestive Cancer in Japan. Karger
Basel, 2007

202

Hepato-biliary- Pancreatic Surgery
Division and Artificial Organ
and Transplantation Surgery
Division
Professor
Norihiro Kokudo, MD.

Associate Professor
Yasuhiko Sugawara, MD.,

Kiyoshi Hasegawa, MD.

Lecturers
Taku Aoki, MD.

Yoshihiro Sakamoto, MD.,

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/hbps_md/index.html
http://www.h.u-tokyo.ac.jp/transplant/
Organization

Teaching Activities

We specialize in hepato-pancreato-biliary surgery andliver transplantation. The Hepato-Biliary-Pancreatic
Surgery Division and Artificial Organ and Transplantation 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
and transplantation division, high care unit andintensive care unit on the A4 floor. Each inpatient istaken care of by senior and junior specialist surgeons
and a resident in the field of his or her disease
throughout the pre- and postoperative periods. Staff
members are responsible for the entire care of thepatients on a 24-hour-a-day basis. Elective operations
are carried out on Monday, Wednesday and Friday.

References (2010)
1.

2.

Song P, Tang W, Tamura S, Hasegawa K,
Sugawara Y, Dong J, Kokudo N. The
management of hepatocellular carcinoma in Asia:a guideline combining quantitative andqualitative evaluation. Biosci Trends 2010;
4:283-7.
Kaneko J, Sugawara Y, Togashi J, Tamura S,
Motoi R, Fukayama M, Kokudo N. Sarcomatouschange of hepatocellular carcinoma in a patient

203

undergoing living donor liver transplantation.
Biosci Trends 2010; 4:279-82.
3. Hasegawa K, Kokudo N, Shiina S, Tateishi R,
Makuuchi M. Surgery versus radiofrequency
ablation for small hepatocellular carcinoma: Startof a randomized controlled trial (SURF trial).
Hepatol Res 2010; 40:851-2.
4. Ishizawa T, Bandai Y, Ijichi M, Kaneko J,
Hasegawa
K,
KokudoN.
Fluorescentcholangiography illuminating the biliary tree
during laparoscopic cholecystectomy. Br J Surg
2010; 97:1369-77.
5. Harada N, Ishizawa T, Muraoka A, Ijichi M,
Kusaka K, Shibasaki M, Yamamoto K, Hasegawa
K, Bandai Y, Kokudo N. Fluorescence navigation
hepatectomy by visualization of localizedcholestasis from bile duct tumor infiltration. J
Am Coll Surg 2010; 210:e2-6.
6. Shindoh J, Imamura H, Kokudo N. Isolated sling
suspension during resection of the Spiegel lobeof the liver: a safe alternative technique fordifficult cases. J Hepatobiliary Pancreat Sci
2010; 17:359-64.
7. Inagaki Y, Tang W, Zhang L, Du G, Xu W,
Kokudo N. Novel aminopeptidase N (APN/
CD13) inhibitor 24F can suppress invasion ofhepatocellular carcinoma cells as well as
angiogenesis. Biosci Trends 2010; 4:56-60.
8. Takamoto T, Hashimoto T, Sano K, Maruyama Y,
Inoue K, Ogata S, Takemura T, Kokudo N,
Makuuchi M. Recovery of liver function after the
cessation of preoperative chemotherapy forcolorectal liver metastasis. Ann Surg Oncol 2010;17:2747-55.
9. Kokudo N, Arita J. Staging for intrahepaticcholangiocarcinoma. Liver Int 2010; 30:931-3.
10. Mise Y, Imamura H, Hashimoto T, Seyama Y,
Aoki T, Hasegawa K, Beck Y, Sugawara Y,
Makuuchi M, Nakajima J, Kokudo N. Cohort
study of the survival benefit of resection forrecurrent hepatic and/or pulmonary metastases
after primary hepatectomy for colorectal
metastases. Ann Surg 2010; 251:902-9.
11. Shindoh J, Mise Y, Satou S, Sugawara Y, Kokudo
N. The intersegmental plane of the liver is notalways flat--tricks for anatomical liver resection.
Ann Surg 2010; 251:917-22.

12. Inoue Y, Takahashi M, Arita J, Aoki T, Hasegawa
K, Beck Y, Makuuchi M, Kokudo N. Intraoperative freehand real-time elastography forsmall focal liver lesions: "visual palpation" fornon-palpable tumors. Surgery 2010; 148:100011.
13. Yamashiki N, Sugawara Y, Tamura S, Tateishi R,
Yoshida H, Kaneko J, Matsui Y, Togashi J,
Akahane M, Makuuchi M, Omata M, Kokudo N.
Postoperative surveillance with monthly serum
tumor markers after living-donor livertransplantation for hepatocellular carcinoma.
Hepatol Res 2010; 40:278-86.
14. Tamura S, Sugawara Y, Yamashiki N, Kaneko J,
Kokudo N, Makuuchi M. Pre-emptive antiviraltherapy in living donor liver transplantation forhepatitis C: observation based on a single-center
experience. Transpl Int 2010; 23:580-8.
15. Ishizawa T, Mise Y, Aoki T, Hasegawa K, Beck Y,
Sugawara Y, Kokudo N. Surgical technique: newadvances for expanding indications andincreasing safety in liver resection for HCC: theEastern perspective. J Hepatobiliary Pancreat Sci
2010; 17:389-93.
16. Hasegawa K, Kokudo N, Sano K, Makuuchi M.
Single HCC between 2 and 5 cm: the grey zon:
surgeon’s perspective. J Hepatobiliary Pancreat
Sci 2010; 17:430-3.
17. Kishi Y, Imamura H, Sugawara Y, Sano K,
Kaneko J, Kokudo N, Makuuchi M. Evaluationof donor vasculobiliary anatomic variations inliver graft procurements. Surgery 2010; 147:
30-9.

204

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

Associate Professor
Haruki Kume, M.D., Ph.D.,

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

Lecturer
Tohru Nakagawa, M.D., Ph.D.,

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

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

Motofumi Suzuki, M.D., Ph.D.

Associate
Yukio Yamada, M.D.,

Daisuke Yamada, M.D., Ph.D.

Jinpei Kumagai, M.D., Ph.D.,

Masayoshi Nagata, M.D., Ph.D.

Taketo Kawai, M.D., Ph.D.,

Akira Nomiya, M.D.

Aya Niimi, M.D.,

Yosuke Sato, M.D.,

Kanae Hiramatsu, 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, andminimum incision endoscopic or laparoscopic
adrenalectomy, nephrectomy, and robot-assisted
prostatectomy substituting open procedures.

Clinical activities
There are 44 beds in the ward (8th floor of the centralward-building). The professor, associate professors,
instructors and associates are involved in in-patientand out-patient cares and teaching of the students aswell as research activities. Clinical visiting professors
are mainly engaged in the teaching. The residents takecare 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 inpatientswas 1,800 from January 2011 to December 2011.
Elective operations are performed on Tuesday,
Wednesday and Thursday. A total of 1,400 operations
were performed in 2011. The numbers of main
operations are adrenalectomy 20, nephrectomy 36,
partial nephrectomy 38, nephroureterectomy 15,

205

radical cystectomy 12, radical prostatectomy 67,transurethral resection of the bladder tumor (TUR-Bt)
155, transurethral resection of the prostate (TUR-P)
21, and laparoscopic surgery 70.
At the weekly professor’s round on Wednesday, dataof 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 26,000 patientdays from January 2011 to December 2011.

Teaching activities
Systematic urological lectures are provided for second
year medical students. Both clinical lectures and bed
side teaching are scheduled for third and fourth year
medical students. Thirteen times of systematic lectures
are performed by professor, associate professors andinstructors concerning their specialties.
Bed side teaching is concentrated on practical care of
the patients. Teachers give lectures mainly regarding
pre- and post-operative management, indication ofoperation, 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 30 English papers every
year.
Renal tumor
Urolithiasis
Kidney Transplantation
Prostate diseases
New surgical technique
Urinary disturbance/ Female Urology

Andrology
Virology

References
1. Kume H, Kakutani S, Yamada Y, Shinohara M,
Tominaga T, Suzuki M, Fujimura T, Fukuhara H,
Enomoto Y, Nishimatsu H, Homma Y. Prognostic
factors for renal cell carcinoma with bonemetastasis: who are the long-term survivors? J
Urol. 2011 May;185(5):1611-4.
2. Sugihara T, Yasunaga H, Horiguchi H, Nishimatsu
H, Kume H, Matsuda S, Homma Y. Impact of
hospital volume and laser use on postoperativecomplications and in-hospital mortality in cases ofbenign prostate hyperplasia. J Urol. 2011 Jun;
185(6):2248-53.
3. Aizawa N, Igawa Y, Nishizawa O, Wyndaele JJ.
Effects of nitric oxide on the primary bladderafferent activities of the rat with and without
intravesical acrolein treatment. Eur Urol. 2011
Feb;59(2):264-71.
4. Homma Y, Gotoh M, Yokoyama O, Masumori N,
Kawauchi A, Yamanishi T, Ishizuka O, Seki N,
Kamoto T, Nagai A, Ozono S; Japanese
Urological Association. Outline of JUA clinicalguidelines for benign prostatic hyperplasia. Int J
Urol. 2011 Nov;18(11):741-56.
5. Fujimura T, Kume H, Tsurumaki Y, Yoshimura Y,
Hosoda C, Suzuki M, Fukuhara H, Enomoto Y,
Nishimatsu H, Homma Y. Core lower urinary tract
symptom score (CLSS) for the assessment offemale lower urinary tract symptoms: acomparative study. Int J Urol. 2011 Nov;18(11):778-84.
6. Nagata M, Kume H, Homma Y. Reassessment of
the UICC revision of T3 renal cell carcinomas in a
Japanese institute. Int J Urol. 2011 Dec;18(12):864-5.
7. Naruse T, Nagata S, Homma Y. Prevalence ofindividuals receiving elimination assistanceamong Japanese community-dwelling elderly. Int
J Urol. 2011 Dec;18(12):873-4.
8. Okamura K, Nojiri Y, Ameda K, Namima T,
Suzuki M, Inoue K, Ogawa T, Gotoh M, Homma
Y. Botulinum toxin A submucosal injection forrefractory non-neurogenic overactive bladder:

206

early outcomes. Int J Urol. 2011 Jun;18(6):483-7.
9. Sugihara T, Yasunaga H, Homma Y. Higher
transfusion rate in bipolar transurethral resectionof the prostate: Is it real? Int J Urol. 2011 Sep;
18(9):677-8.
10. Tsuzaka Y, Matsushima H, Kaneko T, Yamaguchi
T, Homma Y. Naftopidil vs silodosin in medical
expulsive therapy for ureteral stones: arandomized controlled study in Japanese malepatients. Int J Urol. 2011 Nov;18(11):792-5.
11. Homma Y, Kakizaki H, Yamaguchi O, Yamanishi
T, Nishizawa O, Yokoyama O, Takeda M, Seki N,
Yoshida M. Assessment of overactive bladder
symptoms: comparison of 3-day bladder diary andthe overactive bladder symptoms score. Urology.
2011 Jan;77(1):60-4.
12. Ishikawa A, Kawarazaki H, Ando K, Fujita M,
Fujita T, Homma Y. Renal preservation effect ofubiquinol, the reduced form of coenzyme Q10.
Clin Exp Nephrol. 2011 Feb;15(1):30-3.
13. Suzuki M, Liu M, Kurosaki T, Suzuki M, Arai T,
Sawabe M, Kasuya Y, Kato M, Fujimura T,
Fukuhara H, Enomoto Y, Nishimatsu H, Ishikawa
A, Kume H, Homma Y, Kitamura T. Associationof rs6983561 polymorphism at 8q24 with prostatecancer mortality in a Japanese population. Clin
Genitourin Cancer. 2011 Sep;9(1):46-52.
14. Ishikawa A, Homma Y. Beneficial effect ofubiquinol, the reduced form of coenzyme Q10, on
cyclosporine nephrotoxicity. Int Braz J Urol. 2012
Mar-Apr;38(2):230-4.
15. Sugihara T, Yasunaga H, Horiguchi H, Nishimatsu
H, Matsuda S, Homma Y. Incidence and clinicalfeatures of priapism in Japan: 46 cases from theJapanese diagnosis procedure combination
database 2006-2008. Int J Impot Res. 2011 MarApr;23(2):76-80.
16. Kume H, Suzuki M, Fujimura T, Fukuhara H,
Enomoto Y, Nishimatsu H, Ishikawa A, Homma Y.
Docetaxel as a vital option for corticosteroidrefractory prostate cancer. Int Urol Nephrol. 2011
Dec;43(4):1081-7.
17. Kume H, Miyazaki H, Nagata M, Ishikawa A,
Ishibashi Y, Fujita T, Homma Y. Peritoneal
fixation prevents dislocation of Tenckhoff catheter.
Perit Dial Int. 2011 Nov-Dec;31(6):694-7.
18. Fukuhara H, Nishimatsu H, Suzuki M, Fujimura T,

Enomoto Y, Ishikawa A, Kume H, Homma Y.
Lower incidence of inguinal hernia after radical
prostatectomy using open gasless endoscopic
single-site surgery. Prostate Cancer Prostatic Dis.
2011 Jun;14(2):162-5.
19. Mori C, Yamada D, Homma Y. A case of calculus
in the true ureteral diverticulum. Int J Urol. 2011
Feb;18(2):180-1.
20. Nomiya A, Nishimatsu H, Homma Y. Interstitial
cystitis symptoms associated with ketamine
abuse: the first Japanese case. Int J Urol. 2011
Oct;18(10):735.

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Department of Surgical Oncology
Visiting professor
Toshiaki Watanabe, M.D., Ph.D.

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

Lecturer
Eiji Sunami, M.D., Ph.D.,

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

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

Takamitsu Kanazawa, M.D.,

Hironori Yamaguchi, M.D., Ph.D.

Kazushige Kawai, M.D., Ph.D.

Kentaro Yazawa M.D., Ph.D.

Ken Mori M.D., Ph.D.

Tomomitsu Kiyomatsu M.D., Ph.D.

Hiroharau Yamashita M.D., Ph.D.

Homepage

http://all-1su.umin.jp/

Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Surgical
Oncology and the Department of Vascular Surgery.
The staff of the Department of Surgical Oncology
consists of one visiting professor (Jan-Mar 2012), one
Associate Professor, one lecturer and nine Assistants.
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 Surgical Oncology inclinical practice, education, and research aresummarized 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 specialties
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 285 surgically treatedinpatients in the year of 2011. On Monday,
Wednesday and Friday mornings, pre- and postsurgery conferences are held, and the Professor's
Round takes place after the conference every
Wednesday. Operating days are Monday, Tuesday and208

Thursday. In addition to the clinical conferences,
research conferences are held every Monday andSaturday morning. Each research unit holds its own
conference every week. Over 800 colonoscopies are
performed for a year. The newest technologies are
introduced for diagnosis and treatment of colon andrectal cancer and long-term surveillances for
inflammatory bowel disease are performed.

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 2011, various fields werecovered such as surgical oncology and immunology,
injury, somatic reaction to surgery, infectious diseases,
shock, pre- and post-surgical management andnutrition. In the clinical lectures, we presented many
diseases such as colon cancer, colonic polyp, colonicpolyposis and ulcerative colitis. In the postgraduate
education program, new residents are trained to
become qualified surgeons. In addition to pre- andpost-surgery clinical conferences, the residents are
expected to attend research conferences and seminars,
which are held periodically. They are also asked topresent cases at clinical meetings, which are held
locally such as the local meeting of the JapaneseSociety of Gastroenterology.

Research activities
At present, our department has three major research
units divided according to the members’ special fields.
The clinical and academic interests of our department
are the upper and lower gastrointestinal tract, and thebreast. We also apply the techniques used in molecularand cellular biology to our research. The following are
the major themes under research.
1) Preoperative radiotherapy in lower rectal cancer
2) Cancer surveillance in ulcerative colitis
3) Carcinogenesis in ulcerative colitis
4) Laparoscopically assisted colon surgery
5) Local immunity in colorectal cancer
6) Genetic analysis of colorectal cancer andadenoma
7) Prognostic factor of early colorectal cancer8) Surveillance program following colectomy forcolorectal cancer
9) The mechanism of liver metastasis of colorectal
cancer10) 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 analysis on sensitivity to chemotherapeutic 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 carcinomatosis

20924) Immunomodulation in chemoradiotherapy for
locally advanced rectal cancer25) Autophagy in Oncology
26) Robot assisted laparoscopic colorectal surgery (daVinch)

References
1: Satoh Y, Mori K, Kitano K, Kitayama J, Yokota H,
Sasaki H, Uozaki H, Fukayama M, Seto Y,
Nagawa H, Yatomi Y, Takai D. Analysis for the
combination expressionof CK20, FABP1 andMUC2 is sensitive for the prediction of peritoneal
recurrence in gastric cancer. Jpn J Clin Oncol.
2012 Feb;42(2):148-52. Epub 2011 Dec 15.
2: Nozawa H, Kitayama J, Sunami E, Saito S,
Kanazawa T, Kazama S, Yazawa K, Kawai K,
Mori K, Nagawa H. [FOLFOX as adjuvant
chemotherapy after curative resection of distantmetastatic lesions in patients with colorectal
cancer]. Gan To Kagaku Ryoho. 2011 Oct;38(10):1627-32.
3: Shuno Y, Hata K, Sunami E, Shinozaki M, Kawai
K, Kojima T, Tsurita G, Hiyoshi M, Tsuno NH,
Kitayama J, Nagawa H. Is surveillance endoscopy
necessary after colectomy in ulcerative colitis?
ISRN Gastroenterol. 2011;2011:509251.
4: Emoto S, Ishigami H, Yamashita H, Yamaguchi H,
Kaisaki S, Kitayama J. Clinical significance ofCA125 and CA72-4 in gastric cancer withperitoneal dissemination. Gastric Cancer. 2012
Apr;15(2):154-61. Epub 2011 Sep 3.
5: Nozawa H, Kitayama J, Sunami E, Saito S,
Kanazawa T, Kazama S, Yazawa K, Kawai K,
Mori K, Nagawa H. FOLFOX as adjuvant
chemotherapy after curative resection of distantmetastases in patients with colorectal cancer.
Oncology. 2011;80(1-2):84-91.
6: Emoto S, Ishigami H, Yamaguchi H, Yamashita H,
Kaisaki S, Kitayama J. Frequent development of
leptomeningeal carcinomatosis in patients withperitoneal dissemination of gastric cancer. Gastric
Cancer. 2011 Oct;14(4):390-5.
7: Hongo K, Tanaka J, Tsuno NH, Kawai K,
Nishikawa T, Shuno Y, Sasaki K, Kaneko M,
Hiyoshi M, Sunami E, Kitayama J, Takahashi K,
Nagawa H. CD133(-) cells, derived from a single

human colon cancer cell line, are more resistant to
5-fluorouracil (FU) than CD133(+) cells, dependent on the β1-integrin signaling. J Surg Res.
2012 Jun 15;175(2):278-88. Epub 2011 Apr 24.
8: Yasuda K, Nirei T, Sunami E, Nagawa H,
Kitayama J. Density of CD4(+) and CD8(+) T
lymphocytes in biopsy samples can be a predictor
of pathological response to chemoradiotherapy(CRT) for rectal cancer. Radiat Oncol. 2011 May
16;6:49.
9: Yasuda K, Nirei T, Tsuno NH, Nagawa H,
Kitayama
J.
Intratumoral
injectionofinterleukin-2 augments the local and abscopal
effects of radiotherapy in murine rectal cancer.
Cancer Sci. 2011 Jul;102(7):1257-63.
10: Ishigami H, Kitayama J, Kaisaki S, Yamaguchi H,
Yamashita H, Emoto S, Nagawa H. Phase I studyof biweekly intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel for gastriccancer with peritoneal metastasis. Oncology.
2010;79(3-4):269-72. Epub 2011 Mar 4.
11: Kitayama J, Yasuda K, Kawai K, Sunami E,
Nagawa H. Circulating lymphocyte is an
important determinant of the effectiveness of
preoperative radiotherapy in advanced rectal
cancer. BMC Cancer. 2011 Feb 10;11:64.
12: Habeeb BS, Kitayama J, Nagawa H. Adiponectin
supports cell survival in glucose deprivation
through enhancement of autophagic response incolorectal cancer cells. Cancer Sci. 2011 May;
102(5):999-1006.
13: Miyato H, Kitayama J, Ishigami H, Kaisaki S,
Nagawa H. Loss of sympathetic nerve fibers
around intratumoral arterioles reflects malignant
potential of gastric cancer. Ann Surg Oncol. 2011
Aug;18(8):2281-8.
14: Kamei T, Kitayama J, Yamaguchi H, Soma D,
Emoto S, Konno T, Ishihara K, Ishigami H,
Kaisaki S, Nagawa H. Spatial distribution of
intraperitoneallyadministrated
paclitaxel
nanoparticles
solubilized
with
poly
(2-methacryloxyethyl
phosphorylcholine-con-butyl methacrylate) in peritoneal metastatic
nodules. Cancer Sci. 2011 Jan;102(1):200-5.
15: Kawai K, Tsuno NH, Kitayama J, Sunami E,
Takahashi K, Nagawa H. Catechin inhibits
adhesion and migration of peripheral blood B

210

cells by blocking CD11b. Immunopharmacol
Immunotoxicol. 2011 Jun;33(2):391-7.
16: Kawai K, Kitayama J, Tsuno NH, Sunami E,
NagawaH.
Hyperfibrinogenemia
after
preoperative chemoradiotherapy predicts poor
response and poor prognosis in rectal cancer. Int J
Colorectal Dis. 2011 Jan;26(1):45-51.
17: Kazama S, Kitayama J, Aoki J, Mori K, Nagawa
H. Immunohistochemical detection of autotaxin(ATX)/lysophospholipase D (lysoPLD) in submucosal invasive colorectal cancer. J Gastrointest
Cancer. 2011 Dec;42(4):204-11.

211

Department of Vascular Surgery
Associate Professor
Tetsuro Miyata, M.D., Ph.D.

Lecturer
Kunihiro Shigematsu, M.D., Ph.D.

Hospital Lecturer
Hiroyuki Okamoto, M.D., Ph.D.,

Associate
Katsuyuki Hoshina, M.D., Ph.D., Akihiro Hosaka, M.D., Ph.D.

Homepage

http://all-1su.umin.jp/

Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Vascular
Surgery and the Department of Surgical Oncology.
The staff of the Department of Vascular Surgery
consists of one Associate Professor, one lecturer, andthree Associates. The outpatient office is located on
the third floor of the Outpatient Building. The ward issituated on the eighth floor of the Ward Building. The
administrative office and research laboratories arelocated in the Administration and Research Building.
Current activities of the Department of Vascular
Surgery in clinical practice, education, and research
are summarized as follows.

Clinical activities
The Department of Vascular Surgery has anextensive clinical program in both primary and tertiarycare for vascular problems, and manages patients with
peripheral arterial occlusion, abdominal and thoracoabdominal aortic aneurysms, peripheral aneurysm,
visceral arterial occlusion, carotid artery disease andcommon disorders of the venous circulation such asvaricose veins and venous leg ulcers. State-of-the-art
techniques of percutaneous transluminal angioplasty,

angioscopy and intraoperative ultrasonography areavailable for the treatment of peripheral arterial
disease. And endovascular aneurysm repair was alsoavailable for the treatment of abdominal aortic
aneurysm. The outpatient clinic is open from Monday
through Friday, and twenty-four-hour consultation isavailable for urgent or emergency problems.
Included in the department is the non-invasive
Clinical Vascular Laboratory, which sees over 500
patients per year, with broad reaching expertise inperipheral vascular diagnostic modalities. Also thedepartment has an active angiography program, which
encompasses all aspects of diagnostic and therapeuticintervention in over 500 patients per year and a fullrange of other support and collaborative services.
On Monday, Wednesday and Friday mornings, preand post-surgery conferences are held. Operating days
are Monday, Tuesday and Thursday. The vascularclinical conference is held every Tuesday evening.

Teaching activities
The Department of Vascular Surgery also offers afellowship in vascular surgery for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in vascularsurgery. The Department of Vascular Surgery has a
Vascular Surgery Training Program and provides

212

broad reaching experience in technical aspects ofvascular 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.

9) Development of a new drug delivery system fortherapeutic angiogenesis10) Hemodynamic analysis after endovascularaneurysm repair11) Introduction of gene into vascular wall cells byelectroporation
12) Application of nano technology for in-vivo genetransfer to vascular wall cells
13) Basic research for arterialization of artificial
organ
14) Development of a new method for evaluation oflimb ischemia
15) Development of a new machine for autoevaluation of in-vivo endothelial function16) Creating strategy for diagnosis of acute aortic
syndrome.

Research activities

References

The Department of Vascular Surgery includes major
research laboratories for academic development bothalong clinical and basic scientific lines. The clinicalvascular laboratories are approaching completely noninvasive testing for vascular disorders, analyzing
essential physiologic information about the specificproblems being addressed. The basic vascularlaboratories are actively performing research on
endothelial biology, the mechanism of intimal
hyperplasia, microcirculation, application of genetherapy to vascular surgery and vascular prosthesis
development. Vascular research meeting is held every
other Saturday morning. The following are the major
themes under research.
1) Navigation system for less invasive vascularsurgery2) Pathophysiology of the development of theaneurysm
3) Pathophysiology of stent restenosis
4) Analyzing the intercellular transmission of thegrowth signal in the vascular smooth muscle cells5) Tissue oxygen dynamics assessed by near infrared
spectroscopy
6) Genome wide-association studies for arteriosclerosis.
7) Pharmacological analysis of microcirculation in
in-vivo model8) Mechanism of arteriogenesis in ischemic limb.

1. Hosaka A, Kato M, Kato I, Isshiki S, Okubo N.
Ourtcome
after
concomitantunilateralembolization of the internal iliac artery andcontralateral external-to-internal iliac artery
bypass grafting during endovascular aneurysm
repair. J Vasc Surg 2011;54:960-964.
2. Hosaka A, Kato M, Kato I, Isshiki S, Okubo N.
Brachiocephalic venous aneurysm with unusual
clinical observations. J Vasc Surg 2011;54,
supplement :77S-79S.
3. Hoshina K, Kato M, Hosaka A, Miyahara T,
Mikuriya A, Ohkubo N, Miyata T. Middle-term
results of endovascular aneurysm repair in Japan:
does intraoperative endovascular management
against the hostile aneurismal neck preven theproximal type I endoleak? Int Angio 2011;30:
467-473.
4. Kagaya H, Miyata T, Hoshina K, Kimura
H,Okamoto H, Shigemarsu K, Akahana M,
Nagawa H. Long-term results of endo vasculartreatment for splenic artery aneurysms. Int Angio
2011;30:359-365.
5. Kagaya H, Oba M, Miura Y, Koyama H, Ishii T,
Shimada T, Takato T, Kataoka K, Miyata T.
Impact of polyplex micelles installed with cyclic
RGD peptide as ligand on gene delivery tovascular lesions. Gene Ther. Epub 2011 Jun 9.
6. Kamimura W, Hattori R, Koyama H, Miayat T,

213

Takato T. Calcium-cross-linked hydrogel based on
alginate-modified atelocollagen functions as a
scaffold material. J Biomater Sci Polym Ed.
2012;23(5):609-28.
7. Kusunoki M, Tsutsumi K, Sato D, Nakamura A,
Habu S, Mori Y, Morishita M, Yonemoto T,
Miyata T, Nakaya Y, Nakamura T. Activation of
lipoprotein lipase increases serum high density
lipoprotein 2 cholesterol and enlarges high density
lipoprotein 2 particles in rats. Eur J Pharmacol.
2011;668(1-2):337-9.
8. Kusunoki M, Tsutsumi K, Sato D, Nakamura A,
Habu S, Mori Y, Morishita M, Yonemoto T,
Miyata T, Nakaya Y, Nakamura T. Pioglitazoneinduced body weight gain is prevented by
combined administration with the lipoprotein
lipase activator NO-1886. Eur J Pharmacol.
2011;668(3):486-91.
9. Nagayoshi M, Taguchi T, Koyama H, Takato T,
Miayat T, Nagawa H. Enhanced neovascularformation in a novel hydrogel matrix consisitingof citiric acid and collagen. Ann Vasc Dis.
2011:4;196-203.
10. Suzuki J, Miyata T, Hoshina K, Okamoto H,
Kimura H, Shigematsu K. Surgical treatment ofpatients with congenital vascular malformation-associated aneurysms. Eur J Vasc Endovasc Surg
2011;42:517-522.
11. Shigematsu H, Yasuda K, Sasajima T, Takano T,
Miyata T, Ohta T, Tanemoto K, Obitsu Y, Iwai T,
Ozaki S, Ogihara T, Morishita R. Transfection ofhuman HGF plasmid DNA improves limb salvage
in Buerger’s disease patients with critical limb
ischemia. Int Angiol. 2011:30;140-149.

214

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

Mizuho Kikuyama 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 300
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.

215

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.
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 IGFR in breast cancer progression3) Bacterialtranslocation
after
anti-cancer
chemotherapy4) Epigenetic analysis in thyroid cancer tissues5) Detection of circulating tumor cells (CTC) in
breast and thyroid cancer patients
6) Role of oxygen on local and systemic protein
metabolism after major surgery7) Ischemic
preconditioning
preserves
renal
dysfunction after ischemia-reperfusion
8) Detection of new tumor suppressor genes in breast
cancer tissues9) Detection of stem cell in breast cancer tisuues10) Chemo-sensitivity test in breast cancer

Publications
1. Ogawa T, Kanauchi H, Kammori M, Mimura Y,
Ota S, Kaminishi M. Diffuse large B-cell
lymphoma in the thyroid gland associated withprimary hyperparathyroidism. Int J Clin Oncol
12: 48-51, 2007

2. 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
3. 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
4. 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
5. 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.
6. Ogawa T, Tsuji E, Shirakawa K, Hayashibara N,
Kurabayashi R, Terada K, Kikuchi Y, Kanauchi H,
Sakatani T Primary non-Hodgkin’s lymphoma of thebreast treated nonsurgically:report of three cases.
Breast Cancer 18:68-72,2011.
7. Kikuyama M, Takeshima H, Kinoshita T,
Okochi-Takeda E, Wakabayashi M, Akashi-Tanaka
S, Ogawa T, Seto Y, Ushijima T. Development of anovel approach, the epigenome-based outlier
approach,to identify tumorsuppressor genes silenced
by abrrent DNA methylation. Cancer Let
322:204-212,2012.

Surgical Sciences
2. Sensory and Motor System Medicine

217

Department of Dermatology
Professor
Shinichi Sato, M.D., Ph.D.

Associate Professor
Takafumi Kadono, M.D., Ph.D.

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

Lecturer
Yoshihide Asano, M.D.,Ph.D

Hideki Fujita, M.D.,Ph.D

Shinji Kagami, M.D.,Ph.D

Associate
Koichi Yanaba, M.D. Ph.D.

Yoshihiro Kuwano, M.D. Ph.D

Mayuko Araki, M.D.

Sayaka Shibata, M.D., Ph.D.

Yuta Uwajima, M.D.

Hayato Sumita, M.D., Ph.D.

Naohiko Aozasa, M.D., Ph.D.

Ryo Sunaga, M.D.

Home page

http://www.h.u-tokyo.ac.jp/der/Introduction and Organization

Clinical Activities

The Department of dermatology celebrated its
100th anniversary in 1990. Originally it was foundedas the Department of dermatology and Urology, which
also encompassed venereology. In 1946 theDepartment of dermatology was separated from thatof Urology. Regarding venereology, sexually transmitted diseases only related to skin manifestations are
now dealt in our department.
The professor, two associate professors, threelecturers and eight assistants take part in inpatient andoutpatient cares as well as research and teachingactivities. Forty-three doctors who basically belong toour department are currently out in affiliated hospitals
mainly engaged in clinical works there. Additionally,four 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. Clinical and histological discussions by
all staff members including Professor and Associate
Professors are held regularly, which always gives us
invaluable lessons.
Concerning the in-patient clinic, there are about ten
staff members under the supervision of the ward-chief.
Surgical operations such as removal of malignancies
and skin grafting that require general anesthesia arealso performed weekly in the central surgical facilities.

Education
We have twelve dermatologists who are studying in
the postgraduate course under the guidance of staff
members of our department.
In addition to series of lectures, clinical education is218

provided 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.

Research
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.

Publications
1.

2.

3.

4.

Asano Y, Ihn H, Jinnin M, Tamaki K, Sato S:
Altered dynamics of TGF-βreceptors inscleroderma fibroblasts. Ann Rheum Dis. 70: 3847, 2011.
Hamaguchi Y, Kuwana M, Hoshino K, Hasegawa
M, Kenzo Kaji K, Takashi Matsushita T, Komura K,
Nakamura M, Kodera M, Suga N, Akira Higashi A,
Ogusu K, Tsutusi K, Furusaki A, Tanabe H,
Sasaoka S, Muro Y, Yoshikawa M, Ishiguro N,
Ayano M, Muroi E, Fujikawa K, Umeda Y, Kawase
M, Mabuchi E, Asano Y, Sodemoto K, Seishima M,
Yamada H, Sato S, Takehara K, Fujimoto M:
Clinical Correlations with Dermatomyositis (DM)specific Autoantibodies in Adult Japanese Patientswith DM: a Multi-centre, Cross-sectional Study.
Arch Dermatol. 147: 391-8, 2011.
Bujor AM, Asano Y, Haines P, Lafyatis R,
Trojanowska M: The c-abl tyrosine kinase controls
PKC-δ induced Fli1 phosphorylation in humandermal fibroblasts. Arthritis Rheum. 63: 1729-37,
2011.
Yanaba K, Yoshizaki A, Asano Y, Kadono T, Sato S:
IL-10-producing regulatory B10 cells inhibit

7.

8.

9.

10.

11.

12.

13.

intestinal injury in a mouse model. Am J Pathol.
178: 735-43, 2011.
Rizzo HL, Kagami S, Phillips KG, Kurtz SE,
Jacques SL, Blauvelt A: IL-23-mediated psoriasislike epidermal hyperplasia is dependent on IL-17A.
J Immunol. 186:1495-502, 2011.
Kamata M, Tada Y, Uratsuji H, Kawashima T,
Asano Y, Sugaya M, Kadono T, Tamaki K, Sato S:
Semaphorin 7A on keratinocytes induces
Interleukin-8 production by monocytes. J DermatolSci. 62: 176-82, 2011.
Kanda N, Kamata M, Tada Y, Ishikawa T, Sato S,
Watanabe S: Human β-defensin-2 enhances IFN-γ
and IL-10 production and suppresses IL-17
production in T cells. J Leukoc Biol. 89: 935-44,
2011.
Fujimoto S, Komine M, Karakawa M, Uratsuji H,
Kagami S, Tada Y, Saeki H, Ohtsuki M, Tamaki K:
Histamine differentially regulates the production of
Th1 and Th2 chemokines by keratinocytes throughhistamine H1 receptor. Cytokine. 54: 191-9, 2011.
Miyagaki T, Sugaya M, Murakami T, Asano Y, Tada
Y, Kadono T, Okochi H, Tamaki K, Sato S: CCL11CCR3 interactions promote survival of anaplastic
large cell lymphoma cells via ERK1/2 activation.
Cancer Res. 71: 2056-65, 2011.
Noda S, Takekoshi T, Tamaki Z, Asano Y, Sugaya
M, Sato S: Urticarial vasculitis presenting as
erythema gyratum repens-like eruption. J Eur Acad
Dermatol Venereol. 25: 493-5, 2011.
Noda S, Asano Y, Yamazaki M, Ichimura Y, Tamaki
Z, Takekoshi T, Sugaya M, Sato S: Severe livedoid
vasculopathy
associatedwithantiphosphatidylserine-prothrombin complex antibody
successfully treated with warfarin. Arch Dermatol.
147: 621-3, 2011.
Shibata S, Tada Y, Hau C, Tatsuta A, Yamamoto M,
Kamata M, Karakawa M, Asano Y, Mitsui H,
Sugaya M, Kadono T, Saeki H, Kanda N, Sato S:
Adiponectin as an anti-inflammatory factor in thepathogenesis of psoriasis: induction of elevatedserum adiponectin levels following therapy. Br J
Dermatol. 164: 667-70, 2011.
Sugaya M, Reed S, Rose PP, de la Motte S, Raggo
CM, Kurtz SE, Moses AV, Fruh K, Blauvelt A:
Kaposi's sarcoma and human dermal microvascularendothelial cells infected with Kaposi's sarcoma-

219

14.

15.

16.

17.

18.

19.

20.

21.

22.

associated herpesvirus express CCL21. J DermatolSci. 61: 139-42, 2011.
Natsuga K, Nishie W, Shinkuma S, Nakamura H,
Matsushima Y, Tatsuta A, Komine M, Shimizu H:
Expression of exon-8-skipped kindlin-1 does notcompensate for defects of Kindler syndrome. J
Dermatol Sci. 61:38-44, 2011.
Clark RA, Shackelton JB, Watanabe R, Calarese A,
Yamanaka K, Campbell JJ, Teague JE, Kuo HP,
Hijnen D, Kupper TS: High-scatter T cells: a
reliable biomarker for malignant T cells in
cutaneous T-cell lymphoma. Blood. 117: 1966-76,
2011.
Kato T, Saeki H, Tsunemi Y, Shibata S, Tamaki K,
Sato S: TARC/CCL17 accelerates wound healing
by enhancing fibroblast migration. Exp Dermatol.
20: 669-74, 2011.
Noda S, Asano Y, Masuda S, Miyagawa T, Sugita
M, Yamamoto M, Kogure A, Tamaki Z, Mitsui H,
Hoashi T, Sugaya M, Sato S: Bosentan: a novel
therapy for leg ulcerations in Werner’s syndrome. J
Am Acad Dermatol. 65: e54-55, 2011.
Poe JC, Smith SH, Haas KM, Yanaba K, Tsbata T,
Matsushita T, Tedder TF: Amplified B Lymphocyte
CD40 Signaling Drives Regulatory B10 Cell
Expansion in Mice. PLos One. 6: e22464, 2011.
Miyagaki T, Sugaya M, Yokobayashi H, Kato T,
Ohmatsu H, Fujita H, Saeki H, Kikuchi Y, Tamaki T,
Sato S: High Levels of Soluble ST2 and Low
Levels of IL-33 in Sera of Patients with HIV
Infection. J Invest Dermatol. 131: 794-6, 2011.
Fujita H, Shemer A, Suárez-Fariñas M, JohnsonHuang LM, Tintle S, Cardinale I, Fuentes-Duculan
J, Novitskaya I, Carucci JA, Krueger JG, GuttmanYassky E: Lesional dendritic cells in chronic atopic
dermatitis and psoriasis exhibit parallel ability toactivate T-cell subsets. J Allergy Clin Immunol.
128: 574-82, 2011.
Tintle S, Shemer A, Suárez-Fariñas M, Fujita H,
Gilleaudeau P, Sullivan-Whalen M, Cardinale I,
Duan S, Bowcock A, Krueger JG, Guttman-Yassky
E: Reversal of atopic dermatitis with narrow-band
UVB phototherapy and biomarkers for therapeutic
response. J Allergy Clin Immunol. 128: 583-93,
2011.
Suga H, Sugaya M, Miyagaki T, Ohmatsu H, Fujita
H, Asano Y, Tada Y, Kadono T, Sato S: Differential

23.

24.

25.

26.

27.

28.

29.

30.

31.

patterns of CXCR3, CCR3, and CCR10 expression
in mycosis fungoides, Sezary syndrome and CD30+
lymphoproliferative
disorders:immunohistochemical study of 43 samples. J Dermatol Sci. 64:
124-4, 2011.
Hau C, Tada Y, Shibata S, Uratsuji H, Asano Y,
Sugaya M, Kadono T, Kanda N, Watanabe S,
Tamaki K, Sato S: High calcium, ATP and poly
(I:C) augment the immune response to β-glucan innormal human epidermal keratinocytes. J Invest
Dermatol. 131: 2255-62, 2011.
Suga H, Asano Y, Tamaki Z, Yamamoto M, Sugaya
M, Shimizu J, Sato S: A case of systemic sclerosis
with sarcoidosis. Acta Derm Venereol. 91(6): 71820, 2011.
Miyagaki T, Sugaya M, Okochi H, Asano Y, Tada Y,
Kadono T, Blauvelt A, Tamaki K, Sato S: Blocking
MAPK Signaling Down-regulates CCL21 inLymphatic Endothelial Cells and Impairs Contact
Hypersensitivity Responses. J Invest Dermatol.
131(9): 1927-35, 2011.
Noda S, Asano Y, Sato S: Lichen planus in a patientwith long-term exposure to chrome. Eur J
Dermatol. 21(3): 417-8, 2011.
Noda S, Asano Y, Ashida R, Tamaki Z, Tomita M,
Kawashima T, Sato S: Localized scleroderma encoup de sabre exacerbated during pregnancy
followed by postpartum development of rheumatoid
arthritis. Eur J Dermatol. 21(3): 441-2, 2011.
Noda S, Asano Y, Aozasa N, Akamata K, Yamada D,
Masui Y, Tamaki Z, Kadono T, Sato S: Serum Tie2
levels: clinical association with microangiopathies
in patients with systemic sclerosis. J Eur Acad
Dermatol Venereol. 25(12): 1476-9, 2011.
Noda S, Asano Y, Sato S: Pityriasis lichenoides etvarioliformis acuta exacerbated after tonsillectomy.
Eur J Dermatol. 21(4): 648-9, 2011.
Suga H, Tsunemi Y, Sugaya M, Shinkuma S,
Akiyama M, Shimizu H, Sato S: Hair shaft
abnormalities of localized autosomal recessive
hypotrichosis 2 and characteristics of nonsyndromic human alopecias. Acta Derm Venereol.
91(4): 486-8, 2011.
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince
HM, Lessin SR, Wood GS, Willemze R, Demierre
MF, Pimpinelli N, Bernengo MG, Ortiz-Romero PL,
Bagot M, Estrach T, Guitart J, Knobler R, Sanches

220

32.

33.

34.

35.

36.

37.

38.

JA, Iwatsuki K, Sugaya M, Dummer R, Pittelkow
M, Hoppe R, Parker S, Geskin L, Pinter-Brown L,
Girardi M, Burg G, Ranki A, Vermeer M, Horwitz S,
Heald P, Rosen S, Cerroni L, Dreno B, Vonderheid
EC: Clinical endpoints and response criteria in
mycosis fungoides and Sezary syndrome: aconsensus statement of the International Society for
Cutaneous Lymphomas (ISCL), the United States
Cutaneous Lymphoma Consortium (USCLC) andthe cutaneous lymphoma task force of the European
Organization for Research and Treatment of Cancer(EORTC). J Clin Oncol. 29(18): 2598-607, 2011.
Takahashi T, Asano Y, Ichimura Y, Taniguchi T,
Kogure A, Tamaki Z, Takekoshi T, Sugaya M, Sato
S: A case of taxane-induced scleroderma: a different
expression profile of Fli1 proteins in dermal
fibroblasts and microvascular endothelial cells
compared with systemic sclerosis. Br J Dermatol.
164(6): 1393-5, 2011.
Miyagaki T, Sugaya M, Suga H, Kamata M,
Ohmatsu H, Fujita H, Asano Y, Tada Y, Kadono T,
Sato S: IL-22, but not IL-17, Dominant
Environment in Cutaneous T cell Lymphoma Clin
Cancer Res. 17 (24): 7529-38, 2011.
Kanda K, Hau CS, Tada Y, Tatsuta A, Sato S,
Watanabe S: Visfatin Enhances CXCL8, CXCL10,and CCL20 Production in Human Keratinocytes.
Endocrinology. 152(8): 3155-64, 2011.
Yoshizaki A, Yanaba K, Ogawa A, Iwata Y, Ogawa
F, Takenaka M, Shimizu K, Asano Y, Kadono T,
Sato S: The specific free radical scavenger
edaravone suppresses fibrosis in tight-skin andbleomycin-induced mouse models of systemicsclerosis. Arthritis Rheum. 63(10): 3086-97, 2011.
Yoshizaki A, Yanaba K, Ogawa A, Asano Y,
Kadono T, Sato S. Immunization with DNA
topoisomerase I and complete Freund’s adjuvant
induces skin and lung fibrosis and autoimmunity
via interleukin-6 signaling. Arthritis Rheum.
63(11): 3575-85, 2011.
Motegi SI, Leitner WW, Lu M, Tada Y, Sárdy M,
Wu C, Chavakis T, Udey MC: Pericyte-Derived
MFG-E8 Regulates Pathologic Angiogenesis.
Arterioscler Thromb Vasc Biol. 31(9): 2024-34,
2011.
Miyagaki T, Sugaya S: Erythrodermic cutaneous Tcell lymphoma: How to differentiate this rare

39.

40.

41.

42.

43.

44.

45.

46.

disease from atopic dermatitis. J Dermatol Sci.
64(1): 1-6, 2011.
Yanaba K, Yoshizaki A, Asano Y, Kadono T, Sato S:
Serum interleukin-9 levels are increased in patientswith systemic sclerosis: association with lower
frequency and severity of pulmonary fibrosis. J
Rheumatol. 38(10): 2193-7, 2011.
Drury LJ, Ziarek JJ, Gravel S, Veldkamp CT,
Takekoshi T, Hwang ST, Heveker N, Vo lkman BF,
Dwinell MB: Monomeric and dimeric CXCL12
inhibit metastasis through distinct CXCR4interactions and signaling pathways. Proc Natl
Acad Sci USA. 108(43): 17655-60, 2011.
Mabushi T, Takekoshi T, Hwang ST: Epidermal
CCR6+ γδ T cells are essential pro ducers of IL22
and IL17 in a murine model of psoriasiform
dermatitis. J Immunol. 187(10): 5026-31, 2011.
Asahina A, Yokoyama T, Ueda M, Ando Y,
Ohshima N, Saito I, Tadokoro E, Hasegawa K:
ereditary gelsolin amyloidosis: A new Japanese casewith cutis laxa as a diagnostic clue. Acta Derm
Venereol. 91: 201-3, 2011.
Suga H, Sugaya M, Tamaki Z, Yamamoto M, Tada
Y, Sato S: Varicella-like generalized pustulosis
induced by adalimumab. Int J Dermatol. 47 Suppl
1: 25-8, 2011.
Noda S, Mizuno K, Adachi T, Adachi M:
Inflammatory tinea capitis due to Trichophyton
tonsurans in a high school wrestler. Mycoses.
54(6): e862-3, 2011.
Noda S, Asano Y, Tamaki Z, Hirabayashi M,
Yamamoto M, Takekoshi T, Hoashi T, Sugaya M,
Morimoto R, Eto T, Kaji K, Fujimoto M, Kuwana
M, Sato S: Dermatomyositis with anti-OJ antibody.
Rheumatol Int. 31(12): 1673-5, 2011.
Ichimura Y, Asano Y, Hatano M, Tamaki Z,
Takekoshi T, Kogure A, Tomita M, Kawashima T,
Miyazaki M, Taniguchi T, Takahasi T, Mitsui H,
Sugaya M, Yao A, Kinugawa K, Sato S: Significant
attenuation of macrovascular involvements bybosentan in a case of diffuse cutaneous systemicsclerosis with multiple digital ulcers and gangrene.
Mod Rheumatol. 21(5):548-52,2011.

221

Department of Plastic andReconstructive Surgery
Professor
Isao Koshima, M.D., Ph.D.

Lecturer
Kotaro Yoshimura, M.D., Ph.D.

AssociateTakuya Iida, M.D., Ph.D.

Mitsunaga Narushima, M.D.

Makoto Mihara, M.D.

Yukio Seki, M.D.

Takeshi Todokoro, M.D.

Azusa Oshima, M.D.

Kazuki Kikuchi, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/plastic/english/index.html

Organization
The present faculty of the Department of Plastic
and Reconstructive Surgery consists of 1 professor, 1
associate professor, 1 lecturer, 7 associates, 7
physicians, and 4 residents. There are about 100
doctors in the department, including 7 graduate school
students, but most are serving in rotation at affiliatedhospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 25 available beds on the 10th floor in the New
Ward. Our faculty room is located in the Medical
Laboratory Building and laboratory rooms in the East
Laboratory Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized
clinics for trauma, scars and keloids, facial paralysis,
hand, replantation, microsurgery, breasts, head andneck reconstruction, cleft lip and palate, craniofacial
malformation,congenital
anomalies,
vascularmalformations, lymphedema, and cosmetic surgery
including cosmetic dermatology. Each week, theprofessor goes the round of inpatients on Wednesday
morning. Preoperative and postoperative conferences
and seminar that all members of the department
should attend are held on Wednesday evening.
Research conferences are held on every Friday
evening.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd and 4th year medical
students, and also of instructing 4th medical students
in bed side practice. The subjects taken up in thelectures include general concepts of plastic surgery,wound healing, congenital malformations, skin grafts
and flaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine.
In the bed side practice the students have theopportunity of seeing various diseases and disorders in222

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.

References (2011)
1:

2:

Research Activities
Basic and clinical researches are performed ingroups. The major research subjects are as follows:
1) Studies on cell isolation from human tissue suchas adipose, amnion, and placenta.
2) Studies on mechanism of hypermelanogenesis of
the skin.
3) Studies on differentiation induction of humanadult stem cells from adipose, amnion, andplacenta4) Characterization of human adult stem cells anddermal papilla cells.
5) Studies on hair regrowth using epidermal stem
cells and dermal papilla cells.
6) Clinical studies on fat regeneration using
suctioned fat tissue and adipose stromalprogenitor cells.
7) Studies on biological function of extracellularmatrix taken from human adipose tissue.
8) Studies on angiogenesis using human adult stem
cells from adipose.
9) Studies on chondrogenesis and osteogenesis using
human fibrin and adipose stromal cells.
10) Studies on molecular mechanisms of vasculogenesis and angiogenesis in the mouse embryo.
11) Studies on molecular pathogenesis of holoprosencephaly using a mouse model.
12) Studies on MMPs and TIMPs expressed in keloid.
13) Studies on the cultured epidermal cells and thecell adhesive function.
14) Studies on clinical application and growth factor
extraction of a fluid from continuous suction
drainage.
15) Studies on mechanism of biological effects ofretinoids on epidermis and dermis.
16) Studies on regeneration of peripheral nerves.

3:

4:

5:

6:

7:

8:

Mihara M, Murai N, Hayashi Y, Hara H, Iida T,
Narushima M, Todokoro T, Uchida G, Yamamoto T,
Koshima I. Using indocyanine green fluorescent
lymphography and lymphatic-venous anastomosis
for cancer-related lymphedema. Ann Vasc Surg.
2012 Feb;26(2):278.e1-6. Epub 2011 Nov 12..
Suzuki S, Koshima I. Digital artery perforator flap
for reconstruction of fingertip after resection ofmelanoma in situ. Hand Surg. 2011;16(3):395-8.
Iida T, Mihara M, Narushima M, Koshima I. A
sensate superficial circumflex iliac perforator flap
based on lateral cutaneous branches of theintercostals nerves. J Plast Reconstr Aesthet Surg.
2012 Apr;65(4):538-40. Epub 2011 Sep 22.
Yamamoto T, Matsuda N, Doi K, Oshima A,
Yoshimatsu H, Todokoro T, Ogata F, Mihara M,
Narushima M, Iida T, Koshima I. The earliest
finding of indocyanine green lymphography inasymptomatic limbs of lower extremity
lymphedema patients secondary to cancer
treatment: the modified dermal backflow stage andconcept of subclinical lymphedema. Plast Reconstr
Surg. 2011 Oct;128(4):314e-321e.
Narushima M, Yamasoba T, Iida T, Yamamoto T,
Yoshimatsu H, Hara H, Oshima A, Todokoro T,
Kikuchi K, Araki J, Mihara M, Koshima I. Pureskin perforator flap for microtia and congenital
aural atresia using supermicrosurgical techniques. J
Plast Reconstr Aesthet Surg. 2011 Dec;64(12):1580-4. Epub 2011 Sep 7.
Mihara M, Kisu I, Hara H, Iida T, Yamamoto T,
Araki J, Hayashi Y, Moriguchi H, Narushima M,
Banno K, Suganuma N, Aoki D, Koshima I. Uterus
autotransplantation in cynomolgus macaques:intraoperative evaluation of uterine blood flowusing indocyanine green. Hum Reprod. 2011 Nov;
26(11):3019-27. Epub 2011 Sep 6.
Hara H, Mihara M, Narushima M, Yamamoto T,
Todokoro T, Araki J, Iida T, Koshima I, Shim TW.
Flap salvage following postoperative venous
thrombosis diagnosed by blood glucose measurement in the flaps. Eplasty. 2011;11:e28. Epub 2011
Jun 22.
Yamamoto T, Yamamoto N, Hara H, Mihara M,
Narushima M, Koshima I. Upper Extremity

223

9:

10:

11:

12:

13:

14:

15:

16:

Lymphedema Index: A Simple Method for Severity
Evaluation of Upper Extremity Lymphedema. Ann
Plast Surg. 2011 Jul 5. [Epub ahead of print]
Mihara M, Murai N, Hayashi Y, Moriguchi H, Iida
T, Hara H, Yamamoto T, Narushima M, Uchida G,
Koshima I. Popliteal lymphatico-venous anastomosis for ower limb lymphedema to allow patientsto adopt the traditional Japanese "seiza" sitting
position. J Plast Reconstr Aesthet Surg. 2011
Nov;64(11):1544-6. Epub 2011 Jun 24.
Suzuki S, Tanaka H, Koshima I. Reconstruction of
cerebrospinal fluid leakage on the occipital regionof the head with the pedicled pectoralis major
myocutaneous flap. Plast Reconstr Surg. 2011 Jul;
128(1):17e-8e.
Yamamoto T, Iida T, Matsuda N, Kikuchi K,
Yoshimatsu H, Mihara M, Narushima M, Koshima
I. Indocyanine green (ICG)-enhanced lymphography for evaluation of facial lymphoedema. J
Plast Reconstr Aesthet Surg. 2011 Nov;64(11):1541-4. Epub 2011 Jun 17.
Yamamoto T, Yamamoto N, Doi K, Oshima A,
Yoshimatsu H, Todokoro T, Ogata F, Mihara M,
Narushima M, Iida T, Koshima I. Indocyanine
green-enhanced lymphography for upper extremity
lymphedema: a novel severity staging system using
dermal backflow patterns. Plast Reconstr Surg.
2011 Oct;128(4):941-7.
Narushima M, Yamamoto T, Yamamoto Y, Hirai R,
Mihara M, Koshima I. Lateral intercostal artery
perforator-based reversed thoracodorsal artery flap
for reconstruction of a chronic radiation ulcer of thelower back wall. Ann Plast Surg. 2011 Oct;67(4):352-6.
Narushima M, Mihara M, Yamamoto Y, Iida T,
Koshima I, Matsumoto D. Hair Transplantation for
Reconstruction of Scalp Defects Using Artificial
Dermis. Dermatol Surg. 2011 May 17.
Tachi K, Furukawa KS, Koshima I, Ushida T. New
microvascular anastomotic ring-coupling device
using negative pressure. J Plast Reconstr Aesthet
Surg. 2011 Sep;64(9):1187-93. Epub 2011 May 8.
Yamamoto T, Narushima M, Kikuchi K,
Yoshimatsu H, Todokoro T, Mihara M, Koshima I.
Lambda-shaped anastomosis with intravascular
stenting method for safe and effective lymphaticovenular anastomosis. Plast Reconstr Surg. 2011

May;127(5):1987-92.
17: Yamamoto T, Narushima M, Doi K, Oshima A,
Ogata F, Mihara M, Koshima I, Mundinger GS.
Characteristic indocyanine green lymphography
findings in lower extremity lymphedema: thegeneration of a novel lymphedema severity staging
system using dermal backflow patterns. Plast
Reconstr Surg. 2011 May;127(5):1979-86.
18: Kikuchi K, Yoshimatsu H, Mihara M, Narushima M,
Iida T, Koshima I. Vascularized nerve flap for spinal
cord repair-a preliminary study. Eplasty. 2011 Mar
16;11:e13.
19: Hirohi T, Yoshimura K. Vertical enlargement of thepalpebral aperture by static shortening of theanterior and posterior lamellae of the lower eyelid:a cosmetic option for Asian eyelids. Plast Reconstr
Surg. 2011 Jan;127(1):396-406.
20: Yamamoto T, Matsuda N, Todokoro T, Yoshimatsu
H, Narushima M, Mihara M, Uchida G, Koshima I.
Lower extremity lymphedema index: a simple
method for severity evaluation of lower extremity
lymphedema. Ann Plast Surg. 2011 Dec;67(6):637-40.
21: Mihara M, Uchida G, Hara H, Hayashi Y,
Moriguchi H, Narushima M, Iida T, Yamamoto T,
Koshima I. Lymphaticovenous anastomosis for
facial lymphoedema after multiple courses oftherapy for head-and-neck cancer. J Plast Reconstr
Aesthet Surg. 2011 Sep;64(9):1221-5. Epub 2011
Mar 5.
22: Sugawara Y, Tamura S, Kaneko J, Iida T, Mihara M,
Makuuchi M, Koshima I, Kokudo N. Single arteryreconstruction in left liver transplantation. Surgery.
2011 Jun;149(6):841-5. Epub 2011 Feb 12.
23: Pignatti M, Ogawa R, Hallock GG, Mateev M,
Georgescu AV, Balakrishnan G, Ono S, Cubison TC,
D'Arpa S, Koshima I, Hyakusoku H. The "Tokyo"
consensus on propeller flaps. Plast Reconstr Surg.
2011 Feb;127(2):716-22.
24: Yamamoto T, Koshima I, Yoshimatsu H, Narushima
M, Miahara M, Iida T. Simultaneous multi-site
lymphaticovenular anastomoses for primary lower
extremity and genital lymphoedema complicatedwith severe lymphorrhea. J Plast Reconstr Aesthet
Surg. 2011 Jun;64(6):812-5.
25: Yoshimura K, Eto H, Kato H, Doi K, Aoi N. In vivo
manipulation of stem cells for adipose tissue

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26:

27:

28:

29:

repair/reconstruction. Regen Med. 2011 Nov;6(6Suppl):33-41.Review.
Eto H, Suga H, Aoi N, Kato H, Doi K, Kuno S,
Tabata Y, Yoshimura K. Therapeutic potential offibroblast growth factor-2 for hypertrophic scars:
upregulation of MMP-1 and HGF expression. Lab
Invest. Epub 2011 Sep 26.
Eto H, Suga H, Inoue K, Aoi N, Kato H, Araki J,
Doi K, Higashino T, Yoshimura K. Adipose
injury-associated factors mitigate hypoxia in
ischemic tissues through activation of adiposederived stem/progenitor/stromal cells and inductionof angiogenesis. Am J Pathol. 2011 May;178(5):2322-32.
Kurita M, Matsumoto D, Kato H, Araki J,
Higashino T, Fujino T, Takasu K, Yoshimura K.
Tissue reactions to cog structure and pure gold in
lifting threads: a histological study in rats. Aesthet
Surg J. 2011 Mar;31(3):347-51.
Aoi N, Inoue K, Kato H, Suga H, Higashino T, Eto
H, Doi K, Araki J, Iida T, Katsuta T, Yoshimura K.
Clinically applicable transplantation procedure ofdermal papilla cells for hair follicle regeneration. J
Tissue Eng Regen Med. Epub 2011 Feb 8.

225

Department ofOral-Maxillofacial Surgery
Professor
Tsuyoshi Takato, M.D.,Ph.D.

Associate Professor
Takafumi Susami, D.D.S., Ph.D.

Yoshiyuki Mori, D.D.S., Ph.D.

Lecturer
Toru Ogasawara, D.D.S., Ph.D.

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

Ichiro Seto, D.D.S., Ph.D.

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

Associate
Takahiro Abe, D.D.S., Ph.D.

Masanobu Abe, D.D.S., Ph.D.

Hideyuki Suenaga, D.D.S., Ph.D.

Genichiro Takagi, D.D.S.

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

Takato Inokuchi, D.D.S., Ph.D.

Yuko Fujihara, D.D.S., Ph.D.

Yuki Kanno, D.D.S.

Madoka Sugiyama, D.D.S.

Homepage

http://plaza.umin.ac.jp/%7Eoralsurg/

Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is one ofthe oldest departments in Graduate School of
Medicine, the University of Tokyo. This department
consists of wide variety of specialists, such as oral
surgeons, orthodontists and prosthodontists. We
handle all diseases in the oral-maxillofacial region,such as congenital anomalies, jaw deformities, benign
and malignant tumors, trauma and inflammation.
Dental care for the patients who have systemic
disorders or under medical control is another field ofour department. Multidisciplinary treatment teamedby these specialists is characteristic and has performed
excellent results in clinical works. In research fields,
all staffs participate in the clinical and basic researchto support the treatment scientifically and to develop
new treatment protocols, and we have mainly

performed the experimental studies on theregenerative abilities of tissues such as bone,
periosteum, cartilage, perichondrium, vessels, nerve,and skin. At present, we are focusing on tissue
engineering in research works especially in bone,cartilage and vessels. Professor Takato had establishedTissue Engineering Division in the University ofTokyo Hospital and our department has two
endowment departments: Department of Cartilage andBone Regeneration (FUJI SOFT Inc.) and Departmentof Clinical Vascular Regeneration (Daiichi SankyoCo., Ltd.) in Tissue Engineering Division. Eachdepartment has 1 associate professor, 1 assistantprofessor, and several graduate students respectively.
These staffs are focusing on translational researchworks in maxillofacial regions.

226

Clinical activities

Education

In the outpatient clinic, we have 12 dental treatment
booths, one operation room and one speech therapy
room. Average number of patients treated at outpatient
clinic is approximately 100 per day.
Our department has two sections mainly; one is oral
and maxillofacial surgery and another is dental andorthodontic dentistry.
In outward dispensary, oral surgery section
performs dental surgeries such as extraction of
impacted teeth, amputation of infected dental root andgingivoplasty in the operation room. Patients who had
been performed surgical treatment are also followed
up after release from the hospital.
Dentistry and orthodontic dentistry performs facial
growth control and tooth movements for patients withcongenital orofacial anomalies such as cleft lip andpalate, jaw deformities and other congenital
deformities. Speech therapy for the patients with cleft
lip and palate is also performed by speech therapists inour department.
Special section for patients of congenital
deformities is on Monday afternoon examined byplastic surgeon, oral and maxillofacial surgeons,orthodontists and prosthetists. Special section for
temporomandibular arthrosis is on Wednesday
afternoon.
In the ward, we have approximately 400 new
inpatients and surgical treatment is performed on
approximately 300 cases per year. The main surgicaltreatments are chiloplasty and plateplasty for cleft lip
and palate patients, bone grafting in alveolar cleft,orthognatic surgery of orofacial deformities, fixationof orofacial fractures, resection of malignant tumors
combined with reconstruction surgery.
Peculiarity of our treatment strategy is teamapproach that consists of oral and maxillofacial
surgeons, orthodontists and prosthodontists. In our
department, patients with congenital dento-facial
deformity are treated by utilizing several techniquessuch as distraction technique, autologous bone graft
technique, and the original artificial bone graft
technique in addition to orthognatic surgery. The
original bone graft is made from patient’s three
dimensional images of CT data and this technique is
now applied for patent.

Teaching activities are divided into two parts; forundergraduate medical students and for postgraduate
dental students. For undergraduate students, we make5 systematic lectures in their second year of
specialized course, and one lecture and one week
bedside learning in final year. Through thesecurriculums, we demonstrate the characteristics andtreatments of the diseases in oral-maxillofacial region.
Teaching is focused on following points; congenital
anomalies such as cleft lip and palate and branchialarch syndromes, dentofacial deformities caused bydevelopmental and acquired problems, surgicalresection and functional reconstruction of benign andmalignant tumors, temporomandibular joint disorders,
inflammation and maxillofacial trauma. Minimum
dental knowledge concerning jaw movement, toothpain, periodontal disease, malocclusion and dental
restorations are instructed.
For postgraduate dental students, we have two-yearresident course. This course aims to train for a wide
range of dental treatments and to learn about medical
cares. Various specialists instruct dental treatments forthem in outpatient clinic. Dental caries treatments,
periodontal cares and applications of dentures are
instructed by prosthodontists. Tooth extractions andorthodontic treatment are instructed by oral surgeons
and orthodontists. Medical cares in the ward aretaught by medical doctors and oral surgeons.
After two-year residential course, research training at
postgraduate school is positively recommended. Ouraim for education of clinician is to raise up specialists
mastered both clinic and research skills.

Research
Our research project consists of clinic and basic
sections. Each research themes are closely related on
the aim of clinical improvement.
The main projects are as follows.
Clinical research:
1) Multidisciplinary treatment of facial deformities
in patients with cleft lip and palate or othercongenital maxillofacial anomalies

2272) Multidisciplinary treatment of dentomaxillofacial
deformities, trauma and temporomandibulardiseases
3) Multidisciplinary treatment of malignant tumors
in head and neck region4) Distraction technique of orofacial osteogenesis
5) Treatment for oforofacial dysplasia with cleft lip
and palate patients
6) Speech therapy for cleft lip and palate patients
7) Advancement therapy for congenital orofacial
dysplasia
8) Evaluation of therapy for cleft lip and palatepatients
9) Surgery, chemotherapy and irradiation therapy formalignant tumors10) Advancement of orthognatic surgery for orofacial
dysplasia11) Evaluation of treatment for temporomandibular
disorders12) Evaluation of mastication function13) Non-surgical treatment system for orofacial
trauma14) 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 osteochondrocyte differentiation
5) Osteochondrogenic differentiation of bonemarrow derived mesenchymal stem cells by
spheroid culture6) Periodontal tissue regeneration around dental
implants
7) Reconstruction of bone and cartilage of oro-facial
region using tissue engineering techniqueResearch 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.

2.

3.

4.

5.

6.
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

7.

Abe M., Tsai SY., Jin SG., Pfeifer GP. and Szabo
PE. Sex-specific dynamics of global chromatinchanges in fetal mouse germ cells. PLoS One
2011 Aug 19;6(8) :e23848
Broggini N, Hofstetter W, Hunziker E, Bosshardt
DD, Bornstein MM, Seto I, Buser D. The
influence of PRP on early bone formation inmembrane protected defects. A histological andhistomorphometric study in the rabbit calvaria.
Clin. Implant Dent. Res. 2011 Mar;13(1):1-12
Chikazu D, Fujikawa Y, Fujihara H, Suenaga H,
Saijo H, Ohkubo K, Ogasawara T, Mori Y, Iino
M, Takato T. Cyclooxygenase-2 activity isimportant in craniofacial fracture repair. Int J
Oral Maxillofac Surg. 2011 Mar;40(3):322-6.
Deno M, Tashiro M, Miyashita M, Asakage T,
Takahashi K, Saito K, Busujima Y, Mori Y, Saito
H, and Ichikawa Y. Developing the social
distress scale for head and neck cancer
outpatients in Japan. Palliative and Supportive
Care 2011, 9:1–8.
Hatano N, Hikiji H, Matsubara M, Saijo H,
Chikazu D, Ohashi K, Mori Y, Susami T, Yoda T,
Takato T. : Reiter’s syndrome (reactive arthritis)withtrismusafter
intravesicalBCG
immunotherapy. A case report. Asian J Oral
Maxillofac Surg 2011, Mar;23(1) :25-7.
Ko EC, Fujihara Y, Ogasawara T, Asawa Y,
Nishizawa S, Nagata S, Takato T, Hoshi K.
Administration of the insulin into the scaffold
atelocollagen for tissue-engineered cartilage. J
Biomed Mater Res A. 2011 May;97(2):186-92.
Li Q, Bian S, Hong J, Kawase-Koga Y, Zhu E,
Zheng Y, Yang L, Sun T.Timing specificrequirement of microRNA function is essential
for embryonic and postnatal hippocampal

228

8.

9.

10.

11.

12.

13.

14.

development. PLoS One. 2011;6(10):e26000.
Mori Y, Susami T, Haga N, Tamura K, Kanno Y,
Saijo H, Takato T. Extraction of 6 molars undergeneral anesthesia in patient with fibrodysplasia
ossificans progressiva. J Oral Maxillofac Surg.
2011 Jul;69(7):1905-10. .
Ohte S, Shin M, Sasanuma H, Yoneyama K,
Akita M, Ikebuchi K, Jimi E, Maruki Y,
Matsuoka M, Namba A, Tomoda H, Okazaki Y,
Ohtake A, Oda H, Owan I, Yoda T, Furuya H,
Kamizono J, Kitoh H, Nakashima Y, Susami T,
Haga N, Komori T, Katagiri T. A novel mutationof ALK2, L196P, found in the most benign caseof fibrodysplasia ossificans progressiva activates
BMP-specific intracellular signaling equivalent
to a typical mutation, R206H. Biochem Biophys
Res Commun. 2011 Apr1;407(1):213-8.
Saijo H, Kanno Y, Mori Y, Suzuki S, Ohkubo K,
Chikazu D, Yonehara Y, Chung UI, Takato T. A
novel method for designing and fabricating
custom-made artificial bones. Int J Oral
Maxillofac Surg. 2011 Sep;40(9):955-60.
Sato T, Nakamoto N, Abe T, Fukushima Y,
Tomaru Y, Sakata Y, Nakazawa M, Nakamoto A,
Kawasaki H, Wada Y, Ohara H, Araki R, Tanaka
J, Yoda T. Preliminary results of a study
comparing conventional radiography with phasecontrast radiography for assessing root
morphology of mandibular third molars.
Dentomaxillofac Radiol. 2011 Feb;40(2):91-5.
Shimamura Y, Abe T, Nakahira M, Yoda T,
Murata S, Sugasawa M. Immunohistochemical
analysis of oral dysplasia: diagnostic assessment
by fascin and podoplanin expression. Acta
Histochem Cytochem. 2011 Dec 28;44(6):23945.
Thoren H, Seto I, Buettner M, Shaller B,
Suominen AL, Iizuka T. Patterns of frontobasal
and frontobasal fractures in children andteenagers relative to developmental stage of the
facial skelton. Arch Otolaryngok Head Neck Surg.
2011 Jun; 137(6):549-556.
Yokoi M, Hattori K, Narikawa K, Ohgushi H,
Tadokoro M, Hoshi K, Takato T, Myoui A,
Nanno K, Kato Y, Kanawa M, Sugawara K, Kobo
T, Ushida T. Feasibility and limitations of theround robin test for assessment of in vitro

15.

16.

17.

18.

19.

20.

21.

22.

chondrogenesis evaluation protocol in a tissueengineered medical product. J Tissue Eng Regen
Med. 2011 Aug 2.
Yonenaga K, Tohnai I, Mitsudo K, Mori Y, Saijo
H, Iwai T, Yonehara Y, Ota Y,Torigoe K, Takato T.
Anatomical study of the external carotid arteryand its branches for administration of superselective intra-arterial chemotherapy via thesuperficial temporal artery. Int J Clin Oncol.
2011 Dec;16(6):654-9.
Hada N, Okayasu M, Ito J, Nakayachi M,
Hayashida C, Kaneda T, Uchida N, Muramatsu T,
Koike C, Masuhara M, Sato T, Hakeda Y.
Receptor activator of NF-κB ligand-dependent
expression of caveolin-1 in osteoclast precursors,and high dependency of osteoclastogenesis on
exogenous lipoprotein. Bone. (in press)
Hirata M, Kugimiya F, Fukai A, Saito T, Yano F,
Ikeda T, Mabuchi A, Sapkota BR, Akune T,
Nishida N, Yoshimura N, Nakagawa T, Tokunaga
K, Nakamura K, Chung UI, and Kawaguchi H:
C/EBP-β and RUNX2 cooperate to degrade
cartilage with MMP-13 as the target and HIF-2α
as the inducer in chondrocytes. Hum Mol Genet(in press).
Iwata K, Asawa Y, Nishizawa S, Mori Y, Nagata
S, Takato T, Hoshi K. The development of aserum-free medium utilizing the interaction
between growth factors and biomaterials.
Biomaterials. (in press)
Kagaya H, Oba M, Miura Y, Koyama H, Ishii T,
Shimada T, Takato T, Kataoka K, Miyata T.
Impact of polyplex micelles installed with cyclic
RGD peptide as ligand on gene delivery tovascular lesions. Gene Ther. (in press)
Kamimura W, Hattori R, Koyama H, Miyata T,
Takato T. A calcium-cross-linked hydrogel basedon alginate-modified atelocollagen functions as a
scaffold material. J Biomater Sci Polym Ed. (inpress)
Kanazawa S, Fujihara Y, Sakamoto T, Asawa Y,
Komura M, Nagata S, Takato T, Hoshi K. Tissue
responses against tissue-engineered cartilage
consisting of chondrocytes encapsulated within
non-absorbable hydrogel. J Tissue Eng Regen
Med. (in press).
Susami T, Mori Y, Tamura K, Ohkubo K,

229

23.

24.

25.

26.

Nagahama K, Takahashi N, Uchino N, Uwatoko
K, Haga N, Takato T. Facial morphology andocclusion in a patient with fibrodysplasia
ossifficans progressiva (FOP): Growth follow-up
from 8 to 21 years of age. Special Care in
Dentistry (in press).
Takahashi-Ichikawa N, Susami T, Nagahama K,
Ohkubo K, Okayasu M, Uchino N, Uwatoko K,
Saijo H, Mori Y, Takato T. Evaluation ofmandibular hypoplasia in patients withhemifacial microsomia: a comparison between
panoramic radiography and three-dimensional
computed tomography. Cleft Palate Craniofac J.
(in press)
Uchiyama T, Yamashita Y, Susami T, Kochi S,
Suzuki S, Takagi R, Tachimura T, Nakano Y,
Shibui T, Michi K, Nishio J, Hata Y. Primary
treatment for cleft lip and /or palate in children in
Japan. Cleft Palate-Craniofac J. (in press)
Ogasawara T, Mori Y, Abe M, Suenaga H,
Kawase-Koga Y, Saijo H, Takato T. Role ofcyclin-dependent kinase (Cdk)6 in osteoblast,
osteoclast, and chondrocyte differentiation andits potential as a target of bone regenerative
medicine. Oral Sci Int. 2011 May; 8(1):2-6.
Saijo H, Takato T, Manual for oral care.
Differentiating between oral cancer andstomatitis. Quintessence Publishing Co., Ltd.
2011 Feb; 331-3

230

Department ofOrthopaedic Surgery
Professor
Sakae Tanaka, M.D., Ph.D.

Associate Professors
Hiroshi Kawaguchi, M.D., Ph.D.

Lecturers
Katsushi Takeshita, M.D., Ph.D.,

Hirotaka Kawano, M.D., Ph.D.,

Takumi Nakagawa, M.D., Ph.D.,

Toshiki Miura, M.D., Ph.D.,

Associates
Hideya Itoh, M.D.,

Hirotaka Chikuda, M.D., Ph.D.,

Satoru Ohashi, M.D., Ph.D.,

Yusuke Shinoda, M.D., Ph.D.,

Nobuhiro Hara, M.D.,

Juichi Tonosu, M.D.,

Koichi Ogura, M.D.,

Hiroshi Inui, M.D.,

Shuji Taketomi, M.D.,

Tetsuo Yamamoto, M.D.,

Takeyuki Tanaka, M.D.,

Satoshi Baba, M.D.,

Homepage

http://www.u-tokyo-ortho.jp/

Introduction and Organization
In 1906 our department was established as the firsteducational institute of orthopedic surgery in Japan,
by the first Professor Yoshinori Tashiro who hadlearned orthopedic surgery in Germany and Austria.
Initially, the department treated patients with
infectious disorders and congenital malformations,such as poliomyelitis, tuberculosis of the spine,congenital clubfoot and hip dislocation. The numberof outpatients visiting our department in 1910 was
estimated to be no more than 3.3% of that of the twosurgical departments in the University of Tokyo
Hospital.
The number and characteristics of the patients,
however, have changed dramatically in these 100
years. This is because our department addressed theacute needs of society from the beginning. Prof.

Tashiro believed that trauma should be treated byorthopedists, so he provided his pupils with thistraining. Since 1950’s, the department has
increasingly been involved in the treatment of traffic
and industrial accident victims. Prof. Tashiro and his
successor Professor Kenji Takagi devoted themselvesto the establishment of an institute for children withdisabilities. The arthroscope was developed by Prof.
Takagi, and is now considered to represent a
breakthrough in the development of minimallyinvasive surgery. We have recently been conducting
many studies related to the ossification of spinal
ligaments (OPLL), rheumatoid arthritis, biomechanics,
and the degenerative skeletal disorders such as
osteoporosis and osteoarthritis in response to theprogressive aging of our society.
Our department is now adept in the entire field of
medical science and medical practice related to the231human 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 one
professor, one associate professors, four lecturers, 12
associates, 8 medical staff members, 6 senior residents,
and 11 part-time teachers.

Teaching activities
As for undergraduate education, our department
provides a comprehensive series of lectures, physicalassessment classes and problem-based learning (PBL)
program to 4th year medical students, bedsidelearning and clinical clerkship programs to 5th year
students and clinical lectures to 6th year medical
students.
A comprehensive series of lectures provides basic
knowledge of the physiology, pathology, diagnosis
and treatment of various musculoskeletal disorders.
Twelve consecutive lectures in total cover a whole
field of orthopaedics: basic science, pediatricdisorders, rheumatic diseases, metabolic bone diseases,
musculoskeletal neoplasm, trauma and regional
disorders of the musculoskeletal system (spine,
shoulder, elbow, hand, hip, knee, ankle and foot). In
the physical assessment classes, we have provided
physical diagnostic maneuvers and the radiologicalassessment of a variety of musculoskeletal diseases.
PBL has been introduced to a small group of students
to learn medical humanity and to develop a practicalmethodology to resolve clinical problems.
During the 10-day period of bed-side learning,
students have opportunities to experience patient careand orthopaedic practice with residents and faculty
members. We have developed an original text for the
students to learn orthopedics effectively. They areencouraged to participate in clinical conferences andsurgeries. They are also required to submit reportson the cases they are involved in. They learn how to
conduct a medical interview, check physical findings
and draw up actual plans for a diagnosis and treatment
including surgery.
Clinical Clerkship provides 4 weeks of early
exposure to the clinical practice. The students areattached to a clinical team and are involved in most of
the clinical activities performed by the team.
For postgraduate education, junior residents join
our department for 1-8 months. In 10
doctors-in-training 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, bonesystemic disorders, and foot. A total of 34,029 patients
visited the outpatient clinic in 2011.
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.
1,067 operations were performed in 2011. These
include 252 spine surgeries (including 79 cervicalspine surgeries, 143 lumbar spine surgeries, and 30
scoliosis surgeries), 60 surgeries for rheumatoid
arthritis patients, 119 hip surgeries, 190 knee surgeries(including 37 computer-assisted ACL reconstruction,
61 computer-assisted TKA), 6 shoulder surgeries, 130
hand surgeries, 2 limb lengthening and reconstruction
surgeries using external fixators, 80 surgeries for boneand soft tissue tumor and 107 trauma surgeries.
The main disorders of cervical spine surgery weremyelopathy due to spondylosis or OPLL. We
successfully adopted double-door open laminoplasty
by splitting the spinal processes for most of thesecases. This procedure was invented and developed inour department and is now used nationwide. Difficult

232

operations such as subluxation of the cervical spine
due to rheumatoid arthritis, Down’s syndrome or
cerebral palsy were treated using a navigation systemthat has been officially approved as a high-leveladvanced medical treatment.
The lumbar spine group developed a new posterior
decompression technique which preserves the spinous
processes and interspinous ligaments, and successfully
uses it for lumbar spinal canal stenosis. Randomized
clinical trials are now ongoing by this group.
The scoliosis group used the navigation systemespecially for patients with complex deformity. In
addition to the conventional correction surgery,
growth-assist techniques such as dual growing rods
are utilized.
Main operations performed by the rheumatoid
arthritis clinic group were total joint arthroplasty.
They are using image-free navigation system in total
knee arthroplasty operation, which is useful for theaccurate placement of the implants.
The hip surgery group treated mainly acetabular
dysplasia and osteoarthritis of the hip joint. They
performed not only total hip replacements, but also
several osteotomies including rotational acetabularosteotomy (RAO). The RAO was originated andestablished in our department. They conducted aclinical trial for a new artificial hip joint using the
MPC polymer in collaboration with the Department ofMaterials Engineering in Tokyo University.
The knee clinic group developed a new anterior
cruciate ligament reconstruction technique using thenavigation
systembasedonintraoperative
three-dimensional fluoroscopic image to realize ideal
graft placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
The tumor group managed multidisciplinary
treatment for musculoskeletal sarcoma including
chemotherapy, limb sparing surgery and radiotherapy
in coorporation with other departments.
Limb reconstruction operations using external
fixators included non-union, leg lengthening anddeformity correction. One of the main interests of thisgroup is the development of a system to analyze themechanical properties of a skeletal system. During
this period of analysis, the mechanical properties ofthe fracture site in vivo are to be evaluated bymonitoring the motion of a dynamic pin clamp during
simulated walking.

Research activities
Our research activities cover the full range of themusculoskeletal system medicine, using the in-depthsciences of biology and technology. Especially in thefield of molecular biology of bone and cartilage
metabolism, we are regarded as being on the leadingedge in the world. Basic research is performed under
the supervision of the faculty staff members. Four
endowment departments take an active role inresearch activities in close collaboration with our
Department. Two were established in the 22nd Century
Medical Center. They deal with clinical research,which houses the largest clinical database of
osteoarthritis patients in the world for the pursue ofgenomic and etiological research. One department isin the Division of Tissue Engineering, which seeks todevelop epochal bone and cartilage regenerative
medicine. In the collaboration of the departments, theROAD (research on osteoarthritis against disability)
study has been established as the biggest bone andjoint diseases project that covers from basic to clinicalresearches of the disease. The fourth is founded in the
Graduate School of Medicine and the researchers aredeveloping durable artificial joints in cooperation with
the Ishihara, Sakata & Takai Laboratory of the
Graduate School of Engineering. Furthermore, we
collaborate with the Center for Disease Biology andIntegrative Medicine (CDBIM), and are developing
nonviral gene delivery vectors (polyion complex
micelles).
As for research of bone absorption, we have been
researching and released some important reports aboutbone metabolism, especially in osteoclast differentiation, osteoclast activation, and apoptosis of osteoclast.
Recently we are starting and getting achievement in
the new research topics such as “Osteoimmunology”,
a new research field studying on signaling cross-talkbetween bone metabolism and immunology, or “Epigenetics”, new research concept in spotlight using
comprehensive analysis technique.
As for research of cartilage, we have researchedmolecular biology of cartilage with the students of the

233

graduate school and the members of Bone andCartilage Regenerative Medicine, Division of Tissue
Engineering. Our research activities cover thegeneration and differentiation of chondrocytes, thejoint formation, the degeneration of joint cartilage,
and the regenerative methods. In 2011, we reported
the functional roles of COX-2 in joint cartilage, andthe synergetic effects of transcription factor C/EBP
and RUNX2 on the cartilage degeneraton by inducing
MMP-13. We are continuously researching the rolesof GSK3, Notch and NF-kB signal in chondrocytes.
We also take part in National Database of
Rheumatic Diseases by iR-net in Japan (NinJa), a
nationwide observational cohort database of rheumatic
disease.

References
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K, Nakamura K, Chung UI, and Kawaguchi H:
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8. Ishiyama N, Moro T, Ohe T, Miura T, Ishihara K,
Konno T, Ohyama T, Yoshikawa M, Kyomoto M,
Saito T, Nakamura K, Kawaguchi H: Reduction of
peritendinous adhesions by hydrogel containing
biocompatible phospholipid polymer MPC for
tendon repair. J Bone Joint Surg Am 93: 142-149,
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9. Matsumoto T, Nagase Y, Iwasawa M, Yasui T,
Masuda H, Kadono Y, Nakamura K, Tanaka S.
Distinguishing the proapoptotic and antiresorptivefunctions of risedronate in murine osteoclasts:
role of the Akt pathway and the ERK/Bim axis.
Arthritis Rheum. 2011 Dec;63(12):3908-17.
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Kawaguchi H, and Komori T. Overexpression of
bcl2 in osteoblasts inhibits osteoblast differentiation and induces osteocyte apoptosis. PLoS ONE
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11. 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 2011; 5: 91-99.
12. Muraki S, Akune T, Oka H, En-yo Y, Yoshida M,
Saika A, Suzuki T, Yoshida H, Ishibashi H,
Tokimura F, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N. Health-related
Quality of Life in Subjects with Low Back Pain
and Knee Pain in a Population-Based Cohort
Study of Japanese men: The ROAD study. SPINE
2011;36:1312-1319.
13. Muraki S, Oka H, Akune T, En-yo Y, Yoshida M,
Nakamura K, Kawaguchi H, Yoshimura N:
Association of Occupational Activity with Joint
Space Narrowing and Osteophytosis in the Medial
Compartment of the Knee: The ROAD study
Osteoarthritis Cartilage 2011;19:840-846.
14. Muraki S, Akune T, Oka H, En-yo Y, Yoshida M,
Nakamura K, Kawaguchi H, Yoshimura N.
Prevalence of falls and its association with knee
osteoarthritis and lumbar spondylosis as well as
knee and lower back pain in Japanese men andwomen. Arthritis Care Res 2011;63:1425-31.
15. Muraki S, Oka H, Akune T, En-yo Y, Yoshida M,
Suzuki T, Yoshida H, Ishibashi H, Tokimura F,
Yamamoto S, Nakamura K, Kawaguchi H,
Yoshimura N. Independent Association of Joint
Space Narrowing and Osteophyte Formation at
the Knee with Health-related Quality of Life inJapan: A Cross-sectional Study Arthritis Rheum
2011;63:3859-3864.
16. Muraki S, Dennison E, Jameson K, Boucher B,
Akune T, Yoshimura N, Judge A, Arden N, Javaid
K, Cooper C. Association of vitamin D status withknee pain and radiographic knee osteoarthritis.
Osteoarthritis Cartilage 2011;19:1301-1306.
17. Kerkhof HJ, Meulenbelt I, Akune T, Arden NK,
Aromaa A, Bierma-Zeinstra SM, Carr A, Cooper

C, Dai J, Doherty M, Doherty SA, Felson D,
Gonzalez A, Gordon A, Harilainen A, Hart DJ,
Hauksson VB, Heliovaara M, Hofman A, Ikegawa
S, Ingvarsson T, Jiang Q, Jonsson H, Jonsdottir I,
Kawaguchi H, Kloppenburg M, Kujala UM, Lane
NE, Leino-Arjas P, Lohmander LS, Luyten FP,
Malizos KN, Nakajima M, Nevitt MC, Pols HA,
Rivadeneira F, Shi D, Slagboom E, Spector TD,
Stefansson K, Sudo A, Tamm A, Tamm AE,
Tsezou A, Uchida A, Uitterlinden AG, Wilkinson
JM, Yoshimura N, Valdes AM, van Meurs JB:
Recommendations for standardization andphenotype definitions in genetic studies ofosteoarthritis: the TREAT-OA consortium.
Osteoarthritis Cartilage 19: 254-264, 2011.
18. Kyomoto M, Moro T, Takatori Y, Kawaguchi H,
Nakamura K, and Ishihara K: Cartilagemimicking, high-density brush structure improves
wear resistance of cross-linked polyethylene: Apilot study. Clin Orthop Relat R 2011; 469:
2327-2336.
19. Ogata N, Shinoda Y, Wettschureck N, Offerman S,
Takeda S, Nakamura K, Segre GV, Chung UI, andKawaguchi H: The Gαq signal in osteoblasts isinhibitory to the osteoanabolic action of PTH. J
Biol Chem 2011; 286: 13733-13740.
20. Ogata T, Ueno T, Hoshikawa S, Ito J, Okazaki R,
Hayakawa K, Morioka K, Yamamoto S,
Nakamura K, Tanaka S, Akai M: Hes1 functions
downstream of growth factors to maintain oligodendeocyte lineage cells in the early progenitor
stage. Neuroscience 176: 132-141, 2011
21. Takeshita K, Maruyama T, Sugita S, Oshima Y,
Morii J, Chikuda H, Ono T, Nakamura K. Is aright pedicle screw always free from the aorta inscoliosis? Spine 2011;36:E1519-24.
22. Taketomi S, Hiraoka H, Nakagawa T, Miyamoto Y,
Kuribayashi S, Fukuda A, Takeda H, Fukai A,
Hirota J, Nakajima K, Haga N, Nakamura K:
Osteochondral autograft for medial femoral
condyle chondral lesions in a patient withmultiple epiphyseal dysplasia: long-term result. J
Orthop Sci Epub ahead of print, 2011
23. Ueno T, Ohori Y, Ito J, Hoshikawa S, Yamamoto S,
Nakamura K, Tanaka S, Akai M, Tobimatsu Y,
Ogata T: Hyperphosphorylated neurofilament
NF-H as a biomarker of the efficacy of

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Ann N Y Acad Sci. 2011 Dec;1240:7-13.
25. Yasui T, Hirose J, Tsutsumi S, Nakamura K,
Aburatani H, Tanaka S. Epigenetic regulation of
osteoclast differentiation: possible involvement of
Jmjd3 in the histone demethylation of Nfatc1. J
Bone Miner Res. 2011 Nov;26(11):2665-71.
26. Yasui T, Kadono Y, Nakamura M, Oshima Y,
Matsumoto T, Masuda H, Hirose J, Omata Y,
Yasuda H, Imamura T, Nakamura K, Tanaka S.
Regulation of RANKL-induced osteoclastogenesis by TGF-β through molecular interaction
between Smad3 andTraf6. J Bone Miner Res.
2011 Jul;26(7):1447-56.
27. 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 2011;29:96-102.
28. Yoshimura N, Oka H, Muraki S, Akune T,
Hirabayashi N, Matsuda S, Nojiri T, Hatanaka K,
Ishimoto Y, Nagata K, Yoshida M, Tokimura F,
Kawaguchi H, Nakamura K. Reference values forhand grip strength, muscle mass, walking time,and one-leg standing time as indices forlocomotive syndrome and associated disability:
The second survey of the ROAD study J Orthop
Sci 2011;16:768-77.
29. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T. Changes in serum levelsof biochemical markers of bone turnover over 10
years among Japanese men and women:
associated factors and birth-cohort effect; The
Taiji Study. J Bone Miner Metab 2011;29:
699-708.
30. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T. Biochemical markers ofbone turnover as predictors for occurrence ofosteoporosis and osteoporotic fractures in men
and women: Ten-year follow-up of the Taiji
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31. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T. Association of knee
osteoarthritis with the accumulation of metabolicrisk factors such as overweight, hypertension,
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Rheum 2011;38:921-30.

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Department of Ophthalmology
Professor
Shiro Amano, M.D., Ph.D.

Associate Professor
Satoshi Kato, M.D., Ph.D.

Lecturer
Miyuki Nagahara, M.D., Ph.D.,

Toshikatsu Kaburaki, M.D., Ph.D.,

Tomohiko Usui, M.D., Ph.D.,

Yasuo Yanagi, M.D., Ph.D.,

Chihiro Mayama,M.D.,Ph.D.

Research Associate
Yasuo Noda, M.D.,

Ryo Asaoka, M.D., Ph.D.,

Takashi Miyai, M.D.,

Ryo Obata, M.D.,Ph.D.,

Hiroshi Murata, M.D.,

Tomoyasu Shiraya, M.D.,

Hiroyo Hirasawa,M.D.,Ph.D.,

Tatsuya Inoue, M.D.,Ph.D.,

Hitoshi Yoneya, M.D.,

Hiromasa Sawamura, M.D., Ph.D., Takashi Ueta,M.D.,Ph.D.,

Kazuyoshi Otomo,M.D.,

Taku Toyama,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 3000 new outpatients areseen every year in our hospital, which has a total of 44
beds. Residents work in the ambulatory section andtake care of inpatients. Special services are provided
in units devoted to ophthalmic subspecialities such as
cornea,glaucoma,
retina,uveitis,neuroophthalmology, orthoptics, diabetic retinopathy, andgenetic and color blindness problems. The staff
members supervise the ambulatory and special
services depending on each one’s speciality.
Most of the inpatients suffer from cataract, glaucoma,
corneal diseases, retinal detachment, diabetic
retinopathy, uveitis and strabismus. Surgeries are
performed in the operating theater of the hospital
under operating microscopes. Approximately 2100
cases underwent operations in our department.
Surgeries can be monitored by TV system, which ismounted on operating microscopes. Since multiple
observers can watch the same images and sharefindings, this system has a great potential in training
and promoting discussion.

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Teaching activities

References

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.

1.

Research activities
Research topics in our department cover a variety offields in ophthalmology; e.g. ocular pharmacology,
regenerative medicine in the cornea and retina,
aqueous humour dynamics, immunology andmolecular biology. Special laboratories for physiology,
pharmacology and genetic engineering have been
established. Specific fields of research in our
department are as follows.
1. Analysis with laser-speckle method of vascularflow in retina and iris
2. Clinical investigation of normal tension glaucoma
3. Drug effect on glaucoma
4. Screening method of glaucoma
5. Tissue engineering of the cornea
6. Clinical investigation of corneal shape
7. Novel culture system of corneal limbal epitheliumand oral mucosal epithelium for ocular surface
reconstruction
8. Analysis of Meibomian gland with Mibography
9. Clinical and basic research of excimer laser
refractive surgery
10. Molecular analysis of retinal degenerative
diseases
11. Color blindness and visual function
12. Electrophysiological analysis of the effect ofdrugs on the retina
13. Pathophysiology of age-related macular degeneration
14. Molecular analysis of retinal neovascularization
15. Immuno-hereditary analysis of Harada’s disease
and Bechet’s disease
16. Immunosuppressive reagents on Bechet’s disease
17. Pathophysiology and molecular mechanisms of
diabetic retinopahty

2.

3.

4.

5.

6.

7.

8.

9.

Aihara M, Shirato S, Sakata R: Incidence ofdeepening of the upper eyelid sulcus after switchingfrom latanoprost to bimatoprost. Jpn J Ophthalmol
55:600-604, 2011
Araki Y, Matsuyama Y, Kobayashi Y, Toyokawa S,
Inoue K, Suzuki S, Makimoto A: Secondary
neoplasms
afterretinoblastoma
treatment:
Retrospective cohort study of 754 patients in Japan.
Jpn J Clin Oncol 41:373-379, 2011
Fujishiro T, Mayama C, Aihara M, Tomidokoro A,
Araie M: Central 10-degree visual field change
following trabeculectomy in advanced open-angle
glaucoma. Eye (Lond) 25:866-871, 2011
Fukuda R, Tanabe T, Sawamura H, Kawata M,
Tsuji H, Kaburaki T: Case of metastatic pulmonary
carcinoma in optic disc diagnosed from results ofbiopsy performed during vitrectomy surgery.
Graefes Arch Clin Exp Ophthalmol 249:1883-1887,
2011
Fukuoka S, Amano S, Honda N, Mimura T, Usui T,
Araie M: Effect of trabeculectomy on ocular andcorneal higher-order aberrations. Jpn J Ophthalmol
55:460-466, 2011
Girkin CA, McGwin G Jr, Sinai MJ, Sehar GC,
Fingeret M, Wollstein G, Varma R, Greenfield D,
Liebmann J, Araie M, Tomita G, Maeda N,
Garway-Heath DF: Variation in optic nerve andmacular structure with age and race with
spectral-domain optical coherence tomography.
Ophthalmology 118:2403-2408, 2011
Hatou S, Shimmura S, Shimazaki J, Usui T, Amano
S, Yokogawa H, Kobayashi A, Zheng X, Shiraishi
A, Ohashi Y, Inatomi T, Tsubota K: Mathematicalprojection model of visual loss due to Fuchs corneal
dystrophy. Invest Ophthalmol Vis Sci 52:78887893, 2011
Hayashida A, Amano S, Park PW: Syndecan-1
promotes Staphylococcus aureus corneal infection
by counteracting neutrophil-mediated host defense.
J Biol Chem 286:3288-3297, 2011
Henzan IM, Tomidokoro A, Uejo C, Sakai H,
Sawaguchi S, Iwase A, Araie M: Comparison ofultrasound biomicroscopic configurations among
primary angle closure, its suspects, andnonocludable angles: the Kumejima study. Am J

238

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

Ophthalmol 151:1065-1073, 2011
Higa A, Sakai H, Sawaguchi S, Iwase A,
Tomidokoro A, Amano S, Araie M: Prevalence ofand risk factors for cornea guttata in a
population-based study in a southwestern island ofJapan. The Kumejima study. Arch Ophthalmol
129:332-336, 2011
Honda N, Mimura T, Hotehama A, Usui T, Sugisaki
K, Fukuoka S, Amano S: Laser treatment of giant
iris cyst with nanophthalmos. Int Ophthalmol 31:
17-20, 2011
Hotehama A, Mimura T, Usui T, Kawashima H,
Amano S: Sudden onset of amantadine-induced
reversible bilateral corneal edema in an elderly
patient: Case report and literature review. Jpn J
Ophthalmol 55:71-74, 2011
Ito Y, Shimazawa M, Inokuchi Y, Yamanaka H,
Tsuruma K, Imamura K, Onoe H, Watanabe Y,
Aihara M, Araie M, Hara H: Involvement ofendoplasmic reticulum stress on neuronal cell deathin the lateral geniculate nucleus in the monkey
glaucoma model. Eur J Neurosci 33:843-855, 2011
Iriyama A, Oba M, Ishii T, Nishiyama N, Kataoka
K, Tamaki Y, Yanagi Y: Gene transfer using
micellar nanovectors inhibits choroidal neovascularization in vivo. PLoS One 6:e28560, 2011
Iriyama A, Usui T, Yanagi Y, Amano S, Oba M,
Miyata K, Nishiyama H, Kataoka K: Gene transfer
using micellar nanovectors inhibits corneal neovascularization in vivo. Cornea 30:1423-1427, 2011
Iwao K, Inatani M, Tanihara H, Japanese SteroidInduced Glaucoma Multicenter Study Group:
Success rates of trabeculotomy for steroid-induced
glaucoma: a comparative, multicenter, retrospective
cohort study. Am J Ophthalmol 151:1047-1056,
2011
Kadonosono K, Arakawa A, Yamane S, Uchio E,
Yanagi Y: An experimental study of retinal
endovascular surgery with a microfabricated needle.
Invest Ophthalmol Vis Sci 52:5790-5793, 2011
Kawashima D, Ohno T, Kinoshita O, Motomura N,
Kiyosue A, Fujita H, Ando J, Ohtomo K, Shigeeda
T, Kato S, Kadowaki T, Nagai R, Takamoto S, Ono
M: Prevalence of vitreous hemorrhage following
coronary revascularization in patients with diabetic
retinopathy. Circ J 75:329-335, 2011
Kawazoe K, Ohno H, Inoue K, Yanagi Y:

20.

21.

22.

23.

24.

25.

26.

27.

28.

Evaluation of a partial retinal surface tear by opticalcoherence tomography. Clin Ophthalmol 5:733-734,
2011
Kubota M, Shimmura S, Kubota S, Miyashita H,
Kato N, Noda K, Ozawa Y, Usui T, Ishida S,
Umezawa K, Kurihara T, Tsubota K: Hydrogen andN-acetyl-L-cystein rescue oxidative stress-induced
angiogenesis in a mouse corneal alkali-burn model.
Invest Ophthalmol Vis Sci 52:427-433, 2011
Kure K, Obata R, Inoue Y, Iriyama A, Yanagi Y:
Acute progression of electrophysiologicallyaffected fellow eye in unilaterally symptomaticacute zonal occult outer retinopathy. Clin
Ophthalmol 5:1167-1170, 2011
Lo YF, Yang SS, Seki G, Yamada H, Horita S,
Yamazaki O, Fujita T, Usui T, Tsai JD, Yu IS, Lin
SW, Lin SH: Severe metabolic acidosis causes early
lethality in NBC1 W516X knock-in mice as amodel of human isolated proximal renal tubularacidosis. Kidney Int 79:730-741, 2011
Mimura T, Nakashizuka T, Kami J, Kohmura M,
Sato S, Dou K, Mori M: Asymptomatic
subconjunctival entrapment of a cilium. Int
Ophthalmol 31:325-326, 2011
Mimura T, Usui T, Mori M, Funatsu H, Noma H,
Amano S: Rapid immunochromatographic measurement of specific tear immunoglobulin E in moderate
to severe cases of allergic conjunctivitis with
immfast check J1 in the spring. Cornea 30:524-527,
2011
Mimura T, Usui T, Mori M, Funatsu H, Noma H,
Amano S: Specific tear IgE in patients withmoderate-to-severe autumnal allergic conjunctivitis.
Int Arch Allergy Immunol 156:381-386, 2011
Mimura T, Usui T, Mori M, Funatsu H, Noma H,
Yamamoto H, Aixinjueluo W, Amano S: Relation
between total tear IgE and specific serum IgE inseasonal allergic conjunctivitis. Cornea 30:790-795,
2011.
Mimura T, Usui T, Obata H, Yamagami S, Mori M,
Funatsu H, Noma H, Dou K, Amano S: Severity
and determinants of pinguecula in a hospital-based
population. Eye Contact Lens 37:31-35, 2011
Mimura T, Usui T, Yamagami S, Funatsu H, Noma
H, Toyono T, Mori M, Amano S: Relationshipbetween conjunctivochalasis and refractive error.
Eye Contact Lens 37:71-78, 2011

239

29. Miyake K, Ota I, Miyake G, Numaga J: Nepafenac
0.1% versus fluorometholone 0.1% for preventing
cystoid macular edema after cataract surgery. J
Cataract Refract Surg 37:1581-1588, 2011
30. Miyata K, Miyai T, Minami K, Bissen-Miyajima H,
Maeda N, Amano S: Limbal relaxing incision usinga reference point and corneal topographer for
intraoperative identification of the steepest meridian.
J Refract Surg 27:339-344, 2011
31. Miyazaki D, Haruki T, Takeda S, Sasaki S, Yakura
K, Terasaka Y, Komatsu N, Yamagami S, Touge H,
Touge C, Inoue Y: Herpes simplex virus type1-induced transcriptional networks of corneal
endothelial cells indicate antigen presentation
function. Invest Ophthalmol Vis Sci 52:4282-4293,
2011
32. Mori Y, Miyai T, Kagaya F, Nagai N, Osakabe Y,
Miyata K, Amano S: Intraoperative mydriasis byintracameral injection of mydriatic eye drops: invivo efficacy and in vitro safety studies. Clin
Experiment Ophthalmol 39:456-461, 2011
33. Nakayama M, Aihara M, Chen YN, Araie M,
Tomita-Yokotani K, Iwashina T: Neuroprotective
effects of flavonoids on hypoxia-, glutamate-, andoxidative stress-induced retinal ganglion cell death.
Mol Vis 17:1784-1793, 2011
34. Nagahara M, Tamaki Y, Tomidokoro A, Araie M:
In vivo Measurement of Blood Velocity in Human
Major Retinal Vessels Using the Laser Speckle
Method. Invest Ophthalmol Vis Sct 52: 87-92, 2011
35. Noma H, Funatsu H, Mimura T, Eguchi S, Shimada
K, Hori S: Vitreous levels of pigment epitheliumderived factor and vascular endothelial growth
factor in macular edema with central retinal vein
occlusion. Curr Eye Res 36:256-263, 2011
36. Noma H, Funatsu H, Mimura T, Eguchi S, Shimada
K: Role of soluble vscular endothelial growth factor
receptor-2 in macular oedema with central retinal
vein occlusion. Br J Ophthalmol 95:788-792, 2011
37. Noma H, Funatsu H, Mimura T, Eguchi S, Shimada
K: Visual prognosis and vitreous molecules after
vitrectomy for macular edema with branch retinal
vein occlusion. Clin Ophthalmol 5:223-229, 2011
38. Noma H, Funatsu H, Mimura T, Harino S, Shimada
K: Functional-morphologic correlates in patientswith branch retinal vein occlusion and macularedema. Retina 31:2102-2108, 2011

39. Noma H, Funatsu H, Mimura T, Eguch S, Hori S:
Soluble vascular endothelial growth factor
receptor-2 and inflammatory factors in macularedema with branch retinal vein occlusion. Am J
Ophthalmol 152:669-677, 2011
40. Noma H, Funatsu H, Mimura T, Shimada K:
Influence of ischemia on visual function in patientswith branch retinal vein occlusion and macularedema. Clin Ophthalmol 5:679-685, 2011
41. Noma H, Funatsu H, Harino S, Sugawara T,
Mimura T, Shimada K: Association ofelectroretinogram and morphological findings inbranch retinal vein occlusion with macular edema.
Doc Ophthalmol 123:83-91, 2011
42. Noma H, Funatsu H, Mimura T, Shimada K: Visualfunction and serous retinal detachment in patientswith branch retinal vein occlusion and macularedema: a case series. BMC Ophthalmol 11:29, 2011
43. Noma H, Funatsu H, Mimura T, Eguchi S, Shimada
K: Influence of vitreous factors after vitrectomy for
macular edema in patients with central retinal vein
occlusion. Int Ophthalmol 31:393-402, 2011
44. Noma H, Funatsu H, Mimura T, Eguchi S: Vitreous
inflammatory factors and serous retinal detachment
in central retinal vein occlusion: a case control
series. J Inflamm (Lond) 8:38, 2011
45. Nomura Y, Ueta T, Iriyama A, Inoue Y, Obata R,
Tamaki Y, Yamaguchi T, Yanagi Y: Vitreomacularinterface in typical exudative age-related maculardegeneration and polypoidal choroidal vasculopathy.
Ophthalmology 118:853-859, 2011
46. Numaga J: Phase II placebo-controlled study ofnepafenac ophthalmic suspension 0.1% for postoperative inflammation and ocular pain associatedwith cataract surgery in Japanese patients. J
Ophthalmic Inflamm Infect 1:147-155, 2011
47. Ooto S, Hangai M, Tomidokoro A, Saito H, Araie
M, Otani T, Kishi S, Matsushita K, Maeda N,
Shirakashi M, Abe H, Ohkubo S, Sugiyama K,
Iwase A, Yoshimura N: Effects of age, sex, andaxial length on the three-dimensional profile ofnormal mucular layer structures. Invest Ophthalmol
Vis Sci 52:8769-8779, 2011
48. Sato M, Kawagoe T, Meguro A, Ota M, Katsuyama
Y, Ishihara M, Namba K, Kitaichi N, Morimoto S,
Kaburaki T, Ando Y, Takenaka S, Ohno S, Inoko H,
Mizuki N: Toll-like receptor 2 (TLR2) gene

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in the Japanese population. Mol Vis 17:731-736,
2011
Shiraya T, Kato S, Shigeeda T: Influence of ayellow-tinted intraocular lens on beam transmittance. Acta Ophthalmologica 89:37-39, 2011
Shima N, Kimoto M, Yamaguchi M, Yamagami S:
Increased proliferation and replicative lifespan ofisolated human corneal endothelial cells with
L-ascorbic acid 2-phosphate. Invest Ophthalmol Vis
Sci 52:8711-8717, 2011
Shiraya T, Kato S, Shigeeda T, Fukushima H:
Vitreous hemorrhage and fibrovascular proliferation
after laser-induced chorioretinal venous anastomosis. International Journal of Ophthalmology
4:216-217, 2011
Sugita S, Yamada Y, Horie S, Nakamura O, Ishidoh
K, Yamamoto Y, Yamagami S, Mochizuki M:
Induction of T regulatory cells by cytotoxic
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Suzuki S, Yamane T, Mohri M, Kaneko A:
Selective ophthalmic arterial injection therapy for
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Takeda S, Miyazaki D, Sasaki S, Yamamoto Y,
Terasaka Y, Yakura K, Yamagami S, Ebihara N,
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Department ofOtorhinolaryngology andHead & Neck Surgery
Professor
Tatsuya Yamasoba, M.D., Ph.D.

Associate Professor
Takahiro Asakage, M.D.,Ph.D

Shin-ichi Iwasaki, MD.,Ph.D

Lecturer
Kenji Kondo, M.D., Ph.D.

Akinobu Kakigi, M.D., Ph.D,

Takaharu Nito, M.D., Ph.D.

Takashi Sakamoto, M.D., Ph.D.

Specially Appointed Lecturer
Shotaro Karino, M.D., Ph.D．

Munetaka Ushio, M.D., Ph.D.

Research Associate
Yasuhiro Ebihara, M.D.

Takuya Yasui, M.D., Ph.D.

Naoya Egami, M.D.

Keigo Suzukawa, M.D., Ph.D.

Shintaro Baba, M.D.

Akinori Kashio, M.D,

Aki Inoue, M.D.

Kaori Kanaya, M.D.

Yuki Saito, M.D.

Shu Kikuta, M.D., Ph.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 covers all otorhinolaryngological diseases and associated systemic
diseases, and has specialized clinics in middle ear andinner ear diseases, hearing impaired infant andchildren, adult and elderly patients, facial paresis,
vertigo and balance disorders, olfactory disorders andparanasal diseases, voice and speech disorders, taste
and swallowing respiratory disorders, aphasia, central

auditory disorders and head & neck cancers.
A professor, associate professors, lecturers(assistant professors) and associates participate insurgery, out-patient and in-patient care as well as
research and educational activities. One assistantprofessor is abroad at present for basic and clinicalresearch in the U.S.A. Moreover eight Japanese
graduate students and one Chinese foreign graduate
student participate in basic research.
Weekly preoperative and postoperative conferences
are held to discuss surgical cases in detail. Special
lectures on leading research activities are presented byinvited guests on a regular basis. A weekly journal
club is held to introduce current research papers.

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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 and bronchoesophagological surgery, and paranasal surgery andother minor surgery. Peroperative and postoperative
problems are checked and discussed by each group,
the professor’s and associate professor’s rounds.
Approximately 800 operations are performed
annually.
Cochlear implant surgery over 250 cases has been
actively performed for infants, children and adultpatients with profound hearing loss and is very
successful to provide new hearing. Head and necksurgery is performed to extirpate malignant tumor
with neighboring tissues and reconstruct upper
respiratory and swallowing functions at one stage
operation cooperating with plastic surgeons.
Reconstructive surgery of microtia and atresia toreconstruct external ear is routinely performed withplastic surgeons.
Auditory brainstem response is routinely examinedin order to diagnose peripheral and central deafness inneonates, infants and children.
Treatment of acoustic tumor using an ɤ-knife andauditory brainstem implant are performed inconsultation with neurosurgons.

Teaching activities
For the fourth year medical students’ serial lecturesand for the fifth and sixth year medical students
special lectures on current topics are provided by theprofessor and associate professor.
Clinical training is provided for the sixth year classof medical students on a one-to-one basis with staff
doctors. They are requested to write reports on aclinical case or a clinical problem. The students
participate to see surgery, special clinics and clinicalexaminations such as otoscope, fiberscope, auditory
brainstem response, and caloric test. Interview withpatient is encouraged. They are questioned many
aspects of clinical problems in seminars by professor
and associate professor. During half and a week period,
the students participate in surgery special clinics andpractice of clinic examination such otoscope,
fiberscope auditory brainstem, caloric test and so on.

Research activities
Clinical and basic research activities are highly
encouraged. Clinical research, which is supervised bysenior doctors, is very actively pursued even by young
residents. Case reports presentation and writing skills
are regarded as important experience in order todevelop young doctors’ research activity andinvestigate important findings in patients. The clinicalresearch is related to ear surgery, neurotology,
audiology, head and neck surgery, bronchoesophagology and rhinology and is related to caseresersch, clinical statistics and clinical electrophysiology. Basic research is also encouraged to solve
essence of clinical problems and to elucidate basic
phenomena or anatomical and cellular structures. Our
research topics cover:1) Morphology and neurophysiology of the inner ear
focusing on sensory neural deafness: human
temporal bone pathology, electron microscopic
study in animal models, gene therapy, protein
tranasduction, and nanotechnology
2) Clinical application of otoacoustic emissions andauditory brainstem responses.
3) Histochemistry of olfactory epithelium indevelopment and aging.
4) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients.
5) Histochemistry of head and neck cancer
pathology.
6) The central auditory cortex research using MEG.
7) Auditory brainstem response and speech andhearing after the new born hearing screening.
8) Pathology and electrophysiology of the larynx.
9) Vestibular research on the oculomotor and balancesystems in the brain.
10) Vestibular myogenic evoked potentials in cochlear

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implant and inner ear anomaly.
11) Hair cell physiology in the vestibular end organ.
12) Newborn hearing screening and language
development in deaf childen.
13) Physiology bone conduction innovation of bone
conduction hearing and bilateral hearing.
14) Embryology of middle, inner ear and central
auditory system.
Various clinical and basic research are conducted bystaffs, residents, postgraduate doctors and seniordoctors at affiliated hospitals.

References
1. Baba S, Kondo K, Kanaya K, Suzukawa K, Sato T,
Kurata H, Hiruma T, Fujita H, Yahagi N, Yamasoba T.
Tsunami sinusitis. Lancet 378: 1116, 2011
2. Baba S, Kondo K, Kanaya K, Ushio M, Tojima H,
Yamasoba T. Bell’s Palsy in children: relationshipbetween electroneurography findings and prognosis
in comparison with adults. Otol Neurotol 32:
1554-1558, 2011
3. Cabral H, Matsumoto Y, Mizuno K, Chen Q,
Murakami M, Kimura M, Terada Y, Kano M.R,
Miyazono K, Uesaka M, Nishiyama N, Kataoka K.
Accumulation of sub-100mm polymeric micelles inpoorly permeable tumours depends on size. Nature
Nanotechnology 6: 815-823, 2011
4. Chihara Y, Iwasaki S, Kondo K, Yamasoba T.
Responsiveness of rat vestibular ganglion neurons toexogenous neurotrophic factors during postnatal
development in dissociated cultures, Brain. Res
1408: 1-7, 2011
5. Christie R.J, Miyata K, Matsumoto Y, Nomoto T,
Menasco D, Lai T.C, Pennisi M, Osada K,
Fukushima S, Nishiyama N, Yamasaki Y, Kataoka K.
Effect of polymer structure on micelles formed
between siRNA and cationic block copolymer
comprising thiols and amidines. Biomacromolecules
12: 3174-3185, 2011
6. Fujimoto C, Ishimaru Y, Katano Y, Misaka T,
Yamasoba T, Asakura T, Abe K. The Single pore
residue Asp523 in PKD2L1 determines Ca2+
permeation of the PKD1L3/PKD2L1 complex.
Biochemical and Biophysical Research Communications 404: 946-951, 2011

7. Iida H, Nakajima T, Kurano M, Yasuda T, Sakamaki
M, Sato Y, Yamasoba T, Abe T. Effects of walking
with blood flow restriction on limb venous
compliance in elderly subjects. Clin Physiol Funct
Imaging. 31: 472-6, 2011
8. Iwasaki S, Egami N, Fujimoto C, Chihara Y, Ushiio
M, Kashio A, Yamasoba T. The mitochondrial A
3243 G mutation involves the peripheral vestibule aswell as the cochlea. Laryngoscope 121: 1821-4, 2011
9. Iwasaki S, Chihara Y, Ushio M, Ochi A, Murofushi T,
Yamasoba T. Effect of the canalith repositioning
procedure on subjective visual horizontal in patientswith posterior canal benign paroxysmal positionalvertigo. Acta Oto-Laryngologica 131: 41-45, 2011
10. Kakigi A, Okada T, Takeda T, Takeda S, Nishioka R,
Taguchi D, Nishimura M, Yamasoba T. Endocytosisof cationized ferritin in marginal cells of the stria
vascularis is regulated by protein kinase, protein
phosphatase, and MEK/ERK and PI 3-K signaling
pathways. Otol Neurotol. 32: 856-62, 2011
11. Kakigi A, Okada T, Takeda T, Takeda S, Nishioka R,
Taguchi D, Nishimura M, Yamasoba T. Endocytosisof microperoxidase in marginal cells is mainly
regulated by RhoA signaling cascade, but not by
Rho-associated protein kinase, myosin light-chain
kinase and myosin phosphatase. ORL J Otorhinolaryngol Relat Spec. 73: 1-8, 2011
12. Kagoya R, Iwasaki S, Chihara Y, Ushio M, Tsuji S,
Murofushi T, Yamasoba T. Cephalic tetanus
presenting as acute vertigo with bilateral vestibulopathy Acta Otolaryngol 131: 334-336, 2011
13. Karino S, Philip H. Smith, Tom C.T.Yin, Philip X.
Joris. Axonal Branching Patterns as Sources of Delayin the Mammalian Auditory Brainstem: A ReExamination. J. Neurosci. 31: 3016-3031, 2011
14. Kashio A, Ito K, Kakigi A, Karino S, Iwasaki S,
Sakamoto T, Yasui T, Suzuki M, Yamasoba T.
Carhart notch 2-kHz bone conduction threshold dip:a nondefinitive predictor of stapes fixation in
conductive hearing loss with normal tympanic
membrane. Arch Otolaryngol Head Neck Surg. 137:
236-240, 2011
15. Kobayashi K, Nakao K, Kawai K, Ito K, Hukumoto
S, Asakage T, Oota S, Motoi R. Tumor-induced
osteomalacia origination for the temporal bone: acase report. Head Neck 33: 1072-1075, 2011
16. Lin Y, Kashio A, Sakamoto T, Suzukawa K, Kakigi

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A, Yamasoba T. Hydrogen in drinking water
attenuates noiose-induced hearing loss in guinea pigs.
Neurosci Lett. 487: 12-6, 2011
17. Murakami M, Cabral H, Matsumoto Y, Wu S, Kano
M.R, Yamori T, Nishiyama T, Kataoka K. Improving
Drug Potency and Efficacy by Nanocarrier-MediatedSubcellular
Targeting
Science
Translational
Medicine 3: 64 ra 2, 2011
18. Nishijima H, Asakage T, Sugasawa M. Malignant
carotid body tumor with systemic metastases. Ann
Otol Rhinol Laryngol 120: 381-385, 2011
19. Nakajima T, Yasuda T, Sato Y, Morita T, Yamasoba T.
Effects of Exercise and Anti-Aging. Anti-Aging
Medicine 8: 92-102, 2011
20. Nomoto T, Matsumoto Y, Miyata K, Oba M,
Fukushima S, Nishiyama N, Yamasoba T, Kataoka K.
In Situ Quantitative Monitoring of Polyplexes andPolyplex Micelles in the Blood Circulation Using
Intravital Real-Time Confocal Laser Scanning
Microscopy. Journal of Controlled Release 151:
104-109, 2011
21. Narushima M, Yamasoba T, Iida T, Yamamoto T,
Yoshimatsu H, Hara H, Oshima A, Todokoro T,
Kikuchi K, Araki J, Mihara M, Koshima I. Pure skinperforator flap for microtia and congenital auralatresia using supermicrosurgical techniques. J Plast
Reconstr Aesthet Surg 64: 1580-4, 2011
22. Okada K, Yamasoba T, Kiyono H. Craniofacial
mucosal immune system: importance of its uniqueorganogenesis and function in the development of amucosal vaccine. Adv Otorhinolaryngol 72: 31-6,
2011
23. Sakamoto T, Kakigi A, Kashio A, Kanaya K, Suzuki
M, Yamasoba T. Evaluation of the Carhart effect incongenital middle ear malformation with both anintact external ear canal and a mobile stapes footplate.
ORL J Otorhinolaryngol Relat Spec. 73: 61-7, 201124. Suzukawa K, Kondo K, Kanaya K, Sakamoto T,
Watanabe K, Ushio M, Kaga K, Yamasoba T.
Age-related changes of the regeneration mode in themouse peripheral olfactory system following
olfactotoxic drug methimazole-induced damage. J
Comp Neurol 519: 2154-2174, 2011
25. Suzuki M, Goto T, Kashio A, Yasui T, Sakamoto T,
Ito K, Yamasoba T. Preservation of vestibularfunction after scala vestibuli cochlear implantation,
Auris Nasus Larynx 38: 632-42, 2011

26. Ushio M, Minor LB, Della Santina CC, Lasker DM.
Unidirectional rotations produce asymmetric changes
in horizontal VOR gain before and after unilaterallabyrinthectomy in macaques. Exp Brain Res 210:
651-60, 2011

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. Thirteen students haveentered the graduate school by 2010, and eight ofthem were granted Ph.D.

Clinical activities
There is not enough doctors arranged for the
department of rehabilitation medicine, and we cannot
run own beds for rehabilitation patients at present. The
professor serves as a director of Rehabilitation Center,the University of Tokyo Hospital. Both departments
are united and engage in clinical practice. We have atpresent no charged ward, and treat about 1,000 newreferrals annually from almost all the departments of
the university hospital. We always take charge ofabout 250 patients corresponding about 25% of thewhole number of inpatients. We also see 15 people per
day at the outpatient rehabilitation setting. The
numerical ratio of outpatient is being reduced in orderto give priority to the clinical service corresponding toneeds expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on

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, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline ofrehabilitation, and amputation/prostheses. We haveprovided a clinical practice in small group, so-called
bedside learning for 5th year students from
Wednesday to Friday every other week. Theyexperience a few patients and learn how to take apatients’ 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,
occupational therapy, and speech therapy. Twenty
students or more come and stay at the university
hospital annually as a long-term clerkship fromseveral PT/OT/ST training schools.

congenital limb deficiencies
7) Disabilities and handicaps in patients with skeletal
dysplasias
8) Analysis of musculo-skeletal involvement incongenital insensitivity to pain

Research activities3.

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 the elderly
4) Rehabilitation approaches for patients withhemophilia
5) Rehabilitation approaches for patients with spina
bifida6) Treatment and rehabilitation for patients with

References
1.

2.

4.

Mori Y, Susami T, Haga N, Tamura K, Kanno Y,
Saijo H, Takato T: Extraction of six molars undergeneral anesthesia in a patient with fibrodysplasia
ossificans progressiva (FOP). J Oral Maxillofac
Surg 69: 1905-1910, 2011
Ohte S, Shin M, Sasanuma H, Yoneyama K,
Akita M, Ikebuchi K, Jimi E, Maruki Y,
Matsuoka M, Nanba A, Tomoda H, Okazaki Y,
Ohtake A, Oda H, Owan I, Yoda T, Furuya H,
Kamizono J, Kitoh H, Nakashima Y, Susami T,
Haga N, Komori T, Katagiri T: A novel mutationof ALK2, L196P, found in the most benign caseof fibrodysplasia ossificans progressiva activates
BMP-specific intracellular signaling equivalent
to a typical mutation. R206H. Biochem Biophys
Res Commun 407: 213-218, 2011
Taketomi S, Hiraoka H, Nakagawa T, Miyamoto
Y, Kuribayashi S, Fukuda A, Takeda H, Fukai A,
Hirota J, Nakajima K, Haga N, Nakamura K:
Osteochondral autograft for medial femoral
condyle chondral lesions in a patient withmultiple epiphyseal dysplasia: long-term result. J
Orthop Sci, 2011 published online
Kaplan FS, Shore EM, Pignolo RJ (eds), Haga N,
and The International Clinical Consortium on
FOP. The medical management of fibrodysplasia ossificans progressiva: current treatment
considerations. Clin Proc Intl Clin Consort FOP
4: 1-100, 2011

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.

Nobuko Ito, M.D., Ph.D. Kanji Uchida, M.D., Ph.D.

Instructor
Hiroshi Sekiyama, M.D., Nobuhide Kin, M.D.,

Kenichi Kishida, M.D.,

Yoshiteru Mori, M.D.,

Yoshie Suzuki, M.D.,

Makoto Nakamura, M.D.,

Masahiko Bougaki, M.D.,Ph.D.
Kanako Sato, M.D.,

Masahiko Sumitani,M.D.,PhD.,

Gaku Kawamura, M.D.,

Jun Ninagawa, M.D.,

Takamichi Kogure, M.D., Kenji Azuma, M.D.,

Yosuke Imai, M.D.,

Masaaki Asamoto, M.D.

Maiko Obuchi, M.D.,

Yuho Tamai, M.D.,

Ayako Hirai, M.D.,

Go Ichihara, M.D.,

Yoko Hoshino, M.D.,

Satoshi Kasahara, M.D.

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/aprc_md/index.html
http://www.anes.umin.ne.jp/
Introduction and Organization
The Department of Anesthesiology was establishedin 1952. Our department has residents, chief residents
besides the members above. We introduce theactivities about Teaching, Research and Clinical workof our department.

Clinical activities
Our clinical activities can be divided into two areas;
surgical anesthesia in the operating theater and a pain
clinic.
Anesthesia service including pre and post-operative
care is given every day for elective and emergency
surgery. We provide general anesthesia for various
kinds of surgeries including open heart surgery (adults
and pediatrics) and heart / liver transplant,
spinal/epidural anesthesia and monitored anestheticcare for electro-convulsion therapy. Recently, thenumber of high risk or geriatric patents is increasing.
A new operating theater with 11 new ORs opened in
January 2007 and the annual surgery exceeds 10,000
cased.
Pain clinic services are provided for out-patients(including patients in the ward of the otherdepartment) on a daily basis in all areas of diseases
accompanied with pain. We also provide preoperative
anesthetic consult service for patients who havevarious medical complications. From April 2010 toApril 2011, the number of ambulatory patients was
about ten thousand; six hundred of those were
newcomer patients. Currently we have three beds inthe ward. Annually, we provide inpatient service forsixty patients in our ward as well as for seven hundred
and twenty patients in other wards. Preoperative
anesthetic consults were done for about twelve
hundred patients last year.

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, the mechanisms ofanesthesia, inhalational anesthesia, intravenous
anesthesia, anesthesia and respiratory/circulatory
system, the balance of body fluid, acid-base balance,
muscle relaxants, management of the patient during
anesthesia, monitoring, resuscitation, pain clinic andthe physiology and the management of pain.
The curriculum of bedside learning consists of threemajor contents: learning a practice of anesthetic
management for patients undergoing surgeries,
observing a practice of pain management for
outpatients suffering from intractable pain, andinteractive lectures on specific topics. During thepractice of anesthetic management, we teach students
how to evaluate patients in the peri-operative period.
Through the practice of pain management, we teachstudents causes of intractable pain as well asprocedures of nerve block. We schedule 5 lectures
entitled “introduction to anesthesiology”, “airway
management”, “central venous catheterization”,“spinal anesthesia” and “pain clinic”. These 5 lectures
cover fundamental knowledge of basic procedures
which medical students should acquire. Moreover,students can experience procedures of tracheal
intubation, central venous catheterization and spinal
anesthesia using simulators. Each student is required
to submit a report of a case who underwent generalanesthesia and the summary of anesthetics andcardiovascular drugs in peri-operative use. We discuss
the contents of the reports and summaries withstudents at the end of bedside learning, for theirfurther understandings.

Research activities
We have seven research groups and their fields
include respiration, circulation, pain, immune systemand shock.
These are recent major subjects of our research.
1) A role of cytokine signaling in acute lung injury2) Evaluation of optimal ventilatory strategy for

respiratory failure3) Modulation of immune system by anesthetics
4) Signal transduction pathway related to apoptosis
activated by sepsis or ischemia-reperfusion5) Pathophysiology of shock6) A role of lipid mediators in organ damage
mediated by ischemia-reperfusion injury7) A role of lipid mediators in the formation of
hyperalgesia
8) Antihyperalgesic and antipruritic effects of alpha2-adrenergic agonists
9) A role of spinal microglial cells in the development of inflammation-mediated neuropathic pain
10) Spinal contribution for analgesic pathway11) Mechanism of Pruritoceptive and Neurogenic Itch
12) Dose-escalation of sublingual buprenorphine inpatients with chronic pain13) Analysis of electroencephalography during general anesthesia
14) Clinical evaluation of neurological sequelae after
cardiac surgery15) Retrospective analysis of large administrative
database to explore rare complications related toanesthesia and / or association between anesthetic
drug and postoperative outcome16) Effect of anesthetics on glucose metabolism invivo17) Role of new plasma substitutes on hemorrhagic
shock

References(1) Sumitani M, Uchida K, Yasunaga H, Horiguchi H,
Kusakabe Y, Matsuda S, Yamada Y. Prevalence ofmalignant hyperthermia and relationship with
anesthetics in Japan: Data from the Diagnosis
Procedure Combination Database. Anesthesiology.
2011;114:84-90(2) Uchida K, Yasunaga H, Miyata H, Sumitani M,
Horiguchi H, Kuwajima K, Matsuda S, Yamada Y.
Impact of remifentanil introduction on practicepatterns in general anesthesia. J Anesth. 2011;
25:864-71(3) Sumitani M, Yozu A, Tomioka T, Yamada Y,
Miyauchi S. Using the intact hand for objective
assessment of phantom hand perception. European
Journal of Pain 2010;14:261-5

250(4) Sumitani M, Miyauchi S, Yozu A, Otake Y, Saitoh Y,
Yamada Y. Phantom limb pain in the primary motor
cortex. Journal of Anesthesia 2010;24:337-41(5) Sumitani M, Shibata M, Sakaue G, Mashimo T,
Japanese CRPS Research Group. Development ofcomprehensive diagnostic criteria of complex
regional pain syndrome in the Japanese population.
Pain 2010;150:243-9(6) Sakagami T, Beck D, Uchida K, Suzuki T, Carey
BC, Nakata K, Keller G, Wood RE, Wert SE,
Ikegami M, Whitsett JA, Luisetti M, Davies S,
Krischer JP, Brody A, Ryckman F, Trapnell
BC. Patient-derived GM-CSF Autoantibodies
Reproduce Pulmonary Alveolar Proteinosis in
Non-human Primates. Am J Respir Crit Care Med
2010;182(1):49-61(7) Uchida K, Carey B, Suzuki T, Nakata K, Trapnell
BC. Response: Granulocyte/macrophage colonystimulating factor autoantibodies and myeloid cell
immune functions in healthy persons. Blood 2010;
115(2):431-3(8) Watanabe M, Uchida K, Nakagaki K, Trapnell BC,
Nakata K. High avidity cytokine autoantibodies inhealth and disease: pathogenesis and mechanisms.
Cytokine Growth Factor Rev 2010;21(4):263-73(9) Bougaki M, Searles RJ, Kida K, De Yu J, Buys ES,
Ichinose F. NOS3 protects against systemic
inflammation and myocardial dysfunction in murine
polymicrobial sepsis. Shock 2010;34(3):281-90

251

Department of Emergency andCritical Care Medicine
Professor
Naoki Yahagi, M.D.

Associate Professor
Susumu Nakajima, M.D.

Lecturer
Yukio Tanaka, M.D., Ph.D.

Associate
Takeshi Ishii, M.D.,

Masataka Gunshin, M.D.,

Takehiro Matsubara, M.D.,

Jiro Ando, M.D.,

Yumiko Hosoya, M.D.,

Juntaro Matsuyama, M. D.,

Rei Ito, M.D.,

Takahiro Hiruma, M.D.,

Hidenobu Fujita, M.D.,

Yasuyuki Jujo, M.D.,

Kanae Nagatomo, M.D.,

Staff
Ryota Inokuchi, M.D.,

Homepage

Shiho Oide, M.D.,

http://square.umin.ac.jp/todaiqq/※ The following information is the same as that of the previous year for certain reasons.

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, and gynecologic patients. The Life Flight service provides another252

opportunity for exposure to critically ill patients.
Consult services are available from all of the clinicaldepartments of the Medical School. The university ofTokyo hospital was officially designated as emergency
medical care center in December 2010.

Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only
tertiary emergency but also primary and secondary
emergency care on 24-hour-a-day basis. In the 2006,
we had about 6,000 ambulance patients out of total
20,300 ER outpatients.
The new ER, four times the size of the present
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation
rooms for dentistry, ophthalmology, otorhinolaryngology and gynecology, 2 resuscitation bays, 1
operating room and 4 observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery,
surgery, neurosurgery or anesthesiology create “thesemi-closed ICU” model. We are responsible for theentire care of the critically ill patients (i.e. patientswith respiratory insufficiency such as ARDS, withsepsis, with MOF, with shock), post-operative
patients, and tertiary emergency patients, placing anemphasis on evidence-based medical therapy. We
had 2,700 ICU/CCU patients in the 2007. In 2007,
the number of beds in ICU/CCU increased to 16
and the facility included the 24 beds for the highcare ICU2.
3) Bed management
The objective of bed management services is toprovide a timely and appropriate bed allocation for
all the patients. In our hospital, patients areallocated to three types of wards, that is, generalward, ICU2 and ICU/CCU in accordance with theircritical condition. The ICU2 undertakes the leading
bed management in the hospital to ensure maximum

performance as an acute hospital.
4) Risk management
It is split into two categories – in-hospital andout-hospital disasters. In regard to in-hospital risk
management, including “code blue emergency”, weare responsible for patient safety on 24-hour/365day basis. And in regard to out-hospital risk
management, our hospital has been authorized by
the Tokyo Metropolitan Government as a disasterbase hospital, and also the Government hasrequested the formation of Disaster Medical
Assistant Team (DMAT) from us. We are now
proceeding with a drastic revision of in-hospitalmanual for disaster control, holding seminars on
disaster medicine, and enforcing the disastertraining. We have oxygen and medical suction
equipment on the passageways in the new ER since2006 fiscal year in case treating the large number ofdisaster patients.

Teaching activities
1) Six hours of lecture for the 2nd year medical
student, the topics include the prehospitalemergency care, the initial evaluation of emergency
patients, disaster medicine, serious infections
disease, and medical equipment. Four hours ofsimulation training of Basic Life Support.
2) One month of clinical clerkship and 1 week of
bed-side training for the 3rd year. ACLS Basiccourse (ICLS) is held for the participants in theclinical clerkship program, and successful
completion of this course will enable students to be
ICLS certified.
3) Clinical integrated lecture for the 4th year students
includes diagnosis and treatment of serious patientsusing case studies of shock, conscious disorder,
trauma, intoxication, infections disease, burns,
hypothermia, and convulsion. After learning a
ACLS course, students experience the real practiceof emergency medicine as fellow passengers in theambulance and as 2.5-day trainees in affiliatedhospitals’ emergency centers.
In conformity with the guideline by Ministry of
Health, Labour and Welfare, all residents learn andpractice emergency medicine and primary care at

253

every level, primary, secondary and tertiary. The
residents are trained in the ACLS Basic (ICLS)
during resident year to obtain the knowledge andskills in CPR.
Junior residents are also assigned to ICU services
to gain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
In the senior resident program in 2006, we willtrain the new residents to be skilled in advanced
critical care medicine including primary caretrauma, MOF, shock, and equipment support.
As medical aspects of disaster management, we
provide the residents with lectures based on
MIMMS (Major Incident Medical Management andSupport) program, triage training, and risk
communication techniques using wireless network.
In addition, we produce the seminar for nurses suchas medical support in the big earthquake.

4.

5.

6.

Research activities
7.
The on-going researches include “the Vital Care
Network System” which manages the great number ofhigh-risk people continually, electrolyzed water,elucidation of peripheral neural regulation of heart,and brain resuscitation. In collaboration with
Department of Pharmacy, Department of ClinicalLaboratory Medicine, Department of Infectious
Diseases, we focus on several clinical research on
issues including intra-nuclear transcription of β-Dglucan in blood products .

References
1.

2.

3.

Miura T, Nishigaki M, Matsubara T, Sakamoto M,
Kikuchi Y, Nakajima S, Tanaka Y. Nurse-led
educational session for non-medical staff
improved the appropriateness of rapid response
team activation. Jpn J Trauma Emerg Med 2010:
1; 9-15.
Sorimachi M, Nakada Y, Izumi A, Matsubara T.
Cardiac function before operation affects
operative results in patients with hip fractures.
Jpn J Trauma Emerg Med 2010:1; 1-8.
Matsuse S, Hara Y, Ohkura T. Arterial
sevoflurane concentration during one-lung venti-

lation (OLV). Possible influence of pulmonary
arterio-venous shunt and hypoxic pulmonary
vasoconstriction. Anesth Analg 2010 Nov 16.
[Epub ahead of print]
Doi K, Noiri E, Maeda-Mamiya R, Ishii T,
Negishi K, Hamasaki Y, Fujita T, Yahagi N,
Koide H, Sugaya T, Nakamura T. Urinary L-type
fatty acid-binding protein as a new biomarker ofsepsis complicated with acute kidney injury. Crit
Care Med 2010 Jul 22. [Epub ahead of print]
Furumoto N, Yamaoka T, Matsubara T, Gunshin
M, Ishii T, Nakajima S, Tanaka Y, Yahagi N. On
issues with medical responses observed in majordisasters in Japan and the countermeasures (Aninterview study with officials aiming better
readiness). Jap J Disaster Med 2010; 15: 53-62.
Unuma K, Shintani-Ishida K, Yahagi N,
Tsushima K, Shimosawa T, Ueyama T, Yoshida K.
Restraint Stress Induces Connexin-43 Translocation via α-Adrenoceptors in Rat Heart. Circ J
2010; 74: 2693-701.
Inamori S, Fujii Y, Oshita T, Kobayashi Y,
Minamiyama M, Sasaki S, Murakami T, Sakuma
I, Suematsu Y, Gunshin T, Yahagi N. Development of a pulsatile flow-generating circulation
assist device for cardiac management. J Artif
Organs 13: 67-70. 2010

Health Sciences and Nursing
1. Health Sciences

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/※ The following information is the same as that of the previous year for certain reasons.

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.

256

In Undergraduate Courses, School of Health
Sciences and Nursing, our department is in charge ofthe following subjects as: Health Sociology (with alecturer, Dr. Tamura), Social Welfare and Social
Security (with two lecturers, Dr. Sakano from
Okayama Prefectural University and Prof. Takagi
from Keio University), Social Research Method
Practice, Social and Human Relations, Graduation
Thesis (many graduate students the last three subjects
are shared with many graduate students in Dept.of
Health Sociology), and the other two.

4.

5.

Research activities
Our department studies social and psychologicalfactors related to health problems and health caresystems, through developing and applying theories,
concepts and methods, which have been developed insociology, psychology, and social and behavioral
sciences.
We have been conducting the following 7 research
projects on going.
1. Studies on Antonovsky’s Salutogenesis and Sense
of Coherence (SOC) Concept
We have introduced Antonovsky’s Salutogenesis
and its core concept ‘Sense of Coherence (SOC)’
to Japanese fields of health and stress. The
objective of this project is to develop and apply
Japanese version Antonovsky’s SOC scale toexamine SOC and correlates among different
population, people with chronic illness/disability,
and so on.
2. Study on People with Medically Induced HIV
Nearly 1,500 hemophilia patients were infectedwith HIV through blood products in the mid
1980’s in Japan, and so far more than five hundred
patients have died of AIDS and others. They are
suffering not only from health damage but also
various types of stigma and discrimination. In thisproject, several research studies are being
conduced in order to explore the problems of theirlives, and to suggest the needed social supports
3. Studies on Social Differences and Inequalities in
HealthThis project is designed to explore evidence aboutsocio-economic differences in health, especially

6.

7.

among the middle-aged, in Japan. Anotherpurpose of this project is to consider possible
explanations for these differences and theimplications for policy.
Studieson
Changing
Professional-Patient
Relationship and Patient Autonomy
The aim of this project is to examine the current
situation of professional-patient relationship andpatient autonomy in Japan, and to derive newtheories. Both empirical and theoretical studies
have been conducted from various perspectives.
Studies on “Way of Working and Living” andFatigue/Stress of Working People
Recently Japanese industrial society has been
subjected to the never-experienced structuralchanges. The aims of this project are to explore
the effects of these changes on “ways of working
and living”, work-family balance and fatigue/
stress of working people, and to clarify themechanism of the effects.
Studies on Characteristics of the Physical andPsychological Distresses in Human Service Work
Human service work is spread over the many
fields including medicine, nursing and caring. The
aims of this project is to examine thecharacteristics of the psychological and physicaldistress of human service workers and theirrelated factors.
Studies on the Onset of Pneumoconiosis among
Tunnel Construction Workers
In Japan, many tunnel construction workers
suffered from the onset of severe pneumoconiosis
in 1970’s. It is still continuing in 1990’s. The
purpose of this research project is to reveal theprocess and the related factors on the onset ofpneumoconiosis in recent years.

References
1.

2.

Yuko Hirano, Yoshihiko Yamazaki: Ethical issues
in invasive mechanical ventilation for amyotrophic 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)

257

3.

Taisuke Togari, Yoshihiko Yamazaki: How to Use
Sense of Coherence Scales: Versions, Items,
Precautions and Future Issues, Jpn. Nursing
Research 2009.12. 42(7):505-516 (in Japanese)
4. Tomoko Takeuchi, Taisuke Togari, Yoshihiko
Yamazaki: Nurses’ Sense of Coherence andWorkplace: The Workplace Characteristics forLively Nurses, Jpn. Nursing Research 2009.12.
42(7):517-526 (in Japanese)
5. Asami Fujishima, Taisuke Togari, Yoshihiko
Yamazaki: The Experience of Living with
Untreated Illness: Trial of a Qualitative Analysis
Using Sense of Coherence Theory, Jpn. Nursing
Research 2009.12. 42(7):527-538 (in Japanese)
6. Ryoko Taguchi, Yoshihiko Yamazaki, Taisuke
Togari､Development of a family relationships
scale based on the Family Relationships Index(FRI) Japanese version､Jpn J Public Health 2009.
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 health literacy and patientphysician information exchange during a visit,
Family Practice, 2009. 26; 517-523,
8. Michiko Kato, Yoshihiko Yamazaki. An examination of factors related to work-to-family conflictamong employed men and women in Japan.
Journal of Occupational Health, 2009.7. 51(4),303-313,
9. Taisuke Togari, Yoshihiko Yamazaki, The
socioeconomic gradient of sense of coherencefrom representative sample survey of 4,800
Japanese people aged 20 to 40. Bulletin ofSocial Medicine 2009.6 26(2): 45-52, (inJapanese)
10. Taisuke Togari, Reika Otemori, Yoshihiko
Yamazaki, Miho Sato,Yuki Yonekura, Naoko
Kumada, Keiko Seki Sakakibara, Sense of
Coherence (SOC) and its related factors among
Japanese urban high school students -The
relationship between retrospective evaluations ofschool lives in elementary school and Junior andsenior high schools, and the changing pattern of
SOC during a 10 month period. Jpn J Health
Education and Promotion. 2009.5.29.17(2):71-86,(in Japanese)

11. Yuko Hirano, Yoshihiko Yamazaki: Illness
experiences of invasive mechanical ventilatordependent amyotrophic lateral sclerosis patientsin Japan: A study of trajectories and correlatesof psychological well-being, Jpn J Human
Ecology 2009.75(3):79-89,

258

Department of Mental HealthProfessor
Norito Kawakami, M.D., Ph.D.

Associate Professor
Akihito Shimazu, Ph.D.

Assistant Professor
Toshio Mori, Ph.D.

Homepage

http://plaza.umin.ac.jp/heart/

Introduction and Organization
The department was firstly established as
Department of Fourth Clinical Medical Nursing in
School of Health Care and Nursing in 1957. When
the School of Health Care and Nursing was
reorganized as the School of Health Sciences in 1965,
the department was renamed Department of Mental
Health. In 1992, as School of Health Sciences became
The School of Health Science and Nursing,
Department of Mental Health became Department of
Mental Health and Psychiatric Nursing. As the resultof the shift to the chair system of the Graduate Schoolof Medicine in 1996, two departments were
established, Department of Mental Health andDepartment of Psychiatric Nursing. Faculty, staff, andstudents of two departments have been working
cooperatively ever since.
The department currently has faculty members
introduced above, part-time lecturers, a technicalspecialist, visiting research fellows, 6 doctoral course
students, 3 master course students, research associates,and secretaries.
The department has two major objectives: one isto teach mental health to undergraduate and graduate
students in order to produce leading practitioners andclinical researchers in the field. The other is toconduct clinical research in the fields of mental
health.
All of the activities of the department are

conducted in collaboration with staff members in thedepartment of psychiatric nursing.

Teaching activities
The department is responsible for giving lectures
on mental health; mental disorders; clinicalpsychology; and psychometry and behavior evaluation
to undergraduate students. Other than lectures, thedepartment provides students opportunities to practicemental health activities in several relevant mental
health facilities.
The department provides courses on mental
health I and II, featuring research methodology of
epidemiology in mental health and occupational
mental health, respectively, in the fiscal year of 2011.
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.

5.

Coe CL, Love GD, Karasawa M, Kawakami N,
Kitayama S, Markus HR, Tracy RP, Ryff CD.
Population differences in proinflammatory biology:
Japanese have healthier profiles than Americans.
Brain Behav Immun. 2011 Mar ;25(3) :494-502.

6.

Bruffaerts R, Demyttenaere K, Hwang I, Chiu WT,Sampson N, Kessler RC, Alonso J, Borges G, de
Girolamo G, de Graaf R, Florescu S, Gureje O, Hu
C, Karam EG, Kawakami N, Kostyuchenko S,
Kovess-Masfety

V,

Lee

S,

LevinsonD,

Matschinger H, Posada-Villa J, Sagar R, Scott KM,
Stein DJ, Tomov T, Viana MC, Nock MK.
Treatment of suicidal people around the world. Br J
Psychiatry. 2011 Jul ;199:64-70.
7.

Cheng Y, Park J, Kim Y, Kawakami N. The
recognition of occupational diseases attributed toReferences (Jan.-Dec., 2011)

heavy workloads: experiences in Japan, Korea, andTaiwan. Int Arch Occup Environ Health. 2011 Nov;

1.

FunakoshiA,

Miyamoto

Y,

ShimazuA.

Development of a scale of difficulties experienced

23. (Epub ahead of print)
8.

by parents of children with hikikomori syndrome.

Kawakami N. Workaholism and well-being among

Journal of Mie Prefectural College of Nursing.

Japanese dual-earner couples: A spillover-crossover

2011;15:39-55.
2.

perspective. Social Science & Medicine. 2011 ;73.

Miyashita M, Narita Y, Sakamoto A, Kawada N,
Akiyama M, Kayama M, Suzukamo Y, Fukuhara
S.Health-related quality of life among communitydwelling patients with intractable neurologicaldiseases and their caregivers in Japan.Psychiatry
Clin Neurosci. 2011; 65(1): 30-8. PMID: 21105961

3.

Akazawa M, Matsumoto T, Katsumata Y, Kitani M,
Hirokawa S, Kameyama A, Yokoyama Y, Takahashi
Y, Kawakami N, Watanabe N, Hirayama M,
Takeshima T. [Psychosocial and psychiatric characteristics of suicide completers by employment
situation before death: a psychological autopsy
study of 76 cases]. Nippon shakai seishin igakukai
zasshi [Journal of Japanese Society for Social
Psychiatry]. 2011; 20(2): 82-93. (in Japanese)

4.

Kubota K, Shimazu A, Kawakami N, Takahashi M,
Nakata A, Schaufeli W. Distinción Empírica Entre
Engagement

Shimazu A, Demerouti E, Bakker, AB, Shimada K,yTrabajolismo

en

Enfermeras

Hospitalarias de Japón: Efecto Sobre la Calidad delSueño y el Desempeño Laboral. Ciencia & Trabajo.
2011; 13 (41): 152-157 (in Spanish).

399-409. PMID: 21733607
9.

Orui M, Kawakami N, Iwata N, Takeshima T,
Fukao A. Lifetime prevalence of mental disorders
and its relationship to suicidal ideation in a
Japanese rural community with high suicide andalcohol consumption rates. Environ Health Prev
Med. 2011 Nov ;16(6) :384-9.PMID: 21431807

10. Koichi R, Miyamoto Y. Reliability and validity of
the Japanese semistructured interview version of
the Early Signs Scale (ESS-JI) for outpatients withschizophrenia (study 1). International Journal of
Mental Health Nursing. 2011 ;20(2), 144-151.
PMID: 21371230
11. Suzuki M, Tachimori H, Saito M, Koyama andKurita H. Development of a screening scale forhigh-functioning pervasive developmental disorders
using the Tokyo Child Development Schedule andTokyo Autistic Behavior Scale. Research Autism
Spectrum Disorder. 2011; 5: 843-854.
12. Chiba R, Kawakami N, Miyamoto Y. Quantitative

260

relationship between recovery and benefit-finding

Fukasawa M, Ito J. [Evaluation of the reliability

among persons with chronic mental illness in Japan.

and validity of the process evaluation scale based

Nursing and Health Sciences, 2011; 13(2): 126-132.

on

PMID: 21481122

components of assertive community treatment].

13. Bakker AB, Shimazu A, Demerouti E, Shimada K,
Kawakami N. Crossover of work engagement

consumer's

perceptions

of

the

criticalSeishin Igaku [Clinical Psychiatry]. 2011 June;
53(6): 523-533. (in Japanese)among Japanese couples: Perspective taking by

20. Yoshimasu K, Kawakami N, and the WMH-J

both partners. Journal of Occupational Health2002-2006 Survey Group: Epidemiological aspects

Psychology.

of intermittent explosive disorder in Japan;

2011

Jan;16(1):112-25.

PMID:

prevalence and psychosocial comorbidity: findings

21280948
14. Chiba R, Miyamoto Y, Kawakami N. [Recovery infrom the World Mental Health Japan Survey

people with mental illness living in community:

2002-2006 Psychiatry Research 2011 Apr 30;

comparison with or without experience of peer

186(2-3):384-9. Epub 2010 Aug 14.

support]. Seishinka Kango [Psychiatric Nursing],

21. Levinson

D,

LakomaM,

Petukhova

M,

Schoenbaum M, Zaslavsky AM, Angermeyer M,

2011; 38(2): 48-54. (in Japanese)
15. Ogawa M, Miyamoto Y, Kawakami N. Factors

Borges G, Bruffaerts R, de Girolamo G, de Graaf R,

associated with Glycemic control and diabetes

Gureje O, Haro JM, Hu C, Karam AN, Kawakami

self-care among outpatients with Schizophrenia andN, Lee S, Lepine JP, Oakley Browne M, Okoliyski

Type 2 Diabetes. Arch Psychiatr Nurs. 2011;25(1):M, Posada- Villa J, Sagar R, Carmen Viana M,

63-73.PMID: 21251603

Williams D, Kessler RC. Associations of serious

16. Sakurai K, Nishi A, Kondo K, Yanagida K,

mental illness with earnings in the WHO World

Kawakami N. Screening performance of K6/K10

Mental Health surveys. Br J Psychaitry 2010 Aug;and other screening instruments for mood and197(2): 114-21.

anxiety disorders in Japan. Psychiatry Clin
Neurosci.

2011

Aug;65(5):434-41.

PMID:

21851452
17. Sado M, Yamauchi K, Kawakami N, Ono Y,
Furukawa TA, Tsuchiya M, Tajima M, Kashima H;
WMH-J2002-2006 Survey Group, Nakane Y,
Nakamura Y, Fukao A, Horiguchi I, Tachimori H,
Iwata N, Uda H, Nakane H, Watanabe M, Oorui M,
Funayama K, Naganuma Y, Hata Y, Kobayashi M,
Ahiko T, Yamamoto Y, Takeshima T, Kikkawa T.
Cost of depression among adults in Japan in 2005.
Psychiatry Clin Neurosci. 2011 Aug; 65(5):442-50.
PMID: 21851453
18. Ito J, Oshima I, Nishio M, Sono T, Suzuki Y,
Horiuchi K, Niekawa N, Ogawa M, Setoya Y,
Hisanaga F, Kouda M, Tsukada K. The effect ofAssertive Community Treatment in Japan. Acta
Psychiatrica Scandinavica. 2011 May; 123(5):398-401. PMID: 21070193
19. Niekawa N, Oshima I, Sono T, Ogawa M,

261

Department of Biostatistics/
Epidemiology and Preventive
Health Sciences
Professor
Yasuo Ohashi, Ph.D.

Associate Professor
Yutaka Matsuyama, Ph.D.

Research Associate
Ayano Takeuchi, M.S.

Project Research Associate
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 a series of educational courses organizedby ‘The Clinical Bioinformatics Research Unit’ in
2002-2007.

Teaching activities
1.

Undergraduate Courses
Epidemiology and Biostatistics (2 credits)
Applied Mathematics (2 credits)
Statistical Methods and Information Processing (2 credits, practice)4) Design and Analysis of EpidemiologicalResearch (2+1 credits, 1 practice)5) Medical Data analysis (2 credits)
1)
2)
3)

262

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.

2.

3.
4.

5.

Biostatistics and theoretical epidemiology:
Analysis of longitudinal missing /incompletedata
Analysis of multiple events dataAnalysis of QOL dataCausal analysis
Analysis of micro/macro array data
Meta analysis of epidemiological studies
Methodology and Information Systems forClinical Trials:

Design of clinical trials
Data management of large-scale clinical
trialsPharmacoepidemiology
Coordination of collaborative epidemiological/
clinical research:Japan Arteriosclerosis Longitudinal Study
Japan Diabetes Collaborative Study
Consultation Works with Corporate SponsoredResearch Program ‘Clinical Data Management’

3.

4.

5.

6.

7.

References8.
1. Kodama S, Saito K, Tanaka S, Horikawa C, Saito
A, Heianza Y, Anasako Y, Nishigaki Y, Yachi Y,
Iida KT, Ohashi Y, Yamada N, Sone H. Alcohol
consumption and risk of atrial fibrillation. J Am
Coll Cardiol 2011; 57(4): 427-36.
2. Hamaguchi T, Shirao K, Moriya Y, Yoshida S,
Kodaira S, Ohashi Y; NSAS-CC Group. Final
results of randomized trials by the National

9.

Surgical Adjuvant Study of Colorectal Cancer(NSAS-CC). Cancer Chemother Pharmacol 2011;
67(3): 587-96.
Mieno MN, Yamaguchi T, Ohashi Y. Alternative
statistical methods for estimating efficacy ofinterferon beta-1b for multiple sclerosis clinical
trials. BMC Med Res Methodol 2011; 11: 80.
Masuda N, Negoro S, Hausheer F, Nakagawa K,
Matsui K, Kudoh S, Takeda K, Yamamoto N,
Yoshimura N, Ohashi Y, Fukuoka M. Phase I andpharmacologic study of BNP7787, a novel
chemoprotector in patients with advanced nonsmall cell lung cancer. Cancer ChemotherPharmacol 2011; 67(3): 533-42.
Kawasaki R, Tanaka S, Tanaka S, Yamamoto T,
Sone H, Ohashi Y, Akanuma Y, Yamada N,
Yamashita H; Japan Diabetes Complications
Study Group. Incidence and progression ofdiabetic retinopathy in Japanese adults with type 2
diabetes: 8 year follow-up study of the Japan
Diabetes
Complications
Study(JDCS).
Diabetologia 2011; 54(9): 2288-94.
Shiroiwa T, Fukuda T, Shimozuma K, Kuranami
M, Suemasu K, Ohashi Y, Watanabe T.
Comparison
of
EQ-5D
scoresamong
anthracycline-containing regimens followed bytaxane and taxane-only regimens for nodepositive breast cancer patients after surgery: the
N-SAS BC 02 trial. Value Health 2011; 14(5):746-51.
Tobinai K, Igarashi T, Itoh K, Kurosawa M, Nagai
H, Hiraoka A, Kinoshita T, Uike N, Ogura M,
Nawano S, Mori S, Ohashi Y; IDEC-C2B8 Study
Group. Rituximab monotherapy with eight weekly
infusions for relapsed or refractory patients withindolent B cell non-Hodgkin lymphoma mostly
pretreated with rituximab: a multicenter phase II
study. Cancer Sci 2011; 102(9): 1698-705.
Iwata H, Sato N, Masuda N, Nakamura S,
Yamamoto N, Kuroi K, Kurosumi M, Tsuda H,
Akiyama F, Ohashi Y, Toi M. Docetaxel followedby fluorouracil/epirubicin/cyclophospha- mide as
neoadjuvant chemotherapy for patients withprimary breast cancer. Jpn J Clin Oncol 2011;41(7): 867-75.
Shiraki M, Kuroda T, Miyakawa N, Fujinawa N,
Tanzawa K, Ishizuka A, Tanaka S, Tanaka Y,263

Hosoi T, Itoi E, Morimoto S, Itabashi A, Sugimoto
T, Yamashita T, Gorai I, Mori S, Kishimoto H,
Mizunuma H, Endo N, Nishizawa Y, Takaoka K,
Ohashi Y, Ohta H, Fukunaga M, Nakamura T,
Orimo H. Design of a pragmatic approach toevaluate the effectiveness of concurrent treatment
for the prevention of osteoporotic fractures:
rationale, aims and organization of a JapaneseOsteoporosis Intervention Trial (JOINT) initiatedby the Research Group of Adequate Treatment of
Osteoporosis (A-TOP). J Bone Miner Metab
2011; 29(1): 37-43.
10. Ohsumi S, Shimozuma K, Ohashi Y, Shinji M,
Hozumi Y, Mukai H, Takatsuka Y, Aihara T.
Health-related quality of life and psychologicaldistress of breast cancer patients after surgery
during a phase III randomized trial comparing
continuation of tamoxifen with switching toanastrozole after adjuvant tamoxifen for 1-4
years: N-SAS BC 03. Breast Cancer Res Treat.
2011; 127(1): 143-52.
11. Orimo H, Nakamura T, Fukunaga M, Ohta H,
Hosoi T, Uemura Y, Kuroda T, Miyakawa N,
Ohashi Y, Shiraki M; A-TOP (Adequate Treatmentof Osteoporosis) research group. Effects ofalendronate plus alfacalcidol in osteoporosis
patients with a high risk of fracture: the JapaneseOsteoporosis Intervention Trial (JOINT) - 02.
Curr Med Res Opin 2011; 27(6): 1273-84.
12. Sasako M, Sakuramoto S, Katai H, Kinoshita T,
Furukawa H, Yamaguchi T, Nashimoto A, Fujii M,
Nakajima T, Ohashi Y. Five-year outcomes of arandomized phase III trial comparing adjuvant
chemotherapy with S-1 versus surgery alone instage II or III gastric cancer. J Clin Oncol 2011;29(33): 4387-93.
13. Ohashi Y, Shimamoto K, Sato S, Iso H, Kita Y,
Kitamura A, Saito I, Kiyohara Y, Kawano H,
Nakagawa H, Toyoshima H, Ando T, Taguri M,
Haradai A, Ueshima H; Japan Arteriosclerosis
Longitudinal Study Group. [Association ofobesity and other cardiovascular risk factors withstroke the Japan Arteriosclerosis Longitudinal
Study--Existing Cohorts Combined (JALS-ECC)].
Nihon Koshu Eisei Zasshi 2011; 58(12): 1007-15.
(in Japanese)
14. Sone H, Tanaka S, Tanaka S, Iimuro S, Oida K,

Yamasaki Y, Oikawa S, Ishibashi S, Katayama S,
Ohashi Y, Akanuma Y, Yamada N; Japan Diabetes
Complications Study Group. Serum level oftriglycerides is a potent risk factor comparable to
LDL cholesterol for coronary heart disease inJapanese patients with type 2 diabetes:
subanalysis of the Japan Diabetes Complications
Study (JDCS). J Clin Endocrinol Metab 2011;
96(11): 3448-56.
15. Ichikawa K, Konta T, Ikeda A, Fujimoto S, Iseki
K, Moriyama T, Yamagata K, Tsuruya K, Yoshida
H, Asahi K, Kurahashi I, Ohashi Y, Watanabe T.
Significance of past history of renal failure for thedetection of high-risk individuals for cardiovascular and end-stage renal disease: analysis ofdata from a nationwide health checkup. Clin Exp
Nephrol 2011; 15(6): 841-7.
16. Nakaya N, Mizuno K, Ohashi Y, Teramoto T,
Yokoyama S, Hirahara K, Mizutani M, Nakamura
H; MEGA Study Group. Low-dose pravastatin
and age-related differences in risk factors for
cardiovascular disease in hypercholesterolaemic
Japanese: analysis of the management of elevatedcholesterol in the primary prevention group of
adult Japanese (MEGA study). Drugs Aging 2011
Sep 1;28(9):681-92.
17. Nishimura R, Nakagami T, Sone H, Ohashi Y,
Tajima N. Relationship between hemoglobin A1c
and cardiovascular disease in mild-to-moderate
hypercholesterolemic Japanese individuals: subanalysis of a large-scale randomized controlled
trial. Cardiovasc Diabetol 2011; 10: 58.
18. Matsuzaki M, Ogihara T, Umemoto S, Rakugi H,
Matsuoka H, Shimada K, Abe K, Suzuki N, Eto T,
Higaki J, Ito S, Kamiya A, Kikuchi K, Suzuki H,
Tei C, Ohashi Y, Saruta T; Combination Therapyof Hypertension to Prevent Cardiovascular Events
Trial Group. Prevention of cardiovascular eventswith calcium channel blocker-based combination
therapies in patients with hypertension: arandomized controlled trial. J Hypertens 2011;29(8): 1649-59.
19. Sawaki M, Tokudome N, Mizuno T, Nakayama T,
Taira N, Bando H, Murakami S, Yamamoto Y,
Kashiwaba M, Iwata H, Uemura Y, Ohashi Y.
Evaluation of trastuzumab without chemotherapy
as a post-operative adjuvant therapy in HER2-

264

positive
elderlybreastcancerpatients:
randomized controlled trial [RESPECT (N-SAS
BC07)]. Jpn J Clin Oncol 2011; 41(5): 709-12.
20. Akizawa T, Makino H, Matsuo S, Watanabe T,
Imai E, Nitta K, Ohashi Y, Hishida A; Chronic
Kidney Disease Japan Cohort Study Group.
Management of anemia in chronic kidney disease
patients: baseline findings from Chronic Kidney
Disease Japan Cohort Study. Clin Exp Nephrol
2011; 15(2): 248-57.
21. Matsumura N, Nakamura Y, Kohjimoto Y, Inagaki
T, Nanpo Y, Yasuoka H, Ohashi Y, Hara I. The
prognostic significance of human equilibrative
nucleoside transporter 1 expression in patientswith metastatic bladder cancer treated withgemcitabine-cisplatin-based combination chemotherapy. BJU Int 2011; 108 (2 Pt 2): E110-6.
22. Takao T, Ide T, Yanagisawa H, Kikuchi M,
Kawazu S, and Matsuyama Y. The effects offasting plasma glucose variability and timedependent glycemic control on the long-term riskof retinopathy in type 2 diabetic patients. Diabetes
Research and Clinical Practice 2011; 91(2):e40-42.
23. Araki Y, Matsuyama Y, Kobayashi Y, Toyokawa S,
Inoue K, Suzuki S and Makimoto A. Secondary
neoplasms after retinoblastoma treatment:
Retrospective cohort study of 754 patients inJapan. Japanese Journal of Clinical Oncology
2011; 41(3): 373-379.
24. Eguchi S, Kanematsu T, Arii S, Omata M, Kudo
M, Sakamoto M, Takayasu K, Makuuchi M,
Matsuyama Y, Monden M; for the Liver Cancer
Study Group of Japan. Recurrence-free survival
more than 10 years after liver resection forhepatocellular carcinoma. British Journal ofSurgery 2011; 98(4): 552-557.
25. Aoki T, Imamura H, Matsuyama Y, Kishi Y,
Kobayashi T, Sugawara Y, Makuuchi M and
Kokudo N. Convergence process of volumetricliver regeneration after living-donor hepatectomy.
Journal of Gastrointestinal Surgery 2011; 15:1594-1601.
26. Higashi T, Hasegawa K, Kokudo N, Makuuchi M,
Izumi N, Ichida T, Kudo M, Ku Y, Sakamoto M,
Nakashima O, Matsui O, Matsuyama Y, Sobue T;
the Liver Cancer Study Group of Japan.

Demonstration of quality of care measurement
using the Japanese liver cancer registry.
Hepatology Research 2011; 41(12): 1208-1215.
27. Isayama H, Yasuda I, Ryozawa S, Maguchi H,
Igarashi Y, Matsuyama Y, Katanuma A, Hasebe O,
Irisawa A, Itoi T, Mukai H, Arisaka Y, Okushima
K, Uno K, Kida M, Tamada K. Results of aJapanese multicenter, randomized trial ofendoscopic stenting for non-resectable pancreatic
head cancer (JM-TEST): Covered wallstent versus
doublelayer stent. Digestive Endoscopy 2011;23(4): 310-315.

265

Department of Biomedical
Ethics & Department of
Health Promotion Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Jung Su Lee, Ph.D.

Lecturer
Satoshi Kodama, Ph.D.

Research Associate
Misao Fujita, MPH, Ph.D.

Homepage

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

Introduction and Organization
The former Department of Health Administration
was established in 1967 and Dr. Tsuneo Tanaka
became its first professor in 1974. He devoted himself
to the development of the community health caresystem in Japan and published numerous papers
concerning the social theory of health administrationand data management systems for community healthcare. He also contributed to the establishment of the
School of Health Sciences. In 1985, Dr. Atsuaki Gunji
became the second professor of the department.
During Dr. Gunji’s tenure, two major research projects
were undertaken. One was “The effects of physicalactivity and inactivity on health.” From 1990, a20-day bed rest human experimental study was
conducted every year in the context of an international
cooperative research project that was supported bygovernment grants. The other project concerned healthcare systems, especially health care economics and thequality of hospital care.
In 1996, the Department of Health Administration
developed into two departments: the Department of
Health Economics and the Department of Health

Promotion Sciences. Both were established as
departments of the Graduate School of Medicine. In
1998, Dr. Yasuki Kobayashi became the professor of
the Department of Health Economics. He conducted
research into health care delivery systems in Japan. In
2001, he moved to the Department of Public Health.
From 1996 to 2002, Dr. Kiyoshi Kawakubo tookcharge of the Department of Health Promotion
Sciences as the associate professor.
In June 2002, Dr. Akira Akabayashi became
professor of the Department of Health Economics.
Professor Akabayashi’s area of research is biomedical
ethics. In April 2003, the Department of Health
Economics was restructured and named theDepartment of Biomedical Ethics. From 2007, Dr.
Jung Su Lee became the associate professor and tookcharge of the Department of Health Promotion
Sciences.
Staff members of the two departments include a
professor, an associate professor, a lecturer, anassociate, and a technical specialist. All five members,
eight undergraduate lecturers and eight graduate
lecturers from other organizations, and seven visiting
researchers contribute to department teaching and266

research activities.
Department graduate students included ten masterprogram students and five 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. Thirteen bachelor theses, fifteen mastertheses, and six doctoral dissertations were completed
between April 2004 and March 2012. Our
departments’ staff members are also responsible forthe 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 II3) Health Promotion Sciences I
4) Health Promotion Sciences II
In addition to these courses, each department
operates lectures, practical training, and joint seminars
for research guidance on a regular basis.
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. Graduate courses in Health
Promotion Sciences focus on practical study using
theories and empirical models for planning,

implementation, and evaluation of health promotion
programs for the prevention of lifestyle-relateddisease in the community and workplace.

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 for biomedical 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

267

Department of Health Promotion Sciences
The main research activity of the Department of
Health Promotion Sciences is aimed at health policy
proposals concerning health promotion in thecommunity and workplace through experimental andsurvey research. The main research fields include
health behaviors and lifestyle-related disease and
QOL. The focus of health behaviors are physicalactivity, exercise, diet and nutrition, and obesity.
Specific research topics include:1) Development of effective health promotion
programs
2) Assessment of health promotion resources in thecommunity and at the workplace
3) Influence of health behavior change on medical
costs4) Cost-effectiveness analysis for health promotion
programs
5) Development of a physical activity questionnaire
for the Japanese
6) Studies of the social and physical environments
influence on health behaviors
7) Association between family structure and healthbehaviors in pre-school children
8) Influence of maternal health behavior on
children’s health behavior
9) Effects of health behavior modification on
lifestyle-related disease.
10) Life course epidemiology for women’s health11) Social and physical environmental influences on
the health behaviors of people with disease orpain12) Factors related to health check-ups13) Characteristics and determinants associated withthe uptake of influenza vaccination
14) Influence of employment status on self-rated
health

4.

5.

6.

7.

8.
9.

10.

11.
12.

Publications
13.
1.
2.

3.

Akabayashi A. Fukushima research needs world's
support. Science. Aug 5;333(6043):696, 2011.
Akabayshi A. Obligations of physicians near the
Fukushima nuclear power plant disaster (rapid
response), BMJ April, 8, 2011.
Akabayashi A, Kodama S. Lessons from Japan's

March 2011 Earthquake Regarding Dialysis
Patients. (Letter) Therapeutic Apheresis andDialysis. 15(3):334, 2011.
Akabayashi A, Hayashi Y. Mandatory evacuationof residents during the Fukushima nuclear
disaster: an ethical analysis. J Public Health.
2012 Jan 12.
Lee JS, Kondo K, Kawakubo K, Kataoka Y, MoriK, Umezaki M, Yamauchi T, Asami Y, Takagi H,
Akabayashi A. Neighborhood environment
associated with daily physical activity measured
both objectively and subjectively amongresidents in a community in Japan. Jpn J HealthHum Ecol 77(3):94-107, 2011.
Miyazaki Y, Hayashi K, Imazeki S, Lee JS, andSuzuki S. Changes in Smoking and Dietary
Habits among Japanese Female Nurses based on
the Gunma Nurses’ Health Study. Jpn J HealthHum Ecol 77(4):135-149, 2011.
Murakami K, Hashimoto H, Lee JS, Kawakubo K,
Mori K, Akabayashi A. Distinct impact ofeducation and income on habitual exercise: A
cross-sectional analysis in a rural city in Japan.
Soc Sci Med 73:1683-1688, 2011.
Takahashi S, Akabayashi A. Earthquake in Japan.
Lancet 377(9778):1653-54, 2011.
Takimoto Y, Akabayashi A. Clinical ethics consultation in Japan: the University of Tokyo model.
Asian Bioethics Review 3(3):283-292, 2011.
Watanabe E, Lee JS, Kawakubo K. Associationsof maternal employment and three-generation
families with pre-school children's overweight
and obesity in Japan. Int J Obes. 35(7):945-952,
2011.
Yoshiuchi K, Akabayashi A. Japan’s nuclear
crisis. Lancet Oncology 12(8):724-5, 2011.
Yasui T, Hayashi K, Mizunuma H, Kubota T, Aso
T, Matsumura Y, Lee JS, Suzuki S. Association ofEndometriosis-related Infertility with Age at
Menopause. Maturitas 69:279-283, 2011.
Inoue S, Oka K, Shibata A, Arao T, Taneda Y,
Katsumura T, Kumagaya A, Shimomitsu T,
Sugiyama T, Tanaka S, Naito Y, Nakamura Y,
Yamaguchi Y, Lee JS. The Japanese version of
the Toronto Charter for Physical Activity: A
Global Call for Action. Research in Exercise
Epidemiology 13(1):12-29, 2011 (in Japanese).

268

14. Takashima K, Kodama S. The effects of medical
tourism on healthcare services in destination
countries. Journal of Japan Association for
Bioethics 22(1):111-18, 2011 (in Japanese).
15. Watanabe E, Lee JS, Kawakubo K. Associationsof multiple-sets of lifestyle factors with overweight in Japanese preschool children. Japanesejournal of cardiovascular disease prevention 46(2):165-173, 2011(in Japanese).
16. Fujita M. The latest research. M-GTA Study
Group News letter 2011; 56: 52(in Japanese).
17. Fujita M, Akabayashi A. The current situationand issues of stem cell therapy in Japan. Japan
Medical Journal 2011; 4562: 27-31(in Japanese).
18. Kodama S. “Chapter 1: Freedom of smoking andits limitation.” In Practical Political Philosophy.
(Uno S, Inoue A, Yamazaki N eds.) Nakanishiya
Shuppan 2012 (in Japanese).
19. Tashiro S. What is Research Ethics –Clinical
Medical Research and Bioethics. Keiso Shobo
2011 (in Japanese).
20. Tashiro S, Inoue Y. “Basic 4: Ethical principles
and those of the Belmont Report,” ”Applications
4: Review points for dignity.” In Handbook of
Ethical Review for Clinical Research. (Sasaguri T,
Ikematsu H eds.) Maruzen Shuppan 2011 (inJapanese).
21. Maeda S (SV), Kodama S, Takashima K(Japanese translation). Sorry Works! -Disclosure,
Apology, and Relationships Prevent Medical
Malpractice Claims-. (Wojcieszak, D, Saxton JW,
Finkelstein MM.) Igaku Shoin, 2011 (inJapanese).

Health Sciences and Nursing
2. Preventive and Administrative Nursing

270

Department of
Nursing Administration /Advanced Clinical Nursing
Professor
Katsuya Kanda, Ph.D., R.N.

Assistant Professor
Mami Onishi, M.S.N., R.N., Ayako Nagata, M.A., R.N., Satoko Nagai, M.S.N., R.N.

Homepage

http://nurs-adm.umin.jp/

Introduction and Organization
Nursing Administration department provides broad
opportunities to learn about societal issues related to;1) nursing administration, nursing policy, nursing
education, nursing ethics, and 2) safety and quality
issues in nursing.
Advanced Clinical Nursing department provides; 1)
critical analysis and synthesis of conceptual
frameworks, nursing theories and models foradvanced practice, and 2) generation and utilization ofevidence related to practice, understanding of clients,and fundamental skills.
As we expect much of the graduates to develop theirprofessional carriers in various settings, we areconstantly exploring new issues to make students beable to take wide and long viewpoints.

Teaching activities
Graduate courses
Nursing Administration 1 (2 credits, Lectures)Prof. Kanda and Affiliates

Exploration of political and administrative functionalrole in nursing. The course offers critical analysis oftheories in nursing administration related to quality
assurance/ improvement and cost- effective/efficient
care delivery systems. Discussions include concepts
and structures in organization, decision/policy making

process, and application of management theory andnursing process to nursing administration. Theory andpractice in nursing education is also explored.
Nursing Administration 2 (2 credits, Lectures)Prof. Kanda and Affiliates

Studies on application of management theory tonursing administration. Focuses are on; 1) issues innursing management such as budgetary management,
nursing informatics, patient classification systems,
staffing, and quality improvement, and 2) issues instaff management such as staff development andcontinuing education. Students will learn concepts andskills essential to solving economic issues in healthcare and nursing to meet professional demands in thecomplexity of health care systems.
Advanced Clinical Nursing 1 (2 credits, Lectures)Prof. Kanda and Affiliates

An overview on models, theories and research innursing. Focuses are on; 1) conceptual frameworks ofclients' potential and actual physiological andpsychosocial responses to health problems, 2) healthassessment skills in nursing practice, 3) measurementof clients' health and nursing intervention outcome.
Students will establish their own theoreticalknowledge and practical skills essential to advanced
clinical nursing.

271

Advanced Clinical Nursing 2(2 credits, Lectures and practicum)

Clinical Practicum in Fundamental Nursing(2 credits, practicum)

Prof. Kanda and Affiliates

Prof. Kanda, Staffs and Affiliates

This course explores issues related to advanced
clinical practice, research, and education with anemphasis on specific theoretical perspectives,
methodologies, practice and economic implications.

Under instructors' supervision, students haveopportunity to apply their fundamental knowledge andskills of nursing in a variety of settings. Students willassess clients' health and needs through application ofnursing process.

Undergraduate Courses

Nursing Administration (1 credit, Lectures)

Basic Life Support & First Aid(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).
Fundamental Nursing 1 (2 credits, Lectures)Prof. Kanda and Affiliates

This course offers fundamental knowledge of nursing,such as history and theory in nursing, concepts ofprofessional nursing practice, nursing service and caredelivery systems, nursing administration, and nursing
education. Discussions include contemporary challenging issues and future strategies in nursing.
Fundamental Nursing 2 (2 credits, Lectures)Prof. Kanda and Affiliates

This course offers fundamentals in understanding
interpersonal relationships and assessing clients'
health. Students will learn; 1) theory and 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.
Fundamental Nursing 3(4 credits, Lectures and laboratory practicum)
Prof. Kanda and Affiliates

This course provides theory and practice offundamental nursing skills, which are essential toproviding clients with; 1) safe and effective careenvironment, 2) physiological and psychosocial
integrity, and 3) health promotion and maintenance.

Prof. Kanda and Affiliates

This course prepares students for nurse administrators/
managers of all types of health care settings such as
institutions, organizations, community and politics.
Students will learn fundamental theory and practice innursing administration/ management through analyzing current issues in health care and nursing.
Nursing Administration Practicum(1 credit, practicum)
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
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.
Issues of Nursing Administration
Critical analysis and international comparative studyof administrative, socioeconomic and political issues
in contemporary nursing. Focuses are on; 1) patientclassification systems and nursing care delivery
systems, 2) cost- effectiveness of nursing services, 3)
nursing case management, and 4) nursing policy andstrategies to meet the professional demands.

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Quality Improvement, Safety Issues, and Risk
Management in Nursing
This work examines; 1) quality of nursing care, 2)
outcome management for nursing practice, 3) risk
management in acute care settings, 4) occupationalsafety and health of health care workers, and 5)
infection control.
Physiological and Psychological Human Responses
to Stimulus
This area of study aims at exploring the nature, or
determining various effects of physiological andpsychological stimulus to participants' physiologicalbio-information and psychological measurements.
Research scenarios include; 1) patient' daily activities,2) caregivers' workload and sleep deprivations, or 3)
nurses focus of attention, eye movement, and electroencephalography activities. Data collections takeplace through field studies or laboratory/ experimental
settings.
Nursing Assessment and Intervention
Exploration of structure of existing discipline anddevelopment of new nursing theories in clinicalpractice. Emphases are on; 1) explorations of structureof nursing theories and models in nursing, 2)
development of clinical and scholarly knowledge forthe identification of health problems and assessmentof care priorities, and 3) testing hypotheses effective
for nursing interventions
Studies of Nursing Education
Exploration of nursing education systems andfunctional roles of professional nurses in various
settings in advanced countries and developing
countries as well. Higher education for the advanced
practice nurses in Japan is also explored.

References
1.

2.

Ozawa M, Kanda K, Hirata M, Kusakawa I,
Suzuki C. Effect of gender and hand laterality on
pain processing in human neonates. Early Hum
Dev. 2011; 87(1): 45-48.
Ozawa M, Kanda K, Hirata M, Kusakawa I,
Suzuki C. Influence of repeated painfulprocedures on prefrontal cortical pain responses
in newborns. Acta Paediatr. 2011; 100(2):198-203.

3.

Komi K, Onishi M, Kanda K. Development of
the Japanese version of the Jefferson Scale ofAttitudes toward Physician- Nurse Collaborationand measuring physicians’ and nurses’ attitudes
toward collaboration in Japan. Medical Education
2011; 42(1): 9-17. (in Japanese)
4. Kataoka J, Sasaki M, Kanda K. Effects of mental
workload on nurses' visual behaviors duringinfusion pump operation. Jpn J Nurs Sci. 2011;18(1): 47-56.
5. Zhao H, Zhang C, Lu T, Shi Y, Zheng J, Ding Y,
Deng F, Onishi M, Nagata A, Kobayashi H,
Takemura Y, Kanda K. Survey on careea identityof nurses in 6 class III grade I hospitals. Journalof Nursing (China) 2011; 18(4A): 27-30. (inChinese)
6. Sasaki M, Kanda K. Development of theJapanese version of the Nursing Work
Empowerment Scale. Journal of Japan Academyof Nursing Science 2011; 31(2): 52-59. (inJapanese)
7. Kobayashi H, Takemura Y, Kanda K. Patient
perception of nursing service quality; an applied
model of Donabedian's structure-processoutcome approach theory. Scand J Caring Sci.
2011; 25(3): 419-25.
8. Mashimo A, Nakatani K, Jinda Y, Ichikawa I,
Sato K, Takahashi K, Oomizu M, Sakamoto S,
Kanda K. Development of a Scale for Evaluating
Nursing Practice Ability in acute hospitals. J Jpn
Acad Nurs Admin Policies. 2011; 15(1): 5-16. (inJapanese)
9. Sasaki M, Kanda K. Development of a Scale to
Measure Attitude and Behaviors Fostering
Organizational Learning from Incidents. J Jpn
Acad Nurs Admin Policies. 2011; 15(1): 29-38.
(in Japanese)
10. Nagata A, Kanda K. A comparison of university
and minimum curriculum requirements forJapan’s certified care worker license. Social
Work Education (in press)

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Department of Family Nursing
Associate Professor
Kiyoko Kamibeppu, Ph.D., R.N., P.H.N.

Research Associate
Shiho Murayama, M.S., R.N., R.M.
Mari Ikeda, Ph.D., R.N., P.H.N.
Iori Sato, M.S., R.N., P.H.N.

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 three faculty members: an associate professor, andtwo research associates. Also it has 11 doctoral
students, 11 master’s course students, 1 undergraduate
student, and 16 visiting scholars.

Education
1. Graduate Courses, School of Health Sciences andNursing
Advanced Family Nursing I
Advanced Family Nursing II
Laboratory and/or Field Work on Family Nursing
Practice in Translational Research Nursing
2. Undergraduate Courses, School of Integrated
Health Sciences
Family Nursing
Pathophysiologic Immunology
3. Undergraduate Courses of Nursing, School ofIntegrated Health Sciences
Pediatric Nursing
Clinical Practicum in Pediatric Nursing

Research
The topics of our current research projects are as

follows:
4. The aggravation prophylaxis of postpartum
depression and prevention of child abuse andneglect.
5. Development of Pediatric QOL Inventory for childwith chronic illness and their parents.
6. Late effect of treatment and posttraumatic stressdisorder in children with cancer.
7. Care for mothers with severe mental illness andtheir offspring.
8. The roles and expertise of the nursing staffs indaycare centers.
9. Primary caregivers’ burden of the severely
disabled children and the utilization of the respitecare.
10. Care for dying patients and their families (QOL,
Family function)
11. Nurses’ attitudes toward Family Nursing.

Publications(1) Matsumoto K, Nagamura F, Ogami Y, Yamashita
N, Kamibeppu K. Difficulties of nursing staff
involved in phase 1 oncology trials in Japan.
Cancer Nursing. 2011; 34: 369-375.
(2) Tsuji N, Kakee N, Ishida Y, Asami K, Tabuchi K,
Nakadate H, Iwai T, Maeda M, Okamura J,
Kazama T, Terao Y, Ohyama W, Yuza Y, Kaneko
T, Manabe A, Kobayashi K, Kamibeppu K,
Matsushima E. Validation of the Japanese versionof the Pediatric Quality of Life Inventory

274(PedsQL) Cancer Module. Health and Quality ofLife Outcomes. 2011; 9: 22.
(3) Ishida Y, Honda M, Kamibeppu K, Ozono S,
Okamura J, Asami K, Maeda N, Sakamoto N,
Inada H, Iwai T, Kakee N, Horibe K. Social
outcomes and quality of life (QOL) of childhood
cancer survivors in Japan: A cross sectional study
on marriage, education, employment and healthrelated QOL (SF-36). International Journal of
Hematollogy. 2011; 93: 633-644.
(4) Ishida Y, Ozono S, Honda M, Maeda N, Okamura
J, Asami K, lwal T, Kamibeppu K, lnada H,
Sakamoto N, Kakee N, Horibe K. Medical visitsof childhood cancer survivors in Japan: A crosssectional survey. Pediatrics International. 2011;
53(3): 291-299.
(5) Kobayashi K, Kamibeppu K. Quality of life
reporting by parent-child dyads in Japan groupedby depressive status. Nursing and Health
Sciences. 2011; 13(2): 170-177．
(6) Sugishita K, Kurihara K, Furuta M, Ikeda M,
Yamamoto H, Otsuka H, Kamibeppu K.
Approach to perinatal mental health and childabuse prevention in Japanese perinatal centers.
Journal of Japan Society of Perinatal andNeonatal Medicine. 2011; 47(1): 86–91. (inJapanese)(7) Sugishita K, Kurihara K, Shionoya M, Takamiya
T, Hanayama M, Yamashita H, Kamibppu K. The
cooperation with the public health/welfareorganizations pursued in the hospitals. The
Japanese Soceity for Prevention of Child Abuse
and Neglect. 2011;13(1)32-39. (in Japanese)(8) Konishi M, Yamazaki A, Kamibeppu K. Nursing
care and mothers’ experiences regarding tube
feeding for infants in NICU during the Early
Stage of Hospitalization. Japanese Journal of
Research in Family Nursing. 2011; 17(1): 31-41.
(in Japanese)(9) Ikeda M, Kamibeppu K. Prediction of
Postpartum Depression in the way of conversations between nurses and expectant mothers.
The Japanese Journal of Nursing Research, 2011;
44(4):446-453. (in Japanese)(10) Kurihara K, Kamibeppu K. Family Psychoeducation. Psychiatry 2011; 18(4): 425-429. (inJapanese)

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Department ofCommunity Health Nursing /Public Health Nursing
Professor
Sachiyo Murashima, Ph.D., R.N., P.H.N.

Lecturer
Satoko Nagata, Ph.D., R.N., P.H.N.

Research Associate
Atsuko Taguchi, M.H.S., R.N., P.H.N.
Azusa Arimoto, Ph.D., R.N., P.H.N.

Homepage http://park.itc.u-tokyo.ac.jp/chn/※ The following information is the same as that of the previous year for certain reasons.

Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. At present,
there are four faculty members introduced above and
24 graduate course students (14 in master course, 10in doctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

Teaching activities
1. Undergraduate program, in the School ofIntegrated Health Sciences
1) Community Health Nursing (4 credits, lectures)
Community health nursing is a study to develop
the caring techniques and the method to evaluate
the effectiveness of care not only for a person but
also for a whole community. This class is to
study, the concepts and functions of community
health nursing, developing process of community

health nursing, community assessment andactivities of community health nurses.
2) Home Health Nursing (2 credits, lectures)
The aim of this class is to have a deep
understanding of the social context around thehome care patients and the medical, health andwelfare system. Students learn the basics of caremanagement, home health care service, and healthcare system.
3) Health Guidance (2 credits, lectures)This class is to study the methodology andpractice of health guidance, which is the
supporting technique to promote health of thepeople living in the community.
4) Community Health Nursing Practice (2 credits,
practice)This program is intended to understand the systemof health promotion and prevention by attending
the actual community health nursing activities athealth center. Students are expected to realize theprinciple and the common technique ofcommunity health nursing activities by observing
the activities of public health nurses.

2765) Home Health Nursing Practice (1 credits, practice)This program offers opportunities to learn thebasis of home nursing and understand the life ofhome care patients and their family at home-visit
nursing station and hospital’s department ofdischarge planning. Basic techniques and the roleof nursing through collaboration with otherprofession are mastered.
6) Health Assistance Practice I・II (2 credits, practice)In this program, students will comprehend
multilaterally how characteristics of the residents,
health resources and environment of thecommunity effects health and discuss on the healthmatters of the overall community. In addition,
students will visit various working sites for nurses
to deepen their knowledge of multiple healthrelated resources, and learn the actual skills of
health guidance towards individuals/ families/
groups through experience.
2. Graduate program, in the Graduate School of
Health Sciences and Nursing
1) Advanced Community Health Nursing I (2 credits,
lectures)This program is to study the health at thecommunity-level and theory and application of thecommunity organization.
2)Advanced Community Health Nursing II (2 credits,
lectures)This program is to study the research issues onhome care and methodology of qualitative
research for community health nursing.
3) Advanced Public Health Nursing I (2 credits)
This program is to study the theoretical concept ofcommunity health nursing, assessment of thecommunity, problem finding, prioritization
procedure, and planning, operation and evaluationof countermeasures needed in advanced community health nursing practice using the textbook formaster course students in western countries.
4) Advanced Public Health Nursing II (2 credits)
This program is to understand policymaking of
national and local government, method to operate
and evaluate the systems, and approach to policy
development as public health nurses throughlectures by experts of public policy and social
welfare.

5) Advanced Community Health Nursing Seminar I,
II and Practice I, II
Especially in Public Health Nursing course,
practices for sequential home visiting, community
assessment / activity, and community 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

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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 aroundthe-clock in-home care system and discharge planningsystem are examples of these researches which are
now being conducted. Furthermore, we areconducting the research to promote community
organization and interorganizational network.
Especially about the around-the-clock in-homecare system, through the model project at visiting
nurse services stations, we clarify the effects of theservices and the methods to establish the system. Also
we are developing method of measuring effect ofhome-visit nursing with accompany of care staff andefficiency of visiting nurse service stations.
4. Discharge planning
Discharge planning is an interdisciplinary process thatshould be available to aid patients and their families indeveloping a feasible plan for the next place of care,and there is an increasing demand for it. We are trying
to standardize discharge planning activities, todevelop the outcome indicator of discharge planning,
and to produce the educational program of dischargeplanning for ward nurse. We are conducting research
about discharge planning system, developing theguidelines for multisectoral and interagency
cooperation among nurses and the method forevaluation of the capacity of discharge planning
nurses by investigation of actual situation.
5. Support for families with babies and children
We are conducting researches covering two fields,
community health and occupational health. The
former researches are aimed to prevent and reduce
anxieties of mothers and the latter is to support
mothers and fathers balance their work with child-care.
Our interest is specially on health concern and action
in child raising families, mothers’ difficulty ofchild-rearing and their children’s behavioral
characteristics. Also, the network for childrearing wasinvestigated to prevent child abuse.
6. Support for people with diseases or disabilities
We are making researches for people with diseases ordisabilities to improve their QOL.
The research themes in 2009 are 1) Condition,
reason of admission and succession of residents at
geriatric medical care facility for the elderly, 2)
Psychological experience of the mother who delivered
to Down syndrome child, 3) Acceptance to diseases
and experiences in hospitalization for tuberculosis
patients, 4) The characteristics of patients withdelayed hospital visit for tuberculosis diagnosis and 5)
The factors relating to the time of PEG among patientswith ALS.

References
1. Nagata S, Taguchi A, Naruse T, Kuwahara Y,
Murashima S. Actual situation and characteristics ofthe clients who are judged to need home-visiting
nurse services by certified care managers and thecomparison of users and non-users of home-visiting
nurse services among them. Japan Journal of Public
Health，57(12)，1084-1093，2010．
2. Tomura H, Yamamoto-Mitani N, Nagata S,
Murashima S, Suzuki S. Creating an Agreed
Discharge: Discharge Planning for Clients with High
Care Needs. Journal of Clinical Nursing, 20(3), 444453, 2011
3. Naruse T, Nagata S, Taguchi A, Murashima S.
Classification tree model identifies home-based
service needs of Japanese long-term care insurance
consumers.Public Health Nursing, inpress.
4. Shimamura T, Taguchi A, Kobayashi S, Nagata S,
Kushihara Y, Nagata Y, Kobayashi N, Murashima S.
The Perceptions and Feelings of Multi-drug
Resistant Tuberculosis Patients in Their Prolonged
Hospital-life. Journal of Japan Academy of Nursing
Science, 30(2)，3-10，2010
5. Kuwahara Y, Nagata S, Taguchi A, Murashima S.
An investigation of the work a visiting nurse did forpre and post discharge. Journal of the Japan Societyfor Healthcare Administration，47(2)，93-101，2010

278

6. 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, 275-287, 2010
7. Murayama H, Taguchi A, Ryu S, Nagata S,
Murashima S. Is Sekentei Associated with the
Attitude toward Care? Multilevel Analysis in Japan.
Geriatrics & Gerontology International 2010 (inpress)
8. Murayama H, Taguchi A, Murashima S. Exploring
Strategies to Encourage Community Health
Outreach by Health Promotion Volunteers in Japan.
Journal of Ambulatory Care Management (in press)
9. Shimazu T, Kageyama M, Hoshida Y, Taguchi A,
Asahara K. Goals and Skills of Public Health Nurses
Working in Rural Districts in Post-War Japan before
Its Rapid Economic Growth (circa 1945-1970):
Working to Change Traditional Practices in Order to
Save Lives. Japan Academy of Community HealthNursing, 12(2)，22-28，2010
10. Murayama H, Tomaru M, Narabu H, Kojima T,
Murashima S. Development of a Checklist for
Network Building between a Community
Comprehensive Support Center and an Informal
Community Organization. Journal of Japan
Academy of Community Health Nursing,13(1),91-99, 2010
11. Murayama H, Narabu H, Kojima T, Tomaru M,
Tachibana R, Yamaguchi T, Murashima S. Program
Development to promote network building between
disciplinary agencies and informal community
organizations. Japan Journal of Public Health,57(10), 900-908, 2010
12. Murayama H, Narabu H, Kojima T, Tomaru M,
Tachibana R, Yamaguchi T, Murashima S.
Evaluation of a program to promote networkbuilding between disciplinary agencies and informal
community organizations: Trial in a community
comprehensive support center. Japan Journal of
Public Health, 57(10), 909-920, 2010
13. Asahara K, Omori J, Kobayashi M, Hirano Y,
Suzuki Y, Arakida M, Oli S, Okamoto R, Okuyama
N, Kaihara I, Sudo H, Nagae H, Miyazaki M,
Murashima S. A framework for assessing essential
public health nursing skills and achievement levels
required for students graduating from schools thatprovide education for obtaining a license as a publichealth nurse in Japan. Japan Journal of Public Health,57(3), 184-194, 2010

Health Sciences and Nursing
3. Clinical Nursing

280

Department of Adult Nursing /Palliative Care Nursing
Professor
Hiromi Sanada, RN, PhD

Research Associate
Makoto Tanaka, RN, PhD.
Masakazu Nishigaki, RN, PhD.

Project Research Associate
Shiho Kosaka, RN, M.Hlth.Sci.
Tomoko Sakai, RN, PhD.
Yuki Shirai, RN, PhD.

Homepage http://www.adng.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Adult Nursing / Palliative Care
Nursing originated as the “Department of Adult
Health” in the School of Health Sciences (1965-1992),
later becoming the “Department of Adult Health andNursing” in the School of Health Sciences & Nursing(1992-).From 1995 to 1997, the Graduate School of
Medicine shifted to a Graduate School chair system,and our two newest departments were established. The
members of these two departments cooperate ineducational and research projects.
Our department also takes charge of the Certified
Nurse Specialist course newly established in 2008.

Education
In undergraduate courses, our departments have thechair of lecture and school- and hospital-based
practicums in adult nursing. In addition, our departments have the educational responsibility of teaching
students about “disease in adult populations I and II”,
which is a basic discipline for adult nursing.
In graduate courses, the two departments cooperatein education and research. In particular, during thefirst term of the doctoral course (master’s course), in
which students learn basic research skill.
Graduate students prepare their dissertations by
developing research question from their own scientificinterests or by participating in departmental projects.
Since we consider that the process itself is a part ofthe educational training of researchers, we focus ourenergy on seminars for developing master’s anddoctoral theses.

Research
Our department conducts research on adult nursing
from various points of view. One such perspective
focuses on the course of a disease, in which not only
the periods of recovery and terminal treatment but
also the upstream preventive steps, before disease
onset, are assessed with the chronic phase in thecenter; therefore, such nursing comprises an extremely
wide range of periods of practice. We have been
conducting studies which are expected to allow us tounderstand the state of individuals who requirenursing in those periods, and investigations on

281

effective and efficient nursing care for suchindividuals.
Another theme regarding nursing systems is how
care should be provided for individuals in the mostappropriate ways. We have been investigating how
nursing should be provided, and the continuity ofnursing care in various settings, such as outpatient
clinics, at home, and in palliative care facilities, by
focusing on individuals before disease onset, in thechronic phase, in the recovery period, and in theterminal period. We consider that it is essential toeliminate and/or improve the difficulties nurses inthese settings must confront, since they are associatedwith the improvement of care; therefore, such issues
have also been investigated.
Furthermore, one of our research themes is thedevelopment of evaluation measures and scales, which
are required in such studies.
Herein, we describe our current research areas. You
may refer to our homepage for more information, suchas the details of our research achievements, and theacquisition of research funds. The resources that havebeen developed in our research, such as evaluation
scales, are freely available to the public via our
homepage.
1) Nursing for Patients with Chronic Illnesses
It is necessary for individuals with chronic illnesses
to conduct self-management for symptom control intheir daily lives. Nursing has the important role ofsupporting patients to maintain their lifestyle bycontinuing self-management in their daily life.
We have developed various instruments formeasuring the difficulties that patients with chronic
illnesses experience in their daily lives, and havedescribed actual situations of difficulties using these
instruments. Furthermore, we have conducted a study
regarding support for controlling symptoms in order toreduce such difficulties.
The summaries of these studies, including sometheses in preparation for publication, are briefly
described below.
Diabetes (DM): We have developed preventive
strategies for adult offspring of diabetes patients andconfirmed its possible effectiveness and feasibility.
We investigated the effectiveness of the preventive
intervention by randomized controlled trial at medical

checkup institution.
Our activity related to nursing in diabetes field
involves nurse professional education. We developed
the scale to evaluate nurses’ support skill for diabetic
patients who receive insulin therapy.
Inflammatory bowel disease (IBD)：To study theissues associated with self-management of Japanese
IBD patients, we conducted two nationwide surveys
and a one-year prospective study. 1. We investigated
how patients with IBD recognized flare up of theirdisease and how they coped with worsening condition.
The study revealed that although patients recognizedflare up validly, there was considerable number ofpatients who did not visit to a doctor immediately. 2.
The questionnaire survey of expert doctor for IBD was
carried out, concerning direction for starting treatment
before visiting a hospital when patients recognize
relapse. 3. We elucidated prevalence of non-adherence
to their medications in Japanese UC patients, andimpact of the non-adherence to their medications toclinical relapse of UC. Based on these findings, we aredeveloping the intervention program for improving
self-management including medication adherence.
2) Nursing for organ transplantation recipients
Both organ transplantation recipients experiencevarious physical, psychological, and social difficulties.
Reduction of such difficulties is also important innursing.
We focused on self-management behavior in recipients of kidney transplantation. We have investigated
the actual status of self-management behaviors inrecipients. Then we developed an instrument which
will assess recipients’ self-management behavior.
3) Genetic Counseling
Genetic counseling for patient and their family who
have concerns about hereditary disease is an importantand unique research field for our department. Current
researches mainly focused on public health genomics,
disease management in familial cancer patients, andestablishment of medical system about genetic test.
4) Nursing for cancer patients
Cancer nursing is an important research field of ourdepartment, especially of clinical nursing specialist
course. We investigated two research themes in this282

year: palliative care for terminal cancer patients withdyspnea, and collaboration between hematologists andpalliative care teams about care for patients withrelapse or refractory leukemia/lymphoma.

Publications
1.

2.

3.

4.

5.

6.

7.

Nishigaki M, Tokunaga-Nakawatase Y, Nishida J,
Taru C, Miyawaki I, Sanada H, Kazuma K.
Randomized Controlled Trial of the Effectivenessof Genetic Counseling and a Distance, Computerbased, Lifestyle Intervention Program for Adult
Offspring of Patients with Type 2 Diabetes:
Background, Study Protocol, and Baseline
Patient Characteristics. Journal of Nutrition andMetabolism Volume 2012 (2012), Article ID
831735, 13 pages doi:10.1155/2012/831735
Nishigaki M, Shimizu Y, Kuroda K, Mori K,
Ohara Y, Seto N, Yoneda A, Miyatake Y, Kazuma
K, Masaki H, on behalf of JADEN-RG. Development of a support skill scale in insulin therapy: anationwide study in Japan. Nurse Education
Today DOI: 10.1016/j.nedt.2011.09.015
Yamamoto Y, Nishigaki M, Kato N, Hayashi M,
Shiba T, Mori Y, Kobayashi T, Kazuma K.
Knowledge and Demand for Information about
Islet Transplantation in Patients with Type 1
Diabetes. Journal of Transplantation Volume
2011 (2011), Article ID 136298, 6 pages doi:10.
1155/2011/136298
Kawakami A, Tanaka M, Ochiai R, Naganuma M,
Iwao Y, Hibi T, Kazuma K. Difficulties in taking
aminosalicylates for patients with ulcerative
colitis. Gastroenterology Nursing. 2012 Jan-Feb;
35(1):24-31.
Shibayama T, Sato E, Nishigaki M, Ochiai R,
Kazuma K. Influence of Dietary Therapy
Appraisal on Future Perceived Control of Type 2
Diabetes. Journal of Health Psychology 2011
Nov;16(8):1141-50.
Nishigaki M, Sugino Y, Seo J, Shimada M, Ikeda
K, Kazuma K. Influence of allocating HIV
specilized nurses on clinical outcomes in Japan.
Asian Nurs Res. 2011; 5(1): 1-8.
Hori M, Tanaka M, Suzuki Y, Fukao M, Shimizu
H, Mikoshiba N, Tateishi R. Peri-procedural painof radiofrequency ablation for hepatocellular

carcinoma. Gastroenterol Nurs. 2011; 34(2): 129134.
8. Yuri Tokunaga-Nakawatase, Chiemi Taru, Ikuko
Miyawaki. Development of an evaluation scale
for self-management behavior related to physicalactivity of patients with coronary heart disease.
Eur J Cardiovasc Nurs Published online before
print March 6, 2012, doi: 10.1016/j.ejcnurse.2011.
01.001
9. Ochiai R, Murakami A, Toyoda T, Kazuma K,
Niwa K. Opinions of physicians regarding
problems and tasks involved in the medical caresystem for patients with adult congenital heartdisease in Japan. Congenital Heart Disease. 2011
Jul-Aug;6(4):359-65.
10. Ito N, Ishiguro M, Uno M, Kato S, Shimizu S,
Obata R, Tanaka M, Makoto K, Nagano M,
Sugihara K, Kenichi K. Prospective Longitudinal
Evaluation of Quality of Life in Patients With
Permanent Colostomy After Curative Resection
for Rectal Cancer: A Preliminary Study. J Wound
Ostomy Continence Nurs. 2012 Mar-Apr;39(2):172-7.
11. Kato N, Kinugawa K, Sano M, Seki S, Kogure A,
Kobukata K, Ochiai R, Wakita S, Kazuma K.
Development of self-care educational material
for patients with heart failure in Japan: a pilot
study Nursing and Health Science. 2012;14(2):156-164.

283

Department of Midwifery and
Women's HealthProfessor
Sachiyo Murashima, Ph.D., P.H.N., R.N.
(Concurrent office: Community Health Nursing)

Lecturer
Megumi Haruna, Ph.D., R.N.M., P.H.N.
Ryoko Murayama, Ph.D., R.N.M.

Research associate
Masayo Matsuzaki, Ph.D., R.N.M., P.H.N.

Homepage http://park.itc.u-tokyo.ac.jp/midwifery/index.html
Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
Currently, it has 4 faculty members introduced above
and 10 part-time lecturers, 8 graduate students (5 inmaster course, 3 in doctoral course) and a visiting
researcher.

Teaching activities
We have 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 I(2 credits, lectures)
2) Advanced Midwifery and Women’s Health II(2 credits, lectures)
2. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternal-Newborn Nursing(2 credits, lectures)
2) Clinical Practicum in Maternal-Newborn

Nursing (2 credits, practice)
3. Undergraduate Advanced Courses for Midwifery,
School of Health Sciences and Nursing1) Midwifery I (1 credit, lectures)
2) Midwifery II (1 credit, lectures)
3) Midwifery III (2 credit, lectures)
4) Midwifery IV (3 credits, lectures)
5) Administration for Midwifery(1 credit, lectures)
6) Clinical Practicum of Midwifery I(1 credit, practice)7) Clinical Practicum of Midwifery II(7 credits, practice)

Research activities
Our research activities focus on maternal and childhealth with emphasis on the promotion of women's
health and their quality of life at every stage of theirlives.
We conduct the following research projects.
1. Collecting evidence for health guidance during
pregnancy

284•Adequate maternal nutrition and weight management
This study examines maternal body composition,
lipid metabolic biomarkers and nutritional intake
to optimize weight management and a healthy
lifestyle during pregnancy to prevent low birthweight. Based on our investigations into the
optimal maternal nutritional status and gestational
weight gain, we propose health guidance that canhelp pregnant women lower the risk of pregnancy
complications and adverse birth outcomes.
•Lifestyle factors and oxidative stress markers during
pregnancy
This study aims to assess the potential relationships between lifestyle factors and oxidative stressmarkers during pregnancy, and to establish optimal
oxidative stress markers for predicting a healthy
lifestyle for pregnant women.
•Plasma total homocysteine (tHcy) during pregnancy
and its relationship with infant birth weightThis study aims to determine whether tHcy is arisk factor for fetal growth.
•Evaluation of a dietary assessment tool for pregnant
Japanese womenThis study examines the validity and reproducibility of a self-administered diet history questionnaire(DHQ/BDHQ) conducted among pregnant Japanese women.
2. Development of accurate predictors of postpartum
hemorrhage
This study examines the possible associations ofmultiple biomarkers with uterine smooth muscle
contraction or relaxation (13, 14 – dihydro – keto prostaglandin F2α and nitric oxide metabolites)and postpartum hemorrhage.
3. Development of a self-managing support system forthe body after delivery• Postpartum stress urinary incontinence and thetransversus abdominis/pelvic floor muscles
We conduct functional evaluations of postpartum
local muscles using the ultrasonographic method.
These techniques are developed to establish therelationship between the pelvic floor or abdominal

muscles and urinary incontinence in women acrosstheir life-span.
•Development of a preventive and restorative programof pelvic floor muscle hypergasia
This study evaluates the use of the ultrasonographic method as a biofeedback tool for bodymanagement.
•Anal sphincter defects after delivery
This study aims to determine the prevalence andrisk factors of anal sphincter defects among postpartum women using three-dimensional transperineal ultrasound.
•Promotion of women's healthcare after delivery
This study examines the relationship between
maternal body composition and lifestyle factors
among postpartum women, including breastfeeding.
4. Development of a support system for women's
mental health during the perinatal period•"Fear of childbirth" and psychosocial factors among
pregnant Japanese womenThis study aims to translate the Wijma Delivery
Expectancy/Experience Questionnaire into Japanese and examine its validity and reliability, and to
identify the psychosocial risk factors of intense
fear of childbirth.

References
1. Ryoko Murayama, Tomio Kubota, Takamasa
Kogure, Kazuo Aoki. The effects of instruction
regarding sleep posture on the postural changes
and sleep quality among middle-aged and elderly
men: A preliminary study. Bio Science Trends.
2011; 5(3): 111-119.
2. Masayo Matsuzaki, Megumi Haruna, Erika Ota,
Ryoko Murayama, Murashima Sachiyo. Factors
related to the continuation of employment during
pregnancy among Japanese women. Japan Journalof Nursing Science. 2011; 8(2):153-162.
3. Anne Lyberg, Berit Viken, Megumi Haruna,
Elisabeth Severinsson. Diversity and challenges in
the management of maternity care for migrant

285

4.

5.

6.

7.

8.

women. Journal of Nursing Management. 2012;20(2): 287-95.
Takamasa Kogure, Tomio Kubota, Ryoko
Murayama, Hiromi Shinmura. Mobility andcomfort on a mattress influence sleep. Japanese
Journal of Physiological Anthropology. 2011;16(4): 171-176. (in Japanese)
Mie Shiraishi, Megumi Haruna, Masayo
Matsuzaki, Erika Ota, Ryoko Murayama, Etsuko
Watanabe, Satoshi Sasaki, Sachiyo Murashima.
Association between oxidized LDL and folate
during pregnancy. Biological Research For
Nursing. 2011 (in press)
Mie Shiraishi, Megumi Haruna, Masayo
Matsuzaki, Ryoko Murayama, Satoshi Sasaki,
Sachiyo Murashima. Validity and reproducibilityof folate and vitamin B12 intakes estimated from aself-administered diet history questionnaire in
Japanese pregnant women. Nutrition Journal.
2012; 11: 15.
Emiko Nishioka, Megumi Haruna, Erika Ota,
Masayo Matsuzaki, Ryoko Murayama, Yoshimura
Kenichi, Sachiyo Murashima. A prospective studyof the relationship between breastfeeding andpostpartum depressive symptoms appearing at 1-5
months after delivery. Journal of Affective
Disorders. 2011; 133(3): 553-559.
Mizuki Takegata, Megumi Haruna, Ryoko
Murayama,
MasayoMatsuzaki,
SachiyoMurashima. Scales for measuring labor pain: A
literature review. Journal of Japan Academy ofMidwifery. 2011; 25(2): 160-70. (in Japanese)

286

Department of Psychiatric Nursing
Professor
Norito Kawakami, M.D., Ph.D.

Lecturer
Yuki Miyamoto, R.N., P.H.N., P.S.W., Ph.D.

Homepage

http:// plaza.umin.ac.jp/heart/

Introduction and Organization

Teaching activities

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 ever since.
Our department currently has two faculty
members introduced above, part-time lecturers,
visiting research fellows, 4 doctoral course students, 4
master course students, and research associates.
Our department’s mission comprises twoelements. One is to provide education and researchtraining in mental 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.

Our department is responsible for giving lectureson 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
psychiatric nursing. To accomplish this objective, ourdepartment has a specialized lecture course on
psychiatric nursing, and seminars on mental healthand psychiatric nursing for graduate students. These
activities are conducted and supervised by the faculty.
In collaboration with the department of mental health,
we also have the department seminar every
Wednesday evening, where members provide theactual plans for their own research and discuss the
topic.
We also have a variety of study clubs. We havepsychiatric nursing study club, study group for
multi-level analysis, qualitative research study group,and so on.
The following are graduation thesis themes ofundergraduate students in our department in 2011.
 “The uses of theatrical interventions in the healtharena (Review).”
 “Analysis of symptoms of PTSD at city A in
Kanto area after the Great East Japan
Earthquake.” “Mental health and having children.”
The following is a master’s thesis theme from ourdepartment in 2011.

287

 “The relieving process of suicidal ideation
among people with gender identity disorder: A
qualitative study.”
The following are PhD thesis themes from ourdepartment in 2011.
 “Effectiveness of the program to facilitate
recovery focused on enhancing benefit-finding,personal meaning, and well-being for people
with chronic mental illness: a randomized
controlled trial.”
 “Development of Nondirective and Directive
Support Survey Japanese version (NDSS-J）andstudy of the influences of nondirective supportand directive support on anxiety and depression
among people with diabetes.”
 “Burden, health-related quality of life, and gainof social support among family caregivers of
stoke patients.”

3.

4.

5.

Research activities
Our research field covers mental health andpsychiatric nursing. Our department has many
research projects across diverse fields as follows:
study of self-management in mental health; recovery
for people with mental health difficulties; community
support system for the people with mental healthneeds; peer support; stigma; social inclusion; issues ofcaregiver burden in family caregivers; behavioral andpsychological symptoms of dementia; patient satisfaction with psychiatric services; and practice andevaluation of home visiting psychiatric nursing. We
are conducting studies in collaboration withresearchers in other institutions and universities.

6.

7.

References
1. Funakoshi A, Miyamoto Y, Shimazu A.
Development of a scale of difficulties experienced
by parents of children with hikikomorisyndrome.
Journal of Mie Prefectural College of Nursing.
2011;15:39-55.
2. Miyashita M, Narita Y, Sakamoto A, Kawada N,
Akiyama M, Kayama M, Suzukamo Y, Fukuhara
S.Health-related
quality
of
life
among
community-dwelling patients with intractableneurological diseases and their caregivers in

8.

9.

Japan.Psychiatry Clin Neurosci. 2011; 65(1): 30-8.
PMID: 21105961
Akazawa M, Matsumoto T, Katsumata Y, Kitani
M, Hirokawa S, Kameyama A, Yokoyama Y,
Takahashi Y, Kawakami N, Watanabe N,
Hirayama M, Takeshima T. [Psychosocial andpsychiatric characteristics of suicide completersby employment situation before death: apsychological autopsy study of 76 cases]. Nippon
shakai seishin igakukai zasshi [Journal ofJapanese Society for Social Psychiatry]. 2011;20(2): 82-93. (in Japanese)
Kubota K, Shimazu A, Kawakami N, Takahashi M,
Nakata A, Schaufeli W. Distinción Empírica Entre
Engagement y Trabajolismo en Enfermeras
Hospitalarias de Japón: Efecto Sobre la Calidaddel Sueño y el Desempeño Laboral. Ciencia &Trabajo. 2011; 13 (41): 152-157 (in Spanish).
Coe CL, Love GD, Karasawa M, Kawakami N,
Kitayama S, Markus HR, Tracy RP, Ryff CD.
Population differences in proinflammatory
biology: Japanese have healthier profiles than
Americans. Brain Behav Immun. 2011 Mar;25(3) :494-502.
Bruffaerts R, Demyttenaere K, Hwang I, Chiu WT,Sampson N, Kessler RC, Alonso J, Borges G, de
Girolamo G, de Graaf R, Florescu S, Gureje O, Hu
C, Karam EG, Kawakami N, Kostyuchenko S,
Kovess-Masfety V, Lee S, Levinson D,
Matschinger H, Posada-Villa J, Sagar R, Scott
KM, Stein DJ, Tomov T, Viana MC, Nock MK.
Treatment of suicidal people around the world. Br
J Psychiatry. 2011 Jul ;199:64-70.
Cheng Y, Park J, Kim Y, Kawakami N. The
recognition of occupational diseases attributed toheavy workloads: experiences in Japan, Korea,
and Taiwan. Int Arch Occup Environ Health. 2011
Nov; 23. (Epub ahead of print)
Shimazu A, Demerouti E, Bakke, AB, Shimada K,
Kawakami N. Workaholism and well-being
among Japanese dual-earner couples: Aspillovercrossover perspective. Social Science & Medicine.
2011 ;73. 399-409. PMID: 21733607
Orui M, Kawakami N, Iwata N, Takeshima T,
Fukao A. Lifetime prevalence of mental disorders
and its relationship to suicidal ideation in a
Japanese rural community with high suicide and288

alcohol consumption rates. Environ Health Prev
Med. 2011 Nov ;16(6) :384-9.PMID: 21431807
10. Koichi R, Miyamoto Y. Reliability and validity of
the Japanese semistructured interview version of
the Early Signs Scale (ESS-JI) for outpatientswith schizophrenia (study 1). International Journalof Mental Health Nursing. 2011 ;20(2), 144-151.
PMID: 21371230
11. Suzuki M, Tachimori H, Saito M, Koyama andKurita H. Developmentof a screening scale forhigh-functioning pervasive developmental disorders using the Tokyo Child Development
Schedule and Tokyo Autistic Behavior Scale.
Research Autism Spectrum Disorder. 2011; 5:
843-854.
12. Chiba R, Kawakami N, Miyamoto Y. Quantitative
relationship between recovery and benefit-finding
among persons with chronic mental illness inJapan. Nursing and Health Sciences, 2011; 13(2):126-132. PMID: 21481122
13. Bakker AB, Shimazu A, Demerouti E, Shimada ,Kawakami N. Crossover of work engagement
among Japanese couples: Perspective taking byboth partners. Journal of Occupational Health
Psychology. 2011 Jan; 16(1): 112-25. PMID:
21280948
14. Chiba R, Miyamoto Y, Kawakami N. [Recovery inpeople with mental illness living in community:
comparison with or without experience of peer
support]. Seishinka Kango [Psychiatric Nursing],
2011; 38(2): 48-54. (in Japanese)
15. Ogawa M, Miyamoto Y, Kawakami N. Factors
Associated With Glycemic Control and Diabetes
Self-care Among Outpatients With Schizophrenia
and Type 2 Diabetes. Arch Psychiatr Nurs.
2011;25(1):63-73.PMID: 21251603
16. Sakurai K, Nishi A, Kondo K, Yanagida K,
Kawakami N. Screening performance of K6/K10
and other screening instruments for mood andanxiety disorders in Japan. Psychiatry Clin
Neurosci. 2011 Aug;65(5):434-41. PMID:
21851452
17. Sado M, Yamauchi K, Kawakami N, Ono Y,
Furukawa TA, Tsuchiya M, Tajima M, Kashima
H; WMH-J2002-2006 Survey Group, Nakane Y,
Nakamura Y, Fukao A, Horiguchi I, Tachimori H,
Iwata N, Uda H, Nakane H, Watanabe M, Oorui

M, Funayama K, Naganuma Y, Hata Y, Kobayashi
M, Ahiko T, Yamamoto Y, Takeshima T, Kikkawa
T. Cost of depression among adults in Japan in
2005. Psychiatry Clin Neurosci. 2011 Aug;
65(5):442-50. PMID: 21851453
18. Ito J, Oshima I, Nishio M, Sono T, Suzuki Y,
Horiuchi K, Niekawa N, Ogawa M, Setoya Y,
Hisanaga F, Kouda M, Tsukada K. The effect ofAssertive Community Treatment in Japan. Acta
Psychiatrica Scandinavica. 2011 May; 123(5):398-401. PMID: 21070193
19. Niekawa N, Oshima I, Sono T, Ogawa M,
Fukasawa M, Ito J. [Evaluation of the reliability
and validity of the process evaluation scale basedon consumer's perceptions of the criticalcomponents of assertive community treatment].
Seishin Igaku [Clinical Psychiatry]. 2011 June;
53(6): 523-533. (in Japanese)
20. Yoshimasu K, Kawakami N, and the WMH-J
2002-2006 Survey Group: Epidemiologicalaspects of intermittent explosive disorder inJapan; prevalence and psychosocial comorbidity:
findings from the World Mental Health Japan
Survey 2002-2006 Psychiatry Research 2011 Apr
30;186(2-3):384-9. Epub 2010 Aug 14.
21. Levinson D, Lakoma M, Petukhova M,
Schoenbaum M, Zaslavsky AM, Angermeyer M,
Borges G, Bruffaerts R, de Girolamo G, de Graaf
R, Gureje O, Haro JM, Hu C, Karam AN,
Kawakami N, Lee S, Lepine JP, Oakley Browne
M, Okoliyski M, Posada- Villa J, Sagar R,
Carmen Viana M, Williams D, Kessler RC.
Associations of serious mental illness withearnings in the WHO World Mental Healthsurveys. Br J Psychaitry 2010 Aug; 197(2):114-21..

289

Department ofGerontological Nursing /Wound Care Management
Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Project Lecturer
Takashi Nagase, M.D., Ph.D.
Takeo Minematsu, Ph.D.

Lecturer
Gojiro Nakagami, R.N., Ph.D.

Research Associate
Makoto Oe, R.N., Ph.D.

Homepage

http://www.rounenkango.m.u-tokyo.ac.jp/english/index-e.html

Introduction and Organization
The Department of Gerontological Nursing wasestablished in June 2003, followed by theestablishment of the Department of Wound CareManagement in April 2006. These two departments
are currently headed by 1 professor and assisted by 2
project lecturer, 1 lecturer, 1 research associate, and 7
part-time lecturers for undergraduate course (2) andfor graduate course (5). The student body consists of
12 doctoral course students, 12 master course students
and 1 undergraduate student. The goal of ourdepartment is to achieve “Evidence-based practice anddevelopment of gerontological nursing and woundcare management”.

Teaching activities
1.Undergraduate course
1) Gerontological Nursing (3-4th yr/ 4 credits)
The aim of the 3rd year course is for students tounderstand the physical, psychological and social

characteristics of the elderly population, and to learn
fundamental theories of gerontological nursing. The
main themes in the 2011 contents were as follows;a) Practical simulation for gerontological nursingb) Physical, psychological and social characteristicsof the elderly from a nursing standpointc) Gerontological nursing and its theoriesd) Social, health and medical policies for a healthy
life of the elderlye) Geriatric syndrome and nursing (gait disorder,
malnutrition, infection, dementia and pressure
ulcer)
f) Future perspectives of gerontological nursing
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 2011 contents were as follows;a) Age-related changes in the physiologic system,
Aging and dementiab) Aging and osteoporosis, Aging and renal function,
hypertension, and stroke290c) Aging and respiratory disorders, Aging andcardiovascular disordersd) Pharmacological management of the elderlye) Feeding and swallowing difficulty of the elderlyf) Nutritional management of the elderlyg) Relationship and communication skills with theelderly
The above lectures were developed under thecooperation by the Department of Geriatric Medicine
at The University of Tokyo Hospital.
2) Clinical Practice in Gerontological Nursing(4th yr/ 3 credits)
The aim of this practicum is to learn present situationof gerontological nursing through practicing in thelong-term care facility. This program in 2011 was
supported by the long-term care facility owned by
Medical Corporation Tatsuoka.
3) Bachelor’s thesis
The following was the research theme in 2011;“Cross-sectional study of dry skin of the elderly
people in the long-term care insurance facility” This
thesis won the departmental dean prize awarded to themost excellent graduation thesis.
2. Graduate course
1) Gerontological Nursing I(Summer course/ 2 credits)
2) Gerontological Nursing II(Winter course/ 2 credits)
The main theme of Gerontological Nursing I in 2011
was to understand the latest research related to thecare of elderly persons and to discuss future
perspective of gerontological nursing from three
viewpoints: basic biology, clinical research andengineering. Critical reading of the recent papers
selected from the three fields was organized.
Gerontological Nursing II provided lectures regarding
the recent topics around gerontological medicine andnursing from the broad viewpoints including
biological, individual and social aspects by thepart-time lecturers, specialists of each research field.
The aim of this course was to obtain scientific ways ofthinking for gerontological considerations of the
future Japanese community. The main themes in 2011were as follows;a) Basic knowledge and clinical application ofultrasonographyb) Systematization of objective pressure ulcer
assessment technologies by multidisciplinary
approachc) Nursing support to East Japan great earthquake
victims, and caring for early-onset dementia
patients and their family caregiversd) The clarification of the bladder perception
mechanism: For a new therapeutical targete) Community empowerment and elderly people's
healthf) Metabolic changes and nutrition management in
the elderly people, and nutrition management ofkidney disease3) Wound Care Management I(Summer course/ 2 credits)4) Wound Care Management II(Winter course/ 2 credits)
The main theme of Wound Care Management I in
2011 was learning of basic knowledge (basic biology,
clinical research, and engineering) necessary tounderstand the research on the wound management
study.
The theme was as follows.
a) Approach of nursing science to chronic wounds inclinical settingb) Physical and engineering approach to the wound
management studyc) Biological understanding of wound healingd) Overview of current research of this laboratory
The main theme of Wound Care Management II in2011 was to obtain deeper insight in our own researchknowledge through the lectures and discussion by the
specialists with various basic and advanced research
fields.
The theme was as follows.
a) Support surfacesb) Regenerative medicinec) Skin cared) Stoma caree) Diabetic foot ulcerf) Nutrition managementg) Mycosish) Arterial foot ulcer

2915) Master’s thesis
The followings were research themes in 2011;“Development and evaluation of air mattress structureand function for discomfort reduction during head-ofbed elevation”“Risk factors for infection during tissue expansion intissue expander and implant breast reconstruction”“Investigation of the influence of Pseudomonas
aeruginosa quorum sensing signal molecule
N-(3-oxododecanoyl)homoserine
lactoneonkeratinocyte migration”“Factors associated with callus in diabetic patients-focused on planter shear stress during gait-”“Skin maceration with fecal incontinence as a risk forskin lesion -Tissue damage and bacterial invasion in
rat skin macerated by proteolytic solution-”“Ultrasonography reveals structural changes in thedermis and subcutaneous tissues in obesity: Possible
association with oxidative stress”
5) Doctor’s thesis
The followings were research themes in 2011;“Achlhomoserine lactone improves the impaired
basement membrane formation in the epithelializing
tissue during cutaneous wound healing in
hyperglycemic rats”“Estimation of protein requirements for older
hospitalized patients with pressure ulcers according towound severity”“Vibration attenuates a deterioration of deep tissue
injury in rats”“Evaluation of cost effectiveness of advanced wound
management program for prevention of pressure ulcer
deterioration.”“The contact dermatitis and exudates of the breast
cancer patients with malignant fungating wound”“Influence of deterioration of mental well-being on
the turnover desire and the mental sense of coherenceof the new graduate nurses－longitudinal study before
working, after 3 months and after a year－”

Research activities
1. Activity policy
Our gerontological nursing researches are focusing onelderly suffering with geriatric syndrome such aspressure ulcers, incontinence, malnutrition, pain,
dysphagia, osteoporosis and dementia. Our woundcare management researches are focusing on pressure
ulcers, diabetic foot ulcers, ulcers with peripheral
vascular diseases and malignant fungating ulcers.
The majority of our clinical researches is conducted at
the University of Tokyo Hospital as a main field. We
are participating in pressure ulcer ward rounds as
members of the Pressure Ulcer Team of the hospital.
We also attend the Foot Care Outpatient Clinic held
by Department of Metabolic Diseases, and the Stoma
Outpatient Clinic held by Department of Urology andDepartment of Colorectal Surgery. We also actively
perform epidemiological and clinical researches in therelated institutes other than the University hospital, sothat our research is always based on clinical practice.
Our special research missions in 2011 were twofold:(1) We aimed to develop our research system within
our department as a sequential flow of “translational
research,” from the basic biology, through engineeringby industry-academia cooperation, and to theestablishment of clinical evidences returning theachievement of our research to the society. Some ofthe studies described below were performed in thisdirection.
(2) Development of new nursing devices requires
involvement of engineering specialists. We haveinvented a number of nursing products and equipments based on our research by academia-industrial
cooperation. We continued research in 2011 with the
Department of Life Support Technology (Molten) that
had been established last year, as a cooperation
department. The Bioengineering Nursing Meeting wassponsored by our department in January, 2012, aiming
at the development of this new research field. The
related area researchers participated in this meetingfrom all over the country. Their current approaches
were reported, and the directionality of bioengineering
nursing in the future was discussed.
We held the 7th University of Tokyo Open Seminar of
Advanced Wound Care on November 2011 at the
Tetsumon Hall. The theme was the latest informationon the fecal incontinence management for theprevention of Incontinence Associated Dermatitis(IAD). The lecture entitled "Current state of the fecal
incontinence in the acute care settings and purpose of
the advanced incontinence management system" wasgiven by Dr. Jun-ichi Sasaki from Keio University.
The lecture entitled "The present situations of IAD

292

and its new assessment tool" was given by Ms. Donna
Z. Bliss from Minnesota University. The fecal
incontinence management is important also from theviewpoint of wound management. This seminar was achance to obtain the latest information about the fecal
incontinence management based on evidence, and to
discuss skin care for IAD in the future. Ms. Bliss also
introduced Incontinence Associated Dermatitis and its
Severity (IADS) scale, an objective scale to evaluate
the severity of the symptoms of IADs. The permission
to translate the IADS scale into Japanese was obtained
after this seminar. We developed Japanese version of
IADS, and evaluated reliability and validity of thisscale.
As an international activity, our department serves as
the International Board of Director of International
Lymphoedema Framework (ILF), an internationalgroup for lymphoedema management. Moreover, ourdepartment serves as the chief director of the ILF
Japan, where the international standardization oflymphoedema care is aimed at. The system of the datacollection in multiple languages is being developedwith the ILF representative Prof. Christine Moffat(University of Nottingham,UK) for construction of thedata base concerning the diagnosis and treatment
service that can be used in the world.
2. Research fields and themes in 2011
1) Basic experimental studies
・ Development of a novel method for controllingwound infection focusing on gene expression ofbacteria and hosts
・ Evaluation of wound condition using exudates
・ Establishment of the animal model of pressure
ulcer of deep tissue injury type and elucidationof its pathophysiological mechanisms
・ Skin vulnerability and aging in the metabolic
syndrome model mice・ Cutaneous wound healing and diabetes mellitus
・ New animal model of wound infection
・ Mechanisms of skin maceration
2) Nursing engineering
・ Development of a new air-mattress equippedwith interface pressure sensing system andautomatic pressure control
・ Non-invasive detection of tissue injury andpre-injury status using ultrasonography andthermography
・ Development of a handy type kit for diagnosis
of wound infection
・ Development of insole-type simultaneous
measurement system of plantar pressure andshear force during gait3) Clinical studies
・ Cross-sectional study of diabetic foot (ulcers,
callus, fissures, onychomycosis etc.) and its risk
factors
・ Evaluation of wound nutritional status in elderlywith pressure ulcers
・ Cross-sectional study of malignant wounds inbreast cancer patients and its risk factors
・ Retrospective cohort study of infection during
tissue expansion in tissue expander and implantbreast reconstruction
・ Survey and international comparison oflymphoedema (collaboration with International
Lymphoedema Framework)・ Clinical outcomes and cost-effectiveness of
WOC nurse practice with advanced educationand discretion
・ Evaluation of a new concept diaper for elderly
people for incontinence associated dermatitis
management
・ New assessment technology of the aged skin byengineering analysis
・ Thermographic assessment of the footcirculation based on the concept of angiosome
・ Establishment of a novel diagnosis method oflatent dysphagia
・ Cross-sectional study of the skin of elderly
people in the nursing home・ Cross-sectional study of the skin of obese people
Several awards were given to our research as follows.
・ “Development of simultaneous measurement
system of plantar pressure and shear force
during gait” Ms. Masako Hamatani (MasterCourse Student) won the best young researcher’s
presentation prize of Committee of Assistive
Technology, Bio Medical Engineering and Life
Support 2011.
・ “Predicting delayed pressure ulcer healing using

293

thermography: a prospective cohort study” Dr.
Gojiro Nakagami (Lecturer) won the Ohuraprize of the 13th Annual Meeting of the JapaneseSociety of Pressure Ulcer.
・ “Foot complications of high-risk patients fordiabetic foot ulcers; based on the risk
categorization system of the International
Consensus on the diabetic foot” Dr. Makoto Oe(Research Associate) won the best presentation
prize of the 20th Annual Meeting of JapaneseSociety of Wound, Ostomy and ContinenceManagement.
・ ”Foot callus and inflammation of patients withdiabetes” Ms. Masako Hamatani (Master Course
Student) won the best presentation prize of the20th Annual Meeting of Japanese Society ofWound, Ostomy and Continence Management.
・ ”Skin condition and nutritional status of
long-term care hospital residents: possibility ofquantitative skin evaluation as a nutritional
screening tool” Ms. Lijuan Jiao (Graduate of
Master Course) won the best paper prize of the20th Annual Meeting of Japanese Society ofWound, Ostomy and Continence Management.

References
1.

2.

3.

Akase T, Nagase T, Huang L, Ibuki A, Minematsu
T, Nakagami G, Ohta Y, Shimada T, Aburada M,
Sugama J, Sanada H. Aging-Like skin changes
induced by ultraviolet irradiation in an animalmodel of metabolic syndrome. Biol Res Nurs.
2012;14(2):180-7.
Minematsu T, Huang L, Ibuki A, Nakagami G,
Akase T, Sugama J, Nagase T, Yoshimura K,
Sanada H. Altered expression of matrix
metalloproteinases and their tissue inhibitors inmatured rat adipocytes in vitro. Biol Res Nurs.
2012;14(3):242-9.
Yabunaka K, Konishi H, Nakagami G, Sanada H,
Iizaka S, Sanada S, Ohue M. Ultrasonographic
evaluation of geniohyoid muscle movement
during swallowing: a study on healthy adults ofvarious ages. Radiol Phys Technol. 2012;5(1):
34-9.

4.

Oe M, Sanada H, Nagase T, Minematsu T, Ohashi
Y, Kadono T, Ueki K, Kadowaki T. Factors
associated with deep foot fissures in diabetic
patients: A cross-sectional observational study. Int
J Nurs Stud. 2012 ;49(6):739-46.
5. Iizaka S, Jiao L, Sugama J, Minematsu T, Oba M,
Matsuo J, Tabata K, Sugiyama T, Sanada H.
Evaluation of nutritional status and skin condition
among elderly residents in a long-term care
hospital. J Nutr Health Aging. 2012;(16)1:107-11.
6. Ibuki A, Akase T, Nagase T, Minematsu T,
Nakagami G, Horii M, Sagara H,Komeda T,
Kobayashi M, Shimada T, Aburada M, Yoshimura
K, Sugama J, Sanada H. Skin fragility in obese
diabetic mice: possible involvement of elevatedoxidative stress and upregulation of matrix
metalloproteinases. Exp Dermatol. 2011;21(3):178-83.
7. Asada M, Nakagami G, Minematsu T, Nagase T,
Akase T, Huang L, Yoshimura K,Sanada H. Novelbiomarkers for the detection of wound infection
by wound fluid RT-PCR in rats. Exp Dermatol.
2011;21(2):118-22.
8. Iizaka S, Sanada H, Nakagami G, Koyanagi H,
Sugama J. Quantitative estimation of exudate
volume for full-thickness pressure ulcers: the
ESTimation method. J Wound Care. 2011;20(10):453-63.
9. Nakagami G, Sanada H, Higashino T, Kadono T,
Uchida G, Fujita H, Ogawa Y, Yamamoto Y,
Iizaka S, Koyanagi H, Sasaki S, Haga N.
Combination of ultrasonographic and thermographic assessments for predicting partialthickness pressure ulcer healing. WOUNDS.
2011;23(9):285-92.
10. Yamamoto Y, Nakagami G, Mori T, Sakai K,
Sanada H. Evaluation of preventive effect on
buttocks immersion of independently controlled
inner air cell pressure in air mattress. J Jpn
WOCM. 2011;15(3):239-49.
11. Sanada H, Iizaka S, Matsui Y, Furue M,
Tachibana T, NakayamaT, Sugama J, Furuta K,
Tachi M, Tokunaga K , Miyachi Y. Clinicalwound assessment using DESIGN-R total score
can predict pressure ulcer healing: Pooled
analysis from two multicenter cohort studies.
Wound Repair Regen. 2011;19(5):559-67.

294

12. Ichioka S, Yokogawa H, Nakagami G, Sekiya N,
Sanada H. In vivo analysis of skin microcirculation and the role of nitric oxide during
vibration. Ostomy Wound Manage. 2011;57(9):40-7.
13. Mori T, Urushibata R, Noguchi H, Shimosaka M,
Sanada H, Sato T. Sensor arrangement forclassification of life activities with pyroelectric
sensors-arrangement to save sensors and toquasi-maximize classification precision. J Robot
Mechatron. 2011;23(4):494-504.
14. Hiroaki Fukada, Taketoshi Mori, Hiroshi Noguchi,
Tomomasa Sato. Use of active RFID andenvironment-embedded sensors for indoor object
location estimation. Deploying RFID - Challenges,
Solutions, and Open Issues. 2011:219-36.
15. Noguchi H, Mori T, Sato T. Flexible discovery ofcomponents for sensor data processing by RDF in
network middleware for home environment. J
Robot Mechatron. 2011;23(4):505-14.
16. Fukui R, Mori T, Sato T. Home-use object
transfer/storage robot system with compliant
strategy and mechanism (commodities management and its extended application of daily life
support for the elderly). J Robot Mechatron. 2011;23(4):532-43.
17. Iizaka S, Sanada H, Matsui Y, Furue M,
Tachibana T, Nakayama T, Sugama J, Furuta K,
Tachi M, Tokunaga K, Miyachi Y. Serum albumin
level is a limited nutritional marker for predicting
wound healing in patients with pressure ulcer:
Two multicenter prospective cohort studies. Clin
Nutr. 2011;30(6):738-45.
18. Noguchi H, Mori T, Sato T. Object localization bycooperation between human position sensing andactive RFID system in home environment. SICE
Journal of Control, Measurement, and System
Integration. 2011;4(3):191-8.
19. Nanjo Y, Nakagami G, Kaitani T, Naito A,
Takehara K, Lijuan J, Yahagi N, Sanada H.
Relationship between morphological characteristics and etiology of pressure ulcers in intensive
care unit patients. J Wound Ostomy Continence
Nurs. 2011;38(4):404-12.
20. Iizaka S, Sugama J, Nakagami G, Kaitani T, Naito
A, Koyanagi H, Matsuo J, Kadono T, Konya C,
Sanada H. Concurrent validation and reliability ofdigital image analysis of granulation tissue color
for clinical pressure ulcers. Wound Repair Regen.
2011 ;19(4):455-63.
21. Matsui Y, Furue M, Sanada H, Tachibana T,
Nakayama T, Sugama J, Furuta K, Tachi M,
Tokunaga K, Miyachi Y. Development of the
DESIGN-R with an observational study. An
absolute evaluation tool for monitoring pressure
ulcer wound healing. Wound Repair Regen.
2011;19(3):309-15.
22. Minematsu T, Yamamoto Y, Nagase T, Naito A,
Takehara K, Iizaka S, Komagata K, Huang L,
Nakagami G, Akase T, Oe M, Yoshimura K,
Ishizuka T, Sugama J,Sanada H. Aging enhances
maceration-induced ultrastructural alteration of
the epidermis and impairment of skin barrier
function. J Dermatol Sci. 2011 Jun;62(3):160-8.
23. Nakagami G, Minematsu T, Asada M, Nagase T,
Akase T, Huang L, Morohoshi T, Ikeda T, Ohta Y,
Sanada H. The Pseudomonas aeruginosa quorumsensing signal N-(3-oxododecanoyl) homoserine
lactone can accelerate cutaneous wound healing
through myofibroblast differentiation in rats.
FEMS Immunol Med Microbiol. 2011;62(2):157-63.

International Health
1. International Social Medicine

296

Department of
Global Health Policy
Professor
Kenji Shibuya, MD, DrPH

Faculty members
Nayu Ikeda, MA, PhD
Erika Ota, BNurs, MSc, PhD
Stuart Gilmour, MPH, MStat

Homepage

http://www.ghp.m.u-tokyo.ac.jp※ The following information is the same as that of the previous year for certain reasons.

Introduction and Organization

Education

Our mission is to improve population health byenhancing accountability and improving the evidencebase for global health programmes, through theprovision of the best possible information andrigorous monitoring and evaluation. The department's
members generate knowledge and ideas through theirresearch, strengthen technical and leadership skills
through educational programs, and enhance national
capacities through collaborative projects, especially inthe developing world.

Master's program
The
Master's
programisademanding,interdisciplinary program emphasizing studentdirected learning, problem-solving, and theacquisition of fundamental public health skills
required for global health practices (health policy,
statistics, epidemiology, and social sciences). Students
are required to complete a minimum of 30 course
credits and a master’s thesis. Beyond the program andconcentration requirements, students are encouraged
to consult with faculty advisers to choose elective
courses best suited to their needs.

The priority areas of research are:
- Health outcome research (mortality, morbidity anddisability; health service research; health technology assessment and cost-effectiveness; diseasemodeling; and comparative risk factor analysis);- Health system performance assessment, including
the analysis of health system inputs, outputs, andimpact;- Health and foreign policy (e.g. global health architecture and governance, the G8 and global health,donor commitments, and innovations in global
health).
Finally, the fundamental role of the department is to
produce the next generations of leaders in global
health.

PhD program
The PhD program is designed to train the next
generation of leaders in global health. PhD students
are required to complete a minimum of 24 course
credits and a doctoral thesis with which needs to be
published in a peer-reviewed journal. PhD students
without MPH degree should take the lectures toacquire fundamental public health skills such as healthpolicy, biostatistics and epidemiology.
Global Health Policy I and IIThis course introduces the principles and theories of297

global 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

GHP Monday seminar
Every Monday, 13:00-15:00 pm
1) Journal clubStudents present a brief summary of research articles
from the major medical, social science, economics
journals, which are relevant for global health policy.
The major objective is to share knowledge, evoke
debates and facilitate discussions.
2) Research seminar
A guest speaker or a master or doctoral student
presents his/her research. There is a 15-minutepresentation-followed by a 30-minute discussion.

Research
A comprehensive evaluation of risk factors for theprevention of disease. Ministry of Education, Culture,
Sports, Science and Technology, Grants-in-Aid for
Scientific Research (B). PI: Kenji Shibuya.
A comprehensive empirical study of the Japanese
health system. Ministry of Health, Labour and Welfare
Research Grant, Research on Policy Planning and
Evaluation. PI: Kenji Shibuya
Research on epidemiological methodology for the
study of food-borne diseases for policy planning andevaluation of food safety. Ministry of Health, Labourand Welfare Research Grant, Research on Promotionof Food Safety. PI: Kenji Shibuya
Researching Japan’s International Contribution.
Ministry of Health, Labour and Welfare Research
Grant, Research on Promotion of Global Health Issues.
PI: Kenji Shibuya
Researching the medium and long term health system
impact of the Fukushima Daichi nuclear accident.
Toyota Foundation 2012 East Japan Earthquake
Special Policy Development Grants. PI: Kenji
Shibuya
A systematic review of the maternal and child healthworkforce. World Health Organization. PI: Kenji
ShibuyaGlobal Health Leadership Program. Japan Science andTechnology Association. PI: Kenji Shibuya
Research on the extent of effective treatment coverageusing health system assessment indicators. Ministry of
Education, Culture, Sports, Science and Technology,
Grants-in-Aid for Scientific Research (C). PI: Nayu
Ikeda
Establishing standards for birthweight by gestational
age at the population level for Japanese children.
Ministry of Education, Culture, Sports, Science andTechnology, Grants-in-Aid for Young Scientists (B).
PI: Erika Ota

Publications
1. Tobe M, Stickley A, del Rosario R, Shibuya K.
Out-of-pocket medical expenses for inpatient careamong beneficiaries of the National Health
Insurance Program in the Philippines. Healthpolicy and planning. Forthcoming.
2. Tsubokura M, Gilmour S, Takahashi K, Oikawa T,
Kanazawa Y. Internal Radiation Exposure Afterthe Fukushima Nuclear Power Plant Disaster.
JAMA. 2012;308(7):669-670.
3. Ota E, Tobe-Gai R, Mori R, Farrar D. Antenatal
dietary advice and supplementation to increaseenergy and protein intake. Cochrane Database of
Systematic Reviews. 2012, Issue 9. Art. No.:
CD000032.

298

4. Wariki WMV, Mori R, Boo NY, Cheah IGS,
Fujimura M, Lee J, Wong KY. Risk factors
associated with outcomes of very low birth weight
infants in four Asian countries. Journal of
Paediatrics and Child Health. Forthcoming.
5. Li J, Gilmour S, Zhang H, Koyanagi A, Shibuya K.
The epidemiological impact and cost-effectivenessof HIV testing, antiretroviral treatment and harm
reduction programs. AIDS. Forthcoming.
6. Gilmour S, Li J, Shibuya K. Projecting HIV
Transmission in Japan. PLoS ONE. 2012;7(8):e43473.
7. Mori R, Ota E, Middleton P, Tobe-Gai R,
mahomed K, Bhutta ZA. Zinc supplementation forimproving pregnancy and infant outcome.
Cochrane Database of Systematic Reviews 2012,
issue 6. Art. No.: CD000230.
8. Sado M, Ota E, Stickley A, Mori R. Hypnosis
during pregnancy, childbirth, and the postnatal
period for preventing postnatal depression.
Cochrane Database of Systematic Reviews 2012,
Issue 6. Art. No.: CD009062.
9. Sugimoto A, Krull S, Nomura S, Morita T,
Tsubokura M. Voice of the most vulnerable: what
we can learn from the Fukushima nuclear crisis.
Bulletin of the World Health Organization. 2012
Aug 1; 90(8):629-30
10. Roberts B, Stickley A, Murphy A, Kizilova K,
Bryden A, Rotman D, Haerpfer C, McKee M.
Patterns of public support for price increases on
alcohol in the former Soviet Union. Alcohol andAlcoholism. 2012; 27(4): 473-478.
11. Wada K, Kondo N, Gilmour S, Ichida Y, Fujino Y,
Satoh T, Shibuya K. Trends in cause specificmortality across occupations in Japanese men ofworking age during period of economic stagnation,
1980-2005: retrospective cohort study. BMJ. 2012
Mar 6; 344:e1191
12. Roberts B, Stickley A, Balabanova D, Haerpfer C,
McKee M. The persistence of irregular treatmentof hypertension in the former Soviet Union.
Journal of Epidemiology and Community Health.
Forthcoming.
13. Roberts B, Gilmore A, Stickley A, Kizilova K,
Prohoda V, Rotman D, Haerpfer C, McKee M.
Prevalence and psychosocial determinants of
nicotine dependence in nine countries of theformer Soviet Union. Nicotine & Tobacco
Research. Forthcoming.
14. Roberts B, Stickley A, Gasparishvili A, Haerpfer
C, McKee M. Changes in household access towater in countries of the former Soviet Union.
Journal of Public Health. 2012 Aug; 34(3):352-9.
15. Hirayama F, Lee AH. Is caffeine intake associatedwith urinary incontinence in Japanese adults?
Journal of Preventive Medicine & Public Health.
2012 May; 45(3):204-8
16. Hosoda M, Inoue H, Miyazawa Y, Kusumi E,
Shibuya K. Vaccine-associated paralytic poliomyelitis in Japan. Lancet. 2012; 379(9815): 520.
(correspondence)
17. Ikeda N, Inoue M, Iso H, Ikeda S, Satoh T, Noda
M, Mizoue T, Imano H, Saito E, Katanoda K,
Sobue T, Tsugane S, Naghavi M, Ezzati M,
Shibuya K. Adult Mortality Attributable toPreventable Risk Factors for Non-Communicable
Diseases and Injuries in Japan: A Comparative
Risk Assessment.PLoS Medicine. 2012; 9(1):e1001160.
18. Hirayama F, Koyanagi A, Mori R, Zhang J, Souza
JP, Gülmezoglu AM. Prevalence and risk factors
for third- and fourth-degree perineal lacerations
during vaginal delivery: a multi-country study.
BJOG. 2012; 119(3): 340-347.
19. Zhang X, Shirayama Y, Zhang Y, Ba W, Ikeda N,
Mori R, Shibuya K. Duration of maternallyderived antibody against measles: A seroepidemiological study of infants aged under 8months in Qinghai, China.Vaccine. 2012; 17;30(4): 752-757.
20. Wariki WMV, Ota E, Mori R, Koyanagi A, Hori N,
Shibuya K. Behavioral interventions to reduce thetransmission of HIV infection among sex workers
and their clients in low- and middle-income
countries. Cochrane Database of Systematic
Reviews 2012, Issue 2. Art. No.: CD005272.
21. Yamamoto N, Mori R, Jacklin P, Osuga Y, Kawana
K, Shibuya K, Taketani Y. Introducing HPV
vaccine and scaling up screening procedures toprevent deaths from cervical cancer in Japan: A
cost-effectiveness analysis. BJOG. 2012; 119(2):177-186.

299

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 (19961999), Susumu Wakai (1999-2005), and Masamine
Jimba (2006-present).
The mission of the department is to seek equity
and social justice in health within and acrossnations. 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.
4. Our research focuses on how to activate
community-based activities and how a to linkbottom-up approach to national and international
policy. The department currently consists of: our
Department Chair and Professor, 3 AssistantProfessors, 10 Visiting Lecturers, 21 PhD course
students, 19 Master’s course students, 8 research

students, and 20 visiting researchers. About 40%of the students are international students.

International Cooperation
Activities
Among our international cooperation activities
at the global level was a human security project
conducted in collaboration with the Japan Center
for International Exchange (JCIE). Specifically, weorganized a seminar on Health and Human Security
at a side event for the third TICAD (Tokyo
International Conference on African Development)
Ministerial follow-up meeting held in Senegal in
May 2011.
In addition, we contributed todeveloping a WHO’s guideline on human resourcefor health and to conducting the Japan-World Bank
human resource for health research.
We also provided technical support to projects
run by the JICA and NGOs in Lao PDR (healthsystem research), Thailand (HIV/AIDS education
for labor unions), and Vietnam (safe water andbetter nutrition), and have conducted research incollaboration with the Cambodian government. In
addition, we have launched a research project onmaternal and child health in Ghana in collaboration
with JICA.

300

Teaching Activities

References

The main objective of our teaching activities isto train compassionate global health leaders. In
concrete terms, we aim:

1.

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.

2.

3.

4.

Our department has accepted students of various
backgrounds and disciplines: medical doctors,
nurses, co-medical workers, social scientists andothers. 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 and seminars are conducted in
English.

5.

Research activities

6.

The Department aims to contribute to policy
making and promoting actions for better health bymaking the best use of community-based research.
We carry out research by working in tandem withdifferent international organizations, NGOs, anduniversities in developing countries. The major
directions of current research have encompassed
primary health care, health promotion, school
health, health and human rights (including
migrants’ health), human security, conflict andhealth, injury prevention, HIV/AIDS, tuberculosis,
malaria, neglected tropical diseases, and nutrition
among others. Our research has been conducted invarious countries, including Nepal, Myanmar,
Thailand, Bangladesh, Viet Nam, Lao PDR,
Cambodia, Ghana, Tanzania, Kenya, Zambia,
Rwanda, and Peru.

7.

8.

9.

Lim S, Yasuoka J, Poudel KC, Ly P, Nguon C,
Jimba M. Promoting community kowledge andaction for malaria control in rural Cambodia:
potential contributions of Village Malaria
Workers. BMC Res Notes. in press.
Yamamoto TS, Sunguya BF, Shiao LW, Amiya
RM, Saw YM, Jimba M. Migration of HealthWorkers in the Pacific Islands: A Bottleneck to
Health Development. Asia Pac J Public Health.
in press.
Kikuchi K, Poudel KC, Muganda J, Majyambere
A, Otsuka K, Sato T, Mutabazi V, Nyonsenga SP,
Muhayimpundu R, Jimba M, Yasuoka J. Highrisk of ART non-adherence and delay of ART
initiation among HIV positive double orphans inKigali, Rwanda. PLos One. in press.
Yi S, Poudel KC, Yasuoka J, Palmer PH, Yi S,
Jimba M. Exposure to violence in relation todepressive symptoms among male and female
adolescent students in Cambodia. Soc Psychiatry
Psychiatr Epidemiol. in press.
Saito J, Yasuoka J, Poudel KC, Foung L,
Vilaysom S, Jimba M. Receptivity to Tobacco
Marketing and Susceptibility to Smoking among
Non-smoking Male Students in an Urban Setting
in Lao PDR. Tob. Control. in press.
Nonaka D, Jimba M, Mizoue T, Kobayashi J,
Yasuoka J, Ayi I, Jayatilleke AC, Shrestha S,
Kikuchi K, Haque SE, Yi S. Content Analysis ofPrimary and Secondary School Textbooks
Regarding Malaria Control: a Multi-Country
Study. PLoS ONE. in press.
Rahman M. Poudel KC, Yasuoka J, Otsuka K,
Yoshikawa K, Jimba. Maternal exposure to
intimate partner violence and the risk ofundernutrition among under-five children in
Bangladesh. Am J Public Health. in press.
Syed EH, Poudel KC, Sakisaka K, Yasuoka J,
Ahsan H, Jimba M. The quality of life and mental
health status of arsenic-affected patients in a
Bangladeshi population. Journal of Health,Population and Nutrition. in press.
Yi S, Poudel KC, Yasuoka J, Yanagisawa S,
Palmer PH, Yi S, Jimba M. Sibling-care
responsibility and depression among adolescent

301

10.

11.

12.

13.

14.

15.

16.

17.

caretakers in Cambodia. Int J Soc Psychiatry. inpress.
Son DT, Yasuoka J, Poudel KC, Otsuka K, Jimba
M. Massively multiplayer online role-playing
games (MMORPG): association between its
addiction, self-control and mental disorders
among young people in Vietnam. Int J Soc
Psychiatry. in press.
Yi S, Poudel KC, Yasuoka J, Palmer PH, Yi S,
Yanagisawa S, Jimba M. Sibling care, school
performance, and depression among adolescentcaretakers in Cambodia. Asian J Psychiatr. 2012
Jun;5(2):132-6.
Akiyama T, Win T, Maung C, Ray P, Kaji A,
Tanabe A, Jimba M, Kobayashi J. Making
schools healthy among Burmese migrants in
Thailand. Health Promot Int. 2012 Mar 20.
Yasuoka J, Poudel KC, Ly P, Nguon C, Socheat D,
Jimba M. Scale-up of community-based malaria
control can be achieved without degrading
community health workers' service quality: theVillage Malaria Worker project in Cambodia.
Malar J. 2012 Jan 4; 11: 4.
Kikuchi K, Wakasugi N, Poudel KC, Sakisaka K,
Jimba M. High rate of unintended pregnancies
after knowing of HIV infection among HIV
positive women under antiretroviral treatment inKigali, Rwanda. Biosci Trends. 2011 Dec; 5(6):255-63.
Sunguya BF, Poudel KC, Otsuka K, Yasuoka J,
Mlunde LB, Urassa DP, Mkopi NP, Jimba M.
Undernutrition among HIV-positive children in
Dar es Salaam, Tanzania: antiretroviral therapy
alone is not enough. BMC Public Health. 2011
Nov 16; 11: 869.
Naariyong S, Poudel KC, Rahman M, Yasuoka J,
Otsuka K, Jimba M. Quality of antenatal careservices in the Birim North District of Ghana:contribution of the community-based healthplanning and services program. Matern Child
Health J. 2011 Sep 14.
Amiya RM, Poudel KC, Poudel-Tandukar K,
Kobayashi J, Pandey BD, Jimba M. Physicians
are a key to encouraging cessation of smoking
among people living with HIV/AIDS: a crosssectional study in the Kathmandu Valley, Nepal.
BMC Public Health. 2011 Aug 31; 11: 677.

18. Poudel KC, Poudel-Tandukar K, Nakahara S,
Yasuoka J, Jimba M. Knowing the consequencesof unprotected sex with seroconcordant partner isassociated with increased safer sex intentions
among HIV-positive men in Kathmandu, Nepal. J
Health Popul Nutr. 2011 Jun; 29(3): 191-9.
19. Poudel KC, Fujita M, Green K, Poudel-Tandukar
K, Jimba M. Non-communicable diseases insoutheast Asia. Lancet. 2011 Jun 11; 377(9782):
2004-5.
20. Nomoto M, Nonaka D, Mizoue T, Kobayashi J,
Jimba M. Content analysis of school textbooks
on health topics: a systematic review. Biosci
Trends. 2011; 5(2): 61-8.
21. Okawa S, Yasuoka J, Ishikawa N, Poudel KC,
Ragi A, Jimba M. Perceived social support andthe psychological well-being of AIDS orphans inurban Kenya. AIDS Care. 2011 Sep; 23(9):1177-85.
22. Takahashi K, Nguyen TM, Poudel KC, Sakisaka
K, Jimba M, Yasuoka J. Social capital and life
satisfaction: a cross-sectional study on persons
with musculoskeletal impairments in Hanoi,
Vietnam. BMC Public Health. 2011 Apr 1; 11:206.
23. Jimba M, Hubbard S, Sase E, Suzuki T, Otsuka K.
Human Security Approaches for Disaster
Recovery and Resilience. Japan Medical
Association Journal. 2011; 54(5): 338-41.

International Health
2. International Biomedical Sciences

303

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
Minae Kawashima, 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, 15 graduate students, 2 research fellows,
and 8 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 and microsatellite analyses, as well as gene expression profiling,
to better understand the genetic background of avariety 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.

304

References
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Kornum BR, Kawashima M, Faraco J, Lin L,
Rico TJ, Hesselson S, Axtell RC, Kuipers H,
Weiner K, Hamacher A, Kassack MU, Han F,
Knudsen S,Li J, Dong X, Winkelmann J, Plazzi G,
Nevsimalova S, Hong SC, Honda Y, Honda M,
Högl B, Ton TG, Montplaisir J, Bourgin P,
Kemlink D, Huang YS, Warby S, Einen M,
Eshragh JL, Miyagawa T, Desautels A, Ruppert E,
Hesla PE, Poli F, Pizza F, Frauscher B, Jeong JH,
Lee SP, Strohl KP, Longstreth WT Jr, Kvale M,
Dobrovolna M, Ohayon MM, Nepom GT,
Wichmann HE, Rouleau GA, Gieger C, Levinson
DF, Gejman PV, Meitinger T, Peppard P, Young T,
Jennum P, Steinman L, Tokunaga K, Kwok PY,
Risch N, Hallmayer J, and Mignot E: Common
variants in P2RY11 are associated with
narcolepsy. Nat. Genet. 43(1): 66-71, 2011.
Hijikata M, Matsushita I, Tanaka G, Tsushiya T,
Ito H, Tokunaga K, Ohashi J, Honma S, Kobashi
Y, Taguchi Y, Azuma A, Kudoh S, and Keicho N:
Molecular cloning of two novel mucin-like genes
in the disease- susceptibility locus for diffuse
panbronchiolitis. Hum. Genet. 129(2): 117-128,
2011
Otowa T, Kawamura Y, Sugaya N, Yoshida E,
Shimada T, Liu X, Tochigi M, Umekage T,
Miyagawa T, Nishida N, Kaiya H, Okazaki Y,
Tokunaga K, and Sasaki T: Association study of
PDE4B with panic disorder in the Japanese
population. Prog. Neuropsychopharmacol. Biol.
Psychiatry 35(2): 545-549, 2011.
Kurosaki M, Tanaka Y, Nishida N, Sakamoto N,
Enomoto N, Honda M, Sugiyama M, Matsuura K,
Sugauchi F, Asahina Y, Nakagawa M, Watanabe
M, Sakamoto M, Maekawa S, Sakai A, Kaneko S,
Ito K, Masaki N, Tokunaga K, Izumi N,
Mizokami M: Pre-treatment prediction of
response to pegylated-interferon plus ribavirin forchronic hepatitis C using genetic polymorphismin IL28B and viral factors. J. Hepatol. 54(3):439-448, 2011.
Miyagawa T, Miyadera H, Tanaka S, Kawashima
M, Shimada M, Honda Y, Tokunaga K and Honda
M: Abnormally low serum acylcarnitine level innarcolepsy. Sleep 34(3): 349-353, 2011.

6.

Koike A, Nishida N, Yamashita D, and Tokunaga
K: Comparative analysis of copy number
variation detection methods and database
construction. BMC Genetics 12: 29, 2011 Mar[On line pub]
7. Sakamoto N, Nakagawa M, Tanaka Y,
Sekine-Osajima Y, Ueyama M, Kurosaki M,
Nishida N, Tamori A, Nishimura-Sakurai Y, Itsui
Y, Azuma S, Kakinuma S, Hige S, Ito Y, Tanaka
E, Hiasa Y, Izumi N, Tokunaga K, Mizokami M,
and Watanabe M: Association of IL28B
polymorphism with response pegylated-interferonalpha plus ribavirin combination therapy inpatients with chronic genotype 2 hepatitis C. J.
Med. Virol. 83(5): 871-878, 2011.
8. Okamoto K, Tokunaga K, Doi, K, Fujita T,
Suzuki H, Katoh T, Watanabe T, Nishida N,
Mabuchi A, Takahashi A, Kubo M, Maeda S,
Nakamura Y, and Noiri E: Common variation in
GPC5 is associated with acquired nephrotic
syndrome. Nat. Genet. 43(5): 459-463, 2011.
9. Kurotaki N, Tasaki S, Mishima H, Ono S,
Imamura A, Kikuchi T, Nishida N, Tokunaga K,
Yoshiura K, and Ozawa H: Identification of novel
schizophrenia loci by homozygosity mapping
using DNA microarray analysis. PLoS ONE 6(5):e20589, 2011.
10. Kurosaki M, Tanaka Y, Tanaka K, Suzuki Y,
Hoshioka Y, Tamaki N, Kato T, Yasui Y,
Hosokawa T, Ueda K, Tsuchiya K, Kuzuya T,
Nakanishi H, Itakura J, Takahashi Y, Asahina Y,
Matsuura K, Sugauchi F, Enomoto N, Nishida N,
Tokunaga K, Mizokami M, and Izumi N:
Relationship between polymorphisms of theinosine triphosphatase gene and anaemia or
outcome after treatment with pegylated interferon
and ribavirin. Antivir. Ther. 16(5): 685-694, 2011.
11. Tanaka Y, Kurosaki M, Nishida N, Sugiyama M,
Matsuura N, Sakamoto N, Enomoto N,
Yatsuhashi H, NIshiguchi S, Hino K, Hige S, Itoh
Y, Tanaka E, Mochida S, Honda M, Hiasa Y,
Koike A, Sugauchi F, Kaneko S, Izumi N,
Tokunaga K, and Mizokami M: Genome-wide
association study identified ITPA/DDRGK1
variants reflecting thrombocytopenia in pegylated
interferon and ribavirin therapy for chronic
hepatitis C. Hum. Mol. Genet. 20(17): 3507-3516,

305

2011.
12. Kobayashi K, Yuliwulandari R, Yanai H, Lien LT,
Hang NTL, Hijikata M, Keicho N, and Tokunaga
K: Association between CD209 and developmentof tuberculosis in Indonesian and Vietnamese
populations. Hum. Immunol. 72(9): 741-745,
2011.
13. Ogoshi K, Hashimoto SI, Nakatani Y, Qu W,
Oshima K, Tokunaga K, Sugano S, Hattori M,
Morishita S, and Matsushima K: Genome-wide
profiling of DNA methylation in human cancer
cells. Genomics 98(4): 280-287, 2011.
14. Kawamura Y, Otowa T, Koike A, Sugaya N,
Yoshida E, Yasuda S, Inoue K, Takei K, Konishi
Y, Tanii H, Shimada T, Tochigi M, Kakiuchi C,
Umekage T, Liu X, Nishida N, Tokunaga K,
Kuwano R, Okazaki Y, Kaiya H, and Sasaki T: A
genome-wide CNV association study on panic
disorder in a Japanese population. J. Hum. Genet.
56(12): 852-856, 2011.
15. Yang X, Xu S, The HUGO Pan-Asian SNP
Consortium, Indian Genome Variation Consortium: Identification of close relatives in the
HUGO Pan-Asian SNP database. PLoS ONE
6(12): e29502, 2011.

306

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 in experimental
and epidemiologic studies to provide the scientificbases for all the activities to promote the physical andmental health of mothers and children. The
experimental studies include those on the nervous andendocrine systems, infection, immunity and metabolism, whereas the epidemiologic studies deal with
development, mother-to-child relationship and healthpromotion. In 2007, joined by new members, thedepartment 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,
eleven visiting researchers, and fifteen graduate
students, including four 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.

References
1.

Research activities(1) Clinical, genetic and pathologic studies of acuteencephalopathy: Acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures
and late reduced diffusion, and acute encephalitis
with refractory, repetitive partial seizures.
(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) Functional imaging of higher cerebral functions
and their alteration in developmental disorders
using photospectroscopy.
(8) Studies on the virulence and drug resistance ofherpesviruses and poxviruses.
(9) Molecular epidemiology of pediatric viral
infections, in particular gastrointestinal diseases(rotavirus, norovirus, sapovirus and bocavirus) ,respiratory infections (influenza, RS virus andrhinovirus), exanthematous diseases (rubella) andHIV infection.

2.

3.

4.

5.

6.

7.

8.

Chan-It W, Thongprachum A, Dey SK, Phan TG,
Khamrin P, Okitsu S, Nishimura S, Kobayashi M,
Kikuta H, Baba T, Yamamoto A, Sugita K,
Hashira S, Tajima T, Ishida S, Mizuguchi M,
Ushijima
H.
Detection
andgenetic
characterization of rotavirus infections in nonhospitalized children with acute gastroenteritis
in Japan, 2007-2009. Infection and Genetic
Evolution 2011; 11(2): 415-422.
Chan-It W, Thongprachum A, Okitsu S,
Nishimura S, Kikuta H, Baba T, Yamamoto A,
Sugita K, Hashira S, Tajima T, Mizuguchi M,
Ushijima H. Detection and genetic characterization of norovirus infections in children withacute gastroenteritis in Japan, 2007-2009.
Clinical Laboratory 2011; 57(3-4): 213-220.
Dey SK, Mizuguchi M, Okitsu S, Ushijima H.
Novel recombinant sapovirus in Bangladesh.
Clinical Laboratory 2011; 57(1-2): 91-94.
Dey SK, Phan TG, Mizuguchi M, Okitsu S,
Ushijima H. Genetic diversity and emergence of
norovirus GII/4-2006b in Japan during 20062007. Clinical Laboratory 2011; 57(3-4): 193199.
Khamrin P, Okame M, Thongprachum A,
Nantachit N, Nishimura S, Okitsu S,
Maneekarn N, Ushijima H. A single-tube
multiplex PCR for rapid detection in feces of
10 viruses causing diarrhea. Journal of
Virological Methods. 2011; 173(2): 390-393.
Khamrin P, Tran DN, Chan-It W,
Thongprachum A, Okitsu S, Maneekarn N,
Ushijima H. Comparison of the Rapid
Methods for Screening of Group A Rotavirus
in Stool Samples. Journal of Tropical
Pediatrics. 2011; 57(5): 375-377.
Kohno S, Kida H, Mizuguchi M, Hirotsu N,
Ishida T, Kadota J, Shimada J; S-021812
Clinical Study Group. Intravenous peramivir fortreatment of influenza A and B infection in
high-risk patients. Antimicrobial Agents andChemotherapy 2011; 55(6): 2803-2812.
Kohno S, Yen MY, Cheong HJ, Hirotsu N, Ishida
T, Kadota JI, Mizuguchi M, Kida H, Shimada J;
for the S-021812 Clinical Study Group. Phase III

308

9.

10.

11.

12.

13.

14.

15.

randomized, double-blind study comparing
single-dose intravenous peramivir with oral
oseltamivir in patients with seasonal influenza
virus infection. Antimicrobial Agents andChemotherapy 2011; 55(11): 5267-5276.
Kumakura A, Iida C, Saito M, Mizuguchi M,
Hata D. Pandemic influenza A-associated acutenecrotizing
encephalopathy
without
neurological sequelae. Pediatric Neurology
2011; 45 (5): 344-346.
Mizuno Y, Takahashi K, Igarashi T, Saito M,
Mizuguchi
M.
Congenital
infection-like
syndrome with intracranial calcification. Brainand Development (Tokyo) 2011; 33(6): 530-533.
Pham NT, Trinh QD, Chan-It W, Khamrin P,
Nishimura S, Sugita K, Maneekarn N, Okitsu S,
Mizuguchi M, Ushijima H. Human bocavirus
infection in children with acute gastroenteritis inJapan and Thailand. Journal of Medical Virology
2011; 83(2): 286-290.
Pham NT, Chan-It W, Khamrin P, Nishimura S,
Kikuta H, Sugita K, Baba T, Yamamoto A,
Shimizu H, Okitsu S, Mizuguchi M, Ushijima H.
Detection of human parechovirus in stool
samples collected from children with acutegastro- enteritis in Japan during 2007-2008.
Journal of Medical Virology 2011; 83(2): 331336.
Shinohara M, Saitoh M, Takanashi JI,
Yamanouchi H, Kubota M, Goto T, Kikuchi M,
Shiihara T, Yamanaka G, Mizuguchi M.
Carnitine palmitoyl transferase II polymorphism
is associated with multiple syndromes of acuteencephalopathy with various infectious diseases.
Brain and Development (Tokyo) 2011; 33(6):512-517.
Shiota T, Lixin W, Takayama-Ito M, Iizuka I,
Ogata M, Tsuji M, Nishimura H, Taniguchi S,
Morikawa S, Kurane I, Mizuguchi M, Saijo M.
Expression of herpes simplex virus type 1
recombinant thymidine kinase and its application to a rapid antiviral sensitivity assay.
Antiviral Research 2011; 91(2): 142-149.
Takahashi K, Oka A, Mizuguchi M, Saitoh M,
Takita J, Sato A, Mimaki M, Kato M, Ogawa S,
Igarashi T. Interstitial deletion of 13q14.13q32.3 presenting with Arima syndrome and

16.

17.

bilateral retinoblastoma. Brain and Development(Tokyo) 2011; 33(4): 353-356.
Takahashi K, Oka A, Mizuguchi M, Saitoh M,
Takita J, Sato A, Mimaki M, Kato M, Ogawa S,
Igarashi T. I Reply to the letter: “Arima
syndrome and bilateral retino- blastoma ininterstitial deletion of 13q14.13–q32.3”: Whereis the molar tooth sign? Brain and Development (Tokyo) 2011: 33(5): 445-447.
Tran DN, Vu MP, Ha MT, Giang TP, Komase K,
Mizuguchi M, Ushijima H. Viral molecularcharacterization of the first congenital rubella
syndrome case in Vietnam. Clinical Laboratory2011; 57(5-6): 397-401.

309

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.
Kiyoshi TADOKORO, Ph.D (Project Research Associate; Global 30)

Homepage http://www.humeco.m.u-tokyo.ac.jp/index-e.html
Introduction and Organization
We had five research/teaching faculties in FY2011,
including one working for the “Global30” program,taught in English. Apart from the faculty staffs, twosecretaries, four doctoral candidates (two foreign
students), seven master course students (including
four foreign students), one post-doctoral fellow andthree research fellows are working in the department.
There are ten extra-university lecturers delivering
lectures in either graduate or undergraduate course.
Prof. Watanabe holds the additional post in theTransdisciplinary Initiative for Global Sustainability(TIGS) as well as in the Earth Observation Data
Integration &Fusion Research Initiative (EDITORIA).

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 Integrated Health
Sciences, providing the lectures on “Human Ecology”,“Environmental Health”, “Demo-graphy”, “International Health”, and “Medical Anthropology”. We
were also responsible for organizing “Pharmacology
and Toxicology”, “Physiology”, “Anatomy”, as wellas “Environmental Engineering/ Human Engineering”.
At the undergraduate 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 Atlantic College (Maine, USA), where theentire school are devoted for interdisciplinary Human
Ecology program with a high proportion of foreign
students, giving brief lectures and exchanged information regarding recruitment of students, establishing
the curriculum, and operating interactive classes.

310

Research activities
Human ecology is literally the understanding of
human population in the context of their respective
ecology as well as in the global context. Most of ourresearches tackle the tasks that have been dealt in thefield of “Environmental Health” and/or “Population
ecology [of human]”, but with more comprehensive
and broader context. Therefore, we need to adopt
different approaches including fieldwork, experiment,
as well as GIS/GPS analyses. Our study fields include
Asian-Oceanian (including Japan) rural as well urban
communities, focusing on population, nutrition,
growth, and environment and sustainability.
Experimental studies focusing on the effects ofperinatal exposures to heavy metals have been
conducted, emphasizing the factors that modify theeffects. We also have jointed a MEXT-funding
program in which so called “earth-observation data”
will be used to solve health-related issues. Almost all
the studies require “transdisciplinary” approach, hence,
we are collaborating with various domestic andoverseas research institutes. What follows is a list ofmajor activities conducted in the past year.
1. Identification of critical factors that determine
regional sustainability in Asian urban and ruralcommunities:
In West Java, Indonesia, we did field survey tocollect basic information of rural subsistence such as
physical activity and time-allocation of behaviors,
food consumption, which are to be compared with thecollected data with similar data collected in either
several years or 30 years back, we may reconstitutethe past change in the lifestyle in this area, whichshould be related with the changes in lifestyle-relateddisease risks. In addition, we have analyzed urinary
phthalate esters and collected hair samples in terms of
isotopic distribution of several major elements.
In a suburb area close to Bangkok, Thailand, wherewater-reclaiming system will be introduced for nondrinking purposes, we have been conducting survey todevelop an appropriate method/protocol for health risk
assessment.
2. Environmental contamination by metals andmetalloids in South Asia and susceptibility factors

In a suburb of Dhaka, capitol of Bangladesh,
exposure to lead (Pb) among the school children was
evaluated, and Pb toxicity was examined by the effectof delta-aminolevulinic acid dehydratase genotype
associating with urinary ALA on blood Pb level.
Gender-associated differences in Pb exposure and in
genetic susceptibility were identified in lead exposed
Bangladeshi children..
In arsenic (As)-contaminated area in Bangladesh,effects of gender and genetic polymorphism on the
methylation pattern of ingested As were examined.
Several polymorphisms were identified as influencing
on the methylation, some of which being dependent
on gender (gender-specific). Since the methylation
patterns are known to be associated with the toxicityof As, the observed effects of gender andpolymophism were worth to pursue.
Another project has been started in thecontaminated area in Bangladesh, where the effect ofperinatal exposure to As are examined with respect tothe early immune system development. Now thepregnant mothers have been recruited at several
clinics located outside Dhaka.
3. Subsistence transition and adaptation:
In many Asian and Oceania countries, various typesof developmental projects have been undertaken
aiming at economic development, procurement of
natural resources, or accelerating tourism. Attempts todescribe such changes from the viewpoint of political
ecology were made in China as well as Papua New
Guinea.
4. Role of selenium in a population highly exposed
to methylmercury through fish consumption:
Relatively high concentration of methylmercury(MeHg) can be found in some predator fish species
through food chain, and health risks associated withexcessive consumption of such seafood items havebeen debated long time. On the other hand, fish isvery important source of some nutrients including
protein, polyunsaturated fatty acids, and minerals, andsome of these nutrients might interfere with MeHg
toxicity. Thus, net risk/benefit of eating fish are notimmediately clear. We examined the nutritional statusof selenium, a micronutrient for which fish provide
substantial amount.

311

5. Adaptability to low protein diet
In Papua New Guinea, some populations are fed on
low protein diets like sweet potatoes, whereas they do
not appear to be protein deficient. Hypothesizing that
this observation would be associated with a specificcomposition of gut flora in these populations, fieldstudies and experimental studies are now ongoing.
6. Prediction and adaptation measures for healthrisks due to climate change and/or air pollution:
Concerns are growing over the potential healtheffects of climate change, especially global warming,
as well as of air pollution, especially long-range
pollution that could occur beyond national borders.
In collaboration with the Atmosphere and Ocean
Research Institute as well as National Institute ofEnvironmental Studies, we are trying to develop ahealth risk map in a small-scale range like Kanto
plane, taking advantage of the climate prediction
models using assimilation technique. During this year,
basic information about the relationship between
temperature, air pollutants and various health effects
has been collected, which will be fed into this climate
model.
7. Evaluation and Alleviation of Environmental
Burden due to Subsistence Transition in AsiaPacific –Elucidation of Health Impact:
Most communities in Asia-Pacific undergo a very
rapid transition from traditional subsistence to casheconomy agriculture. Such transition entails
introduction chemical substances, such as pesticides
and food additives, into the local ecosystem. Choosing
six regions that represent diversified environments in
Asia-Pacific, we examined the potential effects of theintroduction of chemicals.
8. Neuro-developmental effects of environmental
chemicals:
Effects of metallic mercury combined with methylmercury were examined in an experimental study withmice.

References
1. Yoshinaga J, Takagi M, Yamasaki K, Tamiya S,
Watanabe C, Kaji M. Blood lead levels ofcontemporary Japanese children. Environ HealthPrev Med. 17, 27-33 (2012)
2. Yoshida M., Suzuki M, Satoh M, Yasutake A and
Watanabe C. Neurobehavioral effects of combined
prenatal exposure to low-level mercury vapor andmethylmercury. Journal of Toxicological Sciences,36(1), 73-80, 2011
3. Yoshida M, Honda M, Watanabe C, Satoh M,
Yasutake A. Neurobehavioral changes andalteration of gene expression in the brains ofmetallothionein-I/II null mice exposed to lowlevels of mercury vapor during postnatal development. J Toxicol Sci. 2011 Oct;36(5):539-47
4. Niwa, M, Suzuki, Y., Yoshinaga, J., Watanabe, C.,
Mizumoto, Y. Prenatal exposure to polycyclicaromatic hydrocarbons and birth outcomes.
Polycyclic Aromatic Coumpounds 31, 16-27, 2011.
5. Konishi S, Watanabe C, Umezaki M., and Ohtsuka
R. (2011) Energy and Nutrient Intake of Tongan
Adults Estimated by 24-Hour Recall: The
Importance of Local Food Items. Ecology of Foodand Nutrition, 50: 337-350.
6. Konishi S, Parajuli RP, Takane E, Maharjan M,
Sharma S, Tachibana K, Jiang HW, Pahari K,
Pandey BD, and Watanabe C. Health status ofmarried women residing five communities in
Nepal: Unexpectedly high prevalence of anemia ina well-off community of Kathmandu. Nepal
Medical College Journal 13, 1-16 (2011)
7. Lee JS, Kondo K, Kawakubo K, Kataoka Y, MoriK, Umezaki M, Yamauchi T, Asami Y, Takagi H,
Akabayashi A. (2011) Neighborhood environment
associated with daily physical activity measured
both objectively and subjectively among residents
in a community in Japan. Japanese Journal of
Health and Human Ecology, 77: 94-107.
8. Parajuli RP, Fujiwara T, Umezaki M, Furusawa H,
Ser PH, and Watanabe C. (in press). Cord Blood
Levels of Toxic and Essential Trace Elements andtheir Determinants in the Terai Region of Nepal: A
Birth Cohort Study. Biological Trace Element
Research, 147: 75-83.

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9. Okubo, S., Dendi Muhamad P., Harashina, K.,
Takeuchi, K., and Umezaki, M. Land use/coverclassification of a complex agricultural landscapeusing single-dated very high spatial resolution
satellite-sensed imagery. Canadian Journal of
Remote Sensing (in press)

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Department of
Biomedical Chemistry
Professor
Kiyoshi Kita, Ph.D.

Associate Professor
Yoh-ichi Watanabe, Ph.D.

Associate
Motomichi Matsuzaki, Ph.D.,

Homepage

Daniel Inaoka Ken, 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.

2.

3.

4.

5.

Concatenated mitochondrial DNA of thecoccidian parasite Eimeria tenella. Hikosaka, K.,
Nakai, Y., Watanabe, Y., Tachibana, S., Arisue,N., Palacpac, N. M., Toyama, T., Honma, H.,
Horii, T., Kita, K. and Tanabe, K. (2011)
Mitochondrion, 11, 273-278
A conserved lysine residue in the crenarchaeaspecific loop is important for the crenarchaeal
splicing endonuclease activity. Okuda, M., Shiba,T., Inaoka, D. K., Kita, K., Kurisu, G., Mineki, S.,
Harada, S., Watanabe, Y. and Yoshinari, S.
(2011) J. Mol. Biol. 405, 92-104
Differential Kinetic Activities of Glycerol Kinase
among
African
Trypanosome
Species:Phylogenetic and Therapeutic Implications.
Ohashi-Suzuki, M., Yabu, Y., Ohshim, S.,
Nakamura, K., Kido, Y., Sakamoto, K., Kita, K.,
Ohta, N. and Suzuki, T. (2011) J. Vet. Med. Sci.
73, 615-621
Isolation and Caenorhabditis elegans lifespanassay of flavonoids from onion. Xue YL, Ahiko T,
Miyakawa T, Amino H, Hu F, Furihata K, Kita K,
Shirasawa T, Sawano Y. and Tanokura M. (2011)
J. Agric. Food Chem. 59, 5927-5934
Ukulactones A and B, new NADH-fumarate
reductase inhibitors produced by Penicillium sp.
FKI-3389. Mori, M., Morimoto, H., Kim, Y-P.,
Ui, H., Nonaka, K., Masuma, R., Sakamoto, S.,
Kita, K., Tomoda, H., Shiomi, K. and Ōmura, S.

6.

7.

(2011) Tetrahedron, 67, 6582-6586
Highly conserved gene arrangement of themitochondrial genomes of 23 Plasmodium
species. Hikosaka, K., Watanabe, Y., Kobayashi,F., Waki, S., Kita, K. and Tanabe, K. (2011)
Parasitol. Int. 60, 175-180
Identification of an entire set of tRNA moleculesand characterization of cleavage sites of theintron-containing tRNA precursors in acidothermophilic crenarchaeon Sulfolobus tokodaii
strain 7. Yamazaki, S., Yoshinari, S., Kita, K.,
Watanabe, Y. and Kawarabayasi, Y. (2011) Gene,
489, 103-110

School of Public Health
1. Epidemiology and Health Sciences

316

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 not only provides research methodology in the field of public health but also is considereda practical study for public health and thus a central
field of health science. However, both education andresearch 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, which isessential 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 inJapan.
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 publichealth activities and tasks based on theory of
epidemiology.
We have also several lectures for students in otherschools.

Research activities
Our main topic is basic research for development andapplication of research methodology in the field of
nutritional epidemiology. Based on this basic research,
we also conduct a wide range of epidemiologic
research for investigating the relationship of nutrition
with health and disease. As a characteristic of this317

research field, we conduct many multi-center studies
with various kinds of disease.
Another characteristic is collection of researchfindings (scientific papers) derived from epidemiologic research all over the world on the association ofnutrition with health and disease, which is applied for
health control through nutrition improvement anddisease control.

8.

References
9.
1.

2.

3.

4.

5.

6.

7.

Okubo H, Miyake Y, Sasaki S, Tanaka K,
Murakami K, Hirota Y, Osaka Maternal and Child
Health Study Group. Nutritional adequacy of three
dietary patterns defined by cluster analysis in 997
pregnant Japanese women: the Osaka Maternal andChild Health Study Public Health Nutr 2011; 14(4):611-21.
Murakami K, Sasaki S, Takahashi Y, Uenishi K, theJapan Dietetic Students' Study for Nutrition andBiomarkers Group. Neighborhood restaurant
availability and frequency of eating out in relation
to dietary intake in young Japanese women. J Nutr
Sci Vitaminol 2011; 57(1): 87-94.
Kimura Y, Nanri A, Matsushita Y, Sasaki S, Mizoue
T. Eating behavior in relation to prevalence ofoverweight among Japanese men. Asia Pac J Clin
Nutr 2011; 20(1): 29-34.
Miyake Y, Kiyohara C, Koyanagi M, Fujimoto T,
Shirasawa S, Tanaka K, Sasaki S, Hirota Y.
Case-control study of eczema associated with IL13
genetic polymorphisms in Japanese children. Int
Arch Allergy Immunol 2011; 154(4): 328-35.
Okubo H, Miyake Y, Sasaki S, Tanaka K,
Murakami K, Hirota Y; the Osaka Maternal andChild Health Study Group. Dietary patterns during
pregnancy and the risk of postpartum depression in
Japan: the Osaka Maternal and Child Health Study.
Br J Nutr. 2011; 105(8): 1251-7.
Miyake Y, Sasaki S, Tanaka K, Hirota Y. Maternal
B vitamin intake during pregnancy and wheeze andeczema in Japanese infants aged 16-24 months: The
Osaka Maternal and Child Health Study. Pediatr
Allergy Immunol 2011; 22(1-Part-I): 69-74.
Sato-Mito N, Shibata S, Sasaki S, Sato K. Dietaryintake is associated with human chronotype as
assessed by both morningness-eveningness score

10.

11.

12.

13.

14.

and preferred midpoint of sleep in young Japanesewomen. Int J Food Sci Nutr 2011; 62(5): 525-32.
Miyake Y, Tanaka K, Fukushima W, Sasaki S,
Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki T,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M; Fukuoka Kinki Parkinson's Disease Study
Group. Lack of association of dairy food, calcium,and vitamin D intake with the risk of Parkinson's
disease: A case-control study in Japan.
Parkinsonism Relat Disord 2011; 17: 112-6.
Kobayashi S, Murakami K, Sasaki S, Okubo H,
Hirota N, Notsu A, Fukui M, Date C. Comparisonof relative validity of food group intakes estimatedby comprehensive and brief-type self-administered
diet history questionnaires against 16 d dietary
records in Japanese adults. Public Health Nutr
2011; 14: 1200-11.
Murakami K, Miyake Y, Sasaki S, Tanaka K,
Arakawa M. Dietary glycemic index and glycemic
load in relation to risk of overweight in Japanesechildren and adolescents: the Ryukyus Child HealthStudy. Int J Obes 2011; 35(7): 925-36.
Okubo H, Sasaki S, Murakami K, Takahashi Y, andthe Freshmen in Dietetic Courses Study II group. A
ratio of fish to meat intake is positively associatedwith favorable intake of food groups and nutrientsamong young Japanese women: the Freshmen in
Dietetic Courses Study II. Nutr Res 2011; 31(3):169-77.
Tsuji T, Fukuwatari T, Sasaki S, Shibata K.
Twenty-four-hour urinary water-soluble vitaminlevels correlate with their intakes in free-living
Japanese schoolchildren. Public Health Nutr 2011;14(2): 327-33.
Tanaka K, Miyake Y, Fukushima W, Sasaki S,
Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki T,
Kawamura N, Sakae N, Fukuyama H, Yoshio
Hirotab, Nagai M, the Fukuoka Kinki Parkinson's
Disease Study Group. Intake of Japanese andChinese teas reduces risk of Parkinson's disease.
Parkinsonism Relat Disord 2011; 17: 446-50.
Sato-Mito N, Sasaki S, Murakami K, Okubo H,
Takahashi Y, Shibata S, Yamada K, Sato K, theFreshmen in Dietetic Courses Study II group. The
midpoint of sleep is associated with dietary intake
and dietary behavior among young Japanesewomen. Sleep Med 2011; 12: 289-94.

318

15. Miyake Y, Tanaka K, Sasaki S, Hirota Y. Employment, income, and education and risk of postpartum
depression: The Osaka Maternal and Child HealthStudy. J Affect Disord 2011; 130(1-2): 133-7.
16. Okuda M, Sasaki S, Kunitsugu I, Sakurai R,
Yoshitake N, Hobara T. Iron load and liver enzymes
in 10- and 13-year-olds. J Pediatr Gastroenterol
Nutr 2011; 52(3): 333-8.
17. Okuda M, Hinoda Y, Okayama N, Suehiro Y,
Shirabe K, Sasaki S, Kunitsugu I, Yoshitake N,
Hobara T. Association between the FTO gene andoverweight in Japanese children and adolescents.
Pediatr Diabetes 2011; 12(5): 494-500.
18. Miyake Y, Okubo H, Sasaki S, Tanaka K, Hirota Y.
Maternal dietary patterns during pregnancy and riskof wheeze and eczema in Japanese infants aged
16-24 months:The Osaka Maternal and Child
Health Study. Pediatric Allergy and Immunology
2011; 22: 734-41.
19. Adachi H , Hirai Y, Sasaki S, Enomoto M, Fukami
A,Kumagai E, Esaki E, Imaizumi T. Trends in
Dietary Intakes and Serum Cholesterol Levels over
50 Years in Tanushimaru in Japanese Men. FNS
paper R-1 2011; 2(5): 476-81.
20. Miyake Y, Tanaka K, Fukushima W, Sasaki S,
Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki T,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M; Fukuoka Kinki Parkinson's Disease Study
Group. Dietary intake of metals and risk of
Parkinson's disease: A case-control study in Japan. J
Neurol Sci 2011; 306: 98-102.
21. Miyake Y, Tanaka K, Sasaki S, Arakawa M.
Polyunsaturated fatty acid intake and prevalence ofeczema and rhinoconjunctivitis in Japanesechildren: The Ryukyus Child Health Study BMC
Public Health. 2011; 11(1): 358.
22. Kiyohara C, Miyake Y, Koyanagi M, Fujimoto T,
Shirasawa S, Tanaka K, Fukushima W, Sasaki S,
Tsuboi Y, Yamada T, Oeda T, Shimada H,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M, Study Group FK. Genetic polymorphisms
involved in dopaminergic neurotransmission andrisk for Parkinson's disease in a Japanese population.
BMC Neurol 2011; 11(1): 89.
23. Tanaka K, Miyake Y, Arakawa M, Sasaki S, Ohya Y.
U-shaped association between body mass index andthe prevalence of wheeze and asthma, but not

24.

25.

26.

27.

28.

eczema or rhinoconjunctivitis: the Ryukyus Child
Health Study. J Asthma 2011; 48(8): 804-10.
Kiyohara C, Miyake Y, Koyanagi M, Fujimoto T,
Shirasawa S, Tanaka K, Fukushima W, Sasaki S,
Tsuboi Y, Yamada T, Oeda T, Miki T, Kawamura N,
Sakae N, Fukuyama H, Hirota Y, Nagai M. APOE
and CYP2E1 polymorphisms, alcohol consumption,
and Parkinson's disease in a Japanese population. J
Neural Transm 2011; 118(9): 1335-44.
Sasaki S. The value of the National Health andNutrition Survey in Japan. Lancet 2011; 378(9798):
1205-6.
Tanaka K, Miyake Y, Fukushima W, Sasaki S,
Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki T,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M; the Fukuoka Kinki Parkinson's Disease
Study Group. Occupational risk factors for
Parkinson's disease: a case-control study in Japan.
BMC Neurol 2011; 11(1): 83.
Ito S, Ishida H, Uenishi K, Murakami K, Sasaki S.
The relationship between habitual dietaryphosphorus and calcium intake, and bone mineraldensity in young Japanese women: a cross-sectional
study. Asia Pac J Clin Nutr 2011; 20(3): 411-7.
Miyake Y, Tanaka K, Yasutake A, Sasaki S, Hirota
Y. Lack of association of mercury with risk ofwheeze and eczema in Japanese children: the Osaka
Maternal and Child Health Study. Environ Res
2011; 111(8): 1180-4.

319

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 and Epidemiology Research is a new department established sinceApril 2007, as a part of Master of Public Health(MPH) program under the new School of Public
Health (SPH). The Department is also affiliated with
the Division of Social Medicine for doctoral education.
The mission of the Department is two folds; to help
health professionals obtain scientifically sound basis
and skills for evidence-based practice, and toempirically evaluate the health care system/policy forfurther improvement of the quality of health care inthis country. For this purpose, the Department puts aunique emphasis on quantitative analytic methods andinter-disciplinary theories across economics, epidemiology, and other social sciences.

and hospital management. In the applied course, thestudents are required to build a research hypothesis,
design a study, and prepare an own study protocol forfund proposal. The lecture course on health economics
provides an overview of health care systems in thiscountry and a systematic review on basic microeconomic theories and cost-effectiveness analysis. The
applied course offers students an opportunity forhands-on training of actual cost-effectiveness analysisof health care and technologies.
Health economics course provides an intermediatelevel of micro-economics and health economics
theories of consumer choice, insurance, and humancapital, and enhances discussion to apply these
theories to behaviors of providers and consumers.
The Department accepted five doctoral students and 3
master students for the fiscal years of 2011.

Teaching activities

Research 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 causal inference. Then, the course requires
participating students to apply provided knowledge toempirical examples such as evaluation of effectivenessof screening tests, pharmaceutical cost-effective
analysis, technology assessment of surgical treatment,

Current activities in this Department cover a broad
range of health services research, including clinicalepidemiological studies, economic evaluation ofhealth technology and health policy, quality of life
research, hospital administration and quality assurance,and social epidemiology research.
Consultation for design, data collection, and statisticalanalysis is provided for several clinical studies,mainly in cardiovascular arena. Several questionnaire
tools for evaluating patient’s quality of life have beendeveloped and validated in the area of colon and320

orthopedic surgery. In the collaboration with the
Department of Health Management and Policy in the
22nd Medical Research Center in the University ofTokyo Hospital, the Department also contributes toclinical and health service research using a large claim
database based on the Japanese original patientclassification system, Diagnosis Procedure Combination (DPC). DPC database allows a unique anddetailed analysis on the process of care in acute care
hospitals in this country. DPC database also provides
resource diagnosis in hospital levels as well as
regional levels, when combined with other public data
sources such as the Patient Survey, and Hospital
Census. Socioeconomic status affects people’s health,which is another research focus in this Department.
The association between income distribution andregional health status are widely acknowledged acrosscountries including this country, yet the mechanism isstill a matter of debate. The Department hascontributed to an ongoing research of socioeconomic
status and health among elderly population in thecollaboration with the School of Economics of the
University of Tokyo and the Research Institute of
Economic, Industry, and Technology (Japanese Studyof Ageing and Retirement; J-STAR). Since 2010, theDepartment has launched another panel study ofyounger generation, the Japanese study ofStratification, Health, Income, and Neighborhood(J-SHINE) in collaboration with researcher groups on
neuroscience, economics, sociology, and social
psychology. The aim of this new panel-to-be study is
to identify a mechanism that socio-economic
environment get to “under-skin” to cause social
gradient of health across socio-economic positions.
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. The Department joined this year a project
to review the performance of Japanese healthcare
system as a whole with the Department of Global
Health Policy in the School of International Health.

2.

3.

4.

5.

6.

7.

8.

References
1.

Sakurai K, Kawakami N, Yamaoka K, Ishikawa
H, Hashimoto H. The impact of subjective andobjective social status on psychological distressamong men and women in Japan. Social Scienceand Medicine. 70(11):1832-9 ,2010.
Jono S, Otsuki S, Higashikuni Y, Shioi A, Mori K,
Hara K, Hashimoto H, Ikari Y. Serum
osteoprotegerin levels and long-term prognosis insubjects with stable coronary artery disease.
Journal of Thrombosis and Haemostasis. 8(6):1170-5, 2010.
Kadono Y, Yasunaga H, Horiguchi H, Hashimoto
H, Matsuda S, Tanaka S, Nakamura K. Statistics
for orthopedic surgery 2006-2007: data from theJapanese diagnosis procedure combination
database. Journal of Orthopaedic Science. 15(2):162-70, 2010.
Tomiyama H, Hashimoto H, Tanaka H,
Matsumoto C, Odaira M, Yamada J, Yoshida M,
Shiina K, Nagata M, Yamashina A. Continuous
smoking and progression of arterial stiffening: aprospective study. Journal of American College
of Cardiology. 55(18):1979-87, 2010.
Tomiyama H, Hashimoto H, Tanaka H,
Matsumoto C, Odaira M, Yamada J, Yoshida M,
Shiina K, Nagata M, Yamashina A;
baPWV/cfPWV Collaboration Group. Synergistic
relationship between changes in the pulse wave
velocity and changes in the heart rate in
middle-aged Japanese adults: a prospective study.
Journal of Hypertension. 28(4):687-94, 2010.
Hashimoto H, Shiokawa H, Funahashi K, Saito N,
Sawada T, Shirouzu K, Yamada K, Sugihara K,
Watanabe T, Sugita A, Tsunoda A, Yamaguchi S,
Teramoto T. Development and validation of amodified fecal incontinence quality of life scale
for Japanese patients after intersphinctericresection for very low rectal cancer. Journal of
Gastroenterology. 45(9):928-35, 2010.
Nishiura C, Hashimoto H. A 4-year study of theassociation between short sleep duration andchange in body mass index in Japanese maleworkers. Journal of Epidemiology. 20(5):385-90,
2010.
Nishiura C, Noguchi J, Hashimoto H. Dietary
patterns only partially explain the effect of shortsleep duration on the incidence of obesity. Sleep.
33(6):753-7, 2010.

321

9.

10.

11.

12.

13.

14.

15.

Inoue A, Kawakami N, Tsuchiya M, Sakurai K,
Hashimoto H. Association of occupation,
employment contract, and company size withmental health in a national representative sampleof employees in Japan. Journal of Occupational
Health. 52(4):227-40, 2010.
Matsui H, Hashimoto H, Horiguchi H, Yasunaga
H, Matsuda S. An exploration of the association
between very early rehabilitation and outcome
for the patients with acute ischaemic stroke inJapan: a nationwide retrospective cohort survey.
BMC Health Service Research. 10:213, 2010.
doi:10.1186/1472-6963-10-213.
Horiguchi H, Yasunaga H, Hashimoto H,
Matsuda S. Impact of drug-eluting stents ontreatment option mix for coronary artery diseasein Japan. Circulation Journal. 74(8):1635-43,
2010.
Yasunaga H, Yanaihara H, Fuji K, Horiguchi H,
Hashimoto H, Matsuda S. Impact of hospital
volume on postoperative complications and inhospital mortality after renal surgery: data fromthe Japanese Diagnosis Procedure Combination
Database. Urology. 76(3):548-52, 2010.
Tomiyama H, Tanaka H, Hashimoto H,
Matsumoto C, Odaira M, Yamada J, Yoshida M,
Shiina K, Nagata M, Yamashina A. Arterial
stiffness and declines in individuals with normal
renal function/early chronic kidney disease.
Atherosclerosis. 212(1):345-50, 2010.
Miyata H, Hashimoto H, Horiguchi H, Fushimi K,
Matsuda S. Assessment of hospital performancewith a case-mix standardized mortality modelusing an existing administrative database inJapan. BMC Health Service Research. 19;10:130,
2010.
Hashimoto H, Horiguchi H, Matsuda S. Microdata analysis of medical and long-term careutilization among the elderly in Japan. International Journal of Environmental Research andPublic Health. 7(8):3022-37, 2010.

322

Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Hirono Ishikawa, Ph.D.

Homepage

http://www.umin.ac.jp/hc/

Introduction and Organization
The Department of Health Communication wasestablished as a part of the newly developed School of
Public Health (professional graduate school) in April
2007, which was derived from the University Hospital
Medical Information Network (UMIN) Center. It
consists of two faculty members: a professor and an
associate professor.
Whereas health communication is a major disciplinein the USA and there are many such graduate
programs, our department offers one of the only two
health communication programs in Japan. However,
the importance of the health communication discipline
has gradually been recognized among the academic
society as well as among general public.

Teaching Activities
The Department of Health Communication, within the
School of Public Health, is a newly developed
professional graduate program that aims to foster thedevelopment of medical and public healthprofessionals as well as researchers. We strive to
make the most of our professional activities andexperience at UMIN Center. We provide lectures andpractical instruction in the program. The following is
the current curriculum:[Health Communication Lectures]
1. Introduction to Health Communication

2.
3.
4.
5.

Theories in Health Communication
Science Communication
Communication during Emergency and Disaster
Patient-provider Communication: Patient Perspective
6. Communication Skills for Health Care Providers
7. Mass Media and Communication: Television
8. Internet Communication
9. Mass Media and Communication: News Paper
10. Social Marketing
11. Methodology of Health Communication Research
12. Health Communication Campaign
13. Patient-provider Communication: Provider Perspective[Health Communication Practice]
1. Coaching
2. Manners in Interpersonal Relationship
3. Internet: Research, Analysis and Evaluation of
Websites
4. Internet: Website Development
5. Practice of Media Publicity
6. Evaluation of News
7. MBTI (Myers-Briggs Type Indicator)
8. Image / Film Development
We also provide lectures and practical instruction in
medical informatics / economics as part of the PhD
program of the Faculty of Medicine. In the undergraduate program, Professor Kiuchi presents a lecture
entitled “Medical Literature Informatics.”

323

Research Activities
The followings are two distinguishing characteristicsof the research conducted in our Department of HealthCommunication, as compared to the research at othermedical informatics programs in Japan:(1) A focus on health informatics and communication
The Department of Health Communication is the only
research institute in Japan that carries out healthinformatics and communication-related research,
addressing areas such as the Internet and satellite
communications.
(2) Targeting health information science, not healthcare information practiceCurrently, main topics of the research at most medical
informatics programs in Japan focus on information
for healthcare practice, such as hospital information
systems, electronic medical record systems, telemedicine, and electronic billing systems. In contrast,
the Department of Health Communication has focusedon information systems for medical science, such as
medical literature databases, data registries for clinicalstudies, and information systems for medical
education.
The following are current research topics at the
Department of Health Communication:(1) Research on Health Communication
Currently, “health communication” is becoming animportant concept in the distribution of clinical results
for the improvement of population-based clinicaloutcomes. We have conducted health communication
research focusing on knowledge and skills in“informatics” and “communication.”(2) Research on Patient-Professional Relationship andCommunication
Communication between patients and health care
professionals is the foundation of effective health care.
Based on the analysis of the communication in actual
as well as simulated medical encounters, weinvestigate the relationship of patient and provider
characteristics with their communication behaviors,
and impacts of the communication on patient

outcomes. In addition, we have a seminar to introduce
the Roter Interaction Analysis System (RIAS), one of
the most widely used tools of the analysis of medical
communication,(3) Research on Health Literacy
The increase in media reports and the rapid expansionof the Internet have rendered various sources of healthinformation more available to the general public. Thus,
skills in understanding and applying information
about health issues may have a substantial impact on
health behaviors and health outcomes. These skills
have recently been conceptualized as health literacy.
We have developed a measure of health literacy
considering the social and cultural context of Japan,
and investigated its relationship with patient andprovider communication, and patient health behaviors
and outcomes.
(4) Research Related to UMIN Activities
Most systems developed at the UMIN Center havebeen subjects for research. In particular, we publishedand reported systems utilizing advanced technologies
and having scientifically meaningful concepts at
academic conferences.
(5) Information Systems for Clinical Epidemiologic
Studies
We have developed and applied information systems
for clinical epidemiological studies. Recently, we havefocused on research in electronic formats andstandardization that are related to clinical research,such as the Clinical Data Interchange Standards
Consortium (CDISC). We utilized the achievements
attained by the medical research data center at the
UMIN.
(6) Research Regarding the Security of an Information
Network
The study addresses a Virtual Private Network (VPN),
and secure transactions with electronic mail(encryption), which have been also utilized for systemmanagement at the UMIN Center.

References
1.

Park MJ, Yamazaki Y, Yonekura Y, Yukawa K,

324

2.

3.

Ishikawa H, Kiuchi T, Green J. Predicting
complete loss to follow-up after a healtheducation program: number of absences andface-to-face contact with a researcher. BMC Med
Res Methodol. 2011 Oct 27;11:145.
Yoshikawa H, Kiuchi T, Saida T, Takamori M.
Randomised, double-blind, placebo-controlled
study of tacrolimus in myasthenia gravis. J
Neurol Neurosurg Psychiatry. 2011 Sep;82(9):970-7.
Ishikawa H., Yano E. The relationship of patientparticipation and diabetes outcomes for patientswith high vs. low health literacy. Patient
Education & Counseling 2011; 84(3): 393-397.

School of Public Health
2. Behavioral Health Sciences

326

Department ofSocial Gerontology
Professor
Ichiro Kai, M.D., M.P.H.

Lecturer
Hajime Iwasa, Ph.D.

Associate
Tami Saito, M.Hlth.Sc.

Homepage

http://www.sg.m.u-tokyo.ac.jp※ The following information is the same as that of the previous year for certain reasons.

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 and measurements of quality of life, (2) the influences ofpsychosocial factors on health status, healthbehavior and health belief, and (3) policy
considerations for medical care and prevention.
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.

3272) Practice in Social Surveys: This is for practicing
to conduct social surveys using questionnaire/interview method. The students are divided into
several groups, and each group is given asurvey area. They will go through all theprocesses of a health sociological survey, fromplanning the survey to writing a report based on
the survey. They have the opportunity to reportand discuss their surveys with each other.
3) Health Behavior: This seminar aims to help thestudents to practice the basic research methods
related to health behaviors. Final product will
be a research proposal and the review of
relevant literature.
4) Decision-making in Health: This course
introduces students to recent developments inmedical and health decision-making. Topics
include the definition and measurement ofquality of life (QOL), cost-effectiveness andcost-benefit analysis, technology assessmentand optimal allocation of scarce medical
resources. Readings are selected from extensive
range of literature in behavioral sciences,economics and philosophy as well as medical
decision-making.

Research activities
1) Reciprocity of Social Support on Subjective
Well-being of the Elderly: Traditional support
study emphasizes the importance of receiving
support. We examine the pattern of support
exchange (i.e., receiving and providing) and its
effects on the subjective well-being of the elderly
in rural Japan as well as a number of Asian
countries such as Korea, Nepal, Malaysia, andIndonesia.
Intervention
studiesregardingintergeneration exchanges and targeting therelocated elderly are now in progress.
2) Disability-free Life Expectancy in Japan: We
calculate disability-free expectancy using a largescale cohort of the residents in Nagano Prefectureand examine variables influencing the life
expectancy.
3) Multi-disciplinary
CollaborationinthePsychosocial Care for the People with Cancer in
Clinical Setting: The survey we performed

indicated that Japanese surgeons consideredthemselves mainly responsible for medical aspectsof patient care and paid less attention topsychosocial issues. We examine the possibilities
of integrating other support resources such as
clinical psychologists, psychiatrists and medicalsocial workers in the clinical practices of cancer
in Japan.
4) Activities of Cancer Self-help Groups in Japan:
Although cancer self-help groups are growing
presence in Japan, they do not attract as many
patients as they do in other countries such as US.
Through semi-structured interviews and aquestionnaire survey, we revealed how Japanesecancer survivors and surgeons view peer support
activities implemented by cancer survivors.
5) Socio-cultural Analysis of Sexuality after Cancer:
Researchers have long neglected sexuality aftercancer. Through intensive semi-structured
interviews with Japanese women with breast
cancer, we examine how the cancer diagnosis andthe following treatments have affected theirsexuality and the whole relationship with theirpartners. Based on the findings of the qualitative
approach, we intend to perform a large-scale
survey on sexual complications among Japanesecancer survivors.
6) Role and Function of Ethics Committees in Japan:
In this project, we surveyed and analyzed the roleand function of ethics committees at various
levels, from hospital level to national level.

References
1. Aita K, Kai I:
Physicians’ psychological barriers to different
modes of withdrawal of life support in critical care
―A qualitative study in Japan
Soc. Sci. & Med. 70(4):616-622, 2010
2. Ohta M, Kai I:
Factors affecting attitudes toward care of theelderly mothers ―Urban versus agricultural areas
Arch. Gerontol. Geriatr. 51(3):241-244, 2010
3. Chalise HN, Kai I, Saito T:
Social support and its correlation with loneliness―A cross-cultural study in Nepalese older adults
Int. J. Aging Hum. Dev. 71(2):115-138, 2010

328

4. Fukahori H, Yamamoto-Mitani N, Sugiyama T, etal.:
Psychometric properties of the Caregiving Burden
Scale for Family Caregivers with Relatives in
Nursing Homes ―Scale development
Jpn. J. Nurs. Sci. 7(2):136-147, 2010
5. Sasaki Y, Ali M, Kakimoto K, et al.:Predictors of exclusive breast-feeding in early
infancy ―A survey report from Phnom Penh,
Cambodia
J. Pediatr. Nurs. 25(6):463-469, 2010
6. Sasaki Y, Ali M, Sathiarany V, et al.:Prevalence and barriers to HIV testing among
mothers at a tertiary care hospital in Phnom Penh,
Cambodia
BMC Public Health 10:494 (7 pages), 2010
7. Kim H, Traphagan JW:
Irony and the sociocultural construction of old age
in South Korea ―Perspectives from government,
the medical profession, and the aged
Care Manag. J. 11(3): 183-191, 2010
8. Gautam R, Saito T, Houde SC, et al.:Social interactions and depressive symptoms
among community dwelling older adults in Nepal―A synergic effect model
Arch. Gerontol. Geriatr. 53:24-30, 2011 (available
online)9. Ledesma D, Takahashi M, Kai I:
Interest in a group psychotherapy program among
Philippine breast cancer patients and its associatedfactors
Psycho-Oncology DOI:10.1002/pon.1804 (available
online)10. Sasaki Y, Arifin A, Ali M, et al.:Willingness to undergo HIV testing among factory
workers in Surabaya, Indonesia
AIDS Care (available online)
11. Aita K:
New organ transplant policies in Japan, including
the family-oriented priority donation clauseTransplantation 91:489-491, 2011
12. Takahashi M:
Health promotion for cancer survivors ―New
paradigm beyond prevention and treatment
in Muto T, Nakahara T and Eun WN (Eds.):“Asian Perspectives and Evidence on Health
Promotion and Education”, Springer, 2010

(pp.78-86)

School of Public Health
3. Health Services Sciences

330

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Homepage:

http://home.cie.m.u-tokyo.ac.jp:8080/Plone

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
Reviewing the history of the application ofcomputers in medicine, calculating machines forsupporting scientists and technologists first appearedin the 1950s. In the 1960s, computers were used foraccounting and various statistics. The personal
computer appeared in the 1980s and was adopted for
personal use in many professions. The systematizationof large hospitals, such as university hospitals, pushedahead rapidly.
In the 1990s, the computer began to be used as atool to help human thinking, such as in presentations,design, and discovery. When computers became
connected to each other through the internet, thedistribution of information became very easy andrapid, not only within organizations, but alsointernationally.
In 2003, a high-quality, "finished" sequence of thehuman genome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics,
informatics, statistics, computer science, and biochemistry to solve biological problems. In medicine,advanced information technologies have been applied
to health information infrastructures, electrical clinicalguidelines, 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.
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
progress on their own research projects and discuss
their future directions.

331

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 for single nucleotide polymorphisms (SNPs). These data are distributed andmanaged in various clinical databases. We are
studying ways to integrate distributed biomedical
data and knowledge mining with virtualized
database technologies, such as auto-indexing andtechnical 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 to evaluate aprocedure objectively; and (4) helping patientsand their families to better understand the surgicalprocedure before and after the operation.
(4) Social Information Engineering for Public Health(Public Health Informatics): Our laboratory
researches new tools and methodologies for
applying information and computer science andtechnology to public health practice, research,and learning.
At present, we are studying
differences in the computerization of publichealth in the US and Japan.

References(1) Febiana Hanani, Takashi Kobayashi, Eitetsu Jo,
Sawako Nakajima, Hiroshi Oyama. Public healthinformation and statistics dissemination efforts forIndonesia on the Internet. Online Journal of Public
Health Informatics. 2011; Vol 3, No 2.
(http://ojphi.org/htbin/cgiwrap/bin/ojs/index.php/oj
phi/article/view/3602/3083)(2) Takai K, Kin T , Oyama H , Iijima A, Shojima M ,Nishido H , Saito N . The use of 3D computer
graphics in the diagnosis and treatment of spinal
vascular malformations. J Neurosurg Spine. 2011
Sep 9.

Endowed Department

333

Department ofPharmacoepidemiology
Professor
Kiyoshi Kubota, M.D., Ph.D.

Associate Professor
Soko Setoguchi, M.D., Ph.D.

Associates
Koichi Kimura, M.D., Ph.D., Tsugumichi Sato, Ph.D.

Homepage

http://square.umin.ac.jp/pe/

Introduction and Organization
As of April 2011, the Department of Pharmacoepidemiology consists of a professor (Kiyoshi
Kubota), an associate professor (Soko Setoguchi,
concurrently appointed as an associate professor in
Duke University), two associates (Koichi Kimura andTsugumichi Sato), 3 teaching assistants, 4 clericalassistants.
The department was established as a donateddepartment in April 1993 for a limited time of 3 years
till March 1996. The department has been extended
6 times for 3-year period in each extension and thedepartment is now in the 1st year of the 7th period(March 2011-April 2013).
Pharmacoepidemiology is a new scientific fieldstarting in 1980s. In Japan, Japanese Society for
Pharmacoepidemiology was established led by the lateProfessor Tadashi Kusunoki (deceased in November2011) who was the first Japanese professor ofpharmacoepidemiology in the department between
April 1993 to March 1996.
In the second period from April 1996 to March
1999, two pilot studies of Prescription-Event
Monitoring in Japan were conducted. In the third
period from April 1999 to March 2002, the department
exerted a leadership to establish a non-profitableorganization (NPO) Drug Safety Research Unit Japan(DSRU Japan). This Unit worked as the study officefor two pilot studies on Prescription-Event Monitoring
and also for a case-control study on the association
between non-steroidal anti-inflammatory drugs andupper gastrointestinal bleeding. It also worked as thestudy office of other studies including clinical trials
led by researchers or those sponsored by a drug
company or Ministry of Health and Welfare.

Teaching activities
The department is involved in the teachingactivities inside University of Tokyo including
Graduate School of Medicine and Faculty of Medicine,
Faculty of Pharmaceutical Sciences and School of
Public Health. The department also played a leadingrole to organize a 6-month course of “pharmacoepidemiology seminar” held by Union of Japanese
Scientists and Engineers. This seminar is to educate
those in drug companies, school of pharmacies ofcolleges and universities and those involved inadministration in Pharmaceuticals Medical Devices
Agency (PMDA). The first seminar was held in2006. In 2011, the 6th seminar is being conducted.
Furthermore, the department has been a driving
force to make a textbook of pharmacoepidemilogy inJapanese published in 2010. The department is also
contributing to translate a textbook by Dr Patric334

Waller, a former regulator in the regulatory body in
the UK entitled an “An Introduction to Pharmacovigilance” published sometime in 2011.

Research activities
Like other epidemiological studies, pharmacoepidemiology studies are those on people and the study
requires an organization which supports the study.
NPO Drug Safety Research Unit established in 2001
has been working to support various studies including
pilot studies of Prescription-Event Monitoring inJapan, a case-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 and NPO Drug Safety Research
Unit also studied the baseline incidence of Interstitial
Lung Diseases (ILDs) in 328 patients with malignant
mesothelioma by collaborating with doctors in 26
hospitals in the west part of Japan.
Since April 2010, the department has beenrecognized as a department to manage ‘Safety
Information Division’ of Clinical Research Support
Center of the University of Tokyo Hospital. The
Center will be developed as the center for multiinstitutional 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
research by Japanese Society of Pharmacoepidemiology 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.
One of other research activities is on the use ofelectronic claims database. Some relatively small
data sources of claims data are already commerciallyavailable and the department has already started tosearch for the effective use of Japanese claims
database. The provision of the national claims
database (NDB) for the secondary purposes including
researches started in 2011. The department applied
the use of NDB data for two studies in 2011 and one
application (on ‘epidemiology of psoriasis’) wasapproved by the expert council supposed to discussand decide main issues associated with the trial
scheme for the provision of the NDB.

References
1.

2.

3.

4.

5.

6.

Nojiri S, Gemba K, Aoe K, Kato K, Yamaguchi T,
Sato T, Kubota K, Kishimoto T. Survival andprognostic factors in malignant pleural mesothelioma: a retrospective study of 314 patients in thewest part of Japan. Jpn J Clin Oncol 2011;41(1):32-39. doi: 10, 1093/jjco/hyq159.
Ooba N, Yamaguchi T, Kubota K. The impactof regulatory action on patients prescribeddopamine receptor agonists in Japan: analysis ofclaims database between 2005 and 2008. Drug
Saf. 2011; 34: 329-338.
Kubota K, Wakana A. Sample size formula forcase-cohort studies.
Epidemiology. 2011;22:
279.
Nojiri S, Gemba K, Aoe K, Kato K, Yamaguchi T,
Sato T, Kubota K, Kishimoto T. Incidence ofinterstitial lung disease in patients withmesothelioma in the west part of Japan.
Pharmacoepidemiol Drug Saf 2011; 20: 643-652.
Published online, DOI: 10.1002/pds.2123.
Kubota K, Wakana A. Sample size formula forcase-cohort studies.
Epidemiology. 2011;22:
279.
Hayashi, Kawashima, Nomura, Itoh, Watanabe,
Ohrui, Yokote, Sone, Hattori, Yoshizumi, Ina,
Kubota. Age, gender, insulin and blood glucose
control status alter the risk of ischemic heartdisease and stroke among elderly diabetic
patients.
Cardiovascular Diabetology 2011,
10:86

335

Department of Integrated
Traditional Medicine
Project Associate Professor
Tetsuro Okabe, M.D., Ph.D.

Project Associate
Jing Yu, Ph.D,

Hideki Koizumi, M.D., Ph.D.

Homepage http://square.umin.ac.jp/seitai/
Introduction and Organization
In an attempt to investigate the Japanese traditional
herbal medicine, the Department of Integrated
Traditional Medicine was established in 1996 as the
Department of Bioregulatory Function affiliated with
the Department of Medicine and Physical Therapy.
In 1999, the Department of Geriatric Medicine joined
us as an another affiliated Department. Pharmacological actions by medicinal herbs have been
intensively investigated not only on allergic or
autoimmune diseases, but also the disorders associatedwith aging process. Therapeutic experiments ofherbal medicine have been carried out by using animal
disease models to clarify the mechanisms of thepharmacological actions. In additions, the biologicalactions of the herbs have been investigated at cellularlevels to clarify the intracellular signaling pathways
induced by the medicinal herbs.
In 2003, traditional medicine was introduced into corecurriculum of medical education program. Since 2004,
lecture of traditional medicine has been
started in this university as an essential study. The
lectures have been served by this department. For
postgraduate education, seminars of traditional
medicine have been held at the university.
To avoid the confusion of similar names in western
medicine, the name of this department “Department of
Bioregulatory Function” was changed to “Department
of Integrated Traditional Medicine” in 2005.
Together with the change in the department name, westarted the translational studies on the physiology andpathology of the traditional medicine to translate thetraditional medicine into scientific medicine. 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 the antiaging medicine used in ancient traditional medicine.
Recently, hormone supplemented therapy has been
tried for disorders associated with aging in Western
medicine. Some herbs have been shown to exert theirpharmacological actions through receptors for certain
hormones. The studies on this theme have been
intensively performed at the department.
Postgraduate students have been also engaged in bothbasic and clinical sciences. The department provides awide-ranged clinical, training, and research services.
The weekly official activities of our department are ajournal club on Tuesday and research conferences on
Thursday.

Clinical activities
We have outpatient clinics on Tuesday, Wednesday,and Friday in the Department of General Medicine.

336

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 and demonstration of acupuncture were given for foreign students
from over 40 countries at Harvard Project for Asianand 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 research field covers from clinical, pharmacological, biological, and biophysical activities of
traditional medicinal herbs. We focus on the molecularmechanisms of cell functions and intracellularsignaling pathways.
Traditional medicinal herbs such as Ginseng has long
been used as an anti-aging agent in Asian countries.
Our laboratory studies molecular mechanisms ofaction by such anti-aging herbs. Ginsenoside Rb1, amajor constituent of Ginseng has been demonstrated
to exert the biological action as a phytoandrogen.

Endocrinological activities of anti-aging herbs areinvestigated using various molecular cell biologicalapproaches including biochemistry, immunochemistry,
molecular biology, molecular genetics such as genetargeting and transgenic mouse approaches, molecularbiophysics.
Much current interest is focused on the therapeuticpotential of hormone replacement therapy (HRT).
However, one of the major adverse reactions of HRT
is considered to promote cancer growth. It is urgent
for us to elucidate the mechanisms of action by theanti-aging herbs and to compare them with those ofhormones. Subsequently, we compare the biologicalactivities of the anti-aging herbs and their counterpart
hormones. We have demonstrated ginsenoside Rb1
and icariin exert the biological activity through its
non-genomic action on androgen receptors. Recently,
we have demonstrated that cinnamaldehyde, a major
constituent of cinnamon selectively stimulates progesterone secretion in human adrenal cells. Our studies
are focused on endocrinological actions of anti-aging
herbs which are exerted through their genomic or
non-genomic actions of steroid hormones.
The spinocerebellar ataxias (SCAs) are clinically andgenetically a heterogeneous group of neurodegenerative disorders. At present, we have noeffective therapeutic tools. SCA6 has been
demonstrated to be an autosomal dominant cerebellar
ataxia associated with small polyglutamine-dependent
expansions in the alpha 1A-voltage calcium channel.
Long-term remission of this genetic disease has been
attained with medicinal herbs. The findings of ourstudy imply the therapeutic potential of herbal
medicine for this hereditary neurodegenerative
disorder. Extensive investigations are under way toclarify the mechanisms. It has been also demonstrated
that some herbs are effective against multiple sclerosis
and neuromyelitis optica in our laboratory.
It has been reported that some herbal medicines may
be effective for acute episodes of chronic nonspecific
low back pain. Spondylolisthesis is one of the causesof low back or neck pain. Although surgical treatment
is often performed for symptomatic spondylolisthesis,
we have succeeded in herbal therapy for degenerative
spondylolisthesis.
Physiology, pathology and therapy of traditional
herbal medicine is based on the principle of the337

characteristic 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.

338

Department of Clinical
Epidemiology and Systems
Professor
Tutomu Yamazaki, M.D.,Ph.D.

Associate Professor
Daisuke Koide, R.Rh., HIM, Ph.D.

Homepage

http://cbi.umin.ne.jp/dces/index_e.html

Introduction and Organization
The Department of Clinical Epidemiology and
Systems was established in 2007, supported by Banyu
pharmaceutical company (currently MSD K.K). Our
department took over and enhanced the function andinfrastructures of the Clinical Epidemiology Divisionin Clinical Bio-Informatics Research Unit (CBI)
which had been lead by Professor Ryozo Nagai at the
Department of Cardiovascular Medicine, because theunit had been terminated its five-year programsupported by the Japan Science and Technology
Agency in 2007 as scheduled.
Our objectives are to develop standards for thetransfer of clinical information and improve thequality of clinical epidemiologic researches in the areaof life-style related diseases and preventive medicine,
because large and longitudinal data are necessary.
Through these activities, we evaluate such standards
and establish academic foundations of “Clinical
Epidemiology and Systems” as well as contribute toprofessional training in this field which will be more
and more required in the future.
In order to facilitate our broad activities, ourorganization is subordinate to the Department of
Cardiovascular Medicine, and works with close
collaboration with the staffs in the Center for
Epidemiology and Preventive Medicine which wasestablished in 2007 because professor Yamazaki isconcurrently the head of the both sections. The staffs
of this center overlap with faculty members in the

Department of Ubiquitous Preventive Medicine which
also took over and enhanced the function andinfrastructures of the Genomic Science Division in
CBI. Furthermore, these departments work with the
Department of Clinical Trial Data Management in the
22nd Century Medical and Research Center, andprovide consultation on biostatistics and clinicalresearch. Since associate professor Koide has abackground of medical informatics, he develops andsystemizes the standards of information in the area ofclinical epidemiology in collaboration with the
Department of Planning, Information and Management, the University Hospital Medical Information
Network (UMIN) Center, the Departments of
Epidemiology and Biostatistics, and the Departmentof Pharmacoepidemiology.
Also, professor Yamazaki is a member of ethics
committee in graduate school of medicine and facultyof medicine, the University of Tokyo, and associate
professor Koide is an assistant manager of personal
information that makes any data of studies regarding
human genome or gene anonymous. In the fiscal yearof 2011, we received 34 requests and made 6339
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 “Introduction of Clinical Medicine” by Depart-339

ment of Clinical and Genetic Informatics and related
departments, professor Yamazaki and associate
professor Koide gave lectures at the Large Conference
Hall of our Inpatients' Ward A on May 27, and on June
3 in 2011 respectively.
Also, the basic lectures of Medical Writing took
place at the auditorium in Pharmaceutical Sciences
Research Building as an intensive course on September 1-2 in 2011, hosted by the non-profit organizationof Japan Medical and Scientific Communicators
Association, and supported by the three departmentsof Clinical Epidemiology and Systems, Clinical Trial
Data Management, and Ubiquitous Preventive
Medicine.
In addition, Professor Yamazaki gave a lecture for“-Introduction of Clinical Studies B- Current Statesand Issues of Large Clinical Trials” was held at
Yokohama City University Graduate School of
Medicine on December 21 in 2011. Also, Associate
Professor Koide gave a special lecture for “-ClinicalPharmacology and Pharmacoepidemiology”, which
was given to the sixth-grade students at Tokyo
University of pharmacy and Sciences on May 31 in2011.

Research activities
1) Studies of Clinical Epidemiology (Clinical trials,
prospective cohort studies)
Our department facilitates large-scale clinical trials
by executing the data management with our own
computer servers and Japan Clinical Research Assist
Center (JCRAC).
In particular, our department was in charge of thesecretariat for Japanese Coronary Artery Disease(JCAD) study which was comparison of cardiovascular events between enhanced and normal therapy
for hypertension/hyperlipemia patients with coronary
narrowing, then improved the quality of trials without
any difficulties. Furthermore, we takes the role of data
management including training CRC in EMPATHY
study and J-ART study, and both of them are
randomized controlled trials
And studies for clinical epidemiology, such as
monitoring blood pressure at home by using IT andinvestigational researches into new bio-markers forarteriosclerosis have been carried out by analyzing thedatabase in the Center for Epidemiology andPreventive Medicine.
2) Improving Quality of Health Care
As a member of the quality improvement andassessment committee and chairs of the clinicalpathway committee and the committee for quality careat our university hospital, associate professor Koide
contributes to develop clinical pathways for clinicalprofessionals and patients and hold a large conferenceof clinical pathway, and to assess our quality care byourselves, etc.
3) Standardization of Information in Clinical Epidemiology
As attending the International Conference on
Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH)and Health Level Seven which is one of theinternational standards development organizations, westudy on electronic standards for the transfer
pharmaceutical regulatory information, especially
focusing on electronic standards for safety reporting.
Also, through activities of participating in Clinical
Data Interchange Standards Consortium (CDISC), we
tackle the interoperability of information on clinical
trials.

References
1. Yamashita T., Inoue H., Okumura K., Kodama I.,
Aizawa Y., Atarashi H., Ohe T., Ohtsu H., Kato T.,
Kamakura S., Kumagai K., Kurachi Y., Koretsune Y.,
Saikawa T., Sakurai M., Sato T., Sugi K., Nakaya H.,
Hirai M., Hirayama A., Fukatani M., Mitamura H.,
Yamazaki T., Watanabe E., and Ogawa S., on behalfof the J-RHYTHM II Investigators: Randomized trialof angiotensin II-receptor blocker vs. dihydropiridine
calcium channel blocker in the treatment ofparoxysmal atrial fibrillation with hypertension(J-RHYTHM II Study). Europace 13:473-479,2011
2. Yamamoto K., Ozaki H., Takayasu K., Akehi N.,
Fukui S., Sakai A., Kodama M., Shimonagata T.,
Kobayashi K., Ota M., Horiguchi Y., Ebisuno S.,
Yamazaki T., Ohtsu H., Hori M.: The Effect oflosartan and amlodipine on left ventricular diastolic
function and atherosclerosis in Japanese patients with

340

mild-to-moderate hypertension J-ELAN study.
Hypertens Res 34(3):325-330,2011
3. Yamazaki T., Kishimoto J., Ito C., Noda M., Odawara
M., Terauchi Y., Shiba T., Kitazato H., Iwamoto Y.,
Akanuma Y., Kadowaki T., for the J-PREDICT study
investigators: Japan prevention trial of diabetes by
pitavastatin in patients with impaired glucose
tolerance (the J-PREDICT study): rationale, study
design, and clinical characteristics of 1269 patients.
Diabetol Int 2(3):134-140,2011
4. Kohro T., Yamazaki T., Izumi T., Daida H.,
Kurabayashi M., Miyauchi K., Tojo T., Nagai R., onbehalf of the JCAD II Investigators: Intensively
lowering both low-density lipoprotein cholesterol andblood pressure does not reduce cardiovascular risk inJapanese coronary artery disease patients. Circ J 75:
2062-2070,2011
5. Suzuki T., Yamazaki T., Ogawa S., Nagai R.,
Yamashita T., and the J-RHYTHM II Investigators:
Echocardiographic predictors of frequency ofparoxysmal atrial fibrillation (AF) and its progression
to persistent AF in hypertensive patients withparoxysmal AF: Results from the Japanese rhythm
management trial II (J-RHYTHM II) for atrial
fibrillation study. Heart Rhythm 8:1831-1836,2011
6. Ogawa N., Imai Y., Takahashi Y., Nawata K., Hara K.,
Nishimura H., Kato M., Takeda N., Kohro T., Morita
H., Taketani T., Morota T., Yamazaki T., Goto J.,
Tsuji S., Takemoto S., Nagai R.,and Hirata Y.:
Evaluating Japanese Patients With the Marfan
Syndrome Using High-Throughput MicroarrayBased Mutational Analysis of Fibrillin-1 Gene. Am J
Cardiol 108:1801-1807,2011
7. Kubota T., Kubota N., Kumagai H., Yamaguchi S.,
Kozono H., Takahashi T., Inoue M., Itoh S.,
Takamoto I., Sasako T., Kumagai K., Kawai T.,
Hashimoto S., Kobayashi T., Sato M., Tokuyama K.,
Nishimura S., Tsunoda M., Ide T., Murakami K.,
Yamazaki T., Ezaki O., Kawamura K., Masuda H.,
Moroi M., Sugi K., Oike Y., Shimokawa H.,
Yanagihara N., Tsutsui M., Terauchi Y., Tobe K.,
Nagai R., Kamata K., Inoue K., Kodama T., Ueki K.,
Kadowaki T.: Impaired insulin signaling inendothelial cells reduces insulin-induced glucose
uptake by skeletal muscle. Cell Metab 13:294-307,
2011

341

Department of Ubiquitous
Preventive Medicine
Associate Professor
Toru Suzuki, M.D., Ph.D.

Research Associate
Kenichi Aizawa, M.D., Ph.D., Daigo Sawaki, 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, theDepartment of Ubiquitous Preventive Medicine wasinaugurated in August 1st, 2007 (Heisei 19), with agenerous donation from three pharmaceuticalcompanies, Toa-Eiyo Ltd., Shionogi & Co., Ltd.
and NEC Corporation to the University. Its
predecessor is the Clinical Bio-Informatics
Research Unit in the Graduate School of Medicineof the University of Tokyo (Director: Ryozo Nagai)
which was established in 2002 (Heisei 14) as agovernment-funded
program(Bio-Informatics
Training Program supported by the Ministry of
Education, Culture, Sports, Science and Technology[MEXT] through Special Coordination Funds for
Promoting Science and Technology). When theClinical Bio-Informatics Research Unit completed
its program tenure in 2007, its academic mission
and services were continued by the Department of
Ubiquitous Preventive Medicine and the Department of Clinical Epidemiology and Systems, bothaffiliated with the Department of Cardiovascular
Medicine in the Graduate School of Medicine of the
University of Tokyo.
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 forprevention and early detection of disease. For thispurpose, advanced and highly efficient techniquesof proteome analysis are used with potential clinicalapplication to preventive medicine. We are also
committed to developing surrogate biomarkers forthe discovery of drugs used in the treatment ofcardiovascular diseases as well as the optimizationof their efficacy, and to develop information
infrastructuretechnologies
foradvancingpersonalized medicine by clinically applying thetechniques of proteome analysis in an effort topromote preventive medicine for health promotion.
Our mission is to ultimately establish the academicbasis for Ubiquitous Preventive Medicine.
Our department provides diagnostic/therapeutic
as well as academic support for the Department of
Epidemiology and Preventive Medicine establishedin 2007 within the University of Tokyo Hospital. In
collaboration with our department, the Departmentof Clinical Epidemiology and Systems also support
the management of the Department of Epidemiology and Preventive 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

342

on the development of diagnostic biomarkers anddiagnostic/therapeutic systems. A typical example ismetabolic syndrome which if left untreated may
result in lifestyle-related diseases including
cardiovascular diseases. While cardiovasculardiseases have a very long incubation period, protein
modifications such as processing and denaturation
play a leading role on the development of thediseases. Prevention is therefore of utmost
importance. To this end, we are in the process ofdeveloping methods for the measurement of protein
modifications in cardiovascular diseases and othernew bio-tools for early detection of lifestyle-relateddiseases.
One of the achievements we have made is theworld first biomarker detecting system for ischemic
heart disease, which is a collaborative work by Toru
Suzuki and Shimadzu Corporation. This systemallows to detect conformational change ordegradation of proteins which are important in
cardiovascular pathologies such as ischemic heartdisease and heart failure. This system consists of
two major parts, mass spectrometry analysis whichenables qualitative and quantitative evaluation ofprocessed
degradation
products
orposttranscriptional modification of specific proteins,and immunoprecipitation. We have alreadyconfirmed its utility in clinical practice.
Specifically, the development of diagnostic
biomarkers and diagnostic/therapeutic systems byusing the techniques of proteome analysis ispursued on an ongoing basis with its main research
projects being Medical Equipment Development
Research Project from 2011 to 2013 under the
Ministry of Health, Labour and Welfare andAcademic-Industrial Research Collaboration (joint
research with Shimadzu Corporation).
In addition to the development of proteomicsbased diagnostic methods, we also are developing
information
infrastructuretechnologies
foradvancing personalized medicine by clinically
applying these methods to preventive medicine, as
in comprehensive medical examinations. In this way,
Ubiquitous Preventive Medicine is an appliedscience, based on which a comprehensive system is
to be developed in an effort to promote preventive
medicine and participatory medicine for healthpromotion.

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 andprovides 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 theaffiliate Department of Cardiovascular Medicine.

References
Academic Papers in English
1) Suzuki T, Trimarchi S, Sawaki D, Grassi V, Costa
E, Rampoldi V, Nagai R, Eagle KA. Circulatingtransforming growth factor-beta levels in acuteaortic dissection. J. Am. Coll. Cardiol. 58(7), 775,
2011.
2) Maisel AS, Nakao K, Ponikowski P, Peacock WF,
Yoshimura M, Suzuki T, Tsutamoto T, Filippatos
GS, Saito Y, Seino Y, Minamino N, Hirata Y,
Mukoyama M, Nishikimi T ,Nagai R. JapaneseWestern Consensus Meeting on Biomarkers
Executive Summary. Int. Heart. J. 52(5), 253-265,
2011.

Academic Papers in Japanese
1. 水野由子、相澤健一、山崎力、鈴木亨: 人間ドック・健診の結果と対応- 東京大学検診部における循環器疾患/動脈硬化性疾患の取り組み- .
日本臨床 69 (増刊号 7), 638-644, 2011.
2. 鈴木亨、永井良三：大動脈解離の診断 4.バイオマーカー.特集：大動脈疾患の最新知見. 最新医学 66(7): 1597-1602, 2011.

International Conferences
1. Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Munemasa Y, Ishida J, Friedman SL, Nagai R:
KLF6 Modulates Recruitment and Polarizatin of

343

2.

3.

4.

5.

6.

Inflammatory Cells Through Cardiomyocytes in
Initiation of Cardiac Fibrosis American heart
association scientific sessions 2011 (Orlando, FL,
USA). 2011/11/11-18.
Aizawa K, Suzuki T, Zhan H, Sawaki D, Ishida J,
Mastumura T, Nagai R : Klf5 Mediates a New
Regulatory Pathway of Pathologic Vascular Injury
Through DNA Double-Strand Break/Repair
System. American heart association scientificsessions 2011 (Orlando, USA). 2011/11/11-18.
Ishida J, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Friedman SL, Nagai R: KruppelLike Factor 6 (KLF6) Regulates Obesity and
Glucose Intolerance. American heart association
scientific sessions 2011 (Orlando, USA). 2011/11/
11-18.
Zhan H, Suzuki T, Aizawa K, Miyagawa K, Nagai
R: Identification and characterization of ataxia
telangiectasia mutated (ATM) in regulation ofoxidative stress-induced vascular endothelial cells
senescence. The 22ed Great Wall International
Congress of Cardiology Asia Pacific Heart
Federation Scientific Congress 2011 (Beijing,
China). 2011/10/13-16.
Fujimoto H, Suzuki T, Aizawa K, Sawaki D,
Ishida J, Nagai R: Processed B-type natriuretic
peptide is a biomarker of post-interventional
restenosis in ischemic heart disease. HUPO 2011
10TH
World
Congress(Geneva,
Swiss
Confederation). 2011/9/4-7
Aizawa K, Suzuki T, Zhan H, Miyagawa K and
Nagai
R:
Ataxiatelangiectasia
mutated(ATM)-mediated DNA damage response inoxidativestress-induced vascular endothelial cells
senescence. 2011 Gordon Research Conferences;
Mammalian DNA Repair (Ventura, CA, USA).
2011/2/6-11.

National Conferences
1. 藤本宏隆、鈴木亨、相澤健一、澤城大悟、石田純一、永井良三: プロセスされた B 型ナトリウ
ム利尿ホルモンは冠動脈疾患における経皮的冠動脈インターベンション後再狭窄のマーカーである. 第 36 回日本医用マススペクトル学会年会（大阪）．2011/9/15-16.
2. Zhan H, Suzuki T, Aizawa K, Miyagawa K, Nagai
R: Ataxia telangiectasia mutated (ATM)-mediatedDNA damage response in oxidative stress-induced
vascular endothelial cells senescence. 第 75 回日
本循環器学会総会・学術集会（横浜）2011/8/3-4.
3. Ishida J, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Friedman SL, Nagai R: Kruppel-likefactor 6 (KLF6) is involved in Glucose Intolerance
and obesity. 第 75 回日本循環器学会総会・学術集会（横浜）2011/8/3-4.
4. Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Munemasa Y, Ishida J, Friedman SL, Nagai R:
Kruppel-like facter 6 modulates initiation ofcardiac fibrosis. 第 75 回日本循環器学会総会・学術集会（横浜）2011/8/3-4.

344

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.

345(1) Analysis of Rac1-MR interaction and target organ
injury, using experimental models of metabolic
syndrome (KKAy, SHR/cp, diet- induced obesity,etc.). Search for stimuli causing Rac1 activation.
(2) Generation of cell type-specific (ex. podocytespecific) Rac1 Tg / KO mice.
(3) Identification of ARF, based on the comparative
analysis of fat cell conditioned media from obese
SHR and non-obese SHR.
(4) Elucidation of other mechanisms of MR
activation.
(5) Development of drugs (reagents to inhibit Rac1,
ARF, and newly-identified target molecules),diagnostic tools (indicators of MR activation in thetarget organ), specification of clinical conditions
in which Rac1-MR overactivation is involved.

Teaching activities
The education of post-graduate students is also an
important task of our department. Our staffs help thestudents to plan and perform basic experiments and/or
clinical studies, to make oral or poster presentation at
Japanese or international society, and to publish
scientific article. We have educational programs
including journal club in order to polish theiracademic skills.

References(1) Shibata S, Mu S, Kawarazaki H, Muraoka K,
Ishizawa K, Yoshida S, Kawarazaki W, Takeuchi M,
Ayuzawa N, Miyoshi J, Takai Y, Ishikawa A,
Shimosawa T, Ando K, Nagase M, Fujita T. Rac1
GTPaseinrodentkidneysisessentialforsalt-sensitive hypertension via a mineralocorticoid
receptor-dependent pathway. J Clin Invest. 2011;
121(8):3233-43.
(2) Nagase M, Fujita T. Endocrinological aspects ofproteinuria and podocytopathy in diabetes: role of
the aldosterone/mineralocorticoid receptor system.
Curr Diabetes Rev. 2011; 7(1):8-16.

346

Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Project Associate
Tadayuki Ogawa, Ph. D.

Homepage

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

Teaching activities

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), 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
including cutting edge light microscopies, cryoelectron microscopy of molecular resolution, X-ray
crystallography, biophysics, molecular biology andmolecular genetics. We aim to study the structure anddynamics of the molecular motors in vitro and in vivo
at the highest special and temporal resolution and onthese bases try to elucidate functions of molecularmotors in vivo combining molecular genetics.

References
1. Yin, X,. Y. Takei, M. Kido and N. Hirokawa.
Molecular motor KIF17 is fundamental for
memory and learning via differential support ofsynaptic NR2A.2B levels. Neuron 70; 310-325,
2011
2. Nakata, T., S. Niwa, Y. Okada, F. Perez, and N.
Hirokawa. Preferential binding of a kinesin-1
motor to GTP-tubulin–rich microtubules underlies
polarized vesicle transport. J Cell Biol 194：245-255, 2011.
3. Hirokawa, N. From electron microscopy tomolecular cell biology, molecular genetics andstructural biology: intracellular transport andkinesin superfamily proteins, KIFs: genes,

347

4.

5.

6.

7.

8.

9.

structure, dynamics and functions.
J Electron Microscopy 60 (Supplement 1) (60thAnniversary Issue: Biological): S63–S92, 2011.
Noda Y., S.Niwa, N.Homma, H. Fukuda, S. Imajo-Ohmib, and N. Hirokawa. Phosphatidylinositol
4-phosphate 5-kinase alpha (PIPKα) regulates
neuronal microtubule depolymerase kinesin,
KIF2A and suppresses elongation of axon
branches. Proc Natl Acad Sci, U.S.A 109:
1725-1730, 2012.
Hirokawa N., Y. Tanaka, and Y. Okada. Cilia,
KIF3 Molecular Motor and Nodal Flow.
Curr Opi Cell Biol 24:31-39, 2012.
Kondo, M., Y. Takei, and N. Hirokawa. Motorprotein KIF1A is essential for hippocampal
synaptogenesis and learning enhancement in anenriched environment. Neuron 73: 743-757, 2012.
Yin, X., X. Feng, Y. Takei, and N. Hirokawa.
Regulation of NMDA Receptor Transport: A
KIF17-cargo
Binding/Releasing
Underlies
Synaptic Plasticity and Memory in vivo.
J Neurosci 32: 5486-5499, 2012.
Yajima, H., T. Ogura, R. Nitta. Y. Okada, C.Sato,and N. Hirokawa.
Conformational changes in tubulin in GMPCPP
and GDP-taxol microtubules observed bycryoelectron microscopy. J Cell Biol 198: 315322, 2012
Nakajima, K., X. Yin, Y. Takei, D-H. Seog, N.
Homma, and N. Hirokawa.
Molecular motor KIF5A is essential for GABA A
receptor transport to neuronal surface and is
involoved in inhibitory transmission. Neuron inpress, 2012

348

Department of Molecular Vascular
Endocrinology
Associate Professor
Masashi Isshiki, M.D, Ph.D.

Associate
Risuke Mizuno, Ph.D.

Researcher
Mitsuhiro Nishimoto

Homepage

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

Introduction and Organization
The Department of Molecular Vascular Endocrinology
was established in the Graduate School of Medicine in
April 2009 by a donation from Novartis Pharmaceuticals Japan to collaborate with the Department ofNephrology and Endocrinology and the ClinicalLaboratory.
The vascular system plays an important role in thefunction and maintenance of various organs. Lifestylerelated illnesses such as high blood pressure are
known to cause abnormalities in the blood vessels and,as a result, to cause disorders of important organs likethe heart, kidneys, and brain. Various vasoactive
substances and signal transduction in cells forming thevascular structure are thought to be involved in thisprocess. This department conducts research with theaim of understanding the molecular mechanisms andpathophysiology of vascular disorders brought about
by lifestyle-related illnesses and accumulatingknowledge that can be applied to the treatment ofcardiovascular diseases.

Research activities
1. Understanding vascular endothelial function
regulatory mechanisms by intracellular Ca2+
signaling

The vasoregulator that we are particularly interested inis calcium signaling in vascular endothelial cells.
Calcium ions are extremely important signaling
factors that are involved in many vital phenomena. An
important feature of calcium signaling is that it
enables
diversecellularfunctionsthroughspatiotemporal regulation. We have observed anumber of extremely interesting phenomena using
confocal laser microscope imaging systems. We havereported that, when cultured endothelial cells arestimulated with an agonist such as ATP, the increase in
intracellular calcium spreads to the entire cell in theform of calcium waves, starting from the cell edges
where caveolae are abundant (Isshiki et al., PNAS
1998). Caveloae are invaginations with a diameter ofabout 100 nm in the cell membrane, and their function
has attracted attention in recent years due to thepresence of a variety of signaling transduction
molecules that are considered to be important in
vascular function, such as intracellular calcium
regulatory proteins. In addition, caveolae are dynamic
cell membrane structures, and the sites where they
accumulate, which is where the calcium wave istriggered, contain substances that accumulate on the
upstream side of the flow caused by shear stress andon the opposite side in the direction of travel during
cell migration (Isshiki et al., J Cell Sci 2002). One
candidate that has been proposed as a shear stress349

sensor is P2x4 receptors on the cell membrane, andexperimental data indicating that they are coupledwith the production of nitric oxide (NO) in endothelial
cells has also been obtained (Yamamoto, Isshiki, et al.,Nat Med, 2006). Recently, we have also been involvedin an investigation of the relationship between
intracellular calcium dynamics and endothelial cellfunction using Fluorescence Resonance Energy
Transfer (FRET). For example, when the amount ofcalcium in the intracellular calcium store decreases,
there is an effect called SOCE (store-operated calcium
entry) whereby calcium flows into the cell fromoutside; we have shown that this calcium uptake
pathway is via the caveolae membrane and is linked
with NO production due to activation of endothelial
nitric oxide synthase (eNOS) present in the membrane(Isshiki et al., J Biol Chem 2002). NO is deeply
involved in vascular tonus regulation andantiarteriosclerosis; therefore, this pathway is related
to the pathology of high blood pressure andarteriosclerosis, and research in this area may identify
treatment targets. In addition, we have also been
analyzing the relationship between calcium-dependent
molecular regulation and calcium dynamics directly
under the cell membrane, which may not be
obtainable with conventional calcium indicators,
depending on the extracellular calcium concentration(Isshiki et al., Circ Res 2004).
2. Understanding the pathophysiology of andvasoregulation by STIM1, a new Ca2+ regulatory
molecule
Recently, the important role played by a molecule
called STIM1, which is present in the ER Ca2+ store,
in SOCE control has been discovered, and we havealso been looking at STIM1 in our laboratory toinvestigate its role in endothelial cells.
A study is now underway to investigate STIM1's
relationship with the pathophysiology of vasculardisorders associated with arteriosclerosis and highblood pressure by preparing endothelial-cell-specific
STIM1 knockout mice and analyzing STIM1's effects
on endothelial performance and blood pressure.
3. Searching for new and existing vasoactive
substances and understanding new vasoactive
mechanisms

We are also interested in searching for new vasoactive
substances and understanding new action mechanismsof existing substances. For example, the influence ofaldosterone on vascular endothelial function, which is
not mediated by transcription mechanisms, hasrecently been investigated in cultured cells and by
tonus measurements in rat aortic ring (Muto et al.,Hypertens Res 2008). Also, we have reported thateplerenone, which is a selective aldosterone antagonist,
improves endothelial function by suppressing theexpression of caveolin, which is an eNOS inhibitor(Muto et al., AHA 2008). Recently, we have also been
examining the effects H2S on vascular function,
which is of physiological and pharmacologicalinterest.
4. Physiological investigation of the contribution oflymphatic vessel function in the pathology ofsalt-sensitive hypertension
Recently, it has been reported that lymph capillary
regeneration in the skin, which is caused by saltloading, is related to the pathology of salt-sensitive
hypertension. However, the effects of salt loading on
the regulatory control mechanism of lymphatic
circulation are not yet sufficiently understood.
Research is currently underway to look at the effectsof salt on changes to the functional properties ofcollecting lymphatic vessels that are mainly involvedin the propulsion of lymph, using animal models.

References
Academic Conferences and Lectures
1. Isshiki, M., Nishimoto, M., Takara, Y., Mizuno, R.,
and Fujita, T. Intra-ER Ca2+ flow recharges
preferentially to ER subcompartments at caveolinrich cell edges in endothelial cells. Meeting of theJapan Endocrine Society, April 2011.
2. Mizuno, R., Isshiki, M., Takara, Y., Nishimoto, M.,
Fujita, T. Analysis of stress control mechanism by
L-cystine–H2S pathway in vascular resistance inexcised mouse abdomen. Meeting of the JapaneseSociety of Hypertension, October 2011.
3. Isshiki, M., Nishimoto, M., Mizuno, R., and Fujita,
T. Subplasmalemmal caveolae in the endothelial
cell act as a store for Ca2+ releases Meeting of the350Japanese Society of Hypertension, October 2011.
4. Takara, Y., Isshiki, M., Nishimoto, M., Mizuno, R.,
and Fujita, T. Aldosterone promotes membranetranslocation of the podocyte TRPC6 via Rac1 andaugments Ca2+ signaling.
International Conferences
1. Isshiki, M. and Fujita T. Intra-Endoplasmic Reticulum (ER) Ca2+ Flow Recharges Preferentially to
ER Subcompatments at Cavolin-Rich Cell Edges
in Endothelial Cells. AHA Scientific Sessions
2011.
Review Articles
1. Isshiki, M. Fundamentals of hypertension andrecent treatment guidelines. Biofeedback Research
38(2); 97-100, 2011.

351

Department of Continence
Medicine
Professor
Yasuhiko Igawa, M.D.,Ph.D.

Research Associate
Naoki Aizawa, Ph.D.

Homepage http://cont-med.umin.jp/
Introduction and Organization

Teaching activities

Our department has been established as anendowment department supported by Astellas Pharma
Inc. in close collaboration with the Department ofUrology since July 1st 2010 to facilitate researches
specially focusing on continence medicine. The aim ofour department is to contribute to the advancement ofcontinence medicine through basic and clinicalresearches on regulation mechanisms of lower urinary
tract (LUT) function and pathphysiology of LUT
dysfunction, as well as function/dysfunction of lower
bowel and pelvic floor.
We believe that a multi-disciplinary professionalteam consisted of physicians, surgeons, nurses,
physiotherapists, bio-engineers, social workers andscientists is necessary to achieve greater advancementof continence medicine and care. We hope many
researchers with different specialties are interested inour research themes and collaborate with us for the
purpose of supporting patients with continence
problems by providing them better treatment andmanagement strategies.

We take part in providing systematic urologicallectures for second year medical students, and bed
side teaching for third and fourth year medical
students.

Clinical activities
Professor Igawa offers clinical services specialized
for patients with intractable lower urinary tract
dysfunction as well as for children with urogenital
disorders in conjunction with the Department ofUrology.

Research activities
We are currently investigating regulation
mechanisms of lower urinary tract (LUT) function,and pathophysiological mechanisms of various LUT
dysfunction, including overactive bladder (OAB),
bladder outlet obstruction (BOO), interstitial cystitis/
bladder pain syndrome(IC/BPS), and underactive
bladder dysfunction, especially focusing on:
1. To elucidate bladder sensory transduction
mechanisms
3. To disclose pathophysiology of development of
detrusor overactivity/OAB
3. To find useful biomarkers for IC/BPS
4. To evaluate the effects of metabolic syndrome on
LUT function
5. To develop novel pharmacological treatment forrefractory LUT dysfunction
6. To establish continence-care system consisted ofmulti-disciplinary professionals to contribute to
the advancement of continence medicine

352

References
1.

2.

3.

4.

5.

6.

7.

Aizawa N, Igawa Y, Andersson KE, Iijima K,
Nishizawa O, Wyndaele JJ. Effects of intravesicalinstillation of ATP on rat bladder primary afferent
activity and its relationship with capsaicinsensitivity. Neurourol Urodyn. 2011 Jan;30(1):163-8.
Aizawa N , Iijima K, Rosenbaum JS, Downs TR,
Igawa Y , Andersson KE, Wyndaele JJ.
Comparison of the effects of oestrogen deficiency
and old age on primary bladder afferent activity
and voiding behavior in the ageing female rat.
BJU int. 2011 Jul;108(2Pt2):E10-6.
Kurizaki Y, Ishizuka O, Imamura T, Ichino M,
Ogawa T, Igawa Y, Nishizawa O, Andersson KE.
Relation
betweenexpressionof
α(1)adrenoceptor mRNAs in bladder mucosa andurodynamic findings in men with lower urinary
tract symptoms. Scand J Urol Nephrol. 2011
Feb;45(1):15-9.
Takeda M, Homma Y, Araki I, Kakizaki H,
Yamanishi T, Yokota T, Gotoh M, Igawa Y, Seki
N, Takei M, Yoshida M, Sugaya K, Nishizawa O.
The Japanese Naftopidil Neurogenic Lower
Urinary Tract Dysfunction Study Group.
Predictive factors for the effect of the α1-D/A
adrenoceptor antagonist naftopidil on subjective
and objective criteria in patients with neurogenic
lower urinary tract dysfunction.BJU Int. 2011
Jul;108(1):100-107.
Aizawa N, Igawa Y, Nishizawa O, Wyndaele JJ.
Effects of nitric oxide on the primary bladderafferent activities of the rat with and without
intravesical acrolein-treatment. Eur Urol. 2011
Feb;59(2):264-71.
Michel MC, Ochodnicky P, Homma Y, Igawa Y.
β-Adrenocepter agonist effects in experimental
models of bladder dysfunction. Phamacol Ther.
2011 Jul;131(1):40-9.
Aizawa N, Wyndaele JJ, Homma Y, Igawa Y.
Effects of TRPV4 cation channel activation on
the primary bladder afferent activities of the rat.
Neurourol Urodyn. Epub 2011 Oct 28.

353

Department of Medical Genomics
Professor
Hiroyuki Mano, M.D., Ph.D.

Associate Professor
Young Lim Choi, M.D., Ph.D.

Lecturer
Masahito Kawazu M.D., Ph.D.

Introduction and Organization
Cancer is the leading cause of adult deaths indeveloped countries. While the incidence of brainstroke– and heart attack–related deaths is rapidly
decreasing, that of cancer-related ones is still linearly
increasing today. More than eight millions of people
die of cancer every year worldwide, and, even only inJapan, >30,000 of people die of cancer. It is, therefore,
likely that therapeutic efficacy with current cytotoxic
drugs is coming closely to their limit. To overcome
such limitation, it should be desirable to develop
effective targeted therapies against causative
oncogenic molecules in each cancer.
Recently, we have developed an efficient method
to construct 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 goal 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, and for the lectures forgraduate students in Medical Science Master’s
Program. Additionally, Professor Mano has conducted354

a number of seminars worldwide to propose thesignificant importance in cancer genomics.

Research activities
The Department of Medical Genomics tries to fulfill
our goals mainly through two approaches.
(1) Functional screening with the use of retroviral
cDNA expression libraries.
The “focus formation assay” had been widelyused in 1980s and 1990s to identify oncogenes fromhuman cancer. However, since this technology directly
uses cancer genome to transfer oncogenes into
recipient cells, expression of each gene is regulated byits own promoter/enhancer fragments. Therefore, suchtechnology is theoretically unable to capture
oncogenes whose promoter/enhancer is silent inrecipient cells. To make every gene expressedsufficiently in recipient cells, we here developed ahighly efficient retrovirus–mediated cDNA expression
library system. Our system enables to make a librarywith high complexity (containing millions of
independent cDNA clones) even from < 104 of cells.
Application of this technology to a lung cancer
specimen led to the discovery of a novel fusion-type
oncogene EML4-ALK (Nature 448:561). A tiny
chromosomal inversion, inv(2)(p21p23), within lungcancer cells fuses EML4 (Echinoderm microtubule
associated protein like 4) to ALK (anaplastic
lymphoma kinase), resulting in the production of aconstitutively active tyrosine kinase EML4-ALK.
Many pharmaceutical companies are currently
developing ALK inhibitors, and more than six ofdifferent inhibitors are under clinical trials to treat
EML4-ALK-positive lung cancer. The efficacy of oneof such compounds, crizotinib, has been publishedalready, and, surprisingly treatment with crizotinib
resulted in ~90% of response rate plus the presence of
patients under complete remission. Crizotinib wasapproved as a therapeutic drug against lung cancer asof August, 2011, which is the record-breaking speed in
the history of cancer drug development.
Currently, we are trying to apply our retroviralscreening technologies to other cancer subtypes. For
instance, a cDNA expression library was establishedfrom a cell line (OCUM-1) of scirrhous-type gastriccancer, and, with the focus formation assay, we

identified a Q56P substitution in MAP2K1 (or MEK1).
MAP2K1(Q56P) has a marked transforming potential,
and treatment with a MAP2K1 inhibitor rapidly
induced cell death of OCUM-1 but not of KATO-III
that is a cell line of MAP2K1-wild scirrhous-type
gastric cancer (Carcinogenesis 33:956). Further
screening of MAP2K1 among a panel of humancancer specimens revealed various transforming
mutations of MAP2K1.
(2) Cancer genome resequencing
In addition to the functional screening shown
above, we also tried to search for somatically mutatedgenes in human cancers with the use of “the next
generation sequencers (NGS)”. While development of
NGS has enabled us to determine the full genome
sequence of a cancer specimen even in private
laboratories, it is still a demanding task to conduct
full-genome sequencing for a large number of samples.
Therefore, many laboratories now purify exonic
fragments from a sample genome, and determine theirsequences. However, since gene fusions usually takeplace at intronic regions, such sequencing approachwith captured exons fails to discover fusion genes.
Thus, we have developed a “cDNA-capturesystem”, in which exon capture is conducted on cDNA,
not genomic DNA. With this technology, a single
NGS experiment can detect point mutations,insertions/deletions and gene fusions simultaneously(Cancer Sci 103:131)
We have also succeeded in developing a
resequencing technology with a high accuracy.
Through this technology we are currently pursuing to,in a large scale, discover somatically mutated genes
among human cancer specimens.

References
1. Tominaga-Sato S, Tsushima H, Ando K, Itonaga
H, Imaizumi Y, Imanishi D, Iwanaga M, Taguchi J,
Fukushima T, Yoshida S, Hata T, Moriuchi Y,
Kuriyama K, Mano H, Tomonaga M, Miyazaki Y.
Expression of myeloperoxidase and genemutations in AML patients with normal karyotype:
double CEBPA mutations are associated with highpercentage of MPO positivity in leukemic blasts.
Int J Hematol. 2011;94:81-89.

355

2. Takeuchi K, Soda M, Togashi Y, Sugawara E,
Hatano S, Asaka R, Okumura S, Nakagawa K,
Mano H, Ishikawa Y. Pulmonary inflammatory
myofibroblastic tumor expressing a novel fusion,
PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion
identification. Clin Cancer Res. 2011;17:33413348.
3. Takeuchi K, Soda M, Togashi Y, Ota Y, Sekiguchi
Y, Hatano S, Asaka R, Noguchi M, Mano H.
Identification of a novel fusion, SQSTM1-ALK,in ALK-positive large B-cell lymphoma.
Haematologica. 2011;96:464-467.
4. Suzuki HI, Arase M, Matsuyama H, Choi YL,
Ueno T, Mano H, Sugimoto K, Miyazono K.
MCPIP1 ribonuclease antagonizes dicer andterminates
microRNA
biogenesis
throughprecursor microRNA degradation. Mol Cell. 2011;
44:424-436.
5. Sasaki D, Imaizumi Y, Hasegawa H, Osaka A,
Tsukasaki K, Choi YL, Mano H, Marquez VE,
Hayashi T, Yanagihara K, Moriwaki Y, Miyazaki
Y, Kamihira S, Yamada Y. Overexpression of
Enhancer of zeste homolog 2 with trimethylationof lysine 27 on histone H3 in adult T-cellleukemia/lymphoma as a target for epigenetic
therapy. Haematologica. 2011;96:712-719.
6. Matsuyama H, Suzuki HI, Nishimori H, Noguchi
M, Yao T, Komatsu N, Mano H, Sugimoto K,
Miyazono K. miR-135b mediates NPM-ALKdriven oncogenicity and renders IL-17-producing
immunophenotype to anaplastic large cell
lymphoma. Blood. 2011;118:6881-6892.
7. Iida A, Shinoe T, Baba Y, Mano H, Watanabe S.
Dicer plays essential roles for retinal development
by regulation of survival and differentiation.
Invest Ophthalmol Vis Sci. 2011;52:3008-3017.

356

Department of MolecularPsychiatry
Associate Professor
Kazuya Iwamoto,Ph.D.

Assistant Professor
Miki Bundo, Ph.D.

Homepage

http://www.molpsy.com

Introduction and Organization

banks.

Major mental disorders such as schizophrenia,
affective disorders, and developmental disorders aresevere disorders showing high prevalence rate in every
population. They not only bring long-lasting suffering
to patients and their families, but also cause
tremendous loss from an economical view.
Surprisingly, cause of illness and pathophyshiology ofmental disorders remain largely unclear. The
Department of Molecular Psychiatry has been
established at the Graduate School of Medicine,
University of Tokyo since February 1st 2010, by the
donation from three pharmaceutical companies ―Astellas Pharma, Dainippon Sumitomo Pharma, andYoshitomi Yakuhin. The aim of this department is tocontribute the understanding of cause of illness andpathophysiology of major mental disorders at themolecular level, through the close collaboration with
Department of Neuropsychiatry at the University ofTokyo.

1. Kubota M, Kasahara T, Iwamoto K, Komori A,
Miyauchi T, Ishiwata M, Kato T. Therapeutic
implications of down-regulation of cyclophilin D
in bipolar disorder. Int. J. Neuropsychopharm.
2010;13:1355-1368.

Research activities
Specimen derived from mental disorders as well asanimal models are examined by comprehensive
approaches from genetic, molecular biological,
cellular and behavioral point of views. Especially, we
will focus on the study of blood samples provided
from Department of Neuropsychiatry at the Universityof Tokyo and postmortem brains provided from brain

Publication
1. Kato T, Hayashi-Takagi A, Toyota T, Yoshikawa
T, Iwamoto K. Gene expression analysis inlymphoblastoid cells as a potential biomarker ofbipolar disorder. Journal of Human Genetics inpress
2. Sugawara H, Iwamoto K, Bundo M, Ueda J,
Miyauchi T, Komori A, Kazuno A, Adati N,
Kusumi I, Okazaki Y, Ishigooka J, Kojima T,
Kato T. Hypermethylation of serotonin transporter
gene in bipolar disorder detected by epigenome
analysis of discordant monozygotic twins.
Translational Psychiatry 2011, 1:e24.
3. Yamada K, Iwayama Y, Hattori E, Iwamoto K,
Toyota T, Ohnishi T, Ohba H, Maekawa M, Kato
T, Yoshikawa T. Genome-wide association studyof schizophrenia in Japanese population. PLoS
One 2011, 6:e20468.
4. Iwamoto K, Bundo M†, Ueda J, Oldham MC,
Ukai W, Hashimoto E, Saito T, Gescwind DH,
Kato T. Neurons show distinctive DNA
methylation profile and higher interindividual

357

variations compared with non-neurons. Genome
Research 2011, 21:688-696.
5. Iwamoto K, Ueda J, Bundo M, Kojima T, Kato T.
Survey of the effect of genetic variations on gene
expression in human prefrontal cortex and its
application to genetics of psychiatric disorders.
Neuroscience Research 2011, 70:238-242.
6. Sugawara H, Iwamoto K, Bundo M, Ueda J,
Ishigooka J and Kato T. Comprehensive DNA
methylation analysis of human peripheral blood
leukocytes and lymphoblastoid cell lines.
Epigenetics 2011, 6:508-515.
7. Iwamoto K, Bundo M, Kasai K, Kato T.
Measuring RNA editing of serotonin 2C receptor.
Biochemistry (Moscow) 2011, 76:912-914.

358

Department of Life Support
Technology (Molten)
Project Associate Professor
Taketoshi Mori, Ph.D.

Project Assistant Professor
Hiroshi Noguchi, Ph.D.

Homepage http://www.lifesupport.m.u-tokyo.ac.jp/
Introduction and Organization
Department of Life Support Technology (Molten) was
founded Oct. 1, 2011 as a laboratory in Graduate
School of Medicine of the University of Tokyo.
The aim of the department is to establish life support
technology, which include not only pathophysiology
investigation of diseases and symptoms caused bydaily life activities but also development of directintervention method based on nursing approach andmethodology establishment for supporting daily life
widely.
First, Prof. Hiromi Sanada, who drives translational
research in nursing research area, and Molten Corp.,
which is one of Japanese welfare device development
companies, planned to establish this department. After
planned, Prof. Takeyoshi Dohi, leading person in
welfare and medical device engineering, recommended Taketoshi Mori, Ph.D. as a leader of thedepartment. He arrived at his post and the department
was established.
On May 7, 2011, the celebration for department
establishment was held at Gakushi kaikan. Many
people including president of Molten Corp. Kiyoshi
Tamiaki, Prof. Yasuo Ohashi and Prof. Takeyoshi
Dohi attended the party. Both nursing researchers andengineering researches congratulate the establishment.

Current members include a project associate projector
and a project assistant professor. Two masters course
students of the Department of Gerontological Nursing/ Wound Care Management were associated to thedepartment. They were graduated at this 2011 school
year. The supportive department is the Department ofGerontological Nursing / Wound Care Management.

Teaching activities
As for lectures, our department assisted the lectures ofthe supportive department, the Department ofGerontological Nursing/Wound Care Management. In
a part of Gerontological Nursing for undergraduate
course, Taketoshi Mori lectured monitoring system forelderly people. In a part of Wound Care Management I
for graduate course, Taketoshi Mori taught Material
Mechanics, which is important for skin mechanicalmodeling. In a part of Gerontological Nursing I for
graduate course, the members in the department
lectured the features and reading method of journal
papers of engineering research based on typical
publications.
The members in our department supported the mastercourse students of the Department of GerontologicalNursing / Wound Care Management. Masters thesis
theme of the students are “Factors associated withcallus in diabetic patients ―Focused on plantar shear
stress during gait―” and “Development andevaluation of air mattress structure and function for359

discomfort reduction during head-of-bed elevation.”
As for the other educational activity, we hold lectureclass about finite element method (FEM) software to
the members related to the Department ofGerontological Nursing/Wound Care Management.

Research activities
Our research themes are to investigate causes of
diseases and/or wounds due to daily life activity, andto develop instrument for effective monitoring andpreventing diseases and/or wounds. We study scienceand technology of natural human monitoring, nursing
engineering, and human behavior sensing thoroughly.
We are seeking a new interdisciplinary researchdomain between engineering and nursing, and willing
to realize comfortable daily life through theseresearches.

g) Probabilistic modeling and statistical clustering of
human behavior and mobility operationh) Motion capture system in the next generation andmarker-less motion capture system
As for the clinical field, we attend the Foot Care
Outpatient Clinic held by Department of Metabolic
Diseases.
We achieved collaborative works between engineeringand nursing with the Department of GerontologicalNursing/Wound Care Management.
One work was development of novel measurement
system for the diabetic patients. The system canmeasure pressure distribution and shear stresssimultaneously on the foot planter during walking.
Based on captured data, we investigated features andfactors of shear stress on metatarsal head at diabetic
patient with neuropathy.

References
We are developing the methodology to support healthy
and comfortable daily life by 1) monitoring daily life
naturally, 2) understanding the typical behaviors, and
3) predicting diseases, injuries, and accidents using
various sensing technology.
Main themes of our department are the following:a) Development of monitoring systems for patient on
a bed and vital sign measurement system using
mattressb) Construction of behavior measurement in dailyliving environment using simple sensors andalgorithm for typical behavior pattern extraction
and transition estimation of human behavior
patternc) Three dimensional leg movement measurement
and spatiotemporal 3D leg state measurement for
prevention of foot ulcerd) Human position measurement and behavior
estimation using laser range scannerse) Design and construction of human behavior
database
Collaborative themes with engineering department are
the following:f) Assistance and support of personal mobility
operation

1. Fukada H, Mori T, Noguchi H, Tomomasa S. Useof active RFID and environment-embedded
sensors for indoor object location estimation.
Deploying RFID - Challenges, Solutions, andOpen Issues. InTech, 219-36, 2011.
2. Fukui R, Mori T, Sato T. Home-use object
transfer/storage robot system with compliant
strategy and mechanism (commodities management and its extended application of daily life
support for the elderly). J Robot Mechatron.
2011;(23)4:532-43.
3. Mori T, Hosoda N, Sato T. Object usual places
extraction in smart space: robotic room. Robotics
Research. 2011;(66):111-22.
4. Mori T, Urushibata R, Noguchi H, Shimosaka M,
Sanada H, Sato T. Sensor arrangement forclassification of life activities with pyroelectric
sensors-arrangement to save sensors and toquasi-maximize classification precision. J Robot
Mechatron. 2011;(23)4:494-504.
5. Noguchi H, Mori T, Sato T. Flexible discovery ofcomponents for sensor data processing by RDF in
network middleware for home environment. J
Robot Mechatron. 2011;(23)4:505-14.

360

6. Noguchi H, Mori T, Sato T. Object localization bycooperation between human position sensing andactive RFID system in home environment. SICE
Journal of Control, Measurement, and System
Integration. 2011;(4)3:191-8.
7. Odashima S, Mori T, Shimosaka M, Noguchi H,
Sato T. Event understanding of human-object
interaction: object movement detection via stablechanges. Intelligent Video Event Analysis andUnderstanding. 2011;(332):195-210.
8. Yamamoto Y, Nakagami G, Mori T, Sakai K,
Sanada H. Evaluation of preventive effect on
buttocks immersion of independently controlled
inner air cell pressure in air mattress. J Jpn
WOCM. 2011;(15)3:239-49.

361

Department of Youth Mental
HealthAssociate Professor
Tsuyoshi Araki, M.D., Ph.D.

Lecturer
Syudo Yamazaki, Ph.D.

Associate
Aya Kikutsugi, O.T.

Homepage http:// plaza.umin.ac.jp/~youth-mh/
Introduction and Organization

Clinical activities

The Department of Youth Mental health wasestablished May 2011. This department is supported
by Otsuka Pharmaceutical Co., Ltd. and keeps close
relationship with the department of neuropsychiatry.
Youth means the period of time when someone isyoung, especially the period when someone is ateenager. This period includes the period of puberty
and adolescence. This period is unique to human andis very important for developing the ego function. If
some critical event happens at this time, thedevelopment might be inhibited and this inhibition
may cause mental illness. In order to keep thisdevelopment safely, the close care for teenagers isvery useful. Although the importance of mental healthof children and adult is emphasized in the history ofneuropsychiatry, youth mental health did not attract a
lot of attention of psychiatrists and researchers. Fromthe late 20th century, psychiatrists began to notice theimportance of youth mental health.
This department has a focus on youth mental healthand combines the biological aspect and social aspectof psychiatry. We are trying to create the new conceptof the social psychiatry including early intervention
and education.

We have outpatient clinics especially for the youth.
This clinic is a part of neuropsychiatry clinics but
treats young people especially suffering from earlystage of psychosis. We try to use cognitive and social
therapy for those patients and to minimize the use of
medication.
Psychiatrists and co medical staffs go to highschools and are engaged in educational activities.
School teachers often need some advises about mental
health problems happening in schools, we try to assist
those teachers as well.
Just after the Great East Japan Earthquake, staffs ofthe department of neuropsychiatry went to Miyagi
prefecture and support the staffs working at
Higashimatsushima City. This department also sends
staffs and meets the needs of staffs working at
Higashimatsushima City.

Educational activities
Staffs are participating in several kinds of lectureswith the staffs of the department of psychiatry. We
also manage the mental health research course which
is one of the courses of clinical research training
program in the University of Tokyo.

362

Research activities
Our research field covers Integrative neuroimaging
studies for schizophrenia targeting early intervention
and prevention (IN-STEP), Tokyo teen cohort study,
and the randomized controlled study of earlyintervention.

Endowed Department(22nd Century Medical and Research Center)364

Department of Clinical &Molecular Epidemiology
Project Associate Professor
Takanari Gotoda, M.D., Ph.D.

Project Associate
Takashi Yamamoto, Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/rinsyo_bunshi.html
Introduction and Organization
The Department of Clinical & Molecular
Epidemiology was established in June 2004 as anendowed department (Mitsubishi Tanabe Pharma Co.,
Ltd.) of the Graduate School of Medicine, theUniversity of Tokyo, under supervision of the
Department of Nephrology and Endocrinology of the
University of Tokyo Hospital. At present, ourdepartment is also supported by the Pharmaceutical
Department and belongs to the 22nd Century Medical
and Research Center, which partly represents thetranslational research activities of the University
Hospital. At present, our research laboratory facilities
are located at the 8th floor of the Central Clinical
Service Bldg.2 and at the 10th floor of the Inpatients’
Ward B of the University Hospital. Dr. Gotoda isentirely responsible for the management of thedepartment, keeping close contact and cooperation
with the other departments of the 22nd Century
Medical and Research Center and with laboratories of
the Department of Nephrology and Endocrinology and
the Pharmaceutical Department, and focusing mainly
on research activities.
Our department is established with the main aim of
performing the clinical and epidemiological analysis
on the metabolic syndrome in the Japanese population,of isolating susceptibility gene(s) to metabolic
syndrome through molecular and genetic analysis on
human and rodent animal models, and of contributing
to the development of novel diagnostic method andtherapeutic agents for the prevention and treatment of
the cardiovascular diseases. Above all, recently, we
are focusing on the genetic susceptibility to visceralfat accumulation, a hallmark of the metabolic
syndrome, and also on the genetic susceptibility tohypertension. Furthermore, we are also trying toelucidate the novel mechanistic action of the available
pharmaceutical agents for the treatment of themetabolic syndrome such as the inhibitors of therenin-angiotensin system and the statins.

Clinical activities
Some of the members of our department is closely
involved in clinical services related to both theout-patient and admission departments. We also attend
clinical conferences and contribute to clinicalactivities of the Department of Nephrology and
Endocrinology of the University Hospital, because ourdepartment is under supervision of the Nephrology
and Endocrinology Department. We are also
performing a translational research project using
clinical materials derived from patients withagreement and approval of both the patients and theethics committee of the University Hospital. Also, in
cooperation with outpatient clinics and hospitals
outside, we are collecting and analyzing the clinicaldata on metabolic syndrome from an epidemiologicalstandpoint with the aim of returning the fruitful resultsof the translational research to the clinical practicedepartments.

365

Teaching activities
Our department belongs to the Graduate School of
Medicine and Faculty of Medicine, the University ofTokyo. We are constantly instructing several
postgraduate students and supervising them in order tosucceed in obtaining the medical doctor degrees of the
University of Tokyo. We also contribute to
examination of the applicants for the doctor degrees,and make several lectures for the students in the
Faculty of Medicine at the University of Tokyo as
well.

Research activities
Our research field of interest covers the followings.
● Identification and isolation of novel susceptible
genes and related factors to metabolic syndrome
through systemic molecular and biologicalanalysis on human and rodent animal models of
metabolic syndrome.
● Performance of clinical and epidemiologicalanalysis with regard to metabolic syndrome.
● Development of novel diagnostic method for risk
factors of cardiovascular diseases.
● Contribution to the development of preventive
and therapeutic novel agents to treat patients withmetabolic syndrome.
● Exploration of novel mechanisms of action ofavailable pharmaceutical agents to treat patientswith cardiovascular diseases.
First of all, with regard to analysis on metabolic
syndrome, we analyzed clinical and epidemiological
data in the Japanese population by means of factor
analysis focusing on metabolic syndrome. The results
indicated that, even in the Japanese population where
severe insulin resistance can hardly be seen andcommon, the presence of insulin resistance is a crucial
factor underlying the clustering of risk factors related
to metabolic syndrome.
Recently, through the genetic analysis of animalmodel of metabolic syndrome, we have successfully
isolated and identified a novel gene underlying
visceral fat accumulation, a hallmark of metabolic
syndrome. Its characterization is described below indetail.
The spontaneously hypertensive rat (SHR) is an

important genetic animal model of hypertension,
dyslipidemia, and insulin resistance closely related tometabolic syndrome. We previously reported thegenetic heterogeneity among SHR strains, mostimportantly, the fact that SHR strains could be divided
into two separate groups according to the presence orabsence of genetic null mutation at the CD36 gene.
Representatively, the SHR/NCrj strain lacks CD36
due to the mutation while the SHR/Izm strain has
normal CD36. Although these two strains are quite
different in terms of visceral fat accumulation, insulin
secretion capacity, kidney weight and proteinuria,
very interestingly, these differences could not beascribed to the CD36 gene mutation, indicating thepresence of another important genetic abnormality. By
performing the so-called QTL (quantitative trait
locus ) analysis on the F2 cross population between
the two SHR strains, we have identified a QTL linked
significantly to epididymal fat weights and bloodpressure located near D1Wox28 on rat chromosome 1.
Next, as the result of a systematic screening of genes
located within the candidate QTL region by means ofgene expression analysis with a Gene-chip microarray,
we have identified the SLC22A18 gene located at thepeak of the QTL region. Interestingly, SHR/NCrj has apoint mutation at the donor splice site of an intron of
the SLC22A18 gene, while SHR/Izm lacking themutation found in SHR/Izm has wild-type SLC22A18,
The SLC22A18 gene is most abundantly expressed inliver and kidney, and it is also expressed ubiquitously,
for example, in the adipose tissue and pancreatic islet
cells. While the physiological function of SLC22A18
remains largely unknown, it is postulated as amembranous protein that would be possibly involvedin the membranous transport. It is also predicted thatthe donor splice site mutation found in SHR/NCrj
should cause the skipping of a single exon encoding
34 amino acids that would be crucial for normal
function of SLC22A18. In fact, the kinetic analysis
using a radio-labeled chemical agent that is postulated
to be an exogenous substrate for SLC22A18 on
isolated adipocytes clearly demonstrated that the
adipocytes derived from SHR/NCrj with the
SLC22A18 defect have significantly altered functionin terms of uptake of the substrate into adipocytes ascompared with those from SHR/Izm, establishing thefunctional significance of the mutation.

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Based upon these observations, we hypothesized thatthe genetic and functional abnormality of SLC22A18
could cause visceral fat accumulation, kidney
impairment, hypertension and impaired insulin
secretion. To test this hypothesis, we have establishedcell lines that either overexpress or underexpress
SLC22A18, and also overexpressed in vivo with useof adenovirus vectors. We are also trying to establish
genetically-engineered mice such as transgenic miceoverexpressing rat SLC22A18 and knockout mice
deficient in the SLC22A18 gene. By analyzing thephenotypes of those genetically-engineered mice, weplan to explore the clue to the etiological mechanismof visceral fat accumulation. Interestingly, since thefunction of SLC22A18 can possibly be regulated bysome synthetic exogenous substrate, verification of
the above hypothesis may open a new way to develop
a novel pharmaceutical agent to treat metabolic
syndrome focusing on SLC22A18 as a new target.
As another important approach to metabolic syndrome,
we have also generated knockout mice deficient in thegene for KAT-1 (kynurenine aminotransferase-1),
which we previously identified a promising candidate
gene of hypertension in SHR. Interestingly, thosehomozygous knockout mice developed hypertension
and manifested insulin resistance, sympathetic
hyperactivity, resistance to diet-induced obesity, anddiabetic insipidus. These observations may serve todevelop a novel pharmaceutical agent to treat
metabolic syndrome focusing on KAT-1 as a newtarget as well.
Finally, we also carry out a series of researchexperiments aiming at exploration of novel
mechanisms of action of available pharmaceuticalagents to treat patients with cardiovascular diseases.

Reference
1. Amemiya-Kudo M, Oka J, Takeuchi Y, Okazaki H,
Yamamoto T, Yahagi N, Matsuzaka K, Okazaki S,
Osuga J, Yamada N, Murase T, Shimano H.
Suppressionofthepancreatic
duodenal
homeodomain transcription factor-1 (Pdx-1)
promoter by sterol regulatory element-binding
protein-1c (SREBP-1c). J Biol Chem. 2011;286:
27902-14.

367

Department of
Immunotherapeutics (Medinet)
Project Associate Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Research Associate
Hirokazu Matsushita, M.D., Ph.D.

Homepage

http://immunoth.umin.jp/

Introduction and Organization
The aim of our Department is to execute basic andclinical research on cancer immunology andimmunotherapy and to establish its role in thetreatment of cancer. Cancer immunotherapy requires
the expansion of functional T cells and/or dendritic
cells (DC) that are responsible for the anti-tumor
immune response in vivo. The GMP-level Cell
Processing Center (CPC) was installed in the
Department. Peripheral blood mononuclear cells(PBMC) are isolated from the patients and processedin the CPC to ensure that they maintain optimalfunctionality, or for triggering new functions in vitro
prior to clinical application. Autologous cells derived
from cancer patients are processed for therapeutic use
in our CPC in accordance with all current regulations
and ethical obligations.
To perform reliable high quality translational
research, we designed our Department’s facilities
literally from the bench to the bedside. The
Department consists of three divisions, (1) laboratory
for basic and pre-clinical research (2); Cell Processing
Center and (3) outpatient clinic. Because these threedivisions are situated side-by-side on the same floor,
close cooperation between the members of each groupcan be more easily and better organized. As soon as
blood is drawn from the patient at the outpatient clinic,
it is directly transferred to the CPC through the
pass-box between the two. The cells processed andcultured in the CPC are scrutinized in the laboratorynext door to the clinic and CPC regarding their quality
and function. Those cultured cells which are approved
following this examination are transferred back to theclinic and administered to the patient. The patients arefollowed-up at regular intervals by the research staff
at the laboratory to monitor their immune responses toevaluate the impact of the immunotherapy.
All protocols for cancer immunotherapy
performed in our Department are submitted to theinstitutional review board (IRB). Once approved, theprotocols are registered in the UMIN clinical researchregistration system to provide open access to any
interested parties. Because the cells used for treatment
are derived from each individual patient; it is reallydifficult to guarantee consistent quality. However, we
do everything possible to provide the cultured cellswith the best conditions, by means of well-trained
specialist staff following standard operatingprocedures. All these efforts allow us to reliably
perform cancer immunotherapy clinical trials incooperation with many clinical departments of the
University of Tokyo Hospital.

Clinical activities
We provide outpatient services for cancer patients. Allinterventions performed in the department are definedby the protocols of the particular clinical trial
approved by the IRB. The following clinical trials areunderway in our department:

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Cancer vaccine

1. UMIN registration number ： UMIN000001260
active, not recruiting
IRB number：1935-(2)A phase I study of vaccination with NY-ESO-1f
peptide mixed with Picibanil; OK-432 andMontanide; ISA-51 in patients with cancers
expressing NY-ESO-1 antigen
2. UMIN registration number ： UMIN000001857
completed
IRB number：2475
A phase I study of cancer vaccine with NY-ESO-1
overlapping peptides in patients with advanced
cancers expressing NY-ESO-1 antigen
Condition: advanced esophageal cancer, stomach
cancer, non-small cell lung cancer (NSCLC),
malignant melanoma, bladder cancer.

Dendritic cell therapy

3. UMIN registration number ： C000000451
terminatedClinical study of intratumoral dendritic cell
injection after radiofrequency ablation therapy inhepatitis C virus-related hepatocellular carcinoma
patients
4. UMIN registration number ： UMIN000000971
terminatedClinical study of intratumoral dendritic cells(DC)injection after radiofrequency ablation(RFA)
therapy for the treatment of hepatitis C virusrelated hepatocellular carcinoma(HCC) patients
5. UMIN registration number ： UMIN000002136
active, not recruiting
IRB number：2492
Safety, efficacy and immunogenicity of autologous
tumor lysate-pulsed dendritic cell therapy inpatients with advanced renal cell carcinoma
6. UMIN registration number ： UMIN000002837
active, not recruiting
IRB number：2759
Safety, efficacy and immunogenicity of autologous
tumor lysate-pulsed dendritic cell therapy after
resection of stage2A (T2N0,T3N0) esophageal
cancer
7. UMIN registration number ： UMIN000006646
active, not recruiting
IRB number：P2011025-11Z
Safety, efficacy and immunogenicity ofconcomitant interferon alpha and autologous
tumor lysate-pulsed dendritic cell therapy inpatients with advanced renal cell carcinoma
8. UMIN registration number ： UMIN000006730
active, not recruiting
IRB number：P2011028-11Z
Heat Shock Protein 105 (HSP105) peptide-pulsed

dendritic cell vaccination therapy for patients withadvanced/ recurrent cancer.

γδ T cell therapy for advanced cancer
9. UMIN registration number：C000000336 active,
not recruiting
IRB number：1290-(4)Clinical study on safety and efficacy of adoptive
transfer of autologous gamma/delta T lymphocytes
in patients with non-small cell lung cancer.
10. UMIN registration number ： UMIN000000628
terminated
IRB number：1511-(5)A study to evaluate the safety and efficacy of exvivo expanded autologous gamma/delta T cell
infusion following zoledronic acid sensitization inpatients who received radiotherapy for bonemetastases.
11. UMIN registration number ： UMIN000000854
active, not recruiting
IRB number：1781-(1)Clinical study on efficacy and safety of autologous
gamma/delta T cell transfer therapy after
pulmonary metastasectomy of colorectal cancer
12. UMIN registration number ： UMIN000001419
active, not recruiting
IRB number：2120-(1)The efficacy and safety of autologous
gamma/delta T cell transfer therapy for esophageal
cancer
13. UMIN registration number ： UMIN000001418
terminated
IRB number：2176-(1)The efficacy and safety of autologous gamma/delta T cell transfer therapy for extrahepatic
metastasis of hepatocellular carcinoma

Adjuvant γδT cell therapy

14. UMIN registration number ： UMIN000000931
active, not recruiting
IRB number：1810-(1)Clinical study to investigate safety and efficacy on
combination of gemcitabine and autologous
gamma/delta T cell transfer therapy after resectionof pancreatic cancer
15. UMIN registration number ： UMIN000001417
active, not recruiting
IRB number：2177-(1)The efficacy and safety of autologous gamma/delta T cell transfer therapy after resection of
intrahepatic cholangiocarcinoma
16. UMIN registration number ： UMIN000002839
active, not recruiting
IRB number：2760
The efficacy and safety of autologous gamma/

369

delta T cell transfer therapy after resection ofstage2A (T2N0,T3N0) esophageal cancer
17. UMIN registration number ： UMIN000004130
active, not recruiting
IRB number：P201019-11Z

List of Publications

Teaching activities

2.

Research guidance in molecular immunology isprovided to postgraduate students. Because knowledge
and techniques for evaluation of immune response areimportant for clinicians and medical researchers, we
also provide many opportunities to postgraduate
students to learn how to analyze in vivo immune
responses by means of experiments using animalmodels and by the immunological monitoring of thepatients themselves in clinical research.

3.

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 clinical immunology in humans and basic preclinical immunology
using animal models. We especially focus on thespatiotemporal analysis of anti-tumor immunity inboth humans and experimental animals. During thecourse of each trial, many samples from the clinic aredelivered to the research laboratory to monitor
immune responses in patients. Tumor-specific immunity is evaluated using standardized immunologicalassays, such as ELISA, ELISPOT and flow cytometry.
To develop novel immunological interventions,tumor-bearing mice are used to confirm principles
believed to be the basis for the new immunotherapy.
Using many different TCR-transgenic and human
MHC class I-bearing mice we can provide clear
answers regarding the antigen-specific immune
response. As described above, we pursue a researchstrategy of going back and forth from the bench to thebedside and from basic to clinical immunology inorder to maximize benefit to patients via the rapid
application of new knowledge to clinical practice.

1.

4.

5.

6.

7.

8.

γδ T-cell immunotherapy for lung cancer. Yoshida
Y, Nakajima J, Wada H, Kakimi K. Surg Today.
2011 May;41(5):606-11.
Exploring immune therapy for renal cancer.
Matsushita H, Kakimi K, Tomita Y, Tatsugami K,
Naito S, Suekane S, Noguchi M, Moriya F, Matsuoka K, Itoh K, Kobayashi H, Eto M, Takahashi
W, Kawano Y, Wada Y. Int J Urol. 2011 Jun;
18(6):412-21.
Chemokine receptor CXCR3 facilitates CD8(+) T
cell differentiation into short-lived effector cells
leading to memory degeneration. Kurachi M,
Kurachi J, Suenaga F, Tsukui T, Abe J, Ueha S,
Tomura M, Sugihara K, Takamura S, Kakimi K,
Matsushima K. J Exp Med. 2011 Aug 1;208(8):1605-20.
UV irradiation of immunized mice induces type 1
regulatory T cells that suppress tumor antigen
specific cytotoxic T lymphocyte responses. Toda
M, Wang L, Ogura S, Torii M, Kurachi M, Kakimi K, Nishikawa H, Matsushima K, Shiku H,
Kuribayashi K, Kato T. Int J Cancer. 2011 Sep
1;129(5):1126-36.
Expansion of human peripheral blood γδ T cells
using zoledronate. Kondo M, Izumi T, Fujieda N,
Kondo A, Morishita T, Matsushita H, Kakimi K.
J Vis Exp. 2011 Sep 9;(55). pii: 3182. doi: 10.
3791/3182.
Type I interferon is selectively required by dendritic cells for immune rejection of tumors. Diamond MS, Kinder M, Matsushita H, Mashayekhi
M, Dunn GP, Archambault JM, Lee H, Arthur CD,
White JM, Kalinke U, Murphy KM, Schreiber
RD. J Exp Med. 2011 Sep 26; 208(10):1989-2003.
A phase I study of vaccination with NY-ESO-1f
peptide mixed with Picibanil OK-432 and Montanide ISA-51 in patients with cancers expressing
the NY-ESO-1 antigen. Kakimi K, Isobe M,
Uenaka A, Wada H, Sato E, Doki Y, Nakajima J,
Seto Y, Yamatsuji T, Naomoto Y, Shiraishi K,
Takigawa N, Kiura K, Tsuji K, Iwatsuki K, Oka
M, Pan L, Hoffman EW, Old LJ, Nakayama E.
Int J Cancer. 2011 Dec 15;129(12):2836-46.
B cells regulate antibody responses through the

370

9.

medullary remodeling of inflamed lymph nodes.
Abe J, Ueha S, Yoneyama H, Shono Y, Kurachi
M, Goto A, Fukayama M, Tomura M, Kakimi K,
Matsushima K. Int Immunol. 2012 Jan;24(1):17-27.
Cancer exome analysis reveals a T-cell-dependent
mechanism of cancer immunoediting. Matsushita
H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM,
Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ,
Mardis ER, Schreiber RD. Nature. 2012 Feb
8;482(7385): 400-4.

371

Division of Total Renal Care
Medicine
Associate Professor
Yutaka Enomoto (urologist),

Assistant Professor
Yoshifumi Hamasaki (Nephrologist)

Post-doctoral Fellow
Yohei Takara

Homepage(Nephrologist)

http://www.trc.umin.jp

The Division of Total Renal Care Medicine, sponsoredby Terumo Corporation, was established in 2004. Our
goal is to provide end-stage renal disease (ESRD)
patients with a renal replacement therapy mostsuitable for their way of life. In order to achieve this,
we are making an effort to make peritoneal dialysis(PD) more available for patients, in a country where
for most patients hemodialysis is virtually the only
choice. We are presently conducting the following
projects; (1) Research on establishing optimum PD
therapy, (2) Educational courses for medical
practitioners, and (3) research on improving clinicalskills.
We are providing care for approximately 80 PD
outpatients in our hospital with the support of thedivision of Nephrology and Endocrinology. All the 3
projects mentioned above are in close association withdaily clinical practice. Our activities in 2010 were as
follows:(1) Research on establishing optimum PD therapy.
At the present state, the main cause of PD techniquefailure is deterioration of peritoneal function due tolong-term use of bio-incompatible dialysate. Biocompatible dialysates have been available since 2001,
and our research is focused on peritoneal pathology
after long-term use of new biocompatible PD fluids.
We have reported the results in the Peritoneal Dialysis

International (in press). In addition, we have started
the project of developing non-invasive methodology
of diagnosing peritoneal membrane with the collaboration between medical-engineering institutions.
(2) Educational courses for medical practitioners.
With the help of many nephrologists and nurses in our
hospital, we have trained 27 nephrologists and 41
renal nurses from 25 facilities (either university
hospital or central hospital in their area) from 15
prefectures in Japan in 2010. To date, we have trained
156 nephrologists and 101 renal nurses from 132
facilities between 2006-2010.
(3) Research on improving clinical skills.
PD is a mode of therapy in which the patient greatly
participates in treating his own disease. Therefore, thepatient needs to face up to his own disease, and toknow how to acquire the skills needed for selfmanagement. Based on this standpoint, we have feltthat it is necessary to work with experts of otherdisciplines, such as the humanities. Thus, we havestarted some collaborative research with philosophers,sociologists, and cognitive behavioral therapists.

372

References
1. Kumagai T, Ishibashi Y, Kawarazaki H,
Kawarazaki W, Shimizu H, Kaname S, Fujita T.
Effects of nocturnal oxygen therapy on sleep
apnea syndrome in peritoneal dialysis patients.
Clin Nephrol 70: 332-9, 2008
2. Mori E, Ishibashi Y, Kume H, Ishikawa A, Fujita
T. Two Cases of Catheter Obstruction Caused by
Subcutaneous Catheter Kinking Perit Dial Int 28:
677-678, 2008
3. Mimura I, Ishibashi Y, Tateishi R, Kaname S,
Fujita T. Pegylated interferon alpha-2a monotherapy in a peritoneal dialysis patient withchronic hepatitis C.. Nephrol Dial Transplant Plus
1: 233-235, 2008
4. Hirahara I, Ishibashi Y, Kaname S, Kusano E,
Fujita T: Methylglyoxal induces peritoneal
thickening by mesenchymal-like mesothelial cells
in rats. Nephrol Dial Transplant 24, 437-47, 2009
5. Motonishi S, Ishibashi Y, Kawarazaki H, Katagiri
D, Hirata Y, Kume H, and Fujita T: Peritoneal
catheter obstruction by sigmoid colon wall.
Kidney International 79, 1032, 2011
6. Hirohama D, Ishibashi Y, Kawarazaki H, Kume
H, Fujita: Successful treatment of Mycobacterium
gordonae exit-site and tunnel infection by partial
catheter reimplantation of the Tenckhoff catheter.
Perit Dial Int 31,368-70, 2011
7. Katagiri D, Ishibashi Y, Kawarazaki C, Kume H,
Fujita T: Peritoneal Findings from Two Patientswith Takayasu’s Arteritis on Peritoneal Dialysis.
Perit Dial Int 31, 502-3, 2011
8. Muraoka K, Ishibashi Y, Yamaguchi J,
Kawarazaki H, Kume H, and Fujita T: Early Partial
Reimplantation of Tenckhoff Catheters to Treat
Intractable Exit-Site/Tunnel Infection. Perit Dial
Int 31, 350-3, 2011
9. Ayuzawa N, Ishibashi Y, Takazawa Y, Kume H,
and Fujita T: Peritoneal Morphology after Longterm Peritoneal Dialaysis with Biocompatible
fluid: Recent Clinical Practice in Japan. Perit Dial
Int 32,159-67, 2011
10. Kume H, Miyazaki H, Ishikawa A, Ishibashi Y,
Fujita T, Homma Y: Peritoneal fixation prevents
dislocation of Tenckhoff catheter. Perit Dial Int 31,
694-7, 2011

11. Ishikawa A, Kawarazaki H, Ando K, Fujita M,
Fujita T, Homma Y: Renal preservation effect ofubiquinol, the reduced form of coenzyme Q10.
Clin Exp Nephrol 15, 30-33, 2011
12. Takara Y, Ishibashi Y, Fujishiro M, Fujita T.
Endoscopic treatment of obstructed peritoneal
catheter. Kidney Int. 2011 80, 679, 2011.
13. Ikeda Y, Nangaku M, Ishibashi Y, Hirohama D,
Uozaki H, Tojo A, Ishikawa A, Fujita T. A case of
de novo focal segmental glomerulosclerosis
occurred one and half years after kidney transplantation supposed to be caused by calcineurin.
Clin Transplant. 26 Suppl 24,76-80, 2012

373

Department of Integrated
Molecular Science on Metabolic
Diseases
Project Associate Professor
Kazuo Hara, M.D., Ph.D.

Project Research Associate
Masato Iwabu, M.D.,Ph.D.

Introduction and Organization
The Department of Integrated Molecular Science on
Metabolic Diseases (DIMSMD) is devoted toclarifying the mechanisms of onset of lifestyle-relateddiseases resulting from interactions between genetic
and environmental factors in the Japanese population
as well as to contributing to the prophylaxis, diagnosis
and treatment of these diseases, in response to thedrastic increase in the number of diabetic patients
which is becoming a major social issue of current
interest. In this regard, the DIMSMD strives toestablish an accurate method through which to predictrisk for the onset of lifestyle-related diseases bytapping into a comprehensive database for genetic andenvironmental factors for these diseases which is
being developed to integrate “Informatics on Genetic
Predisposition to Lifestyle-related Diseases” asgenerated by cutting-edge advances such as single
nucleotide polymorphism analyses with “Informatics
on Environmental Factors for Lifestyle-relatedDiseases” that draw on surveys including detailed
questionnaires on diet intake. The DIMSMD istherefore expected to make significant scientific andsocial contributions by providing effective modalities
for primary prevention of diabetes, moleculardiagnosis of onset of diabetes and its pathology, andoptimal treatment of diabetes, and to play a major role
in reducing the number of newly onset diabetes aswell as in raising the treatment standard for diabetes.

The DIMSMD also aims to develop a system thatallows formulas to be developed to predict therapeutic
response to drugs as well as their safety to be
developed based on information available onenvironmental and genetic factors including gene
expression from patients being treated at University ofTokyo Hospital, and which allows safe and effective
use of drugs being developed in patients withlifestyle-related diseases.
The DIMSSMD has set as its final goal the
installment of a human metabolic disease tissue bankat University of Tokyo Hospital, which draws on an“integrated database” that offers comprehensive
information on gene expression in human hepatic andadipose tissue samples, electronic charts, SNP andlifestyle habits, which will allow validation ofmolecular targets in actual human diseases, design ofa clinical trial system based on SNP and gene
expression profiles, development of models forprediction of therapeutic response based on
environmental and genetic interactions, identificationof molecular targets, discovery of novel therapeutic
agents and safe and effective use of drugs thus
developed in time.
The DIMSMD is thus engaged in daily research
activities and clinical care aimed at contributing to theadvancement of health and medical care in the future.

374

Research activities
The DIMSMD Research Laboratory aims to elucidate
the molecular mechanisms of lifestyle-related diseases
such as the metabolic syndrome, diabetes andcardiovascular disease associated with obesity and to
put relevant molecular targets identified in the process
to effective use in the treatment of these diseases. Of
note, the DIMSMD Research Laboratory has animpressive track record in research in this area,
including identification of multiple “key molecules”
implicated in lifestyle-related diseases, such as
adiponectin receptors, which led to an elucidation ofsome of the processes through which lifestyle-relateddiseases develop and progress, based on functional
analyses that tap into developmental engineering and
RNA engineering. The DIMSMD ResearchLaboratory has also been credited with discoveringthat adiponectin is highly active in its high molecularweight form as a ligand to the adiponectin receptors
and that its quantitative measurement is useful in the
diagnosis of insulin resistance and the metabolic
syndrome. Not only that, the DIMSMD ResearchLaboratory has found that, via the adiponectin
receptors, the plant-derived peptide osmotin activates
the AMPK pathway which has a critical role inprotecting against lifestyle-related diseases. Currently,
the DIMSMD Research Laboratory is proactively
engaged in the development of definitive treatments
for lifestyle-related diseases that draw on ligands
specific for the adiponectin receptors.

References(1) Grarup N, Overvad M, Sparso T, Witte DR, Pisinger
C, Jorgensen T, Yamauchi T, Hara K, Maeda S,
Kadowaki T, Hansen T, Pedersen O.: The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432
variant impairs glucose-stimulated insulin response
in 5,722 non-diabetic Danish individuals.
Diabetologia 54, 789-794 (2011)(2) Kobayashi N, Ueki K, Okazaki Y, Iwane A, Kubota
N, Ohsugi M, Awazawa M, Kobayashi M, Sasako T,
Kaneko K, Suzuki M, Nishikawa Y, Hara K,
Yoshimura K, Koshima I, Goyama S, Murakami K,
Sasaki J, Nagai R, Kurokawa M, Sasaki T,
KadowakiT.:
Blockade
of
class
IB

phosphoinositide-3 kinase ameliorates obesityinduced inflammation and insulin resistance. Proc.
Natl Acad. Sci. USA 108, 5753-5758 (2011)(3) Handa N, Takagi T, Saijo S, Kishishita S, Takaya D,
Toyama M, Terada T, Shirouzu M, Suzuki A, Lee S,
Yamauchi T, Okada-Iwabu M, Iwabu M, Kadowaki
T, Minokoshi Y, Yokoyama S.: Structural basis forcompound C inhibition of the human AMPactivated protein kinase alpha 2 subunit kinasedomain. Acta Crystallogr. D Crystallogr. 67, 480487 (2011)(4) Kukimoto-Niino M, Yoshikawa S, Takagi T,
Ohsawa N, Tomabechi Y, Terada T, Shirouzu M,
Suzuki A, Lee S, Yamauchi T, Okada-Iwabu M,
Iwabu M, Kadowaki T, Minokoshi Y, Yokoyama, S.:
Crystal Structure of the Ca2+/Calmodulindependent Protein Kinase Kinase in Complex with
the Inhibitor STO-609. J. Biol. Chem. 286,
22570-22579 (2011)(5) Waki H, Nakamura M, Yamauchi T, Wakabayashi K,
Yu J, Hirose-Yotsuya L, Take K, Sun W, Iwabu M,
Okada-Iwabu M, Fujita T, Aoyama T, Tsutsumi, S,
Ueki K, Kodama T, Sakai J, Aburatani H, Kadowaki
T.: Global Mapping of Cell Type-Specific Open
Chromatin by FAIRE-seq Reveals the Regulatory
Role of the NFI Family in Adipocyte Differentiation.
Plos Genet. 7 e1002311 (2011)(6) Cho YS, Chen CH, Hu C, Long J, Ong RT, Sim X,
Takeuchi F, Wu Y, Go MJ, Yamauchi T, Chang YC,
Kwak SH, Ma RC, Yamamoto K, Adair LS, Aung T,
Cai Q, Chang LC, Chen YT, Gao Y, Hu FB, Kim
HL, Kim S, Kim YJ, Lee JJ, Lee NR, Li Y, Liu JJ,
Lu W, Nakamura J, Nakashima E, Ng DP, Tay WT,
Tsai FJ, Wong TY, Yokota M, Zheng W, Zhang R,
Wang C, So WY, Ohnaka K, Ikegami H, Hara K,
Cho YM, Cho NH, Chang TJ, Bao Y, Hedman ÅK,Morris AP, McCarthy MI; DIAGRAM Consortium;
MuTHER Consortium, Takayanagi R, Park KS, Jia
W, Chuang LM, Chan JC, Maeda S, Kadowaki T,
Lee JY, Wu JY, Teo YY, Tai ES, Shu XO, Mohlke
KL, Kato N, Han BG, Seielstad M.: Meta-analysis
of genome-wide association studies identifies eight
new loci for type 2 diabetes in east Asians. Nature
Genet. 44, 67-72 (2011)(7) Kodama K, Horikoshi M, Toda K, Yamada S, Hara
K, Irie J, Sirota M, Morgan AA, Chen R, Ohtsu H,
Maeda S, Kadowaki T, Butte AJ.:Expression-based

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genome-wide association study links the receptor
CD44 in adipose tissue with type 2 diabetes. Proc.
Natl Acad. Sci. USA 109, 7049-7054 (2012)(8) Imamura M, Maeda S, Yamauchi T, Hara K, Yasuda
K, Morizono T, Takahashi A, Horikoshi M,
Nakamura M, Fujita H, Tsunoda T, Kubo M,
Watada H, Maegawa H, Okada-Iwabu M, Iwabu M,
Shojima N, Ohshige T, Omori S, Iwata M, Hirose H,
Kaku K, Ito C, Tanaka Y, Tobe K, Kashiwagi A,
Kawamori R, Kasuga M, Kamatani N, Nakamura Y,
Kadowaki T, Diabet Genetics Replication, M.:A
single-nucleotide polymorphism in ANK1 is
associated with susceptibility to type 2 diabetes inJapanese populations. Hum. Mol. Genet. 21, 30423049 (2012)

376

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
Kouji Wakayama, M.D., Ph.D.

Homepage

http://square.umin.ac.jp/sentan/

Introduction and Organization
The Department of Advanced Clinical Science andTherapeutics, established at the University of Tokyoin 2004, aims to develop new clinical strategies andtherapy in cardiovascular medicine and other areas.
This department hopes to develop not only basic
research, but also applications to devise new clinicalstrategies.

Research activities
Followings are our recent basic and clinical research
activities.
Basic Research• New strategies to regulate acute rejection and graftarterial diseases in cardiac transplantation.
• New strategies to regulate acute/chronic myocarditis.
• New strategies to regulate acute myocardial
infarction and ischemia/reperfusion injury.
• New strategies to regulate restenosis after coronary
angioplasty.
• New strategies to regulate atherosclerosis andaneurism.
• New strategies to regulate systolic/diastolic heart
failure.
• New strategies to regulate sleep apnea syndromeand circadian rhythm abnormality.

• New strategies to regulate cardio-kidney syndrome.
• New strategies to regulate oral-pathogen induced
cardiovascular diseases.
• Development of gene therapies (anti-inflammationetc.).
• Development of new growth factor treatments(hepatocyte growth factor, etc.).
• Development of new anti-adhesion molecule
treatments (anti-inflammation, etc.).
• Development of new anti-extracellular treatments(anti-inflammation, anti-oxidation, etc.).
• Development of new chemical compounds(anti-inflammation, anti-coagulation, etc.).
• Expanding the use of foods and natural extracts.
• Expanding the application of existing drugs anddevices.
• 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.

377

References
1. Ogawa M, Suzuki J, Yamaguchi Y, Muto S, Itai A,
Hirata Y, Isobe M, Nagai R. The effects ofpharmacological plasminogen activator inhibitor-1
inhibition in acute and chronic rejection in murine
cardiac allografts. Transplantation. 91: 21-6,
2011.
2. Aoyama N, Suzuki J, Wang D, Ogawa M,
Kobayashi N, Hanatani T, Takeuchi Y, Izumi Y,
Isobe M. Porphyromonas gingivalis promotes
murine abdominal aortic aneurysms via matrix
metalloproteinase-2 induction. J Periodontal Res.
46:176-183, 2011.
3. Ngoc PB, Suzuki J, Ogawa M, Hishikari K,
Takayama K, Hirata Y, Nagai R, Isobe M. The
anti-inflammatory mechanism of prostaglandin E2
receptor 4 activation in rat experimental autoimmune myocarditis. J Cardiovasc Pharm. 57:
365-72, 2011.
4. Maejima Y, Adachi S, Suzuki J, Hirao K, Ito H,
Isobe M. Synergistic effect of combined
HMG-CoA reductase inhibitor and angiotensin-II
receptor blocker therapy in patients with chronic
heart failure -The HF-COSTAR Trial-. Circ J. 75:
589-595, 2011.
5. Maejima Y, Okada H, Haraguchi G, Onai Y,
Kosuge H, Suzuki J, Isobe M. Telmisartan, aunique ARB, improves left ventricular remodelingof infarcted heart by activating PPAR gamma. Lab
Invest. 91: 932-44, 2011.
6. Watanabe R, Nakajima T, Ogawa M, Suzuki J,
Muto S, Itai A, Hirata Y, Nagai R, Isobe M. Effectsof pharmacological suppression of plasminogenactivator inhibitor–1 in myocardial remodelingafter ischemia reperfusion injury. Int Heart J. 52:
388-392, 2011
7. Matsumoto K, Ogawa M, Suzuki J, Hirata Y,
Nagai R, Isobe M. Regulatory T lymphocytes
attenuate myocardial infarction-induced ventricular remodeling in mice. Int Heart J. 52: 382-387,
2011.
8. Watanabe R, Ogawa M, Suzuki J, Hirata Y, Nagai R,
Isobe M. A comparison between imidapril andramipril on attenuation of ventricular remodelingafter myocardial infarction. J Cardiovasc Pharm.
2011 Nov 29. [Epub ahead of print]

9. Aoyama N, Suzuki J, Ogawa M, Watanabe R,
Kobayashi N, Hanatani T, Yoshida T, Ashigaki N,
Izumi Y, Isobe M. Clarithromycin suppresses theperiodontal bacteria-accelerated abdominal aortic
aneurysms in mice. J Periodontal Res. 2011 Dec
19. [Epub ahead of print]
10. Sakamoto A, Nagai R, Saito K, Imai Y, Takahashi
M, Hosoya Y, Takeda N, Hirano K, Koike K,
Enomoto Y, Kume H, Homma Y, Maeda D,
Yamada H, Fukayama M, Hirata Y, Ishizaka N.
Idiopathic retroperitoneal fibrosis, inflammatory
aortic aneurysm, and inflammatory pericarditisRetrospective analysis of 11 case histories. J
Cardiol. 2011 Dec 8. [Epub ahead of print]
11. Higashikuni Y, Sainz J, Nakamura K, Takaoka M,
Enomoto S, Iwata H, Tanaka K, Sahara M, Hirata
Y, Nagai R, Sata M. The ATP-Binding CassetteTransporter ATP-Binding Cassette Transporter
Subfamily G Member 2 Protects Against Pressure
Overload-Induced Cardiac Hypertrophy and Heart
Failure by Promoting Angiogenesis andAntioxidant Response. Arterioscler Thromb Vasc
Biol. 2011 Nov 23. [Epub ahead of print]
12. Ikutomi M, Matsumura T, Iwata H, Nishimura G,
Ishizaka N, Hirata Y, Ono M, Nagai R. Gianttumorous legions surrounding the right coronary
artery associated with immunoglobulin-g4-related
systemic disease. Cardiology. 120: 22-6, 2011.
13. Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Ozeki A, Watanabe A, Kawarasaki S,
Nakao T, Taniguchi T, Ichimura Y, Toyama T,
Watanabe M, Hirata Y, Nagai R, Sato S.
Improvement of endothelial function in parallelwith the amelioration of dry cough and dyspnea
due to interstitial pneumonia by intravenous
cyclophosphamide pulse therapy in patients withsystemic sclerosis: a preliminary report of twocases. Mod Rheumatol. 2011 Oct 21. [Epubahead of print]
14. Maisel AS, Nakao K, Ponikowski P, Peacock WF,
Yoshimura M, Suzuki T, Tsutamoto T, Filippatos
GS, Saito Y, Seino Y, Minamino N, Hirata Y,
Mukoyama M, Nishikimi T, Nagai R. JapaneseWestern consensus meeting on biomarkers. Int
Heart J. 52: 253-65, 2011.
15. Fukuda T, Kurano M, Iida H, Takano H, Tanaka T,
Yamamoto Y, Ikeda K, Nagasaki M, Monzen K,

378

Uno K, Kato M, Shiga T, Maemura K, Masuda N,
Yamashita H, Hirata Y, Nagai R, Nakajima T.
Cardiac rehabilitation decreases plasma pentraxin
3 in patients with cardiovascular diseases. Eur J
Cardiovasc Prev Rehabil. 2011 Sep 13. [Epubahead of print]
16. Ogawa N, Imai Y, Takahashi Y, Nawata K, Hara K,
Nishimura H, Kato M, Takeda N, Kohro T, Morita
H, Taketani T, Morota T, Yamazaki T, Goto J, Tsuji
S, Takamoto S, Nagai R, Hirata Y. Evaluating
Japanese patients with the marfan syndrome using
high-throughput microarray-based mutational
analysis of fibrillin-1 gene. Am J Cardiol. 108:
1801-7, 2011.
17. Higashikuni Y, Takaoka M, Iwata H, Tanaka K,
Hirata Y, Nagai R, Sata M. Aliskiren in
combination with valsartan exerts synergistic
protective effects against ventricular remodelingafter myocardial infarction in mice. Hypertens
Res. 35: 62-9, 201118. Hasumi E, Iwata H, Saito K, Fujiu K, Ando J, ImaiY, Fujita H, Hirata Y, Nagai R. Diagnostic efficacy
of coronary CT angiography as a follow-up
modality for procedure-related coronary dissection.
Int Heart J. 52: 240-2, 2011.
19. Hatano M, Yao A, Kinugawa K, Hirata Y, Nagai R.
Acute effect of sildenafil is maintained in pulmonary arterial hypertension patients chronicallytreated with bosentan. Int Heart J. 52: 233-9,
2011.
20. Kiyosue A, Nagata D, Myojo M, Sato T, Takahashi
M, Satonaka H, Nagai R, Hirata Y. Aldosteroneinduced osteopontin gene transcription in vascularsmooth muscle cells involves glucocorticoid
response element. Hypertens Res. 34: 1283-7,
2011.
21. Kamo T, Matsumura T, Hirata Y, Nagai R.
Multiple pulmonary artery fistulas causing partial
lung edema. Intern Med. 50: 1259-60, 2011.
22. Kato N, Kinugawa K, Seki S, Shiga T, Hatano M,
Yao A, Hirata Y, Kazuma K, Nagai R. Quality oflife as an independent predictor for cardiac eventsand death in patients with heart failure. Circ J. 75:
1661-9, 2011.
23. Matsubara TJ, Iwata H, Shiga T, Hatano M, Yao A,
Ono M, Kinugawa K, Hirata Y, Nagai R.
Progressive coronary artery-pulmonary artery

fistula after size-mismatch cardiac transplantation.
ASAIO J. 57: 346-7, 2011.
24. Hatano M, Kinugawa K, Shiga T, Kato N, Endo M,
Hisagi M, Nishimura T, Yao A, Hirata Y, Kyo S,
Ono M, Nagai R. Less frequent opening of theaortic valve and a continuous flow pump are risk
factors for postoperative onset of aortic
insufficiency in patients with a left ventricularassist device. Circ J. 75: 1147-55, 2011.
25. Tanaka K, Nagata D, Hirata Y, Tabata Y, Nagai R,
Sata M. Augmented angiogenesis in adventitia
promotes growth of atherosclerotic plaque inapolipoprotein E-deficient mice. Atherosclerosis.
215: 366-73, 2011.
26. Takahashi M, Shimizu T, Inajima T, Hosoya Y,
Takeda N, Ishizaka N, Yamashita H, Hirata Y,
Nagai R. A case of localized IgG4-related thoracic
periarteritis and recurrent nerve palsy. Am J Med
Sci. 341: 166-9, 2011.
27. Kinugasa S, Tojo A, Sakai T, Tsumura H,
Takahashi M, Hirata Y, Fujita T. Selective
albuminuria via podocyte albumin transport inpuromycin nephrotic rats is attenuated by an
inhibitor of NADPH oxidase. Kidney Int. 80:
1328-38, 2011.
28. Yamane T, Hanaoka K, Muramatsu Y, Tamura K,
Adachi Y, Miyashita Y, Hirata Y, Nagano T. A
Method for Enhancing Cell-penetration of
Gd3+-based MRIContrast Agents by Conjugation
with Hydrophobic Fluorescent Dyes. Bioconjug
Chem. 22: 2227-36, 2011.
29. Saito T, Watanabe M, Kojima T, Matsumura T,
Fujita H, Kiyosue A, Takahashi M, Takeda N,
Maemura K, Yamashita H, Hirata Y, Komatsu S,
Ohtomo K, Nagai R. Successful blood samplingthrough azygos continuation with interrupted
inferior vena cava. Int Heart J. 52: 327-30, 2011.
30. Myojo M, Iwata H, Kohro T, Sato H, Kiyosue A,
Ando J, Sawaki D, Takahashi M, Fujita H, Hirata
Y, Nagai R. Prognostic implication ofmacrocytosis on adverse outcomes after coronary
intervention. Atherosclerosis. 2011 Dec 16. [Epubahead of print]
31. Oba S, Suzuki E, Nishimatsu H, Kumano S,
Hosoda C, Homma Y, Hirata Y. Renoprotective
effect of erythropoietin in ischemia/reperfusion
injury: Possible roles of the Akt/endothelial nitric379

oxide synthase-dependent pathway. Int J Urol.
2011 Nov 29. [Epub ahead of print]
32. Itoh A, Horiuchi M, Wakayama K, Xu J,
Bannerman P, Pleasure D, Itoh T. ZPK/DLK amitogen-activated protein kinase kinase kinase, isa critical mediator of programmed cell death of
motoneurons. J Neurosci. 31: 7223-8, 2011
33. Tada Y, Nakamura T, Funayama H, Sugawara Y,
Ako J, Ishikawa SE, Momomura S. Early
development of hyponatremia implicates shortand long-term outcomes in ST-elevation acute
myocardial infarction. Circ J. 75: 1927-33, 2011.
English Review
1. Suzuki J, Ogawa M, Muto S, Itai A, Hirata Y,
Isobe M, Nagai R. Effects of specific chemical
suppressors of plasminogen activator inhibitor-1 in
cardiovascular diseases. Expert Opin Inv Drug.
20: 255-264, 2011.
2. Suzuki J, Ogawa M, Muto S, Itai A, Isobe M,
Hirata Y, Nagai R. Novel IKB inhibitors for treatment of nuclear factor-kappa B-related diseases.
Expert Opin Inv Drug. 20: 395-405, 2011.
3. Suzuki J, Ogawa M, Watanabe R, Morishita R,
Hirata Y, Nagai R, Isobe M. Autoimmune giant
cell
myocarditisclinicalcharacteristics,
experimental models and future treatments-.
Expert Opin Ther Targets. 15: 1163-72, 2011.
4. Suzuki J, Ogawa M, Watanabe R, Takayama K,
Hirata Y, Nagai R, Isobe M. Roles of
prostaglandin E2 in cardiovascular diseases: focus
on the potential use of a novel selective EP4
receptor agonist. Int Heart J. 52: 266-269, 2011.
5. Suzuki J, Ogawa M, Hishikari K, Watanabe R,
Takayama K, Hirata Y, Nagai R, Isobe M. Noveleffects of macrolide antibiotics on cardiovasculardiseases. Cardiovasc Ther. 2011 Dec 5. [Epubahead of print]

380

Department of Ischemic
Circulatory Physiology,
KAATSU training
Associate Professor
Toshiaki Nakajima, M.D., Ph.D.

Assistant Professor
Tomohumi Yasuda, Ph.D.

Research Associate
Taira Fukuda, M.D., Ph.D. Hiroyuki Imuta, Ph.D.

Fellow Researcher
Toshihiro Morita, M.D., Ph.D., Haruko Iida, M.D., Ph.D., Takaaki Hasegawa

Homepage

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

381

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.

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)

2)

3)

Madarame H, Takano H, Iida H, Hashida H,
Morita T and Nakajima T. Blood Flow restrcited
exercise in a ballet dancer with Churg-Strauss
syndrome. Gazzetta Medica Italiana 2011; 170:
63-67.
Ozaki H, Miyachi M, Nakajima T, Abe T. Effectsof 10- Weeks Walk Training With Leg Blood
Flow Reduction on Carotid Arterial Complianceand Muscle Size in the Elderly Adults. Angiology.
2011: 62; 81-86.
Ozaki H, Sakamaki M, Yasuda T, Fujita S,
Ogasawara R, Sugaya M, Nakajima T, Abe T.
Increases in Thigh Muscle Volume and Strength
by Walk Training with Leg Blood Flow

Reduction in Older Participants. J Gerontol A
Biol Sci Med Sci. 2011; 66: 257-263.
4) Tanaka T, Ikeda K, Yamamoto Y, Iida H, Kikuchi
H, Morita T, Yamasoba T, Nagai R, Nakajima T.
Effects of serum amyloid A and lysophosphatidylchoilne on intracellular calcium
concentration in human coronary smooth muscle
cells. Int Heart J 2011; 52: 185-193.
5) Tsutsumi T, Takano N, Matsuyama N, Higashi Y,
Iwasawa K, Nakajima T. High frequency powers
hidden within QRS complex as an additional
predictor of lethal ventricular arrhythmias toventricular late potential in post-myocardial
infarction patients Heart Rhythm 2011; 8:1509-.
6) Iida H, Nakajima T, Kurano M, Yasuda T,
Sakamaki M, Sato Y, Yamasoba T, Abe T. Effectsof Walking with Blood Flow Restriction on Limb
Venous Compliance in Elderly Subjects. Clin
Physiol Funct Imaging. 2011 Nov;31(6):472-476.
7) Nakajima T, Morita T, Sato Y. Key considerations
when conducting KAATSU training. Int J
KAATSU Training Res 2011; 7: 1-6.
8) Fukuda T, Fukumura K, Uchida Y, Ootsuka T,
Yasuda T, Iida H, Morita T, Nagata T, Sato Y,
Nakajima T. A case of dementia presenting
remarkable improvement in activities of dailyliving through KAATSU training. Int J KAATSU
Training Res 2011; 7: 13-17.
9) Nakajima T, Yasuda T, Sato Y, Morita T,
Yamasoba T. Effects of Exercise and Anti-Aging.
Anti-Aging Medicine 2011; 8: 92-102.
10) Fukuda T, Kurano M, Iida H, Takano H, Tanaka T,
Yamamoto Y, Ikeda K, Nagasaki M, Monzen K,
Uno K, Kato M, Shiga T, Maemura K, Matsuda
N, Yamashita Y, Hirata Y, Nagai R, Nakajima T.
Cardiac rehabilitation decreases plasma pentraxin
3 in patients with cardiovascular diseases.
European Journal of Cardiovascular Prevention
Rehabilitation (in press)
11) Iwasaki S, Nakajima T, Chihara Y, Inoue A,
Fujimoto C, Yamasoba T. Developmental
changes in the expression of Kv1 potassiumchannels in rat vestibular ganglion cells. Brain
Research 2012;1429:29-35.
12) Takano NK, Tsutsumi T, Suzuki H, Okamoto Y,
Nakajima T. Time frequency power profile of
QRS complex obtained with wavelet transform in382

spontaneously hypertensive rats. Comput Biol
Med. 2012 Feb;42(2):205-212.
13) Minami Y, Kaneda H, Inoue M, Ikutomi M,
Morita T, Nakajima T. Endothelial dysfunction
following drug-eluting stent implantation: A
systematic review of the literature. International
Journal of Cardiology (in press)
14) Yasuda T, Fukumura K, Fukuda T, Iida H, Imuta
H, Sato Y, Yamasoba T, Nakajima T. Effects of
low-intensity, elastic band resistance exercise
combined with blood flow restriction on muscle
activation. Scandinavian Journal of Medicine andScience in Sports (in press)
15) Madarame H, Kurano M, Fukumura K, Fukuda T,
Nakajima T. Hemostatic and inflammatory
responses to blood flow-restrcited exercise inpatients with ischemic heart diseases: a pilot
study. Clin Physiol Funct Imaging. 2012 (inpress)

383

Department of Translational
Research for Healthcare andClinical Science
Project Associate Professor
Hiroyuki Morita, M.D.,Ph.D.

Project Research Associate
Takahide Kohro, M.D.,Ph.D.

Homepage

http://www.trhcs.org/en/

Introduction and Organization
Our department was open in January 2005,
contributed by Hitachi, Ltd. and Hitachi Medical
Corporation. Since then, the construction of clinicalinformation database has been performed incollaboration with the Department of Cardiovascular
Medicine of this University (Professor and Chairman;
Dr. Ryozo Nagai). From 2008 to 2010, our research
activities were supported by Theravalues Corporationand Hitachi, Ltd. In January 2011, new mission started
under the contribution of DVx Inc., WIN
INTERNATIONAL CO.,LTD. and Mitsubishi Tanabe
Pharma. The aim of our department is to improve theclinical information database to the better one and putthat into practical use in developing the clinicalresearch.
Our department belongs to the 22nd century medical
center in the University of Tokyo Hospital, which was
founded as the front line of university-industry
partnerships. As our research foothold is located in thehospital, we could keep the close connection with thebedside. Our department is thought to be suited for
obtaining the maximum output in clinical research.

Research activities
The onset and progression of the disease are thought

to be caused by the environmental and/or genetic
factors. What is the best way to identify thepathogenesis and the factors predicting the prognosis?
The answer should be the filing of the clinicalinformation.
We are constructing the effective framework to makethe relevant clinical data available for research andperforming the investigation to resolve the clinicalquestions, followed by the translation of its fruits tothe bedside.
Another mission is to confer the explicit scientificre-evaluation on the health issues (e.g. eating habits,
exercise, lifestyle) which have been believed to be
empirically effective. This mission has to be followedby the prompt publicity of the “accurate” data led byour re-evaluation.
The realization of these missions above could becompleted in a close collaboration with the academic
groups and private enterprises. In this regard, we areready to discuss and think together with anybody
anytime.
In summary, our research field covers the issues asfollows;
1. Development of information analysis system andsystematization of clinical information
2. Clinical and/or genomic research utilizing theclinical information analysis system
3. Scientific verification of eating habits, exercise

384

and lifestyle
4. Analysis on the current state of the medical
system
5. Spread of accurate medical information to society
utilizing the information technology

Research Grants
A Grant from the Ministry of Health, Labour andWelfare (2010-2012) (to Morita H)
A Grant from the Ministry of Education, Culture,
Sports, Science and Technology (2009-2011) (toMorita H)

References
1. Kimura K, Takenaka K, Pan X, Ebihara A, Uno K,
Fukuda N, Kohro T, Morita H, Yatomi Y, Nagai R.
Prediction of coronary artery stenosis using strain
imaging diastolic index at rest in patients withpreserved ejection fraction. J Cardiol. 2011;57:
311-315.
2. Morita H, Nagai R. Vemurafenib in melanoma
with BRAF V600E mutation. New England
Journal of Medicine 2011;365: 1448.
3. Kimura K, Takenaka K, Ebihara A, Uno K, Iwata
H, Sata M, Kohro T, Morita H, Yatomi Y, Nagai R.
Reproducibility and diagnostic accuracy of
three-layer speckle tracking echocardiography in aswine chronic ischemia model. Echocardiography
2011;28: 1148-1155.
4. Ogawa N, Imai Y, Takahashi Y, Nawata K, Hara K,
Nishimura H, Kato M, Takeda N, Kohro T, Morita
H, Taketani T, Morota T, Yamazaki T, Goto J,
Tsuji S, Takamoto S, Nagai R, Hirata Y.
Evaluating Japanese patients with the Marfan
syndrome using high-throughput microarraybased mutational analysis of fibrillin-1 gene. Am J
Cardiol. 2011;108: 1801-1807.

385

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 departments of Orthopaedic
Surgery and Rehabilitation Medicin. Our department
has been established for the epidemipological study toclarify the frequencies and risk factors for bone andjoint 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 for musculoskeletal diseases, including OA and OP. However, few
prospective, longitudinal studies have been undertaken, and little information is available regarding theprevalence and incidence of OA and OP as well as
pain and disability in the Japanese population. It isdifficiult to design rational clinical and public healthapproaches 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. A third comprehensive clinic visit isunderway from 2011.

References
1.

2.

3.

Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Capacity of endogenous
sex steroids to predict bone loss, osteoporosis
and osteoporotic fracture in Japanese men:Ten-year follow-up of the Taiji Cohort Study. J
Bone Miner Metab 29, 96-102, 2011
Matsudaira K, Palmer KT, Reading I, Hirai M,
Yoshimura N, Coggon D: Prevalence andcorrelates of regional pain and associateddisability in Japanese workers. Occup Environ
Med 68, 191-196, 2011
Evangelou E, Valdes AM, Kerkhof HJ,
Styrkarsdottir U, Zhu Y, Meulenbelt I, Lories RJ,
Karassa FB, Tylzanowski P, Bos SD; arcOGEN
Consortium, Akune T, Arden NK, Carr A,
Chapman K, Cupples LA, Dai J, Deloukas P,
Doherty M, Doherty S, Engstrom G, Gonzalez A,
Halldorsson BV, Hammond CL, Hart DJ,
Helgadottir H, Hofman A, Ikegawa S,

386

4.

5.

6.

Ingvarsson T, Jiang Q, Jonsson H, Kaprio J,
Kawaguchi H, Kisand K, Kloppenburg M,
Kujala UM, Lohmander LS, Loughlin J, LuytenFP, Mabuchi A, McCaskie A, Nakajima M,
Nilsson PM, Nishida N, Ollier WE,
Panoutsopoulou K, van de Putte T, Ralston SH,
Rivadeneira F, Saarela J, Schulte-Merker S, Shi
D, Slagboom PE, Sudo A, Tamm A, Tamm A,
Thorleifsson G, Thorsteinsdottir U, Tsezou A,
Wallis GA, Wilkinson JM, Yoshimura N,
Zeggini E, Zhai G, Zhang F, Jonsdottir I,
Uitterlinden AG, Felson DT, van Meurs JB,
Stefansson K, Ioannidis JP, Spector TD;
Translation Research in Europe Applied
Technologies for Osteoarthritis (TreatOA):
Meta-analysis of genome-wide association
studies confirms a susceptibility locus for knee
osteoarthritis on chromosome 7q22. Ann Rheum
Dis 70, 349-355, 2011
Kerkhof HJ, Meulenbelt I, Akune T, Arden NK,
Aromaa A, Bierma-Zeinstra SM, Carr A, Cooper
C, Dai J, Doherty M, Doherty SA, Felson D,
Gonzalez A, Gordon A, Harilainen A, Hart DJ,
Hauksson VB, Heliovaara M, Hofman A,
Ikegawa S, Ingvarsson T, Jiang Q, Jonsson H,
Jonsdottir I, Kawaguchi H, Kloppenburg M,
Kujala UM, Lane NE, Leino-Arjas P,
Lohmander LS, Luyten FP, Malizos KN,
Nakajima M, Nevitt MC, Pols HA, RivadeneiraF, Shi D, Slagboom E, Spector TD, Stefansson K,
Sudo A, Tamm A, Tamm AE, Tsezou A, UchidaA, Uitterlinden AG, Wilkinson JM, Yoshimura N,
Valdes AM, van Meurs JB: Recommendations
for standardization and phenotype definitions in
genetic studies of osteoarthritis: the TREAT-OA
consortium. Osteoarthritis Cartilage 19, 254-264,
2011
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Association of knee
osteoarthritis with the accumulation of
metabolic risk factors such as overweight,
hypertension, dyslipidaemia, and impaired
glucose tolerance in Japanese men and women:
The ROAD Study, J Rheumtol 38, 921-930,
2011
Cooper C, Cole ZA, Holroyd CR, Earl SC,
Harvey NC, Dennison EM, Melton LJ3,

7.

8.

9.

10.

11.

Cummings SR, Kanis JA and the IOF CSA
Working Group on Fracture Epidemiology(Adachi J, Borgström F, Dimai HP, Clark P, Lau
E, Lewiecki EM, Lips P, Lorenc R, McCloskey
E, Ortolani S, Papaioannou A, Silverman S,
Wahl DA, Yoshimura N). Secular trends in theincidence of hip and other osteoporotic fractures.
Osteoporos Int 22, 1277-1288, 2011
Muraki S, Oka H, Akune T, En-yo Y, Yoshida M,
Nakamura K, Kawaguchi H, Yoshimura N:
Association of occupational activity with joint
space narrowing and osteophytosis in the medialcompartment at the knee: The ROAD study.
Osteoarthritis Cartilage 19, 840-846, 2011
Muraki S, Akune T, Oka H, En-yo Y, Yoshida M,
Saika A, Suzuki T, Yoshida H, Ishibashi H,
Tokimura F, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Health-related
quality of life in subjects with low back pain andknee pain in a population-based cohort study ofJapanese men: The Research on Osteoarthritis
Against Disability Study. Spine (Phila Pa 1976)
36, 1312-1319, 2011
Inoue I, Mukoubayashi C, Yoshimura N,
Deguchi H, Watanabe M, Enomoto S, Maekita T,
Ueda K, Iguchi M, Yanaoka K, Tamai H, Oka M,
Fujishiro M, Takeshita T, Iwane M, Mohara O,
Ichinose M: Elevated risk of colorectal adenoma
with Helicobacter pylori-related chronic
gastritis: A population-based case-control study.
Int J Cancer 129, 2704-2711, 2011
Yoshimura N, Oka H, Muraki S, Kawaguchi H,
Nakamura K, Akune T: Changes in serum levelsof biochemical markers of bone turnover over 10
years among Japanese men and women:
associated factors and birth-cohort effect; The
Taiji Study. J Bone Miner Metab 29, 699-708,
2011
Yoshimura N, Oka H, Muraki S, Akune T,
Hirabayashi N, Matsuda S, Nojiri T, Hatanaka K,
Ishimoto Y, Nagata K, Yoshida M, Tokimura F,
Kawaguchi H, Nakamura K: Reference values
for hand grip strength, muscle mass, walking
time, and one-leg standing time as indices forlocomotive syndrome and associated disability:
The second survey of the ROAD study. J Orthop
Sci 16, 768-777, 2011

387

12.

13.

14.

15.

Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Biochemical markers ofbone turnover as predictors for occurrence ofosteoporosis and osteoporotic fractures in men
and women: Ten-year follow-up of the Taiji
cohort study. Mod Rheumatol 21, 608-620, 2011
Muraki S, Dennison E, Jameson K, Boucher BJ,
Akune T, Yoshimura N, Judge A, Arden NK,
Javaid K, Cooper C: Association of vitamin D
status with knee pain and radiographic knee
osteoarthritis. Osteoarthritis Cartilage 19,
1301-1306, 2011
Muraki S, Akune T, Oka H, En-yo Y, Yoshida M,
Nakamura K, Kawaguchi H, Yoshimura N:
Prevalence of falls and its association with knee
osteoarthritis and lumbar spondylosis as well as
knee and low back pain in Japanese men andwomen. Arthritis Care Res 63, 1425-1431, 2011
Muraki S, Oka H, Akune T, En-yo Y, Yoshida M,
Suzuki T, Yoshida H, Ishibashi H, Tokimura F,
Yamamoto S, Nakamura K, Kawaguchi H,
Yoshimura N: Indipendent association of joint
space narrowing and osteophyte formation at theknee with health-related quality of life in Japan:
A cross-sectional study. Arthritis Rheum 63,
3859-3864, 2011

388

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 healthhazards, 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 toprevent karoshi (death from overwork)

389(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.

2.

3.

4.

5.

6.

7.

Yasunaga H, Horiguchi H, Kuwabara K,
Hashimoto H, Matsuda S. Delay in Tetracycline
Treatment Increases the Risk of Complications in
Tsutsugamushi Disease. Intern Med 2011;50(1):37-42.
Yasunaga H, Horiguchi H, Kuwabara K,
Hashimoto H, Matsuda S. Venomous Snake Bites
in Japan. Am J Trop Med Hyg 2011;84(1):135-136.
Yasunaga H, Miyata H, Horiguchi H, Kuwabara
K, Hashimoto H, Matsuda S. Effect of theJapanese herbal Kampo medicine Dai-kenchu-to
on postoperative adhesive small bowel
obstruction requiring long-tube decompression: apropensity score analysis. Evidence-BasedComplementary and Alternative Medicine 2011,
Article ID 264289, 7 pages
Yasunagaa H, Miyata H, Horiguchi H, Tanabe S,
Akahane M, Ogawa T, Koike S, Imamura T.
Population Density, Call-response Interval, andSurvival of Out-of-hospital Cardiac Arrest.
International Journal of Health Geographics
2011; 10:26.
Yasunaga H, Sugihara T, Imamura T. Differencein Willingness-to-pay for Prostate Cancer
Screening between Ill-informed and Wellinformed Men: A Contingent Valuation Survey.
Urology 2011;77(6):1325-9.
Akahane M, Ogawa T, Koike S, Tanabe S,
Horiguchi H, Mizoguchi T, Yasunaga H, Imamura
T. The effects of sex on out-of-hospital cardiac
arrest outcomes. The American Journal of
Medicine 2011;124(4):325-33
Hashimoto H, Ikegami N, Shibuya K, Izumida N,
Noguchi H, Yasunaga H, Miyata H, Acuin JM,
Reich MR. Cost containment and quality of carein Japan: is there a trade-off? Lancet 2011;

378(9797):1174-1182.
8. Horiguchi H, Yasunaga H, Hashimoto H,
Matsuda S. Incidence of severe adverse events
requiring hospital care after trastuzumab infusion
for metastatic breast cancer: a nationwide survey
using an administrative claim database. Breast J
2011;17(6):683-5.
9. Koike K, Tanabe T, Ogawa T, Akahane M,
Yasunaga H, Horiguchi H, Matsumoto S,
Imamura T. Effect of time and day of admission
on 1-month survival and neurologicallyfavourable 1-month outcome in out-of-hospital
cardiopulmonary arrest patients. Resuscitation
2011;82(7):863-8.
10. Koike S, Tanabe T, Ogawa T, Akahane M,
Yasunaga H, Horiguchi H, Matsumoto S,
Imamura T. Immediate defibrillation or
defibrillation after cardiopulmonary resuscitation.
Prehospital Emergency Care 2011; 15(3):393400.
11. Koike S, Ogawa T, Tanabe T, Matsumoto S,
Akahane M, Yasunaga H, Horiguchi H, Imamura
T. Collapse-to-emergency medical service cardiopulmonary resuscitation interval and outcomes ofout-of-hospital cardiopulmonary arrest: a nationwide observational study. Critical Care 20112011;15:R120.
12. Kuwabara K, Matsuda S, Fushimi K, Ishikawa
KB, Horiguchi H, Fujimori K, Yasunaga H,
Miyata H. Quantitative Assessment of theAdvantages of Laparoscopic Gastrectomy and the
Impact of Volume-Related Hospital Characteristics on Resource Use and Outcomes of
Gastrectomy Patients in Japan. Ann Surg 2011;
253(1):64-70.
13. Nagase Y, Yasunaga H, Horiguchi H, Hashimoto
H, Shoda N, Kadono Y, Matsuda S, Nakamura K,
Tanaka S. Risk factors for pulmonary embolism
and the effects of fondaparinux after total hip andknee arthroplasty: a retrospective observational
study with use of a national database in Japan. J
Bone Joint Surg Am 2011; 93:e146 (1-7).
14. Otake H, Yasunaga H, Horiguchi H, Matsutani N,
Matsuda S, Ohe K. Impact of hospital volume onchest tube duration, length of stay and mortality
following lobectomy. Ann Thorac Surg 2011;92:
1069-75.

390

15. Sako A, Yasunaga H, Horiguchi H, Hashimoto H,
Masaki N, Matsuda S. Acute Hepatitis B in
Japan: Incidence, Clinical Practices and Health
Policy. Hepatol Res 2011;41(1):39-45.
16. Sugihara H, Yasunaga H, Horiguchi H,
Nishimatsu H, Kume H, Matsuda S, Homma Y.
Impact of Hospital Volume and Laser Usage on
Postoperative Complications and In-hospital
Mortality After Transurethral Surgery of Benign
Prostate Hyperplasia: Japanese Diagnosis
Procedure Combination Database. J Urol 2011;185:2248-2253.
17. Sugihara T, Yasunaga H, Horiguchi H,
Nishimatsu H, Matsuda S, Homma Y. Incidence
rate and clinical features of priapism in Japan; 46
cases from Japanese Diagnosis Procedure
Combination database 2006-2008. International
Journal of Impotence Research 2011;23(2):76-80.
18. Sumitani M, Uchida K, Yasunaga H, Horiguchi H,
Kusakabe Y, Matsuda S, Yamada Y. Prevalence ofMalignant Hyperthermia and Relationship with
Anesthetics in Japan: Data from the Diagnosis
Procedure Combination Database. Anesthesiology
2011;114(1):84-90.
19. Uchida K, Yasunaga H, Miyata H, Sumitani M,
Horiguchi H, Kuwajima K, Matsuda S, Yamada Y.
Impact of remifentanil introduction on practicepatterns in general anesthesia. J Anesth 2011;25(6):864-71.

391

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.,

Fumiko Mori, M.D., Ph.D.,

Mika Nagasaki, M.D., Ph.D.,

Kensuke Asaba, M.D., Ph.D.,

Homepage

Eriko Maeda, M.D.

http://www.h.u-tokyo.ac.jp/english/center22/en_contribute/computer.html

Introduction and Organization
The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) wasestablished in May 2005. It is under the supervision of
the Department of Radiology.
The aim of our research project is as follows: (1) tocreate a large database of health screening clinicaldata including medical images, (2) to develop methods
to analyze large volumes of medical images and to
search for algorithms to detect subtle abnormal
findings in these images, and (3) to evaluate theclinical usefulness of such image processing methods
and to apply the system in clinical settings.
The department comprises two project associate
professors and three project research associates, alongwith a medical staff of approximately 40 employees in
the health-screening center.

Clinical Activities
CDRPM is responsible for the clinical activities in the
CDRPM Health Screening Center. In this healthscreening center, the following diagnostic imaging
modalities are installed to facilitate high level ofdiagnostic accuracy: positron emission computed
tomography/X-ray computed tomography (PET/CT),

3-tesla magnetic resonance imaging (3T-MRI) systems,
ultrasound imaging systems, and digital mammography.

Teaching Activities
At present, CDRPM does not accept students.
However, CDRPM participates in the education of
students and residents in the Department of Radiology.
CDRPM endeavors to help students whose research
themes include image analysis such as computerassisted detection, or epidemiologic studies employing
health-screening data.

Research Activities
1) Health screening database
We have developed a unique health screening
information system in order to facilitate daily
management of the health screening activities and to
input health screening data. This information systemis still under constant revision. The medical images
acquired in the health screenings are stored in thehospital picture archiving and communication system(PACS) for clinical use. Medical images used solely
for research purposes are stored in an independent
PACS installed inside the CDRPM department.

3922) Image processing software development
We have structured an integrated software developing
system to facilitate the production of image processing
software. The system is divided into the clinical partand the research part, with the data in the latter being
anonymized. The clinical part consists of case entry
for software development, and clinical application of
the developed software. The research part consists ofan interface to obtain images of the representative
cases to develop the software, and an interface to test
the developed software with the accumulated cases.

3) Clinical evaluation, application ofsoftware, and epidemiological studies
Researches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed using thedeveloped software.

References
1.

2.

3.

4.

Goto M, Abe O, Miyati T, Inano S, Hayashi N,
Aoki S, Mori H, Kabasawa H, Ino K, Yano K,
Iida K, Mima K, Ohtomo K. 3 Tesla MRI detects
accelerated hippocampal volume reduction in
postmenopausal women. J.Magn.Reson.Imaging ;33(1):48-53 2011.
Hanaoka S, Fritscher K, Welk M, Nemoto M,
Masutani Y, Hayashi N, Ohtomo K, Schubert R.
3-D graph cut segmentation with Riemannian
metrics to avoid the shrinking problem. Med.
Image Comput.Comput.Assist.Interv. ; 14(Pt 3):
554-561 2011.
Goto M, Abe O, Miyati T, Inano S, Hayashi N,
Aoki S, Mori H, Kunimatsu A, Ino K, Iida K,
Yano K, Ohtomo K. Accelerated hippocampal
volume reduction in post-menopausal women: an
additional study with Atlas-based method.
Radiol.Phys.Technol. ; 4(2):185-188 2011.
Fukuda T, Kurano M, Iida H, Takano H, Tanaka
T, Yamamoto Y, Ikeda K, Nagasaki M, Monzen
K, Uno K, Kato M, Shiga T, Maemura K,
Masuda N, Yamashita H, Hirata Y, Nagai R,
Nakajima T. Cardiac rehabilitation decreases
plasma pentraxin 3 in patients with cardiovascular diseases. Eur.J.Cardiovasc.Prev.Rehabil.
2011.

5.

Takao H, Hayashi N, Inano S, Ohtomo K. Effectof head size on diffusion tensor imaging.
Neuroimage ; 57(3):958-967 2011.
6. Takao H, Hayashi N, Ohtomo K. Effect ofscanner in asymmetry studies using diffusion
tensor imaging. Neuroimage ; 54(2):1053-1062
2011.
7. Takao H, Hayashi N, Ohtomo K. Effect ofscanner in longitudinal studies of brain volume
changes. J.Magn.Reson.Imaging ;34(2):438-444
2011.
8. Inano S, Takao H, Hayashi N, Abe O, Ohtomo K.
Effects of age and gender on white matter
integrity. AJNR Am.J.Neuroradiol.; 32(11):21032109 2011.
9. Goto M, Abe O, Miyati T, Yoshikawa T,
Hayashi N, Takao H, Inano S, Kabasawa H,
Mori H, Kunimatsu A, Aoki S, Ino K, Iida K,
Yano K, Ohtomo K. Entorhinal cortex volume
measured with 3T MRI is positively correlatedwith the Wechsler Memory Scale-Revised
logical/verbal memory score for healthy subjects.
Neuroradiology ;53(8):617-622 2011.
10. Takao H, Hayashi N, Ohtomo K. A longitudinal
study of brain volume changes in normal aging.
Eur.J.Radiol. 2011.
11. Gonoi W, Akai H, Hagiwara K, Akahane M,
Hayashi N, Maeda E, Yoshikawa T, Tada M,
Uno K, Ohtsu H, Koike K, Ohtomo K. Pancreas
divisum as a predisposing factor for chronic andrecurrent idiopathic pancreatitis: initial in vivo
survey. Gut ;60(8):1103-1108 2011.
12. Kimura K, Takenaka K, Pan X, Ebihara A, Uno
K, Fukuda N, Kohro T, Morita H, Yatomi Y,
Nagai R. Prediction of coronary artery stenosis
using strain imaging diastolic index at rest in
patients with preserved ejection fraction.
J.Cardiol. ; 57(3): 311-315 2011.
13. Kimura K, Takenaka K, Ebihara A, Uno K, Iwata
H, Sata M, Kohro T, Morita H, Yatomi Y, Nagai
R. Reproducibility and diagnostic accuracy of
three-layer speckle tracking echocardiography ina swine chronic ischemia model. Echocardiography ; 28(10):1148-1155 2011.
14. Gonoi W, Akahane M, Akai H, Hagiwara K,
Kiryu S, Hayashi N, Ohtomo K. Retroportal
main pancreatic duct with circumportal pancreas:393

radiographic visualization. Clin.Imaging ; 35(6):442-446 2011.
15. Takao H, Hayashi N, Ohtomo K. White matterasymmetry in healthy individuals: a diffusion
tensor imaging study using tract-based spatial
statistics. Neuroscience ;193:291-299 2011.

394

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
and department of Human Genetics. Our department
has been established for the study of locomotor
system medicine.

Research activities
Our research field covers observational and genomic
epidemiology and main target diseases are osteoarthritis, spondylosis and osteoporosis. Osteoarthritis
and osteoporosis are major public health issues in theelderly 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 and evidence-based
prevention strategy. We set up a large-scale nationwide osteoarthritis/osteoporosis cohort study called
ROAD (Research on Osteoarthritis/osteoporosis
Against Disability) in 2005 for the pursue of genomicand etiological evidence. We have to date created abaseline database with detailed clinical and genomic
information on three population-based cohorts withtotal 3,040 participants in urban, mountainous andseacoast communities of Japan. Recruitment andbaseline visits began in October 2005 and werecompleted over a 1.5-year period, with the last visit inMarch 2007. A third comprehensive clinic visit isunderway from 2011 after a follow-up period of 3
years.

References
1. Kerkhof HJ, Meulenbelt I, Akune T, Arden NK,
Aromaa A, Bierma-Zeinstra SM, Carr A, Cooper
C, Dai J, Doherty M, Doherty SA, Felson D,
Gonzalez A, Gordon A, Harilainen A, Hart DJ,
Hauksson VB, Heliovaara M, Hofman A, Ikegawa
S, Ingvarsson T, Jiang Q, Jonsson H, Jonsdottir I,
Kawaguchi H, Kloppenburg M, Kujala UM, Lane
NE, Leino-Arjas P, Lohmander LS, Luyten FP,
Malizos KN, Nakajima M, Nevitt MC, Pols HA,
Rivadeneira F, Shi D, Slagboom E, Spector TD,
Stefansson K, Sudo A, Tamm A, Tamm AE,
Tsezou A, Uchida A, Uitterlinden AG, Wilkinson
JM, Yoshimura N, Valdes AM, van Meurs JB:
Recommendations for standardization andphenotype definitions in genetic studies ofosteoarthritis: the TREAT-OA consortium.
Osteoarthritis Cartilage 19: 254-264, 2011.
2. Evangelou E, Valdes AM, Kerkhof HJ,
Styrkarsdottir U, Zhu Y, Meulenbelt I, Lories RJ,
Karassa FB, Tylzanowski P, Bos SD; arcOGEN
Consortium, Akune T, Arden NK, Carr A,
Chapman K, Cupples LA, Dai J, Deloukas P,
Doherty M, Doherty S, Engstrom G, Gonzalez A,

395

3.

4.

5.

6.

7.

Halldorsson BV, Hammond CL, Hart DJ,
Helgadottir H, Hofman A, Ikegawa S, Ingvarsson
T, Jiang Q, Jonsson H, Kaprio J, Kawaguchi H,
Kisand K, Kloppenburg M, Kujala UM,
Lohmander LS, Loughlin J, Luyten FP, Mabuchi
A, McCaskie A, Nakajima M, Nilsson PM,
Nishida N, Ollier WE, Panoutsopoulou K, van dePutte T, Ralston SH, Rivadeneira F, Saarela J,
Schulte-Merker S, Shi D, Slagboom PE, Sudo A,
Tamm
A,
Tamm
A,
Thorleifsson
G,
Thorsteinsdottir U, Tsezou A, Wallis GA,
Wilkinson JM, Yoshimura N, Zeggini E, Zhai G,
Zhang F, Jonsdottir I, Uitterlinden AG, Felson DT,
van Meurs JB, Stefansson K, Ioannidis JP, Spector
TD; Translation Research in Europe Applied
Technologies for Osteoarthritis (TreatOA):
Meta-analysis of genome-wide association studies
confirms a susceptibility locus for knee
osteoarthritis on chromosome 7q22. Ann Rheum
Dis 70: 349-355, 2011.
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Capacity of endogenous
sex steroids to predict bone loss in Japanese men:
10-year follow-up of the Taiji Cohort Study. J
Bone Miner Metab 29: 96-102, 2011.
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Association of knee
osteoarthritis with the accumulation of metabolicrisk factors such as overweight, hypertension,
dyslipidemia, and impaired glucose tolerance inJapanese men and women: the ROAD study. J
Rheumatol 38: 921-930, 2011.
Muraki S, Akune T, Oka H, Enyo Y, Yoshida M,
Saika A, Suzuki T, Yoshida H, Ishibashi H,
Tokimura F, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Health-related
quality of life in subjects with low back pain andknee pain in a population-based cohort study ofJapanese men: the ROAD study. Spine (Phila Pa
1976) 36: 1312-1319, 2011.
Muraki S, Oka H, Akune T, Enyo Y, Yoshida M,
Nakamura K, Kawaguchi H, Yoshimura N:
Association of occupational activity with joint
space narrowing and osteophytosis in the medialcompartment of the knee: the ROAD study.
Osteoarthritis Cartilage 19: 840-846, 2011.
Yoshimura N, Muraki S, Oka H, Kawaguchi H,

Nakamura K, Akune T: Changes in serum levelsof biochemical markers of bone turnover over 10
years among Japanese men and women:
associated factors and birth-cohort effect; the Taiji
study. J Bone Miner Metab 29: 699-708, 2011.
8. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Biochemical markers ofbone turnover as predictors for occurrence ofosteoporosis and osteoporotic fractures in men
and women: Ten-year follow-up of the Taiji cohort
study. Mod Rheumatol 21: 608-620, 2011.
9. Yoshimura N, Oka H, Muraki S, Akune T,
Hirabayashi N, Matsuda S, Nojiri T, Hatanaka K,
Ishimoto Y, Nagata K, Yoshida M, Tokimura F,
Kawaguchi H, Nakamura K: Reference values forhand grip strength, muscle mass, walking time,and one-leg standing time as indices forlocomotive syndrome and associated disability:
The second survey of the ROAD study. J Orthop
Sci 16: 768-777, 2011.
10. Muraki S, Dennison E, Jameson K, Boucher BJ,
Akune T, Yoshimura N, Judge A, Arden NK,
Javaid K, Cooper C: Association of vitamin D
status with knee pain and radiographic knee
osteoarthritis.
Osteoarthritis
Cartilage19:1301-1306, 2011.
11. Muraki S, Oka H, Akune T, En-Yo Y, Yoshida M,
Suzuki T, Yoshida H, Ishibashi H, Tokimura F,
Yamamoto S, Nakamura K, Kawaguchi H,
Yoshimura N: Independent association of joint
space narrowing and osteophyte formation at theknee with health-related quality of life in Japan: A
cross-sectional study. Arthritis Rheum 63:
3859-3864, 2011.
12. Muraki S, Akune T, Oka H, En-Yo Y, Yoshida M,
Nakamura K, Kawaguchi H, Yoshimura N:
Prevalence of falls and its association with knee
osteoarthritis and lumbar spondylosis as well as
knee and lower back pain in Japanese men andwomen. Arthritis Care Res (Hoboken) 63: 14251431, 2011.

396

Department of Health Care Safety
Management
Project Professor
Yasushi Kodama, M.D., LL.M., Ph.D.

Project Assistant Professor
Kenji Harada, M.D., Ph.D.

Project Researcher
Tomoko Takahashi Matsuura, M.H.Sc.,
Maiko Mizuki, M.P.H.
Reiko Segawa, R.N., M.S.

Homepage http://www.h.u-tokyo.ac.jp/center22/iryou_anzen.html
http://square.umin.ac.jp/MSMCM/
Introduction and Organization
The Department of Health Care Safety Management
was established in the 22nd century medical center of
the University of Tokyo Hospital by the contributionof Tokio Marine & Nichido Fire Insurance Co., Ltd. in
December, 2005.
The public concern to the malpractice and the medical
affairs dispute has risen in developed countries withseveral events such as the public inquiry into
children’s heart surgery at the Bristol Royal Infirmary
and the accidental chemotherapy overdoses occurredin the Dana-Farber Cancer Institute at the end of the20th century. Reports of media in our country
concerning the malpractice and the medical affairs
dispute increase suddenly on the boundary of 1999.
Fears rise to making the criminal case through themandatory reporting to the police by the Medical
Practitioners Law Article 21. Some events becometargets of investigations while several verdicts are put
out as acquittals. There exist various discussions andconfusions over the intervention of the police
authority procedures to the process of medical
treatment.

On the other hand, in the medical affairs dispute overthe civil affairs compensation for damages, a lot ofcases have been done through various channels suchas the correspondence procedures of the explanationand the reconciliation before they become lawsuits. In
spite of such an effort, the civil affairs health carelawsuit number has kept increasing from 1970s (about
100 new cases received per year) to 2004 (1110 new
cases per year), by the pace that doubled every ten
years. Though the civil affairs health care lawsuit
number shows a decreasing tendency after 2004, a lotof medical treatment disputes became lawsuits in 2009,
733 new cases received and 952 cases paid-up.
In our department, while looking straight at the realityof the malpractice and the medical affairs dispute fromeach aspect of the patient, the health care provider,and the society, it aims at a healthy rebuilding of thehealth care and the recovery of confidence to the
medical treatment, by thinking about the ideal way of
a better legal system in cooperation with the clinicalsite. With the best use of the experience in thestate-of-the-art university hospital, we are establishing
an approach that promotes mutual understanding by
the conversation between the patient and the health397

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
Research Article
1. K.Nakajima, S. Honma, N. Tamaki, M. Kaneko, H.
Nagawa, K. Harada, F, Nagamura, A. Okawa, T.
Kurabayashi, S. Toyabe, M. Gotoh, T. Souma, H.
Takeda, R. Takahashi, I. Morisaki, K. Maeda, K.
Ehara, R. Tominaga. Analysis of Utilization andIssues on the “Model Project for the Investigation
and Analysis of Medical Practice-AssociatedDeaths” Experienced in Japanese National
University Hospitals. The Japanese Journal of
Quality and Safety in Healthcare. 2011:6(3):332-345 (in Japanese)Books
1. Medical dispute settlement and ADR. Y. Kodama(coauthor). Edited by Japan Federation of Bar
Associations ADR center. Kobundo 2011 (inJapanese).
2. Bioethics The 1st volume Basic compositionof bioethics. Y. Kodama (coauthor). Edited by M.
Imai and N. Morishita. Mruzen 2011 (inJapanese).
3. Nursing administration study text
SecondeditionNursing management theory third
volume. T. Takahashi, K. Harada (coautors).
Edited by T. Ibe and M. Nakanishi. JapaneseNursing Association 2011 (in Japanese).
4. Healthcare safety and communication. T.
Takahashi (coauthor). Edited by K. Yamauchi.
Reitaku University 2011 (in Japanese).
Conference Presentations
International Meetings
1. S. Andoh, K. Harada, Y. Kodama: PATIENT
SAFETY SUPPORT CENTRES IN JAPAN.
Quality & Safey in Healthcare Amsterdam
2011.5-8 April 2011.
Domestic Meetings
1. K. Harada, Y. Yano, M. Tsukuda. Development of
the e-learning teaching materials for sexual398

harassment prevention, and examination of thevalidity. Japanese Society for Quality and Safety
in Healthcare 6th annual scientific meeting.
2. N. Kodate, A. Ross, K. Taneda, K. Harada.
Beyond Human Error: The trial of a health caresafe systems configuration and the future subject
in Britain. Japanese Society for Quality and
Safety in Healthcare 6th annual scientific meeting.
3. M. Mizuki, T. Takahashi, K. Harada, Y. Kodama.
Analysis of the complaint consultation by which
the medical safe support center was brought nearin the Heisei 22 fiscal year. Japanese Society for
Quality and Safety in Healthcare 6th annual
scientific meeting.

399

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-cardiovascular complication, which is induced by deflective lifestyle (saltexcess, obesity, and so on), the Division of Molecular
Cardiovascular Metabolism was started with donationof Daiichi-Sankyo Company Limited and supportedby the Department of Nephrology and Endocrinology,
in April 1, 2006. This division consists of theabove-mentioned two staffs and a few part-time staff
and graduate fellows. Our academic activity ismajorly basic research using animals. In addition, we
also participate in clinical research.

Teaching activities
In March of 2007, 2008, and 2010, total three graduate
fellows took the medical degree. And now a few
graduate fellows work in our laboratory.

Research activities
Basic Research: We are investigating the role of thecentral sympathetic nervous system on salt-sensitive
hypertension, metabolic syndrome, and their renal
complication, and the sympathetic nervous system andthe renin-angiotensin- aldosterone system (RAAS) on

the onset and progress of kidney disease.
For example, we demonstrated that sympathoexcitation by oxidative stress in the brain mediatedblood pressure (BP) elevation in salt-sensitive
hypertension, obesity-induced hypertension, andchronic kidney disease-associated hypertension. Thisfinding suggests that sympathoexcitation by ROS in thebrain is a common and important mechanism forpathophysiology of many types of hypertensive disease
due to defective lifestyle. In these illnesses, it is wellknown that RAAS also plays an important role andaldosterone has been suggested to contribute toprogress of cardiac and renal injury. Thus, we
examined the role of aldosterone in oxidative
stress-induced sympathoexcitation in the brain of
hypertension with salt excess and obesity and showedinteresting results.
In addition, to elucidate the glomerular-specificrole of the sympathetic nervous system in the onset andprogress of kidney injury in salt-sensitive hypertension,
we examined the effect of specific delivery system ofsiRNA of tyrosine hydroxylase, a rate-limiting enzyme
of norepinephrine synthesis, to glomerulus in kidney
injury of salt-induced hypertensive rats. Interestingly,
this treatment ameliorated glomerular but not interstitialdamage of the kidney.
Also, we demonstrated that prepubertal saltloading caused more sever hypertension and renal

400

injury compared with high salt intake in adulthoodprobably due to mineralocorticoid receptor (MR)
activation, inflammatory and oxidant action, and rac-1
activation. We are recently comparing the effects ofobesity between young and adult hypertensive rats.
In addition, we suggested that MR activation also
contribute to the development of renal injury induced
by inflammation, such as lupus nephritis. We arefurther examining the precise role of MR in lupus
nephritis.
Clinical investigation: Now, we are doing
coordinating and secretarial work of a few clinical
trials and join as a steering committee of clinical trialof the other institute.

References
1. Ishikawa A, Kawarazaki H, Ando K, Fujita M,
Fujita T, Homma Y. Renal preservation effect ofubiquinol, the reduced form of coenzyme Q10.
Clin Exp Nephrol. 2011; 15(1): 30-33.
2. Kawarazaki H, Ando K, Fujita M, Matsui H,
Nagae A, Muraoka K, Kawarasaki C, Fujita T.
Mineralocorticoid receptor activation: a major
contributor to salt-induced renal injury andhypertension in young rats. Am J Physiol Renal
Physiol. 2011; 300(6): F1402-F1409.
3. Shibata S, Mu S, Kawarazaki H, Muraoka K,
Ishizawa K, Yoshida S, Kawarazaki W, Takeuchi
M, Ayuzawa N, Miyoshi J, Takai Y, Ishikawa A,
Shimosawa T, Ando K, Nagase M, Fujita T. Rac1
GTPase in rodent kidneys is essential forsalt-sensitive hypertension via a mineralocorticoid
receptor-dependent pathway. J Clin Invest. 2011;
121(8): 3233-3243.
4. Ando K, Haneda M, Ito S, Kashihara N, Node K,
Nangaku M, Shimosawa T, Kishimoto J, Fujita T:
Design and rationale of Japanese Evaluation
between Formula of Azelnidipine and Amlodipine
Add on Olmesartan to Get Antialbuminuric EffectStudy (J-FLAG): Evaluation of the antialbuminuric effects between calcium channel blocker withsympatholytic action in hypertensive patients withdiabetes and albuminuria. Cardiovasc Drugs Ther
2011: 25: 341-7. Erratum 2011; 25: 365-366.
5. Kawarazaki H, Shibagaki Y, Fukumoto S, Kido R,
Ando K, Nakajima I, Fuchinoue S, Fujita T,

Fukagawa M, Teraoka S. Natural history ofmineral and bone disorders after living donor
kidney transplantation; One-year prospective
observational study. Ther Apher Dial. 2011;15(5): 481-487.
6. Matsuoka H, Ando K, Ueshima K, Babazono T,
Kario K, Sato T, Nakao K, Fujita T, on behalf of
the SAKURA Trial Investigators. Design andrationale of the Study of Assessment for Kidney
function
by
Urinary
microalbuminin
RAndomized (SAKURA) trial: Comparison of theantialbuminuric effects between L-/N-type andL-type calcium channel blocker in hypertensive
patients with diabetes and microalbuminuria. Clin
Exp Hypertens. 2011;33(7):455-462.
7. Fujita M, Ando K, Kawarazaki H, Kawarasaki C,
Muraoka K, Ohtsu H, Shimizu H, Fujita T:
Sympathoexcitation by brain oxidative stressmediates arterial pressure elevation in salt-induced
chronic kidney disease. Hypertension 2012;59(1):105-112.
8. Ando K, Fujita M. Reactive oxygen species andthe central nervous system in salt-sensitive
hypertension: possible relationship to obesityinduced hypertension. Clin Exp Pharmacol
Physiol. 2012; 39(1): 111-116.
9. Ando K, Fujita T. Pathophysiology of saltsensitive hypertension. Ann Med 2012; 44(suppl 1): S119-S126.
10. Kawarazaki H, Ando K, Shibata S, Muraoka K,
Fujita M, Kawarazaki C, Fujita T. Major role ofmineralocorticoid receptor and small GTPase
Rac1 activation in salt induced hypertension andkidney injury in young rats. J Hypertens. in press

401

Department of Healthcare Quality
Assessment
Associate Professor
Hiroaki Miyata, Ph.D.

Assistant Professor
Suguru Okubo, Ph.D.

Researcher
Ai Tomotaki, R.N., M.S.

Homepage

http://hqa.umin.jp/

Introduction and Organization
The Department of Healthcare Quality Assessment(HQA) was established in 2006 and performs
researches on healthcare quality improvement incollaboration with the Department of Cardiothoracic
Surgery in University of Tokyo. HQA has collaborated
with the Department of Health Economics andEpidemiology Research from 2009 and with the
Department of Pediatric Surgery from 2010.
Health care reform should be focus on improving
health and health care value for patients. As improving
the value of health care is something only medical
teams can do, HQA has collaborated with healthcare
professional committees. HQA supports systematic
data collection, data management, practical analysis
and useful feedback. Our benchmarking projects
based on clinical database and will drive quality
improvement in each field. With such positive-sum
competition, patients will receive better care,
physicians will be rewarded for excellence, and costs
will be contained. Three principles should guide thischange: (a) the goal is value for patients, (b) medical
practice should be organized around medical
conditions and care cycles, and (c) results —risk-adjusted outcomes and costs — must be measured.
HQA already developed risk models and provide

several practical tools for medical staff through joint
research with Japan Cardiovascular Surgery Database(JCVSD). One of practical tools is JapanSCORE
which allows a user to calculate a patient’s risk ofmortality and other morbidities. JapanSCORE
incorporates JCVSD risk models that are designed toserve as statistical tools to account for the impact ofpatient risk factors on operative mortality andmorbidity. HQA also conducted policy analysis andclinical researches which might contribute tohealthcare
quality
improvement.
Value-based
competition on results provides a path for reform thatrecognizes the role of healthcare professionals at theheart of the system.

Research activities
For healthcare quality improvement, a) healthcare
quality must be identified and b) quality indicators
must be set and monitored in each healthcare region.
A well-designed database system that collects clinicaldata continuously in reliable and validated manners isneeded to identify healthcare quality, monitor quality
indicators, and improve the quality of healthcare
services. HQA has designed and managed nationwide
database systems in collaboration with the Japan
Surgical Society, the Japanese Society for
Cardiovascular Surgery and the Japanese Society of402

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.
Also, a new project collaborated with National
Clinical Database (NCD) started. More than 2,500
hospitals from around Japan have already participatedin NCD. More than 1,000,000 surgical cases per year
will be expected to submit to NCD.

References
1. Uchida K, Yasunaga H, Miyata H, et al. Impact ofremifentanil introduction on practice patterns ingeneral anesthesia. J Anesth 2011;25(6):864-871.
2. Yasunaga H, Miyata H, Horiguchi H, Kuwabara K,
Hashimoto H, Matsuda S. Effect of the Japanese
herbal kampo medicine dai-kenchu-to on
postoperative adhesive small bowel obstruction
requiring long-tube decompression: a propensity
score analysis. Evid Based Complement Alternat
Med 2011;2011:264289
3. Yasunaga H, Miyata H, Horiguchi H, et al.
Population density, call-response interval, andsurvival of out-of-hospital cardiac arrest. Int J
Health Geogr 2011;10:26.
4. Mogi S, Kohsaka S, Miyata H, et al. Comparison
between working day and holiday acute coronary
syndrome presentation. Int J Cardiol 2011;153(1):85-87.
5. Miyata H, Motomura N, Yozu R, Kyo S,
Takamoto S, Japan Cardiovascular Surgery
Database. Cardiovascular surgery risk prediction
from the patient’s perspective. J Thorac
Cardiovasc Surg 2011;142:e71-e76.
6. Shibuya K, Hashimoto H, Ikegami N, et al Futureof Japan's system of good health at low cost withequity: beyond universal coverage. The Lancet
2011;378(9798): 1265-1273.
7. Hashimoto H, Ikegami N, Shibuya K, et al. Cost
containment and quality of care in Japan: is therea trade-off? The Lancet 2011; 378(9797):11741182.
8. Takahashi M, Kohsaka S, Miyata H, et al.
Association between prehospital time interval andshort-term outcome in acute heart failure patients.
Journal of Cardiac Failure 2011;17(9):742-747.
9. Miyata H, Motomura N, Tsukihara H, Takamoto S;
Japan Cardiovascular Surgery Database. Risk
models including high-risk cardiovascular procedures: clinical predictors of mortality and morbidity.
Eur J Cardiothorac Surg 2011;39(5):667-674.
10. Saito A, Motomura M, Miyata H, Takamoto S, Kyo
S, Ono M; Japan Cardiovascular Surgery Database
Organization. Age-specific risk stratification in
13488 isolated coronary artery bypass grafting
procedures. Interact Cardiovasc Thorac Surg 2011;12(4):575-580.
11. Suzuki H, Gotoh M, Sugihara K, et al. Nationwide
survey and establishment of a clinical database forgastrointestinal surgery in Japan: Targeting
integration of a cancer registration system andimproving the outcome of cancer treatment. Cancer
Sci 2011;102(1):226-230.
12. Kuwabara K, Matsuda S, Fushimi K, et al..
Quantitative assessment of the advantages oflaparoscopic gastrectomy and the impact ofvolume-related hospital characteristics on resource
use and outcomes of gastrectomy patients in Japan.
Ann Surg 2011; 253(1): 64-70.

Presentation
1. Mogi S, Kohsaka S, Miyata H, et al. Percutaneous
coronary intervention for acute coronary
syndrome comparison between weekend versus
weekday presentation. American College of
Cardiology 11& i2 Summit 2011, New Orleans.
2011/4.
2. Endo A, Kohsaka S, Miyata H, et al. Who will notreceive optimized medical therapy after
percutaneous coronary intervention? Analysis
from Japanese prospective multicenter registry.
American College of Cardiology 11& i2 Summit
2011, New Orleans. 2011/4.

403

Department of Anti-Aging
Medicine
Professor
Satoshi Inoue, M.D., Ph.D.

Research Associate
Tomohiko Urano, M.D., Ph.D.

Homepage

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

Introduction and Organization
The Department of Anti-Aging Medicine wasestablished at the 22nd Century Medical and ResearchCenter of University of Tokyo Hospital in 2006. This
department has a close relationship with the
Department of Geriatric Medicine at the Graduate
School of Medicine, University of Tokyo. The goal ofthis research program is to understand the genetic andenvironmental factors that contribute to thepathogenesis of age-related disorders, including
obesity, diabetes, metabolic disorders, osteoporosis,
osteoarthritis, sarcopenia, atherosclerosis, dementia,
age-related macular degeneration, prostate cancer,
mammary carcinoma, and immunocompromised
conditions. In particular, the program aims to clarify
the roles of sex hormones estrogen and androgen in
normal, aging and disease processes. Through basic
biomedical research, our department will reveal
age-dependent changes at cellular, tissue, andwhole-body levels, and will contribute to thedevelopment of molecule-targeted treatment andalternative prevention of age-related processes anddiseases.

Research activities
Aging causes degeneration and dysfunction of cells invarious organs, leading to the development of multiple
disorders in elderly people, as exemplified by obesity,

glucose intolerance, dyslipidemia. Osteoporosis andosteoarthritis are also common bone and cartilage
disorders among elderly people. In addition, aging is
an important risk factor for the prognosis of
hormone-dependent tumors, prostate cancer andmammary carcinoma. Since aging and age-relateddisorders affect the quality of daily living and lifespanof elderly people, we will identify the genetic andenvironmental factors that control aging processes
using recent technology of human genetics andmolecular biology.
Our recent findings contribute to the progress in threefollowing research fields.
1. We originally identified estrogen-responsive finger
protein (Efp/TRIM25) as an estrogen target genethrough genome binding-site cloning technique. Efp
has a structure of the TRIM/RBCC protein, with
RING finger, B-box, and coiled-coil domains, and it
has been shown as a critical molecule that promotes
the progression of mammary carcinoma. In addition
we recently discovered that Efp has anotherimportant role in antiviral defenses. Extending our
findings on TRIM25, we also study the functions ofother TRIM proteins in normal states and in cancer
and immune response, including TRIM5α, TRIM17(Terf), TRIM44 and TRIM63.
2. Using chromatin immunoprecipitation microarray404

analysis and systems biology approach, we
discovered novel androgen responsive genes
including UGT1A1, CDH2, APP, and FOXP1. The
tumor-promoting effect of APP has been shown inin vivo models of prostate cancer.
3. As a genetic approach, we perform single
nucleotide polymorphisms (SNP) analysis to
identify disease-related factors for osteoporosis,
osteoarthritis, and age-related macular degeneration.
Through genome-wide associated study andcandidate gene approach, we identify several
interesting disease-related genes and focus on thefunctional studies for these genes. We also combine
mouse genetics to solve the functions ofdisease-related genes in physiological states as wellas in pathophysiological states.
Our intensive studies will provide novel molecularevidences for aging processes, which will be usefulfor the establishment of anti-aging medicine and thedevelopment of novel therapeutic modalities forage-related disorders.

References
1. Ijichi N, Shigekawa T, Ikeda K, Horie-Inoue K,
Fujimura T, Tsuda H, Osaki A, Saeki T, Inoue S:
Estrogen-related receptor γ modulates cellproliferation and estrogen signaling in breast
cancer. J Steroid Biochem Mol Biol 123, 1-7,
2011.
2. Oyama M, Nagashima T, Suzuki T, Kozuka-Hata
H, Yumoto N, Shiraishi Y, Ikeda K, Kuroki Y,
Gotoh N, Ishida T, Inoue S, Kitano H, OkadaHatakeyama M: Integrated Quantitative Analysisof the Phosphoproteome and Transcriptome in
Tamoxifen-Resistant Breast Cancer. J Biol Chem
286, 818-829, 2011.
3. Tsuchihashi T, Mori K, Horie-Inoue K, Gehlbach
PL, Kabasawa S, Takita H, Ueyama K, Okazaki Y,
Inoue S, Awata T, Katayama S, Yoneya S:
Compliment Factor H and High- Temperature
Requirement A-1 Genotypes and Treatment
Response of Age-related Macular Degeneration.
Ophthalmol 118, 93-100, 2011.
4. Takayama K, Tsutsumi S, Katayama S, Okayama

T, Horie-Inoue K, Ikeda K, Urano T, Kawazu C,
Hasegawa A, Ikeo K, Gojyobori T, Ouchi Y,
Hayashizaki Y, Aburatani H, Inoue S: Integrationof cap analysis of gene expression and chromatin
immunoprecipitation analysis on array reveals
genome-wide androgen receptor signaling inprostate cancer cells. Oncogene 30, 619-630,
2011.
5. Urano T, Narusawa K, Sasaki N, Shiraki M, Hosoi
T, Ouchi Y, Nakamura T, Inoue S: A
single-nucleotide polymorphism in the hyaluronanand proteoglycan link protein 1 (HAPLN1) geneis associated with spinal osteophyte formation anddisc degeneration in Japanese women. Eur Spine
J 20, 572-577, 2011.
6. Kou I, Takahashi A, Urano T, Fukui N, Ito H,
Ozaki K, Tanaka T, Hosoi T, Shiraki M, Inoue S,
Nakamura Y, Kamatani N, Kubo M, Mori S,
Ikegawa S: Common variant s in a novel gene,
FONG on chromosome 2q33.1 confer risk ofosteoporosis in Japanese. PLoS ONE 6, e19641,
2011.
7. Nakajima Y, Osakabe A, Suzuki T, Kishimoto Y,
Kuroda T, Fujimura T, Homma Y, Murayama A,
Inoue S, Yanagisawa J: Estrogen regulates tumor
growth through a nonclassical pathway that
includes the transcription factors ERβ and KLF5.
Sci Signal 4, ra22, 2011.
8. Ikeda K, Tsukui T, Horie-Inoue K, Inoue S:
Conditional expression of constitutively active
estrogen receptor α in osteoblasts increases bonemineral density in mice. FEBS Lett 585, 13031309, 2011.
9. Kabasawa S, Mori K, Horie-Inoue K, Gehlbach
PL, Inoue S, Awata T, Katayama S, Yoneya S:
Associations of cigarette smoking but not serum
fatty acids with age-related macular degeneration
in a Japanese population. Ophthalmology 118,
1082-1088, 2011.
10. Shigekawa T, Ijichi N, Ikeda K, Horie-Inoue K,
Shimizu C, Saji S, Aogi K, Tsuda H, Osaki A,
Saeki T, Inoue S: FOXP1, an estrogen-inducible
transcription factor, modulates cell proliferationin breast cancer cells and 5-year recurrence-freesurvival of patients with tamoxifen-treated breast
cancer. Horm Cancer 2, 286-297, 2011.
11. Azuma K, Urano T, Watabe T, Ouchi Y, Inoue S:

405

PROX1
suppresses
vitamin
K-induced
transcriptional activity of steroid and xenobiotic
receptor. Genes Cells 16, 1063-1070, 2011.
12. Yamashiro K, Mori K, Nakata I, Tsuchihashi T,
Horie-Inoue K, Nakanishi H, Tsujikawa A, Saito
M, Iida T, Yamada R, Matsuda F, Inoue S, Awata
T, Yoneya S, Yoshimura N: Association of
Elastin Gene Polymorphism to Age-related
Macular Degeneration and Polypoidal Choroidal
Vasculopathy. Invest Ophthalmol Vis Sci 52,
8780-8784, 2011.

406

Department of Integrated Imaging
Informatics
Project Associate Professor
Naoki Yoshioka, M.D., Ph.D.

Project Research Associate
Hidemasa Takao, M.D.

Introduction and Organization

References

The recent advent of various medical imaging
modalities including high-field magnetic resonanceimaging, multi-detector row computed tomography,
computed
radiography,
ultrasonography,
andendoscopy enables us to obtain data with high spatial
and temporal resolution. However, the interpretationof large amounts of volumetric data places a burden
on radiologists.
We operate a dedicated image server tosystematically develop the methods of extraction,
analysis, storage, and integration of clinically valuable
information contained within medical image data,
introducing a state-of-the-art engineering technology
and recent evidence obtained by cognitive science. We
aim to apply our results to public health service,teleradiology, professional education, and highpotential expert system that can assist diagnostic
radiologists.

1. Cortical thickness, gray matter volume, and white

Research Activities
Our present research includes the following:
1. Image processing to provide comprehensive 3Ddisplay
2. Computer-aided detection and diagnosis in upper
abdomen
3. Data-mining from medical image databases

matter anisotropy and diffusivity in schizophrenia.
Murakami M, Takao H, Abe O, Yamasue H, Sasaki
H, Gonoi W, Takano Y, Takei K, Kasai K, Ohtomo
K.

Neuroradiology. 2011 Nov; 53(11): 859-66.

Epub 2011 Jan 7.
2. Effect of scanner in asymmetry studies using
diffusion tensor imaging. Takao H, Hayashi N,
Ohtomo K. Neuroimage. 2011 Jan 15;54(2):1053-62
3. MR

imagingofthebiliary

tract

with

Gd-EOB-DTPA: effect of liver function on signal
intensity. Takao H, Akai H, Tajima T, Kiryu S,
Watanabe Y, Imamura H, Akahane M, Yoshioka N,
Kokudo N, Ohtomo K. Eur J Radiol. 2011 Feb;
77(2):325-9.
4. Entorhinal cortex volume measured with 3T MRI is
positively correlated with the Wechsler Memory
Scale-Revised logical/verbal memory score forhealthy subjects. Goto M, Abe O, Miyati T,
Yoshikawa T, Hayashi N, Takao H, Inano S,
Kabasawa H, Mori H, Kunimatsu A, Aoki S, Ino K,
Iida K, Yano K, Ohtomo K. Neuroradiology. 2011
Aug;53(8):617-22. Epub 2011 Apr.
5. Effect of head size on diffusion tensor imaging.
Takao H, Hayashi N, Inano S, Ohtomo K.
Neuroimage. 2011 Aug 1;57(3):958-67. Epub 2011

This course has ended on June 30, 2011.

May 14.

407

6. Effect of scanner in longitudinal studies of brain
volume changes. Takao H, Hayashi N, Ohtomo K. J
Magn Reson Imaging. 2011 Aug;34(2):438-44.
Epub 2011 Jun 20.

408

Department of Clinical Trial DataManagement
Visiting Associate Professor
Takuhiro Yamaguchi, Ph.D.

Project Assistant Professor
Hiroshi Ohtsu, M.S.

Homepage

http://ctdm.umin.jp/

Introduction and Organization

the world.

Why we discuss Clinical Data Management (CDM)?
The reason why the concept of CDM is important has
not been fully discussed and educated in Japan. Our
department was established to answer this question.
The Department of Clinical Trial Data Management
was established in 2007 and carries out educationaland research activities on CDM in collaboration withThe Department of Biostatistics and The ClinicalResearch Support Center in University of Tokyo.
As compared to the situation of CDM in the UnitedStates and Europe, technical aspects (data collection,
entry, check…) have been mainly focused in Japan but
the essence of CDM is to ensure quality of clinicaldata to appropriate level for fair and scientificevaluation. This has not been recognized in manyeducational activities. CDM should be defined as atechnical system to conduct clinical trials scientifically,
ethically and efficiently and to draw correctconclusion and also as a research discipline withtheory and practice that applies statistics, quality
control and clinical knowledge. It can optimize thewhole clinical trial process, keep the level of data
quality appropriately and calculate the trial cost.
One of our missions is to activate researches on CDM
aimed at improving the quality of clinical trials. The
other is to produce data managers trained under the
new education system which can look around all theclinical trial process to adapt rapid change of medical
environment and recent increase of e-clinical trials in

Teaching activities
1. Development of systematic educational programsof CDM and holding of seminars, which include
 Design of clinical trials
 CDM
 Protocol development
 Regulatory science Ethics
 IT
 Safety information and PMS
 Translational research methodology
 …
2. Acceptance of clinical trial staffs from other sites,that is, conducting an on-the-job training (OJT)
3. Support to clinical researchers, especially those in
the University of Tokyo Hospital, in collaboration
with the Department of Clinical and Genetic
Informatics and the Department of Clinical
Epidemiology and Systems
 Consultation works on medical statistics andresearch methodology
 Data center is working at our department
and stuffs are included as a biostatistician ora clinical data manager

Research activities
In addition to activities described above, we are409

developing common tool for clinical research such as
Standardized Operating Procedures (SOPs) in
conducting clinical research.
Research on Clinical Data Interchange Standards
Consortium (CDISC) in collaboration with University
Hospital Medical Information Network (UMIN) is
actively ongoing. The mission of CDISC is to develop
and support global, platform-independent data
standards
thatenableinformation
systeminteroperability to improve medical research andrelated areas of healthcare and we are challenging toconvert several academic clinical trial data to CDISC
Standards formats.
Finally, we started the Eplerenone Combination
Versus Conventional Agents to Lower Blood Pressure
on Urinary Antialbuminuric Treatment Effect Trial(EVALUATE) in collaboration with the Department ofNephrology and Endcrinology, Department ofPharmacoepidemiology, University of Tokyo ClinicalResearch Center and UMIN. The responsibility of theData Center is the data management including
operation of the internet system of the patient registry
and informing data and of handling the individual casesafety reports for the serious adverse events. Also weare supporting a clinical study of a replicationcompetent, recombinant herpes simplex virus type 1(G47delta) in patients with progressive glioblastoma
conducted at Translational Research Center (TRAC)
in University of Tokyo Hospital. We havecollaborative works with several departments which
belong to 22nd Century Medical and Research Centerin the Hospital. We are responsible for Biostatistics /Data management Division of The Clinical Research
Support Center (CresCent) in the Hospital.

References
1) Watanabe N, Noh JY, Narimatsu H, Takeuchi K,
Yamaguchi T, Kameyama K, Kobayashi K, Kami
M, Kubo A, Kunii Y, Shimizu T, Mukasa K,
Otsuka F, Miyara A, Minagawa A, Ito K, Ito K.
Clinicopathological features of 171 cases ofprimary thyroid lymphoma: a long-term study
involving 24553 patients with Hashimoto's
disease. British Journal of Haematology 2011
Mar 4. doi: 10.1111/j.1365-2141.2011.08606.x.
[Epub ahead of print]

2) Kurosawa S, Yamaguchi T, Uchida N, Miyawaki
S, Usuki K, Watanabe M, Yamashita T, Kanamori
H, Tomiyama J, Nawa Y, Yano S, Takeuchi J,
Yakushiji K, Sano F, Uoshima N, Yano T, Nannya
Y, Moriuchi Y, Miura I, Takaue Y, Fukuda T.
Comparison of allogeneic hematopoietic celltransplantation and chemotherapy in elderly
patients with non-M3 acute myeloid leukemia infirst complete remission. Biology of Blood andMarrow Transplantation 2011; 17(3): 401-11.
3) Ooba N, Yamaguchi T, Kubota K. The Impact inJapan of Regulatory Action on Prescribing of
Dopamine Receptor Agonists: Analysis of a
Claims Database between 2005 and 2008. Drug
Safety 2011; 34(4): 329-38.
4) Nojiri S, Gemba K, Aoe K, Kato K, Yamaguchi T,
Sato T, Kubota K, Kishimoto T. Survival andPrognostic Factors in Malignant Pleural
Mesothelioma: A Retrospective Study of 314
patients in the West Part of Japan. Japanese
Journal of Clinical Oncology 2011; 41(1): 32-9.
5) Fukuhara S, Akizawa T, Fukagawa M, Onishi Y,
Yamaguchi T, Hasegawa T, Kurokawa K.
Mineral and Bone Disorders Outcomes Study forJapanese Chronic Kidney Disease Stage 5D
Patients: Rationale and Study Design. Therapeutic Apheresis and Dialysis 2011; 15(2): 169-175.
6) Mieno MN, Yamaguchi T, Ohashi Y. Alternative
statistical methods for estimating efficacy ofinterferon beta-1b for multiple sclerosis clinical
trials. BMC Medical Research Methodology
2011; 26(11): 80-5.
7) Takeda T, Yamaguchi T, Yaegashi N.
Perceptions and attitudes of Japanese gynecologic
cancer patients to Kampo (Japanese herbal)
medicines.
International Journal of ClinicalOncology 2011 Jun 25. [Epub ahead of print]
8) Akizawa T, Kido R, Fukagawa M, Onishi Y,
Yamaguchi T, Hasegawa T, Fukuhara S,
Kurokawa K. Decreases in PTH in JapaneseHemodialysis Patients with Secondary Hyperparathyroidism: Associations with Changing
Practice Patterns. Clinical Journal of American
Society of Nephrology 2011; 6(9): 2280-8.
9) Fukuma S, Yamaguchi T, Hashimoto S, Nakai S,
Iseki K, Tsubakihara Y, Fukuhara S.
Erythropoiesis-Stimulating Agent Responsiveness410

and Mortality in Hemodialysis Patients: Resultsfrom a Cohort Study From the Dialysis Registry
in Japan. American Journal of Kidney Dissease2011 Sep 2. [Epub ahead of print]10) Ueta T, Mori H, Kunimatsu A, Yamaguchi T,
Tamaki Y, Yanagi Y. Stroke and Anti-VEGF
Therapy. Ophthalmology 2011; 118(10): 20932093.
11) Watanabe N, Narimatsu H, Noh JY, Yamaguchi T,
Kobayashi K, Kami M, Kunii Y, Mukasa K, Ito K,
Ito K. Antithyroid Drug-Induced Hematopoietic
Damage: A Retrospective Cohort Study ofAgranulocytosis and Pancytopenia Involving 50,
385 Patients with Graves' Disease. Journal of
Clinical Endocrinology and Metabolism 2011 Nov
2. [Epub ahead of print]12) Kodama Y, Matsumura T, Yamaguchi T, Takita M,
Kawagoe S, Kimura Y, Hirahara S, Suzuki H,
Ohta H, Onozawa S, Wada T, Nakamura Y,
Nakano K, Kami M, Yuji K. Age, gender, will,
and use of home-visit nursing care are criticalfactors in home care for malignant diseases; aretrospective study involving 346 patients inJapan. BMC Palliative Care 2011; 10(1): 17.
[Epub ahead of print]
13) Tsugihashi Y, Kakudate N, Yokoyama Y,
Yamamoto Y, Mishina H, Fukumori N, Nakamura
F, Takegami M, Ohno S, Wakita T, Watanabe K,
Yamaguchi T, Fukuhara S. A novel Internetbased blended learning programme providing corecompetency in clinical research. Journal of
Evaluation Clinical Practice 2011 Dec 2. doi:
10.1111/j.1365-2753.2011.01808.x. [Epub aheadof print]
14) Yanada M, Kurosawa S, Yamaguchi T, Yamashita
T, Moriuchi Y, Ago H, Takeuchi J, Nakamae H,
Taguchi J, Sakura T, Takamatsu Y, Waki F,
Yokoyama H, Watanabe M, Emi N, Fukuda T.
Prognosis of acute myeloid leukemia harboringmonosomal karyotype in patients treated with orwithout allogeneic hematopoietic cell transplantation after achieving complete remission. Haematologica 2011 Dec 16. [Epub ahead of print]15) Inuzuka R, Tatebe S, Wakiguchi S, Nakajima H,
Ohtsu H, Dimopoulos K, Aotsuka H. B-typenatriuretic peptide at the early stage ofuniventricular circulation reflects inadequate

adaptation to volume overload. Int J Cardiol. 2011
Mar 11.
16) Watanabe E, Yamashita T, Suzuki S, Saikawa T,
Hirai M, Yamazaki T, Ohtsu H, Ogawa S,
Investigators TJ. Statin treatment for patients withparoxysmal atrial fibrillation. Int Heart J. 2011;
52(2):103-6.
17) Aikou S, Ohmoto Y, Gunji T, Matsuhashi N,
Ohtsu H, Miura H, Kubota K, Yamagata Y, Seto Y,
Nakajima A, Goldenring JR, Kaminishi M,
Nomura S. Tests for serum levels of trefoil
factor family proteins can improve gastric cancer
screening. Gastroenterology. 2011 Sep;141(3):837-845.e1-7. Epub 2011 May 27.
18) Fujita M, Ando K, Kawarazaki H, Kawarasaki C,
Muraoka K, Ohtsu H, Shimizu H, Fujita T.
Sympathoexcitation by brain oxidative stressmediatesarterialpressureelevationinsalt-induced chronic kidney disease. Hypertension.
2012 Jan;59(1):105-12. Epub 2011 Nov 14.
19) Maeda E, Akahane M, Yoshioka N, Takao H,
Matsuda I, Kamiya K, Hirano K, Tada M, Ohtsu
H, Fukushima N, Ohtomo K. Comparison of CT
findings of biliary tract changes with autoimmune
pancreatitis
andextrahepatic
bile
duct
cholangiocarcinoma. Jpn J Radiol. 2011 Dec 27.
[Epub ahead of print]20) Nakayama A, Morita H, Miyata T, Ando J, Fujita
H, Ohtsu H, Akai T, Hoshina K, Nagayama M,
Takanashi S, Sumiyoshi T, Nagai R. Inverse
association between the existence of coronary
artery disease and progression of abdominal aortic
aneurysm. Atherosclerosis. 2012 Mar 3. [Epubahead of print]21) Nakayama A, Morita H, Ando J, Fujita H, Ohtsu
H, Nagai R. Adverse cardiovascular outcomes
associated with concurrent use of clopidogrel orticlopidine and proton-pump inhibitors in patients
undergoing percutaneous coronary intervention.
Heart Vessels. 2012 Mar 30. [Epub ahead of print]22) Kodama K, Horikoshi M, Toda K, Yamada S,
Hara K, Irie J, Sirota M, Morgan AA, Chen R,
Ohtsu H, Maeda S, Kadowaki T, Butte AJ.
Expression-based genome-wide association study
links the receptor CD44 in adipose tissue with
type 2 diabetes. Proc Natl Acad Sci U S A. 2012
Apr 12. [Epub ahead of print]

411

Pharmacology andPharmacokinetics
Project Associate Professor
Akihiro Hisaka, Ph.D.

Project Research Associate
Yuki Ikebuchi, Ph.D.

Homepage

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

Introduction and Organization

Corporation).

The research of our laboratory, Pharmacology
and Pharmacokinetics, targets quantitative kinetic
analysis of efficacy and safety of drugs by applying
techniques of modeling and simulation, which havebeen developed systematically in the field of
Pharmacokinetics (PK). It includes some topics inseveral relating fields such as system pharmacology,
quantitative pharmacology, and pharmacometrics.
We will survey various issues need to be solved in thecurrent hospital pharmacotherapy and perform various
assays of biomarkers and drug concentrations inbiological specimens kindly provided from patients.
Personalized medicine is one of our important goals toimprove current pharmacotherapies by stabilizing
efficacy without accompanying unpleasant adverse
effects.
The staffs are involved not only in the researchand the education in this university, but also in theactivity of hospital pharmacy, and are evenexperienced experts of new drug development in thepharmaceutical industry. Pharmacology and Pharmacokinetics is supported by the Department ofPharmacy in the Tokyo University Hospital.
Pharmacology and Pharmacokinetics received kind
donations from seven pharmaceutical companies(Takeda Pharma Co Ltd, MSD Co Ltd, Towa
Pharmaceutical Co Ltd, Daiichi Sanko Co Ltd, Eisai
Co Ltd, Chugai Pharmaceutical Co Ltd, Kyowa Hakko
Kirin Co Ltd, Mitsubishi Tanabe Pharma

Education and clinical activities
Although Pharmacology and Pharmacokinetics is
not oriented to education and clinical activities in thehospital, the staffs are hospital pharmacists and are
involved in the education of graduates andunder-graduates in the faculties of medicine andpharmaceutical sciences. Please refer to the annual
report of the Department of Pharmacy.

Research activities
Selectedresearch
topicsongoinginPharmacology and Pharmacokinetics are overviewed
in the following.
Systematic analysis and prediction of drug-druginteraction
In Japan, more than two thousand drugs are usedin pharmacotherapy in hospital. Among them, somecombinations would cause unpleasant adverse effects
due to pharmacokinetic drug-drug interaction (DDI).
We surveyed DDIs caused by inhibition or inductionof drug metabolizing enzyme in the literature, anddeveloped a new framework for prediction of various
pharmacokinetic DDIs (Hisaka A et al. Pharmacol.
Ther., 2010; 125: 230-48. Hisaka A et al. Clin.
Pharmacokinet., 2009: 48: 653-66).
By applying this theory, we have been annually

412

making a comprehensive list of drugs which are
involved in significant pharmacokinetic DDI incollaboration with Prof. Sugiyama in the faculty ofpharmaceutical sciences. It lists more than 300 drugs
which are classified by both clearance pathway anddegree of DDI, and is published in a journal which is
distributed to all pharmacies and relating facilities inJapan for free. The list is used for inspection ofprescriptions in pharmacies, and in addition, forvarious purposes in the industry and regulation.
Evaluation and prediction of absorption andmetabolism in the gut
Oral drugs need to be absorbed from thegastrointestinal tracts in order to exerts therapeutic
effects. In reality, therapeutic potential of many
drugs are unstable or reduced due to low absorbability
and/or extensive metabolism in the gut.
Since
multiple issues are concerned in the absorption
process of a drug, its modeling and simulation havebeen met with limited success. We developed a new
and reliable evaluation method of the intestinal
metabolism. And furthermore, a new PK model wasconstructed for consideration of physiologicalintestinal absorption and metabolism.
Study on ethnic difference in pharmacokinetics
Nowadays, a new drug development is conductedinternationally in general, and hence, clinical studies
are quite often performed first in overseas and thenintroduced in Japan. Therefore, evaluation of ethnic
difference is very important for the success of new
drug development in Japan.
We surveyed and analyzed ethnic differences inPK systematically, and found that ethnic differences
observed in phase 1 study in Japanese subjects areoften unreliable since inter-study difference isapparent. On the other hand, it was revealed that a
degree of ethnic difference in PK is rather small
compared with obvious inter-individual difference.
From the results of this study, it would be needed toreconsider the role of phase 1 studies conducted inJapan.
Furthermore, it may be helpful for
consideration of strategies for new drug developmentin Asian countries in the future.

References (English only)
1.

2.

3.

Koshimichi H, Ito K, Honma M, Hisaka A, andSuzuki H. Analysis and Prediction of Drug
Transfer into Human Milk Taking into Consideration Secretion and Reuptake Clearancesacross the Mammary Epithelia. Drug Metab
Dispos. 2011: 39: 2370-80.
Yamamoto T, Yasuno N, Katada S, Hisaka A,
Hanafusa N, Noiri E, Yahagi N, Fujita T, andSuzuki H. A Proposal of a PharmacokineticallyOptimized Dosage Regimen of Antibiotics inPatients Receiving Continuous Hemodiafiltration.
Antimicrob Agents Chemother. 2011: 55: 580412.
Yamamoto T, Terakawa H, Hisaka A, Suzuki H.
Bayesian Estimation of Pharmacokinetic Parameters of Vancomycin in Patients with Decreasing
Renal Function. J Pharm Sci. 2012; 101:
2968-75.

International Meetings
1.

2.

3.

4.

Hisaka A, Mori A, Koh S, Tsukihashi A, Ando H,
and Suzuki H. Evaluation of Oral Bioavailability
and Intestinal Availability from Pharmacokinetic
Changes Associated with Drug-Drug Interaction.
17th North American ISSX, Atlanta: (Oct 16~20,
2011).
Ando H, Hisaka A, Suzuki H. Prediction ofTime-Course of Drug Concentrations inEnterocytes and Blood during Oral Absorption by
Translocation Model, a New PhysiologicalPharmacokinetic Model for Gastrointestinal
Tracts. 17th North American ISSX, Atlanta: (Oct16~20, 2011).
Hisaka A, Tsukihashi A, et al. Significance ofintestinal metabolism for various substrate drugs
of CYP3A4. International Symposium on BA/BEof Oral Drugs Products, Kobe, Japan: (Jun 29~
Jul 1, 2011).
Ando H, A. Hisaka A, et al. Simulation of drugconcentrations in enterocyte during absorption
with a new pharmacokinetic model of gastrointestinal tracts; translocation model. International Symposium on BA/BE of Oral Drugs
Products, Kobe, Japan: (Jun 29~ Jul 1, 2011).

413

5.

6.

7.

Hisaka A, Tsukihashi A, and Suzuki H.
CalculationofUnambiguous
Intestinal
Availability from Drug-drug Interaction. 4th
APISSX. Tainan, Taiwan：(April 22~25, 2011)
Sasaki Y, Hisaka A, Suzuki H. Selective
Degradation of CYP3A4 in Human LiverMicrosome. 4th APISSX. Tainan, Taiwan：(Apr22~25, 2011).
Hisaka A. True and False in Significant Ethnic
Differences; How Should We Evaluate Them in
Asian Drug Development (Symposium). 26th
JSSX meeting. Hiroshima: (Nov 16~18, 2011).

414

Department of
Therapeutic Strategy forHeart Failure
Professor
Shunei Kyo, M.D.

Associate Professor
Satoshi Gojo, M.D.
Takashi Nishimura,M.D

Project Research Assosiate
Hitoshi Inafuku,M.D

Yoko Ogawa, M.D.

Project Researcher
Tsuyoshi Shimizu, M.D., Hideyuki Nebiya, PhD.

Project Academic Support Specialist
Kumiko Kakuya

Medical Technical AssistantMasaaki Ishii

Homepage

http: http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization

Clinical Activities

The Department of Therapeutic Strategy for Heart
Failure (TSHF) in the University of Tokyo Hospital
was established by the support of the Department of
Cardiac Surgery (Professor Shinichi Takamoto) andthe Department of Cardiology (Professor Ryozo
Nagai) of the University of Tokyo Hospital in May
2008. The purpose to establish the department of
TSHF is to promote surgical and medical innovative
treatment for end-stage heart failure in the Universityof Tokyo Hospital, which includes heart transplant,
pediatric heart transplant, ventricular assist device,
and regenerative therapy. The Department has been
also supported by thirteen companies,

1. Heart Transplant (HTx)Patients who performed heart transplant in our
hospital (22patients) or in abroad transferred from our
hospital (8patients) are followed up once a month inthe out-patient clinic, and undergo myocardial biopsy
once a month in the first year and once a year
afterwards. When some symptom or findings whichsuggest rejection are detected, patients will undergo
in-hospital treatment. The Organ Transplant Law wasrevised in July 2010, the number of brain death
cadaver increased dramatically from August 2010,
Between August 2010 and March 2012 13 patientswere performed heart transplantation in the Universityof Tokyo Hospital.

415

2. Ventricular Assist Device (VAD) Therapy
78 patients were treated with Ventricular assist
device (VAD) since November 2002 when the
University of Tokyo Hospital started hearttransplantation program. All candidates fell into
end-stage heart failure before VAD implantation, anda significant number of them were rescued with hearttransplantation or bridge to recovery. 30 patients weretreated with VAD, 10 were treated in Hospital ward
and 20 were treated in the outpatient clinic. VAD was
implanted in 20 patients in 2011 among them Toyobo
paracorporeal VAD were implanted in 7, EVAHEART
in 6 and DuraHeart was implanted in 7 patients. They
were registered to JOTN (Japanese Organ Transplant
Network), and are waiting for HTx.. We assisted VAD
implantation in 10 patients in affiliate or cooperative
hospital in 2011 to establish VAD network in Shinsyu
University Hospital, Saku General Hospital, Shinsyu
University Hospital, Akita University Hospital,
Gunma Prefectural Cardiovascular Center, andNagoya Tokusyukai Hospital.
3. Compact CP (external counter-pulsation)
Compact CP is a system of external counterpulsation circulatory support system, which has beendeveloped with collaboration of Nishimura Co. Ltd.
and the University of Tokyo Hospital. Compact CPtherapy was performed in collaboration with Tsukuba
Memorial Hospital on 3 post-CABG patients whodeveloped angina pectoris due to graft failure. CCP
was effective in two patients, however, was noteffective in one patient who required re-do CABG.
4.

Waon Therapy
Waon Therapy is innovative physiotherapy fpr
end-stage heart failure developed by Professor Chuwa
Tei. In cooperation with Kagoshima University
Hospital, Waon treatment advanced medical application is made and the multi-institution cooperative
clinical trial for it is advancing with 7 institutions in
the Heisei 23 fiscal year.

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

416

regenerative therapy, 4) establishment of social
support system for patients with implantable LVAD.
We have organized 4series of clinical trial of
implantable rotary blood pump LVAD, EVAHEART,
DuraHeart, Jarvik 2000, and HeartMate II since 2007.
EVAHEART, DuraHeart approved lase December
and insurance reimbursement was obtained this April.
Other two LVAD will be approved within this year.

References
1.

2.

3.

4.

5.

6.

Taro Shiga ,Koichiro Kunugawa, Masaru Hatano,
Atsushi Yao, Takashi Nishimura , Miyoko
Endo ,Naoko Kato, Yasunobu Hirata, Shunei
Kyo,Minoru
Ono,Ryozo
Nagai;AgeandPreoperative Total Bilirubin Lebel Can Stratify
Prognosis After Extracorporeal Pulsatile Left
Ventricular
AssistDeviceImplantation;
Circulation Journal;75(1):121-128;2011
Sawa Y, Tatsumi E, Funakubo A, Iwasaki K,
Kishida A, Masuzawa T,Matsuda K, Myoui A,
Nishimura M, Nishimura T, Tomizawa Y Tono
T, Yamaoka T,Watanabe H;Jounal of Artificial
Organs2010:the year in review; Journal of
Artificial Organs;2011
Tohru Izumi, Michiaki Horie, Mitsuaki Isobe,
Sachio Kawai, Masatoshi Kawaba, Kazuo Kimura,
Makoto Komeda, Shunei Kyo, Akira Matsumori,
Masunori Matsuzaki, Shinichiro Morimoto,
Tsutomu Saji, Chikao Yutani; Guidelines for
Diagnosis and Treatment of Myocarditis(JCS2009)-Digest Version-;JCS Joint Working
Group; Circulation Journal; 75(3):734-743;2011
M. Kawata, T. Nishimura, Y. Hoshino, O.
Kinoshita, M. Hisagi, M. Ando, T. Morota, N.
Motomura, S. Kyo, M. Ono; Negative pressure
wound therapy for left ventricular assist devicerelated mediastinitis: two case reports; Journal of
Artificial Organs; 14:159-162;2011
Chitaru Kurihara, Takashi Nishimura, Osamu
Kinoshita, Mistuhiro Kawata, Motoyuki Hisagi,
Shunei Kyo, Minoru Ono; Successful treatment ofoutflow vascular prosthesis; Journal of Artificial
Organs; 14:155-158;2011
Masahiko Ando, Takashi Nishimura, Kenji
Yamazaki, Shunei Kyo, Minoru Ono, Tomonori
Tsukiya, Toshihide Mizuno, Yoshiyuki Taenaka,

Eisuke Tatsumi; Electrocardiogram-Synchronized
Rotaional Speed Change Mode in Rotary Pumps
Could Omprove Pulatility;Artificial organs;35(10): 941-947;2011
7. Masahiko Ando, Yoshiaki Takewa, Takashi
Nishimura, kenji Yamazaki, Shunei Kyo, Minoru
Ono, Tomonori Tsukiya, Toshihide Mizuno,
Yoshiyuki Taenaka, Eisuke Tatsumi; Coronary
Vascular resistance Increases Under Full Bypass
Support of Centrifugal pumps-Relation Between
Myocardial perfusion and Ventricular Workload
During Pump Support; Artificial organs;DOI:
10.111/j.1525-1594.01298.x;2011
8. Masahiko Ando, Takahi Nishimura, Yoshiaki
Takewa, Daisuke Ogawa, kenji Yamazaki, Koichi
Kashiwa, Shunei Kyo, Minoru Ono, Yoshiyuki
Taenaka, Eisuke Tatsumi;A novel counerpulse
drive mode of continuous0flow left ventricularassist devices can minimize intrciucuit backward
flow suring pump weaning; Journal of Artificial
Organs; 14:74-79;2011
9. Masahiko Ando, Takashi Nishimura, Yoshiaki
Takewa, Daisuke Ogawa, kenji Yamazaki, Koichi
Kashiwa, Shunei Kyo, Minoru Ono, Yoshiyuki
Taenaka, Eisuke Tatsumi;What is the iceal off-test
trial for continuous-flow ventricular-assistadevice explantation? Intracicuit back-flow
analysis in a mock circulation model; Journal of
Artificial Organs ; 14:70-73;2011
10. Chitaru Kurihara, Minoru Ono, Takashi
Nishimura, Kan Nawata, Osamu Kinoshita,
Motoyuki Hisagi, Noboru Motomura, Shunei
Kyo,; Prolonged biventricular assist device
support as a bridge to heart transplantation;Jpirnalof Artificial Organs;s10047-011-0539-5;2011
11. Masahiko Ando, Yoshiaki Takewa, Takashi
Nishimura, kenji Yamazaki, Shunei Kyo, Minoru
Ono, Tomonori Tsukiya, Toshihide Mizuno,
Yoshiyuki Taenaka, Eisuke Tatsumi;A novel
counterpilsation mode of rotary left ventricularassist devices can enhance myocardial perfusion;
Joirnal of Artificial Organs;14:185-191;2011
12. Takafumi Inoue, Takashi Nishimura, Arata
Murakami, Keiichi Itatani, Tetshiro Takaoka,
Kazuo Kitahori, Akihide Umeki, Toshiko Takezoe,
Koichi Kashiwa, Shunei Kyo, Minoru Ono; Leftventricular assist device support with a417

centrifugal pump for2 months in a 5-kg child;
Journal of Artificial Organs;14:253-256;2011
13. Chitaru Kurihara, Takashi Nishimura, Kan
Nawata, Osamu Kinoshita, Motoyuki Hisagi,
Noboru Motomura, Shunei Kyo, Minoru Ono;
Successful bridge to recovery with VAD
implantation for anthracycline-induced cardiomyopathy; Jounal of Artificial Organs; 14:249252:2011
14. Masaru Hatano, koichiro Kinugawa, Taro Shiga,
Naoko Kato, Miyoko Endo, Motoyuki Hisagi,
Takashi Nishimura, Atsushi Yao, Yasunobu Hirata,
Shunei Kyo, Minoru Ono, Ryozo Nagai ;Less
Frequent Opening of the Aortic valve and aContinuous Flow Pump Are Risk Factors for
Postoperative Onset of Aortic Insufficiency inPatients With a Left Ventricular Assist Device;
Circulation Journal; 75859:1147-1155;2011
15. Shunei Kyo, Kazuhito Imanaka, Hiromi
Kurosawa, Munetaka Sueda, Tetsuro Miyata,
Kiyozo Morita, Minoru Nomura, Yoshiki Sawa,
Taijiro Sueda, Koichi Tabayashi, Shinichi
Takamoto, Yuichi Ueda, Ryohei Yozu; Guidelines
for Preoperative Cardiovascular Evaluation andManagement for Moncardiac Surgery(JCS2008)DinestVersion-JCS Joint Working Group;
Circulation Journal; 75(4):989-1009;2011
16. Teruhiko Imamura, Koichiro Kinugawa, Taro
Shiga, Miyoko Endo, Toshiro Inaba, Hisataka
Maki, Atsushi Yao, Takashi Nishimura, Yasunobu
Hirata, Shunei Kyo, Minoru Ono, Ryozo Nagai,;A case of late-flow left ventricular assist device;
Journal of Artificial Organs; 15:200-203;2012
17. Shimizu Tsuyoshi, Shunei Kyo, Sei Morizumi,
Takashi Ando, Shigeyoshi Gon, Yoshihiro
Suematsu; Effect of external counterpulsation on
cardiac work following cardiac surgery;
Ipplications of the mechanism responsible forclinical benefits; Journal of Cardiology; 59:84-90;
2012
18. Koichi Kashiwa, Takashi Nishimura, Aya Saito,
Hitoshi Kubo, Aoi Fukaya, Hisayoshi Tamai,
Tomoyuki Yambe, Shunei Kyo,
Minoru Ono; Left heart bypass support with the
Rotaflow Centrifugal Pump as a bridge todecision and recovery in an adult; Journal of
Artificial Organs; 15:207-210;2012

19. Shunei Kyo, Taishi Minami, Takashi Nishimura,
Satoshi Gojo, Minoru Ono; New era fortherapeutic strategy for heart failure;
Destination therapy by left ventricular assista
device; Journal of Cardiology;59:101-109;2012
20. Mitsuhiro Kawata, Takashi Nishimura, Yasuhiro
Hoshino, Osamu Kinoshita, Motoyuki Hisagi,
Masahiko Ando, tetsuro Morota, Noboru
Motorumra, Shunei Kyo, Minoru Onno; Negative
pressure wound therapy for left ventricular assist
device -related mediastinitis; two case reports;
Journal of Artificial Organs; 14(2): 159-162: 2011
21. Akihide Umeki, Takashi Nishimura, MasahikoAndo, Yoshiaki Takewa, kenji Yamazaki, Shunei
Kyo, Minoru Ono, Tomonori Tsukiya, Toshihide
Mizuno, Yoshiyuki Taenaka, Eisuke Tatsumi;
Alteration of LV end-diastolic volime bycontrolling the power of the continuousflowLVAD, so it is synchronized with cardiac
beat:development of a native heart load control
system (NHLCS); Journal of Artificial organs; 15:
128-133:2012

418

Department of Quality Assessment
and Control of Medical Device
Sterilization
Project Associate Professor
Yushi Uetera, M.D.,Ph.D.

Project Research Associate
Kozue Kishii, Ph.D.

Homepage http: In preparation
Introduction and Organization

Clinical activities

The Department of Quality Assessment and Control of
Medical Device Sterilization was established througha donation of Sakura Seiki Co., Ltd. in 2011. The
parent departments are Surgical Center and
Department of Infection Control and Prevention.
The course is essentially the only one research base inJapan, which studies disinfection and sterilization. To
the best of our knowledge, there are only two researchbases for disinfection and sterilization abroad: one in
Tübingen University, Germany and the other in
University of the Highlands and Islands, UK.
As highly advanced surgical treatments (such as
robotic and neuro-navigational operations) develop, it
is an urgent task to sterilize satisfactorily high-tech
instruments with complex structures or devices that
contain electronic circuits. Moreover, it is extremely
important to come up with measures to combat
emerging and reviving infections.
For these purposes, the course will conduct researches
on sterility assurance based on the ISO international
standard, fighting prion and hepatitis B virus, andwater quality management methods based onheterotrophic bacteria and endotoxin.

Sterilization plays an important role in the surgicalcenter and central sterile service department (CSSD).
To support the quality assurance of sterilization, we
conduct research on the disinfection and sterilization,
the design of central sterile supply department (CSSD)
and so forth.
The international guideline for sterilizing medical
devices (ISO/TC 198) comes in handy to improve thestate of quality assurance. It is also likely that the
globally standardized procedures should help to usher
in many patients from abroad. Incidentally, Uetera is
the domestic convener of ISO/TC 198 in Japan.
For instance, ISO/TC 198 recommends that the
microbiological quality of water should be monitored
closely in the washer-disinfectors. Endotoxin
remaining on the instruments could cause toxic
anterior segment syndrome (TASS) in the cataract
surgery
withintraocularlens
implantation.
Accordingly, water quality has been studied twice ayear over 5 years in the washer-disinfector with areverse osmosis plant.
Furthermore, there are some legal regulations on thepressurized vessels (such as autoclaves) and ethyleneoxide sterilization. As to the autoclaves, they should
undergo the annual inspection by the Labour
Standards Inspection Office. As to the ethylene oxide

419

sterilizers, they should undergo the working
environment measurement twice a year by the experts
with national qualifications. The laboratory has
cooperated with these activities.

Teaching activities
The laboratory participates in all teaching activities
performed by the surgical center. The activities
include the surgical hand antisepsis, gown techniqueand so on. It appears that medical and co-medical
students should learn disinfection and sterilization
more thoroughly to decrease the healthcare-associatedinfection rates. The course should play a pivotal role
for this purpose.

Research activities(1) Evaluation of cleaning efficacy in the washerdisinfector:
Cleaning is essential for successful disinfection andsterilization. Evaluation of cleaning efficacy is
discussed in ISO 15883 on the washer-disinfectors.
Thermal disinfection is also discussed in terms of A0(A naught) concept. David Hurrell introduced thisconcept in UK, and it has been approved in EU. It is
expected that the concept would be approved soon in
North America.
On the other hand, evaluation of cleaning efficacy has
been discussed over 10 years without success.
Incidentally, Uetera and co-workers reported thatcleaning should attain not less than 3 log reduction of
infectivity to inactivate hepatitis B virus (HBV) in the
moist heat disinfection of A0 3000. This finding may
come in handy to standardize the evaluation ofcleaning efficacy.
(2) Evaluation of water quality in the washerdisinfector:
Water quality was evaluated in our washer-disinfector
with a reverse osmosis (RO) plant according to AMMI
TIR34: 2007 Water for the reprocessing of medical
devices. Tap water or hot-supply water was used forcleaning and intermediate rinsing. RO water was used
for final rinsing.
It was revealed that hot-supply water contained
endotoxin to an unacceptable degree in comparison
with tap water. The endotoxin level of RO water wasmuch less than 10 EU / ml and satisfied AMMI
TIR34: 2007. It was suggested that water quality
should be monitored closely in the management of
washer-disinfectors.
(3) Outlook for the future research:
Endotoxin is extremely resistant to conventional
disinfection
andsterilization.
Accordingly,
inactivation or removal of endotoxin should be studied
not only for preventing toxic anterior segment
syndrome (TASS) arising from contaminatedinstruments but also for reducing endotoxin levels inthe dialysate for hemodialysis.
Water with extremely low level of endotoxin is also
required for manufacturing molecular target andantibody drugs. Furthermore, endotoxin removal isimportant for manufacturing biological preparations.
For instance, low endotoxin gelatin has beendeveloped for the regenerative medicine.

References1.

2.

Uetera Y, et al.: Evaluation of water quality in asingle chamber washer-disinfector equipped witha reverse osmosis plant. Zentralsterilisation
20(1): 50–55, 2012
Uetera Y, et al.: Performance of a new type ofcontainers equipped with reusable filters
investigated using wireless loggers andmicrobiological methods. Zentralsterilisation
19(2): 111–116, 2011

420

Department of Molecular
Medicinal Sciences on Metabolic
Regulation
Project Associate Professor
Hiroaki Okazaki, M.D., Ph.D.

Project Research Associate
Miki Okada-Iwabu, Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/english/center22/en_contribute/molecular.html

Introduction and Organization
Diabetes is currently estimated to affect some 8.9
million patients or 22.1 million individuals including
those at risk and thus has become a major social issueof concern in Japan. Indeed, as it continues to spreadworldwide, diabetes has become such an epidemic thatthe development of novel, groundbreaking, antidiabetic drugs is eagerly awaited.
While diabetes treatment has come to employ
anti-diabetic drugs with diverse mechanisms of action
over the years, the development of “radical”
treatments for lifestyle-related diseases has become an
arena of fierce competition globally, as their arrival
continues to be eagerly anticipated.
Against this background, the present course aims to
explore, as part of our endeavor to elucidate themechanism of onset of diabetes, potential anti-diabetic
synthetic small molecules and their mechanisms ofaction and target molecules, and to discover/develop
breakthrough anti-diabetic drugs.
Launched in May 2011, this course aims to develop
innovative anti-diabetic drugs based on molecularinsights into the mechanisms of onset of diabetes, inclose collaboration with its parent course, Department

of Diabetes and Metabolic Diseases, Graduate Schoolof Medicine, The University of Tokyo, working
around the clock to bring innovative drugs into theclinical arena thus contributing to society at large.

Research activities
The objective of the course will be to explore andoptimize potential anti-diabetic synthetic small
compounds for clinical application as novel treatments
for diabetes/lifestyle-related diseases.
A unique screening/assay system of our own devising
is currently being exploited to the hilt to help explore
and analyze a wide array of synthetic small
compounds with anti-diabetic potential, together with
its spin-off in vitro systems drawing on cultured cells
and cell-free systems and in vivo systems drawing on
mouse models of obesity and type 2 diabetes andgenetically modified animals.
We believe that furthering research along these lines
will bring within reach “radical” treatments fordiabetes and lifestyle-related diseases with long-term
insulin-sensitizing and anti-atherosclerotic effects.
Last but not least, our drug discovery/development421

research endeavors are not limited diabetes andlifestyle-related diseases but include their relateddiseases, such as cancer and Alzheimer’s disease,which evidence from Japan and overseas suggests
represent potential targets for novel drug development,
to make research contributions that help advance
healthcare toward the next century.

References(1) Handa N, Takagi T, Saijo S, Kishishita S, Takaya
D, Toyama M, Terada T, Shirouzu M, Suzuki A,
Lee S, Yamauchi T, Okada-Iwabu M, Iwabu M,
Kadowaki T, Minokoshi Y, Yokoyama S.:
Structural basis for compound C inhibition of thehuman AMP-activated protein kinase alpha 2
subunit kinase domain. Acta Crystallogr. D
Crystallogr. 67, 480-487 (2011)(2) Kukimoto-Niino M, Yoshikawa S, Takagi T,
Ohsawa N, Tomabechi Y, Terada T, Shirouzu M,
Suzuki A, Lee S, Yamauchi T, Okada-Iwabu M,
Iwabu M, Kadowaki T, Minokoshi Y, Yokoyama,
S.: Crystal Structure of the Ca2+/Calmodulindependent Protein Kinase Kinase in Complex
with the Inhibitor STO-609. J. Biol. Chem. 286,
22570-22579 (2011)(3) Waki H, Nakamura M, Yamauchi T, Wakabayashi
K, Yu J, Hirose-Yotsuya L, Take K, Sun W, Iwabu
M, Okada-Iwabu M, Fujita T, Aoyama T,
Tsutsumi, S, Ueki K, Kodama T, Sakai J,
Aburatani H, Kadowaki T.: Global Mapping of
Cell Type-Specific Open Chromatin by
FAIRE-seq Reveals the Regulatory Role of the
NFI Family in Adipocyte Differentiation. Plos
Genet. 7 e1002311 (2011)(4) Ohta K, Sekiya M, Uozaki H, Igarashi M, Takase
S, Kumagai M, Takanashi M, Takeuchi Y,
Izumida Y, Kubota M, Nishi M, Okazaki H,
Iizuka Y, Yahagi N, Yagyu H, Fukayama M,
Kadowaki T, Ohashi K, Ishibashi S, Osuga J.:
Abrogation of neutral cholesterol ester hydrolytic
activity causes adrenal enlargement. Biochem.
Biophys. Res. Commun. 404, 254-260 (2011)(5) Sekiya M, Osuga J, Igarashi M, Okazaki H,
Ishibashi S.: The role of neutral cholesterol esterhydrolysis in macrophage foam cells. J.
Atheroscler. Thromb. 18, 359-364 (2011)(6) Amemiya-Kudo M, Oka J, Takeuchi Y, Okazaki H,
Yamamoto T, Yahagi N, Matsuzaka K, Okazaki S,
Osuga J, Yamada N, Murase T, Shimano H.:
Suppression of the pancreatic duodenal
homeodomain transcription factor-1 (pdx-1)
promoter by sterol regulatory element-binding
protein-1c (srebp-1c). J. Biol. Chem. 286,
27902-27914 (2011)

Social Cooperation Program423

Department of Lipidomics
Professor
Takao Shimizu, M.D., Ph.D.

Associate Professor
Yoshihiro Kita, Ph.D.

Assistant Professor
Suzumi Tokuoka, Ph.D.

Homepage

http://lipidomics.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
The Department of Lipidomics was established on
April 2011, funded by Shimadzu Corp. and Ono
Pharmaceutical Co., Ltd. The objective of thelaboratory is to establish and improve mass
spectrometry-based lipidomics methodologies, and its
application to biomedical researches including basic
lipid biology as well as clinical studies.
The laboratory is organized by three staff scientists,
Takao Shimizu (Professor), Yoshihiro Kita (Associate
Professor), and Suzumi Tokuoka (AssistantProfessor).

Teaching activities
The department staffs give several lectures forunder-graduate and graduate students. For undergraduate students, Drs. Shimizu and Kita deliver
several lectures on biochemistry. For master-course
students, Drs. Shimizu and Kita give lectures on“Lipid mediators” and “Proteome and metabolome”,
respectively. For doctor-course students, Dr. Kita
delivers a lecture on “Analytical methods for bioactive
lipids”. Also, Drs. Kita and Tokuoka provide seminars
on biochemistry for under-graduate students.

Research activities
Our research interests cover following topics.

Multiplex quantitation strategy for lipid mediators
Lipid
mediators
including
prostaglandins,
leukotrienes, platelet-activating factor and many otherbioactive lipid metabolites are attracting great
attention as disease-related or physiologicallyimportant molecules. Comprehensive analysis of
known lipid mediators is a useful unbiased method in
disease mechanism studies, and the lipid mediator
profile is a useful parameter that characterizes diseasestatus as well. We have developed an original
multiplex quantification method for trace amounts oflipid mediators using liquid chromatography-tandem
mass spectrometry (LC-MS/MS). We are developing
more sensitive and rapid methods that cover more
lipid mediators, which meet the demands on various
large-scale studies and high-throughput screening
approaches.
Lipid biomarker discovery
Lipidbiomarker
discoverybyliquidchromatography-mass spectrometry-based method
requires high-level integration of chromatography andmass spectrometry, which ensures lipid separation,
semi-quantitative detection, and identification. We arecollaborating with industries to solve known
difficulties in lipid chromatography, develop
differential analysis and feature-extraction methods,
and establish an intelligent analytical system linked
with lipid database.
Methods for clinical samples
Clinical samples such as blood, urine, feces, and424

tissue biopsies vary much as compared with controlled
animal studies. Furthermore, sampling and storage
conditions are not always optimized for lipid analysis.
We are developing techniques for handling clinicalsamples for a practical lipidomics analysis.
Metabolic flux analysis of lipids
A simple lipidomics analysis provides large datasetsthat describe the amount-based profile of lipidome.
However, it is not sufficient to investigate the status oflipid metabolic pathway, because changes inmetabolic flux do not always reflect to static amountof metabolites. To overcome this, we develop aflux-oriented lipidomics analysis using stable-isotope
tracers.
Lipid biomarker/lipid mediator discovery using
animal models
Appling the latest lipidomics technologies to theanalysis of the animal models of various diseases
including metabolic disease, we are trying to discovernovel lipid biomarkers. We also analyze various
gene-deficient mice and transgenic mice to seek
important lipid markers, lipid mediators, and lipid
profiles.
Discovery of novel lipid mediator metabolizing
pathways
Although major biosynthetic and catabolic
pathways for classical lipid mediators have been well
documented so far, there are still possibilities for yet
unidentified lipid mediator metabolizing pathways invivo. We have obtained a preliminary data for novel
lipid mediator producing pathway using genedeficient mice. Using the latest lipidomics techniques
to the cell cultures and animal models, we will
elucidate a novel lipid mediator related pathway andits biological significance.

References
1. Kita Y, Shimizu T. Multiplexed quantitative
analysis of eicosanoids. Rinsho Kensa, 56,
177-187 (2012) (Japanese)
2. Saito Y, Watanabe K, Fujioka D, Nakamura T,
Obata J, Kawabata K, Watanabe Y, Mishina H,
Tamaru S, Kita Y, Shimizu T, Kugiyama K.
Disruption of group IVA cytosolic phospholipase

A2 attenuates myocardial ischemia-reperfusion
injury partly through inhibition of TNFα-mediatedpathway. Am. J. Physiol. Heart Circ. Physiol., 302,
H2018-H2030 (2012)
3. Jönsson F, Mancardi DA, Zhao W, Kita Y,
Iannascoli B, Khun H, van Rooijen N, Shimizu T,
Schwartz LB, Daëron M, Bruhns P. Human
FcγRIIA induces anaphylactic and allergic
reactions. Blood, 119, 2533-2544 (2012)
4. Ueno N, Taketomi Y, Yamamoto K, Hirabayashi T,
Kamei D, Kita Y, Shimizu T, Shinzawa K,
Tsujimoto Y, Ikeda K, Taguchi R, Murakami M.
Analysis of two major intracellular phospholipase
A2s in mast cells reveals crucial contribution ofcPLA2α, not iPLA2β, to lipid mobilization inproximal mast cells and distal fibroblasts. J. Biol.
Chem., 286, 37249-37263 (2011)

425

Functional Regulation of
Adipocytes
Associate Professor
Hironori Waki, M.D., Ph.D.

Assistant Professor
Nozomu Kamei, M.D., Ph.D.

Introduction and Organization
The prevalence of obesity and related diseases arerising to epidemic proportions worldwide. The
identification of secreting molecules including leptin
and adiponectin—termed “adipokines”—led to therecognition that adipose tissue functions as an
endocrine organ, in addition to a storage depot forexcess calories. Today, dysregulation of adipokines isrecognized as an important factor in the pathogenesisof insulin resistance. The discovery that thiazolidinediones — insulin-sensitizing anti- diabetics — areagonists for a nuclear hormone receptor peroxisome
proliferator-activated receptor γ (PPARγ) — themaster regulator of adipocyte differentiation — also
led to the recognition that the adipogenic genetranscription network play a critical role in systemic
glucose and lipid metabolism. Recent researches
employing flow-cytometry and lineage-tracing technology has begun to elucidate characteristics andmarkers of adipocyte progenitor/stem cells in adipose
tissue. There are two types of adipocytes; brown andwhite. Compared to white adipocytes, which are
specialized in storing excess energy, brown adipocytes
are known to burn excess energy and produce heat in
response to various stimuli including cold andconsidered an attractive cellular target for thetreatment of obesity. Recent evidence that brown
adipocytes exist in adult humans and an advance inour understanding of a transcription regulatory
network that defines brown adipocyte- phenotype hasboosted intensive research of this area. Finally, it was
shown that obese adipose tissue contains not only
hypertrophic adipocytes but also inflammatory cells

including macrophages. Role of interaction of thesecells and adipocytes is one of hot topics in the field.
Our laboratory was established as a social
Cooperation Program in 2011 with a contribution ofNovartis Pharma K.K. The aim of our research is tounderstand functional regulation of adipocytes innormal and in disease state, which is critical forunderstanding the pathogenesis of obesity and relateddiseases. In order to accomplish this goal, we conduct
genome-wide analyses of the epigenome of adipocytes
by using a next-generation sequencer and investigate
regulation of chromatin structure and gene expression
by transcription factors that closely relates to obesity
and metabolic diseases. We also employ biochemical,
gene-targeting and immuno- logical methods including a flow-cytometry to elucidate a communication
between immune cells and adipocytes and to find away to control it.

Teaching activities
We teach a class “obesity” in a lecture series ofsymptomatology for the 4th year medical students. We
also teach a class “obesity, diabetes and dyslipidemia”
in Medical Science Graduate Program, The Universityof Tokyo. We train, on a regular basis, graduate andpost-graduate students in Nutrition and Metabolism,
Internal Medicine, Graduate School of Medicine, The
University of Tokyo.

426

Research activities(1) Epigenetic analyses of adipocytes by using
next-generation sequencer (NGS)NGS is one of breakthrough technologies in genome
science. NGS technologies have revolutionized how
we study the epigenome and transcriptional regulationof genes. ChIP, using specific antibodies followed by
NGS (ChIP-seq), allows genome-wide mapping ofbinding sites of transcription factors and genomic
regions of specific chromatin modifications. These
new approaches provide novel insights never before
gained and broaden our understanding of epigenetic
regulation of gene expression. We investigate
epigenome and epigenetic regulation of genes inadipocytes in normal and disease states, particularly
focusing on adipocyte-specific transcription regulatory mechanisms and identification of new regulators.
We mapped adipocyte-specific regulatory elements in
the genome by employing Formaldehyde- Assisted
Isolation of Regulatory Elements coupled with highthroughput sequencing (FAIRE-seq) and demonstrated
the critical role of multiple distal enhancers in
adipogenic gene expression. We also conductedcomputational motif analyses of DNA sequence inthose regions and identified the NFI transcription
factors as novel regulators of adipocyte differentiation(PLoS Genet 7(10), 2011 e1002311). We are currently
conducting epigenetic analyses of brown and white
adipocytes, adipocyte progenitors and adipocytes indisease state and aim to elucidate transcriptional
regulatory network. Its regulation is expected to leadto development of obesity and related diseases.
(2) Investigation of a role of immune cells in adipose
tissue by using flow-cytometry
It has been shown that macrophages accumulate inobese adipose tissue and the role of the cells in thedevelopment of diabetes is one of intensive research
focuses in the field. We investigate various types of
immune cells in adipose tissue by using flowcytometry and aim to identify previously unrecognized role of the cells in an inter-regulation between
such cells and adipocytes and in systemic glucose andlipid homeostasis. We also investigate whether

regulation of functions of immune cells may improvediabetes and insulin resistance seen in obesity.

References
1. Waki H, Nakamura M, Yamauchi T, Wakabayashi
K, Yu J, Yotsuya L, Take K, Sun W, Iwabu M,
Okada-Iwabu M, Fujita T, Aoyama T, Tsutsumi S,
Ueki K, Kodama T, Sakai J, Aburatani H and
Kadowaki T: Global Mapping of Cell-TypeSpecific Open Chromatin by FAIRE-seq Reveals
the Regulatory Role of the NFI Family in
Adipocyte Differentiation. PLoS Genet 2011;
7(10):e1002311.
2. Villanueva CJ, Waki H, Godio C, Nielsen R, Chou
WL, Vargas L, Wroblewski K, Schmedt C, Chao
LC, Boyadjian R, Mandrup S, Hevener A, Saez E
and Tontonoz P: TLE3 is a dual-function
transcriptional coregulator of adipogenesis. Cell
Metab 2011; 56: 413-427.

Social Cooperation Program(22nd Century Medical and Research Center)428

Department of Ubiquitous Health
Informatics
Associate Professor
Hideo Fujita, M.D.,Ph.D.

Assistant Professor
Yuji Uchimura, DDS
Waki Kayo, M.D. Ph.D.

Homepage

http://uhi.umin.jp

Introduction and Organization

Research activities

Our mission is to promote research and developmentof a novel integration system where pieces ofpatients ’ healthcare information are virtuallycombined together that are stored separately in diverse
medical/healthcare facilities. Recently developed
mobile information communication technologies in
conjunction with cloud computing provide sturdy
environment to build a “virtual ubiquitous healthinformation space”. We particularly focus on better
clinical outcomes, as well as efficacy, safety, andsecurity matters achieved by those innovative systems
in the various medical/healthcare fields.

To date we have been working on specific topics
shown below since this lab was established in 2009.
Our products have reached a stage of clinicalvalidation, respectively. Furthermore, we arepromoting collaborative research with several
laboratories both inside and outside the campus,
seeking for frontier fields of interdisciplinary researchand practical medicine/healthcare fields. Throughdevelopment of those specific products, we further
aim to establish a systematic methodology for creating
solutions for virtual ubiquitous health information
space.
1. A 12-lead ECG system based on cloud computing
for emergency care
Treatment of cardiovascular diseases inside medical
facilities have improved dramatically in recent years.
On the other hand, the outcomes of acutecardiovascular disease is not yet sufficient depending
upon the local medical environment. In order to fill up
those “gaps” between inside and outside the medical
facilities, we working on creating a novel ECG system
as a clinically valid approach to this problem. We havedeveloped a cloud computing system with wirelesslytransmission ECG units, potentially clinical usefulness
due to the cloud-based server built. Ongoing studies
include practical usage of mobile cloud ECG in the429clinical settings of emergency care. We arecollaborating with Kitasato University, Oita
University, and Hokuto hospital.
2. Dialbetics: A novel smartphone-based selfmanagement support system for type 2 diabetic
patients
It is fundamentally important for diabetic patients tomaintain appropriate balance of diet and exercise,although the clear solution for it has not yet been
established.
We
have developed a novelsmartphone-based self-management support system
for type 2 diabetic patients. This new system has an
automatic function of stratifying daily patient's
biometric information such as blood glucose, bloodpressure, and food intake retrieved by the home sensor
and router according to medical risk evaluation.
Stratification engine feedback the risk level and raw
data to the patients, as well as to the administrator
only if the risk level indicates extremely high so thathe/she can urge the patient to see or consult his healthprofessionals as soon as possible. It has long been
pointed out that introduction of telemedicine canproblematically increase the burden of healthcare
workers, even if its efficacy may be ascertained,suggesting the difficulties to maintain and promote thesystem. We are also struggling to develop a new
system to overcome this kind of apprehension by
developing a new algorithm to reduce the burden ofhealth care workers. At present we performed series ofpilot studies for about 10 people in accordance withthe reviewed protocol of the ethics committee. We areto conduct 100-scale clinical trial to further confirm
validation, efficacy and safety aspects of Dialbetics in
FY2012. Besides we promote the evolutionalalgorithm in collaboration with a specific researchlaboratory in Faculty of Engineering.
3. Integrated System on Smartphone for Personal
Health Record platform
Various kinds of personal health record systems(PHR) have been developed to promote healthcareawareness of patients. We have developed a novel
PHR system based on mobile ICT and cloudcomputing as a potential platform of medical/
healthcare information designated for patients’ healthpromotion.

4. Advanced smartphone-based guidance system for
outpatients
In order to improve convenience and amenity ofuniversity hospital outpatient services, we havedeveloped a new guidance system on cell phones. Thissystem will provide advanced function for reception
from outside, reducing waiting time, fast-forward ofprescription data to pharmacies, and so on. Thissystem was tested in the outpatient department of the
University of Tokyo Hospital in FY2011 and theeffectiveness of this system has been proven.
5. Various assistance applications on smartphone for
medical/comedical personnel in hospitals
We have launched several development projects ofmobile ICT systems to assist medical staff andmedical technicians in the hospital.
3. Future directions
We further promote development and validation ofthese aspects. In particular, those are expected to exert
clinical efficacy, which in part has been proven inpractical world. In addition to university hospital
outpatient/ward, we will examine various models of
health care, such as community health care, and homecare as joint research. To pursue scientific value ofboth clinical medicine and medical informatics for theestablishment of spatial generalization we will moveonto establishing virtual cyberspace for medical/healthinformatics.

References
1. Hasumi E, Iwata H, Saito K, Fujiu K, Ando J, ImaiY, Fujita H, Hirata Y, Nagai R. Diagnostic efficacy
of coronary CT angiography as a follow-up
modality for procedure-related coronary dissection.
Int Heart J. 2011;52(4):240-2.
2. Kawashima D, Ohno T, Kinoshita O, Motomura N,
Kiyosue A, Fujita H, Ando J, Ohtomo K, Shigeeda
T, Kato S, Kadowaki T, Nagai R, Takamoto S, Ono
M. Prevalence of vitreous hemorrhage following
coronary revascularization in patients withdiabetic retinopathy. Circ J. 2011;75(2):329-35.
3. Myojo M, Iwata H, Kohro T, Sato H, Kiyosue A,
Ando J, Sawaki D, Takahashi M, Fujita H,

430

Hirata Y, Nagai R. Prognostic implication ofmacrocytosis on adverse outcomes after coronary
intervention. Atherosclerosis. 2012 Mar;221(1):148-53.
4. Nakayama A, Morita H, Ando J, Fujita H, Ohtsu H,
Nagai R. Adverse cardiovascular outcomes
associated with concurrent use of clopidogrel orticlopidine and proton-pump inhibitors in patients
undergoing percutaneous coronary intervention.
Heart Vessels. 2012 Mar
5. Nakayama A, Morita H, Miyata T, Ando J, Fujita
H, Ohtsu H, Akai T, Hoshina K, Nagayama M,
Takanashi S, Sumiyoshi T, Nagai R. Inverse
association between the existence of coronary
artery disease and progression of abdominal aortic
aneurysm. Atherosclerosis. 2012 Mar
6. Waki K, Sugawara Y: Implications of integrase
inhibitors for HIV-infected transplantation
recipients: raltegravir and dolutegravir (S/GSK
1349572). Bioscience Trends. 5(5):189-191, 2011.
7. Waki K, Sugawara Y, Tamura S, Mieno MN,
Yamashiki N, Kadowaki T, Kokudo N: Outcomeof liver transplantation for recipients with hepatitis
B and hepatitis C virus coinfection: analysis of the
UNOS data. Transplantation 92(7):809-814, 2011.
8. Waki K, Hayashi A, Ikeda S, Ikeda S, Nagatsuka
K, Honma Y, Kadowaki T, Yoshinoya S:
Measuring platelet aggregation in dialysis patientswith a whole blood agggregometer by the screen
filtration pressure method. Therapeutic Ahpheresis
and Dialysis 15(2):203-206, 2011.
9. Oba S, Noda M, Waki K, Nanri A, Kato M,
Takahashi Y, Poudel-Tandukar K, Matsushita Y,
Inoue M, Mizoue T, Tsugane S: Smoking
Cessation Increases Short-Term Risk of Type 2
Diabetes Irrespective of Weight Gain: The Japan
Public Health Center-Based Prospective Study.
PLoS One, 2011
10. Ohe H, Waki K, Yoshitomi M, Morimoto T,
Nafady-Hego H, Satoda N, Li Y, Sakaguchi S,
Uemoto S, Bishop GA, Koshiba T: Factors
affecting operational tolerance after pediatricliving-donor liver transplantation: impact of earlypost-transplant events and HLA match. Transplant
Internatinal. 25(1): 97-106, 2012.
11. Ohe H, Ying Li, Nafady-Hego H, Waki K,
Sakaguchi S, Wood K, Calne R, Uemoto S,

Koshiba T: Minimal But Essential Doses of
Immunosuppression: A More Realistic Approachto Improve Long-Term Outcomes for Pediatric
Living-Donor Liver Transplantation. Transplantation. 91(7):809-810, 2011.
12. Riichiro Mizoguchi, Kouji Kozakil, Hiroko
Kou ,Yuki Yamagata,Takeshi Imai, Kayo Waki,
Kazuhiko Ohe: River Flow Model of Diseases.
International Conference on Biomedical Ontology.
2011
13. Waki K, Sugawara Y, Tamura S, Yamashiki N,
Fujita H, Kadowaki T, Kokudo N:Simultaneous
pancreas-kidney transplantation in the UnitedStates: an analysis of the UNOS registry. ClinicalTransplant 2010:35-44.
14. Waki K, Fujita H, Uchimura Y, Aramaki E, Omae
K, Kadowaki T, Ohe K DialBetics: Smartphonebased self-management for type 2 diabetes
patients. Diabetes Science and Technology 2012,
6: 983-985

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

433

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., Makoto Kurano, M.D.

Chief Technologist
Hiromitsu Yokota, Ph.D.

Homepage

http://lab-tky.umin.jp/

Introduction and Organization
Clinical Laboratory Center consists of 12 doctors, achief technologist, 74 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
2011, 238,144 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2011, over 4,631,943

serum enzyme tests (such as AST and ALT), and498,489 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2011, 1,077,043 samples were examined forcomplete blood cell counts, cell surface marker
analysis, prothrombin time, fibrinogen, glucose, andHbA1C tests, and 222,991 urine samples were
examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2011, 45,159 ECG, 21,901
pulmonary function tests, 11,065 echocardiography
tests, 14,610 abdominal echography tests, and 9,056
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434

section is going to be further expanded since there isso much demand from clinical doctors.

Teaching activities
Lectures are given to the fourth and fifth grade
medical students on clinical tests including
hematology, chemistry, endocrinology, immunology,
bacteriology, cardiology, and pulmonary function.
The reversed CPC program is presented to the fifthand sixth grade students. Laboratory practice teachingis provided for the fifth year medical students, insmall groups of 6-7 students for one-week duration.
In this course, students learn clinical and practicalknowledge and techniques on various laboratory tests.
Students from professional schools also study
laboratory medicine under the guidance of members inClinical Laboratory Center.

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 andits application into laboratory medicine, ii) platelet
biology, iii) the clinical significance of reticulated
platelets and immature platelet fraction, iv) hepatic
fibrosis and ischemic reperfusion injury of the liver, v)
genetic testing, vi) bioactive peptides, especiallyadrenomedullin, vii) oxidative stress and organ injury,viii) analysis of cardiac functions using ultrasound, ix)
elucidation of abnormality in epigenetics in cancer
and its clinical application, and x) analysis of brain
function using magnetoencephalography and nearinfrared spectroscopy.

References
1. Arano, T., Nakagawa, H., Tateish,i R., Ikeda, H.,
Uchino, K., Enooku, K., Goto, E., Masuzaki, R.,
Asaoka, Y., Kondo, Y., Goto, T., Shiina, S., Omata,M., Yoshida, H., and Koike, K. Serum level ofadiponectin and the risk of liver cancer
development in chronic hepatitis C patients. Int. J.
Cancer. 129:2226-2235, 2011.

2. Chaya, T., Shibata, S., Tokuhara, Y., Yamaguchi,W., Matsumoto, H., Kawahara, I., Kogo, M.,
Ohoka, Y., Inagaki, S. Identification of a negative
regulatory region for the exchange activity andcharacterization of T332I mutant of Rho guanine
nucleotide exchange factor 10 (ARHGEF10). J.
Biol. Chem. 286: 29511-20, 2011.
3. Dohi, T., Miyauchi, K., Okazaki, S., Yokoyama, T.,
Ohkawa, R., Nakamura, K., Yanagisawa, N.,
Tsuboi, S., Ogita, M., Yokoyama, K., Kurata, T.,
Yatomi, Y., Daida, H. Decreased circulating
lipoprotein-associated phospholipase A2 levels
are associated with coronary plaque regression inpatients with acute coronary syndrome.
Atherosclerosis. 219: 907-912, 2011.
4. Enooku, K., Tateishi, R., Kanai, F., Kondo, Y.,
Masuzaki, R., Goto, T., Shiina, S.,Yoshida, H.,
Omata, M., Koike, K. Evaluation of moleculartargeted cancer drug by changes in tumor markerdoubling times. J. Gastroenterol. 47: 71-78, 2011.
5. Ichinose, A., Souri, M. ; Japanese collaborative
research group on "Acquired haemorrha-philia
due to factor XIII deficiency". As many as 12
cases with haemorrhagic acquired factor XIII
deficiency due to its inhibitors were recently
found in Japan. Thromb. Haemost. 105: 925-927,
2011.
6. Ikeda, H., Tateishi, R., Enooku, K., Yoshida, H.,
Nakagawa, H., Masuzaki, R., Kondo, Y., Goto, T.,
Shiina, S., Kume, Y., Tomiya, T., Inoue, Y.,
Nishikawa, T., Ohtomo, N., Tanoue, Y., Ono, T.,
Koike, K., and Yatomi, Y. Prediction ofhepatocellular carcinoma development by plasma
ADAMTS13 in chronic hepatitis B and C. Cancer
Epidemiol Biomarkers Prev. 20: 2204-2211,
2011.
7. Kage, H., Sugimoto, K., Sano, A., Kitagawa, H.,
Nagase, T., Ohishi, N., Takai, D. Suppression ofTgfb1 in lung alveolar epithelium-derived cells
using adeno-associated virus type 2/5 vectors tocarry short hairpin RNA. Exp. Lung Res. 37:
175-185, 2011.
8. Kimura, K., Takenaka, K., Pan, X., Ebihara, A.,
Uno, K., Fukuda, N., Kohro, T., Morita, H.,
Yatomi, Y., Nagai, R. Prediction of coronary
artery stenosis using strain imaging diastolic435

index at rest in patients with preserved ejection
fraction. J. Cardiol. 57: 311-315, 2011.
9. Kimura, K., Takenaka, K., Ebihara, A., Uno, K.,
Iwata, H., Sata, M., Kohro, T., Morita, H., Yatomi,Y., Nagai, R. Reproducibility and diagnostic
accuracy of three-layer speckle tracking echocardiography in a Swine chronic ischemia model.
Echocardiography. 28: 1148-1155, 2011.
10. Kitano, K., Watanabe, K., Emoto, N., Kage, H.,
Hamano, E., Nagase, T., Sano, A., Murakawa, T.,
Nakajima, J., Goto, A., Fukayama, M., Yatomi, Y.,
Ohishi, N., Takai, D. CpG island methylation of
microRNAs is associated with tumor size andrecurrence of non-small-cell lung cancer. Cancer
Sci. 102: 2126-2131, 2011.
11. Kurano, M., Iso-O, N., Hara, M., Noiri, E., Koike,
K., Kadowaki, T., Tsukamoto, K. Plant sterols
increased IL-6 and TNF-α secretion frommacrophages, but to a lesser extent thancholesterol. J. Atheroscler. Thromb. 18: 373-383,
2011.
12. Kurano, M., Iso-O, N., Hara, M., Ishizaka, N.,
Moriya, K., Koike, K., Tsukamoto, K. LXR
agonist increases apoE secretion from HepG2
spheroid, together with an increased production of
VLDL and apoE-rich large HDL. Lipids HealthDis. 10: 134, 2011.
13. Masuda, A., Fujii, T., Iwasawa, Y., Nakamura, K.,
Ohkawa, R., Igarashi, K., Okudaira, S., Ikeda, H.,
Kozuma, S., Aoki, J., Yatomi, Y. Serum autotaxin
measurements in pregnant women: application forthe differentiation of normal pregnancy andpregnancy-induced hypertension. Clin. Chim.
Acta. 412: 1944-1950, 2011.
14. Masuzaki, R., Shiina, S., Tateishi, R., Yoshida, H.,
Goto, E., Sugioka, Y., Kondo, Y., Goto, T., Ikeda,
H., Omata, M., and Koike, K. Utility of contrast
enhanced ultrasonography with sonazoid inradiofrequency ablation for hepatocellular
carcinoma. J. Gastroenterol. Hepatol. 26: 759764, 2011.
15. Mu, S., Shimosawa, T., Ogura, S., Wang, H.,
Uetake, Y., Kawakami-Mori, F., Marumo, T.,
Yatomi, Y., Geller, DS., Tanaka, H., Fujita, T.
Epigenetic modulation of the renal β-adrenergicWNK4 pathway in salt-sensitive hypertension.
Nat Med. 17: 573-580, 2011.

16. Nakagawa, H., Ikeda, H., Nakamura, K., Ohkawa,R., Masuzaki, R., Tateishi, R., Yoshida, H.,
Watanabe, N., Tejima, K., Kume, Y., Iwai, T.,
Suzuki, A., Tomiya, T., Inoue, Y., Nishikawa, T.,
Ohtomo, N., Tanoue, Y., Omata, M., Igarashi, K.,
Aoki, J., Koike, K., and Yatomi, Y. Autotaxin as anovel serum marker of liver fibrosis. Clin. Chim.
Acta, 412: 1201-1206, 2011.
17. Nakai, Y., Ikeda, H., Nakamura, K., Kume, Y.,
Fujishiro, M., Sasahira, N., Hirano, K., Isayama,
H., Tada, M., Kawabe, T., Komatsu, Y., Omata,M., Aoki, J., Koike, K., and Yatomi, Y. Specificincrease in serum autotaxin activity in patientswith pancreatic cancer. Clin. Biochem. 44: 576581, 2011.
18. Soga, T., Sugimoto, M., Honma, M., Mori, M.,
Igarashi, K., Kashikura, K., Ikeda, S., Hirayama,A., Yamamoto, T., Yoshida, H., Otsuka, M., Tsuji,S., Yatomi, Y., Sakuragawa, T., Watanabe, H.,
Nihei, K., Saito, T., Kawata, S., Suzuki, H.,
Tomita, M., and Suematsu, M. Serum
Metabolomics
Reveals
gamma-Glutamyl
Dipeptides as Biomarkers for Discrimination
among Different Forms of Liver Disease. J.
Hepatol.55: 896-905, 2011.
19. Tsukada, K., Sugawara, Y., Kaneko, J., Tamura, S.,
Tachikawa, N., Morisawa, Y., Okugawa, S.,
Kikuchi, Y., Oka, S., Kimura, S., Yatomi, Y.,
Makuuchi, M., Kokudo, N., and Koike, K. Living
donor liver transplantations in HIV- and hepatitis
C virus-coinfected hemophiliacs: experience in asingle center. Transplantation 91: 1261-1264,
2011.
20. Yamamoto, C., Fukuda, N., Jumabay, M., Saito,
K., Matsumoto, T., Ueno, T., Soma, M.,
Matsumoto, K., Shimosawa, T. Protective effectsof statin on cardiac fibrosis and apoptosis in
adrenomedullin-knockout mice treated with
angiotensin II and high salt loading. Hypertens.
Res. 34: 348-353, 2011.
21. Yoshikado, T., Takada, T., Yamamoto, T., Yamaji,
H., Ito, K., Santa, T., Yokota, H., Yatomi, Y.,
Yoshida, H., Goto, J., Tsuji, S., and Suzuki, H.
Itraconazole-induced cholestasis: involvement of
the inhibition of bile canalicular phospholipid
translocator MDR3/ABCB4. Mol. Pharmacol. 79:
241-250, 2011.

436

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Kazuhiro Fukatsu. M.D., Ph.D.
Yushi Uetera, M.D., Ph.D.

Lecturer
Takami Komatsu, M.D., Ph.D.
Ryoji Fukushima, M.D., Ph.D.

Associate
Saito Yuhei, M.S.
Satoshi Murakoshi, M.D., Ph.D.

Homepage
Introduction and Organization
Operating rooms were centralized for the first timein Japan on July 1955. Surgical center was located in
the surgical ward building till December 1987. The
center moved to the new central building on January
1988, when the surgical center had 14 operatingrooms, 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 clinicaldepartments after the new surgical 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 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.
A total of 8,485, 9,550, 9921, 9,944 and 10,394
operations, which counts for 1.5 times comparing tothose in 2001, were performed in 2006, 2007, 2009
and 2010, respectively. More recently, the number ofoperations was 10,170 in 2011.
There has been much concern about the apparent
increase in the patients who undergo laparoscopic/
thoracoscopic surgery. There is also an apparent
increase in the number of patients who are at high risk
and positive for the microbiological tests such as

437

tuberculosis, MRSA, pseudomonas aeruginosa, HBV,HCV and HIV.

Activities of Surgical Center
Our works range from the management of operation
schedule to the teaching and research on healthcare
practices.

Management of Surgical CenterAll operations of in-patients are performed in 23
operating rooms of the surgical center. Computer
system has been introduced in order to deal with theinformation on the operation. In May 1999, on-line
computer system was introduced for ordering systemof the elective and emergency operations. Then, theoperations have become ordered through the computer
terminal of the clinical departments since May l999.
The doctors and nurses became to be able to see
postoperative information through the computer
system since March 2000.
For the efficacy of the operation, the information on
the status of the procedures has been displayed on thecomputer monitor screen since May 1997. This
monitor also tells the hospital staffs whether there are
any operating rooms available on the next day.
Furthermore, since November 2000, the hospital staffs
have become to be able to see how the clinicaldepartments plan the operations through the hospitalcomputer network.
As for digitalized visual information, thephotographs of operative fields, resected organs andreal-time visual images have been distributed to eachclinical department through hospital computer
network since February 1997.
In the new ward building, the SPD and progressive
patient care system started for the management of our
hospital in October 2001. Then, the SPD system wasintroduced for the surgical center in September 2002.
The complicated surgical procedures including
organtransplantation
microvascularsurgery,
cardiovascular surgery, minimally invasive surgery
and orthopedic surgery have increased dramatically. In
addition, more and more patients recently underwent
surgery using artificial implants such as vascular
prosthesis, joint prosthesis and intraocular lenses.

The advanced techniques have been employed in
the operating rooms. Those include navigation surgery
in neurosurgical, orthopedic and ENT (ear, nose andthroat) departments, 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. Organ transplantation andintraoperative three-dimensional echo-guided surgery
are performed in the surgical center. In addition, more
recently, the robotic surgery has started at our center.
Another recent trend is the presence of emergenceand re-emergence infectious diseases such as HIV andtuberculosis among the operated patients. Therefore, it
is mandatory to educate how to prevent nosocomial
and occupational infections in the surgical center. For
instance, the principles of standard precautions andtransmission-based precautions should be informed to
all health care staffs in the surgical center.
The number of immune-compromised hosts andcomplex surgical procedures will continue to increase
throughout the 21 century. Therefore, the surgicalcenter ought to be playing an important role because
the improvement of the management skill ismandatory to meet the increase in the perioperative
healthcare services for those patients.

Teaching Activities
The following lectures are given to theundergraduates and postgraduates: aseptic techniques,
sterilization
methods,
disinfection
methods,
prevention of perioperative infections, humoral andcellular responses to trauma and shock, training ofscrubbing and gown techniques, Curriculum is
updated every year. For example, introductory course
for disinfection, sterilization and preservation ofsurgical instruments and medical devices was added in
the training courses in 1998, which gained interest andpopularity among students.
In the surgical center, the innovative surgicalinstruments and medical devices are recently
introduced to perform highly advanced operations
such as in the navigation surgery, transplantation
surgery, cardiovascular surgery and so forth.
Consequently, education has become one of the mostimportant activities in the surgical center. The lectures438

of advanced technologies are in the curriculum for thesurgeons, nursing staffs and medical electronics
engineers so that they can understand how to use themproperly.
Lectures for the nursing staffs consist of a freshmancourse and an advanced course. The freshman course
is a basic training course as a scrub nurse and acirculating nurse. It consists of lectures of aseptic
techniques, de-contamination methods, sterilization
methods, prevention of perioperative infections, andtraining of scrubbing and gown techniques as wall as
aseptic preparation of surgical instruments in theoperating room. An advanced course is also preparedto the experienced nurses. The purpose of this course
is to upgrade their perioperative nursing skills so thatthey can afford full nursing skills in the complex
surgical procedures such as transplantation surgery,open-heart surgery and neurosurgery.
There is also a training course to medical
electronics engineers and students of medical
electronics. This training course consists ofintroduction on the medical electronic instruments anddevices, precautions of accidental troubles in handlingsurgical
instruments
andmedicaldevices,development of new surgical instruments and medical
devices, cardiopulmonary bypass techniques andillumination techniques in the operating fields. The
contents of this course are summarized in the manual
for the nursing staffs and contribute to decrease thenumber of accidents in handling surgical instruments
and medical devices.
The on-job training are given to the non-nursing
staffs such as technical officials and temporary
employees and performed when they start their careers
in the surgical center. They are lectured on aseptic
techniques, sterilization methods, disinfection
methods, prevention of perioperative infections andhow to check the faults in the reusable surgicalinstruments such as forceps, scissors and clamps.
These contents are summarized in the manual.
Lectures are also given to senior technical officers andtemporary employees to upgrade their technicalknowledge and skills.

Research Activitiesl)Safety management at surgical 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 center4) Safe surgery5) Introduction of surgical environment in theoperating theaters, including aseptic conditions,
air conditioning and surgical lightening
6) Perioperative infection control and prevention7) Development of new sterilization methods8) Development of new surgical instruments andmedical devises
9) Management of surgical devices using UID
10) Reprocess for disposable and reusable surgicalinstruments11) Recording and transmitting of video picture ofsurgical field
12) Improvement of minimally invasive surgery andinflammatory responses
13) Perioperative management of nutrition
14) Others

References（2009-2011）
1. Omata J, Fukatsu K, Maeshima Y, Moriya T,
Murakoshi S, Noguchi M, Okamoto K, Fukazawa
S, Saitoh D, Mochizuki H, Yamamoto J, Hase K.
Enteral nutrition rapidly reverses total parenteralnutrition-induced impairment of hepatic immunity
in a murine model. Clin Nutr 28:668-73, 2009.
2. Furuya Y, Yanagie H, Wakahara T, Mishina Y,
Akimoto H, Quang le M, Hiroshima K, Yasuhara
H. Improved survival in patients with breast
rhabdoid tumors with multi-agent adjuvant
chemotherapy combined with irradiation. Cancer
Chemother Pharmacol 64:623-7, 2009.
3. Uetera Y, Kawamura K, Kobayashi H, Saito Y,
Yasuhara H, Saito R. Studies on viral disinfection:
An evaluation of moist heat disinfection for HBV
by using A0 concept defined in ISO 15883Washer-Disinfectors. PDA Journal of Pharmaceutical Science and Technology 64:327-336,
2010.
4. Uetera Y, Saito Y, Yasuhara H, Kumada N,
Misawa Y. Sterilizing electronic instruments for

439

5.

6.

7.

8.

neuro-navigation using the “Prion Cycle” at 134 C
for 18 min in a prevacuum autoclave. Zentralsterilisation 18:169-179, 2010.
Fukatsu K, Tanabe K, Maeshima Y, Omata J,
Yasuhara H, Saitoh D. Neutrophil elastase
inhibitor restores gut ischemia reperfusioninduced impairment of gut immunity with reduced
plasma interleukin-6 concentrations in mice. Surg
Infect 11:517-22, 2010.
Furuya Y, Wakahara T, Akimoto H, Long CM,
Yanagie H, Yasuhara H. A case of postoperative
recurrent intussusception associated with indwelling bowel tube. World J Gastrointest Surg 2:85-8,
2010.
Uetera Y, Kawamura K, Kobayashi H, Saito Y,
Yasuhara H, Saito R. Studies on Viral
Disinfection: An Evaluation of Moist Heat
Disinfection for HBV by Using A0 Concept
Defined in ISO 15883-Washer-Disinfectors. PDA
J Pharm Sci Technol 64:327-36, 2010.
Furuya Y, Wakahara T, Akimoto H, Kishimoto T,
Hiroshima K, Yanagie H, Yasuhara H. Clear celladenocarcinoma with enteroblastic differentiationof the ascending colon. J Clin Oncol 29:e647-9,2010

9. Fukatsu K, Kudsk KA. Nutrition and gut immunity.
Surg Clin North Am. 91(4):755-70, 2011.
10. Omata J, Fukatsu K, Murakoshi S, Moriya T, Ueno
C, Maeshima Y, Okamoto K, Saitoh D, Yamamoto J,
Hase K. Influence of adding pyrroloquinoline
equinone to parenteral nutrition on gut-associatedlymphoid tissue. JPEN 34:616-24, 2011.
11. Murakoshi S, Fukatsu K, Omata J, Moriya T,
Noguchi M, Saitoh D, Koyama I. Effects of adding
butyric acid to PN on gut-associated lymphoid tissue
and mucosal immunoglobulin A levels. JPEN 35:
465-72, 2011.
12. Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg Res
172:83-4, 2012.
13. Nakamura K, Ogawa S, Dairiki K, Fukatsu K,
Sasaki H, Kaneko T, Yamaji T. A new immunemodulating diet enriched with whey-hydrolyzed
peptide, femented milk, and isomaltulose attenuates

gut ischemia-reperfusion injury in mice. Clin Nutr
30:513-6, 2011

440

Department of Clinical Radiology
Professor (department manager)
Kuni Ohtomo, M.D.,Ph.D.

Associate Professor (vice manager)
Masaaki Akahane, M.D.

Assistant Professor
Hiroki Sasaki, M.D.,Ph.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, 69 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
provided are linear accelerator (LINAC), gammaknife, Remote After Loading System (RALS) andBrachytherapy (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441

data on RIS. 3) Image Computing & Analysis
Laboratory: The clinical section of this project islocated at the reading room in the Diagnostic
Radiology Section. The main services are processingof volume image data into clinical 3D-images andanalysis of imaging data. 4) Researches on new
radiology
techniques:
Ongoingcollaborative
researches are as follows: image-guided radiation
therapy, clinical PET, multi-detector row CT, 3-Tesla
MRI, flat panel detector.

Clinical activities
1) Diagnostic Radiology:
The section of diagnostic radiology is responsible
for all the clinical examinations of CT, MRI, andangiography and vascular interventional procedures
except for cardiac and peripheral arterial studies. Allof these examinations are performed under therequests of clinicians. Over one hundred and fifty CT
examinations are performed using six MDCT scanners
each day. Interventional procedure such as
percutaneous biopsy and abscess drainage are alsodone by CT guidance. About fifty MR examinations
are done using 1.5-Tesla and 3-Tesla scanners everyday. About six angiographies, most of which areinterventional
procedures
includingarterial
embolization, arterial infusion therapy, arterial
infusion port placement, and angioplasty, are done by
the radiologists using two angiographic units.
In clinical research works, efficacy of MDCT has
been investigated in all parts from the head to
extremities. New three-dimensional approaches havebeen also developed. Clinical research and basic
animal experiments are in progress in the field offunctional MR imaging and diffusion and perfusion
MR techniques.
2) Radiation Oncology:
The radiation therapy is performed with three linear
accelerators, an intracavitary irradiation device(RALS), and a gamma knife for radiosurgery. The
network system connecting these radiotherapy
equipments, CT/MR devices, and treatment planningsystems was already constructed. Each year, over 700
new patients receive radiation therapy in the Radiation
Oncology section. Highly accurate 3D radiation

therapy is the most outstanding feature. We havedeveloped a new linear accelerator with C-arm andmultileaf collimator systems, which is utilized mainly
for non-coplanar radiation therapy in many patients
especially with brain tumor or head and neck tumor.
Recently, a new linear accelerator system with conebeam 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
is a service section to all clinical departments. Main

442

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.

443

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://plaza.umin.ac.jp/~todaiyak/

Introduction and Organization
We have 9 faculty members, 59 pharmacy staffs,
and 13 graduate students and 4 undergraduate students
from the faculty of pharmaceutical sciences and 4
graduate students from the faculty of medicine (as ofDecember 1st, 2011). In addition, project associate
professor (Akihiro Hisaka, Ph.D.), 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 a pharmaceutical such as injection medicines, instillation
medicines and decontaminating chemicals. They
prepare capsule medicines, ointment medicines,
suppositories, central vein nutrition (IVH) for
inpatients and in-home care patients. After strict
inspection of prescriptions, they also dispenseanti- malignant tumor medicine (database isconstructed based on the submitted protocols andthe patient information). In order to support
advanced medical care, they develop and check
formulations (characterization of the uniformity,
stability and so on) of the medicine which is quite
necessary for certain patients, but is not marketed.
4) Drug matters and drug management section
Drug matter section manages the adoption of
medical supplies (in-hospital and out-hospital),
periodically reconsiders the adopted medicines,
and also manages the accountings of all the
medicines and other materials used in our
department. This section also takes statistics of444

every information of drug affairs. Drugmanagement section takes care of supplying andsafekeeping of all the in-hospital medicines(2,339 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 2011)
Number of items on in-hospital formulary: 2,339
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
450,008 ps.
(outside :372,475 ps.)(inside :77,533 ps.)out-patient chemotherapy:
10,746 ps.
in-patients :220,922 ps.
injection drugs:
203,842 ps.
IVH:
7,235 pp.
chemotherapy:
9,227 pp.
TDM consultations (annual) :8,049
Numbers of hospital pharmaceutical cares (annual):
7,558

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 integrated health sciences. We also have
our own half a 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 3-days practicecourse as a part of compulsory clinical practice for the
M4 students and teach clinical pharmaceutics andpractical knowledge of prescription and risk
management to them. For the students in the healthsciences and nursing, we are in charge of clinicalpharmacokinetics lectures as a part of a compulsory
subject, "Pharmacology and Toxicology".
For students in the faculty of pharmacy, we are in
charge of two series of lectures for the undergraduate
students: "Clinical Pharmacy I" (compulsory subject)and "Clinical Pharmacy II" (an optional course).
They are educated for the clinical pharmacology andpharmacokinetics. For the graduate students, we arein charge of “Special Lecture Basic Pharmaceutical
Science IV”, “Special Lecture Clinical Science”,"Advanced Course of Medical Pharmacy" as acooperator of the Clinical Pharmacokinetics. Recent
trends of the medical pharmacy as well as the practical445

developments and future visions of the department ofpharmacy are presented in this lecture. In addition tothese, we accept undergraduate and graduate students
from the faculty of pharmaceutical sciences andfaculty of medicine. They are doing various research
activities.
Six year course education system has been launchedin the field of pharmaceutical sciences since 2006.
In this system, the clinical training by the pharmacists
at the hospital is one of the most importantcurriculums. In 2011, we accepted total 42 clinicaltraining students from The University of Tokyo,
Tokyo University of Pharmacy and Life Sciences,
Keio University, Hoshi University, and Musashino
University and educated them for 2.5 months. On
the other hand, we have had an original one-year
post-graduate training course for pharmacists sincelong time before starting the 6-year course education
system. They learned various practical knowledge
and techniques necessary for hospital pharmacists.
Such education style is still continued by shortening
the period to half a year. In 2011, 6 pharmacists
finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

Research activities
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. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids /uric acid, and establishment of new therapy forlife-style related diseases based on those
integrated understanding.
2. Elucidation of the dynamic regulatory mechanismof bone resorption / bone formation, andestablishment of new therapy for bone metabolic
disease based on those integrated understanding.
3. Establishment of the way to quantitative
understanding and prediction of pharmacologicaleffect and side-effect of drugs directed against
particular molecular target. Finally, these outputs
would be feed backed to early drug development
stages.
4. Elucidation of the molecular mechanism related tothe side effect of drugs using large-scale“-omics“ analysis.
Finally, the quantitative
information would be applied to develop strategies
to prevent / treat the side effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its
application to clinical pharmacokinetics andpharmacology field.

References(1) Iwayanagi Y, Takada T, Tomura F, Yamanashi Y,
Terada T, Inui K and Suzuki H. Human NPC1L1
expression is positively regulated by PPARalpha.
Pharm Res 28(2):405-412, 2011
(2) Kariya Y, Honma M, Hanamura A, Aoki S,
Ninomiya T, Nakamichi Y, Udagawa N and
Suzuki H. Rab27a and Rab27b are involved instimulation-dependent RANKL release fromsecretory lysosomes in osteoblastic cells. J Bone
Miner Res 26(4):689-703, 2011
(3) Koshimichi H, Ito K, Hisaka A, Honma M and
Suzuki H. Analysis and prediction of drugtransfer into human milk taking into
consideration secretion and reuptake clearancesacross the mammary epithelia. Drug Metab
Dispos 39(12):2370-2380, 2011(4) Matsuo H, Takada T, Ichida K, Nakamura T,446

Nakayama A, Suzuki H, Hosoya T and
Shinomiya N. ABCG2/BCRP dysfunction as amajor cause of gout. Nucleosides Nucleotides
Nucleic Acids 30(12):1117-1128, 2011(5) Matsuo H, Takada T, Ichida K, Nakamura T,
Nakayama A, Takada Y, Okada C, Sakurai Y,
Hosoya T, Kanai Y, Suzuki H and Shinomiya N.
Identification of ABCG2 dysfunction as a major
factor contributing to gout. Nucleosides
Nucleotides Nucleic Acids 30(12):1098-1104,
2011(6) Nakayama A, Matsuo H, Takada T, Ichida K,
Nakamura T, Ikebuchi Y, Ito K, Hosoya T, Kanai
Y, Suzuki H and Shinomiya N. ABCG2 is ahigh-capacity urate transporter and its genetic
impairment increases serum uric acid levels inhumans. Nucleosides Nucleotides Nucleic Acids
30(12):1091-1097, 2011(7) Sekine S, Ito K, Saeki J and Horie T. Interactionof Mrp2 with radixin causes reversible
canalicular Mrp2 localization induced byintracellular redox status. Biochim Biophys Acta
1812(11):1427-1434, 2011(8) Soga T, Sugimoto M, Honma M, Mori M,
Igarashi K, Kashikura K, Ikeda S, Hirayama A,
Yamamoto T, Yoshida H, Otsuka M, Tsuji S,
Yatomi Y, Sakuragawa T, Watanabe H, Nihei K,
Saito T, Kawata S, Suzuki H, Tomita M and
Suematsu M. Serum metabolomics reveals
gamma-glutamyl dipeptides as biomarkers fordiscrimination among different forms of liverdisease. J Hepatol 55(4):896-905, 2011
(9) Yamamoto N, Honma M and Suzuki H.
Off-target serine/threonine kinase 10 inhibitionby erlotinib enhances lymphocytic activity
leading to severe skin disorders. Mol Pharmacol
80(3):466-475, 2011(10) Yamamoto T, Yasuno N, Katada S, Hisaka A,
Hanafusa N, Noiri E, Yahagi N, Fujita T and
Suzuki H. Proposal of a pharmacokinetically
optimized dosage regimen of antibiotics inpatients receiving continuous hemodiafiltration.
Antimicrob Agents Chemother 55(12):5804-5812,
2011(11) Yamanashi Y, Takada T, Yoshikado T, Shoda J
and Suzuki H. NPC2 regulates biliary cholesterol
secretion via stimulation of ABCG5/G8-mediatedcholesterol transport. Gastroenterology 140(5):1664-1674, 2011(12) Yoshikado T, Takada T, Yamamoto T, Yamaji H,
Ito K, Santa T, Yokota H, Yatomi Y, Yoshida H,
Goto J, Tsuji S and Suzuki H. Itraconazoleinduced cholestasis: involvement of theinhibition of bile canalicular phospholipid
translocator MDR3/ABCB4. Mol Pharmacol
79(2):241-250, 2011

447

Delivery Unit
Professor
Shiro Kozuma

Tomoyuki Fujii

Lecturer
Yoshimasa Kamei

Homepage

Takahiro Yamashita

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

Organization
The Delivery Unit of the University of Tokyo
Hospital is organized by two professors, two lecturers,
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 853 in 2011.
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.]

448

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Lecturer

Naoshi Ogata, M.D.

Associate
Yauo Nakahara, M.D.,

HomepageShun-ichi Furukawa, M.D.

http://todaireh.umin.ne.jp

Introduction and Organization
The physical therapy service started in 1963 at the
University of Tokyo Hospital, and then expanded toinclude occupational therapy and social work section.
In 1966 this service was converted to the central
rehabilitation service department as a part of theCentral Diagnostic and Therapeutic Service
Department. The Central Rehabilitation Service
became an independent unit in 1970. After the
reorganization of the University of Tokyo Hospital
according to major organic classification in 1998,
outpatient clinic as rehabilitation medicine wasinstalled. The formal title of our unit was changed
from the Physical Therapy Department to the
Rehabilitation Department by the budget measures in
the fiscal year 2001, and we integrated the related
personnel categories, which belonged to theorthopedic surgery department and the physicalmedicine department.
At the present time our department consists of four
sections. Rehabilitation physicians’ section includes
four full-time doctors and two other part-time doctors.
They work chiefly for clinical practice in medical
rehabilitation service, but also have to engage inteaching activities for medical students. Sixteen
physical therapists are working in the physical therapy
section. In the occupational therapy section, four
occupational therapists work for the generalrehabilitation service and the other three therapists
work for the psychiatric rehabilitation. Fouracupuncture therapists perform acupuncture andmoxbustion. In the Day-care Unit, clinicalpsychologists and nurses also work. In 2006, speechtherapists and orthoptists who had belonged to otherdepartments in the University of Tokyo Hospital were
included in our department. From 2009, a speechtherapist added to our department, and now two
therapists perform therapy for patients with aphasia,
dysarthria, and dysphagia.

Clinical activities
There is not enough doctors arranged for the
department of rehabilitation medicine, and we cannot
run own beds for rehabilitation patients at present. The
professor serves as a director of Rehabilitation Center,the University of Tokyo Hospital. Both departments
are united and engage in clinical practice. We have atpresent no charged ward, and treat about 1,000 newreferrals annually from almost all the departments of
the university hospital. We always take charge ofabout 250 patients corresponding about 25% of thewhole number of inpatients. We also see 15 people per
day at the outpatient rehabilitation setting. The
numerical ratio of outpatient is being reduced in orderto give priority to the clinical service corresponding toneeds expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on449

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, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline ofrehabilitation, and amputation/prostheses. We haveprovided a clinical practice in small group, so-called
bedside learning for 5th year students from
Wednesday to Friday every other week. Theyexperience a few patients and learn how to take apatients’ 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,
occupational therapy, and speech therapy. Twenty
students or more come and stay at the university
hospital annually as a long-term clerkship fromseveral PT/OT/ST training schools.

6)
7)
8)

References
1.

2.

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 inchildren
3) Early detection, diagnosis, and progression
prevention of musculoskeletal disorders in theelderly4) Rehabilitation approaches for patients withhemophilia
5) Rehabilitation approaches for patients with spina

bifidaTreatment and rehabilitation for patients withcongenital limb deficiencies
Disabilities and handicaps in patients withskeletal dysplasias
Analysis of musculo-skeletal involvement incongenital insensitivity to pain

3.

4.

Mori Y, Susami T, Haga N, Tamura K, Kanno Y,
Saijo H, Takato T: Extraction of six molars undergeneral anesthesia in a patient with fibrodysplasia
ossificans progressiva (FOP). J Oral Maxillofac
Surg 69: 1905-1910, 2011
Ohte S, Shin M, Sasanuma H, Yoneyama K,
Akita M, Ikebuchi K, Jimi E, Maruki Y,
Matsuoka M, Nanba A, Tomoda H, Okazaki Y,
Ohtake A, Oda H, Owan I, Yoda T, Furuya H,
Kamizono J, Kitoh H, Nakashima Y, Susami T,
Haga N, Komori T, Katagiri T: A novel mutationof ALK2, L196P, found in the most benign caseof fibrodysplasia ossificans progressiva activates
BMP-specific intracellular signaling equivalent
to a typical mutation. R206H. Biochem Biophys
Res Commun 407: 213-218, 2011
Taketomi S, Hiraoka H, Nakagawa T, Miyamoto
Y, Kuribayashi S, Fukuda A, Takeda H, Fukai A,
Hirota J, Nakajima K, Haga N, Nakamura K:
Osteochondral autograft for medial femoral
condyle chondral lesions in a patient withmultiple epiphyseal dysplasia: long-term result. J
Orthop Sci, 2011 published online
Kaplan FS, Shore EM, Pignolo RJ (eds), Haga N,
and The International Clinical Consortium on
FOP.
Themedicalmanagementoffibrodysplasia ossificans progressiva: current
treatment considerations. Clin Proc Intl Clin
Consort FOP 4: 1-100, 2011

450

Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D., Ph.D.*

Associate Professor (Deputy Director)
Hiroshi Uozaki, M.D., Ph.D. *Associate Professor
Shumpei Ishikawa, M.D., Ph.D.*

Lecturer
Yutaka Takazawa, M.D., Ph.D.,
Junji Shibahara, M.D., Ph.D. * (visiting researcher, USA)

Lecturer (Hospital)
Tetsuo Ushiku, M.D., Ph.D.,

Associate
Masako Ikemura, M.D., Ph.D.,

Daichi Maeda, M.D., Ph.D.

Keisuke Matsusaka, M.D., Ph.D.
Teppei Morikawa, M.D., Ph.D. (visiting researcher, USA)
Rumi Hino, M.D., Ph.D. *,Aya Shinozaki, M.D., Ph.D. *Yukako Shintani, M.D., Ph.D. *Clinical Fellow
Kyoko Kurotobi, M.D., Ph.D.,

Homepage

Kayoko Ichimura, M.D.,

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology(*) and Division of Diagnostic Pathology of
University Hospital have been organized to function
as a unit.
The proper staffs in the Division of Diagnostic
Pathology include a lecturer, a hospitall lecturer, two
associates, and three clinical staffs. Dr. Shibahara waspromoted to a Lecturer, Department of Pathology on
December.

Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2011
fiscal year consisted of 14,716 cases of histologicalexamination (19,770 specimens), 26,427 specimens ofcytology, 701 of frozen histology, 596 of
intra-operative cytology, 64 of autopsy cases (18% as
autopsy rate), and 2 autopsy cases from otherhospitals.
Clinico-pathological conferences (CPCs) for thetwo autopsy cases are held every month in the hospital.
Furthermore, the following surgical pathology

451

conferences are regularly held with each clinicaldivision; the cases of various tumors of organs (thedoctor in charge of each), such as thoracic organs (Drs.
Maeda), liver and pancreato-biliary tract (Drs.
Shinozaki and Ushiku), male genitourinary (Dr.
Shintani) and female genital tracts (Drs. Maeda and
Takazawa), breast (Dr. Ikemura), and bone and soft
tissues (Dr. Ushiku). Biopsy conferences are also heldin the cases of kidney (Dr. Uozaki), skin (Dr.
Takazawa) and GI tract (Drs. Ushiku and Matsusaka).
Our aim in the pathologic practices is to provide
the correct diagnosis as soon as possible. We are
addressing ‘one-day pathology’ using a rapidhistoprocessing machinery. We also perform double
check review of the reports and slides for all cases ofhistological examination to prevent a potential
misdiagnosis.
Virtual slide scanners have been installed, whichenabled us to save the biopsy specimens as digital
information. We are setting out a future providing
system of pathologic images for clinical divisions. Dr.
Uozaki is mainly in charge of this project.
We continue to participate the autopsy
assessment for “The Model Project for Inspection andAnalysis of the Deaths Related to Medical Treatment(DRMT)”.

Research activities

Teaching activities

References

The lectures and exercise course of systemic
pathology are for the 2nd grade–students. Bed-side
learning (BSL) course of autopsy and surgicalpathology are for the 4th grade students. Four students
of 3rd grade took the clinical clerkship course.
We instructed all interns to submit one report of
CPC case as a requirement of their medical training.
We have made digest version of CPC slides open in
the hospital, and also started e-learning program forinterns to solve the problems in CPC by themselves,
therby facilitating their understanding (Drs. Takazawa
and Ikemura).
The Division of Diagnostic Pathology received
five interns (total 18 months) in 2011 for the second
year program of their internship.

See the corresponding section of Department of
Pathology and Diagnostic Pathology

Dr. Uozaki carried out a co-operative study with Fuji
Xerox and National Institute of Advanced Industrial
Science and Technology (AIST) to develop medical
application of the input supporting system of free text,
based on the ontology and natural language processing.
The project was funded by A-STEP (Adaptable andSeamless Technology transfer Program throughtarget-driven R & D), High-risk challenging type ofJapan Science and Technology Agency
Dr. Takazawa is in charge of the project
investigating usefulness of post mortem CT images
for hospital autopsy, using a CT apparatus in the
autopsy assisting CT room (ref. 7, 8).
We continue the pathological studies ofneoplastic diseases on the basis of surgical pathology
conferences. We are also developing a new antibodybased in vivo imaging and therapy in collaboration
with Genome Science Division, Research Center for
Advanced Science and Technology, the University ofTokyo. We are evaluating the feasibility of antibody
panels for immunohistochemistry to detect themetastasis in the sentinel lymph nodes of the gastriccancer, by constructing the tissue array of primary andmetastatic cancers (Drs. Ushiku and Matsusaka).

452

Department of Corneal
Transplantation
Associate Professor
Satoru Yamagami, 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 and contact lens clinic for special cases areheld every Wednesday. At the corneal service, we
determine indication for corneal transplantation andfollow up patients after the surgery. The patients who
enrolled in the corneal service have exceeded 5000.
Total 88 corneal transplantations were performed in
2011. In addition to the full-thickness corneal
transplantation, we have successfully performed
corneal endothelial transplantation for patients withbullous keratopathy, the most common disease of
cornealtransplantation.
Generally,
cornealtransplantation is performed as emergency operation,
because we need to transplant corneas as soon as

possible.
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 with cooperation of eyebank.
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. This method
allowed us to preserve donor cornea one week
after enucleation.

Teaching activities
As an undergraduate course, we give lectures on
corneal diseases and corneal transplantation. In
addition, we are engaged in practical training for
medical students on ophthalmological examinations at
the outpatient clinic.

Research activities
We have pursued to apply regenerative medicine to453

corneal diseases. In patients with chemical burn ofocular surface, Stevens-Johnson syndrome, and ocular
pemphigoid, we try to reconstruct the ocular surface
with autologous cultivated limbal, conjunctival or oral
epithelial cells. We also have tried to investigate
regenerative medicine of corneal endothelial cellswith primate model.
In addition, we are investigating expression andfunction of novel mucin, Acanthamoeba keratitis
caused by contact lens, corneal graft rejection andstatistical analysis of long term result in corneal
transplantation.

References
1.

2.

3.

4.

5.

6.

Yamaguchi M, Ebihara N, Shima N, Kimoto M,
Funaki T, Yokoo S, Murakami A, Yamagami S:
Adhesion, migration, and proliferation ofcultured human corneal endothelial cells bylaminin-5: Invest Ophthalmol Vis Sci. 52:679-84,
2011.
Shima N, Kimoto M, Yamaguchi M, Yamagami S.
Increased proliferation and replicative lifespan ofisolated human corneal endothelial cells with
L-ascorbic acid 2-phosphate.Invest Ophthalmol
Vis Sci. 52:8711-7, 2011.
Mimura T, Usui T, Obata H, Yamagami S, Mori
M, Funatsu H, Noma H, Dou K, Amano S.
Severity and determinants of pinguecula in a
hospital-based population. Eye Contact Lens.
37:31-5, 2011.
Sugita S, Yamada Y, Horie S, Nakamura O,
Ishidoh K, Yamamoto Y, Yamagami S, Mochizuki
M. Induction of T regulatory cells by cytotoxic
T-lymphocyte antigen-2α on corneal endothelial
cells. Invest Ophthalmol Vis Sci. 52:2598-605,
2011.
Mimura T, Usui T, Yamagami S, Funatsu H,
Noma H, Toyono T, Mori M, Amano S.
Relationship between conjunctivochalasis andrefractive error. Eye Contact Lens. 37:71-8, 2011.
Miyazaki D, Haruki T, Takeda S, Sasaki S,
Yakura K, Terasaka Y, Komatsu N, Yamagami S,
Touge H, Touge C, Inoue Y. Herpes simplex virus
type 1-induced transcriptional networks ofcorneal endothelial cells indicate antigen

7.

presentation function. Invest Ophthalmol Vis Sci.
52:4282-93, 2011.
Takeda S, Miyazaki D, Sasaki S, Yamamoto Y,
Terasaka Y, Yakura K, Yamagami S, Ebihara N,
Inoue Y. Roles played by toll-like receptor-9 incorneal endothelial cells after herpes simplex
virus type 1 infection. Invest Ophthalmol Vis Sci.
52:6729-36, 2011.

454

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Junko Takita, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Associate
Akihide Yoshimi, M.D. , Ph.D. (Hematology-Oncology)

Homepage

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

Introduction and Organization
Department of Cell Therapy and Transplantation
Medicine was institutionally established in 1995, andformally organized in 1996. At present, the staff
consists of three 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 isadministered according to the malignant disease. For
the autologous stem cell support, peripheral blood
stem cell is usually selected as a source of stem cells.
Similar procedures used in the allogeneic stem cell
harvest are performed for leukapheresis andpreservation 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.

Teaching activities
Together with the members of Department of
Hematology/Oncology and Hematology/Oncology
group in the Department of Pediatrics, lecture courses

455

on etiology, pathogenesis, clinical and laboratory
features, differential diagnosis, therapy and prognosis
for all hematological diseases are provided for thesecond grade medical students. Courses for bedsidelearning on diagnostic and therapeutic issues and arts
are given for the third grade medical students on a
man-to-man basis with a senior faculty member.
Clinical clerkship courses are given to the fourth
grade medical students, who join the patient careteams consisting of junior and senior medical doctors
and learn medical practices and patient management,
through playing a role as a junior member of the team,
as well as through discussions and presentations.

Research activities
The major research projects are focused on clinicalstudies such as development of improved/new
methods for hematopoietic stem cell transplantation,
immunotherapy for hematopoietic tumors, and basic
studies on hematopoietic stem cells, leukemogenesis
and regenerative medicine using hematopoietic cells.
In the area of pediatric oncology, we continue thestudies on molecular mechanisms of pediatricmalignancies, such as neuroblastoma, rhabdomyosarcoma, and infant leukemia. Representative
publications from our department published in the past
year are listed in the references.

References
1.

2.

3.

Arai S, Yoshimi A, Shimabe M, Ichikawa M,
Nakagawa M, Imai Y, Goyama S, Kurokawa M.
Evi-1 is a transcriptional target of mixed-lineage
leukemia oncoproteins in hematopoietic stem
cells. Blood. 2011 Jun;117(23):6304-14.
Kagoya Y, Kataoka K, Nannya Y, Kurokawa M.
Pretransplant predictors and posttransplantsequels of acute kidney injury after allogeneic
stem cell transplantation. Biol Blood Marrow
Transplant. 2011 Mar;17(3):394-400.
Kagoya Y, Takahashi T, Yoshimoto T, Ichikawa
M, Hangaishi A, Fukayama M, Kurokawa M.
Recurrent pericardial effusion after treatment for
primary effusion lymphoma-like lymphoma: an
autopsied case. Ann Hematol. 2011 Feb;90(2):219-20.

4.

Kagoya Y, Takahashi T, Nannya Y, Shinozaki A,
Ota S, Fukayama M, Kurokawa M.
Hyperbilirubinemia after hematopoietic stem celltransplantation: comparison of clinical andpathologic findings in 41 autopsied cases. Clin
Transplant. 2011 Sep-Oct;25(5):E552-7.
5. Kataoka K, Sato T, Yoshimi A, Goyama S,
Tsuruta T, Kobayashi H, Shimabe M, Arai S,
Nakagawa M, Imai Y, Kumano K, Kumagai K,
Kubota N, Kadowaki T, Kurokawa M. Evi1 isessential for hematopoietic stem cell self-renewal,
and its expression marks hematopoietic cells withlong-term multilineage repopulating activity. J
Exp Med. 2011 Nov 21;208(12):2403-16.
6. Kobayashi CI, Yamamoto G, Hayashi A, Ota S,
Imai Y, Fukayama M, Kurokawa M. Fatal amebic
colitis after high-dose dexamethasone therapy for
newly diagnosed multiple myeloma. Ann
Hematol. 2011 Feb;90(2):225-6.
7. Kobayashi H, Ichikawa M, Hangaishi A, Imai Y,
Kurokawa M. Concurrent development of"Burkitt-like" lymphoma and BCL-2-rearranged
low-grade B cell lymphoma sharing the same
germinal center origin. Int J Hematol. 2011 Jan;
93(1):112-7.
8. Koya J, Nannya Y, Yoshizato T, Ono K, Seo S,
Nakagawa M, Ichikawa M, Kurokawa M.
Disseminated tuberculosis following unrelated
cord blood transplantation for refractory
peripheral T-cell lymphoma: Clinical role ofserum procalcitonin levels. J Infect. 2011 Mar;62(3):237-40.
9. Masamoto Y, Nannya Y, Kurokawa M.
Voriconazole is effective as secondary antifungal
prophylaxis in leukemia patients with priorpulmonary fungal disease: case series and review
of literature. J Chemother. 2011 Feb;23(1):17-23.
10. Nakagawa M, Shimabe M, Watanabe-Okochi N,
Arai S, Yoshimi A, Shinohara A, Nishimoto N,
Kataoka K, Sato T, Kumano K, Nannya Y,
Ichikawa M, Imai Y, Kurokawa M. AML1/
RUNX1 functions as a cytoplasmic attenuator of
NF-κB signaling in the repression of myeloid
tumors. Blood. 2011 Dec 15;118(25):6626-37.
11. Nannya Y, Kataoka K, Hangaishi A, Imai Y,
Takahashi T, Kurokawa M. The negative impact
of female donor/male recipient combination in

456

12.

13.

14.

15.

16.

17.

18.

19.

allogeneic hematopoietic stem cell transplantation depends on disease risk. Transpl Int.
2011 May;24(5):469-76.
Nishimoto N, Arai S, Ichikawa M, Nakagawa M,
Goyama S, Kumano K, Takahashi T, Kamikubo Y,
Imai Y, Kurokawa M. Loss of AML1/Runx1
accelerates the development of MLL-ENL
leukemia through down-regulation of p19ARF.
Blood. 2011 Sep;118(9):2541-50.
Ogura M, Todo T, Tanaka M, Nannya Y, Ichikawa
M, Nakamura F, Kurokawa M. Temozolomide
may induce therapy-related acute lymphoblastic
leukaemia. Br J Haematol. 2011 Sep;154(5):663-5.
Sakata-Yanagimoto M, Sakai T, Miyake Y, Saito
TI, Maruyama H, Morishita Y, NakagamiYamaguchi E, Kumano K, Yagita H, Fukayama
M, Ogawa S, Kurokawa M, Yasutomo K, Chiba S.
Notch2 signaling is required for proper mast cell
distribution and mucosal immunity in theintestine. Blood. 2011 Jan;117(1):128-34.
Seo S, Nakamoto T, Takeshita M, Lu J, Sato T,
Suzuki T, Kamikubo Y, Ichikawa M, Noda M,
Ogawa S, Honda H, Oda H, Kurokawa M.
Crk-associated substrate lymphocyte type
regulates myeloid cell motility and suppresses the
progression of leukemia induced by p210Bcr/Abl.
Cancer Sci. 2011 Dec;102(12):2109-17.
Yamamoto G, Maki H, Ichikawa M, Kurokawa M.
Pure red cell aplasia with follicular lymphoma
showing regression and progression parallel tolymphoma. Int J Hematol. 2011 Dec;94(6):576-7.
Yamazaki S, Nakamura F, Nasu R, Nannya Y,
Ichikawa M, Kurokawa M. Haemophagocytic
lymphohistiocytosis is a recurrent and specificcomplication of acute erythroid leukaemia. Br J
Haematol. 2011 Jun;153(5):669-72.
Yamazaki S, Fujioka Y, Nakamura F, Ota S,
Shinozaki A, Yamamoto G, Kamikubo Y, Nannya
Y, Ichikawa M, Fukayama M, Kurokawa M.
Composite diffuse large B-cell lymphoma andCD20-positive peripheral T-cell lymphoma.
Pathol Int. 2011 Nov;61(11):662-6.
Yoshimi A, Goyama S, Watanabe-Okochi N,
Yoshiki Y, Nannya Y, Nitta E, Arai S, Sato T,
Shimabe M, Nakagawa M, Imai Y, Kitamura T,
Kurokawa M. Evi1 represses PTEN expression

and activates PI3K/AKT/mTOR via interactions
with polycomb proteins. Blood. 2011 Mar;
117(13):3617-28.
20. Yoshimi A, Kurokawa M. Key roles of histone
methyltransferase
anddemethylaseinleukemogenesis. J Cell Biochem. 2011 Feb;
112(2):415-24.
21. Yoshimi A, Kurokawa M. Evi1 forms a bridge
between the epigenetic machinery and signaling
pathways. Oncotarget. 2011 Jul;2(7):575-86.
22. Yoshizato T, Nannya Y, Yoshiki Y, Nakamura F,
Imai Y, Ichikawa M, Kurokawa M.
Nilotinib-induced hypothyroidism in a patientwith chronic myeloid leukemia. Int J Hematol.
2011 Mar;93(3):400-2.17.

457

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Mitsuhiro Fujishiro, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kogaku.html

Introduction and Organization
Department of Endoscopy and Endoscopic Surgery
were established in April 1997. Although the present
staff of our department is only an associate professor,
about 80 doctors from other departments including thedepartment of internal medicine, surgery, gynecology
and otorhinolaryngology, participate the endoscopic
procedures. The endoscopic rooms moved to the newbuilding in Oct. 2006.

enhanced endoscopy for detail inspection andtherapeuticendoscopy,
includingendoscopic
submucosal dissection for esophageal, gastric andcolorectal tumors, are major advanced fields. Our
recent clinical activities are summarized in Table 1.
Another important activity of our department is thedisinfection and maintenance of endoscopic
apparatuses used in other units including outpatient
clinic, radiographic procedure rooms, surgery rooms
or intensive care units. All endoscopes are collectedin our department after use and disinfected.

Clinical activities
Teaching activities
Endoscopic
procedures,
includinguppergastrointestinal endoscopy, colonoscopy, bronchoscopy, otorhinolaryngological endoscopy and gynecological endoscopy, are performed from Monday to
Friday. Emergency endoscopy is performed in thenighttime or holidays. Enteroscopy by using capsuleendoscopes and balloon-assisted endoscopes are
rapidly increasing in number. Additionally, image

We participate in under-graduate education as a part ofsystemic lectures and bed-side learning by thedepartment of gastroenterology, surgery and otherdepartments. As for post-graduate education, training
opportunities for endoscopy and endoscopic surgery
are given to resident or young doctors in a program ofeach department.

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2002

2003

2004

2005

2006

2007

2008

2009

*

EGD
Colonoscopy
Bronchoscopy
EUS**Enteroscopy
Laryngoscopy
Colposcopy

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

11852

12778

12195

13199

13282

14043

15520

16566

*Esophagogastroduodenoscopy, **Endoscopic ultarasonography

2010
10556
5152
255
551
311
70
361
17256

2011
10963
5208
197
630
282
108
378
17764

458

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

References(1) Ono S, Fujishiro M, Kodashima S, Minatsuki C,
Hirano K, Niimi K, Goto O, Yamamichi N,
Koike K. Controversy on the management of
anticoagulants and antiplatelet agents forscheduled endoscopy. Dig Endosc 23:1-4, 2011(2) Inoue I, Mukoubayashi C, Yoshimura N, Niwa T,
Deguchi H, Watanabe M, Enomoto S, Maekita T,
Ueda K, Iguchi M, Yanaoka K, Tamai H, Arii K,
Oka M, Fujishiro M, Takeshita T, Iwane M,
Mohara O, Ichinose M. Elevated risk ofcolorectal adenoma with Helicobacter pylorirelated chronic gastritis: A population-based
case-control study. Int J Cancer. 129:2704-11,
2011(3) Goto O, Mitsui T, Fujishiro M, Wada I, Shimizu
N, Seto Y, Koike K. New method of endoscopic
full-thickness resection: a pilot study of nonexposed endoscopic wall-inversion surgery in an
ex vivo porcine model. Gastric Cancer. 14:183-7,
2011(4) Nakai Y, Ikeda H, Nakamura K, Kume Y,
Fujishiro M, Sasahira N, Hirano K, Isayama H,
Tada M, Kawabe T, Komatsu Y, Omata M, Aoki
J, Koike K, Yatomi Y. Specific increase in serum
autotaxin activity in patients with pancreaticcancer. Clin Biochem. 44:576-81, 2011
(5) Fujishiro M. Can endoscopists becomemore
aggressive or have more options for patients withantithrombotic agents? Dig Dis Sci. 56:2517–
2519, 2011(6) Enomoto S, Oka M, Ohata H, Mukoubayashi C,
Watanabe M, Moribata K, Muraki Y, Shingaki N,
Deguchi H, Ueda K, Inoue I, Maekita T, Iguchi
M, Yanaoka K, Tamai H, Fujishiro M, Mohara O,
Ichinose M. Assessment of gastroesophageal
reflux disease by serodiagnosis of Helicobacter
pylori-related chronic gastritis stage. World J
Gastrointest Endosc 3: 71-77, 2011
(7) Kawahara Y, Uedo N, Fujishiro M, Goda K,
Hirasawa D, Lee JH, Miyahara R, Morita Y,

Singh R, Takeuchi M, Wang S, Yao T. The
usefulness of NBI magnification on diagnosis ofsuperficial esophageal squamous cell carcinoma.
Dig Endosc. 23 Suppl 1:79-82, 2011.
(8) Uedo N, Fujishiro M, Goda K, Hirasawa D,
Kawahara Y, Lee JH, Miyahara R, Morita Y,
Singh R, Takeuchi M, Wang S, Yao T. The
usefulness of NBI magnification on diagnosis ofsuperficial esophageal squamous cell carcinoma.
Dig Endosc. 23 Suppl 1:58-71, 2011.
(9) Ono S, Fujishiro M, Kanzaki H, Uedo N, Yokoi C,
Akiyama J, Sugawara M, Oda I, Suzuki S, Fujita
Y, Tsubata S, Hirano M, Fukuzawa M, Kataoka
M, Kamoshida T, Hirai S, Sumiyoshi T, Kondo H,
Yamamoto Y, Okada K, Morita Y, Fujiwara S,
Morishita S, Matsumoto M, Koike K. Conflicting
clinical environment about the management ofantithrombotic agents during the periendoscopic
period in Japan. J Gastroenterol Hepatol. 26:
1434–40, 2011(10) Niimi K, Fujishiro M, Goto O, Kodashima S,
Minatsuki C, Hirayama I, Mochizuki S, Ono S,
Yamamichi N, Kakushima N, Ichinose M, Koike
K. Prospective single-arm trial of two-weekrabeprazole treatment for ulcer healing after
gastric endoscopic submucosal dissection. Dig
Endosc 24:110-6, 2012.
(11) Goto O, Isayama H, Fujishiro M, Koike K.
Gastrointestinal: EUS-guided FNA for a
mimicking esophageal submucosal tumor in an
immunocompromised patient. J Gastroenterol
Hepatol. 26:1215, 2011.
(12) Ozawa S, Tachimori Y, Baba H, Fujishiro M,
Matsubara H, Numasaki H, Oyama T, Shinoda
M, Takeuchi H, Tanaka O, Teshima T, Udagawa
H, Uno T, Barron JP. Comprehensive registry ofesophageal cancer in Japan, 2003. Esophagus
8:9–29, 2011(13) Takara Y, Ishibashi Y, Fujishiro M, Fujita T.
Endoscopic treatment of obstructed peritoneal
catheter. Kidney Int. 80:679, 2011.
(14) Nakata H, Enomoto S, Maekita T, Inoue I, Ueda
K, Deguchi H, Shingaki N, Moribata K, Maeda Y,
Mori Y, Iguchi M, Tamai H, Yamamichi N,
Fujishiro M, Kato J, Ichinose M. Transnasal andstandard transoral endoscopies in the screening of459

gastric mucosal neoplasias. World J Gastrointest
Endosc 3: 162-170, 2011.
(15) Goto O, Fujishiro M, Oda I, Kakushima N,
Yamamoto Y, Tsuji Y, Ohata K, Fujiwara T,
Fujiwara J, Ishii N, Yokoi C, Miyamoto S, Itoh T,
Morishita S, Gotoda T, Koike K. A multicenter
survey of the management after gastricendoscopic submucosal dissection related to
postoperative bleeding. Dig Dis Sci. 57:435-9,
2012.
(16) Hotta K, Saito Y, Fujishiro M, Ikehara H,
Ikematsu H, Kobayashi N, Sakamoto N,
Takeuchi Y, Uraoka T, Yamaguchi Y. The
Impact of Endoscopic Submucosal Dissection for
the Therapeutic Strategy of Large Colorectal
Tumors. J Gastroenterol Hepatol. 27: 510–515,
2012(17) Goto O, Fujishiro M, Kodashima S, Minatsuki C,
Niimi K, Ono S, Yamamichi N, Koike K.
Short-term healing process of artificial ulcers
after gastric endoscopic submucosal dissection.
Gut Liver. 5:293-7, 2011.
(18) Ishizaka N, Sakamoto A, Fujishiro M, Nagai R,
Koike K. Gastrointestinal malignancies andcardiovasculardiseases-Non-negligiblecomorbidity in an era of multi-antithrombotic
drug use. J Cardiol. 58:199-207, 2011(19) Tsuji Y, Ohata K, Sekiguchi M, Ito T, Chiba H,
Gunji T, Yamamichi N, Fujishiro M, Matsuhashi
N, Koike K. An effective training system forendoscopic submucosal dissection of gastricneoplasm. Endoscopy 43:1033-8, 2011.
(20) Yamamichi N, Shimamoto T, Minatsuki C,
Yoshida Y, Fujishiro M, Kodashima S, Kato J,
Goto O, Ono S, Niimi K, Takahashi Y,
Konno-Shimizu M, Ichinose M, Koike K.
Postprandial fullness correlates with rapid inflow
of gastric content into duodenum but not withchronic gastritis. BMC Gastroenterol. 11:140,
2011(21) Muraki Y, Enomoto S, Iguchi M, Fujishiro M,
Yahagi N, Ichinose M. Management of bleeding
and artificial gastric ulcers associated withendoscopic submucosal dissection. World J
Gastrointest Endosc 4: 1-8, 2012(22) Tsuji Y, Ohata K, Sekiguchi M, Ohno A, Ito T,
Chiba H, Gunji T, Fukushima JI, Yamamichi N,

Fujishiro M, Matsuhashi N, Koike K. Magnifying
endoscopy with narrow-band imaging helps
determine the management of gastric adenomas.
Gastric Cancer. 2012 Jan 18.
(23) Ono S, Fujishiro M, Kodashima S, Takahashi Y,
Minatsuki C, Mikami-Matsuda R, AsadaHirayama I, Konno-Shimizu M, Tsuji Y,
Mochizuki S, Niimi K, Yamamichi N, Kaneko M,
Yatomi Y, Koike K. Evaluation of safety ofendoscopic biopsy without cessation of
antithrombotic agents in Japan. J Gastroenterol.
2012 Feb 18.
(24) Watanabe M, Kato J, Inoue I, Yoshimura N,
Yoshida T, Mukoubayashi C, Deguchi H,
Enomoto S, Ueda K, Maekita T, Iguchi M, Tamai
H, Utsunomiya H, Nobutake Y, Fujishiro M,
Iwane M, Tekeshita T, Mohara O, Ushijima T,
Ichinose M. Development of gastric cancer in
non-atrophic stomach with highly active
inflammation identified by serum levels of
pepsinogen and Helicobacter pylori antibody
together with endoscopic rugal hyperplastic
gastritis. Int J Cancer. 2012 Mar 2.
(25) Muraki Y, Enomoto S, Iguchi M, Niwa T,
Maekita T, Yoshida T, Moribata K, Shingaki N,
Deguchi H, Ueda K, Inoue I, Tamai H, Kato J,
Fujishiro M, Ichinose M. Diazepam duringendoscopic submucosal dissection of gastricepithelial neoplasias. World J Gastrointest
Endosc 4: 80-86, 2012(26) Niimi K, Fujishiro M, Goto O, Kodashima S,
Koike K. Safety and efficacy of colorectal
endoscopic submucosal dissection by the traineeendoscopists. Dig Endosc. 24 Suppl 1:154-8,
2012(27) Yamamichi N, Mochizuki S, Asada-Hirayama I,
Mikami-Matsuda R, Shimamoto T, KonnoShimizu M, Takahashi Y, Takeuchi C, Niimi K,
Ono S, Kodashima S, Minatsuki C, Fujishiro M,
Mitsushima T, Koike K. Lifestyle factors
affecting gastroesophageal reflux disease
symptoms: a cross-sectional study of healthy
19864 adults using FSSG scores. BMC Med. 10:45, 2012(28) Ono S, Fujishiro M, Koike K Endoscopic
submucosal dissection for superficial esophageal

460

neoplasms. World J Gastrointest Endosc.4:162-6,
2012(29) Fujishiro M, Jung HY, Goda K, Hirasawa K,
Kakushima N, Lee IL, Morita Y, Oda I, Takeuchi
M, Yamamoto Y, Zhou PH, Uedo N. Desirable
training and roles of Japanese endoscopists
towards the further penetration of endoscopic
submucosal dissection in Asia. Dig Endosc. 24
Suppl 1:121-3, 2012(30) Uedo N, Jung HY, Fujishiro M, Lee IL, Zhou PH,
Chiu PW, Chang D, Goda K. Current situation ofendoscopic submucosal dissection for superficial
neoplasms in the upper digestive tract in East
Asian countries: a questionnaire survey. Dig
Endosc. 24 Suppl 1:124-8, 2012(31) Kakushima N, Hirasawa K, Morita Y, Takeuchi
M, Yamamoto Y, Oda I, Goda K, Uedo N,
Fujishiro M. Terminology for training ofendoscopic submucosal dissection. Dig Endosc.
24 Suppl 1:133-5, 2012(32) Goda K, Fujishiro M, Hirasawa K, Kakushima N,
Morita Y, Oda I, Takeuchi M, Yamamoto Y,
Uedo N. How to teach and learn endoscopic
submucosal dissection for upper gastrointestinal
neoplasm in Japan. Dig Endosc. 24 Suppl
1:136-42, 2012

461

Clinical Research Support Center
Professor
Nobuhito Saito, M.D., Ph.D.

Associate Professor
Yoshihiro Arakawa, Ph.D.

Research Associate
Hiroshi Satonaka, M.D., Ph.D.
Kouji Nozaki, M.D., Ph.D. (until Sep., 2011)
Tetsuya Ueda, M.D., Ph.D. (from Oct., 2011)

Homepage

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

History and Organization
The Clinical Research Support Center was
established in 2010. It originated from Clinical Trial
Managing Center, which was established in 1998, andsubsequently the former Clinical Research Center,
which was established in 2001. It belongs to thecentral division of the hospital and supports not only
industry-sponsored, but also investigator-initiated,clinical trials.
With the increasing volume of clinical research
conducted in our hospital, demand mounted for the
structural framework to support investigator-initiated,
especially multicenter, trials.
It is an important mission of university hospitals todevelop novel therapeutics by clinical trials. Highethical and scientific standards as well as highreliability are now being required for the
implementation of clinical research, including
investigator-initiated translational research or trials forthe off-label use of approved drugs.
In response to the above demands, the former
Clinical Research Center was reorganized in April
2010 into the current Clinical Research Support
Center, enabling strengthened support and expeditious
promotion of clinical research.
The Center consists of Site Coordinating Unit,roughly equivalent to the former whole ClinicalResearch Center, and Central Coordinating Unit,
which provides coordinating functions for researchsuch as multicenter trials.
Site Coordinating Unit is comprised of theinstitutional review board (IRB) Secretariat Division,
Investigational Drug/Information Control Division
and Clinical Research Coordinator Division, eachcharged with IRB secretarial affairs, handling of drugs
for clinical trials and assistance with safety
information reporting, and clinical researchcoordinator activities.
In addition to the existing Consultation Division,
the Central Coordinating Unit has added newdivisions such as Biostatistics/Data Management
Division, Safety Information Division, Operation
Division which is responsible for the coordination
among the sites, and Monitoring Division responsiblefor quality control. Activities of these Divisions
include protocol formulation, project management,
data management, monitoring, statistical analysis andassistance with safety information reporting.
The Center was selected as an MHLW-funded
center of excellence for early and exploratory clinical
trials of drugs for psychological and neurologicaldiseases in 2011, thus enabling the Center to reinforce
the staff and to be equipped with phase 1 facilities.
Clinical Research Support Center can now support
both trials registered or not registered for marketing462

approval, and, therefore, can provide seamless support
to research in any phase of development.
As of March 2012, the Center staff includes aprofessor, an associate professor, 2 assistantprofessors, 11 pharmacists, 10 nurses, 4 project
specialists and 3 clerical staff members.

Clinical Research Support
Activities
The duties of the Center range from serving as thesecretariat for the IRB to supporting theimplementation and reporting of clinical trials.
To further improve the quality of trials or clinicalresearch (which includes use of unapproved drugs on
a compassionate basis) respecting the principles of the
globally standard ICH-GCP, we have prepared and asneeded revised the guidelines or SOPs intended foruse in our hospital. These documents include thoserelating to preparation of the study protocol orinformed consent form, implementation of research,and handling of costs to trial participants.
For secure process of the applications ofindustry-sponsored clinical trials to IRB, we hold apreliminary hearing system (named as “protocolpresentation”) before IRB.
The items processed by the Center as the IRB
secretariat in fiscal 2011 included, as forindustry-sponsored trials for marketing approval, 39
new protocol applications, 68 study extension
applications, 570 protocol amendment applications,630 SAE/safety information reports, 41 study closureor termination reports. As for investigator-initiatedclinical research, the Center processed 69 new
protocols(including
13
applications
forcompassionate use of unapproved drugs), 264
applications for protocol amendment, 61 SAE/safety
information reports, 69 study closure or termination
reports.
Protocol presentations of industry-sponsored trials
prior to application to IRB totaled 18 applications.
Preliminary consultation for investigator-initiatedresearch application including cases of compassionate
totaled 72 applications.
To cope with the so-called `drug lag problem`
relating to the drugs unapproved in Japan,
participation in global trials was an urgent necessity.

For this purpose, University Hospital Clinical Trial
Alliance (UHCT Alliance) comprised of 6 national
university hospitals (Tokyo University, Niigata
University, Gunma University, Tsukuba University,
Tokyo Medical and Dental University and Chiba
University) located in the central part of Japan wasestablished in 2006 and has since been incollaboration toward improvement of clinical trial
environments. In 2006, the rotated managerial site wasTokyo University, where the Alliance Office wasbased. In Alliance an organizational structure has been
established that can cooperatively attract trials andsmoothly process them for IRB approval. A scheme toeducate the staff in preparation for global trials has
been put in place. In 2007 Shinshu University joined
the Alliance as the 7th member university.
From April 2009 on, a 5-year special research grantfrom the Ministry of Education, Culture, Sports,
Science and Technology for the promotion of UHCT
Alliance allowed to set up a full-time office (made upof 2 staffers) and further expand the activities.
Operational subsidies that Tokyo University received
were distributed to each university based on a joint
project agreement, which was an unprecedented
attempt for our university. Each university and the
Office was given its own task to cooperatively
promote the mission of the whole Alliance.
Until the end of March 2012, 57 protocols wereintroduced to the Alliance including 29 multinational
trials. The Alliance helped to assess feasibility in 9
trials and to select the participating sites in 39.
Cooperative protocol presentation (hearing) sessions
were held for 36 protocols. Industry sponsors applied
for regulatory drug approval from Ministry of Health,Labour and Welfare based on data of 14 trials and 9
drugs have been so far approved.
The Alliance developed a clinical research support
system, UHCT ACReSS, to support glass-root clinicalresearchers in the quality and project management.
UHCT ACReSS is a Web-based participant-allocationand data collection system, which is easily customized
by researchers. The system is now being usedpractically by 16 projects.
Clinical Research Support Center managed
drug/device inventory for 111 clinical trials forregulatory approval, 2 postmarketing trials, 2 trials ofdevices, 40 investigator-initiated clinical trials, one463

case of compassionate use in fiscal 2011. The numberof prescriptions processed was 1046 for trials forapproval and postmarketing trials combined, 484 forinvestigator-initiated clinical trials. We are currently
managing trial drugs centrally for 3 multicenter
double-blind trials. We are also in charge of the
primary review of clinical trial safety information andof maintaining the database on clinical trials ingeneral.
Clinical research coordinators (CRC) of the Center
have been supporting as a principle all clinical trials
for approval and postmarketing trials since 2002. We
started partially supporting investigator-initiated trials
in 2004 and have already supported 5 trials. In 2005
we started providing CRC support to investigatorinitiated trials on a beneficiary-pays basis and havealready supported 6 trials. CRCs exclusively involved
in investigator-initiated trials have been employed asneeded. The number of trial participants that CRCs
interacted with was 3777 in fiscal 2006, 4853 in 2007,
5172 in 2008, 4761 in 2009, 3776 in 2010 and 3604 in
2011. We started receiving monitoring visits for every
trial participant’s data in 2002. The number ofmonitoring visits increased to 569 in 2007, 952 in
2008, 840 in 2009, 672 in 2010 and 712 in 2011.
As part of patient awareness campaign activity, we
continued updating the Center homepage, preparedleaflets and distributed them at outpatient receptions.
The leaflets contain information about trials currently
recruiting participants.
Our outpatient clinic for trial participants was
moved to the second central clinic building, which
was newly opened in November 2006. The new clinic
has reception desks for consultation and own waiting
space.
At Central Coordinating Unit, which wasestablished in the Center in 2010, 9 projects as ofMarch 2012 were adopted for support by the Unit
including project management, data management etc.
In cases of investigator-initiated post-market clinical
trials financially supported by pharmaceuticalcompanies, potential conflicts of interest weremanaged by introducing the funds directly to theCenter with contracts and by developing protocols
with scientific designs and conducting them
independently to the fund sponsors. In one
investigator-initiated registered clinical trial, a clinical

trial notification was submitted to the regulatory
authority, PMDA, in February, 2012.

Teaching Activities
One resident physician got training for a month in
the Center as part of the M.D. residency training
program. Five students in the Graduate School of
Medicine also got one-day training.
Annual CRC training course for national, public
and private university hospitals in 2011 was held
under the auspices of Tokyo University Hospital for 5days, in which 68 trainees from university hospitals all
across the country participated.
Dr Arakawa also gave lectures in a lecture series onclinical science for graduate course students of theFaculty of Pharmaceutical Sciences.
The 11th University of Tokyo Hospital Clinical
Trial Seminar was held on March 23, 2012
cosponsored with the UHCT Alliance and the Centerof excellence for early and exploratory clinical trials
program..

Research Activities
An endowed course on clinical trial data
management was opened in April 2007 with thecooperation from the Center and the Biostatistics
Department, Graduate School of Medicine,
conducting research and education on data
management and biostatistics focused on practicalapplication to trials.
The Center was involved in 5 scientific meeting
presentations, 18 invited lectures in fiscal 2011 and 5
published papers in 2011. There was 3 news media
article that reported on the Center.

464

University hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Instructor
Hirono Ishikawa, Ph.D.

Homepage

http://www.umin.ac.jp/umin/※ The following information is the same as that of the previous year for certain reasons.

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465

EPOC (Evaluation System of Postgraduate ClinicalTraining) as of 2004.
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

466

•
•

Website preservation service
Video-on-demand (VOD) and streaming
service(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467

Organ Transplantation Service
Director and Professor
Norihiro KOKUDO

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html※ The following information is the same as that of the previous year for certain reasons.

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 heart transplantation and deceased donor liver transplantation.

References (2009)
1.

2.

3.

4.

Song P, Tang W, Tamura S, Hasegawa K,
Sugawara Y, Dong J, Kokudo N. The
management of hepatocellular carcinoma in Asia:a guideline combining quantitative andqualitative evaluation. Biosci Trends 2010;
4:283-7.
Kaneko J, Sugawara Y, Togashi J, Tamura S,
Motoi R, Fukayama M, Kokudo N. Sarcomatouschange of hepatocellular carcinoma in a patientundergoing living donor liver transplantation.
Biosci Trends 2010; 4:279-82.
Hasegawa K, Kokudo N, Shiina S, Tateishi R,
Makuuchi M. Surgery versus radiofrequency
ablation for small hepatocellular carcinoma: Startof a randomized controlled trial (SURF trial).
Hepatol Res 2010; 40:851-2.
Ishizawa T, Bandai Y, Ijichi M, Kaneko J,
Hasegawa
K,
KokudoN.
Fluorescentcholangiography illuminating the biliary tree

during laparoscopic cholecystectomy. Br J Surg
2010; 97:1369-77.
5. Harada N, Ishizawa T, Muraoka A, Ijichi M,
Kusaka K, Shibasaki M, Yamamoto K, Hasegawa
K, Bandai Y, Kokudo N. Fluorescence navigation
hepatectomy by visualization of localizedcholestasis from bile duct tumor infiltration. J
Am Coll Surg 2010; 210:e2-6.
6. Shindoh J, Imamura H, Kokudo N. Isolated sling
suspension during resection of the Spiegel lobe of
the liver: a safe alternative technique for difficult
cases. J Hepatobiliary Pancreat Sci 2010; 17:359-64.
7. Inagaki Y, Tang W, Zhang L, Du G, Xu W,
Kokudo N. Novel aminopeptidase N (APN/
CD13) inhibitor 24F can suppress invasion ofhepatocellular carcinoma cells as well as
angiogenesis. Biosci Trends 2010; 4:56-60.
8. Takamoto T, Hashimoto T, Sano K, Maruyama Y,
Inoue K, Ogata S, Takemura T, Kokudo N,
Makuuchi M. Recovery of liver function after the
cessation of preoperative chemotherapy forcolorectal liver metastasis. Ann Surg Oncol 2010;17:2747-55.
9. Kokudo N, Arita J. Staging for intrahepaticcholangiocarcinoma. Liver Int 2010; 30:931-3.
10. Mise Y, Imamura H, Hashimoto T, Seyama Y,
Aoki T, Hasegawa K, Beck Y, Sugawara Y,
Makuuchi M, Nakajima J, Kokudo N. Cohort
study of the survival benefit of resection forrecurrent hepatic and/or pulmonary metastases
after primary hepatectomy for colorectal
metastases. Ann Surg 2010; 251:902-9.
11. Shindoh J, Mise Y, Satou S, Sugawara Y, Kokudo

468

12.

13.

14.

15.

16.

17.

18.

N. The intersegmental plane of the liver is notalways flat--tricks for anatomical liver resection.
Ann Surg 2010; 251:917-22.
Inoue Y, Takahashi M, Arita J, Aoki T, Hasegawa
K, Beck Y, Makuuchi M, Kokudo N. Intraoperative freehand real-time elastography forsmall focal liver lesions: "visual palpation" fornon-palpable tumors. Surgery 2010; 148:100011.
Yamashiki N, Sugawara Y, Tamura S, Tateishi R,
Yoshida H, Kaneko J, Matsui Y, Togashi J,
Akahane M, Makuuchi M, Omata M, Kokudo N.
Postoperative surveillance with monthly serum
tumor markers after living-donor livertransplantation for hepatocellular carcinoma.
Hepatol Res 2010; 40:278-86.
Tamura S, Sugawara Y, Yamashiki N, Kaneko J,
Kokudo N, Makuuchi M. Pre-emptive antiviraltherapy in living donor liver transplantation forhepatitis C: observation based on a single-center
experience. Transpl Int 2010; 23:580-8.
Ishizawa T, Mise Y, Aoki T, Hasegawa K, Beck Y,
Sugawara Y, Kokudo N. Surgical technique: newadvances for expanding indications andincreasing safety in liver resection for HCC: theEastern perspective. J Hepatobiliary Pancreat Sci
2010; 17:389-93.
Hasegawa K, Kokudo N, Sano K, Makuuchi M.
Single HCC between 2 and 5 cm: the grey zon:
surgeon’s perspective. J Hepatobiliary Pancreat
Sci 2010; 17:430-3.
Kishi Y, Imamura H, Sugawara Y, Sano K,
Kaneko J, Kokudo N, Makuuchi M. Evaluationof donor vasculobiliary anatomic variations inliver graft procurements. Surgery 2010; 147:30-9.
Kyoden Y, Tamura S, Sugawara Y, Matsui Y,
Togashi J, Kaneko J, Kokudo N, Makuuchi M.
Incidenceandmanagementofbiliary
complications after adult-to-adult living donorliver transplantation. Clin Transplant 2010; 24:
535-42.

469

Center for Epidemiology andPreventive Medicine
Director & Professor
Tsutomu Yamazaki, M.D., Ph.D. (Department of Clinical Epidemiology and Systems)

Associate Professor
Toru Suzuki, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Associates
Yumiko Oike, M.D., Ph.D.,

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

Kazushi Suzuki, M.D., Ph.D.,

Tomoko Nakao, M.D., Ph.D.

Satoshi Ono, M.D.,Ph.D.

Kenichi Aizawa, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)
Yoshiko Mizuno,M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Homepage:

http://www.h.u-tokyo.ac.jp/patient/depts/kenshin/index.html

Introduction and Organization
Following the inauguration of a new Central Clinical
Service Building (Central Care 2) in November 2006
(Heisei 18) in the University of Tokyo Hospital, theCenter for Epidemiology and Preventive Medicine
was established on January 1, 2007, within the Central
Clinical Facilities and the relevant regulations wererevised. On January 9, the Working Group for the
Establishment of the Center for Epidemiology andPreventive Medicine was organized; on April 1,
Steering Committee for the Establishment of theCenter for Epidemiology and Preventive Medicine
was organized; preparation for offering its services
continued until May 31; on June 4, the department
started offering its services on a trial basis (in-hospital
services) and was officially inaugurated in July,
starting to provide public services.
The principal objectives of the establishment of
the Center for Epidemiology and Preventive Medicine
are 1) to scientifically demonstrate the utility andeffectiveness of examinations and preventive
interventions, 2) to integrate a vast amount of clinicaldata and health-related information to develop more

efficient models for disease management, 3) by doing
the above 1) and 2), to promote preventive medicine
and medicine for health promotion in an effort tocontribute to the improvement of public health, and 4)
to train medical personnel who can put the above 1),2) and 3) into practice.
In the administrative organization of the Center for
Epidemiology and Preventive Medicine, its Director
directly under the Director of the Hospital is
responsible for the entire organization. The
management of the Department is also supported by
the Department of Clinical Epidemiology and Systems
and the Department of Ubiquitous Preventive
Medicine. In addition, examinations in the
Department are administered in collaboration withthree Central Clinical Facilities (Clinical Laboratory
Center, Radiological Center, and Department ofEndoscopy and Endoscopic Surgery) and five Clinical
Divisions(Breastand
Endocrine
Surgery,
Gynecologic Surgery, Ophthalmology and VisionCollection, Oral-Maxillofacial Surgery, Dentistry andOrthodontics, and Neurology).
The staff of the Center for Epidemiology andPreventive Medicine is composed of eight physicians

470(four regular physicians and four physicians from therelated departments). One of the regular physiciansalso performs upper gastrointestinal endoscopy andcolonoscopy in the Department of Endoscopy andEndoscopic Surgery. Our department also has fiveregular nurses and five regular secretaries. When our
department was established, the number of staff wasincreased in other divisions. Among our staff, one
nurse (full-time), three radiological technologists(full-time) and three medical technologists (fulltime) are assigned respectively to the Department ofEndoscopy and Endoscopic Surgery, the RadiologicalCenter and the Clinical Laboratory Center.

Clinical activities
In addition to basic examinations which are open
to the public, our department provides these elevenoptions: 1) comprehensive cardiovascular examinations, 2) home blood pressure screening, 3) comprehensive cerebrovascular examinations, 4) check up
dementia, 5) colorectal cancer screening, 6) uterine
cancer screening, 7) breast cancer screening, 8) lungcancer screening, 9) tumor marker diagnosis,10) estimation of gastric cancer risk, and 11) oral/
dental examinations. While meeting the needs of
examinees, we have increased the number of theoptional examinations and provided higher levels of
examinations.
The physicians of our department are responsible
for analyzing the results of examinations andscreenings, performing overall evaluations, andconsultations with examinees. One of our important
services is that we take approximately 30 minutes per
examinee to perform comprehensive medical
examinations. Formally, the examinee is notified inwriting of the results within approximately two weeks
after the examination. We also offer each examinee afree 20-minute consultation so that we can help
him/her understand the results or decide whether or
not to have further work-up.

Teaching activities
Although our department has no students directly
under our supervision being a clinical service, weoffer education in epidemiology to graduate students

in the Department of Clinical Epidemiology and
Systems and the Department of Ubiquitous Preventive
Medicine.

Research activities
The University of Tokyo Hospital is expected not only
to provide its service of comprehensive medical
examinations but also to promote evidence-based
practice and scientific examinations, which is themission of our department. Academically, we aim toestablish a database from clinical data and to promoteepidemiological research. This will enable us toprevent disease based on scientific data. In 2007, thefirst year of our department, we collected data on
examinees and designed a pilot database. From 2008
onward, we continue to collect data and conduct theircross-sectional and longitudinal analysis.

Past activities
In the fiscal year (FY) 2011 from April 1, to March 31,
2012, the total number of examinees (who had basic
examinations and optional examinations) was 6,671,
including 2,285 in basic examinations, 460 incomplete cardiovascular examinations, 24 in home
blood pressure screening, 652 in complete cerebrovascular examinations, 94 in check up dementia, 342
in colorectal cancer screening, 407 in uterine cancer
screening, 467 in breast cancer screening, 600 in lungcancer screening, 786 in tumor marker diagnosis, 466
in estimation of gastric cancer risk, 6 in uppergastrointestinal endoscopy (later),and 82 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 2011, we issued 935
letters of referral to other departments in our hospitaland 167 to other hospitals.
We have expanded our public relations efforts andduring the FY 2011 25,000 brochure 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.

471

References
Academic Papers in English(1) Yamashita T., Inoue H., Okumura K., Kodama I.,
Aizawa Y., Atarashi H., Ohe T., Ohtsu H., Kato T.,
Kamakura S., Kumagai K., Kurachi Y., Koretsune
Y., Saikawa T., Sakurai M., Sato T., Sugi K.,
Nakaya H., Hirai M., Hirayama A., Fukatani M.,
Mitamura H., Yamazaki T., Watanabe E., andOgawa S., on behalf of the J-RHYTHM II
Investigators: Randomized trial of angiotensin
II-receptor blocker vs. dihydropiridine calcium
channel blocker in the treatment of paroxysmal
atrial fibrillation with hypertension (J-RHYTHM
II Study). Europace 13:473-479,2011(2) Yamamoto K., Ozaki H., Takayasu K., Akehi N.,
Fukui S., Sakai A., Kodama M., Shimonagata T.,
Kobayashi K., Ota M., Horiguchi Y., Ebisuno S.,
Yamazaki T., Ohtsu H., Hori M.: The Effect oflosartan and amlodipine on left ventricular
diastolic function and atherosclerosis in Japanesepatients with mild-to-moderate hypertension
J-ELAN study. Hypertens Res 34(3):325-330,
2011(3) Yamazaki T., Kishimoto J., Ito C., Noda M.,
Odawara M., Terauchi Y., Shiba T., Kitazato H.,
Iwamoto Y., Akanuma Y., Kadowaki T., for the
J-PREDICT study investigators: Japan prevention
trial of diabetes by pitavastatin in patients with
impaired glucose tolerance (the J-PREDICT
study): rationale, study design, and clinicalcharacteristics of 1269 patients. Diabetol Int
2(3):134-140,2011(4) Kohro T., Yamazaki T., Izumi T., Daida H.,
Kurabayashi M., Miyauchi K., Tojo T., Nagai R.,
on behalf of the JCAD II Investigators:
Intensively lowering both low-density lipoproteincholesterol and blood pressure does not reduce
cardiovascular risk in Japanese coronary arterydisease patients. Circ J 75:2062-2070,2011(5) Suzuki T., Yamazaki T., Ogawa S., Nagai R.,
Yamashita T., and the J-RHYTHM II
Investigators: Echocardiographic predictors of
frequency of paroxysmal atrial fibrillation (AF)and its progression to persistent AF in
hypertensive patients with paroxysmal AF:
Results from the Japanese rhythm management

trial II (J-RHYTHM II) for atrial fibrillation study.
Heart Rhythm 8:1831-1836,2011(6) Ogawa N., Imai Y., Takahashi Y., Nawata K.,
Hara K., Nishimura H., Kato M., Takeda N.,
Kohro T., Morita H., Taketani T., Morota T.,
Yamazaki T., Goto J., Tsuji S., Takemoto S.,
Nagai R.,and Hirata Y.: Evaluating JapanesePatients With the Marfan Syndrome Using
High-Throughput Microarray-Based Mutational
Analysis of Fibrillin-1 Gene. Am J Cardiol
108:1801-1807,2011(7) Kubota T., Kubota N., Kumagai H., Yamaguchi S.,
Kozono H., Takahashi T., Inoue M., Itoh S.,
Takamoto I., Sasako T., Kumagai K., Kawai T.,
Hashimoto S., Kobayashi T., Sato M., TokuyamaK., Nishimura S., Tsunoda M., Ide T., Murakami
K., Yamazaki T., Ezaki O., Kawamura K.,
Masuda H., Moroi M., Sugi K., Oike Y.,
Shimokawa H., Yanagihara N., Tsutsui M.,
Terauchi Y., Tobe K., Nagai R., Kamata K., Inoue
K., Kodama T., Ueki K., Kadowaki T.: Impaired
insulin signaling in endothelial cells reduces
insulin-induced glucose uptake by skeletal
muscle. Cell Metab 13:294-307,2011(8) Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Ozeki A, Watanabe A, Kawarasaki S,
Nakao T, Taniguchi T, Ichimura Y, Toyama T,
Watanabe M, Hirata Y, Nagai R, Sato S.
Improvement of endothelial function in parallelwith the amelioration of dry cough and dyspnea
due to interstitial pneumonia by intravenous
cyclophosphamide pulse therapy in patients withsystemic sclerosis: a preliminary report of twocases. Mod Rheumatol. 2011 Oct 21. [Epub aheadof print](9) Kazushi Suzuki, Jiayi Zhou, Toshiya Sato,
Mutsuo Oyake, Mitunori Yamada, Hitoshi
Takahashi, Yuji Takahashi, Jun Goto, Shoji Tsuji:
DRPLA transgenic mouse substrains carrying
single copy of full-length mutant human DRPLA
gene with variable sizes of expanded CAG
repeats exhibit CAG-repeat-length- and agedependent changes in behavioral abnormalities
and gene expression profiles. Neurobiology of
Disease 2012; 46: 336-350.
(10) Suzuki T, Trimarchi S, Sawaki D, Grassi V, Costa
E, Rampoldi V, Nagai R, Eagle KA. Circulating472

transforming growth factor-beta levels in acuteaortic dissection. J. Am. Coll. Cardiol. 58(7), 775,
2011.
(11) Maisel AS, Nakao K, Ponikowski P, Peacock WF,
Yoshimura M, Suzuki T, Tsutamoto T, Filippatos
GS, Saito Y, Seino Y, Minamino N, Hirata Y,
Mukoyama M, Nishikimi T ,Nagai R. JapaneseWestern Consensus Meeting on Biomarkers
Executive Summary. Int. Heart. J. 52(5), 253-265,2011.
(12) Ono S, Fujishiro M, Kodashima S, Minatsuki C,
Hirano K, Niimi K, Goto O, Yamamichi N, Koike
K. Controversy on the management of
anticoagulants and antiplatelet agents forscheduled endoscopy. Dig Endosc. 2011 Jan;
23(1):1-4.
(13) Ono S, Fujishiro M, Kanzaki H, Uedo N, Yokoi C,
Akiyama J, Sugawara M, Oda I, Suzuki S, Fujita
Y, Tsubata S, Hirano M, Fukuzawa M, Kataoka
M, Kamoshida T, Hirai S, Sumiyoshi T, Kondo H,
Yamamoto Y, Okada K, Morita Y, Fujiwara S,
Morishita S, Matsumoto M, Koike K. Conflicting
clinical environment about the management ofantithrombotic agents during the periendoscopic
period in Japan. Gastroenterol Hepatol. 2011 Sep;
26(9):1434-40.
(14) Goto O, Fujishiro M, Kodashima S, Minatsuki C,
Niimi K, Ono S, Yamamichi N, Koike K.
Short-term healing process of artificial ulcers after
gastric endoscopic submucosal dissection. Gut
Liver. 2011 Sep;5(3):293-7.
(15) Yamamichi N, Shimamoto T, Minatsuki C, YoshidaY, Fujishiro M, Kodashima S, Kato J, Goto O, Ono
S, Niimi K, Takahashi Y, Konno-Shimizu M,
Ichinose M, Koike K. Postprandial fullness
correlates with rapid inflow of gastric content into
duodenum but not with chronic gastritis. BMC
Gastroenterol. 2011 Dec 21;11:140.
International Conferences(1) Suzuki T., Yamazaki T., Ogawa S., Nagai R.,
Yamashita T, and the J-RHYTHM II investigators.
Left atrial dimension and frequency of atrial
fibrillation in patients with paroxysmal atrial
fibrillation and hypertension: result from theJapanese rhythm management trial II for atrial
fibllation (J-RHYTHM II) study. American

(2)

(3)

(4)

(5)

(6)

(7)

(8)

College of Cardiology 60th Annual Scientific
Session. (New Orleans, Louisiana, USA:
2011/4/2-5)
Suzuki T., Yamazaki T., Ogawa S., Nagai R.,
Yamashita T, and the J-RHYTHM II investigators.
Echocardiographic predictors of progression fromparoxysmal to persistent atrial fibrillation: result
from the Japanese rhythm management trial II for
atrial fibllation (J-RHYTHM II) study.
American Heart Association Scientific Sessions
2011 (Orlando, Florida, USA:2011/11/12-16)
Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Munemasa Y, Ishida J, Friedman SL, Nagai R:
KLF6 Modulates Recruitment and Polarizatin of
Inflammatory Cells Through Cardiomyocytes in
Initiation of Cardiac Fibrosis American heart
association scientific sessions 2011 (Orlando, FL,
USA). 2011/11/11-18.
Aizawa K, Suzuki T, Zhan H, Sawaki D, Ishida J,
Mastumura T, Nagai R : Klf5 Mediates a New
Regulatory Pathway of Pathologic Vascular
Injury Through DNA Double-Strand Break/Repair System. American heart association
scientific sessions 2011 (Orlando, USA).
2011/11/11-18.
Ishida J, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Friedman SL, Nagai R:
Kruppel-Like Factor 6 (KLF6) Regulates Obesity
and Glucose Intolerance. American heart
association scientific sessions 2011 (Orlando,
USA). 2011/11/11-18.
Zhan H, Suzuki T, Aizawa K, Miyagawa K,
Nagai R: Identification and characterization of
ataxia telangiectasia mutated (ATM) in regulationof oxidative stress-induced vascular endothelial
cells senescence. The 22ed Great Wall
International Congress of Cardiology Asia PacificHeart Federation Scientific Congress 2011
(Beijing, China). 2011/10/13-16.
Fujimoto H, Suzuki T, Aizawa K, Sawaki D,
Ishida J, Nagai R: Processed B-type natriuretic
peptide is a biomarker of post-interventional
restenosis in ischemic heart disease. HUPO 2011
10TH
World
Congress(Geneva,
Swiss
Confederation). 2011/9/4-7
Aizawa K, Suzuki T, Zhan H, Miyagawa K and
Nagai
R:
Ataxiatelangiectasia
mutated473(ATM)-mediated DNA damage response inoxidativestress-induced vascular endothelial cells
senescence. 2011 Gordon Research Conferences;
Mammalian DNA Repair (Ventura, CA, USA).
2011/2/6-11.
(9) Age effect on cerebral blood flow in adults using
pseudo-continuous arterial spin labeling. The
17th Annual meeting of the Organization of
Human Brain Mapping.
(10) Association between cognitive deterioration andlifestyle-related diseases - study on normal
populations attending comprehensive medical
checkups. The 11th Alzheimer's Association
International Conference on Alzheimer's Disease.

474

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D.

Vice Director
Kazuto Hoshi, M.D., Ph.D.

Project Associate Professors
Seishi Ogawa, M.D., Ph.D.,

Hiroyuki Koyama, M.D., Ph.D.,

Taku Saito, M.D., Ph.D.,

Keiichi Hishikawa, M.D., Ph.D.,

Kazuto Hoshi, M.D., Ph.D.

Yamagami Satoru, M.D., Ph.D.

Research Associates
Makoto Komura, M.D., Ph.D.,

Yuko Fujihara, D.D.S., Ph.D.,

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

Yutaka Miura, Ph.D.,

Yutaka Morizaki, M.D., Ph.D.,

Seiichi Yokoo, Ph.D.

Homepage

http://square.umin.ac.jp/t-e/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped
800 m2 laboratory on the 8th floor of the Inpatient
Word B. Division of Tissue Engineering consists of
Department of Bone & Cartilage Regenerative
Medicine, Department of Vascular Regeneration,
Department of Clinical Renal Regeneration,
Department of Cartilage & Bone Regeneration,
Project for Regeneration Medicine of Hematopoiesis,
Corneal Tissue Regeneration Project, and Laboratory
for Pediatric Regenerative Medicine. We have invited
talented personnel of various fields from home andabroad. One project associate professor and one or
two project research associates who are assigned toeach department are conducting research with many
post graduate students. Aiming at clinical application
within a few years, the researchers continue theirstudies to make the center function as a translational
research center.

Tie-up with companies, technical transfer, patenting
developed technologies, producing materials fortreatment at a GMP level, safety evaluation studies
and organization for clinical trials are necessary inorder to realize regenerative medicine, which is now
recognized as a national project. As foundation andoperation of venture companies as well as industryuniversity-government cooperation is essential to thesuccess, it seems that state-level efforts are necessary.
It is expected that broad progress in tissue engineering
technologies and regenerative medicine contributes totreatment and drug discovery of all medical fields
regardless of specialties.
October, 2001 Division of Tissue Engineeringfounded as special medical office in the University ofTokyo Hospital.
June, 2002 Department of Corneal Tissue
Engineering founded by a donation from HOYA healthcare CO., Ltd.
July, 2002 Department of Vascular Regeneration
founded by a donation from Daiichi Pharmaceutical

475

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
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 a more
improved corneal epithelial sheet transplantation forocular surface reconstruction and establishment andclinical application of corneal endotheliumtransplantation. To achieve these goals, we areconducting functional analysis on cultured corneal

cells, reconstruction of cornea with cultured
epithelium and endothelium, and artificial stroma,
research on adult stem cell biology and manipulation
technology in corneal tissues and immunologicalanalysis 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

476(CB-HSCs) and its clinical application to humanhematopoietic stem cell transplantation, and for
inducing various hematopoietic components from
HSCs and embryonic stem cells. To achieve thesegoals, we are conducting research on the regulatory
mechanisms of proliferation, self-renewal, anddifferentiation of human hematopoietic stem cells(HSCs), plasticity of HSCs and clinical application of
the in vitro expansion and differentiation system of
HSCs.
In the department donated by FUJISOFT ABC, we
aim to produce regenerated cartilage and bone withhigh safety and usefulness, to realize production
system and establish practical quality control and topromote the application of regenerated cartilage andbone. To achieve these goals, we are conducting
research on adult stem cell biology in mesenchymal
tissues, application of molecular biology on cartilage
repair for regenerative medicine, development ofnovel scaffolds in cartilage and bone regeneration,
development of 3-D reconstruction system forregenerated tissues, evaluation on biochemical andbiophysical properties of regenerated tissues in vivo
and clinical trials and application of regenerated
cartilage and bones. On Mar 18th 2011, our clinicalstudy “Development of implant-type tissueengineered cartilage for patients with nasal deformity
in cleft lip and palate” was authorized to conduct after
being discussed based on “Guideline for Human Stem
Cell Therapy Clinical Research”.
In the laboratory for pediatric regenerative
medicine, we are doing research to fabricate anengineered airway by cells originated from trachea
tissue. In addition, the fundamental study of theamniotic fluid cell is performed to create new therapy
for new born babies.
Basic Research on human ES cells
Besides, to promote basic research on humanembryonic stem cells with our eyes set on applicationsin the future, Department of Clinical Renal
Regeneration and Department of Bone and Cartilage
Regenerative Medicine are carrying forward theapplication procedures to obtain human ES cells from
Institute for Frontier Medical Sciences, Kyoto
University, which will be approved shortly.

Clinical Studies
Of particular note is clinical studies started in thefour departments as a result of basic research. In
Project for Regenerative Medicine of Hematopoiesis,
clinical study on expansion of human cord blood
hematopoietic cells (Institutional Review Board
approval number #351) has been started. In
Department of Vascular Regeneration, clinical studies
on claudication limbs and severe ischemic limbs
caused by peripheral vascular diseases (IRB approval
number #825 and #826) have been started andcontinued without causing major side effects. In
Department of Corneal Tissue Regeneration, clinicalstudies on transplantation of cultured autologous oral
mucous epithelial sheet on amniotic membrane forocular surface reconstruction, and corneal endothelial
stem cell transplantation for decrease in number ofcorneal endotheliums (IRB approval number #363 and#898) have been started. In Department of Bone &Cartilage Regenerative Medicine, a clinical study onbone implants into non-loading parts (IRB approval
number #1310) was conducted on 10 patients
successfully and a large-scale clinical trial was started
across the nation. In project for cartilage regeneration,
the clinical study “Development of implant-type
tissue-engineered cartilage for patients with nasal
deformity in cleft lip and palate” was authorized to
conduct on Mar 18th 2011, and is supposed to startsoon. As stated above, we are proceeding translational
research aiming at clinical application of tissue
engineering and regenerative medicine.
Contribution to the Hospital
Division of Tissue Engineering, as a cooperative
research facility in the Hospital, opens expensive
special machines that each laboratory cannot afford toequip with, such as a confocal laser scanningmicroscope, a cell analyzer and a cell sorter to the
Hospital staff, letting them use with cost sharing.
Department of Plastic Surgery is conducting researchusing this facility.

References
1.

Ogata N, Shinoda Y, Wettschureck N,
Offermanns S, Takeda S, Nakamura K, Segre GV,
Chung UI, Kawaguchi H. G{alpha}q Signal in

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Osteoblasts Is Inhibitory to the Osteoanabolic
Action of Parathyroid Hormone. J Biol Chem.
2010; 286:13733-40.
Ishiyama N, Moro T, Ohe T, Miura T, Ishihara K,
Konno T, Ohyama T, Yoshikawa M, Kyomoto M,
Saito T, Nakamura K, Kawaguchi H. Reductionof peritendinous adhesions by hydrogel
containing biocompatible phospholipid polymer
MPC for tendon repair. J Bone Joint Surg Am.
2010; 93:142-9.
Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F,
Ohba S, Nishida N, Akune T, Yoshimura N,
Nakagawa T, Nakamura K, Tokunaga K, Chung
UI, Kawaguchi H. Transcriptional regulation of
endochondral ossification by HIF-2alpha duringskeletal growth and osteoarthritis development.
Nat Med. 2010; 16:678-86
Kato M, Takaishi H, Yoda M, Tohmonda T,
Takito J, Fujita N, Hosogane N, Horiuchi K,
Kimura T, Okada Y, Saito T, Kawaguchi H,
Kikuchi T, Matsumoto M, Toyama Y, Chiba K.
GRIP1 enhances estrogen receptor alphadependent extracellular matrix gene expression inchondrogenic cells. Osteoarthritis Cartilage.
2010; 18:934-41.
Fukai A, Kawamura N, Saito T, Oshima Y, Ikeda
T, Kugimiya F, Higashikawa A, Yano F, Ogata N,
Nakamura K, Chung UI, Kawaguchi H. Akt1 inmurinechondrocytes
controls
cartilage
calcification during endochondral ossification
under physiologic and pathologic conditions.
Arthritis Rheum. 2010; 62:826-36.
Nagase Y, Iwasawa M, Akiyama T, Ogata N,
Kadono Y, Nakamura M, Oshima Y, Yasui T,
Matsumoto T, Masuda H, Bouillet P, Nakamura K,
Tanaka S. Antiapoptotic molecule Bcl-2 isessential for the anabolic activity of parathyroid
hormone in bone. Ann N Y Acad Sci. 2010;
1192:330-7.
Shinoda Y, Kawaguchi H, Higashikawa A, Hirata
M, Miura T, Saito T, Nakamura K, Chung UI,Ogata N. Mechanisms underlying catabolic andanabolic functions of parathyroid hormone onbone by combination of culture systems of mouse
cells. J Cell Biochem. 2010; 109:755-63.
Morizaki Y, Zhao C, An KN, Amadio PC. The
Effects of Platelet-Rich Plasma on Bone Marrow

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Stromal Cell Transplants for Tendon Healing In
Vitro. J Hand Surg Am. 2010; 35:1833-41.
Ogata N. Cytokines in bone diseases. Genetic
defects of PTH/PTHrP receptor in chondrodysplasia. Clin Calcium. 20:1481-8, 2010.
Yoshikawa M, Hishikawa K, Idei M, Fujita T.
Trichostatin a prevents TGF-beta1-induced
apoptosis by inhibiting ERK activation in humanrenal tubular epithelial cells. Eur J Pharmacol.
2010; 642(1-3):28-36.
Inowa T, Hishikawa K, Matsuzaki Y, Isagawa T,
Takeuchi T, Aburatani H, Kitamura T, Fujita T.
GADD45β Determines Chemoresistance andInvasive Growth of Side Population Cells of
Human Embryonic Carcinoma. Stem Cells Int.
2010; 782967.
Marumo, T., Hishikawa, K., Yoshikawa, M.,
Hirahashi, J., Kawachi, S., and Fujita, T. Histone
deacetylase modulates the proinflammatory and-fibrotic changes in tubulointerstitial injury. Am J
Physiol Renal Physiol 2010; 298:F133-141.
Fujihara Y, Takato T, Hoshi K Immunologicalresponse to tissue-engineered cartilage derived
from auricular chondrocytes and a PLLA scaffold
in transgenic mice. Biomaterials 2010; 31:
1227-34.
Iwata K, Asawa Y, Fujihara Y, Tanaka Y,
Nishizawa S, Nakagawa T, Nagata S, Takato T,
Hoshi K. The effects of rapid- or intermediateacting insulin on the proliferation anddifferentiation of the cultured chondrocytes. Curr
Aging Sci 2010; 3:26-33.
Ko E, Fujihara Y, Ogasawara T, Asawa Y,
Nishizawa S, Nagata S, Takato T, Hoshi K.
Administration of the insulin into the scaffold
atelocollagen for tissue engineered cartilage. J
Biomed Mater Res A in press.
Tanaka Y, Yamaoka H, Nishizawa S, Nagata S,
Ogasawara T, Asawa Y, Fujihara Y, Takato T,
Hoshi K. The optimization of porous polymericscaffolds for chondrocyte-atelocollagen based
tissue-engineered cartilage. Biomaterials 2010;
31:4506-16.
Yamaoka H, Nishizawa S, Asawa Y, Fujihara, Y,
Ogasawara T, Yamaoka K, Nagata S, Takato T,
Hoshi K. Involvement of Fibroblast Growth
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Chondrocytes. Cell Prolif 2010; 43:67-76.
18. Yamaoka H, Tanaka Y, Nishizawa S, Asawa Y,
Takato T, Hoshi K. The application of
atelocollagen gel in combination with porous
scaffolds for cartilage tissue engineering and its
suitable conditions. J Biomed Mater Res A
2010; 93: 123-132.
19. Yonenaga K, Nishizawa S, Fujihara Y, Asawa Y,
Sanshiro K, Nagata S, Takato T, Hoshi K. The
optimal conditions of chondrocyte isolation andits seeding in the preparation for cartilage tissue
engineering. Tissue Eng Part C Methods. 2010;
16:1461-9.
20. Yonenaga K, Nishzawa S, Akisawa M, Asawa Y,
Fujihara Y, Takato T, Hoshi K. Utility of Nucleo
Counter for the chondrocyte count in thecollagenase digest of human native cartilage.
Cytotechnology 2010; 62:539-45.

479

Hospital Planning andManagement
Associate Professor
Soichi Koike M.D., M.P.H., M.B.A., Ph.D.

Assistant Professor
Hiroo Ide, M.A., Ph.D.,

Homepage

Hidenao Atarashi, C.E., M.P.H.

http://www.h.u-tokyo.ac.jp/patient/depts/kikakukeiei/index.html

Introduction and Organization
In recent years, the medical system in Japan has
been experiencing times of major change. University
hospitals, as well, have been under pressure forsweeping reforms. There are demands, greater thanever before, for the development and practicalapplication of high-quality advanced medical
treatment, and for the efficient promotion of graduate
and postgraduate education, and of clinical research.
And there are demands for those results to be
expressed clearly to Japanese citizens in specific terms.
In April 2004, as the University of Tokyo wasincorporated under the National University
Corporation Law, the University of Tokyo Hospital
underwent drastic organizational restructuring. In
addition to the establishment of Hospital Executives,
there was also the launch of four organizations that
support hospital management (Hospital Planning andManagement; Personnel Administration and Human
Resources;
Performance
Monitoring,
Risk
Management, and Staff Development; and Education
and Research Support) and three organizations that
support clinical management (Inpatient Service
Administration; Outpatient Service Administration;
and Central Hospital Service Administration).
Hospital Planning and Management is a key
working organization in the management of thehospital. It has two full-time faculty members fromthe Department of Planning, Information andManagement, and boasts a team of two pharmacists,

two nurses, one engineering staff member, and 12
administrative staff.

Clinical activities
Hospital Planning and Management is responsible
for all of the organizational and strategic businessaffairs of the University of Tokyo Hospital. It
conducts the following kinds of clinical-management
duties.
(1) Analysis of hospital management
The division manages and analyzes hospital
accounting information, and conducts hospitalmanagement analyses by utilizing management
information
andstandardized
hospital
information.
(2) Planning
Based on the hospital management analyses, thedivision designs short-term management planningand strategy, and provides effective support for
the Hospital Executives to make swift
management decisions. The division is also
responsible for formulating medium- andlong-term plans. Following is a list of hospitalmanagement achievements in which Hospital
Planning and Management was deeply involved.
・ “22nd Century Medical Center” launched・ new central hospital building launched
・ Enhanced functions in the inpatient ward
(expansion of ICU/CCU, increase in number ofbeds in the Psychiatry Department, GCU and480

MFICU, expansion of GCU)
・ To reduce the average length of hospital stays,
and improve the bed occupancy rate・ To achieve reduce drug costs and costs for
medical materials
・ Critical Care Center launched
In addition to these achievements, the division
has also strived to improve innovative patient
services, such as introducing a credit card forpatients, attracting commercial stores in thehospital, and illuminating the hospitalbuildings. At the same time, the division has
worked to develop an environment in which
medical care staff can provide high-quality andsafe medical treatment in a more composed
fashion.
(3) Medical policy recommendations
The division is not just restricted to the
management of the University of Tokyo Hospital.
It also actively implements policy recommendations aimed at improving the medical system inJapan and at deregulating medical care.
Furthermore, we point out issues related toJapan’s medical insurance system based onevidence, and we constantly issue messages fortheir improvement.

Teaching activities
Turning to postgraduate education, the division
accepts 2 research students from the Department ofMedical Informatics and Economics at the Graduate
School of Medicine.
Postgraduate students and research students pursue
their own research projects, not just from the researchareas of healthcare management and hospitalmanagement, but also from such areas as healthcare
economics and healthcare policy. The students review
previous literature and materials, and they are actively
engaged in developing research designs and thecollection of data. The students present regularresearch progress reports, they are given thoroughinstruction on writing academic papers, and they also
follow a rigid schedule of academic presentations.

Research activities
The research activities of the division are notlimited to merely healthcare management and hospitalmanagement, but cover a broader area, including
health policy and health economics.
(1) Research in healthcare management
In the past, the division analyzed the impact thata prospective payment system, which is based on
Diagnosis Procedure Combination (DPC), has on
the healthcare workplace, and it conducted
research to estimate the effects that this system
has on the length of hospital stays. The divisionalso conducted research related to the efficientuse of medical facilities, by studying therelationship between the running of operatingrooms and the number of hospital beds.
In an attempt to systemize healthcare management,
the division edited a standard textbook.
(2) Research in healthcare policy
The division undertook comparative studies
between medical systems in Japan and otherdeveloped countries. Empirical studies related tothe disparity in domestic and imported prices of
medical materials among multi countries, andstudies into the career paths of medical doctors
and health workers’ migration are ongoing.
The division carried out assessments related toJapan’s medical insurance system, and inparticular, conducted research into improvements
to the prospective payment system based on DPC,
and the effectiveness of such improvements.
(3) Research in healthcare economics
In cooperation with hospitals providing cares for
HIV/AIDS patients, the division is conducting
cost-accounting study in HIV/AIDS care.
Recently, we began cost-effectiveness analysis
for hepatitis B prevention strategies.
(4) Other research topic
The division commits a research project
regarding socio-economic impacts on childhood
obesity using a large panel data set, with otherresearch institutes

481

References(1) Koike S, Tanabe S, Ogawa T, Akahane M,
Yasunaga H, Horiguchi H, Matsumoto S,
Imamura T. Effect of time and day of admission
on 1-month survival and neurologicallyfavourable 1-month outcome in out-of-hospital
cardiopulmonary arrest patients. Resuscitation
2011: 82(7); 863～868.
(2) Koike S, Tanabe S, Ogawa T, Akahane M,
Yasunaga H, Horiguchi H, Matsumoto S,
Imamura T. Immediate defibrillation or
defibrillation after cardiopulmonary resuscitation.
Prehospital Emergency Care 2011: 15(3); 393～
400.
(3) Koike S, Tanabe S, Ogawa T, Akahane M,
Yasunaga H, Horiguchi H, Matsumoto S,
Imamura T. Time and CPR quality data innational OHCA database. Prehospital Emergency
Care 2011: 15(4); 579～580.
(4) Koike S, Ogawa T, Tanabe S, Matsumoto S,
Akahane M, Yasunaga H, Horiguchi H, Imamura
T. Collapse-to-emergency medical service
cardiopulmonary resuscitation interval andoutcomes of out-of-hospital cardiopulmonaryarrest: a nationwide observational study. Critical
Care 2011: 15(3);R120.

482

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

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

Homepage

http://kokoro.umin.jp/

Introduction and Organization
The Department of Child Psychiatry wasestablished in April 2005 as the clinical counterpart
to the Clinical Education Center of Mental
Development, both of which are funded by the
special grant for faculty development. The major
aim of the Clinical Education Center is to train
mental health specialists in various fields with afundamental grounding in child psychiatry andneurosciences. Much of the services provided are
based on the 37 years of experience in intervention
and treatment for developmentally disabled children
established in the former child psychiatry divisionof Department of Neuropsychiatry. Our department
uses a multidisciplinary approach by working incollaboration not only with the Department of
Neuropsychiatry, Department of Pediatrics andGraduate School of Education in the University ofTokyo but also several other educational and/or
clinical facilities on mental development ordevelopmental disorders. The Department of Child
Psychiatry complemented the Clinical Education
Center by providing fieldwork for clinical training
and offered clinical services to patients with various
development problems also.
The Clinical Education Center of Mental
Development was closed in March 2010 because oftime limit of the fund, and Department of Child
Neuropsychiatry, Graduate School of Medicine wasestablished in April 2010. The Department of Child
Psychiatry, as the clinical counterpart to thedepartment in graduate school, focuses on clinicalactivity related to research as well as quality
practice of child psychiatry and education ofleading child psychiatrists and allied professionals.
In addition to 3 professors of the graduate school, 2
psychiatrists and 3 psychologists are officiallyassigned to the Department of Child Psychiatry.

Clinical activities
In the year 2011, the Department of Child
Psychiatry consisted of 10 psychiatrists and 7
psychologists (full-time and part-time). Althoughpatients with various disorders are seen, the focusof the department is mainly on patients with
developmental disorders. We offer services topatients with a broad range of developmental
disorders including Autism Spectrum Disorder(ASD), Attention-Deficit/Hyperactivity Disorder(ADHD), Learning Disabilities (LD), Mental
Retardation (MR), tic disorders and child &adolescentObsessive-Compulsive
Disorders(OCD).
Compared to the small number of new patients
related to reconstruction of clinical activity in 2010,
their number became slightly larger and about 200
in 2011. A large part of the new patients consistedof patients with ASD, tic disorder or ADHD.
Although establishment of Tic/OCD clinic mightmake a slight change, general trend of the patientswere similar to that of the previous years.
The follow-up clinic consisted of general clinicand special clinics (high-functioning ASD clinic
and Tic/OCD clinic). At the general clinic, a483

rigorous diagnosis based on detailed assessment
and decision about treatment course are provided
for children and adolescents with any kinds ofmental problems. After fine adjustment of treatment
course within a given period, the patients arereferred to community hospitals/clinics orintervention/education facilities with a detailed
report. The special clinics meet a need for highlevel services and work with research for special
diseases.
Services for the general child psychiatry
outpatients are provided by psychiatrists in theareasofpharmacotherapy,
psychotherapy,
psychoeducation and also work closely with theschools and community.
Interventions for developmentally disabledindividuals consist of “developmental psychology
outpatient services” and “group therapy”. Patients
involved in interventions are individuals with
developmental disabilities, and individualized
treatment based on cognitive developmental therapy
is planned for each. “Developmental psychology
outpatient clinic” provides services in the following
areas: (1) evaluation of cognitive and behavioral
development, (2) individualized treatment of thedisabled individual (3) counseling of parents andproviding information to the disabled individual’s
support network (relatives, schools). “Grouptherapy” for preschool children with ASD consistsof 10 sessions.
Group cognitive behavior therapy for adults withhigh-functioning ASD, which started in 2010, isprovided after revision of the program.
In response to the rising demand, parent-training
for parents with ADHD children started in 2011.
This program aimed that the parents learn deeper
understanding of difficult children and appropriate
strategy of coping with them.
In addition to these outpatient services, trial of“inpatient assessment on developmental disorders”
service started in 2010. This service is provided in
the inpatient ward of neuropsychiatry foradolescents or adults who have mental problems
such as depression and wish a detailed examination
about possibility of hidden developmental disorders
including ASD and ADHD.
We also focus on psychiatric liaison activity withother departments in the University hospital,
especially pediatrics.

Education
Undergraduates of the University of Tokyo haveopportunities to participate in an assessment anddiagnosis session at the general first visit outpatient
clinic and “group therapy” for preschool children.
Graduate students in clinical psychology course
from several universities participate in “short-termgroup therapy” for preschoolers also.
One month training course is offered to juniorresidents especially in pediatric specialty course.
This course includes intake interview of first visit
patients, observation of assessment and treatment
for follow-up patients and “group therapy” forpreschoolers, and visit to community hospital andintervention/guidance facilities for child andadolescent mental health. Several senior residentsof neuropsychiatry participated in one program suchas parent-training actively for 3 months, and hadsome experience of above-mentioned activities.
In response to the increasing interest to adults
with developmental disorders, a seminar ofdevelopmental disorders was held in June 2011, andover 60 medical doctors, psychologists, and allied
professionals attended.

Research
We participate in investigation of etiology anddevelopment of effective treatment on ASD and
ADHD, which are organized in collaboration with
the Department of Neuropsychiatry and otherresearch, educational and clinical facilities. In
addition, research related specifically to the clinicalactivities in the Department of Child Psychiatry iscurrently being investigated.
Clinical evaluation and treatment
The reexamination of reliability and validity of
Ohta Staging (an evaluation system using symbol
development for cognitive developmental therapy
developed in the former child division of the
Department of Neuropsychiatry) and investigationof the effectiveness of present interventions for484

children with ASD are being conducted.
A comparison study of the effectiveness of
individual treatment and “group therapy” forpreschoolers with ASD is being undertaken.
A program of group cognitive behavior therapy
for adults with high-functioning ASD was revised
basedon
preliminary
examination,andeffectiveness of the revised program is currently
investigated in a randomized control trial.
The
possible
relationsamongclinicalcharacteristics such as tics and obsessivecompulsive symptoms in Tourette syndrome(chronic tic disorder with multiple motor tics andone or more vocal tics) and child & adolescent
OCD are being evaluated.
Neuropsychological research
Neuropsychological data on ASD, ADHD andTourette syndrome are being collected. Analysis of
the relations among neuropsychological findings
and the clinical evaluation as well as comparisons
between patients and their healthy siblings arebeing conducted.
Genetic research
Research exploring susceptibility genes of ASD
in chromosome 2, long arm of chromosome 7 andlong arm of chromosome 15 was conducted. As weare interested in gene-environment interaction, weare examining influence of age of parents andassisted reproduction technologies on emergence of
ASD. We are analyzing samples of individuals froma multiplex family of ASD by exome sequencing
also.
Neuroimaging
Studies include structural MRI, Near-Infrared
Spectroscopy (NIRS) and functional MRI with
exploring the pathogenesis of developmental
disorders such as ASD. One of the intensive study
is the examination of prefrontal blood flow in ASD
and ADHD by NIRS which is non invasive andeasily applicable to children and developmentallydisabled individuals. Possibility of NIRS as apredictor of efficacy of methylphenidate forchildren with ADHD is intensively examined also.
Functional MRI study of adults with ADHD andadults with Tourette syndrome by delayed rewardtask is in process.

References
1. Kawakubo Y, Suga M, Tochigi M, Yumoto M,
Itoh K, Sasaki T, Kano Y, Kasai K: Effects ofmetabotropic glutamate receptor 3 genotype onphonetic mismatch negativity. PLoS ONE.
6(10): e24929, 2011.
2. Kawakubo Y, Kono T, Takizawa R, Kuwabara
H, Ishii-Takahashi A, Kasai K: Developmental
changes of prefrontal activation in humans: anear-infrared spectroscopy study of preschool
children and adults. PLoS ONE 6(10): e25944,
2011.
3. Marui T, Funatogawa I, Koishi S, Yamamoto K,
Matsumoto H, Hashimoto O, Jinde S, Nishida
H, Sugiyama T, Kasai K, Watanabe K, Kano Y,
Kato N: The NADH-ubiquinone oxidoreductase
1 alpha subcomplex 5 (NDUFA5) gene variants
are associated with autism. Acta Psychiatr
Scand. 123(2):118-124, 2011.
4. Sumiyoshi C, Kawakubo Y, Suga M, Sumiyoshi
T, Kasai K: Impaired ability to organize information in individuals with autism spectrum
disorders and their siblings. Neurosci Res.
69:252-257, 2011.
5. Iwanami A, Okajima Y, Ota H, Tani M,
Yamada T, Hashimoto R, Kanai C, Watanabe H,
Yamasue H, Kawakubo Y, Kato N: Task dependent prefrontal dysfunction in persons withAsperger’s disorder investigated with multi-channel near-infrared spectroscopy. Researchin Autism Spectrum Disorders, 5(3): 1187-1193,
2011.
6. Kuroda M, Wakabayashi A, Uchiyama T, Yoshida Y, Koyama T, Kamio Y: Determining differences in social cognition between
high-functioning autistic disorder and otherpervasive developmental disorders using new
advanced “mind-reading” tasks. Research inAutism Spectrum Disorders 5, 554-561, 2011.

485

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
three full-time staff doctors, two full-time doctor, andthe designated hospice care nurse who take an
initiative in working. They visited the general ward
and offer palliative care to the patient who hasreceived the cancer care in cooperation with patients’attending doctors and ward staff and rehabilitation
staff, etc.
Hereafter, we concretely show the consultation
situation in fiscal year 2011.
The cumulative number of patients who consulted our
palliative care team was over 2500. The maximum
monthly patients were 55 of February. According tosite of the cancer, 470 cancers were divided into63
stomach, 37 pancreas, 36 lungs, 30 uterine, 26 liver,23 breasts, 15 ovaries, 14 esophagus, 14 colon and soon. We visited almost all the ward in the hospital.
These figures proved significantly the importance ofthe palliative care.

Education
In the training at the Department of Palliative
Medicine, medical students of the first and second
year can learn the basic knowledge of palliative careby selecting an optional subject for one, two, four oreight months. And then they can participate in thepalliative care team and attend the daily conference ofpalliative care on weekdays.

486

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 (around 40 consultation
patients a day): They acquire the outline of controlof physical and psychiatric symptoms of thepatients with common disease in Japan such asdigestive cancers in the general ward. They alsoacquire 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) 9:0010:30･ Ward consultation: Monday - Friday (every day);up to the end of request patient's consultation after
conference.
･ The cancer registry: They input data in the ward
round with the HIS (Hospital information system)
terminal on each floor.
System of guidance･ The ward consultation: Resident participate in the
consultation team (or palliative care team) thatconsists of two guidance medical doctors (oneassistant or lecturer, one designated hospice carenurse, and one resident physician). A palliative careteam examines about 30 – 40 in-patients a day.
･ The conference: Psychiatrist, morphine special
pharmacist, and nurse of The Tokyo University
Graduate School of Medicine and others participate
in the daily conference besides the regular memberof the palliative care team in the ward round. They
discuss the multidisciplinary palliative careprogram that the palliative care team offers. They
also guide the resident's palliative care program487

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.

2.

3.

Sakumi A. Shiraishi K. Onoe T. Yamamoto
K. Haga A. Yoda K. Ohtomo K. Nakagawa
K. Single-arc volumetric modulated arc therapy
planning for left breast cancer and regional nodes.
Journal of Radiation Research. 2012;53(1):151-3
Takahashi W.
Yamashita H.
Saotome N.
Iwai Y. Sakumi A. Haga A. Nakagawa K.
Evaluation of heterogeneity dose distributions for
Stereotactic Radiotherapy (SRT): comparison ofcommercially available Monte Carlo dose
calculation with other algorithms. Radiation
Oncology. 2012;7:20, 2012.
Hashimoto M. Uematsu M. Ito M. Hama Y.
Inomata T. Fujii M. Nishio T. Nakamura N.
Nakagawa K. Investigation of the feasibility of asimple method for verifying the motion of abinary multileaf collimator synchronized with therotation of the gantry for helical tomotherapy.

Journal of Applied Clinical Medical Physics.
2012; 13(1):3700.
4. Yamashita H.
Nakagawa K.
Okuma K.
Sakumi A. Haga A. Kobayashi R. Ohtomo K.
Correlation between bladder volume andirradiated dose of small bowel in CT-basedplanning of intracavitary brachytherapy forcervical cancer. Japanese Journal of ClinicalOncology. 2012;42(4):302-8.
5. Kida S. Saotome N. Masutani Y. Yamashita
H. Ohtomo K. Nakagawa K. Sakumi A.
Haga A. 4D-CBCT reconstruction using MV
portal imaging during volumetric modulated arc
therapy. Radiotherapy & Oncology. 2011;100(3):380-5.
6. Sakumi A. Haga A. Kida S. Saotome N.
Okano Y. Shiraishi K. Onoe T. Yoda K.
Ohtomo K. Nakagawa K. First in-situ dose
calculation report using in-treatment kilovoltage
cone-beam ct and in-treatment linac parameters
during volumetric modulated arc therapy. Journalof Radiation Research. 2011;52(4):536-7.
7. Yoda K.
Nakagawa K. Technical note:
Extension of Van Herk's treatment margin model
for anisotropic systematic positioning errors incartesian coordinate systema. Medical Physics.
2011.38(7):3913-4.
8. Nakagawa K.
Ohkuma K.
Yamashita H.
Masuda M. Matsumoto Y. Gotoh T. Radiation
therapy did not alleviate complete paralysis due tometastasis of lung adenocarcinoma to thoracic
vertebrae until four months later. Acta Oncologica.
2011;50(4):606-8.
9. Yamashita H.
Okuma K.
Wakui R.
Kobayashi-Shibata S. Ohtomo K. Nakagawa
K. Details of recurrence sites after elective nodal
irradiation
(ENI)
using
3D-conformal
radiotherapy(3D-CRT)
combinedwithchemotherapy for thoracic esophageal squamous
cellcarcinoma--aretrospective
analysis.
Radiotherapy & Oncology. 2011;98(2):255-60.
10. Yamashita H. Kida S. Sakumi A. Haga A.
Ito S. Onoe T. Okuma K. Ino K. Akahane
M.
Ohtomo K.
Nakagawa K. Fourdimensional measurement of the displacement ofinternal fiducial markers during 320-multislice
computed tomography scanning of thoracic

488

esophageal cancer. International Journal of
Radiation Oncology, Biology, Physics. 2011;
79(2):588-95.
11. Sakumi A. Shiraishi K. Onoe T. Yamamoto
K. Haga A. Yoda K. Ohtomo K. Nakagawa
K. Single-arc volumetric modulated arc therapy
planning for left breast cancer and regional nodes.
Journal of Radiation Research. 2012;53(1):151-3.
12. Murakami I. Takeuchi T. Mori-Uchino M.
Mori S. Fujii T. Aoki D. Nakagawa K.
Kanda T. An adeno-associated virus vector
efficiently and specifically transduces mouseskeletal muscle. Molecular Biotechnology.
2011;49(1):1-10.
13. Koga T, Maruyama M, Ito Y, Nakagawa K,
Shibahara J, Todo T. Extended field stereotactic
radiosurgery for recurrent glioblastoma. Cancer :Equb ahead of print , 2011
14. Nakamura N, Shikama N, Takahashi O, Sekiguchi
K, Hama Y, Akahane K, Nakagawa K. The
relationship between the bladder volume andoptimal treatment planning in definitive
radiotherapy for localized prostate cancer. Acta
Oncol : Epub ahead of print, 2011
15. Nakagawa K. Kida S. Haga A. Masutani Y.
Yamashita H. Imae T. Tanaka K. Ohtomo K.
Iwai Y.
Yoda K. Cone beam computed
tomography data acquisition during VMAT
delivery with subsequent respiratory phase sorting
based on projection image cross-correlation.
Journal of Radiation Research. 2011; 52(1):112-3.
16. Kawaguchi T.
Iwase S.
Koinuma M.
Onodera Y.
Takeuchi H.
Umeda M.
Matsunaga T.
Unezaki S.
Nagumo Y.
Determinants
affectingqualityoflife:
implications for pharmacist counseling forpatients with breast cancer in Japan. Biological &Pharmaceutical Bulletin. 2012; 35(1):59-64.
17. Yamamoto D. Iwase S. Yoshida H. Kuroda Y.
Yamamoto C.
Kitamura K.
Odagiri H.
Nagumo Y. Efficacy of meloxicam in combination
with preoperative chemotherapy for breast cancer- Japan Breast Cancer Research Network(JBCRN) 02-1 trial. Anticancer Research. 2011;31(10):3567-71.
18. Matsuo N. Morita T. Iwase S. Efficacy andundesirable effects of corticosteroid therapy

experienced by palliative care specialists in Japan:
a nationwide survey. Journal of Palliative
Medicine. 2011;14(7): 840-5.
19. Iwase S.
Yamamoto D.
Kuroda Y.
Kawaguchi T.
Kitamura K.
Odagiri H.
Teramoto S. Akazawa K. Nagumo Y. Phase II
trial of preoperative chemotherapy for breast
cancer: Japan Breast Cancer Research Network(JBCRN)-02 trial. Anticancer Research. 2011;31(4):1483-7

489

Cancer Resource Center
Associate Professor
Sachiyo Nomura, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/cancer_support/index.html

Introduction and Organization
As part of national efforts to address cancer, thegovernment has been establishing a network of“cancer care hub hospitals”. In response to its being
designated as a regional cancer care hub hospital in2008, the University of Tokyo Hospital established theCancer Resource Center to provide consultations tocancer patients and their families as well as residents
in neighboring communities with aim of leading them
to appropriate departments and facilities.
The Center consists of a chief of the center, and two
consultant nurses. In addition, staff from the Cancer
Board, an in-hospital interdisciplinary cancer
treatment team, may join consultations depending on
issues to be discussed.

when receiving treatment, such as medical
expenses, how to get along after being discharged
from hospital, and nursing services. The Center
provides patients with advice and support, so thatthey can resolve such worries.
3. Provision of information on second opinion
The Center provides information on how to get asecond opinion and on facilities that provide
second opinions.
4. Provision of general information and advice on
cancer
The Center sends out and provides information topeople who do not have cancer but who want tofind out about cancer, for instance, the treatment
and screening for it.

Scope
Clinical activities
1. Provision of information if patient contracts
cancer
If a person gets cancer, the first thing they need to
do is collect information on cancer. This Center
provides information and booklets on different
types of cancer. Furthermore, in order to select thebest treatment for oneself from among thetherapies presented by doctors, the person needs
to accurately understand the doctors’ explanations.
At the Center, we explain difficult medical terms
in simple language, and we help patients
understand their doctors’ advice.
2. Various kinds of advice on the medical care ofcancer
If a person contracts cancer, besides the medical
problem of what kind of treatment to undergo andwhere, there are also issues related to medical care

We are going to meet patients and their families not
only of our patients but also from all over Japan. We
will make effort to have many patients receive goodtherapies with their satisfy.

490

Center for Genome Medicine
Clinical Genomics
Director & Professor
Takashi Kadowaki, M.D., Ph.D.

1. Organization
The Department of Genome Informatics started
as a special unit conducting research on clinicalepidemiology and human genetics in 2003. Our
section functions as the unit to establish/support
clinical and epidemiological data sampling/ management and to accomplish an appropriate and efficient
application of results of recently advanced human
genetics and genomics. In addition,
as the unit of training and educating specialists ofclinical epidemiology and human genetics. It consistsof one professor and different specialties participatingin the department. They include cardiologists, diabetologists, epidemiologists, and statisticians.
Oursection also supported designing of clinical / genetic
studies and provided services of anonymizing clinicaldata / samples derived from study participants.

2. Activities
In collaboration with RIKEN, we explored thecomprehensive catalog of genomic variations
provided by the 1000 Genomes Project to identify
variations conferring susceptibility to T2D in theJapanese population that were not detected in theprevious scans. We imputed 10,811,164 variants
derived from 286 East Asian subjects in 5,976 casesand 20,829 controls genotyped by 610K
single-nucleotide polymorphism (SNP) array. We
tested associations for T2D before and after adjusting
for age, sex, and body mass index. We found that inaddition to variants of the previously reported loci,there were 19 loci harboring multiple variants possibly
associated with T2D. We are conducting a replication

study to confirm the association in another 13,718
cases and 10,588 controls. Our study highlights thebenefits of using data derived from next-generation
sequencing of the human genome such as the 1000
Genomes Project to explore T2D loci morecomprehensively. We also took part in the Asian
Genetic Epidemiology Network (AGEN) consortium
which conducted a large-scale GWAS comprising up
to 6,952 cases and 11,865 controls and found novel
T2D loci in East Asian populations. These findings
highlight the usefulness of conducting GWAS toclarify the genetic predisposition to T2D in East
Asians as well as in European-origin populations.
In cardiology and vascular medicine, we focusedon atherosclerotic diseases such as coronary stenosis
and myocardial infarction. It is important toaccumulate and analyze data obtained in daily practiceto gain insight into a larger clinical picture. Thus, we
designed and developed a coronary angiography andintervention reporting system (CAIRS) to collect data
and analyze outcomes of coronary intervention. The
resulting advanced CAIRS can record detailed data on
coronary angiographic and interventional procedures.
To date, data on 10,025 cases of coronary angiography,of which 3,574 were interventional, have beencollected over a 5.5 year period. There were 4,343
unique patients. About one-third of the patients neverunderwent a PCI procedure at our institution. We havealso implemented the same system at other institutions
and sampled larger-scale CAD patients. Implementing
the same system at more institutions and analyzing
data collected in the same scheme will provide
detailed and timely insight into the 'real world' ofcoronary atherosclerotic diseases and their clinicaloutcome. Also, using the aforementioned database in491

our institution, we showed that (1) macrocytosis, as aqualitative
abnormalityoferythrocytes,
issignificantly and independently associated withadverse outcomes after percutaneous coronary
intervention (aHR of cardiac death: 3.45, 95%CI:
1.22-9.80, P=0.019) and (2) serum concentrations of
IgG4 and sIL-2R were increased in patients with
CAD.
Concerning genetic analysis of monogenic
diseases, our department has provided service ofgenetic analysis of Marfan syndrome (MFS), one of
the representative connective tissue diseases.
Approximately 70-80% of MFS is caused bygenetic mutations of FBN1 gene. We performed
mutational analysis using a high-throughput
microarray-based resequencing system. In our strategy
mutation detection rate for patients who fulfilled the
Ghent diagnostic criteria reached 71%. Of note,
splicing mutations accounted for 19% of all mutations,which is more than previously reported. We also
showed the clinical characteristics of Japanese MFS
patients including wide difference in musculoskeletal
phenotypes compared with Caucasians.

3. References
1: Iwata M, Maeda S, Kamura Y, Takano A, Kato H,
Murakami S, Higuchi K, Takahashi A, Fujita H,
Hara K, Kadowaki T, Tobe K. Genetic risk scoreconstructed using 14 susceptibility alleles for type2 diabetes is associated with the early onset of
diabetes and may predict the future requirement of
insulin injections among Japanese individuals.
Diabetes Care 35:1763-70, 2012
2: Kodama K, Horikoshi M, Toda K, Yamada S, Hara
K, Irie J, Sirota M, Morgan AA, Chen R, Ohtsu H,
Maeda S, Kadowaki T, Butte AJ. Expression-based
genome-wide association study links the receptor
CD44 in adipose tissue with type 2 diabetes. Proc
Natl Acad Sci U S A. 109: 7049-54, 2012
3: Imamura M, Maeda S, Yamauchi T, Hara K,
Yasuda K, Morizono T, Takahashi A, Horikoshi M,
Nakamura M, Fujita H, Tsunoda T, Kubo M,
Watada H, Maegawa H, Okada-Iwabu M, Iwabu
M, Shojima N, Ohshige T, Omori S, Iwata M,
Hirose H, Kaku K, Ito C, Tanaka Y, Tobe K,
Kashiwagi A, Kawamori R, Kasuga M, Kamatani
N; Diabetes Genetics Replication and Meta-

4:

5:

6:

7:

analysis (DIAGRAM) Consortium, Nakamura Y,
Kadowaki T. A single-nucleotide polymorphism in
ANK1 is associated with susceptibility to type 2
diabetes in Japanese populations. Hum Mol Genet.
21:3042-9, 2012
Kohro T, Iwata H, Fujiu K, Manabe I, Fujita H,
Haraguchi G, Morino Y, Oguri A, Ikenouchi H,
Kurabayashi M, Ikari Y, Isobe M, Ohe K, Nagai
R. Development and implementation of anadvanced coronary angiography and intervention
database system. Int Heart J 2012;53: 35-42.
Sakamoto A, Ishizaka N, Saito K, Imai Y, Morita
H, Koike K, Kohro T, Nagai R. Serum levels of
IgG4 and soluble interleukin-2 receptor in patientswith coronary artery disease. Clinica Chimica
Acta. 2012;413:577-81
Myojo M, Iwata H, Kohro T, Sato H, Kiyosue A,
Ando J, Sawaki D, Takahashi M, Fujita H,
Hirata Y, Nagai R. Prognostic implication ofmacrocytosis on adverse outcomes after coronary
intervention. Atherosclerosis 2012;221:148-53
Ogawa N, Imai Y, Takahashi Y, Nawata K, HaraK, Nishimura H, Kato M, Takeda N, Kohro T,
Morita H, Taketani T, Morota T, Yamazaki T,
Goto J, Tsuji S, Takamoto S, Nagai R, Hirata Y.
Evaluating Japanese patients with the Marfan
syndrome using high-throughput microarray-based
mutational analysis of fibrillin-1 gene. Am J
Cardiol 2011;108: 1801-7.

492

Center for Genome Medicine
Clinical Genomics Department
Director & Professor
Shoji Tsuji, M.D., Ph.D.

Vice-director & Lecturer
Jun Goto, M.D., Ph.D.

Organization
The Department of Clinical Genomics started asa special unit conducting genomic medicine or clinicalhuman genetics services in 2003. Our department
functions as the core unit to accomplish an appropriate
and efficient application of results of recently
advanced human genetics and genomics to clinicalpractice in the hospital and as the unit of training andeducating specialists of human genetics practice. It
consists of one professor and many different
specialties participate in the department. They include
pediatricians, obstetricians, internist (cardiologists,diabetologists, and neurologists), dermatologists, andstaffs 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
Wednesday every month.
Counseling of participants in researches
including genome or gene analysis is a duty withwhich the hospital and the faculty charge thedepartment.
To build suitable clinical systems including
modern genomic medicine we are cooperating withother departments. We are participating in Marfan’sSyndrome Clinic which is managed collaboratively by

the Departments of Cardiovascular Surgery,
Cardiovascular Medicine, Pediatrics, Spinal Surgery
and Ophthalmology.
In collaboration with Clinical Laboratory Center,
Pharmaceutical Services, Departments of Planning
Information and Management, and several clinicaldepartments we started pharmacogenetics tests in2006. Those include tests for proton inhibitor,
warfarin, irinotecan, and tacrolimus.

References
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Y, Morita H, Ikeda S, Kato R, Tsurusaki Y,
Miyake N, Saitsu H, Sakai H, Miyatake S, ShiinaM, Nukina N, Koyano S, Tsuji S, Kuroiwa Y,
Matsumoto N. Exome Sequencing Reveals a
Homozygous SYT14 Mutation in Adult-Onset,
Autosomal-Recessive Spinocerebellar Ataxia with
Psychomotor Retardation. Am. J. Hum. Genet.
89: 320-327, 2011
2. Iida A, Takahashi A, Kubo M, Saito S, Hosono N,
Ohnishi Y, Kiyotani K, Mushiroda T, Nakajima M,
Ozaki K, Tanaka T, Tsunoda T, Oshima S, Sano M,
Kamei T, Tokuda T, Aoki M, Hasegawa K,
Mizoguchi K, Morita M, Takahashi Y, Katsuno M,
Atsuta N, Watanabe H, Tanaka F, Kaji R, Nakano
I, Kamatani N, Tsuji S, Sobue G, Nakamura Y,
Ikegawa S. A functional variant in ZNF512B is
associated with susceptibility to amyotrophic
lateral sclerosis in Japanese. Hum. Mol. Genet.
20:3684-3692, 2011
3. Ishiura H, Fukuda Y, Mitsui J, Nakahara Y, Ahsan

493

4.

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B, Takahashi Y, Ichikawa Y, Goto J, Sakai T, Tsuji
S. Posterior column ataxia with retinitis
pigmentosa in a Japanese family with a novel
mutation in FLVCR1. Neurogenet. 12:117-21,
2011.
Matsukawa T, Asheuer M, Takahashi Y, Goto J,
Suzuki Y, Shimozawa N, Takano H, Onodera O,
Nishizawa M, Aubourg P and Tsuji S.
Identification of novel SNPs of ABCD1, ABCD2,
ABCD3 and ABCD4 genes in patients with
X-linked adrenoleukodystrophy (ALD) based oncomprehensive resequencing and association
studies with ALD phenotypes. Neurogenet. 12:
41-50, 2011.
Matsukawa T, Wang X, Liu R, Onuki Y, Kubota A,
Hida A, Kowa H, Fukuda Y, Ishiura H, Mitsui J,
Takahashi Y, Aoki S, Takizawa T, Shimizu J, Goto
J, Proud CG and Tsuji S. Adult-onset leukoencephalopathies with vanishing white matter withnovel missense mutations in EIF2B2, EIF2B3,
and EIF2B5. Neurogenet. 12:259-61, 2011
Ogawa N, Imai Y, Takahashi Y, Nawata K, Hara K,
Nishimura H, Kato M, Takeda N, Kohro T, Morita
H, Taketani T, Morota T, Yamazaki T, Goto J,
Tsuji S, Takamoto S, Nagai R, Hirata Y.
Evaluating Japanese patients with the Marfan
syndrome using high-throughput microarraybased mutational analysis of fibrillin-1 gene. Am.
J. Cardiol. 108:1801-1807,2011
Seki N, Takahashi Y, Tomiyama H, Rogaeva E,
Murayama S, Mizuno Y, Hattori N, Marras C,
Lang AE, St George-Hyslop P, Goto J and Tsuji S.
Comprehensive mutational analysis of LRRK2
reveals variants supporting association with
autosomal dominant Parkinson's disease. J. Hum.
Genet. 56:671-675, 2011
Yokoseki A, Ishihara T, Koyama A, Shiga A,
Yamada M, Suzuki C, Sekijima Y, Maruta K,
Tsuchiya M, Date H, Sato T, Tada M, Ikeuchi T,
Tsuji S, Nishizawa M and Onodera O. Genotypephenotype correlations in early onset ataxia withocular motor apraxia and hypoalbuminaemia.
Brain 134:1387-99, 2011.
Fujisawa T, Homma K, Yamaguchi N, Kadowaki
H, Tsuburaya N, Naguro I, Matsuzawa A, Takeda
K, Takahashi Y, Goto J, Tsuji S, Nishitoh H, andIchijo H. A novel monoclonal antibody reveals a

conformational alteration shared by amyotrophic
lateral sclerosis-linked SOD1 mutants. Ann.
Neurol. (in press)
10. Hashimoto Maeda M, Mitsui J, Soong B-W,
Takahashi Y, Ishiura H, Hayashi S, Shirota Y,
Ichikawa Y, Matsumoto H, Arai M, Okamoto T,
Miyama S, Shimizu J, Inazawa J, Goto J and Tsuji
S. Increased gene dosage of myelin protein zero
causes Charcot-Marie-Tooth disease. Ann Neurol.
71:84-92, 2012
11. Hida A, Ishiura H, Arai N, Fukuoka H, Kurono H,
Hasuo K, Shimizu K, Goto J, Uesaka Y, Tsuji S
and Takeuchi S. Title: Adult-onset Alexander
disease with a novel R66Q mutation of GFAP
gene presenting severe vocal cord paralysis during
sleep. J. Neurol. (in press)
12. Iizuka T, Takahashi Y, Sato M, Yonekura J,
Miyakawa S, Endo M, Hamada J, Kan S,
Mochizuki H, Momose Y, Tsuji S, Sakai F.
Neurovascular changes in prolonged migraine
aura in FHM with a novel ATP1A2 gene mutation.
J. Neurol. Neurosurg. Psych. 83: 205-212, 2012
13. Ishiura H, Takahashi Y, Mitsui J, Yoshida S,
Kihira T, Kokubo Y, Kuzuhara S, Ranum LPW,
Tamaoki T, Ichikawa Y, Date H, Goto J, and Tsuji
S. C9ORF72 repeat expansion in amyotrophic
lateral sclerosis in the Kii peninsula of Japan.
Arch. Neurol. (in press)
14. Lee Y-C, Durr A, Majczenko K, Huang Y-H, Liu
Y-C, Lien C-C, Ichikawa Y, Goto J, Monin M-L,
Li JZ, Chung M-Y, Mundwiller E, Dell' Orco J,
Shakkottai V, Liu T-T, Tesson C, Lu Y-C, Tsai P-C,
Brice A, Tsuji S, Burmeister A, Stevanin G, Soong
B-W. Mutations in KCND3 cause spinocerebellar
ataxia type 22. Ann. Neurol. (in press)
15. Majounie E, Renton AE, Mok K, Dopper EGP,
Waite A, Rollinson S, Chi? A, Restagno G,
Nicolaou N, Simon-Sanchez J, van Swieten JC,
Abramzon Y, Johnson JO, Sendtner M, Pamphlett
R, Orrell RW, Mead S, Sidle KC, Houlden H,
Rohrer JD, Morrison KE, Pall H, Talbot K,
Ansorge O, The Chromosome 9-ALS/FTD
Consortium, The French research network on
FTLD/FTLD/ALS, The ITALSGEN Consortium,
Hernandez DG, Arepalli S, Sabatelli M, Mora G,
Corbo M, Giannini F, Calvo A, Englund E,
Borghero G, Floris GL, Remes AM, Laaksovirta H,

494

McCluskey L, Trojanowski JQ, Van Deerlin VM,
Schellenberg GD, Nalls MA, Drory VE, Lu C-S,
Yeh T-H, Ishiura H, Takahashi Y, Tsuji S, Ber IL,
Brice A, Drepper C, Williams N, Kirby J, Shaw P,
Hardy J, Tienari PJ, Heutink P, Morris HR,
Pickering-Brown S, *Traynor BJ. C9ORF72
hexanucleotide repeat expansion in sporadic ALS
and FTD around the world. Lancet Neurol. 11:
323-30, 2012
16. Martins S, Soong, B-W. Wong VCN, Giunti P,
Brice A, Ranum LPW, Sasaki H, Riess O, Tsuji S,
Coutinho P, Amorim A, Sequeiros J, Nicholson
GA. Mutational Origin of Machado-Joseph
Disease in the Australian Aboriginal Communities
of Groote Eylandt and Yirrkala. Arch. Neurol. 69:
746-751, 2012.
17. Mitsui J, Matsukawa T, Ishiura H, Higasa K,
Yoshimura J, Saito TL, Ahsan B, Takahashi Y,
Goto J, Iwata A, Niimi Y, Riku Y, Goto Y, Mano K,
Yoshida M, Morishita M, and Tsuji S. CSF1R
mutations identified in three families with
autosomal
dominantly
inheritedleukoencephalopathy. Amer. J. Med. Genet. Neuropsych.
Genet. (in press)
18. Montenegrob G, Rebelo AP, Connell J, Allison R,
Babalini C, D'Aloia M, Montieri P, Schüle-Freyer
R, Ishiura H, Price J, Strickland A, Gonzalez MA,
Baumbach-Reardon L, Deconinck T, Huang J,
Bernardi G, Vance JM, Rogers MT, Tsuji S, deJonghe P, Pericak-Vance MA, Schöls L, Orlacchio
A, Reid E, and Züchner S. Mutations in human
Reticulon2 cause axonal degeneration in
Hereditary Spastic Paraplegia type 12. J. Clin.
Invest. 122: 538-544, 2012
19. Naruse H, Takahashi Y, Kihira T, Yoshida S,
Kokubo Y, Kuzuhara S, Ishiura H, Amagasa M,
Murayama S, Tsuji S and Goto J. Mutational
Analysis of Familial and Sporadic Amyotrophic
Lateral Sclerosis with OPTN Mutations inJapanese Population. Amyotrophic Lateral
Sclerosis 13: 562-566, 2012.
20. Suzuki K, Zhou J, Sato T, Takao K, Miyagawa T,
Oyake M, Yamada M, Takahashi H, Takahashi Y,
Goto J, and Tsuji S. DRPLA transgenic mouse
substrains carrying single copy of full-lengthmutant human DRPLA gene with variable sizes of
expanded CAG repeats exhibit CAG repeat

length- and age-dependent changes in behavioral
abnormalities and gene expression profiles.
Neurobiol. Dis. 46: 336-350, 2012
21. Tsuji S. Neurogenomics view of neurologicaldiseases. Arch. Neurol. (in press)
22. Iwata M, Maeda S, Kamura Y, Takano A, Kato H,
Murakami S, Higuchi K, Takahashi A, Fujita H,
Hara K, Kadowaki T, Tobe K. Genetic risk scoreconstructed using 14 susceptibility alleles for type2 diabetes is associated with the early onset of
diabetes and may predict the future requirement of
insulin injections among Japanese individuals.
Diabetes Care. 35:1763-70, 2012
23. Kodama K, Horikoshi M, Toda K, Yamada S,
Hara K, Irie J, Sirota M, Morgan AA, Chen R,
Ohtsu H, Maeda S, Kadowaki T, Butte AJ.
Expression-based genome-wide association study
links the receptor CD44 in adipose tissue with
type 2 diabetes. Proc Natl Acad Sci U S A.
109:7049-54, 2012
24. Imamura M, Maeda S, Yamauchi T, Hara K,
Yasuda K, Morizono T, Takahashi A,Horikoshi M,
Nakamura M, Fujita H, Tsunoda T, Kubo M,
Watada H, Maegawa H,Okada-Iwabu M, Iwabu M,
Shojima N, Ohshige T, Omori S, Iwata M, Hirose
H, Kaku K,Ito C, Tanaka Y, Tobe K, Kashiwagi A,
Kawamori R, Kasuga M, Kamatani N; Diabetes
Genetics
Replication
andMeta-analysis(DIAGRAM)
Consortium,
NakamuraY,
Kadowaki T. A single-nucleotide polymorphism in
ANK1 is associated with susceptibility to type 2
diabetes in Japanese populations. Hum Mol Genet.
21:3042-9, 2012

495

Center for Genome Medicine
Genomic Analysis Department
Director
Shoji Tsuji, M.D., Ph.D.

Organization
Center for Genome Medicine was newly
established in 2011, which is composed of Clinical
Genomics, Genetics Informatics and Genomic
Analysis Departments. The Genomic Analysis
Department was newly established as the core facilityof next generation sequencers and genome informatics.
Currently, two Hiseq2000s (Illumina) and one 5500xl(Life Technologies) are installed.
The throughput of genome sequencing is
3,000Gb/month and the major applications include
whole genome sequencing and whole-exome
sequencing. Genome informatics analyses, which are
the difficult part of genome analyses, are smoothly
conducted in collaboration with Prof. Shinichi
Morishita at Graduate School of Frontier Sciences.
The major projects at Genomic Analysis
Department include the search for genes involved inhereditary diseases as well as for those involved indiseases with complex trait.
It has been difficult to identify the causative
genes when the family sizes are small. With the highthroughput of genome sequencing using next
generation sequencers, it has become feasible toidentify causative genes, even if the candidate region
cannot be sufficiently narrowed. Applying comprehensive genome sequencing using next generation
sequencers, we have recently identified the causative
gene for hereditary motor and sensory neuropathy
with proximal dominant involvement ( HMSN-P).
For diseases with complex trait, genome-wide
association studies (GWAS) employing common SNPs
(single nucleotide polymorphisms) has been
intensively applied to search for disease susceptibility

genes. Although, GWAS has been successful for
identifying disease susceptible genes, odds ratios
associated with genes are generally small, accounting
for only a limited portion of disease processes. Recent
progresses have demonstrated the role of common
disease-multiple rare variants hypothesis to identify
disease susceptibility genes with substantially highodds ratios. With this background, comprehensive
whole-exome sequencing of large resources of casesand controls is being conducted to identify diseasesusceptibility genes for sporadic diseases.
To facilitate these research activities, our
Department has been putting effort to preparereference genome sequences and variation databasesof Japanese population.
Next generation sequencing technologies are also
applied for diagnostic purposes. Not infrequently,
analyses of multiple genes are required to establish thediagnosis of diseases. Applying comprehensive
genome sequencing for the diagnosis of early-onset
ataxia and leukoencephalopathy, we were able toidentify the causative mutations.

Publication
1. Ishiura H, Fukuda Y, Mitsui J, Nakahara Y, Ahsan
B, Takahashi Y, Ichikawa Y, Goto J, Sakai T, Tsuji
S. Posterior column ataxia with retinitis
pigmentosa in a Japanese family with a novel
mutation in FLVCR1. Neurogenet. 12:117-21,
2011.
2. Ishiura H, Sako W, Yoshida M, Kawarai T,
Tanabeb O, Goto J, Takahashi Y, Date H, Mitsui J,
Ahsan B, Ichikawa Y, Iwata A, Yoshino H, Izumi
Y, Fujita K, Maeda K, Goto S, Koizumi H,

496

Morigaki R, Ikemura M, Yamauchi N, Murayama
S, Nicholson GA, Ito H, Sobue G, Nakagawa N,
Kaji R and Tsuji S. The TRK-Fused Gene Is
Mutated in Hereditary Motor and Sensory
Neuropathy with Proximal Dominant Involvement.
Am. J. Hum. Genet. 91: 320-329.
3. Mitsui J, Matsukawa T, Ishiura H, Higasa K,
Yoshimura J, Saito TL, Ahsan B, Takahashi Y,
Goto J, Iwata A, Niimi Y, Riku Y, Goto Y, Mano K,
Yoshida M, Morishita M, and Tsuji S. CSF1R
mutations identified in three families with
autosomal
dominantly
inheritedleukoencephalopathy. Amer. J. Med. Genet. Neuropsych.
Genet. (in press)

497

Cooperative Unit of Medicine andEngineering Research
Organization
The University of Tokyo Hospital
Cardiovascular Medicine, Nutrition and Metabolism, Surgical Oncology, Vascular Surgery,
Artificial Organ and Transplantation, Cardiac Surgery, Thoracic Surgery, Neurosurgery,
Urology, Orthopaedic Surgery, Oral and maxillofacial Surgery, Radiology, Tissue
Engineering Unit, Department of Clinical Epidemiology & Systems, Clinical Vascular
Regeneration, Bone & Cartilage Regenerative Medicine, Cartilage of Bone Regeneration,
Department of Immunotherapeutics (Medinet)

Engineering and Pharmaceutical Research
Chemical System Engineering, Mechanical Engineering, Precision Engineering, Quantum
Engineering and System Science, Nuclear Engineering and Management, Chemistry andBiotechnology, Material Engineering, Information Science and Technology, Frontier
Sciences, Pharmaceutical Sciences Laboratory of Chemistry and Biology, Center for Disease
Biology and Integrative Medicine, Center for Disease Biology and Integrative Medicine
Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine
Clinical Biotechnology, Research Center for Advanced Science and Technology, Institute ofIndustrial Science

Homepage

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

Introduction and Organization
The application of an advanced bioscience to a newtechnical development of clinical medicine has
become an important subject for research in the 21st
century. We’ve established Cooperative Unit ofMedicine and Engineering Research at The Universityof Tokyo Hospital to create a new research andeducation center, which cross-sectionally unites
medicine with engineering research for thedevelopment of a next generation medical technology.
2002 June. The establishment of Cooperative Unitof Medicine and Engineering Research was approvedby a hospital administration committee as a special
practice unit that belongs to The University of Tokyo
Hospital.
2002 September. A steering committee of
Cooperative Unit of Medicine and Engineering

Research was organized by representative members of
relevant clinical departments. The committee made adecision of the following basic principles; recruitment
for the participation to this unit should be, as a generalrule, an open call for a joint project of clinicaldepartment and engineering or pharmaceuticalresearch group in The University of Tokyo, an
equipment/administration expense of a laboratory
should be a responsibility of the user, and a basic
participation period to this unit should be three years
and for the continued participation in the unit, areview and approve of the steering committee is
indispensable.
2002 October. An open call for participants to thisunit started. There were 18 applications and thesteering committee approved all projects after review.
A liaison conference of Cooperative Unit of Medicine
and Engineering Research was organized by arepresentative member of each project. Configuration

498

of each project in a space of 554.4m2 that is consistedof a portion of the first floor and the basement of an
administration building came to a decision by theconference.
2003 May. The construction of Cooperative Unit ofMedicine and Engineering Research was completed.
The cost of the construction was shared by theparticipation groups.
2003 May 22. The first research meeting of
Cooperative Unit of Medicine and Engineering
Research took place and research activities started.
2004 September 3. The second research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2005 September 13. The third research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2006 December 21. The fourth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2007 December 13. The fifth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2009 December 3. The sixth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 February 2. The seventh research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 December 17. The eighth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place

Department of Surgical Oncology
To develop an exact diagnosis and treatment system
for the micro-metastasis of neoplasm by using
nano-crystal particles, and to introduce it to clinicaluse. To visualize peritoneum metastases (peritonitis)
and micro-metastasis of neoplasm which cannot bechecked in naked eye, and apply it to an operation or
the determination of a medical treatment plan. To
search for the new method for treating neoplasm byusing biological changes of the cells after up taking
nano-crystal particles.
LaboratoryofMedicalUltrasoundwithMicrobubbles in Oncology
Department of Mechanical Engineering, Fluids
Engineering Laboratory
Department of Surgical Oncology
To develop easy, precise, non-invasive systems to treat
human disease. To devise a method to induce
microbubbles effectively to treat human tumors indeep situ. To make a precise assessment on tumor
invasion in μm order by injecting microbubbles into
tumor arteries. To develop a non-invasive treatment
system using HIFU devise and microbubble contrast
agents.
Medico-engineering Laboratory for Microsurgical
Robotics and Virtual Simulation Laboratory (MRVLabo)
Laboratories of A Morita, Neurosurgery
Dept. Engineering Synthesis, M Mitsuishi
To develop Microsurgical robotic system and 3D
visual system for telesurgery

Research activities
Development of Advanced Sterotactic Rediation
Cancer Therapy System
Department of Radiation Oncology
Nuclear Professional school, Department of Nuclear
Engineering and Management
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Theraoy
System. Development of Advanced Compact Electron
Linear Accelerator for Cancer Inspection and Therapy
Laboratory of Nano-crystals in Oncology
Department of Chemical System Engineering

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499

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,etc.). Other analyses and development are also quite
active, such as creation of transgenic animals,
analyses of genomic functions, clinical safety
monitoring by clinical database and assessments ofclinical information systems.
Surgical Robot System Lab.
Robotics, Dynamics, and Control Laboratory
Department of Mechano-Informatics
University of Tokyo
Development of motion synchronization technology
for in-vivo molecular imaging of small animals, basedon robot systems for endoscopic cardiac surgery.
Neuro-musculo-skeletal model and its parameter
identification for diagnosis and rehabilitation ofneuromuscular disorders.
Vascular Biomebical Engineering Laboratory
Department of Vascular Surgery
Department of Tissue Engineering, The University ofTokyo Hospital
Bio-Medical Precision Engineering Laboratory,
Department of Precision Engineering , The Universityof Tokyo
Development of minimally invasive diagnostic andtherapeutic technologies for vascular surgery throughcollaboration research.
Orthopedic clinical biomechanics laboratory
The Department of Orthopaedic Surgery, The
University of Tokyo.
Graduate School of Information Science andTechnology, The University of Tokyo.
To develop a non-invasive method for predicting bonestrength by finite element method analysis.
To develop a new method for evaluation of fracture
healing by echo tracking.
To develop a non-invasive method for morphologicalevaluation of articular cartilage.

To develop a device for assisting in fracture reduction
and fixation.
Minimally invasive cardiac surgery with the
integral videography system
Department of Cardiothoracic Surgery, Graduate
School of Medicine, University of Tokyo
Advanced Therapeutic and Rehabilitation Engineering
Laboratory, Department of Mechano-Informatics,
Graduate School of Information Science andTechnology, University of Tokyo
To develop: real-time three-dimensional echocardiography, suture device with liner probe, integral
videography, and minimal invasive cardiac surgery
monitored by real-time three-dimensional echocardiography without cardiopulmonary bypass
Division of Neutron Capture Therapy &Immunotherapy for Cancer
Department of Cardiothoratic Surgery, Graduate /School of Medicine
Department of Radiology, University of Tokyo
Hospital
Department of Nuclear Engineering and Management,
School of Engineering
Endowment
Department,
Department
ofImmunotherapeutics (Medinet)
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (BNCT) using
small neutron accerelator equipped to hospital andalso develp more effective immumotherapeutic
approaches.
Molecular Imaging Laboratory, Cooperative Unitof Medicine, Engineering and Pharmaceutical
ReserchTetsuo Nagano, Laboratory of Chemistry and Biology,
Graduate School of Pharmaceutical Sciences
Yasunobu Hirata, Department of Cardiovascular
Medicine
To develop chemical probes for imaging of
biomolecules. To visualize arteriosclerotic andischemic lesions by using fluorescent probes and MRI
contrast media.
Development of a novel device for bioartificial
pancreas and development of adhesion barrier

500materials using a new animal model ofliver-peritoneal adhesion
Artificial Organ and Transplantation Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Hepato-Biliary-Pancreatic
Surgery
Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Organs and Biosystems Engineering Laboratory,
Institute of Industrial Science, The University of Tokyo
Laboratory of Regenerative Medical Engineering,
Center for Disease Biology and Integrative Medicine,
Graduate School of Medicine, The University of Tokyo
Department of Chemical System Engineering,
Graduate School of Engineering, The University ofTokyo
Department of Bioengineering, Graduate School ofEngineering, The University of Tokyo
Islet transplantation has potential to become the mostphysiologically advantageous and minimally invasive
procedure for the treatment of type 1 diabetes mellitus.
The most serious problem is that long term insulin
independence of five years has been substantialy stillquite low. Our concern is to improve poor long term
insulin independence, of which the one cause isconsidered to be transplant site.
Adhesions between liver and other organs are an
important issue in the cases of second surgeries suchas hepatic resection. Adhesions extend operative
duration; in addition, they increase the risk ofsurgeries. Thus, it is important to avoid adhesions at afirst surgery. However, no one report both the animalmodel and adhesion barrier materials of liver adhesion.
We try to develop a new adhesion model by hepatic
resection, instead of a usual peritoneal abrasion model.
Also, we develop new materials for preventing theadhesions.

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 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

Laboratory of Hard-Tissue Nanomedicine
Kataoka & Yamasaki Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Department of ″Menicon″ Cartilage & BoneRegeneration, Graduate School of Medicine, The
University of Tokyo
Department of Bone & Cartilage Regenerative
Medicine, Graduate School of Medicine, The

Laboratory of Biomaterial Science
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Laboratory of Regenerative Medical Engineerin,
Center for Disease Biology and Integrative Medicine,
Faculty of Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery,
Faculty of Medicine, The University of Tokyo
Inhibition of aseptic loosening of artificial joints bynano-grafting of a novel biocompatible polymer MPC.
Creation of biocompatible biomaterials optimized forbone,
cartilage
andvascularregeneration.
Regeneration of bone and cartilage tissue in vitro
promoted by physical stimulation
Molecular and cellular mechanics laboratory forthe development of multi-scale heart simulator
Department of Cardiothoracic Surgery, The Universityof Tokyo Hospital
Biomechanics Laboratory, Graduate School of
Frontier Sciences, The University of Tokyo
We are developing multi-scale, multi-physics heart
simulator for the in-silico diagnosis and treatment ofheart diseases by the synergistic effort of cellularphysiology and computational mechanics. For
collecting quantitative data for the simulator,
mechanical analysis of cardiomyocytes is performed.

501

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

the 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.

Cooperative Unit of Kataoka Laboratory andDepartment of Vascular Regeneration
Department of Vascular Regeneration, Division of
Tissue Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we aredeveloping non-viral gene vectors based on nanoscaled polymer assemblies (polymeric micelles).
Polymeric micelles, which are spontaneously formed
from block copolymers, have a core containing
packaged genes surrounded by biocompatiblepoly(ethylene glycol) (PEG) palisades, and a varietyof pilot molecules can be installed on the surface ofpolymericmicelles.
This"virusmimicking"
nanoparticles might achieve efficient gene transfer to4.

References
1.

2.

3.

5.

6.

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 149:51-57,
2011
Murakami M, Cabral H, Matsumoto Y, Wu S,
Kano MR, Yamori T, Nishiyama N, Kataoka K.
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Oba M, Miyata K, Osada K, Christie RJ, Sanjoh
M, Li W, Fukushima S, Ishii T, Kano MR,
Nishiyama N, Koyama H, Kataoka K. Polyplex
micellespreparedfromω-cholesteryl
PEG-polycation block copolymers for systemic
gene delivery. Biomaterials 32 :652-663, 2011
Pittella F, Zhang M, Lee Y, Kim HJ, Tockary T,
Osada K, Ishii T, Miyata K, Nishiyama N,
Kataoka K. Enhanced endosomal escape ofsiRNA-incorporating hybrid nanoparticles from
calcium phosphate and PEG-block chargeconversional polymer for efficient geneknockdownwithnegligible
cytotoxicity.
Biomaterials 32:3106-3114, 2011
Nomoto T, Matsumoto Y, Miyata K, Oba M,
Fukushima S, Nishiyama N, Yamasoba T,
Kataoka K. In situ quantitative monitoring ofpolyplexes and polyplex micelles in the blood
circulation using intravital real-time confocal
laser scanning microscopy. J Control Release
151:104-109, 2011
Christie RJ, Miyata K, Matsumoto Y, Nomoto T,
Menasco D, Lai TC, Pennisi M, Osada K,
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Kataoka K. Effect of polymer structure on
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Uchida H, Miyata K, Oba M, Ishii T, Suma T,
Itaka K, Nishiyama N, Kataoka K. Odd-even
effect of repeating aminoethylene units in theside chain of N-substituted polyaspartamides ongene transfection profiles. J Am Chem Soc 133:
15524-15532, 2011
Herlambang S, Kumagai M, Horie S, Fukushima
S, Oba M, Nomoto T, Miyazaki K, Morimoto Y,
Nishiyama N, Kataoka K. Disulfide crosslinked
polyioncomplexmicellesencapsulating
dendrimer phthalocyanine directed to improved
efficiency of photodynamic therapy. J Control
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Murakami M, Kimura M, Terada Y, Kano MR,
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Yan Z, Schiaffino S, Asahara H, Ushida T, Akimoto
T. Translational suppression of atrophic regulators
by microRNA-23a integrates resistance to skeletal
muscle atrophy. J Biol Chem. 286:38456-3865,
2011
Yamashita T, Inoue H, Okumura K, Kodama I,
Aizawa Y, Atarashi H, Ohe T, Ohtsu H, Kato T,
Kamakura S, Kumagai K, Kurachi Y, Koretsune Y,
Saikawa T, Sakurai M., Sato T, Sugi K, Nakaya H,
Hirai M, Hirayama A, Fukatani M, Mitamura H,
Yamazaki T, Watanabe E, Ogawa S, on behalf of
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Yamazaki T, Ohtsu H, Hori M. The Effect oflosartan and amlodipine on left ventricular diastolic
function and atherosclerosis in Japanese patientswith mild-to-moderate hypertension J-ELAN study.
Hypertens Res 34:325-330, 2011
15. Yamazaki T, Kishimoto J, Ito C, Noda M., Odawara
M, Terauchi Y, Shiba T, Kitazato H, Iwamoto Y,
Akanuma Y, Kadowaki T for the J-PREDICT study
investigators. Japan prevention trial of diabetes by
pitavastatin in patients with impaired glucose
tolerance (the J-PREDICT study): rationale, study
design, and clinical characteristics of 1269 patients.
Diabetol Int 2:134-140, 2011
16. Kohro T, Yamazaki T, Izumi T, Daida H,
Kurabayashi M, Miyauchi K., Tojo T, Nagai R on
behalf of the JCAD II Investigators. Intensively
lowering both low-density lipoprotein cholesteroland blood pressure does not reduce cardiovascularrisk in Japanese coronary artery disease patients.
Circ J 75:2062-2070, 201117. Suzuki T, Yamazaki T, Ogawa S, Nagai R,
Yamashita T and the J-RHYTHM II Investigators.
Echocardiographic predictors of frequency ofparoxysmal atrial fibrillation (AF) and its
progression to persistent AF in hypertensive
patients with paroxysmal AF: Results from theJapanese rhythm management trial II (J-RHYTHM
II) for atrial fibrillation study. Heart Rhythm
published on line 03 August, 2011
18. Ogawa N, Imai Y, Takahashi Y, Nawata K, Hara K,
Nishimura H, Kato M, Takeda N, Kohro T, Morita
H, Taketani T, Morota T, Yamazaki T, Goto J, Tsuji
S, Takemoto S, Nagai R, Hirata Y. Evaluating
Japanese Patients With the Marfan Syndrome Using
High-Throughput Microarray-Based Mutational
Analysis of Fibrillin-1 Gene. Am J Cardiol
108:1801-1807, 2011
19. Awazawa M, Ueki K, Inabe K, Yamauchi T,
Kubota N, Kaneko K, Kobayashi M, Iwane A,
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Kadowaki T. Adiponectin Enhances Insulin
Sensitivity by Increasing Hepatic IRS-2 Expression via a Macrophage-Derived IL-6-Dependent
Pathway. Cell Metab 13:401-412, 2011
Kobayashi N, Ueki K, Okazaki Y, Iwane A,
Kubota N, Ohsugi M, Awazawa M, Kobayashi M,
Sasako T, Kaneko K, Suzuki M, Nishikawa Y,
Hara K, Yoshimura K, Koshima I, Goyama S,
Murakami K, Sasaki J, Nagai R, Kurokawa M,
Sasaki T, Kadowaki T. Blockade of class IB
phosphoinositide-3 kinase ameliorates obesityinduced inflammation and insulin resistance.
Proc Natl Acad Sci U S A 108:5753-5758, 2011
Kubota T, Kubota N, Kumagai H, Yamaguchi S,
Kozono H, Takahashi T, Inoue M, Itoh S,
Takamoto I, Sasako T, Kumagai K, Kawai T,
Hashimoto S, Kobayashi T, Sato M, Tokuyama K,
Nishimura S, Tsunoda M, Ide T, Murakami K,
Yamazaki T, Ezaki O, Kawamura K, Masuda H,
Moroi M, Sugi K, Oike Y, Shimokawa H,
Yanagihara N, Tsutsui M, Terauchi Y, Tobe K,
Nagai R, Kamata K, Inoue K, Kodama T, Ueki K,
Kadowaki T. Impaired insulin signaling inendothelial cells reduces insulin-induced glucose
uptake by skeletal muscle. Cell Metab 13:
294-307, 2011
Ueki K, Kadowaki T. The other sweet face of
XBP-1. Nat Med 17:246-248, 2011
Waki H, Nakamura M, Yamauchi T, Wakabayashi
K, Yu J, Hirose-Yotsuya L, Take K, Sun W,
Iwabu M, Okada-Iwabu M, Fujita T, Aoyama T,
Tsutsumi S, Ueki K, Kodama T, Sakai J,
Aburatani H, Kadowaki T. Global Mapping of
Cell Type-Specific Open Chromatin by
FAIRE-seq Reveals the Regulatory Role of the
NFI Family in Adipocyte Differentiation. PLoS
Genet 7:e1002311, 2011
Okada J, Washio T, Maehara A, Momomura S,
Sugiura S, Hisada T. Transmural and apicobasal
gradients i 1 n repolarization contribute to T
wave genesis in human surface ECG Am J
Phsyiol 301: H200–H208, 2011
Hatano A, Okada J, Washio T, Hisada T, Sugiura
S. A 3-D simulation model of cardiomyocyte
integrating excitation-contraction coupling andmetabolism
Biophys J 101: 2601-2610, 2011
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Ohashi S, Ohnishi I, Matsumoto T, Matsuyama J,
Bessho M, Tobita K, Kaneko M, Nakamura K.
Comparison of ultrasound speed in articularcartilage measured by different time-of-flightmethods, J Med Ultrasonics 38:225–234, 2011
Bessho M, Ohnishi I, Kaneko M, Ohashi S,
Nakamura K. Diagnostic imaging of bonemetabolism diseases. Prediction of bone strength
using a quantitative computed tomography based
finite element method, Clinical calcium.
21(7):1021-1027, 2011
Tobita K, Ohnishi I, Matsuyama J, Sakai R,
Ohashi S, Ogawa K, Minagawa E, Miyasaka K,
Nakamura K. Measurement of mechanicalproperties with respect to gap healing in a rabbit
osteotomy model using echo tracking, Ultrasound
Med Biol. 38(2):287-295, 2011
Yoshida Y, Inoh S, Murakawa T, Ota S,
Fukayama M, Nakajima J. Preoperative
localization of small peripheral pulmonary
nodules by percutaneous marking undercomputed tomography guidance. Interact
Cardiovasc Thorac Surg. 13(1):25-28, 2011
Murakawa T, Murayama T, Nakajima J, Ono M.
Lung lobectomy in a patient with an implantable
left ventricular assist device. Interact Cardiovasc
Thorac Surg. 13(6):676-678, 2011
Maisel AS, Nakao K, Ponikowski P, Peacock WF,
Yoshimura M, Suzuki T, Tsutamoto T, Filippatos
GS, Saito Y, Seino Y, Minamino N, Hirata Y,
Mukoyama M, Nishikimi T, Nagai R. JapaneseWestern consensus meeting on biomarkers. Int
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Yamane T, Hanaoka K, Muramatsu Y, Tamura K,
Adachi Y, Miyashita Y, Hirata Y, Nagano T.
Method for enhancing cell penetration of
Gd3+-based MRI contrast agents by conjugation
with hydrophobic fluorescent dyes. Bioconjug
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Ogawa N, Imai Y, Takahashi Y, Nawata K, HaraK, Nishimura H, Kato M, Takeda N, Kohro T,
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Evaluating Japanese Patients With the Marfan
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Kiyosue A, Nagata D, Myojo M, Sato T,
Takahashi M, Satonaka H, Nagai R, Hirata Y.
Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves
glucocorticoid response element. Hypertens Res.
34:1283-1287, 2011
Tanaka K, Nagata D, Hirata Y, Tabata Y, Nagaia
R, Sata M. Augmented angiogenesis in adventitia
promotes growth of atherosclerotic plaque inapolipoprotein E-deficient mice. Atherosclerosis.
215:366-373, 2011
Suzuki J, Ogawa M, Muto S, Itai A, Hirata Y,
Isobe M, Nagai R. Effects of specific chemical
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Kawaguchi M, Okabe T, Okudaira S, Hanaoka K,
Fujikawa Y, Terai T, Komatsu T, Kojima H,
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12021-12030, 2011
Sasakura K, Hanaoka K, Shibuya N, Mikami Y,
Kimura Y, Komatsu T, Ueno T, Terai T, Kimura
H, Nagano T. Development of a highly selective
fluorescence probe for hydrogen sulfide. J Am
Chem Soc. 133, 18003-18005, 2011
Egawa T, Hanaoka K, Koide Y, Ujita S,
Takahashi N, Ikegaya Y, Matsuki N, Terai T,
Ueno T, Komatsu T, Nagano T. Development ofa far-red to near-infrared fluorescence probe for
calcium ion and its application to multicolor
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Ikushima I, Morishita Y, Shinohara A, Fijihara M,
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Hiroshima K, Yanagie H, Yasuhara H. Clear celladenocarcinoma with enteroblastic differentiationof the ascending colon.
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Horiguchi H, Nakamura T, Kumada H, Yanagie
H, Suzuki M, Sagawa H. Investigation ofirradiation conditions for recurrent breast cancer
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2011
Umano M, Uechi K, Uriuda T, Murayama S,
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Nagayoshi M, Taguchi T, Koyama H, Takato T,
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505

Medical Specialists Training Center
Associate Professor
Nobuyuki Shimizu, M.D., Ph.D.

Homepage※ The following information is the same as that of the previous year for certain reasons.

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.

Center for Disease Biology andIntegrative Medicine

507

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 the body.
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
and/or the translocation of the MBT-1 gene (locus).

508

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. Miyazaki, T., Kurokawa, J. & Arai, S. AIMingat metabolic syndrome-Towards the developmentof novel therapies for metabolic diseases via
apoptosis inhibitor of macrophage (AIM)-.
Circulation Jounral 75(11): 2522-2531 (2011)
2. Kurokawa, J., Nagano, H., Ohara, O., Kubota, N.,
Kadowaki, T., Arai, S. & Miyazaki, T.
Apoptosis inhibitor of macrophage (AIM) is
required for obesity-associated recruitment ofinflammatory macrophages into adipose tissue.
PNAS 108(29): 1272-12077 (2011)
3. Mori, M., Kitazume, M., Ose, R., Kurokawa, J.,
Osuga, Y., Arai, S. & Miyazaki, T. Death509

effector domain-containing protein (DEDD) isrequired for uterine decidualization during earlypregnancy in mice. J Clin Invest 121: 318-327(2011)
4. Kurokawa, J., Arai, S., Nakashima, K., Nagano, H.,
Nishijima, A., Miyata, K., Ose, R., Mori, M.m
Kubota, N., Kadowaki, T., Oike, Y., Koga, H.,
Febbraio, M., Iwanaga, T., Miyazaki, T.
Macrophage-derived AIM is endocytosed into
adipocytes and decreases lipid droplets via inhibitionof fatty acid synthase activity. Cell Metab 11: 479492 (2010)
5. 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 theirstability.Biochem. Biophy. Res.Commun. 391:
1708-1713 (2010)
6. Bhatia, H., Hallock, J.L., Sterner, L.S., Karkashon,S., Miyazaki, T., Dean, A., & Little, J.A. A shortchain fatty acid mediated reversed globin geneswitch in primary definitive erythroid cells. Blood
113: 6440-8 (2009)
7. Kurabe, N., Arai, S., Nishijima, A., Kubota, N.,
Suizu, F., Mori, M., Kurokawa, J., KondoMiyazaki, M., Ide, T., Murakami, K., Miyake, K.,
Ueki, K., Koga, K., Yatomi, Y., Tashiro, F.,
Noguchi, M., Kadowaki, T., & Miyazaki, T. The
death effector domain-containing DEDD supports
S6K1 activity via preventing Cdk1-dependent
inhibitory phosphorylation. J. Biol. Chem. 284 :
5050-5055 (2009)
8. 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).
9. 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).
10. Arai, S., Miyake, K., Voit, R., Nemoto, S.,
Wakeland, E.K., Grummt, I. & Miyazaki, T. The
death-effector domain containing protein DEDD
is a novel mitotic inhibitor requisite for cell

growth. Proc. Natl. Acad. Sci. USA 104: 22892294 (2007).
11. Koltsova, E.K, Ciofani, M., Benezra, R.,
Miyazaki, T., Clipstone, N., Zuniga-Pflucker, J.C.,
Wiest, D.L. Early Growth Response 1 and NFATc1 Act in Concert to Promote Thymocyte
Development beyond the beta-Selection Checkpoint. J. Immunol. 179: 4694-4703 (2007).
12. 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).
13. 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).
14. 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).
15. 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).
16. 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).
17. 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 cells
in Corynebacterium-induced Granuloma formation in mice. Am. J. Pathol 162: 837-847 (2003).
18. 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).
19. Miyazaki, T., Ohura, T., Kobayashi, M.,
Shigematsu, Y., Yamaguchi, S., Suzuki, Y., Hata,
I., Aoki, Y., Yang, X., Minjares, C., Haruta, I., Uto,

510

H., Ito, Y. & Muller, U. Fatal propionic acidemia
in mice lacking propionyl-CoA carboxylase andits rescue by postnatal, liver-specific supplementation via a transgene. J. Biol. Chem. 276:
35995-35999 (2001).
20. 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).
21. Miyazaki, T., Hirokami, Y., Matsuhashi, N.,
Takatsuka, H. & Naito, M. Increased susceptibility of thymocytes to apoptosis in mice 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).
22. 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).
23. 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).
24. Miyazaki, T., Müller, U. & Campbell, K.S.
Normal development but differentially alteredproliferative responses of lymphocytes in micelacking CD81. EMBO. J. 16: 4217-4225. (1997).
25. 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).
26. Miyazaki, T., Dierich, A., Benoist, C. & Mathis D.
Independentmodesofnaturalkilling
distinguished in mice lacking Lag3. Science 272:405-408 (1996).
27. Miyazaki, T., Matsuda, Y., Toyonaga, T., Miyazaki,J., Yazaki, Y. & Yamamura, K. Prevention of
autoimmune insulitis in non-obese diabetic miceby expression of major histocompatibility
complex class I Ld molecules. Proc. Natl. Acad.

Sci. USA. 89: 9519-9523 (1992).
28. Miyazaki, T., Uno, M., Uehira, M., Kikutani, H.,
Kishimoto, T., Kimoto, M., Nishimoto, H.,
Miyazaki, J. & Yamamura, K. Direct evidence forthe contribution of the unique I-ANOD to thedevelopment of insulitis in non-obese diabetic
mice. Nature 345: 722-724 (1990).

511

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Lecturer
Noriko Takahashi, M.D., Ph.D.

Research Associate
Satoshi Watanabe, Ph.D., Akiko Hayashi, M.D.,Ph.D., Jun Noguchi, Ph.D.

Homepage

http://www.bm2.m.u-tokyo.ac.jp/

Introduction and Organization
The Center for Disease Biology and Integrative
Medicine (CDBIM) has been established in 2003, andelected Dr. Kasai as the professor of the Division of
Basic Medical Sciences (2) of CDBIM in July of 2004.
Dr. Kasai was in the National Institute forPhysiological Sciences, and officially took office inthe University of Tokyo in November, 2005. The
Kasai laboratory has moved to the first building ofFaculty of Medicine in January, 2006. It belongs to theSection of Functional Biology in the Graduate Schoolof Medicine. Its name has been changed from
Division of Biophysics to Laboratory of Structural
Physiology in the April, 2008.

Teaching activities
We have 6 doctor and 1 master course students in
2011. We were also involved in undergraduate
education of Physiology. In particular, we were
responsible for the lectures and student experiments of
endocrine physiology.

Research activities
Functional imaging is a central theme in modern
biology and medicine. All biological functions involvea multitude of interactions at the molecular, cellular,
and system levels, and it is ultimately desirable toperform molecular and cellular imaging in intact
preparations in which the original in vivo functions
are preserved. We have been exploring two-photon
excitation microscopy with a new type of laser, an
infrared femtosecond-pulse laser, as a means toachieve this goal. The two-photon microscope has theability to penetrate deep into tissues and is the only
imaging instrument that allows investigations of intact
tissues at the cellular and molecular levels. Twophoton microscopy can also be readily combined withmolecular biological and other physiological methods,
and it promises to provide important insight into
various biological processes in the coming years. Our
research interests have two main focuses: (1) the
dynamics of synapses in the cerebral cortex and (2)exocytosis in both neurons and secretory cells. We
welcome multidisciplinary collaborations to promote
our research goals and to help to adapt the new
microscopic techniques and lasers to a wide range of
biomedical applications. We will explain three
representative works of this year in some detail.
1) Spatial distributions of GABA receptors and local
inhibition of Ca2+ transients studied with GABA
uncaging in the dendrites of CA1 pyramidal neurons.
GABA(γ-amino-butylic acid)-mediated inhibition

512

in the dendrites of CA1 pyramidal neurons wascharacterized by twophoton uncaging of a
caged-GABA compound, BCMACM-GABA, andone-photon uncaging of RuBi-GABA in rat
hippocampal slice preparations. Although we foundthat GABAA-mediated currents were diffusely
distributed along the dendrites, currents elicited at thebranch points of the apical dendritic trunk wereapproximately two times larger than those elsewherein the dendrite. We examined the inhibitory action of
the GABA-induced currents on Ca2+ transients
evoked with a single back-propagating action
potential (bAP) in oblique dendrites. We found that
GABA uncaging selectively inhibited the Ca2+transients in the region adjacent (20 µm) to theuncaging site, and that GABA uncaging was effective
only within a short period after bAP (20 ms). The
strength of inhibition was linearly related to theamplitudes of the GABA currents, suggesting that thecurrents inhibited a sustained, subthreshold afterdepolarization without preventing
propagation of bAP. GABA uncaging at the dendritic
branch points inhibited Ca2+ transients farther into
dendritic branches (20 µm). Our data indicate that
GABA inhibition results in spatially confined
inhibition of Ca2+ transients shortly after bAP, andsuggest that this effect is particularly potent at thedendritic branch points where GABA receptors cluster(ref. 4).
2) In vivo two-photon uncaging of glutamate revealing
the structure–function relationships of dendritic spines
in the neocortex of adult mice.
Neurons communicate with each other withsynapses using chemical messengers. The major
synapses in the cerebral cortex utilize glutamate as amessenger and are made on special submicron
structures, called dendritic spines. Dendritic spines arediverse in their size and densely packed in the cortex.
Therefore, an optical technique for application of
glutamate to single spines (two-photon (TP) uncaging)has been intensively used to clarify their functions invitro. We have here extended 2P uncaging to living
adult brain, and found that spine sizes display tightcorrelations with their functions, such as rapid
glutamate sensing and an increase in cytosolic Ca2+
concentrations, even in vivo, as they were reported forin vitro preparations. Our data suggest that thestructure and motility of dendritic spines play a keyrole in the adult brain function. (Ref. 2).
Two-photon (2P) uncaging of caged neurotransmitters can efficiently stimulate individual
synapses and is widely used to characterize synaptic
functions in brain slice preparations. Here we
extended 2P uncaging to neocortical pyramidal
neurons in adult mice in vivo where caged glutamate
was applied fromthe pial surface. To validate themethodology, we applied a small fluorescent probe
using the same method, and confirmed that its
concentrations were approximately homogenous up to
200 µm below the cortical surface, and that theextracellular space of the neocortex was as large as
22%. In fact, in vivo whole-cell recording revealed
that 2P glutamate uncaging could elicit transientcurrents (2pEPSCs) very similar to excitatory
postsynaptic currents (EPSCs). A spatial resolution of
glutamate uncaging was 0.6–0.8 µm up to the depth of
200 µm, and in vivo 2P uncaging was able to stimulate
single identified spines. Automated three-dimensional(3D) mapping of such 2pEPSCs which covered thesurfaces of dendritic branches revealed thatfunctionalAMPAreceptor expression was stable
andproportional to spine volume.Moreover, in vivo 2P
Ca2+ imaging and uncaging suggested that theamplitudes of glutamate-induced Ca2+ transients wereinversely proportional to spine volume. Thus, the key
structure–function relationships hold in dendritic
spines in adult neocortex in vivo, as in young
hippocampal slice preparations. In vivo 2P uncaging
will be a powerful tool to investigate properties ofsynapses in the neocortex.

References
1. Cai, T., Hirai, H., Zhang, G., Zhang, M., Takahashi,N., Kasai, H., Satin, L.S., Leapman, R.D. &Notkins, A.L. (2011) Decreased in the number ofdense core vesicles is responsible for the impaired
secretion if insulin in IA-2 and IA-2ß null mice.
Diabetologia, 54, 2347-57.
2. Noguchi, J., Nagaoka, A., Watanabe, S.,
Ellis-Davies, G.C.R., Kitamura, K., Kano, M.,
Matsuzaki, M. & Kasai H. (2011). In vivo
two-photon uncaging of glutamate revealing the513

structure-function relationships o f dendritic
spines in the neocortex of adult mice. J.Physiol.
589, 2320-2329.
3. Kanemoto, Y., Matsuzaki, M., Morita, S., Hayama,T., Noguchi, J., Senda, N., Momotake, A., Arai, T.,
and Kasai, H. (2011). Spatial distributions of
GABA receptors and local inhibition of Ca2+transients studied with GABA uncaging in thedendrites of CA1 pyramidal neurons. PLoS ONE,6, e22652.
4. Matsuzaki, M. & Kasai, H. (2011). Two-Photon
Uncaging Microscopy. Imaging in Neuroscience:
A Laboratory Manual (eds.Helmchen andKonnerth). CSHL Press, Cold Spring Harbor,
NY,USA.
5. Ako, R., Wakimoto, M., Ebisu, H., Tanno, K., Hira,
R., Kasai, H., Matsuzaki, M. and Kawasaki, H.
(2011). Simultaneous visualization of multiple
neuronal properties with single-cell resolution in
the living rodent brain. Mol. Cell. Neurosci., 48,
246-257.
6. Kimura, Y., Momotake, A., Takahashi, N., Kasai,
H. & Arai, T. (2012)
Polarity-dependent photophysical properties ofhemicyanine dyes and their application in
2-photonmicroscopy
biologicalimaging.
Chemistry Letters 41, 528-530.

514

Laboratory of Regenerative
Medical Engineering
Professor
Takashi Ushida, Ph.D.

Associate Professor
Taichi Ito, Ph.D.

Lecturer
Takayuki Akimoto, Ph.D.

Homepage

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

Introduction and Organization
The Division is composed of two laboratories, Ushidalaboratory and Sakai Laboratory. The Division tightly
collaborates with Faculty of Engineering. Prof. Ushidais also charged at Department of MechanicalEngineering, where the laboratory members include
Assistant Professor, two Associates and 15 graduate
students (as of April 1, 2004). Prof. Sakai also holds a
position in Institute of Industrial Science (IIS),
University of Tokyo.
The current laboratory
members at IIS (as of April 1, 2004) include one
research associate, one JSPS postdoctoral fellow, one
technical assistant, and six graduate students from
Department of Chemical System Engineering,
Graduate School of Engineering. In addition, four
graduate students who belong to other universities do
research in our laboratory.

Teaching activities
Prof. Ushida and Prof. Ito are sharing duties forundergraduate and graduate students of both Graduate
School of Medicine and Graduate School ofEngineering. They give lectures on biomedical
engineering at Graduate School of Medicine. Prof.
Ushida has also lectures on tissue engineering,
advanced biomaterials and biomechanics at Graduate

School of Engineering. Prof. Ito gives a lecture
concerning biosystem engineering at the Chemical
System Engineering course and Bioengineering course
at Graduate School of Engineering School.

Research activities
Prof. Ushida’s laboratory aims to establish key
technologies for regenerative medicine. One of the
projects of our research targets the hard tissue
regeneration, such as cartilage or bone by tissue
engineering technology. Hard tissue engineering
requires the control of its shape in addition to the cell
accumulation and scaffold play a key role in meeting
this requirement. We focus on the development of
biocompatible materials such as synthetic polymer orinorganic materials combined with stem cellbiotechnology. Secondly, we try to elucidate
mechanisms of cellular responses to physicalstimulations such as hydrostatic pressure, shear stress,
stretch, through observing intracellular signaling, andto adopt those effects to tissue engineering.
1) Tissue engineering of cartilage or bone defect- Design and development of biocompatible materials
for cartilage or bone using synthetic polymer,
inorganic materials or those combination.
- Development of osteoinductive biomaterials
hybridized with bioactive substances.

515- 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.

3.
2) Cellular signal transduction induced by physicalstimulations- Hydrostatic pressure loading to chondrocytes orarticular cartilage- Shear stress loading to endothelial cells- Stretch loading to endothelial cells, smooth muscle
cells
Biomaterials are one of important keys in medicine
and medical engineering. In the field of tissue
engineering, scaffold materials are extremely
important. In the drug delivery field, drugs areencapsulated in various materials which achieve ideal
release kinetics. The functions of these biomaterials
and phenomena inside and outside biomaterials invivo are complicated both in terms of chemistry andbiology. Ito Laboratory is trying to design and develop
novel biomaterials for tissue engineering and drugdelivery by the combination of medicine and chemicalsystem engineering. Especially we focus on hydrogels
which can be utilized for islet regeneration and drugdelivery in peritoneum.
1) Biomaterilas- Development of novel in situ crosslinked hydrogels
for a medical use using hyaluronan, chitosan,
dextran and synthetic dendritic polymers
2) Drug delivery- Peritoneal adhesion prevention by hydrogels- Peritoneal dissemination treatment by hydrogels
3) Tissue engineering- Hydrogel scaffolds for islet regeneration- Development of oxygen carriers by membraneemulsification

References
1.

Seo CH, Furukawa K, Montagne K, Jeong H,
Ushida T. , The effect of substrate microtopography on focal adhesion maturation andactin organization via the RhoA/ROCK pathway.
Biomaterials; 32(36):9568-75 (2011)

4.

5.

Tachi K, Furukawa KS, Koshima I, Ushida T. ,New microvascular anastomotic ring-coupling
device using negative pressure., J Plast Reconstr
Aesthet Surg. Sep;64(9):1187-93 (2011)
Wada S, Kato Y, Okutsu M, Miyaki S, Suzuki K,
Yan Z, Schiaffino S, Asahara H, Ushida T,
Akimoto T. , Translational suppression ofatrophic regulators by microRNA-23a integrates
resistance to skeletal muscle atrophy., J Biol
Chem. Nov 4;286(44):38456-65 (2011)
Hidenori Kuroki, Taichi Ito, Hidenori Ohashi,
Takanori Tamaki, and Takeo Yamaguchi,
Biomolecule-Recognition Gating Membrane Using
Biomolecular Cross-Linking and Polymer Phase
Transition, Analytical Chemistry 83(24): 9226-9229(2011)
Hyangmi Jung, Keitaro Fujii, Takanori Tamaki,
Hidenori Ohashi, Taichi Ito, and Takeo Yamaguchi,
Low Fuel Crossover Anion Exchange Pore-Filling
Membrane for Solid-State Alkaline Fuel Cell:
Journal of Membrane Science 373:(1-2)107-111(2011)

516

Laboratory of Clinical
Biotechnology
Professor
Kazunori Kataoka, Ph.D.

Associate Professor
Nobuhiro Nishiyama, Ph.D.

Research Associate Professor
Keiji Itaka, M.D., Ph.D.

Assistant Professor
Kanjiro Miyata, Ph.D.

Homepage:

http://www.cdbim.m.u-tokyo.ac.jp/research/01_04.html
http://www.bmw.t.u-tokyo.ac.jp/

Introduction and Organization
Division of Clinical Biotechnology in The Center for
Disease Biology and Integrative Medicine (CDBIM)
was established in April 2003. This Division wishes tocontribute to the realization of nanomedicine. We
actively collaborate and have an interchange of
graduate students with Graduate Schools ofEngineering & Medicine at The University of Tokyoand Division of Tissue Engineering at The Universityof Tokyo Hospital. Our division also plays a majorrole in the Global COE (GCOE) program, whichstarted in 2008, as a novel medicine-engineeringinterdisciplinary program, and tries to contribute to
the production of medical ventures by promoting
liaison with the industrial sector and to the productionof professionals who understand both advanced
medicine and nanotechnology. The division consistsof one professor, one research associate professor, one
research associate professor, one assistant professor
and several project staff members.
Our division focuses on the realization of
nanomedicine. Nanotechnology, which has recently
been attracting tremendous attention as a leading

scientific field in the 21st century, attempts to process
and assemble materials with precision at the atomic/
molecular level to produce units with sophisticatedfunctions. Nanodevices produced by nanotechnology
integrate materials and systems on a nanometer scale,and hold the key to realizing the futuristic medical
system that can serve the needed function at the righttime and the right place with minimal invasiveness.
Furthermore, nanodevices are expected to become an
important interface between basic biomedical scienceand clinical medicine by facilitating the translation ofbasic achievements into clinical applications. Our
division wishes to produce revolutionary medical
nanodevices based on nanotechnology and thereby tospread the idea of "Nanomedicine" intranationally andinternationally.

Teaching activities
Traditional medicine-engineering interdisciplinary
programs have focused on the exchange of researchers
and the promotion of collaborative researches between
these two different academic areas. However, the next
generation medicine such as "minimum-invasive

517

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 thetumor-selective delivery of several antitumor drugs
including adriamycin (ADR), cisplatin (CDDP) andoxaliplatin 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.

3.

K. Miyata, N. Nishiyama, K. Kataoka, Rational
design of smart supramolecular assemblies for genedelivery: Chemical challenges in the creation of
artificial viruses. Chem. Soc. Rev. 41 (7)2562-2574 (2012)
K. Itaka, K. Kataoka, Progress and prospects ofpolyplex nanomicelles for plasmid DNA delivery.
Curr Gene Ther 11 (6) 457-465 (2011)
H. Cabral, N. Nishiyama, K. Kataoka, Supramolecular nanodevices: From design validation
to theranostic nanomedicine. Acc. Chem. Res. 44(10) 999-1008 (2011)

518

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

K. Miyata, R. J. Christie, K. Kataoka, Polymeric
micelles for nano-scale drug delivery. React.
Funct. Polym. 71 (3) 227-234 (2011)
K. Osada, T. Shiotani, T. A. Tockary, D. Kobayashi,
H. Oshima, S. Ikeda, K. Itaka, K. Kataoka,
Enhanced gene expression promoted by thequantized folding of pdna within polyplex micelles.
Biomaterials 33 (1) 325-332 (2012)
H. Hosoya, K. Kadowaki, M. Matsusaki, H. Cabral,
H. Nishihara, H. Ijichi, K. Koike, K. Kataoka, K.
Miyazono, M. Akashi, M. R. Kano, Engineering
fibrotic tissue in pancreatic cancer: a novel threedimensional model to investigate nanoparticle
delivery. Biochem. Bioph. Res. Co. 419 (1) 32-37(2012)
J. -H. Kim, E. Lee, J. -S. Park, K. Kataoka, W. -D.
Jang, Dual stimuli-responsive dendritic-linear block
copolymers. Chem. Commun. 48 (30) 3662-3664(2012)
K. Sakai-Kato, K. Ishikura, Y. Oshima, M. Tada, T.
Suzuki, A. Ishii-Watabe, T. Yamaguchi, N.
Nishiyama, K. Kataoka, T. Kawanishi, H. Okuda,
Evaluation of intracellular trafficking and clearance
from HeLa cells of doxorubicin-bound block
copolymers. Int. J. Pharm. 423 (2) 401-409 (2012)
A. Matsumoto, T. Ishii, J. Nishida, H. Matsumoto,
K. Kataoka, Y. Miyahara, A synthetic approach
toward a self-regulated insulin delivery system.
Angew. Chem. Int. Ed. 51 (9) 2124-2128 (2012)
M. Baba, Y. Matsumoto, A. Kashio, H. Cabral, N.
Nishiyama,K.
Kataoka,T.
Yamasoba,
Micellization of cisplatin (NC-6004) reduces its
ototoxicity in guinea pigs. J. Control. Release 157(1) 112-117 (2012)
T. Suma, K. Miyata, T. Ishii, S. Uchida, H. Uchida,
K. Itaka, N. Nishiyama, K. Kataoka, Enhanced
stability and gene silencing ability of siRNA-loadedpolyion complexes formulated from polyaspartamide derivatives with a repetitive array of
amino groups in the side chain. Biomaterials 33 (9)2770-2779 (2012)
H. Kagaya, M. Oba, Y. Miura, H. Koyama, T. Ishii,
T. Shimada, T. Takato, K. Kataoka, T. Miyata,
Impact of polyplex micelles installed with cyclic
RGD peptide as ligand on gene delivery to vascularlesions. Gene Ther. 19 (1) 61-69 (2012)
H. -J. Kim, M. Oba, F. Pittella, T. Nomoto, H.

Cabral, Y. Matsumoto, K. Miyata, N. Nishiyama, K.
Kataoka, PEG-detachable cationic polyaspartamide
detivatives bearing stearoyl moieties for systemicsiRNA delivery toward subcutaneous BxPC3
pancreatic tumor. J. Drug Target. 20 (1) 33-42(2012)
14. A. Iriyama, M. Oba, T. Ishii, N. Nishiyama, K.
Kataoka, Y. Tamaki, Y. Yanagi, Gene transfer
using micellar nanovectors inhibits choroidal neovascularization in vivo. PLoS One. 6 (12) e28560(2011)

15. A. Iriyama, T. Usui, Y. Yanagi, S. Amano, M. Oba,
K. Miyata, N. Nishiyama, K. Kataoka, Genetransfer using micellar nanovectors inhibits
corneal neovascularization in vivo. Cornea 30(12) 1423-1427 (2011)16. H. Cabral, Y. Matsumoto, K. Mizuno, Q. Chen,
M. Murakami, M. Kimura, Y. Terada, M. R.
Kano, K. Miyazono, M. Uesaka, N. Nishiyama,
K. Kataoka, Accumulation of sub-100nm
polymeric micelles in poorly permeable tumours
depends on size. Nat. Nanotech. 6 (12) 815-823(2011)
17. F. M. Mickler, Y. Vachutinsky, M. Oba, K.
Miyata, N. Nishiyama, K. Kataoka, C. Brachle, N.
Ruthardt, Effect of integrin targeting and PEG
shielding on polyplex micelle internalization
studied by live-cell imaging. J. Control. Release156 (3) 364-373 (2011)18. H. -L. Lu, W. -J. Syu, N. Nishiyama, K. Kataoka,
P. -S. Lai, Dendrimer phthalocyanineencapsulated polymeric micelle-mediated photochemical internalization extends the efficacy ofphotodynamic therapy and overcome the drugresistance in vivo. J. Control. Release 155 (3)458-464 (2011)19. S. Herlambang, M. Kumagai, S. Horie, S.
Fukushima, M. Oba, T. Nomoto, K. Miyazaki, Y.
Morimoto, N. Nishiyama, K. Kataoka, Disulfide
crosslinked polyion complex micelles encapsulating dendrimer phthalocyanine directed to
improved efficiency of photodynamic therapy. J.
Control. Release 155 (3) 449-457 (2011)
20. S. Uchida, K. Itaka, Q. Chen, K. Osada, K.
Miyata, T. Ishii, M. Harada-Shiba, K. Kataoka,
Combination of chondroitin sulfate and polyplex
micelles from Poly(ethylene glycol)-poly{N’-[N-

519

21.

22.

23.

24.

25.

26.

27.

(2-aminoethyl)-2-aminoethyl]aspartamide} block
copolymer for prolonged in vivo genetransfection with reduced toxicity. J. Control.
Release 155 (2) 296-302 (2011)
H. Uchida, K. Miyata, M. Oba, T. Ishii, T. Suma,
K. Itaka, N. Nishiyama, K. Kataoka, Odd-even
effect of repeating aminoethylene units in theside chain of N-substituted polyaspartamides ongene transfection profiles. J. Am. Chem. Soc. 133(39) 15524-15532 (2011)
R. J. Christie, K. Miyata, Y. Matsumoto, T.
Nomoto, D. Menasco, T. -C. Lai, M. Pennisi, K.
Osada, S. Fukushima, N. Nishiyama, Y.
Yamasaki, K. Kataoka, Effect of polymer
structure on micelles formed between siRNA andcationic block copolymer Comprising thiols andamidines. Biomacromolecules 12 (9) 3174-3185(2011)
T. -C. Lai, K. Kataoka, G. S. Kwon, Pluronicbased cationic block copolymer for forming
pDNA polyplexes with enhanced cellular uptake
and improved transfection efficiency. Biomaterials 32 (20) 4594-4603 (2011)
T. Nomoto, Y. Matsumoto, K. Miyata, M. Oba, S.
Fukushima, N. Nishiyama, T. Yamasoba, K.
Kataoka, In situ quantitative monitoring ofpolyplexes and polyplex micelles in the blood
circulation using intravital real-time confocal
laser scanning microscopy. J. Control. Release151 (2) 104-109 (2011)
Y. Anraku, A. Kishimura, A. Kobayashi, M. Oba,
K. Kataoka, Size-controlled long-circulating
PICsome as ruler to measure critical cut-off
disposition size into normal and tumor tissues.
Chem. Commun. 47 (21) 6054-6056 (2011)
F. Pittella, M. Zhang, Y. Lee, H. -J. Kim, T.
Tockary, K. Osada, T. Ishii, K. Miyata, N.
Nishiyama, K. Kataoka, Enhanced endosomal
escape of siRNA-incorporating hybrid nanoparticles from calcium phosphate and PEG-block
charge-conversional polymer for efficient geneknockdownwithnegligible
cytotoxicity.
Biomaterials 32 (11) 3106-3114 (2011)
R. Plummer, R. H. Wilson, H. Calvert, A. V.
Boddy, M. Griffin, J. Sludden, M. J. Tilby, M.
Eatock, D. G. Pearson, C. J. Ottley, Y.
Matsumura, K. Kataoka, T. Nishiya, A Phase I

clinical study of cisplatin-incorporated polymeric
micelles (NC-6004) in patients with solid
tumours. Br. J. Cancer 104 (4) 593-598 (2011)
28. M. Oba, K. Miyata, K. Osada, R. J. Christie, M.
Sanjoh, W. Li, S. Fukushima, T. Ishii, M. R.
Kano, N. Nishiyama, H. Koyama, K. Kataoka,
Polyplex micelles prepared from ω-cholesteryl
PEG-polycation block copolymers for systemic
gene delivery. Biomaterials 32 (2) 652-663(2011)
29. M. Murakami, H. Cabral, Y. Matsumoto, S. Wu,
M. R. Kano, T. Yamori, N. Nishiyama, K.
Kataoka, Improving drug potency and efficacy bynanocarrier-mediated subcellular targeting. Sci.
Transl. Med. 3 (64) 64ra2 (2011)
30. 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
149 (1) 51-57 (2011)

520

Laboratory of Environmental
Health Sciences
Professor
Chiharu Tohyama, Ph.D., Dr.Med.Sci.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Assistant Professor
Masaki Kakeyama, Ph.D.

Project Research Associate
Wataru Yoshioka, Ph.D.

Homepage

http://env-health.m.u-tokyo.ac.jp

Introduction and Organization
Laboratory of Environmental Health Sciences is alaboratory established as a part of the Center for
Disease Biology and Integrative medicine in 2005.
Since then the size of the laboratory was markedly
expanded, and the number of members in 2011 was 25,
including postdoctoral fellows, graduate andundergraduate students.

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. This laboratory has been tackling such problemsby the standpoint of environmental toxicology. For
this end, our experimental investigations have been

performed in (1) identifying and characterizing themolecular target, i.e., ‘molecular target toxicology’,
and in (2) elucidating epigenetic mechanisms that alter
the susceptibility to chemicals, i.e., ‘epigenetic
mechanism, and in (3) clarifying effects of chemicals
on the learning/memory, emotion and sociality of therodents, i.e, behavioral and cognitive toxicology.
Our research efforts are further directed to develop
methodologies for evaluating behavioral toxicities invivo and to establish in vitro toxicity techniques atcellular and molecular levels. In addition to thesebasic approaches to the environmental toxicology, we
aim to provide data for obtaining the safety standard
in environmental factors and food, and to contribute to
the development of research in life and clinicalsciences.
Among a variety of potentially toxic substances inthe environment, we focus especially on dioxin and its
related-compounds and heavy metals which react withspecific receptors and proteins.
As to a major study on the ‘molecular target
toxicology’, we have been studying how lactational
exposure to dioxin induces hydronephrosis. It has
been established that aryl hydrocarbon receptor (AhR)
is required to elicit the majority of dioxin toxicity.

521

However, it has not been clear how dioxin induces avariety of toxicity including carcinogenicity,
immunotoxicity, reproductive toxicity, and disorder ofhigher brain function. We previously elucidated that
cyclooxygenase-2 (COX-2) play a critical role in theonset of hydronephrosis in the mouse neonates. This
year, we have clarified that a kind of prostaglandin
synthase is a critical factor for the onset of dioxininduced hydronephrosis.
As to the study on ‘epigenetic toxicology’, we havebeen studying why mice born to dams that wereadministered dioxin during gestation are prone todevelop benzo[a]pyren-induced stomach cancer. We
found that the mice that were exposed to dioxin inutero had the enhanced demethylated status in CpG aswell as histone modifications in a specific region of
the promoter of cytochrome P450 1A1, theobservation of which is thought to loosen thechromatin stricter. In another study, we found that low
zinc status during gestation affect the gene regulationof metallothionein in adulthood. Using mouse andhuman ES cell lines, we have been also studying
possible programing abnormality by environmental
factors. ,As to the study on ‘behavioral and cognitive
toxicology’, we have been extensively studying how
chemical exposure at a low-dose level during
gestation affects higher brain functions in later in
adulthood. The mice that were born to dams exposed
to dioxin during gestation were found to develop
behavioral inflexibility, compulsive repetitive
behavior, and low social dominance. In this study, we
found that neuronal activity makers, Arc and c-FOS,
support the observations in the behavioral experiments.
Furthermore, we have established a method todetermine mRNA abundance from specifically labeledcells, as small as 10 cells.
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.

Laboratory’s Research Themes1.

Elucidation of mechanisms involved in the
manifestation of toxicity at the molecular and

2.
3.

4.

cellular 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 and to give toxicology andenvironmental health courses for graduate andundergraduate students. The following lectures havebeen provided to students.
1. Undergraduate educationa. School of Medicine
Hygiene(Required):In
chargeof‘Environmental Toxicology’
b. School of Health Sciences
Pharmacology and Toxicology (Required): In
charge of Toxicology
Food Safety Assessment (Opition):Laboratory Methods in Health Sciences(Required): In charge of Toxicology
2. Graduate education
Lectures, Seminar, and laboratory practice, as wellas guidance for the dissertation for thee Master’s andDoctor’s degrees have been provided.
Master Course in the Graduate School of Medical
Sciences: Toxicology (Lecture)
Master and Doctor Courses in the Graduate Schoolof International Health: International Environmental
Medicine (Lecture and Laboratory Practice)
Master Course in the School of Public Health:Environmental Health Medicine (Lecture)522

Doctor Course in the Graduate School of Medicine:
Environmental Health Sciences (Laboratory Practiceand Seminars)
From 2008 this laboratory has become a member ofa Global COE project, ‘Medical system innovation’,and provided a lecture series of ‘Nano-toxicology’ not
only to graduate students but also to the public.

Publications
1. Tse D, Takeuchi T, Kakeyama M, Kajii Y, Okuno H,
Tohyama C, Bito H, Morris RG. Schema-Dependent
Gene Activation and Memory Encoding in
Neocortex. Science.333:891-895, 2011.2011.
2. Ohsako S. Perinatal exposure to environmental
chemicals induces epigenomic changes in offspring.
Genes Environ. 33:43-49, 2011.
3. Yoshioka W, Higashiyama W, Tohyama C.
Involvement of microRNAs in dioxin-induced liver
damage in the mouse. Toxicol Sci. 122:457-465,
2011.
4. Yoshioka W, Peterson RE, Tohyama C. Moleculartargets that link dioxin exposure to toxicity
phenotypes. J Steroid Biochem Mol Biol. 127:
96-101, 2011.
5. 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 a dioxincontaminated area in Tokyo. Environ Health Prev
Med. 16:6-15, 2011.
6. Endo T, Maekawa F, Voikar V, Haijima A, Uemura
Y, Zhang Y, Miyazaki W, Suyama S, Shimazaki K,
Wolfer DP, Yada T, Tohyama C, Lipp HP,
Kakeyama M. Automated test of behavioral
flexibility in mice using a behavioral sequencing
task in IntelliCage. Behav Brain Res. 221:172-181,
2011.

523

Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Kazuki Nakao, Ph.D.

Assistant Professor
Hidetoshi Kassai, Ph.D., Takeshi Harada, Ph.D.,

Homepage

Harumi Nakao, Ph.D.

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 5
teaching staffs, 4 technical support staffs, an assistantmanager of CDBIM, an administrative staff, ateaching assistant, 7 assistant laboratory animal
technicians, and 4 assistant clerks. In addition, about
10 contracted employees are involved in animal
breeding and maintenance of the animal facility.
The laboratory animals in our facility include
macaque monkeys, dogs, swine, rabbits, rats, and mice.
The number of registered users of our facility was 677
at the end of academic year 2011.
We provide quality care for all animals in our facility
and assist animal experimentation carried out by the
researchers. The office of our section is in charge ofthe secretariat of the Institutional Animal Care and the
Use Committee (IACUC) of the Graduate School of

Medicine, the University of Tokyo. The committee(Chair, Prof. Atsu Aiba) reviews the plans of animal
experimentation and helps 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 theFaculty of Medicine. The lecture includes animal
welfare, refinement of animal experiments, animal
breeding, infectious diseases of laboratory animals
and zoonoses. We also give a lecture on mouse
molecular genetics and molecular embryology.
We are also involved in lectures by IACUC for the
researchers at the Graduate School of Medicine.

Research activities
Our laboratory focuses on understanding themolecular mechanisms which underlie the synaptic
plasticity, activity dependent formation of neuronal
circuitry, and learning and memory. We also study cell
metabolism. We generate knockout mice andtransgenic mice of signal transduction molecules
including the glutamate receptors and mammaliantarget of rapamycin (mTOR). We applied proteomics
analysis to these mice. We also try to generate murine

524

models for human genetic diseases.
1. Generation of hyperactive mTOR transgenic micemTOR (mammalian target of rapamycin) is aevolutionarily conserved protein kinase that regulates
protein synthesis and autophagy in response toenvironmental or intracellular nutrient status. Aberrant
activation of mTOR pathway implicates in many
human diseases including cancers and tuberous
sclerosis. Therefore, we have established the animalmodel of chronically activated mTOR signaling. We
have generated transgenic mice in which hyperactivemTOR is expressed in the forebrain at embryonic or
postnatal stage. Embryonic activation of mTOR
induced the abnormal apoptosis of neuronalprogenitor cells, whereas transgenic mice withpostnatal activation of mTOR displayed the severe
epilepsy with enlarged cortical neurons, faithfully
tracing tuberous sclerosis phenotypes. We are
currently investigating the molecular mechanisms
underlying these phenotypes of mTOR transgenic
mice. Also, we are generating the mutant mice withprostate-specific activation of mTOR kinase inpreparation of analysis of mTOR functions in
carcinogenesis and metastasis.
2. Role of mGluR1 in melanoma formation
We previously demonstrated that ectopic expression of
metabotropic glutamate receptor subtype-1 (mGluR1)
induces melanoma formation in mice. To elucidate
molecular mechanisms underlying mGluR1-induced
melanoma formation, we are currently generating
several transgenic mouse lines carrying mGluR1
mutant genes.
3. Study of obese mice
We generated mutant mice in which a histone
H2B-Kik GR fusion gene is introduced into the
ROSA26 locus by homologous recombination using
ES cells. R26-H2B-Kik-GR/+ heterozygous micedevelop obesity. Body weights of R26-H2B-KikGR/+ mice remarkably increased in comparison with
control mice at the age of 6 weeks. Leptin and insulinlevels in serum of R26-H2B-Kik-GR/+ mice weresignificantly higher than those of control mice, while
glucose level in R26-H2B-Kik-GR/+ mice was not
significantly changed. To determine whether foodconsumption was increased in R26-H2B-Kik-GR/+
mice, food intake of heterozygous and wild-type mice
was observed for over twenty weeks. Food intake wasincreased in R26-H2B-Kik-GR/+ mice compared withwild-type mice. Now, R26-H2B-Kik-GR transgenic
mice were generated by DNA injection into
pronuclear.

References
1. Yamasaki M, Miyazaki T, Azechi H, Abe M,
Natsume R, Hagiwara T, et al. Glutamate
Receptorδ2 Is Essential for Input PathwayDependent Regulation of Synaptic AMPAR
Contents in Cerebellar Purkinje Cells. J Neurosci.
2011 Mar; 31(9): 3362-74.
2. Yamamoto K, Ueta Y, Wang L, Yamamoto R,
Inoue N, Inokuchi K, et al. Suppression of aneocortical potassium channel activity byintracellular amyloid-β and its rescue with
Homer1a. J Neurosci. 2011 Aug; 31(31): 11100-9.
3. Aizawa R, Yamada A, Suzuki D, Iimura T, Kassai
H, Harada T, et al. Cdc42 is required forchondrogenesis and interdigital programmed cell
death during limb development. Mech Dev. 2012
Mar-Jun; 129(1-4): 38-50.

525

Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, M.D., Ph.D.

Lecturer
Takahiko Suzuki, Ph.D., Noriko Hosoya, M.D., Ph.D.

Associate
Atsushi Enomoto, 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.

Teaching 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
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 emergency medicine is included in thiscourse. Even though radiation casualty is rare, allclinicians should know how to treat patients exposed
to radiation. The importance of this education has
been widely recognized since the accident at
Fukushima nuclear power plant.
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, the education
molecular biology of DNA damage response toradiation and DNA repair is more intensively
integrated.
In addition, education courses for users ofradioactive materials frequently take place.

Research activities
Before the present professor took the position, a vide
range of radiation biology, including biological effectsof low-dose irradiation, nonhomologous end joining(NHEJ) for DNA double-strand breaks, apoptosis that
responds to DNA damage, and radio-sensitization had
been topics in this department. Since 2005,
homologous recombinational repair has been the main526

subject.
RecA in E. coli and its homolog Rad51 in budding
yeast play a central role in homologous
recombinational repair. Historically, mechanism ofhomologous recombination was extensively studied inthese organisms, whereas homologous recombination
had been recognized as a minor pathway of DNA
double-strand break repair in higher organisms.
However,
subsequentstudiesrevealedthathomologous recombination as well as NHEJ plays animportant role in DNA double-strand break repair inhigher organisms. There are two major differences
between these two pathways. NHEJ functions at any
stages of the cell cycle, whereas homologous
recombination is restricted to the S to M phases.
Another difference is that NHEJ is an error-prone
repair pathway and homologous recombination is anerror-free repair pathway.
We have tried to understand the significance ofhomologous recombination repair in genomic
instability underlying cancer pathology. Since theincidence of mutations in genes involved inhomologous recombination is low in cancer, we haverecently focused on its epigenetic aberrations.
Particularly, we are investigating the roles of cancer
testis antigens, which are expressed in meiosis and incancer, in somatic cells.
We have identified biological functions of SYCP3,
a member of the synaptonemal complex, which isformed between homologous chromosomes to ensure
their connection in meiosis. Expression of SYCP3 wasobserved in adrenal tumor, liver tumor, gastric tumor,
and kidney tumor, confirming that SYCP3 is a cancer
testis antigen. Treatment of SYCP3-nonexpressing
cells with a methylation inhibitor induced its
expression, indicating that methylation alteration incancer is responsible for its ectopic expression.
Since biological significance of cancer testis
antigens in somatic cells is largely unknown, weinvestigated the effects of SYCP3 expression on
cellular functions in somatic cells. This study revealed
that SCYP3-expressing cells are hypersensitive toradiation or cisplatin, and are characterized byincreased aneuploidy. As these phenotypes are
consistent with those of defective homologous
recombination, we screened the molecule thatco-localizes with SYCP3 by immunofluorescence.

Consequently, we identified that the tumor suppressor
BRCA2, whose mutations are found in hereditarybreast and ovarian cancers, co-localizes with SYCP3.
We also confirmed that these proteins form a complex.
Furthermore, we found that binding of SYCP3 to
BRCA2 inhibits the homologous recombination repair
activity mediated by binding of BRCA2 to Rad51.
Since cells with BRCA2 mutations are
hypersensitive to PARP inhibitors, their clinical trials
are internationally ongoing. However, the problem isthat the application of the trial is limited due to low
incidence of their mutations. Our findings implicatethat SYCP3-expressing cancers, even if they do nothave BRCA mutations, are sensitive to PARP
inhibitors, providing novel insight into cancer therapy(Hosoya et al. EMBO Rep, 2012).
Thus, our study on homologous recombination
contributes to the establishment of principals of cancer
therapy. Radiation and many DNA-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 willdevelop the fundamental research in this field.

527

Office ofInternational Academic Affairs
HeadYasuyuki Seto

Assistant Professor
Joseph Green
Toshiyuki Maruyama
Christopher Holmes

Homepage：http://koryu.m.u-tokyo.ac.jp/homepage10.html
Status and functions
The Office of International Academic Affairs isunder the direct authority of the Dean of the Facultyof Medicine. Its three most important roles, as definedby the Committee on International Academic Affairs,
are i) international educational exchange, ii)
international contacts in research and scientific fields,
and iii) international cooperation in health care andmedicine.

Activities
This document reports on the office's activities inthese areas over the academic year 2011 (April
through March).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2011, there were 138 foreign students (35countries) 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 66 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 70 people attended in 2011, 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 2011 Contest
foreign students gave oral presentations based on theirresearch papers to interested fellow students andfaculty, and the five best speakers were given awards.
A formal agreement for academic exchange
between the University of Pennsylvania and the
University of Tokyo was renewed in May 2004. Since
that time, eleven University of Tokyo students havetaken research electives at the University of528

Pennsylvania, 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, eighteen 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, nine 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,
seven University of Tokyo students visited to attend
research electives at Munich University, and three
students from Munich University have taken clinicalelectives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the University of Washington
Medical School in November 2005. Since the start ofthe program in 2005, six University of Tokyo students
have attended clinical electives at the University ofWashington Medical School, and one student from the
University of Washington Medical School has taken
clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Taipei Medical University inNovember 2005. Since the start of the program in
2005, three 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 38 requests from students forcounseling regarding pre-graduation or postgraduation studies abroad are received by the Officeof International Academic Affairs. The office responds
to these requests by providing information, advice,and letters of recommendation.
2. New project (International Training Program)This project (total budget: 100,000,000 yen/5 years)
provides opportunities for young researchers from the
Graduate School of Medicine at the University ofTokyo to receive instruction and training at partner
institutions in the USA, with the goal of helping themexcel not only as scientists, but also as educators forthe next generation and as administrators of theirresearch groups.
The details of the plans for the young researchers at
the partner institution in USA are as follows.
(1) They should carry out highly advanced medical
research.
(2) They should observe and experience participatory,
student-centered forms of education (tutorials,etc.) used with medical students.
(3) They should observe and experience themanagement of research laboratories, particularly
with regard to the importance of the activities ofgraduate students and postdoctoral fellows.
(4) They should observe how teaching assistants
contribute in education and research, and how
teaching assistants are trained to become leadersand mentors.
In 2011, seven young researchers from the Graduate
School of Medicine at the University of Tokyo havebeen studying at the partner institutions in the USA.

529

3. Education and research
3.1 Education
In 2011, 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 2011, 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. Park MJ, Yamazaki Y, Yonekura Y, Yukawa K,
Ishikawa H, Kiuchi T, Green J.
Predicting complete loss to follow-up after ahealth-education program:
number of absences and face-to-face contact witha researcher. BMC Med Res Methodol. 2011 Oct
27;11(1):145.
2. Suzukamo Y, Fukuhara S, Green J, Kosinski M,
Gandek B, Ware JE.
Validation testing of a three-component model of
Short Form-36 scores. J Clin Epidemiol. 2011
Mar;64(3):301-8.

530

Museum of Health and Medicine
Director
Kazuhiko Ohe

Specially-appointed technical expert
Atsushi Kitade

Homepage

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

History and overview
The origins of the School of Medicine and the
University of Tokyo Hospital can be traced back to theestablishment of the Kanda Otamaga-Ike Vaccination
Center in 1858. In 2008, it celebrated its 150th
anniversary. The Museum of Health and Medicine wasplanned as part of commemorative projects tocelebrate the 150th anniversary of the founding of the
School and the Hospital, and was opened on January
20, 2011.
One of the themes for the commemorative projects
marking the 150th anniversary was the “developmentof communication between health science and careand society,” and the Museum of Health and Medicine
forms one of the pillars of this.
In establishing the Museum of Health andMedicine, we renovated the School of Medicine’s
Central Building (Medical Library), which hadoriginally been instituted as part of thecommemorative projects celebrating the 100th
anniversary of the founding of the School and the
Hospital. The Museum has about 400m2 areas,
including about 70m2 of a permanent gallery and230m2 of special exhibition rooms.
The aims of the Museum are to: (1) provide healthand medical information to the public, (2) educate
medical students and students, (3) research the historyof medicine and health care through archives,
instruments and technology, and (4) preserve andinvestigate valuable medical archives and instruments,
etc.
In addition to the permanent gallery exhibiting

accomplishments related to the School and the
Hospital and its contributions made to modern andcontemporary development in Japan, a feature of theexhibitions is that a large space has also been set aside
for special exhibitions to promote understanding
among the public regarding the latest advances inmedicine and health care. Planning and supervision of
the permanent exhibition and special exhibition isdone with the cooperation of the various research
units within the School and the Hospital, otherdepartments within the University, industry, andmuseums. Special exhibitions will be changed several
times a year.
The first permanent exhibition since the openingof the Museum was a display of medical texts andinstruments from the early Meiji era, an Ishihara’s
Color Blind Test Chart and a gastroscope developed at
the University. The first special exhibition was related
to the beginnings of the School and the Hospital,
Entitled “the Challenge to Infectious Diseases”. It
introduced the history of vaccinations against
smallpox, research into infectious diseases conductedin the University and its graduates since the Meiji era(1868-1912), and the latest information about
infectious diseases. The second from Sep.15 wasentitled “the Secret of Vessel System”, which
introduced the circulatory system.
Since the opening of the Museum, more than
20397 people had visited until the end of FY.2011.
The Museum will continue to plan and organize
according to the aforementioned purposes of theMuseum.

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Overview of operations
The opening hours are 10:00-17:00. The Museum
is closed every Monday and during the New Yearholidays (however, it will open if Monday is a public
holiday). Admission is free.

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The International Research Center
for Medical Education (IRCME)
Director & Professor
Kazuhiko Yamamoto, M.D., Ph.D.

Professor
Kiyoshi Kitamura, M.D., Ph.D.

Lecturer
Hirotaka Onishi, M.D., M.H.P.E.

Lecturer
Daisuke Son, M.D., Ph.D.

Homepage

http://www.ircme.u-tokyo.ac.jp

History and organization

Tokyo Hospital is also our fundamental role.

The University of Tokyo has establishedInternational Research Center for Medical Education(IRCME) in 2000. The Ministry of Education (in2001 reformed to Ministry of Education, Culture,
Science and Sports), the University of Tokyo, and the
Graduate School of Medicine positioned IRCME as abase for promoting international cooperative studiesof medical education. In 2010 IRCME cerebrated the10th anniversary.
IRCME consists of three departments ofInternational Cooperative Study for Medical
Education, Planning & Coordination for International
Cooperative Projects and Information on Medical
Education, and visiting professor from abroad. We
hope that the research in medical education carried out
by IRCME will improve medical education and healthcare in many countries.
The mission of IRCME includes research ininternational cooperation in medical education,
research in medical education, and development of
human resource in medical education. Promotion ofand contribution to education in the Faculty of
Medicine, University of Tokyo and University of

Activities of Each Department
1. International Cooperative Study in Medical
Education
The University of Tokyo, especially the Faculty of
Medicine, takes pride in its academic excellenceinternationally.
Compared with other Western
distinguished universities, however, activities andresearch in medical education have been weak for along time.
To fulfill the mission, faculty and staff in IRCME
conduct research on a wide range of topics inundergraduate, postgraduate and continuing medical
education. One of our objectives is to establish acenter for medical education research in Asian PacificArea to collaborate with variety of medical education
researchers.
IRCME also makes important contributions toundergraduate and postgraduate medical curricula of
the Faculty of Medicine, the University of Tokyo
directly. As medical education experts, we are giving
appropriate information to all the faculty members

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about teaching and learning in medicine.
2. Planning & Cooperation for International
Cooperative Projects and Information on
Medical Education
This department is responsible for developing
international cooperation in health professions
education area (medicine, dentistry, pharmacy, nursing,public health, rehabilitation, etc) facilitated by the
Ministry of Education, Culture, Sports, Science, andTechnology. This department should lead any international cooperation projects in health professions
education area in Japan and aim at face-to-face andheart-to-heart international cooperation. Activities arelisted below.
a.

IRCME worked for the follow-up scheme of the
JICA Medical Education Project. Counterpart ofthe project has been Ministry of Higher Education
and Kabul Medical University. In 2011 IRCME
accepted two groups, 28 medical educators fromseven medical schools for the training of medical
education in January and November 2011.
b. IRCME was involved in the follow-up of the
Project for Medical Education and Research for
the Setthathirath Hospital, the Lao People’s
Democratic Republic. Onishi visited the hospitalto provide trainings and to write up the draft ofclinical education guideline of Lao PDR.
3. 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 2011, we welcomed a visiting professor:
Dr. Clarence D. Kreiter (19 Jul – 30 Nov 2011),
Professor, Department of Family Medicine &Office of Consultation and Research in Medical
Education, University of Iowa, USA

Printed Products
1. Lambert Schuwirth, Jerry Colliver, Larry Gruppen,
Clarence Kreiter, Stewart Mennin, Hirotaka Onishi,Louis Pangaro, Charlotte Ringsted, David
Swanson, Cees Van Der Vleuten, et al. Research inassessment: consensus statement and recommendations from the Ottawa 2010 Conference.
Medical Teacher 33, 224-233, 2011
2. Nishigori H, Masuda K, Kikukawa M, et al. A
model teaching session for the hypothesis-driven
physical examination. Medical Teacher 33: 410417, 2011