ISSN 1883-9606

2013

Vol.127

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2012 ---- March 2013

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2012-March 2013

Introduction
This is volume 127(the edition of year 2013) 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, 2013

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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 Cell Biology & Anatomy (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

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

56

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

57

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

61

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

62

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

71

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

72

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

74

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

78

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

79

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

82

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

87

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

89

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

90

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

92

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

94

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

95

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

99

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

105

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

110

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

111

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

114

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

117

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

118

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

122

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

125

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

126

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

131

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

135

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

141

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

142

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

147

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

153

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

157

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

160

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

164

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

166

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.438] )Department of Transfusion Medicine ·········································································

167

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

170

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

171

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

173

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

179

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

180

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

181

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

186

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

190

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

191

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

194

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

195

Department of Cardiac Surgery ················································································

198

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

203

Hepato-biliary-Pancreatic Surgery Division and Artificial Organ
and Transplantation Surgery Division ······································································

207

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

209

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

213

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

217

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

220

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

222

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

223

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

227

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

232

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

237

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

242

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

247

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

250

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

252

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

253

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

256

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

260

Department of Health Sociology / Health Study and Education(See Departments of Health and Social Behavior / Health Education and Sociology [P.331])
Department of Mental Health ··················································································

261

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

264

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

268

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

272

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

273

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

276

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

278

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

282

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

283

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

287

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

289

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

292

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

298

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

299

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

304

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

307

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

308

v

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

312

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

315

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

319

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

321

Department of Biostatistics (See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.264] )Department of Social and Preventive Epidemiology ························································

322

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

325

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

327

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

330

Department of Mental Health(See Department of Mental Health [P.261] )Department of Health and Social Behavior / Health Education and Sociology ···························

331

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.268] )3. Health Services Sciences ·························································································

334

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.114] )Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.122] )Department of Clinical Information Engineering ····························································

335

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.118] )Endowed Department ···································································································

337

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

338

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

341

Department of Bone & Cartilage Regenerative Medicine(See Department of Orthopaedic Surgery [P.237] )Department of Cartilage & Bone Regeneration (Fujisoft)(See Department of Oral- Maxillofacial Surgery [P.232] )Department of Clinical Epidemiology and Systems ·························································

344

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

347

Science for Joint Reconstruction ( See Department of Orthopaedic Surgery [P.237] )Department of Molecular Neuroscience on Neurodegeneration(See Department of Neurology [P.99] )Department of Chronic Kidney Disease (CKD) ·····························································

351

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

353

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

355

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

358

vi

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

360

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

363

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

364

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

367

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

369

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

370

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

373

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

376

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

378

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

381

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

385

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

388

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

390

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

392

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

395

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

398

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

400

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

403

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

405

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

407

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

410

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

413

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

416

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

420

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

422

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

424

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

425

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

427

Department of Advanced Nursing Technology ······························································

429

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

432

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

433

University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.126] )

436

vii

Respiratory Medicine (See Department of Respiratory Medicine [P.131] )Gastroenterology (See Department of Gastroenterology [P.135] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.142] )Diabetes and Metabolic Diseases (See Department of Diabetes and Metabolic Diseases [P.147] )Hematology and Oncology (See Department of Hematology and Oncology [P.153] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.157] )Infectious Diseases (See Department of Infectious Diseases [P.160] )Neurology (See Department of Neurology [P.99] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.191] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.164] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.203] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.213] )Hepatobiliary Pancreatic Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Surgery Division [P.207] )Vascular Surgery (See Department of Vascular Surgery [P.217] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.220] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Surgery Division [P.207] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.198] )Thoracic Surgery (See Department of Thoracic Surgery [P.195] )Neurosurgery (See Department of Neurosurgery [P.105] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.253] )Urology and Andrology (See Department of Urology [P.209] )Gynecologic Surgery (See Obstetrics and Gynecology [P.173] )Sensory and Motor System Medicine
Dermatology and Photolaser Medicine (See Department of Dermatology [P.223] )Ophthalmology and Vision Correction (See Department of Ophthalmology [P.242] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.237] )Otorhinolaryngology, and Auditory and Voice Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.247] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.250] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.227] )viii

Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.232] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.181] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.186] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.171, 173, 179] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.95] )Radiology
Radiology (See Department of Radiology [P.62] )Central Clinical Facilities ···························································································

437

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

438

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

442

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

446

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

448

Department of Emergency Services(See Department of Emergency and Critical Care Medicine [P.256] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.167] )Delivery Unit ·····································································································

452

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

453

Central Supply Service ··························································································

455

Department of Intensive Care Unit
(See Department of Emergency and Critical Care Medicine [P.256] )Division of Diagnostic Pathology ··············································································

457

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

459

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

461

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

463

Department of Hemodialysis and Apheresis ·································································

467(See Department of Nephrology and Endocrinology[P.142]
Clinical Research Support Center ··············································································
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.122] )

470

ix

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

475

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

478

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

480

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

484

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

489

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

492

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

496

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

500

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

501

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

503

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

506

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

508

Department of Disaster Medical Management ·······························································

517

International Medical Center ···················································································

519

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

520

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

521

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

525

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

528

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

530

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

534

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

537

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

539

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

541

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

544

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

546

x

The Tokyo Journal of Medical Sciences. Vol. 127, October 2013

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. 127, October 2013

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. 127, October 2013

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.

2002

Mar.

Nursing School and Midwives School was Closed.

2002

Mar.

Experimental Building (First Stage) was constructed.

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.
2005

Mar.

Experimental Building (Second Stage) was constructed.

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. 127, October 2013

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

Microbiology
Pathology, Immunology
and Microbiology

Microbiology
Infection Control and Prevention

Immunology

Molecular Immunology
Clinical Immunology
Infection Pathology

Collaborative Department

Tumor Pathology
Molecular Oncology
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

Graduate School of
Medicine

Developmental Neuroscience
Neuroscience

Integrativ Medical Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience
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. 127, October 2013

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. 127, October 2013
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
Health and Social Behavior
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. 127, October 2013
Office of International Academic Affairs
Medical Library
Institution

Medical Scientist Training Program
Museum of Health and Medicine
Office for Research Ethics Support
Pharmacoepidemiology
Integrated Traditional Medicine (Tsumura)
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
Clinical Motor System Medicine

Endowed Department

Health Care Safety Management(Tokio Marine & Nichido)
Molecular Cardiovascular Metabolism
Healthcare Quality Assessment
Anti-Aging Medicine
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
Advanced Nephrology and Regenerative Medicine
Sensory-recognition and Locomotive-function Sciences in the Super-aged Society

Social Cooperation Program

AXA Chair on Health and Human Security

General Affairs Office

Ubiquitous Health Informatics

Personnel Office

Lipidomics

Research Support Office

Functional Regulation of Adipocytes

Educational Affairs

Advanced Nursing Technology

Graduate Student Affairs
Finance Office

Administrative officeContract Office
External Fund Management Office

xvii

The Tokyo Journal of Medical Sciences. Vol. 127, October 2013

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. 127, October 2013

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

Office of General Administration

Administration Office

Office of Procurement andFacility Management

Clinical Laboratory
Operation Center
Imaging Center
Central Clinical Facilities

Emergency Services
Blood Transfusion
Perinatal Center
Rehabilitation Service
Medial Engineering

Office of Management Planning
Office of Medical Accounting

xix

The Tokyo Journal of Medical Sciences. Vol. 127, October 2013

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
Medical Community Network and Discharge Planning
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
Department of Chemotherapy
Department of Health Record Management
Critical Care Center
Department of Palliative Medicine
Children's Medical Center
Department of Disaster Medical Management
International Medical 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. 127, October 2013xx

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

Noboru Mizushima

professor

Hiroki Kurihara

professor

Yasushi Miyashita

professor

Kensaku Mori

professor

Masanobu Kano

professor

Masamitsu Iino

professor

Masashi Fukayama

professor

Kohei Miyazono

professor

Masanori Hatakeyama

professor

Kyoji Moriya

professor

Hiroshi Takayanagi

Department of Radiology

professor

Kuni Otomo

Department of Biomedical Engineering

professor

Yasuteru Urano

professor

Takeshi Iwatsubo

Professor

Kenzo Hirose

professor

Kiyoto Kasai

Department of Biochemistry and Molecular Biology

Functional Biology
Department of Physiology

Department of Pharmacology
Pathology, Immunology and Microbiology
Department of Pathology

Department of Microbiology

Department of Immunology
Radiology and Biomedical Engineering

Neuroscience
Department of Basic Neuroscience

Department of Integrative Medical Neuroscience
Department of Clinical Neuroscience

The Tokyo Journal of Medical Sciences. Vol. 127, October 2013xxi

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

Issei Komuro

professor

Takahide Nagase

professor

Kazuhiko koike

professor

Masaomi Nangaku

professor

Takashi Kadowaki

professor

Mineo Kurokawa

professor

Kazuhiko Yamamoto

professor

Akira Akabayashi

professor

Yutaka Yatomi

professor

Koki Takahashi

professor

Tomoyuki Fujii

professor

Shiro Kozuma

Department of Pediatric Science

professor

Tadashi Iwanaka

Department of Aging Science

professor

Yasuyoshi Ouchi

professor

Jun Nakajima

professor

Minoru Ono

professor

Yasuyuki Seto

professor

Norihiro Kokudo

professor

Yukio Homma

professor

Toshiaki Watanabe

professor

Shinichi Sato

professor

Isao Koshima

professor

Tsuyoshi Takato

Professor

Sakae Tanaka

professor

Shiro Amano

professor

Tatsuya Yamasoba

professor

Nobuhiko Haga

Professor

Yoshitsugu Yamada

professor

Naoki Yahagi

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

Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

Department of Vital Care Medicine

xxii

The Tokyo Journal of Medical Sciences. Vol. 127, October 2013

Health Sciences and Nursing
Department of Health Sciences

Department of Preventive and Administrative Nursing

professor

Norito Kawakami

professor

Yasuo Ohashi

professor

Hideki Hashimoto

professor

Akira Akabayashi

professor

Noriko Yamamoto

professor

Kiyoko Kamibeppu

professor

Noriko Yamamoto

professor

Norito Kawakami

professor

Hiromi Sanada

professor

Kenji Shibuya

professor

Masamine Jinba

professor

Katsushi Tokunaga

professor

Masashi Mizuguchi

professor

Chiho Watanabe

professor

Kiyoshi Kita

professor

Yasuo Ohashi

professor

Satoshi Sasaki

professor

Hideki Hashimoto

professor

Takahiro Kiuchi

professor

Norito Kawakami

professor

Hideki Hashimoto

professor

Akira Akabayashi

professor

Yasuki Kobayashi

professor

Kazuhiko Ohe

professor

Hiroshi Oyama

professor

Kenichi Yoshida

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. 127, October 2013

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

Medical LibraryProfessor

Kazuhiko Ohe

International Academic Affairs

professor

Yasuyuki Seto

Medical Scientist Training Program

Professor

Masahide Kikkawa

Museum of Health and Medicine

Professor

Kazuhiko Ohe

Office for Research Ethics Support

Professor

Yutaka Yatomi

professor

Kiyoshi Kubota

Associate professor

Soko Setoguchi

Department of Integrated Traditional Medicine(Tsumura)professor

Tetsuro Okabe

Department of Bone & Cartilage Regenerative Medicine

Associate professor

Taku Saito

Department of

Associate professor

Kazuto Hoshi

Division of Research Resources and Support

Faculty of Medicine
Endowed Departments
Department of Pharmacoepidemiology

Cartilage & Bone Regeneration(Fujisoft)

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

Takanari Gotoda

Immunotherapeutics (Medinet)

Associate professor

Kazuhiro Kakimi

Total Renal Care Medicine

Associate professor

Yutaka Enomoto

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

Associate professor

Hiroaki Miyata

Molecular Cardiovascular Metabolism (Daiich-Sankyo Company, Limited)
The Department of Healthcare Quality Assessment

xxiv

The Tokyo Journal of Medical Sciences. Vol. 127, October 2013

Anti-Aging Medicine

professor

Satoshi Inoue

Clinical Epidemiology and Systems

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

Koichiro Kinugawa

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

Continence medicine

Professor

Yasuhiko Igawa

Department of Molecular Psychiatry

Associate Professor

Kazuya Iwamoto

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 Clinical Renal Regeneration

Associate professor

Keiichi Hishikawa

Department of Sensory-recognition and Locomotive-function

Associate professor

Kimihiko Kameyama

Professor

Manami Inoue

Department of Ubiquitous Health Informatics

Associate Professor

Hideo Fujita

Department of Lipidomics

Professor

Takao Shimizu

Associate Professor

Yoshihiro Kita

Functional Regulation of Adipocytes

Associate Professor

Hironori Waki

Advanced Nursing Technology

Associate Professor

Ryoko Murayama

Director

Kazuhiko Yamamoto

professor

Kiyoshi Kitamura

Head

Takahide Nagase

Department of Therapeutic Strategy for Heart Failure

Sciences in the Super-aged Society
AXA Chair on Health and Human Security

Social Cooperation Program

International Research Center for Medical Education

University Hospital
Clinical Divisions
General Medicine

The Tokyo Journal of Medical Sciences. Vol. 127, October 2013

xxv

Cardiovascular Medicine

Head

Issei Komuro

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Kazuhiko Koike

Nephrology and Endocrinology

Head

Masaomi Nangaku

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

HeadToshiaki Watanabe

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

Yutaka Ohsuga

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

Sachiko Kitanaka

Pediatric Surgery

Head

Tadashi Iwanaka

Obstetrics and Gynecology

Head

Shiro Kozuma

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Kuni Ohtomo

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Clinical Laboratory

Head

Yutaka Yatomi

Central Clinical Facilites

xxvi

The Tokyo Journal of Medical Sciences. Vol. 127, October 2013

Surgical Center

Head

Hiroshi YasuharaRadiological Center

Head

Kuni Ohtomo

Emergency Services

Head

Naoki Yahagi

Blood Transfusion

Head

Koki Takahashi

Perinatal Center

Head

Tomoyuki Fujii

Rehabilitation Service

Head

Nobuhiko Haga

Central Supply Service

Head

Masahiko Sumitani

Department of Medical Engineering

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoki Yahagi

Division of Diagnostic Pathology

Head

Masashi Fukayama

Corneal Transplantation

Head

Satoru Yamagami

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Department of Endoscopy and Endoscopic Surgery

Head

Mitsuhiro FujisiroCenter for Hemodialysis and Apheresis

Head

Masaomi Nangaku

Medical Community Network

Head

Yasuyoshi Ouchi

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

Labor Safety and Health Management Office

HeadShin Onishi

Department of Child Psychiatry

Head

Yukiko Kano

Tissue Bank

Head

Noboru Motomura

Epidemiology and Preventive Medicine

Head

Tsutomu Yamazaki

Cancer Resource Center

Head

Sachiyo Nomura

Center for Liaison and Public Relations

Head

Kazuhiko Ohe

Outpatient Chemotherapy Department

Head

Norihiro Kokudo

Department of Health Record Management

Head

Yasuyoshi Ouchi

Critical Care Center

Head

Susumu Nakajima

Department of Palliative Medicine

Head

Keiichi Nakagawa

Children’s Medical Center

Head

Tadashi Iwanaka

Department of Disaster Medical Management

Head

Hiroyuki Nakao

International Medical Center

Head

Isao Koshima

Clinical Research Support Center

Head

Tsutomu Yamazaki

22nd Century Medical and Research Center

Head

Tuyoshi Takato

Division of Tissue Engineering

Head

Tsuyoshi Takato

Cooperative Unit of Medicine and Engineering Research

Head

Tetsuro Miyata

Translational Research Center

Head

Mineo Kurokawa

Department of Clinical Genomics

Head

Shoji Tsuji

Unit for Early and Exploratory Clinical Development

Head

Takeshi Iwatsubo

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
Yosuke Tanaka, M. D.,

Ryo Nitta, M. D.,

Noriko Homma, Ph. D.,

Harukata Miki, Ph. D.,

Homepage

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

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

Research activities
Our research field covers the molecular cell biologyof the cytoskeleton. We focus on the molecularmechanisms of cell morphogenesis and intracellulartransports.
Our laboratory studies molecular architecture,dynamics and function of the neuronal cytoskeleton
using various new molecular cell biologicalapproaches including new electron microscopy suchas the quick freeze deep etch electron microscopy,
cryoelectron microscopy at atomic resolution, andcryoultramicrotomy,
biochemistry,
immunocytochemistry, molecular biology, molecular genetics 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.

2.

3.

4.

5.

6.

7.

8.

Noda Y., S.Niwa, N.Homma, H. Fukuda, S.
ImajoOhmib,
andN.
Hirokawa.
Phosphatidylinositol 4-phosphate 5-kinase alpha(PIPKα)regulates
neuronal
microtubule
depolymerase kinesin, KIF2A and suppresses
elongation of axon branches. Proc Ntl Acad Sci
U.S.A 109:1725-1730, 2012. citation: A-IMBN
Research Highlights - Making the rightconnections.
(http://www.natureasia.com/A-IMBN/article.php?id=597)
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 intubulin in GMPCPP and GDP-taxol microtubules
observed by cryoelectron microscopy. J Cell Biol
198: 315-322, 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 ininhibitory transmission. Neuron 76 (5): 945-961,
2012.
Niwa, S., K. Nakajima, H. Miki, Y. Minato, D.
Wang, N. Hirokawa.
KIF19A Is a
Microtubule-Depolymerizing Kinesin for Ciliary
Length Control. Dev Cell 23: 1167-1175, 2012.
doi.org/10.1016/j.devcel.2012.10.016.
Zhou, R., S. Niwa, L. Guillaud, Y. Tong, and N.

9.

Hirokawa. A Molecular Motor, KIF13A, Controls
Anxiety by Transporting the Serotonin type 1A
Receptor. Cell Reports 3:509-519, 2013.
Niwa S., H. Takahashi, and N. Hirokawa. beta
tubulin mutation that cause severe neuropathies
disrupt axonal transport. EMBO Journal
32:1352-1364, 2013. doi:10.1038/emboj.2013.59.

4Department of Cell Biology &Anatomy (Structural Biology)
Professor
Masahide Kikkawa, M.D.,Ph.D.

Lecturer
Toshiki Yagi, Ph.D.

Associate
Toshiyuki Oda, Ph. D.

Homepage

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

Introduction and Organization

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.
Currently the lab members includes: Masahide
Kikkawa (Professor), Toshiki Yagi (Lecturer), Haruaki
Yanagisawa (Joshu), Toshiyuki Oda (Joshu), Anindito
Sen (Post-doc), Hitoshi Kurio (Post-doc), Yuma Tani,
Shohei Fujita, Itsuki Abe (student), Akiko Osakaya(Technician) and Mikako Yanagiuchi (secretary).

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.
To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope incombination 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
toobtainnano-meter
resolutionofmacromolecular complexes such as axonemes. We
have been developing new techniques, such asasymmetric helical reconstruction and Ruby-Helix
software.
By using these new techniques, we are currently
studying dynein-microtubule complex, dynein
stalk-microtubule complex to elucidate the mechanismof dynein’s motor functions.

5Model 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
1. Oda T. and M. Kikkawa
Novel Structural Labeling Method using Cryoelectron Tomography and Biotin-Streptavidin
SystemJournal of Structural Biology, in press
2. Kikkawa M.
Big steps toward understanding dynein
Journal of Cell Biology, 202:15-23, 2013
3. Oda T., T. Yagi, H. Yanagisawa, and M. Kikkawa
Identification of the Outer-Inner Dynein Linker asa Hub Controller for Axonemal Dynein Activities
Current Biology, 23:656-64, 2013

6

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

Lecturer
Hirohide Iwasaki, Ph.D

Research Associate
Shinji Tanaka, Ph.D.

Homepage

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

Introduction and Organization

Research activities

The Department of Cellular Neurobiolgy was
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 20 members.

Brain functions, which are dependent on mutualcommunication of a tremendous number of neuronalcells, regulate the behavior of animals and humans.
The main structure specifically differentiated for
information exchange between neurons is called"synapse". Long-term maintenance of synaptic
properties underlies stability and reproducibility of
behavior in responses to external stimuli. In turn,
alterations of synaptic properties are thought to be thebasis of behavioral change in the course of animal
development and also after learning. Therefore,
synapses should be stabilized for a long term to realize
fidelity of various animal behaviors, but also shouldbe altered rapidly when animals adapt to a newenvironment. Molecular basis of this dichotomy,
which is unique to synapses, is the main interest of ourlaboratory.
Synapse formation during development
Synapse is one of the major elements to transduce
information from neuron to neuron. Most of thesynapses are formed during the early development andthereafter they become stable after the intensive
pruning. We are interested in how synapse is formed
and maintained.
The postsynaptic densities (PSDs) are protein dense
structures which are located closely to postsynaptic
membranes. PSDs include a variety of receptors,

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

7

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 andsome 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.

2.

3.

4.

Ito-Ishida, A., Miyazaki, T., Miura, E., Matsuda,K., Watanabe, M., Yuzaki, M and S. Okabe
Presynaptically released Cbln1 induces dynamic
axonal structural changes by interacting with
GluD2 during cerebellar synapse formation.
Neuron 76, 549-564, 2012
Okabe, S.
Molecular dynamics of the excitatory synapse
Advances in Experimental Medicine and Biology
970, 131-185, 2012
Kawabata, I., Kashiwagi, Y., Obashi, K., Ohkura,M., Nakai, J., Wynshaw-Boris, A., Yanagawa, Y.,
and S. Okabe.
LIS1-dependent retrograde translocation of
excitatory synapses in developing interneuron
dendrites.
Nature Communications 3, 722, 2012.
Hirai S., Miwa, A., Ohtaka-Maruyama, C., Kasai
M., Okabe, S., Hata, Y, and H. Okado.
RP58
controls
neuronandastrocyte
differentiation by downregulating the expressionof Id1-4 genes in the developing cortex.
EMBO Journal 31, 1190-1202, 2012.

Molecular Cell Biology
2. Biochemistry and Molecular Biology

9Department of Molecular Biology
Professor
Noboru Mizushima, M.D., Ph.D.

Associate Professor
Shigeki Jinno, Ph.D.

Associate
Akiko Kuma, Ph.D., Taki Nishimura, Ph.D.

Homepage

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

Introduction and Organization
Established in 1893 as a part of Department of
Physiology, this Department became independent in
1897. It was renamed Department of Biochemistry in
1927, First Department of Biochemistry in 1974, andDepartment of Molecular Biology in 1997, according
to the creation of new related departments and thereorganization of Faculty of Medicine. This
Department has been headed by seven professors, eachof whom made significant contributions to thedevelopment of biochemistry, nutrition and molecularbiology in Japan.
Professor Muneo Kumagawa, who established this
Biochemistry or Medical Chemistry Department for
the first time in Japan, graduated from The Universityof Tokyo Faculty of Medicine in 1882. In 1884 hewent to Germany to study in Department of Pathology,
The University of Berlin headed by Dr. Rudolf
Virchow under the supervision of Dr. Ernst Salkowski.
After returning to Japan, he became Lecturer and waspromoted to Professor of this Department. In 1908, hediscovered lack of glycogenecity in lipids, which has
been firmly established besides some exceptions, andsucceeded in purification of vitamin B1, which had
been discovered by Dr. C. Eijkman in 1906. His lab
produced many famous researchers including Dr.
Masahiro Sakaguchi, who developed a world-famouscolorimetric method for arginine and Dr. Takaoki
Sasaki, who first succeeded in generating liver cancer

with chemicals.
Professor Samuro Kakiuchi graduated from theImperial University of Tokyo, Faculty of Medicine in1906 and studied under Professor Kumagawa. After
studying in the US, he came back to succeed the late
Kumagawa. He launched the Journal of Biochemistry
and founded the Japanese Society of Biochemistry.
His students included Professors Kodama andShimazono.
Professor Keizo Kodama graduated from the Imperial
University of Tokyo in 1918. After studying at
Cambridge University, he became Professor of
Biochemistry at Kyushu Imperial University. In 1943,
he took up a professorship at this Department. His
research was on oxidation and reduction, andnutrition.
Professor Norio Shimazono, a graduate of the Imperial
University of Tokyo Faculty of Medicine in 1928,
became a professor at Niigata Medical School. In
1952 he succeeded Professor Kodama. He studied
vitamin B1/ cocarboxylase, ketoacid metabolism andhexose metabolism.
Professor Tamio Yamakawa graduated from theImperial University of Tokyo Faculty of Medicine,and began studies at the Institute for Infectious
Diseases, the University of Tokyo. He took up a
professorship to succeed Professor Shimazono. He
was a pioneer in glycolipid research and discovered
the involvement of sialic acid in the ABO blood typeantigens.

10

Professor Masami Muramatsu graduated from the
University of Tokyo Faculty of Medicine in 1955. He
began studies at the Department of Internal Medicine,and then went to Baylor College of Medicine to study
under Dr. H. Busch. After coming back to Japan, hetook a position at the Cancer Institute and the took up
a professorship at Tokushima University School of
Medicine. In 1982, he succeeded Professor Yamakawa.
He studied ribosomal RNA and cloned interferon andp450 genes.
Professor Hiroto Okayama graduated from 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 Dr. P.
Berg. After working at the NIH, USA, he became
Professor of Molecular Genetics, at Osaka University
Institute for Infectious Diseases. In 1993 he succeeded
Professor Muramatsu. At Stanford and the NIH, hestudied gene cloning and developed a full length
cDNA cloning method and a cDNA expression
cloning vector system, and, after returning to Japan, he
studied cell cycle control and cancer.
Professor Noboru Mizushima graduated from Tokyo
Medical and Dental University, Faculty of Medicine in
1991. After receiving Ph.D., he studied at National
Institute for Basic Biology in Okazaki and started
works on autophagy in yeast and mammals at Dr.
Yoshinori Ohsumi’s laboratory. Taking a position as a
PI at the Tokyo Metropolitan Institute of Medical
Science in 2004, he started studies on physiologicalroles of autophagy. He was promoted to Professor of
Physiology and Cell Biology, in Graduate School andFaculty of Medicine at Tokyo Medical and Dental
University in 2006, and succeeded Professor Okayama
in 2012.

Research Activities
Our current study focuses on the understanding of themolecular mechanism and physiological roles of
autophagy.
1. Molecular mechanism of autophagy
The lysosome is a degradative organelle, and its
fusion with other organelles is strictly regulated.
We identified the autophagosomal SNARE
syntaxin 17 (STX17) and found that it is required

for the autophagosome-lysosome fusion. STX17
has a hairpin-type structure mediated by twotransmembrane domains, each containing glycine
zipper motifs. This unique transmembrane
structure contributes to its specific localization tocompleted autophagosomes but not to theisolation membrane (unclosed intermediate
structures). Thus, the late recruitment of the
SNARE to the autophagosome can prevent
premature fusion with the lysosome.
Autophagosome formation is governed bysequential functions of autophagy-related (ATG)
proteins. We have determined their genetic
hierarchy and their temporal recruitment and tried
to understand their functional relationships. In
particular, we found that FIP200, which is
involved in proximal events, directly interacts
with Atg16L1, one of the downstream Atg factors.
We proposed that FIP200 regulates not only early
events but also late events of autophagosome
formation through direct interaction with
Atg16L1.
2. Regulation of autophagy in vivo
We examined the role of insulin and amino acids
using
hyperinsulinemic–euglycemic
clamp
techniques. Insulin administration showed a clear
effect on the mTORC1–autophagy pathway inmuscle, but had only a very weak effect in theliver. By contrast, amino acids were able toregulate the mTORC1–autophagy pathway in theliver, but less effectively in muscle. These results
suggest that autophagy is differentially regulated
by insulin and amino acids in a tissue-dependent
manner.
It has been speculated that autophagy could
be induced during muscle atrophy, we found that
autophagy is rather suppressed in denervatedmuscles by a constitutive activation of mTORC1.
mTORC1 is activated via a proteasome-mediatedincrease in intramuscular amino acids, which
occurs following denervation.
3. Mechanism of selective autophagy
The Parkinson disease-associated ubiquitin ligase
Parkin can trigger autophagy of depolarized
mitochondria. We found that at least two Atg units,

11

Atg9A and the ULK1 complex, are involved in
the initial stages of mitochondrial recognition.
Autophagosomal LC3 is important for efficientincorporation of damaged mitochondria into the
autophagosome at a later stage.
4. Physiological and pathological roles of
autophagy
In collaboration with Dr. Naomichi Matsumoto’s
group (Yokohama City University), we identified
de novo heterozygous mutations in WDR45/
WIPI4 gene, which encodes one of the humanhomolog of yeast Atg18, in patients with Static
encephalopathy of childhood with neurodegeneration in adulthood (SENDA). We found that
autophagy was indeed impaired in lymphoblastoid
cell lines derived from SENDA patients. We also
found that autophagy is essential for quality
control of lens; lens-specific autophagy-deficient
mice develop cataract.

4.

5.

6.

Education
To medical students, we give lectures on biochemistry
and molecular biology. General metabolism, protein
synthesis, protein degradation, and metabolism ofamino acids and nucleic acids are the topics in our
lectures. To graduate course students, the molecularbiology course consisting of lectures and experiments
is provided.

7.

8.

Publication
1.

2.

3.

Itakura, E., Kishi-Itakura, C., Koyama-Honda, I.,
Mizushima, N. Structures containing Atg9A andthe ULK1 complex independently target
depolarized mitochondria at initial stages ofParkin-mediated mitophagy. J. Cell Sci. 125:1488-1499 (2012).
Itakura, E., Kishi-Itakura, C., Mizushima, N. The
hairpin-type tail-anchored SNARE syntaxin 17
targets to autophagosomes for fusion withendosomes/lysosomes. Cell 151: 1256-1269(2012)
Quy, P.N., Kuma, A., Pierre, P., Mizushima, N.
Proteasome-dependent activation of mammaliantarget of rapamycin complex 1 (mTORC1) isessential for autophagy suppression and muscle
remodeling following denervation. J. Biol. Chem.
288: 1125-1134 (2013)
Nishimura, T., Kaizuka, T., Cadwell, K., Sahani,
M.H., Saitoh, T., Akira, S., Virgin, H.W.
Mizushima, N. FIP200 regulates targeting of
Atg16L1 to the isolation membrane. EMBO Rep.
14: 284-291 (2013).
Saitsu, H., Nishimura, T., Muramatsu, K., Kodera,
H., Kumada, S., Sugai, K., Kasai-Yoshida, E.,
Sawaura, N., Nishida, H., Hoshino, A., Ryujin, F.,
Yoshioka, S., Nishiyama, K., Kondo, Y.,
Tsurusaki, Y., Nakashima, M., Miyake, N.,
Arakawa, H., Kato, M., Mizushima, N.,
Matsumoto, N. De novo mutations in the
autophagy gene encoding WDR45 (WIPI4) cause
static encephalopathy of childhood withneurodegeneration in adulthood. Nat. Genet. 45:
445-449 (2013).
Morishita, H., Eguchi, S., Kimura, H., Sasaki, J.,
Sakamaki, Y., Robinson, M.L., Sasaki, T.,
Mizushima, N. Deletion of autophagy-related 5(Atg5) and Pik3c3 in the lens causes cataract
independent of programmed organelle degradation. J. Biol. Chem. 288:11436-11447 (2013).
Naito, T., Kuma, A., Mizushima, N. Differential
contribution of insulin and amino acids to themTORC1-autophagy pathway in the liver andmuscle. J. Biol. Chem. 2013 Jun 6. [Epub aheadof print]
Koyama-Honda, I., Itakura, E., Fujiwara, T.K.,
Mizushima, N. Temporal analysis of recruitmentof mammalian ATG proteins to the autophagosome formation site. Autophagy in press

12

Department of Cellular Signaling
Professor
Associate Professor
Motonao Nakamura, Ph.D.

Research Associate

Homepage
Introduction and Organization

Research

MN has 3 undergraduate students and a foreignscientist (postdoc) from USA. Ms. Toshie Takahashi(Assistant belongs to the Dean of the Faculty), Ms.
Fumie Hamano (Research associate) and Mr. Shinji
Ichihara (Technical staff) are in charge of maintenanceand education of various instruments for common use.
This laboratory had been managed by professor
emeritus Takao Shimizu till March 2012. Afterretirement, he became the director-general of National
Center for Global Health and Medicine (NCGM) andthe head of Lipid Signaling Project. He is also theproject professor of Department of Lipidomics at the
University of Tokyo. In 2012, this laboratory is doing
the collaboration with Department of Lipidomics andDepartment of Lipid Signaling, NCGM.

1. Collaboration with Department of Lipidomics andDepartment of Lipid Signaling, NCGM
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
a novel ligand for BLT2 which has been recognized as
the low affinity second LTB4 receptor. We also
succeeded in molecular cloning of lung-typeacyl-coA:lysophosphatidylcholine acyltransferase 1(LPCAT1) involving in production of pumonary
surfactant and other various lysophospholipid acyltransferases. The physiological and pathophysiologicalsignificance of these enzymes are studying at
Department of Lipid Signaling, NCGM.
These research are supported by Grant-in-Aids
from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan, the Ministry of
Health, Labour, and Welfare of Japan (Health andLabour Sciences Research Grants), Nanobio
Integration Program of the University of Tokyo, and a
global COE program.

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 2012 is over
30. We also have an eight-week laboratory course
for clinical scientists from the University Hospital.

13

2. Lipid mediator and lipid metabolism.
Oxygenated products of arachidonic acid(prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids) as well as bioactive phospholipids(platelet-activating factor and other related
phospholipids) activate cellular signaling pathways invarious cells.
These lipid mediators, working
together with other bioactive substances such asneurotransmitters and cytokines, are now considered
to play significant roles in neuronal plasticity and selfdefense systems.
To identify the roles of lipid mediators in theliving systems, principally three approaches are
ongoing with different strategies; (1) isolation of
enzymes involved in syntheses and degradation oflipid mediators, cloning of cDNAs and genes,
elucidation of enzyme regulation at transcriptional andposttranscriptional 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, weare able to explain the molecular mechanism andbiological 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. All these researches arecarrying out in collaboration with Department of
Lipidomics and Department of Lipid Signaling(NCGM).
3. Simultaneous quantitation of lipid mediators(Department of 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 have recently
developed a quantitation system for multiplex lipid
mediators by column-switching HPLC–tandem mass
spectrometry (LC-MS/MS). When optimized, thesystem enables the rapid analysis of 14 lipid mediatorswith a throughput of 96 samples/24 h, lower limits ofquantitation 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.
4. 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.

Publications
1.

2.

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, Apr 30, 10:80, 2012
Yoshida, T., Kakegawa, J., Yamaguchi, T.,
Hantani, Y., Okajima, N., Sakai, T., Watanabe, Y.,
and Nakamura, M. : Identification andcharacterization of a novel chemotype MEK
inhibitor able to alter the phosphorylation state of

14

3.

4.

5.

MEK1/2. Oncotarget, 3, 1533-1545, 2012
Nakamura, M., Yasuda, D., Hirota, N., Yamamoto,T., Yamaguchi, S., Shimizu, T., and Nagamune,
T. : Amino acid residues of G-protein coupled
receptors critical for endoplasmic reticulum
export and trafficking., Methods in Enzymol., 521,
203-216, 2013
Taygerly, J.P., McGee, L.R., Rubenstein, S.M.,
Houze, J.B., Cushing, T.D., Li, Y., Motani, A.,
Chen, J-L., Frankmoelle, W., Ye, G., Learned,
M.R., Jaen, J., Miao, S., Timmermans, P.B.,
Thoolen, M., Kearney, P., Flygare, J., Beckmann,
H., Weiszmann, J., Lindstrom, M., Walker, N.,
Liu, J., Biermann, D., Wang, Z., Hagiwara, A.,
Iida, T., Aramaki, H., Kitao, Y., Shinkai, H.,
Furukawa, N., Nishiu, J., and Nakamura, M. :Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity. Bioorganic& Medicinal Chemistry., 21, 979-992, 2013
Taketomi, Y., Ueno, N., Kojima, T., Kawana, M.,
Tanaka, S., Sakanaka, M., Nakamura, M., Sato,
H., Nishito, Y., Kambe, N., Yamamoto, K., Gelb,
M.H., Arita, M., Yokomizo, T., Watanabe, K,.
Nakamura, M., Shimizu, T., Hirai, H., Aritake, K.,
Urade, Y., Morimoto, K., Sugimoto, Y., Narumiya,S., Hara, S., and Murakami, M. : PLA2G3, amammalian homolog of anaphylactic phospholipase A2 in bee venom, facilitates proper
maturation of mast cells through the paracrine
PGD2 loop. Nature immunology, 14, 554-566,
2013

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.

Homepage

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

Introduction and Organization

Research Activities

The Department of Physiological Chemistry andNutrition, the predecessor of the present department,
was founded in 1952. Upon the restructuring of theuniversity system in 1997, the department was
renamed ‘Department of Physiological Chemistry andMetabolism’ as one unit of the Specialty of Molecular
Cell Biology. The present members include the above
stuffs, 2 postdoctoral fellows, 5 graduate students, 2technical staffs and 1 secretary.

1. Developmental Biology and Medicine(1) Neural crest and craniofacial development
We have investigated the role of endothelin-1(ET-1) signaling in neural crest and craniofacial
development and identified the ET-1/ETA-receptor
to Dlx5/6 pathway in the dorsoventral axis
patterning of crest-driven branchial arch structures.
To further clarify the underlying mechanism, we
have established mice in which gene cassettes canbe efficiently knocked-in into the Ednra locus using
recombinase-mediated cassette exchange (RMCE)
based on the Cre-lox system. Using this system,
we have demonstrated that the dorsoventral axis
patterning of pharyngeal arches is regulated by the
ETA-receptor-selective, Gq/G11-dependent signaling,
while the formation of the distal pharyngeal regionis under the control of a Gq/G11-independent
signaling.
We also identified Calpain6 as adownstream molecule of the ET-1 pathway and its
biological function in cytoskeletal organization andcell motility. We further identified TAZ as a proteinthat binds to and coactivates Pax3, a key transcription factor in neural crest development and its role

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

16

in 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.

3.

4.

5.

6.
2. Mouse Genetics
Collaborative works as follows are going on byusing gene manipulation approach in mice.
(1) Physiological roles of vasoactive peptides(2) Pathophysiological roles of defensin(3) Developmental roles of non-coding RNA

References
1.

2.

Arima Y, Miyagawa-Tomita S, Maeda K, Asai R,
Seya D, Minoux M, Rijli FM, Nishiyama K, Kim
KS, Uchijima Y, Ogawa H, Kurihara Y, Kurihara
H. Preotic neural crest cells contribute tocoronary artery smooth muscle involving
endothelin signalling. Nat. Commun. 3:1267,
2012.
Minamiyama M, Katsuno M, Adachi H, Doi H,
Kondo N, Iida M, Ishigaki S, Fujioka Y,
Matsumoto S, Miyazaki Y, Tanaka F, Kurihara H,

7.

Sobue G. Naratriptan mitigates CGRP1associated motor neuron degeneration caused by
an expanded polyglutamine repeat tract. Nat.
Med. 18:1531-1538, 2012.
Nakatsu Y, Otani Y, Sakoda H, Zhang J, Guo Y,
Okubo H, Kushiyama A, Fujishiro M, Kikuchi T,
Fukushima T, Ohno H, Tsuchiya Y, Kamata H,
Nagamachi A, Inaba T, Nishimura F, Katagiri H,
Takahashi S, Kurihara H, Uchida T, Asano T.
Role of pin1 protein in the pathogenesis of
nonalcoholic steatohepatitis in a rodent model. J.
Biol. Chem. 287:44526-44535, 2012.
Yamanishi Y, Takahashi M, Izawa K, Isobe M, Ito
S, Tsuchiya A, Maehara A, Kaitani A, Uchida T,
Togami K, Enomoto Y, Nakahara F, Oki T,
Kajikawa M, Kurihara H, Kitamura T, Kitaura J.
A soluble form of LMIR5/CD300b amplifies
lipopolysaccharide-induced lethal inflammationin sepsis. J. Immunol. 189:1773-1779, 2012.
Kushiyama A, Okubo H, Sakoda H, Kikuchi T,
Fujishiro M, Sato H, Kushiyama S, Iwashita M,
Nishimura F, Fukushima T, Nakatsu Y, Kamata H,
Kawazu S, Higashi Y, Kurihara H, Asano T.
Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis
development. Arterioscler. Thromb. Vasc. Biol.
32:291-298, 2012.
Iwashita M, Sakoda H, Kushiyama A, Fujishiro
M, Ohno H, Nakatsu Y, Fukushima T, Kumamoto
S, Tsuchiya Y, Kikuchi T, Kurihara H, Akazawa
H, Komuro I, Kamata H, Nishimura F, Asano T.
Valsartan, independently of AT1 receptor or
PPARgamma, suppresses LPS-induced macrophage activation and improves insulin resistancein cocultured adipocytes. Am. J. Physiol.
Endocrinol. Metab. 302:E286-2E96, 2012.
Kushiyama A, Sakoda H, Oue N, Okubo M,
Nakatsu Y, Ono H, Fukushima T, Kamata H,
Nishimura F, Kikuchi T, Fujishiro M, Nishiyama
K, Aburatani H, Kushiyama S, Iizuka M, Taki N,
Encinas J, Sentani K, Ogonuki N, Ogura A,
Kawazu S, Yasui W, Higashi Y, Kurihara H,
Katagiri H, Asano T. Resistin-like molecule β
is abundantly expressed in foam cells and is
involved in atherosclerosis development.
Arterioscler. Thromb. Vasc. Biol. 33:1986-1993,
2013.

17

8.

9.

Zhang J, Nakatsu Y, Shinjo T, Guo Y, Sakoda H,
Yamamotoya T, Otani Y, Okubo H, Kushiyama A,
Fujishiro M, Fukushima T, Tsuchiya Y, Kamata H,
Iwashita M, Nishimura F, Katagiri H, Takahashi
S, Kurihara H, Uchida T, Asano T. Par14 protein
associates with insulin receptor substrate 1(IRS-1), thereby enhancing insulin-induced
IRS-1 phosphorylation and metabolic actions. J.
Biol. Chem. 288:20692-20701, 2013.
Kim K-S, Arima Y, Kitazawa T, Nishiyama K,
Asai R, Uchijima Y, Sato T, Levi G, Kitanaka S,
Igarashi T, Kurihara Y, Kurihara H. Endothelin
regulates neural crest deployment and fate toform great vessels through Dlx5/Dlx6independent mechanisms. Mech. Dev. (in press)

Functional Biology
1. Physiology

19

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

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

Project Lecturer
Toshiyuki Hirabayashi, Ph.D.,

Masaki Takeda, Ph.D.,

Research Associate
Takahiro Osada, Ph.D.,

Homepage

Yusuke Adachi, Ph.D.,

Yohei Ohashi, M.D., 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.
Sugiura, H.
Yamamoto and Y. Sasai) take part in giving lecturesand laboratory courses to the undergraduate studentsof the Medical School. The lectures are aimed atproviding a clear understanding of the hierarchicalfunctional organizations of living systems. The

curriculum is updated every year. For example, a newelectrocardiogram experiment in humans wasintroduced to the laboratory course, in which students
learned human physiology of electrocardiogram, its
practical procedure in clinical settings and its cellularphysiological origins. This practice gained popularity
and interest among students. We accept Free-Quarter
students every year. Usually these students' activities
are not limited to one Quarter, and 2 students
continued to enjoy their researches from 2010 through2013. 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 a20monthly 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, inwhich the graduate students learn how to givepresentations and hold discussions and debates inEnglish.

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system :(1) higher functions of vision and memory, (2)non-invasive measurements of human brain activitiesand (3) non-invasive functional measurements ofmonkey brain activities that links above (1) and (2).
The results of such research have been published infirst-rate journals, as listed in the reference. A briefsummary of each topic follows:(1) In the primate, visual information processing in
the cerebral cortex proceeds along the neuralpathway originating from the primary visual areain the occipital lobe to the anterior part of thetemporal association cortex. Our laboratory
discovered several classes of important 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 for noninvasive measurements of human brain activities,
especially of functional magnetic resonanceimaging (fMRI), allows us to observe parallel
activation of functional brain modules in humans
engaged in various mental tasks. We contributed
to development of a new method called “eventrelated fMRI”, which enables to utilize the time
resolution of fMRI. We applied this “event-related
fMRI” method to the analysis of human cognition,and identified several functional centers in thehuman 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

Miyamoto, K., Hirabayashi, T. and Miyashita,
Y. : To bet, or not to bet: that is the question of
SEF spikes. Neuron 75, 358 - 360, 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.
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. 24, 2171-2185, 2012.
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 211, 49-57,
2012.

21

5

Tsubota, T., Ohashi, Y., Tamura, K. andMiyashita, Y. : Optogenetic inhibition of
Purkinje cell activity reveals cerebellar controlof blood pressure during postural alterations inanesthetized rats. Neuroscience 210, 137–144,
2012.
6 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.
7 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.
8 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.
9 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. andYamasue, H. : Diminished medial prefrontal
activity behind autistic social judgments ofincongruent information.
PloS One 7, e39561, 2012.
10 Iwai, L., Ohashi, Y., van der List, D., Usrey,
W.M., Miyashita, Y. and Kawasaki, H. : FoxP2 isa parvocellular-specific transcription factor in
the visual thalamus of monkeys and ferrets.
Cereb. Cortex, in press, doi:10.1093/cercor/
bhs207, 2012.
11 Hirose, S., Kimura, H.M., Kunimatsu, A., Abe,O., Ohtomo, Kuni, Miyashita, Y. and Konishi,
S. : Temporo-parietal networks associated withepisodic retrieval revealed by task-related
functional connectivity. Cereb. Cortex, in press,
doi:10.1093/cercor/bhs268, 2012.
12 Matsui, T., Koyano, K.W., Tamura, K., Osada, T.,
Adachi, Y., Miyamoto, K., Chikazoe, J.,

13

14

15

16

Kamigaki, K. and Miyashita, Y. : fMRI activity
in the macaque cerebellum evoked byintracortical microstimulation of the primarysomatosensory cortex: evidence for polysynaptic
propagation.
PLoS One 7, e47515, 2012.
Hirabayashi, T., Takeuchi, D. and Tamura, K. andMiyashita, Y. : Functional micro-circuit recruitedduring retrieval of object association memory inmonkey perirhinal cortex. Neuron 77, 192–203,
2013.
Watanabe, T. Hirose, S., Wada, H., Imai, Y.,
Machida, T., Shirouzu, I., Konishi, S., Miyashita,
Y. and Masuda, N. : A pairwise maximum
entropy model accurately describes resting-statehuman brain networks. Nat. Commun. 4, 1370,
2013.
Miyamoto, K., Osada, T., Adachi, Y., Matsui, T.,
Kimura, H.M. and Miyashita, Y. : Functional
differentiation of memory retrieval network in
macaque posterior parietal cortex. Neuron 77,
787-799, 2013.
Hirabayashi, T., Takeuchi, D., Tamura, K. andMiyahsita, Y. : Microcircuits for Hierarchical
Elaboration of Object Coding Across Primate
Temporal Areas. Science 341, 191-195, 2013.

22

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

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

Research Associate
Hiroyuki Manabe, Ph.D., Hiromi Naritsuka, Ph.D., Koshi Murata, Ph.D.

Homepage

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, 4
graduate students and 1 secretary stuff.

Using multidisciplinary approaches including
electrophysiology, optical imaging, molecular andcellular biology, molecular genetics and behavioral
analysis, we at the Department of Cellular andMolecular Physiology aim at understanding neuronal
circuit mechanisms for the translation of olfactory
sensory information to a variety of behavioral andemotional responses in the mammalian brain. Our
recent focus includes the functional and spatialorganization of the odor maps in the olfactory bulb,
parallel mitral and tufted cell pathways from olfactory
bulb to olfactory cortex, gamma oscillation couplings
among olfactory bulb, olfactory cortex, and olfactory
cortical mechanisms for the recognition of odor
objects. We study also behavioral state-dependentchange in the information processing mode in theolfactory bulb and olfactory cortex, focusing on theexperience-dependent reorganization of neuronal
circuitry in the olfactory cortex and bulb during
postprandial slow-wave sleep.

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

Granule cells in the olfactory bulb continue to begenerated in adulthood, with nearly half incorporated
and remainder eliminated into or from the neuronal
circuit of the olfactory bulb. We have been investigating the neuronal mechanisms during olfactory

23experience and those during postprandial sleep for thesensory-experience dependent incorporation and/or
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 for reliable
responses than mitral cells. The shorter latency
response of tufted cells was maintained in a 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 of the olfactorycortex, whereas individual mitral cells dispersedly
projected to all olfactory cortex areas. In theanterior 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 todifferent 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 olfactory cortex
sharp waves play a role in the reorganization of
bulbar neuronal circuits during slow-wave sleep.
(3) Sniff rhythm-paced fast andoscillations in the olfactory bulb

slow

gamma

Oder signals are conveyed from the olfactory
bulb to the olfactory cortex by two types ofprojection neurons, tufted cells and mitral cells,
which differ in signal timing and firing frequency
in response to odor inhalation. Whereas tufted
cells respond with early-onset high frequency
burst discharges starting at the middle of theinhalation phase of sniff, mitral cells show odor
responses with later-onset lower frequency burst
discharges. Since odor inhalation induces
prominent gamma oscillations of local fieldpotentials in the olfactory bulb during thetransition period from inhalation to exhalation that
accompany synchronized spike discharges oftufted cells and mitral cells, we addressed thequestion of whether the odor-induced gamma
oscillations encompass two distinct gamma
oscillatory sources, tufted cell-circuits and mitralcell-circuits, by simultaneously recording the sniff
rhythms and local field potentials in the olfactory
bulb of freely behaving rats. We observed that
individual sniffs induced nested gamma oscillations with two distinct parts during theinhalation-exhalation transition period: early-onset
fast gamma oscillations followed by later-onset
slow gamma oscillations. These results suggestthat tufted cells carry odor signals with early-onset
fast gamma synchronization at the early phase ofsniff, whereas mitral cells send them with

24

later-onset slow gamma synchronization. We also
observed that each sniff typically induced both fastand slow gamma oscillations during awake
whereas respiration during slow-wave sleep andREM sleep failed to induce these oscillations.
These results suggest that behavioral states
regulate the generation of sniff rhythm-paced fastand slow gamma oscillations in the olfactory bulb.

Publications (2012~)
1. 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).
2. 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).
3. 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 inthe olfactory cortex. J. Neurosci. 32(23):79707985 (2012).
4. Mizuguchi, R., Naritsuka, H., Mori, K., Mao,
C-A., Klein, W.H., and Yoshihara, Y., Tbr2
deficiency in mitral and tufted cells disrupts
excitatory-inhibitory balance of neural circuitry
in the mouse olfactory bulb. J. Neurosci. 32(26):8831-8844 (2012).
5. Furutani, Y., Kawasaki, M., Matsuno, H., Mitsui,S., Mori, K., and Yoshihara, Y. Vitronectin
induces phosphorylation of ezrin/radixin/moesin
actin-binding proteins through binding to its
novel neuronal receptor telencephalin J Biol.
Chem. 287(46): 39041-39049 (2012)
6. Saito-Iizumi K, Nakamura A, Matsumoto T,
Fujiki A, Yamamoto N, Saito T, Nammoku T, andMori K Ethylmaltol Odor Enhances Salivary
Hemodynamic Responses to Sucrose as Detectedby Near-Infrared Spectroscopy Chem. Percept.
6(2): 92-100 (2013)
7. Manabe H and Mori K Sniff rhythm-paced fastand slow gamma oscillations in the olfactory
bulb: relation to tufted and mitral cells andbehavioral states J Neurophysiol. (in press)

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), 5 postdoctoral fellows, 9 graduate students,
3 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
teachneurophysiology
formedicalundergraduates in lectures and practical courses.
Lectures are designed for students to learn basic
mechanisms underlying the generation of electricalsignals, synaptic transmission and their regulations in
the nervous system. Students also learn how
functional neural circuits in the brain are formed andmatured during postnatal development. In the practicalcourses, students perform two types of classicalexperiments of neurophysiology. First, students makeintracellular recording from frog skeletal muscle
fibers and examine the endplate potential forunderstanding
basic
properties
ofsynaptictransmission. Second, students record electromyogram(EMG) from human gastrocnemius muscles and learn
how the stretch reflex works.
We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in dissociatedculture, or to experience recordings of neuronal
activities from living animals.
For the training of Master and Ph.D. course
students, we have a weekly conference for discussing
current research activities. A laboratory member
summarizes his/her recent experimental data orpresents papers closely related to his/her research.
Moreover, for mutual communication between thelaboratories with similar interests in neuroscience, wehave a weekly joint seminar with Department of
Cellular Neurobiology, 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 methodological approaches including electrophysiology, pharmacology,

26morphology, and genetic engineering of mouse. We
particularly focus on observing neuronal activities inreal 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(2)(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.

(3)(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.

(5)(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.

(4)

(6)

(7)

(8)

References(1) Uesaka N, Mikuni T, Hashimoto K, Hirai H,
Sakimura K, & Kano M: Organotypic Coculture

Preparation for the Study of Developmental
Synapse Elimination in Mammalian Brain. J.
Neurosci. 32: 11657-11670 (2012).
Tanimura A, Uchigashima M, Yamazaki M,
Uesaka N, Mikuni T, Abe M, Hashimoto K,
Watanabe M, Sakimura K & Kano M: Synapse
type-independentdegradationof
theendocannabinoid 2-arachidonoylglycerol after
retrograde synaptic suppression. Proc Natl Acad
Sci U S A. 109: 12195-121200 (2012).
Kimura R, Saiki A, Fujiwara-Tsukamoto Y,
Ohkubo F, Kitamura K, Matsuzaki M, Sakai Y &Isomura Y: Reinforcing operandum: rapid andreliable learning of skilled forelimb movements
by head-fixed rodents. J. Neurophysiol., 108:
1781-1792 (2012).
Nakayama H, Miyazaki T, Kitamura K,
Hashimoto K, Yanagawa Y, Obata K, Sakimura
K, Watanabe M & Kano M: GABAergic
inhibition regulates developmental synapse
elimination in the cerebellum. Neuron 74:
384-396 (2012).
Ohi K, Hashimoto R, Nakazawa T, Okada T,
Yasuda Y, Yamamori H, Fukumoto M,
Umeda-Yano S, Iwase M, Kazui H, Yamamoto T,
Kano M, Takeda M: The p250GAP gene isassociated with risk for schizophrenia andschizotypal personality traits. PLoS One 7:
e35696 (2012).
Sugaya Y, Cagniard B, Yamazaki M, Sakimura
K & Kano M: The endocannabinoid
2-arachidonoylglycerol negatively regulates
habituation by suppressing excitatory recurrent
network activity and reducing long-term
potentiation in the dentate gyrus. J. Neurosci. 33:
3588-3601 (2013).
Hira R, Ohkubo F, Ozawa K, Isomura Y,
Kitamura K, Kano M, Kasai H & Matsuzaki M:
Spatiotemporal dynamics of functional clustersof neurons in the mouse motor cortex during a
voluntary movement. J. Neurosci. 33: 1377-1390(2013).
Kano M, Nakayama H, Hashimoto K, Kitamura
K, Sakimura K, Watanabe M:
Calciumdependent regulation of climbing fiber synapse
elimination during postnatal cerebellar development. J. Physiol. (Lond) 591, 3151-3158 (2013).

27(9) 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,281-299, 2012(10) Kano M, Watanabe M: Cerebellar Circuits. In:
RUBENSTEIN J. L. R. and RAKIC P. (ed.)
Comprehensive Developmental Neuroscience:
Neural Circuit Development and Function in the
Brain, volume 3, pp. 75-93 Amsterdam: Elsevier,2013

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/index_e.html

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

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

Research activities
Our department has a strong background in the fieldof Ca2+ signalling. Ca2+ signal is now known tofunction as a molecular switch in almost every
important cell function including muscle contraction,

exocytosis, cell proliferation, immune responses andregulation of synaptic functions. This is the reason
why this field is expanding rapidly and our research
activity is now diversifying. We are particularlyinterested in Ca2+ signalling in the central nervous
system.
1) Spatiotemporal regulation of Ca2+ signals
Ca2+ signals show very dynamic, temporal andspatial changes within the cell. This property
allows the Ca2+ signal to be an extremely versatile
cellular switch regulating diverse cell functions.
One of the most notable spatiotemporal patterns of
Ca2+ signals is the oscillatory change inintracellular Ca2+ concentration ([Ca2+]i), or Ca2+
oscillation. Many cellular functions are regulatedby the Ca2+ oscillation frequency. However,fundamental questions remain. How and why does
[Ca2+]i oscillate? We have addressed thesequestions. First, 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.

2.

3.

4.

Yano, F., Saito, T., Ogata, N., Yamazawa, T., Iino,
M., Chung, U.I. and Kawaguchi, H. β-catenin
regulates PTH/PTHrP receptor signals andchondrocyte hypertrophy through binding to its
intracellular C-terminal region. Arthritis Rheum.
65, 429-435, 2013.
Kakizawa, S., Yamazawa, T. and Iino, M. Nitricoxide-induced calcium release: activation of type1 ryanodine receptor by endogenous nitric oxide.
Channels 7, 1–5, 2013
Iino, M. Synaptic function monitored using
chemobiomolecular indicators. In Chembiomolecular Science: At the Frontier of Chemistry
and Biology. pp. 207–215, 2013.
Kakizawa, S., Takeshima, H. and Iino, M. Nitric

32

5.

6.

oxide-induced calcium release: A novel
calcium-mobilizing mechanism mediated by
S-nitrosylation-dependent modulation of ryanodine receptor. Messenger. 1, 133–140, 2012.
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.
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.

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
Shumpei Ishikawa, M.D., Ph.D., Junji Shibahara, M.D., Ph.D.

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

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

Associates
Rumi Hino, M.D., Ph.D.,

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

Akiko Kunita, Ph.D.,

Mariko Tanaka, M.D., Ph.D.,

Aya Ushiku-Shinozaki, M.D., Ph.D. (visiting researcher, USA)
Teppei Morikawa, M.D., Ph.D.*,

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

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

Keisuke Matsusaka, M.D., Ph.D.*

Naoko Yamauchi, M.D., Ph.D. (Global COE Program)Technical Support Specialist
Yasuyuki Morishita, M.T., Shinichi Harada, Kei Sakuma

Homepage

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology is
responsible for the practice of diagnostic pathology,
education, and research in conjunction with Divisionof Diagnostic Pathology of the University Hospital*.
Our aim is the construction of “pathology as clinicalmedicine” as well as “next-generation pathology fortranslational research”.
Dr. Ushiku and Dr. Ushiku-Shinozaki worked at
Massachusetts General Hospital, USA as a visiting
researcher in 2012. Associate Professor, Dr. Shumpei
Ishikawa, moved to Tokyo Medical and Dental

University as Professor of Department of Genome
Pathology, Tokyo, on October, 2012. Dr. Hino moved
to Department of Pathology, Cancer Institute, JapaneseFoundation of Cancer Research, on January, 2013, and
Dr. Aya Ushiku returned to the job on February.
Five postgraduate students (Abe, Ito, Morita,
Yoshimoto, and Miyazaki) finished the course andreceived Ph.D. In the new fiscal year, 2013, five newstudents will enter the postgraduate course, and there
will be 17 postgraduates (including one foreign
student).
We are responsible for the pathology practice of
the University Hospital, and are carrying forward the40morphology-based research targeting human diseases.
As for the education for the medical students, we takecharge of the following courses; General Pathology
Course for the 1st grade students in collaboration with
Department of Molecular Pathology, Systemic
Pathology for the 2nd grade, Clinical Clerkship for the
3rd grade, and Bedside-learning (BSL) for the 4th gradestudents. Programs for postgraduates and juniorresidents are also included in our education activities.
The year 2012 was the 125th anniversary of the
Department of Pathology. We held the memorial
lecture meeting on May 19, and speakers were Dr.
Tetsuichiro Muto, President Emeritus of Cancer
Institute Ariake Hospital, and Dr. Kohei Miyazono,
President of Postgraduate School of Medicine, theUniversity of Tokyo. We also invited Dr. Kadowaki,
the President of Tokyo University Hospital as a main
guest, and had the cerebration party.

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 are discussed, including thoracic organs, liverand pancreato-biliary tract, urology, gynecology,
breast, and orthopedics, as well as biopsy cases ofkidney, skin and GI tract.
Clinico-pathological conferences (CPCs) for two
autopsy cases are held every month in the hospital.
Both CPCs and weekly autopsy conferences are usefulfor the education of clinical residents. Digest versionsof CPC slides are now open in the hospital, and we
also started e-learning programs for interns tofacilitate the understanding of the CPC contents. (Dr.
Takazawa and Dr. Ikemura).
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.
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).
In BSL for 4th grade medical students, 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
examination questions for graduation and Systemic
Pathology for the second grade students are referred to
the website. Two students chose the clinical clerkshipcourse for 3rd grade medical students.
As for the free quarter program, we received four
students of M0 and three of M1 in this fiscal year.
We also set up 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. Ushiku, Hino,
Ushiku-Shinozaki, Matsusaka, and Kunita). We arefocusing on the mechanisms of abnormalities in CpG
island methylation and microRNA molecules in thedevelopment and progression of EBV-associated GC(ref.10). Mutations of ARID1A gene, a constituent
protein of chromatin remodeling complex of
SWI/SNIF, were reported in various types of cancer,
and the frequencies were rather high in two GC
subtypes, EBV-associated and microsatellite unstable
GC. We demonstrated by immunohistochemistry thatthe mutation occurs characteristically in an early stagein EBV-associated GC, which is different from othertypes of GC (ref. 2).
The second major theme is ‘traslational researchpathology’. We are engaged in search of target
molecules for cancer therapy by global analysis of

41

expression profiles of various cancers, in collaboration
with Research Center for Advanced Science andTechnology (RCAST), the University of Tokyo. In
addition, we take part in a global COE program,Comprehensive Center of Education and Research
for Chemical Biology of the Diseases , in which weare investigating the morphological analysis of gene
expression abnormalities of the key molecules forseveral diseases (Dr. Yamauchi, ref. 38).
Dr. Ishikawa’s group is engaged in developing
the precisely analyzing methods for genome
information to establish a new field of pathology. They
introduced a quantitative analysis using digital PCR
for the investigation of Merkel cell polyoma virus,
which was recently discovered from human tumors(ref. 28).
The third theme is to re-evaluate the disease
entities and tumor entities from the standpoint ofclassical histopathology. Dr. Ushiku reported thatclaudin 6 is expressed in germ cell tumors and subsets
of cancers of stomach, lung and ovary (ref. 32).
Dr. Morikawa accomplished a significant
achievement in molecular epidemiology of coloncancer in USA, and participated in the basic researchof microenvironment of cancer, demonstrating thecontribution of cancer-associated fibroblast in drug
resistance of cancer (ref. 31). Dr. Tanaka received the100th Anniversary Memorial Award for Young
Pathology Investigator for her thesis research about
the carcinogenesis of the pancreas.
The research works closely related withpathology practice are described in Diagnostic
Pathology Division.

References

(3)

(4)

(5)

(6)

(7)

(including those of Diagnostic Pathology Division)(1) Asawa Y, Sakamoto T, Komura M, Watanabe M,
Nishizawa S, Takazawa Y, Takato T, Hoshi K.
Early-stage foreign body reaction against biodegradable polymer scaffolds affects tissue
regeneration during the autologous transplantationof tissue engineered cartilage in the canine model.
Cell Transplant. 2012;21(7):1431-42.
(2) Abe H, Maeda D, Hino R, Otake Y, Isogai M,
Ushiku AS, Matsusaka K, Kunita A, Ushiku T,
Uozaki H, Tateishi Y, Hishima T, Iwasaki Y,

(8)

(9)

Ishikawa S, Fukayama M. ARID1A expression loss
in gastric cancer: pathway-dependent roles with andwithout Epstein-Barr virus infection and microsatellite instability. Virchows Arch. 2012;461(4):367-77.
Horst D, Chen J, Morikawa T, Ogino S, Kirchner T,
Shivdasani RA. Differential WNT activity incolorectal cancer confers limited tumorigenic
potential and is regulated by MAPK signaling.
Cancer Res. 2012;72(6):1547-56.
Ikeda Y, Oda K, Nakagawa S, MurayamaHosokawa S, Yamamoto S, Ishikawa S, Wang L,
Takazawa Y, Maeda D, Wada-Hiraike O, Kawana K,
Fukayama M, Aburatani H, YanoT, Kozuma S,
Taketani Y. Genome-wide single nucleotide polymorphism arrays as a diagnostic tool in patients withsynchronous endometrial and ovarian cancer. Int J
Gynecol Cancer. 2012;22(5):725-31.
Imamura Y, Morikawa T, Liao X, Lochhead P,
Kuchiba A, Yamauchi M, Qian ZR, Nishihara R,
Meyerhardt JA, Haigis KM, Fuchs CS, Ogino S.
Specific mutations in KRAS codons 12 and 13, andpatient prognosis in 1075 BRAF-wild-type
colorectal cancers. Clin Cancer Res. 2012;18(17):4753-63.
Ishiura H, Sako W, Yoshida M, Kawarai T, Tanabe
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, Morigaki R, Ikemura
M, Yamauchi N, Murayama S, Nicholson GA, Ito H,
Sobue G, Nakagawa M, Kaji R, Tsuji S. The
TRK-fused gene is mutated in hereditary motor andsensory neuropathy with proximal dominant
involvement. Am J Hum Genet. 2012;91(2):320-9.
Ishibashi Y, Takara Y, Tsukamoto M, Kinugasa S,
Sugaya M, Takazawa Y, Kume H, Fujita T.
Epithelium is absent from the subcutaneous tunnel
in long-term peritoneal dialysis patients. Perit Dial
Int. 2012;32(6):652-6.
Ito T, Murakawa T, Sato H, Tanabe A, Maekawa M,
Yoshida Y, Fukayama M, Nakajima J. Simple
preoperative computed tomography image analysis
shows good predictive performance for pathologicalvessel invasion in clinical stage IA non-small cell lungcancer. Interact Cardiovasc Thorac Surg. 2012;15(4):633-8.
Kaji Y, Oshika T, Takazawa Y, Fukayama M, Fujii N.

42Co-localisation of advanced glycation end products and
D-β-aspartic acid-containing proteins in gelatinous
drop-like corneal dystrophy. Br J Ophthalmol. 2012;
96(8):1127-31.
(10) Kaneda A, Matsusaka K, Aburatani H, Fukayama M.
Epstein-Barr virus infection as an epigenetic driver oftumorigenesis. Cancer Res. 2012;72(14):3445-50.

(11) Kaneko MK*, Kunita A*, Abe S, Tsujimoto Y,
Fukayama M, Goto K, Sawa Y, Nishioka Y, Kato Y.
(*; equal contributor) A chimeric anti-podoplaninantibody suppresses tumor metastasis via neutralization and antibody-dependent cellular cytotoxicity.
Cancer Sci. 2012;103(11):1913-9.
(12) Kitagawa H, Watanabe K, Kage H, Inoh S, Goto A,
Fukayama M, Nagase T, Ohishi N, Takai D.
Pulmonary venous invasion, determined by chest
computed tomographic scan, as a potential early
indicator of zygomycosis infection: a case series. J
Thorac Imaging. 2012;27(4):W97-9.
(13) Koga T, Maruyama K, Tanaka M, Ino Y, Saito N,
Nakagawa K, Shibahara J, Todo T. Extended field
stereotactic radiosurgery for recurrent glioblastoma.
Cancer. 2012;118(17):4193-200.
(14) Kuchiba A, Morikawa T, Yamauchi M, Imamura Y,
Liao X, Chan AT, Meyerhardt JA, Giovannucci E,
Fuchs CS, Ogino S. Body mass index and risk ofcolorectal cancer according to fatty acid synthase
expression in the nurses' health study. J Natl Cancer
Inst. 2012;104(5):415-20.
(15) Liao X, Morikawa T, Lochhead P, Imamura Y,
Kuchiba A, Yamauchi M, Nosho K, Qian ZR,
Nishihara R, Meyerhardt JA, Fuchs CS, Ogino S.
Prognostic Role of PIK3CA Mutation in Colorectal
Cancer: Cohort Study and Literature Review. Clin
Cancer Res. 2012;18(8):2257-68.
(16) Liao X, Lochhead P, Nishihara R, Morikawa T,
Kuchiba A, Yamauchi M, Imamura Y, Qian ZR,
Baba Y, Shima K, Sun R, Nosho K, Meyerhardt JA,
Giovannucci E, Fuchs CS, Chan AT, Ogino S.
Aspirin use, tumor PIK3CA mutation status, andcolorectal cancer survival. N Engl J Med. 2012;
367(17):1596-606.
(17) Lin JH, Morikawa T, Chan AT, Kuchiba A, Shima K,
Nosho K, Kirkner G, Zhang SM, Manson JA,
Giovannucci E, Fuchs CS, Ogino S.
Postmenopausal hormone therapy is associated witha reduced risk of colorectal cancer lacking CDKN1A

expression. Cancer Res 2012;72(12):3020-8.
(18) Lochhead P, Imamura Y, Morikawa T, Kuchiba A,
Yamauchi M, Liao X, Qian ZR, Nishihara R, Wu K,
Meyerhardt JA, Fuchs CS, Ogino S. IGF2BP3(IMP3) expression is a marker of unfavourable
prognosis in colorectal cancer. Eur J Cancer. 2012;
48(18):3405-13.
(19) Matsubara D, Kanai Y, Ishikawa S, Ohara S,
Yoshimoto T, Sakatani T, Oguni S, Tamura T,
Kataoka H, Endo S, Murakami Y, Aburatani H,
Fukayama M, Niki T. Identification of CCDC6-RET
fusion in the human lung adenocarcinoma cell line,
LC-2/ad. J Thorac Oncol. 2012;7(12):1872-6.
(20) Miyauchi M, Yoshimi A, Nannya Y, Takazawa Y,
Ichikawa M, Fukayama M, Kurokawa M. Efficacy
of pleural biopsy for diagnosis of pleural effusion
due to chronic GVHD after hematopoietic stem celltransplantation. Int J Hematol. 2012;96(1):146-8.
(21) Miyazaki H, Uozaki H, Tojo A, Hirashima S,
Inaga S, Sakuma K, Morishita Y, Fukayama M.
Application of low-vacuum scanning electron
microscopy for renal biopsy specimens. Pathol Res
Pract. 2012;208(9):503-9.
(22) Morikawa T, Kuchiba A, Qian ZR, Mino-Kenudson
M, Hornick JL, Yamauchi M, Imamura Y, Liao X,
Nishihara R, Meyerhardt JA, Fuchs CS, Ogino S.
Prognostic significance and molecular associationsof tumor growth pattern in colorectal cancer. Ann
Surg Oncol. 2012;19(6):1944-53.
(23) Morikawa T, Shima K, Kuchiba A, Yamauchi M,
Tanaka N, Imamura Y, Liao X, Qian ZR,
Brahmandam M, Longtine JA, Lindeman NI, Fuchs
CS, Ogino S. No evidence for interference of H&E
staining in DNA testing: usefulness of DNA
extraction from H&E-stained archival tissue
sections. Am J Clin Pathol. 2012;138(1):122-9.
(24) Morikawa T, Tanaka N, Kuchiba A, Nosho K,
Yamauchi M, Hornick JL, Swanson RS, Chan AT,
Meyerhardt JA, Huttenhower C, Schrag D, Fuchs
CS, Ogino S. Predictors of lymph node count incolorectal cancer resections: Data from U.S.
nationwide prospective cohort studies. Arch Surg.
2012;147(8):715-23.
(25) Morikawa T, Kuchiba A, Liao X, Imamura Y,
Yamauchi M, Qian ZR, Nishihara R, Sato K,
Meyerhardt JA, Fuchs CS, and Ogino S. Tumor
TP53 expression status, body mass index, and43prognosis in colorectal cancer. Int J Cancer. 2012;
131(5):1169-78.
(26) Morita K, Nakamura F, Nannya Y, Nomiya A, Arai
S, Ichikawa M, Maeda D, Homma Y, Kurokawa M.
Primary MALT lymphoma of the urinary bladder inthe background of interstitial cystitis. Ann Hematol.
2012;91(9):1505-6.
(27) Nagata M, Sakurai-Yageta M, Yamada D, Goto A,
Ito A, Fukuhara H, Kume H, Morikawa T,
Fukayama M, Homma Y, Murakami Y. Aberrationsof a cell adhesion molecule CADM4 in renal clear
cell carcinoma. Int J Cancer. 2012;130(6):1329-37.
(28) Ota S, Ishikawa S, Takazawa Y, Goto A, Fujii T,
Ohashi K, Fukayama M. Quantitative analysis ofviral load per haploid genome revealed the different
biological features of Merkel cell polyomavirus
infection in skin tumor. PLoS One. 2012;7(6):e39954.
(29) 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
expression of CK20, FABP1 and MUC2 is sensitive
for the prediction of peritoneal recurrence in gastriccancer. Jpn J Clin Oncol. 2012;42(2):148-52.
(30) Soma K, Abe H, Takeda N, Shintani Y, Takazawa Y,
Kojima T, Fujiu K, Semba H, Yamashita H, Hirata
Y, Fukayama M, Nagai R. Myocardial involvementin patients with osteogenesis imperfecta. Int Heart J.
2012;53(1):75-7.
(31) Straussman R, Morikawa T, Shee K, Barzily-Rokni
M, Qian ZR, Du J, Davis A, Mongare MM, Gould J,
Frederick DT, Cooper ZA, Chapman PB, Solit DB,
Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA,
Golub TR. Tumour micro-environment elicits innate
resistance to RAF inhibitors through HGF secretion.
Nature. 2012;487(7408):500-4.
(32) Sun M, Uozaki H, Hino R, Kunita A, Shinozaki A,
Ushiku T, Hibiya T, Takeshita K, Isogai M, Takada
K, Fukayama M. SOX9 expression and its
methylation status in gastric cancer. Virchows Arch.
2012;460(3):271-9.
(33) Ushiku T, Shinozaki-Ushiku A, Maeda D, Morita S,
Fukayama M. Distinct expression pattern ofclaudin-6, a primitive phenotypic tight junction
molecule, in germ cell tumours and visceralcarcinomas. Histopathology. 2012;61(6):1043-56.
(34) Watanabe K, Emoto N, Hamano E, Sunohara M,

Kawakami M, Kage H, Kitano K, Nakajima J,
Goto A, Fukayama M, Nagase T, Yatomi Y,
Ohishi N, Takai D. Genome structure-based
screening identified epigenetically silenced
microRNA associated with invasiveness in nonsmall-cell lung cancer. Int J Cancer. 2012;130(11):2580-90.
(35) Yamauchi M, Lochhead P, Morikawa T,
Huttenhower C, Chan AT, Giovannucci E, Fuchs
CS, Ogino S. Colorectal cancer: a tale of two sides,
or a continuum? Gut. 2012;61(6):794-7.
(36) Yamauchi M, Morikawa T, Kuchiba A, Imamura Y,
Qian ZR, Nishihara R, Liao X, Waldron L, Hoshida
Y, Huttenhower C, Chan AT, Giovannucci E, Fuchs
CS, Ogino S. Assessment of colorectal cancer
molecular features along bowel subsites challenges
the conception of distinct dichotomy of proximal vs.
distal colorectum. Gut. 2012;61(6):847-54.
(37) Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Takazawa Y, Aoki T, Hasegawa K, Sakamoto Y,
Koike K, Kokudo N. Living-donor livertransplantation for autoimmune hepatitis andautoimmune hepatitis-primary biliary cirrhosis
overlap syndrome. Hepatol Res. 2012;42(10):1016-23.
(38) Yamauchi N, Takazawa Y, Maeda D, Hibiya T,
Tanaka M, Iwabu M, Okada-Iwabu M, Yamauchi T,
Kadowaki T, Fukayama M. Expression levels of
adiponectin receptors are decreased in humanendometrial adenocarcinoma tissues. Int J Gynecol
Pathol. 2012;31(4):352-7.
(39) Yoshida A, Sekine S, Tsuta K, Fukayama M, Furuta
K, Tsuda H. NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma. Am J Surg
Pathol. 2012;36(7):993-9.
(40) Zong Y, Huang J, Sankarasharma D, Morikawa T,
Fukayama M, Epstein JI, Chada KK, Witte ON.
Stromal epigenetic dysregulation is sufficient toinitiate mouse prostate cancer via paracrine Wnt
signaling. Proc Natl Acad Sci U S A. 2012;
109(50):E3395-404.

44

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

Associate Professor

Tetsuro Watabe, Ph.D.
Project Associate Professor

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. In July 2012,
Dr. Mitsunobu R. Kano promoted to a professor of the
Graduate School of Medicine, Dentistry, andPharmaceutical Sciences at Okayama University. Dr.
Daizo Koinuma promoted to a project associate
professor in July 2012. In the end of 2012, theDepartment consists of a professor, an associate
professor, a project associate professor, two assistantprofessors, a project assistant professor, technicalassistants, and some research fellows, including 10
graduate students and 5 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, because most of the experiments
can be 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-β family
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-β Family Signaling”

45

of Japan Society for the Promotion of Science (JSPS)(http://c2ctgfb.umin.jp/). We have annual TGF-β
meeting in Sweden or in the Netherlands every year,
and six graduate students participated in the TGF-β
meeting in Leiden in 2012. At the 1st internationalcore-to-core symposium held at the Showa
Pharmaceutical University, a post-doctoral fellow
presented his data by oral presentation, and eightstudents presented their data at the poster session.
Some of our graduate students are supported by the
GPLLI Graduate Program for Leaders in Life
Innovation at the University of Tokyo from the MEXT.
GPLLI was designed for the purpose of guiding
outstanding students to be globally active leaders inindustry, academia and government. This program also
stimulates interaction between students and scientists
in the program as well as those from other laboratories(http://square.umin.ac.jp/gplli/).

Research activities
Our major research interest is to elucidate how
members of the TGF-β (transforming growth factor-β)family transduce signals, and how they regulate
growth, differentiation, and apoptosis of various cells.
We are also interested in the regulation ofangiogenesis and lymphangiogenesis using embryonicstem (ES) cell-derived vascular progenitor cells andother endothelial cells.
Epithelial-mesenchymal transition (EMT) is an
important event under various physiological andpathological conditions. EMT is particularly importantin the process of invasion and metastasis of cancer.
TGF-β induces EMT in epithelial cells. In the processof EMT induced by TGF-β, isoform switching offibroblast growth factor (FGF) receptors occurs byalternative splicing. We performed a DNA microarray
analysis at single exon level to determine changes insplicing variants generated during TGF-β-induced
EMT. We found that TGF-β induces broad alterationof splicing patterns by down-regulation of epithelial
splicing regulatory protein (ESRP) 1 and 2, which wasachieved by induction of δEF1 family proteins, ZEB1
(δEF1) and ZEB2 (SIP1), by TGF-β. Both ZEB1 andZEB2 repressed ESRP2 expression by binding to the
ESRP2 promoter in NMuMG mouse mammary
epithelial cells. Knock-down of both ZEB1 and ZEB2,

but not either alone, cancelled the TGF-β-induced
repression of ESRP2. Moreover, the expression
patterns of ESRP1 and 2 were reciprocally correlatedwith those of ZEB1 and ZEB2 in human breast cancer
cell lines and tumor specimens. Furthermore,
overexpression of ESRPs in breast cancer cells
resulted in restoration of the epithelial splicing profiles
as well as attenuation of certain EMT phenotypes.
Therefore, δEF1 family proteins repress the expressionof ESRPs to regulate alternative splicing of FGF
receptors and other proteins during EMT induced by
TGF-β and thus are involved in the progression ofbreast cancers (Horiguchi et al., Oncogene 2012).
SimilartoEMT,
endothelial-mesenchymaltransition (EndMT) plays crucial roles in various
physiological and pathological processes. TGF-βsignals have been reported to be involved in EndMT,
but the molecular mechanisms underlying it have notbeen fully determined. We studied the effects of
TGF-β signals on EndMT using MS-1 mousepancreatic microvascular endothelial cells. TGF-β
induced EndMT characterized by re-organization ofactin stress fiber and increased expression of various
mesenchymal markers, e.g. α-SMA, through activationof Rho signals. Furthermore, we found that Arhgef5, aguanine nucleotide exchange factor, is induced by
TGF-β-Smad signals and involved in the increased
expression of α-SMA. We also revealed that TGF-β
induces the expression and nuclear accumulation of
MRTF-A by Smad signals, and that MRTF-A isessential for TGF-β-induced α-SMA expression. Thesefindings strongly suggest that TGF-β-Smad signals
induces the activation of Rho signals and MRTF-A,
leading to EndMT of MS-1 endothelial cells (Mihira etal., J. Biochem. 2012).
Interaction between cancer cells and bone
microenvironment contributes to the development ofbone metastasis. Bone metastasis of prostate cancer isoften characterized by an osteosclerotic phonotype.
However, the molecular mechanisms involved in theprocess of bone metastasis of prostate cancer have notbeen fully elucidated. We investigated the roles ofbone morphogenetic proteins (BMPs), members of the
TGF-β family, in the interaction between prostatecancer cells and bone stromal cells. BMP-4 induced
osteoblastic differentiation of MC3T3-E1 cells. In the
LNCaP human prostate cancer cells, BMP-4 induced

46

the production of Sonic hedgehog in a Smaddependent fashion. Stimulation of MC3T3-E1 cellswith BMP-4 and Sonic hedgehog accelerarted theexpression of osteoblastic markers, e.g. alkaline phosphatase and bone sialoprotein. Under the co-culture of
MC3T3-E1 cells and LNCaP cells, the effect of
BMP-4 on MC3T3-E1 cells was enhanced by Sonic
hedgehog derived from LNCaP cells. Moreover, in thepresence of LNCaP cells, BMP-4 efficiently induced
the production of certain growth factors from
MC3T3-E1 cells, which possibly led to the stimulationof the growth of LNCaP cells. Thus, BMPs provide
favorable microenvironment for the growth andsurvival of prostate cancer cells and the differentiationof bone stromal cells, which may result in theosteoblastic metastasis of prostate cancer (Nishimori
et al., J. Biol. Chem. 2012).
ALDH1 (aldehyde dehydrogenase 1) is now wellknown to serve as an important marker forcancer-initiating cells (CICs; or cancer stem cells).
However, little is known about the functions of
ALDH1 in CICs. We isolated ALDH1+ cells fromhuman diffuse-type gastric carcinoma cell lines
OCUM-2MLN and HSC-39, and characterized thesecells. ALDH1+ cells were more tumorigenic in
immuno-compromised mice than ALDH1- cells, andwere able to self-renew and generate ALDH1- cell
populations. Using DNA microarray analyses, we
identified REG4 (regenerating islet-derived family,
member 4) as a gene up-regulated in ALDH1+ cells
compared to ALDH1- cells, suggesting that REG4
may be a novel marker for ALDH1+ cells. Forced
expression of REG4 enhanced the colony-forming
ability of OCUM-2MLN cells in soft agar, whereassilencing of REG4 expression attenuated thetumorigenic function of ALDH1+ cells. TGF-βsignaling suppressed the expression of ALDH1 and
REG4, and reduced the size of the ALDH1+ cell
populations. Immunohistochemistry analysis using
human gastric carcinoma tissues revealed that theexpression of ALDH1 and REG4 correlated with eachother, whereas ALDH1 expression reciprocallycorrelated with the expression of phospho-Smad3.
These findings suggest that in diffuse-type gastriccarcinoma, REG4 is up-regulated in ALDH1+ CICs,
and plays a role in the tumorigenesis of ALDH1+ cells.
TGF-β suppresses the expression of ALDH1 and

REG4, and reduces the size of CIC populations andtumorigenic ability of human diffuse-type gastriccarcinoma cells (Katsuno et al., J. Pathol. 2012).

References
1. Mihira, H., Suzuki, H.I., Akatsu, Y., Yoshimatsu,
Y., Igarashi, T., Miyazono, K., and Watabe, T.
(2012) TGF-β-induced mesenchymal transition ofMS-1 endothelial cells requires Smad-dependent
cooperative activation of Rho signals and
MRTF-A. J. Biochem. 151 (2): 145-156.
2. Kawata, M., Koinuma, D., Ogami, T., Umezawa,
K., Iwata, C., Watabe, T., and Miyazono, K.
(2012) TGF-β-induced epithelial-mesenchymaltransition of A549 lung adenocarcinoma cells isenhanced by pro-inflammatory cytokines derived
from RAW 264.7 macrophage cells. J. Biochem.
151 (2): 205-216.
3. Hosoya, H., Kadowaki, K., Matsusaki, M., Cabral,
H., Nishihara, H., Ijichi, H., Koike, K., Kataoka,
K., Miyazono, K., Akashi, M., and Kano, M.R.
(2012) Engineering fibrotic tissue in pancreaticcancer: A novel three-dimensional model toinvestigate nanoparticle delivery. Biochem.
Biophys. Res. Commun. 419 (1): 32-37.
4. Horiguchi, K., Sakamoto, K., Koinuma, D.,
Semba, K., Inoue, A., Inoue, S., Fujii, H.,
Yamaguchi, A., Miyazawa, K., Miyazono, K., andSaitoh, M. (2012) TGF-β drives epithelialmesenchymal transition through δEF1-mediateddownregulation of ESRP. Oncogene 31 (26):3190-3201.
5. Tojo, M., Takebe, A., Takahashi, S., Tanaka, K.,
Imamura, T., Miyazono, K., and Chiba, T. (2012)
Smad7-deficient mice show growth retardation
with reduced viability. J. Biochem. 151 (6):621-631.
6. Ishii, R., Isogaya, K., Seto, A., Koinuma, D.,
Watanabe, Y., Arisaka, F., Yaguchi, S.I., Ikushima,H., Dohmae, N., Miyazono, K., Miyazawa, K.,
Ishitani, R., and Nureki, O. (2012) Structure of adominant-negative helix-loop-helix transcriptional
regulator suggests mechanisms of autoinhibition.
EMBO J. 31 (11): 2541-2552.
7. Nishimori, H., Ehata, S., Suzuki, H.I., Katsuno, Y.,
and Miyazono, K. (2012) Prostate cancer cells and47bone stromal cells mutually interact with eachother through bone morphogenetic proteinmediated signals. J. Biol. Chem. 287 (24):20037-20046.
8. Katsuno, Y., Ehata, S., Yashiro, M., Yanagihara,
K., Hirakawa, K., and Miyazono, K. (2012)
Coordinated expression of REG4 and aldehyde
dehydrogenase 1 regulating tumorigenic capacityof diffuse-type gastric carcinoma-initiating cells is
inhibited by TGF-β. J. Pathol. 228 (3): 391-404.
9. Kawabata, K.C., Ehata, S., Komuro, A., Takeuchi,K., and Miyazono, K. (2012) TGF-β-induced
apoptosis of B-cell lymphoma Ramos cells
through reduction of MS4A1/CD20. Oncogene 32(16): 2096-2106.
10. Takaesu, N.T., Stinchfield, M.J., Shimizu, K.,
Arase, M., Quijano, J.C., Watabe, T., Miyazono,
K., and Newfeld, S.J. (2012) Drosophila CORL is
required for Smad2-mediated activation of
ecdysone receptor expression in the mushroom
body. Development 139 (18): 3392-3401.
11. Ikushima, H., and Miyazono, K. (2012) TGF-βsignal transduction spreading to a wider field: abroad variety of mechanisms for contextdependent effects of TGF-β. Cell Tissue Res. 347(1): 37-49.
12. Miyazono, K., Ehata, S., and Koinuma, D. (2012)
Tumor-promoting functions of transforming
growth factor-β in progression of cancer. Ups. J.
Med. Sci. 117 (2): 143-152.

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 25 members; 1 professor (Dr. Hatakeyama),
1 lecturer (Dr. Kamiya), 2 associates (Drs. Tsutsumi
and Saito), 3 Post-doc (Drs. Zhang, Takahashi,
Takeda), 4 technical staffs (Ms. Sekiguchi, Morohashi,
Kashiba, Yamahashi), 14 Graduate School students(Ms. and Mrs. Fujii, Hayashi, Suzuki, Yanagiya,
Kikuchi, Nagase, Hashi, Bingo, Noda, Saju, Senda,
Masoudi, Tajiri, Lin).

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 for biotechnology
6) Socioeconomic impact of microbial diseases

50

1. Identification of parafibromin/Cdc73 as a key
substrate of SHP2 tyrosine phosphatase toderegulate Wnt signaling
Upon delivery into gastric epithelial cells via type IV
secretion, CagA undergoes tyrosine phosphorylation
by Src family kinases (SFKs) or c-Abl kinase at the
Glu-Pro-Ile-Tyr-Ala (EPIYA) motif. Tyrosinephosphorylated CagA acquires the ability to
specifically bind to and aberrantly activate SHP2
tyrosine phosphatase. SHP2 is expressed in a wide
range of cell types, and exists in both the cytoplasm
and nucleus. Whereas SHP2 functions as a positive
regulator of RAS-ERK signaling pathway in thecytoplasm, 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.
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.

regulating kinase (MARK) via CagA multimerization(CM) sequence in a tyrosine phosphorylationindependent manner and inhibits the kinase activity,
resulting in loss of epithelial cell polarity.
To investigate the role of CagA-SHP2 and/or
CagA-PAR1 interaction in the pathophysiologicalaction of cagA-positive H. pylori using an in vitro
bacterial infection system, we generated H. pylori
isogenic strains carrying a gene encoding
phosphorylation-resistant CagA (PR-CagA) or CagA
lacking the CM sequence (CagA-ΔCM) byhomologous recombination. We showed thatbacterially delivered CagA interacts with SHP2 in atyrosine phosphorylation-dependent manner as
previously described. We also confirmed thatbacterially delivered CagA interacts with PAR1 via
CM sequence in a manner independent of tyrosine
phosphorylation as previously described.
Aberrant activation of oncoprotein, such as Ras, notonly elicits unrestrained cell proliferation but also
provokes highly elevated cell movement, suggestingthat deregulated cell motility is also involved intransformation of cells. We therefore investigated thebiological effect of isogenic H. pylori infection on themobility of gastric epithelial cells. Upon infection with
cagA-positive strains, either wild-type (wt) or mutant,cells exhibited elevated cell motility when comparedwith cells infected with cagA-deficient strain. Among
cagA-positive H. pylori strains, H. pylori strain
carrying wt-CagA enhanced cell mobility mosteffectively. Furthermore, infection with H. pylori
strain producing wt-CagA induced an elongatedcell-morphological change termed hummingbird
phenotype. In contrast, infection with H. pylori strain
producing PR-CagA or CagA-ΔCM hardly induced
cells with the hummingbird phenotype. Thus, both
CagA-SHP2 and CagA-PAR1 interactions are
involved in the pathogenicity of cagA-positive H.
pylori.

2. Stimulation of epithelial cell migration via
CagA-SHP2 and CagA-PAR1 interactions
Inside the host cells, tyrosine-phosphorylated CagA
specifically interacts with and aberrantly activates
SHP2, thereby stimulating cell proliferation and cell
motility. Also, CagA specifically interacts withpartitioning-defective 1 (PAR1)/microtubule affinity-

3. Elucidation of the three-dimensional structureof Helicobacter pylori CagA
Upon delivery into gastric epithelial cells, CagA
localizes to the inner face of the plasma membrane
and then interacts with a number of host proteins, suchas SHP2 and PAR1, thereby deregulating multiple cellsignaling pathways. CagA has been under intense

51

study in the field of molecular and cellular biology,
but has never been resolved in the field of structural
biology.
CagA is an approximately 130-kDa protein
consisting of approximately 1200 amino acids, which
does not share sequence homology with any of the
known proteins. In this study, we elucidated thetertiary structure of CagA by X-ray crystallographic
analysis and NMR analysis. We found that CagA
consists of a N-terminal region (~70% of the entire
protein) and C-terminal region (~30% of the entire
protein) in which both EPIYA motif and CM sequence
are involved. NMR analysis revealed that the CagA
C-terminal region is intrinsically disordered andtherefore lacks a solid structure. Intrinsicallydisordered regions are gaining significant attention
due to its structural flexibility. The intrinsicallydisordered nature of C-terminal CagA enables
versatile protein interactions because of its structural
flexibility. X-ray crystallographic analysis revealed
that N-terminal CagA consists of three domains,termed Domains I-III. Domain II contains a basic
amino-acid cluster (basic patch) that provides a
positive electrostatic surface potential. CagA is
tethered to the inner face of the plasma membrane
through interaction between the basic patch andmembrane phosphatidylserine. Domain III interacts
intramolecularly with the intrinsically disordered
C-terminal region. This intramolecular interaction
potentiates the pathogenic scaffold/hub function of
CagA. Our study provides a tertiary-structural basis
for the pathophysiological/oncogenic action of H.
pylori CagA.
4. Induction of reprogramming by a transcription
factor CDX1 in gastric epithelial cells
Intestinal metaplasia of the stomach, a mucosal change
characterized by the conversion of gastric epithelium
into an intestinal phenotype, is a precancerous lesion
from which intestinal-type gastric adenocarcinoma
arises. Chronic infection with H. pylori is a major
cause of gastric intestinal metaplasia. We previously
reported that CagA aberrantly induces CDX1, anintestine-specific caudal-related homeobox transcription factor, in gastric epithelial cells. Furthermore, it
was reported that ransgenic expression of Cdx1 inmouse stomach causes intestinal metaplasia. However,

the mechanism though which CDX1 causes intestinal
metaplasia of the stomach remained to be elucidated.
In order to elucidate the mechanism of CDXgoverned intestinal metaplasia, we established humangastric epithelial cell-derived stable transfectant clones
that inductively express CDX1 under a tet-off system.
Expression microarray analysis and ChIP-chip
analysis revealed that CDX1 directly activatedstemness-associated reprogramming factors SALL4
and KLF5 in gastric epithelial cells. In cultured gastricepithelial cells, sustained expression of CDX1 gave
rise to the induction of early intestinal-stemness
markers, followed by the expression of intestinaldifferentiation markers. Furthermore, the induction ofthese markers was suppressed by inhibiting either
SALL4 or KLF5 expression. These results indicatedthat CDX1-induced SALL4 and KLF5 converted
gastric epithelial cells into tissue stem-like progenitor
cells, which then transdifferentiated into intestinal
epithelial cells. Our study places the stemness-related
reprogramming factors as critical components of
CDX1-directed transcriptional circuitries that promoteintestinal metaplasia.

References
1.

2.

3.

Tsugawa H, Suzuki H, Seya H, Hatakeyama M,
Hirayama T, Hirata K, Nagano O, Matsuzaki J,
Hibi T. Reactive oxygen species-induced
autophagic degradation of Helicobacter pylori
CagA is specifically suppressed in cancer stemlike cells. Cell Host Microbe 2012:6:764-777.
Fujii Y, Yoshihashi K, Suzuki H, Tsutsumi S,
Mutoh H, Maeda S, Yamagata Y, Seto Y,
Aburatani H, Hatakeyama M. CDX1 confers
intestinal phenotype on gastric epithelial cells via
induction of stemnes-associated reprogramming
factors SALL4 and KLF5. Proc Natl Acad Sci
USA 2012:109:20584-20589.
Hayashi T, Senda M, Morohashi H, Higashi H,
Horio M, Kashiba Y, Nagase L, Sasaya D,
Shimizu T, Venugopalan N, Kumeta H, Noda N
N, Inagaki F, Senda T, Hatakeyama M. Tertiary
structure-function analysis reveals the pathogenic
signaling
potentiation
mechanismofHelicobacter pylori oncogenic effector CagA.
Cell Host Microbe 2012:12:20-33.

52

4.

5.

Lee K S, Kalantzis A, Jackson C B, O'Connor L,
Murata-Kamiya N, Hatakeyama M, Judd L M,
Giraud A S, Menheniott T R. Helicobacter pylori
CagA Triggers Expression of the Bactericidal
Lectin REG3γ via Gastric STAT3 Activation.
PLoS One 2012:7:e30786.
Kikuchi K, Murata-Kamiya N, Kondo S,
Hatakeyama M. Helicobacter pylori stimulates
epithelial cell migration via CagA-mediatedperturbation of host cell signaling. Microbes
Infect 2012:14:470-476.

53

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

LectureShu Okugawa,M.D.,Ph.D.

Research Associate
Youko Nukui, M.D., Ph.D.
Keita Tatsuno, M.D., Ph.D.
Masashi Suzuki,M.D.,Ph.D.
Kazuhito Yuhashi,MD.,Ph.D.
Mahoko Ikeda,MD.,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, one lecture, five guest
lecturers, five research associates, 11 laboratory
technicians, and two office assistants. For isolationand identification of microorganisms from clinicalspecimens, we amalgamated the microbiology unit
from the Department of Clinical Laboratory in 2001.

methicillin-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.

Clinical activities
Teaching activities
Our daily activities are as follows:
1) Surveillance and control of hospital-acquired
infection, such as infection or colonization of

We have been charged for education of undergraduate
students on the course of medicine (lectures and54practical exercises on the infection control for the 4th
grade students). These lectures and exercises contain
subjects not only on the hospital infection but also on
clinical microbiology. We are also engaged in the
education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed
to the guidance for new postgraduates and residents
on the hospital and occupational infection control. We
have been also offering our information and techniqueon occasions of request.

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) Two cases of bacteremia caused by Leptotrichia
trevisanii in patients with febrile neutropenia.
Higurashi Y, Tatsuno K, Fujimoto F, Kobayashi I,
Ida K, Seto Y, Ohkusu K, Ezaki T, Okugawa S,
Moriya K. J Infect Chemother. 2013 Apr 14.
(2) Simultaneous increase in 1,3-β-d-glucan andprocalcitonin levels in Pseudomonas aeruginosa
infection.Koya J, Nannya Y, Kobayashi H,
Okugawa S, Moriya K, Kurokawa M.J Infect.

2013 Aug;67(2):164-6(3) Molecular characterization of carbapenemaseproducing clinical isolates of Enterobacteriaceae
in a teaching hospital, Japan.Koyano S, Saito R,
Nagai R, Tatsuno K, Okugawa S, Okamura N,
Moriya K. J Med Microbiol. 2013 Mar;62 (Pt
3):446-50.
(4) High plasma linezolid concentration andimpaired renal function affect development oflinezolid-induced thrombocytopenia.Nukui Y,
Hatakeyama S, Okamoto K, Yamamoto T, Hisaka
A, Suzuki H, Yata N, Yotsuyanagi H, Moriya K.
J Antimicrob Chemother. 2013 Apr26(5) High Levels of HBV after the Onset Lead toChronic Infection in Patients with Acute
Hepatitis B.Yotsuyanagi H, Ito K, Yamada N,
Takahashi H, Okuse C, Yasuda K, Suzuki M,
Moriya K, Mizokami M, Miyakawa Y, Koike K.
Clin Infect Dis. 2013 May 23.
(6) Dengue hemorrhagic fever in an adult traveler
returning to Japan.Goto K, Hatakeyama S,
Okamoto K, Kitazawa T, Abe K, Moriya K,
Koike K, Yotsuyanagi H.Intern Med. 2012;
51(13):1779-82.
(7) Chronic hepatitis B in patients coinfected withhuman immunodeficiency virus in Japan: aretrospective multicenter analysis. Yanagimoto
S, Yotsuyanagi H, Kikuchi YTsukada K, Kato M,
Takamatsu J, Hige S, Chayama K, Moriya K,
Koike K.J Infect Chemother. 2012 Dec;18(6):883-90(8) Hepatocarcinogenesis in hepatitis C: HCVshrewdly exacerbates oxidative stress bymodulating both production and scavenging ofreactive oxygen species.Fujinaga H, Tsutsumi T,
Yotsuyanagi H, Moriya K, Koike K.Oncology.
2011;81 Suppl 1:11-7(9) LXR agonist increases apoE secretion from
HepG2 spheroid, together with an increased
production of VLDL and apoE-rich large HDL.
Kurano M, Iso-O N, Hara M, Ishizaka N, Moriya
K, Koike K, Tsukamoto K. Lipids Health Dis.
2011 Aug 5;10:134(10) Liquid chromatographic separation of proteinsderivatized with a fluorogenic reagent at
cysteinyl residues on a non-porous column fordifferential proteomics analysis. Koshiyama A,

55

Ichibangase T, Moriya K, Koike K, Yazawa I,
Imai K.J Chromatogr A. 2011 Jun 3;1218(22):3447-52.
(11) Pathogenesis of lipid metabolism disorder inhepatitis C: polyunsaturated fatty acids
counteract lipid alterations induced by the coreprotein. 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. J Hepatol.
2011 Mar;54(3):432-8.
(12) 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.
(13) Hepatitis C virus core protein compromises ironinduced activation of antioxidants in mice and
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.
(14) Animal models for hepatitis C and related liverdisease.Koike K, Moriya K, Matsuura Y.Hepatol
Res. 2010 Jan;40(1):69-82.
(15) Inflammasome sensor Nlrp1b-dependent resistanceto 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.
(16) Anthrax toxin targeting of myeloid cells throughthe CMG2 receptor is essential for establishment ofBacillus 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.
(17) 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.
(18) 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.

(19) Defective membrane expression of the Na(+)HCO(3)(-) cotransporter NBCe1 is associated withfamilial 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

57

Department of Immunology
Professor
Hiroshi Takayanagi, M.D., Ph.D.

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

Assistant Professor
Kazuo Okamoto, Ph.D.; Takako Negishi-Koga, Ph.D.; Koji Atarashi, Ph.D.;
Shinichiro SAWA, M.D., Ph.D.

Homepage

http://www.osteoimmunology.com/

Introduction and Organization
The history of the Department of Immunology,
formerly the Department of Serology, dates back to1918. The department adopted its present name when
Dr. Tomio Tada took his position as professor andchair in 1977 . Through his innovative research andgreat contributions to the international community of
immunologists, Dr. Tada raised the stature of thedepartment to a world-renowned status. After Dr.
Tada’s retirement in 1994, Dr. Tadatsugu Taniguchi,
presently the designated professor of the Departmentof Molecular Immunology at the Institute of Industrial
Science, the University of Tokyo, performed
cutting-edge, internationally recognized research in
the field of immunology especially cytokine systems
in the context of the regulation of immunity andoncogenesis. Dr. Taniguchi’s major achievements
were the discovery of interferon-β and a new familyof transcription factors, termed interferon regulatory
factors (IRFs). At 2003, Dr. Taniguchi was elected as aforeign associate of the National Academy of Science(in the United States) in recognition of his
distinguished scientific achievements.

Teaching activities
All members of our department take very seriously
their responsibilities to teach and train the next

generation of scientists. Undergraduate students of thefaculty take part in departmental class work throughlectures on immunobiology, immunochemistry andmolecular immunology as well as practical training by
way of laboratory courses on basic immunology
experimental techniques. The education of graduate
students is based on weekly seminars where students
present the progress of their own research projects,
discuss the future directions of their research and theresearch of others, and are exposed to the latest
cutting-edge questions confronting the research fieldof 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, such as Dr.
Shizuo Akira, Dr. Shimon Sakaguchi (Both are
Professors of Osaka University), Dr. Takehiko
Sasazuki (Prof. of Kyushu Univ.) and Dr. Tadatsugu
Taniguchi (Prof. of the Univ. of Tokyo).

Research activities
The final goal of our research is to develop
epoch-making strategies for the treatment of immune
disorders such as autoimmune diseases and severe
infectious diseases. At the present moment, knowl-

58

edge in this field, especially about the molecularmechanisms of immune tolerance are quite limited.
Therefore, initially, we aim to achieve further
understanding about whole immunity, including
hematopoietic cell development and regulation of bothinnate and adaptive immune systems,. broadly covered
within these 4 subjects.
1) Bone marrow microenvironment
The bone marrow is a primary lymphoid organ thatplays a critical role in immune cell development. It
has been proposed by several groups that marrow
resident non-hematopoietic cells i.e. osteoblasts,
endothelial cells, neurons or reticular cells (named
CXCL12 expressing CAR cells) play critical roles onhematopoiesis. However, the crucial cell types that
support hematopoietic cell development in the marrow
have not been clarified. We aim to identify groups of
cells
and
molecules(withinthemarrow
microenvironment) that support lymphoid lineage
development.
2) Osteoclast and osteoimmunology
Osteoclasts are polynuclear cells derived from themonocyte/macrophage lineage, which are responsible
for bone resorption. Aberrant osteoclast function anddevelopment is involved in the pathogenesis of several
diseases such as the inflammatory bone destruction
observed in rheumatoid arthritis as well as postmenopausal osteoporosis and Albers-Schoenberg's
disease. Osteoclast development is dependent on TNF
family cytokine receptor activator of nuclear factor
kappa-B ligand (RANKL). We studied the receptor
signal transduction pathway for RANKL and
identified nuclear factor of activated T cells c1(NFATc1) as a master regulator for osteoclastdifferentiation (Takayanagi et al., Dev Cell. 2002;
Asagiri et al., J. Exp. Med., 2005). Recently, we
revealed roles of Semaphorin 4D on osteoblast
differentiation (Negishi-Koga et. al., Nature Med.,
2011) and Semaphorin3A on inhibition of boneabsorption as well as promotion of bone formation(Hayashi et. al., Nature 2012).
3) Development and regulation of lymphoid cells
Human and murine peripheral organs harbor large
numbers of lymphocytes such as T, B and recently

re-categorized innate lymphoid cells, which lackantigen receptors. Mucosal tissue, such as oral cavity,
lung, intestine and urogenital tracts maintain an
equilibrium interface for both the host immune systemand commensal microorganisms. Aberrant hostmicrobe interactions are supposed to be a cause of
inflammatory bowel disease such as Crohn’s disease.
Focusing on the nuclear hormone receptor RORγt
expressing innate lymphoid cell (Sawa et al., Science,2010), we are trying to understand the cellular andmolecular mechanisms that underlie maintenance ofthe gut immune system in the steady state, and thepathogenicity of such innate lymphoid cells in the
inflammatory state.
Fetal RORγt expressing innate lymphoid cells,
termed lymphoid tissue inducer (LTi) cells play
critical roles on the lymphoid tissue development.
However, the precise molecular network that governs
LTi activation in lymph node anlagen has not beenclarified. We are tackling this issue focusing on
several TNF family cytokines, some of which also
play critical roles on the development and function ofthymic epithelial cells.
4) Mechanism of autoimmune disease
The IL-17 producing helper T cell subset (Th17cell) plays critical roles in several autoimmune diseasemodels such as collagen induced arthritis (CIA) andexperimental encephalomyelitis (EAE). We haveidentified IkBζ as an indispensable transcription
factor for Th17 cell differentiation. However, in both
RA and EAE models, effector mechanisms of Th17
cells have been unclear. We are now trying tounderstand the molecular mechanisms of autoimmune
diseases conducted by Th17 cells using animal diseasemodels. Our final goal is to develop new therapeuticstrategies for human autoimmune diseases.

References
1.

2.

Takayanagi H.: New developments in osteoimmunology. Nat Rev Rheumatol. 8(11): 684-9(2012)
Miyazaki T, Iwasawa M, Nakashima T, Mori S,
Shigemoto K, Nakamura H, Katagiri H,
Takayanagi H, Tanaka S. :Intracellular andextracellular ATP coordinately regulate the59inverse correlation between osteoclast survivaland bone resorption., J Biol Chem. 287(45):37808-23 (2012)
3. O'Brien CA, Nakashima T, Takayanagi H.:
Osteocyte control of osteoclastogenesis., Bone.
54(2): 258-63 (2012).
4. Nakashima T, Hayashi M, Takayanagi H.: New
insights
intoosteoclastogenic
signalingmechanisms., Trends Endocrinol Metab.
23(11): 582-90 (2012)
5. Shinohara M, Nakamura M, Masuda H, Hirose J,
Kadono Y, Iwasawa M, Nagase Y, Ueki K,
Kadowaki T, Sasaki T, Kato S, Nakamura H,
Tanaka S, Takayanagi H.: Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone
resorption through Akt-mediated vesicletransport. J Bone Miner Res. 27(12): 2464-75.
(2012)
6. Hara-Yokoyama M, Kukimoto-Niino M,
Terasawa K, Harumiya S, Podyma-Inoue KA,
Hino N, Sakamoto K, Itoh S, Hashii N, Hiruta Y,
Kawasaki N, Mishima-Tsumagari C, Kaitsu Y,
Matsumoto T, Wakiyama M, Shirouzu M,
Kasama T, Takayanagi H, Utsunomiya-Tate N,
Takatsu K, Katada T, Hirabayashi Y, Yokoyama
S, Yanagishita M.: Tetrameric Interaction of theEctoenzyme CD38 on the Cell Surface Enables
Its Catalytic and Raft-Association Activities.
Structure. 20(9): 1585-95 (2012)
7. Komatsu N. and Takayanagi H.: Inflammation
and bone destruction in arthritis: synergistic
activity of immune and mesenchymal cells in
joints. Front Immunol. 3:77 (2012)
8. Komatsu N, Takayanagi H.: Autoimmune
Arthritis: The Interface Between the Immune
System and Joints, Adv Immunol., 115:45-71(2012)
9. Hayashi, M., Nakashima, T., Taniguchi, M.,
Kodama, T., Kumanogoh, A., Takayanagi. T.:
Osteoprotection by Semaphorin 3A. Nature.
485(7396): 69-74 (2012)
10. Otero, K., Shinohara, M., Zhao, H., Cella, M.,
Gilfillan, S., Colucci, A., Faccio, R., Ross, F, P.,
Teitelbaum, S, L., Takayanagi, H., Colonna, M.:
TREM2 and β-Catenin Regulate Bone Homeostasis by Controlling the Rate of Osteoclastogenesis. J Immunol. 188(6): 2612-21 (2012)

11. Fujita, K., Iwasaki, M., Ochi, H., Fukuda, T., Ma,
C., Miyamoto, T., Takitani, K., Negishi-Koga, T.,
Sunamura, S., Kodama, T., Takayanagi, H.,
Tamai, H., Kato, S., Arai, H., Shinomiya, K., Itoh,H., Okawa, A., Takeda, S.: Vitamin E decreases
bone mass by stimulating osteoclast fusion. Nat
Med. 18(4): 589-94 (2012)
12. Tsuji-Takechi, K., Negishi-Koga, T., Sumiya, E.,
Kukita, A., Kato, S., Maeda, T., Pandolfi P,P.,Moriyama, K., Takayanagi, H.: Stage-specificfunctions of leukemia/lymphoma-related factor(LRF) in the transcriptional control of osteoclast
development. Proc Natl Acad Sci U S A. 109(7):2561-6
13. Takayanagi H.: New developments in osteoimmunology. Nat Rev Rheumatol. 8(11): 684-9(2012)
14. Miyazaki T, Iwasawa M, Nakashima T, Mori S,
Shigemoto K, Nakamura H, Katagiri H,
Takayanagi H, Tanaka S. :Intracellular andextracellular ATP coordinately regulate theinverse correlation between osteoclast survivaland bone resorption., J Biol Chem. 287(45):37808-23 (2012 )15. O'Brien CA, Nakashima T, Takayanagi H.:
Osteocyte control of osteoclastogenesis., Bone.
54(2): 258-63 (2012).
16. Nakashima T, Hayashi M, Takayanagi H.: New
insights
intoosteoclastogenic
signalingmechanisms., Trends Endocrinol Metab.
23(11): 582-90 (2012)17. Shinohara M, Nakamura M, Masuda H, Hirose J,
Kadono Y, Iwasawa M, Nagase Y, Ueki K,
Kadowaki T, Sasaki T, Kato S, Nakamura H,
Tanaka S, Takayanagi H.: Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone
resorption through Akt-mediated vesicletransport. J Bone Miner Res. 27(12): 2464-75.
(2012)
18. Hara-Yokoyama M, Kukimoto-Niino M,
Terasawa K, Harumiya S, Podyma-Inoue KA,
Hino N, Sakamoto K, Itoh S, Hashii N, Hiruta Y,
Kawasaki N, Mishima-Tsumagari C, Kaitsu Y,
Matsumoto T, Wakiyama M, Shirouzu M,
Kasama T, Takayanagi H, Utsunomiya-Tate N,
Takatsu K, Katada T, Hirabayashi Y, Yokoyama
S, Yanagishita M.: Tetrameric Interaction of the

60

19.

20.

21.

22.

23.

24.

Ectoenzyme CD38 on the Cell Surface Enables
Its Catalytic and Raft-Association Activities.
Structure. 20(9): 1585-95 (2012)
Komatsu N. and Takayanagi H.: Inflammation
and bone destruction in arthritis: synergistic
activity of immune and mesenchymal cells in
joints. Front Immunol. 3:77 (2012)
Komatsu N, Takayanagi H.: Autoimmune
Arthritis: The Interface Between the Immune
System and Joints, Adv Immunol., 115:45-71(2012)
Hayashi, M., Nakashima, T., Taniguchi, M.,
Kodama, T., Kumanogoh, A., Takayanagi. T.:
Osteoprotection by Semaphorin 3A. Nature.
485(7396): 69-74 (2012)
Otero, K., Shinohara, M., Zhao, H., Cella, M.,
Gilfillan, S., Colucci, A., Faccio, R., Ross, F, P.,
Teitelbaum, S, L., Takayanagi, H., Colonna, M.:
TREM2 and β-Catenin Regulate Bone Homeostasis by Controlling the Rate of Osteoclastogenesis. J Immunol. 188(6): 2612-21 (2012)
Fujita, K., Iwasaki, M., Ochi, H., Fukuda, T., Ma,
C., Miyamoto, T., Takitani, K., Negishi-Koga, T.,
Sunamura, S., Kodama, T., Takayanagi, H.,
Tamai, H., Kato, S., Arai, H., Shinomiya, K., Itoh,H., Okawa, A., Takeda, S.: Vitamin E decreases
bone mass by stimulating osteoclast fusion. Nat
Med. 18(4): 589-94 (2012)
Tsuji-Takechi, K., Negishi-Koga, T., Sumiya, E.,
Kukita, A., Kato, S., Maeda, T., Pandolfi P,P.,Moriyama, K., Takayanagi, H.: Stage-specificfunctions of leukemia/lymphoma-related factor(LRF) in the transcriptional control of osteoclast
development. Proc Natl Acad Sci U S A. 109(7):2561-6 (2012)

Radiology and Biomedical
Engineering
1. Radiology

62

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

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

Jiro Sato, M.D.,

Hidemasa Takao, MD., Ph.D.,

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

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

Wataru gonoi, M.D., Ph.D.,

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

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

Shouhei Hanaoka, 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, two cyclotronsand several remote or processor-controlled automateddevices are installed, which facilitate standardized
procedures in the PET tracer production and theimplementation of GMP in PET related work. There
are two SPECT rooms and four PET rooms. These
nuclear imaging procedures are chiefly performed andreported by nuclear medicine physicians andcardiologists.
Each year, over 700 new patients receive radiation
therapy in the Radiation Oncology section. Highly
accurate 3D radiation therapy is the most outstanding

63

feature. Stereotactic radiation therapy for small lungor liver tumors has been carried out.
In the 9th floor of the new inpatient building, there
are 12 beds in the Radiology ward, which are usuallyused for oncology patients receiving radiation therapy
and chemotherapy. Some of them are sometimes used
for patients receiving invasive diagnostic procedures
such as interventional radiology (IVR), angiography
and myelography. There are two special beds forradionuclide (RN) therapy in the same floor. In
addition, four beds are allotted to terminal care ward
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 such as the optimization of dose
distribution in the radiation therapy (RT) and the otheris reduction of injuries due to radiation exposure in
vitro and in vivo. This group pushes forward studies
mainly on a brain tumor, head and neck cancer,
esophageal cancer, uterine cervical cancer, prostatecancer in conformity with recent EBM in the clinicalstudy, and was active in studies of the physicalengineering traditionally and took a main role in thehighly precise radiation therapy of our country until
now. With the purpose of achieving precise external
irradiation, a new linear accelerator with C-arm andmultileaf collimator systems was developed andinstalled, which is utilized mainly for non-coplanar
radiation therapy in many patients especially withbrain tumor or head and neck tumor. Dynamic conicalconformal radiotherapy (Dyconic therapy) formetastatic brain tumors using the accelerator is underevaluation. In addition to gamma knife radiosurgery,this new accelerator based stereotactic radiotherapy
for brain diseases has been undergone, and stereotactic
radiotherapy (SRT) for body tumors, such as head andneck cancer, prostate cancer, rectal cancer and lungcancer, has been investigated (intensity modulation
radiation therapy; IMRT) for the reduction of theadverse radiation damage. A new technology to track

64

mobile tumors, represented by lung tumors is underinvestigation in collaboration with accelerator makers.
Novel approach to terminal care of patients withvarious cancers has been investigated and implemented 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 in combination 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 promotes clinical researchon functional imaging and the development ofradio-immunotherapy (RIT) by the application ofradioisotope-labeled tracer technology, combinedwith molecular biology. In particular, emission
tomography (PET and SPECT) is applied for theevaluation of cerebral blood flow and metabolism inpatients with dementia, epilepsy, and cerebrovasculardiseases. Cerebral blood flow, glucose metabolism andneural synaptic functions are measured for theunderstanding of normal and pathophysiological statesof CNS disorders, using a variety of positron-emitterradiotracer, such as [O-15] H2O, CO2, O2, CO, [F-18]
FDG, [C-11] methionine, [F-18] Dopa, [C-11] NMSP,NMPB, [C-11] raclopride and [C-11] PiB. The studyof dementia using SPECT and the standard brain atlas
has made it possible to categorize the type of dementia.
Evaluation of dopaminergic function by PET is very
important in the differential diagnosis of Parkinsonism.
Cardiac PET and SPECT are also active fields.
Myocardial viability, vascular reserve and sympathetic
nerve denervation in the ischemic heart disease are
evaluated with [F-18] FDG, [N-13] NH3, Tl-201 and[I-123] MIBG. Higher brain functions such as reading,speech and thinking have been studied with PET bycomparing blood flow and receptor binding potential(BP) under various tasks and at rest. For the precise
localization of activated brain function, computer
processing and reconstruction of composite images offunction and anatomy is an essential subject forinvestigation. At present, whole body FDG-PET is oneof the most effective tool for exploring metastatic
lesions of cancer patients. Combination display of
SPECT/PET with XCT/MRI would be a routine job
and anatomo-functional images would play animportant role in the clinical management of thepatients.

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Ohkawa R, Kishimoto T, Kurano M, Dohi T,
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Development of an enzymatic assay forsphingomyelin with rapid and automatableperformances: Analysis in healthy subjects andcoronary heart disease patients.
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63. Onoe T, Nose T, Yamashita H, Yoshioka M,
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64. Ota M, Ishikawa M, Sato N, Hori H, Sasayama D,
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Glutamatergic changes in the cerebral whitematter associated with schizophrenic exacerbation.
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65. Ota M, Sato N, Nakata Y, Arima K, Uno M.
Relationship between apathy and diffusion tensor
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66. Ota M, Sato N, Ishikawa M, Hori H, Sasayama D,
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morphometry.
Psychiatry Clin Neurosci 66(7): 611-7, 2012
67. Shibata-Kobayashi S, Yamashita H, Okuma K,
Shiraishi K, Igaki H, Ohtomo K, Nakagawa K.
Correlation among 16 biological factors [p53,p21(waf1), MIB-1 (Ki-67), p16(INK4A), cyclin
D1, E-cadherin, Bcl-2, TNF-α, NF-κB, TGF-β,
MMP-7, COX-2, EGFR, HER2/neu, ER, andHIF-1α] and clinical outcomes following curative
chemoradiation therapy in 10 patients withesophageal squamous cell carcinoma.
Oncol Lett 5(3): 903-10, 2013
68. Shimojima K, Okumura A, Mori H, Abe S, Ikeno
M, Shimizu T, Yamamoto T.
De novo microdeletion of 5q14.3 excluding
MEF2C in a patient with infantile spasms,
microcephaly, and agenesis of the corpus
callosum.
Am J Med Genet A 158A(9): 2272-6, 2012
69. Soma T, Momose T, Takahashi M, Koyama K,
Kawai K, Murase K, Ohtomo K.
Usefulness of extent analysis for statisticalparametric mapping with asymmetry index using
inter-ictal FGD-PET in mesial temporal lobe

70.

71.

72.

73.

74.

75.

76.

77.

epilepsy.
Ann Nucl Med 26(4): 319-26, 2012
Suzuki D, Yamaguchi M, Furuta T, Okuyama Y,
Yoshikawa K, Fujii H.
Central high signal in inflammatory swollen
lymph nodes on SPIO-enhanced interstitial MR
lymphograms: a mimic of lymph node metastasis.
Magn Reson Med Sci 11(1): 61-3, 2012
Tajima T, Akahane M, Takao H, Akai H, Kiryu S,
Imamura H, Watanabe Y, Kokudo N, Ohtomo K.
Detection of liver metastasis: is diffusionweighted imaging needed in Gd-EOB-DTPAenhanced MR imaging for evaluation ofcolorectal liver metastases?
Jpn J Radiol 30(8): 648-58, 2012
Takahashi M, Soma T, Kawai K, Koyama K,
Ohtomo K, Momose T.
Voxel-based comparison of preoperative FDGPET between mesial temporal lobe epilepsy
patients with and without postoperative seizurefree outcomes.
Ann Nucl Med 26(9): 698-706, 2012
Takahashi W, Yamashita H, Niibe Y, Shiraishi K,
Hayakawa K, Nakagawa K.
Stereotactic body radiotherapy for metastatic
lung cancer as oligo-recurrence: ananalysis of 42cases.
Pulm Med 2012: 454107, 2012
Takao H, Hayashi N, Ohtomo K.
A longitudinal study of brain volume changes innormal aging.
Eur J Radiol 81(10): 2801-4, 2012
Tomizawa N, Nojo T, Akahane M, Torigoe R,
Kiryu S, Ohtomo K.
Adaptive Iterative Dose Reduction in coronary
CT angiography using 320-row CT: assessmentof radiation dose reduction and image quality.
J Cardiovasc Comput Tomogr 6(5): 318-24, 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 in coronary computed tomography angiography.
Eur J Radiol 81(11): 3250-3, 2012
Tomizawa N, Yamamoto K, Akahane M, Torigoe
R, Kiryu S, Ohtomo K.

70

78.

79.

80.

81.

82.

83.

84.

The feasibility of halfcycle reconstruction in highheart rates in coronary CT angiography using
320-row CT.
Int J Cardiovasc Imaging: Epub ahead of print,
2012
Tomizawa N, Nojo T, Akahane M, Torigoe R,
Kiryu S, Ohtomo K.
Shorter delay time reduces interpatient variability
in coronary enhancement in coronary CT angiography using the bolus tracking method with
320-row CT.
Int J Cardiovasc Imaging 29(1): 185-90, 2013
Toyoda K, Oba H, Kutomi K, Furui S, Oohara A,
Mori H, Sakurai K, Tsuchiya K, Kan S,
Numaguchi Y.
Magnetic resonance imaging of IgG4-relateddisease in the head and neck and brain.
AJNR Am J Neuroradiol 33(11): 2136-9, 2012
Tsukamoto M, Akahane M, Nangaku M.
Image of Erdheim-Chester disease requiring
hemodialysis.
Clin Exp Nephrol 16(5): 811-2, 2012
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 KJ, Kato N, Kano Y,
Miyashita Y, Kasai K, Yamasue H.
Diminished medial prefrontal activity behind
autistic social judgments of incongruent
information.
PLoS One 7(6): e39561, 2012
Yamaguchi M, Mitsuda M, Ezawa K, Nakagami
R, Furuta T, Sekine N, Niitsu M, Fujii H.
Artifact-reduced simultaneous MRI of multiple
rats with liver cancer using PROPELLER.
J Magn Reson Imaging: Epub ahead of print,
2012
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.
Jpn J Clin Oncol 42(4): 302-8, 2012
Yamashita H, Okuma K, Takahashi W, Sakumi A,
Haga A, Ino K, Akahane M, Ohtomo K,

Nakagawa K.
Four-dimensional
measurementofthedisplacement of metal clips or postoperative
surgical staples during 320-multislice computed
tomography scanning of gastric cancer.
Radiat Oncol 7: 137, 2012
85. Yamashita H, Okuma K, Tada K, Shiraishi K,
Takahashi W, Shibata-Mobayashi S, Sakumi A,
Saotome N, Haga A, Onoe T, Ino K, Akahane M,
Ohtomo K, Nakagawa K.
Four-dimensional measurement of the displacement of internal fiducial and skin markers during
320-multislice computed tomography scanning ofbreast cancer.
Int J Radiat Oncol Biol Phys 84(2): 331-5, 2012
86. Yoshida M, Hori M, Yokoyama K, Fukunaga I,
Suzuki M, Kamagata K, Shimoji K, Nakanishi A,
Hattori N, Masutani Y, Aoki S.
Diffusional kurtosis imaging of normal-appearing
white matter in multiple sclerosis: preliminary
clinical experience.
Jpn J Radiol 31(1): 50-5, 2013
87. Yoshikawa T, Hayashi N, Tajiri Y, Satake Y,
Ohtomo K.
Brain reorganization in patients with brachial
plexus injury: a longitudinal functional MRI study.
ScientificWorldJournal 2012: 501751, 2012

Radiology and Biomedical
Engineering
2. Biomedical Engineering

72

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 three postdocs, two PhD student, threemaster course students and one technician has joinedby the end of FY2012.

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 2012, 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.,

73

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. Especially, a novel fluorescence probe for
γ-glutamyltranspeptidase which was developed in2011, was applied for various real human resected
tumor samples under several collaborations withsurgeons including those in Tokyo University Hospitalin order to examine the efficiency of the new probe.

References
1. Urano Y: Novel live imaging techniques ofcellular functions and in vivo tumors based on
precise design of small molecule-based‘Activatable’ fluorescence probes. Current
Opinion in Chemical Biology 16:602-608, 2012.
doi:10.1016/j.cbpa.2012.10.023
2. Kojima R, Takakura H, Ozawa T, Tada Y,
Nagano T, Urano Y: Rational Design andDevelopment of Near-Infrared-Emitting Firefly
Luciferins Available In Vivo. Angew Chem Int
Ed
Engl
21;52(4):1175-9,
2012.
doi:
10.1002/anie.201205151.
3. Kobayashi T, Komatsu T, Kamiya M, Campos C,
González-Gaitán M, Terai T, Hanaoka K, Nagano
T, Urano Y: Highly Activatable and Environmentinsensitive Optical Highlighters for Selective
Spatiotemporal Imaging of Target Proteins. J. Am.
Chem. Soc.134(27) 11153-11160, 2012. doi: 10.
1021/ja212125w
4. Takakura H, Kojima R, Ozawa T, Nagano T,
Urano Y: Development of 5'- and 7'-Substituted
Luciferin Analogues as Acid-Tolerant Substratesof Firefly Luciferase. Chembiochem 13(10):1424-7, 2012. doi: 10.1002/cbic.201200142.
5. McCann TE, Kosaka N, Koide Y, Mitsunaga M,
Choyke PL, Nagano T, Urano Y, Kobayashi H:
Activatable optical imaging with a silica-

rhodamine based near infrared (SiR700)
fluorophore: a comparison with cyanine baseddyes. Bioconjug Chem. 21;22(12):2531-8, 2011.
doi: 10.1021/bc2003617.
6. Koide Y, Kawaguchi M, Urano Y, Hanaoka K,
Komatsu T, Abo M, Terai T, Nagano T: A
reversible near-infrared fluorescence probe forreactive oxygen species based on Te-rhodamine
Chem Commun (Camb). 48(25):3091-3, 2012.
doi: 10.1039/c2cc18011a.
7. Koide Y, Urano Y, Hanaoka K, Piao W,
Kusakabe M, Saito N, Terai T, Okabe T, Nagano
T: Development of NIR fluorescent dyes based on
Si-rhodamine for in vivo imaging. J Am Chem
Soc. 134(11): 5029-31, 2012. doi: 10.1021/
ja210375e.
8. Mitsunaga M, Kosaka N, Choyke PL, Young MR,
Dextras CR, Saud SM, Colburn NH, Sakabe M,
Nagano T, Asanuma D, Urano Y, Kobayashi H:
Fluorescence endoscopic detection of murine
colitis-associated colon cancer by topicallyapplied enzymatically rapid-activatable probe.
Gut 2012 Jun 14. [Epub ahead of print]
9. Terai T, Kikuchi K, Urano Y, Kojima H, Nagano
T: A long-lived luminescent probe to sensitively
detect arylamine N-acetyltransferase (NAT)
activity of cells. Chem Commun (Camb). 48(16):2234-6, 2012. doi: 10.1039/c2cc17622j.
10. Terai T, Urano Y, Izumi S, Kojima H, Nagano T:
A practical strategy to create near-infrared
luminescent probes: conversion from fluoresceinbased sensors. Chem Commun (Camb). 48(23):2840-2, 2012. doi: 10.1039/c2cc16553h.

74

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.
Today, medical engineering has grown up not only toa very 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 to the present title sinceApril 1, 1997.
The current members include 1 associate professor, 1lecturer, 1 research fellow, 7 graduate students, 1
professor emeritus, 14 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 can choose to perform their researchworks 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 3rdyear medical students, and provide practice in the“free quarter” course for the 3rd and 4th year medical
students. In systematic lectures, we teach introduction
to the advanced diagnostic and therapeutic medical
engineering technologies. The lectures for artificialorgan technologies are included.
For post-graduate education, we provide lectures forthe master course students, and we take a part in seriesof lectures for the doctor course students. For the
master course students, we offer lectures on artificialorgan technologies. For the doctor course students, weoffer lectures on advanced medical engineering
technologies.
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 thedoctor course students is not limited to the field of theartificial organs but is found from the wide area ofadvanced medical engineering technologies.

75

Students must attend to the weekly meeting. They canlearn how to perform the research work and how toreport it through the meeting.
The education for the leaders of medical engineers andclinical engineers is another important role of ourdepartment.

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.
Concerning the artificial heart, almost all the
researches and developments for driving mechanisms,
energy converters, blood pumps, artificial valves,biomaterials, power transmissions, measurement
techniques, control methods, anatomical fitting, bloodcompatibility, tissue compatibility, computer fluid
dynamics, physiology, pathology, and so on, havebeen 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 theparacorporeal total artificial heart (TAH) with noanticoagulant, which is still the longest surviving
record of TAH animals in the world.
Our artificial heart research at present is to develop asmall size TAH enough to be implanted in the body ofsmall stature like Japanese with high performance,
good anatomical fitting, high durability, highreliability, high efficiency, good controllability,
excellent biological compatibility and a physiologicalflow control. To meat the purpose, we had beendeveloping the TAH using undulation pumps, named
undulation pump TAH (UPTAH). The undulation
pump is our original blood pump invented in 1992.
The UPTAH revealed to have an excellent
performance and the goat whose heart was replacedwith the UPTAH survived for 153 days. However, the
UPTAH had a problem in the durability of the drive
shaft mechanism. To improve the problem of the
UPTAH, a new blood pump, named the helical flow
pump (HFP), was invented in our laboratory in 2005.

The HFP is a novel blood pump having ahydrodynamic levitating impeller, which promises
high durability. The animal experiment of the helicalflow TAH (HFTAH) had started in 2011. The HFTAH
could be implanted in the goat successfully with goodanatomical fitting. The goat whose heart was replacedwith the HFTAH survived for 100 days. We are
expecting to develop an ideal TAH that surpass theoutcome of the heart transplantation with combinationof the technologies of the physiological control andhybrid materials described later.
How to control the output of a TAH is primary interest.
We have developed our original physiological control
method of the TAH, named 1/R control. The 1/R
control was developed with 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 a 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 ametabolic demand of the animal.
The problem of the 1/R control was a mismatching of
the time constants between the control systems of thedevice and the body. As a consequence, the 1/R
control occasionally diverged in the animal
experiment of the UPTAH and HFTAH. To improve
the problem of instability in the 1/R control, a newcontrol method based on the fluctuation of arterial andvenous pressures (named ΔP control) was developedby reforming the 1/R control function. The newcontrol method has been under the experiment.
The 1/R control was applied to the UPTAH and the
HFTAH to perform a physiological study with a
nonpulsatile TAH by changing the drive mode frompulsatile to nonpulsatile in a single goat. The result
showed that the 1/R control could be promising not
only with a pulsatile mode, but also with a
nonpulsatile mode. The general conditions and organfunctions were not changed by the application of the
nonpulsatile mode. The cardiac output and the arterialpressure changed with the condition of the goat in thepulsatile and also nonpulsatile modes, which seemedalmost identical. However, under the physiologicalatrial pressure, the sucking effect of atria was moresignificant in the nonpulsatile mode than the pulsatile

76

mode. 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 materials, we have been developing a
new method to develop hybrid materials. In general, it
is not easy to develop mechanical parts for
implantable artificial organs from the components ofliving tissue because these components haveinsufficient strength and durability, even though they
have excellent tissue compatibility. To overcome these
problems, an insert molding method, which iscommonly used for the molding of resin in theindustrial field, was introduced. In this method, themold, in which an artificial material was inserted, was
implanted in the animal, and the tissue grew into themold to make a hybrid material. The method was first
applied to the Jellyfish valve that was originally apolymer valve for the artificial hearts. The hybrid
Jellyfish valve demonstrated a good result. Then, we
started to develop the hybrid conduit of the inflow
cannula for the left ventricular assist device (LVAD).
The conduit is inserted into the apex of the left
ventricle where the thrombus often formed. In thismethod, the mold in which the core of the conduit wasinserted was implanted under the skin of a goat. Afterseveral months, the hybrid conduit was extirpated, andthen freeze-dried, sterilized and used. The experimentof the LVAD using the hybrid conduit is going on witha goat. This hybrid technique will be an 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 than nonseeding 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,
which can be used as an extracorporeal membrane
oxygenator (ECMO), has been started in 2004. The
device consists of a blood pump, an oxygenator, adrive and control unit, and a battery unit. A new
membrane oxygenator and a new blood pump were
designed and integrated into one piece. An
experimental model exhibited good performance. The
improved model of the ELSS is under thedevelopment to realize up to one-month support. The
whole system components will be packed in a casehaving 180 mm in diameter and 390 mm in length.
The whole weight will be about 20 kg.
Our research of the application of IT (information
technology) to medicine has been focused to the home
medical care. The research and development formonitoring the condition of the patients living at home
has been performed utilizing the miniaturized wireless
ECG (electro cardiogram) unit. The ECG unit is
attached on the patient’s chest at home. The ECG datais transmitted to the laptop computer set in thepatient’s home. The data is then transmitted to the dataserver set at our laboratory through the mobile
Internet communication. The client computers in theclinic or doctor’s smart phone receive the real-timedata through the Internet lines from the data server.
This system has been tested experimentally in a clinic.
The system revealed to be very useful especially fortaking care of the patients who were going to be indeathbed. To obtain more detailed diagnosis of suchpatients, a breathing monitor is necessary. The
transmitter unit contains a three-axis acceleration
sensor that is used usually for detecting the motion or
posture of the patient. We are trying to detect the
respiratory frequency using the three-axis acceleration

77

sensor contained in the unit.
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, Ishii K, Isoyama T, Saito I, Inoue Y, Ono T,
Nakagawa H, Nakano E, Fukazawa K, Ishihara K,Fukunaga K, Ono M, Imachi K. The helical flow
pump with a hydrodynamic levitation impeller. J
Artif Organs 2012;15: 331-40

2.

Isoyama T, Yamada H, Saito I, Sato M, Okada Y,
Miyahara K, Ohta H, Abe Y. Real-time in-homepatient monitoring systems using high-speed mobile
Internet and remote access. Proc of International
Conference on uHealthcare 2012 2012: 25-6

3.

Inoue Y, Saito I, Isoyama T, Nakagawa H, Ono T,
Ishii K, Ariyoshi K, Nakano E, Imachi K, Abe Y.
Development of an Implantable Small Observation
Camera with Scaffold Chamber for Angiogenesis.
Proc of World Congress 2012 Medical Physics andBiomedical Engineering 2012: TH08011-3

4. Ishii K, Saito I, Isoyama T, Nakagawa H, Nakano E,
Ono T, Shi W, Inoue Y, Abe Y. Development of
Normal-Suction Boundary Control Method Basedon Inflow Cannula Pressure Waveform for the
Undulation Pump Ventricular Assist Device. Artif
Organs 2012;36: 812-6

Neuroscience
1. Basic Neuroscience

79

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,

80

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 ishighlighted as a milestone work that elucidated themechanistic roles of protein cofactors in the formationand function of γ-secretase (see reviews; Iwatsubo
Mol Psychiatr, 2004; Curr Opin Neurobiol, 2004). His
group has also shown by establishing in vitro
γ-secretase assays that sulindac sulfide, a major
non-steroidal anti-inflammatory drugs, directly acts on
γ-secretase and selectively reduce Aβ42-generating
activities (Takahashi et al., J Biol Chem, 2003),
providing important implications to the therapeuticstrategies of AD by γ-secretase modulation. Recently,
he has established a novel method for an efficient invitro reconstituion of γ-secretase complex, paving theway towards the structural analysis of active
γ-secretase (Hayashi et al. J Biol Chem, 2004), andusing thus highly purified γ-secretase particles, they
have partially unveiled the submolecular structure ofthis complex by single-particle EM analysis (Ogura etal. BBRC, 2006). Very recently, his group has
established an elegant strategy to analyze thestructure-function relationship within the catalytic
structure of γ-secretase complex by cystein chemistry,and demonstrated that γ-secretase harbors a waterpermeable catalytic pore (Sato et al. J Neurosci, 2006),
and that substrate proteins enter the catalytic porethrough the lateral gate located at the C terminal sideof 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
as a major component of Lewy bodies.

Using cortical Lewy bodies purified frompostmortem brains of patients with dementia with
Lewy bodies (DLB) by his original method (Iwatsubo
et al. Am J Pathol 1996) as immunogens, Dr.
Iwatsubo’s group, in collaboration with Drs. Virginia
Lee and John Trojanowski at Univ. Penn, performed
an extensive immunochemical search for componentsof Lewy bodies. They have demonstrated by raising a
specific monoclonal antibody that α-synuclein, thatproved to be a product of pathogenic gene for familial
form of Parkinson’s disease, is one of the major
constituent of Lewy bodies in sporadic Parkinson’s
disease and DLB (Baba et al. Am J Pathol 1998). His
group then purified aggregated α-synuclein from DLB
cortices using fine biochemical techniques, purified it
to near homogeneity, and demonstrated using mass
spectrometry and specific antibodies that α-synuclein
deposited in synucleinopathy lesions is highly
phosphorylated at a specific serine residue (Fujiwara
et al. Nature Cell Biol 2002). This finding led to arange of studies focusing on the role of synuclein
phosphorylation in neurodegeneration. Also, thephospho-specific α-synuclein antibody is widely usedas the most sensitive marker for α-synucleinopathy
lesions, and they have characterized a wide spectrumof α-synuclein pathologies in neurodegenerative
disorders.
3. Identification of a non-Aβ Alzheimer amyloid 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

81

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
CLAC-positive senile plaques constitute a uniquesubset of plaques distinct from the classical,
β-sheet-rich amyloid deposits, underscoring thepathobiological role of CLAC in amyloid formation(Kowa et al. Am J Pathol, 2004), and that CLAC
inhibits fibrillization of Aβ in vitro (Osada et al. J Biol
Chem, 2005). Transgenic mice studies are confirming
the role of CLAC in the morphogenesis of senile
plaques in vivo.
4. Japanese ADNI: clinical studies for 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) Ito G, Iwatsubo T: Re-examination of the
dimerization state of leucine-rich repeat kinase 2:
predominance of the monomeric form. Biochem J
441:987-994, 2012
2) Hayashi I, Takatori S, Urano Y, Iwanari H, Osawa
S, Morohashi Y, Li T, Wong PC, Chiba S, Kodama
T, Hamakubo T, Tomita T, Iwatsubo T:
Neutralization of the g-secretase activity by
monoclonal antibody against extracellular domainof nicastrin. Oncogene 31:787-798, 2012
3) Kuwahara T, Tonegawa R, Ito G, Mitani S,
Iwatsubo T: Phosphorylation at Ser129 reduces

4)

5)

6)

7)

8)

a-synuclein neurotoxicity by lowering its
membrane-binding property in Caenorhabditis
elegans. J Biol Chem 287:7098-7109, 2012
Colla E, Coune P, Liu Y, Pletnikova O, Troncoso
JC, Iwatsubo T, Schneider B, Lee M:
Endoplasmic reticulum stress is important for the
manifestations of a-synucleinopathy in vivo. J.
Neurosci 32:3306-3320, 2012
Goto M, Abe O, Kabasawa H, Takao H, Miyati T,
Hayashi N, Kurosu T, Iwatsubo T, Yamashita F,
Matsuda H, Inano S, Mori H, Kunimatsu A, Aoki
S, Ino K, Yano K, Ohtomo K, Japanese
Alzheimer’s Disease Neuroimaging Initiative:
Effects of Image Distortion Correction on
Voxel-based Morphometry. Magneteic Resonancein Medical Sciences 11:27-34, 2012
Goto M, Abe O, Miyati T, Kabasawa H, Takao H,
Hayashi N, Kurosu T, Iwatsubo T, Yamashita F,
Matsuda H, Mori H, Kunimatsu A, Aoki S, Ino K,
Iida K, Yano K, Ohtomo K, Japanese Alzheimer’s
Disease Neuroimaging Initiative: Influence of
signal intensity non-uniformity on brain
volumetry using an atlas-based method. Korean
Journal of Radiology 13:391-402, 2012
Takeo K, Watanabe N, Tomita T, Iwatsubo T:
Contribution of g-secretase cofactors to theformation of catalyitic pore of presenilin 1. J Biol
Chem 287:25834-25843, 2012
Suzuki K, Hayashi Y, Nakahara S, Kumazaki H,
Prox J, Horiuchi K, Zheng M, Tanimura S,
Nishiyama Y, Osawa S, Sehara-Fujisawa A, Saftig
P, Yokoshima S, Fukuyana T, Matsuki N, Koyama
R, Tomita T, Iwatsubo T: Activity-dependent
proteolytic cleavage of neuroligin-1. Neuron
76:410-422, 2012

82

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83

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

84

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. In addition to
the transcriptional regulation, we are currently
investigating about the physiological function and its
molecular mechanism of Arc, which is thought to be a
key player that contributes activity dependentneuronal plasticity at post synaptic sites (Okuno et al.
Cell 2012).
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

85

local distribution of induced gene products have beenmonitored. Using state-of-the-art multi-wavelength
fluorescence imaging techniques, we are now
quantitatively assessing how local distribution of these
newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature
Mol. Pages, 2006).
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Both synaptic maturation and synaptic plasticity
have been shown to include a morphologicalcomponent that is directed by the dynamics of actin
cytoskeleton, a major cytoskeletal component both in
the dendritic spines and at the very proximity ofboutons in the axon terminals. Few studies in the past,
however, had directly addressed what moleculardeterminants regulate actin dynamics in living central
neurons undergoing synaptic activity. This was in part
because actin filament assembly and disassembly wereclassically studied mostly at the moving edges oflamellipodia of large growth cones in large-size
neurons from either mollusc or peripheral nerve cells.
Such visualization turned out to be much moredifficult in seemingly far less mobile spine structures
tightly apposed to presynaptic active zones.
We (and others) used GFP-actin imaging to try tounderstand how neuronal actin cytoskeleton in
hippocampal neurons was organized and reorganizedby exposure to synaptic activity. In our 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

86(Arakawa et al., J. Cell Biol., 2003).
Whether similar or distinct mechanisms also
operate during spinogenesis and spine maturation
remains to be determined, though a role for Rho andROCK has already been postulated in control of spinecomplexity and spine stability. However, multiple
small GTPase signaling cascades clearly seem tocontribute together, in a tightly coordinated manner, tospine regulation, since many distinct classes of GEFs
and GAPs have now been shown to be localized in 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 2012- December 2012)
1. Wei G, Yin Y, Li W, Bito H, She H, Mao Z.
Calpain-mediated degradation of myocyte enhancer
factor 2D contributes to excitotoxicity by activationof extrasynaptic N-methyl-D-aspartate receptors. J
Biol Chem., 287(8):5797-805, 2012.
2. Okuno H, Akashi K, Ishii Y, Yagishita-Kyo N,

Suzuki K, Nonaka M, Kawashima T, Fujii H,
Takemoto-Kimura S, Abe M, Natsume R,
Chowdhury S, Sakimura K, Worley PF, Bito H.
Inverse synaptic tagging of inactive synapses via
dynamic interaction of Arc/Arg3.1 with CaMKIIβ.
Cell, 149(4):886-98, 2012.
3. Kim R, Okuno H, Bito H. Deciphering themolecular rules governing synaptic targeting of thememory-related protein Arc. Commun Integr Biol.,
5(5):496-8, 2012.
4. Watakabe A, Kato S, Kobayashi K, Takaji M,
Nakagami Y, Sadakane O, Ohtsuka M, Hioki H,
Kaneko T, Okuno H, Kawashima T, Bito H,
Kitamura Y, Yamamori T. Visualization of corticalprojection neurons with retrograde TET-off lentiviral
vector. PLoS One, 7(10):e46157, 2012.
5. Endo T, Kakeyama M, Uemura Y, Haijima A, Okuno
H, Bito H, Tohyama C. Executive function deficits
and social-behavioral abnormality in mice exposed
to a low dose of dioxin in utero and via lactation.
PLoS One, 7(12):e50741, 2012.

87

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

Assistant Professor
Shigeyuki Namiki, Ph.D.,

Homepage

Daisuke Asanuma, Ph.D.

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.

883) 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
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. Tokunaga T, Namiki S, Yamada K, Imaishi T,
Nonaka H, Hirose K, Sando S. Cellsurface-anchored fluorescent aptamer sensor
enables imaging of chemical transmitter
dynamics. J Am Chem Soc. 134(23):9561-4,
2012.

Neuroscience
2. Integrative Medical Neuroscience90

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

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

Homepage

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

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

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

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

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

91

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.

92

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

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

Homepage

http: //childpsy.umin.jp/

Introduction and Organization
Recently, mental problems of child and 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.

Teaching activities
In the year of 2012, we had 6 graduate students.
In addition to research training, educational program

including full-year lectures of child psychiatry, caseconference and journal club was arranged.

Research activities
Main subjects of our research are ASD including
autism and Asperger syndrome, ADHD, Tourette
syndrome which is a severe and chronic tic disorder,and child & adolescent obsessive-compulsive disorder(OCD). We are trying to combine scientific analysis ofobjective mental and behavioral indicators withneuropsychological, brain-imaging, and genetic
studies into comprehensive and multidimensional
approach to problems in development of brain andmind. We are applying this comprehensive approach
to intervention studies including pharmacotherapy.
Major research projects with full or preliminary
performance in 2012 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

93

References
1. Kuwabara H, Kono T, Shimada T, Kano Y:
Factors affecting clinicians' decision as to whether
to prescribe psychotropic medications or not intreatment of tic disorders. Brain Dev. 34(1): 39-44,
2012.
2. Matsuda N, Kono T, Nonaka M, Shishikura K,
Konno C, Kuwabara H, Shimada T, Kano Y:
Impact of obsessive-compulsive symptoms in
Tourette's syndrome on neuropsychological
performance. Psychiatry Clin Neurosci. 66(3):
195-202, 2012.
3. Shimada T, Kitamoto A, Todokoro A,
Ishii-Takahashi A, Kuwabara H, Kim SY,
Watanabe K, Minowa I, Someya T, Ohtsu H,
Osuga Y, Kano Y, Kasai K, Kato N, Sasaki T:
Parental age and assisted reproductive technology
in autism spectrum disorders, attention deficit
hyperactivity disorder, and Tourette syndrome in a
Japanese population. Res Autism Spectr Disord.
6(1): 500-507, 2012.
4. Watanabe T, Yahata N, Abe O, Kuwabara H,
Inoue H, Takano Y, Iwashiro N, Natsubori T,
Aoki Y, Takao T, Sasaki H, Gonoi W, Murakami
M, Katsura M, Kunimatsu A, Kawakubo Y,
Matsuzaki H, Tsuchiya KJ, Kato N, Kano Y,
Miyashita Y, Kasai K, Yamasue H: Diminishedmedial prefrontal activity behind autistic social
judgments of incongruent information. PLoS ONE.
7(6): e39561, 2012.
5. Aoki Y, Abe O, Yahata N, Kuwabara H,
Natsubori N, Iwashiro N, Takano Y, Inoue H,
Kawakubo Y, Gonoi W, Sasaki H, Murakami M,
Katsura M, Nippashi Y, Takao H, Kunimatsu A,
Matsuzaki H, Tsuchiya KJ, Kato N, Kasai K,
Yamasue H: Absence of age-related prefrontal
NAA change in adults with autism-spectrum
disorders. Translational Psychiatry, 2: e178, 2012.
6. Kamio Y, Inada N, Moriwaki A, Kuroda M,
Koyama T, Tsujii H, Kawakubo Y, Kuwabara H,
Tsuchiya K, Uno Y, Constantino JN: Quantitative
autistic traits ascertained in a national survey of
22,529 Japanese schoolchildren. Acta Psychiatr
Scand (in press).
7. Yamagishi T, Horita Y, Mifune N, Hashimoto H,
Li Y, Shinada M, Miura A, Inukai K, Takagishi H,

Simunovic D: Rejection of unfair offers in theultimatum game is no evidence of strong
reciprocity. Proc Natl Acad Sci U S A. 109(50):20364-20368, 2012.

Neuroscience
3. Clinical Neuroscience95

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.

Research Associate
Shinsuke Kondo, M.D.

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

Go Taniguchi, M.D., Ph.D.

Kayo Ichihashi, M.D.

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

Eisuke Sakakibara, M.D.

Kingo Sawada, M.D.

Yosuke Kumakura, M.D.

Ayaka Ishii, M.D., Ph.D.

Tomoko Ando, M.D.

Namiko Kaji, M.D.

Homepage

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

Introduction and Organization

Clinical activities

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.

For outpatient services, we have more than 20 staff
psychiatrists, 4 clinical psychologists and 2 psychiatric social workers. Approximately 1000 new patients
visited yearly (2011), and the total visits per day was
about 150.
The secluded ward has 26 beds including 3
seclusion rooms. We also have 28 beds for the open
general ward. Approximately 500 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, mood disorder 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 in

96rehabilitation 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
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 focusedon Epilepsy, PTSD, autism and schizophrenia.

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) Kuwabara H, Kono T, Shimada T, Kano Y. Factors
affecting clinicians' decision as to whether toprescribe psychotropic medications or not in treatment of tic disorders.Brain Dev. 2012;34(1):39-44.
(2) Kaminsky Z, Tochigi M, Jia P, Mill J, Kwan A,
Ioshikhes I, Vincent JB, Kennedy J L, Strauss J, Pai
S, Wang SC, Petronis A. A multi-tissue analysis
identifies HLA Complex Group 9 gene methylationdifferences in bipolar disorder. Mol Psychiatr y 17:
728-740, 2012.
(3) Jahshan C, Cadenhead KS, Rissling AJ, Kirihara
K, Braff DL, Light GA. Automatic sensory information processing abnormalities across the illness
course of schizophrenia. Psychol Med. 2012;42(1):85-97(4) Horiuchi Y, Iida S, Koga M, Ishiguro H, Iijima Y,
Inada T, Watanabe Y, Someya T, Ujike H, Iwata
N, Ozaki N, Kunugi H, Tochigi M, Itokawa M,
Arai M, Niizato K, I ritani S, Kakita A Takahashi H,
Nawa H, Arinami T. Association of SNPs linked toincreased expression of SLC1A1 with schizophrenia. Am J Med Genet 159B: 30-37, 2012.
(5) Watanabe Y, Egawa J, Iijima Y, Nunokawa A,
Kaneko N, Shibuya M, Arinami T, Ujike H, Inada
T, Iwata N, Tochigi M, Kunugi H, Itokawa M,
Ozaki N, Hashimoto R, Some ya T. A two-stage
case-control association study between tryptophanhydroxylase2 (TPH2) gene and schizophrenia in a
Japanese population. Schizophr Res 137: 264 -266,
2012(6) Kirihara K, Rissling AJ, Swerdlow NR, Braff DL,
Light GA. Hierarchical organization of gamma andtheta oscillatory dynamics in schizophrenia. Biol
Psychiatry. 2012;71(10):873-80(7) Matsuda N, Kono T, Nonaka M, Shishikura K,
Konno C, Kuwabara H, Shimada T, Kano Y.

97

Impact of Obsessive Compulsive Symptoms in
Tourette's syndrome on neuropsychological performance. Psychiatry and Clinical Neurosciences.
2012; 66(3):195-202(8) Ando S, Kawakami N, World Mental Health Japan
Survey Group. Utility of self-reported sleep
disturbances as a marker for major depressive
disorder (MDD): Findings from the World Mental
Health Japan Survey 2002-2006. 2012; 198:
146-153(9) Kunimatsu N, Aoki S, Kunimatsu A, Abe O,
Yamada H, Masutani Y, Kasai K, Yamasue H,
Ohtomo K. Tract-specific analysis of white matter
integrity disruption in schizophrenia. Psychiatry
Res 2012 201: 136-143(10) Kirihara K, Kasai K, Tada M, Nagai T, Kawakubo
Y, Yamasaki S, Onitsuka T, Araki T:
Neurophysiological impairment in emotional faceprocessing is associated with low extraversion inschizophrenia. Prog Neuropsychopharmacol Biol
Psychiatry 2012 37: 270-275(11) Iwashiro N, Suga M, Takano Y, Inoue H, Natsubori
T, Satomura Y, Koike S, Yahata N, Murakami M,
Katsura M, Gonoi W, Sasaki H, Takao H, Abe O,
Kasai K, Yamasue H: Localized gray mattervolume reductions in the pars triangularis of theinferior frontal gyrus in individuals at clinicalhigh-risk for psychosis and first episode forschizophrenia. Schizophr Res 2012 137: 124-131(12) Sakakibara E, Nishida T, Sugishita K, Jinde S,
Inoue Y, Kasai K: Acute psychosis during postictal
period in a patient with idiopathic generalized
epilepsy: Postictal psychosis or aggravation ofschizophrenia? A case report and review of theliterature. Epilepsy Behav 2012 24(3):373-376(13) Oshima N, Nishida A, Shimodera S, Tochigi M,
Ando S, Yamasaki S, Okazaki Y, Sasaki T. The
suicidal feelings, self-injury, and mobile phone use
after lights out in adolescents. J Pediatr Psychol,
2012; 37, 1023-1030(14) 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, Kawakubo Y, Matsuzaki H, Tsuchiya K,
Kato N, Kano Y, Miyashita Y, Kasai K, Yamasue
H: Diminished Medial Prefrontal Activity Behind
Autistic Social Judgments of Incongruent

Information. PLoS ONE 2012 7: e39561(15) Aoki Y, Kasai K, Yamasue H: Age-related change
in brain metabolite abnormalities in autism: A
meta-analysis of proton magnetic resonancespectroscopy studies. Transl Psychiatry 2012 2: e69(16) Erhardt A, Akula N, Schumacher J, Czamara D,
Karbalai N, Muller-Myhsok B, Mors O, Borglum A,
Kristensen AS, Woldbye DP, Koefoed P, Eriksson
E, Maron E, Metspalu A, Nurnberger J, Philibert
RA, Kennedy J, Domschke K, Reif A, Deckert J,
Otowa T, Kawamura Y, Kaiya H, Okazaki Y, Tanii
H, Tokunaga K, Sasaki T, Ioannidis JP, McMahon
FJ, Binder EB. Replication and meta-analysis of
TMEM132D gene variants in panic disorder. Transl
Psychiatry. 2012 Sep 4;2:e156.
(17) Khare T, Pai S, Koncevicius K, Pal M, Kriukiene E,
Liutkeviciute Z, Irimia M, Ji a P, Ptak C, Xia M,
Tice R, Tochigi M, Morera S, Nazarians A,
Belsham D, Wong AH C, Blencowe BJ, Wang SC,
Kapranov P, Kustra R, Labrie V, Klimasauskas S,
Petroni s A. 5-hmC in the brain is abundant insynaptic genes and shows differences at t he exonintron boundary. Nat Struct Mol Biol 19: 10371043, 2012.
(18) Tochigi M, Nishida A, Shimodera S, Oshima N,
Inoue K, Okazaki Y, Sasaki T. Irreg ular bedtime
and nocturnal cellular phone usage as risk factors
for being involv ed in bullying: a cross-sectional
survey of Japanese adolescents. PLoS One 7: e45736, 2012.
(19) Yu CC, Furukawa M, Kobayashi K, Shikishima C,
Cha PC, Sese J, Sugawara H, Iwamoto K, Kato T,
Ando J, Toda T. Genome-wide DNA methylationand gene expression analyses of monozygotic twins
discordant for intelligence levels. PLoS ONE
2012;7:e47081(20) Otowa T, Kawamura Y, Nishida N, Sugaya N,
Koike A, Yoshida E, Inoue K, Yasuda S, Nishimura
Y, Liu X, Konishi Y, Nishimura F, Shimada T,
Kuwabara H, Tochigi M, Kakiuchi C, Umekage T,
Miyagawa T, Miyashita A, Shimizu E, Akiyoshi J,
Someya T, Kato T, Yoshikawa T, Kuwano R, Kasai
K, Kato N, Kaiya H, Tokunaga K, Okazaki Y, Tanii
H, Sasaki T: Meta-analysis of genome-wide
association studies for panic disorder in theJapanese population. Translational Pcychiatry(2012) 2: e186

98(21) Bundo M, Sunaga F, Ueda J, Kasai K, Kato T,
Iwamoto K: A systematic evaluation of wholegenome amplification of bisulfate-modified DNA.
Clin Epigenetics, 2012 4(1):22(22) Nishioka M, Shimada T, Bundo M, Ukai W,
Hashimoto E, Saito T, Kano Y, Sasaki T, Kasai K,
Kato T, Iwamoto K: Neuronal cell-type specific
DNA methylation patterns of the Cacna1c gene. Int
J Dev Neurosci., 2012 31(2):89-95(23) Sugaya N, Yoshida E, Yasuda S, Tochigi M, Takei
K, Otani T, Otowa T, Minato T, Umekage T,
Konishi Y, Sakano Y, Chen J, Nomura S, Okazaki
Y, Kaiya H, Sasaki T, Tanii H. Prevalence ofbipolar disorder in panic disorder patients in theJapanese population. J Affect Disord. 2012 Nov 30.
(24) Nishioka M, Bundo M, Kasai K, Iwamoto K: DNA
methylation in schizophrenia: progress andchallenges of epigenetic studies. Genome Med.,2012 4(12):96(25) Nishioka M, Bundo M, Koike S, Takizawa R,
Kakiuchi C, Araki T, Kasai K, Iwamoto K:
Comprehensive DNA methylation of peripheral
blood cells derived from patients with first-episodeschizophrenia. J Hum Genet. 2012(26) Jinde S, Zsiros V, Jiang Z, Nakao K, Pickel J,
Kohno K, Belforte JE, Nakazawa K. Hilar mossy
cell degeneration causes transient dentate granulecell hyperexcitability and impaired patternseparation. Neuron. 2012 Dec 20;76(6):1189-200

99

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

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

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

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

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

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

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

Yuji Takahashi, M.D.,PhD.

Homepage

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

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

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

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

Teaching activities
As for under-graduate education, our Department
takes a part in lectures of Neurology for the 4th and5th grade medical students, and bed-side learning forthe 5th grade medical students, and clinical clerkshipfor the 5th grade medical students.
In the bed-side learning we include small group
lectures covering neurological examination, neurophysiology, neuroradiology, neuropathology, neuropsychology, neuroimmunology, and neurogenetics. We
are also putting our effort for Free Quarters where weoffer various opportunities for medical students to be100

involved in research activities, and 2-3 medical
students are conducting their research activities in thelaboratories.
In postgraduate education we offer the integrated
program including Neurology as the part of the
program of Internal Medicine.
For training of board-certified Neurologists, weoffer the excellent program including patients’care,training in Neurophysiology and Neuropathology,
consultation for Neurology, and supervising of juniortrainees. This program is integrated with clinicalpractice at the affiliated hospitals where 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 have develop
Medical Genome Center, and introduced nextgeneration 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 arebeing conducted to identify disease susceptibility
genes. We have established excellent animal models

fordentatorubral-pallidoluysian
atrophy,andconducting studies for development of therapeutics.
As the new protein degradation pathway, the role ofautophagy was investigated. (Tsuji, S., Goto, J.,
Takahashi, Y., Ichikawa, Y., Date, H., Suzuki, K.,
Mitsui, J., Ishiura, H., Matsukawa, T., Taira, M.,
Hahimoto, A)
Development of pathomechanism-based therapy foramyotrophic 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 thedevelopment of 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 frompatients with myopathy or neuropathy. We also
provide autoantibody testing for anti-gangliosideantibodies,musclespecific
antibodies
and

101

paraneoplastic neurological antibodies. In research
field, using biopsied muscles and collected serum
samples, we have been studying the mechanisms ofinflammatory myopathies especially in polymyositis,
cancer associated myositis, dermatomyositis, collagendisease associated myositis and myositis withautoantibodies. We have also been studying themechanism of muscle fiber regeneration in various
myopathies including inclusion body myositis. We
aim to increase understanding of the etiology andpathogenesis of neuromuscular diseases. (Shimizu, J.,
Hashimoto, H., Kubota, A.,Tokimura, N., Sagishima,M., Tokimura, N., Nishizawa, M.).
Department of Molecular Neuroscience on Neurodegeneration is funded by Janssen Pharmaceuticals.
Several projects are ongoing/ We found new ubiquitin
ligase UHRF-2 and new ubiquitin-like modulator
FAT10 related to the pathogenesis of polyglutamine
diseases. Studies on epigenetics of Parkinson’s disease
revealed abnormal epigenetic changes in the disease.
We also reported a novel 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 white matter withnovel 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

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halogenated volatile anesthetics via intrinsic
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,
KusunokiS.
Chondroitin
beta-1,4-N-acetylgalactosaminyltransferase-1
missense mutations are associated withneuropathies. 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

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disease with a novel R66Q mutation of GFAP
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 inherited leukoencephalopathy. 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,

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Hayashi and Tsuji S. Culture-negative brain
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.
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40. Tsuji S. Neurogenomics view of neurologicaldiseases. Arch. Neurol. (in press)
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Abnormal processing of TDP-43 does not regulate
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42. Yamashita T, Tadami C, Nishimoto Y, Hideyama T,
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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, endovascular intervention, epilepsy, and gamma knife treatment. From
April 2012 to March 2013, 15,986 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 2011 and 2012, 854 and 881 patientswere admitted to the Neurosurgical Ward, respectively.
482 and 444 surgical procedures were performed with
126 and 148 gamma knife procedures in each year.
Our practice covers a wide variety of neurosurgicaldiseases including malignant and benign brain tumors,hemorrhagic and occlusive cerebrovascular diseases,
spinal disorders, epilepsy, pain and movement
disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used to106preserve brain function as much as possible. State-ofthe-art techniques including intraoperative computeraided navigation and intravascular procedures help
our continuous effort to increase the safety of surgicaltreatment.
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 2012 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 residents 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

107

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 function-preserving
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 established a new
intraoperative monitoring method of vagus-nerve
evoked potential. Efficacy evaluation and development of surgical instruments were promoted for novel
function-preserving techniques, multiple subpial
transection and multiple hippocampal transection.
Basic and clinical research on gamma knife treatmentof epilepsy has been performed as well. For the
purpose of more precise localization of epileptic fociand elucidation of epileptogenesis, we are 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 (2012)
1.

2.

Amemiya S, Kunimatsu A, Saito N, Ohtomo K.
Impaired hemodynamic response in the ischemic
brain assessed with BOLD fMRI. Neuroimage.
61(3): 579-90, 2012
Fukushima Y, Ota T, Mukasa A, Uozaki H,
Kawai K, Saito N. Tumor-to-tumor metastasis:
Lung adenocarcinoma metastasizing to vestibular

108

schwannoma suspected on preoperative [(18)f]fluorodeoxyglucose positron emission tomography
imaging. World Neurosurg 78(5): 553 e559-553
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3. Hanakita S, Kawai K, Shibahara J, Kawahara N,
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Neurol Med Chir (Tokyo) 52(10): 747-750, 2012
4. Hanakita S, Koga T, Shin M, Shojima M, Igaki H,
Saito N. Role of gamma knife surgery in thetreatment of intracranial dural arteriovenous fistulas.
J Neurosurg 117 Suppl: 158-163, 2012
5. Hanakita S, Koga T, Shin M, Shojima M, Igaki H,
Saito N. Role of stereotactic radiosurgery in thetreatment of high-grade cerebral arteriovenous
malformation. Neurol Med Chir (Tokyo) 52(12):845-851, 2012
6. Hanakita S, Takai K, Kin T, Shojima M, Saito N.
Double independent spinal dural arteriovenous
fistulas at the thoracic spine. Acta Neurochir(Wien). 154(7): 1157-1158, 2012
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Shin M, Teraoka A. Intramedullary recurrence ofgerminoma in the spinal cord 15 years after
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Murayama T, Oyamada H, Kurebayashi N, Sato O,
Watanabe M, Mori N, Oguchi K, Sakurai T,
Takeshima H, Saito N, Iino M. Nitric oxide-induced
calcium release via ryanodine receptors regulates
neuronal function. EMBO Journal 31(2): 417-428,
2012
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K, Ohtomo K. Two cases of spontaneous temporal

encephalocele. J Neuroradiol. 39(5): 360-363,
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13. Kin T, Nakatomi H, Shojima M, Tanaka M, Ino K,
Mori H, Kunimatsu A, Oyama H, Saito N. A newstrategic neurosurgical planning tool for brainstem
cavernous
malformations using interactive
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J Neurosurg. 117(1): 78-88, 2012.
14. Koga T, Maruyama K, Kamada K, Ota T, Shin M,
Itoh D, Kunii N, Ino K, Terahara A, Aoki S,
Masutani Y, Saito N. Outcomes of diffusion tensor
tractography-integrated stereotactic radiosurgery.
Int J Radiat Oncol Biol Phys 82(2): 799-802,
2012
15. Koga T, Maruyama K, Tanaka M, Ino Y, Saito N,
Nakagawa K, Shibahara J, Todo T. Extended field
stereotactic radiosurgery for recurrent glioblastoma.
Cancer 118(17): 4193-4200, 2012
16. Koga T, Saito N. Efficacy and limitations of stereotactic radiosurgery in the treatment of glioblastoma.
Neurol Med Chir (Tokyo) 52(8): 548-552, 2012
17. Koga T, Shin M, Maruyama K, Kamada K, Ota T,
Itoh D, Kunii N, Ino K, Aoki S, Masutani Y, Igaki
H, Onoe T, Saito N. Integration of Corticospinal
Tractography Reduces Motor Complications AfterRadiosurgery. Int J Radiat Oncol Biol Phys.
83(1): 129-133, 2012.
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Nakatomi H, Saito N. Identification of a genetic
variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke 43(12): 3371-3374, 2012
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Matsushima N, Suzuki H, Saito N, Ohtomo K.
Reversible splenial lesion in the corpus callosum
following rapid withdrawal of carbamazepine after
neurosurgical decompression for trigeminal neuralgia. J Clin Neurosci. 19(8): 1182-1184, 2012
20. Mukasa A, Takayanagi S, Saito K, Shibahara J,
Tabei Y, Furuya K, Ide T, Narita Y, Nishikawa R,
Ueki K, Saito N. Significance of IDH mutations
varies with tumor histology, grade, and genetics inJapanese glioma patients. Cancer Sci. 103(3):587-592, 2012
21. Norden AD, Bartolomeo J, Tanaka S, Drappatz J,
Ciampa AS, Doherty LM, LaFrankie DC, Ruland S,
Quant EC, Beroukhim R, Wen PY. Safety of109

concurrent bevacizumab therapy and anticoagulation in glioma patients. J Neurooncol 106(1): 121-125, 2012.
22. Ota T, Usami K, Iijima A, Saito N. Staged surgicaltreatment for symptomatic vertebrobasilar arterystenosis: Combined treatment with endovascularangioplasty and bypass surgery. World Neurosurg.
78(1-2): 90-94 2012
23. Otani R, Fukuhara N, Ochi T, Oyama K, Yamada S.
Rapid growth hormone measurement during transsphenoidal surgery: analysis of 252 acromegalicpatients. Neurol Med Chir (Tokyo). 52(8): 558562, 2012
24. Oya S, Kawai K, Nakatomi H, Saito N.
Significance of Simpson grading system in modern
meningioma surgery: integration of the grade with
MIB-1 labeling index as a key to predict the recurrence of WHO Grade I meningiomas. J Neurosurg.
117(1): 121-128, 2012.
25. Saito N, Hida A, Koide Y, Ooka T, Ichikawa Y,
Shimizu J, Mukasa A, Nakatomi H, Hatakeyama S,
Hayashi T, Tsuji S. Culture-negative brain abscesswith Streptococcus intermedius infection withdiagnosis established by direct nucleotide sequence
analysis of the 16s ribosomal RNA gene. Intern
Med. 51(2): 211-216, 2012.
26. Sakai K, Hamaguchi T, Noguchi-Shinohara M,
Nozaki I, Sato T, Takumi I, Sanjo N, Nakamura Y,
Kitamoto T, Saito N, Mizusawa H, Yamada M.
Prion protein propagation in dura mater graftassociated creutzfeldt-jakob disease. Prion 6: 130130, 2012
27. Sheehan JP, Tanaka S, Link MJ, Pollock BE,
Kondziolka D, Mathieu D, Duma C, Young AB,
Kaufmann AM, McBride H, McBride H, Weisskopf
PA, Xu Z, Kano H, Yang W, Lunsford LD. Gamma
knife radiosurgery for the management of glomus
tumors: a multicenter study. J Neurosurg 117(2):246-254, 2012.
28. Shin M, Kondo K, Saito N. Neuroendoscopictransnasal surgery for skull base tumors: Basic
approaches, avoidance of pitfalls, and recent
innovations. Neurol Med Chir (Tokyo) 52(10):697-703, 2012
29. Soma T, Momose T, Takahashi M, Koyama K,
Kawai K, Murase K, Ohtomo K. Usefulness ofextent analysis for statistical parametric mappingwith asymmetry index using inter-ictal FGD-PET inmesial temporal lobe epilepsy. Ann Nucl Med.
26(4): 319-326, 2012.
30. Takahashi H, Takahashi S, Kanzaki R, Kawai K.
State-dependent precursors of seizures incorrelation-based functional networks of electrocorticograms of patients with temporal lobe
epilepsy. Neurol Sci. 33(6): 1355-1364, 2012.
31. Takahashi M, Soma T, Kawai K, Koyama K,
Ohtomo K, Momose T. Voxel-based comparison ofpreoperative FDG-PET between mesial temporal
lobe epilepsy patients with and without postoperative seizure-free outcomes. Ann Nucl Med.
26(9): 698-706, 2012.
32. Tanaka S, Batchelor TT, Louis DN, Curry WT,
Dietrich J. Emerging diagnostic and therapeutic
avenues in patients with glioblastoma – no longer adeal end? Nat Rev Clin Oncol 10(1): 14-26, 2012.
33. Tanaka S, Meyer FB, Buckner JC, Uhm JH, Yan ES,
Parney IF. Presentation, management, and outcome
in elderly patients with newly-diagnosed anaplastic
astrocytomas. J Neurooncol 110(2): 227-235,
2012.
34. Tanaka S, Pollock BE, Stafford SL, Link MJ.
Stereotactic radiosurgery for trigeminal pain
secondary to benign skull base tumors. World
Neurosurg 2012 Feb 10. pii: S1878-8750(12)00130-1
35. Tanaka S, Puffer RC, Hoover JM, Goerss SJ,
Haugen LM, Parney IF. Increased framelessstereotactic accuracy with high-field intra-operative
MRI. Neurosurgery 71 (2 Suppl Operative): 321328, 2012
36. Usami K, Kawai K, Koga T, Shin M, Kurita H,
Suzuki I, Saito N. Delayed complication after
gamma knife radiosurgery for mesial temporal lobe
epilepsy. J Neurosurg 116(6): 1221-1225, 2012.
37. Yoshida K, Saito N, Iriki A, Isoda M. Social error
monitoring in macaque frontal cortex. Nat
Neurosci 15(9): 1307-U1180, 2012
38. Yoshino M, Kin T, Nakatomi H, Saito N, Oyama H.
Preoperative prediction of the facial nerve locationin large vestibular schwannoma: segmentation
under difficult donditions. JJMVR 10: 27-34, 2012Social Medicine
1. Occupational, Environmental
and Preventive Medicine

111

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

Lecturer
Satoshi Ueha, Ph. D.

Assistant professor
Takeshi Shimaoka, Ph.D.,

Homepage

Yuya Terashima, 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 twenty 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 andGraft-versus-host Disease.
3) Molecular analysis of chemokine receptor
signaling pathway.
4) Development of vaccines against pathogenic
microorganisms and cancer
5) Genome-wide transcriptome and epigenetic
signature of various types of cells and tissues innormal as well as disease state112

References
(1)

(2)

(3)

(4)

(5)

(6)

Tsukui T, Ueha S, Abe J, Hashimoto SI, Shichino S,
Shimaoka T, Shand FH, Arakawa Y, Oshima K,
Hattori M, Inagaki Y, Tomura M, Matsushima K.
Qualitative Rather than Quantitative Changes Are
Hallmarks of Fibroblasts in Bleomycin-Induced
Pulmonary Fibrosis. Am J Pathol. 2013 (in press)
Atarashi K, Tanoue T, Oshima K, Suda W, Nagano
Y, Nishikawa H, Fukuda S, Saito T, Narushima S,
Hase K, Kim S, Fritz JV, Wilmes P, Ueha S,
Matsushima K, Ohno H, Olle B, Sakaguchi S,
Taniguchi T, Morita H, Hattori M, Honda K.
Treg induction by a rationally selected mixture of
Clostridia strains from the human microbiota.
Nature. 2013 (in press)
Miyabe C, Miyabe Y, Miura NN, Takahashi K,
Terashima Y, Toda E, Honda F, Morio T,
Yamagata N, Ohno N, Shudo K, Suzuki J, Isobe M,
Matsushima K, Tsuboi R, Miyasaka N, Nanki T.
Am80, a retinoic acid receptor agonist, ameliorates
murine vasculitis through the suppression ofneutrophil migration and activation. Arthritis
Rheum. 2013, 65 (2):503-12.
Sekiguchi S, Kimura K, Chiyo T, Ohtsuki T,
Tobita Y, Tokunaga Y, Yasui F, TsukiyamaKohara K, Wakita T, Tanaka T, Miyasaka M,
Mizuno K, Hayashi Y, Hishima T, Matsushima K,
Kohara M. Immunization with a recombinantvaccinia virus that encodes nonstructural proteinsof the hepatitis C virus suppresses viral protein
levels in mouse liver. PLoS One. 2013, 7 (12):e51656.
Hoshino A, Ueha S, Hanada S, Imai T, Ito M,
Yamamoto K, Matsushima K, Yamaguchi A,
Iimura T. Roles of chemokine receptor CX3CR1 inmaintaining murine bone homeostasis through theregulation of both osteoblasts and osteoclasts. J
Cell Sci. 2013, 126 (Pt 4):1032-45.
Hashimoto S, Ogoshi K, Sasaki A, Abe J, Qu W,
Nakatani Y, Ahsan B, Oshima K, Shand FH,
Ametani A, Suzuki Y, Kaneko S, Wada T, Hattori
M, Sugano S, Morishita S, Matsushima K.
Coordinated changes in DNA methylation in
antigen-specific memory CD4 T cells. J Immunol.
2013, 190 (8):4076-91.

(7)

Hara A, Sakai N, Furuichi K, Sakai Y, Takeya M,
Bucala R, Mukaida N, Takuwa Y, Matsushima K,
Kaneko S, Wada T. CCL2/CCR2 augments the
production of transforming growth factor-beta1,
type 1 collagen and CCL2 by humanCD45-/collagen 1-positive cells under high glucose
concentrations. Clin Exp Nephrol. 2013, in press.
(8) Onai N, Kurabayashi K, Hosoi-Amaike M,
Toyama-Sorimachi N, Matsushima K, Inaba K,
Ohteki T. A Clonogenic Progenitor with Prominent
Plasmacytoid Dendritic Cell Developmental
Potential. Immunity. 2013, 38(5):943-57.
(9) 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.
(10) Ishida Y, Kimura A, Kuninaka Y, Inui M,
Matsushima K, Mukaida N, Kondo T. Pivotal roleof the CCL5/CCR5 interaction for recruitment ofendothelial progenitor cells in mouse woundhealing. J Clin Invest. 2012, 122 (2):711-21.
(11) Matsushima K, Nagai S. Unraveling the mystery of
the hygiene hypothesis through Helicobacter pylori
infection. J Clin Invest. 2012, 122 (3):801-4.
(12) Fujimura S, Takahashi H, Yuda K, Ueta T, Iriyama
A, Inoue T, Kaburaki T, Tamaki Y, Matsushima K,
Yanagi Y. Angiostatic effect of CXCR3 expressedon choroidal neovascularization. Invest Ophthalmol
Vis Sci. 2012, 53 (4):1999-2006.
(13) Furuichi K, Shintani H, Sakai Y, Ochiya T,
Matsushima K, Kaneko S, Wada T. Effects ofadipose-derived mesenchymal cells on ischemiareperfusion injury in kidney. Clin Exp Nephrol.
2012, 16 (5):679-89.
(14) Ueha S, Shand FH, Matsushima K. Cellular andmolecular mechanisms of chronic inflammationassociated organ fibrosis. Front Immunol. 2012,
3:71.
(15) Yamada Y, Okubo Y, Shimada A, Oikawa Y,
Yamada S, Narumi S, Matsushima K, Itoh H.
Acceleration of diabetes development in CXC
chemokine receptor 3 (CXCR3)-deficient NOD
mice. Diabetologia. 2012, 55 (8):2238-45.
(16) Furuichi K, Kokubo S, Hara A, Imamura R, Wang
Q, Kitajima S, Toyama T, Okumura T, Matsushima
K, Suda T, Mukaida N, Kaneko S, Wada T. Fas

113

Ligand Has a Greater Impact than TNF-α on
Apoptosis and Inflammation in Ischemic Acute
Kidney Injury. Nephron Extra. 2012, 2 (1):27-38.
(17) Nagao K, Kobayashi T, Moro K, Ohyama M,
Adachi T, Kitashima DY, Ueha S, Horiuchi K,
Tanizaki H, Kabashima K, Kubo A, Cho YH,
Clausen BE, Matsushima K, Suematsu M, Furtado
GC, Lira SA, Farber JM, Udey MC, Amagai M.
Stress-induced production of chemokines by hairfollicles regulates the trafficking of dendritic cells
in skin. Nat Immunol. 2012, 13 (8):744-52.
(18) Qu W, Hashimoto S, Shimada A, Nakatani Y,
Ichikawa K, Saito TL, Ogoshi K, Matsushima K,
Suzuki Y, Sugano S, Takeda H, Morishita S.
Genome-wide genetic variations are highly
correlated with proximal DNA methylation patterns.
Genome Res. 2012, 22 (8):1419-25.

114

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, clinical epidemiology, health services research, and so on. In addition,
the staff members of the Department have offeredpublic and occupational health services to the governments, industries, and local communities.
In the academic year of 2012, the Department
consists of four faculty members above listed, twoproject researcher, three supporting staffs, 16 graduate
students (nine in PhD program and seven in MPH
program), 16 part-time lecturers, and 15 visiting
fellows.

Teaching activities
1) Undergraduate Program (Medical School)

115

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 School of Integrated
Health Sciences, Faculty of Arts and Sciences, andFaculty of Engineering.
2) MPH Program
Various courses (about 35 courses) are given by
those departments affiliated with School of Public
Health. Among them, our Department offers threecourses;“HealthPolicy”,“Public
HealthPreparedness”, and “Public Health Practice”. The
Department also provides a research course forindividual students, in which he or she carries out aspecific research task under the supervision of afaculty member of the Department.
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 epidemiological studies, (2) how to use epidemiological andstatistical methods, (3) how to use economic concepts
and methods in the health fields, (4) how to establish
the collaboration with health professionals in thevarious 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

116

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
arrest patients, (7) assessment of health care access in
Afghanistan, and (8) epidemiological study on
incidence and survival rate of children with cerebral
palsy.

References
1. Sabawoon W, Sato H, Kobayashi Y: Delay in thetreatment of pulmonary tuberculosis: a reportfrom Afghanistan. Environmental Health andPreventive Medicine 2012; 17(1): 53-61.
2. Kaneto C, Toyokawa S, Inoue K, Inoue M, Senba
T, Suyama Y, Miyoshi Y, Kobayashi Y:
Association between periodontal disease andpeptic ulcers among Japanese workers: MY
Health Up Study. Global Journal of Health
Science 2012; 4(2): 42-49.
3. Machii R, Saika K, Higashi T, Aoki A,
Hamashima C, Saito H: Evaluation of feedback
interventions for improving the quality assuranceof cancer screening in Japan: study design andreport of the baseline survey. Japanese Journal of
Clinical Oncology 2012; 42(2): 96-104.
4. Higashi T, Fukuhara S, Nakayama T: Opinion ofJapanese rheumatology specialists on methods ofassessing the quality of rheumatoid arthritis care.
Journal of Evaluation in Clinical Practice 2012;18(2): 290-295.
5. Toyokawa S, Uddin M, Koenen KC, Galea S:
How does the social environment 'get into themind'? Epigenetics at the intersection of socialand psychiatric epidemiology. Social Science &Medicine 2012; 74(1):67-74.
6. Nakahara S, Tomio J, Nishida M, Morimura N,
Ichikawa M, Sakamoto T: Association between
timing of epinephrine administration and intact
neurologic survival following out- of-hospital
cardiac arrest in Japan: a population-based
prospective observational study. Academic
Emergency Medicine 2012; 19 (7): 782-792.
7. Nakamura F, Higashi T: Pattern of prophylaxis
administration for chemotherapy-induced nausea
and vomiting: an analysis of city-based healthinsurance data. International Journal of ClinicalOncology 2012 doi: 10. 1007/ s10147-0120477-6.
8. Higashi T, Yoshimoto T, Matoba M: Prevalence ofanalgesic prescriptions among patients withcancer in Japan: an analysis of health insurance
claims data. Global Journal of Health Science
2012; 4(6): 197-203.
9. Davison KK, Nishi A, Kranz S, Wyckoff L, May J,
Earle-Richardson G, Strogatz D, Jenkins P:
Associations among social capital, parenting foractive lifestyles, and youth physical activity inrural families living in upstate New York. Social
Science & Medicine 2012; 75 (8): 1488-96.
10. Nishi A, McWilliams JM, Noguchi H, Hashimoto
H, Tamiya N, Kawachi I: Health benefits fromreduced patient cost sharing in Japan. Bulletin of
the World Health Organization 2012; 90 (6): 426435A.
11. Nishi A, Kawachi I, Shirai K, Hirai H, Jeong S,
Kondo K: Sex/gender and socioeconomic differences in the predictive ability of self-rated healthfor mortality. PLoS ONE 2012; 7 (1): doi:
10.1371/ journal. pone. 0030179.
12. Nishi A, Noguchi H, Hashimoto H, Tamiya N:
Scale development of health status for secondary
data analysis using a nationally representative
survey. Environmental Health and Preventive
Medicine 2012; 17 (3): 252-257.

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

118

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

Lecturer
Kaori Shintani, Ph.D.

Assistant Professor
Hisashi Nagai, M.D., Ryohei Kuroda, M.D., Ph.D.

Homepage

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

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

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

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

119than 11,344 cases since 1897. Some of these cases arevery famous in criminology in Japan.
In forensic autopsy, we examine the pathological,
alcohol, toxicological, and blood type testing of eachcase, too. Finally, forensic pathologists in our
department diagnose the cause of death. Expert
opinions expresses the cause of death and forensic
judgment for each case. We have kept them since first
autopsy case in 1897. We have serious responsibility
in the determination of cause of death.
Since 2005, we also performed autopsies on
medical practice-related deaths (MPAD) in corroboration with Department of Human Pathology. The both
departments lead the pilot study on the investigation
and analysis of MPAD (supported by government). We
also contribute to evolve new way of presenting expert
opinions for the jury courts that has been enacted in2009.

Education
As for under-graduate education, our department
provides lectures for the 4th year medical students,
Free Quarter training course for the 3-4th year medical
students, and Clinical Clerkship learning for the 5thyear medical students.
The lectures are based on the autopsy and court
cases for the better understanding of the deathinvestigation and medical law. In the Free Quarter
training course, students experience laboratory
practices (toxicology, DNA typing, histology) or
experiments. In the clinical clerkship, each student
experiences the process from autopsy to presentationof expert opinion. They can also attend the practicesof medical examiner’s activities and the court.
In addition, students of school of public health and(undergraduate & graduate) law school are provided
with somewhat practical lectures with exercises. 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 andcell death in ischemia-reperfusion
We autopsy many cases suddenly died inassociation with accidents, violence, restraint, or
medical practices. Particularly, cardiac lesion andarrhythmias related to a brief ischemia andemotional stress respectively are important inforensic practices. The diagnosis and demonstrationof scientific evidence are very difficult in thesecases. We study the mechanism of these phenomenain the models of coronary occlusion, isolated
perfused heart, or cultured cardiomyocytes throughcirculatory physiology, biochemistry, histology, andmolecular biology.
Previously, we reported that calpain (Ca2+-dependent protease) following intracellular Ca2+
overloading contributes to the myocardial injury,
contractile dysfunction and development of infarction in reperfusion via proteolysis of cytoskeletal
proteins. Meanwhile, shortage of sarcoplasmic
reticulum (SR) Ca2+ uptake by the dephosphorylation of phospholamban (PLN) underlies heart
failure, and the blockade of PLN to restore SR Ca2+
uptake has been an important therapeutic target.
Recently, we found that prevention of cytosolic
Ca2+ overloading by the restoration of SR Ca2+
uptake by introduction of anti-PLN antibody in theheart paradoxically promotes myocardial infarction.
The findings led us to find the presence of calpain
in the mitochondria, and the implication of themitochondrial calpain in the development of
myocardial infarction after ischemia-reperfusion.
2. Research on cardiovascular risk and sudden deathin sleep apnea syndrome（SAS）
This is the most challenging theme in the field ofcardiovascular research, but the production of agood animal model has been difficult. We havesuccessfully developed an apparatus for the rat

120model of SAS with intermittent hypoxia (IH), andhave undertaken the investigation on the molecularmechanism on hypertension. We have organizedmulti-facility research groups. We found that IH
induces autophagy, and the inhibition of autophagy
induces heart failure in IH rats. Additionally, we
found that IH induces β-AR-dependent protective
mechanisms against hypoxic pulmonary vasoconstriction, and development of pulmonary hypertension and right ventricular failure. Moreover, wefound the effects of IH in multiple organs
depending on age and diseases such as obesity,
diabetes or ovariectomy.
3. Mechanism of MDMA cardiotoxicity.
3,4-Methylendioxymethyl-amphetamine (MDMA,"ecstasy") abuse often causes sudden death, but themechanism is largely unknown. We found that
MDMA induces activation of autophagy andlysosome, myofibril lysis with proteolysis via
lyososomal protease, and contractile dysfunction.
4. Mechanism of sudden cardiac death in restrain.
Restraint of excited persons cause sudden death,and the restrainer may be accused. We have foundthat restraint can cause sudden death of rats with
inhibition of gap-junction communication of cardiomyocytes that has been known in many heartdiseases. Meanwhile, restraint is known to induce
emotional stress, and emotional stress andcatecholamine overflow induces stress (takotsubo)
cardiomyopathy characterized by transient andregional reduction of wall motion, with takotsubolike ventriculogram. Recently, we found that
α-AR-Gi (inhibitory G protein) coupling underlie
the transient and regional reduction of left
ventricular contraction in restraint.
5. Investigation on the law and social system related
to death investigation, medical safety, and lawsuit.
The disclosure of the information and bereavement
service related to medico-legal autopsy have been
limited by law. Additionally, the information related
to medico-legal autopsy cannot be used for accident
prevention. To find a clue to improve the situations,
we have conducted the conference on the autopsy
cases after emergency medical practices, andpotentially therapeutic deaths, with attendance ofmany emergency doctors, forensic practitioners,
lawyers, prosecutors, and clinical experts (fortherapeutic deaths). The discussion at theconference has disclosed the discrepancy of clinicaland autopsy diagnoses in 30~40% cases, and manycases of overlook of injuries after imaging analyses.
A few cases warranted the attendance of the dangerof misdiagnoses as traumatic or iatrogenic led toguilty or responsible of the suspects, but the discussion at the conference avoided the false accusation.
Moreover, the attendants have learned much fromeach other. The sharing of the experiences between
the attendants will lead to the change in legal
system to take the advantage of death investigationand the conference to the prevention of similar
accidents. .
4. 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.
5. 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 many papers in clinical & pathology
journals.

Publications
1. Shintani-Ishida K, Inui M, Yoshida K. Ischemiareperfusion induces myocardial infarction throughmitochondrial Ca2+ overload. J Mol Cell Cardiol.
2012;53:233-239.
2. Harada K, Kuroda R, Nakajima M, Takizawa A,
Yoshida K. An autopsy case of a decomposed
body with keyhole gunshot wound and secondary
skull fracture. Legal Med. 2012;14:255-257.
3. Unuma K, Uozaki H, Kuroda R, Uemura K,
Yoshida K. Death from axillary haemorrhage
during haemodialysis in a patient with a history of
microscopic polyangiitis. BMJ Case Rep. 2012;
18: doi: pii: bcr1120115194.10.1136/bcr.11.2011.
5194.

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4. Yamaguchi K, Hikiji W, Takino M, Saka K,
Hayashida M, Fukunaga T, Ohno Y. Analysis of
tolfenpyrad and its metabolites in plasma in atolfenpyrad poisoning case. J Anal Toxicol. 2012;36(7):529-537.
5. Nara A, Aki T, Funakoshi T, Unuma K, Uemura K.
Hyperstimulation of macropinocytosis leads tolysosomal dysfunction during exposure to methamphetamine in SH-SY5Y cells. Brain Res. 2012;
23:1466:1-14.
6. Noritake K, Aki T, Funakoshi T, Unuma K, Nara
A, Kato C, Uemura K. Critical roles of Rhoassociated kinase in membrane blebbing andmitochondrial pathway of apoptosis caused by
1-butanol. Toxicol In Vitro. 2012;26(6):849-55.
7. Bessho M, Unuma K, Nara A, Uemura K. A casein which a bone fragment caused by a bullet madea second channel in addition to the bullet channel.
Leg Med. 2012; 4(4):188-90.
8. Aki T, Nara A, Uemura K. Cytoplasmic
vacuolization during exposure to drugs and othersubstances. Cell Biol Toxicol. 2012;28(3):125-31.

122

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,
medical knowledge engineering, hospital epidemiology, quality assessment of healthcare, clinical andbioinformatics engineering, privacy protection andencryption, analysis of hospital management, 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 ofTokyo Hospital. DPIM is the department that deals
with information analyses and future planning for the
University of Tokyo Hospital by using 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
in 1997. Then, one professor and one associate

123

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 andpassing 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.
The students in FY2012 are two in doctor’s course
for Medical Informatics and Economics, one inmaster’s course for Health Informatics.
The students’ researches cover various topics;
development of self medication management systemusing smart-phone devices, medical ontology, etc.

Research activities
The research domains are 1) application studies ondevelopments of clinical information systems, hospital
information system and electronic health records
system, 2) studies on medical safety infromation
systems, 3) medical knowledge discovery and 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 and concepts :This research develops the methods to build thelarge scale medical ontology, which is a database124

for 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 for WorldLeading 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, 2007-2012).
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. Koike S, Ide H, Kodama T, Matsumoto S,
Yasunaga H, Imamura T. Physician-scientists inJapan: attrition, retention, and implications for the
future. Acad Med. 2012 May;87(5):662-7.
2. Kodama T, Koike S, Matsumoto S, Ide H,
Yasunaga H, Imamura T. The working status ofJapanese female physicians by area of practice:cohort analysis of taking leave, returning to work,and changing specialties from 1984 to 2004.
Health Policy. 2012 May;105(2-3):214-20.
3. 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. 2012;51(3):221-8.
4. Waki K, Fujita H, Uchimura Y, Aramaki E, Omae
K, Kadowaki T, Ohe K. DialBetics: smartphonebased self-management for type 2 diabetes
patients. J Diabetes Sci Technol. 2012 Jul 1;6(4):983-5.
5. Kozaki K, Mizoguchi R, Imai T, Ohe K Identity
Tracking of a Disease as a Causal Chain Proc of

the 3rd International Conference on Biomedical
Ontology (ICBO 2012) 20129.
6. Yasunaga H, Horiguchi H, Matsuda S, Fushimi K,
Hashimoto H, Ohe K, Kokudo N. Relationshipbetween hospital volume and operative mortality
for liver resection: Data from the JapaneseDiagnosis Procedure Combination database.
Hepatol Res. 2012 Nov;42(11):1073-1080.
7. 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 an advanced
coronary angiography and intervention databasesystem. Int Heart J. 2012;53(1):35-42.
8. Kozaki K, Mizoguchi R, Imai T, Ohe K. A
Consideration on Identity od Diseases. Proc. of
the Fifth Interdisciplinary Ontology Conference:
75-80. 2012
9. Yamagata Y, Kou H, Kozaki K, Mizoguchi R,
Imai T, Ohe K Ontological Modeling of Interoperable Abnormal States Proc of the 2nd Joint
International Semantic Technology Conference(JIST2012) LNCS7774:33-48. 2012
10. Horiguchi H, Yasunaga H, Hashimoto H, Ohe K.
A user-friendly tool to transform large scale
administrative data into wide table format using a
MapReduce program with a Pig Latin based script.
BMC Med Inform Decis Mak. 2012 Dec 22;12:151.

Internal Medicine
1. Medicine Ⅰ126

Department of Cardiovascular
Medicine
Professor
Issei Komuro, 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

Outline of department

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

Staff: one professor (Issei Komuro), 3 lecturers, 16
research associates, 12 staff members, 28 graduate
school students.

Clinical activities
In 2012, 1,782 patients were newly admitted to our
hospital ward of approximately 50 beds.
Cardiovascular angiograms were conducted in 2,281
patients, of which 636 cases were interventional
procedures. CT coronary angiography was examinedin 376 patients and cardiovascular MRI in 80. For
arrhythmias, there were 84 cases of implantation or
replacement of a pacemaker, 98 cases of catheter
ablation, and other specialized pacemaker devices
such as 25 cases of implantation or replacement of a
implantable cardioverter-defibrillator (ICD), and 31
cases of implantation or replacement of a cardiac
resynchronization device (CRTD).
As we are an authorized facility for heart transplantation, left ventricular assist device (LVAD) use
for severe heart failure cases has been increasing. In
2006, the first case of heart failure from our department underwent a heart transplant procedure at the
Department of Cardiovascular Surgery. The hearts

127

were transplanted to 6 cases in 2012 (total 27 cases).
Duration of hospitalization is on average 12.8 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, heart failure and arrhythmia in addition
to hypertension and peripheral artery disease. Outpatient clinics are open both mornings and afternoons
from Monday to Friday. Approximately 233 patients
visit each day. Acute cases of coronary heart disease
and aortic disease are also 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, three or four students are placed under theguidance of one research associate allowing forteaching in small groups. Specialized groups provide
lectures. As for post-graduate education, residents are
educated through specialized group conferences,
grand rounds and clinical conferences.

diseases
10. Genetic polymorphisms and risk factors in
cardiovascular disease
11. Optimization of individual treatment using theComputer Heart Simulator
12. Development of new integrated databases forclinical information and research
13. Investigation of disease pathophysiology anddevelopment of novel therapies (severe heart
failure, cardiac transplantation, congenital heartdisease)
14. Diagnosis and treatment of Marfan syndrome andadult congenital heart disease
15. New treatment for pulmonary hypertension
16. Ischemic heart disease in patients with diabetic
retinopathy
17. Aerobic threshold and cardiac rehabilitation
18. Imaging techniques (echocardiography, MRI, CT,
SPECT) in cardiovascular diseases

References (2012)1)

Imamura T, Shiga T, Yamazaki T, Sonoda M,
Kinugawa K, Shiota T, Suzuki J, Takenaka K,
Hirata Y, Nagai R. Volumetric and functional
assessment of ventricles in pulmonary hyper-

Research activities
Areas of interest are as follows:
1. Molecular mechanisms of human heart diseases using iPS cells 2. Interplay between organs, cells, and molecules inchronic inflammation
3. Cardiac hypertrophy and heart failure: analyses ofpathogenic mechanisms and development of novel
therapies (gene therapy, etc.)
4. Transcriptional regulation of various genes
involved in cardiovascular development andpathogenesis
5. Differentiationofsmoothmusclecells(atherosclerosis and restenosis after vascularinterventions)
6. Nitric oxide and endothelial function
7. Mechanisms for cardiorenal association
8. Regeneration therapy for cardiovascular disease
9. Roles of hypoxia signaling in cardiovascular

Inaba T, Yao A, Nakao T, Hatano M, Maki H,

tension on 3-dimensional echocardiography. Circ
J. 2012;77(1):198-206.
2)

Imamura T, Kinugawa K, Shiga T, Endo M, Kato
N, Inaba T, Maki H, Hatano M, Yao A, Nishimura
T, Hirata Y, Kyo S, Ono M, Nagai R. Preoperative
levels of bilirubin or creatinine adjusted by age
can predict their reversibility after implantationof left ventricular assist device.

Circ J. 2012;

77(1):96-104.
3)

Shiga T, Kinugawa K, Imamura T, Kato N, Endo
M, Inaba T, Maki H, Hatano M, Yao A,
Nishimura T, Hirata Y, Kyo S, Ono M, Nagai R.
Combination evaluation of preoperative risk
indices predicts requirement of biventricularassist device.

4)

Circ J. 2012;76(12):2785-91.

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,

128

Yamashita H, Hirata Y, Nagai R, Nakajima T.
Cardiac rehabilitation decreases plasma pentraxin
3 in patients with cardiovascular diseases.
5)

6)

8)

9)

12) Imamura T, Kinugawa K, Shiga T, Kato N, Endo

M, Inaba T, Maki H, Hatano M, Yao A, Hirata Y,

Prev Cardiolog. 2012;19(6):1393-400.

Nishimura T, Kyo S, Ono M, Nagai R. Correction

Asanuma T, Higashikuni Y, Yamashita H, Nagai

of

R, Hisada T, Sugiura S. Discordance of the areas

ventricular assist device implantation.

of peak wall shear stress and tissue stress in

J. 2012;53(6):391-3.

hyponatremiabytolvaptan

beforeleft

Int Heartcoronary artery plaques as revealed by fluid-13) Ishida J, Kinugawa K, Shiga T, Imamura T,

structure interaction finite element analysis: a

Hatano M, Maki H, Inaba T, Yao A, Hirata Y,

case study.

Nishimura T, Kyo S, Ono M, Nagai R. Rapidly

Int Heart J. 2013;54(1):54-8.

Imamura T, Kinugawa K, Shiga T, Endo M, Kato

progressive cardiac allograft vasculopathy in

N, Inaba T, Maki H, Hatano M, Yao A, Nishimura

early onset regressed with everolimus treatment

T, Hirata Y, Kyo S, Ono M, Nagai R. An elevatedin an adult cardiac recipient.

ratio of early to late diastolic filling velocity

53(6):388-90.

Int Heart J. 2012;a14) Soma K, Takahashi M, Sato T, Nagai R. Angina

time-dependent manner. J Cardiol. 2012;60(4):as a manifestation of constrictive pericarditis.

295-300.

Intern Med. 2012;51(14):1939.

recovers

7)

Eur J

Cardiovasc Imaging. 2012;13(10):826.

after

heart

transplantationinNakao T, Watanabe H, Takeda N, Takanashi S,15) Takahashi T, Asano Y, Amiya E, Hatano M,

Nagai R. The efficacy of real-time three-

Tamaki Z, Ozeki A, Watanabe A, Kawarasaki S,

dimensional transoesophageal echocardiography

Nakao T, Taniguchi T, Ichimura Y, Toyama T,

in detecting unicuspid aortic valve.

Watanabe M, Hirata Y, Nagai R, Sato S.

Eur Heart J

Cardiovasc Imaging. 2012;13(11):966.

Improvement of endothelial function in parallel

Asada K, Fujiu K, Imai Y, Kojima T, Sugiyama H,

with the amelioration of dry cough and dyspnea

Suzuki T, Kinugawa K, Hirata Y, Nagai R.

due to interstitial pneumonia by intravenous

Intrathoracic impedance monitoring in patients

cyclophosphamide pulse therapy in patients with

with heart failure: correlation with dehydration

systemic sclerosis: a preliminary report of two

and bleeding events. Circ J. 2012;76(11):2592-8.

cases.

Mod Rheumatol. 2012;22(4):598-601.

Kato N, Kinugawa K, Shiga T, Hatano M, Takeda

16) Ishida J, Suzuki T, Aizawa K, Sawaki D, Nagai R.

N, Imai Y, Watanabe M, Yao A, Hirata Y, Kazuma

Comparison of analytical performance of two

K, Nagai R. Depressive symptoms are common

single-step measurement devices of B-type

and associated with adverse clinical outcomes innatriuretic Peptide.

heart failure with reduced and preserved ejection

320-3.

Int Heart J . 2012 ;53(5):17) Fukuda T, Matsumoto A, Kurano M, Takano H,

fraction. J Cardiol. 2012;60(1):23-30.
10) Imamura T, Kinugawa K, Shiga T, Endo M, Inaba

Iida H, Morita T, Yamashita H, Hirata Y, Nagai R,

T, Maki H, Hatano M, Imai Y, Yao A, Hirata Y,

Nakajima T. Cardiac output response to exercise

Nishimura T, Kyo S, Ono M, Nagai R. Earlyin chronic cardiac failure patients.

decision for a left ventricular assist device

2012 ;53(5):293-8.

implantation is necessary for patients withmodifier A.

Int Heart J .

18) Imamura T, Kinugawa K, Shiga T, Endo M, Kato

N, Inaba T, Maki H, Hatano M, Yao A, Nishimura

J Artif Organs. 2012;15(3):301-4.

11) Abe H, Takayama M, Takeda N, Takanashi S,

T, Hirata Y, Kyo S, Ono M, Nagai R. Novel risk

Nagai R. Successful surgical repair of a giant

scoringcoronary-pulmonaryofparameters gives a good prediction of 1-year

Eur Heart J

mortality in patients with a left ventricular assist

arteryfistula:magnetic resonance imaging.

role

systemwithpreoperative

objective

129

device.

Circ J . 2012 ;76(8):1895-903.

278-83.

19) Suzuki J, Ogawa M, Hirata Y, Nagai R, Isobe M.

27) Kimura K, Takenaka K, Ebihara A, Okano T, Uno

Effects of immunoglobulin to prevent coronary

K, Fukuda N, Ando J, Fujita H, Morita H, Yatomi

allograft vasculopathy in heart transplantation.

Y, Nagai R. Speckle tracking global strain rate

Expert Opin Ther Targets . 2012;16(8):783-9.

E/E' predicts LV filling pressure more accurately

20) Semba H, Sawada H, Uejima T, Takeda N, Soma

K, Abe H, Yamashita T, Nagai R. Basicechocardiographic features of patients with latent

than

traditional

tissueDoppler

E/E'.

Echocardiography. 2012;29(4):404-10.
28) Sahara M, Sata M, Morita T, Hirata Y, Nagai R.

left ventricular outflow tract obstruction without

Nicorandilleft ventricular hypertrophy.

vascular endothelial damage and pulmonary

Int Heart J . 2012 ;attenuates

monocrotaline-induced

arterial hypertension. PLoS ONE. 2012 ;7(3):53(4):230-3.
21) Imamura T, Kinugawa K, Mohri D, Shiga T, Endoe33367.

M, Inaba T, Maki H, Hatano M, Isayama H, Yao29) Sakamoto A, Hongo M, Saito K, Nagai R,

A, Hirata Y, Koike K, Nagai R. A case of

Ishizaka N. Reduction of renal lipid content andpancreatic cancer after heart transplantation.

proteinuria by a PPAR-agonist in a rat model of

Int

Heart J . 2012 ;53(3):205-7.

angiotensin II-induced hypertension.

22) Imamura T, Shiga T, Kinugawa K, Kato N, Endo

Eur J

Pharmacol . 2012;682(1-3):131-6.

M, Inaba T, Maki H, Hatano M, Yao A, Hirata Y,30) Sakamoto A, Ishizaka N, Imai Y, Nagai R. Serum

Nagai R. Successful conversion to everolimus

levels of IgG4 and soluble interleukin-2 receptor

after cytomegalovirus infection in a heartin patients with abdominal and thoracic aortictransplant recipient. Int Heart J . 2012 ;53(3):aneurysm who undergo coronary angiography.

199-201.

Atherosclerosis. 2012;221(2):602-3.

23) Imamura T, Kinugawa K, Shiga T, Endo M, Inaba

31) Soma K, Abe H, Takeda N, Shintani Y, Takazawa

T, Maki H, Hatano M, Yao A, Nishimura T, Hirata

Y, Kojima T, Fujiu K, Semba H, Yamashita H,

Y, Kyo S, Ono M, Nagai R. A case of late-onset

Hirata Y, Fukayama M, Nagai R. Myocardial

right ventricular failure after implantation of a

involvementincontinuous-flow left ventricular assist device.

imperfecta.

Int Heart J . 2012; 53(1):75-7.

J

patients

withosteogenesis32) Semba H, Kinugawa K, Takeda N, Shiga T,

Artif Organs . 2012;15(2):200-3.
24) Abe H, Takeda N, Aoki H, Nagai R. Sinus of

Nishimura G, Inajima T, Uchino Y, Iwata H,

Valsalva aneurysm accompanying bicuspid aortic

Hasumi E, Abe H, Terada Y, Yonenaga A, Hirata

valve.

Intern Med. 2012;51(10):1275.

Y, Nagai R. Preliminary report of tolvaptan25) Eguchi K, Manabe I, Oishi-Tanaka Y, Ohsugi M,

treatment in Japanese patients with heart failure.

Kono N, Ogata F, Yagi N, Ohto U, Kimoto M,

Int Heart J. 2012;53(1):72-4.

Miyake K, Tobe K, Arai H, Kadowaki T, Nagai R.

33) Suzuki J, Ogawa M, Sakai Y, Hirata Y, Isobe M,

Saturated fatty acid and TLR signaling link cell

Nagai R. A prostacycline analog prevents chronic

dysfunction and islet inflammation.

myocardial

remodelingallografts.

Int Heart J. 2012;53(1):64-7.

Cell Metab .

2012;15(4):518-33.

inmurinecardiac26) Nakayama A, Morita H, Miyata T, Ando J, Fujita34) Kohro T, Iwata H, Fujiu K, Manabe I, Fujita H,

H, Ohtsu H, Akai T, Hoshina K, Nagayama M,

Haraguchi G, Morino Y, Oguri A, Ikenouchi H,

Takanashi S, Sumiyoshi T, Nagai R. Inverse

Kurabayashi M, Ikari Y, Isobe M, Ohe K, Nagai

association between the existence of coronary

R. Development and implementation of anartery disease and progression of abdominal

advanced coronary angiography and intervention

aortic aneurysm. Atherosclerosis . 2012;222(1):database system. Int Heart J . 2012 ;53(1):35-42.

13035) Sakamoto A, Nagai R, Saito K, Imai Y, Takahashi41) Sakamoto A, Ishizaka N, Saito K, Imai Y, Morita

M, Hosoya Y, Takeda N, Hirano K, Koike K,

H, Koike K, Kohro T, Nagai R. Serum levels of

Enomoto Y, Kume H, Homma Y, Maeda D,

IgG4 and soluble interleukin-2 receptor in

Yamada H, Fukayama M, Hirata Y, Ishizaka N.

patients with coronary artery disease.

Idiopathic retroperitoneal fibrosis, inflammatory

Chim Acta. 2012;413(5-6):577-81.

aortic aneurysm, and inflammatory pericarditis -retrospective analysis of 11 case histories.

J

Clin

42) Higashikuni Y, Takaoka M, Iwata H, Tanaka K,

Hirata Y, Nagai R, Sata M. Aliskiren in
combination with valsartan exerts synergistic

Cardiol. 2012;59(2):139-46.
36) Nishimura S, Manabe I, Nagasaki M, Kakuta S,

protective effects against ventricular remodeling

Iwakura Y, Takayama N, Ooehara J, Otsu M,

after myocardial infarction in mice.

Kamiya A, Petrich BG, Urano T, Kadono T, Sato

Res . 2012;35(1):62-9.

Hypertens

S, Aiba A, Yamashita H, Sugiura S, Kadowaki T,43) Fujiu K, Manabe I, Sasaki M, Inoue M, Iwata H,

Nakauchi H, Eto K, Nagai R. In vivo imaging

Hasumi E, Komuro I, Katada Y, Taguchi T, Nagai

visualizes discoid platelet aggregations without

R.

endothelium

formation following coronary stent implantation.

contribution

disruptionofandinflammatory

integrin signaling.

implicates
cytokine

andBlood . 2012;119(8):e45-56.

37) Myojo M, Iwata H, Kohro T, Sato H, Kiyosue A,

Ando J, Sawaki D, Takahashi M, Fujita H, Hirata
Y,

Nagai

R.

Prognostic

implicationofmacrocytosis on adverse outcomes after coronary
intervention.

Atherosclerosis.

2012;221(1):148-53.
38) 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 ABCG2 protects against pressure
overload-induced cardiac hypertrophy and heart
failurebypromotingantioxidant response.

angiogenesis

andArterioscler Thromb Vasc

Biol. 2012;32(3):654-61.
39) Tamaki Z, Asano Y, Hatano M, Yao A,

Kawashima T, Tomita M, Kinugawa K, Nagai R,
Sato S. Efficacy of low-dose imatinib mesylate
for cutaneous involvement in systemic sclerosis:
a preliminary report of three cases.

Mod

Rheumatol. 2012;22(1):94-9.
40) Suzuki T, Kohro T, Hayashi D, Yamazaki T,

Nagai R. Frequency and impact of lifestylemodification in patients with coronary arterydisease: the Japanese Coronary Artery Disease(JCAD) study.
268-73.

Am Heart J. 2012;163(2):Nickel-free stainless steel avoids neointima

Sci Technol Adv Mater 2012;13:064218.
44) Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Ozeki A, Itoh C,
Sugiyama T, Kadowaki T, Yamazaki T, Nagai R.
Associations of variations in the MRF2/ARID5B
gene with susceptibility to type 2 diabetes in theJapanese population. J Hum Genet. 2012;57(11):727-33.

131

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

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

Associate
Goh Tanaka, M.D. Ph.D., Taisuke Jo, M.D.,Ph.D., Reiko Okudaira, M.D.,Ph.D.,
Nobuaki Hirota, M.D.,Ph.D., Yasushi Goto, M.D.,Ph.D., Osamu Narumoto, M.D.,Ph.D.,
Kousuke Watanabe, M.D.,Ph.D., Mitsuhiro Sunohara, M.D.,Ph.D.

Homepage

http://kokyuki.umin.jp/

Introduction and Organization

Clinical Activities

The staff of the Department of Respiratory Medicine,
Graduate School of Medicine, University of Tokyo,
consists of 1 professor, 2 lecturers, and 8 associates. In
the University of Tokyo, affiliated hospitals andforeign institutions, approximately 50 members
belong to the Department. In the University of Tokyo
Hospital, about 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 this era, we areconducting basic and clinical researches for wide
variety of respiratory disorders including primary lungcancer, COPD, asthma and interstitial lung diseases.
Especially, we have been intensively studying themolecular mechanisms underlying the pathogenesis oflung disorders. Our research goal is to develop novel
diagnostic and therapeutic modalities for better
management of these pulmonary diseases.

The Department of Respiratory Medicine is
responsible for the out-patient care as well as care of
in-patients (35 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 primary lung cancer,
respiratory infections, interstitial pneumonia, asthma,
COPD and pneumothorax. Many patients withprimary lung cancer also have COPD or interstitial
pneumonia as their back ground pulmonary diseases.
There are many emergency visits and admission due
to pneumonia, 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 in an effort to rescue them. A
specialized clinical conference for respiratory diseasehas been held once a week since late 1990s, where
staff of our department, department of thoracic
surgery and department of radiology join and discuss
together to make best diagnostic and therapeutic

132

approach to individual patients. This conference isappreciated as prototype of Cancer Board of the
University of Tokyo Hospital, and, now, is still one of
the most frequently held Cancer Board in our hospital.
Our department contributes to the pre- and postsurgical evaluation 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. Recently,
it is also noteworthy for the development ofmolecular-targeted therapy in primary lung cancer.
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 2012
1. Primary lung cancer
2. Respiratory infection
3. Interstitial pneumonia
4. Asthma
5. COPD
6. Pneumothorax

335
57
52
21
12
6

A weekly chart round and professor’s round arescheduled for Tuesday afternoon.
A specialized clinical conference for patients withrespiratory diseases is held as Respiratory Cancer
Board on every Thursday evening, together withthoracic surgeons and radiologists. In this conference,
radiological diagnosis, indication of CT-guided biopsy
and thoracoscopic 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 respiratory physicians fromseveral leading affiliated hospitals.
In systematic lectures, comprehensive presentation for
the understanding of basic knowledge about theconcept, pathogenesis, pathology, diagnosis and treatment of common respiratory diseases is performed.
In clinical lectures, we present clinical cases ofimportant diseases such as primary lung cancer andpneumothorax, and try to discuss several important
points on the diagnostic evaluation and treatment incollaboration with the Faculty of the Department ofThoracic 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 aphysician during this period.
As for post-graduate education, respiratory physicians(one senior resident and one associate) assemble ateam with one junior resident, and provide medical
cares for patients with various respiratory diseases.
Under these processes, residents are able to acquire

133

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.

Research Activities
Our department is conducting basic and clinicalresearches for various respiratory disorders including
primary lung cancer, COPD, asthma, interstitial
pneumonia, respiratory infections and others.
Epidemiological, clinical, cellular and molecularbiological techniques are utilized for the elucidationof pathogenic mechanisms and for the development ofnovel diagnostic and therapeutic modalities in
respiratory medicine. Postgraduate students as well as
the Faculty members make considerable effort tostudy about genetic alterations in primary lung cancer,
cell biological analysis using airway epithelial cells,
fibroblast and smooth muscle cells, both incollaboration with the Faculty of the Department ofThoracic Surgery, analysis of genetically-engineered
mice as disease-models and so on. These results havebeen presented and/or published in the Scientific
Meeting and/or peer-review Journals. Our main
research projects are as follows.
Search for diseases-susceptibility genes in respiratory
diseases.
Analysis of disease-models using geneticallyengineered mice.
Analysis of DNA methylation and miRNA in primarylung cancer and their clinical applications.
Search for previously unidentified oncogenic fusion
kinases in lung cancer
Analysis of functional alterations of airway epithelial
cells and fibloblasts in relation to tissue repair andremodeling, especially epithelial-mesenchymal transition, and the roles of various cytokines andchemokines, in asthma and COPD.
Detection of small airway disease using impulse
oscillometry and its clinical application.
Search for predictive factors for responses to chemotherapy in malignancy including primary lung cancer.
Takahide Nagase is GOLD National Leader; APSR,

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

References
1. Asahina H, Tamura Y, Nokihara H, Yamamoto N,
Seki Y, Shibata T, Goto Y, Tanioka M, Yamada Y,
Coates A, Chiu YL, Li X, Pradhan R, Ansell PJ,
McKeegan EM, McKee MD, Carlson DM,
Tamura T. An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics oflinifanib (ABT-869) in Japanese patients withsolid tumors. Cancer Chemother Pharmacol.
2012; 69(6): 1477–86.
2. Goto Y, Nagase T. Oncology Information on theInternet. Jpn J Clin Oncol. 2012; 42(5): 368–74.
3. Goto Y, Sekine I, Tanioka M, Shibata T, Tanai C,
Asahina H, Nokihara H, Yamamoto N, Kunitoh H,
Ohe Y, Kikkawa H, Ohki E, Tamura T.
Figitumumab combined with carboplatin andpaclitaxel in treatment-naïve Japanese patientswith advanced non-small cell lung cancer.
Investigational new drugs. 2012; 30(4): 1548–56.
4. Hirota N, Risse PA, Novali M, McGovern T,
Al-Alwan L, McCuaig S, Proud D, Hayden P,
Hamid Q, Martin JG. Histamine may induce
airway remodeling through release of epidermal
growth factor receptor ligands from bronchial
epithelial cells. FASEB J. 2012; 26(4): 1704-16
5. 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(1): 158-63.
6. Horie M, Ugajin M, Suzuki M, Noguchi S,
Tanaka W, Yoshihara H, Kawakami M,
Kichikawa Y, Sakamoto Y. Diagnostic andprognostic value of procalcitonin in communityacquired pneumonia. Am J Med Sci. 2012;
343(1): 30-5.
7. Kage H, Borok Z. EMT and interstitial lungdisease: a mysterious relationship. Curr Opin
Pulm Med. 2012; 18(5): 517-23.
8. 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134allergic airway inflammation induced by house
dust mite exposure. Cell Immunol. 2012; 275(1-2): 24-32.
9. Kitagawa H, Watanabe K, Kage H, Inoh S, GotoA, Fukayama M, Nagase T, Ohishi N, Takai D.
Pulmonary Venous Invasion, Determined by Chest
Computed Tomographic Scan, as a Potential Early
Indicator of Zygomycosis Infection: A Case Series.
J Thorac Imaging. 2012; 27(4): W97-9.
10. Mikami Y, Yamauchi Y, Horie M, Kase M, Jo T,
Takizawa H, Kohyama T, Nagase T. Tumor
necrosis factor superfamily member LIGHT
induces epithelial-mesenchymal transition in
A549 human alveolar epithelial cells. Biochem
Biophys Res Commun. 2012; 428(4): 451-7.
11. 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(1): 18-25.
12. Nokihara H, Yamamoto N, Yamada Y, Yamada K,
Hirata T, Goto Y, Tanioka M, Ikeda Y, Tamura T.
A phase I study of BMS-690514 in Japanesepatients with advanced or metastatic solid tumors.
Cancer Chemother Pharmacol. 2012; 70(4):559–65.
13. Sapkota BR, Hijikata M, Matsushita I, Tanaka G,
Ieki R, Kobayashi N, Toyota E, Nagai H,
Kurashima A, Tokunaga K, Keicho N.
Association of SLC11A1 (NRAMP1) polymorphisms with pulmonary Mycobacterium
avium complex infection. Hum Immunol. 2012;
73(5): 529-536.
14. 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 expression of CK20, FABP1 andMUC2 is sensitive for the prediction of peritoneal
recurrence in gastric cancer. Jpn J Clin Oncol.
2012; 42(2): 148-52.
15. Shalaby KH, Jo T, Nakada E, Allard-Coutu A,
Tsuchiya K, Hirota N, Qureshi ST, Maghni K,
Rioux CR, Martin JG. ICOS-expressing CD4 T
cells induced via TLR4 in the nasal mucosa arecapable of inhibiting experimental allergic
asthma. J Immunol. 2012; 189(6): 2793-804.

16. Tsuchiya K, Siddiqui S, Risse PA, Hirota N,
Martin JG. The presence of LPS in OVA
inhalations affects airway inflammation and AHR
but not remodeling in a rodent model of asthma.
Am J Physiol Lung Cell Mol Physiol. 2012;
303(1): L54-63.
17. Venkatesan N, Siddiqui S, Jo T, Martin JG,
Ludwig MS. Allergen-induced airway remodeling in brown norway rats: structural andmetabolic changes in glycosaminoglycans. Am J
Respir Cell Mol Biol. 2012; 46(1): 96-105.
18. Watanabe K, Emoto N, Hamano E, Sunohara M,
Kawakami M, Kage H, Kitano K, Nakajima J,
Goto A, Fukayama M, Nagase T, Yatomi Y,
Ohishi N, Takai D. Genome structure-based
screening identified epigenetically silenced
microRNA associated with invasiveness in
non-small-cell lung cancer. Int J Cancer. 2012;
130(11): 2580-90.
19. Yamamoto N, Nokihara H, Yamada Y, Goto Y,
Tanioka M, Shibata T, Yamada K, Asahina H,
Kawata T, Shi X, Tamura T. A Phase I, dosefinding and pharmacokinetic study of olaparib(AZD2281) in Japanese patients with advanced
solid tumors. Cancer Sci. 2012; 103(3): 504–9.
20. Yamauchi Y, Kohyama T, Jo T, Nagase T. Dynamicchange in respiratory resistance during inspiratory
and expiratory phases of tidal breathing in patientswith chronic obstructive pulmonary disease. Int J
Chron Obstruct Pulmon Dis 2012; 7: 259-6.

135

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

LecturerHaruhiko Yoshida, M.D., Ph.D.
Minoru Tada, M.D., Ph.D.
Hiroyuki Isayama, M.D., Ph.D.

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

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

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

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

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

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

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

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

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

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

Yasuo Tanaka, 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.

Masashi Izumiya, 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 reorganization 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, 55 graduates and 5 othervisiting researchers including students from abroad(March, 2013). 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 anaverage hospital stay of 12.3 days. Resident, juniorand senior staff members bear the responsibility for a
medical management of each inpatient, in collaboration with subspecialty groups concerned. The staff

136

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 clinical conferences are held on Monday evening.
Hepatocellular carcinoma is the most common
disease in patients who are admitted to the department(〜1,000 cases in 2012). 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 undergoingradiofrequency ablation for metastatic liver tumors is
also increasing recent years (80 cases in 2012). 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 with endoscopic 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 formany 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, gastroduodenal endoscopy
on 8,200, and colonoscopy on 4,200 patients each year,
leading the detection of about 240 cases of gastriccancer and 250 cases of colorectal cancer annually.
About 40 % of them are treated endoscopically, but
we also aim to perform basic studies using specimen,
and turn these efforts to clinical activities.

Educational Activities
Systematicandclinicallectureson
gastroenterology are given regularly 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 clinical clerkship for the fourth andfifth grade students, where each student is allotted to
an inpatient by joining the group of physicians andoffering the opportunity to learn digestive diseases
practically. The results are reported to the professor at
the end of the course in the style of oral examination.
Students are also required to summarize and outline
articles from world’s leading medical journals.
Residents of internal medicine join the
Department of Gastroenterology for 1-6 months inrotation in their first year as a doctor, where they learn
therapeutics and diagnostics in gastroenterology
together with general internal medicine. Giving
presentations at the scientific meeting is highly
encouraged. If they are interested in gastroenterology
in particular, they may learn advanced techniques ingastroenterology in affiliated hospitals for a few years.
Usually, they will come back to the department afterthat period, and improve their clinical skills still
further while at the education course. The majority ofthem also become graduate student, and starts medical
researches either in a basic or clinical research area.
Currently, the department has 55 students, who were
graduated from more than 30 medical schools inJapan.

137

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 of carcinogenesis in gastroenterological neoplasms, metabolic
aspects of viral hepatitis, mechanisms of replication ofhepatitis viruses, mechanisms of liver regenerationand fibrosis, pathogenesis of Helicobacter 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, SNPs analyses for anti-viraltreatment for hepatitis C, TS-1 alone or combinedwith gemcitabine, for pancreatic and bile duct cancers,
gemcitabine alone or combined with cisplatin,
additional mosapride in therapy of gastro-esophageal
reflux disease, and investigation and treatment trial of
the small intestinal lesions in NSAID users by capsuleendoscopy.
The department is dedicated to pursuing bettermedical services from all facets of the subspecialty ofgastroenterology, which is brought about by bothbasic and clinical researches.

References
1)

2)

Hayakawa Y, Hirata Y, Sakitani K, Nakagawa H,
Nakata W, Kinoshita H, Takahashi R, Takeda K,
Ichijo H, Maeda S, Koike K. Apoptosis signalregulating kinase-1 inhibitor as a potent therapeutic
drug for the treatment of gastric cancer. Cancer Sci
2012;103(12):2181-2185.
Sakitani K, Hirata Y, Hayakawa Y, Serizawa T,
Nakata W, Takahashi R, Kinoshita H, Sakamoto K,
Nakagawa H, Akanuma M, Yoshida H, Maeda S,
Koike K. The role of Interleukin-32 in Helicobacter
pylori--induced gastric inflammation. Infect Immun
2012;80(11):3795-803. PMID: 22890997.

3)

Nakai Y, Ishigami H, Isayama H, Sasaki T,
Kawakubo K, Kogure H, Emoto S, Yamaguchi H,
Kitayama J, Yamamoto N, Sasahira N, Hirano K,
Tada M, Koike K. Role of intervention for biliary
and gastric/intestinal obstruction in gastric cancer
with peritoneal metastasis. J Gastroenterol Hepatol
2012;27(12):1796-1800 PMID: 22849855.
4) Minami T, Kishikawa T, Sato M, Tateishi R,
Yoshida H, Koike K. Meta-analysis: mortality andserious adverse events of peginterferon plus
ribavirin therapy for chronic hepatitis C. J
Gastroenterol 2013;48(2):254-268.
5) Mizuno S, Nakai Y, Isayama H, Yanai A, Takahara
N, Miyabayashi K, Yamamoto K, Kawakubo K,
Mohri D, Kogure H, Sasaki T, Yamamoto N,
Sasahira N, Hirano K, Tsujino T, Ijichi H, Tateishi
K, Akanuma M, Tada M, Koike K. Risk factors andearly signs of pancreatic cancer in diabetes:
screening strategy based on diabetes onset age. J
Gastroenterol 2013;48(2):238-246.
6) Goto O, Kambe H, Niimi K, Mochizuki S, AsadaHirayama I, Minatsuki C, Ono S, Kodashima S,
Yamamichi N, Yamaji Y, Fujishiro M, Koike K.
Discrepancy in diagnosis of gastric submucosal
tumor among esophagogastroduodenoscopy, CT,and endoscopic ultrasonography: a retrospective
analysis of 93 consecutive cases. Abdom Imaging
2012;37(6):1074-1078. PubMed PMID: 22752557.
7) Sasaki T, Isayama H, Nakai Y, Takahara N, Sasahira
N, Kogure H, Mizuno S, Yagioka H, Ito Y,
Yamamoto N, Hirano K, Toda N, Tada M, Omata
M, Koike K. Improvement of prognosis forunresectable biliary tract cancer. World J
Gastroenterol 2013;19(1):72-77. PMID:23326165.
8) Takata A, Otsuka M, Yoshikawa T, Kishikawa T,
Hikiba Y, Obi S, Goto T, Kang YJ, Maeda S,
Yoshida H, Omata M, Asahara H, Koike K.
MiRNA-140 acts as a liver tumor suppressor bycontrolling NF-κB activity via directly targetingDnmt1 expression. Hepatology 2013;57:162-170.
PMID: 22898998.
9) Kurano M, Hara M, Tsuneyama K, Okamoto K,
Iso-O N, Matsushima T, Koike K, Tsukamoto K.
Modulation of lipid metabolism with the overexpression of NPC1L1 in mice liver. J Lipid Res
2012;53(11):2275-2285. PMID: 22891292.
10) Shiina S, Tateishi R, Imamura M, Teratani T, Koike

138

Y, Sato S, Obi S, Kanai F, Kato N, Yoshida H,
Omata M, Koike K. Percutaneous ethanol injection
for hepatocellular carcinoma: 20-year outcome andprognostic factors. Liver Int 2012;32(9):1434-1442.
PubMed PMID: 22712520.
11) Kegeyama Y, Ikeda H, Watanabe N, Nagamine M,
Kusumoto Y, Yashiro M, Satoh Y, Shimosawa T,
Shinozaki K, Tomiya T, Inoue Y, Nishikawa T,
Ohtomo N, Tanoue Y, Yokota H, Koyama T,
Ishimaru K, Okamoto Y, Takuwa Y, Koike K,
Yatomi Y. Antagonism of sphingosine 1-phosphate
receptor 2 causes a selective reduction of portal
vein pressure in bile duct-ligated rats. Hepatology
2012;56(4):1427-1438. PubMed PMID: 22505286.
12) Hamada T, Nakai Y, Isayama H, Togawa O, Kogure
H, Kawakubo K, Tsujino T, Sasahira N, Hirano K,
Yamamoto N, Ito Y, Sasaki T, Mizuno S, Toda N,
Tada M, Koike K. One- and two-step selfexpandable metal stent placement for distal malignant biliary obstruction: a propensity analysis. J
Gastroenterol 2012; 47(11): 1248-1256. PubMed
PMID: 22526271.
13) 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;15(4):414-418.
14) Okuse C, Yotsuyanagi H, Yamada N, Ikeda H,
Kobayashi M, Fukuda Y, Takahashi H, Matsunaga
K, Matsumoto N, Okamoto M, Ishii T, Sato A,
Koike K, Suzuki M, Itoh F. Changes in levels of
hepatitis B virus markers in patients positive forlow-titer hepatitis B surface antigen. Hepatol Res.
2012;42(12):1236-1240.
15) Niimi K, Fujishiro M, Koike K. An unusual case of
submucosal tumor in the stomach. Gastroenterology 2012 Oct;143(4):895-1121.
16) Uchino K, Obi S, Tateishi R, Sato S, Kanda M, Sato
T, Arano T, Enooku K, Goto E, Masuzaki R,
Nakagawa H, Asaoka Y, Kondo Y, Yamashiki N,
Goto T, Shiina S, Omata M, Yoshida H, Koike K.
Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated
interferon alfa-2a for advanced hepatocellular
carcinoma. J Gastroenterol 2012;47(10):1152-1159.
17) Sato M, Tateishi R, Yasunaga H, Horiguchi H,

Yoshida H, Matsuda S, Koike K. Mortality andmorbidity of hepatectomy, radiofrequency ablation,and embolization for hepatocellular carcinoma: anational survey of 54,145 patients. J Gastroenterol
2012;47(10):1125-1133.
18) Kumar V, Yi Lo PH, Sawai H, Kato N, Takahashi A,
Deng Z, Urabe Y, Mbarek H, Tokunaga K, Tanaka
Y, Sugiyama M, Mizokami M, Muroyama R,
Tateishi R, Omata M, Koike K, Tanikawa C,
Kamatani N, Kubo M, Nakamura Y, Matsuda K.
Soluble MICA and a MICA Variation as Possible
Prognostic Biomarkers for HBV-Induced Hepatocellular Carcinoma. PLoS One 2012;7(9):e44743.
PMID: 23024757.
19) Yamamichi N, Oka M, Inada KI, Konno-Shimizu
M, Kageyama-Yahara N, Tamai H, Kato J,
Fujishiro M, Kodashima S, Niimi K, Ono S,
Tsutsumi Y, Ichinose M, Koike K. Rebamipide
induces dendritic cell recruitment to N-methylN'-nitro-N-nitrosoguanidine(MNNG)-exposed rat
gastric mucosa based on IL-1β upregulation.
Biochem Biophys Res Commun 2012;424(1):124-129. PubMed PMID: 22732404.
20) Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Takazawa Y, Aoki T, Hasegawa K, Sakamoto Y,
Koike K, Kokudo N. Living-donor liver transplantation for autoimmune hepatitis and autoimmune hepatitis-primary biliary cirrhosis overlap
syndrome. Hepatol Res 2012;42(10):1016-1023.
PubMed PMID: 22548727.
21) Yoshikawa T, Takata A, Otsuka M, Kishikawa T,
Kojima K, Yoshida H, Koike K. Silencing of
microRNA-122 enhances interferon-α signaling in
the liver through regulating SOCS3 promoter
methylation. Sci Rep 2012;2:637. PubMed PMID:
22957141.
22) Mikami S, Tateishi R, Akahane M, Asaoka Y,
Kondo Y, Goto T, Shiina S, Yoshida H, Koike K.
Computed Tomography Follow-up for the
Detection of Hepatocellular Carcinoma Recurrence
after Initial Radiofrequency Ablation: A Singlecenter Experience. J Vasc Interv Radiol 2012;23(10):1269-1275.
23) Ohki T, Tateishi R, Akahane M, Shiina S,
Yamashiki N, Mikami S, Enooku K, Goto E,
Masuzaki R, Kondo Y, Goto T, Inoo S, Ohtomo K,
Omata M, Yoshida H, Koike K. Characteristics of

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hepatocellular carcinoma nodules newly detectedby computed tomography during arteriography andarterial portography: preliminary report of arandomized controlled trial. Hepatol Int 2012;6(3):639-645. PubMed PMID: 22020826.
24) Takata A, Otsuka M, Kogiso T, Kojima K,
Yoshikawa T, Tateishi R, Kato N, Shiina S, Yoshida
H, Omata M, Koike K. Direct differentiation ofhepatic cells from human induced pluripotent stem
cells using a limited number of cytokines. Hepatol
Int 2011;5(4)890-898. PubMed PMID: 21484132.
25) Takahara N, Isayama H, Sasaki T, Tsujino T, Toda
N, Sasahira N, Mizuno S, Kawakubo K, Kogure H,
Yamamoto N, Nakai Y, Hirano K, Tada M, Omata
M, Koike K. Endoscopic papillary balloon dilation
for bile duct stones in patients on hemodialysis. J
Gastroenterol 2012;47(8):918-923.PubMed PMID:
22354661.
26) Nakagawa H, Isogawa A, Tateishi R, Tani M,
Yoshida H, Yamakado M, Koike K. Serum gammaglutamyltransferase level is associated with serum
superoxide dismutase activity and metabolic
syndrome in a Japanese population. J Gastroenterol
2012;47(2):187-194. PubMed PMID: 21976134.
27) Ono S, Fujishiro M, Kodashima S, Takahashi Y,
Minatsuki C, Mikami-Matsuda R, Asada-Hirayama
I, Konno-Shimizu M, Tsuji Y, Mochizuki S, Niimi
K, Yamamichi N, Kaneko M, Yatomi Y, Koike K.
Evaluation of safety of endoscopic biopsy without
cessation of antithrombotic agents in Japan. J
Gastroenterol 2012;47(7):770-774.
28) Kawakubo K, Isayama H, Sasahira N, Kogure H,
Takahara N, Miyabayashi K, Mizuno S, Yamamoto
K, Mohri D, Sasaki T, Yamamoto N, Nakai Y,
Hirano K, Tada M, Koike K. Clinical utility ofsingle operator cholangiopancreatoscopy using a
SpyGlass probe through an endoscopic retrograde
cholangiopancreatography catheter. J Gastroenterol
Hepatol 2012;27(8):1371-1376.
29) Yasui K, Hashimoto E, Tokushige K, Koike K,
Shima T, Kanbara Y, Saibara T, Uto H, Takami S,
Kawanaka M, Komorizono Y, Okanoue T; The
Japan NASH Study Group. Clinical and pathological progression of non-alcoholic steatohepatitis
to hepatocellular carcinoma. Hepatol Res 2012;
42(8):767-773.
30) Soroida Y, Ohkawa R, Nakagawa H, Satoh Y,

Yoshida H, Kinoshita H, Tateishi R, Masuzaki R,
Enooku K, Shiina S, Sato T, Obi S, Hoshino T,
Nagatomo R, Okubo S, Yokota H, Koike K, Yatomi
Y, Ikeda H. Increased activity of serum mitochondrial isoenzyme of creatine kinase in hepatocellular
carcinoma patients predominantly with recurrence.
J Hepatol 2012;57(2):330-336.
31) Nakai Y, Isayama H, Ijichi H, Sasaki T, Kogure H,
Yagioka H, Miyabayashi K, Mizuno S, Yamamoto
K, Mouri D, Kawakubo K, Yamamoto N, Hirano K,
Sasahira N, Tateishi K, Tada M, Koike K. Phase I
trial of gemcitabine and candesartan combination
therapy in normotensive patients with advanced
pancreatic cancer: GECA1. Cancer Sci 2012 Aug;
103(8):1489-1892.
32) Fukuhara T, Kambara H, Shiokawa M, Ono C,
Katoh H, Morita E, Okuzaki D, Maehara Y, Koike
K, Matsuura Y. Expression of miR-122 facilitates
an efficient replication in nonhepatic cells upon
infection with HCV. J Virol 2012;86(15):79187933.
33) Isayama H, Nakai Y, Kawakubo K, Kogure H,
Hamada T, Togawa O, Sasahira N, Hirano K,
Tsujino T, Koike K. Endoscopic retrograde
cholangiopancreatography for distal malignant
biliary stricture. Gastrointest Endoscopy Clin N Am
2012;22:479-490.
34) Goto K, Hatakeyama S, Okamoto K, Kitazawa T,
Abe K, Moriya K, Koike K, Yotsuyanagi H.
Dengue hemorrhagic Fever in an adult traveler
returning to Japan. Intern Med 2012;51(13):17791782.
35) Isayama H, Nakai Y, Kawakubo K, Kogure H,
Hamada T, Togawa O, Sasahira N, Hirano K,
Tsujino T, Koike K. Endoscopic retrograde
cholangiopancreatography for distal malignant
biliary stricture. Gastrointest Endosc Clin N Am
2012;22(3):479-490. PubMed PMID: 22748244.
36) Sasaki T, Isayama H, Nakai Y, Togawa O, Kogure
H, Kawakubo K, Mizuno S, Yashima Y, Ito Y,
Yamamoto N, Sasahira N, Hirano K, Tsujino T,
Toda N, Tada M, Omata M, Koike K. Predictive
factors of solid food intake in patients withmalignant gastric outlet obstruction receiving
self-expandable metallic stents for palliation. Dig
Endosc 2012;24(4):226-230.
37) Hirano K, Isogawa A, Tada M, Isayama H,

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Takahara N, Miyabayashi K, Mizuno S, Mohri D,
Kawakubo K, Sasaki T, Kogure H, Yamamoto N,
Sasahira N, Toda N, Nagano R, Yagioka H,
Yashima Y, Hamada T, Ito Y, Koike K. Long-Term
Prognosis of Autoimmune Pancreatitis in Terms of
Glucose Tolerance. Pancreas 2012;41(5):691-695.
PubMed PMID: 22249131.
38) Isayama H, Tsujino T, Nakai Y, Sasaki T, Nakagawa
K, Yamashita H, Aoki T, Koike K. Clinical benefitof radiation therapy and metallic stenting forunresectable hilar cholangiocarcinoma. World J
Gastroenterol 2012;18(19):2364-2370. PubMed
PMID: 22654427.
39) Gonoi W, Akai H, Hagiwara K, Akahane M,
Hayashi N, Maeda E, Yoshikawa T, Kiryu S, Tada
M, Uno K, Ohtsu H, Okura N, Koike K, Ohtomo K.
Meandering main pancreatic duct as a relevant
factor to the onset of idiopathic recurrent acutepancreatitis. PLoS One 2012;7(5):e37652.
40) Ono S, Fujishiro M, Koike K. Endoscopic
submucosal dissection for superficial esophageal
neoplasms. World J Gastrointest Endosc 2012;4(5):162-166. PubMed PMID: 22624067.
41) Yamamichi N, Mochizuki S, Asada-Hirayama I,
Mikami-Matsuda R, Shimamoto T, Konno-Shimizu
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 crosssectional study of healthy 19864 adults using FSSG
scores. BMC Med 2012;10(1):45. PubMed PMID:
22554226.
42) Takata A, Otsuka M, Yoshikawa T, Kishikawa T,
Kudo Y, Goto T, Yoshida H, Koike K. A miRNAmachinery component DDX20 controls NF-κB via
microRNA-140 function. Biochem Biophys Res
Commun 2012;420(3):564-569.
43) Masuzaki R, Tateishi R, Yoshida H, Arano T,
Uchino K, Enooku K, Goto E, Nakagawa H,
Asaoka Y, Kondo Y, Goto T, Ikeda H, Shiina S,
Omata M, Koike K. Assessment of diseaseprogression in patients with transfusion-associatedchronic hepatitis C using transient elastography.
World J Gastroenterol 2012;18(12):1385-1390.
44) Hirata Y, Ohmae T, Yanai A, Sakitani K, Hayakawa
Y, Yoshida S, Sugimoto T, Mitsuno Y, Akanuma M,
Yamaji Y, Ogura K, Maeda S, Koike K.

Sitafloxacin resistance in Helicobacter pylori
isolates and sitafloxacin-based triple therapy as athird-line regimen in Japan. Int J Antimicrob Agents2012;39(4):352-355. PMID: 22321702.
45) Isayama H, Sasaki T, Nakai Y, Togawa O, Kogure
H, Sasahira N, Yashima Y, Kawakubo K, Ito Y,
Hirano K, Tsujino T, Toda N, Tada M, Omata M,
Koike K. Management of malignant gastric outlet
obstruction with a modified triple-layer covered
metal stent. Gastrointest Endosc 2012;75(4):757763. PubMed PMID: 22284092.
46) Hosoya H, Kadowaki K, Matsusaki M, Cabral H,
Nishihara H, Ijichi H, Koike K, Kataoka K,
Miyazono K, Akashi M, Kano MR. Engineering
fibrotic tissue in pancreatic cancer: A novel threedimensional model to investigate nanoparticle
delivery. Biochem Biophys Res Commun 2012 2;419(1):32-37.
47) Kudo Y, Tateishi K, Yamamoto K, Yamamto S,
Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani
H, Koike K. Loss of 5-hydroxymethylcytosine isaccompanied with malignant cellular transformation. Cancer Sci 2012;103(4):670-676. PubMed
PMID: 22320381.
48) Goto E, Masuzaki R, Tateishi R, Kondo Y, Imamura
J, Goto T, Ikeda H, Akahane M, Shiina S, Omata M,
Yoshida H, Koike K. Value of post-vascular phase(Kupffer imaging) by contrast-enhanced ultrasonography using Sonazoid in the detection ofhepatocellular carcinoma. J Gastroenterol. 2012;
47(4):477-485.
49) Shiina S, Tateishi R, Arano T, Uchino K, Enooku K,
Nakagawa H, Asaoka Y, Sato T, Masuzaki R,
Kondo Y, Goto T, Yoshida H, Omata M, Koike K.
Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am
J Gastroenterol 2012; 107(4): 569-577. PMID:
22158026.
50) Yamada A, Watabe H, Kobayashi Y, Yamaji Y,
Yoshida H, Koike K. Timing of capsule endoscopy
influences the diagnosis and outcome in obscureovert gastrointestinal bleeding. Hepatogastroenterology 2012; 59(115): 676-679. doi: 10.5754/hge
12180. PMID: 22469708.

Internal Medicine
2. Medicine Ⅱ142

Department of Nephrology and
Endocrinology
Professor
Masaomi Nangaku, 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.,

Kent Doi, M.D., Ph.D.

Associate
Katsutoshi Takahashi, M.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.,

Tetsuhiro Tanaka, M.D., Ph.D.,

Yoshifumi Hamasaki, 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. We are intimately
working together in all clinical activities under thesupervision of the professor, the associate professor,
and the lecturers.

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 of

143

treatment to the patients. We also treat diabetic
patients with proteinuria and end-stage renal failure.
Each staff of our division also works at the
hemodialysis unit, thus we can manage patients inevery stage of renal disease. In collaboration with
Department of Urology, we are conducting renaltransplantation and promoting peritoneal dialysis.
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.
Particularly, we have put emphasis on participation of
the students in clinical practice including medical
investigations, diagnosis, and treatment. In the ward,
we are also educating residents during daily clinicalworks and periodical lectures concerning kidney andendocrine diseases. Our department also participatesin Metabolism Research Course for educating young
clinical researchers and fellows in collaboration with
Department of Diabetes and Metabolic Diseases,
Department of Cardiology, and Department ofGeriatric 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
journals of nephrology, hypertension and endocrinology.
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. Development of new treatment for anti-neutrophil
cytoplasmic antibody-related vasculitis.
3. Roles of renal proximal tubule transport in theregulation of plasma volume and blood pressure.
4. Physiological and pathological significance of
Na-HCO3 cotransporter NBCe1.
5. Investigation on pathogenesis of disorders ofmineral and bone metabolism
6. Molecular mechanism of G protein-coupled
receptor-mediated signal transduction
7. 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 their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for Hemodialysis in 2000 at the University Hospital. The Centerfor 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 ahemodialysis controlling system is a hub to transfer all
digital and analog data from patients and to monitor
machines, including blood purification machines, tothe host computer in our hospital, centralizing all data
and administering medical coding and billing robustly.
Blood purification machines in the ICU can bemonitored seamlessly under the cloud system of our
hospital. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational

144

quality of staff members.
4.
Clinical activities
1. Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
2. Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does
not accept holiday dialysis.
3. Emergency hemodialysis and hemodiafiltration
for ICU patients.
4. Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
5. DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
6. LDL apheresis for nephrotic syndrome and ASO
patients.
7. White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.
Education
1. A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.
2. Technical development course for medical
engineers and nurses.
3. Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
4. Exposure in hemodialysis & apheresis course to
second year residents on request.
5. Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual].
6. Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.
Research
1. Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
2. Development and application of a non-invasive
pulse hemoglobin meter.
3. Genome wide association study for Nephrotic

5.
6.
7.
8.
9.

syndrome and those functional analyses.
Reevaluation of screening approaches to Fabry
disease to elucidate the patient cohort; theenzyme-replacement therapy is indispensable.
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) Tanaka T, Yamaguchi J, Shoji K, Nangaku M.
Anthracycline inhibits recruitment of hypoxiainducible transcription factors and suppresses
tumor cell migration and cardiac angiogenic
response in the host. J Biol Chem 2012; 287:
34866-82.
(2) Mimura I, Nangaku M, Kanki Y, Tsutsumi S,
Inoue T, Kohro T, Yamamoto S, Fujita T,
Shimamura T, Suehiro JI, Taguchi A, Kobayashi
M, Tanimura K, Inagaki T, Tanaka T, Hamakubo
T, Sakai J, Aburatani H, Kodama T, Wada Y.
Dynamic change of the chromatin conformationin response to hypoxia enhances the expressionof GLUT3 (SLC2A3) by cooperative interactionof HIF1 and KDM3A. Mol Cell Biol 2012; 32:3018-32(3) Muratsu-Ikeda S Nangaku M, Ikeda Y, Tanaka T,
Wada T, Inagi R. Downregulation of miR-205
modulates cell susceptibility to oxidative andendoplasmic reticulum stresses in renal tubularcells. PLoS One 2012;7: e41462(4) Ikeda Y, Nangaku M, Ishibashi Y, Hirohama D,
Uozaki H, Tojo A, Ishikawa A, Fujita T. A caseof de novo focal segmental glomerulosclerosis
occurred one and half years after kidney transplantation supposed to be caused by calcineurin
inhibitor. Clin Transplant 2012; 26 Suppl 24;
76-80.

145(5) Tsukamoto M, Akahane M, Nangaku M. Imageof Erdheim-Chester disease requiring hemodialysis. Clin Exp Nephrol 2012;16: 811-2.
(6) Committee for the Standardization of Renal
Pathological Diagnosis and for Renal Biopsy andDisease Registry of the Japanese Society ofNephrology, and the Progressive Renal Disease
Research of the Ministry of Health, Labour andWelfare of Japan. Renal disease in the elderly
and the very elderly Japanese: analysis of theJapan Renal Biopsy Registry (J-RBR). Clin Exp
Nephrol 2012; 16: 903-20.
(7) Tanaka T, Nangaku M: Recent advances andclinical application of erythropoietin anderythropoiesis-stimulating agents. Exp Cell Res
2012; 318: 1068-73.
(8) Chiang CK, Tanaka T, Nangaku M: Dysregulated
oxygen metabolism of the kidney by uremic
toxins. J Ren Nutr 2012;22:77-80.
(9) Tojo A, Kinugasa S. Mechanisms of glomerular
albumin filtration and tubular reabsorption. Int J
Nephrol 2012; Volume 2012, Article ID 481520,
9 pages, doi:10.1155/2012/481520(10) Hirahashi J, Jo A, Ueda K, Tojo A, Fujita T.
Successful treatment of antineutrophil cytoplasmic antibody-associated vasculitis with eicosapentaenoic acid. Ann Intern Med 2012; 156(10):755-756.
(11) Miyazaki H, Uozaki H, Tojo A, Hirashima S,
Inaga S, Sakuma K, Morishita Y, Fukayama M.
Application of low-vacuum scanning electron
microscopy for renal biopsy specimens. Pathol
Res Pract 2012; 208(9):503-9.
(12) Hanamura K, Tojo A, Kinugasa S, Asaba K,
Fujita T. The resistive index is a marker of renal
function, pathology, prognosis, and responsiveness to steroid therapy in chronic kidney disease
patients. International Journal of Nephrology.
Volume 2012, Article ID 139565, 9 pages, doi:10.
1155/2012/139565.
(13) Takahashi K, Makita N, Manaka K, Hisano M,
Akioka Y, Miura K, Takubo N, Iida, Ueda N,
Hashimoto M, Fujita T, Igarashi T, Sekine T and
Iiri T. V2R mutations in partial nephrogenic
diabetes insipidus highlight protean agonism of
V2R antagonists. J. Biol. Chem. 2012; 287:
2099-2016.

(14) Oishi A, Makita N, Sato J and Iiri T. Regulationof RhoA signaling by the cAMP-dependent
phosphorylation of RhoGDIα. J. Biol. Chem.
2012; 287: 38705-15.
(15) Makita N, Kabasawa Y, Otani Y, Firman, Sato J,
Hashimoto M, Nakaya M, Nishihara H, Nangaku
M, Kurose H, Ohwada T and Iiri T. Attenuateddesensitization of β-adrenergic receptor bywater-soluble N-nitrosamines that induce
S-nitrosylation without nitric oxide release.
Circ. Res. 2012; Epub Dec 4.
(16) Nakamura M, Seki G, Iwadoh K, Nakajima I,
Fuchinoue S, Fujita T and Teraoka S: Acute
Kidney Injury as Defined by the RIFLE criteria is
a risk factor for kidney transplant graft failure.
Clin Transplant 2012; 4:520-8(17) Seki G, Endo Y, Suzuki M, Yamada H, Horita S,
Fujita T: Role of renal proximal tubule transport
in thiazolidinediones-induced volume expansion.
World Journal of Nephrology 2012; 6; 1(5): 14650(18) Suzuki M, Seki G, Yamada H, Horita S, Fujita T.
Functional roles of electrogenic sodium
bicarbonate cotransporter NBCe1 in ocular
tissues. The Open Ophthalmology Journal 2012;
6: 36-41.
(19) Seki G, Horita S, Suzuki M, Yamazaki O,
Yamada H. Pathophysiological roles of mutationsin the electrogenic Na+-HCO3- cotransporter
NBCe1. Mutations in Human Genetic Disease,2012; pp167- pp180, ISBN 978-953-51-0790-3,
edited by David N. Cooper and Jian-Min Chen(20) Vaisbich MH, Henriques Ldos S, Igarashi T,
Sekine T, Seki G, Koch VH. The long-term use ofenalapril and hydrochlorothiazide in two novel
mutations patients with Dent's disease type 1. J
Bras Nefrol 2012; 34(1):78-81(21) Yamada H, Takano K, Ayuzawa N, Seki G, andToshiro. Relowering of SerumNa for Osmotic
Demyelinating Syndrome. Case Reports in
Neurological Medicine. 2012;2012:704639.
(22) Horita S, Nakamura M, Suzuki M, Yamada H,
Seki G: Role of renal sodium transport in insulin
resistance and hypertension. Obesity Epidemic(iConcept Press) 2012; ISBN (Paperback) 97814775549-6(23) Tanaka M, Ishibashi Y , Hirahashi J & Fujita T.

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Peritoneal dialysis with Takayasu arteritis: areport of three cases. Ther Apher Dial. 2012; 16:
198-9.
(24) Doi K., Katagiri D., Negishi K., Hasegawa S.,
Hamasaki Y., Fujita T., Matsubara T., Ishii T.,
Yahagi N., Sugaya T., Noiri E. Mild elevation ofurinary biomarker in prerenal acute kidney injury.
Kidney Int. 2012; 82, 1114-1120(25) Doi K, Noiri E, Ishizu T, Negishi K, Suzuki Y,
Hamasaki Y, Honda K, Fujita T, Tsukimura T,
Togawa T, Saito S, Sakuraba H. High-throughput
screening identified disease-causing mutants andfunctional variants of α-galactosidase A gene inJapanese male hemodialysis patients. J. Hum.
Genet. 2012: 57, 575-9.
(26) Hamasaki Y, Doi K, Okamoto K, Ijichi H, Seki G,
Maeda-Mamiya R, Fujita T, Noiri E. 3-hydroxy3-methylglutaryl-coenzyme A reductase inhibitor
simvastatin ameliorates renal fibrosis through
HOXA13–USAG-1 pathway. Lab. Invest. 2012;
92:1161-7.
(27) Katagiri D, Doi K, Honda K, Negishi K, Fujita T,
Hisagi M, Ono M, Matsubara T, Yahagi N,
Iwagami M, Ohtake T, Kobayashi S, Sugaya T,
Noiri E. Combination of two urinary biomarkers
predicts acute kidney injury after adult cardiac
surgery. Ann. Thorac. Surg. 2012; 93:577-83.
(28) Okamoto K, Iwasaki N, Doi K, Noiri E, Iwamoto
Y, Uchigata Y, Fujita T, Tokunaga K. Inhibitionof glucose stimulated insulin secretion by
KCNJ15, a newly identified susceptibility geneto type 2 diabetes mellitus. Diabetes 2012; 61,
1734-41(29) Susantitaphong P, Siribamrungwong M, Doi K,
Noiri E, Terrin N, Jaber BL. Performance ofurinary liver-type fatty acid-binding protein in
acute kidney injury: A meta-analysis. Am. J.
Kidney Dis. 2012; 61, 430-9.
(30) Togawa T, Tsukimura T, Kodama T, Tanaka T,
Kawashima I, Saito S, Ohno K, Fukushige T,
Kanekura T, Satomura A, Kang DH, Lee BH,
Yoo HW, Doi K, Noiri E, Sakuraba H. Fabry
diseases: biochemical, pathological and structural
studies of α-galactosidase A with E66Q aminoacid substitution. Mol. Genet. Metab. 2012; 105,615-29.
(31) Mitobe S, Togawa T, Tsukimura T, Kodama T,

Tanaka T, Doi K, Noiri E, Akai Y, Saito Y,
Yoshino M, Takenaka T, Saito S, Ohno K,
Sakuraba H. Mutant α-galactosidase A with
M2961 does not cause elevation of the plasma
globotriaosylsphingosine level. Mol. Genet.
Metab. 2012; 107, 623-626.

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

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

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

Project Lecturer
Ryo Suzuki, M.D., Ph.D.

Assistant Professor
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.,

Iseki Takamoto, M.D., Ph.D.,

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

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

Hirotsugu Suwanai, M.D., Ph.D.,

Masato Iwabu, M.D., Ph.D. (Apr - Sep),

Nozomu Kamei, M.D., Ph.D. (Oct - Mar)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. Since Dr. Kadowaki was elected as
Director of the University of Tokyo Hospital in 2011,
Dr. Kohjiro Ueki has served as Manager of the
Department of Diabetes and Metabolic Diseases.
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 of Tokyo Hospital, and take careof more than 30 inpatients constantly. Besides thestaffs listed above, our division holds faculties inbranches, for example, Department of Integrated
Molecular Science on Metabolic Diseases (Project
Associate Professor, Dr. Kazuo Hara and Project
Assistant Professor, Dr. Masato Iwabu), Departmentof Translational Systems Biology and Medicine

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Initiative (Project Associate Professor, Dr. Naoto
Kubota and Project Assistant Professor, Dr. Takayoshi
Sasako), Functional Regulation of Adipocytes (Project
Associate Professor, Dr. Hironori Waki and Project
Assistant Professor, Dr. Nozomu Kamei), Molecular
Medicinal Sciences on Metabolic Regulation (Project
Associate Professor, Dr. Hiroaki Okazaki and Project
Assistant Professor, Dr. Miki Okada-Iwabu), Patient
Safety & Risk Management (Project AssistantProfessor, Dr. Kenji Harada), Division of Biophysics,
Center for Disease Biology and Integrative Medicine(Lecturer, Dr. Noriko Takahashi), Ubiquitous Health
Informatics (Project Assistant Professor, Dr. Kayo
Waki), Clinical Epidemiology and Systems (Project
Assistant Professor, Dr. Mikio Takanashi), andDivision for Health Service Promotion, The
University of Tokyo (Assistant Professor, Dr. Midori
Kubota). 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 67
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.

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Research activities

References

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. Kadowaki, T., Ueki, K., Yamauchi, T., andKubota, N. 2012. SnapShot: Insulin signaling
pathways. Cell 148:624, 624 e621.
2. Kadowaki, T., Kubota, N., Ueki, K., andYamauchi, T. 2012. SnapShot: physiology of
insulin signaling. Cell 148:834-834 e831.
3. Nio, Y., Yamauchi, T., Iwabu, M., Okada-Iwabu,
M., Funata, M., Yamaguchi, M., Ueki, K., andKadowaki, T. 2012. Monocyte chemoattractant
protein-1 (MCP-1) deficiency enhances alternatively activated M2 macrophages and ameliorates
insulin resistance and fatty liver in lipoatrophic
diabetic A-ZIP transgenic mice. Diabetologia 55:
3350-3358.
4. Shojima, N., Hara, K., Fujita, H., Horikoshi, M.,
Takahashi, N., Takamoto, I., Ohsugi, M.,
Aburatani, H., Noda, M., Kubota, N., et al. 2012.
Depletion of homeodomain-interacting protein
kinase 3 impairs insulin secretion and glucose
tolerance in mice. Diabetologia 55:3318-3330.
5. Yamada, T., Hara, K., Umematsu, H., Suzuki, R.,
and Kadowaki, T. 2012. Erectile dysfunction andcardiovascular events in diabetic men: a metaanalysis of observational studies. PLoS One 7:
e43673.
6. Yamada, T., Hara, K., and Kadowaki, T. 2012.
Association of adenovirus 36 infection withobesity and metabolic markers in humans: ameta-analysis of observational studies. PLoS One
7:e42031.
7. Fujita, H., Hara, K., Shojima, N., Horikoshi, M.,
Iwata, M., Hirota, Y., Tobe, K., Seino, S., andKadowaki, T. 2012. Variations with modest
effects have an important role in the genetic background of type 2 diabetes and diabetes-related
traits. J Hum Genet 57:776-779.
8. Waki, K., Sugawara, Y., Kokudo, N., andKadowaki, T. 2012. Long-term pancreas allograft
survival in simultaneous pancreas-kidney transplantation by era. Clin Transpl:13-22.
9. Kadowaki, T., Ohtani, T., and Odawara, M. 2012.
Potential formula for the calculation of startingand incremental insulin glargine doses: ALOHA
subanalysis. PLoS One 7:e41358.
10. Waki, K., Fujita, H., Uchimura, Y., Aramaki, E.,

1) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, we are
exploring the signal transduction pathways andphysiological roles of insulin and adipokines invarious tissues and the mechanisms of insulin
secretion under the normal or pathological conditions,such as diabetes and obesity, using a number oftransgenic and knockout animal models, in 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.
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.

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Omae, K., Kadowaki, T., and Ohe, K. 2012.
DialBetics: smartphone-based self-management
for type 2 diabetes patients. J Diabetes Sci
Technol 6:983-985.
11. Kadowaki, T. 2012. [Disease concept of type 2
diabetes]. Nihon Rinsho 70 Suppl 3:375-382.
12. Kadowaki, T. 2012. [Action plan 2010 of Japan
Diabetes Society (DREAMS)]. Nihon Rinsho 70
Suppl 3:51-59.
13. Ueki, K. 2012. [Endocrine disease: progress indiagnosis and treatment. Topics: I. Progress indiagnosis: 4. New diagnostic criteria of diabetes
and international harmonization of HbA1c].
Nihon Naika Gakkai Zasshi 101:959-964.
14. Yamauchi, T., and Kadowaki, T. 2012. [Pathophysiological roles of adipocytokines in thedevelopment of insulin resistance]. Nihon Rinsho
70 Suppl 3:166-174.
15. Waki, H., Yamauchi, T., and Kadowaki, T. 2012.
The epigenome and its role in diabetes. Curr
Diab Rep 12:673-685.
16. Okazaki, Y., and Ueki, K. 2012. [Japan Diabetes
Outcome Intervention Trial 3]. Nihon Rinsho 70
Suppl 3:290-294.
17. Okada-Iwabu, M., Yamauchi, T., and Kadowaki,
T. 2012. [New drug targets for the metabolic
syndrome and obesity]. Nihon Rinsho 70 Suppl
8:372-377.
18. Okada-Iwabu, M., Yamauchi, T., and Kadowaki,
T. 2012. [Functional food component--osmotin].
Nihon Rinsho 70 Suppl 3:746-749.
19. Yamauchi, N., Takazawa, Y., Maeda, D., Hibiya,
T., Tanaka, M., Iwabu, M., Okada-Iwabu, M.,
Yamauchi, T., Kadowaki, T., and Fukayama, M.
2012. Expression levels of adiponectin receptors
are decreased in human endometrial adenocarcinoma tissues. Int J Gynecol Pathol
31:352-357.
20. Kurano, M., Hara, M., Tsuneyama, K., Okamoto,K., Iso, O.N., Matsushima, T., Koike, K., andTsukamoto, K. 2012. Modulation of lipid
metabolism with the overexpression of NPC1L1
in mouse liver. J Lipid Res 53:2275-2285.
21. Odawara, M., Ohtani, T., and Kadowaki, T. 2012.
Dosing of insulin glargine to achieve thetreatment target in Japanese type 2 diabetes on abasal supported oral therapy regimen in real life:

ALOHA study subanalysis. Diabetes Technol
Ther 14:635-643.
22. Eto, T., Inoue, S., and Kadowaki, T. 2012. Effects
of once-daily teneligliptin on 24-h blood glucose
control and safety in Japanese patients with type2 diabetes mellitus: a 4-week, randomized,
double-blind, placebo-controlled trial. Diabetes
Obes Metab 14:1040-1046.
23. Eguchi, K., Manabe, I., Oishi-Tanaka, Y., Ohsugi,M., Kono, N., Ogata, F., Yagi, N., Ohto, U.,
Kimoto, M., Miyake, K., et al. 2012. Saturated
fatty acid and TLR signaling link beta cell
dysfunction and islet inflammation. Cell Metab
15:518-533.
24.Kodama, K., Horikoshi, M., Toda, K., Yamada, S.,
Hara, K., Irie, J., Sirota, M., Morgan, A.A., Chen,
R., Ohtsu, H., et al. 2012. Expression-based
genome-wide association study links the receptor
CD44 in adipose tissue with type 2 diabetes. Proc
Natl Acad Sci U S A 109:7049-7054.
25. Lu, M., Wan, M., Leavens, K.F., Chu, Q., Monks,
B.R., Fernandez, S., Ahima, R.S., Ueki, K., Kahn,
C.R., and Birnbaum, M.J. 2012. Insulin regulates
liver metabolism in vivo in the absence of hepatic
Akt and Foxo1. Nat Med 18:388-395.
26. Nishimura, S., Manabe, I., Nagasaki, M., Kakuta,
S., Iwakura, Y., Takayama, N., Ooehara, J., Otsu,
M., Kamiya, A., Petrich, B.G., et al. 2012. In vivo
imaging visualizes discoid platelet aggregations
without endothelium disruption and implicatescontribution of inflammatory cytokine andintegrin signaling. Blood 119:e45-56.
27.Cipolletta, D., Feuerer, M., Li, A., Kamei, N., Lee,J., Shoelson, S.E., Benoist, C., and Mathis, D.
2012. PPAR-gamma is a major driver of theaccumulation and phenotype of adipose tissue
Treg cells. Nature 486:549-553.
28. Kushiyama, A., Okubo, H., Sakoda, H., Kikuchi,T., Fujishiro, M., Sato, H., Kushiyama, S.,
Iwashita, M., Nishimura, F., Fukushima, T., et al.
2012. Xanthine oxidoreductase is involved inmacrophage foam cell formation and atherosclerosis development. Arterioscler Thromb Vasc
Biol 32:291-298.
29. Iwata, M., Maeda, S., Kamura, Y., Takano, A.,
Kato, H., Murakami, S., Higuchi, K., Takahashi,A., Fujita, H., Hara, K., et al. 2012. Genetic risk

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score constructed using 14 susceptibility alleles
for type 2 diabetes is associated with the early
onset of diabetes and may predict the future
requirement of insulin injections among Japaneseindividuals. Diabetes Care 35:1763-1770.
30. Iwashita, M., Sakoda, H., Kushiyama, A.,
Fujishiro, M., Ohno, H., Nakatsu, Y., Fukushima,T., Kumamoto, S., Tsuchiya, Y., Kikuchi, T., et al.
2012. Valsartan, independently of AT1 receptor or
PPARgamma, suppresses LPS-induced macrophage activation and improves insulin resistancein cocultured adipocytes. Am J Physiol
Endocrinol Metab 302:E286-296.
31.Nakatsu, Y., Otani, Y., Sakoda, H., Zhang, J., Guo,
Y., Okubo, H., Kushiyama, A., Fujishiro, M.,
Kikuch, T., Fukushima, T., et al. 2012. Role ofPin1 protein in the pathogenesis of nonalcoholicsteatohepatitis in a rodent model. J Biol Chem
287:44526-44535.
32. Oe, M., Sanada, H., Nagase, T., Minematsu, T.,
Ohashi, Y., Kadono, T., Ueki, K., and Kadowaki,
T. 2012. Factors associated with deep footfissures in diabetic patients: a cross-sectional
observational study. Int J Nurs Stud 49:739-746.
33. Wan, M., Easton, R.M., Gleason, C.E., Monks,
B.R., Ueki, K., Kahn, C.R., and Birnbaum, M.J.
2012. Loss of Akt1 in mice increases energy
expenditure and protects against diet-induced
obesity. Mol Cell Biol 32:96-106.
34. Aoyagi, K., Ohara-Imaizumi, M., Nishiwaki, C.,
Nakamichi, Y., Ueki, K., Kadowaki, T., andNagamatsu, S. 2012. Acute inhibition of PI3KPDK1-Akt pathway potentiates insulin secretion
through upregulation of newcomer granulefusions in pancreatic beta-cells. PLoS One
7:e47381.
35.Townsend, K.L., Suzuki, R., Huang, T.L., Jing, E.,
Schulz, T.J., Lee, K., Taniguchi, C.M., Espinoza,
D.O., McDougall, L.E., Zhang, H., et al. 2012.
Bone morphogenetic protein 7 (BMP7) reverses
obesity and regulates appetite through a central
mTOR pathway. FASEB J 26:2187-2196.
36. Imamura, M., Maeda, S., Yamauchi, T., Hara, K.,
Yasuda, K., Morizono, T., Takahashi, A.,
Horikoshi, M., Nakamura, M., Fujita, H., et al.
2012. A single-nucleotide polymorphism in
ANK1 is associated with susceptibility to type 2

diabetes in Japanese populations. Hum Mol
Genet 21:3042-3049.
37.Shirakawa, J., Tanami, R., Togashi, Y., Tajima, K.,
Orime, K., Kubota, N., Kadowaki, T., Goshima,Y., and Terauchi, Y. 2012. Effects of liraglutide
on beta-cell-specific glucokinase-deficient neonatal
mice. Endocrinology 153:3066-3075.
38. Nakamura, A., Tajima, K., Zolzaya, K., Sato, K.,
Inoue, R., Yoneda, M., Fujita, K., Nozaki, Y.,
Kubota, K.C., Haga, H., et al. 2012. Protection
from non-alcoholic steatohepatitis and liver
tumourigenesis in high fat-fed insulin receptor
substrate-1-knockout mice despite insulin
resistance. Diabetologia 55:3382-3391.
39. Nakamura, A., Togashi, Y., Orime, K., Sato, K.,
Shirakawa, J., Ohsugi, M., Kubota, N., Kadowaki,T., and Terauchi, Y. 2012. Control of beta cellfunction and proliferation in mice stimulated bysmall-molecule glucokinase activator undervarious conditions. Diabetologia 55:1745-1754.
40. Saheki, T., Inoue, K., Ono, H., Katsura, N.,
Yokogawa, M., Yoshidumi, Y., Furuie, S., Kuroda,E., Ushikai, M., Asakawa, A., et al. 2012. Effectsof supplementation on food intake, body weightand hepatic metabolites in the citrin/mitochondrial
glycerol-3-phosphate dehydrogenase doubleknockout mouse model of human citrin deficiency.
Mol Genet Metab 107:322-329.
41. Sato, K., Nakamura, A., Shirakawa, J., Muraoka,
T., Togashi, Y., Shinoda, K., Orime, K., Kubota,N., Kadowaki, T., and Terauchi, Y. 2012. Impactofthedipeptidyl
peptidase-4
inhibitor
vildagliptin on glucose tolerance and beta-cellfunction and mass in insulin receptor
substrate-2-knockout mice fed a high-fat diet.
Endocrinology 153:1093-1102.
42. Shibata, S., Tada, Y., Asano, Y., Hau, C.S., Kato,
T., Saeki, H., Yamauchi, T., Kubota, N.,
Kadowaki, T., and Sato, S. 2012. Adiponectin
regulates cutaneous wound healing by promoting
keratinocyte proliferation and migration via the
ERK signaling pathway. J Immunol 189:32313241.
43. Shinohara, M., Nakamura, M., Masuda, H.,
Hirose, J., Kadono, Y., Iwasawa, M., Nagase, Y.,
Ueki, K., Kadowaki, T., Sasaki, T., et al. 2012.
Class IA phosphatidylinositol 3-kinase regulates

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osteoclastic bone resorption through protein
kinase B-mediated vesicle transport. J Bone
Miner Res 27:2464-2475.
44. Wang, G., Watanabe, M., Imai, Y., Hara, K.,
Manabe, I., Maemura, K., Horikoshi, M., Ozeki,
A., Itoh, C., Sugiyama, T., et al. 2012.
Associations of variations in the MRF2/ARID5B
gene with susceptibility to type 2 diabetes in theJapanese population. J Hum Genet 57:727-733.

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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.

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

Assistant Professor
Akihito Shinohara, M.D., Ph. D.,

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

Nahoko Nishimoto, 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
Department of Hematology and Oncology is
responsible for clinical activities in outpatient as wellas inpatient clinics of hematological disorders,
research activities for hematology/oncology, and education of undergraduate as well as graduate students.
We are also engaged in continuous education of
post-graduate doctors who develop into sophisticatedhematologists of eminent distinction. These activities
are performed by the united efforts of all members
who belong to the department. Dr. Mineo Kurokawa
was assigned as Professor of Department of
Hematology and Oncology in 2005. Other staff of ourdepartment consists of two lecturers, two special
lecturer (hospital), and 6 assistant professors.

Clinical activities
On average, 60-70 patients with hematologicaldiseases are treated in the ward. Clinical facilities
include patient rooms with high-efficiency particulate
air filtration and filtrated water supply. Patients whoare eligible for the treatment with high-grade infection
prophylaxis are admitted to the facilities. Patient careis provided by team management and three doctors
composed of a junior resident, a senior resident, andan assistant professor are assigned to one patient.
Since clinical issues especially for patients withhematological diseases are highly related tohematopoietic stem cell transplantation, a substantial
portion of our clinical conferences are shared withstaff members of Department of Cell Therapy andTransplantation Medicine and Department ofPediatrics (Hematology/Oncology). A number ofclinical problems involved in the patient management
are discussed in the morning clinical conference held
thrice a week. Diagnostic and therapeutic issues aswell as pathological aspects of thought-provoking
cases are also discussed twice per month in clinicalconferences, each focusing on hematological diseases,
lymphomas, or hematopoietic stem cell transplant.
Outpatient clinical services are provided from
Monday to Friday in the morning and afternoon using
three booths. Approximately 1200 patients visit our
outpatient clinic every month. One of our final goals

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in the clinical 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 andplanning 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 isperformed with the use of an automated continuous flow blood cell separator, and harvested cells
are preserved in cooperation with Department ofTransfusion Medicine. Recently, transplantation
conditioned with reduced intensity regimen (RIST,
reduced-intensity stem cell transplantation) is
commonly performed for the elderly patients andpatients with organ impairment. The developmentof this strategy expands the eligibility of transplant
recipients. Allogeneic hematopoietic stem celltransplantation for the elderly are performed under
the admission of ethical committee of the Facultyof Medicine. Cord blood cells are also used as thesources of hematopoietic stem cells.
3. We also started the clinical study of maintenancetherapy after autologous stem cell transplantationof multiple myeloma patients under the admissionof 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
Clinical clerkships 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 who is erudite both in general internal
medicine and in hematology and oncology. During thecourse, students are required to learn the basic
techniques of medical interview and physical 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 provided. 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 isalso performed. Every effort has been made to achieve
the highest quality in both clinical and basic medical
research. The ultimate aims of our research are theapplication of epoch-making discoveries in research
fields to the clinical hematology and oncology.
Representative publications from our departments
published in the past year are listed in the reference.

References
1. Fujioka Y, Kurokawa M. Follicular lymphoma
presenting with massive splenomegaly. Int J
Hematol. 2012 Jan;95(1):3-4.

155

2. Goyama S, Takeuchi K, Kanda Y, Nannya Y,
Chiba S, Fukayama M, Kurokawa M. Posttransplant endothelial disorder after hematopoietic
SCT: a blinded autopsy study. Bone Marrow
Transplant. 2012 Sep;47(9):1243-5.
3. Hangai S, Nakamura F, Yamada A, Watabe H,
Ichikawa M, Koike K, Kurokawa M. Usefulnessof double-balloon enteroscopy for evaluation ofduodenal follicular lymphoma. Ann Hematol.
2012 Nov;91(11):1819-20.
4. Kagoya Y, Nannya Y, Kurokawa M. Thalidomide
maintenance therapy for patients with multiple
myeloma: meta-analysis. Leuk Res. 2012 Aug;36(8):1016-21.
5. Kagoya Y, Seo S, Nannya Y, Kurokawa M.
Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on
prognosis. Clin Transplant. 2012 Mar-Apr;26(2):E168-75.
6. Kataoka K, Kurokawa M. Ecotropic viral
integration site 1, stem cell self-renewal andleukemogenesis. Cancer Sci. 2012 Aug;103(8):1371-7.
7. Koya J, Iwata A, Nakamura F, Nagashima Y,
Ichikawa M, Tsuji S, Kurokawa M. Fludarabine
may overcome resistance to rituximab in IgMrelated neuropathy. J Neurol Sci. 2012 Apr;315(1-2):150-2.
8. Koya J, Nannya Y, Ichikawa M, Kurokawa M. The
clinical role of procalcitonin in hematopoietic SCT.
Bone Marrow Transplant. 2012 Oct;47(10):132631.
9. Koya J, Nannya Y, Kurokawa M. Evaluation ofprocalcitonin with liquid-phase binding assay inhematological malignancy. Clin Chim Acta. 2012
Oct;413(19-20):1633-6.
10. Kumano K, Arai S, Hosoi M, Taoka K, Takayama
N, Otsu M, Nagae G, Ueda K, Nakazaki K,
Kamikubo Y, Eto K, Aburatani H, Nakauchi H,
Kurokawa M. Generation of induced pluripotent
stem cells from primary chronic myelogenous
leukemia patient samples. Blood. 2012 Jun;119(26):6234-42.
11. Miyauchi M, Yoshimi A, Nannya Y, Takazawa Y,
Ichikawa M, Fukayama M, Kurokawa M. Efficacy
of pleural biopsy for diagnosis of pleural effusion
due to chronic GVHD after hematopoietic stem

cell transplantation. Int J Hematol. 2012 Jul;96(1):146-8.
12. Morita K, Nakamura F, Kamikubo Y, Mizuno N,
Miyauchi M, Yamamoto G, Nannya Y, Ichikawa M,
Kurokawa M. Pituitary lymphoma developing
within pituitary adenoma. Int J Hematol. 2012 Jun;95(6):721-4.
13. Morita K, Nakamura F, Nannya Y, Kamikubo Y,
Ichikawa M, Kurokawa M. Lymphoma withspecific affinity to endocrine organs. Ann Hematol.
2012 Jul;91(7):1149-50.
14. Morita K, Nakamura F, Nannya Y, Nomiya A, Arai
S, Ichikawa M, Maeda D, Homma Y, Kurokawa M.
Primary MALT lymphoma of the urinary bladderin the background of interstitial cystitis. Ann
Hematol. 2012 Sep;91(9):1505-6.
15. Nakazaki K, Hosoi M, Hangaishi A, Ichikawa M,
Nannya Y, Kurokawa M. Comparison between
pulsed high-dose dexamethasone and daily
corticosteroid therapy for adult primary immune
thrombocytopenia: a retrospective study. Intern
Med. 2012 Apr;51(8):859-63.
16. Taoka K, Kumano K, Nakamura F, Hosoi M,
Goyama S, Imai Y, Hangaishi A, Kurokawa M.
The effect of iron overload and chelation onerythroid differentiation. Int J Hematol. 2012 Feb;
95(2):149-59.
17. Taoka K, Yamamoto G, Kaburaki T, Takahashi T,
Araie M, Kurokawa M. Treatment of primary
intraocular lymphoma with rituximab, high dose
methotrexate, procarbazine, and vincristinechemotherapy, reduced whole-brain radiotherapy,
and local ocular therapy. Br J Haematol. 2012 Apr;
157(2):252-4.
18. Toya T, Nannya Y, Narukawa K, Ichikawa M,
Kurokawa M. A comparative analysis ofmeropenem and doripenem in febrile patients withhematologic malignancies: a single-center retrospective study. Jpn J Infect Dis. 2012 Sep;65(3):228-32.
19. Toya T, Nishimoto N, Koya J, Nakagawa M,
Nakamura F, Kandabashi K, Yamamoto G, Nannya
Y, Ichikawa M, Kurokawa M. The first case of
blastic plasmacytoid dendritic cell neoplasm with
MLL-ENL rearrangement. Leuk Res. 2012 Jan;36(1):117-8.
20. Yamamoto G, Hosoi M, Miyagawa T, Ohmatsu H,

156

Ichikawa M, Sugaya M, Kurokawa M. Evanssyndromewithcytomegalovirus
infection
followed by emerging peripheral T-cell lymphoma.
Ann Hematol. 2012 Jan;91(1):123-4.
21.Yamazaki S, Nakamura F, Nannya Y, Nakagawa M,
Ichikawa M, Kurokawa M. Early-onset Therapyrelated Myelodysplastic Syndrome Originating
from
Prolonged
Myelosuppression
after
Fludarabine-based Therapy. Intern Med. 2012
Dec;51(24):3427-30.
22. Yoshiki Y, Yamamoto G, Takazawa Y, Nannya Y,
Ishida J, Nagai R, Fukayama M, Kurokawa M. AL
amyloidosis with severe gastrointestinal invasion
and acute obstructive suppurative cholangitis. Ann
Hematol. 2012 Mar;91(3):467-8.
23. Yoshimi A, Yamamoto G, Goto T, Koike K,
Kurokawa M. Hepatocellular carcinoma in
cirrhotic liver with graft-versus-host disease. Ann
Hematol. 2012 Sep;91(9):1501-2.
24. Yoshimi M, Goyama S, Kawazu M, Nakagawa M,
Ichikawa M, Imai Y, Kumano K, Asai T, Mulloy
JC, Kraft AS, Takahashi T, Shirafuji N, Kurokawa
M. Multiple phosphorylation sites are importantfor RUNX1 activity in early hematopoiesis andT-cell differentiation. Eur J Immunol. 2012 Apr;
42(4):1044-50.

157

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

Lecturer (Hospital)
Keishi Fujio, M.D., Ph.D. (Rheumatology)

Research Associate
Kanae Kubo, M.D., Ph.D. (Rheumatology)
Hirofumi Syoda、M.D., Ph.D. (Rheumatology)
Syuji Sumitomo，M.D., Ph.D. (Rheumatology)
Mihoko Shibuya，M.D., Ph.D. (Allergology)
Yukiko Iwasaki，M.D., Ph.D. (Allergology)

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

The Department of Allergy and Rheumatology
presently consists of 12 staff mentioned above, who
preside over 5 medical staff, 14graduate 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

158clinicalimmunology,
molecular
rheumatology and allergology.

immunology,

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 using transgenicmice.
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

2012
1. Okada Y, Shimane K, Kochi Y, Tahira T, Suzuki A,
Higasa K, Takahashi A, Horita T, Atsumi T, Ishii T,
Okamoto A, Fujio K, Hirakata M, Amano H, Kondo
Y, Ito S, Takada K, Mimori A, Saito K, Kamachi M,
Kawaguchi Y, Ikari K, Mohammed O W, Matsuda K,
Terao C, Ohmura K, Myouzen K, Hosono N,
Tsunoda T, Nishimoto N, Mimori T, Matsuda F,
Tanaka Y, Sumida T, Yamanaka H, Takasaki Y,
Koike T, Horiuchi T, Hayashi K, Kubo M, Kamatani
N. Yamada R, Nakamura Y, Yamamoto K. A
genome-wide association study identified AFF1 as asusceptibility locus for systemic lupus eyrthematosus in Japanese. PLoS Genet. 2012;8:e1002455.
2. Yukinori Okada, Michiaki Kubo, Hiroko Ohmiya,Atsushi Takahashi, Natsuhiko Kumasaka, Naoya
Hosono, Shiro Maeda, Wanqing Wen, Rajkumar
Dorajoo, Min Jin Go, Wei Zheng, Norihiro Kato,
Jer-Yuarn Wu, Qi Lu, the GIANT consortium,
Tatsuhiko Tsunoda, Kazuhiko Yamamoto, Yusuke
Nakamura, Naoyuki Kamatani, and Toshihiro
Tanaka. Common variants at CDKAL1 and KLF9
are associated with body mass index in East Asian
populations. Nat Genet. 2012;44:302-6.
3. Tanikawa C, Espinosa M, Suzuki A, Masuda K,
Yamamoto K, Tsuchiya E, Ueda K, Daigo Y,
Nakamura Y, Matsuda K. Regulation of histone
modification and chromatin structure by the p53PADI4 pathway. Nat Commun. 2012;3:676. PMID:
22334079
4. Kurreeman FA, Stahl EA, Okada Y, Liao K, Diogo
D, Raychaudhuri S, Freudenberg J, Kochi Y,
Patsopoulos NA, Gupta N; CLEAR investigators,
Sandor C, Bang SY, Lee HS, Padyukov L, Suzuki A,
Siminovitch K, Worthington J, Gregersen PK,
Hughes LB, Reynolds RJ, Bridges SL Jr, Bae SC,
Yamamoto K, Plenge RM. Use of a Multiethnic
Approach to Identify Rheumatoid- ArthritisSusceptibility Loci, 1p36 and 17q12.Am J Hum

159

5.

6.

7.

8.

Genet. 2012;90:524-32.
Okada Y, Terao C, Ikari K, Kochi Y, Ohmura K,
Suzuki A, Kawaguchi T, Stahl EA, Kurreeman FA,
Nishida N, Ohmiya H, Myouzen K, Takahashi M,
Sawada T, Nishioka Y, Yukioka M, Matsubara T,
Wakitani S, Teshima R, Tohma S, Takasugi K,
Shimada K, Murasawa A, Honjo S, Matsuo K,
Tanaka H, Tajima K, Suzuki T, Iwamoto T,
Kawamura Y, Tanii H, Okazaki Y, Sasaki T,
Gregersen PK, Padyukov L, Worthington J,
Siminovitch KA, Lathrop M, Taniguchi A,
Takahashi A, Tokunaga K, Kubo M, Nakamura Y,
Kamatani N, Mimori T, Plenge RM, Yamanaka H,
Momohara S, Yamada R, Matsuda F, Yamamoto K.
Meta-analysis identifies nine new loci associatedwith rheumatoid arthritis in the Japanese population.
Nat Genet. 2012;44:511-6.
Okada Y, Sim X, Go MJ, Wu JY, Gu D, Takeuchi F,
Takahashi A, Maeda S, Tsunoda T, Chen P, Lim SC,
Wong TY, Liu J, Young TL, Aung T, Seielstad M,
Teo YY, Kim YJ, Lee JY, Han BG, Kang D, Chen
CH, Tsai FJ, Chang LC, Fann SJ, Mei H, Rao DC,
Hixson JE, Chen S, Katsuya T, Isono M, Ogihara T,
Chambers JC, Zhang W, Kooner JS; The KidneyGen
Consortium; The CKDGen Consortium, Albrecht E;
The GUGC consortium, Yamamoto K, Kubo M,
Nakamura Y, Kamatani N, Kato N, He J, Chen YT,
Cho YS, Tai ES, Tanaka T. Meta-analysis identifiesmultiple loci associated with kidney function-related
traits in East Asianpopulations. NatGenet. 2012;44:904-9.
Tsutomu Takeuchi, Masayoshi Harigai, Yoshiya
Tanaka, Hisashi Yamanaka, Naoki Ishiguro,
Kazuhiko Yamamoto, Nobuyuki Miyasaka, Takao
Koike, Minoru Kanazawa, Takuya Oba, Toru
Yoshinari, Daniel Baker the GO-MONO study
group. Golimumab monotherapy in Japanesepatients with active rheumatoid arthritis despite priortreatment with disease-modifying antirheumatic
drugs: results of the phase 2/3, multicentre,
randomised, double-blind, placebo-controlled GOMONO study through 24 weeks. Ann Rheum Dis.
2012 [Epub ahead of print]
Katsuhiko Nakashima1*, Satoko Arai1, Akari
Suzuki2, Yuko Nariai3, Takeshi Urano3, Manabu
Nakayama4, Osamu Ohara4, Ken-ichi Yamamura5,
Kazuhiko Yamamoto2, Toru Miyazaki1. PAD4

regulates proliferation of multipotent hematopoietic
cells by controlling c-myc expression. Nature
Communications. 2013;4:1836.
9. Takeuchi T, Kawai S, Yamamoto K, Harigai M,
Ishida K, Miyasaka N. POST-MARKETINGSURVEILLANCE OF THE SAFETY AND
EFFECTIVENESS OF TACROLIMUS IN 3,267
JAPANESE PATIENTS WITH RHEUMATOIDARTHRITIS. Mod Rheumatol. 2013 May 14. [Epubahead of print]
10. Koketsu R, Yamaguchi M, Suzukawa M, Tanaka Y,
Tashimo H, Arai H, Nagase H, Matsumoto K, Saito
H, Ra C, Yamamoto K, Ohta K. Pretreatment with
low-levels of FceRI-crosslinking stimulation
enhances basophil mediator release. Int Arch Allergy
Immunol.2013, 161(Suppl 2):23-31.

160

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, a departmental library and a computer room as own properties.
In clinical and research activities, we are collaboratingwith the Department of Infection Control andPrevention. An associate professor, 6 guest lecturers, anassociate, 2 graduate students and full-time staff
members are all performing their own duties in clinical,
educational and research activities.

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

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

Teaching activities
Our department takes a part in clinical lectures andbed-side learning of the internal medicine for undergraduate medical students according to the educational
programs of the University of Tokyo. For the fourthyear medical students, six lectures of infectious
diseases are given. In addition, principles of medical
diagnosis are taught at the bedside. During the bed-side
teaching for fifth and sixth year students, our associates
teach them on man-to man basis 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 pro-161

cedures on each case. The education of junior residents
is performed as described in “Clinical Activities”.

Research activities
Both clinical and basic researches are necessary to
improve the diagnosis and treatment. The members ofour department are doing best to obtain new findings
using highly sophisticated methodologies. A monthly
intramural research conference is held, in which 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 ourtransgenic 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, Keita Tatsuno, Mahoko Ikeda, Haruka
Nakamura, Makoto Saito, Hideki Hashimoto, Hideki
Hashimoto..

References
1) 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;30:5030-7.
2) 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. Intern Med. 2012;51:1779-82.
3) Yanagimoto S, Yotsuyanagi H, Kikuchi Y, Tsukada
K, Kato M, Takamatsu J, Hige S, Chayama K,
Moriya K, Koike K. Chronic hepatitis B in patientscoinfected with human immunodeficiency virus in
Japan: A retrospective multicenter analysis. J InfectChemother 2012;18:883-90.
4) Okazaki T, Yamazaki K, Iwasaki T, Okano T,
Kurosaki Y, Nakamura K, Fujioka T, Yotsuyanagi H.
α2-HS glycoprotein is an essential component ofcryoglobulin associated with chronic hepatitis C.
Clin Chem Lab Med. 2012 Jul 27. doi:pii:/j/cclm.
ahead-of-print/cclm-2012-0293/cclm-2012-0293.xm
l.10.1515/cclm-2012-0293.[Epub ahead of print]5) Ikeda K, Izumi N, Tanaka E, Yotsuyanagi H,
Takahashi Y, Fukushima J, Kondo F, Fukusato T,
Koike K, Hayashi N, Kumada H. Fibrosis scoreconsisting of four serum markers successfully
predicts pathological fibrotic stages of chronic
hepatitis B. Hepatol Res. 2012 Nov 2. doi: 10.1111/
j.1872-034X.2012.01115.x. [Epub ahead of print]

1626) Okuse C, Yotsuyanagi H, Yamada N, Ikeda H,
Kobayashi M, Fukuda Y, Takahashi H, Matsunaga K,
Matsumoto N, Okamoto M, Ishii T, Sato A, Koike K,
Suzuki M, Itoh F. Changes in levels of hepatitis B
virus markers in patients positive for low-titerhepatitis B surface antigen. Hepatol Res. 2012;42:1236-1240.
7) Nukui Y, Hatakeyama S, Kitazawa T, Mahira T,
Shintani Y, Moriya K. Pandemic 2009 influenza A(H1N1) virus among Japanese healthcare workers:
seroprevalence and risk factors. Infect Control Hosp
Epidemiol. 2012; 33: 58-62
8) Yamaguchi Y, Nukui Y, Tajima S et al.
Characterization of a serine-to-asparagine substituion at position 123 in the Japanese encephalitis
virus E protein. J Gen Virol. Epub 2012 Oct 109) Saito N, Hida A, Koide Y, Ooka T, Ichikawa Y,
Shimizu J, Mukasa A, Nakatomi H, Hatakeyama S,
Hayashi T, Tsuji S. Culture-negative brain abscesswith Streptococcus intermedius infection withdiagnosis established by direct nucleotide sequence
analysis of the 16s ribosomal RNA gene. Intern Med.
2012;51:211-6.
10) Koyano S, Saito R, Nagai R, Tastuno K, Okugawa S,
Okamura N, Moriya K. J Med Microbiol. 2012 Nov
15. [Epub ahead of print]11) Yoshino Y, Okugawa S, Kimura S, Makita E, Seo K,
Koga I, Matsunaga N, Kitazawa T, Ota Y. Infective
endocarditis due to Enterobacter cloacae resistant tothird- and fourth-generation cephalosporins. J
Microbiol Immunol Infect. 2012 Sep 24. doi:pii:
S1684-1182(12)00159-4. 10.1016/j.jmii.2012.07.015.
[Epub ahead of print]12) Okugawa S, Moayeri M, Pomerantsev AP, Sastalla I,
Crown D, Gupta PK, Leppla SH. Lipoprotein
biosynthesis by prolipoprotein diacylglyceryl transferase is required for efficient spore germination andfull virulence of Bacillus anthracis. Mol Microbiol.
2012;83:96-109.
13) Yoshino Y, Kitazawa T, Kamimura M, Tatsuno K,
Ota Y, Yotsuyanagi H. Pseudomonas putida bacteremia in adult patients: five case reports and a reviewof the literature. J Infect Chemother. 2011;17:27882.
14) 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.
15) 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 disorderin hepatitis C: Polyunsaturated fatty acids counteract
lipid alterations induced by the core protein. J
Hepatol. 2011;54:432-8.
16) Chayama K, Hayes CN, Yoshioka K, Moriwaki H,
Okanoue T, Sakisaka S, TakeharaT, 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 responsefollowing 72 weeks of combination therapy for
genotype 1b hepatitis C. JGastroenterol. 2011;46s:
545-55..
17) 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.
18) 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.
19) 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.
20) Yamaguchi Y, Nukui Y, Tajima S, Kurane I et al. An
amino acid substitution (V3I) in the Japanese
encephalitis virus NS4A protein increases its
virulence in mice, but not its growth rate in vitro. J
Gen Virol. 2011; 92:1601-621) Nomura M, Shin M, Ohta M, Nukui Y, Ohkusu K,
Saito N. Atypical osteomyelitis of the skull base andcraniovertebral junction caused by Actinomyces
infection--case report. Neurol Med Chir. 2011; 51:
64-66
22) Ishioka H, Umezawa M, Hatakeyama S. Fulminantamebic colitis in an HIV-infected homosexual man.

163

Intern Med. 2011;50:2851-4
23) Hatakeyama S, Ozawa M, Kawaoka Y. In vitro
selection of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. Clin Microbiol
Infect. 2011;17:1332-5.
24) 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 liver transplantations inHIV- and hepatitis C virus-coinfected hemophiliacs:
experience in a single center. Transplantation. 2011;91:1261-4.
25) Hicks CW, Li Y, Okugawa S, Solomon SB, Moayeri
M, Leppla SH, Mohanty A, Subramanian GM,
Mignone TS, Fitz Y, Cui X, Eichacker PQ. Anthrax
edema toxin has cAMP-mediated stimulatory effects
and high-dose lethal toxin has depressanteffects in
an isolated perfused rat heart model. Am J Physiol
Heart Circ Physiol.2011;300:H1108-18.
26) Okugawa S, Moayeri M, Eckhaus MA, Crown D,
Miller-Randolph S, Liu S, Akira S, Leppla SH.
MyD88-dependent signaling protects against anthrax
lethal toxin-induced impairment of intestinal barrier
function. Infect Immun. 2011;79:118-24.
27) Iwatsuki-Horimoto K, Horimoto T, Tamura D, Kiso
M, Kawakami E, Hatakeyama S, Ebihara Y,
Koibuchi T, Fujii T, Takahashi K, Shimojima M,
Sakai-Tagawa Y, Ito M, Sakabe S, Iwasa A,
Takahashi K, Ishii T, Gorai T, Tsuji K, Iwamoto A,
Kawaoka Y. Seroprevalence of pandemic 2009
(H1N1) influenza A virus among schoolchildren andtheir parents in Tokyo, Japan. Clin Vaccine Immunol.
2011;18:860-6.

164

Department of Stress Science andPsychosomatic Medicine
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Kazuhiro Yoshiuchi, M.D., Ph.D.

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

Homepage

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, one associate, and5 adjunct professors, and other members are 1 seniorresidents, 6 graduate students, and 2 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 2012 January to 2012 December, 48 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

2012 January to 2012 December, the numbers of the
new outpatients and of the overall outpatients in our
department were 122 and 2760, respectively.

Teaching activities
We are giving 6 methodical lectures on
psychosomatic medicine for fourth grade medical
students, ‘clinical clerkship’ for fifth grade students
lasting two weeks, ‘advanced clinical clerkship’ for 3
to 4 fifth grade students lasting 4 weeks each, andclinical lectures on psychosomatic diseases in
cardiology for fifth grade students and on eating
disorders for sixth grade students. We are trying toteach them not only basic knowledge of specificdiseases, ways of physical examination, orinterpretation of laboratory data, but also relevantways of clinical interview, doctor-patient relationshipbuilding, and behavior modification.
As for education for junior residents, our seniorresidents and an associate provide man-to-man
instruction. In addition, they can learn how to present
the history of newly-admitted patients at the weekly
professor’s round from our teaching staff.

Research activities
Targeting stress-related diseases such as not only

165

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. Grassi L, Watson M, on behalf of the IPOS
Federation of psycho-oncology societies. Psychosocial care in cancer: national cancer plans andpsychosocial programmes in countries within theInternational Federation of Psycho-Oncology
Societies. Psycho-Oncology 21:1027-1033, 2012

2. Kikuchi H, Yoshiuchi K, Yamamoto Y, Komaki G,
Akabayashi A. Diurnal variation of tension-type
headache intensity and exacerbation: An investigation using computerized ecological momentary
assessment. BioPsychoSocial Medicine 6:18, 2012
3. Sano W, Nakamura T, Yoshiuchi K, Kitajima T,
Tsuchiya A, Esaki Y, Yamamoto Y, Iwata N.
Enhanced persistency of resting and active periodsof locomotor activity in schizophrenia. PLoS ONE
7:e43539, 2012
4. Fukui S, Yoshiuchi K. Associations with theJapanese population’s preferences for the place of
end-of-life care and their need for receiving
healthcare services. J Palliat Med 15:1106-1112,
2012.

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

167

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

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

Associate
Toshiyuki Ikeda, M.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 ex-Professor Yoichi
Shibata contributed enourmously to the field ofplatelet immunology. In 1997, the Department ofTransfusion Medicine was established as a chair of theDivision of Internal Medicine of the Graduate Schoolof Medical Sciences, the University of Tokyo.
Actually, the department is composed of 6 medical
doctors (4 full-time, and 2 partial-time), 10 laboratory
technicians, 2-3 nurses 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 and its
derivatives;
II. Laboratory tests

1681) 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 cell transplantation 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
testing 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 the department. The mixed-passive hemagglutination (MPHA)
method, the most popular methodology for platelet
serology in Japan, was developed by ex-Professor
Yoichi Shibata and its applicability is now extended
for granulocyte as well as endothelial cell serology.
Transplantation immunology, including stem cellbiology is also an important subject. Also, the roleof pre-storage leukocyte reduction of autologous
blood products, especially focusing on cytokine/
chemokines and bioactive lipids, and the improvements of the preservation methods of autologous
blood are being investigated. Recently, developmentof 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 evaluationof platelet function.
9. Development of new strategies for the treatment ofcancer patients, by targeting the tumor vascu-

169

lature.
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. Matsuhashi M, Tsuno NH, Kawabata M, Mishima
Y, Okochi N, Santoso S, Tozuka M, Takahashi K.
The frequencies of human neutrophil alloantigens
among the Japanese population. Tissue Antigens.
2012; 80(4):336-40.
2. Miyato H, Tsuno NH, Kitayama J. Semaphorin 3C
is involved in the progression of gastric cancer.
Cancer Sci. 2012 Nov;103(11):1961-6.
3. Okamoto A, Fujio K, Tsuno NH, Takahashi K,
Yamamoto K. Kidney-infiltrating CD4+ T-cellclones promote nephritis in lupus-prone mice.
Kidney Int. 2012; 82(9):969-79.
4. Hiyoshi M, Tsuno NH, Otani K, Kawai K,
Nishikawa T, Shuno Y, Sasaki K, Hongo K,
Kaneko M, Sunami E, Takahashi K, Nagawa H,
Kitayama J. Adiponectin receptor 2 is negatively
associated with lymph node metastasis ofcolorectal cancer. Oncol Lett. 2012; 3(4):756-760.
5. Sasaki K, Tsuno NH, Sunami E, Kawai K, Hongo
K, Hiyoshi M, Kaneko M, Murono K, Tada N,
Nirei T, Takahashi K, Kitayama J. Resistance ofcolon cancer to 5-fluorouracil may be overcome
by combination with chloroquine, an in vivo study.
Anticancer Drugs. 2012; 23(7):675-82.
6. Kaneko M, Nozawa H, Sasaki K, Hongo K,
Hiyoshi M, Tada N, Murono K, Nirei T, Kawai K,
Sunami E, Tsuno NH, Kitayama J. Elevatedneutrophil to lymphocyte ratio predicts poor prognosis in advanced colorectal cancer patients
receiving oxaliplatin-based chemotherapy. Oncology.
2012; 82(5):261-8.
7. Murono K, Tsuno NH, Kawai K, Sasaki K, Hongo
K, Kaneko M, Hiyoshi M, Tada N, Nirei T,
Sunami E, Takahashi K, Kitayama J. SN-38
overcomes chemoresistance of colorectal cancer
cells induced by hypoxia, through HIF1alpha.
Anticancer Res. 2012; 32(3):865-72.
8. Kawai K, Sunami E, Tsuno NH, Kitayama J,

Watanabe T. Polyp surveillance after surgery forcolorectal cancer. Int J Colorectal Dis. 2012;27(8):1087-93.
9. Hongo K, Kazama S, Sunami E, Tsuno NH,
Takahashi K, Nagawa H, Kitayama J. Immunohistochemical detection of CD133 is associatedwith tumor regression grade after chemoradiotherapy in rectal cancer. Med Oncol. 2012; 29(4):2849-57.
10. Oki T, Kitaura J, Watanabe-Okochi N, Nishimura
K, Maehara A, Uchida T, Komeno Y, Nakahara F,
Harada Y, Sonoki T, Harada H, Kitamura T.
Aberrant expression of RasGRP1 cooperates withgain-of-function NOTCH1 mutations in T-cellleukemogenesis. Leukemia. 2012; 26(5):1038-45.
11. Itoh S, Saito T, Hirata M, Ushita M, Ikeda T,
Woodgett JR, Algül H, Schmid RM, Chung UI,Kawaguchi H. GSK-3α and GSK-3β proteins are
involved in early stages of chondrocyte differentiation with functional redundancy through RelA
protein phosphorylation. J Biol Chem. 287(35):29227-36. 201212. Hojo H, Ohba S, Yano F, Saito T, Ikeda T,
Nakajima K, Komiyama Y, Nakagata N, Suzuki
K, Takato T, Kawaguchi H, Chung UI. Gli1
protein participates in Hedgehog-mediated specification of osteoblast lineage during endochondral
ossification. J Biol Chem. 287(21):17860-9. 2012
13. 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, Kawaguchi H.
C/EBPβ and RUNX2 cooperate to degrade
cartilage with MMP-13 as the target and HIF-2α
as the inducer in chondrocytes. Hum Mol Genet.
21(5):1111-23. 2012
14. Fukai A, Kamekura S, Chikazu D, Nakagawa T,
Hirata M, Saito T, Hosaka Y, Ikeda T, Nakamura
K, Chung UI, Kawaguchi H. Lack of a chondroprotective effect of cyclooxygenase 2 inhibition ina surgically induced model of osteoarthritis inmice. Arthritis Rheum. 64(1):198-203. 2012

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

171

Department of
Reproductive Endocrinology
Professor
Tomoyuki Fujii

Associate Professor
Kei Kawana

Lecturer
Osamu Hiraike

Kaori Koga

Homepage http://plaza.umin.ac.jp/ivf/index.html
http://square.umin.ac.jp/tkyobgyn/
Organization
The Department of Reproductive Endocrinology isorganized by one professor, one associate professor
and two lecturers. All the staff members are taking
part in both clinical and research activities. For theclinical aspect, we are engaged with in-patient andout-patient care including the activities in the delivery
units.

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases, genetic
counseling and assisted reproductive technologies(ART). We also perform minimal access surgery forendometriosis, uterine fibroid, benign tumor and soon.
We have a highly organized infertility clinic, where
every patient is systemically examined and after diagnosis of underlying infertility factor (s) appropriate
treatment is performed following our protocol. Once itturns out that higher level of treatment is necessary,
ART is applied to such cases. We have been engaged
in in vitro fertilization and embryo transfer (IVF-ET)
as a main axis of ART for nineteen years.
Conventional IVF-ET is mainly indicated to caseswith tubal factor, mild male factor, immunologicalfactor or of unexplained infertility factor. In case of
severe male factor or other fertilization disorderintracytoplasmic sperm injection (ICSI) is performed.
Now we have about 200 OPU cycles of IVF-ET every
year, which conventional IVF-ET and ICSI sharealmost equally. The clinical pregnancy rate of conventional IVF-ET is around 30% per embryo transfer
cycle, which is comparable with that of ICSI. OtherART techniques such as embryo cryopreservation andassisted 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 of wellequipped instruments and well-trained expertise, morethan 90% of surgery cases for benign gynecologicaldisorders 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 already established172

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

References published in 2012
(1) Yoshino O,et.al. Myomectomy decreases abnormal
uterine peristalsis and increases pregnancy rate. J
Minim Invasive Gynecol. 2012 Jan-Feb;19(1):63-7(2) Akiyama I, et.al. Follistatin is induced by IL-1β and
TNF-α in stromal cells from endometrioma. Reprod
Sci. 2013 Jun;20(6):675-9(3) Takemura Y, et.al. Increased risk of placenta previa
is associated with endometriosis and tubal factor
infertility in assisted reproductive technology
pregnancy. Gynecol Endocrinol. 2013 Feb;29(2):113-5.
(4) Nakae H, et.al. Müllerian cyst of the uterus treatedwith laparoscopy and diagnosed using immunohistology. J Obstet Gynaecol Res. 2013 Jan;39(1):430-3.
(5) Oishi H, et.al. Spontaneous cessation andrecurrence of massive uterine bleeding can occur inuterine artery pseudoaneurysm after laparoscopically assisted myomectomy. J Obstet Gynaecol
Res. 2013(6) Hasegawa A, et.al. Uterine arteriovenous fistula
treated with repetitive transcatheter embolization:case report. J Minim Invasive Gynecol. 2012 NovDec;19(6):780-4.
(7) Zenri F, et.al. Expression of retinoic acid-relatedorphan receptor alpha and its responsive genes inhuman endometrium regulated by cholesterol
sulfate. J Steroid Biochem Mol Biol. 2012 Jan;
128(1-2):21-8.
(8) Tsutsumi R, et.al. Successful pregnancy following
low-dose hCG administration in addition to hMG ina patient with hypothalamic amenorrhea due toweight loss. Gynecol Endocrinol. 2012 Jun;28(6):460-2.
(9) Osuga Y, et.al. Proteinase-activated receptors in theendometrium and endometriosis. Front Biosci (Elite
Ed). 2012 Jan 1;4:755-67.
(10) Shi J,et.al. Growth differentiation factor 3 isinduced by bone morphogenetic protein 6 (BMP-6)
and BMP-7 and increases luteinizing hormone
receptor messenger RNA expression in humangranulosa cells. Fertil Steril. 2012 Apr;97(4):97983.
(10) Isono W, et.al. Diameter of dominant leiomyoma is
a possible determinant to predict coexistentendometriosis. Eur J Obstet Gynecol Reprod Biol.
2012 May;162(1):87-90.
(11) Ogura-Nose S, et.al. Anti-Mullerian hormone(AMH) is induced by bone morphogenetic protein(BMP) cytokines in human granulosa cells. Eur J
Obstet Gynecol Reprod Biol. 2012 Sep;164(1):44-7.
(12) Shirane A, et.al. Regulation of SIRT1 determines
initial step of endometrial receptivity by controlling
E-cadherin expression. Biochem Biophys Res
Commun. 2012 Aug 3;424(3):604-10.
(13) Zhao Y, et.al. Thrombin enhances soluble Fms-liketyrosine kinase 1 expression in trophoblasts;
possible involvement in the pathogenesis ofpreeclampsia. Fertil Steril. 2012 Oct;98(4):917-21(14) Ito M, et.al. The progesterone-responsive gene
14-3-3τ enhances the transcriptional activity ofprogesterone receptor in uterine cells. J Mol
Endocrinol. 2012 Oct 10;49(3):193-202.
(15) Urata Y, et.al. Interleukin-1β stimulates thesecretion of thymic stromal lymphopoietin (TSLP)
from endometrioma stromal cells: possible
involvement of TSLP in endometriosis. Hum
Reprod. 2012 Oct;27(10):3028-35.
(16) Takamura M, et.al. Interleukin-17A is present inneutrophils in endometrioma and stimulates thesecretion of growth-regulated oncogene-α (Gro-α)
from endometrioma stromal cells. Fertil Steril. 2012
Nov;98(5):1218-24.e1-2.
(17) Akiyama I, et.al. The localization and regulationof proprotein convertase subtilisin/kexin (PCSK)
6 in human ovary. Am J Reprod Immunol. 2012
Dec;68(6):491-8.

173

Department of
Gynecologic Oncology
Professor
Yutaka Osuga

Associate Professor
Kei Kawana

Lecturer
Katsutoshi Oda

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika01.html#d03

Organization
The Department of Gynecologic Oncology isorganized by one professor, one associate professor
and one lecturer, being directed practically byProfessor Tomoyuki Fujii, the Chairman of the
Department of Obstetrics and Gynecology. The staff
members are taking part in both clinical and research
activities, as well as teaching activities, with 18
associates of the University of Tokyo Hospital. For theclinical aspect, they are engaged with in-patient andout-patient care.

Activities(1) Oncology research
In our division, the pathogenesis of uterine cervicalcancer has been investigated these two decades. To
identify the risk factors for cervical intraepithelial
neoplasia (CIN), we reanalysed the data from ourprevious case-control study by adjusting for humanpapillomavirus (HPV) antibodies. Unlike our previous
study based only on HPV DNA, smoking andChlamydia trachomatis infection were revealed as
significant risk factors for CIN after adjustment for
HPV antibodies. The enhanced oncogenicity ofparticular human papillomavirus type 16 (HPV16) E6variants is population-dependent, implying the in-volvement 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. Fiftyseven women with HPV16-positive cervical cancer
were analyzed for E6 sequence variation and its
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 cervicalintraepithelial neoplasia (CIN1), we investigated an
association between the presence of the NAs and thefate of the HPV16-related CIN1. The incidence of thepresence of the NAs in the women with a nonpathological cervix (85.7%) was significantly higher

174

than in the CIN1 cases (21.5%), the CIN2/3 cases(15.7%), and the cervical cancer cases (0%)(p<0.0001). The regression of the CIN1 lesion wasclosely associated with the presence of the NAs(p=0.0002). The presence of the NAs was associatedwith 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 associated with a higher
regression rate of HPV-related CIN1 lesions. The NAsseem to have a role in deterring HPV-related cervicallesions from progressing to CIN2/3 by inhibiting theinfection with de novo replicated HPV. Then we
designed a placebo-controlled trial in healthy adults toevaluate the safety and immunogenicity of a synthetic
peptide consisting of the aa 108-120 of HPV16 L2(L2-108/120) region, because this region contains across-neutralization epitope against genital HPV.. A
total of 13 volunteers were given nasal inoculations
with 0.1 (n=5) or 0.5mg (n=5) doses of the peptides orplacebo (n=3) without adjuvant at weeks 0, 4, and 12.
Sera were collected before inoculation and at 6, 16
and 36 weeks. The inoculation caused no serious local
and systemic complications. The inoculation generated anti-L2 antibodies binding to both HPV16 and 52
L1/L2-capsids in four of the five recipients in the
0.5mg group. Sera of the four recipients showedneutralizing activities against HPV16 and 52.
Serological responses to the peptides were not foundin the 0.1mg group and the placebo group recipients.
This study suggests the L2-108/120 peptide istolerable in humans and has the potential as a broadspectrum 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 cervical high-grade squamous intraepithelial lesions (H-SIL). Although quantitative RTPCR revealed no significant downregulation of hScribmRNA expression in the H-SIL, it revealed a clear
downregulation in the invasive cancers. These results
suggest the possibility that degradation by HPV E6 is
one of the causal roles for the progressive decrease of
hScrib expression during the disease progression fromlow-grade squamous intraepithelial lesions to H-SIL,
and a cooperative role of downregulation of hScribmRNA expression and ubiquitin-mediated degradationof hScrib by E6 and E6AP led to the complete
decrease of hScrib expression during the process ofcarcinogenesis from H-SIL to invasive cancer. These
data underscore the importance of hScrib in theconstruction of tissue architecture and prevention ofcancer development.
Another basic research is focused on analysis oftumor suppressor genes in gynecological malignancies
as following.
1 Human Scribble
Recently, a LAP protein, scribble, was identified in
Drosophila epithelia as a basolateral protein that
controls the apical-basolateral polarity. Loss ofscribble causes disorganisation and overgrowth of theepithelia. Scribble has a human homologue, humanscribble (hScrib), which is a substrate of ubiquitinmediated degradation by human papillomavirus E6
and the E6AP ubiquitin-protein ligase. In the present
study, we revealed that hScrib localised to thebasolateral regions of the epithelial cell line MDCKand human uterine cervical epithelial tissues byimmunofluorescence. Human scribble colocalised
rather with the adherens junction protein E-cadherin,
but not with the tight junction protein ZO-1.
Histochemical analysis showed a dramatic decrease in
the expression of hScrib with the progression of
disease from normal uterine cervical tissues toinvasive cervical cancers through the precursor lesions.
In contrast, the expression of hScrib was retained in
the throughout epithelial layer of the HPV-negative

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cervical high-grade squamous intraepithelial lesions(H-SIL). Although quantitative RT-PCR revealed nosignificant downregulation of hScrib mRNA
expression in the H-SIL, it revealed a clear
downregulation in the invasive cancers. These results
suggest the possibility that degradation by HPV E6 is
one of the causal roles for the progressive decrease of
hScrib expression during the disease progression fromlow-grade squamous intraepithelial lesions to H-SIL,
and a cooperative role of downregulation of hScribmRNA expression and ubiquitin-mediated degradationof hScrib by E6 and E6AP led to the complete
decrease of hScrib expression during the process ofcarcinogenesis from H-SIL to invasive cancer. These
data underscore the importance of hScrib in theconstruction of tissue architecture and prevention ofcancer development.
Drosophila discs large (Dlg) is one of neoplastic
tumor suppressors, which genetically links to scribble.
E6 also targets human Dlg (hDlg) for ubiquitinmediated degradation. Ubiquitin-protein ligase
involved in this process has not been identified thus
far. Here we investigated mechanism underlying
degradation of three target proteins of E6, hScrib,
hDlg, and p53 by using eighteen HPV 16 E6 mutants
with single amino acid substitution. In vitro
degradation ability of each E6 mutant was equivalent
for these tumor suppressors. We investigated whether
E6AP is involved in ubiquitin-mediated degradationof hDlg. In vitro binding assay revealed that hDlg
formed ternary complex with E6-E6AP complex. The
ability of E6 mutants to degrade these tumor
suppressors was correlated with their ability tointeract with E6AP. Furthermore, hDlg was targeted
for in vitro ubiquitination in the presence of both E6
and E6AP. These data revealed that E6AP isextensively involved in the ubiquitin-mediateddegradation of E6-dependent substrates as a cellular
E3 ubiquitin-protein ligase.
Human Scribble, classified as a LAP protein
containing leucine-rich repeats and PDZ domains,interacts with E6 through its PDZ domains andC-terminal PDZ domain-binding motif of E6 protein.
Interaction between human Discs Large (hDlg), which
is a substrate of E6 for the ubiquitin-mediateddegradation, and adenomatous polyposis coli (APC)
has been shown. Here, we investigated whether hScrib

and APC interact with each other in vitro and in vivo.
Interaction between hScrib and APC is mediated by
the PDZ domains 1 and 4 of hScrib and C-terminal
PDZ domain-binding motif of APC. Human Scribble
co-localized with APC at the synaptic sites ofhippocampal neuron and at the tip of membrane
protrusion in the epithelial cell line. Interference of
the interaction between hScrib and APC caused
disruption of adherens junction. Knockdown of hScrib
expression by RNAi disrupts localization of APC at
the adherens junction. These data suggest that hScrib
may participate in the hDlg-APC complex through its
PDZ domains and regulate cell cycle and neuralfunction by associating with APC.
Drosophila tumor suppressor Scribble has been
identified as an apical-basolateral polarity determinant
in epithelia. A human homolog of Drosophila Scribble,
human Scribble (hScrib), has been identified as aprotein targeted by human papillomavirus E6 for theubiquitin-mediated degradation dependent on E6AP, acellular ubiquitin-protein ligase. Human Scribble isclassified as a LAP protein, having leucine-richrepeats (LRRs) and PDZ domains. We investigatedwhether hScrib, which is thought to have a role inpolarity determination based on the data of its
Drosophila homolog, is involved in cell-cycle
regulation and proliferation control of epithelia.
Transfection of hScrib inhibits cell-cycle progression
from G1 to S phase, and it up- and down-regulates
expression of adenomatous polyposis coli and cyclins
A and D1, respectively. Knockdown of hScrib
expression by siRNA leads to cell-cycle progression
from G1 to S phase. We explored functional domain
mapping to reveal which domains of hScrib are
critical for its cellular proliferation control andlocalization at the basolateral membrane. We foundthat LRRs and PDZ domain 1 are indispensable for
hScrib to inhibit cell growth by blocking cell-cycle
progression and to keep its proper localization. These
data indicate that basolateral membrane localization of
hScrib is closely related to its proliferation control.
Our findings suggest the possibility that hScrib isinvolved in signal transduction to negatively regulate
cell proliferation by localizing at the basolateral
membrane of epithelial cells through LRRs and PDZ
domains.

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We also investigated which E3 ubiquitin-protein
ligase is involved in the ubiquitin-mediated degradation of hDlg. Human scribble (hScrib), which was
identified as substrate 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.
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 caspase-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.
2 PTEN
Although the mutation of PTEN, a tumor suppressor, is known to be involved in tumorigenesis ofendometrioid adenocarcinomas of the endometrium
and ovary, the role of PTEN alteration in endometrioid
adenocarcinoma of the cervix remains to be investigated. To elucidate the molecular pathogenesis of
cervicaladenocarcinoma
andadenosquamous
carcinoma, and in particular to examine the potential
role of PTEN mutation in endometrioid-type cancer ofthe cervix, we analyzed 32 cervical adeno- or
adenosquamous carcinomas (8 endometrioid adenocarcinomas, 14 mucinous adenocarcinomas and 10
adenosquamous carcinomas) for PTEN mutations and
HPV infections. PTEN mutation was detected in 2 of
8 (25.0%) endometrioid cases, 2 of 14 (14.3%)
mucinous cases, and none of 10 (0%) adenosquamous
cases. HPV DNA was detected in 11 out of 18 (61.1%)
PTEN wild-type adenocarcinomas and 8 out of 10(80.0%) adenosquamous carcinomas. Among 11
HPV-negative adenocarcinomas, 40.0% (2/5) endometrioid cases and 33.3% (2/6) mucinous cases wereshown to be PTEN mutated, while no cases (0/21)
were PTEN-mutant in the remainder (i.e.
adenosquamous carcinomas and HPV-positive adenocarcinomas). The current observations suggest that
PTEN mutation is frequently detected in HPVnegative adenocarcinomas of the cervix and the mostprevalent occurrence of PTEN mutation in
endometrioid subtype is keeping with endometrial andovarian carcinomas.
Next, we analyzed involvement of PTEN intreatment of endometrial cancer. Young patients withcomplex atypical hyperplasia (CAH) or stage Ia, G1
adenocarcinoma (IaG1) of the endometrium, who
desire to preserve fertility, can select the conservative
therapy by oral progestin, medroxyprogesterone

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acetate (MPA). However, conservative treatments
involve potential risks of progression and recurrence.
In an attempt to find out molecular markers forsensitivity to MPA, we performed immunohistochemical analysis of PTEN, phospho-Akt, p53, ER
and PgR in MPA-treated 31 cases with CAH or IaG1.
Eleven of 12 cases (92%) with CAH and 15 of 19
cases (79%) with IaG1 demonstrated an initial
complete response, while five patients underwent
hysterectomy due to no response. Four of 11
responders (36%) with CAH and five of 15 responders(33%) with IaG1 later developed relapse. Five of ninepatients (56%) with CAH and three of 11 patients(27%) with IaG1 became pregnant after infertility
treatment. Immunohistochemical analysis revealed
that phospho-Akt expression was significantly
decreased by MPA administration (p=0.002). Furthermore, combination of two factors, weak phosho-Akt
or PTEN-null expression, was found to besignificantly associated with receiving hysterectomy(p=0.04), while each factor showed a trend without
statistical significance (p=0.07 and 0.2, respectively).
Strong expression of both ER and PgR significantly
correlated with successful pregnancy after infertility
treatment following complete response to MPA(p=0.02). Our observations in vivo suggest thatanti-tumor action of MPA may be mediated bydephosphorylation of Akt, and that immunohistochemical evaluation of phospho-Akt and PTEN
may be able to predict the outcome of MPA therapy.
3 SFRP1 gene
The SFRP1 gene on chromosome 8p11.2 encodes a
Wnt signaling antagonist, and was recently demonstrated to be a new tumor suppressor that isinactivated by promoter methylation in human coloncancers. Here, we analyzed promoter methylation of
the SFRP1 gene in human ovarian cancers, in whichloss of heterozygosity in 8p is frequently observed andinvolvement of the Wnt signaling pathway has beensuggested. Methylation-specific PCR (MSP) analysis
showed that four of 13 ovarian cancer cell lines andtwo of 17 primary ovarian cancers had methylated
SFRP1, while an immortalized ovarian epithelial cellline, HOSE, and seven ovarian endometrial cyst
samples did not. In the four ovarian cancer cell lines
with the methylation, SFRP1 was not expressed at all
as determined by quantitative RT-PCR analysis. These

results show that SFRP1 is inactivated by promoter
methylation in human ovarian cancers, as well ascolon cancers.
4 hMSH2
The DNA mismatch repair gene is a key regulator
in the elimination of base-base mismatches andinsertion/deletion loops (IDLs). Human MutS
homologue 2 (hMSH2), originally identified as ahuman homologue of the bacterial MutS, is a tumour
suppressor gene frequently mutated in hereditary
non-polyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer is characterised by theearly onset of colorectal cancer and the developmentof extracolonic cancers such as endometrial, ovarian,and urological cancers. Oestrogen receptor (ER) alphaand beta are members of a nuclear receptor (NR)superfamily. Ligand-dependent transcription of ER is
regulated by the p160 steroid receptor coactivatorfamily, the thyroid hormone receptor-associatedproteins/the vitamin D receptor-interacting proteins(TRAP/DRIP) mediator complex, and the TATA boxbinding protein (TBP)-free TBP associated factor
complex (TFTC) type histone acetyltransferase
complex. We identified the interaction between ER
alpha/beta and hMSH2. Immunoprecipitation andglutathione-S-transferase pull-down assay revealed
that ER alpha and hMSH2 interacted in a liganddependent manner, whereas ER beta and hMSH2
interacted in a ligand-independent manner. Oestrogen
receptor alpha/beta bound to hMSH2 through the
hMSH3/hMSH6 interaction domain of hMSH2. In atransient expression assay, hMSH2 potentiated thetransactivation function of liganded ER alpha, but notthat of ER beta. These results suggest that hMSH2
may play an important role as a putative coactivator in
ER alpha dependent gene expression.
(2) Clinical oncology
To compare treatment outcome results of conventional surgery vs. radiotherapy (RT) for carcinomaof the uterine cervix. A retrospective analysis was
conducted of 152 patients with uterine cervical cancer
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

178(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 2012
(1) Kawana K. [Development of new generation
HPV vaccines: prophylactic and therapeutic].
Nihon Rinsho. 2012 Jun;70 Suppl 4:184-90.
(2) Kawana K. [Human papillomavirus prophylactic
vaccine]. Uirusu. 2012 Jun;62(1):79-86.
(3) Arimoto T, et.al. Retreatment with nedaplatin inpatients with recurrent gynecological cancer after
the development of hypersensitivity reaction tocarboplatin. J Obstet Gynaecol Res. 2013 Jan;39(1):336-40.
(4) Kashiyama T, et.al. Low-grade endometrial
stromal sarcoma developing in a postmenopausal
woman under toremifene treatment for breast
cancer. J Obstet Gynaecol Res. 2013 Jan;39(1):424-9.
(5) Taguchi A, et.al. Adjuvant effect of Japanese
herbal medicines on the mucosal type 1 immune
responses to human papillomavirus (HPV) E7 inmice immunized orally with Lactobacillus-based
therapeutic HPV vaccine in a synergistic manner.
Vaccine. 2012 Aug 3;30(36):5368-72.
(6) Kawana K, et.al. Therapeutic Human Papillomavirus (HPV) Vaccines: A Novel Approach. Open

Virol J. 2012;6:264-9.
(7) Kojima S, et.al. The prevalence of cervicalregulatory T cells in HPV-related cervical intraepithelial neoplasia (CIN) correlates inverselywith spontaneous regression of CIN. Am J
Reprod Immunol. 2013 Feb;69(2):134-41.
(8) Miyamoto Y, et.al. Sequential effects of theproteasome inhibitor bortezomib and chemotherapeutic agents in uterine cervical cancer celllines. Oncol Rep. 2013 Jan;29(1):51-7.
(9) Yamamoto N, et.al. Introducing HPV vaccine andscaling up screening procedures to prevent deaths
from cervical cancer in Japan: a costeffectiveness analysis. BJOG. 2012 Jan;119(2):177-86.
(10) Ikeda Y, et.al. Genome-wide single nucleotide
polymorphism arrays as a diagnostic tool inpatients with synchronous endometrial andovarian cancer. Int J Gynecol Cancer. 2012 Jun;
22(5):725-31.
(11) Shoji K, et.al. Genotype-dependent efficacy of adual PI3K/mTOR inhibitor, NVP-BEZ235, andan mTOR inhibitor, RAD001, in endometrial
carcinomas. PLoS One. 2012;7(5):e37431.

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Department of Perinatal Medicine
Professor
Tomoyuki Fujii

Associate Professor
Takahiro Yamashita

Homepage http://www.iiosan.umin.jp/index.htm
Organization
The Department of Perinatal Medicine is organized
by one professor and one associate professor, being
directed practically by Professor Tomoyuki Fujii, thechairman of the Department of Obstetrics andGynecology. All the staff members are taking part inboth the clinical and research activities, as well as theteaching activities, with 15 associates of the
University of Tokyo Hospital. For the clinical aspect,they are engaged with in-patient and out-patient careincluding the activities in the delivery units.

Activities
The clinical service for perinatology in the
University of Tokyo Hospital consists of out-patient
clinic and the Delivery Unit. [See Delivery Unit of the
University of Tokyo Hospital]
By the advance of the techniques for prenatal
diagnosis of fetal growth and congenital malformations, the area of fetal medicine is enlarging.
Strict measurement of fetal growth during pregnancy
has made possible the accurate diagnosis of 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,
especially with antiphospholipid 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 2012(1) Iriyama T, et.al. Management of patient witharrhythmogenic right ventricular cardiomyopathy
during pregnancy. J Obstet Gynaecol Res. 2013
Jan;39(1):390-4.2010

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

181

Department ofPediatrics, Department ofDevelopmental Pediatrics
Professor
Akira Oka, M.D.,Ph.D.

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

Lecturer
Junko Takita, M.D., Ph.D. (Department of Cell Therapy and Transplantation Medicine),
Shinya Tsuchida, M.D., Ph.D., Masakazu Mimaki, M.D., Ph.D., Yutaka Harita, M.D., Ph.D.,
Inutuzuka Ryo, M.D., PhD

Associate
Nobutaka Shimizu, M.D., Ph.D., Ken-ichirou Miura, M.D., Mitsuteru Hiwatari, M.D., Ph.D.,
Masato Takeuchi, M.D., Hiroyuki Iwasaki, M.D., Tsuyoshi Isojima, M.D., Youichirou Hirata,
M.D., Ph.D., Takahiro Shindo,M.D., Koujirou Yasui, M.D., Taiyu Hayashi, M.D., Yuki
Kimura, M.D., Nagahisa Takahashi, M.D., Konomi Shimoda, M.D., Yohko Mizuno, M.D.,
Sayaka Ohta, M.D., Ryosuke Shiozawa, M.D., Atsushi Itoh, M.D., Yoshihiko Shidara, M.D.,
Kentarou Watanabe, M.D., Misa Yoshida, 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, 2 associate
professors, 5 lecturers, 19 associate professors, 9senior residents, 1 research fellow, and 17 graduate
students on March 31, 2013.

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.

182

Clinical activities
We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In
July, 2008, the capacity of the pediatric and pediatricsurgery ward was increased to 100 beds, including 9
beds in the neonatal intensive care unit (NICU), 15
beds in the growing care unit (GCU) and 6 beds in 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, and neonatology. We also have multidisciplinary research groups and laboratories such ascell biology, genetic molecular biology and epidemiology. The main subjects of research during the lastyear are listed as follows.
① Hematology/Oncology
group:
To
exploremolecular mechanisms of pediatric solid tumors,
we performed whole-exome sequencing and target
capturesequencing
inrhabdomyosarcoma,neuroblastoma, pleuropulmonary blastoma, andhepatoblastoma using next-generation sequence
technology. Mutations of TP53, FGFR4 pathway,
and RAS pathway were recurrently detected inrhabdomyosarcoma, and frequent biallelic DICER1
mutations were observed in pleuropulmonary
blastoma. In addition, somatic mutations ofbeta-catenin and/or germline mutations of
Wnt-signaling pathway were detected in all
hepatoblastoma cases examined. We also foundmutations of ASH1L, histone methylation-related

183

gene, in approximately 10% of neuroblastoma
cases. Our findings suggest that these genemutations would be involved in the pathogenesisof pediatric solid tumors.
② Nephrology group: We found signal-regulatory
protein (SIRP) α as a novel slit diaphragmcomponent, which is crucial structure forprevention of proteinuria or nephrotic syndrome.
We also unraveled a novel mechanism of distal
tubular acidosis caused by mutations of
ATP6V1B1 and ATP6V0A4.
③ Endocrinology and Metabolism group: We
analyzed genes involved in hereditary rickets andfound several novel insights. Genetic factors forvitamin D deficiency are analyzed. Previously
unknown presentation of LMX1B abnormality
was found. We also determined a disease causing
gene by exome sequencing using next-generation
sequencer.
④ Cardiology group: We performed genome-wide
association studies for congenital heart disease andstudies to develop a novel treatment for Kawasaki
disease using mouse models.
⑤ Neurology Group: The pathogenetic mechanism ofacute 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: Neonatal brain function has
been investigated using near infra-red spectroscopy (NIRS) with researchers of Department of
Education. The pharmacological function in
extremely low birth weight infants has been
investigated with Pharmaceutical Department. A
clinical trial of formula supplied with biotin has
been planed with groups of the other Universities.
⑦ Immunology group: Research area of interest
includes refractory Kawasaki disease andepidemiology of childhood infectious disease.

Referencess
1.

Kato M, Horikoshi Y, Okamoto Y, Takahashi Y,
Hasegawa D, Koh K, Takita J, Inoue M,
Kigasawa H, Ogawa A, Sasahara Y, Kawa K,
Yabe H, Sakamaki H, Suzuki R, Kato K: Second

2.

3.

4.

5.

6.

7.

8.

9.

allogeneic hematopoietic SCT for relapsed ALL
in children. Bone Marrow Transplant. 47:13071311, 2012
Takita J, Yoshida K, Sanada M, Nishimura R,
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Oshima K, Uchisaka N, Gocho Y, Arakawa A,
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Department of Pediatric Surgery
Professor
Tadashi Iwanaka, M.D., Ph.D.

Associate Professor
Hiroaki Komuro, M.D., Ph.D.

Lecturer
Jun Fujishiro, M.D., Ph.D.

Research Associate
Masahiko Sugiyama, M.D.,

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

Tetsuya Ishimaru, 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, three research
associates. 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.

187

The pediatric surgical outpatient clinic takes place inthe same location as the pediatric outpatient clinic andwe closely cooperate with pediatricians to diagnose
and treat patients. We also have specialized outpatient
clinics, liver and biliary tract clinics and a tumor clinic.
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).
To establish safe endoscopic surgery for low birthweight infants, we investigate effectiveness andproblems of endoscopic surgery for low birth weight
infants by developing animal model for necrotizing
enterocolitis.
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.
The tumor study group analyzes the genes related totumor development and suppression. Further more,
new tumor marker is studying by using tumor tissues

188

and blood samples.

References
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Yoshida M, Matsuoka K, Nakazawa A, Yoshida
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yolk sac tumor developing after teratoma: aclinicopathological study of pediatric crococcygeal germ cell tumors and a proposal of thepathogenesis of sacrococcygeal yolk sac tumors.
J Pediatr Surg.2013;48(4):776-81.
Ishimaru T, Komura M, Komura H, Otani Y,
Komuro H, Sugiyma M, et al. Slow release ofbasic fibroblast growth factor (b-FGF) promotes
growth of tracheal cartilage. J Pediatr Surg.
2013;48(2):288-92.
Tanaka Y, Uchida H, Kawashima H, Sato K,
Takazawa S, Jimbo T, et al. Successful two-stage
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atresia using simple internal traction and delayed
primary anastomosis in a neonate: report of acase. Surg Today. 2013;43(8):906-9.
Suzuki K, Kanamori Y, Sugiyama M, Komura M,
Terawaki K, Kodaka T, et al. Plasma citrulline
may be a good marker of intestinal functions in
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Ishimaru T, Iwanaka T, Hatanaka A, Kawashima
H, Terawaki K. Translumenal esophageal
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Laparoendosc Adv Surg Tech A.2012;22(7):724-9.
Fujii M, Sugita N, Ishimaru T, Iwanaka T,
Mitsuishi M. A novel approach to the design of aneedle driver with multiple DOFs for pediatriclaparoscopic surgery. Minim Invasive Ther Allied
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Komuro H, Gotoh C. A case of intrauterine
gastric perforation in congenital diaphragmatic
hernia. Pediatric Radiology.2012;42:1267-1268.
Komuro H, Gotoh C, Urita Y, Fujishiro J, Shinkai
T. A pediatric case of an unusual type ofannular pancreas presenting with duodenopancreatic reflux. Pediatric Surgery International.
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Kanamori Y, Terawaki K, Takayasu H, Sugiyama
M, Komura M, Kodaka T, et al. Interleukin 6 andinterleukin 8 play important roles in systemic
inflammatory response syndrome of meconium
peritonitis. Surg Today. 2012;42(5):431-4.
Fujishiro J, Hori T, Kaneko M, Fukunaga K,
Ohkouchi N, Takada Y, et al. Liver Transplantation From a Donor With AsymptomaticType IV-A Choledochal Cyst: The Long-Term
Postoperative Course. Transplantation. 2012;94:
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Fujishiro J, Komuro H, Ono K, Urita Y, Shinkai T,
Minami Y, et al. Massive pneumatic expansion oflymphatic vessel resulting in cystic lesions in thepulmonary parenchyma: A rare case of persistentinterstitial pulmonary emphysema in a nonventilated infant. J Pediatr Surg.2012; 47:e21-5.
Komuro H, Gotoh C, Urita Y, Fujishiro J, Shinkai
T. A pediatric case of an unusual type of annularpancreas presenting with duodenopancreatic
reflux. Pediatr Surg Int. 2012;28:715-7.
Pech T, Fujishiro J, Finger T, Ohsawa I,
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therapy of tacrolimus and infliximab reduces
inflammatory response and dysmotility inexperimental small bowel transplantation in rats.
Transplantation. 2012;93:249-56.
Suzuki K, Kanamori Y, Sugiyama M, Komura M,
Terawaki K, Kodaka T, et al. Plasma citrulline
may be a good marker of intestinal functions in
intestinal dysfunction. Pediatr Int.2012;54: 899904.
Kanamori Y, Terawaki K, Takayasu H, Sugiyama
M, Komura M, Kodaka T, et al. Interleukin 6 andinterleukin 8 play important roles in systemic
inflammatory response syndrome of meconium
peritonitis. Surg Today. 2012; 431-434.
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Tanaka Y, Takazawa S, et al. Differences in thecharacteristics and management of pyriform sinus
fistula between neonates and young children.
Pediatr Surg Int. 2012;28(1):15-20.
Nagata K, Usui N, Kanamori Y, Takahashi S,
Hayakawa M, Okuyama H, et al. The current
profile and outcome of congenital diaphragmatic
hernia: a nationwide survey in Japan. J Pediatr
Surg. 2013;48(4):738-44.
Kanamori Y, Sato K, Yamada K, Yamada W,
Kitami M. A case of absence of extrahepatic
portal bifurcation in biliary atresia. J Pediatr
Surg.2013;48(2):e29-31.
Yamada K, Kanamori Y, Tanaka H, Fujino A,
Watanabe T, Takeda N, et al. Congenital prepubic
sinus associated with a urachal remnant: report ofa case. Surg Today. 2012 Dec 25. [Epub ahead ofprint]
Usui N, Kitano Y, Sago H, Kanamori Y, Yoneda
A, Nakamura T, et al. Outcomes of prenatallydiagnosed sacrococcygeal teratomas: the resultsof a Japanese nationwide survey. J Pediatr Surg.
2012 ;47(3):441-7.
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peritonitis. Surg Today. 2012 ;42(5):431-4.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

191

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. 355 new
and a total of 19,663 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192

examination, interpretation of laboratory tests, andactual medical procedures. Interpretation of the resultsof geriatric assessment is studied through lectures in acase-oriented manner with an emphasis placed on themultidisciplinary basis of geriatric patients.

Research
1) Research on the molecular mechanism of vascular
calcificationi) Molecular biology of vascular calcification 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

disorderPublications
1. Abe Y, Ijichi N, Ikeda K, Kayano H, Horie-Inoue
K, Takeda S, Inoue S: Forkhead box transcription
factor, forkhead box A1, shows negative
association with lymph node status in endometrial
cancer, and represses cell proliferation andmigration of endometrial cancer cells. Cancer Sci
103:806-12, 2012
2. 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 realizationof a better aged society: messages from gerontology and geriatrics. Geriatr Gerontol Int 12:16-22,
2012
3. 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 and its targeted
gene CYP3A4 in human prostate cancer. Cancer
Sci 103:176-80, 2012
4. Hibi S, Yamaguchi Y, Umeda-Kameyama Y,
Yamamoto H, Iijima K, Momose T, Akishita M,
Ouchi Y. The high frequency of periodic limb
movements in patients with Lewy body dementia.
J Psychiatr Res 46:1590-4, 2012
5. Iijima K, Iimuro S, Ohashi Y, Sakurai T,
Umegaki H, Araki A, Yoshimura Y, Ouchi Y, Ito
H; Japanese Elderly Diabetes Intervention Trial
Study Group: Lower physical activity, but notexcessive calorie intake, is associated withmetabolic syndrome in elderly with type 2
diabetes mellitus: the Japanese Elderly Diabetes
Intervention Trial. Geriatr Gerontol Int 12:68-76,
2012
6. Iijima K, Iimuro S, Shinozaki T, Ohashi Y,
Sakurai T, Umegaki H, Araki A, Ouchi Y, Ito H;
Japanese Elderly Diabetes Intervention Trial
Investigator Group. Lower physical activity is astrong predictor of cardiovascular events inelderly patients with type 2 diabetes mellitus
beyond traditional risk factors: the Japanese

193

Elderly Diabetes Intervention Trial. Geriatr
Gerontol Int 12:77-87, 2012
7. Ijichi N, Shigekawa T, Ikeda K, Horie-Inoue K,
Shimizu C, Saji S, Aogi K, Tsuda H, Osaki A,
Saeki T, Inoue S: Association of double-positive
FOXA1 and FOXP1 immunoreactivities withfavorable prognosis of tamoxifen-treated breast
cancer patients. Horm Cancer 3:147-59, 2012
8. Ikeda K, Tsukui T, Imazawa Y, Horie-Inoue K,
Inoue S: Conditional expression of constitutively
active estrogen receptor α in chondrocytes
impairs longitudinal bone growth in mice.
Biochem Biophys Res Commun 425:912-7, 2012
9. Ikeda K, Tsukui T, Tanaka D, Maruyama Y,
Horie-Inoue K, Inoue S: Conditional expressionof human bone Gla protein in osteoblasts causes
skeletal abnormality in mice. Biochem Biophys
Res Commun 424:164-9, 2012
10. Ito M, Urano T, Hiroi H, Momoeda M, Saito M,
Hosokawa Y, Tsutsumi R, Zenri F, Koizumi M,
Nakae H, Horie-Inoue K, Fujii T, Yano T,
Kozuma S, Inoue S, Taketani Y: Theprogesterone-responsive gene 14-3-3τ enhances
the transcriptional activity of progesterone
receptor in uterine cells. J Mol Endocrinol 49:
193-202, 2012
11. Kojima T, Akishita M, Nakamura T, Nomura K,
Ogawa S, Iijima K, Eto M, Ouchi Y:
Polypharmacy as a risk for fall occurrence ingeriatric outpatients. Geriatr Gerontol Int 12:42530, 2012
12. Murata T, Takayama K, Urano T, Fujimura T,
Ashikari D, Obinata D, Horie-Inoue K, Takahashi
S, Ouchi Y, Homma Y, Inoue S. 14-3-3ζ, a novel
androgen-responsivegene, is upregulated in
prostate cancer and promotes prostate cancer cellproliferation and survival. Clin Cancer Res 18:
5617-27, 2012
13. 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 130:2240-8, 2012
14. 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
130:1021-8, 2012.
15. Ohta S, Misawa A, Fukaya R, Inoue S, Kanemura
Y, Okano H, Kawakami Y, Masahiro Toda M:
Macrophage migration inhibitory factor (MIF)
promotes cell survival and proliferation of neural
stem/progenitor cells. J Cell Sci 125:3210-20,
2012
16. Ota H, Akishita M, Akiyoshi T, Kahyo T, Setou M,
Ogawa S, Iijima K, Eto M, Ouchi Y: Testosterone
Deficiency Accelerates Neuronal and VascularAging of SAMP8 Mice: Protective Role of eNOS
and SIRT1. PLoS One 7:e29598, 2012
17. Takagi K, Miki Y, Onodera Y, Nakamura Y,
Ishida T, Watanabe M, Inoue S, Sasano H, Suzuki
T: Krüppel-like factor 5 in human breast
carcinoma: a potent prognostic factor induced byandrogens. Endocr Relat Cancer 19:741-50, 2012
18. Takayama K, Horie-Inoue K, Suzuki T, Urano T,
Ikeda K, Fujimura T, Takahashi S, Homma Y,
Ouchi Y, Inoue S. TACC2 is an androgenresponsive cell cycle regulator promoting
androgen-mediatedandcastration-resistant
growth of prostate cancer. Mol Endocrinol 26:
748-61, 2012
19. Urano T, Shiraki M, Ouchi Y, Inoue S.
Association of circulating sclerostin levels with
fat mass and metabolic disease--related markers
in Japanese postmenopausal women. J Clin
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20. 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
97:E565-74, 2012
21. Yu J, Akishita M, Eto M, Koizumi H, Hashimoto
R, Ogawa S, Tanaka K, Ouchi Y, Okabe T. Src
kinase-mediates androgen receptor-dependent
non-genomic activation of signaling cascade
leading to endothelial nitric oxide synthase.
Biochem Biophys Res Commun 424:538-43,
2012Surgical Sciences
1. Surgery

195

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Murakawa, Tomohiro

StaffsAnraku, Masaki
Nagayama, Kazuhiro
Sano, Atsushi
Kitano, Kentaro

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 the treatment of the pulmonary tuberculosis in 1934. They
initiated thoracoscopy for the treatment of the
tuberculosis in our country. After the successful
application of the antituberculosis 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 cure 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
Six staffs (Nakajima J, Murakawa T, Anraku M,
Nagayama K, Sano A, and Kitano K), who are
certificated as members of the Japanese Board ofGeneral Thoracic Surgery, are in charge of the
Department of Thoracic Surgery, University of Tokyo
Hospital. They specialize in surgical treatment for
diseases of the respiratory and the mediastinal organs
and the chest wall, except for diseases of theesophagus and mammary glands.
Lung cancer is the leading cause of cancer death inour country: Ministry of Health, Labour and Welfare
documented that number of deaths from malignant
neoplasms in 2011 was approximately 360,000 out of196

1.2 million total deaths in Japan. Of them, 70
thousand people were killed by tracheal andpulmonary neoplasms.
Surgical therapy for non-small cell lung cancer(NSCLC) is thus the most important issue in our
department. By the practice of treatment based on
EBM, We perform basic training of thoracic surgery
for medical school students, graduate students andclinical residents, as well as doing the professional
education for training physicians who wish to becomeboard-certified thoracic surgeons. Approximately 300
thoracic surgeries are performed in our department in2012.
We have performed the modern-style thoracoscopy
for the diagnosis and treatment of the thoracic disease
with less surgical invasiveness since 1992. We
currently conduct a standard surgery for clinical stage
IA NSCLC, i.e. lobectomy and lymphadenectomy
through thoracoscopy: In 2012, 70% of patients with
NSCLC was the candidate for thoracoscopic surgery
in our department. Researches on less-invasiveness,oncological advantage of the thoracoscopic surgery
are thus actively done.
We also treat patients with advanced, unresectable
NSCLC and those with recurrent NSCLC
postoperatively by an immunotherapy. We are now
performing a cell-transfer therapy with activatedautologous gammadelta T-lymphocytes which has
been approved by the Ministry of Health, Labour andWelfare.
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 patients withpulmonary metastasis who are eligible for surgicaltherapy through thoracoscopy
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. Although they are
relatively rare diseases, we sought to establish thestrategies on diagnosis and treatment of these diseases,
which are still yet to be determined, from our clinicalexperiences of more than 200 cases with the diseases
in our department. We are now actively participating a

multiinstitutional study on malignant thymic epithelial
neoplasms database led by Japanese Association for
Research on the Thymus.
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 able to participate theclinical clerkship of the thoracic surgery, an elective
course for 4 weeks. We also conduct a further researchtraining for medical students who like to study
thoracic surgery. The Department of Thoracic Surgery
also offers the 4-year postgraduate program for
qualified surgeons who are willing to specialize in thethoracic surgery. We have a training program forsurgeons who wish to be a board-certified thoracic
surgeon after 4-year residency.

Current researches
Main subjects of current research at present include
basic and clinical studies on the malignant neoplasmsin the thorax, and transplantation of the thoracic
organs. Recently we conducted clinical studies on the
immunotherapy with adopted gammadelta- T-cell forthe treatment of the patients with unresectable orrecurrent NSCLC.

197

The following are the major themes under research:(1) Minimally invasive surgeries for thoracic
malignant neoplasms.
(2) Image analysis of the lung cancer focusing on its
degree of malignancy.
(3) Studies on diagnostics of the lung cancer.
(4) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(5) Single and multi-institutional studies on thymic
epithelial malignant neoplasms.
(6) Single and multi-institutional studies on surgicaltherapeutics for pulmonary metastasis.
(7) Basic and clinical research on immunotherapy
for NSCLC with gammadelta T-lymphocytes.
(8) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea after
allogeneic transplantation.

Selected publications
1. Sakamoto M, Murakawa T, Konoeda C, Inoue Y,
Kitano K, Sano A, Nakajima J, et al. Survival after
extended thymectomy for thymoma. Eur J
Cardiothorac Surg. 2012; 41(3): 623-7
2. Hino H, Murakawa T, Nagayama K, Nakajima J.
Bronchopleural fistula after lower lobectomy of
the right lung following thoracic endovascularaortic repair. Interact Cardiovasc Thorac Surg.
2012; 14(5): 655-7
3. Kitano K, Murayama T, Sakamoto M, Nagayama
K, Ueno K, Murakawa T, Nakajima J, et al.
Outcome and survival analysis of pulmonary
metastasectomy for hepatocellular carcinoma. Eur
J Cardiothorac Surg. 2012;41(2):376-82.
4. Ito T, Murakawa T, Sato H, Tanabe A, Maekawa
M, Yoshida Y, Nakajima J, et al. Simple
preoperative computed tomography image
analysis shows good predictive performance forpathological vessel invasion in clinical stage IA
non-small cell lung cancer. Interact Cardiovasc
Thorac Surg. 2012;15(4):633-8
5. Yoshida Y, Ueda R, Murakawa T, Ota S, Nakajima
J. Thymoma hyalinized by steroid therapy inmyasthenia gravis. Asian Cardiovasc Thorac Ann.
2012; 20(4): 479-81
6. Nozawa H, Sunami E, Nakajima J, Nagawa H,
Kitayama J. Synchronous and metachronous lungmetastases in patients with colorectal cancer: A
20-year monocentric experience. Exp Ther Med.
2012;3(3):449-456
7. 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. Thorac
Cardiovasc Surg. 2012; 60(2):170-1.
8. Watanabe K, Emoto N, Hamano E, Sunohara M,
Kawakami M, Kage H, Kitano K, Nakajima J, et al.
Genome structure-based screening identified
epigenetically silenced microRNA associated withinvasiveness in non-small-cell lung cancer. Int J
Cancer. 2012;130(11):2580-90
9. Horie M, Saito A, Mikami Y, Ohshima M,
Morishita Y, Nakajima J, et al. Characterization ofhuman lung cancer- associated fibroblasts inthree-dimensional in vitro co-culture model.
Biochem Biophys Res Commun. 2012; 423(1):158-63
10. Lang G, Taghavi S, Aigner C, Rényi-Vámos F,
Jaksch P, Augustin V, Nagayama K, et al. Primarylung transplantation after bridge with extracorporeal membrane oxygenation: a plea for a shift in
our paradigms for indications. Transplantation.
2012; 93(7): 729-36.
11. Nakajima J. Preoperative pathological diagnosisof lung cancer: is it always necessary? Ann Thorac
Cardiovasc Surg. 2012;18(3):183-5.

198

Department of
Cardiac Surgery
Professor
Minoru Ono, M.D.

Associate Professor
Noboru Motomura, M.D.

Lecturer
Yasutaka Hirata, M.D.

Associate
Tetsuhiro Takaoka, M.D.,

Aya Saito, M.D.,

Kan Nawata, M.D.,

Akihiro Masuzawa, M.D.,

Haruo Yamauchi, M.D.,

Akihide Umeki, M.D.,

Osamu Kinoshita, M.D.,

Masahiko Ando, M.D.,

Takuma Satsu, 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 an199

increasing number of patients who require ventricularassist device treatment. Present staffs are one Chief
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
and Friday. Patient round is on Tuesday. Adult patientsare hospitalized in the South Wing of 5th floor, andpediatric patients in the South Wing of 2nd floor.
Clinics are open Monday through Friday for thefollow-up visit as well as for patient referral.
Case volume in recent years has been about 350,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There arenine 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 2013, 28 cases ofheart transplantation and more than 110 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 Regular Clinical Clerkship, in which he/she isrequired to learn preoperative patient evaluation andmanagement, surgical treatment and postoperative
care, based on participatory practice. There are also
eleven small key-lectures on cardiovascular surgery.
Hands-on practice is provided during the Advanced
Clinical Clerkship one-month course in the lastmonths 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 10-11th 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) devel-200

opment of a newly-designed surgical robotic system,4) application of regenerative medicine to end-stage
heart failure, 5) mechanism analysis of right heart
failure and development of effective pharmacologicaltherapy, 6) development of versatile suture device, 7)
development of new heart preserving solution .

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Hisagi M, Imai H, Iijima A, Motomura N, Kyo,
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Noiri E: Combination of Two Urinary Biomarkers
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Yamazaki K, Kyo S, Ono M, Tsukiya T, Mizuno T,
Taenaka Y, Tatsumi E: Alteration of LV enddiastolic volume by controlling the power ofcontinuous-flow LVAD, so it is synchronized withcardiac beat: development of a native heart load
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128-133(6) Kimura M, Nishimura T, Kinoshita O, Kashiwa K,
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Taenaka Y, Tatsumi E: Creating an ideal "off-test
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201

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Hatano M, Maki H, Inaba T, Yao A, Hirata Y,
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Yoshikawa Y, Takeda K, Motomura N, Tsukihara
H, Sawa Y. Coronary artery bypass grafting inhemodialysis-dependent patients: analysis ofJapan Adult Cardiovascular Surgery Database.
Circ J 2012, 76: 1115-1120(29) Handa N, Miyata H, Motomura N, Nishina T,
Takamoto S; Japan Adult Cardiovas- cular
Database Organization: Procedure- and agespecific risk stratification of single aortic valve
replacement in elderly patients based on Japan
Adult Cardiovascular Surgery Database. Circ J
2012, 76: 356-364(30) Jacobs JP, Jacobs ML, Maruszewski B, Lacour-

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Gayet FG, Tchervenkov CI, Tobota Z, Stellin G,
Kurosawa H, Murakami A, Gaynor JW, Pasquali
SK, Clarke DR, Austin EH 3rd, Mavroudis C:
Initial application in the EACTS and STS
Congenital Heart Surgery Databases of anempirically derived methodology of complexity
adjustment to evaluate surgical case mix andresults. Eur J Cardiothorac Surg 2012, 42:775-779

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Department of
Gastrointestinal Surgery
Professor
Yasuyuki Seto MD. PhD.

Associate Professor
Sachiyo Nomura MD. PhD.

Lectuler
Kazuhiko Mori MD. PhD.

Hiroharu Yamashita MD. PhD.

Associates
Masato Nishida MD. PhD.

Susumu Aikou MD. PhD.

Yukinori Yamagata MD. PhD.

Koichi Yagi MD. PhD.

Ryuta Yamamoto MD.

Yoshiyuki Miwa MD.

Masayuki Urabe MD.

General Affairs:
Since 1997, 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.
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, the development of new basic research activities which can muchcontribute to clinical fields, and indications ofdesirable modes of terminal care.
Fostering good surgeons as well as scientists whomeet both clinical and academic needs has always
been the guiding principle of our Department.

Educational Activities:
The new system of clinical clerkship for medical
students has begun from 2013. During those periods,
the students are educated strictly and gently by staffs.
Clinical exercises, e.g., blood sampling, injection, andligation, etc, are performed. They can attend theoperations as an assistant.

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They learn general patient care which encompasses
not only perioperative management of diseases but
also non-surgical management of postoperative
disorders and terminal care. Our educational systemprovides medical students with a great deal ofpractical information from the medical point of view
as well as better opportunities to ponder the
implications of life and death.
For the medical students, the clinical clerkshiplectures are held two or three times a week. The
experts (from outside hospital) other than the staff
give special unique and informative lectures, which
are popular among the students.
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:
Our goal is to cure the cancer patients by muchbetter surgery. The development of better surgicalmethods has the highest priority. Better surgery means
radicality of the cancer control, minimal invasiveness,and good QOL after surgery. Recently, nontransthoracic radical esophagectomy with extended
lymphadenectomy (NOVEL) has been applied, whichshows less pulmonary complications and good
respiratory functions after surgery. New methods ofendoscopic full-thickness resection (NEWS) has beendeveloped for some gastric tumor as a collaboration ofendoscopy and laparoscopy. The elimination of thepulmonary complications after esophagectomy and thedetection of minute metastasis for the establishment ofbetter surgery are also our important targets.
Another main research activities of the department
of Gastrointestinal Surgery has been focused on
diagnosis and therapy for gastrointestinal diseases andclinical and basic research for gastrointestinal
carcinogenesis from the view point of “Surgery andInflammation”. The department's research activities
have focused on a wide spectrum of research topics,
ranging from basic research topics to clinical ones.
Our research activities have been well organized andultimately achieved by maintaining a close connection
between hospital and laboratory activities. Our
medical staffs make every effort to promote theresearch activities and obtain successful results.

Clinical Activities:
We have outpatient clinics from Monday throughFriday. We have specialized divisions for outpatientmanagement of esophageal, gastric diseases. The ward
is divided into four subgroups, and each of them has
one medical staff for supervision, one assistantsupervisor, one chief resident, and one or two juniorresidents in rotation. They are on duty for daily patientcare under the supervision of medical staffs. Ordinary,each subgroup takes care of 10-15 patients.
We have our own multidisciplinary diseaseevaluation systems for inpatients and outpatients, suchas endoscopy for upper and lower gastrointestinal
tracts, and barium roentgenogram. These multidisciplinary services provide good opportunities toevaluate the diseases systematically from thesurgeon's standpoint.
The weekly official activities of our department are
Ward Rounds by the Professor on Monday. We havepost- and preoperative case conferences on Wednesday,Thursday, and Friday morning, respectively, and ajournal club on Monday. We also have a specialized
upper gastrointestinal case conference on Wednesday
evening. And, cancer board is held bi-weekly, where
the radiologists and endoscopists as well as surgeonsattend together and have discussions frankly.
Generally, elective surgery is scheduled on Tuesday，
Wednesday and Thursday. The statistics shows morethan 150 gastric and 50 esophageal cancer surgeries
performed a year, respectively. All residents andmedical personnel work many extra hours with highmotivation whenever it is necessary for the good of
the patients.

References
1. Noji S, Hosoi A, Takeda K, Matsushita H,
Morishita Y, Seto Y, Kakimi K.. Targeting
spatiotemporal expression of CD137 on tumorinfiltrating cytotoxic T lymphocytes as a novel
strategy for agonistic antibody therapy. J

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2.

3.

4.

5.

6.

7.

8.

Immunother 35(6):460-72,2012
Nunobe S, Kiyokawa T, Hatao F, Wada I, Shimizu
N, Nomura S, Mise Y, Sugawara Y, Kokudo N,
Seto Y. Pathological complete response ofsynchronous multiple liver metastases associatedwith advanced gastric cancer to gastrectomy andprompt S-1 treatment in combination withfractional cisplatin: report of a case.
Hepatogastroenterology 59(113):307-9,2012
Yagi K, Takahashi H, Akagi K, Matsusaka K,
Seto Y, Aburatani H, Nakajima A, Kaneda
A.Intermediate methylation epigenotype and its
correlation to KRAS mutation in conventional
colorectal adenoma. Am J Pathol 180(2):616-25,
2012
Hiki N, Kaminishi M, Yasuda K, Uedo N, Kobari
M, Sakai T, Hiratsuka T, Ohno K, Honjo H,
Nomura S, Yahagi N, Tajiri H, Suzuki H.
Multicenter phase II randomized study evaluating
dose-response of antiperistaltic effect of L-menthol
sprayed onto the gastric mucosa for uppergastrointestinal endoscopy. Dig Endosc 24(2):79-86,2012
Yamagata Y, Aikou S, Fukushima T, Kataoka H,
Seto Y, Esumi H, Kaminishi M, Goldenring JR,
Nomura S. Loss of HGF activator inhibits
foveolar hyperplasia induced by oxyntic atrophy
without altering gastrin levels.Am J Physiol
Gastrointest Liver Physiol 303(11):G1254-61,
2012
Yamagata Y, Amikura K, Kawashima Y, Yatsuoka
T, Nishimura Y, Sakamoto H, Tanaka Y, Seto
Y.Staging Laparoscopy in Advanced Gastric
Cancer: Usefulness and Issues Requiring
Improvement. Hepatogastroenterology 60(124),
2012
Fujii Y, Yoshihashi K, Suzuki H, Tsutsumi S,
Mutoh H, Maeda S, Yamagata Y, Seto Y,
Aburatani H, Hatakeyama M. CDX1 confers
intestinal phenotype on gastric epithelial cells via
induction of stemness-associated reprogramming
factors SALL4 and KLF5.Proc Natl Acad Sci U S
A 109(50):20584-9,2012
Yamashita H, Okuma K, Tada K, Shiraishi K,
Takahashi W, Shibata-Mobayashi S, Sakumi A,
Saotome N, Haga A, Onoe T, Ino K, Akahane M,
Ohtomo K, Nakagawa K. Four-dimensional

measurement of the displacement of internal
fiducial and skin markers during 320-multislice
computed tomography scanning of breast cancer.
Int J Radiat Oncol Biol Phys 84(2):331-5,2012
9. Kubota K, Kuroda J, Yoshida M, Ohta K,
Kitajima M. Medical image analysis: computeraided diagnosis of gastric cancer invasion on
endoscopic images. Surg Endosc 26(5):1485-9,
2012
10. Nunobe S, Hiki N, Tanimura S, Nohara K, Sano T,
Yamaguchi T. The Clinical Safety of Performing
Laparoscopic Gastrectomy for Gastric Cancer by
Trainees after Sufficient Experience in Assisting.
World J Surg 37(2):424-9,2012
11. Nunobe S, Hiki N, Gotoda T, Murao T, Haruma K,
Matsumoto H, Hirai T, Tanimura S, Sano T,
Yamaguchi T. Successful application of
laparoscopic and endoscopic cooperative surgery(LECS) for a lateral-spreading mucosal gastriccancer. Gastric Cancer 15(3):338-42,2012
12. Kaminishi M, Niwa H.Past, present, and future of
the Korea-Japan Joint Symposium on Gastrointestinal Endoscopy.Clin Endosc 44(1):1-5,2011
13. 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 141(3):837-45,2011
14. 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(2):183-7,2011
15. Tsuchida Y, Hatao F, Fujisawa M, Murata T,
Kaminishi M, Seto Y, Hori M, Ozaki H. Neuronalstimulation with 5-hydroxytryptamine 4 receptor
induces anti-inflammatory actions via α7nACh
receptors on muscularis macrophages associatedwith postoperative ileus. Gut 60(5):638-47,2011
16. Hiki N, Kaminishi M, Tanabe S, Fujisaki J,
Yoshino J, Iguchi M, Kobayashi H, Ashida K,
Kawabe T, Kawano T, Nomura S, Yahagi N, Tajiri
H, Suzuki H.An open-label, single-arm study
assessing the efficacy and safety of L: -menthol
sprayed onto the gastric mucosa during upper

206

gastrointestinal endoscopy. J Gastroenterol 46(7):873-82,2011
17. Hiki N, Kaminishi M, Hasunuma T, Nakamura M,
Nomura S, Yahagi N, Tajiri H, Suzuki H.A phase I
study evaluating tolerability, pharmacokinetics,
and preliminary efficacy of L-menthol in uppergastrointestinal endoscopy. Clin Pharmacol Ther
90(2):221-8,2011
18. Hiki N, Kaminishi M, Yasuda K, Uedo N, Honjo
H, Matsuhashi N, Hiratsuka T, Sekine C, Nomura
S, Yahagi N, Tajiri H, Suzuki H.Antiperistaltic
effect and safety of L-menthol sprayed on thegastric mucosa for upper GI endoscopy: a phase
III, multicenter, randomized, double-blind, placebocontrolled study. Gastrointest Endosc 73(5):932-41,2011
19. Shimoyama S. Statins and gastric cancer risk.
Hepatogastroenterology 58(107-108):1057-61,
2011
20. Shimoyama S. Statins are logical candidates forovercoming limitations of targeting therapies onmalignancy: their potential application to
gastrointestinal cancers. Cancer ChemotherPharmacol 67(4):729-39,2011
21. Shimoyama S. BRAF mutations and theirimplications in molecular targeting therapies for
gastrointestinal cancers. J Pharmacogeenom
Pharmacoproteomics 2: e102.doi104172,2011
22. Yamashita H, Katai H, Morita S, Saka M,
Taniguchi H, Fukagawa T.Optimal extent oflymph node dissection for Siewert type II
esophagogastric junction carcinoma. Ann Surg
254(2):274-80,2011
23. Kubota K, Tatsutomi Y, Kitajima M, Mafune K,
Ohta K, Yoshida M, Suwa T, Kuroda J, Hiki N,
Seto Y, Kaminishi M.Physiological evaluation ofresidual stomach motility after local resection in
conscious dogs. Surg Today 41(5):680-7,2011
24. Kubota K, Adachi M, Takao Y, Kitajima M. A
novel technique for postoperative perineal hernia
repair. Surgery 150(3):572-3,2011
25. Kubota K, Okada A, Kuroda J, Yoshida M, Ohta
K, Adachi M, Itabashi M, Osamura Y, Kitajima M.
Neuroendocrine carcinoma of the stomach: a casestudy.Case Rep Med 948328. doi: 10.1155,2011
26. Nunobe S, Hiki N, Ohyama S, Aikou S, Sano T,
Yamaguchi T. Outcome of surgical treatment forpatients with locoregional recurrence of gastriccancer. Langenbecks Arch Surg 396(2):161-6,
2011
27. Nunobe S, Hiki N, Tanimura S, Kubota T,
Kumagai K, Sano T, Yamaguchi T.Three-stepesophagojejunal anastomosis with atraumatic
anvil insertion technique after laparoscopic total
gastrectomy. J Gastrointest Surg 15(9):1520-5,
2011
28. Kaneda A, Yagi K. Two groups of DNA
methylation markers to classify colorectal cancer
into three epigenotypes. Cancer Sci 102(1):18-24,
2011
29. Kaneda A, Fujita T, Anai M, Yamamoto S, Nagae
G, Morikawa M, Tsuji S, Oshima M, Miyazono K,
Aburatani H.Activation of Bmp2-Smad1 signal
and its regulation by coordinated alteration of
H3K27 trimethylation in Ras-induced senescence.
PLoS Genet 7(11):e1002359,2011
30. Shimizu N, Hatao F, Kiyokawa T, Goto O,
Fujishiro M, Seto Y. Single port surgery for
gastric tumors. IGCC 2011 9th International
Gastric Cancer Congress. SH Noh, YJ Mok, HK
Yang (ed.) Monduzzi Editore, Bologna, Italy 247252,2011
31. Sawano M. Analysis of breath CO And
application to hemodynamic monitoring. Gas
Biology Research in Clinical Practice. Yoshikawa
T, Naito (eds): Karger, Switzerland:24-34,2011

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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.,

Homepages http://www.h.u-tokyo.ac.jp/patient/depts/hbps_md/index.html
http://www.h.u-tokyo.ac.jp/transplant/
Introduction
The Hepato-Biliary-Pancreatic Surgery Division,
Artificial Organ and Liver Transplantation Division,
Department of Surgery (HPB Surg Division) is
originated from Second Department of Surgery (2ndDept of Surg), which was established in 1893. This
department has a history of 120 years and has madetremendous contribution to the Japanese surgicaladvancement, such as the foundation of Japanese
surgical society. As departments in the style ofgraduate school have been increasingly founded in
The Tokyo University, and organ-specific medication
has been progressively recommended, 2nd Dept ofSurg has been replaced to HPB Surg Division sinceJune 1st, 1998.

departments. Since 2013, the bed-side practice wasrearranged as “Clinical Clerkship,” more practical
medical training than conventional “Bed-Side
Teaching”. Our division precedes Clinical Clerkshipin the Tokyo University Hospital, and recommends
students to aggressively attend the surgical activities.
Clinical Clerkship is designed to consist of 2 parts;
2 weeks clinical practice in Tokyo University and 1
week practice in other hospitals. Medical students are
expected to join the surgical team and the surgicaloperations. They can learn about preoperative examinations & care of the patients, informed consents,
diagnosis, presentation at the conferences, operative
procedures, and postoperative managements. They
also are expected to submit a report on a theme of
specific surgical topics.

1. Education

2. Research

Education for medical students includes systematic
lectures of surgery for M2 students, and clinicallectures and bed-side practice for M3 and M4 students,
in accordance with other surgical and non-surgical

We have published papers on Hepato-BiliaryPancreatic Surgery and liver transplantations 20-30/
year. The ongoing topics involve clinical applicationof ICG fluorescent images, especially for visualization

208

of
biliary
trees,
hepatic
tumors,hepatic
hemodynamics, prospective clinical trials of adjuvant
chemotherapy for hepatocellular carcinoma, metastatic colorectal cancer, utility of contrast-enhanced
intraoperative ultrasonography, and preoperative
navigation for hepatic surgery.

3. Clinical Activities
Our division deals with patients with hepato-biliarypancreatic malignancies, liver cirrhosis, and HBP
benign diseases. We perform about 200 hepatectomies
for HCC and colorectal mets, 50 Whipples, and 20
liver transplantations, mainly from living donors. The
overall number of operation is about 430/year.
Elective operations are carried out on Monday,
Wednesday and Friday. The perioperative management is strictly controlled, with nearly zero mortality.
Adjuvant chemotherapy is performed in a style ofprospective clinical trials.

Publications (2012)
1. Ishizawa T, Gumbs AA, Kokudo N, Gayet B.
Laparoscopic segmentectomy of the liver: fromsegment I to VIII. Ann Surg 2012; 256:959-64.
2. Takahashi M, Hasegawa K, Arita J, et al.
Contrast-enhanced
intraoperative
ultrasonography using perfluorobutane microbubbles
for the enumeration of colorectal liver metastases. Br J Surg 2012; 99:1271-7.
3. Kishi Y, Hasegawa K, Kaneko J, et al. Resectionof segment VIII for hepatocellular carcinoma. Br
J Surg 2012; 99:1105-12.
4. Yamashiki N, Sugawara Y, Tamura S, et al.
Outcomes after living donor liver transplantation
for acute liver failure in Japan: results of anationwide survey. J Transplant 2012; 18:106977.
5. Ishizawa T, Zuker NB, Kokudo N, Gayet B.
Positive and negative staining of hepatic
segments by use of fluorescent imaging
techniques during laparoscopic hepatectomy.
Arch Surg 2012; 147:393-4.
6. Shindoh J, Sugawara Y, Akamatsu N, et al.
Thrombotic microangiopathy after living-donorliver transplantation. Am J Transplant 2012;

12:728-36.
7. Yamashita S, Sakamoto Y, Kaneko J, et al.
Resection of the second portion of the duodenum
sacrificing the minor papilla but preserving thepancreas for a recurrent duodenal adenocarcinoma: report of a case. Biosci Trends 2012;
6:44-7.
8. Shindoh J, Akahane M, Satou S, et al. Vasculararchitecture in anomalous right-sided ligamentum teres: three-dimensional analyses in 35
patients. HPB 2012; 14:32-41.
9. Gao J, Feng X, Inagaki Y, et al. Des-γ-carboxy
prothrombin and c-Met were concurrently andextensively expressed in hepatocellular carcinoma and associated with tumor recurrence.
Biosci Trends 2012; 6:153-9.
10. Hasegawa K, Takahashi M, Ohba M, et al.
Perioperative chemotherapy and liver resection
for hepatic metastases of colorectal cancer. J
Hepatobiliary Pancreat Sci 2012; 19:503-8.

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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.,

Tomoyuki Kaneko, M.D.

Akira Nomiya, M.D.,

Aya Niimi, M.D.

Yuta Takeshima, M.D., Ph.D.,

Yuta Yamada, M.D.

Jimpei Miyagawa, M.D.,

Akiyoshi Takeuchi, M.D.

Tetsuji Minami, 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,
lecturers and associates are involved in in-patient andout-patient cares and teaching of the students as well
as research activities. Clinical visiting professors aremainly 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 about 1,200 from January 2012 to December 2012.
Elective operations are performed on Tuesday,
Wednesday and Thursday. About 1,300 operations
were performed in 2012. The numbers of main

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operations are adrenalectomy 24, nephrectomy 19,
partial nephrectomy 37, nephroureterectomy 16,
radical cystectomy 15, radical prostatectomy 64,transurethral resection of the bladder tumor (TUR-Bt)
165, transurethral resection of the prostate (TUR-P)
24, and laparoscopic surgery 66.
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 renal tumor, adrenal surgery, bladdercancer, prostate cancer, andrology, neurourology,
urolithiasis, kidney transplantation, second opinion,
pediatric urology and female urology receive
sophisticated care on the particular day of the week.
The total number of out-patients was 20,000 patientdays from January 2012 to December 2012.

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. Sugihara T, Yasunaga H, Horiguchi H, Tsuru N,
Fujimura T, Nishimatsu H, Kume H, Ohe K,
Matsuda S, Fushimi K, Homma Y. Wide range andvariation in minimally invasive surgery for renalmalignancy in Japan: a population-based analysis.
Int J Clin Oncol. 2012 Nov 23. [Epub ahead ofprint].
2. Aizawa N, Homma Y, Igawa Y. Effects ofmirabegron, a novel β3-adrenoceptor agonist, on
primary bladder afferent activity and bladdermicrocontractions in rats compared with theeffects of oxybutynin. Eur Urol. 2012 Dec;62(6):1165-73.
3. Murata T, Takayama K, Urano T, Fujimura T,
Ashikari D, Obinata D, Horie-Inoue K, Takahashi
S, Ouchi Y, Homma Y, Inoue S. 14-3-3ζ, a novel
androgen-responsive gene, is upregulated in
prostate cancer and promotes prostate cancer cellproliferation and survival. Clin Cancer Res. 2012
Oct 15;18(20):5617-27.
4. Kaneko T, Matsushima H, Homma Y. Dopaminesecreting corticomedullary mixed tumor of theadrenal gland. Int J Urol. 2012 Dec;19(12):11234.
5. Sugihara T, Yasunaga H, Horiguchi H, Fujimura T,
Ohe K, Matsuda S, Fushimi K, Homma Y. Impact
of surgical intervention timing on the case fatality
rate for Fournier's gangrene: an analysis of 379
cases. BJU Int. 2012 Dec; 110 (11 Pt C): E1096100.
6. Yamada Y, Minowada S, Aruga T, Homma Y.
Contracted bladder developing after prostatebrachytherapy. Int J Urol. 2012 Oct;19(10):951-3.
7. Taguchi S, Enomoto Y, Homma Y. Bladder
endometriosis developed after long-term estrogentherapy for prostate cancer. Int J Urol. 2012 Oct;19(10):964-5.
8. Igawa Y, Schneider T, Yamazaki Y, Tatemichi S,
Homma Y, Nishizawa O, Michel MC. Functional

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investigation of β-adrenoceptors in humanisolated detrusor focusing on the novel selective
β3-adrenoceptor agonist KUC-7322. Naunyn
Schmiedebergs Arch Pharmacol. 2012 Aug;385(8):759-67.
9. Miyazaki H, Nishimatsu H, Kume H, Suzuki M,
Fujimura T, Fukuhara H, Enomoto Y, Ishikawa A,
Igawa Y, Hirano Y, Homma Y. Leukopenia as arisk factor for osteonecrosis of the jaw inmetastatic prostate cancer treated using zoledronic
acid and docetaxel. BJU Int. 2012 Dec; 110 (11 Pt
B): E520-5.
10. 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; discussion 234.
11. Takayama K, Horie-Inoue K, Suzuki T, Urano T,
Ikeda K, Fujimura T, Takahashi S, Homma Y,
Ouchi Y, Inoue S. TACC2 is an androgenresponsive cell cycle regulator promoting
androgen-mediatedandcastration-resistant
growth of prostate cancer. Mol Endocrinol. 2012
May;26(5):748-61.
12. Taguchi S, Takahashi S, Iida K, Mizutani T,
Yamaguchi K, Tominaga T, Niwa N, Yoshimi M,
Takahashi T, Homma Y. Spermatic cord
lymphoma: a case report and literature review.
Case Rep Med. 2012;2012:513707.
13. Sugihara T, Yasunaga H, Horiguchi H, Nishimatsu
H, Hirano Y, Matsuda S, Homma Y. Renal
haemorrhage risk after extracorporeal shockwave
lithotripsy: results from the Japanese Diagnosis
Procedure Combination Database. BJU Int. 2012
Oct; 110 (8 Pt B): E332-8.
14. Sugihara T, Yasunaga H, Horiguchi H, Nishimatsu
H, Fukuhara H, Enomoto Y, Kume H, Ohe K,
Matsuda S, Homma Y. Management trends,
angioembolization performance and multiorgan
injury indicators of renal trauma from Japaneseadministrative claims database. Int J Urol. 2012
Jun; 19(6): 559-63; author reply 564.
15. Uemura H, Sano F, Nomiya A, Yamamoto T,
Nakamura M, Miyoshi Y, Miki K, Noguchi K,
Egawa S, Homma Y, Kubota Y. Usefulness of
perflubutane microbubble-enhanced ultrasound inimaging and detection of prostate cancer: phase II
multicenter clinical trial. World J Urol. 2012 Feb

4. [Epub ahead of print]
16. Morita K, Nakamura F, Nannya Y, Nomiya A,
Arai S, Ichikawa M, Maeda D, Homma Y,
Kurokawa M. Primary MALT lymphoma of theurinary bladder in the background of interstitial
cystitis. Ann Hematol. 2012 Sep;91(9):1505-6.
17. Sugihara T, Yasunaga H, Horiguchi H, Nakamura
M, Nishimatsu H, Kume H, Ohe K, Matsuda S,
Homma Y. In-hospital outcomes and cost assessment between bipolar versus monopolar transurethral resection of the prostate. J Endourol.
2012 Aug;26(8):1053-8.
18. Nakamura M, Fujimura T, Nagata M, Hosoda C,
Suzuki M, Fukuhara H, Enomoto Y, Nishimatsu H,
Kume H, Igawa Y, Homma Y. Association
between lower urinary tract symptoms and sexual
dysfunction assessed using the core lower urinary
tract symptom score and International Index of
Erectile Function-5 questionnaires. Aging Male.
2012 Jun;15(2):111-4.
19. Yoshida M, Kudoh J, Homma Y, Kawabe K. New
clinical evidence of silodosin, an α(1A) selective
adrenoceptor antagonist, in the treatment forlower urinary tract symptoms. Int J Urol. 2012
Apr;19(4):306-16.
20. Fujimura T, Kume H, Nishimatsu H, Sugihara T,
Nomiya A, Tsurumaki Y, Miyazaki H, Suzuki M,
Fukuhara H, Enomoto Y, Homma Y. Assessmentof lower urinary tract symptoms in men byinternational prostate symptom score and core
lower urinary tract symptom score. BJU Int. 2012
May;109(10):1512-6.
21. Taguchi S, Fujimura T, Kume H, Homma Y.
Zoledronic Acid administration in aggressive
castration- resistant prostate cancer. Asian Pac J
Cancer Prev. 2012;13(12):6539-40.
22. 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 pericarditis-retrospective analysis of 11 case histories. J
Cardiol. 2012 Mar;59(2):139-46.
23. Oba S, Suzuki E, Nishimatsu H, Kumano S,
Hosoda C, Homma Y, Hirata Y. Renoprotective
effect of erythropoietin in ischemia/reperfusion

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injury: possible roles of the Akt/endothelial nitricoxide synthase-dependent pathway. Int J Urol.
2012 Mar;19(3):248-55.
24. 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 and its targeted
gene CYP3A4 in human prostate cancer. Cancer
Sci. 2012 Feb; 103(2): 176-80. Sugihara T,
Yasunaga H, Horiguchi H, Nishimatsu H, Kume H,
Ohe K, Matsuda S, Fushimi K, Homma Y. A
nomogram predicting severe adverse events after
ureteroscopic lithotripsy: 12372 patients in a
Japanese national series. BJU Int. 2013 Mar;111(3):459-66.
25. Nishimatsu H, Suzuki E, Kumano S, Nomiya A,
Liu M, Kume H, Homma Y. Adrenomedullin
mediates adipose tissue-derived stem cell-induced
restoration of erectile function in diabetic rats. J
Sex Med. 2012 Feb;9(2):482-93.

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Department of Surgical Oncology
Professor
Toshiaki Watanabe, M.D., Ph.D.

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

Lecturer
Eiji Sunami, M.D., Ph.D.,

Associate
Shinsuke Saito, M.D., Ph.D.

Shinsuke Kazama, M.D., Ph.D.

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

Takamitsu Kanazawa, M.D., Ph.D.

Kazushige Kawai, M.D., Ph.D.

Kentaro Yazawa, M.D., Ph.D.

Tomomichi Kiyomatsu M.D., Ph.D.

Toshiaki Tanaka, M.D., Ph.D.

Junichiro Tanaka, M.D., Ph.D.

Homepage

http://all-1su.umin.jp/

Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Surgical
Oncology and the Department of Vascular Surgery.
The staff of the Department of Surgical Oncology
consists of one Professor, one Associate Professor, one
Lecturer and nine Assistant Professors. The outpatient
office is located on the third floor of the Outpatient
Building. The ward is situated on the eighth floor of
the Ward Building. The administrative office andresearch laboratories are located in the Administration
and Research Building. Current activities of the
Department of Surgical Oncology in clinical practice,education, and research are summarized as follows.

Clinical activities
The Department of Surgical Oncology provides
comprehensive evaluation, diagnosis, treatment andmanagement for adult patients with both general andoncologic surgical problems, in the ambulatory as wellas inpatient setting. In particular, we are trying to
identify the best way to treat each patient with theleast surgical stress by minimally invasive surgery
such as laparoscopic surgery and robotic surgery (daVinci), and preoperative chemoradiotherapy for rectal
cancer. The department is also well known for its
innovative therapy for inflammatory bowel disease.
Department specialists have expertise in biologicalcancer immunotherapy, chemotherapy for a variety ofmalignancies, and radiotherapy for rectal cancer. The
outpatient clinic is open from Monday through Friday,
and twenty-four-hour consultation is available forurgent or emergency problems.
The outpatient clinic is specialized in the lower GI
tract. The Department was responsible for 395
surgically treated inpatients in the year of 2012. On
Monday, Wednesday and Friday mornings, pre- andpost-surgery conferences are held, and the Professor's
Round takes place after the conference every
Wednesday. Operating days are Monday, Tuesday andThursday. In addition to the clinical conferences,

214

research conferences are held every Monday morning.
Each research unit holds its own conference every
week. Over 1200 colonoscopies are performed for ayear. The newest technologies are introduced for
diagnosis and treatment of colon and rectal cancer andlong-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 other departments of surgery. In the systemic lectures on surgery
for the fiscal year of 2012, various fields were covered
such as surgical oncology and immunology, injury,
somatic reaction to surgery, infectious diseases, shock,pre- and post-surgical management and nutrition. In
the clinical lectures, we presented many diseases suchas colon cancer, colonic polyp, colonic polyposis andulcerative colitis. In the postgraduate education
program, new residents are trained to become
qualified surgeons. In addition to pre- and postsurgery 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
We apply the techniques used in molecular andcellular biology to our research. The following are themajor 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) Fibroblast Growth Factor (FGF) in inflammatory
bowel disease21) Genetic analysis of undifferentiated colorectal
cancer22) High Frequency Ultrasonography (HIFU) for
solid cancer23) Quantitative analysis of intraperitoneal cancer
cells in peritonitis carcinomatosis24) Immunomodulation in chemoradiotherapy for
locally advanced rectal cancer25) Autophagy in Oncology
26) Robot assisted laparoscopic colorectal surgery (daVinci)

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References
1: Hongo K, Kazama S, Sunami E, Tsuno NH,
Takahashi K, Nagawa H, Kitayama J.
Immunohistochemical detection of CD133 is
associated with tumor regression grade after
chemoradiotherapy in rectal cancer. Med Oncol.
2012 Dec;29(4):2849-57.
2: Miyato H, Tsuno NH, Kitayama J. Semaphorin 3C
is involved in the progressionof gastric cancer.
Cancer Sci. 2012 Nov;103(11):1961-6.
3: Emoto S, Ishigami H, Hidemura A, Yamaguchi H,
Yamashita H, Kitayama J,Watanabe T.
Complications and management of an implanted
intraperitoneal accessport system for intraperitoneal chemotherapy for gastric cancer withperitoneal metastasis. Jpn J Clin Oncol. 2012 Nov;
42(11):1013-9.
4: Nozawa H, Kitayama J, Sunami E, Watanabe T.
Impact of chronic kidney diseaseon outcomes ofsurgical resection for primary colorectal cancer: aretrospective cohort review. Dis Colon Rectum.
2012 Sep;55(9):948-56.
5: Sasaki K, Tsuno NH, Sunami E, Kawai K, Hongo
K, Hiyoshi M, Kaneko M, Murono K,Tada N,
Nirei T, Takahashi K, Kitayama J. Resistance ofcolon cancer to 5-fluorouracil may be overcome
by combination with chloroquine, an in vivo study.
Anticancer Drugs. 2012 Aug;23(7):675-82.
6: Kawai K, Sunami E, Tsuno NH, Kitayama J,
Watanabe T. Polyp surveillance after surgery forcolorectal cancer. Int J Colorectal Dis. 2012 Aug;27(8):1087-93.
7: Emoto S, Yamaguchi H, Kishikawa J, Yamashita
H, Ishigami H, Kitayama J.Antitumor effect andpharmacokinetics of intraperitoneal NK105, a
nanomicellar paclitaxel formulation for peritoneal
dissemination. Cancer Sci. 2012 Jul;103(7):130410. PubMed PMID: 22429777.
8: Kazama S, Hongo K, Sunami E, Sugawara Y,
Kokudo N, Kitayama J. Six cases of primarycolorectal cancer after living-donor liver transplantation: a single-institution experience in Japan.
Jpn J Clin Oncol. 2012 Jul;42(7):586-90.
9: Miyato H, Kitayama J, Nagawa H. Vagus nerve
preservation results in visceral fat maintenanceafter distal gastrectomy. Hepatogastroenterology.

2012 Jun;59(116):1299-301.
10: Hiyoshi M, Tsuno NH, Otani K, Kawai K,
Nishikawa T, Shuno Y, Sasaki K, Hongo K,
Kaneko M, Sunami E, Takahashi K, Nagawa H,
Kitayama J. Adiponectin receptor 2 is negatively
associated with lymph node metastasis ofcolorectal cancer. Oncol Lett. 2012 Apr 1;3(4):756-760.
11: Murono K, Tsuno NH, Kawai K, Sasaki K, Hongo
K, Kaneko M, Hiyoshi M, Tada N, Nirei T,
Sunami E, Takahashi K, Kitayama J. SN-38
overcomes chemoresistance of colorectal cancer
cells induced by hypoxia, through HIF1alpha.
Anticancer Res. 2012 Mar;32(3):865-72.
12: Sasaki K, Kazama S, Sunami E, Tsuno NH,
Nozawa H, Nagawa H, Kitayama J.One-stage
segmental colectomy and primary anastomosis
after intraoperative colonic irrigation and totalcolonoscopy for patients with obstruction due toleft-sided colorectal cancer. Dis Colon Rectum.
2012 Jan;55(1):72-8.
13: Kaneko M, Nozawa H, Sasaki K, Hongo K,
Hiyoshi M, Tada N, Murono K, Nirei T, Kawai K,
Sunami E, Tsuno NH, Kitayama J. Elevatedneutrophil to lymphocyte ratio predicts poor
prognosis in advanced colorectal cancer patients
receiving
oxaliplatin-based
chemotherapy.
Oncology. 2012;82(5):261-8.
14: Sasaki K, Kawai K, Tsuno NH, Sunami E,
Kitayama J. Impact of preoperative thrombo
cytosis on the survival of patients with primarycolorectal cancer. World J Surg. 2012 Jan;36(1):192-200.
15: Nozawa H, Sunami E, Nakajima J, Nagawa H,
Kitayama J. Synchronous and metachronous lungmetastases in patients with colorectal cancer: a
20-year monocentric experience. Exp Ther Med.
2012 3(3) : 449-56.
16: Watanabe T, KobunaiT, Yamamoto Y, Matsuda K,
Ishihara S, Nozawa K, Yamada H, Hayama T,
Inoue E, Iinuma H. Chromosomal instability(CIN) phenotype, CIN-high and CIN-low, predicts
survival for colorectal cancer. J clin Oncol. 30(18)17: Watanabe T, Sasaki I, Sugita A, Fukushima K,
Futami K, Hibi T, Watanabe M. Time trend andrisk factors for reoperation in Crohn’s disease inJapan. Hepatogastroenterology. 59(116) : 1081-6.

216

2012
18. Watanabe T, Itabashi M, Shimada Y, Tanaka S, Ito
Y, Ajioka Y, Hamaguchi T, Hyodo I, Igarashi M,
Ishida H, Ishiguro M, Kanemitsu Y, Kokudo N,
Muro K, Ochiai A, Oguchi M, Ohkura Y, Saito Y,
Sakai Y, Ueno H, Yoshino T, Fujimori T, Koinuma
N, Morita T, Nishimura G, Sakata Y, Takahashi K,
Takiuchi H, Tsuruta O, Yamaguchi T, Yoshida M,
Yamaguchi N, Kotake K, Sugihara K; JapaneseSociety for Cancer of the Colon and Rectum.
Japanese Society for Cancer of the Colon and
Rectum (JSCCR) guidelines 2010 for thetreatment of colorectal cancer. Int J clin Oncol.
17(1) : 1-29. 2012
19. Watanabe T, Kazama S, Nagawa H. A 1cm distalbowel margin is safe for rectal cancer after
preoperative radiotherapy. Hepatogastroenterology.
59 : 1068-74. 2012
20. Watanabe T, Matsuda K, Ishihara S, Nozawa K,
Hayama T, Yamada H, Iinuma H. Significance of
microsatellite instability (MSI) for colorectal
cancer following adjuvant therapy with
doxifluridine. Med Oncol. 29(1) : 133. 2012
21. Watanabe T, Sasaki I, Sugita A, Fukushima K,
Futami K, Hibi T, Watanabe M. Interval of lessthan 5 years between the first and second
operation is a risk factor for a third operation for
Crohn's disease. Inflamma Bowel Dis. 18(1) :17-24. 2012

217

Department of Vascular Surgery
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.,

Takuya Miyahara, M.D., Ph.D.,

Ayako Nishiyama, 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

218

surgeons who have completed their training in generalsurgery and wish to further specialize in vascularsurgery. The Department of Vascular Surgery has a
Vascular Surgery Training Program and provides
broad reaching experience in technical aspects ofvascular surgery, development of surgical judgment,
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. The
Department of Vascular Surgery is involved with theeducation program of the post-graduate education
meeting, which is held monthly. In addition to preand post-surgery clinical conferences, the residents are
expected to attend research conferences and seminars,
which are held periodically.

Research activities
The Department of Vascular Surgery includes major
research laboratories for academic development bothalong clinical and basic scientific lines. The clinicalvascular laboratories are approaching completely noninvasive testing for vascular disorders, analyzing
essential physiologic information about the specificproblems being addressed. The basic vascularlaboratories are actively performing research on
endothelial biology, the mechanism of intimal
hyperplasia, microcirculation, application of genetherapy to vascular surgery and vascular prosthesis
development. Vascular research meeting is held every
other Saturday morning. The following are the major
themes under research.
1) 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.
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.
17) Analysis of ambulatory system and muscle
mechanics in claudicants with peripheral arterydisease.

References
1. Hoshina K, Hosaka A, Takayama T, Kato M, ,Ohkubo N, Okamoto H, Shigematsu K, Miyata T.
Ourtcome after open surgery and endovascularaneurysm repair for abdominal aortic aneurysm inpatients with massive neck atheroma. Eur J Vasc
Endovasc Surg 2012;54:257-261.
2. Hoshina K, Kaneko M, Hosaka A, Okamoto H,
Shigematsu K, Miyata T. Lessons learned from acase of abdominal aortic aneurysm accompanied byunstable coagulopathy. Case Report Vasc Med.
2012; 2012:265860.doi:10.1155/2012/265860.
3. 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 delivasry to vascularlesions. Gene Ther. 2012;19:61-69.

219

4. Kamimura W, Hattori R, Koyama H, Miyata T,
Takato T. A calcium-cross-linked hydrogel based on
alginate-modified atelocollagen functions as a
scaffold material. J Biomater Sci Polym Ed 2012;23:609-623.
5. Morito H, Hoshina K, Hosaka A, Okamoto H,
Shigematsu K, Miyata T. Endovascular Surgery for
inflammatory abdominal aortic aneurysm with
contrast allergy – usefulness of carbon dioxide
angiography and intravascular ultrasound: A casereport. Ann Vasc dis. 2012;5:104-108.
6. Nishikawa Y, Hoshina K, Sasaki H, Hosaka A,
Yamamoto K, Okamoto H, Shigematsu K, Miyata T.
Acute remodeling of an adjoining aneurysm after
endovascular treatment of a ruptured splanchnicarterial aneurysm: A case of clinically diagnosed
segmental arterial mediolysis. Ann Vasc Dis. 2012;
5:449-453.
7. Yamamoto K, Fukui T, Matsuyama S, Tabata M,
Aramoto H, Takahashi S. Prior cardiac and thoracic
aortic surgery as a complication risk factor for
abdominal aortic aneurysm repair. Circ J. 2012;76:1380-1384.
8. Yamamoto K, Aramoto H, Asanao R, Yoshida T,
Yamada M, Takanashi S. Use of Zenith iliac plug toocclude an artificial graft during endovascular repairof an abdominal aortic aneurysm. Gazz Med Ital.
2012;171:357-359.

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

Associate Professor
Toshihisa Ogawa MD. PhD.

Lectuler
Keiichiro Tada MD. PhD.

Associates
Ei-ichi Tsuji MD.

Kotoe Nishioka MD. PhD

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.

221

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) Bacterial translocation 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 of postesophageal 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 than myoepithelial 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

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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

Yoshihiro Kuwano, M.D. Ph.D

Hospital Lecturer
Koichi Yanaba, M.D. Ph.D.

Tomonori Takekoshi, M.D.,Ph.D

Associate
Mayuko Araki, M.D.

Sayaka Shibata, M.D., Ph.D.

Masahiro Kamata, M.D., Ph.D.

Hayato Sumita, M.D., Ph.D.

Naohiko Aozasa, M.D., Ph.D.

Takuya Miyagawa, 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, two hospital lecturers and six associates takepart in inpatient and outpatient cares as well as
research and teaching activities. Forty-three doctors
who basically belong to our department are currently
out in affiliated hospitals mainly engaged in clinicalworks there. Additionally, four staff members areabroad at present, mainly involved in advanced
research activities in cell biology and molecularbiology.

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.

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In addition to series of lectures, clinical education
is 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.

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. Suga H, Sugaya M, Sato S: CCR3 expression in
lymphomatoid papulosis, but not in mycosis
fungoides from the same patient. Clin Exp
Dermatol. 37(1):75-77, 2012.
2. Kagami S, Kai H, Kakinuma T, Miyagaki T,
Kamata M, Sugaya M, Tamaki T, Sato S: Highlevels of CCL26 in blister fluid and sera ofpatients with bullous pemphigoid. J Invest
Dermatol. 132(1):249-251, 2012.
3. Taniguchi T, Asano Y, Hatano M, Tamaki Z,
Tomita M, Kawashima T, Miyazaki M, Sumida H,
Akamata K, Takahashi T, Ichimura Y, Toyama T,
Sugita M, Noda S, Yao A, Kinugawa K, Sato S:
Effects of bosentan on non-digital ulcers inpatients with systemic sclerosis. Br J Dermatol.
166(2):417-421, 2012.
4. Clark RA, Watanabe R, Teague JE, Schlapbach C,
Tawa M, Adams N, Dorosario A, Chaney K,
Cutler CS, LeBoeuf N, Carter JB, Fisher DC,
Kupper TS: Distinct recirculation patterns ofhuman central and effector memory T cells:
lessons from CTCL patients treated withalemtuzumab. Skin effector memory T cells do notrecirculate and provide immune protection in
alemtuzumab-treated CTCL patients. Sci Transl
Med. 4(117):117ra7, 2012.
5. Uratsuji H, Tada Y, Kawashima T, Kamata M, Hau
CS, Asano Y, Sugaya M, Kadono T, Asahina A,
Sato S, Tamaki K: P2Y6 receptor signaling
pathway mediates inflammatory responses
induced by monosodium urate crystals. J
Immunol. 188(1):436-444, 2012.
6. Kennedy-Crispin M, Billick E, Mitsui H, Gulati N,
Fujita H, Gilleaudeau P, Sullivan-Whalen M,
Johnson-Huang LM, Suárez-Fariñas M, Krueger
JG: Human keratinocytes have a response to injury
that upregulates CCL20 and other genes linking
innate and adaptive immunity. J Invest Dermatol.
132 (1):105-113, 2012.
7. Asahina A, Uno K, Fujita H: Sequential
occurrenceof
pemphigus
vulgaris
andpalmoplantar pustulosis: possible role of cytokine
profile. Acta Derm-Venereol. 92(1):89-90, 2012.
8. Yamamoto G, Hosoi M, Miyagawa T, Ohmatsu H,
Ichikawa M, Sugaya M, Kurokawa M: Evanssyndromewithcytomegalovirus
infection
followed by emerging peripheral T-cell lymphoma.
Ann Hematol. 91(1):123-124, 2012.
9. Asahina A, Shirai A, Horita A, Saito I: Annularelastolytic giant cell granuloma associated withprostate carcinoma: demonstration of human
metalloelastase-12 expression. Clin Exp Dermatol.
37(1):70-72, 2012.
10. Kamiyama T, Ohshima N, Satoh H, Fukumoto H,
Katano H, Imakado S: Metachronous merkel cell
carcinoma on both cheeks. Acta Derm-Venereol.
92(1):54-56, 2012.
11. Sugaya M, Kuwano Y, Suga H, Miyagaki T,
Ohmatsu H, Kadono T, Okochi H, Blauvelt A,
Tamaki K, Sato S: Lymphatic dysfunction impairs
antigen-specific immunization, but augments
tissue swelling following contact with allergens. J
Invest Dermatol. 132(3): 667-676, 2012.
12. Masui Y, Asano Y, Shibata S, Noda S, Aozasa N,
Akamata K, Yamada D, Tamaki Z, Tada Y, Sugaya
M, Sato S, Kadono T: Serum adiponectin levels
inversely correlate with the activity of progressive
skin sclerosis in patients with diffuse cutaneous

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systemic sclerosis. J Eur Acad Dermatol Venereol.
26(3):354-360, 2012.
13. Kamata M, Tada Y, Tatsuta A, Kawashima T,
Shibata S, Mitsui H, Asano Y, Sugaya M, Kadono
T, Kanda N, Watanabe S, Sato S: Serum lipocalin2 levels are increased in patients with psoriasis.
Clin Exp Dermatol. 37(3):296-299, 2012.
14. Taniguchi T, Asano Y, Akamata K, Noda S, Masui
Y, Yamada D, Takahashi T, Ichimura Y, Toyama T,
Tamaki Z, Tada Y, Sugaya M, Kadono T, Sato S:
Serum levels of galectin-3: possible association
with fibrosis, aberrant angiogenesis, and immune
activation in patients with systemic sclerosis. J
Rheumatol. 39(3):539-544, 2012.
15. Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T,
Sato S: Clinical significance of circulatingplatelet-activating factor acetylhydrolase levels in
systemic sclerosis. Arch Dermatol Res. 304(3):203-208, 2012.
16. Nishimura S, Manabe I, Nagasaki M, Kakuta S,
Iwakura Y, Takayama N, Ooehara J, Otsu M,
Kamiya A, Petrich B, Urano T, Kadono T, Sato S,
Aiba A, Yamashita H, Sugiura S, Kadowaki T,
Nakauchi H, Eto K, Nagai R: In vivo imaging
visualizes discoid platelet aggregations without
endothelium disruption and implicates contribution of inflammatory cytokine and integrin
signaling. Blood. 119(8):e45-56, 2012.
17. Miyagaki T, Sugaya M, Suga H, Morimura S,
Ohmatsu H, Fujita H, Asano Y, Tada Y, Kadono T,
Sato S: Low HVEM expression on dermal
fibroblasts contributes to a Th2-dominant microenvironment in advanced cutaneous T cell
lymphoma. J Invest Dermatol. 132(4):1280-1289,
2012.
18. Noda S, Asano Y, Akamata K, Aozasa N,
Taniguchi T, Takahashi T, Ichimura Y, Toyama T,
Sumida H, Yanaba K, Tada Y, Sugaya M, Kadono
T, Sato S: A possible contribution of alteredcathepsin B expression to the development of skinsclerosis and vasculopathy in systemic sclerosis.
PLoS One. 7(2):e32272, 2012.
19. Fujimoto M, Hamaguchi Y, Kaji K, Matsushita T,
Ichimura Y, Kodera M, Ishiguro N, UedaHayakawa I, Asano Y, Ogawa F, Fujikawa K,
Miyagi T, Mabuchi E, Hirose K, Akimoto N, Hatta
N, Tsutsui K, Higashi A, Igarashi A, Seishima M,

Hasegawa M, Takehara K: Myositis-specific anti155/140 autoantibodies target transcription intermediary factor 1 family proteins. Arthritis Rheum.
64(2):513-522, 2012.
20. Taniguchi T, Sugaya M, Miyagaki T, Kogure A,
Takekoshi T, Asano Y, Mitsui H, Sato S: Leukemic
variant of cutaneous T cell lymphoma with CD3CD4+ phenotype. Clin Exp Dermatol. 37(4)：443-445, 2012.
21. Miyagaki T, Sugaya M, Kamata M, Suga H,
Morimura S, Tatsuta A, Uwajima Y, Yamamoto M,
Shibata S, Fujita H, Asano Y, Kadono T, Sato S,
Tada Y: Serum angiogenin levels are decreased inpatients with psoriasis. Clin Exp Dermatol.
37(7):792-793, 2012.
22. Fujita H, Suárez-Fariñas M, Gonzalez J, Mitsui H,
Bruce MJ, Johnson-Huang LM, Fuentes-Duculan J,
Krueger JG, Carucci JA: Langerhans cells fromhuman cutaneous squamous cell carcinoma induce
strong type 1 immunity.J Invest Dermatol. 132(6):1645-1655, 2012.
23. Mitsui H, Suárez-Fariñas M, Levenkova N,
Fuentes-Duculan J, Belkin D, Cardinale I, Costs I,
Fujita H, Krueger JG: Combined use of laser
capture microdissection and cDNA microarray
analysis identifies locally expressed diseaserelated genes in focal regions of psoriasis vulgaris
skin lesions. J Invest Dermatol. 132(6):1615-1626,
2012.
24. Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T,
Hamaguchi Y, Sato S: Increased serum soluble
CD147 levels in patients with systemic sclerosis :association with scleroderma renal crisis. Clin
Rheumatol. 31(5):835-839, 2012.
25. Ohmatsu H, Sugaya M, Suga H, Morimura S,
Miyagaki T, Kai H, Kagami S, Fujita H, Asano Y,
Tada Y, Kadono T, Sato S: Serum IL-31 levels are
increased in patients with cutaneous T-cell
lymphoma. Acta Derm-Venereol. 92(3):282-283,
2012.
26. Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T,
Sato S: A possible contribution of elevated serum
clusterin levels to the development of digitalulcers and pulmonary arterial hypertension insystemic sclerosis. Arch Dermatol Res. 304(6):459-463, 2012.

226

27. Yamada D, Asano Y, Takahashi T, Masui Y,
Aozasa N, Akamata K, Noda S, Tamaki Z, Tada Y,
Sugaya M, Sato S, Kadono T: Clinical significanceof serum decoy receptor 3 levels in patints withsystemic sclerosis. Eur J Dermatol. 22(3):351357, 2012.
28. Kanda N, Hau CS, Tada Y, Sato S, Watanabe S:
Decreased serum LL-37 and vitamin D3 levels in
atopic dermatitis: relationship to IL-31 andoncostatin M. Allergy. 67(6):804-812, 2012.
29. Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T,
Sato S: Proteasome inhibitor bortezomib ameliorates intestinal injury in mice. PLoS One. 7(3):e34587, 2012.
30. Miyagaki T, Sugaya M, Miyamoto A, Tamaki K,
Ota S, Sato S: A case of primary cutaneous
anaplastic large cell lymphoma with prominent
epidermotropism. Int J Hematol. 95(6):711-715,
2012.
31. Ohmatsu H, Sygaya M, Miyagaki T, Suga H,
Fujita H, Asano Y, Kadono T, Sato S: BAFF levels
are increased in lesional skin and sera in patientswith cutaneous T cell lymphoma. Br J Dermatol.
167(2): 359-367, 2012.
32. Hasebe N, Kawasaki A, Ito I, Kawamoto M,
Hasegawa M, Fujimoto M, Furukawa H, Tohma S,
Sumida T, Takehara K, Sato S, Kawaguchi Y,
Tsuchiya N: Association of UBE2L3 polymorphisms with diffuse cutaneous systemicsclerosis in a Japanese population. Ann Rheum
Dis. 71(7):1259-1260, 2012.
33. Takeuchi S, Saeki H, Tokunaga S, Sugaya M,
Ohmatsu H, Tsunemi Y, Torii H, Nakamura K,
Kawakami T, Soma Y, Gyotoku E, Hide M, Sasaki
R, Ohya Y, Kido M, Furue M: A randomized,
open-labeled, multicenter trial of topicaltacrolimus for treatment of pruritus in patientswith atopic dermatitis. Ann Dermatol. 24(2):144150, 2012.
34. Miyagaki T, Sugaya M, Suga H, Akamata K,
Ohmatsu H, Fujita H, Asano Y, Tada Y, Kadono T,
Sato S: Angiogenin levels are increased in lesional
skin and sera in patients with erythrodermic
cutaneous T cell lymphoma. Arch Dermatol Res.
304(5):401-406, 2012.
35. Yanaba K, Asano Y, Noda S, Akamata K, Aozasa
N, Taniguchi T, Takahashi T, Ichimura Y, Toyama

T, Sumida H, Kuwano Y, Tada Y, Sugaya M,
Kadono T, Sato S: Augmented production ofsoluble CD93 in patients with systemic sclerosis
and clinical association with severity of skinsclerosis. Br J Dermatol. 167(3):542-547, 2012.
36. Sugaya M, Miyagaki T, Ohmatsu H, Suga H, Kai
H, Kamata M, Fujita H, Asano Y, Tada Y, Kadono
T, Okochi H, Sato S: Association of the numbersof CD163+ cells in lesional skin and serum levelsof soluble CD163 with disease progression of
cutaneous T cell lymphoma. J Dermatol Sci.
68(1):45-51, 2012.
37. Shibata S, Tada Y, Asano Y, Hau CS, Kato T, Saeki
H, Yamauchi T, Kubota N, Kadowaki T, Sato S:
Adiponectin regulates cutaneous wound healing
by promoting keratinocyte proliferation andmigration via the ERK signaling pathway. J
Immunol. 189(6):3231-3241, 2012.
38. Sundd P, Gutierrez E, Koltsova EK, Kuwano Y,
Fukuda S, Pospieszalska MK, Groisman A, Ley K:'Slings' enable neutrophil rolling at high shear.
Nature. 488(7411):399-403, 2012.
39. Noda S, Asano Y, Akamata K, Aozasa N,
Taniguchi T, Takahashi T, Ichimura Y, Toyama T,
Sumida H, Yanaba Y, Tada Y, Sugaya M, Kadono
T, Sato S: Constitutive activation of c-Abl/protein
kinase C- /Fli pathway in dermal fibroblasts
derived from patients with localized scleroderma.
Br J Dermatol. 167(5):1098-105, 2012.
40. Takekoshi T, Ziarek JJ, Volkman BF, Hwang ST: A
locked, dimeric CXCL12 variant effectively inhibits pulmonary metastasis of CXCR4-expressing
melanoma cells due to enhanced serum stability.
Mol Cancer Ther. 11(11):2516-25, 2012.
41. Yoshizaki A*, Miyagaki T*, DiLillo DJ,
Matsushita T, Horikawa M, Kountikov EI, Spolski
R, Poe JC, Leonard WJ, Tedder TF: Regulatory B
cells control T cell autoimmunity through IL-21dependent cognate interactions. Nature. 491(7423):264-8, 2012.
42. Ishibashi Y, Takara Y, Tsukamoto M, Kinugasa S,
Sugaya M, Takazawa Y, Kume H, Fujita T:
Epithelium is absent from the subcutaneous tunnel
in long-term peritoneal dialysis patients:. Perit
Dial Int. 32(6):652-6, 2012.

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Department of Plastic andReconstructive Surgery
Professor
Isao Koshima, M.D., Ph.D.

Lecturer
Kotaro Yoshimura, M.D., Ph.D.

Takuya Iida, M.D., Ph.D.

Associate
Mitsunaga Narushima, M.D.

Makoto Mihara, M.D.

Yukio Seki, M.D.

Kazuki Kikuchi, M.D.

Takumi Yamamoto, M.D.

Hisako Hara, 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, 2 lecturer, 6 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
the field of plastic surgery and attending outpatient
clinics, surgical operations and clinical lectures by

228

faculty 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 (2012)1:

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.

2:

3.

4.

5.

6.

7.

8.

Sequential Anastomosis for Lymphatic Supermicrosurgery: Multiple Lymphaticovenular Anastomoses
on 1 Venule.
Yamamoto T, Yoshimatsu H, Narushima M,
Yamamoto N, Shim TW, Seki Y, Kikuchi K, Karibe
J, Azuma S, Koshima I.
Ann Plast Surg. 2012 Dec 13. [Epub ahead of print]
Minimally Invasive Lymphatic Supermicrosurgery:Indocyanine Green Lymphography-Guided Simultaneous Multisite Lymphaticovenular Anastomoses
via Millimeter Skin Incisions.
Yamamoto T, Narushima M, Yoshimatsu H, Seki Y,
Yamamoto N, Oka A, Hara H, Koshima I.
Ann Plast Surg. 2012 Dec 13. [Epub ahead of print]
Effective treatment of pelvic lymphocele bylymphaticovenular anastomosis.
Todokoro T, Furniss D, Oda K, Kawana K,
Narushima M, Mihara M, Kikuchi K, Hara H, Yano
T, Koshima I.
Gynecol Oncol. 2013 Feb; 128(2): 209-14. doi:
10.1016/j.ygyno.2012.11.014. Epub 2012 Nov 16.
LEC score: a judgment tool for indication of
indocyanine green lymphography.
Yamamoto T, Yamamoto N, Yoshimatsu H,
Narushima M, Koshima I.
Ann Plast Surg. 2013 Feb;70(2):227-30.
Versatility of a near-infrared vein visualization
device in plastic and reconstructive surgery.
Iida T, Mihara M, Yoshimatsu H, Hara H,
Narushima M, Koshima I.
Plast Reconstr Surg. 2012 Oct;130(4):636e-638e.
A modified side-to-end lymphaticovenular anastomosis.
Yamamoto T, Yoshimatsu H, Narushima M, Seki Y,
Yamamoto N, Shim TW, Koshima I.
Microsurgery. 2013 Feb;33(2):130-3.
Reconstruction of an extensive anterior skull basedefect using a muscle-sparing rectus abdominis
myocutaneous flap in a 1-year-old infant.
Iida T, Mihara M, Yoshimatsu H, Hara H, Koshima
I, Kawai K, Tsuchiya T, Asakage T.
Microsurgery. 2012 Nov;32(8):622-6.
Reconstruction of the external auditory canal using
a super-thin superficial circumflex iliac perforator
flap after tumour resection.

229

9.

10.

11.

12.

13.

14.

15.

Iida T, Mihara M, Yoshimatsu H, Narushima M,
Koshima I.
J Plast Reconstr Aesthet Surg. 2013 Mar;66(3):430-3. doi: 10.1016/j.bjps.2012.08.005. Epub 2012
Sep 10.
The development of a canine anorectal autotransplantation model based on blood supply: apreliminary case report.
Araki J, Nishizawa Y, Nakamura T, Sato T, Naito M,
Fujii S, Mihara M, Koshima I.
PLoS One. 2012;7(9):e44310.
Low-invasive lymphatic surgery and lymphatic
imaging for completely healed intractable pudendal
lymphorrhea after gynecologic cancer treatment.
Mihara M, Hara H, Narushima M, Mitsui K, Murai
N, Koshima I.
J Minim Invasive Gynecol. 2012 Sep-Oct;19(5):658-62.
Pathological steps of cancer-related lymphedema:histological changes in the collecting lymphatic
vessels after lymphadenectomy.
Mihara M, Hara H, Hayashi Y, Narushima M,
Yamamoto T, Todokoro T, Iida T, Sawamoto N,
Araki J, Kikuchi K, Murai N, Okitsu T, Kisu I,
Koshima I.
PLoS One. 2012;7(7):e41126.
Antegrade and retrograde lymphatico-venous
anastomosis for cancer-related lymphedema withlymphatic valve dysfuction and lymphatic varix.
Mihara M, Hara H, Iida T, Todokoro T, Yamamoto
T, Narushima M, Tashiro K, Murai N, Koshima I.
Microsurgery. 2012 Oct;32(7):580-4.
Handheld thermography for flap monitoring.
Yamamoto T, Todokoro T, Koshima I.
J Plast Reconstr Aesthet Surg. 2012 Dec;65(12):1747-8.
Versatility of the Superficial Circumflex Iliac Artery
Perforator Flap in Head and Neck Reconstruction.
Iida T, Mihara M, Yoshimatsu H, Narushima M,
Koshima I.
Ann Plast Surg. 2012 Aug 3. [Epub ahead of print]
Scarless lymphatic venous anastomosis for latentand early-stage lymphoedema using indocyanine
green lymphography and non-invasive instrumentsfor visualising subcutaneous vein.
Mihara M, Hara H, Kikuchi K, Yamamoto T, Iida T,
Narushima M, Araki J, Murai N, Mitsui K, Gennaro

16.

17.

18.

19.

20.

21.

22.

P, Gabriele G, Koshima I.
J Plast Reconstr Aesthet Surg. 2012 Nov;65(11):1551-8.
Presence of thoracic duct abnormalities in patientswith primary lymphoedema of the extremities.
Hara H, Mihara M, Okuda I, Hirota A, Narushima
M, Iida T, Yamamoto T, Todokoro T, Koshima I.
J Plast Reconstr Aesthet Surg. 2012 Nov;65(11):e305-10.
Indocyanine green (ICG) lymphography is superior
to lymphoscintigraphy for diagnostic imaging of
early lymphedema of the upper limbs.
Mihara M, Hara H, Araki J, Kikuchi K, Narushima
M, Yamamoto T, Iida T, Yoshimatsu H, Murai N,
Mitsui K, Okitsu T, Koshima I.
PLoS One. 2012;7(6):e38182.
Uterine autotransplantation in cynomolgus macaques: the first case of pregnancy and delivery.
Mihara M, Kisu I, Hara H, Iida T, Araki J, Shim T,
Narushima M, Yamamoto T, Moriguchi H, Kato Y,
Tonsho M, Banno K, Aoki D, Suganuma N,
Kagawa N, Takehara Y, Kato O, Koshima I.
Hum Reprod. 2012 Aug;27(8):2332-40.
Perforator-bridged lymphaticovenular anastomosis.
Yoshimatsu H, Yamamoto T, Narushima M, Iida T,
Koshima I.
J Plast Reconstr Aesthet Surg. 2012 Oct;65(10):1438-9.
Famotidine suppresses osteogenic differentiation of
tendon cells in vitro and pathological calcificationof tendon in vivo.
Yamamoto K, Hojo H, Koshima I, Chung UI,
Ohba S.
J Orthop Res. 2012 Dec;30(12):1958-62.
Upper-limb lymphedema treated aesthetically withlymphaticovenous anastomosis using indocyanine
green lymphography and noncontact vein visualization.
Mihara M, Hara H, Hayashi Y, Iida T, Araki J,
Yamamoto T, Todokoro T, Narushima M, Murai N,
Koshima I.
J Reconstr Microsurg. 2012 Jun;28(5):327-32.
A new device expanding operability of fingertip
replantation: subzone 1 fingertip replantation assisted by non-enhanced angiography in a 2-year-oldboy.
Yoshimatsu H, Yamamoto T, Seki Y, Narushima M,

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23.

24.

25.

26.

27.

28.

29.

Iida T, Koshima I.
J Plast Reconstr Aesthet Surg. 2012 Nov;65(11):1592-4.
Preexcisional artery reconstruction: a new strategy
in multiple hepatic artery reconstruction for
reducing ischemic injury of the liver.
Iida T, Mihara M, Narushima M, Yoshimatsu H,
Hara H, Koshima I.
Microsurgery. 2012 Sep;32(6):493-6.
Autologus groin lymph node transfer for “sentinel
lymph network” reconstruction after head-and-neckcancer resection and neck lymph node dissection: acase report.
Mihara M, Iida T, Hara H, Hayashi Y, Yamamoto T,
Narushima M, Hayami S, Sawamoto N, Naito M,
Koshima I.
Microsurgery. 2012 Feb;32(2):153-7.
Blood glucose measurement in flap monitoring forsalvage of flaps from venous thrombosis.
Hara H, Mihara M, Iida T, Narushima M,
Koshima I.
Plast Reconstr Surg. 2012 Mar;129(3):587e-589e.
Infrared fluorescence imaging of lymphatic regeneration in nonhuman primate facial vascularizedcomposite allografts.
Mundinger GS, Narushima M, Hui-Chou HG, Jones
LS, Ha JS, Shipley ST, Drachenberg CB, Dorafshar
AH, Koshima I, Bartlett ST, Barth RN, Rodriguez
ED.
Ann Plast Surg. 2012 Mar;68(3):314-9.
Instruments for supermicrosurgery in Japan.
Mihara M, Hayashi Y, Iida T, Narushima M,
Koshima I.
Plast Reconstr Surg. 2012 Feb;129(2):404e-406e.
Lower limb lymphedema treated with lymphaticovenous anastomosis based on pre- and intraoperative icg lymphography and non-contact vein
visualization: A case report.
Mihara M, Hara H, Narushima M, Hayashi Y,
Yamamoto T, Oshima A, Kikuchi K, Murai N,
Koshima I.
Microsurgery. 2012 Mar;32(3):227-30.
Dynamic reconstruction of full-thickness abdominal
wall defects using free innervated vastus lateralis
muscle flap combined with free anterolateral thighflap.
Iida T, Mihara M, Narushima M, Todokoro T, Hara

30.

31.

32.

33.

34.

35.

36.

37.

H, Yoshimatu H, Koshima I, Kadono T.
Ann Plast Surg. 2013 Mar;70(3):331-4.
Recent advancement on surgical treatments for
lymphedema.
Koshima I, Narushima M, Yamamoto Y, Mihara M,
Iida T.
Ann Vasc Dis. 2012;5(4):409-15.
Lymphatic-venous anastomosis for the radical cureof a large pelvic lymphocyst.
Mihara M, Hayashi Y, Hara H, Todokoro T,
Koshima I, Murai N.
J Minim Invasive Gynecol. 2012 Jan-Feb;19(1):125-7.
Prevention of intubation-induced mucosal damage
using a tube coated with 2-methacryloyloxyethyl
phosphorylcholine polymer.
Ito S, Shimohata N, Iwanaga S, Ito W, Ohba M,
Mochizuki M, Nakagawa T, Suzuki S, Sasaki N,
Koshima I, Chung UI.
Eur J Anaesthesiol. 2012 Feb;29(2):100-4.
Reconstruction of the larynx and aryepiglottic foldusing a free radial forearm tendocutaneous flap
after partial laryngopharyngectomy: a case report.
Mihara M, Iida T, Hara H, Hayashi Y, Yamamoto T,
Mitsunaga N, Todokoro T, Uchida G, Koshima I.
Microsurgery. 2012 Jan;32(1):50-4.
Adipofascial turnover perforator flap for dorsal
hand reconstruction based on both the posterior
interosseous artery and radial artery.
Suzuki S, Iwamoto T, Koshima I.
J Hand Surg Eur Vol. 2012 Feb;37(2):178-80.
A simple method for preventing pharyngocutaneous
fistula after pharyngolaryngectomy using amesenteric turnover flap.
Iida T, Mihara M, Narushima M, Koshima I.
J Plast Reconstr Aesthet Surg. 2012 Jun;65(6):830-1.
Using indocyanine green fluorescent lymphography
and lymphatic-venous anastomosis for cancerrelated lymphedema.
Mihara M, Murai N, Hayashi Y, Hara H, Iida T,
Narushima M, Todokoro T, Uchida G, Yamamoto T,
Koshima I.
Ann Vasc Surg. 2012 Feb;26(2):278.e1-6.
A sensate superficial circumflex iliac perforator flap
based on lateral cutaneous branches of theintercostal nerves.

231

38.

39.

40.

41.

42.

43.

44.

45.

Iida T, Mihara M, Narushima M, Koshima I.
J Plast Reconstr Aesthet Surg. 2012 Apr;65(4):538-40.
1α,25-dihydroxyvitamin D3 modulates thehair-inductive capacity of dermal papilla cells:
therapeutic potential for hair regeneration.
Aoi N, Inoue K, Chikanishi T, Fujiki R, Yamamoto
H, Kato H, Eto H, Doi K, Itami S, Kato S,
Yoshimura K.
Stem Cells Transl Med. 2012 Aug;1(8):615-26.
Characterization of human adipose tissue-resident
hematopoietic cell populations reveals a novel
macrophage subpopulation with CD34 expression
and mesenchymal multipotency.
Eto H, Ishimine H, Kinoshita K, Watanabe-Susaki
K, Kato H, Doi K, Kuno S, Kurisaki A, Yoshimura
K.
Stem Cells Dev. 2013 Mar 15;22(6):985-97.
Isolation and characterization of human hair follicle
epithelial cells.
Inoue K, Yoshimura K.
Methods Mol Biol. 2013;946:411-21.
Aging-like skin changes in metabolic syndromemodel mice are mediated by mineralocorticoid
receptor signaling.
Nagase T, Akase T, Sanada H, Minematsu T, Ibuki
A, Huang L, Asada M, Yoshimura K, Nagase M,
Shimada T, Aburada M, Nakagami G, Sugama J.
Aging Cell. 2013 Feb;12(1):50-7.
Novel models for bacterial colonization andinfection of full-thickness wounds in rats.
Asada M, Nakagami G, Minematsu T, Nagase T,
Akase T, Huang L, Yoshimura K, Sanada H.
Wound Repair Regen. 2012 Jul-Aug;20(4):601-10.
Stromal vascular fraction isolated from lipoaspirates using an automated processing system:
bench and bed analysis.
Doi K, Tanaka S, Iida H, Eto H, Kato H, Aoi N,
Kuno S, Hirohi T, Yoshimura K.
J Tissue Eng Regen Med. 2012 Mar 22.
The fate of adipocytes after nonvascularized fat
grafting: evidence of early death and replacement of
adipocytes.
Eto H, Kato H, Suga H, Aoi N, Doi K, Kuno S,
Yoshimura K.
Plast Reconstr Surg. 2012 May;129(5):1081-92.
Mammographic changes after fat transfer to thebreast compared with changes after breast
reduction: a blinded study.
Rubin JP, Coon D, Zuley M, Toy J, Asano Y, Kurita
M, Aoi N, Harii K, Yoshimura K.
Plast Reconstr Surg. 2012 May;129(5):1029-38.
46. Skin fragility in obese diabetic mice: possible
involvement of elevated oxidative stress andupregulation of matrix metalloproteinases.
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.
Exp Dermatol. 2012 Mar;21(3):178-83.
47. Novel biomarkers for the detection of wound
infection by wound fluid RT-PCR in rats.
Asada M, Nakagami G, Minematsu T, Nagase T,
Akase T, Huang L, Yoshimura K, Sanada H.
Exp Dermatol. 2012 Feb;21(2):118-22.

232

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.

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

Noriko Hatano, D.D.S., Ph.D.

Takato Inokuchi, D.D.S., Ph.D.

Madoka Sugiyama, D.D.S.

Yuki Kanno, 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 the regener-

ative abilities of tissues such as bone, periosteum,
cartilage, perichondrium, vessels, nerve, and skin. At
present, we are focusing on tissue engineering inresearch works especially in bone, cartilage andvessels. Professor Takato had established Tissue
Engineering Division in the University of Tokyo
Hospital and our department has an endowment
department: Department of Cartilage and BoneRegeneration (FUJI SOFT Inc.). The department has 1
associate professor, 1 assistant professor, and several
graduate students. These staffs are focusing ontranslational research works in maxillofacial regions.

Clinical activities
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.

233

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.
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 patients.

Education
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 bedsidelearning in final year. Through these curriculums, wedemonstrate the characteristics and treatments of thediseases in oral-maxillofacial region. Teaching isfocused on following points; congenital anomalies
such as cleft lip and palate and branchial arch
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. Tooth extractions and orthodontic treatment are instructed by oral surgeons and orthodontists.
Medical cares in the ward are taught by medical
doctors and oral surgeons.
After two-year residential course, research training
at postgraduate school is positively recommended.
Our aim 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) Treatment of facial deformities and malocclusionin patients with cleft lip/palate
2) Research on facial growth in patients withcraniofacial anomalies
3) Reconstruction of oral and maxillofacial area bycustom-made artificial bone (CT bone) (clinical
trial)
4) Transplantation of implant-type tissue-engineered
cartilage for cleft lip-nose patients (clinical study)5) Management of occlusion in patients withfibrodysplasia ossificans progressiva (FOP)2346) QOL study of oral health care system inpreoperative cancer patients
7) Clinical study of antifungal susceptibility inpatients with oral candidiasis
Basic and experimental research:
1) Regeneration of bone and cartilage with tissueengineering approach2) Development of intelligent artificial bone with theability of bone induction3) Development of micro-tetrapod bone implant4) Molecular biology of cartilage repair and its
application to cartilage regenerative medicine
5) Cartilage regenerative medicine using iPS cells6) Development of novel scaffolds for cartilage andbone regeneration
7) In vivo evaluation of tissue-engineered cartilage
and bone8) Study on the control of mesenchymal celldifferentiation
9) Elucidation of epigenetic abnormalities in oral
cancers and oral premalignant lesions
10) Elucidation of sphingosine-1-phosphate signaling
and its role in multistage oral cancer11) Functional analysis of microRNAs in humandental pulp stem cells

Publications
1. 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. 2012 Jan; 33(2):444-54.
2. 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. 2012 Jan; 50(1):226-36.
3. 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. 2012 Jan;19(1):61-9.

4. Deno M, Tashiro M, Miyashita M, Asakage T,
Takahashi K, Saito K, Busujima Y, Mori Y,
Saito H, Ichikawa Y. The mediating effects ofsocial support and self-efficacy on the relationshipbetween social distress and emotional distress inhead and neck cancer outpatients with facialdisfigurement. Psychooncology. 2012 Feb;21(2):144-52.
5. Tanaka Y, Saijo Y, Fujihara Y, Yamaoka H,
Nishizawa S, Nagata S, Ogasawara T, Asawa Y,
Takato T, Hoshi K. Evaluation of the implant typetissue-engineered cartilage by scanning acoustic
microscopy. J Biosci Bioeng. 2012 Feb;113(2):252-7.
6. Ko EC, Fujihara Y, Ogasawara T, Asawa Y,
Nishizawa S, Nagata S, Takato T, Hoshi K.
BMP-2 embedded atelocollagen scaffold fortissue-engineered cartilage cultured in themedium containing insulin and triiodothyronine--a new protocol for three-dimensional in vitro
culture of human chondrocytes. Tissue Eng Part C
Methods. 2012 May;18(5):374-86.
7. 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. 2012 May;49(3):291-8.
8. Hojo H, Ohba S, Yano F, Saito T, Ikeda T,
Nakajima K, Komiyama Y, Nakagata N, Suzuki K,
Takato T, Kawaguchi H, Chung UI. Gli1 protein
participates in Hedgehog-mediated specificationof osteoblast lineage during endochondral
ossification. J Biol Chem. 2012 May 18;287(21):17860-9.
9. Mori Y, Susami T, Saijo H, Okubo K, Uchino N,
Hoshi K, Takato T: Mandibular body ostectomy
for correction of mandibular prognathism – atechnical note. Oral Sci Int. 2012 May; 9(1):21-5.
10. Okayasu M, Nakayachi M, Hayashida C, Ito J,
Kaneda T, Masuhara M, Suda N, Sato T, Hakeda
Y. Low-density lipoprotein receptor deficiency
causes impaired osteoclastogenesis and increasedbone mass in mice because of defect inosteoclastic cell-cell fusion. J Biol Chem. 2012
Jun 1;287(23):19229-41.
11. Ochiai H, Okada S, Saito A, Hoshi K, Yamashita235

H, Takato T, Azuma T. Inhibition of insulin-likegrowth factor-1 (IGF-1) expression by prolonged
transforming growth factor-β1 (TGF-β1) administration suppresses osteoblast differentiation: J
Biol Chem. 2012 Jun 29;287(27):22654-61.
12. 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 the roundrobin test for assessment of in vitro chondrogenesis evaluation protocol in a tissue-engineered
medical product. J Tissue Eng Regen Med. 2012
Jul;6(7):550-8.
13. Susami T, Mori Y, Tamura K, Ohkubo K,
Nagahama K, Takahashi N, Uchino N, Uwatoko K,
Haga N, Takato T. Facial morphology and occlusion in a patient with fibrodysplasia ossifficans
progressiva (FOP): Growth follow-up from 8 to
21 years of age. Spec Care Dentist.2012 Jul-Aug;
32(4): 165-70.
14. Sato T, Nakamoto A, Hori N, Enoki Y, Fukushima
Y, Nakamoto N, Sakata Y, Yamanaka H, Chida D,
Abe T, Yoda T. Proteomic analysis of masticatory
muscle tendon–aponeurosis hyperplasia: A preliminary study using a 2D-DIGE system. J Oral
Maxillofac Surg Med Pathol. 2012 Nov; 24(4):185–8.
15. Abe M, Mori Y, Saijo H, Hoshi K, Ohkubo K,
Ono T, Takato T. The efficacy of dental therapy
for an adult case of Henoch-Schönlein Purpura.
Oral Sci Int. 2012 Nov; 9(2):59-62.
16. Matsuzaki Y, Kadota Y, Inoue K, Uzuka K,
Suenaga H, Sasaki K, Morita T. Non-contact
actuation of less-invasive bone lengthening device
using embedded cycloidal motor driven bypermanent magnets from the outside. Key Eng
Mater. 2012 Nov;(523-524): 722-6.
17. Sugiyama M, Saijo H, Hoshi K, Ohkubo K, MoriY, Takato T. Secondary repair of an obliquefacial cleft with an absorbable mesh tray andparticulate cancellous bone and marrow. Oral Sci
Int. 2012 Nov; 9(2):63-6.
18. Yonenaga K, Nishizawa S, Fujihara Y, Asawa Y,
Kanazawa S, Nagata S, Takato T, Hoshi K.
Application of floating cells for improved harvest
in human chondrocyte culture. Biomed Res.
2012;33(5):281-9.

19. 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.
2012;23(5):609-28.
20. Ogasawara T, Ohba S, Yano F, Kawaguchi H,
Chung UI, Saito T, Yonehara Y, Nakatsuka T,
Mori Y, Takato T, Hoshi K. Nanog promotes
osteogenic differentiation of the mouse mesenchymal cell line C3H10T1/2 by modulatingbone morphogenetic protein (BMP) signaling. J
Cell Physiol. (in press)
21. 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 with hemifacial
microsomia: a comparison between panoramic
radiography and three-dimensional computed
tomography. Cleft Palate Craniofac J. (in press)
22. Asawa Y, Sakamoto T, Komura M, Watanabe M,
Nishizawa S, Takazawa Y, Takato T, Hoshi K.
Early-stage foreign body reaction against
biodegradable polymer scaffolds affects tissue
regeneration during the autologous transplantationof tissue engineered cartilage in the canine model.
Cell Transplant. (in press)
23. Yano F, Hojo H, Ohba S, Fukai A, Hosaka Y,
Ikeda T, Saito T, Hirata M, Chikuda H, Takato T,
Kawaguchi H, Chung UI. A novel diseasemodifying osteoarthritis drug candidate targeting
Runx1. Ann Rheum Dis. (in press)
24. Saito T, Mashimo T, Shiratsuchi H, Namaki S,
Matsumoto K, Mori Y, Ogasawara T, Arai Y,
Honda K, Yonehara Y. Evaluation of regenerative
processes in a rat model of mandibular condyledefect using in vivo micro X-ray computed
tomography. J Hard Tissue Biol. (in press)
25. Saijo H, Kawase-Koga Y, Mori Y, Seto I, Abe M,
Ohkubo K, Hoshi K, Takato T. Application of
percutaneous zygomatic arch osteotomy for
protrusion deformity of the zygoma following
facial fracture surgery. J Oral Maxillofac Surg
Med Pathol. (in press)
26. Suenaga H, Unami M, Hoshi K, Mori Y, Takato T.
Rare case of composite embryonal rhabdomyosarcoma and leiomyosarcoma of the tongue of an
adult. J Oral Maxillofac Surg Med Pathol. (in236press)
27. Suenaga H, Unami M, Hoshi K, Mori Y, Takato T.
Ectopic mixed odontoma of the nasal cavity: A
rare case. J Oral Maxillofac Surg Med Pathol.
(in press)
28. Kadota Y, Inoue K, Uzuka K, Suenaga H, Morita
T. Non-contact operation of a miniature cycloid
motor by magnetic force. IEEE ASME Trans
Mechatron. (in press)
29. Hojo H, Ohba S, Taniguchi K, Shirai M, Yano F,
Saito T, Ikeda T, Nakajima K, Komiyama Y,
Nakagata N, Suzuki K, Mishina Y, Yamada M,
Konno T, Takato T, Kawaguchi H, Kambara H,
Chung UI. Hedgehog-Gli activators directosteochondrogenic function of bone morphogenetic
protein toward osteogenesis in the perichondrium.
J Biol Chem. (in press)
30. Hoshi K, Fujihara Y, Asawa Y, Nishizawa S,
Kanazawa S, Sakamoto T, Watanabe M,
Ogasawara T, Saijo H, Mori Y, Takato T. Recent
trends of cartilage regenerative medicine and its
application to the oral and maxillofacial surgery.
Oral Sci Int. (in press)

237

Department ofOrthopaedic Surgery
Professor
Sakae Tanaka, M.D., Ph.D.

Associate Professors
Hiroshi Kawaguchi, M.D., Ph.D.,

Katsushi Takeshita, M.D., Ph.D.

Lecturers
Hirotaka Kawano, M.D., Ph.D.

Hirotaka Chikuda, M.D., Ph.D.

Associates
Hideya Itoh, M.D.,

Nobuhiro Hara, M.D.,

Satoru Ohashi, M.D., Ph.D.,

Yusuke Shinoda, M.D., Ph.D.,

Yasushi Oshima, M.D., Ph.D.,

Tetsuro Yasui, M.D., Ph.D.,

Shuji Taketomi, M.D.,

Hiroshi Inui, M.D.,

Kensuke Nakamura, M.D,

Yasuhiko Koizumi, M.D.,

Yujiro Takeshita, M.D.,

Yutaka Morizaki, M.D.,

Kuniomi Sakai, M.D.,

Yoshitaka Matsubayashi, M.D.,

Hirofumi Oshima, M.D.,

Kosuke Uehara, M.D.,

Ryoko Sawada, 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 andindustrial 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 minimally invasive
surgery. We have recently been conducting manystudies related to the ossification of spinal ligaments

238(OPLL), rheumatoid arthritis, biomechanics, and thedegenerative skeletal disorders such as osteoporosis
and osteoarthritis in response to the progressive agingof our society.
Our department is now adept in the entire field of
medical science and medical practice related to thehuman locomotor system, the importance of which is
now clearly recognized not only in Japan, but also all
over the world. To meet the expanding needs ofsociety, we have been conducting the teaching,clinical, and research activities described below.
Faculty members of the department are one
professor, two associate professors, three lecturers, 18
associates, 6 medical staff members, 9 senior residents,
and 10 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 12 doctors-intraining completed our program during this fiscal
year. Since the training period is short, they areencouraged to experience emergency cases as often as
possible. A postgraduate seminar and a basic research
conference are held weekly.
Including the postgraduate training, a ten-year
course has been adopted with clinical and researchtraining taking place either in the University of Tokyo
Hospital or in our 50 affiliated hospitals.

Clinical activities
We have the outpatient clinic open from Monday
through Friday, with specialized divisions for spine,
hip, rheumatoid arthritis, tumor, scoliosis, limb
reconstruction and bone lengthening, knee, hand,elbow, shoulder, sports, peripheral nerves, bonesystemic disorders, and foot. A total of 37,410 patients
visited the outpatient clinic in 2012.
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.
1202 operations were performed in 2012. These
include 296 spine surgeries (including 88 cervicalspine surgeries, 140 thoracolumbar spine surgeries,and 45scoliosis surgeries), 72 surgeries for rheumatoid
arthritis patients, 129 hip surgeries, 238 knee surgeries(including 47 computer-assisted ACL reconstruction,
53 computer-assisted TKA, 37 UKA), 3 shoulder
surgeries, 195 hand surgeries, 6 limb lengthening andreconstruction surgeries using external fixators, 118
surgeries for bone and soft tissue tumor and 155

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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
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 system based on intraoperative threedimensional 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

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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 thegraduate 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 2012, we reported
the molecular mechanisms in which the GSK3 signal
regulates chondrocyte differentiation, and themechanisms of cartilage degradation by Notch
signaling. We are continuously researching the rolesof Notch and NF-kB signaling 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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Kawaguchi H, Matsuda S, Nakamura K. Mortality
and morbidity in dialysis-dependent patients
undergoing spinal surgery: analysis of a national
administrative database in Japan. J Bone Joint Surg
Am 2012;94(5):433-8.
2. Kanazawa T, Nishino J, Tohma S, Tanaka S.
Analysis of the affected joints in rheumatoid arthritis
patients in a large Japanese cohort. Mod Rheumatol.
2012 Mar 31. [Epub ahead of print]
3. Kato S. Hozumi T, Takeshita K, Kondo T, Goto T,
Yamakawa K. Neurological Recovery after Posterior
Decompression Surgery for Anterior Dural
Compression in Paralytic Spinal Metastasis.
Archives of Orthop Trauma Surg 2012;132(6):765-71.
4. Kato S, Takeshita K, Matsudaira K, Tonosu J, Hara
N, Chikuda H. Normative Score and Cut-off Valueof the Neck Disability Index. J Orthop Sci 2012;
17:687-93.
5. Shoda N, Yasunaga H, Horiguchi H, Kadono Y,
Matsuda S, Tanaka S. Surgical treatment reduces
in-hospital mortality after hip fracture: retrospective

analysis using the Japanese Diagnosis Procedure
Combination database. BMJ Open 2012;2:e000416
doi:10.1136/bmjopen-2011-000416
6. Itoh S, Saito T, Hirata M, Ushita M, Ikeda T,
Woodgett JR, Algül H, Schmid RM, Chung UI,Kawaguchi H. GSK-3α and GSK-3β proteins are
involved in early stages of chondrocyte differentiation with functional redundancy through RelA
protein phosphorylation. J Biol Chem. 287:29227-36,
2012.
7. Hojo H, Ohba S, Taniguchi K, Shirai M, Yano F,
Saito T, Ikeda T, Nakajima K, Komiyama Y,
Nakagata N, Suzuki K, Mishina Y, Yamada M,
Konno T, Takato T, Kawaguchi H, Kambara H,
Chung UI. Hedgehog-Gli activators direct osteochondrogenic function of bone morphogenetic
protein toward osteogenesis in the perichondrium. J
Biol Chem. 288:9924-32,2013.
8. Hojo H, Ohba S, Yano F, Saito T, Ikeda T, Nakajima
K, Komiyama Y, Nakagata N, Suzuki K, Takato T,
Kawaguchi H, Chung UI. Gli1 Protein Participatesin Hedgehog-mediated Specification of Osteoblast
Lineage during Endochondral Ossification. J Biol
Chem. 287:17860-9, 2012.
9. Hosaka Y, Saito T, Sugita S, Hikata T, Kobayashi H,
Fukai A, Taniguchi Y, Hirata M, Akiyama H, Chung
UI, Kawaguchi H. Notch signaling in chondrocytes
modulates endochondral ossification and osteoarthritis development. Proc Natl Acad Sci U S A.
110:1875-80,2013.
10. Jujo Y, Yasui T, Nagase Y, Kadono Y, Oka H, Tanaka
S. Patellar fracture after total knee arthroplasty forrheumatoid arthritis. J Arthroplasty 28: 40-43, 2013.
11. Masuda K, Chikuda H, Yasunaga H, Hara N,
Horiguchi H, Matsuda S, Takeshita K, Kawaguchi H,
Nakamura K. Factors affecting the occurrence ofpulmonary embolism after spinal surgery: data fromthe national administrative database in Japan. Spine
J 2012;12(11):1029-34.
12. Matsudaira K, Konishi H, Miyoshi K, Isomura T,
Takeshita K, Hara N, Yamada K, Machida H.
Potential Risk Factors for New-onset of Back Pain
Disability in Japanese Workers: Findings from theJapan Epidemiological Research of OccupationRelated Back Pain (JOB) Study. Spine 2012;37:
1324-33.
13. Matsumoto T, Nagase Y, Hirose J, Tokuyama N,

241

Yasui T, Kadono Y, Ueki K, Kadowaki T, Nakamura
K, Tanaka S. Regulation of bone-resorption andsealing zone formation in osteoclasts occurs throughAkt-mediated microtubule stabilization. J Bone
Miner Res. 2012 Dec 13. doi: 10.1002/jbmr.1844.
[Epub ahead of print]
14. Miyamoto H, Miura T, Morita E, Morizaki Y,
Uehara K, Ohe T, Tanaka S. Fungal arthritis of thewrist caused by Candida parapsilosis during
infliximab therapy for rheumatoid arthritis. Mod
Rheumatol. 2012 Feb 15. [Epub ahead of print]
15. Miyazaki T, Iwasawa M, Nakashima T, Mori S,
Shigemoto K, Nakamura H, Katagiri H, Takayanagi
H, Tanaka S. Intracellular and extracellular ATP
coordinately regulate the inverse correlation
between osteoclast survival and bone resorption. J
Biol Chem. 287:37808-23, 2012.
16. Mochizuki A, Takami M, Miyamoto Y, Nakamaki T,
Tomoyasu S, Kadono Y, Tanaka S, Inoue T, Kamijo
R. Cell Adhesion Signaling Regulates RANK
Expression in Osteoclast Precursors. PLoS One.
2012; 7(11): e48795. doi: 10. 1371/ journal. pone.
0048795. Epub 2012 Nov 6.
17. Muraki S, Akune T, Ishimoto Y, Nagata K, Yoshida
M, Tanaka S, Oka H, Kawaguchi H, Nakamura K,
Yoshimura N. Risk factors for falls in a longitudinal
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S, Takayanagi H. Class IA phosphatidylinositol
3-kinase regulates osteoclastic bone resorption

through protein kinase B-mediated vesicle transport.
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26. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Tanaka S, Akune T. Does mild
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Print 2012. PMID: 23166128 [PubMed - in process]242

Department of Ophthalmology
Professor
Shiro Amano, M.D., Ph.D.

Associate Professor
Satoshi Kato, M.D., Ph.D.

Miyuki Nagahara, M.D., Ph.D.,

Lecturer
Toshikatsu Kaburaki, M.D., Ph.D.,
Yasuo Yanagi, M.D., Ph.D.,

Tomohiko Usui, 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 byproducing significant basic research in ophthalmology.
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, neuro-ophthalmology, orthoptics, diabetic retinopathy, and genetic
and color blindness problems. The staff members
supervise the ambulatory and special services
depending on each one’s speciality.
Most of the inpatients suffer from cataract, glaucoma,
corneal diseases, retinal detachment, diabetic
retinopathy, uveitis and strabismus. Surgeries are
performed in the operating theater of the hospital
under operating microscopes. Approximately 2100
cases underwent operations in our department.
Surgeries can be monitored by TV system, which ismounted on operating microscopes. Since multiple
observers can watch the same images and sharefindings, this system has a great potential in training
and promoting discussion.

Teaching activities
As an undergraduate course, we give lectures on

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corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged inpractical training for medical students on
ophthalmological examinations at the outpatient clinic.
As a postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

Research activities
Research topics in our department cover a variety offields in ophthalmology; e.g. ocular pharmacology,
regenerative medicine in the cornea and retina,
aqueous humour dynamics, immunology andmolecular biology. Special laboratories for physiology,
pharmacology and genetic engineering have been
established. Specific fields of research in our
department are as follows.
1. Analysis with laser-speckle method of vascularflow in retina and iris
2. Clinical investigation of normal tension glaucoma
3. 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

References
1. Aihara M, Otani S, Kozaki J, Unoki K, Takeuchi M,
Minami K, Miyata K. Long-term effect of
BAK-free travoprost on ocular surface andintraocular pressure in glaucoma patients after
transition from latanoprost. J Glaucoma 21:60-64,
2012
2. Araie M, Shirato S, Yamazaki Y, Matsumoto C,
Kitazawa Y, Ohashi Y; Niprodilol-Timolol Study
Group. Risk factors for progression of normaltension glaucoma under β-blocker monotherapy.
Acta Ophthalmol 90:e337-e343, 2012
3. Arita R, Itoh K, Maeda S, Maeda K, Furuta A,
Tomidokoro A, Aihara M, Amano S. Effects oflong-term topical anti-glaucoma medications on
meibomian glands. Graefes Arch Clin Exp
Ophthalmol 250:1181-1185, 2012
4. Arita R, Itoh K, Maeda S, Maeda K, Furuta A,
Tomidokoro A, Aihara M, Amano S. Comparisonof the long-term effects of various topicalantiglaucoma medications on meibomian glands.
Cornea 31:1229-1234, 2012
5. Arita R, Itoh K, Maeda S, Maeda K, Tomidokoro
A, Amano S. Association of contact lens-related
allergic conjunctivitis with changes in themorphology of meibomian glands. Jpn J
Ophthalmol 56:14-19, 2012
6. Arita R, Yanagi Y, Honda N, Maeda S, Maeda K,
Kuchiba A, Yamaguchi T, Yanagihara Y, Suzuki
H, Amano S. Caffeine increases tear volume
depending on polymorphisms within the adenosine
A2a receptor gene and cytochrome P450 1A2.
Ophthalmology 119:972-978, 2012
7. Fujimura S, Takahashi H, Yuda K, Ueta T, Iriyama
A, Inoue T, Kaburaki T, Tamaki Y, Matsushima K,
Yanagi Y. Angiostatic effect of CXCR3 expressedon choroidal neovascularization. Invest Ophthalmol
Vis Sci 53:1999-2006, 2012
8. Fukuda R, Usui T, Tomidokoro A, Mishima K,
Magagi N, Miyai T, Amano S, Araie M.
Noninvasive obseracation of peripheral angle ineyes with penetrating keratoplasty using anterior
segment fourier-domain optical coherence tomography. Cornea 31:259-263, 2012
9. Hayashi K, Tomidokoro A, Lee KY, Konno S, Saito
H, Mayama C, Aihara M, Iwase A, Araie M.

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Spectral-domain optical coherence tomography ofß-zone peripapillary atrophy: influence of myopia
and glaucoma. Invest Ophthalmol Vis Sci 53:14991505, 2012
10. Ida Y, Sugita N, Ueta T, Tamaki Y, Tanimoto K,
Mitsuishi M. Microsurgical robotic system for
vitreoretinal surgery. Int J Comput Assist Radiol
Surg 7:27-34, 2012
11. Inoue K, Fujimoto T, Higa R, Moriyama R,
Kohmoto H, Nagumo H, Wakakura M, Tomita G.
Efficacy and safety of a switch to latanoprost
0.005%+timolol maleate 0.5% fixed combination
eyedrops from latanoprost 0.005% monotherapy.
Clin Ophthalmol 6:771-775, 2012
12. Inoue K, Iwasa M, Wakakura M, Tomita G. Effectsof BAK-free travoprost treatment for 3 years inpatients with normal tension glaucoma. Clin
Ophthalmol 6:1315-1319, 2012
13. Inoue K, Okayama R, Higa R, Wakakura M, Tomita
G. Assessment of ocular hypotensive effect andsafety 12 months after changing from an unfixed
combination to a latanoprost 0.005% + timolol
maleate 0.5% fixed combination. Clin Ophthalmol
6:607-612, 2012
14. Inoue K, Setogawa A, Higa R, Moriyama R,
Wakakura M, Tomita G. Ocular hypotensive effectand safety of travoprost 0.004%/timolol maleate
0.5% fixed combination after change of treatment
regimen from β-blockers and prostaglandin analogs.
Clin Ophthalmol 6:231-235, 2012
15. Inoue K, Shiokawa M, Higa R, Sugahara M, Soga T,
Wakakura M, Tomita G. Adverse periocular
reactions to five types of prostaglandin analogs. Eye
26:1465-1472, 2012
16. Inoue K, Shiokawa M, Sugahara M, Higa R,
Wakakura M, Tomita G. Iris and periocular adverse
reactions to bimatoprost in Japanese patients withglaucoma or ocular hypertension. Clin Ophthalmol
6:111-116, 2012
17. Inoue K, Shiokawa M, Sugahara M, Wakakura M,
Soeda S, Tomita G. Three-month evaluation of
dorzolamide hydrochloride/timolol maleate fixedcombination eye drops versus the separate use ofboth drugs. Jpn J Ophthalmol 56:559-563, 2012
18. Iriyama A, Kadonosono K, Tamaki Y, Yanagi Y.
Effect of Brilliant Blue G on the retinal ganglion
cells of rats. Retina 32:613-616,2012

Ito Y, Shimazawa M, Tsuruma K, Mayama C, Ishii
K, Onoe H, Aihara M, Araie M, Hara H. Inductionof amyloid-β (1-42) in the retina and optic nerve
head of chronic ocular hypertensive monkeys. Mol
Vis 18:2647-2657,2012
19. Kimoto M, Shima N, Yamaguchi M, Amano S,
Yamagami S. Role of hepatocyte growth factor inpromoting the growth of human corneal endothelial
cells stimulated by L-ascorbic acid 2-phosphate.
Invest Ophthalmol Vis Sci 53:7583-7589, 2012
20. Kimura K, Usui Y, Goto H; Japanese Intraocular
Lymphoma Study Group. Clinical features anddiagnostic significance of the intraocular fluid of
217 patients with intraocular lymphoma. Jpn J
Ophthalmol 56:383-389, 2012
21. Matsumoto Y, Ohashi Y, Watanabe H, Tsubota K;
Diquafosol Ophthalmic Solution Phase 2 Study
Group.Efficacy and safety of diquafosol ophthalmic
solution in patients with dry eye syndrome:aJapanese phase 2 clinical trial. Ophthalmology 119:1954-1960, 2012
22. Mayama C, Ishii K, Ota T, Tomidokoro A, Araie M.
Changes in optic nerve head circulation in response
to vasoactive agents: intereye comparison inmonkeys with experimental unilateral glaucoma.
Invest Ophthalmol Vis Sci 53:5771-5778, 2012
23. Meguro A, Ideta H, Ota M, Ito N, Ideta R,
Yonemoto J, Takeuchi M, Uemoto R, Nishide Y,
Iijima Y, Kawagoe T, Okada E, Shiota T, Hagihara Y,
Oka A, Inoko H, Mizuki N. Common variants in the
COL4A4 gene confer susceptibility to latticedegeneration of the retina. Plos One 7:e39300, 2012
24. Mimura T, Obata H, Usui T, Mori M, Yamagami S,
Funatsu H, Noma H, Amano S. Pinguecula anddiabetes mellitus. Cornea 31:264-268, 2012
25. Mimura T, Mori M, Obata H, Usui T, Yamagami S,
Funatsu H, Noma H, Amano S. Conjunctivochalasis: associations with pinguecula in a hospitalbased study. Acta Ophthalmol. 90:773-782, 2012.
26. Mimura T, Usui T, Yamagami S, MiyaiT, Amano S.
Relationship between total tear IgE and severity ofacute seasonal allergic conjunctivitis. Curr Eye Res
37:864-870, 2012
27. Minami K, Kataoka Y, Matsunaga J, Ohtani S,
Honbou M, Miyata K. Ray-tracing intraocular lens
power calculation using anterior segment opticalcoherence tomography measurements. J Cataract

245

Refract Surg 38:1758-1763, 2012
28. Miyata K, Honbo M, Otani S, Nejima R, Minami K.
Effect on visual acuity of increased surface lightscattering in intraocular lenses. J Cataract Refract
Surg 38:221-226, 2012
29. Mori M, Gargowitsch L, Bornert JM, Garnier JM,
Mark M, Chambon P, Metzger D. Temporally
controlled targeted somatic mutagenesis in mouseeye pigment epithelium. Genesis 50:828-832, 2012
30. Murakami N, Suzuki S, Ito Y, Yoshimura R, Inaba K,
Kuroda Y, Morota M, Mayahara H, Sakudo M,
Wakita A, Okamoto H, Sumi M, Kagami Y,
Nakagawa K, Ohtomo K, Itami J. 106Ruthenium
plaque therapy (RPT) for retinoblastoma. Int J
Radiat Oncol Biol Phys 84:59-65, 2012
31. Nakagawa S, Usui T, Yokoo S, Omichi S, Kimakura
M, Mori Y, Miyata K, Aihara M, Amano S, Araie M.
Toxicity evaluation of antiglaucoma drugs using
stratified human cultivated corneal epithelial sheets.
Invest Ophthalmol Vis Sci 53:5154-5160, 2012
32. Ninomiya T, Sawamura H, Inoue K, Takada M.
Segregated pathways carrying frontally derived
top-down signals to visual areas MT and V4 inmacaques. J Neurosci 32:6851-6858, 2012
33. Ninomiya T, Sawamura H, Inoue K, Takada M.
Multisynaptic inputs from the medial temporal lobe
to v4 in macaques. PLoS One. 7:e52115, 2012
34. Nishida T, Chikama T, Sawa M, Miyata K, Matsui T,
Shigeta K. Differential contributions of impaired
corneal sensitivity and reduced tear secretion tocorneal epithelial disorders. Jpn J Ophthalmol 56:
20-25, 2012
35. Nomura Y, Obata R, Yanagi Y. Intravitreal
bevacizumab for iatrogenic choroidal neovascularization due to laser photocoagulation in central
serous chorioretinopathy. Jpn J Ophthalmol 56:245249, 2012
36. Ohno H, Inoue K. A long cannula for microincision
vitrectomy. Retina 32:1435-1437, 2012
37. Okada AA, Goto H, Ohno S, Mochizuki M, Kitaichi
N, Namba K, Keino H, Watanabe T, Ishibashi T, Ito
T, Sonoda K, Nakai K, Ohguro N, Sugita S, Kezuka
T, Kaburaki T, Takamoto M, Mizuki N. Multicenter
study of infliximab for refractory uveoretinitis in
Behcet's disease. Arch Ophthalmol 130:592-598,
2012
38. Omori Y, Araki F, Chaya T, Kajimura N, Irie S,

Terada K, Muranishi Y, Tsujii T, Ueno S, Koyasu T,
Tamaki Y, Kondo M, Amano S, Furukawa T.
Presynaptic dystroglycan-pikachurin complex regulates the proper synaptic connection between
retinal photoreceptor and bipolar cells. J Neurosci
32:6126-6137, 2012
39. Otomo K, Kaburaki T, Shigeeda T, Takamoto M,
Kawashima H, Araie M. Bilateral anterior uveitis ina patient with bacgterial meningitis. Int Ophthalmol
32:401-403, 2012
40. Sakuyama K, Meguro A, Ota M, Ishihara M,
Uemoto R, Ito H, Okada E, Namba K, Kitaichi N,
Morimoto S, Kaburaki T, Ando Y, Takenaka S,
Yuasa T, Ohno S, Inoko H, Mizuki N. Lack ofassociation between IL10 polymorphisms andsarcoidosis in Japanese patients. Mol Vis 18:512518, 2012
41. Japanese Society of Ophthalmic Diabetology,
Subcommittee on the Study of Diabetic Retinopathy
Treatment,Sato Y, Kojimahara N, Kitano S, Kato S,
Ando N, Yamaguchi N, Hori S. Multicenter
randomized clinical trial of retinal photocoagulation
for preproliferative diabetic retinopathy. Jpn J
Ophthalmol 56:52-59, 2012
42. Sawaguchi S, Sakai H, Iwase A, Yamamoto T, Abe
H, Tomita G, Tomidokoro A, Araie M. Prevalenceof primary angle closure and primary angle-closure
glaucoma in a shouthewestern rural population ofJapan: the Kumejima Study. Ophthalmology 119:1134-1142, 2012
43. Shimazawa M, Ito Y, Inokuchi Y, Yamanaka H,
Nakanishi T, Hayashi T, Ji B, Higuchi M, Suhara T,
Imamura K, Araie M, Watanabe Y, Onoe H, Hara H.
An alteration in the lateral geniculate nucleus ofexperimental glaucoma monkeys: in vivo positronemission tomography imaging of glial activation.
PLoS One 7:e30526, 2012
44. Sugita S, Kawazoe Y, Yamada Y, Imai A, Horie S,
Yamagami S, Mochizuki M. Inhibitory effect ofcorneal endothelial cells on IL-17-producing Th17
cells. Br J Ophthalmol 96:293-299,2012.
45. Suzuki H, Ota M, Meguro A, Katsuyama Y,
Kawagoe T, Ishihara M, Asukata Y, Takeuchi M, Ito
N, Shibuya E, Nomura E, Uemoto R, Nishide T,
Namba K, Kitaichi N, Morimoto S, Kaburaki T,
Ando Y, Takenaka S, Nakamura J, Saeki K, Ohno S,
Inoko H, Mizuki N. Genetic characterization and246

susceptibility for sarcoidosis in Japanese patients:
risk factors of BTNL2 gene polymorphisms andHLA class II alleles. Invest Ophthalmol Vis Sci
53:7109-7115, 2012.
46. Suzuki S: A case of recurrent lacrimal gland tumor
treated by orbital exenteration. Int J Clin Oncol
42:560, 2012
47. Taira M, Ishiura H, Mitsui J, Takahashi Y, Hayashi T,
Shimizu J, Matsukawa T, Saito N, Okada K, Tsuji S,
Sawamura H, Amano S, Goto J, Tsuji S. Clinicalfeatures and haplotype analysis of newly identified
Japanese patients with gelsolin-related familial
amyloidosis of Finnish type. Neurogenetics 13:237243, 2012
48. Takaoka-Sugihara N, Yamagami S, Yokoo S,
Matsubara M, Yagita K. Cytopathic effect ofAcanthamoeba on human corneal fibroblasts. Mol
Vis 18:2221-2228, 2012.
49. Takamoto M, Kaburaki T, Mabuchi A, Araie M,
Amano S, Aihara M, Tomidokoro A, Iwase A,
Mabuchi F, Kashiwagi K, Shirato S, Yasuda N,
Kawashima H, Nakajima F, Numaga J, Kawamura
Y, Sasaki T, Tokunaga K. Common variants on
chromosome 9p21 are associated with normal
tension glaucoma. PLoS One 7:e40107, 2012
50. Takamura E, Tsubota K, Watanabe H, Ohashi Y;
Diquafosol Ophthalmic Solution Phase 3 Study
Group. A randomised, double-masked comparison
study of diquafosol versus sodium hyaluronate
ophthalmic solutions in dry eye patients. Br J
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51. Taoka K, Yamamoto G, Kaburaki T, Takahashi T,
Araie M, Kurokawa M. Treatment of primary
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methotrexate, procarbazine, and vincristinechemotherapy, reduced whole-brain radiotherapy,
and local ocular therapy. Br J Haematol 157:252254, 2012
52. Totsuka K, Kato S, Shigeeda T, Honbo M, Kataoka
Y, Nakahara M, Miyata K. Influence of cataract
surgery on pupil size in patients with diabetes
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53. Tsuruga H, Murata H, Araie M, Aihara M. A modelfor the easy assessment of pressure-dependent
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Vis 18:2468-2478, 2012

54. Tsutsumi T, Tomidokoro A, Araie M, Iwase A,
Sakai H, Sawaguchi S. Planimetrically determinedvertical cup/disc and rim width/disc diameter ratios
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Y, Imai H, Yanagi Y: Glutathione peroxidase 4 isrequired for maturation of photoreceptor cells. J
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2012
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Ochiai M. Relationship between the vision-related
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Recovery of visual function in patient withmelanoma-associated retinopathy treated withsurgical resection and interferon-beta. Doc
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Kawashima H, Fujino Y. Clinical backgroundcomparison of patients with and without ocularinflammatory attacks after initiation of infliximab
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Yanagi Y. Adrenomedullin inhibits choroidal
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epithelium. Am J Pathol 181:1464-1472, 2012

247

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.

Naoya Egami, M.D.

Keigo Suzukawa, M.D., Ph.D.

Shintaro Baba, M.D.

Yu Matsumoto, M.D., Ph.D.

Akinori Kashio, M.D.

Aki Inoue, M.D.

Kaori Kanaya, M.D.

Yuki Saito, M.D.

Chisato Fujimoto, M.D, Ph.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

248

are held to discuss surgical cases in detail. Special
lectures on leading research activities are presented byinvited guests on a regular basis. A weekly journal
club is held to introduce current research papers.

Clinical activities
In the out-patient clinic, general and special
services are provided to approximately 150 outpatients 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. Preoperative 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 neurosurgeons.

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, pure-toneaudiometry, auditory brainstem response, and caloric
test. Interview with patient is encouraged. They arequestioned on many aspects of clinical problems inseminars by professor and associate professor.

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 andrhinology and is related to case research, clinical statistics and clinical electrophysiology. Basic research isalso encouraged to solve essence of clinical problems
and to elucidate basic phenomena or anatomical andcellular 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, proteintransduction, 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.

24910) Vestibular myogenic evoked potentials in cochlear
implant and inner ear anomaly.
11) Hair cell physiology in the vestibular end organ.
12) Newborn hearing screening and language
development in deaf children.
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 researches are conductedby staffs, residents, and graduate students as well as
doctors at affiliated hospitals.

References
1. Yamasoba T, Miller JM, Ulfendal M. Altschuler
RA. Frontier in the treatment of hearing loss.
LePrell CG, Henderson D, Fay RR, Popper AN (eds)
Noise-induced hearing loss: Scientific advances.
Springer Handbook of Auditory Resaerch 40. pp.
339-367
2. Iwasaki S, Nakajima T, Chihara Y, Inoue A,
Fujimoto C, Yamasoba T. Developmental changes
in the expression of Κv1 potassium channels in rat
vestibular ganglion cells. Brain Res. 2012;1429:
29-35
3. Baba M, Matsumoto Y, Kashio A, Cabral H,
Nishiyama N, Kataoka K, Yamasoba T.
Micellization of cisplatin (NC-6004) reduces its
ototoxicity in guinea pigs. J Control Release.
2012;157:112-7
4. Kashio A, Sakamoto T, Kakigi A, Suzuki M,
Suzukawa K, Kondo K, Sato Y, Asoh S, Ohta S,
Yamasoba T. Topical application of the antiapoptotic
TAT-FNK protein prevents aminoglycoside-induced
ototoxicity. Gene Ther. 2012;19:1141-1149
5. Fujimoto C, Murofushi T, Sugasawa K, Chihara Y,
Ushio M, Yamasoba T, Iwasaki S. Assessment of
postural stability using foam posturography at thechronic stage after acute unilateral peripheral
vestibular dysfunction. Otol Neurotol. 2012;33:
432-436
6. Suzuki M, Iwamura H, Kashio A, Sakamoto T,
Yamasoba T. Short-term functional and morphological changes in guinea pig cochlea following
intratympanic application of Burow's solution. Ann

Otol Rhinol Laryngol. 2012;121:67-72
7. Yamauchi A, Imagawa H, Yokonishi H, Nito T,
Yamasoba T, Goto T, Takano S, Sakakibara KI,
Tayama N. Evaluation of Vocal Fold Vibration withan Assessment Form for High-Speed Digital
Imaging: Comparative Study between Healthy
Young and Elderly Subjects. J Voice. 2012;26:742-750
8. Yasui T, Iwasaki S, Sugasawa K, Sakamoto T,
Kashio A, Suzuki M, Kakigi A, Yamasoba T.
Admittance tympanometry with 2-kHz probe tones
in patients with low-frequency hearing loss.
Laryngoscope. 2012;122:2252-5
9. Fujimoto C, Murofushi T, Sugasawa K, Chihara Y,
Ushio M, Yamasoba T, Iwasaki S. Bilateral
vestibulopathy with dissociated deficits in the
superior and inferior vestibular systems. Ann Otol
Rhinol Laryngol. 2012;121:383-8
10. Takeda T, Takeda S, Egami N, Kakigi A, Nishioka
R, Yamasoba T. Type 1 allergy-induced endolymphatic hydrops and the suppressive effect of
leukotriene receptor antagonist. Otol Neurotol.
2012;33:886-90
11. Okada K, Ishimoto S, Fujimaki Y, Yamasoba T.
Trial of chinese medicine wu-ling-san for acutelow-tone hearing loss. ORL J Otorhinolaryngol
Relat Spec. 2012;74:158-63.
12. Iwasaki S, Chihara Y, Egami N, Fujimoto C,
Murofushi T, Yamasoba T. Different effects of headtilt on ocular vestibular-evoked myogenic potentials in response to bone-conducted vibration andair-conducted sound. Exp Brain Res. 2012;223:
389-96
13. Chihara Y, Iwasaki S, Murofushi T, Yagi M, Inoue
A, Fujimoto C, Egami N, Ushio M, Karino S,
Sugasawa K, Yamasoba T. Clinical characteristics
of inferior vestibular neuritis. Acta Otolaryngol.
2012;132:1288-1294
14. Suzukawa M, Morita H, Nambu A, Arae K,
Shimura E, Shibui A, Yamaguchi S, Suzukawa K,
Nakanishi W, Oboki K, Kajiwara N, Ohno T, Ishii
A, Körner H, Cua DJ, Suto H, Yoshimoto T,
Iwakura Y, Yamasoba T, Ohta K, Sudo K, Saito H,
Okumura K, Broide DH, Matsumoto K, Nakae S.
Epithelial cell-derived IL-25, but not Th17
cell-derived IL-17 or IL-17F, is crucial for murine
asthma. J Immunol. 2012;189:3641-52

250

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. Fourteen students haveentered the graduate school by 2012, and ten of themwere granted Ph.D.

Clinical activities
There is not enough doctors arranged for the
department of rehabilitation medicine, and we cannot
run own beds for rehabilitation patients at present. The
professor serves as a director of Rehabilitation Center,the University of Tokyo Hospital. Both departments
are united and engage in clinical practice. We have atpresent no charged ward, and treat about 1,000 newreferrals annually from almost all the departments of
the university hospital. We always take charge ofabout 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

251

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.

7) Disabilities and handicaps in patients with skeletal
dysplasias
8) Analysis of musculo-skeletal involvement incongenital insensitivity to pain
Additionally, in October 2012, an endowed
department named “Department of Sensoryrecognition and Locomotive-function Sciences in the
Super-aged Society” was established, supported by
Kinoshita Care Co., Ltd. and in close collaboration
with the Department of Rehabilitation Medicine. The
objectives of this department are to acquire knowledgeof adequate way of estimation and life-long course on
the sensory-recognition function and its influence on
locomotion, and to propose a new health care systemthat is comprehensive medical, nursing , and homecare.

References
1.

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 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 withcongenital limb deficiencies

2.

3.

4.

5.

Hamasaki M, Hashizume Y, Yamada Y, Katayama
T, Hohjoh H, Fusaki N, Nakashima Y, Furuya H,
Haga N, Takami Y, Era T: Pathogenic mutation of
ALK2 inhibits iPS cell reprogramming andmaintenance: mechanisms of reprogramming andstrategy for drug identification. Stem Cells 30:
2437-2449, 2012
Kawashima N, Abe MO, Iwaya T, Haga N:
Abnormal capacity for grip force control inpatients with congenital insensitivity to pain. Exp
Brain Res 218: 579-288, 2012
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 17: 507-511, 2012
Susami T, Mori Y, Tamura K, Ohkubo K,
Nagahara K, Takahashi N, Uchino N, Uwatoko K,
Haga N, Takato T: Facial morphology and occlusion of a patient with fibrodysplasia ossificans
progressiva (FOP): Follow-up from 8 to 21 yearsof age. Spec Care Dentist 32: 165-170, 2012
Yozu A, Haga N, Tojima M, Zhang Y, Sumitani
M, Otake Y: Vertical peak ground force in humaninfant crawling. Gait Posture 37: 293-295, 2013

Surgical Sciences
3. Vital Care Medicine

253

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.

Masahiko Sumitani, M.D., Ph.D.

Masahiko Bougaki, M.D., Ph.D.

Associate
Hiroshi Sekiyama, M.D.,

Nobuhide Kin, M.D.,

Kenichi Kishida, M.D.,

Yoshiteru Mori, M.D.,

Yoshie Suzuki, M.D.,

Kanako Sato, M.D.,

Gaku Kawamura, M.D.,

Masaaki Asamoto, M.D.

Maiko Obuchi, M.D.,

Yuho Tamai, M.D.,

Ayako Hirai, M.D.,

Go Ichihara, M.D.,

Yoko Hashimoto, M.D.,

Ken Kuwajima, M.D.,

Hiroaki Abe, M.D.,

Keisuke Ishikawa, M.D.,

Michiko Ushio, M.D.,

Jun Hozumi, M.D.,

Kazuhito Mietani, M.D.,

Kanae Nagatomo, 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 anesthetic care forelectro-convulsion therapy. Recently, the number ofhigh risk or geriatric patients is increasing. A new
operating theater with 11 new ORs opened in January
2007 and the annual surgery exceeds 10,000 cases.
Pain clinic services are provided for out-patients(including patients in the ward of the otherdepartments) 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 2012 toApril 2013, 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.

254

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

Publications(1) Muroya M, Chang K, Uchida K, Bougaki M,
Yamada Y. Analysis of cytotoxicity induced byproinflammatory cytokines in the humanalveolar epithelial cell line A549. Bioscience
trends. 2012;6:70-80(2) Uchida K, Yasunaga H, Miyata H, Sumitani M,
Horiguchi H, Matsuda S, Yamada Y. Impact ofremifentanil use on early postoperative outcomes
following brain tumor resection or rectal cancer
surgery. J Anesth. 2012;26:711-20(3) Tokuda K, Kida K, Marutani E, Crimi E,
Bougaki M, Khatri A, Kimura H, Ichinose F.
Inhaled hydrogen sulfide prevents endotoxininduced systemic inflammation and improves
survival by altering sulfide metabolism in mice.

255

Antioxid Redox Signal. 2012;17:11-21(4) Kitamura T, Sato K, Kawamura G, Yamada Y.
The involvement of adenosine triphosphatesensitive potassium channels in the different
effects of sevoflurane and propofol on glucose
metabolism in fed rats. Anesth Analg. 2012;114:
110-6(5) Jacquin-Courtois S, Legrain V, Sumitani M,
Miyauchi S, Rossetti Y. Visuo-motor adaptation
and bodily representations: From neglect tocomplex regional pain syndrome. Lett Med Phys
Readapt. 2012;28:93-8(6) Sumitani M, Uchida K, Yasunaga H, Horiguchi
H, Kusakabe Y, Matsuda S, Yamada Y.
Prevalence of malignant hyperthermia andrelationship with anesthetics in Japan: Data fromthe Diagnosis Procedure Combination Database.
Anesthesiology. 2011;114:84-90(7) Uchida K, Yasunaga H, Miyata H, Sumitani M,
Horiguchi H, Kuwajima K, Matsuda S, Yamada
Y. Impact of remifentanil introduction on
practice patterns in general anesthesia. J Anesth.
2011;25:864-71(8) 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(9) 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(10) Sumitani M, Shibata M, Sakaue G, Mashimo T,
Japanese CRPS Research Group. Developmentof comprehensive diagnostic criteria of complex
regional pain syndrome in the Japanese
population. Pain 2010;150:243-9(11) 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
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Autoantibodies
Reproduce Pulmonary Alveolar Proteinosis in
Non-human Primates. Am J Respir Crit Care
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BC. Response: Granulocyte/macrophage colonystimulating factor autoantibodies and myeloid

cell immune functions in healthy persons. Blood
2010;115(2):431-3(13) Watanabe M, Uchida K, Nakagaki K, Trapnell
BC, Nakata K. High avidity cytokine autoantibodies in health and disease: pathogenesis
and mechanisms. Cytokine Growth Factor Rev
2010;21(4):263-73(14) Bougaki M, Searles RJ, Kida K, De Yu J, Buys
ES, Ichinose F. NOS3 protects against systemic
inflammation and myocardial dysfunction inmurine polymicrobial sepsis. Shock 2010;34(3):281-90256

Department of Emergency andCritical Care Medicine
Professor
Naoki Yahagi, M.D.

Associate Professor
Susumu Nakajima, M.D.

Yoichi Kitsuta, M.D.

LecturerTakeshi Ishii, M.D.

Takehiro Matsubara, M.D.

Kent Doi, M.D.

Masataka Gunshin, M.D.

Shinji Matsuse, M.D.

Masahiro Ueda, M.D.,

Rei Ito, M.D.

Masahiro Nishida, M.D.

Kanae Nagatomo, M.D.

Yusuke Komiyama, D.D.S. Tomohiro Sonoo, M.D.

Hiroaki Kobayashi, M.D.

Kazuma Oshima, M.D.

Michiko Nomori, M.D.

Associate

Taro Kasai, M.D.

Staff
Akitomo Maeda, M.D.

Eriko Takahashi, M.D.

Homepage

http://plaza.umin.ac.jp/todaiqq/

Introduction and Organization
Department of Emergency and Critical Care
Medicine was established in 1965, as the emergency
service within the Central Clinical Service Facilitiesof the University of Tokyo Hospital and at the sametime as the intensive care service for in-hospitalpatients, it became a tertiary emergency care andcritical care center in the metropolitan Tokyo and also
became the principal teaching facility of the
University of Tokyo. It is a designated Level I Trauma
Center, and also the home of one of the newest Life
Flight aeromedical services in the country.
The Emergency Center sees approximately 17,000
patients per year. It contains major trauma and cardiac
resuscitation rooms complete with STAT X-ray andfull monitoring and resuscitation equipment. There are
9 treatment spaces including space for orthpedics,

gynecology, and Optho-ENT evaluations.
10overnight-stay monitored beds, X-ray, rapid spiral CT,
ultrasound, angiography and STAT Lab are locatedadjacent to the Emergency Center.
In September, 2001, the University of Tokyo
Hospital opened the In-patient Ward A and ourdepartment has necessarily extended services for
management of Critical patients in the new Critical
Care Center now containing adult ICU/CCU of 16
beds, high care unit (ICU2) of 24 beds, pediatricintensive care unit (PICU) of 6 beds and neonatal
intensive care unit (NICU) of 6 beds.
The Emergency Care Center and the Critical Care
Center see an excellent mix of multiple trauma,
high-acuity medical, surgical, pediatric, and gynecologic patients. The Life Flight service provides anotheropportunity for exposure to critically ill patients.
Consult services are available from all of the clinical257

departments 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
every level, primary, secondary and tertiary. The
residents are trained in the ACLS Basic (ICLS)

258

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.

Research activities
As a basic experiment, we investigate themechanism of sepsis and ARDS using splenectomized
animal model.
As clinical study, we are searching for the new
biomarkers to predict the severity of AKI at the timeof intensive care unit admission.
With the faculty of technology, we are also
developing the new method to evaluate the body fluid
distribution by chasing the dynamic change of IVC
diameter.

References
1. Inokuchi R, Wada T, Ohta F, Sonoo T, Aoki Y,
Asada T, Hiruma T, Shinohara K, Nakajima S,
Yahagi N: A Healthy Young Man with Neck
Sprain. Ann Emer Med 2013 (in press)
2. Tanaka K, Inokuchi R, Namai Y, Yahagi N:
Retropharyngeal cellulitis in adolescence. BMJ
Case Reports 2013 (in press)
3. Komiyama Y, Ohba S, Shimohata N, Nakajima K,
Hojo H, Yano F, Takato T, Docheva D, Shukunami
C, Hiraki Y, Ung-il Chung: Tenomodulin
expression in the periodontal ligament enhances
cellular adhesion. PLOS ONE 2013 (in press)
4. Fukuda T, Yasunaga H, Horiguchi H, Ohe K,
Fushimi K, Matsubara T, Yahagi N: Health carecosts related to out-of-hospital cardiopulmonaryarrest in Japan. Resuscitation 2013 (in press)
5. Sonoo T, Wada T, Nakamura K, Yahagi N:
Putamen hemorrhage occurred simultaneouslywith Stanford type A acute aortic dissection. Am J
Emer Med 2013 (in press)
6. Fukuda T, Mochizuki T, Otani N, Yahagi N,
Ishimatsu S: Pitfalls in diagnosis and treatment of
non-traumatic hemoperitoneum. Journal of
Vascular Medicine and Surgery. 2013 ( in press )7. Fukuda T, Sato T, Ohashi N, Hayase N, Gunshin
M, Matsubara T, Ishii T, Nakajima S, Yahagi N:
Management of Acid Toilet Bowl DetergentInduced Chemical Injuries. J Clinic Toxic. 2013
( in press )8. Fukuda T, Ohashi N, Gunshin M, Matsubara T,
Ishii T, Kitsuta Y, Nakajima S, Yahagi N: Impact
of TOR for OHCA in Japan. Critical Care. 2013
( in press )9. Inokuchi R, Kurata H, Harada Y, Aoki Y,
Matsubara T, Doi K, Ishii T, Gunshin M, Hiruma T,
Nakajima S, Yahagi N: Coronary artery aneurysms
after adult-onset Kawasaki disease. Circulation2013 (in press)
10. Katagiri D, Doi K, Matsubara T, Negishi K,
Hamasaki Y, Nakamura K, Ishii T, Yahagi N, Noiri
E: New biomarker panel of plasma neutrophil
gelatinase-associated lipocalin and endotoxin
activity assay for detecting sepsis in acute kidney
injury. J Crit Care 2013 (in press)
11. Inokuchi R, Nakamura K, Sato H, Shinohara K,
Aoki Y, Doi K, Gunshin M, Ishii T, Matsubara T,
Hiruma T, Nakajima S, Yahagi N: Bronchialulceration as a prognostic indicator for varicellapneumonia: Case report and systematic literature
review. J Clin Vilor 2013 (in press)
12. Inokuchi R, Sato H, Nakajima S, Shinohara K,
Nakamura K, Gunshin M, Hiruma T, Ishii T,
Matsubara T, Kitsuta Y, Yahagi N: Development of
information systems and clinical decision support
systems for emergency departments: A long roadahead for Japan. Emer Med J 2013 (in press)
13. Hiruma T, Nakamura K, Inokuchi R, Kurata H,
Gunshin M, Matsubara T, Ishii T, Nakajima S,
Yahagi N, Shinohara K: Tsunami lungaccompanied by disorders. Am J Resp Crit Care
Med 2013 (in press)

259

14. Nagai H, Yahagi N, Yoshida K: Lethal pulmonary
air embolism caused by the removal of a doublelumen haemodialysis catheter. American Journalof Forensic medicine and Pathology 2013 (inpress)
15. Nakamura N, Tomida M, Ando T, Inokuchi R,
Matsubara T, Kobayashi E, Nakajima S, Yahagi N,
Sakuma I: IVC cardiac variation: New concept forevaluation of intravascular water volume. J Med
Ultrasonic 2013 (in press)
16. Nakamura K, Doi K, Inokuchi R, Fukuda T,
Hiruma T, Ishii T, Nakajima S, Noiri E, Yahagi N:
Endotoxin adsorption by polymyxin B cokumn or
intraaortic balloon pumping use for severe septic
cardiomyopathy. Am J Emer Med 2013 (in press)
17. Nakamura K, Doi K, Okamoto K, Arai S, Ueha S,
Matsushima K, Yahagi N, Noiri E: Evidence for
specific
antibody-mediatedprotectionof
intravenous immunoglobulin treatment for post
splenectomy sepsis by pneumococcus. Crit Care
Med 2013 (in press)

Health Sciences and Nursing
1. Health Sciences

261

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, 3 doctoral course
students, 9 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 2012.
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,

262

which is part of a WHO international collaboration, isa largest epidemiologic study of common mental
disorders in the community in Japan. Assessment ofhealth effects of job stressors and effectiveness ofinterventions to reduce job stress are also coreresearch activities of the department. Current issues
around occupational mental health (e.g., work
engagement, workaholism, organizational justice,bullying, and work-life balance) are also actively
investigated. Furthermore, research in the department
includes various other topics, such as psychiatricrehabilitation, clinical psychology, psychotherapy,
child and adolescent psychiatry; and developmental
disorders. Most of the research has been conducted ina close collaboration with researchers in otherdomestic and foreign institutions/universities.

References (Jan.-Dec., 2012)
1. Bakker AB, Shimazu A, Demerouti E, Shimada K,
Kawakami N. Work engagement versus workaholism: a test of the spillover-crossover model. Journalof Business Psychology. (in press)
2. Eguchi H, Tsuda Y, Tsukahara T, Washizuka S,
Kawakami N, Nomiyama T. The effects ofworkplace occupational mental health and related
activities on psychological distress among workers:a multilevel cross-sectional analysis. J Occup
Environ Med. 2012 Aug；54(8):939-47.
3. Furukawa TA, Horikoshi M, Kawakami N, Kadota
M, Sasaki M, Sekiya Y, Hosogoshi H, Kashimura M,
Asano K, Terashima H, Iwasa K, Nagasaku M,
Grothaus LC, on behalf of the GENKI Project.
Telephone cognitive-behavioral therapy for subthreshold depression and presenteeism in workplace:a randomized controlled trial. PLoS ONE.2012；
7(4):e35330.
4. Hirokawa K, Taniguchi T, Tsuchiya M, Kawakami N.
Effects of a stress management program for hospital
staffs on their coping strategies and interpersonal
behaviors. Ind Health. 2012；50(6):487-98.
5. Hirokawa S, Kawakami N, Matsumoto T, Inagaki A,
Eguchi N, Tsuchiya M, Katsumata Y, Akazawa M,
Kameyama A, Tachimori H, Takeshima T. Mental
disorders and suicide in Japan: a nation-wide
psychological autopsy case-control study. J Affect
Disord. 2012 Oct；140(2):168-75.

6. Hirokawa S, Matsumoto T, Katsumata Y, Kitani M,
Akazawa M, Takahashi Y, Kawakami N, Watanabe
N, Hirayama M, Kameyama A, Takeshima T.
Psychosocial and psychiatric characteristics ofsuicide completers with psychiatric treatment before
death: A psychological autopsy study of 76 cases.
Psychiatry Clin Neurosci. 2012 Jun ;66(4):292-302.
7. Kawakami N, Abdulghani EA, Alonso J, Bromet EJ,
Bruffaerts R, Caldas-de-Almeida JM, Chiu WT, deGirolamo G, de Graaf R, Fayyad J, Ferry F, Florescu
S, Gureje O, Hu C, Lakoma MD, Leblanc W, Lee S,
Levinson D, Malhotra S, Matschinger H, MedinaMora ME, Nakamura Y, Oakley Browne MA,
Okoliyski M, Posada-Villa J, Sampson NA, Viana
MC, Kessler RC. Early-life mental disorders andadult household income in the World Mental Health
Surveys. Biol Psychiatry. 2012 Aug 1；72(3):228-37.
8. Kessler RC, McLaughlin KA, Koenen KC,
Petukhova M, Hill ED, The WHO World Mental
Health Survey Consortium. The importance of
secondary trauma exposure for post-disaster mental
disorder. Epidemiology and Psychiatric Sciences.
2012；21(1):35-45.
9. Kubota K, Shimazu A, Kawakami N, Takahashi M,
Nakata A, Schaufeli, WB. The Empirical Distinctiveness of Workaholism and Work Engagement
among Hospital Nurses in Japan: the effect on Sleep
Quality and Job Performance. Ciencia & Trabajo.
2012；14:31-36.
10. Kubota K, Shimazu A, Kawakami N, Takahashi M.
Workaholism and sleep quality among Japaneseemployees: A prospective cohort study. International
Journal of Behavioral Medicine. (in press)
11. Lim SS, Vos T, Flaxman AD, Danaei G, et al. A
comparative risk assessment of burden of disease
and injury attributable to 67 risk factors and risk
factor clusters in 21 regions, 1990-2010: asystematic analysis for the Global Burden of Disease
Study 2010. Lancet. 2013 Dec 15 ； 380(9859):
2224-60. doi:10.1016/S0140-6736(12)61766-8.
12. Miyaki K, Song Y, Htun NC, Tsutsumi A,
Hashimoto H, Kawakami N, Takahashi M, Shimazu
A, Inoue A, Kurioka S, Shimbo T. Folate intake anddepressive symptoms in Japanese workers considering SES and job stress factors: J-HOPE study. BMC
Psychiatry. 2012；12(1):33.
13. Murray CJ, Vos T, Lozano R, et al. Disability-

263

adjusted life years (DALYs) for 291 diseases andinjuries in 21 regions, 1990-2010: a systematic
analysis for the Global Burden of Disease Study
2010. Lancet. 2013 Dec 15；380(9859):2197-223.
doi:10.1016/S0140-6736(12)61689-4.
14. Okamoto M, Kawakami N, Kido Y, Sakurai K.
Social capital and suicide: an ecological study inTokyo, Japan. Environ Health Prev Med. (in press)
15. Park J, Kitayama S, Karasawa M, Curhan K,
Markus HR, Kawakami N, Miyamoto Y, Love GD,
Coe CL, Ryff C. Clarifying the links between social
support and health: culture, stress, and neuroticism
matter. J Health Psychol. 2012. (in press)
16. Shimazu A, Schaufeli WB, Kubota K, Kawakam N.
Do workaholism and work engagement predict
employee well-being and performance in opposite
directions? Ind Health. 2012；50:316-321.
17. Shimazu A, Sonnentag S, Kubota K, Kawakami N.
Validation of the Japanese version of Recovery
Experience Questionnaire. J Occup Health. 2012；
54:196-205.
18. Tsuchiya M, Kawakami N, Ono Y, Nakane Y,
Nakamura Y, Fukao A, Tachimori H, Iwata N, Uda
H, Nakane H, Watanabe M, Oorui M, Naganuma Y,
Furukawa TA, Kobayashi M, Ahiko T, Takeshima T,
Kikkawa T. Impact of mental disorders on work
performance in a community sample of workers inJapan: the World Mental Health Japan Survey
2002-2005. Psychiatry Research. 2012;198:140-145.
19. Umeda M, Kawakami N, the World Mental HealthJapan Survey Group 2002-2006. Association ofchildhood family environments with the risk ofsocial withdrawal ('hikikomori') in the community
population in Japan. Psychiatry Clin Neurosci. 2012
Mar；66:121-129.
20. Vos T, Flaxman AD, Naghavi M, et al. Years lived
with disability (YLDs) for 1160 sequelae of 289
diseases and injuries 1990-2010: a systematic
analysis for the Global Burden of Disease Study
2010. Lancet. 2013 Dec 15;380(9859):2163-96. doi:
10.1016/S0140-6736(12)61729-2.
21. Yasumura S, Hosoya M, Yamashita S, Kamiya K,
Abe M, Akashi M, Kodama K, Ozasa K;Fukushima
Health Management Survey Group. Study protocol
for the Fukushima Health Management Survey. J
Epidemiol. 2012 Sep 5；22(5):375-83.

264

Department of Biostatistics/
Epidemiology and Preventive
Health Sciences
Professor
Yasuo Ohashi, Ph.D.

Associate Professor
Yutaka Matsuyama, Ph.D.

Research Associate
Kosuke Kashiwabara, M.S., Tomohiro Shinozaki, M.P.H.

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 aseries of educational courses organized by ‘The
Clinical Bioinformatics Research Unit’ in 2002-2007.

Teaching activities
1. Undergraduate Courses
1) Epidemiology and Biostatistics (2 credits)
2) Applied Mathematics (2 credits)
3) Statistical Methods and Information Processing(2 credits, practice)4) Design and Analysis of EpidemiologicalResearch (2+1 credits, 1 practice)5) Medical Data analysis (2 credits)
6) Biostatistics (2 credits; for the School of265

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)3.

4.

Research activities
1. Biostatistics and theoretical epidemiology:
 Analysis of longitudinal missing /incompletedata Analysis of multiple events data
 Analysis of QOL data Causal analysis
 Analysis of micro/macro array data
 Meta analysis of epidemiological studies
2. Methodology and Information Systems for Clinical
Trials: Design of clinical trials
 Data management of large-scale clinical trials
3. Pharmacoepidemiology
4. Coordination of collaborative epidemiological/
clinical research:
 Japan Arteriosclerosis Longitudinal Study Japan Diabetes Collaborative Study
5. Consultation Works with Corporate SponsoredResearch Program ‘Clinical Data Management’

5.

6.

7.

References
8.
1. Yano Y, Fujimoto S, Sato Y, Konta T, Iseki K,
Moriyama T, Yamagata K, Tsuruya K, Yoshida H,
Asahi K, Kurahashi I, Ohashi Y, Watanabe T.
Association between prehypertension and chronic
kidney disease in the Japanese general population.
Kidney Int. 2012 Feb;81(3):293-9.
2. Iseki K, Asahi K, Moriyama T, Yamagata K,
Tsuruya K, Yoshida H, Fujimoto S, Konta T,
Kurahashi I, Ohashi Y, Watanabe T. Risk factor
profiles based on estimated glomerular filtration
rate and dipstick proteinuria among participants

9.

of the Specific Health Check and Guidance
System in Japan 2008. Clin Exp Nephrol. 2012
Apr;16(2):244-9.
Taguri M, Matsuyama Y, Ohashi Y, Harada A,
Ueshima H. Doubly robust estimation of thegeneralized impact fraction. Biostatistics 2012;
13: 455-467.
Konta T, Ikeda A, Ichikawa K, Fujimoto S, Iseki
K, Moriyama T, Yamagata K, Tsuruya K, Yoshida
H, Asahi K, Kurahashi I, Ohashi Y, Watanabe T.
Blood pressure control in a Japanese population
with chronic kidney disease: a baseline survey ofa nationwide cohort. Am J Hypertens. 2012 Mar;25(3):342-7.
Kageyama S, Ueda S, Mochizuki K, Miyakawa M,
Sugawara M, Nakayama M, Ohashi Y, Saito I,
Saruta T; OCEAN Study Group. Optimal
Combination of Effective ANtihypertensives(OCEAN) study: a prospective, randomized,
open-label, blinded endpoint trial--rationale,
design and results of a pilot study in Japan.
Hypertens Res. 2012 Feb;35(2):221-7.
Wakasugi M, Narita I, Iseki K, Moriyama T,
Yamagata K, Tsuruya K, Yoshida H, Fujimoto S,
Asahi K, Kurahashi I, Ohashi Y, Watanabe T.
Weight gain after 20 years of age is associatedwith prevalence of chronic kidney disease. Clin
Exp Nephrol. 2012 Apr;16(2):259-68.
Mizuno K, Nakaya N, Teramoto T, Yokoyama S,
Ohashi Y, Ueki A, Takahashi S, Kubota Y,
Nakamura H. Usefulness of LDL-C-relatedparameters to predict cardiovascular risk andeffect of pravastatin in mild-to-moderate hypercholesterolemia. J Atheroscler Thromb. 2012;19(2):176-85.
Hagino H, Shiraki M, Fukunaga M, Nakano T,
Takaoka K, Ohashi Y, Nakamura T, Matsumoto T.
Three years of treatment with minodronate inpatients with postmenopausal osteoporosis. J
Bone Miner Metab. 2012 Jul;30(4):439-46.
Sawaki A, Ohashi Y, Omuro Y, Satoh T,
Hamamoto Y, Boku N, Miyata Y, Takiuchi H,
Yamaguchi K, Sasaki Y, Nishina T, Satoh A, Baba
E, Tamura T, Abe T, Hatake K, Ohtsu A. Efficacyof trastuzumab in Japanese patients with HER2positive advanced gastric or gastroesophageal
junction cancer: a subgroup analysis of the266

Trastuzumab for Gastric Cancer (ToGA) study.
Gastric Cancer. 2012 Jul;15(3):313-22.
10. Takei H, Ohsumi S, Shimozuma K, Takehara M,
Suemasu K, Ohashi Y, Hozumi Y. Health-related
quality of life, psychological distress, and adverse
events in postmenopausal women with breast
cancer who receive tamoxifen, exemestane, or
anastrozole as adjuvant endocrine therapy:
National Surgical Adjuvant Study of Breast
Cancer 04 (N-SAS BC 04). Breast Cancer Res
Treat. 2012 May;133(1):227-36.
11. Kodama S, Saito K, Tanaka S, Horikawa C,
Fujiwara K, Hirasawa R, Yachi Y, Sone Y, Tada
Iida K, Shimano H, Ohashi Y, Yamada N, Sone H.
Fasting and post-challenge glucose as quantitative
cardiovascular risk factors: a meta-analysis. J
Atheroscler Thromb. 2012;19(4):385-96.
12. Ogihara T, Matsuzaki M, Umemoto S, Rakugi H,
Matsuoka H, Shimada K, Higaki J, Ito S, Kamiya
A, Suzuki H, Ohashi Y, Shimamoto K, Saruta T;
Combination Therapy of Hypertension to Prevent
Cardiovascular Events Trial Group. Combination
therapy for hypertension in the elderly: a
sub-analysis of the Combination Therapy ofHypertension to Prevent Cardiovascular Events(COPE) Trial. Hypertens Res. 2012 Apr;35(4):441-8.
13. Sone H, Tanaka S, Tanaka S, Iimuro S, Ishibashi S,
Oikawa S, Shimano H, Katayama S, Ohashi Y,
Akanuma Y, Yamada N; Japan Diabetes
Complications Study Group. Comparison ofvarious lipid variables as predictors of coronary
heart disease in Japanese men and women with
type 2 diabetes: subanalysis of the Japan Diabetes
Complications Study. Diabetes Care. 2012
May;35(5):1150-7.
14. 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 Dec;58(12):1007-15. Japanese.
15. Ohsumi S, Shimozuma K, Ohashi Y, Takeuchi A,

Suemasu K, Kuranami M, Ohno S, Watanabe T.
Subjective and objective assessment of edema
during adjuvant chemotherapy for breast cancer
using taxane-containing regimens in a randomized
controlled trial: The National Surgical Adjuvant
Study of Breast Cancer 02. Oncology. 2012;82(3):131-8.
16. Shiroiwa T, Takeuchi T, Fukuda T, Shimozuma K,
Ohashi Y. Cost-effectiveness of adjuvant
FOLFOX therapy for stage III colon cancer inJapan based on the MOSAIC trial. Value Health.
2012 Mar-Apr;15(2):255-60.
17. Ozono S, Ueda T, Hoshi S, Yamaguchi A, Maeda
H, Fukuyama Y, Takeda K, Ohashi Y, Tsukamoto
T, Naito S, Akaza H. The efficacy and safety ofdegarelix, a GnRH antagonist: a 12-month, multicentre, randomized, maintenance dose-finding
phase II study in Japanese patients with prostatecancer. Jpn J Clin Oncol. 2012 Jun;42(6):477-84.
18. Yano Y, Sato Y, Fujimoto S, Konta T, Iseki K,
Moriyama T, Yamagata K, Tsuruya K, Yoshida H,
Asahi K, Kurahashi I, Ohashi Y, Watanabe T.
Association of high pulse pressure withproteinuria in subjects with diabetes, prediabetes,or normal glucose tolerance in a large Japanesegeneral population sample. Diabetes Care. 2012
Jun;35(6):1310-5.
19. Araie M, Shirato S, Yamazaki Y, Matsumoto C,
Kitazawa Y, Ohashi Y; Nipradilol ‐ TimololStudy Group. Risk factors for progression of
normal-tension glaucoma under β-blocker
monotherapy. Acta Ophthalmol. 2012 Aug;90(5):e337-43.
20. Matsushima T, Nakaya N, Mizuno K, Ohashi Y,
Teramoto T, Yokoyama S, Ichikawa S, Ishikura N,
Kamiyama K, Nakamura H; MEGA Study Group.
The effect of low-dose pravastatin in metabolic
syndrome for primary prevention of cardiovascular disease in Japan: a post hoc analysis of
the MEGA study. J Cardiovasc Pharmacol Ther.
2012 Jun;17(2):153-8.
21. Shimozuma K, Ohashi Y, Takeuchi A, Aranishi T,
Morita S, Kuroi K, Ohsumi S, Makino H,
Katsumata N, Kuranami M, Suemasu K,
Watanabe T, Hausheer FH. Taxane-induced
peripheral neuropathy and health-related qualityof life in postoperative breast cancer patients267

undergoing adjuvant chemotherapy: N-SAS BC
02, a randomized clinical trial. Support Care
Cancer. 2012 Dec;20(12):3355-64.
22. Sato Y, Yano Y, Fujimoto S, Konta T, Iseki K,
Moriyama T, Yamagata K, Tsuruya K, Yoshida H,
Asahi K, Kurahashi I, Ohashi Y, Watanabe T.
Glycohemoglobin not as predictive as fasting
glucose as a measure of prediabetes in predicting
proteinuria. Nephrol Dial Transplant. 2012 Oct;27(10):3862-8.
23. Takayasu K, Arii S, Kudo M, Ichida T, Matsui O,
Izumi N, Matsuyama Y, Sakamoto M,
Nakashima O, Ku Y, Kokudo N, Makuuchi M.
Superselective transarterial chemoembolization
for hepatocellular carcinoma: Validation of treatment algorithm proposed by Japanese guidelines.
Journal of Hepatology 2012; 56(4): 886-892.
24. Shinozaki T, Matsuyama Y, Iimuro S, Umegaki
H, Sakurai T, Araki A, Ohashi Y, Ito H, theJapanese Elderly Diabetes Intervention Trial
Research Group. Effective prevention ofcardiovascular disease and diabetes-related eventswith atorvastatin in Japanese elderly patients with
type 2 diabetes mellitus: Adjusting for treatmentchanges using a marginal structural proportional
hazards model and a rank-preserving structural
failure time model. Geriatrics and Gerontology
International 2012; 12(Suppl.1): 88-102.
25. Shinozaki T, Matsuyama Y. Mixed models.
Domyaku Kouka Yobou 2012; 11(2): 93-95.
Japanese.
26. Sawaki M, Mukai H, Tokudome N, Nakayama T,
Taira N, Mizuno T, Yamamoto Y, Horio A,
Watanabe T, Uemura Y, Ohashi Y. Safety of
adjuvant trastuzumab for HER-2-overexpressing
elderly breast cancer patients: a multicenter
cohort study. Breast Cancer. 2012 Jul;19(3):253-8.
27. Yamauchi T, Tamaki N, Kasanuki H, Kimura T,
Uemura Y, Iimuro S; Japanese CoronaryAngiography or Myocardial Imaging for Angina
Pectoris Study (J-COMPASS) Multicenter Study
Group. Optimal initial diagnostic strategies for theevaluation of stable angina patients: a multicenter,
prospective study on myocardial perfusion
imaging, computed tomographic angiography, andcoronary angiography. Circ J. 2012;76(12):28329.

28. Endo T, Kakeyama M, Uemura Y, Haijima A,
Okuno H, Bito H, Tohyama C. Executive function
deficits and social-behavioral abnormality in mice
exposed to a low dose of dioxin in utero and via
lactation. PLoS One. 2012;7(12):e50741.

268

Department of Biomedical Ethics &Department of Health Promotion
Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Jung Su Lee, Ph.D.
Yoshiyuki Takimoto, M.D., Ph.D.

Research Associate
Eisuke Nakazawa, Ph.D.

Homepage

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

Introduction and Organization
The former Department of Health Administration wasestablished in 1967 and Dr. Tsuneo Tanaka became its
first professor in 1974. He devoted himself to thedevelopment of the community health care system inJapan and published numerous papers concerning thesocial theory of health administration and data
management systems for community health care. 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 physical activity
and inactivity on health.” From 1990, a 20-day bed
rest human experimental study was conducted every
year in the context of an international cooperative
research project that was supported by government
grants. The other project concerned health caresystems, especially health care economics and thequality of hospital care.
In
1996,
the
Department
ofHealthAdministration developed into two departments: theDepartment of Health Economics and the Department
of Health Promotion Sciences. Both were establishedas 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 the Department of Biomedical Ethics. From 2007, Dr. Jung Su
Lee became the associate professor and took charge of
the Department of Health Promotion Sciences.
Staff members of the two departments include a
professor, two associate professors, an associate, and atechnical specialist. All five members, seven
undergraduate lecturers and eight graduate lecturers
from other organizations, and seven visiting
researchers contribute to department teaching andresearch activities.
Department graduate students included fivemaster program students and seven doctoral program269

students.
In this annual report, the organization andteaching activities are reviewed followed by an
explanation of research activities.

Teaching activities
Our departments highly prioritize the teaching andguidance of graduate students and their research
activities. Fifteen bachelor theses, twenty mastertheses, and six doctoral dissertations were completed
between April 2004 and March 2013. 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 forresearch guidance on a regular basis.
Graduate level courses in Biomedical Ethics
focus on the analytical study of ethical theories and on
the review 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 (CBEL)―a new interdisciplinary and international education
research center aimed to address bioethical issues
relevant to Japan and the international community.
Our center will form an international network by
establishing partnerships with research centersoverseas (GABEX: Global Alliance of Biomedical
Ethics Centers Project). Through these efforts, we will
foster the next generation of bioethics experts inpolicy-making, research, and clinical medicine whoare capable of providing 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 forbio-medical ethics education
5) Ethical and psychosocial aspects of living relatedorgan transplantation
6) Publication of a medical ethics case book forJapan7) Comparative study of clinical ethics in the Asian
region8) Historical analyses for the term “bioethics” in theJapanese context
Department of Health Promotion Sciences
The main research activity of the Department of
Health Promotion Sciences is aimed at health policy
proposals concerning health promotion in the270

community 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
healthReferences
1. Akabayashi A. Must I stay? The Obligations ofPhysicians in Proximity to the Fukushima Nuclear
Power Plant. Camb Q Healthc Ethics 21(3):392–395. 2012.
2. Akabayashi A, Hayashi Y. Mandatory evacuationof residents during the Fukushima nuclear
disaster: an ethical analysis. J Public Health (Oxf).
34(3): 348–351. 2012.
3. Akabayashi A, Takimoto Y, Hayashi Y. Physician
obligation to provide care during disasters: should

physicians have been required to go to
Fukushima? J Med Ethics. 38(11): 697–698.
2012.
4. Chen T, Lee JS, Kawakubo K, Watanabe E, MoriK, Kitaike T, Akabayashi A. Features of perceived
neighborhood environment associated with daily
walking time or habitual exercise: differences
across gender, age, and employment status in acommunity-dwelling population of Japan. Environ
Health Prev Med 2012 (in press).
5. Chin JJ, Ho CW, Arima H, Ozeki R, Heo DS,
Gusmano MK, Berlinger N. Integration of
palliative and supportive cancer care in Asia.
Lancet Oncol. 13(5): 445–446.2012.
6. Lee JS, Hayashi K, Mishra G, Yasui T, Kubota T,
Mizunuma H. Independent association between
age at natural menopause and hypercholesterolemia, hypertension, and diabetes mellitus:
Japan Nurses’ Health Study. J Atheroscler
Thromb 20(2): 161–169, 2013.
7. Mishra GD, Anderson D, Schoenaker DAJM,
Adami H-O, Avis NE, Brown D, Bruinsma F,
Brunner E, Cade JE, Crawford SL, Dobson AJ,
Elliott J, Giles GG, Gold EB, Hayashi K, Kuh D,
Lee KA, Lee JS, Melby MK, Mizunuma H,
Sievert LL, Weiderpass E. InterLACE: A newinternational collaboration for a life course
approach to women’s reproductive health andchronic disease events. Maturitas 74(3): 203–290,
2013.
8. Takahashi S, Fujita M, Fujimoto A, Fujiwara T,
Yano T, Tsutsumi O, Taketani Y, Akabayashi A.
The decision-making process for the fate offrozen embryos by Japanese infertile women: aqualitative study. BMC Medical Ethics 13: 9,2012.
9. Yasui T, Hayashi K, Mizunuma H, Kubota T, Aso
T, Matsumura Y, Lee JS, Suzuki S. Factors
associated with premature ovarian failure, earlymenopause and earlier onset of menopause inJapanese women. Maturitas 72: 249–255, 2012.
10. Akabayashi A, Takashima K, Tashiro S, Hayashi
Y, Fujita M. Managing of incidental findings inneuroimaging research. Strategic Research
Program for Brain Sciences by the Ministry of
Education, Culture, Sports, Science andTechnology of Japan 2012 (in Japanese).

271

11. Fujita M. Basics of biomedical ethics(Psychosomatic medicine course). Japanese
Journal of Psychosomatic Medicine 52(12): 1117–
123, 2012 (in Japanese).
12. Fujita M, Akabayashi A. The cutting-edge of
medicine: approaching ethical issues in clinicalsettings. The Journal of the Japanese Society ofInternal Medicine 101(7): 2059–2064, 2012 (inJapanese).
13. Kodama S. Utilitarianism and public health. The
Annals of Legal Philosophy 2011: 7–22, 2012 (inJapanese).
14. Kodama S. Introduction to Utilitarianism: Ethics
for the First Time. Chikuma Shobo 2012 (inJapanese).
15. Kodama S, Akabayashi A. “Bioethics.” In A Basic
Encyclopediaof
Current
Terms,
2013.
Jiyukokuminsha, 811–815, 2013 (in Japanese).
16. Ozeki R. What is advance care planning? The
Japanese Journal of Palliative Care 22(5):403–406, 2012 (in Japanese).
17. Saito S, Kodama S, Shiroiwa T, Shimozuma K,
Noto S, Goto R. The ethics of the allocation ofhealth care resources and QALY. Jpn J Pharmacoepidemiol 17(1): 47–53, 2012 (in Japanese).
18. Takashima K, Kodama S. Controversy in the UK
on assisted dying and “suicide tourism” to
Switzerland: Possible effects of cross-borderhealth care on domestic regulations. Journal of theJapan Association for Bioethics 22(1): 75–85,
2012 (in Japanese).
19. Watanabe E, Lee JS, Kawakubo K. Associationsof family and neighborhood environments withoutside playing time and screen time on weekdays
of preschool children in Japan. Research in
Exercise Epidemiology 14(1): 37–46, 2012 (inJapanese).

Health Sciences and Nursing
2. Preventive and Administrative Nursing

273

Department of
Nursing Administration /Advanced Clinical Nursing
Professor
Noriko Yamamoto-Mintani, Ph.D., R.N.

Assistant Professor
Makoto Tanaka, Ph.D., R.N. (2012.Oct ~)Ayako Nagata, M.A., R.N.

Project Assistant Professor
Mami Onishi, Ph.D., R.N.
Makoto Tanaka, Ph.D., R.N. (~ 2012.Sep)

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)
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)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)
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) health274

assessment 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.
Advanced Clinical Nursing 2(2 credits, Lectures and practicum)This course explores issues related to advanced
clinical practice, research, and education with anemphasis on specific theoretical perspectives,
methodologies, practice and economic implications.

Undergraduate Courses
First Aid & CPR (1 credit, Lectures & practicum)
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)This course offers fundamental knowledge of nursing,such as history and theory in nursing, concepts ofprofessional nursing practice, nursing service and caredelivery systems, nursing administration, and nursing
education.
Discussions
includecontemporary
challenging issues and future strategies in nursing.
Fundamental Nursing 2 (2 credits, Lectures)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)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.

Clinical Practicum in Fundamental Nursing(2 credits, practicum)
Under instructors' supervision, students haveopportunity to apply their fundamental knowledge andskills of nursing in a variety of settings. Students willassess clients' health and needs through application ofnursing process.
Nursing Administration (1 credit, Lectures)This
coursepreparesstudentsfor
nurse
administrators/managers of all types of health caresettings such as institutions, organizations, communityand politics. Students will learn fundamental theory
and practice in nursing administration/ management
through analyzing current issues in health care andnursing.
Nursing Administration Practicum(1 credit, practicum)
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.
Quality Improvement, Safety Issues, and Risk
Management in Nursing
This work examines; 1) quality of nursing care, 2)

275

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. Onishi M, Komi K, Kanda K. Physicians'
perceptions of physician-nurse collaboration in
Japan: Effects of collaborative experience. Journalof Interprofessional Care 2012 (Early Online)
2. Nagata A, Kanda K. A comparison of university
and minimum curriculum requirements for Japan’s
certified care worker license. Social Work
Education 2012; 31(3): 347-363.
3. Segawa R, Onishi M, Takeuchi T, Nagata A.
Nurses' recognition of coworkers' responses totheir errors. Journal of the Japan Academy of
Nursing Evaluation 2012; 2(1): 1-8.(in Japanese)

4. Tanaka M, Kawakami A, Iwao Y, Fukushima T,
Takai Y, Yamamoto-Mitani N. The gap between
flare-up recognition and judgment of need forphysician visit in patients with ulcerative colitis.
Gastroenterology Research. (in press)
5. Takai Y, Yamamoto-Mitani N, Okamoto Y,
Fukahori H, Kou A, Tanaka M. Family caregiver
strategies to encourage older relatives withdementia to use social services. Journal ofAdvanced Nursing. (In press).
6. Kawakami A, Tanaka M, Nishigaki M, Naganuma
M, Iwao Y, Hibi T, Sanada H, Yamamoto-Mitani
N,
KazumaK.
Relationshipbetweennon-adherence to aminosalicylate medication andthe risk of clinical relapse among Japanesepatients with ulcerative colitis in clinicalremission: a prospective cohort study. Journal of
Gastroenterology. 2012; doi: 10.1007/s00535012-0721-x
7. Igarashi A, Yamamoto-Mitani N, Gushiken Y,
Takai Y, Tanaka M, Okamoto Y． Prevalence andincidence of pressure ulcers in Japanese
long-term-care hospitals. Archives of Gerontology
and Geriatrics. 2012 pii:S0167-4943(12) 00182-3.
8. Mikoshiba N, Tateishi R, Tanaka M, Sakai T,
Blazeby JM, Kokudo N, Koike K, Kazuma K.
Validation of the Japanese version of the EORTC
hepatocellular carcinoma-specific quality of life
questionnaire module (QLQ- HCC18). Health andquality of life outcomes. 2012; 10:58.
9. Ito N, Ishiguro M, Uno M, Kato S, Shimizu S,
Obata R, Tanaka M, Tokunaga K, Nagano M,
Sugihara K, Kazuma K. Prospective longitudinalevaluation of quality of life in patients withpermanent colostomy after curative resection forrectal cancer: A preliminary study. Journal ofwound ostomy continence nursing. 2012; 39(2):172-7.
10. 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; 35(1):24-31.

276

Department of Family Nursing
Professor
Kiyoko Kamibeppu, Ph.D., R.N., P.H.N.

Assistant Professor
Mari Ikeda, Ph.D., R.N., P.H.N.
Iori Sato, Ph.D., 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: a professor, and two
assistant professors. Also it has 5 doctoral students, 11
master’s course students, 3 undergraduate students, 1
research student, and 25 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
Clinical Immunology
3. Undergraduate Courses of Nursing, School ofIntegrated Health Sciences
Pediatric and Child Health Nursing
Clinical Practicum in Pediatric and Child HealthNursing

Research
The topics of our current research projects are as

follows:
1. The aggravation prophylaxis of postpartum
depression and prevention of child abuse andneglect.
2. Development of Pediatric QOL Inventory forchild with chronic illness and their parents.
3. Late effect of treatment and posttraumatic stressdisorder in children with cancer.
4. Care for mothers with severe mental illness andtheir offspring.
5. The roles and expertise of the nursing staffs indaycare centers.
6. Primary caregivers’ burden of the severely
disabled children and the utilization of the respitecare.
7. Care for dying patients and their families (QOL,
Family function)
8. Nurses’ attitudes toward Family Nursing.
Above all, in our research project entitled“Establishment of family nursing skills anddevelopment of medical collaboration system model
for child abuse prevention from perinatal period”, weare developing a support system on perinatal mental
health and child care, collaborating with the
University of Tokyo Hospital and people in thecommunity settings. In December 2012, we held afamily care forum on child abuse prevention, wheremore than 150 participants gathered from all over thecountry. We discussed child abuse prevention bystrengthening support network for parents and theirchildren without having them socially isolated.

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The studies entitled “Late effects of pediatriccancer survivors” and “Supporting pediatric cancer
survivors reentry to school” have been ongoing,
cooperating with pediatric cancer researchers andvarious organizations for family support across thecountry. Funding for these research projects was
succeeded from the Scientific Research Fund of
2004-2006 under the Ministry of Education, Culture,
Sports, Science and Technology Japan to the Health toLabour Sciences Research Grant.
Our newly engaged research studies included
exploring various experiences of children with cancer
and their family who were extensively affected by the
Tohoku Earthquake of 2011.
Furthermore, we hold Family Care Group
Supervisions bimonthly where we promote greater
understanding about family nursing practice and aim
at quality enhancement of clinical practice andresearch in family nursing and the establishment of
the science of family nursing.

Publications(1) Yonemoto T, Kamibeppu K, Ishii T, Iwata S,
Tatezaki S. Posttraumatic stress symptom (PTSS)
and posttraumatic growth (PTG) in parents ofchildhood, adolescent and young adult patientswith high-grade osteosarcoma. International
Journal of Clinical Oncology. 2012; 17(3): 272-5.
(2) Ueno R, Kamibeppu K. Perspectives of Japanesemothers with severe mental illness regarding thedisclosure of their mental health status to theirchildren. Archives of Psychiatric Nursing. 2012;26(5): 392-403.
(3) Komachi M, Kamibeppu K, Nishi D, Matsuoka Y.
Secondary traumatic stress and associated factors
among Japanese nurses working in hospitals.
International Journal of Nursing Practice. 2012;18(2): 155-63.
(4) Matsumoto K, Sumino K, , Fukahori H, Kitaoka
K, Kamibeppu K, Nagamura F. Stressor scale forclinical research coordinators: development andpsychometric testing. Journal of Advanced
Nursing. 2012; 68(7): 1636-45.
(5) IshidaY, Honda M, Sakamoto N, Ozono S,
Kamibeppu K, Iwai T, Kakee N, Okamura J,
Asami K, InadaH, Maeda N, Horibe K. An

analysis of free writing sections in a crosssectional survey of childhood cancer survivors．
Journal of the Japanese Society of PediatricSurgeons. 2012; 116(3): 526-536．
(6) Kamibeppu K, Toju K, Takeda T, Horibe K.
School re-entry practice for children with cancer
by medical teams and hospital school teachers inJapan: Current status by questionnaire survey.
The Journal of Pediatric Hematology Oncology
2012; 49(1), (2): 79-85.
(7) Soejima T, Toju K, Sato I, Takeda T, Kamibeppu
K. Evaluation of elementary and junior highschool students’ understanding of and attitudes
toward childhood cancer and the survivors. The
Journal of Child Health. 2012; 71(6): 858-866.
(8) Toju K, Yoshikawa K, Kamibeppu K. Support forschool reentry of children with cancer: Provisionof information from nurses about infectious
disease. Journal of Japanese Society of PediatricOncology Nursing. 2012; 7: 7-16．
(9) Sasaki A, Kamibeppu K. Male Nurses’
Perceptions of their gender and occupational
experiences. Journal of Japan Academy ofCommunity Health Nursing. 2012; 14(2): 24-31．
(10) Ikeda M ． Relationships carrying over to thesubsequent generations. Family Nursing:Research, understanding, and support for families(2). Health Care．2012; 54(9): 618-622．
(11) Sato I ． Differences in descriptions amongfamily informants． Family Nursing: Research,understanding and support for families (2).
Health Care．2012; 54(9): 607-612．

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Department ofCommunity Health Nursing /Public Health Nursing
Associate Professor
Satoko Nagata, Ph.D., R.N., P.H.N.

Research Associate
Atsuko Taguchi, M.H.S., R.N., P.H.N. (until August)Takashi Naruse, Ph.D., R.N., P.H.N.
Masako Kageyama, Ph.D., R.N., P.H.N. (from September)

Homepage

http://park.itc.u-tokyo.ac.jp/chn/

Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. At present,
there are three faculty members introduced above and
10 graduate course students (6 in master course, 4 indoctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

Education
1. Undergraduate program, in the School ofIntegrated Health Sciences
1) Community Health Nursing (4 credits, lectures)
Community health nursing is a study to develop
the caring techniques and the method to evaluate
the effectiveness of care not only for a person but
also for a whole community. This class is to
study, the concepts and functions of community
health nursing, developing process of community
health nursing, community assessment andactivities of community health nurses.
2) Home Health Nursing (2 credits, lectures)

The aim of this class is to have a deep
understanding of the social context around thehome care patients and the medical, health andwelfare system. Students learn the basics of caremanagement, home health care service, and healthcare system.
3) Health Guidance (2 credits, lectures)This class is to study the methodology andpractice of health guidance, which is the
supporting technique to promote health of thepeople living in the community.
4) Community Health Nursing Practice (2 credits,
practice)This program is intended to understand the systemof health promotion and prevention by attending
the actual community health nursing activities athealth center. Students are expected to realize theprinciple and the common technique ofcommunity health nursing activities by observing
the activities of public health nurses.
5) Home Health Nursing Practice (2 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 role279

of nursing through collaboration with otherprofession are mastered.
6) Health Assistance Practice (1 credit, 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.
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 Community Health Nursing Seminar I,
II and Practice I, II
We hold departmental meetings (journal reading
and introduction of research) every Tuesday andmonthly research seminars every third Friday toenhance research capacity.

Research
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity health care systems, and standardizationof skills among public health nurses in response to thehealth care needs of individuals, families, aggregatesand communities. Our research is supported by aGrant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science andTechnology, Health Science research, as well as grants
from the Ministry of Health, Labour and Welfare, andother foundations.
Ongoing research projects in our department are listed
below.
1. Discharge planning
Discharge planning is an interdisciplinary process that

is ideally available to aid patients and their families indeveloping a feasible plan for the next step of care.
Demand for discharge planning is increasing. We areattempting to standardize discharge planning activities
and develop outcome indicators and an educational
program on discharge planning for ward nurses. We
are also conducting research on the discharge planningsystem, developing guidelines for multi-sectional andinter-agency cooperation among nurses, andevaluating the capacity of discharge-planning nurses
in real-world settings.
2. Developing a community care system and fosteringcollaboration between home-care service providers
Fostering collaboration between home-care service
providers is an international concern in community
care, especially elderly health care. We are conducting
a study to measure the status of collaboration between
care providers in a community setting; it also aims todevelop efficient and feasible strategies to improve
this status.
3. Support for families with infants and children
Recently, custodial parents have faced manydifficulties and challenges. To address this, we areconducting research on social support and the
reduction of mothers’ anxiety, group approaches
toward the prevention of child abuse, and support forparents of hospitalized children in NICUs.
4. Support for families of people with mental illness
Some mental health professionals have recognizedthat families of people with severe mental illness
should be easy to receive support from professionals
in the last few years. We are conducting research on
the support provided to families of people with severe
mental illness, especially family support groups andself-help groups. We are also evaluating a family peer
education program.
5. Community health care for the elderly
We are conducting research on the health of theelderly to support favorable living conditions for thispopulation. Our research includes (1) the developmentof preventive care programs (e.g., preventive care
exercises, programs for (pre-) house-bound prevention,(2) identification of service needs among frail elderly

280

persons in community dwellings, (3) evaluation ofcommunity care services’ impact on the elderly andtheir family caregivers, and (4) the development of an
approach aimed at providing care for the terminally ill
in community settings (e.g., monitoring of resident
transfers).
6. Support for people with diseases or disabilities
Since the Great East Japan Earthquake on the 11th ofMarch, 2011, we have studied health conditions ofaffected individuals living in temporary housing inorder to improve their QOL in Otsuchi town, Iwate
prefecture. We aim to determine the relationshipbetween their health conditions and other related
factors, as well as develop an exercise program as apreventive measure.
7. Skills of public health nurses
Public health nurses use high-level support skills;
however, many of these skills have not been identified
through research. We aim to identify and standardize
the skills of public health nurses, focusing inparticular on skills regarding child-rearing, supporting
untreated residents in the community, and groupdynamics.

Publications(1) Satoko Nagata, Hikari Tomura, Sachiyo
Murashima. Expansion of discharge planningsystem in Japan: Comparison of results of anationwide survey between 2001 and 2010.
BMC Health Services Research, 12, 237, 2012.
(2) Takashi Naruse, Atsuko Taguchi, Satoko Nagata,
Yuki Kuwahara, Sachiyo Murashima.Prevalenceof home visiting nurse service clients who
received insufficient number of nurse visits in theJapanese long-term care insurance. Japanese
Journal of Nursing and Health Sciences, 10, 2-8,
2012.
(3) Takashi Naruse, Atsuko Taguchi, Yuki Kuwahara,
Satoko Nagata, Izumi Watai, Sachiyo Murashima.
Relationship between perceived time pressureduring visits and burnout among home visiting
nurses in Japan. Japan Journal of Nursing
Sciences, 9(2), 185-194, 2012.
(4) Takashi Naruse, Atsuko Taguchi, Yuki Kuwahara,

Satoko Nagata, Sachiyo Murashima. Effects of
non-nursing assistance on home visit nurses' timespent in Japan: one group repeated pretestposttest trial.The Home Health Care Management& Practice, 25(1), 18-22, 2013.
(5) Satoko Nagata, Atsuko Taguchi, Takashi Naruse,
Yuki Kuwahara, Sachiyo Murashima. Unmet
needs for visiting nurse services among older
people after hospital discharge and related factors
in Japan: Cross-sectional survey. Japan Journal of
Nursing Science, doi:10.1111/jjns.12012, 2013.
(6) Takashi Naruse, Mahiro Sakai, Izumi Watai,
Atsuko Taguchi, Yuki Kuwahara, Satoko Nagata,
Sachiyo Murashima. Individual and organizational factors related to work engagement among
home visiting nurses in Japan. Japan Journal of
Nursing Sciences, DOI: 10.1111/jjns.12003,
2013.
(7) Yuki Kuwahara, Satoko Nagata, Atsuko Taguchi,
Takashi Naruse, Hiroyuki Kawaguchi, Sachiyo
Murashima. Measuring the efficiencies ofvisiting nurse service agencies using dataenvelopment analysis. Health Care Management
Science, 1007/s10729-013-9228-0, 2013.
(8) Shigemi Suzuki, Satoko Nagata, Joyce Zerwekh,
Takuhiro Yamaguchi, Hikari Tomura, Yukie
Takemura, Sachiyo Murashima. Effects of amulti-method discharge planning educational
program for medical staff nurses. Japan Journalof Nursing Sciences, 9(2), 201-215, 2012.
(9) Hiroshi Murayama, Atsuko Taguchi, Sachiyo
Murashima. Exploring the ideal combination ofactivity satisfaction and burden among healthpromotion volunteers: a cross-sectional study inJapan . BMC Public Health, 2012.
(10) Hiroshi Murayama, Takuhiro Yamaguchi, Satoko
Nagata, Sachiyo Murashima. The effects of anintervention program for promoting interorganizational network building between
multidisciplinary agencies and community-basedorganizations: a cluster trial in Japan. BMC
Public Health, 12: 178, 2012.
(11) Toshiko Tada, Reiko Okamoto, Sachiyo
Murashima, Ruriko Suzuki, Yoko Sakai, Emiko
Kishi, Michie Nomura, Noriko Jojima, Masumi
Nishida, Keiko Koide, Chie Teramoto, Emiko
Kusano, Saori Iwamoto, Miki Saito. The Health281

and Livelihood of Seniors Affected by the
Tsunami after the Great East Japan Earthquake.
Journal of Shikoku Public Health Society, 58(1),134-140, 2013.
(12) Michie Nomura, Reiko Okamoto, Minori Tanaka,
Mie Okuda, Keiko Koide, Saori Iwamoto, Emiko
Kusano, Miki Saito, Masumi Nishida, Noriko
Jojima, Emiko Kishi, Yoko Sakai, Chie Teramoto,Toshiko Tada, Ruriko Suzuki, Sachiyo
Murashima. Community Profile of the Tohoku
Earthquake, 2011: Affected Areas as Perceived
by External PHNs. Journal of Shikoku Public
Health Society, 58(1), 119-125, 2013.
(13) Michie Nomura, Reiko Okamoto, Keiko Koide,
Saori Iwamoto, Emiko Kusano, Miki Saito,
Masumi Nishida, Takako Sao, Tomoko Kurata,
Reiko Kan, Noriko Jojima, Emiko Kishi, Yoko
Sakai, Chie Teramoto, Toshiko Tada, Ruriko
Suzuki, Sachiyo Murashima. Health Concerns in
Tsunami-Affected Areas as Perceived by External
PHNs in Japan 2011. Journal of Shikoku Public
Health Society, 58(1), 126-133, 2013.
(14) Satoko Nagata，Yuki Kuwahara，Atsuko Taguchi，Takashi Naruse，Sachiyo Murashima．Visiting
nurse’s work contents and time spent according
to client condition, Focused on work other thandirect care. Journal of Japan Academy of Home
Care, 16(2)，61-68，2013．
(15) Atsuko Taguchi，Satoko Nagata，Takashi Naruse，
Yuki Kuwahara ， Takashi Fukuda, Masako
Yamada, Yumiko Yoshiike, Shintaro Yamaki,
Kyoko Nakao, Yutaka Tagami, Sachiyo
Murashima．Estimaton of home visiting nurse
service needs and the unmet needs. Journal of
Health and Welfare Statistics, 59(4), 16-22, 2012.
(16) Masako Kageyama，Yumi Shirota，Mieko Toga，
Kanako Kawabata，Atsuko Taguchi．Professional
mental support provided by local government tofamilies of people with schizophrenia in need oftreatment. Japan Journal of Public Health，59(4),259-268, 2012.
(17) Masako Kageyama，Keiko Yokoyama．Skills tofacilitate a family-led education program formental illness. Japanese Journal of PsychiatricRehabilitation，16(2), 62-69, 2012.
(18) Yuki Kuwahara，Satoko Nagata， Atsuko Taguchi，Takashi Naruse，Shintaro Yamaki, Yutaka Tagami,

Sachiyo Murashima ． Classification of home
visiting nurse clients according to proportion of
direct / indirect tasks. Journal of the Japan
Society for Healthcare Administration, 49(4), 3747, 2012.
(19) Masako Kageyama ． The process of family
experiences in caring for persons with serious
mental illnesses: common stages identified througha literature review. Journal of Japan Academy of
Nursing Science，32(4), 63-70, 2012.
(20) Mahiro Sakai，Takashi Naruse，Izumi Watai,
Azusa Arimoto, Sachiyo Murashima. A literature
review on work engagement of nurses. Journal ofJapan Academy of Nursing Science，32(4), 71-78,
2012.

Health Sciences and Nursing
3. Clinical Nursing

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Department of Adult Health /Palliative Care Nursing
Professor
Noriko Yamamoto-Mitani, PhD, RN.

Associate Professor
Masakazu Nishigaki, PhD, RN, CGC.

Assistant Professor
Ayako Okuyama, MS, RN.
Mikako Yoshida, PhD, RN. (~2012.7)
Miho Suzuki, PhD, RN, ANP-BC. (2012.8~)

Project Assistant Professor
Nahoko Harada, MS, RN. (2012.5~2012.12)

Homepage

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

History and Organization
The Department of Adult Health Nursing/ Palliative
Care Nursing has almost 50 years of history andtradition. Originally the department was started as the
Department of Adult Health in 1965 and it underwent
several re-organizations. The current structure with
two sub-divisions of Adult Health Nursing and
Palliative Care Nursing has started in 2006. This year,
the department was re-started with Dr. Noriko
Yamamoto-Mitani as the new professor anddepartment chair.

Education
In the undergraduate program, our department is incharge of the lectures and clinical practicums for adult
health nursing. In graduate education, each graduate
student completes his/her Master’s thesis or doctoral
dissertation either by developing research question
from their own scientific interests, informed bylectures and seminars that this and other departments
provide, by taking responsibility in a part of larger

research project owned by the faculty. In education,
we emphasize the critical thinking process as a
researcher who conduct unique and original research:from cultivating perspectives as a researcher to comeup with original research interests, developing
research interests into unique research questions/hypotheses, choosing appropriate research methods,
and to developing valid research protocols.

Research
We conduct studies on various topics in the field of
adult and gerontological nursing. One major topic isquality management and improvement in long-termcare and home care nursing. We have been examining
systems that enable quality nursing care provided byhomecare nurses and in long-term facilities. The issueof nursing care quality to meet diverse needs of clients
at home or long-term care facilities will increase its
importance in coming years given the limited financial
resources and shortage of human resources in theseareas of practice.
Another topic is chronic pain and its management.

284

We have examined the current status of care forchronic pain, have been developing effective care
protocols for chronic pain, and examining effective
mechanisms to educate clinical nurses and care
workers on effective care strategies for pain
management. We aim to establish a new standard ofcare for persons in chronic pain in the community andlong-term care facilities, particularly older adults
including persons with dementia. Pain among older
adults tends to be overlooked by healthcare providers;
it is important to maintain and improve their physicalfunction and quality of life by managing pain
effectively.
We also conduct studies on a range of topics innursing of chronic conditions, from preventive to
end-of-life phase. We have been conducting studies
which are expected to allow us to understand the stateof individuals who require nursing in those periods,
and investigate effective and efficient nursing care forsuch individuals.
As research methods, along with conventional
statistical methods, we often utilize qualitative
methods in order to understand experiences ofindividual patients and/or nurses and to conceptualize
and theorize them. By developing the framework to
explain human experience of suffering and aging aswell as taking care of others, we hope to establish
nursing knowledge originated from the clinical realityof nursing in Japan, not from abroad.
The listed below are research projects that we haveconducted to date. Details of our publications andfunding are shown in our department website andannual report.
1) Effectiveness of internet homecare nursing
support system using the homecare nursing
quality indicators for elderly.
Homecare nursing in Japan is a relatively new formof nursing services, which have been utilized since
1992 when the homecare nurse stations for the elderly
were regulated. The current supply of homecare
nursing is still far to the goal level and some efforts toclose the gap are needed. Some tasks such as
reorganization of contents of homecare nursing
activities and establishment of the standards are

identified. Since 2004, we have been working on thedevelopment of the process-oriented quality indicatorsfor homecare nursing for elderly and examining theassociation between the implementation andoutcomes.
From 2008 to this year, to support homecare nurses
and attempt to improve the quality of care, thehomecare nursing support website using the homecare
nursing quality indicators for elderly has been triedand examined its effectiveness. On the website,
two-way communication between nursing providers
and researchers was available and they exchanged theinformation on such topics as dementia care, family
support, end-of-life care, fall prevention, bowel
movement care and rehabilitation. After one year trial,
we examined the change from pre- topost-implementation of the website in nurses’
self-evaluation on knowledge and practice. Also, we
studied the use of information technology devices athomecare nursing stations and nurses’ learning needs.
We gained new knowledge about the utilization andeffectiveness of a website as a self-learning andquality management tool that is useful and easy to use
in homecare nursing settings.
In addition, we have started a study on staff
management at homecare nursing stations as a part ofquality management issue in homecare nursing. In thisstudy, characteristics of homecare nursing stations thatretain nursing staff are explored.
2) Development of care standards for older people
with chronic pain
Chronic pain, such as back and knee pain caused byaging-associated diseases and neuropathic pain e.g.
postherpetic neuralgia, adversely affects older
people’s physical and living function and quality oflife. Yet it has been paid little attention for a long timein Japan. Older people with dementia are unable toexpress their pain appropriately and their pain is often
overlooked. Since 2008, we have explored pain in
residents in long-term care facilities, developed
instruments to measure by observation the pain inpeople who are unable to express verbally, andcomprehensively examined the perception andperformance with regard to pain care in nursing andcare staff working in long-term care facilities. This
year, we have joined a project that aims to develop

285pain care standards for nursing and care staff working
in long-term care facilities.
3) 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 those difficulties, particularly in people withdiabetes, inflammatory bowel diseases, and cancer.
This year we have been studying about quality oflife (QOL) among patients undergoing chemotherapy
and with hand-foot syndrome and factors associatedtheir QOL. We are about to start another study onneeds for supporting care among patients undergoinghematopoietic stem cell transplantation.

Publications (selected)
1. Takai Y, Yamamoto-Mitani N, Okamoto Y, Fukahori
H, Kou A, & Tanaka M. Family caregiver strategies
to encourage older relatives with dementia to use
social services. Journal of Advanced Nursing (inpress).
2. Adachi N, Munesada M, Yamada N, Suzuki H,
Futohashi A, Shigeeda T, Kato S, Nishigaki M.
Effects of aromatherapy massage on face-down
posture-related pain after vitrectomy: a randomized
controlled trial．Pain Management Nursing (in press)
3. Kayama M, Gregg F Misuzu, Asahara K,
Yamamoto-Mitani N, Okuma K, Oota K, &Kinoshita Y. Mentoring Doctoral Students for
Qualitative Research: Interviews to Experienced
Nursing Faculty in Japan. Journal of Nursing
Education (in press).
4. Kawakami A, Tanaka M, Nishigaki M, Naganuma
M, Iwao Y, Hibi T, Sanada H, Yamamoto-Mitani N,
Kazuma K. Relationship between non-adherence toaminosalicylate medication and the risk of clinicalrelapse among Japanese patients with ulcerative

colitis in clinical remission: a prospective cohort
study. Journal of Gastroenterology. DOI 10.1007/
s00535-012-0721-x
5. 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.
Gastroenterology
Nursing. 2012; 35(12): 24-31.
6. Suzuki M. Quality of life, uncertainty, and perceived
involvement in decision making in patients withhead and neck cancer. Oncology Nursing Forum,
2012; 39(6):541-548. DOI 10.1188/12.ONF.541-548
7. Nishigaki M, Shimizu Y, Kuroda K, Mori K, Ohara
Y, Seto N, Yoneda A, Miyatake Y, Kazuma K,
Masaki H as The Japan Academy of Diabetes
Education and Nursing Research Group.
Development of a support skill scale in insulin
therapy: A nationwide study in Japan. Nurse
Education Today. 2012;32(8):892-896.
8. Takai Y, Yamamoto-Mitani N, Ko A, & Heilemann
M. Differences in pain measures by MMSE scoresof residents in aged care facilities: Examining theusability of the Abbey Pain Scale- Japanese version,
Pain Management Nursing (in press).
9. Takai Y, Yamamoto-Mitani N, Chiba Y, & Kato A.
Feasibility and clinical utility of the Japanese
Version of the Abbey Pain Scale in Japanese agedcare, Pain Management Nursing (in press).
10. Takai Y, Yamamoto-Mitani N, Fukahori H,
Kobayashi S, Chiba Y. Nursing ward managers'
perception on pain prevalence at the aged carefacilities in Japan: A nationwide survey. PainManagement Nursing (in press).
11. Takai Y, Yamamoto-Mitani N, Nishikawa Y, Chiba Y,
Sugai Y, Hayashi K. Prevalence of pain amongresidents in Japanese nursing homes. PainManagement Nursing (in press).
12. Mikoshiba N, Tateishi R, Tanaka M, Sakai T,
Blazeby JM, Kokudo N, Koike K, Kazuma K.
Validation of the Japanese version of the EORTC
hepatocellular carcinoma-specific quality of life
questionnaire module (QLQ-HCC18). Health andQuality of Life Outcomes 2012;10:58.
13. Nishigaki M, Tokunaga-Nakawatase Y, Nishida J,
Taru C, Miyawaki I, Sanada H, Kazuma K.
Randomized Controlled Trial of the Effectiveness of
Genetic Counseling and a Distance, Computer-based,

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Lifestyle Intervention Program for Adult Offspringof Patients with Type 2 Diabetes: Background, Study
Protocol, and Baseline Patient Characteristics.
Journal of Nutrition and Metabolism Volume 2012(2012), Article ID 831735, 13 pages doi:10.1155/
2012/831735
14. Igarashi A, Yamamoto-Mitani N, Gushiken Y, Takai
Y, Tanaka M, Okamoto Y. Prevalence and incidenceof pressure ulcers in Japanese long-term-care
hospitals. Archives of Gerontology and Geriatrics.
2012 pii: S0167-4943(12)00182-3. doi: 10.1016/j.
archger.2012.08.011.
15. Ko A, Takasaki K, Igarashi A, Fukahori H, Chiba Y,
Yamamoto-Mitani N. Aggression toward caregivers
by older persons with dementia in long-term care
hospitals in Japan. Journal of Elder Abuse & Neglect.
2012;24(1):1-16.

287

Department ofMidwifery and Women's Health
Associate Professor
Megumi Haruna, Ph.D., R.N.M., P.H.N.

Assistant Professor
Masayo Matsuzaki, Ph.D., R.N.M., P.H.N.
Mie Shiraishi, 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 3 faculty members introduced
above and 9 graduate students (7 in master course, 2
in doctoral course) and a visiting researcher.

3) Midwifery III (2 credits, lectures)
4) Midwifery IV (3 credits, lectures)
5) Administration for Midwifery(1 credit, lectures)
6) Clinical Practicum in Midwifery I(1 credit, practices)
7) Clinical Practicum in Midwifery II(8 credits, practices)

Education
Research
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, practices)
3. Undergraduate Advanced Courses for Midwifery,
School of Health Sciences and Nursing1) Midwifery I (1 credit, lectures)
2) Midwifery II (1 credit, lectures)

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• Adequate maternal nutrition and weight
management
This study examines maternal body composition,
lipid metabolic biomarkers and nutritional intake tooptimize weight management and a healthy lifestyleduring pregnancy to prevent low birth weight. Basedon our investigations into the optimal maternal
nutritional status and gestational weight gain, we
propose health guidance that can help pregnant

288

women lower the risk of pregnancy complications
and adverse birth outcomes.
• Lifestyle factors and oxidative stress markers
during pregnancy
This study investigates 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.
• 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) 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
for the body after childbirth• Urinary and rectal incontinence after childbirthThis study investigates the prevalence and risk
factors of urinary and rectal incontinence among
women within five years after childbirth.
• Anal sphincter defects after delivery
This study investigates the prevalence and risk
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, to examine its validity and reliability, and to
identify the psychosocial risk factors of intense
fear of childbirth.

Publications
1. Haruna M, Watanabe E, Matsuzaki M, Ota E,
Shiraishi M, Murayama R, Yoshida M, Yeo S. The
effects of an exercise program on health-related
quality of life in postpartum mothers: A
randomized controlled trial. Health. 2013; 5(3):432-439.
2. Kitamura T, Ohashi Y, Kita S, Haruna M, Kubo R.
Depressive mood, bonding failure, abusive
parenting among mothers with three-month oldbabies in a Japanese community. Open Journal of
Psychiatry. 2013; 3: 1-7.
3. Murayama R, Tsuda M, Haruna M, Matsuzaki M,
Aoki K. Relationship between perceived sleep
posture and subjective sleep quality: Changes
related to progression of pregnancy. J So Nurs
Pract. 2013; 25(1): 49-57.
4. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Validity of a diet history
questionnaire estimating β-carotene, vitamin C,
and α-tocopherol intakes in Japanese pregnant
women. Int J Food Sci Nutr. 2013 (in press).
5. Takegata T, Haruna T, Matsuzaki M, Shiraishi M,
Murayama R, Okano T, Severinsson E.
Translation and validation of the Japanese versionof the Wijma Delivery Expectancy/Experience
Questionnaire version A. Nurs Health Sci. 2013(in press).

289

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, 3
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.

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 of290caregiver 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.

References
1. Eguchi H, Tsuda Y, Tsukahara T, Washizuka S,
Kawakami N, Nomiyama T. The effects ofworkplace occupational mental health and related
activities on psychological distress among
workers: a multilevel cross-sectional analysis. J
Occup Environ Med. 2012 Aug;54(8):939-47.
2. Lim SS, Vos T, Flaxman AD, Danaei G, et al. A
comparative risk assessment of burden of disease
and injury attributable to 67 risk factors and risk
factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease
Study 2010. Lancet. 2013 Dec 15;380(9859):
2224-60. doi: 10.1016/S0140-6736(12)61766-8.
3. Murray CJ, Vos T, Lozano R, et al. Disabilityadjusted life years (DALYs) for 291 diseases andinjuries in 21 regions, 1990-2010: a systematic
analysis for the Global Burden of Disease Study
2010. Lancet. 2013 Dec 15;380(9859):2197-223.
doi: 10.1016/S0140-6736(12)61689-4.
4. Vos T, Flaxman AD, Naghavi M, et al. Years lived
with disability (YLDs) for 1160 sequelae of 289
diseases and injuries 1990-2010: a systematic
analysis for the Global Burden of Disease Study
2010. Lancet. 2013 Dec 15;380(9859):2163-96.
doi: 10.1016/S0140-6736(12)61729-2..
5. Hirokawa K, Taniguchi T, Tsuchiya M, Kawakami
N. Effects of a stress management program for
hospital staffs on their coping strategies andinterpersonal behaviors. Ind Health. 2012;50(6):487-98.
6. Tsuchiya M, Kawakami N, Ono Y, Nakane Y,
Nakamura Y, Fukao A, Tachimori H, Iwata N, Uda
H, Nakane H, Watanabe M, Oorui M, Naganuma
Y, Furukawa TA, Kobayashi M, Ahiko T,
Takeshima T, Kikkawa T. Impact of mental
disorders on work performance in a community
sample of workers in Japan: the World Mental
Health Japan Survey 2002-2005. Psychiatry

Research. 2012; 198:140-145.
7. Shimazu A, Schaufeli WB, Kubota K, Kawakam
N. Do workaholism and work engagement predict
employee well-being and performance in opposite
directions? Ind Health. 2012;50: 316-321.
8. Chiba R, Kido Y, Miyamoto Y, Kawakami N.
[Aspects regarded as insufficient by community
residents for living in harmony with people withmental illness: A qualitative analysis of aquestionnaire survey of Tokyo citizens.] (inJapanese)]. Iryo to Shakai. 2012; 22(2): 127-138.
9. Shimazu A, Sonnentag S, Kubota K, Kawakami N.
Validation of the Japanese version of Recovery
Experience Questionnaire. J Occup Health. 2012;
54:196-205.
10. Hirokawa S, Matsumoto T, Katsumata Y, Kitani
M, Akazawa M, Takahashi Y, Kawakami N,
Watanabe N, Hirayama M, Kameyama A,
Takeshima T. Psychosocial and psychiatric characteristics of suicide completers with psychiatrictreatment before death: A psychological autopsy
study of 76 cases. Psychiatry Clin Neurosci. 2012
Jun;66(4):292-302.
11. Miyamoto Y, Sono T. Lessons from peer support
among individuals with mental health difficulties:
A review of the literature. Clinical Practice &Epidemiology in Mental Health. 2012;8:22-9.
12. Park J, Kitayama S, Karasawa M, Curhan K,
Markus HR, Kawakami N, Miyamoto Y, Love GD,
Coe CL, Ryff C. Clarifying the links betweensocial support and health: culture, stress, andneuroticism matter. J Health Psychol. 2012
13. Furukawa TA, Horikoshi M, Kawakami N,
Kadota M, Sasaki M, Sekiya Y, Hosogoshi H,
Kashimura M, Asano K, Terashima H, Iwasa K,
Nagasaku M, Grothaus LC, on behalf of the
GENKI Project. Telephone cognitive-behavioral
therapy for subthreshold depression andpresenteeism in workplace: a randomized
controlled trial. PLoS ONE. 2012; 7(4): e35330
14. Kubota K, Shimazu A, Kawakami N, Takahashi M,
Nakata A, Schaufeli, W. B. The Empirical
Distinctiveness of Workaholism and WorkEngagement among Hospital Nurses in Japan: theeffect on Sleep Quality and Job Performance.
Ciencia & Trabajo. 2012; 14: 31-36.
15. Funakoshi A, Miyamoto Y. Quality study of291

attitudinal changes in parents with a child with
Hikikomori. Japanese Journal of Child andAdolescent Psychiatry. 2011；52(Supplement):1831.
16. Kawakami N, Abdulghani EA, Alonso J, Bromet
EJ, Bruffaerts R, Caldas-de-Almeida JM, Chiu
WT, de Girolamo G, de Graaf R, Fayyad J, Ferry F,
Florescu S, Gureje O, Hu C, Lakoma MD,
Leblanc W, Lee S, Levinson D, Malhotra S,
Matschinger H, Medina-Mora ME, Nakamura Y,
Oakley Browne MA, Okoliyski M, Posada-Villa J,
Sampson NA, Viana MC, Kessler RC. Early-lifemental disorders and adult household income in
the World Mental Health Surveys. Biol Psychiatry.
2012 Aug 1;72(3):228-37.
17. Umeda M, Kawakami N, the World Mental HealthJapan Survey Group 2002-2006. Association ofchildhood family environments with the risk ofsocial withdrawal ('hikikomori') in the community
population in Japan. Psychiatry Clin Neurosci.
2012 Mar; 66:121-129.
18. Kessler RC, McLaughlin KA, Koenen KC,
Petukhova M, Hill ED, The WHO World Mental
Health Survey Consortium. The importance of
secondary trauma exposure for post-disastermental disorder. Epidemiology and Psychiatric
Sciences. 2012; 21(1):35-45.
19. Hirokawa S, Kawakami N, Matsumoto T, Inagaki
A, Eguchi N, Tsuchiya M, Katsumata Y, Akazawa
M, Kameyama A, Tachimori H, Takeshima T.
Mental disorders and suicide in Japan: a nationwide psychological autopsy case-control study. J
Affect Disord. 2012 Oct;140(2):168-75.
20. Cheng Y, Park J, Kim Y, Kawakami N. The
recognition of occupational diseases attributed toheavy workloads: experiences in Japan, Korea, andTaiwan. Int Arch Occup Environ Health. 2012 Oct;85(7):791-9.
21. Ando S, Kawakami N; World Mental Health Japan
Survey Group. Utility of self-reported sleep
disturbances as a marker for major depressive
disorder (MDD): findings from the World Mental
Health Japan Survey 2002-2006. Psychiatry Res.
2012 Jun 30;198(1):146-53.

292

Department ofGerontological Nursing /Wound Care Management
Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Lecturer
Gojiro Nakagami, R.N., Ph.D.

Project Lecturer
Takashi Nagase*, M.D., Ph.D.,

Takeo Minematsu, Ph.D.

Research Associate
Makoto Oe*, R.N., Ph.D.,

Nao Tamai, R.N., Ph.D.,

Mikako Yoshida*, R.N., M.W., Ph.D.

* by December 2012

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, 3 research associate, and 7
part-time lecturers for undergraduate course (2) andfor graduate course (5). The student body consists of 6
doctoral course students and 14 master course students.
The goal of our department is to achieve “Evidencebased practice and development of gerontologicalnursing and wound care 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 2012 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 2012 contents were as follows;a) Age-related changes in the physiologic system,
Aging and dementiab) Aging and osteoporosis, Aging and respiratory
disorders.
c) Aging and cardiovascular disorders, Aging and293

renal function, hypertension, and stroked) 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 2012 was
supported by the long-term care facility owned by
Medical Corporation Tatsuoka.
3) Bachelor’s thesis
There was no undergraduate student in 2012.
2. Graduate course
1) Gerontological Nursing I(Summer course/ 2 credits)
The main theme of Gerontological Nursing I in 2012
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.
2) Gerontological Nursing II(Winter course/ 2 credits)
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 2012were as follows;a) Analysis of walking in rehabilitation medicineb) Evaluation of gait and posture in the elderly
patientc) Technology to maintain health and support cared) Team approach for rehabilitation of feeding andswallowing difficulty.
e) Metabolic changes and nutritional management in
the elderly people, and nutritional management ofcancerf) Dementia care focusing on patients withearly-onset dementia and their family.
g) Medical economics as behavioral science
3) Wound Care Management I(Summer course/ 2 credits)
The main theme of Wound Care Management I in2012 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
4) Wound Care Management II(Winter course/ 2 credits)
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) Nutrition managementb) Support surfacesc) Alopeciad) Basic knowledge and clinical application ofultrasonographye) Advanced wound caref) Nursing pharmacology
Systematization of objective pressure ulcer assessment
technologies by multidisciplinary approach
5) Master’s thesis
The followings were research themes in 2012;“Elevated plantar pressure in diabetic patients and its
relationship with their gait features”

294“Molecular markers of biological responses tocompressive loading for the prediction of delayed
wound healing due to pressure”“Exploring the prevalence of skin tears and skinproperties related to tissue tolerance in elderly patientsat a long-term medical facility in Japan”“Method for detection of silent aspiration based on
B-mode video ultrasonography assisted by image
processing”“Fundamental research on skin hygiene care using
isotonic solution in elderly – Hypoosmotic
shock-induced subclinical inflammation of skin inhairless rats (in Japanese)”5) Doctor’s thesis
The followings were research themes in 2012;“Relationship between performance of feet washingand tinea pedis in patients with diabetes (in Japanese)”

Research activities
1. Activity policy
Our gerontological nursing research focuses on
elderly persons suffering with geriatric syndromes
such as pressure ulcers, incontinence, malnutrition,
pain, dysphagia, osteoporosis and dementia. Our
wound care management research focuses on pressure
ulcers, diabetic foot ulcers, ulcers with peripheral
vascular diseases, and malignant fungating ulcers.
The majority of our clinical research is conducted
at The University of Tokyo Hospital. We areparticipating in pressure ulcer ward rounds as
members of the Pressure Ulcer Team of the hospital.
We also attend the Foot Care Outpatient Clinic heldby the Department of Metabolic Diseases and the
Stoma Outpatient Clinic held by the Departments ofUrology and Colorectal Surgery. In addition, we
support the Department of Advanced Nursing
Technology which was developed in December 2012as a social cooperation program to promote team
medical treatment and research involving the clinicaldivision, the nursing department, and the graduate
nursing school. Through this program, nurses canstudy the subject of nursing scientifically, including
research in epidemiologic surveys and molecular- andgene-level topics in cooperation with a university
professor. Furthermore, the technology and medical

equipment developed by companies can now be
evaluated in the hospital, offering new nursing
technology suitable for needs in clinical sites.
Our special research missions in 2012 were
twofold:(1) We aimed to develop the research system
within our department as a sequential flow of“translational research” from basic biology throughengineering by industry-academia cooperation to theestablishment of clinical evidence that returns theresults of our research to the society. Some of thestudies described below were performed in thisdirection.
(2) Development of new nursing devices requires
the involvement of engineering specialists. We haveinvented a number of nursing products and equipment
based on our research through academia-industry
cooperation. We continued research in 2012 with the
Department of Life Support Technology (Molten) that
had been established in 2010 as a cooperating
department. The Bioengineering Nursing Meeting wassponsored by our department in June, 2012, aiming at
the development of this new research field. We thenheld the kickoff symposium of Nursing Science andEngineering. Researchers, from nursing, engineering,and industry discussed future perspectives in this area.
From this symposium, the Society for Nursing Scienceand Engineering has been established to promote
cooperation among nurses, clinicians and engineers
and to improve human health and quality of life
through bioengineering nursing. We will have the 1stannual meeting of Nursing Science and Engineering at
The University of Tokyo in 2013.
We held the 8th University of Tokyo Open
Seminar of Advanced Wound Care on November 2012.
The lecture entitled "Gerontological care and life
support technology" was given by Dr. Taketoshi Morifrom the Department of Life Support Technology(Molten) at The University of Tokyo.
As the international activity, the 4th Congress ofthe World Union of Wound Healing Societies was heldin Japan and Prof. Sanada served as vice-president.
Our department offered 25 oral presentations and 18
posters of research to disseminate scientific evidence
in wound care from Japan. Also, our department
serves on the International Board of Directors of theInternational Lymphoedema Framework (ILF), an295international group for lymphoedema management.
Moreover, our department serves as the chief directorof the ILF Japan, where the aim is the international
standardization of lymphoedema care. A system ofdata collection in multiple languages is being
developed with ILF representative Prof. Christine
Moffat (University of Nottingham, UK) for
construction of a data base concerning this diagnosis
and treatment services that can be used around theworld.
2. Research fields and themes in 2012
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 elucidation of
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 equipped withinterface pressure sensing system and automaticpressure control
・ Non-invasive detection of tissue injury andpre-injury status using ultrasonography andthermography
・ Development of a handy type kit for diagnosis ofwound 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
・ 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)・ 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 foot circulation
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.
・ The best young researcher’s presentation prize ofCommittee of Assistive Technology, Bio Medical
Engineering and Life Support 2012
“Comparison of diabetic patients gait with
non-diabetic subjects gait using plantar pressure
sensor and dorsal feet motion sensors”
・ The 4th Congress of the World Union of Wound
Healing Societies Poster Prize“Granulation tissue color evaluated by digital
analysis of wound photographs and nutritional
status for patients with deep pressure ulcers, Part
I: A cross sectional study”“Risk factors for infection during tissue
expansion in tissue expander and implant breastreconstruction”“Application of wound blotting method forassessment of pressure ulcers: case reports”
・ The 21th Annual Meeting of Japanese Society ofWound, Ostomy and Continence Management.
The best presentation prize“Evaluationofparastomal
herniabyultrasonography (in Japanese)”
The best paper prize“Initial study of a scale to assess cooperation
skills of wound, ostomy and continence nurses
in the systematic management of pressure ulcers– reliability and validity of the scale items. J Jpn
WOCM. 2011;15(4):282-91 (in Japanese)”“Evaluation of preventive effect on buttocks

296

immersion of independently controlled inner air
cell pressure in air mattress. J Jpn WOCM.
2011;15(3):239-49”
・ The Otsuka prize of the 14th Annual Meeting of
the Japanese Society of Pressure Ulcer“Serum albumin level is a limited nutritional
marker for predicting wound healing in patientswith pressure ulcer: Two multicenter prospective
cohort studies. Clin Nutr. 2011;30(6):738-45”

References
1. Minematsu T, Nakagami G, Yamamoto Y,
Kanazawa T, Huang L, Koyanagi H, Sasaki S,
Uchida G, Fujita H, Haga N, Yoshimura K,
Nagase T, Sanada H. Wound blotting: A
convenient biochemical assessment tool for
protein components in exudate of chronic wounds.
Wound Repair Regen. 2013;21(2):329-34.
2. Zhong X, Nagase T, Huang L, Kaitani T, Iizaka S,
Yamamoto Y, Kanazawa T, Sanada H. Reliability
and validity of the Chinese version of DESIGN-R,
an assessment instrument for pressure ulcers.
Ostomy Wound Manage. 2013;59(2):36-43.
3. Murayama R, Tsuda M, Haruna M, Matsuzaki M,
Sanada H, Aoki K. Relationship between
perceived sleep posture and subjective sleep
quality: Changes related to progression ofpregnancy. J So Nurs Pract. 2013;25(1):49-57.
4. Dai M, Okuwa M, Katayama M, Nakatani T,
Ueyama T. Minamiyama T, Iuchi T, Higi K,
Sugama J, Sanada H. Addition of vibration tosimple lymphatic drainage in the management ofbreast cander-related lymphedema: A randomized
controlled cross over pilot study. J So Nurs Pract.
2013;25(1):58-66.
5. Mori T, Sato T,Kuroda A, Tanaka M, Shimosaka
M, Sato T, Sanada H, Noguchi H. Outdoor map
construction based on aerial photography andelectrical map using multi-plane laser range scandata. J Robot Mechatron. 2013;25(1):5-15.
6. Higashino T, Nakagami G, Kadono T, Ogawa Y,
Iizaka S, Koyanagi H, Sasaki S, Haga N, Sanada
H. Combination of thermographic and ultrasonographic assessments for early detection of deep
tissue injury. Int Wound J. 2012 Nov 22. [Epubahead of print]

7. Tamai N, Kaitani T, Takehara K, Oe M, Nagase T,
Murayama R. Evaluation of skin temperature,humidity, and comfort of two types of absorbent
products for urinary incontinence. J Jpn WOCM.
2012;16(4):345- 52.
8. Kawakami A, Tanaka M, Nishigaki M, Naganuma
M, Iwao Y, Hibi T, Sanada H, Yamamoto-Mitani
N, Kazuma K. Relationship between nonadherence to aminosalicylate medication and therisk of clinical relapse among Japanese patientswith ulcerative colitis in clinical remission: aprospective cohort study. J Gastroenterol. 2012
Dec 4. [Epub ahead of print]
9. Oe M, Sanada H, Nagase T, Minematsu T, Ohashi
Y, Kadono T, Ueki K, Kadowaki T. Sweat gland
atrophy of the heel in diabetic patients with
angiopathy. J Clin Nurs. 2013;22(1-2):289-92.
10. Iizaka S, Matsuo J, Konya C, Sekine R, Sugama J,
Sanada H. Estimation of protein requirements
according to nitrogen balance for older
hospitalized adults with pressure ulcers according
to wound severity in Japan. J Am Geriatr Soc.
2012;60(11):2027-34.
11. Iizaka S, Kaitani T, Sugama J, Nakagami G, Naito
A, Koyanagi H, Konya C, Sanada H. Predictive
validity of granulation tissue color measured bydigital image analysis for deep pressure ulcer
healing: a multicenter prospective cohort study.
Wound Repair Regen. 2013;21(1):25-34.
12. Paes C, Nakagami G, Minematsu T, Nagase T,
Huang L, Sari Y, Sanada H. The Pseudomonas
aeruginosa quorum sensing signal molecule
N-(3-oxododecanoyl)homoserine
lactoneenhances keratinocyte migration and induces
Mmp13 gene expression in vitro. Biochem
Biophys Res Commun. 2012;427(2):273-9.
13. Nagase T, Akase T, Sanada H, Minematsu T, Ibuki
A, Huang L, Asada M, Yoshimura K, Nagase M,
Shimada T, Aburada M, Nakagami G, Sugama J.
Aging-like skin changes in metabolic syndromemodel mice are mediated by mineralocorticoid
receptor signaling. Aging Cell. 2013;12(1):50-7.
14.
Mori T, Ishino T, Noguchi H, Sato T, Miura
Y, Nakagami G, Oe M, Sanada H. Life patternestimation of the elderly based on accumulated
activity data and its application to anomaly
detection. J Robot Mechatron. 2012;24(5):754-65.

297

15. Mori T, Hamatani M, Noguchi H, Oe M, Sanada
H. Insole-type simultaneous measurement systemof plantar pressure and shear force during gait fordiabetic patients. J Robot Mechatron. 2012;24(5):766-72.
16. Fukui R, Mori T, Sato T. An electrostatic
capacitive floor sensor system for human position
monitoring in a living space. Advanced Robotics.
2012;26(10):1127-42.
17. Iizaka S, Sanada H, Matsui Y, Furue M, Tachibana
T, Nakayama T, Sugama J, Furuta K, Tachi M,
Tokunaga K, Miyachi Y; Scientific Education
Committee of the Japanese Society of Pressure
Ulcers. Predictive validity of weekly monitoringof wound status using DESIGN-R score change
for pressure ulcer healing: A multicenterprospective cohort study. Wound Repair Regen.
2012;20(4): 473-81.
18. Iwahira Y, Nagase T, Nakagami G, Huang L, Ohta
Y, Sanada H. Histopathological comparisons ofirradiated and non-irradiated breast skin from thesame individuals. J Plast Reconstr Aesthet Surg.
2012;65(11):1496-505.
19. Oe M, Yotsu RR, Sanada H, Nagase T, Tamaki T.
Thermographic findings in a case of type 2
diabetes with foot ulcer and osteomyelitis. J
Wound Care. 2012;21(6): 274-8.
20. Asada M, Nakagami G, Minematsu T, Nagase T,
Akase T, Huang L, Yoshimura K, Sanada H.
Novel models for bacterial colonization andinfection of full-thickness wounds in rats. Wound
Repair Regen. 2012;20(4):601-10.
21. Sugama J, Sanada H, Shigeta Y, Nakagami G,
Konya C. Efficacy of an improved absorbent pad
on incontinence-associated dermatitis in older
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22. Sasaki N, Nakagami G, Sakai K, Kato H, Nanjo Y,
Sanada H. Determining the optimal inner air cellpressure for the effective reduction of interfacepressure. J Tissue Viability. 2012; 21(2):47-53.
23. Sugimoto T, Huang L, Minematsu T, Yamamoto Y,
Asada M, Nakagami G, Akase T, Nagase T, Oe M,
Mori T, Sanada H. Impaired aquaporin 3
expression in reepithelialization of cutaneous
wound healing in the diabetic rat. Biol Res Nurs.
2013;15(3):347-55.

24. Mori T, Tominaga S, Noguchi H, Shimosaka M,
Fukui R, Sato T. Predicting behaviors of residents
by modeling preceding action transition fromtrajectories. J Robot Mechatron. 2012;24(2):320-9.

International Health
1. International Social Medicine

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Department of
Global Health Policy
Professor
Kenji Shibuya, MD, DrPH

Faculty members
Manami Inoue, MD, PhD
Nayu Ikeda, MA, PhD
Mariko Gakiya, MA, EdD
Stuart Gilmour, MPH, MStat
Naoko Jinjo, BA, MA
Mayuka Yamazaki, BA, MA
Tomohiro Hamakawa, BA, MPP

Homepage

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

Introduction and Organization
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. As of March 2013 thedepartment, headed by Professor Kenji Shibuya,
included the following staff complement: one project
professor (Minami Inoue); two project lecturers (Nayu
Ikeda, Mariko Gakiya); one assistant professor; threeproject assistant professors (Naoko Jinjo, Mayuka
Yamazaki, and Tomohiro Hamakawa); two postdoctoral fellows; 12 adjunct lecturers; seven doctoral
students; and six master’s students.
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 healtharchitecture 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 generation of leaders in global
health.

Education
All lectures in the department are conducted in
English, in order to ensure that student writing andpresentation skills are held to an international standard.
Furthermore, through the Global Health Leadership
Program students are able to develop skills andexperience to become future leaders in global health.

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Master's program
The Master's program is a demanding, interdisciplinary program emphasizing student-directed
learning, problem-solving, and the acquisition of
fundamental public health skills required for global
health practices (health policy, statistics, epidemiology,
and social sciences). Students are required to completea minimum of 30 course credits and a master’s thesis.
Beyond the program and concentration requirements,
students are encouraged to consult with faculty
advisers to choose elective courses best suited to theirneeds.
PhD program
The PhD program is designed to train the next
generation of leaders in global health. PhD students
are required to complete a minimum of 24 course
credits and a doctoral thesis with which needs to be
published in a peer-reviewed journal. PhD students
without MPH degree should take the lectures toacquire fundamental public health skills such as healthpolicy, biostatistics and epidemiology.
Global Health Policy I and IIThis course introduces the principles and theories ofglobal health problems, as well as practicalapplications of quantitative methods (demography,
statistics, epidemiology and econometrics) to analyze
and interpret issues and challenges for policy.
The following topics are covered in the 2012
academic year:- Global health policy- Global health governance- Health-related MDG- Acute disease surveillance- Quantifying burden of disease- Comparative risk factor analysis- Health system performance assessment- Health financing and priority setting

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
AXA Chair on Health and Human Security, AXA
Research Fund
Comprehensive

ResearchonLife-Style

Related301

Diseases Including Cardiovascular Diseases andDiabetes Mellitus: Projection of disease burden andeconomic burden allowing for change in population
structure, socioeconomic status, and lifestyles in Japan.
Ministry of Health, Labour, and Welfare Health andLabour Science Research Grants. PI: Manami Inoue.

Researching new global strategies for the treatment of
HIV and Tuberculosis. Ministry of Education, Culture,
Sports, Science and Technology, Grants-in-Aid for
Challenging Exploratory Research. PI: Stuart
Gilmour.

Publications
Third Term Comprehensive Control Research forCancer: Research to improve cancer prevention, cancer
screening, and cancer treatment in Asian countries.
Ministry of Health, Labour, and Welfare, Health andLabour Science Research Grants. CI: Manami Inoue.
Development and Evaluation of Cancer Prevention
Strategies in Japan. National Cancer Center, National
Cancer Center Research and Development Fund. CI:
Manami Inoue
The burden of cancer attributable to diabetes mellitus
in Japan. Ministry of Education, Culture, Sports,
Science and Technology, Grants-in-Aid for Scientific
Research (C). PI: Manami Inoue
Development of standardized dish-based nutrient
database for nutrition research in Japan. Ministry of
Education, Culture, Sports, Science and Technology,
Grants-in-Aid for Scientific Research (C). CI:
Manami Inoue
Integrated research of social and health science toinvestigate the pathogenesis of cardiovascular diseases
attributable to social and psychological factors.
Ministry of Education, Culture, Sports, Science andTechnology, Grants-in-Aid for Scientific Research (C).
CI: Manami Inoue
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

1. Inoue M, Nagata C, Tsuji I, Sugawara Y, Wakai K,
Tamakoshi A, Matsuo K, Mizoue T, Tanaka K,
Sasazuki S, Tsugane S. Impact of alcohol intake on
total mortality and mortality from major causes inJapan: a pooled analysis of six large-scale cohort
studies. Journal of Epidemiology and Community
Health. 2012;66:448-56.
2. Eshak ES, Iso H, Kokubo Y, Saito I, Yamagishi K,
Inoue M, Tsugane S. Soft drink intake in relation toincident ischemic heart disease, stroke, and stroke
subtypes in Japanese men and women: the Japan
Public Health Centre-based study cohort I.
American Journal of Clinical Nutrition. 2012;96:1390-7.
3. Zhang X, Spiegelman D, Baglietto L, Bernstein L,
Boggs DA, van den Brandt PA, Buring JE, Gapstur
SM, Giles GG, Giovannucci E, Goodman G,
Hankinson SE, Helzlsouer KJ, Horn-Ross PL, Inoue
M, Jung S, Khudyakov P, Larsson SC, Lof M,
McCullough ML, Miller AB, Neuhouser ML,
Palmer JR, Park Y, Robien K, Rohan TE, Ross JA,
Schouten LJ, Shikany JM, Tsugane S, Visvanathan
K, Weiderpass E, Wolk A, Willett WC, Zhang SM,
Ziegler RG, Smith-Warner SA. Carotenoid intakes
and risk of breast cancer defined by estrogen
receptor and progesterone receptor status: a pooled
analysis of 18 prospective cohort studies. American
Journal of Clinical Nutrition. 2012;95:713-25.
4. Hara A, Sasazuki S, Inoue M, Iwasaki M, Shimazu
T, Sawada N, Yamaji T, Takachi R, Tsugane S.
Zinc and heme iron intakes and risk of colorectal
cancer: a population-based prospective cohort study
in Japan. American Journal of Clinical Nutrition.
2012;96:864-73.
5. Inoue M, Tsugane S. Insulin resistance and cancer:
epidemiological evidence. Cancer Science.
2012;19:F1-F8.
6. Inoue M, Sawada N, Matsuda T, Iwasaki M,
Sasazuki S, Shimazu T, Shibuya K, Tsugane S.

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Attributable causes of cancer in Japan in 2005--systematic assessment to estimate current burdenof cancer attributable to known preventable risk
factors in Japan. Annals of Oncology. 2012;23:
1362-9.
7. Ikeda N, Inoue M, Iso H, Ikeda S, Satoh T, Noda M,
Mizoue T, Imano H, Saito E, Katanoda K, Sobue T,
Tsugane S, et al. Adult mortality attributable topreventable risk factors for non-communicablediseases and injuries in Japan: a comparative risk
assessment. PLoS Medicine. 2012;9:e1001160.
8. Tanaka K, Tsuji I, Tamakoshi A, Matsuo K, Ito H,
Wakai K, Nagata C, Mizoue T, Sasazuki S, Inoue M,
Tsugane S. Obesity and liver cancer risk: anevaluation based on a systematic review of epidemiologic evidence among the Japanese population.
Japanese Journal of Clincal Oncology. 2012;42:212-21.
9. Shimazu T, Sasazuki S, Wakai K, Tamakoshi A,
Tsuji I, Sugawara Y, Matsuo K, Nagata C, Mizoue
T, Tanaka K, Inoue M, Tsugane S. Alcohol drinking
and primary liver cancer: a pooled analysis of fourJapanese cohort studies. International Journal ofCancer. 2012;130:2645-53.
10. Murray CJL, Ezzati M, Flaxman AD, Lim S,
Lozano R, Michaud C, Naghavi M, Salomon JA,
Shibuya K, Vos T, Wikler D, Lopez AD. GBD
2010: a multi-investigator collaboration for global
comparative descriptive epidemiology. Lancet.
2012;380:2055-58.
11. Hisashige A. The Effectiveness and Efficiency of
Disease Management Programs for Patients with
Chronic Diseases. Global Journal of Health Science.
2013;5(2): 27-49.
12. Murray CJL, Ezzati M, Flaxman AD, Lim S,
Lozano R, Michaud C, Naghavi M, Salomon JA,
Shibuya K, Vos T, Wikler D, Lopez AD. GBD
2010: design, definitions, and metrics. Lancet.
2012;380:2063-66.
13. Yoshida M, Murayama R, Ota E, Nakata M,
Kozuma S, Homma Y. Reliability and validity of
the Japanese version of the pelvic floor distressinventory-short form 20. International Urogynecology Journal. 2012 (Online First).
14. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K,
Adair-Rohani H, Amann M, Anderson HR, et al. A
comparative risk assessment of burden of disease

and injury attributable to 67 risk factors and risk
factor clusters in 21 regions, 1990–2010: asystematic analysis for the Global Burden of
Disease Study 2010. Lancet. 2012; 380: 2224–60.
15. Vos T, Flaxman AD, Naghavi M, Lozano R,
Michaud C, Ezzati M, Shibuya K, Salomon J, et al.
Years lived with disability (YLDs) for 1160
sequelae of 289 diseases and injuries 1990–2010: asystematic analysis for the Global Burden of
Disease Study 2010. Lancet. 2012; 380: 2163–96.
16. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya
K, Aboyans V, Abraham J, Adair T, et al. Global
and regional mortality from 235 causes of death for
20 age-groups in 1990 and 2010: A systematic
analysis. Lancet. 2012; 380: 2095–128.
17. Murray CJL, Vos T, Lozano R, Naghavi M,
Flaxman AD, Michaud C, Ezzati M, Shibuya K,
Salomon JA, et al. Disability-adjusted life years(DALYs) for 291 diseases and injuries in 21 regions,
1990–2010: a systematic analysis for the Global
Burden of Disease Study 2010. Lancet. 2012; 380:
2197–223
18. Stevens GA, Finucane MM, Paciorek CJ, Flaxman
SR, White RA, Donner AJ, Ezzati M, on behalf ofNutrition Impact Model Study Group (Child
Growth). Trends in mild, moderate, and severe
stunting and underweight, and progress towards
MDG 1 in 141 developing countries: a systematic
analysis of population representative data. Lancet.
2012;380:824-34.
19. Hisashige A, Ohura T. Cost-effectiveness ofnutritional intervention on healing of pressure
ulcers. Clinical Nutrition. 2012; 31(6): 868-874.
20. 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. Health policy
and planning. Forthcoming.
21. Tsubokura M, Gilmour S, Takahashi K, Oikawa T,
Kanazawa Y. Internal Radiation Exposure After the
Fukushima Nuclear Power Plant Disaster. JAMA.
2012;308(7):669-670.
22. 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.

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23. 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.
24. 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.
25. Gilmour S, Li J, Shibuya K. Projecting HIV
Transmission in Japan. PLoS ONE. 2012;7(8):e43473.
26. Mori R, Ota E, Middleton P, Tobe-Gai R, mahomed
K, Bhutta ZA. Zinc supplementation for improving
pregnancy and infant outcome. Cochrane Databaseof Systematic Reviews 2012, issue 6. Art. No.:
CD000230.
27. 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.
28. 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
29. 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.
30. 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
31. Roberts B, Stickley A, Balabanova D, Haerpfer C,
McKee M. The persistence of irregular treatment ofhypertension in the former Soviet Union. Journal of
Epidemiology and Community Health. Forthcoming.
32. 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 the former

Soviet Union. Nicotine & Tobacco Research.
Forthcoming.
33. Roberts B, Stickley A, Gasparishvili A, Haerpfer C,
McKee M. Changes in household access to water incountries of the former Soviet Union. Journal of
Public Health. 2012 Aug; 34(3):352-9.
34. 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
35. Hosoda M, Inoue H, Miyazawa Y, Kusumi E,
Shibuya K. Vaccine-associated paralytic poliomyelitis in Japan. Lancet. 2012; 379(9815): 520.
(correspondence)
36. 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.
37. 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.
38. Zhang X, Shirayama Y, Zhang Y, Ba W, Ikeda N,
Mori R, Shibuya K. Duration of maternally derived
antibody against measles: A seroepidemiologicalstudy of infants aged under 8 months in Qinghai,
China.Vaccine. 2012; 17; 30(4): 752-757.
39. Wariki WMV, Ota E, Mori R, Koyanagi A, Hori
N, Shibuya K. Behavioral interventions to reduce
the transmission 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.
40. Yamamoto N, Mori R, Jacklin P, Osuga Y, Kawana
K, Shibuya K, Taketani Y. Introducing HPV vaccine
and scaling up screening procedures to prevent
deaths from cervical cancer in Japan: A costeffectiveness analysis. BJOG. 2012; 119(2): 177186.

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Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH

Assistant Professors
Krishna C. Poudel, PhD, MHSc (~ July 2012)
Junko Yasuoka, DSc, MPH
Keiko Otsuka, MD
Akira Shibanuma, MID (October 2012~)

Specially-Appointed Assistant Professor
Kimiyo Kikuchi, PhD, MHSc (June 2012~)

Homepage http://www.ich.m.u-tokyo.ac.jp/en/index.html
Introduction and Organization
The Department of Community and Global Health(formerly Department of International Community
Health) has been headed by four professors since
1993: Professors Gen Ohi (1993-1996), Som-Arch
Wongkhomthong (1996-1999), Susumu Wakai(1999-2005), and Masamine Jimba (2006-present).
The mission of the department is to seek equity andsocial justice in health within and across nations. To
achieve this, we aim toward:
1. Investigating how to improve the health status of
the most vulnerable people, in particular, indeveloping countries;
2. Undertaking research on the influence of
globalization on health and social development;
3. Investigating mechanisms to reduce inequalities
between and within nations on health anddevelopment.
Our research focuses on how to activate
community-based activities and how a to linkbottom-up approach to national and international

policy. The department currently consists of: our
Department Chair and Professor, 1 Lecturer, 2
Assistant Professors, 1 specially-appointed assistantprofessor, 10 Visiting Lecturers, 22 PhD course
students, 18 Master’s course students, 3 research
students, and 22 visiting researchers. About 50% of
the students are international students.

International Cooperation
Activities
Among our international cooperation activities at
the global level was a human security project
conducted in collaboration with the Japan Center forInternational Exchange (JCIE) and JICA. Specifically,
we organized a seminar on Health and Human
Security in Peru in cooperation with PAHO in 2012.
In addition, we contributed to developing a WHO’s
guideline on human resource for health.
We also provided technical support to projects run
by the JICA and NGOs in Lao PDR (health system
research), and Vietnam (safe water and better
nutrition), and have conducted research in collaboration with the Cambodian government. In addition,
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we have launched a research project on maternal andchild health in Ghana in collaboration with JICA.

Teaching Activities
The main objective of our teaching activities is totrain compassionate global health leaders. In concreteterms, we aim:
1. To train future leaders in the field of global 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) health promotion, 3)
school health in developing countries, 4) communitybased health interventions, 5) social capital, 6)
medical anthropology, and 7) reproductive health.
Our department has accepted students of various
backgrounds and disciplines: medical doctors, nurses,
co-medical workers, social scientists and others. The
academic year for the Master’s course (MA, 2 years)
as well as the Doctor’s course (PhD, 3 years) starts in
April and ends in March every year. All lectures andseminars are conducted in English. We also provided
trainings to young leaders from overseas run by the
JICA and lectures in different universities.

Research activities
The department aims to contribute to policy making
and promoting actions for better health by making thebest use of community-based research. We carry out
research by working in tandem with different research
institutes, international organizations, JICA, NGOs,
and universities in developing countries. The major
directions of current research have encompassed
health and development, health promotion, andecological approach in infectious disease control.
Our research has been conducted in various countries,
including Nepal, Myanmar, Thailand, Bangladesh,
Viet Nam, Lao PDR, Cambodia, Ghana, Tanzania,
Kenya, Zambia, Rwanda, and Peru.

References
1. Fujita M, Poudel KC, Do TN, Bui DD, Nguyen
VK, Green K, Nguyen TM, Kato M, Jacka D, Cao
TT, Nguyen TL, Jimba M. A new analyticalframework of 'continuum of prevention and care'
to maximize HIV case detection and retention incare in Vietnam. BMC Health Serv Res. 2012 Dec
29;12:483.
2. Mlunde LB, Poudel KC, Sunguya BF, Mbwambo
JK, Yasuoka J, Otsuka K, Ubuguyu O, Jimba M.
A call for parental monitoring to improve condom
use among secondary school students in Dar es
Salaam, Tanzania. BMC Public Health. 2012 Dec
9;12:1061.
3. Inoue M, Binns CW, Otsuka K, Jimba M,
Matsubara M. Infant feeding practices andbreastfeeding duration in Japan: A review. Int
Breastfeed J. 2012 Oct 25;7(1):15.
4. Poudel-Tandukar K, Poudel KC, Jimba M,
Kobayashi J, Johnson CA, Palmer PH. Serum
25-hydroxyvitamin D levels and C-reactive
protein in persons with Human Immunodeficiency Virus infection. AIDS Res Hum
Retroviruses. AIDS Res Hum Retroviruses. 2013
Mar;29(3):528-34.
5. Shrestha S, Poudel KC, Poudel-Tandukar K,
Kobayashi J, Pandey BD, Yasuoka J, Otsuka K,
Jimba M. Perceived Family Support andDepression among People Living with HIV/AIDS
in the Kathmandu Valley, Nepal. J Int Assoc
Physicians AIDS Care (Chic). . 2012 Sep 19.
6. 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. 2013 Mar;48(3):397-405.
7. 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. 2012 May 26.
8. 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
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Psychiatry. 2012 Jun 19.
9. Shiao LW, Chiang TL. Adverse birth outcomesamong native-born and foreign-born mothers in
Taiwan: A population-based birth cohort study.
BMC Pregnancy Childbirth. 2012 Oct 13;12(1):110.
10. 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. J Health Popul Nutr
2012 Sep;30(3):262-269.
11. Sunguya BF, Poudel KC, Mlunde LB, Otsuka K,
Yasuoka J, Urassa DP, Mkopi NP, Jimba M.
Ready to Use Therapeutic Foods (RUTF)
improves undernutrition among ART-treated,
HIV-positive children in Dar es Salaam, Tanzania.
Nutr J. 2012 Aug 29;11(1):60.
12. Yoshikawa K, Agrawal NR, Poudel KC, Jimba M.
A lifetime experience of violence and adverse
reproductive outcomes: Findings from population
surveys in India. Biosci Trends. 2012 Jun;6(3):115-21.
13. 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. 2012 Aug 3;5(1):405.
14. 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.
2012 Jul;24(4):697-709.
15. Kikuchi K, Poudel KC, Muganda J, Majyambere
A, Otsuka K, Sato T, Mutabazi V, Nyonsenga SP,
Muhayimpundu R, Jimba M, Yasuoka J. High riskof ART non-adherence and delay of ART
initiation among HIV positive double orphans inKigali, Rwanda. PLoS One. 2012;7(7):e41998.
16. 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. 2012;7(5):e36629.
17. 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. 2012 Jul;
102(7):1336-45.
18. Yi S, Poudel KC, Yasuoka J, Yanagisawa S,
Palmer PH, Yi S, Jimba M. Sibling-care
responsibility and depression among adolescentcaretakers in Cambodia. Int J Soc Psychiatry.
Asian J Psychiatr. 2012 Jun;5(2):132-6.
19. 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.
20. 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.
21. 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.

306

International Health
2. International Biomedical Sciences

308

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 was establishedin 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 for their 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.

309

References
1. Sugihara S, Ogata T, Kawamura T, Urakami T,
Takemoto K, Kikuchi N, Takubo N, Tsubouchi K,
Horikawa R, Kobayashi K, Kasahaera Y, Kikuchi
T, Koike A, Mochizuki T, Minamitani K, Takaya
R, Mochizuki H, Nishii A, Yokota I, Kizaki Z,
Mori T, Shimura N, Mukai T, Matsuura N,
Fujisawa T, Ihara K, Kosaka K, Kizu R,
Takahashi T, Matsuo S, Hanaki K, Igarashi Y,
Sasaki G, Soneda S, Teno S, Kanzaki S, Saji H,
Tokunaga K, Amemiya, S, The Japanese Study
Group of Insulin Therapy for Childhood andAdolescent Diabetes (JSGIT): HLA-class II andclass I genotypes among Japanese children with
Type1A diabetes and their families. PediatricDiabetes 13(1): 33-44, 2012.
2. Ohnishi Y, Totoki Y, Toyoda A, Watanabe T,
Yamamoto Y, Tokunaga K, Sakaki Y, Sasaki H,
and Hohjoh H: Active role of small non-coding
RNAs derived from SINE/B1 retrotransposon
during early mouse development. Mol. Biol. Rep.
39(2): 903-909, 2012.
3. Nishida N, Mawatari Y, Sageshima M, andTokunaga K: Highly parallel and short-acting
amplification with locus-specific primers to detect
single nucleotide polymorphisms by the DigiTag2
assay. PLoS ONE 7(1): e29967, 2012.
4. Shimogiri T, Nishida† N, Kudo M, K. Niwa K,
Nishibori M, Kinoshita K, Okamoto S, Maeda Y,
Tokunaga K, and Yasue H: Genetic relationships
between Japanese native and commercial breeds
using 70 chicken autosomal SNP genotypes by the
DigiTag2 assay. Anim. Genet. 43(1): 98-103,
2012
5. Kobayashi K, Yuliwulandari R, Yanai H, Naka I,
Lien L, Hang NTL, Hijikata M, Keicho N, andTokunaga K: Association study of TLR
polymorphisms with development of tuberculosis.
Tissue Antigens 79(3): 190-197, 2012.
6. 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 U, and Kawaguchi H:
C/EBpβ and RUNX2 cooperate to degrade
cartilage with MMP-13 as the target and HIF-2α
as the inducer in chondrocytes. Hum. Mol. Genet.

21(5): 1111-1123, 2012.
7. Hirayasu K, Ohashi J, Kashiwase K,
Hananantachai H, Naka I, Ogawa A, Takanashi M,
Satake M, Nakajima K, Parham P, Arase H,
Tokunaga K, Patarapotikul J, and Yabe T:
Significant association of KIR2DL3-HLA-C1
combination with cerebral
malaria andimplications for co-evolution of KIR and HLA.
PLoS Pathogens 8(3): e1002565, 2012.
8. Xu S, Pugach I, Stoneking M, Kayser M, Jin L,
and HUGO Pan-Asia SNP Consortium: Genetic
dating indicates that the Asian-Papuan admixture
through Eastern Indonesia corresponds to theAustronesian expansion. Proc. Natl. Acad. Sci.
USA 109(12): 4574-4579, 2012.
9. He Y, Wang WR, Xu S, Jin L, and Pan-Asia SNP
Consortium: Paleolithic Contingent in Modern
Japanese: Estimation and inference using genomewide data. Sci. Rep. 2: 355, 2012.
10. Hijikata M, Shojima J, Matsushita I, Tokunaga K,
Ohashi J, Hang NT, Horie T, Sakurada S, Hoang
NP, Thuong PH, Lien LT, and Keicho N:
Association of IFNGR2 gene polymorphisms withpulmonary tuberculosis among the Vietnamese.
Hum. Genet. 131(5): 675-682, 2012.
11. Sapkota BR, Hijikata M, Matsushita I, Tanaka G,
Ieki R, Kobayashi N, Toyota E, Nagai H,
Kurashima A, Tokunaga K, and Keicho N:
Association of SLC11A1 (NRAMP1) polymorphisms with pulmonary Mycobacterium
avium complex (MAC) infection. Hum. Immunol.
73(5): 529-536, 2012.
12. Okada Y, Terao C, Ikari K, Kochi Y, Ohmura K,
Suzuki A, Kawaguchi T, Stahl E, Kurreman F,
Nishida N, Ohmiya H, Myouzen K, Takahashi M,
Sawada T, Nishioka Y, Yukioka M, Matsubara T,
Wakitani S, Teshima R, Tohma S, Takasugi K,
Shimada K, Murasawa A, Honjo S, Matsuo K,
Tanaka H, Tajima K, Suzuki T, Iwamoto T,
Kawamura Y, Tanii H, Okazaki Y, Sasaki T,
Gregersen PK, Padyukov L, Worthigton J,
Siminovitch KA, Lathrop M, Taniguchi A,
Takahashi A, Tokunaga K, Kubo M, Nakamura Y,
Kamatani N, Mimori T, Plenge RM, Yamanaka H,
Momohara S, Yamada R, Matsuda F, andYamamoto K: Meta-analysis identifies nine newloci associated with rheumatoid arthritis in the310Japanese population. Nat. Genet. 44(5): 511-517,
2012.
13. Ueta M, Tamiya G, Tokunaga K, Sotozono C,
Ueki M, Sawai H, Inatomi T, Matsuoka T, Akira
S, Narumiya S, Tashiro K, and Kinoshita S:
Epistatic interaction between Toll-ike receptor(TLR3) and prostaglandin E receptor 3 (PTGER3)
genes. J. Allergy Clin. Immunol. 129(5): 14131416, 2012.
14. Okamoto K, Iwasaki N, Doi K, Noiri E, Iwamoto
Y, Uchigata Y, Fujita T, and Tokunaga K:
Inhibition of glucose-stimulated insulin secretion
by KCNJ15, a newly identified susceptibility genefor type 2 diabetes mellitus. Diabetes 61(7): 17341741, 2012.
15. Mahasirimongkol S, Yanai H, Mushiroda T,
Promphittayarat W, Wattanapokayakit S, Promjai
J, Yuliwulandari R, Wichukchinda N, Yowang A,
Yamada N, Kantipong P, Takahashi A, Kubo M,
Sawanpanyalert P, Kamatani N, Nakamura Y, andTokunaga K: Genomic-wide association studies oftuberculosis in Asians identify distinct at-risk
locus for young tuberculosis. J. Hum. Genet.
57(6): 363-367, 2012.
16. Nishida N, Sawai H, Matsuura K, Sugiyama M,
Ahn SH, Park JY, Hige S, Kang JH, Suzuki K,
Kurosaki M, Asahina Y, Mochida S, Watanabe M,
Tanaka E, Honda M, Kaneko S, Orito E, Itoh Y,
Mita E, Tamori A, Murawaki Y, Hiasa Y, Sakaida I,
Korenaga M, Hino K, Ide T, Kawashima M,
Mawatari Y, Sageshima M, Ogasawara Y, Koike A,
Izumi N, Han K, Tanaka Y, Tokunaga K, andMizokami M: Genome-wide association study
confirming association of HLA-DP withprotection against chronic hepatitis B and viralclearance in Japanese and Korean. PLoS ONE
7(6): e39175, 2012.
17. Takamoto M, Kaburaki T, Mabuchi A, Araie M,
Amano S, Aihara M, Tomidokoro A, Iwase A,
Mabuchi F, Kashiwagi K, Shirato S, Yasuda N,
Kawashima H, Nakajima F, Numaga J, Kawamura
Y, Sasaki T, and Tokunaga K: Common variants
on chromosome 9p21 are associated with normal
tension glaucoma. PLoS ONE 7(7): e40107, 2012.
18. Sawai H, Nishida N, Mbarek H, Matsuda K,
Mawatari Y, Yamaoka M, Hige S, Kang J H, Abe K,
Mochida S, Watanabe M, Kurosaki M, Asahina Y,

Izumi N, Honda M, Kaneko S, Tanaka E, Matsuura
K, Itoh Y, Mita E, Korenaga M, Hino K, Murawaki
Y, Hiasa Y, Ide T, Ito K, Sugiyama M, Sang Ahn S
H, Han K H, Park J Y, Yuen M F, Nakamura Y,
Tanaka Y, Mizokami M and Tokunaga K: No
association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other
East Asian populations. BMC Med. Genet. 13(1):47, 2012.
19. Ueta M, Tokunaga K, Sotozono C, Sawai H,
Tamiya G, Inatomi T, and Kinoshita S:
HLA-A*0206 with TLR3 polymorphisms exerts
more than additive effects in stevens-Johnson
syndrome with severe ocular surface complications. PLoS ONE 7(8): e43650, 2012.
20. Erhardt A, Akula N, Schumacher J, Czamara D,
Karbalai N, Mu ̈ller-Myhsok B, Mors O, Borglum
A, Kristensen AS, Woldbye DPD, Koefoed P,
Eriksson E, Maron E, Metspalu A, Nurnberger J,
Philibert RA, Kennedy J, Domschke K, Reif A,
Deckert J, Otowa T, Kawamura Y, Kaiya H,
Okazaki Y, Tanii H, Tokunaga K, Sasaki T,
Ioannidis JPA, McMahon FJ, and Binder EB:
Replication and meta-analysis of TMEM132D
gene variants in panic disorder. Transl. Psychiatry
2:e156, 2012.
21. Nakamura M, Nishida N, Kawashima M, Aiba Y,
Tanaka A, Yasunami M, Nakamura H, Komori A,
Nakamuta M, Zeniya M, Hashimoto E, Ohira H,
Yamamoto K, Onji M, Kaneko S, Honda M,
Yamagiwa S, Nakao K, Ichida T, Takikawa H,
Seike M, Umemura T, Ueno Y, Sakisaka S,
Kikuchi K, Ebinuma H, Yamashiki N, Tamura S,
Sugawara Y, Mori A, Yagi S, Shirabe K, Taketomi
A, Arai K, Monoe K, Ichikawa T, Taniai M,
Miyake Y, Kumagi T, Abe M, Yoshizawa K,
Joshita S, Shimoda S, Honda K, Takahashi H,
Hirano K, Takeyama Y, Harada K, Migita K, Ito M,
Yatsuhashi H, Fukushima N, Ota H, Komatsu T,
Saoshiro T, Ishida J, Kouno H, Kouno H, Yagura
M, Kobayashi M, Muro T, Masaki N, Hirata K,
Watanabe Y, Nakamura Y, Shimada M, Hirashima
N, Komeda T, Sugi K, Koga M, Ario K,
Takesaki E, Maehara Y, Uemoto S, Kokudo N,
Tsubouchi H, Mizokami M, Nakanuma Y,
Tokunaga K, and Ishibashi H: Genome-wide
association study identifies TNFSF15 and311

POU2AF1 as susceptibility loci for primarybiliary cirrhosis in Japanese. Am. J. Hum. Genet.
91(4): 721-728, 2012.
22. Kumar V, Yi Lo PH, Sawai H, Kato N, Takahashi
A, Deng Z, Urabe Y, Tokunaga K, Tanaka Y,
Sugiyama M, Mizokami M, Muroyama R,
Tateishi R, Omata M, Koike K, Tanikawa C,
Kamatani N, Kubo M, Nakamura Y, and Matsuda
K: Soluble MICA and a MICA variation as
possibl prognostic biomarkers for HBV-induced
hepatocellular carcinoma. PLoS ONE 7(9):e44743, 2012.
23. Kawashima M, Ohashi J, Nishida N, andTokunaga K: Evolutionary Analysis of Classical
HLA Class I and II Genes Suggests That Recent
Positive Selection Acted on DPB1*04 ∶ 01 in
Japanese Population. PLoS ONE. 7(10): e46806,
2012.
24. Dinu I, Mahasirimongkol S, Liu Q, Yanai H,
El-Din NS, Kreiter E, Wu X, Jabbari S, Tokunaga
K, and Yasui Y: SNP-SNP interactions discoveredby logic regression explain Crohn’s disease
genetics. PLoS ONE 7(10): e43035, 2012.
25. Jinam TA, Hong LC, Phipps ME, Stoneking M,
Ameen M, Edo J; HUGO Pan-Asian SNP
Consortium, and Saitou N: Evolutionary historyof continental Southeast Asians: "early train"
hypothesis based on genetic analysis of
mitochondrial and autosomal DNA data. Mol.
Biol. Evol. 29(11): 3513-27, 2012.
26. Otowa T, Kawamura Y, Nishida N, Sugaya N,
Koike A, Yoshida E, Inoue K,Yasuda S,
Nishimura Y, Liu X, Konishi Y, Nishimura F,
Shimada T, Kuwabara H, Tochigi M, Kakiuchi C,
Umekage T, Miyagawa T, Miyashita A, Shimizu
E, Akiyoshi J, Someya T, Kato T, Yoshikawa T,
Kuwano R, Ihara Y, Kasai K, Kato N, Kaiya H,
Tokunaga K, Okazaki Y, Tanii H, and Sasaki T:
Meta-analysis of genome-wide association studies
for Panic disorder in the Japanese population.
Translat. Psych. 2012(2), e186, 2012.
27. Jinam T, Nishida N, Hirai M, Kawamura S, Oota
H, Umetsu K, Kimura R, Ohashi J, Tajima A,
Yamamoto T, Tanabe H, Mano S, Suto Y,
Kaname T, Naritomi K, Yanagi K, Niikawa N,
Omoto K, Tokunaga K, and Saitou N: The historyof human populations in the Japanese Archipelagoinferred from genomewide SNP data with a
special reference to the Ainu and the Ryukyuan
populations. J. Hum. Genet. 57(12): 787-95, 2012.
28. Hitomi Y, Adachi T, Tsuchiya N, Honda ZI,
Tokunaga K, and Tsubata T: Human CD72
splicing isoform responsible for resistance tosystemic lupus erythematosus regulates serum
immunoglobulin level and is localized in
endoplasmic reticulum. BMC Immunol. 13(1):e72, 2012.
29. Koganebuchi K, Katsumura T, Nakagome S,
Ishida H, Kawamura S, Oota H, and The AsianArchivalDNA
Repository
Consortium:
Autosomal and Y-chromosomal STR markers
reveal a close relationship between Hokkaido
Ainu and Ryukyu islanders. Anthrop. Sci. 120(3):199-208, 2012.
30. Han F, Lmin L, Li J, Dong SX, An P, Zhao L, Liu
NY, Li QY, Yan H, Gao ZC, Faraco J, Strohl KP,
Liu X, Miyadera H, Mignot E. HLA-DQ
association and allele competition in Chinese
narcolepsy. Tissue Antigens. 80(4):328-35, 2012.

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Department of Developmental
Medical Sciences
Professor
Masashi Mizuguchi, M.D., Ph.D.

Associate Professor
Teruyuki Tanaka, M.D., Ph.D.

Research Associate
Makiko Saitoh, M.D., Ph.D.

Homepage

Sayaka Takanashi, M.D., Ph.D.

http://www.sih.m.u-tokyo.ac.jp/devt.html

Introduction and Organization
Founded in 1966 as the Department of Maternal andChild Health, our department was the first one
established in Japan. With the subsequent expansionof research activities and the foundation of the
Graduate School of Medicine, it was renamed in 1992
as the Department of Developmental Medical
Sciences. Up to now, it has been engaged inexperimental and epidemiologic studies to provide thescientific bases for all the activities to promote thephysical and mental health of mothers and children.
The experimental studies include those on the nervousand endocrine systems, infection, immunity andmetabolism, whereas the epidemiologic studies deal
with development, mother-to-child relationship andhealth promotion. In 2007, joined by new members,
the department has entered a new era, putting moreemphasis than ever on the research on developmental
disorders of the human nervous system.
At present, our department consists of one professor,
one associate professor, two associates, one assistantclerk, one technical assistant, fifteen visiting lecturers,
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

313

In addition to lectures and laboratory courses by ourown staff, special lectures are given by experts both
inside and outside the University.

Research activities(1) Clinical, genetic and pathologic studies of acuteencephalopathy: 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 pathologic studies on childhood
intractable epilepsy and developmental disorders,such as West syndrome and Rett syndrome, using
genetically engineered animals.
(4) Molecular genetic and cell biologic studies
combined with post-genomic approaches onmolecules regulating neuronal migration, such as
Doublecortin and Cdk5.
(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.

References
1. Abe Y, Hashimoto K, Iinuma K, Ohtsuka Y,
Ichiyama T, Kusuhara K, Nomura K, Mizuguchi

9.

M, Aiba H, Suzuki Y, Mizusawa H, Hosoya M.
Survey of subacute sclerosing panencephalitis inJapan. Journal of Child Neurology 2012; 27(12):1529-1533.
Bergamino L, Capra V, Biancheri R, Rossi A,
Tacchella A, Ambrosini L, Mizuguchi M, Saitoh
M, Marazzi MG. Immunomodulatory therapy inrecurrent acute necrotizing encephalopathy
ANE1: Is it useful? Brain and Development 2012;34(5): 384-391.
Chaimongkol
N,
KhamrinP,
Malasao
R, Thongprachum A, Ushijima H, Maneekarn N.
Genotypic linkages of gene segments ofrotaviruses circulating in pediatric patients withacute gastroenteritis in Thailand. Infection,
Genetics and Evolution 2012; 12(7): 1381-1391.
Chaimongkol N, Khamrin P, Suantai B,
Saikhreang W, Thongprachum A, Malasao R,
Ukarapol N, Kongsricharoern T, Ushijima H,
Maneekarn N. A wide variety of diarrheal viruses
circulating in pediatric patients in Thailand.
Clinical Laboratory 2012; 58(1-2): 117-123.
Chan-It W, Thongprachum A, Khamrin P,
Kobayashi M, Okitsu S, Mizuguchi M, Ushijima
H. Emergence of a new norovirus GII.6 variant inJapan, 2008-2009. Journal of Medical Virology
2012; 84(7): 1089-1096.
Dey SK, Nishimura S, Okitsu S, Hayakawa S,
Mizuguchi M, Ushijima H. Comparison of
immunochromatoghraphy, PCR and culture
methods for the detection of Campylobacter
bacteria. Journal of Microbiological Methods
2012; 91(3): 566-568.
Dey SK, Phathammavong O, Nguyen TD,
Thongprachum A, Chan-It W, Okitsu S,
Mizuguchi M, Ushijima H. Seasonal pattern andgenotype distribution of sapovirus infection in
Japan, 2003-2009. Epidemiology and Infection
2012; 140(1): 74-77.
Hoshino A, Saitoh M, Oka A, Okumura A,
Kubota M, Saito Y, Takanashi JI, Hirose S,
Yamagata T, Yamanouchi H, Mizuguchi M.
Epidemiology of acute encephalopathy in Japan,
with emphasis on the association of viruses andsyndromes. Brain and Development 2012; 34(5):337-343.
Khamrin P, Chaimongkol N, Malasao R, Suantai

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B, Saikhruang W, Kongsricharoern T, Ukarapol N,
Okitsu S, Shimizu H, Hayakawa S, Ushijima H,
Maneekarn N. Detection and molecular characterization of cosavirus in adults with diarrhea,
Thailand. Virus Genes 2012; 44(2): 244-246.
10. Khamrin P, Malasao R, Chaimongkol N,
Ukarapol N, Kongsricharoern T, Okitsu S,
Hayakawa S, Ushijima H, Maneekarn N.
Circulating of human bocavirus 1, 2, 3, and 4 inpediatric patients with acute gastroenteritis in
Thailand. Infection, Genetics and Evolution
2012; 12(3): 565-569.
11. Khamrin P, Thongprachum A, Shimizu H, Okitsu
S, Mizuguchi M, Hayakawa S, Maneekarn N,
Ushijima H. Detection of human bocavirus 1 and2 from children with acute gastroenteritis in Japan.
Journal of Medical Virology 2012; 84(6):901-905.
12. Kobayashi K, Ohzono H, Shinohara M, Saitoh M,
Ohmori I, Ohtsuka Y, Mizuguchi M. Acuteencephalopathy with a novel point mutation in the
SCN2A gene. Epilepsy Research 2012; 102(1-2):
109-112.
13. Kuroda Y, Mimaki M, Terashima H, Sato A,
Takahashi K, Kano H, Oka A, Mizuguchi M,
Igarashi T. A case of Kawasaki disease
complicated by Guillain-Barre syndrome. The
Journal of the Japanese Pediatric Society 2012;
116(6): 985-989.
14. Malasao R, Khamrin P, Chaimongkol N, Ushijima
H, Maneekarn N. Diversity of Human Astrovirus
genotypes circulating in children with acutegastroenteritis in Thailand during 2000 – 2011.
Journal of Medical Virology 2012; 84(11):1751-1756.
15. Okitsu S, Khamrin P, Thongprachum A, Hidaka S,
Kongkaew S, Kongkaew A, Maneekarn N,
Mizuguchi M, Hayakawa S, Ushijima H.
Sequence analysis of porcine kobuvirus VP1region detected in pigs in Japan and Thailand.
Virus Genes 2012; 44(2): 253-257.
16. Saitoh M, Shinohara M, Hoshino H, Kubota M,
Amemiya K, Takanashi JL, Hwang SK, Hirose S,
Mizuguchi M. Mutations of the SCN1A gene inacute encephalopathy. Epilepsia 2012; 53(3):558-564.
17. Sato A, Kasai S, Kobayashi T, Takamatsu Y, Hino

O, Ikeda K, Mizuguchi M: Rapamycin reverses
impaired social interaction in mouse models oftuberous sclerosis complex. Nature Communications 2012; 3: 1292.
18. Tien Y-Y, Ushijima H, Mizuguchi M, Liang S-Y,
Chiou C-S. Use of multilocus variable-number
tandem repeat analysis 1 in molecular subtypingof Salmonella enterica serovar Typhi isolates.
Journal of Medical Microbiology 2012; 61(Pt2):
223-232.
19. Thongprachum A, Khamrin P, Tran DN, Okitsu S,
Mizuguchi M, Hayakawa S, Maneekarn N,
Ushijima H. Evaluation and comparison of theefficiency of immunochromatography methods
for norovirus detection. Clinical Laboratory2012; 58(5-6): 489-493.
20. Tran DN, Pham NT, Tran TT, Khamrin P,
Thongprachum A, Komase K, Hayakawa S,
Mizuguchi M, Ushijima H. Phylogenetic analysis
of rubella viruses in Vietnam during 2009-2010.
Journal of Medical Virology 2012; 84(4): 705710.
21. Trinh QD, Pham NT, Le Nguyen NT, Lam BQ, Le
Phan KT, Truong KH, Izumi Y, Komine-Aizawa S,
Mizuguchi M, Ushijima H, Hayakawa S. Drug
resistance mutations in the HIV-1 protease andreverse transcriptase genes in antiretroviral-naïve
Vietnamese children. AIDS Research and Human
Retroviruses 2012; 28(10): 1305-1307.

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Department of Human Ecology
Professor
Chiho WATANABE, D. Hlth Sc.

Associate Professor
Masahiro UMEZAKI, Ph.D.

Research Associate
Hana SHIMIZU, Ph.D.
Shoko KONISHI, Ph.D.

Project Research AssociateAndrew STICKLEY, Ph.D (Global 30)
Kiyoshi TADOKORO, Ph.D (Global 30)
Eriko TOMITUKA, Ph.D (NEXT project)
Ayako MORITA, Ph.D (NEXT project)

Homepage

http://www.humeco.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
We had eight research/teaching faculties in FY2012,
including two working for the “Global 30” program,taught in English, and two for “NEXT” program.
Apart from the faculty staffs, two secretaries, two
doctoral candidates (one foreign students), six mastercourse students (including three foreign students), andtwo 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&
FusionResearch
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”, “Demography”, “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

316(including Japan) has been facing. Another emphasis
was on the relation between human activities andchemical contamination of the environment.

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, capital 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

317

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.
5. Adaptability to low protein diet
In Papua New Guinea Highlands, the people are fed
on low protein diets like sweet potatoes, whereas they
do not appear to be protein deficient. Hypothesizingthat this observation would be associated with a
specific composition of gut microbiome in these
populations, field studies and experimental studies
have been conducted.
For the estimation of protein intake of individuals,
food frequency questionnaire was developed andvalidated. The analysis of gut microbiome revealed
several bacteria that might support “efficient” protein
utilization of host.
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. Stickley A., Koyanagi A., Richardson E., Roberts
B., Balabanova D., and McKee M. (2013)
Prevalence and factors associated with the use ofalternative (folk) medicine practitioners in 8
countries of the former Soviet Union. BMC
Complementary and Alternative Medicine 13:83.
2. Bagrowicz R., Umezaki M., and Watanabe C.
(2013) Is Obesity Contagious by Way of Body
Image? A Study on Japanese Female Students in
the United States. Journal of Community Health(in press).
3. Yoshida M., Watanabe C., Honda A., Satoh M.,
and Yasutake A. (2013) Emergence of delayed
behavioral effects in offspring mice exposed to
low levels of mercury vapor during the lactation
period. Journal of Toxicological Science 38(1):
1-6.
4. Honda A., Watanabe C., Yoshida M., Nagase H.,
and Satoh M. (2013) Microarray analysis ofneonatal brain exposed to cadmium during
gestation and lactation. Journal of Toxicological
Science 38(1): 151-3.
5. Parajuli R.P., Fujiwara T., Umezaki M., and
Watanabe C. (2013) Association of Cord Blood
Levels of Lead, Arsenic, and Zinc with
Neurodevelopmental Indicators in Newborns: A
Birth Cohort Study in Chitwan Valley, Nepal.
Environmental Research 121:45-51.
6. Zhou R., Li Y., Umezaki M., Ding Y., Jiang H.W.,
Comber A., and Fu H. (2013) Association
between physical activity and neighborhood
environment among middle-age adults inShanghai. Journal of Environmental and Public
Health (in press).
7. Sakamoto M., Yasutake A., Kakita A., Ryufuku
M., Chan H.M., Yamamoto M., Oumi S.,
Kobayashi S., and Watanabe C. (2013)
Selenomethionine Protects against Neuronal
Degeneration by Methylmercury in the318

Developing Rat Cerebrum. Environ Sci Technol.
47(6):2862-8.
8. Yasumoto S., Jones A., and Shimizu C. (2013)
Longitudinal trends in equity of park accessibility
in Yokohama, Japan: An investigation of the roleof causal mechanisms. Environment and Planning
A (in press).
9. Inoue Y., Umezaki M., and Watanabe C. (2013)
Geographic Clustering of the Secondary Sex
Ratio in Japan: Association with Demographic
Attributes. Journal of Biosocial Science 45(2):279-284.
10. Yoshida M., Suzuki M., Satoh M., Yasutake A.,
and Watanabe C. (2012) Blood lead levels ofcontemporary Japanese children. Environ HealthPrev Med. 17(1): 27-33.
11. Parajuli R.P., Fujiwara T., Umezaki M., Furusawa
H., Ser P.H., and Watanabe C. (2012) 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(1-3): 75-83.
12. Ser P.H. and Watanabe C. (2012) Fish advisories
in the USA and Japan: Risk communication andpublic awareness of a common idea with different
backgrounds. Asia Pacific Journal of ClinicalNutrition 21(4):487-94.
13. Yasutake A., Yoshida M., Honda A., Watanabe C.,
and Satoh M. (2012) Distribution of mercury inmetallothionein-null mice after exposure tomercury vapor: Amount of metallothionein
isoform does not affect accumulation of mercury
in the brain. Journal of Toxicological Sciences
37(4):765-771.
14. Konishi S., Brindle E., Guyton A., and O'Connor
K.A. (2012) Salivary concentration ofprogesterone and cortisol significantly differs
across individuals after correcting for blood
hormone values. American Journal of Physical
Anthropology 149:231-241.
15. Vengiau G., Umezaki M., Phuanukoonnon S.,
Siba P., and Watanabe C. (2012) Diet and physicalactivity among migrant Bougainvilleans in Port
Moresby, Papua New Guinea: association withanthropometric measures and blood pressure.
American Journal of Human Biology. 24(5):716-718.

16. Comber A., Umezaki M., Zhou R., Ding Y., Li Y.,
Fu H., Jiang H.W., and Tewkesbury A. (2012)
Using shadows in high-resolution imagery to
determine building height. Remote Sensing
Letters. 3(7): 551-556.
17. Yoshinaga, J., Takagi, M., Yamasaki, K., Tamiya,S., Watanabe, C., and Kaji, M. (2012) Blood leadlevels of contemporary Japanese children.
Environmental Health and Preventive Medicine.
17(1):27-33.
18. Inoue, Y., Umezaki, M., and Watanabe, C. (2012)
Emergence of income inequality and its impact on
subjective quality of life in an ethnic minority
community in Hainan Island, China. Anthropological Science 120(1):51-60.

319

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 and Nutrition was
renamed on April 1st, 1996 to The Department of
Biomedical Chemistry as newly affiliating with
Biomedical Science Division of International Health,Graduate School of Medicine, The University of Tokyo.
Prof. Kita has moved from The Institute of Medical
Science, The University of Tokyo on March 1st, 1998.

Teaching activities
Teaching activity in our department cover a broad
spectrum of biochemistry-oriented life sciences frompremise to frontiers and in either conceptual orexperimental point of view
Graduate Course: Biochemistry and Nutrition I, IIThis course is comprised of lectures and seminars toprovide basic concepts and newer vistas forunderstanding nutrition with special reference tobiochemistry and molecular biology. These include thestructure and function of biomolecules, metabolism, its
regulation, and underlying mechanism at either
molecular, cellular and systemic level.

Undergraduate Course: Biochemistry, Molecular
Biology, Laboratory Method in Health Science,
Physiological Chemistry, Nutrition, Medical Chemistry,
Practice on Medical Chemistry, Parasitology.

Research activities
Energy metabolism is essential for the survival,continued growth and reproduction of living organisms.
From the standpoint of biological adaptation, we havebeen studying on the molecular mechanism of energy
transducing systems such as mitochondrial andbacterial respiratory chain. In addition, we areinterested in the basic biological reactions such asprotein synthesis. Our research have been focusing on
I. Human mitochondria
1) succinate-ubiquinone reductase
2) mitochondrial myopathy
II. Ascaris suum and Caenorhabditis elegans
1) molecular mechanism of adaptation to low
oxygen tension (regulation of gene expression of
mitochondrial proteins)2) mitochondrial fumarate reductase (structure
function relationship, enzyme evolution)3) C. elegans as a model system of parasitic
nematode (expression of foreign genes or cDNAs,
gene knockout)

320

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. Orexin 2 receptor as a potential target for the
immunotoxin and antibody-drug conjugate cancer
therapy. Kishida, M., Ishige, K., Horibe, T., Tada,
N., Koibuchi, N., Shoda, J., Kita, K. and Kawakami,
K. (2012) Oncology Lett. 3, 525-529.
2. Critical importance of the de novo pyrimidine
biosynthesis pathway for Trypanosoma cruzi
growth in the mammalian host cell cytoplasm.
Hashimoto, M., Morales, J., Fukai, Y., Suzuki, S.,
Takamiya, S., Tsubouchi, A., Inoue, S., Inoue, M.,
Kita, K., Harada, S., Tanaka, A., Aoki, T. and Nara,
T. (2012) Biochem. Biophys. Res. Commun. 417,
1002-1006
3. Molecular interaction of the first 3 enzymes of thede novo pyrimidine biosynthetic pathway of
Trypanosoma cruzi. Nara, T., Hashimoto, M.
Hirawake, H., Liao, C-W., Fukai, Y., Suzuki, S.,
Tsubouchi, A., Morales, J., Takamiya, S., Fujimura,T., Taka, H., Mineki, R., Fan, C-K., Inaoka, D. K.,
Inoue, M., Tanaka, A., Harada, S., Kita, K. andAoki, T. (2012) Biochem. Biophys. Res. Commun.
418, 140-143
4. Age-related changes in the activities of respiratory
chain complexes and mitochondrial morphology in
Drosophila. Oda, Y., Yui, R., Sakamoto, K., Kita, K.
and Matsuura, E. T. (2012) Mitochondrion, 12,345-351
5. An anticancer agent, pyrvinium pamoate inhibits
the NADH-fumarate reductase system –a uniquemitochondrial metabolism in tumor microenvironments. Tomitsuka, E., Kita, K. and Esumi,
H. (2012) J. Biochem. 152, 171-183
6. Crystal structure of mitochondrial quinol-fumarate
reductase from the parasitic nematode Ascarissuum. Shimizu, H., Osanai, A., Sakamoto, K.,
Inaoka, D. K., Shiba, T., Harada, S. and Kita, K.
(2012) J. Biochem. 151, 589-592
7. Critical roles of the mitochondrial complex II inoocyst formation of rodent malaria parasite
Plasmodium berghei. Hino, A., Hirai, M., Tanaka,
Q. T., Watanabe, Y., Matsuoka, H. and Kita, K.
(2012) J. Biochem. 152, 259-268
8. Towards understanding the role of mitochondrialcomplex II in the intraerythrocytic stages of
Plasmodium falciparum: gene targeting of the Fp
subunit. Tanaka, Q. T., Hirai, M., Watanabe, Y. andKita, K. (2012) Parasitol. Int. 61, 726-728
9. Plasmodium cynomolgi genome sequences provide
insight into Plasmodium vivax and the monkey
malaria clade. Tachibana, S., Sullivan, S.A., Kawai,S., Nakamura, S., Kim, H.R., Goto, N., Arisue, N.,
Palacpac, N.M.Q., Honma, H., Yagi, M., Tougan,T., Katakai, Y., Kaneko, O., Mita, T., Kita, K.,
Yasutomi, Y., Sutton, P.L., Shakhbatyan, R., Horii,
T., Yasunaga, T., Barnwell, J.W., Escalante, A.A.,
Carlton, J.M. and Tanabe K. (2012) Nature
Genetics, 44, 1051-1055
10. Autophagy-related Atg8 localizes to the apicoplastof the human malaria parasite Plasmodium
falciparum. Kitamura, K., Kishi-Itakura, C., Tsuboi,
T., Sato, S., Kita, K., Ohta, N. and Mizushima, N.
(2012) PLoS ONE 7(8), e42977
11. Novel type of linear mitochondrial genomes withdual flip-flop inversion system in apicomplexanparasites, Babesia microti and Babesia rodhaini.
Hikosaka, K., Tsuji, N., Watanabe, Y., Kishine, H.,
Horii, T., Igarashi, I., Kita, K. and Tanabe, K.
(2012) BMC Genomics 13, 622
12. Adherence to antiretroviral therapy (ART) during
the early months of treatment in rural Zambia:
influence of demographic characteristics and social
surroundings of patients. Sasaki, Y., Kakimoto,K., Dube, C., Sikazwe I., Moyo, C., Syakantu, C.,
Komada, K., Miyano, S., Ishikawa, N., Kita, K. andKai, I. (2012) Ann. Clin. Microbiol. Antimicrob. 11,34
13. Mitochondrial fumarate reductase as a target of
chemotherapy: from parasites to cancer cells. Sakai,C., Tomitsuka, E., Esumi, H., Harada, S. and Kita,
K. (2012) Biochim. Biophys. Acta, 1820, 643-651

School of Public Health
1. Epidemiology and Health Sciences

322

Department of Social andPreventive Epidemiology
Professor
Satoshi Sasaki, M.D., Ph.D.

Associate
Keiko Asakura, M.D.,M.P.H.,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 also important topics in epidemiologic
research. Epidemiologic data are 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323

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.

References
1. Sakurai M, Nakamura K, Miura K, Takamura T,
Yoshita K, Morikawa Y, Ishizaki M, Kido T, Naruse
Y, Suwazono Y, Kaneko S, Sasaki S, Nakagawa H.
Dietary glycemic index and risk of type 2 diabetes in
middle-aged Japanese men. Metabolism 2012; 61:
47-55.
2. Miyake Y, Tanaka K, Okubo H, Sasaki S, Arakawa
M. Dairy food, calcium, and vitamin D intake andprevalence of allergic disorders in pregnant Japanesewomen. Int J Tuberc Lung Dis 2012; 16(2): 255-61.
3. Murakami K, Miyake Y, Sasaki S, Tanaka K,
Arakawa M. Characteristics of under- andover-reporters of energy intake among Japanesechildren and adolescents: the Ryukyus Child HealthStudy. Nutrition 2012; 28: 532-8.
4. Okubo H, Miyake Y, Sasaki S, Tanaka K, Murakami
K, Hirota Y; Osaka Maternal and Child Health Study
Group. Maternal dietary patterns in pregnancy andfetal growth in Japan: the Osaka Maternal and Child
Health Study. Br J Nutr 2012; 107: 1526-33.
5. Okubo H,Miyake Y, Sasaki S, Murakami K, Tanaka
K, Fukushima W, Kiyohara C, Tsuboi Y, Yamada T,
Oeda T, Shimada H, Kawamura N, Sakae N,
Fukuyama H, Hirota Y, Nagai M, the Fukuoka Kinki
Parkinson's Disease Study Group. Dietary patterns
and risk of Parkinson's disease: a case-control study
in Japan. Eur J Neurol 2012; 19(5): 681-8.
6. Kobayashi S, Honda S, Murakami K, Sasaki S,
Okubo H, Hirota N, Notsu A, Fukui M, and Date C.
Both comprehensive and brief self-administered diethistory questionnaires satisfactorily rank nutrient
intakes in Japanese adults. J Epidemiol 2012; 22:
151-9.
7. Yoshitake N, Okuda M, Sasaki S, Kunitsugu I,
Hobara T. Validity of self-reported body mass index
of Japanese children and adolescents. Pediatr Int

2012; 54(3): 397-401.
8. Kunitsugu I, Okuda M, Sugiyama S, Yoshitake N,
Tanizawa Y, Sasaki S, Hobara T. Meat intake
frequency and anemia in Japanese children andadolescents. Nurs Health Sci 2012; 14(2): 197-203.
9. Nakade M, Aiba N, Morita A, Miyachi M, Sasaki S,
Watanabe S. What behaviors are important forsuccessful weight maintenance? J Obes 2012; 2012:202037.
10. Sugiyama S, Okuda M, Sasaki S, Kunitsugu I,
Hobara T. Breakfast habits among adolescents andtheir association with daily energy and fish,
vegetable, and fruit intake: a community-based
cross-sectional study. Environ Health Prev Med
2012; 17(5): 408-14.
11. Miyake Y, Tanaka K, Okubo H, Sasaki S, Arakawa
M. Dietary meat and fat intake and prevalence ofrhinoconjunctivitis in pregnant Japanese women:baseline data from the Kyushu Okinawa Maternaland Child Health Study. Nutr J 2012; 11: 19.
12. Shiraishi M, Haruna M, Matsuzaki M, Murayama R,
Sasaki S, Murashima S. Validity and reproducibilityof folate and vitamin B12 intakes estimated from aself-administered diet history questionnaire in
Japanese pregnant women. Nutr J 2012; 11: 15.
13. Nakade M, Aiba N, Suda N, Morita A, Miyachi M,
Sasaki S, Watanabe S, SCOP Group. Behavioral
change during weight loss program and one-year
follow-up: Saku Control Obesity Program (SCOP)
in Japan. Asia Pac J Clin Nutr 2012; 21(1): 22-34.
14. Miyake Y, Tanaka K, Sasaki S, Hirota Y. Parental
employment, income, education and allergic
disorders in children: a prebirth cohort study inJapan. Int J Tuberc Lung Dis 2012; 16(6): 756-61.
15. Murakami K, Miyake Y, Sasaki S, Tanaka K,
Arakawa M. An energy-dense diet is crosssectionally associated with an increased risk ofoverweight in male children, but not in female
children, male adolescents, or female adolescents inJapan: the Ryukyus Child Health Study. Nutr Res
2012; 32: 486-94.
16. Murakami K, Sasaki S, Okubo H, the Freshmen in
Dietetic Courses Study II Group. Characteristics ofunder- and over-reporters of energy intake among
young Japanese Women. J Nutr Sci Vitaminol 2012;
58: 253-62.
17. Kohri T, Kaba N, MurakamiT, Narukawa T,324

Yamamoto S, Sakai T and Sasaki S. Search forpromotion factors of ultrasound bone measurementin Japanese males and pre/post-menarcheal females
aged 8-14 Years. J Nutr Sci Vitaminol 2012; 58:
263-71.
18. Kobayashi S, Murakami K, Sasaki S, Uenishi K,
Yamasaki M, Hayabuchi H, Goda T, Oka J, Baba K,
Ohki K, Watanabe R, Sugiyamama Y. Dietary total
antioxidant capacity from different assays in relation
to serum C-reactive protein among young Japanesewomen. Nutr J 2012; 11: 91.
19. Ohkuma T, Fujii H, Iwase M, Kikuchi Y, Ogata S,
Idewaki Y, Ide H, Doi Y, Hirakawa Y, Mukai N,
Ninomiya T, Uchida K, Nakamura U, Sasaki S,
Kiyohara Y, Kitazono T. Impact of eating rate on
obesity and cardiovascular risk factors according to
glucose tolerance status: the Fukuoka Diabetes
Registry and the Hisayama Study. Diabetologia
2012; 56(1): 70-7.
20. Goto A, Morita A, Goto M, Sasaki S, Miyachi M,
Aiba N, Terauchi Y, Noda M, Watanabe S.
Associations of sex hormone-binding globulin andtestosterone with diabetes among men and women(the Saku Diabetes study): a case control study.
Cardiovasc Diabetol 2012; 11: 130.
21. Miyake Y, Tanaka K, Fukushima W, Kiyohara C,
Sasaki S, Tsuboi Y, Yamada T, Oeda T, Shimada H,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M; Fukuoka Kinki Parkinson's Disease Study
Group. Lack of association between BST1 polymorphisms and sporadic Parkinson's disease in a
Japanese population. J Neurol Sci 2012; 323: 162-6.
22. Cao ZB,Sasaki A,Oh T,Miyateke N,Tsushita
K,Higuchi M,Sasaki S,Tabata I. Association
between dietary intake of micro nutrients andcardiorespiratory fitness in Japanese men. J Nutr Sci
2012; 1: e12.
23. Takayama M, Arai Y, Sasaki S, Hashimoto M,
Shimizu K, Abe Y, Hirose N. Association of marineorigin n-3 polyunsaturated fatty acids consumption
and functional mobility in the community-dwellingoldest old. J Nutr Health Aging 2012; 17(1): 82-9.
24. Tanaka K, Miyake Y, Sasaki S, Hirota Y. Dairy
products and calcium intake during pregnancy anddental caries in children. Nutr J 2012; 11: 33.
25. Miyake Y, Tanaka K, Fukushima W, Kiyohara C,
Sasaki S, Tsuboi Y, Yamada T, Oeda T, Shimada H,

Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M, Study Group TF. UCHL1 S18Y variant is
a risk factor for Parkinson's disease in Japan. BMC
Neurol 2012; 12: 62.
26. Sakai M, Kakutani S, Horikawa C, Tokuda H,
Kawashima H, Shibata H, Okubo H, Sasaki S.
Arachidonic acid and cancer risk: a systematic
review of observational studies. BMC Cancer 2012;12(1): 606.
27. Murakami K, Sasaki S, Uenishi K; Japan Dietetic
Students’ Study for Nutrition and Biomarkers Group.
The degree of misreporting of the energy-adjusted
intake of protein, potassium, and sodium does notdiffer among under-, acceptable, and over-reportersof energy intake. Nutr Res 2012; 32: 741-50.

325

Department of Health Economics
and Epidemiology Research
Professor
Hideki Hashimoto, M.D.,DPH.

Associate Professor
Naoki Kondo, M.D., 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.

Teaching activities
Under the MPH program, the Department is
responsible for 5 courses, two on clinicalepidemiology, two on health economics, and one on
healthcare organization management. 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. The course requires participating
students to apply provided knowledge to empiricalexamples such as evaluation of effectiveness of
screening tests, pharmaceutical cost-effective analysis,

technology assessment of surgical treatment, andhospital management. The applied course supports thestudents to build a research hypothesis, design a study,
and prepare a study protocol for fund proposal. Healtheconomics course provides an intermediate level ofmicro-economics and health economics theories ofconsumer choice, insurance, and human capital, andenhances discussion to apply these theories tobehaviors of providers and consumers. The 3-day
intensive course supported by Dr. Takashi Fukuda andhis colleague offers students an opportunity forhands-on training of actual cost-effectiveness analysisof health care and technologies. In collaboration with
Department of Health Informatics, a course on healthcare organization management was offered in theacademic year of 2012. The course provides basics offinancial accounting, and management frameworks onhuman resource, strategy, information, and risk,
helping the students deepen the knowledge throughin-class discussion over real-case scenarios.
The Department accepted six doctoral students and 5
master students for the fiscal years of 2012.

Research activities
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.

326

In the collaboration with the Department of HealthManagement and Policy in the 22nd Medical ResearchCenter in the University of Tokyo Hospital, theDepartment also contributes to clinical and healthservice research using a large claim database based on
the Japanese original patient classification system,
Diagnosis Procedure Combination (DPC). DPC
database allows a unique and detailed analysis on theprocess of care in acute care hospitals in this country.
DPC database also provides resource diagnosis in
hospital levels as well as regional levels, whencombined with other public data sources such as thePatient Survey, and Hospital Census.
Social epidemiology research is a topic that the
department newly puts an emphasis as a health policy
agenda in global movement. Health disparity is known
to exist across socio-economic statuses, and Japan isof no exception even though it has been believed as anegalitarian country. The impact of social determinantsof health has become even more relevant after
long-standing economic instability since 2000, which
affects health statuses differentially across social,economic, occupational, and regional conditions.

References
1. Takeuchi M, Osamura T, Yasunaga H, Horiguchi H,
Hashimoto H, Matsuda S. Intussusception among
Japanese children: an epidemiologic study using an
administrative database. BMC Pediatr. 2012 Mar
22;12:36.
2. Yasunaga H, Horiguchi H, Matsuda S, Fushimi K,
Hashimoto H, Ohe K, Kokudo N.Relationshipbetween hospital volume and operative mortality forliver resection: Data from the Japanese Diagnosis
Procedure Combination database. Hepatol Res.2012
Apr 10. doi: 10.1111/j.1872-034X.2012.01022.x.
3. Yasunaga H, Horiguchi H, Hashimoto H, Matsuda S,
Fushimi K. The Burden of Clostridium difficile–
Associated Disease following Digestive Tract
Surgery in Japan. J Hosp Infect 2012; 82(3):175-80.
4. Tomiyama H, O'rourke MF, Hashimoto H,
Matsumoto C, Odaira M, Yoshida M, Shiina K,
Nagata M, Yamashina A. Central blood pressure: apowerful predictor of the development ofhypertension. Hypertens Res. 2012 Aug 9. doi:
10.1038/hr.2012.123.
5. Kawaguchi H, Hashimoto H, Matsuda S. Efficacy of
a numerical value of a fixed-effect estimator instochastic frontier analysis as an indicator of hospital
production structure. BMC Health Serv Res. 2012
Sep 22;12(1):334.
6. Yasunaga H, Hashimoto H, Horiguchi H, Miyata H,
Matsuda S. Variation in cancer surgical outcomes
associated with physician and nurse staffing: a
retrospective observational study using the JapaneseDiagnosis Procedure Combination Database. BMC
Health Serv Res. 2012 May 28;12:129. doi: 10.1186/
1472-6963-12-129.
7. Horiguchi H, Yasunaga H, Hashimoto H, Ohe K. A
User-friendly Tool to Transform Large Scale
Administrative Data into Wide Table Format using a
MapReduce Program with a Pig Latin based Script.
BMC Medical Informatics and Decision Making
2012;12:151
8. Nishiura C, Hashimoto H. Screening for measles
vaccination in young Japanese non-healthcare
workers through self-reported history. J Occup
Health. 2012;54(2):154-7.
9. Wada K, Kondo N, Gilmour S, Ichida Y, Fujino Y,
Satoh T, Shibuya K. Trends in cause-specificmortality across occupations among working-age
Japanese men during the period of economic
stagnation, 1980-2005: Retrospective cohort study.
British Medical Journal 2012; 344, e1191.
10. berg Yngwe M, Kondo N, Hgg S, Kawachi I.
Relative deprivation and mortality; a longitudinal
study in a Swedish population of 4,7 million, 19902006. BMC Public Health 2012; 12, 664.
11. Saito M, Kondo N, Kondo K, Ojima T, Hirai H.
Gender differences on the impacts of social
exclusion on mortality among older Japanese: AGES
cohort study. Social Science & Medicine 2012:
75(5), 940-945.
12. Yamamoto T, Kondo K, Misawa J, Hirai H, Nakade
M, Aida J, Kondo N, Kawachi I, Hirata Y. Dental
status and incident falls among older Japanese: aprospective cohort study. BMJ Open 2012: 2(4),e001262.

327

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.
Health communication is a major discipline in schoolof public health, especially in the US, and there aremany graduate programs and research centers forhealth communication. On the other hand, there havebeen few such departments in Japan, although theimportance of the health communication discipline
has gradually been recognized among the academic
society as well as among general public. Our department was established one of the few departments
specialized in health communication in Japan.

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. Health counseling
3. Patient-provider Communication (1): Provider
perspective
4. Patient-provider Communication (2): Patient perspective
5. Patient-provider Communication (3): Communication skills for health care providers
6. Mass Media and Communication: Television
7. Mass Media and Communication: News paper
8. Internet communication
9. Social marketing
10. Entertainment education
11. Health Communication Campaign
12. Evaluation and research in health communication[Health Communication Practice]
1. Coaching
2. Manners in interpersonal relationship3. MBTI (Myers-Briggs Type Indicator) (1)4. MBTI (Myers-Briggs Type Indicator) (2)5. Mass communication: Press conference
6. Internet communication (1)7. Internet communication (2)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.”

328

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.

329

References
1. Anazawa, R., Ishikawa, H., Park, MJ., Kiuchi, T.
Preliminary study of online machine translation
use of nursing literature: quality evaluation andperceived usability. BMC Res Notes. 2012; 14(5):635.
2. Anazawa, R., Ishikawa, H., Kiuchi, T. The
accuracy of medical interpretations: a pilot studyof errors in Japanese-English interpreters during asimulated medical scenario. International Journalof Translation and Interpreting Research. 2012;
4(1):1-20.
3. Park MJ., Green J., Ishikawa H., Kiuchi T. Hidden
decay of impact after education for selfmanagement of chronic illnesses: hypotheses.
Chronic Illness. 2013; 9(1):73-80.
4. Park MJ, Yamazaki Y, Yonekura Y, Yukawa K,
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.
5. Anazawa R., Ishikawa H., Kiuchi T. The
perceived need for Japanese nursing faculty
members to learn English: issues related to careerdevelopment. J Contin Educ Nurs. 2012;43(4):188-91.

School of Public Health
2. Behavioral Health Sciences

331

Departments ofHealth and Social Behavior& Health Education andSociology
Professor in health and social behavior
Hideki Hashimoto, M.D., D.PH.

Associate Professor in health sociology and health education
Lecturer

currently vacancy

currently vacancy

Associate
Misato Takada, Ph.D.

Homepage

Under construction

Introduction and Organization
The department originated as one of the firstdepartments dedicated to health education andbehavioral science in Japan, led by Prof. Emeritus
Tadao Miyasaka, who had double degrees of M.D.
from the University of Tokyo and MPH in healtheducation from Harvard School of Public Health in1950s. He was succeeded by a sociologist, former Prof.
Kyoichi Sonoda who founded the first healthsociology department affiliated with the medical
school in Japan. Since then, the program has beenleading research focusing on socio-behavioral aspectsof health in this country. The legend was extended by
Prof. Chieko Kawada who raised academic andpractical attention on the concept of empowerment
and adult pedagogy in health education. Since 1997,
the department was further evolved by Prof. Ichiro
Kai who integrated diverse health and social science
disciplines into social gerontology program, and by
Associate Prof. Yoshihiko Yamazaki who ledsociological research projects on salutogenesis, social
stigma, power, and agency in health settings. The

departments were reorganized under the newly
established School of Public Health since 2007. In
2012, the Department of Social Gerontology has beenrenamed the Department of Health and Social
Behavior to apply a life-course perspective to a wider
range of social conditions and human wellbeing.
The new department intends to further integrate
health science (medicine and public health) and social
science (economics, sociology, and psychology) toreveal a causal mechanism linking social structure andindividual health for realizing health equity as afundamental goal to human security.

Teaching activities
The departments offer two courses in the master
degree program for public health, and five courses in
the undergraduate program for the Integrated Health
Sciences track.
1. Graduate Courses, School of Public Health
1) Health and Society: The course highlights thesignificance of social determinants of health(SDH) as a key exposure causing social gradient332

of health. A series of omnibus lectures, each ofwhich focusing a specific topic of SDH (e.g.
income distribution, gender, job stress, anddiscrimination), are provided by invited lecturers
specialized in the field.
2) Health Education; The course provides basic
knowledge on relevant behavioral theories forhealth promotion and behavioral modification,
followed by case studies of health educational
intervention in community, school, and work
places. The case discussion was facilitated byinvited lecturers to reach practical lessons for
effective communication.
2. Undergraduate Courses, School of Integrated
Health Sciences
1) Introduction to social survey and practice: The
course emphasizes that needs for specificknowledge and subsequent research question
define the modes of survey. The course gives thestudents a virtual situation where a social survey
is required to obtain data to support somedecision making, e.g. market research situation.
The students are asked to define an inquired
concept, refine a research question, design themode of survey, and conduct a small pilot survey
within the class. The survey results werereported with some practical implication, andwere opened to in-class discussion.
2) Health sociology: The course was offered as apart of “Health and Society” in the academic
year of 2012.
3) Health education: The course was offered as apart of “Health Education” in the academic yearof 2012.
4) Social security and welfare program: Lecture
series on the history and the current systems ofhealth care security and welfare policies in thiscountry.
5) Occupational health management; Lecture series
on risk/needs assessment, strategic managementof health resource, and health promotion intervention in work place.

Research activities
The Department has contributed to an ongoing
research of socioeconomic status and health/functions

among elderly population in the collaboration with the
School of Economics of the University of Tokyo andthe Research Institute of Economic, Industry, andTechnology. The Japanese Study of Ageing andRetirement (J-STAR) is a sister study with the U.S.
Health and Retirement Study, Study of Health, Ageing,
and Retirement in Europe (SHARE), EnglandLongitudinal Survey of Ageing (ELSA), and theirglobal sisters in Asian countries. The scope of JSTAR
is diverse; contribution of health for successful ageing,social economic conditions and access to health care,household economy and its impact on life styles suchas eating habits and nutrition, impact of retirement
onto cognitive function, etc..
Since 2010, the Department has launched anotherpanel study of younger generation, the Japanese studyof Stratification, 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 how socio-economic environments get to “under-skin” to cause social gradient ofhealth across socio-economic positions. In the year of
2011, the JSHINE conducted a supplemental survey torespondent’s spouse and children. A preliminary result
suggests that socioeconomic conditions of parents andgrand parents are influential on the sociobehavioral
development of children.
Panel data of these surveys are planned to open for
academic use to a global researcher circle to shareanalytic scheme and to enhance comparative studies
so as to better identify common factors as well as
unique factors affecting health in Japanese context.

References
1. Friel S, Loring B, Aungkasuvapala N, Baum F,
Blaiklock A, Chiang TL, Cho Y, Dakulala P, Guo
Y, Hashimoto H, Horton K, Jayasinghe S,
Matheson D, Huong NT, Otto C, Rao M, Reid P,
Surjadi C. Policy Approaches to Address theSocial and Environmental Determinants of HealthInequity in Asia-Pacific. Asia Pac J Public Health.
2012 Nov; 24(6): 896-914. doi: 10.1177/
1010539512460569
2. Watanabe R, Hashimoto H. Horizontal inequity inhealthcare access under the universal coverage in333Japan; 1986-2007. Soc Sci Med. 2012 Oct;75(8):1372-8. doi: 10.1016/j.socscimed.2012.06.006.
3. Nishi A, McWilliams JM, Noguchi H, Hashimoto
H, Tamiya N, Kawachi I. Health benefits ofreduced patient cost sharing in Japan. Bull World
Health Organ. 2012 Jun 1;90(6):426-435A. doi:
10.2471/BLT.11.095380.
4. Miyaki K, Song Y, Htun NC, Tsutsumi A,
Hashimoto H, Kawakami N, Takahashi M,
Shimazu A, Inoue A, Kurioka S, Shimbo T. Folate
intake and depressive symptoms in Japanese
workers considering SES and job stress factors:
J-HOPE study. BMC Psychiatry. 2012 Apr 20;
12:33. doi: 10.1186/1471-244X-12-33.

School of Public Health
3. Health Services Sciences

335

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Homepage:

http://home.cie.m.u-tokyo.ac.jp:8080/ciemutk

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.

336

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. Takai K, Kin T, Oyama H, Shojima M, Saito N.
3D analysis of the angioarchitecture of spinal
dural arteriovenous fistulas with special reference
to intradural retrograde venous drainage system. J
Neurosurg Spine. 2012 [Epub ahead of print].
2. Yoshino M, Kin T, Shojima M, Nakatomi H,
Oyama H, Saito N. A high-resolution methodwith increased matrix size can characterize small
arteries around a giant aneurysm in three
dimensions. Br J Neurosurg. 2012 Jun 19.
3. Kin T, Nakatomi H, Shojima M, Tanaka M, Ino K,
Mori H, Kunimatsu A, Oyama H, Saito N. A newstrategic neurosurgical planning tool for brainstem cavernous malformations using interactive
computer graphics with multimodal fusion
images. J Neurosurg. 2012 Jul; 117(1):78-88.
Epub 2012 May 11.

Endowed Department

338

Department ofPharmacoepidemiology
Professor
Kiyoshi Kubota, M.D.,Ph.D.

Associate Professor
Soko Setoguchi, M.D., Ph.D.

Lecturer
Hideo Nomo, 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, 5 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 2nd 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 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

339

Agency (PMDA). The first seminar was held in2006. In 2012, the 7th seminar is being conducted.
Furthermore, the department has been a driving force
to make a textbook of pharmacoepidemilogy inJapanese published in 2010. The department is also
contributing to translate a textbook by Dr PatricWaller, a former regulator in the regulatory body in
the UK entitled an “An Introduction to Pharmacovigilance” 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 is developing 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 data.

References
1. Ooba N, Setoguchi S, Ando T, Sato T, Yamaguchi
T, Mochizuki M, Kubota K. Climas-based
definition of death in Japanese claims database:validity and implcations. PlosOne, in press..
2. Andersen M, Bergman U, Choi NK, Gerhard T,
Huang C, Jalbert J, Kimura M, Kimura T, Kubota
K, Lai ECC, Ooba N, Ösby U, Park BJ, Pratt N,
Roughead EE, Sato T, Setoguchi S, Shin JY,
Sundström A, Yang YHK. The Asian
Pharmacoepidemiology
Network(AsPEN):
Promoting multi-national collaboration forpharmaco-epidemiologic research in Asia.
Pharmacoepidemiol Drug Saf. in press.
3. Pratt N, Andersen M, Bergman U, Choi NK,
Gerhard Y, Huang C, Kimura M, Kimura T,
Kubota K, Lai ECC, Ooba N, Ösby U, Park BJ,
Sato T, Shin JY, Sundström A, Yang YHK,Roughead EE. Multi-country rapid adverse drug
event assessment: The Asian Pharmacoepidemiology Network (AsPEN) antipsychotic and acute
hyperglycaemia study. Pharmacoepidemiol Drug
Saf. in press..
4. Kubota K, Okazaki M, Dobashi A, Yamamoto M,
Hashiguchi M, Horie A, Inagaki A, Kikuchi T,

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Mochizuki M. Temporal relationship between
multiple drugs and multiple events in patientreports on adverse drug reactions: findings in apilot study in Japan. Pharmacoepidemiol Drug
Saf. in press.

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Department of Integrated
Traditional Medicine
Project Professor
Tetsuro Okabe, M.D., Ph.D.

Project Associate
Jing Yu, Ph.D,

Homepage

Hideki Koizumi, M.D., Ph.D.

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.

342

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 no effective
therapeutic tools. SCA6 has been demonstrated to be
an autosomal dominant cerebellar ataxia associatedwith small polyglutamine-dependent expansions in thealpha 1A-voltage calcium channel. Long-term
remission of this genetic disease has been attainedwith medicinal herbs. The findings of our study imply
the therapeutic potential of herbal medicine for thishereditary neurodegenerative disorder. Extensive
investigations are under way to clarify themechanisms. It has been also demonstrated that someherbs are effective against multiple sclerosis ,neuromyelitis optica, epilepsy, Parkinson’s disease ordepression 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

343

herbal medicine is based on the principle of thecharacteristic systems biology. According to theguideline of the traditional herbal medicine, we haveexamined the clinical effect by systems therapy withmedicinal herbs in patients with bronchial asthma andessential hypertension. Long- term remission has beenobtained in both disorders. Extensive studies are under
way to elucidate the mechanisms by which systems
therapy exerts the therapeutic activities.

References
1. Yu, J.,Akishita, M., Eto, M., Koizumi, H.,
Hashimoto, R., Ogawa, S., Tanaka, K., Ouchi, Y.,
Okabe, T. Src Kinase-mediates androgen receptordependent non-genomic activation of signalingcascade leading to endothelial nitric oxide synthase.
Biochem. Biophys. Res. Commun. 424:538-543,
2012
2. Hashimoto, R., Yu, J., Koizumi, H., Ouchi, Y.,
Okabe, T. Ginsenoside Rb1 prevents MPP(+)induced apoptosis in PC12 cells by stimulating
estrogen receptors with consequent activation of
ERK1/2, Ark and inhibition of SAPK/JNK, p38
MAPK. Evid Based Complement Alternat Med.
2012;2012:693717,8 pages 2012.doi:10.1155/2012/
693717

344

Department of Clinical
Epidemiology and Systems
Associate Professor
Daisuke Koide, R.Rh., HIM, Ph.D.

Associate
Mikio Takanashi, M.D., Ph.D.

Researcher
Yoshiko Mizuno, M.D., 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 led by Professor Ryozo Nagai at the
Department of Cardiovascular Medicine (currently
President of Jichi Medical University), because theunit had been terminated its five-year programsupported by the Japan Science and Technology
Agency in 2007 as scheduled. At the time ofestablishment, the staffs were professor Yamazaki andassociate professor Koide.
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(currently director and professor of clinical researchsupport center) is also the head of the both sections.
The staffs of this center overlap with faculty membersin 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.
The first term for five-year passed in March 2012,
and the second term has been started since April 2012.
When it was renewed, professor Yamazaki moved to
the Clinical Research Support Center as director. Also,
this department has been supported by the department

345

of Diabetes and Metabolic Medicine (Professor
Takashi Kadowaki) since then. And associate
Takanashi became a member of this department andthe Center for Epidemiology and Preventive Medicine.
In 2013, the department of Cardiovascular Medicine(Professor Issei Komuro) became the parental
department again. In addition to that, the ClinicalResearch Support Center (Professor Tsutomu
Yamazaki) joined as the parental department newly.
Through this cooperation with many departments
and centers, we have been conducting education andresearch. As before, associate professor Koide is anassistant manager of personal information that makes
any data of studies regarding human genome or geneanonymous. In the fiscal year of 2012, we received 33
requests and made 8013 samples anonymous.
In addition, our department has been incollaboration with many institutions within andoutside the university, since the times of the CBI.

profession" for three years since 2012. Therefore, we
expand our cope of human resource development for
not only clinical epidemiology, but also clinicalresearch and trial.

Teaching activities

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.

As “Introduction of Clinical Medicine” by
Department of Clinical and Genetic Informatics andrelated departments, associate professor Koide gave alecture which was entitled "development of clinicaldatabase" at the middle Conference Hall of ourCentral Clinical Service Building II on June 22 in
2012.
Also, the basic lectures of Medical Writing took
place as an intensive course on September 25-26 in2012, hosted by the non-profit organization of Japan
Medical and Scientific Communicators Association,and supported by the three departments of Clinical
Epidemiology and Systems, Clinical Trial DataManagement, and Ubiquitous Preventive Medicine.
In addition, associate professor Koide gave a
special lecture for “-Clinical Pharmacology,
Evaluation of Drug Efficacy and Safety" (3)Pharmacoepidemiology”, which was given to thesixth-grade students at Tokyo University of pharmacy
and Sciences on July 12 in 2012.
By the way of public subscription, associate
professor Koide has been selected as a research leaderof the "collaborative study with universities ondevelopment of the e-learning system for clinicalresearch and trial according to the level of skill andResearch activities
1) Development of Medical Information Database forClinical Epidemiology and its validation study
The Ministry of Health, Labor and Welfare in Japan
started "10 Million patient's medical data project" forimproving safety measures, and selected 10 medical
institutions including the University of Tokyo in 2011.
At first, the system development has been launched in
the University of Tokyo Hospital. Associate professor
Koide is in charge of this system development andvalidation. In the future, this system infrastructure will
be available with other medical institutions for clinicalepidemiology

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.

3464) In Vivo Analysis on Lipid Metabolism
In order to elucidate the pathophysiological role ofneutral lipid accumulation (so called "lipotoxicity") in
metabolic diseases, we take advantage of mousemodels of lipase deficiency and genetic hyperlipidemia, such as hormone-sensitive lipase (Lipe)
deficient mice, neutral cholesterol ester hydrolase 1(Nceh1) deficient mice, Ldlr/Apoe and Apoa5
deficient mice.
Specifically, our recent findings suggest theunprecedented roles of these lipases in diabetic
dyslipidemia, non-alcoholic steatohepatitis (NASH)
and atherosclerosis. In addition, we recently established an obesity-resistant mutant mouse strain which
may lead to the identification of new therapeutictargets to combat obesity-related disorders.
5) Preventive Medicine for Cardiovascular Disease
Cardiovascular disease is one of the main causes ofdeath in Japan and the related medical expenses arebigger than those of cancer. Preventive cardiology,
which has been initiated by the Japanese medical
society since 2000, is now regarded as the key
solution to the problem. Hence, we take advantage ofthe uniqueness of "Ningen Dock" and create databaseof the patient information. The purpose of our study is
to conduct epidemiological research by using thesedata and contribute to preventive cardiology.

References
1. Kimura T, Koide D, Orii T.: Large, AutomatedAdministrative and Clinical Databases Available
for Pharmacoepidemiology Studies in Japan.
Japanese Journal of Pharmacoepidemiology 17(2):135-44, 2012.
2. Koide D, Kimura M.: Clinical and post-marketing
trials/research -the present and future-. Japan
Journal of Medical Informatics 32(Suppl.): 112-3.
2012.
3. Koide D.: ICH-E2B (R3) Implementation Guide.
Pharmaceutical and Medical Device Regulatory
Science 43(2): 104-109. 2012.

347

Department of Ubiquitous
Preventive Medicine
Associate Professor
Toru Suzuki, M.D., Ph.D.

Research Associate
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, the Departmentof Ubiquitous Preventive Medicine was inaugurated inAugust 1st, 2007 (Heisei 19), with a donation fromthree pharmaceutical companies, Toa-Eiyo Ltd.,
Shionogi & Co., Ltd. and NEC Corporation to the
University (since August 2010, from Shionogi & Co.).
Its predecessor is the Clinical Bio-Informatics
Research Unit in the Graduate School of Medicine of
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 andservices were continued by the Department of
Ubiquitous Preventive Medicine and the Departmentof Clinical Epidemiology and Systems, both affiliatedwith the Department of Cardiovascular Medicine in
the Graduate School of Medicine of the University ofTokyo.
The first head of the Department of Ubiquitous
Preventive Medicine is Toru Suzuki, appointed inAugust 1st, 2007, as Associate Professor. Kenichi
Aizawa serves as Research Associate.

Our objectives are to develop diagnostic biomarkers
and diagnostic/therapeutic systems for prevention andearly detection of disease.
For this purpose,advanced and highly efficient techniques of proteome
analysis are used with potential clinical application topreventive medicine. We are also committed todeveloping surrogate biomarkers for the discovery ofdrugs used in the treatment of cardiovascular diseases
as well as the optimization of their efficacy, and todevelop information infrastructure technologies foradvancing personalized medicine by clinically
applying the techniques of proteome analysis in aneffort to promote preventive medicine for healthpromotion. Our mission is to ultimately establish theacademic basis for Ubiquitous Preventive Medicine.
Our department provides diagnostic/therapeutic aswell as academic support for the Department of
Epidemiology and Preventive Medicine established in2007 within the University of Tokyo Hospital. In
collaboration with our department, the Department ofClinical Epidemiology and Systems also support the
management of the Department of Epidemiology andPreventive Medicine.

Research Activities
The principal objectives of our research are to develop
diagnostic technologies for prevention and early
detection of disease by using advanced and highly
efficient techniques of proteome analysis, focusing on

348

the development of diagnostic biomarkers anddiagnostic/therapeutic systems, and to promotetranslational research which connects basic scientificfindings such as defined disease mechanism totangible clinical application. A typical example is that
we are in the process of developing methods for themeasurement of protein modifications in cardiovascular diseases and other new bio-tools for early
detection of lifestyle-related diseases.
One of the achievements we have made is the world
first biomarker detecting system for ischemic heartdisease, which is a collaborative work by Toru Suzuki
and Shimadzu Corporation. This system allows to
detect conformational change or degradation ofproteins which are important in cardiovascularpathologies such as ischemic heart disease and heart
failure. This system consists of two major parts, mass
spectrometry analysis which enables qualitative andquantitative evaluation of processed degradation
products or post-transcriptional modification of
specific proteins, and immunoprecipitation. We havealready confirmed and published its utility in clinicalpractice (Clin Chem, in press), further, issued
press-release from the University of Tokyo hospital.
(http://www.h.u-tokyo.ac.jp/press/press_archives/2013
0516.html)
Specifically, the development of diagnostic
biomarkers and diagnostic/therapeutic systems byusing the techniques of proteome analysis is pursued
on an ongoing basis with its main research projects
being Medical Equipment Development Research
Project from 2011 to 2013 under the Ministry of
Health, Labour and Welfare and Academic-Industrial
Research Collaboration (joint research with Shimadzu
Corporation).
In addition to the development of proteomics-based
diagnostic methods, we also are developing
information infrastructure technologies for advancing
personalized medicine by clinically applying thesemethods to preventive medicine, as in comprehensive
medical examinations. In this way, Ubiquitous
Preventive Medicine is an applied science, based on
which a comprehensive system is to be developed inan effort to promote preventive and participatory
medicine for health promotion, and translational
research which refines basic findings to clinicalapplication.

Clinical activities
The Department of Ubiquitous Preventive Medicine
is involved in the management of the Department of
Epidemiology and Preventive Medicine in the
University of Tokyo Hospital and provides diagnostic/
therapeutic as well as academic support for the
department.

Teaching activities
The Department of Ubiquitous Preventive Medicine
offers education and research supervision to graduate
students and post-doctoral fellows in the affiliate
Department of Cardiovascular Medicine.

References
Academic Papers in English
1. Garrido-Martín EM, Blanco FJ, Roque M,
Novensà L, Tarocchi M, Lee UE, Suzuki T,
Friedman SL, Botella LM, Bernabeu C.Vascular
injury triggers Krüppel-like factor 6 (KLF6)
mobilization and cooperation with Sp1 to promote
endothelial activation through upregulation of the
Activin Receptor-Like Kinase 1 (ALK1) gene.Circ
Res. 2012, 112(1): 113-127.
2. Di Eusanio M, Trimarchi S, Patel HJ, Hutchison S,
Suzuki T, Peterson MD, Di Bartolomeo R,
Folesani G, Pyeritz RE, Braverman AC,
Montgomery DG, Isselbacher EM, Nienaber CA,
Eagle KA, Fattori R. Clinical presentation,
management, and short-term outcome of patientswith type A acute dissection complicated bymesenteric malperfusion: Observations from theInternational Registry of Acute Aortic Dissection.
J Thorac Cardiovasc Surg. 2012, 145(2): 385-390.
3. Ishida J, Suzuki T, Aizawa K, Sawaki D, Nagai
R.Comparison of Analytical Performance of Two
Single-step Measurement Devices of B-type
Natriuretic Peptide. Int Heart. 2012, 53: 320-323.
4. Suzuki T, Tomiyama H, Higashi Y. Vascular
dysfunction even after 20 years in children
exposed to passive smoking- alarming results andneed for awareness. Arterioscler Thromb Vasc Bio.
2012, 32: 841-842,

349

5. Suzuki T, Isselbacher EM, Nienaber CA, Pyeritz
RE, Eagle KA, Tsai TT, Cooper JV, Januzzi JL Jr,
Braverman AC, Montgomery DG, Fattori R, Pape
L, Harris KM, Booher A, Oh J, Peterson M,
Ramanath VS, Froehlich JB. Type-selective
benefits of medications in treatment of acute aortic
dissection; (from the International Registry of
Acute Aortic Dissection [IRAD]). Am J Cardiol.
2012, 109: 122-127.

2.

3.
Academic Papers in Japanese
1. 相澤健一、鈴木亨
バイオマーカーの探索・発見・同定の試み.
Heart View 2012, 16(12): 306-310
2. 相澤健一、鈴木亨
新しい動脈硬化のバイオマーカー開発 − 新しいプロテオーム技術を用いて −.
循環器専門医. 2012, 20(2): 237-244
3. 澤城大悟、鈴木亨、
特集『バイオマーカーupdate ―診断から治療評価へ―』「急性大動脈解離」「ICU と CCU」, 2013, vol 37(1) 21-26
4. 澤城大悟、鈴木亨、
特集「循環器病のバイオマーカー」2．循環器疾患診療ツールとしてのバイオマーカー f.
大動脈解離・大動脈瘤,
Heart View, 2012, vol.16 No12(増刊号), 72-78
5. 石田 純一、鈴木亨
慢性炎症と疾患 11.心血管病の分子マーカー
hsCRP，Pentraxin 3，Myeloperoxidase 他
別冊 BIO Clinica（バイオクリニカ）2012,10, 20
vol1-(1)
6. 石田 純一, 永井良三
分子標的薬 Ⅱ-5.疾患領域別分子標的薬の基礎研究 (4) 血管・循環器系疾患の分子標的薬
研究日本臨牀増刊号 2012, 11, 12, 378-382
International Conferences
American heart association scientific session 2012
(Los Angeles, CA, USA: 2012/11/5-8)
1. Toru Suzuki, Eric M Isselbacher, Kim A Eagle,
Christoph A Nienaber, Daigo Sawaki, Lindsay M
Hagan, Daniel G Montgomery, James B Froehlich,
Effect of Medical Treatment for Aortic Dissection
on In-Hospital Mortality and Follow-Up Aortic
Expansion in Patients with and Without Marfan

4.

5.

6.

7.

Syndrome; Observations from the International
Registry of Acute Aortic Dissection
Eduardo Bossone, Kevin M Harris, Toru Suzuki,
Rossella Fattori, Stuart Hutchison, Marek P Ehrlich,
Reed E Pyeritz, P. Gabriel Steg, Kevin Greason,
Arturo Evangelista, Matthias Voehringer, Daniel G
Montgomery, Eric M Isselbacher, Christoph A
Nienaber, Kim A Eagle, Stroke and Outcomes inPatients with Acute Type A Aortic Dissection
Dan Gilon, Reed E Pyeritz, Arturo Evangelista,
Patrick O'Gara, Kevin M Harris, Alan C Braverman,
Mark D Peterson, Matthias Voehringer, Toru Suzuki,
Lori D Conklin, Daniel G Montgomery, Eric M
Isselbacher, Christoph A Nienaber, Kim A Eagle,
Amit Korach, Is Conservative Treatment Justified in
Marfan Syndrome Patients with Non-ComplicatedAcute Type B Aortic Dissection? Insights from theInternational Registry of Acute Aortic Dissection
Junichi Ishida, Toru Suzuki, Kenichi Aizawa,
Daigo Sawaki, Takayoshi Matsumura, Scott L
Friedman, Ryozo Nagai, Krüppel-like Factor 6
Promotes Obesity and Glucose Intolerance
Through Adipocyte Differentiation
Bo Kyung Son, Toru Suzuki, Daigo Sawaki,
Kenichi Aizawa, Hong Zhan, Junichi Ishida,
Takayoshi Matsumura, Ryozo Nagai, KLF6
Modulates Aortic Aneurysm Formation by
Balancing Between Inflammatory and TGFβ
Signaling Pathways
Daigo Sawaki, Toru Suzuki, Kenichi Aizawa,
Takayoshi Matsumura, Yoshiko Munemasa, Junichi
Ishida, Scott Friedman, Ryozo Nagai, Cardiomyocyte Regulates Cardiac Fibrosis through Cell to
Cell Interaction Mediated by KLF6
Yoshiko Mizuno, Toru Suzuki, Takahide Kohro,
Satoshi Iimuro, Tsutomu Yamazaki, B-type
Natriuretic Peptide and Subclinical Atherosclerosis
in Healthy Population

European society of cardiology congress 2013
(Munich, Germany: 2012/8/25-29)
8. E. Bossone, A. Korach, R. Fattori, G.C. Hughes,
T.T. Tsai, D.G. Montgomery, K.A. Eagle, C.A.
Nienaber, E.M. Isselbacher, T. Suzuki, Racialdifferences in acute aortic dissection: insightsfrom the International Registry of Acute Aortic
Dissection

350

9. Suzuki T, Biomarkers of aortic disease, invited
session, The aorta: a mysterious organ
FASEB Summer Research Conference “Biology &Pathobiology of Kruppel-Like Factors (KLFs)”(Snowmass, Colorado, USA: 2012/8/5-9)
10. Suzuki T, KLF6 in cardiovascular and metabolic
disease
11. Sawaki D, Krüppel-like Factor 6 Modulates
Recruitment and Polarization of Inflammatory
Cells through Cardiomyocytes in Initiation of
Cardiac Fibrosis.
National Conferences
第 76 回日本循環器学会総会・学術集会（福岡:2012/3/16-18）
1. Son BK, Suzuki T, Sawaki D, Aizawa K,
Matsumura T, Munemasa Y, Zhan H, Okamoto Y,
Ishida J, Nagai R, Aortic remodeling stimulates
aneurysm formation in apoE-/- mice throughgp130/STAT3 signaling.
2. Daigo Sawaki, Toru Suzuki, Kenichi Aizawa,
Takayoshi Matsumura, Yoshiko Munemasa,
Junichi Ishida, Scott L Friedman, Ryozo Nagai,
KLF6 Modulates Recruitment and Polarization of
Inflammatory Cells through Cardiomyocytes in
Initiation of Cardiac Fibrosis.
3. Kenichi Aizawa, Regulation of cardiac hypertrophy by DNA damage response as mediated by
KLF5

351

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 ofUrology (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.

352(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.
We found that renal Rac1 is activated in thekidneys of obese diabetic mice. Rac inhibitor
suppresses their renal MR activity and its
downstream gene expression, and ameriolates
renal pathology. Our previous study reported thecritical role of Rac1 in MR activation undernormal or low aldosterone condition. Obesediabetic mice shows significant high plasma
aldosterone concentration, and this is the firststudy that proves the important role of Rac1 in
MR activation under high aldosterone condition.
In vitro study revealed that high glucose
stimulation activates Rac1 and MR in cultured
mesangial cells. Glucose induced ligandindependent MR activation is perfectly inhibitted
by Rac1 inactivation. We are now submitting apaper on this project.
(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. We also try to identify
the aldosterone releasing factor (ARF) derived
from fat cell. The renin-angiotensin-aldosterone
system (RAAS) of diabetic patients is generally
suppressed. However, obese dabetic patientsshows hyperaldosteronism. Non-diabetic obese
patients also exhibited high plasma aldosterone
concentration, and it is not correlated with plasma
angiotensin II concentration. These clinicalobservation strongly suggest the presence of afactor which stimulates aldosterone production
other than old RAAS in obese patients. We andothers reproted that fat cell derived factor
stimulates aldosterone production in cultured
adrenal cells. Now we are narrowing thecandidates of the factor.
(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.
(6) We explore the effect of renin inhibition in whole
RAAS suppression. Renin is the rate-limiting stepof the RAAS and lacks any known alternative
pathway. We found that relatively small amount ofrenin inhibitor dramatically suppresses both ofplasma angiotensin I and II in Tsukuba hypertensive mice which are carrying human genes forboth renin and angiotensinogen. Angiotensin
coverting enzyme inhibitor (ACE-I) significantly
increases their plasma angiotensin I, and therefore
it is inferior to renin inhibitor in angiotensin II
suppressing effect instead of its significant
decrease of plasma angiotenisin II / angiotensin I
ratio. Along with plasma angiotensin II concentration, renin inhibitor is superior to ACE-I inrenoprotective effect in high salt loaded Tsukuba
hypertensive mice. We are aldo submitting a paperon this project.

Teaching activities
The education of post-graduate students is also an
important task of our department. Our staffs help thestudents to plan and perform basic experiments and/or
clinical studies, to make oral or poster presentation at
Japanese or international society, and to publish
scientific article. We have educational programs
including journal club in order to polish theiracademic skills.

References
1. Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K,
Ueda K, Yoshida S, Fujita T: Oxidative stress causes
mineralocorticoid receptor activation in rat
cardiomyocytes: role of small GTPase Rac1.
Hypertension 2012 59: 500-6.
2. Kawarazaki W, Nagase M, Yoshida S, Takeuchi M,
Ishizawa K, Ayuzawa N, Ueda K, Fujita T:
Angiotensin II- and salt-induced kidney injury
through Rac1-mediated mineralocorticoid receptor
activation. J Am Soc Nephrol 2012 23: 997-1007.

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Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Project Associate
Ryo Nitta, M.D., 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. 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.
citation: A-IMBN Research Highlights - Making theright connections.
(http://www.natureasia.com/A-IMBN/article.php?id=597)
2. Hirokawa N., Y. Tanaka, and Y. Okada. Cilia,
KIF3 Molecular Motor and Nodal Flow. Curr Opi
Cell Biol 24:31-39, 2012.
3. Kondo, M., Y. Takei, and N. Hirokawa. Motor

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4.

5.

6.

7.

8.

9.

protein 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 observedby cryoelectron microscopy. J Cell Biol 198:315-322, 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 toneuronal surface and is involoved in inhibitorytransmission. Neuron 76 (5): 945-961, 2012.
Niwa, S., K. Nakajima, H. Miki, Y. Minato, D.
Wang, N. Hirokawa. KIF19A is a microtubuledepolymerizing kinesin for ciliary length control.
Dev Cell 23: 1167-1175, 2012. doi.org/10.1016/
j.devcel.2012.10.016.
Zhou, R., S. Niwa, L. Guillaud, Y. Tong, and N.
Hirokawa. A Molecular Motor, KIF13A, Controls
Anxiety by Transporting the Serotonin type 1A
Receptor. Cell Reports 3:509-519, 2013.
Niwa S., H. Takahashi, and N. Hirokawa. beta
tubulin mutation that cause severe neuropathies
disrupt axonal transport. EMBO Journal 32:13521364, 2013. doi:10.1038/emboj.2013.59.

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Department of Molecular Vascular
Endocrinology
Associate Professor
Masashi Isshiki, M.D, Ph.D.

Associate
Risuke Mizuno, D.V.M., Ph.D.

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.
Lifestyle-related 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
like the 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 stresssensor 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

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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).

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 pharmacological interest.

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.

References

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

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.

Academic Conferences and Lectures
1. Mizuno, R., Isshiki, M., and Fujita, T.
Lymphatic vessels work as microcirculatory
system for molecular transportation andexchanges. Meeting of the Japanese Society of
Veterinary Science. March 2012.
2. Isshiki, M., Nishimoto, M., Mizuno, R., and Fujita,
T. Ca2+ imaging of intra-caveolar vesicles by
FRET and pyroantimonate precipitation methods.
Meeting of the Japan Endocrine Society. April
2012.
3. Isshiki, M., and Fujita, T. Subplasmalemmal
caveolae work as Ca2+-releasable Ca2+ store
subcompartments in endothelial cells. Meeting of
the Japanese Society of Molecular Medicine.
April 2012.
4. Mizuno, R., Isshiki, M., Nishimoto, M., and Fujita,
T. High concentration of salt dysfunctions
lymphatic activity through Na+-K+-ATPasedependent mechanisms. Meeting of the JapaneseSociety of Hypertension. September 2012.
5. Isshiki, M., Nishimoto, M., Mizuno, R., and Fujita,

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T. Subplasmalemmal caveolae work as
Ca2+-releasable Ca2+ store subcompartments inendothelial cells. Meeting of the Japanese Societyof Hypertension. September 2012.
6. Nishimoto, M., Isshiki, M., Mizuno, R., Takara, Y.,
and Fujita, T. Stim1 plays a role in blood pressure
regulation via NO production in vascularendothelial cells. Meeting of the Japanese Societyof Hypertension. September 2012.
7. Mizuno, R., Isshiki, M., and Fujita, T. Is lymph
node dissection essential? Basic of microcirculatory lymphatic system and its clinicalapplication to veterinary medicine. Meeting of theJapanese Society of Veterinary Anesthesia andSurgery. 2012. 12.
International Conferences
1. Isshiki, M., Nishimoto, M. Mizuno, R., and Fujita
T. A-FRET-based sensor detects caveolae arespatially distinct Ca2+ stores in endothelial cells.
Oral presentation of AHA Scientific Sessions
2012, 11.
2. Mizuno, R., Isshiki, M., Nishimoto, and Fujita T.
High concentration of salt dysfunctions lymphatic
activity through Na+-K+-ATPase-dependent mechanisms. Poster presentation of AHA Scientific
Sessions 2012, 11.

358

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

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Publications
1. 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. 2012 Jan;31(1):148-55.
2. Nakamura M, Fujimura T, Nagata M, Hosoda C,
Suzuki M, Fukuhara H, Enomoto Y, Nishimatsu
H, Kume H, Igawa Y, Homma Y. Association
between lower urinary tract symptoms and sexual
dysfunction assessed using the core lower urinary
tract symptom score and International Index of
Erectile Function-5 questionnaires. Aging Male.
2012 Jun;15(2):111-4.
3. Igawa Y, Schneider T, Yamazaki Y, Tatemichi S,
Homma Y, Nishizawa O, Michel MC. Functional
investigation of β-adrenoceptors in humanisolated detrusor focusing on the novel selective
β3-adrenoceptor agonist KUC-7322. Naunyn
Schmiedebergs Arch Pharmacol. 2012 Aug;385(8):759-67.
4. Minagawa T, Aizawa N, Igawa Y, Wyndaele JJ.
Inhibitory effects of phosphodiesterase 5 inhibitor,
tadalafil, on mechanosensitive bladder afferent
nerve activities of the rat, and on acrolein-induced
hyperactivity of these nerves. BJU Int. 2012 Sep;
110(6 Pt B):E259-66.
5. Miyazaki H, Nishimatsu H, Kume H, Suzuki M,
Fujimura T, Fukuhara H, Enomoto Y, Ishikawa A,
Igawa Y, Hirano Y, Homma Y. Leukopenia as arisk factor for osteonecrosis of the jaw inmetastatic prostate cancer treated using zoledronic
acid and docetaxel. BJU Int. 2012 Dec;110(11 Pt
B):E520-5.
6. Aizawa N, Homma Y, Igawa Y. Effects ofmirabegron, a novel β3-adrenoceptor agonist, on
the primary bladder afferent activity and bladdermicrocontractions in rats compared with the effectof oxybutynin. Eur Urol. 2012 Dec;62(6):116573.

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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 had 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. Starting as of
September 1, 2012, The Department of Medical
Genomics has been supported only by the donationfrom Astellas Pharma 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.
In 2012, Professor Mano was awarded The Medalwith Purple Ribbon from The Emperor of Japan, and
The Keio Medical Science Prize from The Keio

361

University Medical Science Fund.

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
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.
(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
experimentcandetectpoint
mutations,insertions/deletions and gene fusions simultaneously(Cancer Sci 103:131)
Dr. Kawazu applied this technology to a humanfibrosarcoma cell line, HT1080, leading to thediscovery of oncogenic mutants among small GTPases,
NRAS(Q61K) and RAC1(N92I) (PNAS 110:3029).
While both mutants transform mouse 3T3 cells,
growth of HT1080 was markedly suppressed only by
the siRNAs against RAC1(N92I), but not those against
NRAS(Q61K). These data thus suggest that HT1080 is
addicted to RAC1(N92I) for growth, and that
RAC1(N92I) is a good candidate for therapeutictargets in cancer treatment.

References
1. Yamada T, Takeuchi S, Nakade J, Kita K,
Nakagawa T, Nanjo S, Nakamura T, Matsumoto K,
Soda M, Mano H, Uenaka T, Yano S. Paracrine
receptor activation by microenvironment triggers
bypass survival signals and ALK inhibitor

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2.

3.

4.

5.

6.

7.

resistance in EML4-ALK lung cancer cells. Clin
Cancer Res. 2012;18:3592-3602.
Ueno T, Yamashita Y, Soda M, Fukumura K, Ando
M, Yamato A, Kawazu M, Choi YL, Mano H.
High-throughput resequencing of target-captured
cDNA in cancer cells. Cancer Sci. 2012;103:131135.
Togashi Y, Soda M, Sakata S, Sugawara E, Hatano
S, Asaka R, Nakajima T, Mano H, Takeuchi K.
KLC1-ALK: a novel fusion in lung cancer
identified using a formalin-fixed paraffinembedded tissue only. PLoS ONE. 2012;7:e31323.
Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata
S, Hatano S, Asaka R, Hamanaka W, Ninomiya H,
Uehara H, Choi YL, Satoh Y, Okumura S,
Nakagawa K, Mano H, Ishikawa Y. RET, ROS1
and ALK fusions in lung cancer. Nat Med. 2012;
18:378-381.
Sugawara E, Togashi Y, Kuroda N, Sakata S,
Hatano S, Asaka R, Yuasa T, Yonese J, Kitagawa
M, Mano H, Ishikawa Y, Takeuchi K. Identificationof anaplastic lymphoma kinase fusions in renal
cancer: Large-scale immunohistochemical screening
by the intercalated antibody-enhanced polymer
method. Cancer. 2012;118:4427-4436.
Soda M, Isobe K, Inoue A, Maemondo M, Oizumi
S, Fujita Y, Gemma A, Yamashita Y, Ueno T,
Takeuchi K, Choi YL, Miyazawa H, Tanaka T,
Hagiwara K, Mano H. A prospective PCR-based
screening for the EML4-ALK oncogene in nonsmall cell lung cancer. Clin Cancer Res. 2012;18:5682-5689.
Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK,
Teo AS, Ariyaratne PN, Takahashi N, Sawada K,
Fei Y, Soh S, Lee WH, Huang JW, Allen JC, Jr.,
Woo XY, Nagarajan N, Kumar V, Thalamuthu A,
Poh WT, Ang AL, Mya HT, How GF, Yang LY,
Koh LP, Chowbay B, Chang CT, Nadarajan VS,
Chng WJ, Than H, Lim LC, Goh YT, Zhang S, Poh
D, Tan P, Seet JE, Ang MK, Chau NM, Ng QS,
Tan DS, Soda M, Isobe K, Nothen MM, Wong TY,
Shahab A, Ruan X, Cacheux-Rataboul V, Sung
WK, Tan EH, Yatabe Y, Mano H, Soo RA, Chin
TM, Lim WT, Ruan Y, Ong ST. A common BIM
deletion polymorphism mediates intrinsic resist-ance and inferior responses to tyrosine kinase
inhibitors in cancer. Nat Med. 2012;18:521-528.
8. Mano H. ALKoma: a cancer subtype with a sharedtarget. Cancer Discov. 2012;2:495-502.
9. Kimura H, Nakajima T, Takeuchi K, Soda M,
Mano H, Iizasa T, Matsui Y, Yoshino M, Shingyoji
M, Itakura M, Itami M, Ikebe D, Yokoi S,
Kageyama H, Ohira M, Nakagawara A. ALK
fusion gene positive lung cancer and 3 cases treatedwith an inhibitor for ALK kinase activity. Lung
Cancer. 2012;75:66-72.
10. Choi YL, Soda M, Ueno T, Hamada T, Haruta H,
Yamato A, Fukumura K, Ando M, Kawazu M,
Yamashita Y, Mano H. Oncogenic MAP2K1
mutations in human epithelial tumors. Carcinogenesis.
2012;33:956-961.
11. Butler MO, Imataki O, Yamashita Y, Tanaka M,
Ansen S, Berezovskaya A, Metzler G, Milstein MI,
Mooney MM, Murray AP, Mano H, Nadler LM,
Hirano N. Ex vivo expansion of human CD8 T
cells using autologous CD4 T cell help. PLoS ONE.
2012;7:e30229.

363

Department of MolecularPsychiatry
Associate Professor
Kazuya Iwamoto,Ph.D.

Assistant Professor
Miki Bundo, Ph.D.

Homepage

http://www.molpsy.com

Introduction and Organization
Major mental disorders such as schizophrenia,
affective disorders, and developmental disorders aresevere disorders showing high prevalence rate in every
population. They not only bring long-lasting suffering
to patients and their families, but also cause
tremendous loss from an economical view.
Surprisingly, cause of illness and pathophyshiology ofmental disorders remain largely unclear. The
Department of Molecular Psychiatry has been
established at the Graduate School of Medicine,
University of Tokyo from February 2010 to January
2013, by the donation from Astellas Pharma,
Dainippon Sumitomo Pharma, and Yoshitomi Yakuhin,
and from February 2013, by the donation from
Dainippon Sumitomo Pharma, and Yoshitomi Yakuhin.
The aim of this department is to contribute theunderstanding of cause of illness and pathophysiology
of major mental disorders at the molecular level,
through the close collaboration with Department of
Neuropsychiatry at the University of Tokyo.

Research activities
Specimen derived from mental disorders as well asanimal models are examined by comprehensive
approaches from genetic, molecular biological,
cellular and behavioral point of views. Especially, we
will focus on the study of blood samples provided
from Department of Neuropsychiatry at the Universityof Tokyo and postmortem brains provided from brainbanks.

Publication
1. Asai T, Bundo M, Sugawara H, Sunaga F, Ueda J,
Tanaka G, Ishigooka J, Kasai K, Kato T, Iwamoto K.
Effect of mood stabilizers on DNA methylation inhuman neuroblastoma cells. International Journal of
Neuropsychopharmacology in press
2. Ikegame T, Bundo M, Murata Y, Kasai K, Kato T,
Iwamoto K. DNA methylation of the BDNF geneand its relevance to psychiatric disorders. Journal of
Human Genetics in press.
3. Sugawara H, Bundo M, Ishigooka J, Iwamoto K,
Kato T. Epigenetic regulation of serotonin transporter in psychiatric disorders. Journal of Genetics
and Genomics in press.
4. Bundo M, Sunaga F, Ueda J, Kasai K, Kato T,
Iwamoto K. A systematic evaluation of wholegenome amplification of bisulfite-modified DNA.
Clinical Epigenetics 2012,4:22.
5. Yu CC, Furukawa M, Kobayashi K, Shikishima C,
Cha PC, Sese J, Sugawara H, Iwamoto K, Kato T,
Ando J, Toda T. Genome-wide DNA methylationand gene expression analyses of monozygotic twins
discordant for intelligence levels. PLoS One 2012,
7:e47081.
6. Nishioka M, Bundo M, Kasai K, Iwamoto K. DNA
methylation in schizophrenia: progress andchallenges of epigenetic studies. Genome Medicine
2012,4:96.

364

Department of Life Support
Technology (Molten)
Project Associate Professor
Taketoshi Mori, Ph.D.

Project Assistant Professor
Hiroshi Noguchi, Ph.D., Nao Tamai, Ph.D. RN, Mikako Yoshida, Ph.D.

Homepage

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

Introduction and Organization
Department of Life Support Technology (Molten) was
founded Oct. 1, 2010 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 two project assistant professors. Our department
accepted two master course students. Two masters
course students of the Department of GerontologicalNursing / Wound Care Management were associatedto the department. They were graduated at this 2011
school year. The supportive department is the
Department of Gerontological Nursing / Wound CareManagement.

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. Hiroshi Noguchi also lectured nursing
engineering. In a part of Wound Care Management I
for graduate course, Taketoshi Mori taught Material
Mechanics, which is important for skin mechanicalmodeling. We invited Prof. Yuji Ota, Ochanomizu
University and Masaaki Mochimaru, Director of
Digital Human Research Center National Institute ofAdvanced Industrial Science and Technology (AIST)
to lecture for Wound Care Management II. In a part ofGerontological Nursing I for graduate course, themembers in the department lectured the features andreading method of journal papers of engineeringresearch based on typical publications.

365

The members in our department supported the mastercourse students of the Department of GerontologicalNursing / Wound Care Management. Masters thesis
theme of the students are “Elevated plantar pressure indiabetic patients and its relationship with their gaitfeatures”, and “Method for detection of silent
aspiration based on B-mode video ultrasounography
assisted by image processing”
As for the other educational activity, we hold small
study meeting about Matlab, which is a kind of
software for numerical computing, to the Departmentof Gerontological 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.

estimation using laser range scannerse) Design and construction of human behavior
database
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 on the foot plantar andmotion of the foots and the hip simultaneously during
walking. Based on captured data, we investigatedrelationship between elevated foot plantar pressureand gait features of diabetic patients. Our engineeringknowledge assists to develop this new measurement
system.

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.

Another work was development of new method todetect silent aspiration using ultrasonography. While
traditional approach requires small invasion to assess
silent aspiration and medical doctor only can use thesedevices, our developed technique enables for thenurses to assess the silent aspiration directly. Since itis difficult to detect aspiration only fromultrasonographic images, we also developed the newimage processing technique to emphasize bolus in theimage. Our engineering knowledge and techniquesupported development of the image processing.

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

We achieved the prize about the following
presentation.
 Hirofumi Kato. The 4th Congress of the World
Union of Wound Healing Societies Poster Prize.
Hirofumi Kato, Gojiro Nakagami, Yoshiko
Iwahira, Takashi Nagase, Shinji Iizaka, Nao
Tamai, Yutaka Matsuyama, Reiko Otani, Hiromi
Sanada,P526,
RISK
FACTORSFOR
INFECTION DURING TISSUE EXPANSIONIN TISSUE EXPANDER AND IMPLANT
BREAST
RECONSTRUCTION,
the
4thCongress of the World Union of Wound Healing
Societies. 9 2012.

We are seeking a new interdisciplinary researchdomain between engineering and nursing, and willing
to realize comfortable daily life through theseresearches.

366



Ayumi Amemiya. Young Presentation Award of
LIFE 2012 (domestic conference). Ayumi
Amemiya, Hiroshi Noguchi, Oe Makoto, Kimie
Tkaehara, Yumiko Ohasi, Koujiro Ueki, Takashi
Kadowaki, Hiromi Sanada, "Comparison ofdiabetic patients gait with non-diabetic subjects
gait using plantar pressure sensor and dorsal feetmotion sensors". 11 2012.

References
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.
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.

367

Department of Youth Mental
HealthAssociate Professor
Tsuyoshi Araki, M.D., Ph.D.

Lecturer
Yukika Nishimura, 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.

368

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)370

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. Our department also
belongs to the 22nd Century Medical and ResearchCenter, which partly represents the translational
research activities of the University Hospital. At
present, our research laboratory facilities are locatedat 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 is entirely responsible
for the management of the department, keeping close
contact and cooperation with the other departments ofthe 22nd Century Medical and Research Center andwith laboratories of the Department of Nephrology
and Endocrinology, 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 clinicalmaterials derived from patients with agreement andapproval of both the patients and the ethics committeeof the University Hospital. Also, in cooperation with
outpatient clinics and hospitals outside, we arecollecting and analyzing the clinical data on metabolic
syndrome from an epidemiological standpoint with theaim of returning the fruitful results of the translational
research to the clinical practice departments.

371

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 makeseveral 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 andtherapeutic 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.
Based upon these observations, we hypothesized that372

the 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. Gotoda T, Shirai K, Ohta T, Kobayashi J,
Yokoyama S, Oikawa S, Bujo H, Ishibashi S, Arai
H, Yamashita S, Harada-Shiba M, Eto M, Hayashi
T, Sone H, Suzuki H, Yamada N; ResearchCommittee for Primary Hyperlipidemia, Researchon Measures against Intractable Diseases by the
Ministry of Health, Labour and Welfare in Japan.
Diagnosis and management of type I and type V
hyperlipoproteinemia. J Atheroscler Thromb.
2012;19:1-12.

2. Arai H, Ishibashi S, Bujo H, Hayashi T,
Yokoyama S, Oikawa S, Kobayashi J, Shirai K,
Ota T, Yamashita S, Gotoda T, Harada-Shiba M,
Sone H, Eto M, Suzuki H, Yamada N; ResearchCommittee for Primary Hyperlipidemia, Researchon Measures against Intractable Diseases by the
Ministry of Health, Labour and Welfare in Japan.
Management of type IIb dyslipidemia.
J
Atheroscler Thromb. 2012;19:105-14.
3. Yokoyama S, Yamashita S, Ishibashi S, Sone H,
Oikawa S, Shirai K, Ohta T, Bujo H, Kobayashi J,
Arai H, Harada-Shiba M, Eto M, Hayashi T,
Gotoda T, Suzuki H, Yamada N. Background to
discuss guidelines for control of plasma HDLcholesterol in Japan. J Atheroscler Thromb.
2012;19:207-1

373

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:

374

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 ： 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
4. 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
5. 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
6. 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
7. UMIN registration number ： UMIN000006128
active, recruiting
IRB number：P2011018-11Z
Adoptive immunotherapy using zoledronateexpanded autologous γδ T cells for patients with
non-small cell lung cancer refractory to standard
treatment.

8. UMIN registration number ： UMIN000001419
active, not recruiting
IRB number：2120-(1)The efficacy and safety of autologous γδ T celltransfer therapy for esophageal cancer
9. UMIN registration number ： UMIN000004130
active, not recruiting
IRB number：P201019-11Z
Intraperitoneal autologous γδ T cell therapy forrefractory gastric cancer with ascites
10. UMIN registration number ： UMIN000008097
active, not recruiting
IRB number：P201019-11Z
Combination of chemotherapy with docetaxel /cisplatin / fluorouracil (DCF) and autologous γδ Tcell transfer therapy for esophageal cancer.

Adjuvant γδT cell therapy
11. 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
12. 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
13. UMIN registration number ： UMIN000002839
active, not recruiting
IRB number：2760
The efficacy and safety of autologous gamma/delta T cell transfer therapy after resection ofstage2A (T2N0,T3N0) esophageal cancer

Teaching activities
Research guidance in molecular immunology isprovided to postgraduate students. Because knowledge
and techniques for evaluation of immune response areimportant for clinicians and medical researchers, we
also provide many opportunities to postgraduate
students to learn how to analyze in vivo immune
responses by means of experiments using animalmodels and by the immunological monitoring of thepatients themselves in clinical research.

375

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.

List of Publications
1 Eikawa S, Kakimi K, Isobe M, Kuzushima K,
Luescher I, Ohue Y, Ikeuchi K, Uenaka A,
Nishikawa H, Udono H, Oka M, Nakayama E.
Induction of CD8 T-cell responses restricted tomultiple HLA class I alleles in a cancer patient byimmunization with a 20-mer NY-ESO-1f(NY-ESO-1 91-110) peptide. International journalof cancer 2013 Jan 15;132(2):345-54.
2 Noji S, Hosoi A, Takeda K, Matsushita H,
Morishita Y, Seto Y, Kakimi K. Targeting
Spatiotemporal Expression of CD137 on Tumorinfiltrating Cytotoxic T Lymphocytes as a Novel
Strategy for Agonistic Antibody Therapy. J
Immunother. 2012;35(6):460-72.
3 Kato Y, Kajiwara C, Ishige I, Mizukami S,
Yamazaki C, Eikawa S, Kakimi K, Udono H.
HSP70 and HSP90 Differentially Regulate

Translocation of Extracellular Antigen to the
Cytosol for Cross-Presentation. Autoimmune Dis.
2012;2012:745962.
4 Shimizu K, Mizuno T, Shinga J, Asakura M,
Kakimi K, Ishii Y, Masuda K, Maeda T, Sugahara
H, Sato Y, Matsushita H, Nishida K, Hanada KI,
Dörrie J, Schaft N, Bickham K, Koike H, Ando T,
Nagai R, Fujii SI. Vaccination with antigentransfected, NKT cell ligand-loaded, human cells
elicits robust in situ immune responses bydendritic cells. Cancer Res. 2013 Jan 1;73(1):62-73.
5 Izumi T, Kondo M, Takahashi T, Fujieda N, Kondo
A, Tamura N, Murakawa T, Nakajima J,
Matsushita H, Kakimi K. Ex vivo characterizationof γδ T-cell repertoire in patients after adoptive
transfer of Vγ9Vδ2 T cells expressing theinterleukin-2 receptor β-chain and the common
γ-chain. Cytotherapy. 2013 Apr;15(4):481-91.
6 Dewi N, Yanagie H, Zhu H, Demachi K, Shinohara
A, Yokoyama K, Sekino M, Sakurai Y, Morishita Y,
Iyomoto N, Nagasaki T, Horiguchi Y, Nagasaki Y,
Nakajima J, Ono M, Kakimi K, Takahashi H.
Tumor growth suppression by gadolinium-neutron
capture therapy using gadolinium-entrapped
liposome as gadolinium delivery agent. Biomed
Pharmacother. 2012 Dec 26. doi:pii: S0753-3322(12) 00124-2. 10.1016/j.biopha.2012.11.01

376

Division of Total Renal Care
Medicine
Associate Professor
Yutaka Enomoto, M.D., Ph.D.

Associate
Yoshifumi Hamasaki, M.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/jinsikkan.html
Introduction and Organization

Clinical activities

More than 300 thousands of patients receive dialysis
treatment due to end-stage renal disease in Japan.
These dialysis therapies comprise hemodialysis andperitoneal dialysis. Ninety seven percent of patients
who receive dialysis treatment are currently treated byhemodialysis.
Peritoneal
dialysishasadvantages
overhemodialysis in terms of higher quality of life and of
higher probability of working, because this therapy isdone at home and requires less frequent visits tomedical facilities. Hemodynamic stability is one of themost beneficial aspects of peritoneal dialysis fromperspective of medical care. These points makeperitoneal dialysis suitable for the patients with severe
derangement of cardiac function; such patients
become common among dialysis population because
demographics have quite largely changed recent years.
Moreover, existence of ample residual renal function,
which reportedly relates to the better survival or
relates to less morbidity among end-stage renal
disease patients, can be maintained during longer
periods by peritoneal dialysis than by hemodialysis.
This division is established in 2004 sponsored by
Terumo Co. Ltd. in collaboration with Department ofNephrology and Endocrinology, in order to make theknowledge and the technics of peritoneal dialysis
more popular among dialysis community.

We have been focusing on total renal care medicine,including pre-dialysis care, therapeutic option forrenal replacement therapies, and above all, peritoneal
dialysis. Vascular access placement had been within
the scope of our division.

Teaching activities
As for education, we take part in providing
information of peritoneal dialysis for those who
consider to commence the therapy. We are making
lectures at CKD school designed for the patients withCKD twice a year. Brief lectures are made for medical
staffs at the clinical wards in collaboration with
Terumo, Co., Ltd. Moreover, we also are making
lectures about peritoneal dialysis for medical students
at bed-side learning programs or at systematic lecture
courses.

Research activities
As for research, we are studying advantages of“hybrid therapy” in which patients are treated byperitoneal dialysis combined with hemodialysis.
Encapsulating peritoneal sclerosis is also the target ofour research. This is a potentially fatal complication of
peritoneal dialysis. We are studying the strategies
against or preventing this complication both in vivo
and in vitro.

377

We are developing the system by which we canconvey proper information about choice of renal
replacement therapies both inside and outside of ouruniversity hospital. Moreover, we are focusing on thedevelopment of better peritoneal dialysis technics.

References
1. Hamasaki Y., Doi K., Okamoto K., Ijichi H., Seki
G., Maeda-Mamiya R., Fujita T., Noiri E.:
3-Hydroxy-3-methylglutaryl-coenzyme A reductase
inhibitor simvastatin ameliorates renal fibrosis
through HOXA13-USAG-1 pathway. Lab Invest
92: 1161-70, 2012
2. Miyazaki H., Nishimatsu H., Kume H., Suzuki M.,
Fujimura T., Fukuhara H., Enomoto Y., Ishikawa
A., Igawa Y., Hirano Y., Homma Y.: Leukopenia
as a risk factor for osteonecrosis of the jaw inmetastatic prostate cancer treated using zoledronic
acid and docetaxel. BJU Int 110: E520-5, 2012
3. Nakamura M., Fujimura T., Nagata M., Hosoda C.,
Suzuki M., Fukuhara H., Enomoto Y., Nishimatsu
H., Kume H., Igawa Y., Homma Y.: Association
between lower urinary tract symptoms and sexual
dysfunction assessed using the core lower urinary
tract symptom score and International Index of
Erectile Function-5 questionnaires. Aging Male
15: 111-4, 2012
4. Sugihara T., Yasunaga H., Horiguchi H.,
Nishimatsu H., Fukuhara H., Enomoto Y., Kume
H., Ohe K., Matsuda S., Homma Y.: Management
trends, angioembolization performance andmultiorgan injury indicators of renal trauma fromJapanese administrative claims database. Int J
Urol 19: 559-63; author reply 564, 2012
5. Taguchi S., Enomoto Y., Homma Y.: Bladder
endometriosis developed after long-term estrogentherapy for prostate cancer. Int J Urol 19: 964-5,
2012
6. Doi K., Katagiri D., Negishi K., Hasegawa S.,
Hamasaki Y., Fujita T., Matsubara T., Ishii T.,
Yahagi N., Sugaya T., Noiri E.: Mild elevation ofurinary biomarkers in prerenal acute kidney injury.
Kidney Int 82: 1114-20, 2012
7. Doi K., Noiri E., Ishizu T., Negishi K., Suzuki Y.,
Hamasaki Y., Honda K., Fujita T., Tsukimura T.,
Togawa T., Saito S., Sakuraba H.: High-throughput

screening identified disease-causing mutants andfunctional variants of alpha-galactosidase A genein Japanese male hemodialysis patients. J Hum
Genet 57: 575-9, 2012

378

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.

379

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.

(3)

(4)

(5)

(6)

(7)

References(1) 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. 21,3042-3049 (2012)(2) Kodama K, Horikoshi M, Toda K, Yamada S, Hara
K, Irie J, Sirota M, Morgan AA, Chen R, Ohtsu H,

(8)

(9)

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. USA 109, 7049-7054 (2012)
Shojima N, Hara K, Fujita H, Horikoshi M,
Takahashi N, Takamoto I, Ohsugi M, Aburatani
H, Noda M, Kubota N, Yamauchi T, Ueki K,
Kadowaki T.: Depletion of homeodomaininteracting protein kinase 3 impairs insulin
secretion and glucose tolerance in mice.
Diabetologia 55, 3318-3330 (2012)
Yamauchi N, Takazawa Y, Maeda D, Hibiya T,
Tanaka M, Iwabu M, Okada-Iwabu M, Yamauchi T,
Kadowaki T, Fukayama M.: Expression levels of
adiponectin receptors are decreased in humanendometrial adenocarcinoma tissues. Int. J.
Gynecol. Pathol. 31, 352-357 (2012)
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 type 2
diabetes is associated with the early onset of
diabetes and may predict the future requirement of
insulin injections among Japanese individuals.
Diabetes Care 35, 1763-1770 (2012)
Yamada T, Hara K, Kadowaki T.: Association of
adenovirus 36 infection with obesity and metabolic
markers in humans: a meta-analysis ofobservational studies. PLoS One 7, e42031 (2012)
Yamada T, Hara K, Umematsu H, Suzuki R,
Kadowaki T.: Erectile dysfunction andcardiovascular events in diabetic men: ameta-analysis of observational studies. PLoS
One 7, e43673 (2012)
Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Ozeki A, Itoh C,
Sugiyama T, Kadowaki T, Yamazaki T, Nagai R.:
Associations of variations in the MRF2/ARID5B
gene with susceptibility to type 2 diabetes in theJapanese population. J. Hum. Genet. 56,
727-733 (2012)
Fujita H, Hara K, Shojima N, Horikoshi M, Iwata
M, Hirota Y, Tobe K, Seino S, Kadowaki T.:
Variations with modest effects have an importantrole in the genetic background of type 2 diabetes
and diabetes-related traits. J. Hum. Genet. 57,
809 (2012)

380(10) Saxena R, Saleheen D, Been LF, Garavito ML,
Braun T, Bjonnes A, Young R, Ho WK, Rasheed
A, Frossard P, Sim X, Hassanali N, Radha V,
Chidambaram M, Liju S, Rees SD, Peng-Keat Ng
D, Wong TY, Yamauchi T, Hara K, Tanaka Y,
Hirose H, McCarthy MI, Morris AP; DIAGRAM;
MuTHER; AGEN, Basit A, Barnett AH,
Katulanda P, Matthews D, Mohan V, Wander GS,
Singh JR, Mehra NK, Ralhan S, Kamboh MI,
Mulvihill JJ, Maegawa H, Tobe K, Maeda S, Cho
YS, Tai ES, Kelly MA, Chambers JC, Kooner JS,
Kadowaki T, Deloukas P, Rader DJ, Danesh J,
Sanghera DK.:
Genome-Wide Association
Study Identifies a Novel Locus Contributing toType 2 Diabetes Susceptibility in Sikhs of
Punjabi Origin From India. Diabetes 62, 17461755 (2013)(11) Takase S, Osuga JI, Fujita H, Hara K, Sekiya M,
Igarashi M, Takanashi M, Takeuchi Y, Izumida Y,
Ohta K, Kumagai M, Nishi M, Kubota M, Masuda
Y, Taira Y, Okazaki S, Iizuka Y, Yahagi N, Ohashi K,
Yoshida H, Yanai H, Tada N, Gotoda T, Ishibashi S,
Kadowaki T, Okazaki H.: Apolipoprotein C-II
Deficiency with No Rare Variant in the APOC2
Gene. J. Atheroscler. Thromb. 20, 481-493 (2013)(12) Ma RCW, Hu C, Tam CH, Zhang R, Kwan P,
Leung TF, Thomas GN, Go MJ, Hara K, Sim X,
Ho JSK, Wang C, Li H, Lu L, Wang Y, Li JW,
Wang Y, Lam VKL, Wang J, Yu W, Kim Y, Ng
DP, Fujita H, Panoutsopoulou K, Day-Williams A,
Lee HM, Ng ACW, Fang Y, Kong APS, Jiang F,
Ma X, Hou X, Tang S, Lu J, Yamauchi T, Tsui
SKW, Woo JLF, Leung PC, Zhang X., Tang NLS,Sy H Y, Liu J, Wong TY, Lee JY, Maeda S, Xu G,
Cherny SS, Chan TF, Ng MCY, Xiang K, MorrisAP, DIAGRAM Consortium, Keildson S,
MuTHER Consortium, Hu R, Ji L, Lin X, Cho Y
S, Kadowaki T, Tai ES, Zeggini E, McCarthy M I,
Hon K L, Baum L, Tomlinson B, So W Y, Bao Y,
Chan J C N, Jia W.: Genome-wide association
study in a Chinese population identifies asusceptibility locus for type 2 diabetes at 7q32
near PAX4. Diabetologia 56, 1291-1305 (2013)

381

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 Tokyo in
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 (antiinflammation, 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.

382

References
1. Ashigaki N, Suzuki JI, Ogawa M, Watanabe R,
Aoyama N, Kobayashi N, Hanatani T, Sekinishi A,
Zempo H, Tada Y, Takamura C, Wakayama K,
Hirata Y, Nagai R, Izumi Y, Isobe M. Periodontal
bacteria aggravate experimental autoimmune
myocarditis in mice. Am J Physiol Heart Circ
Physiol. 2012 Dec 21. [Epub ahead of print]
2. Miyabe C, Miyabe Y, Miura NN, Takahashi K,
Terashima Y, Toda E, Honda F, Morio T,
Yamagata N, Ohno N, Shudo K, Suzuki JI, Isobe
M, Matsushima K, Tsuboi R, Miyasaka N, Nanki
T. Am80, a retinoic acid receptor agonist, ameliorates murine vasculitis through the suppression ofneutrophil migration and activation. Arthritis
Rheum. 2012 Nov 30. [Epub ahead of print]
3. Tanaka T, Ogawa M, Suzuki J, Sekinishi A, Itai A,
Hirata Y, Nagai R, Isobe M. Inhibition of IκBphosphorylation prevents load-induced cardiac
dysfunction in mice. Am J Physiol Heart Circ
Physiol. 2012 Dec;303(12):H1435-45, 2012.
4. Sekinishi A, Suzuki J, Aoyama N, Ogawa M,
Watanabe R, Kobayashi N, Hanatani T, Ashigaki
N, Hirata Y, Nagai R, Izumi Y, Isobe M.
Periodontal pathogen Aggregatibacter actinomycetemcomitans deteriorates pressure overloadinduced myocardial hypertrophy in mice. Int
Heart J. 53(5):324-30, 2012.
5. Ogawa M, Suzuki J, Takayama K, Senbonmatsu T,
Hirata Y, Nagai R, Isobe M. Impaired
post-infarction cardiac remodeling in chronic
kidney disease is due to excessive renin release.
Lab Invest. Dec;92(12):1766-76, 2012.
6. Hanatani T, Suzuki J, Ogawa M, Aoyama N,
Kobayashi N, Hirata Y, Nagai R, Izumi Y, Isobe
M. The periodontal pathogen Aggregatibacter
actinomycetemcomitans deteriorates ventricularremodeling after myocardial infarction in mice.
Int Heart J. 53(4):253-6, 2012.
7. Kobayashi N, Suzuki J, Ogawa M, Aoyama N,
Hanatani T, Hirata Y, Nagai R, Izumi Y, Isobe M.
Porphyromonas gingivalis accelerates neointimal
formation after arterial injury. J Vasc Res. 49(5):417-24, 2012.
8. Nagashima A, Watanabe R, Ogawa M, Suzuki J,
Masumura M, Hishikari K, Shimizu T, Takayama

K, Hirata Y, Nagai R, Isobe M. Different roles of
PPAR-γ activity on physiological and pathologicalalteration after myocardial ischemia. J Cardiovasc
Pharmacol. 2012 Aug;60(2):158-64.
9. Tezuka D, Haraguchi G, Ishihara T, Ohigashi H,
Inagaki H, Suzuki J, Hirao K, Isobe M. Role of
FDG PET-CT in Takayasu arteritis: sensitive
detection of recurrences. JACC Cardiovasc
Imaging. Apr;5(4):422-9, 2012.
10. Suzuki J, Ogawa M, Sakai Y, Hirata Y, Isobe M,
Nagai R. A prostacycline analog prevents chronic
myocardial remodeling in murine cardiac
allografts. Int Heart J. 53(1):64-7, 2012.
11. 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
Pharmacol. Apr;59(4):323-30, 2012.
12. Hamaya R, Ogawa M, Kobayashi N, Suzuki J, Itai
A, Hirata Y, Nagai R, Isobe M. A novel IKK
inhibitor prevents progression of restenosis afterarterial injury in mice. Int Heart J. 53(2):133-8,
2012.
13. 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. Aug;47(4):463-9, 2012.
14. Imamura T, Kinugawa K, Shiga T, Kato N, Endo
M, Inaba T, Maki H, Hatano M, Yao A, Hirata Y,
Nishimura T, Kyo S, Ono M, Nagai R. Correctionof hyponatremia by tolvaptan before left
ventricular assist device implantation. Int Heart J.
53(6):391-3, 2012.
15. Ishida J, Kinugawa K, Shiga T, Imamura T,
Hatano M, Maki H, Inaba T, Yao A, Hirata Y,
Nishimura T, Kyo S, Ono M, Nagai R. Rapidly
progressive cardiac allograft vasculopathy in early
onset regressed with everolimus treatment in an
adult cardiac recipient. Int Heart J. 53(6):388-90,
2012.
16. Fukuda T, Matsumoto A, Kurano M, Takano H,
Iida H, Morita T, Yamashita H, Hirata Y, Nagai R,
Nakajima T. Cardiac output response to exercise
in chronic cardiac failure patients. Int Heart J.
53(5):293-8, 2012.

383

17. Inaba T, Yao A, Nakao T, Hatano M, Maki H,
Imamura T, Shiga T, Yamazaki T, Sonoda M,
Kinugawa K, Shiota T, Suzuki J, Takenaka K,
Hirata Y, Nagai R. Volumetric and Functional
Assessment of Ventricles in Pulmonary Hypertension on 3-Dimensional Echocardiography. Circ
J. 25;77(1):198-206, 2012
18. Imamura T, Kinugawa K, Shiga T, Endo M, Kato
N, Inaba T, Maki H, Hatano M, Yao A, Nishimura
T, Hirata Y, Kyo S, Ono M, Nagai R. Preoperative
Levels of Bilirubin or Creatinine Adjusted by Age
Can Predict Their Reversibility After Implantationof Left Ventricular Assist Device. Circ J. 25;
77(1):96-104, 201219. Shiga T, Kinugawa K, Imamura T, Kato N, Endo
M, Inaba T, Maki H, Hatano M, Yao A, Nishimura
T, Hirata Y, Kyo S, Ono M, Nagai R. Combination
evaluation of preoperative risk indices predicts
requirement of biventricular assist device. Circ J.
2012 Nov 22;76(12):2785-9, 2012.
20. Asada K, Fujiu K, Imai Y, Kojima T, Sugiyama H,
Suzuki T, Kinugawa K, Hirata Y, Nagai R.
Intrathoracic impedance monitoring in patientswith heart failure: correlation with dehydration
and bleeding events. Circ J. 76(11):2592-8, 2012
21. Imamura T, Kinugawa K, Shiga T, Kato N, Endo
M, Inaba T, Maki H, Hatano M, Yao A, Hirata Y,
Akahane M, Nishimura T, Kyo S, Ono M, Nagai
R. How to demonstrate the reversibility of
end-organ function before implantation of left
ventricular assist device in INTERMACS profile
2 patients? J Artif Organs. Dec;15(4):395-8, 2012.
22. Imamura T, Kinugawa K, Mohri D, Shiga T, Endo
M, Inaba T, Maki H, Hatano M, Isayama H, Yao A,
Hirata Y, Koike K, Nagai R. A case of pancreaticcancer after heart transplantation. Int Heart J.
53(3):205-7, 2012.
23. Imamura T, Shiga T, Kinugawa K, Kato N, Endo
M, Inaba T, Maki H, Hatano M, Yao A, Hirata Y,
Nagai R. Successful conversion to everolimus
after cytomegalovirus infection in a heart transplant recipient. Int Heart J. 53(3):199-201, 2012.
24. Imamura T, Kinugawa K, Shiga T, Endo M, Kato
N, Inaba T, Maki H, Hatano M, Yao A, Nishimura
T, Hirata Y, Kyo S, Ono M, Nagai R. An elevatedratio of early to late diastolic filling velocity
recovers after heart transplantation in atime-dependent manner. J Cardiol. Oct;60(4):295300, 2012.
25. Imamura T, Kinugawa K, Shiga T, Endo M, Kato
N, Inaba T, Maki H, Hatano M, Yao A, Nishimura
T, Hirata Y, Kyo S, Ono M, Nagai R. Novel riskscoring system with preoperative objective
parameters gives a good prediction of 1-year
mortality in patients with a left ventricular assist
device. Circ J. 2012;76(8):1895-903, 2012
26. Imamura T, Kinugawa K, Shiga T, Endo M, Inaba
T, Maki H, Hatano M, Imai Y, Yao A, Hirata Y,
Nishimura T, Kyo S, Ono M, Nagai R. Early
decision for a left ventricular assist device implantation is necessary for patients with modifier
A. J Artif Organs. Sep;15(3):301-4, 2012.
27. Sahara M, Sata M, Morita T, Hirata Y, Nagai R.
Nicorandil attenuates monocrotaline-induced vascular endothelial damage and pulmonary arterial
hypertension. PLoS One. 7(3):e33367, 2012.
28. Kato N, Kinugawa K, Shiga T, Hatano M, Takeda
N, Imai Y, Watanabe M, Yao A, Hirata Y, Kazuma
K, Nagai R. Depressive symptoms are common
and associated with adverse clinical outcomes inheart failure with reduced and preserved ejection
fraction. J Cardiol. Jul;60(1):23-30, 2012.
29. Soma K, Abe H, Takeda N, Shintani Y, Takazawa
Y, Kojima T, Fujiu K, Semba H, Yamashita H,
Hirata Y, Fukayama M, Nagai R. Myocardial
involvement in patients with osteogenesis
imperfecta. Int Heart J. 53(1):75-7, 2012.
30. Semba H, Kinugawa K, Takeda N, Shiga T,
Nishimura G, Inajima T, Uchino Y, Iwata H,
Hasumi E, Abe H, Terada Y, Yonenaga A, Hirata Y,
Nagai R. Preliminary report of tolvaptan
treatment in Japanese patients with heart failure.
Int Heart J. 53(1):72-4, 2012.
31. Imamura T, Kinugawa K, Shiga T, Endo M, Inaba
T, Maki H, Hatano M, Yao A, Nishimura T, Hirata
Y, Kyo S, Ono M, Nagai R. A case of late-onset
right ventricular failure after implantation of acontinuous-flow left ventricular assist device. J
Artif Organs. Jun;15(2):200-3, 2012.
32. Myojo M, Iwata H, Kohro T, Sato H, Kiyosue A,
Ando J, Sawaki D, Takahashi M, Fujita H, Hirata
Y, Nagai R. Prognostic implication of macrocytosis
on adverse outcomes after coronary intervention.
Atherosclerosis. Mar;221(1):148-53, 2012.

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33. 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 pericarditis--retrospective analysis of 11 case histories. J
Cardiol. Mar;59(2):139-46, 2012.
34. 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 ABCG2 protects against pressure
overload-induced cardiac hypertrophy and heart
failure by promoting angiogenesis and antioxidant
response. Arterioscler Thromb Vasc Biol.
Mar;32(3):654-61, 2012.
35. 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. Aug;22(4):598-601, 2012.
36. 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
Prev Cardiol. Dec;19(6):1393-400, 2012.
37. 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. Jan;35(1):62-9, 2012.
38. 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 nitricoxide synthase-dependent pathway. Int J Urol.
19(3):248-55, 2012English Review
1. Suzuki J, Ogawa M, Hirata Y, Nagai R, Isobe M.
Effects of immunogloblin to prevent coronary
allograft vasculopathy in heart transplantation.
Expert Opin Ther Targets. 16: 783-9, 2012
2. Suzuki J, Isobe M, Morishita R, Nagai R.
Applications of nucleic acid drugs for organtransplantation. Curr Top Med Chem. 12:
1608-12, 2012.
3. Suzuki J, Morishita R. A new era of gene therapy.
Curr Top Med Chem. 12: 1593, 2012.
4. Suzuki J, Ogawa M, Hishikari K, Watanabe R,
Takayama K, Hirata Y, Nagai R, Isobe M. Noveleffects of macrolide antibiotics on cardiovasculardiseases. Cardiovasc Ther. 30: 301-7, 2012.

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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.

Fellow Researcher
Toshihiro Morita, M.D., Ph.D., Haruko Iida, M.D.

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386

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) 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.Eur J
Prev Cardiol. 2012 Dec;19(6):1393-400.
2) Iwasaki S, Nakajima T, Chihara Y, Inoue A,
Fujimoto C, Yamasoba T. Developmental changes
in the expression of Kv1 potassium channels in rat
vestibular ganglion cells. Brain Research 2012;
1429:29-35.
3) Takano NK, Tsutsumi T, Suzuki H, Okamoto Y,
Nakajima T. Time frequency power profile of QRS

complex obtained with wavelet transform inspontaneously hypertensive rats. Comput Biol
Med. 2012 Feb;42(2):205-212.
4) Fukuda T, Matsumoto A, Kurano M, Takano H,
Iida H, Morita T, Yamashita H, Hirata Y, Nagai R,
Nakajima T. Cardiac output response to exercise inchronic cardiac failure patients.: Role of strokevolume. Int Heart J 2012; 53: 293-298.
5) Uchida Y, Morita T, Fukumura K, Otsuka T,
Fukuda T, sato Y, Nakajima T. Effects of KAATSU
training on a patient with benign fasciculation
syndrome. Int J KAATSU Training Res 2012; 8:
9-12.
6) Yasuda T, Loenneke JP, Thiebaud RS, Abe T.
Effects of low-intensity blood flow restrictedconcentric or eccentric training on muscle size andstrength. PLoS One 2012; 7 (12) e52843.
7) Ogawa M, Yasuda T, Abe T. Component
characteristics of thigh muscle volume in young
and older men. Clinical Physiology and Functional
Imaging 2012; 32 (2): 89-93.
8) Ogawa M, Loenneke JP, Yasuda T, Fahs CA,
Rossow LM, Thiebaud RS, Bemben MG, Abe T.
Time course changes in muscle size and fatigue
during walking with restricted leg blood flow inyoung men. Journal of Physical Education andSports Management 2012; 3 (1): 14-19.
9) Sakamaki M, Yasuda T, Abe T. Comparison of
low-intensity blood flow restricted traininginduced muscular hypertrophy in eumenorrheic
women in the follicular phase and luteal phase andage-matched men. Clinical Physiology andFunctional Imaging 2012; 32 (3): 185-191.
10) Ozaki
H,
YasudaT,
Ogasawara
R,
Sakamaki-Sunaga M, Naito H, Abe T. Effects ofhigh-intensity and blood flow-restricted lowintensity resistance training on carotid arterial
compliance: Role of blood pressure during
training sessions. European Journal of Applied
Physiology 2012; 113 (1) 167-174.
11) 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 2013; 165(2): 222-228.
12)Yasuda T, Fukumura K, Fukuda T, Iida H, Imuta H,
Sato Y, Yamasoba T, Nakajima T. Effects of

387

low-intensity, elastic band resistance exercise
combined with blood flow restriction on muscle
activation. Scandinavian Journal of Medicine andScience in Sports (in press)13) 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. 2013; 33: 11-7.
14) Yamamoto Y, Morita T, Tanaka T, Ikeda K,
Kikuchi H, Oguri G, Nakamura F, Nakajima T,
Nagai R. Amiodarone inhibits tissue factor
expression in monocytic THP-1 cells. Eur J
Pharmacol. 2013 Feb 15;701(1-3):14-9.
15) Yasuda Y, Fukumura K, Fukuda T, Uchida Y, Iida
H, Meguro M, Sato Y, Yamasoba T, Nakajima T.
Muscle size and arterial stiffness after blood
flow-restricted low-intensity resistance training inolder adults. Scand J Med Sci Sports (in press)
16) Ikeda K, Nakajima T, Yamamoto Y, Takano N,
Tanaka T, Kikuchi H, Oguri G, Morita T,
Nakamura F, Komuro I. Roles of transient receptor
potential canonical (TRPC) channels andreverse-mode Na+/Ca2+ exchanger on cellproliferation in human cardiac fibroblasts: Effectsof transforming growth factor β1. Cell Calcium (inpress)
17) Fukuda T, Kurano M, Fukumura K, Yasuda T, Iida
H, Morita T, Yamamoto Y, Takano N, Komuro I,
Nakajima T. Cardiac rehabilitation increases
exercise capacity with a reduction of oxidative
stress. Korean Circ J (in press)18) Ogasawara R, Yasuda T, Ishii N, Abe T.
Comparison of muscle hypertrophy following
6-month of continuous and periodic strength
training. European Journal of Applied Physiology(in press).
19) Thiebaud RS, Yasuda T, Loenneke JP, Abe T.
Indirect markers of muscle damage induced by
low-intensity blood flow restricted concentric or
eccentric muscle action. Interventional Medicine
and Applied Science (in press).

388

Department of Translational
Research for Healthcare andClinical Science
Project Associate Professor
Hiroyuki Morita, M.D.,Ph.D.

Project Research Associate
Tomokazu Sumida, 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

389

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. 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. Clin Chim Acta.
2012; 413: 577-581.
2. Kimura K, Takenaka K, Ebihara A, Okano T, Uno
K, Fukuda N, Ando J, Fujita H, Morita H, Yatomi
Y, Nagai R. Speckle tracking global strain rate
E/E' predicts LV filling pressure more accurately
than
traditional
tissueDoppler
E/E'.
Echocardiography 2012; 29: 404-410.
3. 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; 222: 278-283.
4. Morita H, Nagai R. Pharmacogenetic guidance
for antiplatelet treatment. Lancet 2012; 380: 725.
5. Inajima T, Imai Y, Shuzo M, Lopez G, Yanagimoto
S, Iijima K, Morita H, Nagai R, Yahagi N, Yamada
I. Relation between blood pressure estimated bypulse wave velocity and directly measured arterialpressure. J Robotics Mechatronics. 2012; 24:
811-819.

390

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, andprevention of OA and OP without such epidemiological data.
We therefore established a large-scale nationwide
osteoarthritis/osteoporosis cohort study called ROAD

(Research on Osteoarthritis/osteoporosis Against
Disability) consisted of total 3,040 participants, ofwhich aims at the elucidation of an environmental andgenetic 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. 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 U, Kawaguchi H: C/EBPβ and RUNX2 cooperate to degrade cartilage with
MMP-13 as the target and HIF-2 α as the inducer
in chondrocytes. Human Molecular Genetics 21,
1111-1123, 2012
2. Muraki S, Akune T, Oka H, Ishimoto Y, Nagata K,
Yoshida M, Tokimura F, Nakamura K, Kawaguchi
H, Yoshimura N: Incidence and risk factors forradiographic knee osteoarthritis and knee pain in
Japanese men and women: A longitudinal
population-based cohort study. Arthritis Rheum
64, 1447-1456, 2012
3. Muraki S, Akune T, Oka H, Ishimoto Y, Nagata K,
Yoshida M, Tokimura F, Nakamura K, Kawaguchi
H, Yoshimura N: Incidence and risk factors forradiographic lumbar spondylosis and lower back

391

4.

5.

6.

7.

8.

9.

pain in Japanese men and women: the ROAD
study. Osteoarthritis Cartilage 20, 712-718, 2012
Kwok AWL, Leung JCS, Chan AYH, Au1 NSK,
Lau EMC, Yurianto H, Yuktanandana P,
Yoshimura N, Muraki S, Oka H, Akune T, Leung
PC: The prevalence of vertebral fracture in Asianmen and women: Comparison between Hong
Kong, Thailand, Indonesia and Japan. Public
Health 126, 523-531, 2012
Yoshimura N, Muraki S, Oka H, Tanaka S.
Kawaguchi H, Nakamura K, Akune T:
Accumulation of metabolic risk factors such as
overweight, hypertension, dyslipidaemia, andimpaired glucose tolerance raises the risk ofoccurrence and progression of knee osteoarthritis:
A 3-year follow-up of the ROAD study.
Osteoarthritis Cartilage 20, 1217-1226, 2012
Watanabe M, Kato J, Yoshimura N, Inoue I,
Mukoubayashi C, Yoshida T, Deguchi H,
Enomoto S, Ueda K, Maekita T, Iguchi M, Tamai
H, Utsunomiya H, Yamamichi N, Fujishiro M,
Inada K, Iwane M, Takeshita T, Mohara O,
Ushijima T, Ichinose M: Development of gastriccancer 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 131, 2632-2642, 2012
Nagata K, Yoshimura N, Muraki S, Hashizume H,
Ishimoto Y, Yamada H, Takiguchi N, Nakagawa Y,
Oka H, Kawaguchi H, Nakamura K, Akune T,
Yoshida M: Prevalence of cervical cord compression and its association with physical performancein a population-based cohort in Japan: the
Wakayama Spine Study. Spine 37, 1892-1898,
2012
Watanuki A, Tsutsui S, Yamada H, En-yo Y,
Yoshida M, Yoshimura N: Radiographic featuresand risk for curve progression of de novo lumbar
scoliosis in the elderly. A 15-year follow-up study
in a community-based cohort. J Orthop Sci 17,
526-531, 2012
Coggon D, Ntani G, Palmer KT, Felli VE, Harari R,
Barrero LH, Felknor SA, Gimeno D, Cattrell A,
Serra C, Bonzini M, Solidaki E, Merisalu E, Habib
RR, Sadeghian F, Kadir M, Warnakulasuriya SS,
Matsudaira K, Nyantumbu B, Sim MR, Harcombe

H, Cox K, Marziale MH, Sarquis LM, Harari F,
Freire R, Harari N, Monroy MV, Quintana LA,
Rojas M, Salazar Vega EJ, Harris EC,
Vargas-Prada S, Martinez JM, Delclos G,
Benavides FG, Carugno M, Ferrario MM, Pesatori
AC, Chatzi L, Bitsios P, Kogevinas M, Oha K,
Sirk T, Sadeghian A, Peiris-John RJ, Sathiakumar
N, Wickremasinghe AR, Yoshimura N,
Kielkowski D, Kelsall HL, Hoe VC, Urquhart DM,
Derrett S, McBride D, Gray A: The CUPID(Cultural and Psychosocial Influences on
Disability) study: methods of data collection andcharacteristics of study sample. PLoS One 7(7),e39820, 2012, Correction (authors' affiliation),
Plos One 7(10) doi: 10.1371/annotation/3faf76e5f73e-427f-9d60-8f94939b0f7e
10. Ishimoto Y, Yoshimura N, Muraki S, Yamada H,
Nagata K, Hashizume H, Takiguchi N, Minamide
A, Oka H, Kawaguchi K, Nakamura K, Akune T,
Yoshida M: Prevalence of lumbar spinal stenosis
and its association with physical performance in a
population-based cohort in Japan: the Wakayama
Spine Study. Osteoarthritis Cartilage 20, 11031108, 2012
11. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Tanaka S, Akune T:Does mild
cognitive impairment affect the occurrence ofradiographic knee osteoarthritis? A 3-year
follow-up in the ROAD study. BMJ Open at:
http://bmjopen.bmj.com/cgi/content/full/bmjopen2012-001520

392

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)

393(h) Research on systems that contribute to medical
safety(i) Research for the sustainable development ofregional healthcare systems(j) Research on nationwide public-access defibrillators and improvement of outcomes after
out-of-hospital cardiac arrests

References
1. Nakamura M, Yasunaga H, Toda AA, Sugihara T,
Imamura T. The impact of media reports on the2008 outbreak of hydrogen sulfide suicides inJapan. Int J Psychiatry Med. 2012;44(2):133-40.
2. Horiguchi H, Yasunaga H, Hashimoto H, Ohe K. A
user-friendly tool to transform large scale
administrative data into wide table format using a
MapReduce program with a Pig Latin based script.
BMC Med Inform Decis Mak. 2012;12:151.
3. Masuda K, Chikuda H, Yasunaga H, Hara N,
Horiguchi H, Matsuda S, Takeshita K, Kawaguchi
H, Nakamura K. Factors affecting the occurrenceof pulmonary embolism after spinal surgery: datafrom the national administrative database in Japan.
Spine J. 2012;12(11):1029-34.
4. Tanabe S, Yasunaga H, Koike S, Akahane M,
Ogawa T, Horiguchi H, Hatanaka T, Yokota H,
Imamura T. Monophasic versus biphasic defibrillation for pediatric out-of-hospital cardiac arrest
patients: a nationwide population-based study inJapan. Crit Care. 2012;16(6):R219.
5. Akahane M, Tanabe S, Koike S, Ogawa T,
Horiguchi H, Yasunaga H, Imamura T. Elderly
out-of-hospital cardiac arrest has worse outcomeswith a family bystander than a non-family
bystander. Int J Emerg Med 2012;5(1):41.
6. Tanabe S, Yasunaga H, Ogawa T, Koike S,
Akahane M, Horiguchi H, Hatanaka T, Yokota H,
Imamura T. Comparison of outcomes after use of
biphasic or monophasic defibrillators among
out-of-hospital cardiac arrest patients: a nationwide population-based observational study. Circ
Cardiovasc Qual Outcomes. 2012;5(5):689-96.
7. Sugihara T, Yasunaga H, Horiguchi H, Fujimura T,
Ohe K, Matsuda S, Fushimi K, Homma Y. Impact
of surgical intervention timing on the case fatality
rate for Fournier's gangrene: an analysis of 379

cases. BJU Int. 2012;110(11 Pt C):E1096-100.
8. Yasunaga H, Hashimoto H, Horiguchi H, Miyata H,
Matsuda S. Variation in cancer surgical outcomes
associated with physician and nurse staffing: a
retrospective observational study using theJapanese Diagnosis Procedure Combination
Database. BMC Health Serv Res. 2012;12:129.
9. Shoda N, Yasunaga H, Horiguchi H, Matsuda S,
Ohe K, Kadono Y, Tanaka S. Risk factors affecting
inhospital mortality after hip fracture: retrospective analysis using the Japanese Diagnosis
Procedure Combination Database. BMJ Open.
2012;2(3)10. Uchida K, Yasunaga H, Miyata H, Sumitani M,
Horiguchi H, Matsuda S, Yamada Y. Impact ofremifentanil use on early postoperative outcomes
following brain tumor resection or rectal cancer
surgery. J Anesth. 2012;26(5):711-20.
11. Yasunaga H, Horiguchi H, Matsuda S, Fushimi K,
Hashimoto H, Ohe K, Kokudo N. Relationshipbetween hospital volume and operative mortality
for liver resection: Data from the JapaneseDiagnosis Procedure Combination database.
Hepatol Res. 2012;42(11):1073-1080.
12. Koike S, Ide H, Kodama T, Matsumoto S,
Yasunaga H, Imamura T. Physician-scientists inJapan: attrition, retention, and implications for the
future. Acad Med. 2012;87(5):662-7.
13.Takeuchi M, Osamura T, Yasunaga H, Horiguchi H,
Hashimoto H, Matsuda S. Intussusception among
Japanese children: an epidemiologic study using
an administrative database. BMC Pediatr. 2012;12:36.
14. Akahane M, Ogawa T, Tanabe S, Koike S,
Horiguchi H, Yasunaga H, Imamura T. Impact of
telephone dispatcher assistance on the outcomes ofpediatric out-of-hospital cardiac arrest. Crit CareMed. 2012;40(5):1410-6.
15. Sato M, Tateishi R, Yasunaga H, Horiguchi H,
Yoshida H, Matsuda S, Koike K. Mortality andmorbidity of hepatectomy, radiofrequency ablation,and embolization for hepatocellular carcinoma: anational survey of 54,145 patients. J Gastroenterol.
2012 ;47(10):1125-33.
16. Sugihara T, Yasunaga H, Horiguchi H, Nishimatsu
H, Hirano Y, Matsuda S, Homma Y. Renal
haemorrhage risk after extracorporeal shockwave

394

lithotripsy: results from the Japanese Diagnosis
Procedure Combination Database. BJU Int. 2012;
110(8 Pt B):E332-8.
17. Sugihara T, Yasunaga H, Horiguchi H, Nishimatsu
H, Fukuhara H, Enomoto Y, Kume H, Ohe K,
Matsuda S, Homma Y. Management trends,
angioembolization performance and multiorgan
injury indicators of renal trauma from Japaneseadministrative claims database. Int J Urol. 2012;19(6):559-63
18.Chikuda H, Yasunaga H, Horiguchi H, Takeshita K,
Kawaguchi H, Matsuda S, Nakamura K. Mortality
and morbidity in dialysis-dependent patients
undergoing spinal surgery: analysis of a national
administrative database in Japan. J Bone Joint
Surg Am. 2012;94(5):433-8.
19. Sugihara T, Yasunaga H, Horiguchi H, Nakamura
M, Nishimatsu H, Kume H, Ohe K, Matsuda S,
Homma Y. In-hospital outcomes and costassessment between bipolar versus monopolartransurethral resection of the prostate. J Endourol.
2012;26(8):1053-8.
20. Takeuchi M, Yasunaga H, Horiguchi H, Matsuda S.
Clinical features of infants hospitalized for 2009
pandemic influenza A (H1N1) in Japan: analysis
using a national hospital discharge database.
Pediatr Infect Dis J 2012;31(4):368-72.
21. Nakamura M, Yasunaga H, Miyata H, Shimada T,
Horiguchi H, Matsuda S. Mortality of neuroleptic
malignant syndrome induced by typical andatypical antipsychotic drugs: a propensity-matchedanalysis from the Japanese Diagnosis Procedure
Combination database. J Clin Psychiatry 2012;
73(4):427-30.
22. Sugihara T, Yasunaga H, Horiguchi H, Nakamura
M, Nomiya A, Nishimatsu H, Matsuda S, Homma
Y. Admissions related to interstitial cystitis inJapan: an estimation based on the Japanesediagnosis procedure combination database. Int J
Urol 2012;19(1):86-9
23. Kodama T, Koike S, Matsumoto S, Ide H,
Yasunaga H, Imamura T. The working status ofJapanese female physicians by area of practice:cohort analysis of taking leave, returning to work,and changing specialties from 1984 to 2004.
Health Policy 2012;105(2-3):214-20.
24 Kuwabara K, Matsuda S, Fushimi K, Ishikawa KB,

Horiguchi H, Fujimori K. Contribution of theadministrative database and the geographicalinformation system to disaster preparedness andregionalization. American Journal of Disaster
Medicine 2012; 7(2):95-104
25. Murata A, Okamoto K, Matsuda S, Kuwabara K,
Ichimiya Y, Matsuda Y, Kubo T, Fujino Y, Fujimori
K, Horiguchi H. The Care Processes for Acute
Cholecystitis According to Clinical Practice
Guidelines Based on the Japanese Administrative
Database. The Tohoku Journal of Experimental
Medicine 2012; 227(4):237-244
26. Kuwabara K, Matsuda S, Fushimi K, Ishikawa
K.B, Horiguchi H, Fujimori K. Comparative Studyon the Difference in Functional Outcomes at
Discharge
between
ProximalandTotal
Gastrectomy. Case Reports in Gastroenterology
2012; 6(2):400-409
27. Murata A, Matsuda S, Mayumi T, Okamoto K,
Kuwabara K, Ichimiya Y, Fujino Y, Kubo T,
Fujimori K, Horiguchi H. Multivariate analysis offactors influencing medical costs of acutepancreatitis hospitalizations based on a national
administrative database. Digestive and Liver
Disease 2012; 44(2):143-148395

Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Associate Professor
Naoto Hayashi, M.D., Ph.D., Kansei Uno, M.D., Ph.D., Takeharu Yoshikawa, M.D., Ph.D.

Project Research Associate
Mika Nagasaki, M.D., Ph.D., Kensuke Asaba, M.D., Ph.D., Eriko Maeda, M.D., PhD.,
Junichi Ishida, M.D., PhD, Soichiro Miki, MD, PhD

Homepage

http://www.h.u-tokyo.ac.jp/english/center22/en_contribute/computer.html

Introduction and Organization
The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) wasestablished in May 2005. It is under the supervision of
the Department of Radiology.
The aim of our research project is as follows: (1) tocreate a large database of health screening clinicaldata including medical images, (2) to develop methods
to analyze large volumes of medical images and to
search for algorithms to detect subtle abnormal
findings in these images, and (3) to evaluate theclinical usefulness of such image processing methods
and to apply the system in clinical settings.
The department comprises two project associate
professors and three project research associates, alongwith a medical staff of approximately 40 employees in
the health-screening center.

Clinical Activities
CDRPM is responsible for the clinical activities in the
CDRPM Health Screening Center. In this healthscreening center, the following diagnostic imaging
modalities are installed to facilitate high level ofdiagnostic accuracy: positron emission computed
tomography/X-ray computed tomography (PET/CT),

3-tesla magnetic resonance imaging (3T-MRI) systems,
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.

3962) 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) 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.Prev.Cardiol. ;19(6):1393-1400 2012.
(2) Gonoi W, Akai H, Hagiwara K, Akahane M,
Hayashi N, Maeda E, Yoshikawa T, Kiryu S, Tada
M, Uno K, Ohtsu H, Okura N, Koike K, Ohtomo K.
Meandering main pancreatic duct as a relevant
factor to the onset of idiopathic recurrent acutepancreatitis. PLoS One ;7(5):e37652 2012.
(3) Goto M, Abe O, Aoki S, Miyati T, Takao H,
Hayashi N, Mori H, Kunimatsu A, Ino K, Yano K,
Ohtomo K. Bilateral pre- and postcentral gyrus
volume positively correlates with T2-SNR of
putamen in healthy adults. Neuroradiology 2012.
(4) Goto M, Abe O, Kabasawa H, Takao H, Miyati T,
Hayashi N, Kurosu T, Iwatsubo T, Yamashita F,
Matsuda H, Inano S, Mori H, Kunimatsu A, Aoki S,
Ino K, Yano K, Ohtomo K, Japanese Alzheimer's
Disease Neuroimaging Initiative. Effects of image
distortion correction on voxel-based morphometry.
Magn.Reson.Med.Sci. ;11(1):27-34 2012.
(5) Goto M, Abe O, Miyati T, Aoki S, Takao H,

Hayashi N, Mori H, Kunimatsu A, Ino K, Yano K,
Ohtomo K. Association between iron content andgray matter missegmentation with voxel-based
morphometry in basal ganglia. J.Magn. Reson.
Imaging 2012.
(6) Goto M, Abe O, Miyati T, Kabasawa H, Takao H,
Hayashi N, Kurosu T, Iwatsubo T, Yamashita F,
Matsuda H, Mori H, Kunimatsu A, Aoki S, Ino K,
Yano K, Ohtomo K, Japanese Alzheimer's Disease
Neuroimaging Initiative. Influence of signal
intensity non-uniformity on brain volumetry using
an atlas-based method. Korean J.Radiol.; 13(4):391-402 2012.
(7) Goto M, Miyati T, Abe O, Takao H, Kurosu T,
Hayashi N, Aoki S, Mori H, Kunimatsu A, Ino K,
Yano K, Ohtomo K. Repeatability of measured
brain volume by atlas-based method using
T1-weighted image. J.Digit. Imaging; 25(1):173178 2012.
(8) Hanamura K, Tojo A, Kinugasa S, Asaba K, Fujita
T. The resistive index is a marker of renal function,
pathology, prognosis, and responsiveness to steroid
therapy in chronic kidney disease patients. Int. J.
Nephrol.; 2012:139565 2012.
(9) Hanaoka S, Masutani Y, Nemoto M, Nomura Y,
Yoshikawa T, Hayashi N, Ohtomo K. Automatic
categorization of anatomical landmark-local
appearances based on diffeomorphic demons andspectral clustering for constructing detector
ensembles. Med.Image Comput. Comput. Assist.
Interv.; 15(Pt 2):106-113 2012.
(10) Inano S, Takao H, Hayashi N, Yoshioka N, Mori H,
Kunimatsu A, Abe O, Ohtomo K. Effects of age
and gender on neuroanatomical volumes. J.Magn.
Reson. Imaging 2012.
(11) Ishida J, Kinugawa K, Shiga T, Imamura T, Hatano
M, Maki H, Inaba T, Yao A, Hirata Y, Nishimura T,
Kyo S, Ono M, Nagai R. Rapidly progressive
cardiac allograft vasculopathy in early onset
regressed with everolimus treatment in an adultcardiac recipient. Int.Heart J. ;53(6):388-390 2012.
(12) Ishida J, Suzuki T, Aizawa K, Sawaki D, Nagai R.
Comparison of analytical performance of two
single-step measurement devices of B-typenatriuretic Peptide. Int.Heart J. ; 53(5):320-323
2012.
(13) Kimura K, Takenaka K, Ebihara A, Okano T, Uno

397

K, Fukuda N, Ando J, Fujita H, Morita H, Yatomi Y,
Nagai R. Speckle Tracking Global Strain Rate E/E'
Predicts LV Filling Pressure More Accurately Than
Traditional Tissue Doppler E/E'. Echocardiography;
29(4):404-410 2012.
(14) 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 and extrahepatic bile duct cholangiocarcinoma. Jpn.J.Radiol. ;30(3):227-234 2012.
(15) Nishimura S, Manabe I, Nagasaki M, Kakuta S,
Iwakura Y, Takayama N, Ooehara J, Otsu M,
Kamiya A, Petrich BG, Urano T, Kadono T, Sato S,
Aiba A, Yamashita H, Sugiura S, Kadowaki T,
Nakauchi H, Eto K, Nagai R. In vivo imaging
visualizes discoid platelet aggregations without
endothelium disruption and implicates contributionof inflammatory cytokine and integrin signaling.
Blood ;119(8):e45-56 2012.
(16) Ohkawa R, Kishimoto T, Kurano M, Dohi T,
Miyauchi K, Daida H, Nagasaki M, Uno K,
Hayashi N, Sakai N, Matsuyama N, Nojiri T,
Nakamura K, Okubo S, Yokota H, Ikeda H, Yatomi
Y. Development of an enzymatic assay forsphingomyelin with rapid and automatableperformances: Analysis in healthy subjects andcoronary heart disease patients. Clin. Biochem.;
45(16-17):1463-1470 2012.
(17) Takao H, Hayashi N, Kabasawa H, Ohtomo K.
Effect of scanner in longitudinal diffusion tensor
imaging studies. Hum.Brain Mapp. ;33(2):466-477
2012.
(18) Takao H, Hayashi N, Ohtomo K. A longitudinal
study of brain volume changes in normal aging.
Eur.J.Radiol. ;81(10):2801-2804 2012.
(19) Yoshikawa T, Hayashi N, Tajiri Y, Satake Y,
Ohtomo K. Brain reorganization in patients withbrachial plexus injury: a longitudinal functional
MRI study. ScientificWorldJournal ;2012:501751
2012.

398

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. Muraki S, Akune T, Oka H, Ishimoto Y, Nagata K,
Yoshida M, Tokimura F, Nakamura K, Kawaguchi
H, Yoshimura N: Incidence and risk factors forradiographic knee osteoarthritis and knee pain in
Japanese men and women: A longitudinal
population-based cohort study. Arthritis Rheum
64: 1447-1456, 2012.
2. Muraki S, Akune T, Oka H, Ishimoto Y, Nagata K,
Yoshida M, Tokimura F, Nakamura K, Kawaguchi
H, Yoshimura N: Incidence and risk factors forradiographic lumbar spondylosis and lower backpain in Japanese men and women: the ROAD
study. Osteoarthritis Cartilage 20: 712-718, 2012.
3. Kwok AW, Leung JC, Chan AY, Au BS, Lau EM,
Yurianto H, Yuktanandana P, Yoshimura N,
Muraki S, Oka H, Akune T, Leung PC: Prevalenceof vertebral fracture in Asian men and women:
Comparison between Hong Kong, Thailand,
Indonesia and Japan. Public Health 126: 523-531,
2012.
4. Yoshimura N, Muraki S, Oka H, Tanaka S,
Kawaguchi H, Nakamura K, Akune T:
Accumulation of metabolic risk factors such as399

overweight, hypertension, dyslipidaemia, andimpaired glucose tolerance raises the risk ofoccurrence and progression of knee osteoarthritis:a 3-year follow-up of the ROAD study.
Osteoarthritis Cartilage 20: 1217-1226, 2012.
5. Ishimoto Y, Yoshimura N, Muraki S, Yamada H,
Nagata K, Hashizume H, Takiguchi N, Minamide
A, Oka H, Kawaguchi H, Nakamura K, Akune T,
Yoshida M: Prevalence of symptomatic lumbar
spinal stenosis and its association with physicalperformance in a population-based cohort inJapan: the Wakayama Spine Study. Osteoarthritis
Cartilage 20: 1103-1108, 2012.
6. Nagata K, Yoshimura N, Muraki S, Hashizume H,
Ishimoto Y, Yamada H, Takiguchi N, Nakagawa Y,
Oka H, Kawaguchi H, Nakamura K, Akune T,
Yoshida M: Prevalence of cervical cord
compression and its association with physicalperformance in a population-based cohort inJapan: the Wakayama spine study. Spine (Phila Pa
1976) 37: 1892-1898, 2012.
7. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Tanaka S, Akune T: Does mild
cognitive impairment affect the occurrence ofradiographic knee osteoarthritis? A 3-year
follow-up in the ROAD study. BMJ Open 2:
e001520, 2012.

400

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 December, 2005 within the “22ndCentury Medical and Research Center” at the
University of Tokyo Hospital based upon
contributions by the Tokio Marine & Nichido Fire
Insurance Co., Ltd.
Public concern regarding malpractice and the medical
related disputes has risen in developed countries
accompany several publicized cases such as the public
inquiry into children’s heart surgery at the Bristol
Royal Infirmary and the accidental chemotherapy
overdoses occurring at the Dana-Farber Cancer
Institute at the end of the 20th century. Reports of themedia in our country concerning malpractice and the
medical related disputes increased suddenly from1999. Fears also rose regarding possible criminal
prosecutions through the mandatory reporting to thepolice provided in the Medical Practitioners Law
Article 21. Some incidents become targets ofinvestigations although several verdicts resulted inacquittals. Nonetheless, there exist various discussions
and some confusion over the intervention of the police

authority and criminal procedures into the process of
medical treatment.
On another front, in medical related disputes
involving civil claims for compensation for damages,
many cases have been dealt with and resolved throughvarious measures such as explanation andreconciliation settlement before becoming a lawsuit.
In spite of such efforts, the number of civil health carelawsuits has kept increasing from the 1970s (about
100 new cases received per year) to 2004 (1110 new
cases per year), with a the pace that has doubled every
ten years. Though the number of civil health carelawsuits shows a trend for decrease after 2004, many
medical treatment disputes resulted in lawsuits in
2009, with 733 new cases received and 952 cases
resolved (preliminary figures).
In our department, while looking straight at therealities of malpractice and the medical related
disputes, we aim, from each aspect of the patient, thehealth care provider, and society, for a healthy
rebuilding of the health care system and the recoveryof confidence in medical treatment via thinking about
the ideal ways to build a better legal system. Together
therewith, making the best use of the experience of a

401state-of-the-art university hospital, we are establishing
an approach that promotes mutual understanding by
conversations between the patient and the health careprovider.

Research activities
Basic researches concerning both the prevention of
malpractice and the honest resolution of medical
accidents (including the preventing of disputes andlawsuits) are urgent issues. In addition, research for“Effective Providing of Service in the Patient Safety
Support Center” as Health & Labour Sciences
Research has been conducted since 2012. Such
research activities are vigorously carried out in our
department to return the results widely in society by
the development of educational 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.

References
Research Articles
1. Reiko Segawa, Mami Onishi, Tatsunobu Takeuchi,
Ayako Nagata. Nurses' recognition of coworkers’
responses to their errors. Journal of the Japan
Academy of Nursing Evaluation. 1-8, Vol. 2(2012) No. 1. (in Japanese)
2. Takahide Kohro, Tsutomu Yamazaki, Hiroki Sato,
Kenji Harada, Kazuhiko Ohe, Issei Komuro,Ryozo Nagai. Trends in Antidiabetic Prescription
Patterns in Japan from 2005 to 2011. International
Heart Journal Vol. 54 (2013) No. 2.
Books
1. Internal Medicine. Law and Medicine. Yasushi
Kodama. 30-32. Nishimura-shoten. 2012. (inJapanese).
2. The Tangle of Medical Treatment and Law Medical Ethics and Solutions to Medical Disputes.
The modern meaning of editorials about medical
disputes. Tatsuo Kuroyanagi, Yasushi Kodama.
Junji Maeda, Michiharu Hayashi.
253-302.
Shojihomu. 2012 (in Japanese).
3. 100 selected U.S. judicial precedents. Futoshi
Iwata. Yasushi Kodama 204-205. Yuhikaku. 2012
(in Japanese).
4. Internal Medicine. Practice of Safe and Reliable
Medical Treatment. Kenji Harada. 38-40.
Nishimura-shooten. 2012. (in Japanese).
5. Healthcare Safety for Doctors. Kenji Harada.
Iryobunyateikeikyogikai. 2012. (in Japanese).

Clinical activities
Based on the research results described above, thisdepartment supports on-site measures at the place oftreatment; and together therewith promote research
related to topics transmitted from such sites andeducation for staff of the site.
*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).

Conference Presentations
Domestic Meetings
1. Maiko Mizuki, Utako Miyazaki, Yasuyo Kuroiwa,
Yuki Sasaki, Masatomo Suzuki. The cooperationof medical treatment and care welfare in the homecare medical system. The 32nd joint Conference
on Medical Informatics. Nov. 15-17, 2012.
2. Reiko Segawa, Tomoko Matsuura, Takeshi Fujii,
Kenji Harada, Yasushi Kodama. Expectation for a
Patient Safety Support Center from medical
workers. Japanese Society for Quality and Safety
in Healthcare 7th annual scientific meeting. Nov.
23-24, 2012.
3. Maiko Mizuki, Kayoko Kato, Masako Suzuki,
Tomoko Matsuura, Reiko Segawa, Kenji Harada,

402

Yasushi Kodama. The measures to achieve thecooperation of in-hospital and out-of-hospitalconsultation offices for patients. Japanese Society
for Quality and Safety in Healthcare 7th annual
scientific meeting. Nov. 23-24, 2012.
4. Kenji Harada, Shiho Ando, Yasushi Kodama.
Investigation of learning situations about
healthcare safety for pre- and post-graduation of
medical schools. Japanese Society for Quality and
Safety in Healthcare 7th annual scientific meeting.
Nov. 23-24, 2012.
5. Hiroshi Iwasaki, Maiko Mizuki, Kenji Harada,
Yasushi Kodama, Hidemitsu Nakaguma, Kumi
Yonai, Chieko Koga, Reiko Yamamoto, Hisae
Miyata. The measures of patient counseling andcomplaint correspondence, and information
dissemination in a medical safe support center.
Japanese Society for Quality and Safety in
Healthcare 7th annual scientific meeting. Nov.
23-24, 2012.
6. Masato Tanimizu, Kenji Harada. The present
condition and topics regarding organization for
consultation and support - Securement of quality
in consultation, support, and safety for cancer
patients and families. Japanese Society for
Quality and Safety in Healthcare 7th annual
scientific meeting. Nov. 23-24, 2012.

403

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, 2012 total fivegraduate 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 stressinduced 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

404

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. 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.
2. 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.
3. Ando K, Fujita T. Pathophysiology of saltsensitive hypertension. Ann Med 2012; 44 (suppl
1): S119-S126.
4. Kawarazaki H, Shibagaki Y, Kido R, Nakajima I,
Fuchinoue S, Ando K, Fujita T, Fukagawa M,
Teraoka S, Fukumoto S. Kidney transplantation
restored uncoupled bone turnover in end-stage
renal disease. Clin Nephrol. 2012; 78(1): 10-6.
5. Kawarazaki H, Ando K, Shibata S, Muraoka K,
FujitaM,
Kawarazaki
C,FujitaT.
Mineralocorticoid receptor-Rac1activation andoxidative stress play major roles in salt-induced
hypertension and kidney injury in prepubertal rats.
J Hypertens. 2012; 30(10):1 977-85.
6. Sadanaga T, Ando K, Hirota S, Mitamura H,
Tsuchihashi T, Kohsaka S, Fukuda K, Ogawa S.
B-type natriuretic peptide levels are decreased by
reducing dietary salt intake in patients withcompensated heart failure with preserved ejection

fraction. Intern Med J. 2013; 43(6): 663-667
7. Ando K, Ueshima K, Tanaka S, Kosugi S, Sato T,
Matsuoka H, Nakao K, Fujita T.. Comparison of
the antialbuminuric effects of L-/N-type andL-type calcium channel blockers in hypertensive
patients with diabetes and microalbuminuria: The
Study of Assessment for Kidney Function by
Urinary Microalbumin in Randomized (SAKURA)
Trial. Internat J Med Sci. 2013; 10(9): 1209-1216.

405

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406

Gastroenterological Surgery.
5.
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 3,900
hospitals from around Japan have already participatedin NCD. More than 1,000,000 surgical cases per year
will be expected to submit to NCD.

6.

7.

References
1. Arai T, Yuasa S, Miyata H, Kawamura A, Maekawa
Y, Ishikawa S, Noma S, Inoue S, Sato Y, Kohsaka S,
Fukuda K. Incidence of periprocedural myocardial
infarction and cardiac biomarker testing after
percutaneous coronary intervention in Japan: resultsfrom a multicenter registry. Heart Vessels. 2012 Dec
29. [Epub ahead of print]
2. Yamauchi T, Miyata H, Sakaguchi T, Miyagawa S,
Yoshikawa Y, Takeda K, Motomura N, Tsukihara
H, Sawa Y. Coronary artery bypass grafting inhemodialysis-dependent patients: analysis ofJapan Adult Cardiovascular Surgery Database.
Circ J 2012; 76(5): 1115-1120.
3. Endo Y, Kohsaka S, Nagai T, Koide K, Takahashi
T, Nagatomo Y, Oshima K, Miyata H, Fukuda K,
Yoshikawa T. Steady-state levels of troponin andbrain 3 natriuretic peptide for prediction of
long-term 4 outcome after acute heart failure withor 5 without stage 3 to 4 chronic kidney disease.
Br J Med Med Res 2012; 2(4): 490-500.
4. Yasunaga H, Hashimoto H, Horiguchi H, Miyata
H, Matsuda S. Variation in cancer surgicaloutcomes associated with physician and nurse
staffing: a retrospective observational study using
the Japanese Diagnosis Procedure Combination

8.

Database. BMC Health Serv Res 2012; 12: 129.
Usui A, Miyata H, Ueda Y, Motomura N,
Takamoto S. Risk-adjusted and case-matchedcomparative study between antegrade andretrograde cerebral perfusion during aortic arch
surgery: based on the Japan Adult Cardiovascular
Surgery Database. Gen Thorac Cardiovasc Surg
2012; 60(3): 132-139.
Nobuhiro Handa, Hiroaki Miyata, Noboru
Motomura, Takeshi Nishina, Shinichi Takamoto;Japan Adult Cardiovascular Database Organization. Procedure and age-specific risk stratificationof single aortic valve replacement in elderly
patients based on Japan Adult Cardiovascular
Surgery Database. Circulation J 2012; 76(2): 356364.
Miyata H, Motomura N, Murakami A, Takamoto S,
Japan Cardiovascular Surgery Database. Effect ofbenchmarking projects on outcomes of coronary
artery bypass graft surgery: challenges and prospects
regarding the quality improvement initiative. J
Thorac Cardiovasc Surg 2012; 143(6): 1364-1369.
Uchida K, Yasunaga H, Miyata H, Sumitani M,
Horiguchi H, Matsuda S, Yamada Y. Impact ofremifentanil use on early postoperative outcomes
following brain tumor resection or rectal cancer
surgery. J Anesth. 2012; 26(5): 711-20.

407

Department of Anti-Aging
Medicine
Professor
Satoshi Inoue, M.D., Ph.D.

Lecturer
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 aging, and thepathogenesis of age-related disorders, including
obesity, diabetes, metabolic disorders, osteoporosis,
osteoarthritis, sarcopenia, atherosclerosis, dementia,
age-related macular degeneration, prostate cancer,
mammary carcinoma, and immunocompromised
conditions. In particular, the program aims to clarify
the roles of sex hormones estrogen and androgen in
normal, aging and disease processes. Through basic
biomedical research, our department will reveal agedependent changes at cellular, tissue, and whole-bodylevels, and will contribute to the development ofmolecule-targeted
treatment
andalternative
prevention of age-related processes and diseases.

Research activities
Aging causes degeneration and dysfunction of cells invarious organs, leading to the development of multiple
disorders in elderly people, as exemplified by obesity,
glucose intolerance, dyslipidemia. Osteoporosis,
osteoarthritis, and sarcopenia are also common bone,

joint, and muscle disorders, respectively, among
elderly people. In addition, aging is an important risk
factor for the prognosis of hormone-dependent tumors,
prostate cancer and mammary carcinoma. Since aging
and age-related disorders affect the quality of dailyliving and lifespan of elderly people, we will identify
the genetic and environmental factors that control
aging processes using recent technology of human
genetics, genomics and molecular and cellularbiology.
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 (ChIP)
microarray analysis, ChIP-sequencing, RNAsequencing, CAGE-sequencing and systems

408

biological approach, we discovered novel androgen
responsive genes including UGT1A1, CDH2, APP,
FOXP1, ArfGAP3, 14-3-3ζ, miR148a and a
non-coding RNA CTBP1-AS. The tumor-promoting
effects of APP and CTBP1-AS have been shown inin vivo models of prostate cancer.
3. As a genetic approach, we performed large-scale
single nucleotide polymorphisms (SNP) analyses to
identify disease-related factors for osteoporosis,
osteoarthritis, sarcopenia, and age-related maculardegeneration. Through genome-wide associatedstudy (GWAS) and candidate gene approach, we
identified several interesting disease-related genes
and focused on the functional studies for thesegenes. We also combined mouse genetics to solve
the functions of disease-related genes inphysiological states as well as in pathophysiologicalstates.
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. 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
130, 1021-1028, 2012.
2. Endo H, Ikeda K, Urano T, Horie-Inoue K, Inoue
S: Terf/TRIM17 stimulates degradation of
kinetochore protein ZWINT and regulates cellproliferation. J Biochem 151, 139-144, 2012.
3. 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 103, 176-180, 2012.
4. 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 130, 2240-2248, 2012
and Cover.
5. Abe Y, Ijichi N, Ikeda K, Kayano H, Horie-Inoue
K, Takeda S, Inoue S: Forkhead box transcription
factor, forkhead box A1, shows negative association with lymph node status in endometrial cancer,
and represses cell proliferation and migration ofendometrial cancer cells. Cancer Sci 103, 806812, 2012.
6. 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
97, E565-E574, 2012.
7. Takayama K, Horie-Inoue K, Suzuki T, Urano T,
Ikeda K, Fujimura T, Takahashi S, Homma Y,
Ouchi
Y,
Inoue
S:
TACC2
is
an
androgen-responsive
cell
cycle
regulator
promoting androgen-mediated and castrationresistant growth of prostate cancer. Mol
Endocrinol 26, 748-761, 2012 and Editorial.
8. Ikeda K, Tsukui T, Tanaka D, Maruyama Y,
Horie-Inoue K, Inoue S: Conditional expressionof human bone Gla protein in osteoblasts causes
skeletal abnormality in mice. Biochem Biophys
Res Commun 424, 164-169, 2012.
9. Ijichi N, Shigekawa T, Ikeda K, Horie-Inoue K,
Shimizu C, Saji S, Aogi K, Tsuda H, Osaki A,
Saeki T, Inoue S: Association of double-positive
FOXA1 and FOXP1 immunoreactivities withfavorable prognosis of tamoxifen-treated breast
cancer patients. Horm Cancer 3, 147-159, 2012.
10. Urano T, Shiraki M, Ouchi Y, Inoue S:
Association of circulating sclerostin levels with
fat mass and metabolic disease-related markers inJapanese postmenopausal women. J Clin
Endocrinol Metab 97, E1473-1477, 2012.
11. Murata T, Takayama K, Urano T, Fujimura T,
Ashikari D, Obinata D, Horie-Inoue K, Takahashi
S, Ouchi Y, Homma Y, Inoue S: 14-3-3ζ, a novel
androgen-responsive gene, is upregulated in
prostate cancer and promotes prostate cancer cellproliferation and survival. Clin Cancer Res 18,
5617-5627, 2012.
12. Ito M, Urano T, Hiroi H, Momoeda M, Saito M,

409

Hosokawa Y, Tsutsumi R, Zenri F, Koizumi M,
Nakae H, Horie-Inoue K, Fujii T, Yano T,
Kozuma S, Inoue S, Taketani Y: Theprogesterone-responsive gene 14-3-3τ enhances
the transcriptional activity of progesterone
receptor in uterine cells. J Mol Endocrinol 49,
193-202, 2012.
13. Ohta S, Misawa A, Fukaya R, Inoue S, Kanemura
Y, Okano H, Kawakami Y, Masahiro Toda M:
Macrophage migration inhibitory factor (MIF)
promotes cell survival and proliferation of neural
stem/progenitor cells. J Cell Sci 125, 3210-3220,
2012.
14. Ikeda K, Tsukui T, Imazawa Y, Horie-Inoue K,
Inoue S: Conditional expression of constitutively
active estrogen receptor α in chondrocytes
impairs longitudinal bone growth in mice.
Biochem Biophys Res Commun 425, 912-917,
2012.
15. Takagi K, Miki Y, Onodera Y, Nakamura Y,
Ishida T, Watanabe M, Inoue S, Sasano H, Suzuki
T: Krüppel-like factor 5 in human breast
carcinoma: a potent prognostic factor induced byandrogens. Endocr Relat Cancer 19, 741-750,
2012.

410

Department of Clinical Trial DataManagement
Project Associate Professor
Takuhiro Yamaguchi, Ph.D.

Project Assistant Professor
Hiroshi Ohtsu, M.S.

Homepage

http://ctdm.umin.jp/

Introduction and Organization

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411

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 that enable information system interoperability to improve medical research and relatedareas of healthcare and we are challenging to convert
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.

3)

4)

5)

References

6)1) Morita T, Miyashita M, Yamagishi A, Akizuki N,
Kizawa Y, Shirahige Y, Akiyama M, Hirai K,
Matoba M, Yamada M, Matsumoto T, Yamaguchi
T, Eguchi K. A region-based palliative careintervention trial using the mixed-method
approach: Japan OPTIM study. BMC Palliative
Care 2012; 11(1): 2. [Epub ahead of print]
2) Arita R, Yanagi Y, Honda N, Maeda S, Maeda K,
Kuchiba A, Yamaguchi T, Yanagihara Y, Suzuki H,
Amano S. Caffeine Increases Tear Volume,

7)

Depending on Polymorphisms within the
Adenosine A2a Receptor Gene and Cytochrome
P450 1A2. Ophthalmology 2012 Feb 14. [Epubahead of print]
Fever and Antipyretic in Critically ill patients
Evaluation (FACE) Study Group, Lee BH, Inui D,
Suh GY, Kim JY, Kwon JY, Park J, Tada K,
Tanaka K, Ietsugu K, Uehara K, Dote K, Tajimi K,
Morita K, Matsuo K, Hoshino K, Hosokawa K,
Lee KH, Lee KM, Takatori M, Nishimura M,
Sanui M, Ito M, Egi M, Honda N, Okayama N,
Shime N, Tsuruta R, Nogami S, Yoon SH, Fujitani
S, Koh SO, Takeda S, Saito S, Hong SJ,Yamamoto T, Yokoyama T, Yamaguchi T,
Nishiyama T, Igarashi T, Kakihana Y, Koh Y.
Association of body temperature and antipyretic
treatments with mortality of critically ill patientswith and without sepsis: multi-centered prospective observational study. Critical Care 2012;16(1): R33. [Epub ahead of print]
Murayama H, Yamaguchi T, Nagata S, Murashima
S. The effects of an intervention program forpromoting interorganizational network building
between multidisciplinary agencies and communitybased organizations: a cluster trial in Japan.
BMC Public Health 2012; 12(1): 178. [Epubahead of print]
Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S,
Sekiya K, Kosuga Y, Suzuki M, Matsumoto M,
Kunii Y, Watanabe N, Mukasa K, Ito K, Ito K.
Treatment of Graves' Disease with Antithyroid
Drugs in the First Trimester of Pregnancy and thePrevalence of Congenital Malformation. Journalof Clinical Endocrinology & Metabolism 2012;
97(7): 2396-403.
Wakita A, Ohtake S, Takada S, Yagasaki F,
Komatsu H, Miyazaki Y, Kubo K, Kimura Y,
Takeshita A, Adachi Y, Kiyoi H, Yamaguchi T,
Yoshida M, Ohnishi K, Miyawaki S, Naoe T,
Ueda R, Ohno R. Randomized comparison of
fixed-schedule versus response-oriented individualized induction therapy and use of ubenimex
during and after consolidation therapy for elderly
patients with acute myeloid leukemia: the JALSG
GML200 Study. International Journal of
Hematology 2012 May 26. [Epub ahead of print]
Yamaguchi T, Morita T, Shinjo T, Inoue S,

412

Takigawa C, Aruga E, Tani K, Hara T, Tamura Y,
Suga A, Adachi S, Katayama H, Osaka I, Saito Y,
Nakajima N, Higashiguchi T, Hayashi T, Okabe T,
Kohara H, Tamaki T, Chinone Y, Aragane H,
Kanai Y, Tokura N, Yamaguchi T, Asada T,
Uchitomi Y.
Effect of parenteral hydration
therapy based on the Japanese national clinicalguideline on quality of life, discomfort, andsymptom intensity in patients with advanced
cancer. Journal of Pain Symptom Management
2012 Jun; 43(6): 1001-12.
8) Kato S, Andoh H, Gamoh M, Yamaguchi T,
Murakawa Y, Shimodaira H, Takahashi S, Mori T,
Ohori H, Maeda S, Suzuki T, Kato S, Akiyama S,
Sasaki Y, Yoshioka T, Ishioka C; Tohoku ClinicalOncology Research and Education.
Safetyverification trials of mFOLFIRI and sequential
IRIS + bevacizumab as first- or second-line
therapies for metastatic colorectal cancer inJapanese patients. Oncology 2012; 83(2): 101-7.
9) Fukagawa M, Fukuma S, Onishi Y, Yamaguchi T,
Hasegawa T, Akizawa T, Kurokawa K, Fukuhara
S. Prescription Patterns and Mineral Metabolism
Abnormalities in the Cinacalcet Era: Results from
the MBD-5D Study. Clinical Journal of American
Society of Nephrology 2012; 7(9): 1473-80.
10) Mori J, Ohashi K, Yamaguchi T, Ando M,
Hirashima Y, Kobayashi T, Kakihana K, Sakamaki
H. Risk assessment for acute kidney injury after
allogeneic hematopoietic stem cell transplantation
based on acute kidney injury network criteria.
Internal Medicine 2012; 51(16): 2105-10.
11) Ogawa T, Niho S, Nagai S, Kojima T, Nishimura
Y, Ohe Y, Kondo N, Yamaguchi T, Endo K, Izumi
K, Minami H. Moderate renal dysfunction may
not require a cisplatin dose reduction: aretrospective study of cancer patients with renal
impairment. International Journa of ClinicalOncology 2012 Oct 5. [Epub ahead of print]12) Iwase S, Yamaguchi T, Miyaji T, Terawaki K, Inui
A, Uezono Y. The clinical use of Kampo
medicines (traditional Japanese herbal treatments)
for controlling cancer patients' symptoms inJapan: a national cross-sectional survey. BMC
Complementary Alternative Medicine 2012 Nov
20;12:222. doi: 10.1186/1472-6882-12-222.
13) Suzuki S, Nagata S, Zerwekh J, Yamaguchi T,

Tomura H, Takemura Y, Murashima S. Effects
of a multi-method discharge planning educational
program for medical staff nurses.
Japanese
Journal of Nursing Science 2012 Dec; 9(2):201-15. doi: 10.1111/j.1742-7924.2011.00203.x.
Epub 2012 Feb 17.
14) 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; 222(1):27883.
15) 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]16) 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;
1;109(18):7049-54.
17) Gonoi W, Akai H, Hagiwara K, Akahane M,
Hayashi N, Maeda E, Yoshikawa T, Kiryu S,Tada
M, Uno K, Ohtsu H, Okura N, Koike K, Ohtomo
K.Meandering main pancreatic duct as a relevant
factor to the onset of idiopathic recurrent acutepancreatitis.PLoS One. 2012;7(5):e37652. doi:
10.1371/journal.pone.0037652. Epub 2012 May
24.
18) Kato S, Chikuda H, Seichi A, Ohtsu H, Kimura A,
Toyama Y.Radiographical risk factors for major
intraoperative blood loss during laminoplasty inpatients with ossification of the posterior
longitudinal ligament.Spine (Phila Pa 1976). 2012
Dec 1;37(25): E1588-93. doi: 10.1097/BRS.0b013
e3182712b74.
19) Yamamoto T, Yokota K, Amao R, Maeno T, Haga
N, Taguri M, Ohtsu H, Ichikawa Y,Goto J, Tsuji
S.An open trial of long-term testosterone
suppression in spinal and bulbar muscular atrophy.
Muscle Nerve. 2012 Dec 14. doi: 10.1002/mus.
23759.

413

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
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 andPharmacokinetics 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,
Corporation).

Mitsubishi

TanabePharmaEducation and clinical activities
Although Pharmacology and Pharmacokinetics is notoriented to education and clinical activities in thehospital, the staffs are hospital pharmacists and are
involved in the education of graduates andunder-graduates in the faculties of medicine andpharmaceutical sciences. Please refer to the annual
report of the Department of Pharmacy.

Research activities
Selected research topics ongoing in Pharmacology andPharmacokinetics are overviewed in the following.
Systematic analysis and prediction of drug-druginteraction
In Japan, more than two thousand drugs are usedin pharmacotherapy in hospital. Among them, somecombinations would cause unpleasant adverse effects
due to pharmacokinetic drug-drug interaction (DDI).
We surveyed DDIs caused by inhibition or inductionof drug metabolizing enzyme in the literature, anddeveloped a new framework for prediction of various
pharmacokinetic DDIs (Hisaka A et al. Pharmacol.
Ther., 2010; 125: 230-48. Hisaka A et al. Clin.
Pharmacokinet., 2009: 48: 653-66).

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By applying this theory, we have been annually
making a comprehensive list of drugs which are
involved in significant pharmacokinetic DDI incollaboration with Prof. Sugiyama in the faculty 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. 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.
2. 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.
3. 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. 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).
2. 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).
3. 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).
4. 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).
5. Hisaka A, Tsukihashi A, and Suzuki H.

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Calculation of Unambiguous Intestinal Availability from Drug-drug Interaction. 4th APISSX.
Tainan, Taiwan：(April 22~25, 2011)
6. Sasaki Y, Hisaka A, Suzuki H. Selective
Degradation of CYP3A4 in Human LiverMicrosome. 4th APISSX. Tainan, Taiwan：(Apr22~25, 2011).
7. 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).

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Department of
Therapeutic Strategy forHeart Failure
Professor
Shunei Kyo, M.D.

Associate Professor
Koichiro Kinugawa, M.D.
Takashi Nishimura,M.D

Project Research Assosiate
Mitsutoshi Kimura, M.D

Project Researcher
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 (34 patients) or in abroad transferred from our
hospital (9 patients) 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 2013, 20 patientswere performed heart transplantation in the Universityof Tokyo Hospital.

417

2. Ventricular Assist Device (VAD) Therapy
122 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. 34 patients weretreated with VAD, 8 were treated in Hospital ward and
26 were treated in the outpatient clinic. VAD was
implanted in 23 patients in 2011 among them Toyobo
paracorporeal VAD were implanted in 8, EVAHEART
in 14 and DuraHeart was implanted in 1 patients. They
were registered to JOTN (Japanese Organ Transplant
Network), and are waiting for HTx. We also assisted
VAD implantation in affiliate or cooperative hospitalin 2012 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 12 institutions.

Teaching Activities
We have the chair of systematic review ofcardiovascular surgery in the spring term at the 2nd
grade of medical course. We also take charge inclinical practice on diagnosis of cardiovasculardisease in the autumn term at the 2nd grade. We expose
the students to daily clinical works as well as researchworks during the course of “Free Quarter” and“Research Lab Visit”, which are scheduled in thesummer and spring vacations at 1st and 2nd grade. Joint
lectures with the Cardiology Department arescheduled 3rd through 4th grades. Each student is
assigned one or two cardiovascular surgical cases in
the Bed Side Learning, in which he/she is required tolearn preoperative patient evaluation and management,
surgical treatment and postoperative care, based onparticipatory practice. There are also twelve small
key-lectures on cardiovascular surgery. Hands-on
practice is provided during the “Clinical clerkship”
one-month course in the last months of 3rd grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/ subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments forheart failure, it is essential for our department of the
University to have active research programs in clinicaland basic subjects related to assisted circulations andheart transplantation. We created highly active
research programs in the every field of medical andsurgical heart failure treatment, played aninternationally leading role and contributed to its
development. A research meeting is held every
Saturday on a research project with Department of
Cardiothoracic Surgery.
Basic and/or clinical research activities are focusedon 1) development of new driving method of rotary
blood pump, 2) development of Compact CP externalcounterpulsation, 3) basic and clinical research on
regenerative therapy, 4) establishment of social

418

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. 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-onset right ventricular failure after
implantation of a continuous-flow left ventricularassist device;Journal of Artificial Organs; 15:200-203
2. Shimizu T, Shunei Kyo, Sei Morizumi, Takashi
Ando, Shigeyoshi Gon, Yoshihiro Suematsu;
Effect of external counterpulsation on cardiac
work following cardiac surgery:Implications of
the mechanism responsible for clinical benefits;
Journal of Cardiology; 59:84-90
3. Kashiwa K; Koichi Kashiwa, Takashi Noshimura,Aya Saito, Hitoshi Kubo, Aoi Fukaya, Hisayoshi
Tamai, Tomoyuki Yambe, Shunei Kyo, Minoru
Ono; Left heart bypass support with the Rotaflow
Centrifugual Pump as a bridge to decision andrecovery in an adult; Journal of Artificial Organs;
15:207-210
4. Kyo S, Taishi Minami, Takashi Nishimura,
Satoshi Gojo, Minoru Ono, New era fortherapeutic strategy for heart failure: Destination
therapy by left ventricular assist device; Journalof Cardiology; 59:101-109
5. 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 volume bycontrolling the power of the continuous-flow
LVAD, so it is synchronized with cardiac beat:development of a native heart load control system(NHLCS); Journal of Artificial Organs; 15:128133
6. Keigo UKITA, Moru MASUZAWA, Hiroyuki

ONUMA, Takashi NISHIMURA, Shunei KYO;
A Radial Type Self-Bearing Motor for Small
Maglev Regenerative Blood pump; The Japan
Society of Applied Electromagnetics andMechanics; 20(2):312-317
7. Junichi Ishida, Koichiro Kinugawa, Taro Shiga,
Teruhiko Imamura, Masaru Hatano, Hisataka
Maki, Toshiro Inaba, Atsushi Yao, Yasunobu
Hirata, Takashi Nishimura, Shunei Kyo, Minoru
Ono, Ryozo Nagai; Rapidly Progressive Cardiac
Allograft Vasculopathy in Early Onset RegressedWith Everolimus Treatment in an Adult Cardiac
Recipient; International Heart Journal; 53(6);388-390
8. Teruhiko Imamura, koichiro Kinugawa, Taro
Shiga, Naoko Kato, Miyoko Endo, Toshiro Inaba,
Hisataka Maki, Masaru Hatano, Atsushi Yao,
Yasunobu Hirata, Takashi Nishimura, Shunei Kyo,
Minoru Ono, Ryozo Nagai; Correction of Hyponatremia by Tolvaptan Before Left Ventricular
Assist Device Implantation; Int. heart J.; 53(6)391-393
9. Mitsutoshi Kimura, Takashi Nishimura, Osamu
Kinoshita, Shuichi Okada, Hitoshi Inafuku,
Shunei Kyo, Minoru Ono；Successful Treatmentof Pump Pocket Infection after Left Ventricular
Assist device Implamnaion by Negative Pressure
Wound Therapy and Omental Transposition ；Ann.Thorac Cardiovasc Surg；in print
10. Umeki A, Nishimura T, Takewa Y, Ando M,
Arakawa M, Kishimoto Y, Tsukiya T, Mizuno T,
Kyo S, Ono M, Taenaka Y, Tatsumi E；Change inmyocardial oxygen consumption employing
contimuous-flow LVAD with cardiac beatsynchronizing system,in acute ischemic heart
failure models；J Artif Organs; in print
11. Umeki A, Nishimura T, Ando M, Takewa Y,
Yamazaki K, Kyo S, Ono M, Tsukiya T, Mizuno T,
Taenaka Y, Tatsumi E；Change of coronary flowby continuous-flow left ventricular assist device
with cardiac beat synchronizing system(native
heart load control system) in acute ischemic heart
failure model; Circ.J; 77(4):995-1000
12. Imamura T, Kinugawa K, Shiga T, Endo M, Kato
N, Inaba T, Maki H, Hatano M, Yao A, Nishimura
T, Hirata Y, Kyo S, Ono M, Nagai R; Preoperative
levels of billirubin or creatinine adjusted by age

419

can predict their reversibillity after implantationof left ventricular assist device; Circ J.; 77(1):96-104
13. Kashiwa K, Nishimura T, Nakahata A, Momose
N, Umeda C, Kubo H, Tamai H, Kinugawa K,
Adachi H, Yamaguchi A, Yambe T, Katohgi T,
Kyo S, Ono M; Survey of blood pimp diaphragmdamage in NIPRO-ventricular assist device; J
Artif Organs; 15(4):341-346
14. Shiga T, Kinugawa K, Imamura T, Kato N, Endo
M, Inaba T, Maki H, Hatano M, Yao A,
Nishimura T, Hirata Y, Kyo S, Ono M, Nagai R;
Combination evaliation of preoperative risk
indices predicts requirement of biventricularassist device; Circ J.; 76(12):2785-2791
15. Imamura T, Kinugawa K, Shiga T, Endo M, Kato
N, Inaba T, Maki H, Hatano M, Yao A, Nishimura
T, Kyo S, Ono M,Nagai R; An elevated ratio of
early to late diastolic filling velocity recovers
after heart transplantation in a time-dependent
manner; J Cardiology; 60(4):295-300
16. Kurihara C, Nishimura T, Imanaka K, Kyo S;
Spontaneous increase in EVAHEART® Pump
flow at aconstant pump speed during examination; Ann Thorac Cardiovasc Surg.; 18(6):514518
17. Imamura T, Kinugawa K, Shiga T, Endo M, Kato
N, Inaba T, Maki H, Hatano M, Yao A, Nishimura
T, Hirata Y, Kyo S, Ono M, Nagai R; Novel riskscoring system with preoperative objective
parameters gives a good prediction of 1-year
moetality in patients with a left ventricular assist
device; Circ J.; 76(8):1895-1903
18. Imamura T, Kinugawa K, Shiga T, Endo M, Inaba
T, Maki H, Hatano M, Imai Y, Yao A, Hirata Y,
Nishimura T, Kyo S, Ono M, Nagai R; Early
decision for a left ventricular assist device
implantation is necessary for patients withmodifier A; J Artif Organs; 15(3):301-304

420

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 laboratory in Japan,
which studies disinfection and sterilization. To thebest 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 the high-tech
instruments with complex structures or devices that
contain electronic circuits. Moreover, it is extremely
important to come up with the 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) is useful to improve the quality
assurance in the reprocessing of surgical instruments
and medical devices. It is likely that the globally
standardized procedures help to attract many patientsfrom abroad in the medical tourism. 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 reusable surgical instruments could
cause toxic anterior segment syndrome (TASS) in thecataract surgery with intraocular lens implantation.
Accordingly, water quality has been studied twice ayear over 5 years in the washer-disinfector with areverse osmosis plant in our surgical center.
Incidentally, ISO/TC 150 on the joint prostheses has
begun to discuss the standards on the remaining
amount of endotoxin per an implant.

421

There are some legal regulations on the pressurized
vessels (such as autoclaves) and ethylene oxide
sterilization in Japan. Autoclaves should undergo theannual inspection by the Labour Standards Inspection
Office. When ethylene oxide sterilizers are used, thesafety of working environment should be assessed
twice a year. The laboratory has cooperated with these
activities.

Teaching activities
The laboratory participates in all teaching activities
performed in the surgical center. The activities include
the surgical hand antisepsis, gown technique and so on.
It appears that medical and co-medical students should
learn disinfection and sterilization more thoroughly todecrease the healthcare-associated infection rates. The
course plays 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. Mr. David Hurrell introduced thisconcept in UK, and it has been approved in EU.
Practically, the concept has been also approved 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) prior
to the moist heat disinfection of A0 3000. This finding
may be helpful to standardize the methods forevaluating cleaning 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 AAMI
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 AAMI TIR34:
2007. It was suggested that water quality should bemonitored closely in the management of
washer-disinfectors. The authors have reported thatthe systematic method using the Ishikawa fishbone
diagram, a famous diagram for the quality control in
the industry, also helps to improve the water quality
for final rinsing in the washer-disinfectors employedin the hospitals.
(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.
The authors have shown that ultrafiltration using theheat-tolerant hollow fibers was useful to remove
endotoxin from the aquatic environment in the thermal
disinfection of contaminated reverse osmosis plants.

References
1. Uetera Y, et al.: A 5 year longitudinal study ofwater quality for final rinsing in the single
chamber washer-disinfector with a reverse
osmosis plant. PDA Journal of Pharmaceutical
Science and Technology 67(4): 399-411, 2013.
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

422

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
research endeavors are not limited diabetes and423

lifestyle-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) Nio Y, Yamauchi T, Iwabu M, Okada-Iwabu M,
Funata M, Yamaguchi M, Ueki K, Kadowaki T.
Monocyte chemoattractant protein-1 (MCP-1)
deficiency enhances alternatively activated M2
macrophages and ameliorates insulin resistanceand fatty liver in lipoatrophic diabetic A-ZIP
transgenic mice. Diabetologia. 255, 3350-3358(2012)(2) Yamauchi N, Takazawa Y, Maeda D, Hibiya T,
Tanaka M, Iwabu M, Okada-Iwabu M, Yamauchi
T, Kadowaki T, Fukayama M.: Expression levelsof adiponectin receptors are decreased in humanendometrial adenocarcinoma tissues. Int. J.
Gynecol. Pathol. 31, 352-357 (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 Metaanalysis (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, 3042-3049 (2012)Social Cooperation Program425

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
Lipid biomarker discovery by liquid chromatographymass spectrometry-based method requires high-level
integration of chromatography and mass spectrometry,
which ensures lipid separation, semi-quantitative
detection, and identification. We are collaboratingwith industries to solve known difficulties in lipid
chromatography, develop differential analysis andfeature-extraction methods, and establish an
intelligent analytical system linked with lipid
database.

426

Methods for clinical samples
Clinical samples such as blood, urine, feces, andtissue 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. 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, Sasaki N. Trehalose treatment
suppresses inflammation, oxidative stress, andvasospasm induced by experimental subarachnoid
hemorrhage. J. Transl. Med., 10, 80 (2012)
3. 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)
4. 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)
5. 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)

427

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.

428

Research activities

References(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.

1. Waki H, Yamauchi T, Kadowaki T. The Epigenome
and Its Role in Diabetes. Curr Diab Rep. 2012
Dec;12(6):673-85..
2. Cipolletta D, Feuerer M, Li A, Kamei N, Lee J,
Shoelson SE, Benoist C, Mathis D. PPAR-γ is amajor driver of the accumulation and phenotype of
adipose tissue Treg cells. Nature. 486: 549-553,
2012(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.

429

Department ofAdvanced Nursing Technology
Project Associate Professor
Ryoko Murayama, Ph.D., R.N.M.

Project Lecturer
Makoto Oe, Ph.D., R.N.

Collaborative Researcher
Hidenori Tanabe, MS.

Homepage

http://ant.m.u-tokyo.ac.jp/index.html

Introduction and Organization
The Department of Advanced Nursing Technology
was established in December 2012, seeking to develop
new academic fields for creating advanced nursing
technology based on clinical evidence. Our primary
belief is that “Never let patients endure in healthcare.” and we hope that through our activities, we canassist patients to live longer, healthier lives.
Till date, significant difficulties regarding thecreation of an advanced nursing technology havecreated a gap between academic research and clinicalneeds of the clinical setting. Thus, the strategies ofadvanced nursing technology could not be applied tohospitals because of their unsuitability to this clinicalsetting, despite being useful to academic nursing
researchers at universities. In contrast, new nursing
technologies are often developed because of nurses’
experiences in clinical settings with limitations suchas the unavailability of scientific processes.
Furthermore, systems to promote and support nurses
who wish to undertake research in the clinical setting
are insufficient.
The Department of Advanced Nursing Technology
was established at the University of Tokyo Hospital,
supported by Terumo Co., Tokyo, Japan, as a social
cooperation program. The United Cooperation
Program, established to develop solutions for theabovementioned difficulties and to further thedevelopment of nursing technology, comprise thefollowing departments at the University of Tokyo:
Department of Gerontological Nursing/Wound CareManagement, Department of Nursing, and Department
of Diabetes and Metabolic Diseases. We aim todevelop a new research model through collaborative
research with Tokyo Hospital’s Departments ofNursing and Medical examination and School of
Health Science at the university. In addition, we aim
to disseminate advances in nursing technology basedon the needs of clinical practices worldwide.
The following are the members from various
departments at the University of Tokyo: Ryoko
Murayama (Project Associate Professor; from Department of Nursing) and Makoto Oe (Project Lecturer;
from Department of Gerontological Nursing/Wound
Care Management) as well as Hidenori Tanabe(Collaborative Researcher; from Terumo Co.).

Teaching activities
We advised Master’s and PhD course students fromthe Department of Gerontological Nursing/Wound
Care management on matters concerning researchplanning and practical work. We were not involved inproviding lectures for any major student body(undergraduates, master course students, or PhD

430

course students) between December 2012 and March
2013.

•

Research activities•

1. Activity policy
We will develop a new nursing research scheme aimed
at identifying clinical needs (i.e., “Never let patientsendure in health care.”). An online survey of all nurses
at the University of Tokyo hospital was therefore
initiated to identify clinical needs in the clinicalsetting. This survey was conducted as a collaborative
research with the Department of nursing (Universityof Tokyo hospital), and is ongoing. The survey will beanalyzed in April 2013.
Several research projects are ongoing in our
department. These include development of a nursing
device for early ambulation and development of aself-monitoring blood glucose device for the elderly.
In addition, we are conducting a cross-sectional studyof extravasation at our laboratory. These researches
are conducted in collaboration with nurses at the
University of Tokyo hospital.
We provided nurses with information as the career
ladder system in the Department of nursing at the
University of Tokyo Hospital. A cross-sectional studyof pelvic floor disorders, the risk factors fordevelopment of diabetic foot disorders, andvenipuncture are all components of this system.
We offer consultations on research matters andprovide guidance on article writing in order topromote nursing research in the clinical setting. A
study meeting was planned with the graduate schoolof the University of Tokyo to educate nurses regarding
research. In addition, cross-sectional studies of pelvic
floor disorders and diabetic foot were conducted as
per the researcher’s area of expertise.
2. Research fields and themes in 2012
• Investigation of clinical needs in the clinicalsetting.
• Early ambulation: the management of infusion
systems, drains, and catheters for early
ambulation and early discharge from the hospital.
• Determining the mechanism of extravasation anddevelopment of an indwelling needle forprevention of extravasation.
• Development of a blood glucose self-monitoring

device for the elderly.
Risk assessment for pelvic floor disorders during
the postpartum period.
The diabetic foot and associated risk factors.

References
1. Tamai N, Kaitani T, Takehara K, Oe M, Nagase T,
Murayama R. Evaluation of skin temperature,humidity, and comfort of two types of absorbent
products for urinary incontinence. J Jpn WOCM.
2012;16(4):345-52.
2. Oe M, Sanada H, Nagase T, Minematsu T, Ohashi
Y, Kadono T, Ueki K, Kadowaki T. Sweat gland
atrophy of the heel in diabetic patients with
angiopathy. J Clin Nurs. 2013;22(1-2):289-92.
3. Murayama R, Tsuda M, Haruna M, Matsuzaki M,
Sanada H, Aoki K. Relationship between
perceived sleep posture and subjective sleep
quality: Changes related to progression ofpregnancy. J So Nurs Pract. 2013; 25(1):49-57.
4. Haruna M, Watanabe E, Matsuzaki M, Ota E,
Shiraishi M, Murayama R, Yoshida M, Yeo S.
The effects of an exercise program on
health-related quality of life in postpartum
mothers: A randomized controlled trial. Health.
2013; 5(3): 432-439.
5. Takeuchi T, Togari T, Oe M, Takemura Y, Sanada
H. Variations in the mental health and sense ofcoherence (SOC) of new graduate nurses and theeffects of SOC on variatons in mental health.
Open Journal of Nursing. 2013;3(1).doi:10.4236/
ojn.2013.31016
6. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Validity of a diet history
questionnaire estimating β-carotene, vitamin C,
and α-tocopherol intakes in Japanese pregnant
women. Int J Food Sci Nutr. 2013 (in press)
7. Takegata T, Haruna T, Matsuzaki M, Shiraishi M,
Murayama R, Okano T, Severinsson E.
Translation and validation of the Japanese versionof the Wijma Delivery Expectancy/Experience
Questionnaire version A. Nurs Health Sci. 2013(in press).
8. Sari Y, Minematsu T, Huang L, Noguchi H, Mori
T, Nakagami G, Nagase T, Oe M, Sugama J,
Yoshimura K, Sanada H. Establishment of a novel431

rat model for deep tissue infury deterioration. Int
Wound J.2013 May 7.doi:10.1111/iwj.12082. (inpress)
9. Oe M, Yotsu R, Sanada H, Nagase T, Tamaki T.
Screening for osteomyelitis using thermography
in patients with diabetic foot. Ulcers. 2013.
doi:org/10.1155/2013/284294 (in press)
10. Tamai N, Horii M, Takehara K, Kato S,
Yamamoto Y, Naito A, Tayama M, Tamahashi Y,
Nakamura S, Kadono T, Oe M, Nagase T, Sanada
H. Morphological characteristics of and factors
relatedtomoisture-associateddermatitis
surrounding malignant wounds in breast cancer
patients. Eur J Oncol Nurs. 2013. doi:10.1016/j.
ejon. (in press)
11. Horii M, Sugama J, Oe M, Minematsu T, agase T,
Yabunaka K, Akase T, Nakagami G, Ibuki A,
Sanada H. Ultrasonography reveals structuralchanges in the dermis and subcutaneous tissues ofobese males; investigation of the association withoxide active stress. J Jpn WOCM. 2013;17(1):22-32.

Social Cooperation Program(22nd Century Medical and Research Center)433

Department of Ubiquitous Health
Informatics
Associate Professor
Hideo Fujita, M.D.,Ph.D.

Assistant Professor
Yuji Uchimura, DDS
Waki Kayo, M.D. Ph.D.

Homepage

http://uhi.umin.jp

Introduction and Organization
Our mission is to promote research and developmentof a novel integration system where pieces 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.

Research activities
To date we have been working on specific topics
shown below since this lab was established in 2009.
Our products have reached a stage of clinical validation, respectively. Furthermore, we are promoting
collaborative research with several laboratories both
inside and outside the campus, seeking for frontier
fields of interdisciplinary research and practical
medicine/healthcare fields. Through development of
those specific products, we further aim to establish asystematic methodology for creating solutions forvirtual 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 acute cardiovascular disease is not yet sufficient depending upon
the local medical environment. In order to fill up those“gaps” between inside and outside the medical
facilities, we working on creating a novel ECG system
as a clinically valid approach to this problem. We havedeveloped a cloud computing system with wirelesslytransmission ECG units, potentially clinical usefulness
due to the cloud-based server built. Ongoing studies
include practical usage of mobile cloud ECG in theclinical settings of emergency care. We are collaborating with Kitasato University, Oita University, andHokuto 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 novel smartphonebased self-management support system for type 2
diabetic patients. This new system has an automaticfunction of stratifying daily patient's biometric
information such as blood glucose, blood pressure,434

and food intake retrieved by the home sensor androuter 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. We conducted clinical studies
including 56 diabetics patients in accordance with thereviewed protocol of the ethics committee. Safety andefficacy aspects of Dialbetics is to be shown 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.

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. 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.
2. Waki K, Sugawara Y, Kokudo N, Kadowaki T.
Long-Term Pancreas Allograft Survival in
Simultaneous Pancreas-Kidney Transplantation
by Era. Clin Transpl. 2012: 1-9.
3. Hasumi E, Iwata H, Kohro T, Manabe I,
Kinugawa K, Morisaki N, Ando J, Sawaki D,
Takahashi M, Fujita H, Yamashita H, Ako J,
Hirata Y, Komuro I, Nagai R Diagnostic
implication of change in b-type natriuretic peptide(BNP) for prediction of subsequent target lesion
revascularization following silorimus-eluting stent
deployment. Int J Cardiol. 2013 Jan 7.
4. Waki K, Sugawara Y, Mizuta K, Taniguchi M,
Ozawa M, Hirata M, Nozawa M, Kaneko J,
Takahashi K, Kadowaki T, Terasaki PI, andKokudo N. Predicting Operational Tolerance inPediatric Living-Donor Liver Transplantation by
Absence of HLA Antibodies. Transplantation.
2013 Jan 15;95(1):177-83.
5. Waki K, Fujita H, Uchimura Y, Aramaki E, Omae

435

6.

7.

8.

9.

K, Kadowaki T, Ohe K. DialBetics: smartphonebased self-management for type 2 diabetes
patients. J Diabetes Sci Technol. 2012 Jul 1;6(4):983-5.
Oba S, Noda M, Waki K, Nanri A, Kato M,
Takahashi Y, Poudel-Tandukar K, Matsushita Y,
Inoue M, Mizoue T, Tsugane S; Japan Public
Health Center-Based Prospective Study Group.
Smoking cessation increases short-term risk oftype 2 diabetes irrespective of weight gain: theJapan Public Health Center-Based Prospective
Study. PLoS One. 2012;7(2):e17061. Epub 2012
Feb 13.
Hayakawa M, Uchimura Y, Omae K, Waki K,
Fujita H, Ohe K. A Smartphone-based Medication
Self-management
Systemwith
Realtime
Medication Monitoring. Appl Clin Inform. 2013
Jan 30;4(1):37-52.
Takeuchi I, Fujita H, Ohe K, Imaki R, Sato N,
Soma K, Niwano S, Izumi T. Initial experience ofmobile cloud ECG system contributing to theshortening of door to balloon time in an acute
myocardial infarction patient. Int Heart J. 2013;
54(1):45-7
Takeuchi I, Fujita H, Ohe K, Imaki R, Sato N,
Soma K, Niwano S, Izumi T. Initial experience ofmobile cloud ECG system contributing to theshortening of door to balloon time in an acute
myocardial infarction patient. Int Heart J.2013;
54(1):45-7

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

438

Department of Clinical Laboratory
Professor
Yutaka Yatomi, M.D.

Associate Professor
Hitoshi Ikeda, M.D.

Lecturer
Masao Daimon, 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, and 80 technicians, and is divided
into the following sections. The second - generation
Laboratory Automation System is in full operation,and ordering of laboratory tests, the flow of samples,
operation of laboratory analyzers, quality control ofanalysis, and data reporting are all controlled by the
Laboratory Automation computer system.
Thissystem has greatly improved the quality, safety, andefficiency of the laboratory and contributed to bothpatients and doctors by providing rapid andhigh-quality laboratory testing.
The 1st Section
This section deals mainly with the maintenance oflaboratory system and blood and urine sampling. In
2012, 241,630 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2012, over 4,890,229

serum enzyme tests (such as AST and ALT), and536,256 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2012, 1,217,913 samples were examined forcomplete blood cell counts, cell surface marker
analysis, prothrombin time, fibrinogen, glucose, andHbA1C tests, and 234,869 urine samples were
examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2012, 46,590 ECG, 23,807
pulmonary function tests, 10,751 echocardiography
tests, 14,932 abdominal echography tests, and 9,486
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439

section is going to be further expanded since there isso much demand from clinical doctors.
2.

Teaching activities
Lectures are given to the fourth and fifth grade
medical students on clinical tests including
hematology, chemistry, endocrinology, immunology,
bacteriology, cardiology, and pulmonary function.
The reversed CPC program is presented to the fifthand sixth grade students. Laboratory practice teachingis provided for the fifth year medical students, insmall groups of 6-7 students for one-week duration.
In this course, students learn clinical and practicalknowledge and techniques on various laboratory tests.
Students from professional schools also study
laboratory medicine under the guidance of members inClinical Laboratory Center.

3.

4.

Research activities
The main goal of our research projects is thedevelopment of new and useful laboratory tests, andelucidation of pathophysiology of diseases throughlaboratory tests. The areas included are: i)(Patho)physiological roles of lysophospholipid
mediators and its application into laboratory medicine,ii) platelet biology, iii) the clinical significance ofreticulated platelets and immature platelet fraction, iv)
hepatic fibrosis and ischemic reperfusion injury of theliver, v) genetic testing, vi) bioactive peptides,
especially adrenomedullin, vii) oxidative stress andorgan injury, viii) analysis of cardiac functions using
ultrasound, ix) elucidation of abnormality inepigenetics in cancer and its clinical application, andx) analysis of brain function using magnetoencephalography and near-infrared spectroscopy.

5.

6.

7.

References
Original article:
1. Araki, J., Jona, M., Eto, H., Aoi, N., Kato, H., Suga,
H., Doi, K., Yatomi, Y., Yoshimura, K. Optimized
Preparation Method of Platelet-Concentrated Plasma
and Noncoagulating Platelet-Derived Factor
Concentrates:
MaximizationofPlatelet8.

Concentration and Removal of Fibrinogen. Tissue
Eng Part C Methods. 18: 176-185, 2012.
Banno, F., Nojiri, T., Matsumoto, S., Kamide, K.,
Miyata, T. RGS2 deficiency in mice does notaffect platelet thrombus formation at sites ofvascular injury. J. Thromb. Haemost. 10: 309-311,
2012.
Dohi, T., Miyauchi, K., Ohkawa, R., Nakamura,K., Kishimoto, T., Miyazaki, T., Nishino, A.,
Nakajima, N., Yaginuma, K., Tamura, H., Kojima,T., Yokoyama, K., Kurata, T., Shimada, K.,
Yatomi, Y., Daida, H. Increased circulatingplasma lysophosphatidic acid in patients withacute coronary syndrome. Clin. Chim. Acta 413:
207-212, 2012.
Dohi, T., Miyauchi, K., Ohkawa, R., Nakamura,K., Thuboi, S., Ogita, M., Miyazaki, T., Nishino,A., Yokoyama, K., Kurata, T., Yatomi, Y., Daida,
H. Higher lipoprotein-associated phospholipase
A2 levels are associated with coronary
atherosclerosis
documented
bycoronary
angiography. Ann Clin Biochem. 49: 527-533,
2012.
Goto, E., Masuzaki, R., Tateishi, R., Kondo, Y.,
Imamura, J., Goto, T., Ikeda, H., Akahane, M.,
Shiina, S., Omata, M., Yoshida, H., and Koike, K.
Value of post-vascular phase (Kupffer imaging)by contrast-enhanced ultrasonography using
Sonazoid in the detection of hepatocellular
carcinoma. J. Gastroenterol. 47: 477-485, 2012.
Hashimoto, T., Okudaira, S., Igarashi, K., Hama,
K., Yatomi, Y., Aoki, J. Identification andbiochemical characterization of a novel autotaxin
isoform, ATXδ, with a four-amino acid deletion. J.
Biochem. 151: 89-97, 2012.
Hikita, H., Enooku, K., Satoh, Y., Yoshida, H.,
Nakagawa, H., Masuzaki, R., Tateishi, R., Soroida,Y., Sato, M., Suzuki, A., Gotoh, H., Iwai, T.,
Yokota, H., Koike, K., Yatomi, Y., Ikeda, H.
Perihepatic lymph node enlargement is a negative
predictor for sustained responses to pegylated
interferon-a and ribavirin therapy for Japanesepatients infected with hepatitis C virus genotype 1.
Hepatol Res. 2012:265860.
Ikeda, H., Tejima, K., Masuzaki, R., Yatomi, Y.,
and Koike, K. Reply to the letter by H. Mawatari
et al. regarding "Thrombocytopenia is more440

severe in patients with advanced chronic hepatitis
C than B with the same grade of liver stiffness
and splenomegaly". J. Gastroenterol. 47: 608,
2012.
9. Kageyama, Y., Ikeda, H., Watanabe, N.,
Nagamine, M., Kusumoto, Y., Yashiro, M., Satoh,Y., Shimosawa, T., Shinozaki, K., Tomiya, T.,
Inoue, Y., Nishikawa, T., Ohtomo, N., Tanoue, Y.,
Yokota, H., Koyama, T., Ishimaru, K., Okamoto,Y., Takuwa, Y., Koike, K., and Yatomi, Y.
Antagonism of sphingosine 1-phosphate receptor
2 causes a selective reduction of portal veinpressure in bile duct-ligated rodents. Hepatology
56: 1427-1438, 2012.
10. Kimura, K., Takenaka, K., Ebihara, A., Okano, T.,
Uno, K., Fukuda, N., Ando, J., Fujita, H., Morita,
H., Yatomi, Y., Nagai, R. Speckle Tracking Global
Strain Rate E/E' Predicts LV Filling Pressure
More Accurately Than Traditional Tissue Doppler
E/E'. Echocardiography. 29: 404-410, 2012.
11. Kurano, M., Hara, M., Tsuneyama, K., Okamoto,K., Iso-O, N., Matsushima, T., Koike, K.,
Tsukamoto, K. Modulation of lipid metabolism
with the over-expression of NPC1L1 in mice liver.
J. Lipid Res. 53: 2275-2285, 2012.
12. Masuzaki, R., Tateishi, R., Yoshida, H., Arano, T.,
Uchino, K., Enooku, K., Goto, E., Nakagawa, H.,
Asaoka, Y., Kondo, Y., Goto, T., Ikeda, H., Shiina,
S., Omata, M., and Koike, K. Assessment ofdisease progression in patients with transfusionassociated chronic hepatitis C using transient
elastography. World J. Gastroenterol. 18:1385-90,
2012.
13. Mori, F.K., Shimosawa, T., Wang, H., Ogura, S.,
Mu, S., Yatomi, Y., Fujita, T. NADPH
oxidase-mediated Rac1 GTP activity is necessary
for non-genomic actions of the mineralocorticoid
receptor in the CA1 region of the rat hippocampus.
Am. J. Physiol. Endocrinol. Metab. 302: E425E432, 2012.
14. Nakamura, K., Igarashi, K., Ohkawa, R., Yokota,
H., Masuda, A., Nakagawa, S., Yano, T., Ikeda, H.,
Aoki, J., Yatomi, Y. Serum Autotaxin is not a
Useful Biomarker for Ovarian Cancer. Lipids. 47:
927-930, 2012.
15. Norimatsu, Y., Ohmori, T., Kimura, A., Madoiwa,
S., Mimuro, J., Seichi, A., Yatomi, Y., Hoshino, Y.,

and Sakata, Y. FTY720 improves functional
recovery after spinal cord injury by primarily
nonimmunomodulatory mechanisms. Am. J.
Pathol. 180: 1625-1635, 2012. Referred to by"This Month in AJP"
16. Ohkawa, R., Kishimoto, T., Kurano, M., Dohi, T.,
Miyauchi, K., Daida, H., Nagasaki, M., Uno, K.,
Hayashi, N., Sakai, N., Matsuyama, N., Nojiri, T.,
Nakamura, K., Okubo, S., Yokota, H., Ikeda, H.,
Yatomi, Y. Development of an enzymatic assay
for sphingomyelin with rapid and automatableperformances: Analysis in healthy subjects andcoronary heart disease patients. Clin. Biochem.
45: 1463-1470, 2012.
17. 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.
47: 770-774, 2012.
18. Osada, M., Kaneko, M., Sakamoto, M., Endoh, M.,
Takigawa, K., Suzuki-Inoue, K., Inoue, O., Satoh,K., Enomoto, N., Yatomi, Y., Ozaki, Y. Causes ofThrombocytopenia in Chronic Hepatitis C Viral
Infection. Clin. Appl. Thromb. Hemost. 18:272280, 2012.
19. Osada, M., Inoue, O., Ding, G., Shirai, T., Ichise,H., Hirayama, K., Takano, K., Yatomi, Y.,
Hirashima, M., Fujii, H., Suzuki-Inoue, K., Ozaki,
Y. Platelet activation receptor CLEC-2 regulates
blood/lymphatic vessel separation by inhibiting
proliferation, migration, and tube formation oflymphatic endothelial cells. J. Biol. Chem. 287:
22241-22252, 2012.
20. Saito, R., Shimosawa, T., Ogihara, T., Fujita, T.,
Maruyama, N., Okamura, N., Nakahara, K.
Function of adrenomedullin in inflammatory
responseofliver
againstLPS-induced
endotoxemia. APMIS. 120: 706-711, 2012.
21. 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 Expression of
CK20, FABP1 and MUC2 is Sensitive for the441

Prediction of Peritoneal Recurrence in Gastric
Cancer. Jpn. J. Clin. Oncol. 42: 148-152, 2012.
22. Soroida, Y., Ohkawa, R., Nakagawa, H., Satoh, Y.,
Yoshida, H., Kinoshita, H., Tateishi, R., Masuzaki,
R., Enooku, K., Shiina, S., Sato, T., Obi, S.,
Hoshino, T., Nagatomo, R., Okubo, S., Yokota, H.,
Koike, K., Yatomi, Y., and Ikeda, H. Increased
activity of serum mitochondrial isoenzyme ofcreatine kinase in hepatocellular carcinoma
patients predominantly with recurrence. J.
Hepatol. 57: 330-336, 2012.
23. Sugiura, T., Dohi, Y., Yamashita, S., Ohte, N., Ito,
S., Iwaki, S., Hirowatar,i .Y, Ohkawa, R.,
Mishima, Y., Yatomi, Y., Kimura, G., Fujii, S.
Analytical evaluation of plasma serotonin andsphingosine 1-phosphate and their clinicalassessment in early atherosclerosis. Coron Artery
Dis. 23: 234-238, 2012.
24. Uno, K., Tanaka-Ishikawa, M., Ebihara, A., Sonoda,
M., Kimura, K., Yatomi, Y., and Takenaka, K.
Multiple coronary artery fistulae with biventricular
hypertrophy. J. Echocardiography. 10: 132-134,
2012.
25. Yashima, Y., Sasahira, N., Isayama, H., Kogure,
H., Ikeda, H., Hirano, K., Mizuno, S., Yagioka, H.,
Kawakubo, K., Sasaki, T., Nakai, Y., Tada, M.,
Yoshida, H., Omata, M., and Koike, K. Acoustic
radiation force impulse elastography fornoninvasive assessment of chronic pancreatitis. J.
Gastroenterol. 47: 427-432, 2012.
26. Watanabe, K., Emoto, N., Hamano, E., Sunohara,
M., Kawakami, M., Kage, H., Kitano, K.,
Nakajima, J., Goto, A., Fukayama, M., Nagase, T.,
Yatomi, Y., Ohishi, N., Takai, D. Genome
structure-based screening identified epigeneticallysilenced microRNA associated with invasivenessin non-small-cell lung cancer. Int. J. Cancer. 130:2580-2590, 2012.
Review article
1. Ikeda H., and Yatomi Y. Autotaxin in liver fibrosis.
Clin. Chim. Acta 413: 1817-21, 2012.
2. Kashiwagi, A., Kasuga, M., Araki, E., Oka, Y.,
Hanafusa, T., Ito, H., Tominaga, M., Oikawa, S.,
Noda, M., Kawamura, T., Sanke, T., Namba, M.,
Hashiramoto, M.,Sasahara, T., Nishio, Y., Kuwa,
K., Ueki, K., Takei, I., Umemoto, M., Murakami,M., Yamakado, M., Yatomi, Y., and Ohashi, H.
International clinical harmonization of glycatedhemoglobin in Japan: From Japan Diabetes Society
to National Glycohemoglobin Standardization
Program values. Diabetol. Int. 3: 8-10, 2012.
3. Kashiwagi, A., Kasuga, M., Araki, E., Oka, Y.,
Hanafusa, T., Ito, H., Tominaga, M., Oikawa, S.,
Noda, M., Kawamura, T., Sanke, T., Namba, M.,
Hashiramoto, M., Sasahara, T., Nishio, Y., Kuwa,
K., Ueki, K., Takei, I., Umemoto, M., Murakami,M., Yamakado, M., Yatomi, Y., and Ohashi, H.
International clinical harmonization of glycatedhemoglobin in Japan: From Japan Diabetes Society
to National Glycohemoglobin Standardization
Program values. J. Diabetes Invest. 3: 39-40,
2012.

442

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

http://www.h.u-tokyo.ac.jp/patient/depts/syujutsu/index.html

Introduction and Organization
Operating rooms were centralized for the first timein Japan on July 1955. Surgical center was located in
the Old Central Building till December 1987. The
center moved to the new Central Clinical Service
Building 1 on January 1988, when the surgical centerhad 14 operating rooms, including one bio-clean room.
The administration staffs consisted of 4 doctors, 75
nurses, 6 technical officials, 5 part-time employees.
The surgical center became to afford services to 18
clinical departments after the new surgical centerstarted.
The total number of operations remained to be low
between 1999 and 2000, partly because of the limited
number of operating rooms and the nursing staff.
In July 2001, the branch hospital, which was
located in Mejiro, merged to the University of Tokyo
Hospital in Hongo and a new Ward B Building openedin October 2001. After that, the number of elective
operations remarkably increased and became over
7500. As the volume of operations exceeded an
acceptable range of the surgical center, two new
operating rooms were tentatively set up to overcome

the abrupt increase in the number of elective
operations. The one was on the ICU/CCU/HCU floor
in the new Ward A Building and the other was in the
Outpatient Clinic Building, which had been used forthe orthopedic outpatients. This operating room
became to be used for the short-stay and day surgeryof orthopedics.
Until September 2001, the elective operations had
been performed daily in 9 operating rooms. After
October 2001, 12 rooms began to be used for elective
operations. In the year 2007, the newest Central
Clinical Service Building 2, which had 11 operatingrooms, was open to solve the relative shortage of
operating rooms. As a result, the total number ofoperating rooms became 23, and then the number ofoperations has been dramatically increased.
A total of 8,485, 9,550, 9921, 9,944, 10,394 and
10,170 operations were performed in 2006, 2007,2008, 2009 2010 and 2011 fiscal year, respectively.
The number of operations in 2011 counts forapproximately 1.5 times comparing to that in 2001.
More recently, the number of operations was 10,752 in2012 fiscal year.
These days more and more patients undergo the443

operation assisted by endoscopic technique, such as
laparoscopic/thoracoscopic operation. There is also anapparent increase in the number of patients who are athigh risk and with positive test for the particular typesof pathogenic bacteria, such as tuberculosis, MRSA,
pseudomonas aeruginosa, HBV, HCV and HIV.

Scope of Activities of Surgical Center
The surgical center covers broad range of activities
from the arrangement of operation schedule to theeducation of the medical students and research on
healthcare practices.

Arrangement of Operation Schedule
All operations of in-patients are performed in 23
operating rooms of the surgical center. Computer
system has been utilized 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. After thatthe operations have become ordered through thecomputer terminal of the clinical departments since
May l999. The doctors and nurses became to be able
to see postoperative information using the computer
system since March 2000.
For the arrangement of the operation schedule, theinformation on the status of the procedures has been
displayed on the computer monitor screen since May
1997. This monitor also tells the hospital staff whether
there are any operating rooms available on the nextday. Furthermore, since November 2000, the hospital
staff has become to be able to see how the clinicaldepartments plan the operations through the hospitalcomputer network.
As for digitalized visual information of operation,
the photographs of surgical sites, resected organs andreal-time visual images have been distributed to eachclinical department through the hospital computer
network since February 1997.
In the Ward A Building and Central Clinical Service
Building 2, the SPD system and progressive patientcare system started to improve the workflow of thehospital in October 2001. 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 are lately undergoing
surgery using artificial implants such as vascular
prosthesis, joint prosthesis and intraocular lenses.
The advanced techniques have been frequently
employed in the present operation. Those include
navigation surgery in neurosurgical, orthopedic and
ENT (ear, nose and throat) departments, and arterial
stent for the thoracic aortic aneurysms. The minimallyinvasive surgery such as MIDCAB operations is also
performed in the CABG as well as a in the treatmentof heart anomalies such as ASD and VSD. Organtransplantation and intraoperative three-dimensional
echo-guided surgery are also frequently performed.
More recently, the robotic surgery has started at thesurgical center.
Another recent issue is the operation of the patientswith emergence and re-emergence infectious diseases
such as HIV and tuberculosis. Therefore, it ismandatory to educate how to prevent healthcare
associated infections (HAI) and occupational
infections in the surgical center. The principles ofstandard
precautions
andtransmission-based
precautions should be informed to all health care staff
in the surgical center.
The refinement of management skill is prerequisite
to improve the quality in perioperative healthcare
services. Therefore, the surgical center will continue
to be playing an important role in arrangement of theenvironmental circumstances around operation as thenumber of complicated and advanced operations
increases.

Teaching Activities
The following lectures are given to theundergraduates and postgraduates: aseptic techniques,
sterilization/disinfection methods, prevention of
perioperative infections, humoral and cellularresponses to trauma and shock, training of scrubbing
and gown techniques. The curriculum is updated eachyear. For example, introductory course for disinfection,sterilization and preservation of surgical instruments
and medical devices was added in the training courses
in 1998, which gained interest and popularity among

444

many 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 concerning those subjects
has become one of the most important activities in thesurgical center. The lectures of advanced technologies
are in the curriculum for the surgeons, the nursing
staff and clinical engineers so that they can understandhow to use them properly.
Lectures for the nursing staff consist of a freshmancourse and an advanced course. The freshman course
is a basic training course for a scrub nurse or acirculating nurse. It consists of lectures of aseptic
techniques, de-contamination/sterilization methods,
prevention of perioperative infections, and on-sitetraining of scrubbing and gown techniques as wall as
aseptic preparation of surgical instruments in theoperating room. An advanced course is prepared to theexperienced nurses as well. The purpose of this course
is to upgrade their perioperative nursing skills so thatthey can afford full nursing skills even in thecomplicated operations such as transplantation surgery,open-heart surgery, neurosurgery and robotic surgery.
There is also a training course to clinical engineers
and students of biomedical engineers. This training
course consists of introduction on the medical devices
and electronic instruments, precautions of accidental
troubles in handling surgical instruments/medical
devices, development of new surgical instruments/
medical devices, cardiopulmonary bypass techniques
and illumination techniques in the operating fields.
The contents of this course are summarized in the
manual for the nursing staff and contribute to decrease
the frequency of incident associated with surgicalinstruments and medical devices.
The on-job training are given to the non-nursing
staff including technical officials and temporary
employees and performed when they start their careers
in the surgical center. They are lectured on the aseptic
techniques, the sterilization/disinfection methods, theprevention of perioperative infections, and themaintenance of reusable surgical instruments such as
forceps, scissors and clamps. These contents are also
summarized in the manual. Lectures are given tosenior technical officers and temporary employees to
upgrade their technical knowledge 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（2010-202）
1. 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.
2. Uetera Y, Saito Y, Yasuhara H, Kumada N,
Misawa Y. Sterilizing electronic instruments forneuro-navigation using the “Prion Cycle” at 134 C
for 18 min in a prevacuum autoclave. Zentralsterilisation 18:169-179, 2010.
3. Fukatsu K, Tanabe K, Maeshima Y, Omata J,
Yasuhara H, Saitoh D. Neutrophil elastase
inhibitor restores gut ischemia reperfusion-445

induced impairment of gut immunity with reduced
plasma interleukin-6 concentrations in mice. Surg
Infect 11:517-22, 2010.
4. 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.
5. 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.
6. 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
7. Fukatsu K, Kudsk KA. Nutrition and gut immunity.
Surg Clin North Am. 91(4):755-70, 2011.
8. 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.
9. 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.
10. Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg Res
172:83-4, 2012.
11. 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
12. Okamoto K, Fukatsu K, Hashiguchi Y, Ueno H,
Shinto E, Moriya T, Saitoh D, Yamamoto J, Hase
K. Lack of Preoperative Enteral Nutrition
Reduces Gut-Associated Lymphoid Cell Numbersin Colon Cancer Patients: A Possible Mechanism
Underlying Increased Postoperative Infectious

Complications During Parenteral Nutrition. Ann
Surg. 2012 Nov 26. [Epub ahead of print]
13. Fukatsu K. The long road to optimizing theparenteral provision of nutrients. JPEN J Parenter
Enteral Nutr. 2012 Mar;36(2):157-8.
14. Moriya T, Fukatsu K, Maeshima Y, Ikezawa F,
Hashiguchi Y, Saitoh D, Miyazaki M, Hase K,
Yamamoto J. The effect of adding fish oil toparenteral nutrition on hepatic mononuclear cellfunction and survival after intraportal bacterial
challenge in mice. Surgery. 2012 May;151(5):745-55.
15. Yasuhara H, Fukatsu K, Komatsu T, Obayashi T,
Saito Y, Uetera Y.Prevention of medical accidents
caused by defective surgical instruments. Surgery.
2012 Feb;151(2):153-61.
16. Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg
Res. 2012 Jan;172(1):83-4.
17. Fukatsu K, Moriya T, Murakoshi S, Yasuhara H.
Interleukin-7 treatment reverses parenteralnutrition-induced impairment of resistance tobacterial pneumonia with increased secretory
immunoglobulin A levels. J Surg Res. 2012 May
15;174(2):334-8.

446

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, 70 radiological
technicians, 2 assistants, and 1 technical official of theradiation 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 of otherdepartments and the nurses cooperate and are also
engaged in the clinical radiology activities.
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
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 sixty MR examinations
are done using four of 1.5-Tesla and two of 3-Teslascanners every day. Diagnostic and interventional
procedures are performed using six angiographic
units.
2) Nuclear medicine:
The section of nuclear medicine is responsible for447

all the radionuclide imaging examinations including
conventional scintigraphy such as bone, kidney,
thyroid scans, SPECT, and PET scans. Scanning is
performed at the first basement floor in the Central
Clinic Building 1. Blood flow, metabolism andreceptor functions are measured for the understandingof normal and pathophysiological states, using avariety of positron-emitter radiotracer with F-18, C-11,
N-13 and O-15. Whole body FDG-PET for staging of
malignancy plays an important role in the clinicalmanagement of the patients. These nuclear imaging
procedures are performed and reported by radiologists
and cardiologists.
3) Radiation Oncology:
The radiation therapy is performed with three linear
accelerators, an intracavitary irradiation device(RALS), a brachytherapy, and a gamma knife forradiosurgery. The network system connecting theseradiotherapy equipments, CT/MR devices, andtreatment planning systems was already constructed.
Each year, over 700 new patients receive radiation
therapy in the Radiation Oncology section. Highly
accurate 3D radiation therapy is the most outstanding
feature. We have developed a new linear accelerator
with C-arm and multileaf collimator systems, which isutilized mainly for non-coplanar radiation therapy inmany patients especially with brain tumor or head andneck tumor. The linear accelerator system with conebeam CT technology has been introduced to our
hospital, which enabled image-guided radiation
therapy.
4) Radiation safety control:
The educational training and registration of theradiation engaging persons are controlled according to
the University of Tokyo Hospital Ionizing Radiation
Injury Prevention Rules.
In conclusion, the department of clinical radiology
is a service section to all clinical departments. Main
supporter as the doctor is a radiologist. However, thecooperation with the radiation diagnosis and treatment
engaging persons of other clinical departments,
technicians and nurses must be reinforced. We want tomake still more effort to achieve the cooperation andimprove clinical activities in the department ofclinical radiology.

References
See the corresponding part of the department ofRadiology.

448

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Associate Professor
Kousei Ito, Ph.D.

Lecturer
Tappei Takada, Ph.D.

Research Associate
Yoshiyuki Ohno, Ph.D.,

Yoshiaki Kariya, 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 10 faculty members, 65 pharmacy staffs,
and 11 graduate students and 1 undergraduate student
from the faculty of pharmaceutical sciences and 3
graduate students from the faculty of medicine (as ofDecember 1st, 2012). In addition, project associate
professor (Akihiro Hisaka, Ph.D.) and project research
associate (Yuki Ikebuchi, Ph.D., Shogo Miura, Ph.D.)
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 medical persons, executes and supports the
medicine management to inpatients. In addition,
the section prepares materials for pharmaceuticalaffair committee, where each medicine isdiscussed whether it should be adopted or deleted.
Preparation of several periodicals regarding drug
information for clinicians is also included.

2) The dispensing section
After inspecting all prescriptions for contraindications or improper use, medications are
dispensed. Drug information is given to outpatientsfrom this section, using a private room ifnecessary. The computerized order system islinked with automatic packaging machines fororal medicines, automatic dispensing system andbarcode 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 andpatients’ 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.

4494) 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 ofevery information of drug affairs. Drugmanagement section takes care of supplying andsafekeeping of all the in-hospital medicines(2,355 items), out-patient medicines, anesthetics,
muscle relaxation drugs, psychotropic drugs,
poison medicines.
5) Narcotic section
Under the supervision of authorized manager fornarcotics (the director of the department ofpharmacy), narcotics are properly managed,
recorded, reported, inspected and directed.
Narcotics are properly arranged and managed at
the dispensing section and each medical caresection.
6) Ward section
They contribute to the team medical care byproviding specialized drug information andsharing them with all the staffs involved in thetreatment as follows;① Supporting the proper use of medication bypharmacists stationed at 1st and 2nd ICU section.
② Arrangement and mixing of injections forpatients at the staff station of Hematology andOncology.
③ Investigation of carrying medicines and theadverse effect histories, allergy histories etc. at
the time of hospitalization. Participation for
conferences. Procurement and appraisal ofpatient’s basic information about the disease,compilation of the medicine history. Monitoringof medication guidance and the adverse effectfor patients, and compilation of guidance record.
Offering the doctor with drug information,prescription design support and detailed
contents of medication 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 2012)
Number of items on in-hospital formulary: 2,355
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
452,829 ps.
(outside :365,472 ps.)(inside :87,357 ps.)out-patient chemotherapy:
12,888 ps.
in-patients :237,208 ps.
injection drugs:
212,617 ps.
IVH:
7,492 pp.
chemotherapy:
10,946 pp.
TDM consultations (annual) :16,189 pp.
Numbers of hospital pharmaceutical cares (annual):
9,544 pp.

Education
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 ourown 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 are in

450charge 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 practicaldevelopments and future visions of the department ofpharmacy are presented in this lecture. In addition tothem, 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 pharmacists at thehospital is one of the most important curriculums. In
2012, we accepted clinical training students from The
University of Tokyo, Tokyo University of Pharmacy
and Life Sciences, Showa Pharmaceutical University,
Hoshi University, and Musashino University andeducated them for 2.5 months. On the other hand, we
have had an original one-year post-graduate training
course for pharmacists since long time before startingthe 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
2012, 18 pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

“system pharmacology”, we will be able to identify amolecular 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
andpredictionofpharmacological-effect and side-effect of drugs
directed against particular molecular target.
Finally, these outputs would be feedbacked toearly drug development stages.
4. Elucidation of the molecular mechanism related tothe adverse effect of drugs using large-scale“-omics“ analysis. Finally, the quantitative
information would be applied to develop strategies
to prevent / treat the adverse effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its
application to clinical pharmacokinetics andpharmacology field.

Research
Publications
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 effects. We
need to understand not only the detailed molecularmachinery of drug target, but also its environment
surrounding the target (ex. other associated 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 “livingbody” as “system”. By further promoting this idea to(1) Ichida K, Matsuo H, Takada T, Nakayama A,
Murakami K, Shimizu T, Yamanashi Y, Kasuga H,
Nakashima H, Nakamura T, Takada Y, Kawamura
Y, Inoue H, Okada C, Utsumi Y, Ikebuchi Y, Ito K,
Nakamura M, Shinohara Y, Hosoyamada M,
Sakurai Y, Shinomiya N, Hosoya T, Suzuki H.
Decreased extra-renal urate excretion is acommon cause of hyperuricemia. Nat Commun 3:764, 2012(2) Yamamoto T, Terakawa H, Hisaka A, Suzuki H.
Bayesian estimation of pharmacokinetic parameters of vancomycin in patients with decreasing
renal function. J Pharm Sci 101:2968-2975, 2012

451

(3) Arita R, Yanagi Y, Honda N, Maeda S, Maeda K,
Kuchiba A, Yamaguchi T, Yanagihara Y, Suzuki H,
Amano S. Caffeine increases tear volume
depending on polymorphisms within the
adenosine A2a receptor gene and cytochrome
P450 1A2. Ophthalmology 119:972-978, 2012(4) Ikebuchi Y, Shimizu H, Ito K, Yoshikado T,
Yamanashi
Y,
TakadaT,
SuzukiH.
Ursodeoxycholic acid stimulates the formation of
the bile canalicular network. Biochem Pharmacol
84:925-935, 2012
(5) Yamanashi Y, Takada T, Shoda J, Suzuki H. Novelfunction of Niemann-Pick C1-like 1 as a negative
regulator of Niemann-Pick C2 protein. Hepatology.
55:953-964, 2012

452

Delivery Unit
Professor
Tomoyuki Fujii

Associate Professor
Takahiro Yamashita

Homepage

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

Organization
The Delivery Unit of the University of Tokyo
Hospital is organized by one professor, one associate
professor 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 858 in 2012.
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.]

453

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.

454

Teaching activities

4)

We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such ascerebrovascular disturbances, 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.

5)

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 theelderly

6)
7)
8)

Rehabilitation approaches for patients withhemophilia
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

References
1. Hamasaki M, Hashizume Y, Yamada Y, Katayama
T, Hohjoh H, Fusaki N, Nakashima Y, Furuya H,
Haga N, Takami Y, Era T: Pathogenic mutation of
ALK2 inhibits iPS cell reprogramming andmaintenance: mechanisms of reprogramming andstrategy for drug identification. Stem Cells 30:
2437-2449, 2012
2. Kawashima N, Abe MO, Iwaya T, Haga N:
Abnormal capacity for grip force control inpatients with congenital insensitivity to pain. Exp
Brain Res 218: 579-288, 2012
3. 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 17: 507-511, 2012
4. Susami T, Mori Y, Tamura K, Ohkubo K,
Nagahara K, Takahashi N, Uchino N, Uwatoko K,
Haga N, Takato T: Facial morphology andocclusion of a patient with fibrodysplasia
ossificans progressiva (FOP): Follow-up from 8 to
21 years of age. Spec Care Dentist 32: 165-170,
2012
5. Yozu A, Haga N, Tojima M, Zhang Y, Sumitani M,
Otake Y: Vertical peak ground force in humaninfant crawling. Gait Posture, Epub ahead of print

455

Central Supply Service
Associate Professor
Kazuhiko Fukatsu, M.D., Ph.D.

Associate
Satoshi Murakoshi, M.D., Ph.D.

Homepage

http://www.cc.h.u-tokyo.ac.jp/mulins/zairyobu/

Introduction
Central supply service is an integrated place inthe hospital for cleaning and sterilization ofpreviously used devices. All re-usable devices aretransported to our division via automated guided
vehicle system from surgical center, ward andoutpatient clinics. The used instruments are cleaned
using standard precautionary procedures, disinfected,
reassembled, packaged, and sterilized. The sterilized
instruments are then placed at designated sites for use.
One associate professor and one instructor, twonurses, 10 staff members, and 26 members fromexternal staff sources are the main members of thisdivision.

Facilities
The following facilities are located in an area of
1,077 square meters :Cleaning equipment : 7 washer disinfectors (WDs), 1
vacuum-ultrasonic cleaning unit.
Drying equipment : 5 system drying units.
Sterilizing equipment : 6 autoclaves, 2 ethylene oxide
gas sterilizers, 2 hydrogen peroxide plasma sterilizers.

Activities
Used devices are cleaned with automated washer
disinfectors and/or manual washing, then packaged
carefully into container sets or paper bags. The
packaged materials are sterilized with autoclaves,

ethylene oxide gas sterilizer or hydrogen peroxide
plasma sterilizer according to their characteristics.
The cleaning procedure is checked with test device.
All sterilization process is recorded and ensured bychemical indicators and biological indicators.
The number of devices handled in the central
supply service is dramatically increasing withincreased number of operations in the surgical centers(number of containers: 30085 for surgical center,
13693 for wards and outpatient clinics in 2012).
Staffs of central supply service have also worked
for re-counting of used surgical devices on surgicalcenter floor since 2011. The work has contributed
towards risk management in the hospital. The numberof operations for which the staff re-counted devices
was 6857 in 2012.

Research activities
To establish more efficient procedures for cleaning,
intensive trials have been performed and the data havebeen presented at academic conferences. Moreover,basic research on host response to surgical insult isanother theme of our division. The research isimportant for improving outcome of surgical patientsand our data have been published as original articles

References
1. Okamoto K, Fukatsu K, Hashiguchi Y, Ueno H,
Shinto E, Moriya T, Saitoh D, Yamamoto J, Hase
K. Lack of Preoperative Enteral Nutrition

456

2.

3.

4.

5.

6.

Reduces Gut-Associated Lymphoid Cell Numbersin Colon Cancer Patients: A Possible Mechanism
Underlying Increased Postoperative Infectious
Complications During Parenteral Nutrition. Ann
Surg. 2012 Nov 26. [Epub ahead of print]
Fukatsu K. The long road to optimizing theparenteral provision of nutrients. JPEN J Parenter
Enteral Nutr. 2012 Mar;36(2):157-8.
Moriya T, Fukatsu K, Maeshima Y, Ikezawa F,
Hashiguchi Y, Saitoh D, Miyazaki M, Hase K,
Yamamoto J. The effect of adding fish oil toparenteral nutrition on hepatic mononuclear cellfunction and survival after intraportal bacterial
challenge in mice. Surgery. 2012 May;151(5):745-55.
Yasuhara H, Fukatsu K, Komatsu T, Obayashi T,
Saito Y, Uetera Y.Prevention of medical accidents
caused by defective surgical instruments. Surgery.
2012 Feb;151(2):153-61.
Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg
Res. 2012 Jan;172(1):83-4.
Fukatsu K, Moriya T, Murakoshi S, Yasuhara H.
Interleukin-7 treatment reverses parenteralnutrition-induced impairment of resistance tobacterial pneumonia with increased secretory
immunoglobulin A levels. J Surg Res. 2012 May
15;174(2):334-8.

457

Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D., Ph.D.*

Associate Professor (Deputy Director)
Junji Shibahara, M.D., Ph.D.*

Associate Professor
Shumpei Ishikawa, M.D., Ph.D.*

Lecturer
Yutaka Takazawa, M.D., Ph.D.,

Lecturer (Hospital)
Tetsuo Ushiku, M.D., Ph.D., (visiting researcher, USA)

Associate
Teppei Morikawa, M.D., Ph.D.

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

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

Keisuke Matsusaka, M.D., Ph.D.

Rumi Hino, M.D., Ph.D. *,Yukako Shintani, M.D., Ph.D. *Mariko Tanaka, M.D., Ph.D. *Aya Ushiku-Shinozaki, M.D., Ph.D. * (visiting researcher, USA)

Clinical Fellow
Ruri Saito, M.D., Atsuko Hosoi, M.D.,

Homepage

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology(*) and Division of Diagnostic Pathology of
University Hospital have been organized to function
as a unit.
The proper staffs in the Division of Diagnostic
Pathology include a lecturer, four associates, and two
clinical staffs.
We applied to the staff reallocation program of
the University of Tokyo for the promotion of
telepathology cooperating with local community. One
staff position will be supplied next year, and Dr.
Takeshi Sasaki, Associate Professor of Yokohama

Manicipal niversity Medical Center, will move to thechief, Division of Telepathology and Promotion of
Cooperation.

Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2011
fiscal year consisted of 15,931 cases of histologicalexamination (21,813 specimens), 19,244 cases ofcytology, 695 of frozen histology, 553 of
intra-operative cytology, 52 casees of autopsy (15.5%of the autopsy rate), and 2 autopsy cases from otherhospitals.

458

Clinico-pathological conferences (CPCs) for thetwo autopsy cases are held every month in the hospital.
Furthermore, the following surgical pathology
conferences are regularly held with each clinicaldivision for the cases of various tumors of organs;thoracic organs (Dr. Morikawa in charge), liver andpancreato-biliary tract (Drs. Shibahara and Tanaka),
male genitourinary (Dr. Morikawa) and female genitaltracts (Drs. Maeda and Takazawa), breast (Dr.
Ikemura), and bone and soft tissues (Dr. Maeda).
Biopsy conferences are also held in the cases ofkidney (Dr. Shintani in charge), skin (Dr. Takazawa)
and GI tract (Dr. 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 for reviewing the reports and slides for all casesof histological examination to prevent a potential
misdiagnosis.
Virtual slide scanners have been installed, whichenabled us to reposit 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 in the autopsy
assessment for “The Model Project for Inspection andAnalysis of the Deaths Related to Medical Treatment(DRMT)”.

Teaching activities
The lectures and exercise course of systemic
pathology are for the 2nd grade–students. Bed-side
learning (BSL) courses 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 a report of
CPC case as an obligatory requirement of their
medical training for each of them. We have made out
the digest version of CPC slides open in the hospital,
and also started e-learning program for interns tosolve the problems in CPC by themselves, therby
facilitating their understanding (Drs. Takazawa and
Ikemura).
The Division of Diagnostic Pathology received
ten interns (total 25 months) in 2011 for their second

year program of the internship.

Research activities
Cooperative study was carried out with Fuji Xerox
and National Institute of Advanced Industrial Scienceand 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 the usefulness of post mortem CT
images for hospital autopsy, using a CT apparatus in
the autopsy-assisting CT room.
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 Department of Upper GI tract surgery, andGenome Science Division, Research Center for
Advanced Science and Technology, the University ofTokyo (Dr. Matsusaka). We are evaluating thefeasibility of antibody panels for immunohistochemistry to detect the metastasis in the sentinel
lymph nodes of the gastric cancer, by constructing thetissue array of primary and metastatic cancers. We
also cooperate with projects developing PET and invivo imaging of cancers (Dr. Matsusaka).

References
See the corresponding section of Department of
Pathology and Diagnostic Pathology

459

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 78 corneal transplantations were performed in2012. 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460

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. Mimura T, Mori M, Obata H, Usui T, Yamagami S,
Funatsu H, Noma H, Amano S.
Conjunctivochalasis: associations with pingueculain a hospital-based study. Acta Ophthalmolologica.
90:773-82, 2012.
2. Sugita S, Kawazoe Y, Yamada Y, Imai A, Horie S,
Yamagami S, Mochizuki M. Inhibitory effect ofcorneal endothelial cells on IL-17-producing Th17
cells. British Journal of Ophthalmology. 96:293-9,
2012.
3. Mimura T, Obata H, Usui T, Mori M, Yamagami S,
Funatsu H, Noma H, Amano S. Pinguecula anddiabetes mellitus. Cornea. 31:264-8, 2012.
4. Mimura T, Usui T, Yamagami S, Miyai T, Amano
S. Relation between total tear IgE and severity ofacute seasonal allergic conjunctivitis. Current Eye
Research. 37:864-70, 2012.
5. Takaoka-Sugihara N, Yamagami S, Yokoo S,
Matsubara M, Yagita K. Cytopathic effect ofAcanthamoeba on human corneal fibroblasts.
Molecular Vision. 18:2221-8, 2012.
6. Kimoto M, Shima N, Yamaguchi M, Amano S,
Yamagami S. Role of hepatocyte growth factor inpromoting the growth of human corneal
endothelial cells stimulated by L-ascorbic acid2-phosphate. Investigative Ophthalmology &Visual Science. 53:7583-9, 2012.

461

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)

Assistant Professor
Akihide Yoshimi, M.D. , Ph.D. (Hematology-Oncology)
Yasuhiko Kamikubo, 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, andwas formally organized in 1996. At present, the staff
consists of the above-mentioned medical doctors.
Clinical facilities include 8 single-patient rooms withhigh- efficiency particulate air filtration and otherhigh standards. Patients who are eligible for thetreatment with high-grade infectious prophylaxis areadmitted to the facilities.

Clinical activities
Approximately 750 patients have undergone
hematopoietic stem cell transplantation (HSCT) in our
department since 1995. Allogeneic bone marrowtransplantation from donors Japan Marrow Donor
Program (JMDP) as well as international bone marrowdonor programs, HSCT from HLA-mismatcheddonors, and donor lymphocyte infusion are available.
In 2012, 49 patients (including 10 pediatric patients)
received HSCTs. We cooperate with the staffs ofDepartment
ofHematology
andOncology,
Hematology/Oncology group in the Department ofPediatrics, and Department of Transfusion Medicine.

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 HSCT or NST for nonmyeloablative HSCT) is commonly performed for theelderly and patients with organ dysfunction. The
development of this strategy is expanding theeligibility of transplant recipients. Allogeneic HSCT
for the elderly is 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.

462

Clinical conference for hematopoietic stem celltransplantation: The conference is held monthly. The
members of Department of Hematology and Oncology,
Hematology/Oncology group in Department ofPediatrics, and Department of Transfusion Medicine
join the conference and discuss on HSCT recipients.

3.

4.

Teaching activities
5.
Together with the members of Department of
Hematology and Oncology and Hematology/Oncology
group in the Department of Pediatrics, lecture courses
on etiology, pathogenesis, clinical and laboratory
features, differential diagnosis, therapy and prognosis
for all hematological diseases are provided to thesecond grade medical students. Clinical clerkshipcourses are given to the third grade medical students,
who join the patient care teams consisting of juniorand senior medical doctors and learn medical practices
and patient management, through playing a role as a
junior member of the team, as well as throughdiscussions 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 malignancies, andbasic studies on hematopoietic stem cells,
leukemogenesis and regenerative medicine using
hematopoietic cells. In the area of pediatric oncology,
we continue the studies on molecular mechanisms ofpediatric malignancies such as neuroblastoma,
rhabdomyosarcoma, and infant leukemia.

References
1. Goyama S, Takeuchi K, Kanda Y, Nannya Y, Chiba S, Fukayama M, Kurokawa M. Post-transplant
endothelial disorder after hematopoietic SCT: ablinded autopsy study. Bone Marrow Transplant.
2012 Sep;47(9):1243-5.
2. Kagoya Y, Seo S, Nannya Y, Kurokawa M. Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on
prognosis. Clin Transplant. 2012 Mar-Apr;26(2):

6.

7.

8.

9.

E168-75.
Kataoka K, Kurokawa M. Ecotropic viral integration site 1, stem cell self-renewal and leukemogenesis. Cancer Sci. 2012 Aug;103(8):1371-7.
Koya J, Nannya Y, Ichikawa M, Kurokawa M.
The clinical role of procalcitonin in hematopoietic
SCT. Bone Marrow Transplant. 2012 Oct;47(10):1326-31.
Miyauchi M, Yoshimi A, Nannya Y, Takazawa Y,
Ichikawa M, Fukayama M, Kurokawa M. Efficacy
of pleural biopsy for diagnosis of pleural effusion
due to chronic GVHD after hematopoietic stem
cell transplantation. Int J Hematol. 2012 Jul;96(1):146-8.
Yoshimi A, Yamamoto G, Goto T, Koike K, Kurokawa M. Hepatocellular carcinoma in cirrhotic
liver with graft-versus-host disease. Ann Hematol.
2012 Sep;91(9):1501-2.
Miura K, Sekine T, Takamizawa M, Terashima H,
Furuya A, Koh K, Takita J, Ida K, Igarashi T.
Early occurrence of nephrotic syndrome associated with cord blood stem cell transplantation.
Clin Exp Nephrol. 2012 Feb;16(1):180-2.
Kato M, Horikoshi Y, Okamoto Y, Takahashi Y,
Hasegawa D, Koh K, Takita J, Inoue M, Kigasawa
H, Ogawa A, Sasahara Y, Kawa K, Yabe H,
Sakamaki H, Suzuki R, Kato K. Second allogeneic hematopoietic SCT for relapsed ALL in children. Bone Marrow Transplant. 2012 Oct;47(10):1307-11.
Kato M, Shiozawa R, Koh K, Nagatoshi Y, Takita
J, Ida K, Kikuchi A, Hanada R. The Effect of theOrder of Total Body Irradiation and Chemotherapy on Graft-Versus-Host Disease. J Pediatr Hematol Oncol. 2012 Dec 13. [Epub ahead of print]

463

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Mitsuhiro Fujishiro, M.D., Ph.D.

Associate
Hirofumi Kogure, 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
regular staffs of our department are only two doctors,
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.

for detail inspection and therapeutic endoscopy,
including endoscopic submucosal dissection foresophageal, gastric and colorectal tumors, are majoradvanced 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, including upper gastrointestinal endoscopy, colonoscopy, bronchoscopy,
otorhinolaryngological endoscopy and gynecologicalendoscopy, are performed from Monday to Friday.
Emergency endoscopy is performed in the nighttime
or holidays. Enteroscopy by using capsule endoscopes
and balloon-assisted endoscopes are rapidly increasing
in number. Additionally, image enhanced endoscopy

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.

464

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2003

2004

2005

2006

2007

2008

2009

EGD*
Colonoscopy
Bronchoscopy
EUS**Enteroscopy
Laryngoscopy
Colposcopy

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

12778

12195

13199

13282

14043

15520

16566

2010
10556
5152
255
551
311
70
361
17256

2011
10963
5208
197
630
282
108
378
17764

2012
11376
5688
196
698
282
83
365
18688

*Esophagogastroduodenoscopy, **Endoscopic ultrasonography

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

References(1) 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 gastricendoscopic submucosal dissection. Dig Endosc 24:
110-6, 2012.
(2) 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 gastric endoscopic
submucosal dissection related to postoperative
bleeding. Dig Dis Sci. 57:435-9, 2012.
(3) 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 Strategyof Large Colorectal Tumors. J Gastroenterol
Hepatol. 27: 510–515, 2012(4) 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
(5) 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. 15:414-8, 2012(6) Ono S, Fujishiro M, Kodashima S, Takahashi Y,
Minatsuki C, Mikami-Matsuda R, Asada-Hirayama
I, Konno-Shimizu M, Tsuji Y, Mochizuki S, Niimi
K, Yamamichi N, Kaneko M, Yatomi Y, Koike K.
Evaluation of safety of endoscopic biopsy without
cessation of antithrombotic agents in Japan. J
Gastroenterol. 47:770-4, 2012
(7) 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. 131:2632-42,
2012(8) 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 during endoscopic submucosal dissection of gastric epithelial neoplasias.
World J Gastrointest Endosc 4: 80-86, 2012(9) Niimi K, Fujishiro M, Goto O, Kodashima S, Koike
K. Safety and efficacy of colorectal endoscopic
submucosal dissection by the trainee endoscopists.
Dig Endosc. 24 Suppl 1:154-8, 2012(10) Yamamichi N, Mochizuki S, Asada-Hirayama I,
Mikami-Matsuda R, Shimamoto T, Konno-Shimizu

465M, 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: across-sectional study of healthy 19864 adults using
FSSG scores. BMC Med. 10:45, 2012(11) Ono S, Fujishiro M, Koike K Endoscopic
submucosal dissection for superficial esophageal
neoplasms. World J Gastrointest Endosc.4:162-6,
2012(12) 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(13) 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(14) Kakushima N, Hirasawa K, Morita Y, Takeuchi M,
Yamamoto Y, Oda I, Goda K, Uedo N, Fujishiro M.
Terminology for training of endoscopic submucosal
dissection. Dig Endosc. 24 Suppl 1:133-5, 2012(15) 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 inJapan. Dig Endosc. 24 Suppl 1:136-42, 2012(16) Yamamichi N, Oka M, Inada KI, Konno-Shimizu
M, Kageyama-Yahara N, Tamai H, Kato J,
Fujishiro M, Kodashima S, Niimi K, Ono S,
Tsutsumi Y, Ichinose M, Koike K. Rebamipide
induces dendritic cell recruitment to N-methyl-N'nitro-N-nitrosoguanidine(MNNG)-exposed
rat
gastric mucosa based on IL-1β upregulation.
Biochem Biophys Res Commun. 424:124-9, 2012(17) Goto O, Kambe H, Niimi K, Mochizuki S,
Asada-Hirayama I, Minatsuki C, Ono S,
Kodashima S, Yamamichi N, Yamaji Y, Fujishiro
M, Koike K. Discrepancy in diagnosis of gastricsubmucosal tumor among esophagogastroduodenoscopy, CT, and endoscopic ultrasonography: a retrospective analysis of 93

consecutive cases. Abdom Imaging. 37:1074-8,
2012(18) Ozawa S, Tachimori Y, Baba H, Fujishiro M,
Matsubara H, Numasaki H, Oyama T, Shinoda M,
Takeuchi H, Teshima T, Udagawa H, Uno T,
Barron JP. Comprehensive registry of esophageal
cancer in Japan, 2004. Esophagus 9:75-98, 2012(19) Niimi K, Fujishiro M, Koike K. An Unusual Caseof Submucosal Tumor in the Stomach.
Gastroenterology. 143:895,1121, 2012(20) Enomoto S, Watanabe M, Yoshida T,
Mukoubayashi C, Moribata K, Muraki Y, Shingaki
N, Deguchi H, Ueda K, Inoue I, Maekita T, Iguchi
M, Tamai H, Kato J, Fujishiro M, Oka M, Mohara
O, Ichinose M. Relationship between vomitingreflex during esophagogastroduodenoscopy anddyspepsia symptoms. Dig Endosc. 24:325-30, 2012(21) Hirano K, Yamamichi N, Fujishiro M, Koike K.
Gastrointestinal: Esophageal hematoma: A rarecause of upper gastrointestinal bleeding. J
Gastroenterol Hepatol. 27:1642, 2012(22) Li Y, Ge ZZ, Fujishiro M, Li XB. Current ClinicalApplications of Magnifying Endoscopy with
Narrow Band Imaging in the Stomach. Diagn Ther
Endosc. 2012:271914, 2012(23) Niimi K, Goto O, Fujishiro M, Kodashima S, Ono
S, Mochizuki S, Asada-Hirayama I, KonnoShimizu M, Mikami-Matsuda R, Minatsuki C,
Yamamichi N, Koike K. Endoscopic mucosal
resection with a ligation device or endoscopic
submucosal dissection for rectal carcinoid tumors:
An analysis of 24 consecutive cases. Dig Endosc.
24:443-7, 2012(24) 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 incidenceof biliary carcinoma in patients with primarysclerosing cholangitis and high serum levels of
immunoglobulin E. Clin Gastroenterol Hepatol.
10:79-83, 2012(25) 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. Risk factors for pancreatitis

466

following transpapillary self-expandable metal stentplacement. Surg Endosc. 26:771-6, 2012(26) Yashima Y, Sasahira N, Isayama H, Kogure H,
Ikeda H, Hirano K, Mizuno S, Yagioka H,
Kawakubo K, Sasaki T, Nakai Y, Tada M, Yoshida
H, Omata M, Koike K. Acoustic radiation force
impulse elastography for noninvasive assessment ofchronic pancreatitis. J Gastroenterol. 47:427-32,
2012(27) Isayama H, Sasaki T, Nakai Y, Togawa O, Kogure
H, Sasahira N, Yashima Y, Kawakubo K, Ito Y,
Hirano K, Tsujino T, Toda N, Tada M, Omata M,
Koike K. Management of malignant gastric outlet
obstruction with a modified triple-layer covered
metal stent. Gastrointest Endosc. 75:757-63, 2012(28) Takahara N, Isayama H, Sasaki T, Tsujino T, Toda
N, Sasahira N, Mizuno S, Kawakubo K, Kogure H,
Yamamoto N, Nakai Y, Hirano K, Tada M, Omata
M, Koike K. Endoscopic papillary balloon dilation
for bile duct stones in patients on hemodialysis. J
Gastroenterol. 47:918-23, 2012(29) Kawakubo K, Isayama H, Sasahira N, Kogure H,
Takahara N, Miyabayashi K, Mizuno S, Yamamoto
K, Mohri D, Sasaki T, Yamamoto N, Nakai Y,
Hirano K, Tada M, Koike K. Clinical utility ofsingle-operator cholangiopancreatoscopy using a
SpyGlass probe through an endoscopic retrograde
cholangiopancreatography catheter. J Gastroenterol
Hepatol. 27:1371-6, 2012(30) Isayama H, Mukai T, Itoi T, Maetani I, Nakai Y,
Kawakami H, Yasuda I, Maguchi H, Ryozawa S,
Hanada K, Hasebe O, Ito K, Kawamoto H,
Mochizuki H, Igarashi Y, Irisawa A, Sasaki T,
Togawa O, Hara T, Kamada H, Toda N, Kogure H.
Comparison of partially covered nitinol stents withpartially covered stainless stents as a historicalcontrol in a multicenter study of distal malignant
biliary obstruction: the WATCH study. Gastrointest
Endosc. 76:84-92, 2012(31) Nakai Y, Isayama H, Ijichi H, Sasaki T, Kogure H,
Yagioka H, Miyabayashi K, Mizuno S, Yamamoto
K, Mouri D, Kawakubo K, Yamamoto N, Hirano K,
Sasahira N, Tateishi K, Tada M, Koike K. Phase I
trial of gemcitabine and candesartan combination
therapy in normotensive patients with advanced
pancreatic cancer: GECA1. Cancer Sci. 103:148992, 2012(32) Hamada T, Nakai Y, Isayama H, Togawa O,
Kogure H, Kawakubo K, Tsujino T, Sasahira N,
Hirano K, Yamamoto N, Ito Y, Sasaki T, Mizuno S,
Toda N, Tada M, Koike K. One- and two-step
self-expandable metal stent placement for distal
malignant biliary obstruction: a propensity analysis.
J Gastroenterol. 47:1248-56, 2012(33) Nakai Y, Isayama H, Sasaki T, Sasahira N, Tsujino
T, Toda N, Kogure H, Matsubara S, Ito Y, Togawa
O, Arizumi T, Hirano K, Tada M, Omata M, Koike
K. A multicentre randomised phase II trial of
gemcitabine alone vs gemcitabine and S-1
combination therapy in advanced pancreatic cancer:
GEMSAP study. Br J Cancer. 106:1934-9, 2012(34) Matsubara S, Tada M, Akahane M, Yagioka H,
Kogure H, Sasaki T, Arizumi T, Togawa O, Nakai
Y, Sasahira N, Hirano K, Tsujino T, Isayama H,
Toda N, Kawabe T, Ohtomo K, Omata M.
Incidental pancreatic cysts found by magnetic
resonance imaging and their relationship withpancreatic cancer. Pancreas. 41:1241-6, 2012(35) Sasaki T, Isayama H, Nakai Y, Togawa O, Kogure
H, Kawakubo K, Mizuno S, Yashima Y, Ito Y,
Yamamoto N, Sasahira N, Hirano K, Tsujino T,
Toda N, Tada M, Omata M, Koike K. Predictive
factors of solid food intake in patients withmalignant gastric outlet obstruction receiving
self-expandable metallic stents for palliation. Dig
Endosc. 24:226-30, 2012(36) Kawakubo K, Isayama H, Nakai Y, Sasahira N,
Kogure H, Sasaki T, Hirano K, Tada M, Koike K.
Simultaneous Duodenal Metal Stent Placement and
EUS-Guided
Choledochoduodenostomy
for
Unresectable Pancreatic Cancer. Gut Liver. 6:399402, 2012(37) Nakai Y, Ishigami H, Isayama H, Sasaki T,
Kawakubo K, Kogure H, Emoto S, Yamaguchi H,
Kitayama J, Yamamoto N, Sasahira N, Hirano K,
Tada M, Koike K. Role of intervention for biliary
and gastric/intestinal obstruction in gastric cancer
with peritoneal metastasis. J Gastroenterol Hepatol.
27:1796-800, 2012

467

Department of Hemodialysis andApheresis
Professor
Masaomi Nangaku, M.D.,Ph.D.

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

LecturerTakeshi Azuma, M.D., Ph.D.

Clinical Fellow
Tetsushi Kinugasa
Motonobu Nakamura

Introduction and Organization

Clinical activities

Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for
Hemodialysis in 2000 at the University Hospital. The
Center for Hemodialysis was further renovated andstarted operations in Fall of 2006. This new Center for
Hemodialysis is equipped with one pressure control
unit in addition to 12 hemodialysis machines under astate-of-the-art hemodialysis control system. Ourconcept of a hemodialysis controlling system is a hub
to transfer all digital and analog data from patients andto monitor machines, including blood purification
machines, to the host computer in our hospital,
centralizing all data and administering medical coding
and billing robustly. Blood purification machines in
the ICU are also connectable to this system, which
was developed collaboratively with Nihon Kohden
Corp. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.

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-liver transplantpatients.
DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
LDL apheresis for nephrotic syndrome and ASO
patients.
White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.

Teaching activities
1.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.

468

2.
3.
4.
5.

6.

Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to
second year residents on request.
Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. In this year, Chinese version of“Apheresis Pocket Manual” is available for
Chinese experts of Apheresis therapy.
Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.

Research activities
1.
2.
3.
4.
5.
6.
7.
8.

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

References
1. Katagiri D, Doi K, Matsubara T, Negishi K,
Hamasaki Y, Nakamura K, Ishii T, Yahagi N,
Noiri E: New biomarker panel of plasma
neutrophil gelatinase-associated lipocalin andendotoxin activity assay for detecting sepsis inacute kidney injury. J Crit Care 2013 [PMID:
23499422]

2. Torato T, Doi K, Negishi K, Hamasaki Y,
Satonaka H, Hanafusa N, Noiri E: Efficacy ofvitamin E-bonded polysulfone dialyzer on a seriesof non-anticoagulant hemodialysis. ASAIO J
59:284-52013
3. VEESA study group: Randomized controlled
open-label trial of vitamin E-bonded polysulfone
dialyzer and erythropoiesis-stimulating agent
response. Clin J Am Soc Nephrol 8:969-78, 2013
4. Harano K, Minami K, Noiri E, Okamoto K,
Nakamura E: Protein-coated nanocapsules via
multilevel surface modification. Controlled
preparation and microscopic analysis at nanometer
resolution. Chem Commun (Camb) 49:3525-7,
2013
5. Hanafusa N, Noiri E, Nangaku M: Differences in
reduction of coagulation factor XIII (F13)
between immunoadsorption plasmapheresis anddouble filtration plasmapheresis. Ther Apher Dial
17:241-2, 2013
6. Hanafusa N, Hamasaki Y, Kawarasaki H, Kido R,
Shibagaki Y, Ishikawa A, Enomoto Y, Fujita T,
Noiri E, Nangaku M: The effect of different
apheresis modalities on coagulation factor XIII
level during antibody removal in ABO-blood typeincompatible living related renal transplantation.
Transfus Apher Sci, 2013 [PMID:23827327]
7. Nakamura K, Doi K, Inokuchi R, Fukuda T,
Hiruma T, Ishii T, Nakajima S, Noiri E, Yahagi N:
Endotoxin adsorption by polymyxin B column or
intraaortic balloon pumping use for severe septic
cardiomyopathy. Am J Emerg Med 31:e1-e3,
2013
8. Susantitaphong P, Siribamurungwong M, Doi K,
Noiri E, Terrin N, Jaber BL: Performance ofurinary liver-type fatty acid-binding protein in
acute kidney injury: a meta-analysis. Am J Kidney
Dis 61:430-9, 2013
9. Katagiri D, Doi K, Honda K, Negishi K, Fujita T,
Hisagi M, Ono M, Matsubara T, Yahagi N,
Iwagami M, Ohtake T, Kobayashi S, Sugaya
T,Noiri E: Combination of two urinary biomarkers
predicts acute kidney injury after adult cardiac
surgery. Ann Thorac Surg 93:577-83, 2012
10. Hamasaki Y, Doi K, Okamoto K, Ijichi H, Seki G,
Maeda-Mamiya R, Fujita T, Noiri E: 3-Hydroxy3-methylglutaryl-coenzyme A reductase inhibitor

469

simvastatin ameliorates renal fibrosis through
HOXA13-USAG-1 pathway. Lab Invest 92:116170, 2012
11. Okamoto K, Iwasaki N, Doi K, Noiri E, Iwamoto
Y, Uchigata Y, Fujita T, Tokunaga K: Inhibition of
Glucose-Stimulated Insulin Secretion by KCNJ15,
a Newly Identified Susceptibility Gene for Type 2
Diabetes. Diabetes 61:1734-41, 2012
12. Togawa T, Tsukimura T, Kodama T, Tanaka T,
Kawashima I, Saito S, Ohno K, Fukushige T,
Kanekura T, Satomura A, Kang DH, Lee BH, Yoo
HW, Doi K, Noiri E, Sakuraba H: Fabry disease:biochemical, pathological and structural studies ofthe α-galactosidase A with E66Q amino acidsubstitution. Mol Genet Metab 105615-20, 2012

470

Clinical Research Support Center
Professor
Tsutomu Yamazaki, M.D., Ph.D.

Associate Professor
Yoshihiro Arakawa, Ph.D.

Project Associate Professor
Takashi Moritoyo, M.D., Ph.D.

Research Associate
Hiroshi Satonaka, M.D., Ph.D. (until June 2012)
Tetsuya Ueda, M.D., Ph.D.
Satoshi Iimuro, M.D., Ph.D.

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 Clinical Research Support Center,enabling strengthened support and expeditious

promotion of clinical research.
The Center at the beginning consisted of Site
Coordinating Unit, roughly equivalent to the former
whole Clinical Research Center, and Central
Coordinating Unit, which provides coordinating
functions for research such 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 in 2011 as an

471

MHLW-funded center of excellence for early stageand exploratory clinical trials of drugs for psychiatricand neurological diseases, thus enabling the Center toreinforce the staff and to be equipped with phase 1
facilities. Thus, the third unit, i.e., Phase 1 unit (P1unit) was established in May 2012 with 13 beds
exclusively used for clinical trials. It is featured as anintegrated phase 1 unit with expertise from both
exploratory researchers and clinical investigators in
the relevant fields.
Clinical Research Support Center can now support
both trials registered or not registered for marketing
approval, and, therefore, can provide seamless support
to research in any phase of development.
As of March 2013, the Center staff includes aprofessor, an associate professor, a project associate
professor, 3 assistant professors, 13 pharmacists, 19
nurses (FTE), 6 laboratory technicians (FTE), 3
clinical psychologists, 7 project specialists and 7
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 compassionate use ofunapproved drugs) respecting the principles of the
globally standard ICH-GCP, we have laid down and asneeded revised the in-house guidelines or SOPs. These
documents include those relating to preparation of thestudy protocol or informed consent form,
implementation of research, and handling of costs totrial 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 2012 included, as forindustry-sponsored trials for marketing approval, 38
new protocol applications, 68 study extension
applications, 747 protocol amendment applications,813 SAE/safety information reports, 32 study closureor termination reports. As for investigator-initiatedclinical research, the Center processed 68 new
protocols (including 5 applications for compassionate
use of unapproved drugs), 334 applications for
protocol amendment, 82 SAE/safety information
reports, 96 reports for study closure or termination.
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 70 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 (The University of Tokyo, 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. The Alliance Office was based in the
University of Tokyo Hospital. In Alliance anorganizational structure has been established that cancooperatively attract trials and smoothly process themfor IRB approval. A course to educate the staff in
preparation for global trials has been put in place. In
2007 Shinshu University and in 2013 Yamanashi
University joined the Alliance as the 7th and 8th
member university, respectively.
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 andfurther expand the activities. Operational subsidies
that the University of Tokyo received were distributed
to each university based on a joint project agreement.
Each university and the Office were given its own task
to cooperatively promote the mission of the whole
Alliance.
Until the end of March 2013, 67 protocols wereintroduced to the Alliance including 38 multinational
trials. The Alliance helped to assess feasibility in 9
trials and to select the participating sites in 41.
Cooperative protocol presentation (hearing) sessions
were held for 37 protocols. Based on the data of 15
trials, industry sponsors applied for drug approval

472

from Ministry of Health, Labour and Welfare and 11
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 by21 projects.
In October 2012, National University Hospital
Clinical Research Initiative (NUH-CRI) wasestablished with our leading role and included allnational university hospitals in Japan (42 universities
and 45 hospitals). The office of the Initiative was also
taken charge of by the Alliance Office since thepreparatory meeting in July 2012. First general
meeting was held in January 2013 in Tokyo Medical
and Dental University.
Clinical Research Support Center managed
drug/device inventory for 109 clinical trials forregulatory approval, 2 postmarketing trials, 1 trial ofdevices, 32 investigator-initiated clinical trials, andone case of compassionate use in fiscal 2012. The
number of prescriptions processed was 1111 for trials
for approval and postmarketing trials combined, 562
for investigator-initiated clinical trials. We are
currently managing trial drugs centrally for 2
multicenter trials. We masked investigational drugs
for 2 double-blind placebo controlled trials including
one trial for marketing approval and one
investigator-initiated clinical research. We are also incharge of the primary review of clinical trial safety
information and of maintaining the database on
clinical trials in general.
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 supporting in part investigator-initiated trials in
2004. In 2005 we started providing CRC support toinvestigator-initiated trials on a beneficiary-pays basis.
CRCs exclusively involved in investigator-initiatedtrials have been employed as needed. The number oftrial participants that CRCs interacted with was 3777
in fiscal 2006, 4853 in 2007, 5172 in 2008, 4761 in
2009, 3776 in 2010, 3604 in 2011 and 4785 in 2012.
We started receiving monitoring visits for every trial
participant’s data in 2002. The number of monitoring

visits increased to 569 in 2007, 952 in 2008, 840 in
2009, 672 in 2010, 712 in 2011 and 855 in 2012.
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, 12 projects as ofMarch 2013 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 second
investigator-initiated registered clinical trial (afirst-in-human study), a clinical trial notification was
submitted to the regulatory authority, PMDA, in
December 2012 and the trial launched in February
2013.

Teaching Activities“Research Ethics Seminars” for investigators havebeen provided three times a year since the fiscal year
2003. Dr. Arakawa teach “Clinical Science” in a seriesof lectures in the graduate course of the Faculty of
Pharmaceutical Sciences.
Two resident physicians 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 2012 was held
under the auspices of Tokyo University Hospital for 5days, in which 81 trainees from university hospitals all
across the country participated.
The 12th University of Tokyo Hospital Clinical
Trial Seminar was held on March 22, 2013

473

cosponsored with the UHCT Alliance and the Centerof excellence for early and exploratory clinical trials
program with ca. 300 attendees.

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 28 presentations infiscal 2012 as presenters in scientific meetings or as
invited lectures and 48 published papers in 2012.
There was one press release and 12 news media
articles that reported on the Center: 6 for the center of
excellence for early stage and exploratory clinical
trials and 6 for NUH-CRI.

Publications
1)

2)

3)

4)

5)

Suzuki T, Kohro T, Hayashi D, Yamazaki T,
Nagai R. Frequency and impact of lifestylemodification in patients with coronary arterydisease: The Japanese Coronary Artery Disease(JCAD) Study. Am Heart J. 2012;163:268-273.
Miyauchi K, Yamazaki T, Watada H, Tanaka Y,
Kawamori R, Imai Y, et al. Management of Home
Blood Pressure by Amlodipine Combined With
Angiotensin Ⅱ Receptor Blocker in Type 2
Diabetes. Circ J. 2012;76:2159-2166.
Gotoh H, Enoku K, Sorida Y, Sato M, Hikita H,
Suzuki A, Iwai T, Yokota H, Yamazaki T, et al.
Perihepatic lymph node enlargement observed ata general health examination: A cross-sectional
study. Hepatol Res. 2012 Nov 27; doi:10.1111/
hepr.12029.
Kohro T, Yamazaki T. Will diagnosing
polyvascular disease in coronary heart disease
patients improve their outcomes? Circ J. 2012;77:
43-44.
Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Ozeki A, Itoh C,
Sugiyama T, Kadowaki T, Yamazaki T, Nagai R.
Associations of variations in the MRF2/ARID5B

gene with susceptibility to type 2 diabetes in theJapanese population. J Hum Genet. 2012; 57:
727-33.
6) Tomiyama H, Kohro T, Higashi Y, Takase B,
Suzuki T, Ishizu T, Ueda S, Yamazaki T, et al. A
multicenter study design to assess the clinicalusefulness of semi-automatic measurement offlowmediated vasodilatation of the brachial artery.
Int Heart 2012;53:170-175.
7) Nohara R, Daida H, Hata M, Kaku K, Kawamori
R, Kishimoto J, Kurabayashi M, Masuda I,
Sakuma I, Yamazaki T, et al. Effect of intensive
lipid-lowering therapy with rosuvastatin on
progression of carotid intima-media thickness inJapanese patients: Justification for Atherosclerosis Regression Treatment (JART) study.
Circ J. 2012;76:221-229.
8) Maruoka Y, Kanaya F, Hoshino A, Iimura T, Imai
H, Otsuka R, Ueha S, Fujioka K, Katsura Y,
Shimbo T, Mimori A, Yamazaki T, et al. Study ofOsteo-/Chondropenia Caused by Impaired
Chemokine Receptor and for Progressive/
Idiopathic Condylar Resorption. Jpn J Jaw
Deform. 2012;22(Suppl):S15-S22.
9) Komaki S.,Ishikawa K. and Arakawa Y. Trk andcAMP-dependent survival activity of adenosine
A2A agonist CGS21680 on rat motoneurons in
culture. Neurosci Lett. 2012;522, 21-24.
10) Moritoyo T, Hasunuma T, Harada K, Tateishi T,
Watanabe M, Kotegawa T, et al. Effect of renal
impairment on the pharmacokinetics ofmemantine. J Pharmacol Sci. 2012;18;119(4):324-329.
11) Araki A, Iimuro S, et al. Long-term multiple risk
factor interventions in Japanese elderly diabetic
patients: the Japanese Elderly Diabetes
Intervention Trial--study design, baseline characteristics and effects of intervention. Geriatr
Gerontol Int. 2012;12 S1:7-17.
12) Araki A, Iimuro S, et al. Non-high-density
lipoprotein cholesterol: an important predictor ofstroke and diabetes-related mortality in Japaneseelderly diabetic patients. Geriatr Gerontol Int.
2012;12 S1:18-28.
13) Araki S, Nishio Y, Araki A, Umegaki H, Sakurai
T, Iimuro S, et al. Factors associated with
progression of diabetic nephropathy in Japanese474

elderly patients with type 2 diabetes: sub-analysisof the Japanese Elderly Diabetes Intervention
Trial. Geriatr Gerontol Int. 2012;12 S1:127-33.
14) Iijima K, Iimuro S, Ohashi Y, et al. Lower
physical activity, but not excessive calorie intake,is associated with metabolic syndrome in elderlywith type 2 diabetes mellitus: the Japanese
Elderly Diabetes Intervention Trial. Geriatr
Gerontol Int. 2012;12 S1:68-76.
15) Iijima K, Iimuro S, Shinozaki T, Ohashi Y, et al.
Lower physical activity is a strong predictor of
cardiovascular events in elderly patients with
type 2 diabetes mellitus beyond traditional risk
factors: the Japanese Elderly Diabetes Intervention Trial. Geriatr Gerontol Int. 2012;12 S1:
77-87.
16) Iimuro S, Yoshimura Y, Umegaki H, Sakurai T,
Araki A, Ohashi Y, et al. Dietary pattern andmortality in Japanese elderly patients with type 2
diabetes mellitus: does a vegetable- and fish-richdiet improve mortality? An explanatory study.
Geriatr Gerontol Int. 2012;12 S1:59-67.
17) Kamada C, Yoshimura H, Okumura R, Takahashi
K, Iimuro S, Ohashi Y, et al. Optimal energy
distribution of carbohydrate intake for Japaneseelderly patients with type 2 diabetes: theJapanese Elderly Intervention Trial. Geriatr
Gerontol Int. 2012;12 S1:41-9.
18) Sakurai T, Iimuro S, Sakamaki K, Umegaki H,
Araki A, Ohashi Y, et al. Risk factors for a 6-year
decline in physical disability and functional
limitations among elderly people with type 2
diabetes in the Japanese Elderly Diabetes
Intervention Trial. Geriatr Gerontol Int. 2012;12
S1:117-26.
19) Shinozaki T, Matsuyama Y, Iimuro S, et al.
Effective prevention of cardiovascular disease
and diabetes-related events with atorvastatin in
Japanese elderly patients with type 2 diabetes
mellitus: adjusting for treatment changes using amarginal structural proportional hazards modeland a rank-preserving structural failure timemodel. Geriatr Gerontol Int. 2012;12 S1:88-102.
20) Sone H, Tanaka S, Iimuro S, et al. Comparison ofvarious lipid variables as predictors of coronary
heart disease in Japanese men and women with
type 2 diabetes: subanalysis of the Japan Diabetes

Complications Study. Diabetes care. 2012;35(5):1150-7.
21) Takahashi K, Kamada C, Yoshimura H, Okumura
R, Iimuro S, Ohashi Y, et al. Effects of total andgreen vegetable intakes on glycated hemoglobin
A1c and triglycerides in elderly patients with
type 2 diabetes mellitus: the Japanese ElderlyIntervention Trial. Geriatr Gerontol Int. 2012;12
S1:50-8.
22) Umegaki H, Iimuro S, et al. Risk factors
associated with cognitive decline in the elderlywith type 2 diabetes: baseline data analysis of theJapanese Elderly Diabetes Intervention Trial.
Geriatr Gerontol Int. 2012;12 S1:103-9.
23) Umegaki H, Iimuro S, et al. Risk factors
associated with cognitive decline in the elderlywith type 2 diabetes: pooled logistic analysis of a
6-year observation in the Japanese Elderly
Diabetes Intervention Trial. Geriatr Gerontol Int.
2012;12 S 1:110-6.
24) Yamamoto T, Iimuro S, Ohashi Y, et al.
Long-term risk factors for diabetic retinopathy
and diabetic maculopathy in elderly Japanesepatients with type 2 diabetes mellitus. Geriatr
Gerontol Int. 2012;12 S1:141-4.
25) Yamamoto T, Iimuro S, Ohashi Y, et al.
Prevalence and risk factors for diabetic
maculopathy, and its relationship to diabetic
retinopathy in elderly Japanese patients with type2 diabetes mellitus. Geriatr Gerontol Int. 2012;12
S1:134-40.
26) Yamauchi T, Tamaki N, Kasanuki H, Kimura T,
Uemura Y, Iimuro S. Optimal initial diagnostic
strategies for the evaluation of stable angina
patients: a multicenter, prospective study on
myocardial perfusion imaging, computed tomographic angiography, and coronary angiography.
Circulation journal : official journal of theJapanese Circulation Society. 2012;76(12):2832-9.
27) Yoshimura Y, Kamada C, Takahashi K, Kaimoto
T, Iimuro S, Ohashi Y, et al. Relations of
nutritional intake to age, sex and body massindex in Japanese elderly patients with type 2
diabetes: the Japanese Elderly Diabetes
Intervention Trial. Geriatr Gerontol Int. 2012;12
S1:29-40.

475

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476

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 360,000
registrants, and approximately 60,000,000 monthly
website accesses, which is currently in the scale of theworld’s highest access rates. The service extends tostudy / education / medical examination and treatment/ hospital duties and encompasses many divergences
as indicated below:
 Research: http://www.umin.ac.jp/research
AC:
Information for Academic Conferences
ELBIS:
Electronic Library for Biomedical
Sciences
FIND:
Fund Information Database
INDICE: Internet Data and Information Center ofClinical Research

ROCOLS: Recruiting System for Our Colleagues’
and Students’ Education:
http://www.umin.ac.jp/education/
A Web-QME:
Web-based Quality Management System
for Education
SUPERCOURSE:
Online Lectures Compiled by Pittsburgh
Univ., U.S.A
VHP:
Visible Human Project Image Data
EPOC:
Evaluation System of Postgraduate
Clinical Training
Debut:
Dental Training Evaluation andTabulation System
 Medical Examination and Treatment
http://www.umin.ac.jp/uhosp/• Intoxication database• HIV treatment manual• Medical supplies and materials database• Drug information text database for patients• Drug information text database forpharmacists• Standardized nursing procedures database• Ministry of Education, Culture, Sports,
Science and Technology document public
information system• Basic hospital statistics database• National university hospital-related medical
dispute report• Collection of advanced medical procedures
application• Lists for people and committees• Various government official appointments,
administrative websites and ML
 General Services(1) General information and search• Medical / biology related websites• Medical terminology• A medical research organization / medical
institution database(2) Services for information providers• Web service for public• Web service for members• Website preservation service

477

•

Video-on-demand (VOD) and streaming
service(3) Communication support• E-mail• Listserv• 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 of Health Communication about research activities.

References
See Department of Health Communication page

478

Organ Transplantation Service
Director and Professor
Norihiro KOKUDO

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html

The University of Tokyo Hospital has aggressively
performed organ transplantation. In 1966, the firstkidney transplantation in Japan was performed. In
1996, the first living donor liver transplantation was
performed. Organ Transplant Service started tofunction since 2003. Until today, more than 400 casesof living donor liver transplantation has been
performed, and the 5-year survival rate is around 85%
which is much superior to the national average(~70%). The University of Tokyo Hospital has been
one of the authorized institutions for hearttransplantation
anddeceased
donor
liver
transplantation.

References (2010)
1. Song P, Tang W, Tamura S, Hasegawa K,
Sugawara Y, Dong J, Kokudo N. The managementof hepatocellular carcinoma in Asia: a guideline
combining quantitative and qualitative evaluation.
Biosci Trends 2010; 4:283-7.
2. 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.
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 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 of hepatocellular 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

479

K, Beck Y, Makuuchi M, Kokudo N. Intraoperative freehand real-time elastography forsmall focal liver lesions: "visual palpation" fornon-palpable tumors. Surgery 2010; 148:1000-11.
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 liver transplantation 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 and increasing
safety in liver resection for HCC: the Eastern
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. Evaluation ofdonor vasculobiliary anatomic variations in livergraft procurements. Surgery 2010; 147:30-9.
18. Kyoden Y, Tamura S, Sugawara Y, Matsui Y,
Togashi J, Kaneko J, Kokudo N, Makuuchi M.
Incidence and management of biliary complications after adult-to-adult living donor livertransplantation. Clin Transplant 2010; 24:535-42.

480

Center for Epidemiology andPreventive Medicine
Director & Professor
Tsutomu Yamazaki, M.D., Ph.D. (Clinical Research Support Center)

Associate Professor
Toru Suzuki, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Associate ＆Deputy Director
Yumiko Ohike, M.D., Ph.D.

Associates
Satoshi Ono, M.D.,Ph.D., Tomoko Nakao, M.D.,Ph.D., Lumine Matsumoto, M.D., Ph.D.
Daito Sawaki, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)
Yoshiko Mizuno,M.D., Ph.D. (Department of Clinical Epidemiology and Systems)
Mikio Takanashi, M.D., Ph.D. (Department of Clinical Epidemiology and Systems)

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 theCenter for Epidemiology and Preventive Medicine are1) 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481

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 nine physicians(four regular physicians and five 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 (full-time)
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) 2012 from April 1, to March 31,
2013, the total number of examinees (who had basic
examinations and optional examinations) was 6,519,
including 2,253 in basic examinations, 448 incomplete cardiovascular examinations, 24 in home
blood pressure screening, 601 in complete cerebrovascular examinations, 84 in check up dementia, 370
in colorectal cancer screening, 374 in uterine cancer
screening, 470 in breast cancer screening, 635 in lungcancer screening, 786 in tumor marker diagnosis, 394
in estimation of gastric cancer risk, 12 in uppergastrointestinal endoscopy (later),and 68 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 2012, we issued 812
letters of referral to other departments in our hospitaland 115 to other hospitals.
We have expanded our public relations efforts andduring the FY 2012 15,000 brochure were delivered.

482

We also prepared posters which were placed within
our hospital and on the campus of the University ofTokyo as well (60 posters). Our homepage (the above
URL) has been constantly updated to provide thelatest information for examinees.

References
Academic Papers in English(1) Garrido-Martín EM, Blanco FJ, Roque M,
Novensà L, Tarocchi M, Lee UE, Suzuki T,
Friedman SL, Botella LM, Bernabeu C. Vascular
injury triggers Krüppel-like factor 6 (KLF6)
mobilization and cooperation with Sp1 topromote endothelial activation through upregulation of the Activin Receptor-Like Kinase 1(ALK1) gene.Circ Res, 2012, 112(1), 113-27.
(2) Bossone E, Suzuki T, Eagle KA, Weinsaft JW.
Diagnosis of Acute Aortic Syndromes - Imaging
and Beyond. Herz, 2012 Dec 23.
(3) Di Eusanio M, Trimarchi S, Patel HJ, Hutchison
S, Suzuki T, Peterson MD, Di Bartolomeo R,
Folesani G, Pyeritz RE, Braverman AC,
Montgomery DG, Isselbacher EM, Nienaber CA,
Eagle KA, Fattori R. Clinical presentation,
management, and short-term outcome of patientswith type A acute dissection complicated bymesenteric malperfusion: Observations from theInternational Registry of Acute Aortic Dissection.
J Thorac Cardiovasc Surg, 2012, 145(2): 385390.
(4) Ishida J, Suzuki T, Aizawa K, Sawaki D, Nagai R.
Comparison of Analytical Performance of Two
Single-step Measurement Devices of B-type
Natriuretic Peptide. Int Heart J, 2012, 53:320323.
(5) Suzuki T, Tomiyama H, Higashi Y. Vascular
dysfunction even after 20 years in children
exposed to passive smoking- alarming results andneed for awareness. Arterioscler Thromb Vasc
Biol, 2012, 32:841-842,(6) Suzuki T, Isselbacher EM, Nienaber CA, Pyeritz
RE, Eagle KA, Tsai TT, Cooper JV, Januzzi JL Jr,
Braverman AC, Montgomery DG, Fattori R,
Pape L, Harris KM, Booher A, Oh J, Peterson M,
Ramanath VS, Froehlich JB. Type-selective
benefits of medications in treatment of acuteaortic dissection; (from the International Registryof Acute Aortic Dissection [IRAD]). Am J
Cardiol, 2012, 109:122-127.
(7) Ono S, Fujishiro M, Kodashima S, Takahashi Y,
Minatsuki C, Mikami-Matsuda R, Asada-Hirayama
I, Konno-Shimizu M, Tsuji Y, Mochizuki S, Niimi
K, Yamamichi N, Kaneko M, Yatomi Y, Koike K.
Evaluation of safety of endoscopic biopsy
without cessation of antithrombotic agents inJapan. J Gastroenterol 2012;47(7):770-4(8) Ono S, Fujishiro M, Koike K. Endoscopic
submucosal dissection for superficial esophageal
neoplasms. World J Gastrointest Endosc 2012;
4(5):162-6(9) Nakao T, Watanabe H, Takeda N, Takanashi S,
Nagai R. The efficacy of real-time threedimensional transoesophageal echocardiography
in detecting unicuspid aortic valve. Eur Heart J
Cardiovasc Imaging. 2012 ;13(11): 966.
International Conferences(1) American heart association scientific session
2012 (Los Angeles, CA, USA: 2012/11/5-8) Toru
Suzuki, Eric M Isselbacher, Kim A Eagle,
Christoph A Nienaber, Daigo Sawaki, Lindsay M
Hagan, Daniel G Montgomery, James B
Froehlich, Effect of Medical Treatment for Aortic
Dissection on In-Hospital Mortality and FollowUp Aortic Expansion in Patients with andWithout Marfan Syndrome; Observations fromthe International Registry of Acute Aortic
Dissection(2) American heart association scientific session
2012 (Los Angeles, CA, USA: 2012/11/5-8)
Eduardo Bossone, Kevin M Harris, Toru Suzuki,
Rossella Fattori, Stuart Hutchison, Marek P
Ehrlich, Reed E Pyeritz, P. Gabriel Steg, Kevin
Greason, Arturo Evangelista, Matthias Voehringer,
Daniel G Montgomery, Eric M Isselbacher,
Christoph A Nienaber, Kim A Eagle, Stroke andOutcomes in Patients with Acute Type A Aortic
Dissection.
(3) American heart association scientific session
2012 (Los Angeles, CA, USA: 2012/11/5-8) Dan
Gilon, Reed E Pyeritz, Arturo Evangelista,
Patrick O'Gara, Kevin M Harris, Alan C
Braverman, Mark D Peterson, Matthias

483

Voehringer, Toru Suzuki, Lori D Conklin, Daniel
G Montgomery, Eric M Isselbacher, Christoph A
Nienaber, Kim A Eagle, Amit Korach, Is
Conservative Treatment Justified in Marfan
Syndrome Patients with Non-Complicated AcuteType B Aortic Dissection? Insights from theInternational Registry of Acute Aortic Dissection.
(4) American heart association scientific session
2012 (Los Angeles, CA, USA: 2012/11/5-8)
Junichi Ishida, Toru Suzuki, Kenichi Aizawa,
Daigo Sawaki, Takayoshi Matsumura, Scott L
Friedman, Ryozo Nagai, Krüppel-like Factor 6
Promotes Obesity and Glucose Intolerance
Through Adipocyte Differentiation.
(5) American heart association scientific session
2012 (Los Angeles, CA, USA: 2012/11/5-8) Bo
Kyung Son, Toru Suzuki, Daigo Sawaki, Kenichi
Aizawa, Hong Zhan, Junichi Ishida, Takayoshi
Matsumura, Ryozo Nagai, KLF6 Modulates Aortic
Aneurysm Formation by Balancing Between
Inflammatory and TGFβ Signaling Pathways(6) American heart association scientific session
2012 (Los Angeles, CA, USA: 2012/11/5-8)
Daigo Sawaki, Toru Suzuki, Kenichi Aizawa,
Takayoshi Matsumura, Yoshiko Munemasa,
Junichi Ishida, Scott Friedman, Ryozo Nagai,
Cardiomyocyte Regulates Cardiac Fibrosis throughCell to Cell Interaction Mediated by KLF6.
(7) European society of cardiology congress 2013
(Munich, Germany: 2012/8/25-29 E. Bossone, A.
Korach, R. Fattori, G.C. Hughes, T.T. Tsai, D.G.
Montgomery, K.A. Eagle, C.A. Nienaber, E.M.
Isselbacher, T. Suzuki, Racial differences inacute aortic dissection: insights from theInternational Registry of Acute Aortic Dissection(8) FASEB Summer Research Conference "Biology& Pathobiology of Kruppel-Like Factors (KLFs)"(Snowmass, Colorado, USA: 2012/8/5-9) Suzuki
T. KLF6 in cardiovascular and metabolic disease.
(9) FASEB Summer Research Conference "Biology& Pathobiology of Kruppel-Like Factors (KLFs)"(Snowmass, Colorado, USA: 2012/8/5-9) Sawaki
D. Krüppel-like Factor 6 Modulates Recruitment
and Polarization of Inflammatory Cells throughCardiomyocytes in Initiation of Cardiac Fibrosis.
(10) Mizuno Y, Suzuki T, Takahide K, Yamazaki
T, Nagai R. B-type Natriuretic Peptide and

Subclinical Atherosclerosis in Healthy Population.
American Heart Association Scientific Sessions
2012 (Los Angeles 11/3-7, 2012)(11) American college of cardiology scientific session
2012 (Chicago, IL, USA: 2012/3/24-27) Hasan
Siddiqi, Eric Isselbacher, Toru Suzuki, Daniel
Montgomery, Linda Pape, Rossella Fattori,
Patrick O'Gara, Guillaume Jondeau, Emil Missov,
Alberto Forteza, Eduardo Bossone, Alan Hirsch,
Adam Rogers, Christoph Nienaber, Kim Eagle,Is
Size a Good Predictor of Dissection Risk inPatients with Marfan Syndrome or Bicuspid
Aortic Valves? Insights from the International
Registry of Acute Aortic Dissection (IRAD)(12) American college of cardiology scientific session
20132 (Chicago, IL, USA: 2012/3/24-27)
Lindsay Hagan, Kevin Greason, Artur
Evangelista Masip, Daniel Montgomery, Patrick
O'Gara, Mark Peterson, Gilbert Upchurch, Toru
Suzuki, Stuart Hutchison, Eva Kline-Rogers,
Nicole Corriveau, Thomas Gleason, ChristophNienaber, Eric Isselbacher, Kim Eagle, John
Ritter Syndrome - Acute Type A Dissection
Causing Acute Myocardial Infarction: Insightsfrom the International Registry of Acute Aortic
Dissection (IRAD)(13) American college of cardiology scientific session
2012 (Chicago, IL, USA: 2012/3/24-27) Alan C.
Braverman, Kevin Harris, Reed Pyeritz, Stuart
Hutchison, Linda Pitler, Arturo Evangelista,
Magnus Larsen, Jane Humphrey, Andrea
Bullinger, Matthias Voehringer, Patrick O'Gara,
Toru Suzuki, Christoph Nienaber, Eric
Isselbacher, Kim Eagle, Aortic Dissection During
Pregnancy: Results from the International
Registry of Acute Aortic Dissection (IRAD)

484

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.

Satoru Yamagami, M.D., Ph.D.

Research Associates
Makoto Komura, M.D., Ph.D.,

Osamu Takase, M.D., Ph.D.

Yuko Fujihara, D.D.S., Ph.D.,

Hironari Masuda, M.D., Ph.D.,

Yutaka Miura, 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 Advanced Nephrology & Regenerative
Medicine, Department of Cartilage & BoneRegeneration, 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 and abroad. One project associate
professor and one or two project research associates
who are assigned to each department are conducting
research with many post graduate students. Aiming at
clinical application within a few years, the researchers
continue their studies to make the center function as atranslational 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

485

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.
March, 2012 Department of Advanced Nephlorogy
and Regenerative Medicine founded by a donationfrom Zenjinkai.

Research activities
As for corneal regeneration, we aim at constructionof regenerated cornea, clinical application of more
improved corneal epithelial sheet transplantation forocular surface reconstruction, and establishment andclinical application of corneal endotheliumtransplantation.
To achieve these goals, we are conducting
functional analysis on reconstruction of cornea with
cultured epithelium, endothelium, and artificial stroma,
research on adult stem cell biology and manipulation
technology in corneal tissues and amniotic membranefor ocular surface reconstruction. We perform a
research to make it possible to create regenerative
tissues with low cost. This should be useful togenerate industries of regenerative medicine.
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 achieve thesegoals, we are conducting research on angiogenic genetherapy 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. Regarding theclinical study “Development of implant-type tissueengineered cartilage for patients with nasal deformity
in cleft lip and palate”, which was authorized to
conduct on Mar 18th 2011, we have completed thetransplantation on 3 patients as had been planned. The
outcomes have been good so far with no majorcomplications.

486

As for renal regeneration, we aim at specificmethod to differentiate human iPS cells to kidney cells.
To achieve these goals, we are conducting epigenetic
analysis of human kidney derived iPS cells.
Moreover, we are trying to establish 3-D culture
system for safe clinical application of human iPS cells,
and determining new target of cancer therapy bycomprehensive epigenetic analysis of cancer dereived
iPS cells.
As for regenerative medicine for hematopoiesis, we
aim to develop effective systems for in vitro
expansion of cord blood hematopoietic stem cells(CB-HSCs) and its clinical application to humanhematopoietic stem cell transplantation, and for
inducing various hematopoietic components from
HSCs and embryonic stem cells. To achieve thesegoals, we are conducting research on the regulatory
mechanisms of proliferation, self-renewal, anddifferentiation of human hematopoietic stem cells(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 the four
departments as a result of basic research. In Projectfor Regenerative Medicine of Hematopoiesis, clinicalstudy 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 we have conducted 3
cases of the clinical study according to our originalplan. As stated above, we are proceeding translational
research aiming at clinical application of tissue
engineering and regenerative medicine.

487

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. Nakagawa S, Usui T, Yokoo S, Omichi S,
Kimakura M, Mori Y, Miyata K, Aihara M,
Amano S, Araie M. Toxicity evaluation of
antiglaucoma drugs using stratified humancultivated corneal epithelial sheets. Invest
Ophthalmol Vis Sci..2012;Aug 3;53(9) :5154-60.
2. Takaoka-Sugihara N, Yamagami S, Yokoo S,
Matsubara M, Yagita K. Cytopathic effect ofAcanthamoeba on human corneal fibroblasts. Mol
Vis. 2012;18:2221-8. Epub 2012 Aug 9.
3. Kimoto M, Shima N, Yamaguchi M, Amano S,
Yamagami S. Role of hepatocyte growth factor inpromoting the growth of human corneal
endothelial cells stimulated by L-ascorbic acid2-phosphate. Invest Ophthalmol Vis Sci. 2012
Nov 9;53(12):7583-9.
4. Mimura T, Obata H, Usui T, Mori M, Yamagami S,
Funatsu H, Noma H, Amano S. Pinguecula anddiabetes mellitus. Cornea. 2012 Mar;31(3):264-8.
5. Sugita S, Kawazoe Y, Yamada Y, Imai A, Horie S,
Yamagami S, Mochizuki M. Inhibitory effect ofcorneal endothelial cells on IL-17-producing Th17
cells. Br J Ophthalmol. 2012 Feb;96(2):293-9.
6. Itoh S, Saito T, Hirata M, Ushita M, Ikeda T,
Woodgett JR, Algül H, Schmid RM, Chung UI,Kawaguchi H. GSK-3α and GSK-3β proteins are
involved in early stages of chondrocyte
differentiation with functional redundancy
through RelA protein phosphorylation. J Biol
Chem. 287:29227-36, 2012.
7. 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, Kawaguchi H.

C/EBPβ and RUNX2 cooperate to degrade
cartilage with MMP-13 as the target and HIF-2α
as the inducer in chondrocytes. Hum Mol Genet.
21:1111-23, 2012.
8. Fukai A, Kamekura S, Chikazu D, Nakagawa T,
Hirata M, Saito T, Hosaka Y, Ikeda T, Nakamura
K, Chung UI, Kawaguchi H. Lack of a chondroprotective effect of cyclooxygenase 2 inhibition ina surgically induced model of osteoarthritis inmice. Arthritis Rheum. 64:198-203, 2012.
9. Yonenaga K, Nishizawa S, Fujihara Y, Asawa Y,
Kanazawa S, Nagata S, Takato T, Hoshi K.
Application of floating cells for improved harvest
in human chondrocyte culture. Biomed Res. 2012;33(5):281-9.
10. Ochiai H, Okada S, Saito A, Hoshi K, Yamashita
H, Takato T, Azuma T. Inhibition of insulin-likegrowth factor-1 (IGF-1) expression by prolonged
transforming growth factor-β1 (TGF-β1) administration suppresses osteoblast differentiation. J
Biol Chem. 2012 Jun 29;287(27):22654-61.
11. Asawa Y, Sakamoto T, Komura M, Watanabe M,
Nishizawa S, Takazawa Y, Takato T, Hoshi K.
Early stage foreign body reaction against
biodegradable polymer scaffolds affects tissue
regeneration during the autologous transplantationof tissue-engineered cartilage in the canine model.
Cell Transplant. 2012;21(7):1431-42.
12. Suzuki K, Kanamori Y, Sugiyama M, Komura M,
Terawaki K, Kodaka T, et al. Plasma citrulline
may be a good marker of intestinal functions in
intestinal dysfunction. Pediatr Int. 2012;54(6):899-904.
13. Asawa Y, Sakamoto T, Komura M, Watanabe M,
Nishizawa S, Takazawa Y. et al. Early stage
foreign body reaction against biodegradable
polymer scaffolds affects tissue regeneration
during the autologous transplantation of tissueengineered cartilage in the canine model. Cell
Transplant. 2012;21(7):1431-42.
14. Suzuki K, Kanamori Y, Sugiyama M, Komura M,
Terawaki K, Kodaka T, et al. Plasma citrulline
may be a good marker of intestinal functions in
intestinal dysfunction. Pediatr Int.2012;54: 899904.
15. Kanamori Y, Terawaki K, Takayasu H, Sugiyama
M, Komura M, Kodaka T, et al. Interleukin 6 and488

interleukin 8 play important roles in systemic
inflammatory response syndrome of meconium
peritonitis. Surg Today. 2012; 431-434.
16. Kanamori Y, Terawaki K, Takayasu H, Sugiyama
M, Komura M, Kodaka T, et al. Interleukin 6 andinterleukin 8 play important roles in systemic
inflammatory response syndrome of meconium
peritonitis. Surg Today. 2012 ;42(5):431-4.

489

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.,Hidenao Atarashi, C.E., M.P.H.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kikakukeiei/index.html

Introduction and Organization
In recent years, the medical system in Japan has
been experiencing times of major change. University
hospitals, as well, have been under pressure forsweeping reforms. There are demands, greater thanever before, for the development and practicalapplication of high-quality advanced medical
treatment, and for the efficient promotion of graduate
and postgraduate education, and of clinical research.
And there are demands for those results to be
expressed clearly to Japanese citizens in specific terms.
In April 2004, as the University of Tokyo wasincorporated under the National University
Corporation Law, the University of Tokyo Hospital
underwent drastic organizational restructuring. In
addition to the establishment of Hospital Executives,
there was also the launch of four organizations that
support hospital management (Hospital Planning andManagement; Personnel Administration and Human
Resources;
Performance
Monitoring,
Risk
Management, and Staff Development; and Education
and Research Support) and three organizations that
support clinical management (Inpatient Service
Administration; Outpatient Service Administration;
and Central Hospital Service Administration).
Hospital Planning and Management is a key
working organization in the management of thehospital. It has two full-time faculty members fromthe Department of Planning, Information andManagement, and boasts a team of two pharmacists,

two nurses, one engineering staff member, and 12
administrative staff.

Clinical activities
Hospital Planning and Management is responsible
for all of the organizational and strategic businessaffairs of the University of Tokyo Hospital. It
conducts the following kinds of clinical-management
duties.
(1) Analysis of hospital management
The division manages and analyzes hospital
accounting information, and conducts hospitalmanagement analyses by utilizing management
information and standardized hospital information.
(2) Planning
Based on the hospital management analyses, thedivision designs short-term management planningand strategy, and provides effective support for
the Hospital Executives to make swift management decisions. The division is also responsible
for formulating medium- and long-term plans.
Following is a list of hospital management
achievements in which Hospital Planning andManagement was deeply involved.
・ “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490

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 hospital buildings.
At the same time, the division has worked todevelop an environment in which medical carestaff can provide high-quality and safe medical
treatment in a more composed fashion.
(3) Medical policy recommendations
The division is not just restricted to the
management of the University of Tokyo Hospital.
It also actively implements policy recommendations aimed at improving the medical system 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

491

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.

492

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 2012, the Department of Child
Psychiatry consisted of 11 psychiatrists and 10
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 &adolescent Obsessive-Compulsive Disorders (OCD).
Number of new patients in 2012 was 252 andlarger than that in 2011. A large part of the newpatients consisted of patients with ASD, tic disorderor ADHD. Although establishment of Tic/OCD
clinic might make a slight change, general trend of
the patients were similar to that of the previous
years. Seventy-one patients were aged 6-10 years
old and 73 patients were older than 20 years old,suggesting that needs for assessment and treatmentof adults with developmental disorders are
increasing.

493

The follow-up clinic consisted of general clinicand special clinics (high-functioning ASD clinic
and Tic/OCD clinic). At the general clinic, arigorous diagnosis based on detailed assessment
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 theareas of pharmacotherapy, psychotherapy, psychoeducation and also work closely with the schools
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 was provided. This CBT
program included sessions about features of ASD,
emotion, stress coping and relaxation.
Parent-training for parents with ADHD children,which started in 2011, was provided.
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. A senior resident ofneuropsychiatry who wanted training of childpsychiatry participated in one program for a few
months, and had some experience of abovementioned activities.
In response to the increasing interest to adults
with developmental disorders, a seminar ofdevelopmental disorders was held in June 2012, andover 240 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494

Ohta Staging (an evaluation system using symbol
development for cognitive developmental therapy
developed in the former child division of the
Department of Neuropsychiatry) and investigationof the effectiveness of present interventions forchildren with ASD are being conducted.
A comparison study of the effectiveness of
individual treatment and “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. Kuwabara H, Kono T, Shimada T, Kano Y:
Factors affecting clinicians' decision as towhether to prescribe psychotropic medications
or not in treatment of tic disorders. Brain Dev.
34(1): 39-44, 2012.
2. Matsuda N, Kono T, Nonaka M, Shishikura K,
Konno C, Kuwabara H, Shimada T, Kano Y:
Impact of obsessive-compulsive symptoms in
Tourette's syndrome on neuropsychological
performance. Psychiatry Clin Neurosci. 66(3):
195-202, 2012.
3. Shimada T, Kitamoto A, Todokoro A,
Ishii-Takahashi A, Kuwabara H, Kim SY,
Watanabe K, Minowa I, Someya T, Ohtsu H,
Osuga Y, Kano Y, Kasai K, Kato N, Sasaki T:
Parental age and assisted reproductive technology in autism spectrum disorders, attention
deficit hyperactivity disorder, and Tourette
syndrome in a Japanese population. Res Autism
Spectr Disord. 6(1): 500-507, 2012.
4. Watanabe T, Yahata N, Abe O, Kuwabara H,
Inoue H, Takano Y, Iwashiro N, Natsubori T,
Aoki Y, Takao T, Sasaki H, Gonoi W,
Murakami M, Katsura M, Kunimatsu A,
Kawakubo Y, Matsuzaki H, Tsuchiya KJ, Kato
N, Kano Y, Miyashita Y, Kasai K, Yamasue H:
Diminished medial prefrontal activity behind
autistic social judgments of incongruent
information. PLoS ONE. 7(6): e39561, 2012.
5. Aoki Y, Abe O, Yahata N, Kuwabara H,
Natsubori N, Iwashiro N, Takano Y, Inoue H,
Kawakubo Y, Gonoi W, Sasaki H, Murakami
M, Katsura M, Nippashi Y, Takao H,
Kunimatsu A, Matsuzaki H, Tsuchiya KJ, Kato
N, Kasai K, Yamasue H: Absence of
age-related prefrontal NAA change in adults
with autism-spectrum disorders. Translational

495

Psychiatry, 2: e178, 2012.
6. Kamio Y, Inada N, Moriwaki A, Kuroda M,
Koyama T, Tsujii H, Kawakubo Y, Kuwabara
H, Tsuchiya K, Uno Y, Constantino JN: Quantitative autistic traits ascertained in a national
survey of 22,529 Japanese schoolchildren. Acta
Psychiatr Scand (in press).
7. Yamagishi T, Horita Y, Mifune N, Hashimoto
H, Li Y, Shinada M, Miura A, Inukai K,
Takagishi H, Simunovic D: Rejection of unfair
offers in the ultimatum game is no evidence ofstrong reciprocity. Proc Natl Acad Sci U S A.
109(50): 20364-20368, 2012.

496

Department of Palliative Medicine
Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/pailiative.html

History and outline of organization
About a half of the cancer patients die of cancer
despite of the recent innovation of anticancer therapy.
It mainly depends on the efficacy of the first-line
strategies whether the cancer is curable or not. Almost
all the patients whose initial treatment was
unsuccessful die after the distressing struggle against
his disease within several years. It is clear for suchpatients that both sufficient anticancer therapies andappropriate approaches to improve their quality of life
(QOL) are simultaneously indispensable.
However in our country, most attention has been
entirely paid to the improvement of cure rate andsurvival time of cancer patients. On the other hand, we
have to say that their QOL is scarcely concentrated
until quite recently.
Palliative care means the combination of active
therapeutic approach and total human care for thepatients no matter which his cancer does or does not
respond to anticancer treatments. Pain relief, othersymptom management, psychological, social andspiritual cares are as a top priority for these patients. It
is also emphasized that palliative care is necessary to
be applied in the cancer treatment even for patients inearly stage of their diseases as well as the progressiveor terminal phase of their clinical courses.
In Department of Palliative Medicine of The
University of Tokyo Hospital, we palliative care teamtakes a leading role not only to control physicalsymptoms of patients but also to care for the mental
and social support at the same time, and to improve
the overall QOL of patients. Moreover, we also
promote the education, research and innovation of
palliative medicine of our hospital and university.
Palliative care is described clearly in the law "Cancer
Control Act" approved by the National Diet on June

2006 that "The medical treatment to aim at relieving
many kinds of pain and problems of cancer patients is
applicable from the early course of the illness".

Consultation
In The University of Tokyo Hospital, we palliative
care team are composed of many kinds of specialists
containing three full-time staff doctors, two full-time
doctors, and two certificated cancer and hospice carenurses who take an initiative in this multidisciplinary
team. We visit to bedsides, consultation rooms andeverywhere in the hospital, and offer palliative care to
the patients who have received cancer care incooperation with patients’ attending doctors, ward
staff, therapists of rehabilitation, social workers andevery kind of professionals.
In 2012, the annual number of consultation by thepalliative care team was 492, the maximum number ofconsultations since team was organized. To date wehave become to collaborate with almost all
departments treating cancer in our hospital. These
results indicate that the hospital understands thesignificance of palliative care well and relies on our
team.

Education
In the Department of Palliative Medicine, juniorresidents of the first and second year can learn thebasic knowledge and practice of palliative care by
selecting an optional subject for one, two, four oreight months. And then they can participate in thepalliative care team and attend the daily
team-conference on weekdays.

4971) Palliative care training program
The training course (selection) for two months ( or *for one month )･ Program to acquire basic knowledge and practice ofpalliative care for targeting all junior residents. *Only in "Comprehensive Internal Medicine”
selection.
The training course (selection) for four or eightmonths･ Program to acquire basic knowledge, practice, andskills of communication for doctors who need to beclinical oncologists or palliative care specialists.
2) CurriculumContents of training･ All junior residents are assigned to the palliative
care team. They chiefly participate in palliative carepractice as a member of the team.
･ In the course for four and eight months, they learn
to make palliative care plans for inpatients, discuss
palliative care of the cases with patients’ attending
doctors, ward staff, and execute these palliative careplans.
Goal to attain･ Palliative care for inpatients (around 40 cases aday): They acquire the outline of control of physicaland psychiatric symptoms of the patients with
common diseases in our country such as digestivecancers. They also learn the outline of spiritual andfamily 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 theclinical data about palliative care of such patientsconcisely to the database. They acquire the outlineof data management of the palliative care connected
directly to a clinical research.
･ Communicative competence: The clinician often
has to break "Bad news" to his patients time after
time along the course of their illness. It is very
difficult for the clinician to provide the appropriate
information about diagnoses, recurrence, progression and prognosis of illness to his patients.

The oncologist has to deal with patients’ strong grief
and feeling of loss when their illness is obviously
progressive as well as has to manage both theiraccepting realities and expecting hopes. We practiceaccording to the guidelines of communication that isrecommended by the Japanese Psycho-Oncology
Society.
Educational･ In the intensive course for the first-year residents,
we prepare lectures about:# pain management# diagnoses and management of delirium# Introduction of guidelines in the field of palliative
medicine and their use# Basic medication for palliative care
# Spirituality and whole person care for Japanesepatients facing death
Daily and weekly schedule･ Conference: Monday-Friday (every weekday);9:00-10:30am･ Consultation: Monday-Friday (every weekday);from the end of morning conference, up to thecompletion of all the requested consulting of theday.
･ The cancer registry: They input data in the ward
round with the HIS (Hospital information system)
terminal on each floor.
The instruction system･ Inpatient care: Residents participate in the
consultation team (palliative care team) that
contains medical instructors. We palliative careteam take charge of about 30-50 inpatients usually.
･ Multidisciplinary conference: Psychiatrists, pain
clinicians, orthopaedicians, pharmacists, medicalsocial workers and others participate in the daily or
weekly conference besides the regular member ofthe palliative care team. Residents can discuss
actively the multidisciplinary palliative care plans
which our team should carry out. Participants fromeach occupation also guide the care plans from their
viewpoints of experts.

Research
The clinical information accumulated from thepalliative care consultation is input to the concise
database simultaneously and utilized for various kinds

498of clinical researches to submit to the international
medical journal such as "International Journal of
Radiation Oncology Biology Physics", "Journal ofPain and Symptom Management" and so on.
To date, we the Department of Palliative Medicine
have contributed to the progress of following fields ofinvestigations. Please refer to our homepage forresults in details and acquisition of the research fund.
1) Evaluation and quality assurance of special
palliative care team2) Development of the scale to measure thedesirability of the death and bereavement and its
application to the nationwide survey3) 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
1. 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
2. Takahashi W. Yamashita H. Saotome N. Iwai Y.
Sakumi A. Haga A. Nakagawa K. Evaluation ofheterogeneity dose distributions for Stereotactic
Radiotherapy (SRT): comparison of commerciallyavailable Monte Carlo dose calculation with otheralgorithms. Radiation Oncology. 2012;7:20, 2012.
3. 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 a binary
multileaf collimator synchronized with the rotationof the gantry for helical tomotherapy. Journal ofApplied 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 and irradiateddose of small bowel in CT-based planning of
intracavitary brachytherapy for cervical cancer.
Japanese Journal of Clinical Oncology. 2012;42(4):302-8.
5. 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.
6. Kawaguchi T. Iwase S. Koinuma M. Onodera
Y. Takeuchi H. Umeda M. Matsunaga T.
Unezaki S. Nagumo Y. Determinants affecting
quality of life: implications for pharmacist
counseling for patients with breast cancer in Japan.
Biological & Pharmaceutical Bulletin. 2012; 35(1):59-64.
7. Yamaguchi T, Morita T, Shinjo T, Inoue S,
Takigawa C, Aruga E, Tani K, Hara T, Tamura Y,
Suga A, Adachi S, Katayama H, Osaka I, Saito Y,
Nakajima N, Higashiguchi T, Hayashi T, Okabe
T, Kohara H, Tamaki T, Chinone Y, Aragane H,
Kanai Y, Tokura N, Yamaguchi T, Asada T,
Uchitomi Y.Effect of Parenteral Hydration
Therapy Based on the Japanese National Clinical
Guideline on Quality of Life, Discomfort, andSymptom Intensity in Patients With Advanced
Cancer. Journal of Pain and Symptom
Management. 2012; 43(6):1001-12.
8. Shibata-Kobayashi S, Yamashita H, Okuma K,
Shiraishi K, Igaki H, Ohtomo K, Nakagawa K.
Correlation among 16 biological factors [p53,p21(waf1), MIB-1 (Ki-67), p16(INK4A), cyclin
D1, E-cadherin, Bcl-2, TNF-α, NF-κB, TGF-β,
MMP-7, COX-2, EGFR, HER2/neu, ER, andHIF-1α] and clinical outcomes following curative
chemoradiation therapy in 10 patients with esophageal squamous cell carcinoma. Oncol Lett. 2013;
5(3):903-10.
9. Onoe T, Nose T, Yamashita H, Yoshioka M,
Toshiyasu T, Kozuka T, Oguchi M, Nakagawa K.
High-dose-rate interstitial brachytherapy for
gynecologic malignancies-dosimetric changes
during treatment period. J Radiat Res. 2013 Jan 7.
10. Haga A, Sakumi A, Okano Y, Itoh S, Saotome N,
Kida S, Igaki H, Shiraishi K, Yamashita H,
Ohtomo K, Nakagawa K. Dose verification of
volumetric modulated arc therapy (VMAT) by useof in-treatment linac parameters. Radiol Phys
Technol. 2013 Mar 12.
11. Takahashi W, Yamashita H, Kida S, Masutani Y,499

Sakumi A, Ohtomo K, Nakagawa K, Haga A.
Verification of planning target volume settings involumetric modulated arc therapy for stereotactic
body radiation therapy by using in-treatment
4-dimensional cone beam computed tomography.
Int J Radiat Oncol Biol Phys. 2013;86(3):426-31.

500

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 tobe 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.

501

Genome Informatics
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 andefficient application of results of recently advanced
human genetics and genomics. In addition, as the unitof training and educating specialists of clinicalepidemiology and human genetics. It consists of one
professor and different specialties participating in thedepartment. They include cardiologists, diabetologists,
epidemiologists, and statisticians. Our section also
supported designing of clinical / genetic studies andprovided services of anonymizing clinical data /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 10,524,368 variants
derived from 286 East Asian subjects (November
2010 Release) in 5,976 cases and 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 in addition to variants of the previously
reported loci, there were 25 loci harboring multiple
variants possibly associated with T2D. We areconducting a replication study to confirm theassociation in another 7,000 cases and 3,500 controls.
Our study highlights the benefits of using data derived

from next-generation sequencing of the humangenome such as the 1000 Genomes Project to explore
T2D loci more comprehensively. 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 andfound novel T2D loci in East Asian populations.
These findings highlight the usefulness of conducting
GWAS to clarify the genetic predisposition to T2D in
East Asians as well as in European-origin populations.
In cardiology and vascular medicine, we focused onatherosclerotic diseases such as coronary stenosis andmyocardial infarction. It is important to accumulate
and analyze data obtained in daily practice to 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
our institution, we showed that (1) macrocytosis, as aqualitative abnormality of erythrocytes, is significantly and independently associated with adverse
outcomes after percutaneous coronary intervention(aHR of cardiac death: 3.45, 95%CI: 1.22-9.80,

502

P=0.019) and (2) serum concentrations of IgG4 andsIL-2R were increased in patients with CAD.
Concerning genetic analysis of monogenic diseases,
our department has provided service of genetic
analysis of Marfan syndrome (MFS), one of therepresentative connective tissue diseases.
Approximately 70-80% of MFS is caused by genetic
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 theclinical 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 requirementof 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 Metaanalysis (DIAGRAM) Consortium, Nakamura Y,
Kadowaki T. A single-nucleotide polymorphismin ANK1 is associated with susceptibility to type

4:

5:

6:

7:

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 of macrocytosis 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 microarraybased mutational analysis of fibrillin-1 gene. Am
J Cardiol 2011;108: 1801-7.

503

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 as a
special unit conducting genomic medicine or clinicalhuman genetics services in 2003. Our department
functions as the core unit to accomplish an appropriate
and efficient application of results of recently
advanced human genetics and genomics to clinicalpractice in the hospital and as the unit of training andeducating specialists of human genetics practice. It
consists of one professor and many different
specialties participate in the department. They include
pediatricians, obstetricians, internist (cardiologists,diabetologists, and neurologists),dermatologists,and staffs of the Departments of Clinical Laboratory
Medicine, Human Genetics and Nursing Science.

Activities
The exclusive consultation room (Room 200) is
allocated in the outpatient clinic. Consultation andcounseling is performed by a team of medical doctor
and non-M.D. staffs. All cases are reviewed anddiscussed at the conference which is held on the 1st
Wednesday every month.
Counseling of participants in researches including
genome or gene analysis is a duty with which thehospital and the faculty charge the department.
To build suitable clinical systems including
modern genomic medicine we are cooperating withother departments. We are participating in Marfan’sSyndrome Clinic which is managed collaboratively by
the Departments of Cardiovascular Surgery, Cardio-

vascular Medicine, Pediatrics, Spinal Surgery andOphthalmology.
In collaboration with Clinical Laboratory Center,
Pharmaceutical Services, Departments of Planning
Information and Management, and several clinicaldepartments we started pharmacogenetics tests in2006. Those include tests for proton inhibitor,
warfarin, irinotecan, and tacrolimus.

References
1. 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
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 B,
Takahashi Y, Ichikawa Y, Goto J, Sakai T, Tsuji S.

504

4.

5.

6.

7.

8.

9.

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 whitematter with novel 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,
McCluskey L, Trojanowski JQ, Van Deerlin VM,

505

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 requirementof 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, Nakamura Y, Kadowaki
T. A single-nucleotide polymorphism in ANK1 is
associated with susceptibility to type 2 diabetes inJapanese populations. Hum Mol Genet. 21:3042-9,
2012

506

Center for Genome Medicine
Genomic Analysis Department
Director
Shoji Tsuji, M.D., Ph.D.

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,
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507

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 inherited leukoencephalopathy. Amer. J. Med. Genet. Neuropsych. Genet.
(in press)

508

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 the development of a next generation medical technology.
2002 June. The establishment of Cooperative Unitof Medicine and Engineering Research was approvedby a hospital administration committee as a special
practice unit that belongs to The University of Tokyo
Hospital.
2002 September. A steering committee of
Cooperative Unit of Medicine and Engineering

Research 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

509

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 place2013 January 25. Development forum of advanced
medical seeds took place

Research activities
Development of Advanced Sterotactic Rediation
Cancer Therapy System
Department of Radiology
Nuclear Professional school, Department of Nuclear
Engineering and Management
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Therapy
System. Development of Advanced Compact Electron
Linear Accelerator for Cancer Inspection and Therapy
In order to develop the motion prediction system for areal-time tumor-tracking radiation therapy, the centerof-mass motion of the tumor and the two-dimensional
projection images for lung cancer patients have been
predicted by a multi-channel singular spectrum
analysis. This system will remove a delay problem
during the real-time tumor-tracking radiation therapy,
and will provide a safer radiation therapy than thecurrent ones because this will be able to detect anirregular breathing motion of the tumor. In theprediction using movie, the tumor deformation is
involved in the evaluation. In addition, the intreatment cone-beam CT reconstruction system has
been developed by simultaneous kV radiography
irradiation during rotational treatment. The
image-based phase recognition technique whichenables to construct the respiratory signal during
treatment has been developed.
Laboratory of Nano-crystals in Oncology
Department of Chemical System Engineering
Department of Surgical Oncology
To develop an exact diagnosis and treatment system
for the micro-metastasis of neoplasm by using
nano-crystal particles, and to introduce it to clinicaluse. To visualize peritoneum metastases (peritonitis)
and micro-metastasis of neoplasm which cannot bechecked in naked eye, and apply it to an operation or
the determination of a medical treatment plan. To
search for the new method for treating neoplasm byusing biological changes of the cells after up taking
nano-crystal particles.
Laboratory of Medical Ultrasound with Microbubbles in Oncology
Department of Mechanical Engineering, Fluids
Engineering Laboratory
Department of Surgical Oncology
To develop easy, precise, non-invasive systems to treat
human disease. To devise a method to induce
microbubbles effectively to treat human tumors 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.

510

Medico-engineering Laboratory for Microsurgical
Robotics and Virtual Simulation Laboratory (MRVLabo)
Laboratories of A Morita, Neurosurgery
Dept. Engineering Synthesis, M Mitsuishi
To develop Microsurgical robotic system and 3D
visual system for telesurgery
Laboratory of Cavitation & Lithotripsy
Department of Urology, Faculty of Medicine
Department of Mechanical Engineering, School ofEngineering
Development of a new method of lithotripsy using
high intensity focused ultrasound induced cavitation.
Development of Support Systems for Risk
Reduction in the Clinical Process
Department of Pharmacoepidemiology
Chemical System Engineering
Department of Clinical Epidemiology & Systems
Our specific targets are research and education on the
integration of biological and clinical information
including genome. In particular, they consist of establishment of personalized medicine as translational
research, selection of drug targets by proteomics,
interpretation of transcriptional regulations and drug
development by targeting transcription factors in
cardiovascular diseases (arteriosclerosis, cardiac
hypertrophy, cardiac failure, etc.). Other analyses anddevelopment are also quite active, such as creation oftransgenic animals, analyses of genomic functions,clinical safety monitoring by clinical database andassessments of clinical information systems.
Surgical Robot System Lab.
Robotics, Dynamics, and Control Laboratory
Department of Mechano-Informatics
University of Tokyo
Development of motion synchronization technology
for in-vivo molecular imaging of small animals, basedon robot systems for endoscopic cardiac surgery.
Neuro-musculo-skeletal model and its parameter
identification for diagnosis and rehabilitation ofneuromuscular disorders.
Vascular Biomedical Engineering Laboratory
Department of Vascular Surgery

Department of Tissue Engineering, The University ofTokyo Hospital
Bio-Medical Precision Engineering Laboratory,
Department of Precision Engineering, Medical Device
Development and Regulation Research Center, The
University of 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 of Immuno-

511

therapeutics (Medinet)
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (BNCT) using
small neutron accerelator equipped to hospital andalso develop more effective immumotherapeutic
approaches.
Molecular Imaging Laboratory, Cooperative Unitof Medicine, Engineering and Pharmaceutical
Research
Tetsuo Nagano, Laboratory of Chemistry and Biology,
Graduate School of Pharmaceutical Sciences
Yasunobu Hirata, Department of Cardiovascular
Medicine
To develop chemical probes for imaging of
biomolecules. To visualize arteriosclerotic andischemic lesions by using fluorescent probes and MRI
contrast media.
Development of adhesion barrier materials using a
new animal model of liver-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
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.
Laboratory of Applied Metabolic Biotechnology
Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Metabolic Diseases, Graduate Schoolof Medicine
Department of Chemistry and Biotechnology, Schoolof Engineering
To establish the system and methods for engineering
the novel model mice of life style-related diseases
using RNAi technology and biotechnology. To
elucidate the mechanisms by which adipose tissue
derived factors, adipokines, contribute to thedevelopment of the metabolic syndrome. To explore
the signal transduction pathways of major adipokines
including adiponectin
Laboratory of Biomaterial Science
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Laboratory of Regenerative Medical Engineering,
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,

512

mechanical analysis of cardiomyocytes is performed.
Laboratory of Hard-Tissue Nanomedicine
Kataoka & Yamasaki Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Department of ″Menicon″ Cartilage & BoneRegeneration, Graduate School of Medicine, The
University of Tokyo
Department of Bone & Cartilage Regenerative
Medicine, Graduate School of Medicine, The
University of Tokyo
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo Department of Oraland Maxillofacial Surgery, Faculty of Medicine, The
University of Tokyo
Division of Clinical Biotechnology, Center for Disease
Biology and Integrative
Medicine, Graduate School of Medicine, The
University of Tokyo
Division of Tissue Engineering, The University ofTokyo Hospital
Development of a non-viral gene delivery system bysupramolecular nanotechnology. Development of anon-viral siRNA delivery system by supramolecular
nanotechnology. Production of regenerated cartilage
and bone with high safety and usefulness.
Establishment of practical production and quality
control systems. Promotion of the clinical applicationof regenerated cartilage and bone. Development ofeasy, precise, non-invasive systems to detect
osteoblastic and chondroocytic differentiation.
Determination of a finite set of signaling factors
sufficient for induction of osteoblasts andchondrocytes. Development of a method to induce
osteogenesis and angiogenesis simultaneously.
Development of a cell-sheet culture system for bone
and cartilage. Screening for compounds that inducebone and cartilage regeneration
Cooperative Unit of Kataoka Laboratory andDepartment of Vascular Regeneration
Department of Vascular Regeneration, Division of
Tissue Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo

To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we aredeveloping non-viral gene vectors based on 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 ofpolymeric micelles. This "virusmimicking" nanoparticles might achieve efficient gene transfer to thetargeted tissues or cells because of protection of theloaded DNA from nuclease attack, their lowered
non-specific interaction with proteins and cells andfacilitated internalization by the targeted cells throughspecific interaction of the pilot molecules. Currently,
our research has been focused on in vivo gene transfer
to artery walls and muscles using polymeric micelles
incorporated genes.

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Tsuyoshi Takato, Akira Myoui, Katsuhiko Nanno,
Yukio Kato, Masami Kanawa, Katsura Sugawara,
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58. Yusuke MITSUOKA, Akira TSUKAMOTO,
Shunsuke IWAYOSHI, Katsuko S. FURUKAWA
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HUVEC, J Biomech Sci & Eng 7, (2), 188-198,
2012

517

Department of Disaster Medical
Management
Associate Professor
Hiroyuki Nakao, M.D.,Ph.D.

Lecturer
Jun Tomio, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/~uth-dmm/

Introduction and Organization
Responding to the Great East Japan Earthquake in 2011,
the University of Tokyo Hospital has decided to set out
to establish “disaster medical management studies“ interms of need not only to provide medical treatment at
the time of disaster but also to develop a new academic
field that provides bird’s-eye view on overall disastermedicine. In March 2012, we made an announcement
to establish “Department of Disaster Medical
Management” in the Public Comment.
Associate Professor, Dr. Hiroyuki Nakao, who
experienced disasters such as the Great Hanshin-Awaji
Earthquake in 1995 and studied and engaged in disastermedicine at the Disaster and Emergency Medicine
Course in Faculty of Medicine of Kobe University, wasassigned post as the first General Manager of the
Department of Disaster Medical Management in July2012 and was appointed as the chairman of the
in-hospital Disaster Prevention Committee. Also, in
March 2013, Dr. Jun Tomio, Assistant Professor of the
Public Health Course of this University, was assigned
as the instructor of the Department of Disaster Medical
Management in order to develop approaches bymethods of public health.
This department belongs to the Central ClinicalFacilities Division and is involved in activities within
this hospital and inside/outside of the University.
In order to establish disaster medical management

studies, we are aiming at 1) fostering leaders who candevelop plans for disaster medicine and educate
personnel engaged in disaster medicine, 2) relationshipbuilding with relevant institutions for establishing asystem for the University of Tokyo Hospital to leaddisaster medicine and 3) developing a system as a baseof formation of organizations at the time of disaster(Japanese version of HEICS: Hospital Emergency
Incident Command System).

Clinical activities
In September 2012, the Disaster Prevention Committee
carried out planning and conducted the University ofTokyo Disaster Drill 2012 and the first In-hospital
Comprehensive Disaster Drill. As a result, it was foundout that mobile access from the Gotenshita Groundwhere rescue helicopters take off and land at the time ofdisaster is not good and improvement works was done.
In March 2013, with the participation of a part of theCentral Clinical Facilities Division, the second
In-hospital Comprehensive Disaster Drills was
conducted in the Outpatient Division where no
hospital-wide major disaster drill has been conducted.

Teaching activities
We have started “Disaster Medicine System Lecture”
on a monthly basis for personnel of this hospital,
Hongou Fire Department and Hon-Fuji Police Station

518

since December 2012.
The first lecture was Organization Theory, and thesecond one was Organization Theory II (by an outside
instructor) for this year. In these lectures, we try not
only to give lectures but also to do practices at the sametime.
As educational activities outside of the University,
we are teaching in the Japan DMAT workshops,
Trauma Primary Care education and Disaster Medicine
workshops for national and public universities tocooperate with their development.

Research activities
We are seeking ways of cooperation between
institutions through workshops with relevant
institutions from the perspective that day-to-day
cooperation with relevant institutions can be alsoutilized at the time of disaster. We consider that it canbe also utilized for cross-business formation oforganizations at the time of disaster.
As a business-academic collaboration activity, we
have developed medical equipment for pupil
observation and a patent is pending. This equipment isunder development with expectation that it can beutilized for evaluation of brain function in disaster area
without precision medical equipment such as CT
scanner.
Other than that, we are participating in outside
research groups and cooperating for mental health careat the time of disaster and establishment of emergency
medical system.

References
1. Hiroyuki Nakao, Hiroshi Kodaira, Shinichi Sato,
Shinichi Nakayama, Shuichi kozawa, Noboru Ishii.
Development of a triage system using mobile
phones and image recognition software on themarket. J.J.Disast. Med. 2012;17:345-350.
2. Yasuyuki Hayashi, Masato Nishino, Hiroyuki
Nakano, Yoshimi Kitagawa, Katsuhiko Sugimoto,Atsushi Katsumi, Naoto Morimura, Kazutoshi
Kuboyama, Tatsuro Kai.
Actual situation of
medical relief dispatch services at events in Japan.

J.J.Disast. Med. 2012;17:372-376.
3. Kazutoshi Kuboyama, Noboru Ishii, Shuichi
Ozawa, Joji Kotani, Hiroyuki Nakao, Shinichi
Nakayama,
NorikoMurakami,
Kazumasa
Yoshinaga. Construction "of the support system
for the family of the study on disease in the" 2011
area and medical care investigation great disasterdead. Shinryoku society academic journal 2012;28:
11-16.

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International Medical Center
Director and Associate Professor
Sumihito Tamura, M.D.,Ph.D.

Homepage

http://www.cc.h.u-tokyo.ac.jp/mulins/kokusai/index.html

Introduction and Organization
One of the University of Tokyo’s significant
challenges is globalization. The International Medical
Center was launched on October 1, 2012 as asignificant step forward in enhancing The Universityof Tokyo Hospital’s development as an international
hub. Designated director position has been assigned
starting June 2013.

Activities and challenges
The University of Tokyo Hospital offers sophisticatedsurgery and state-of-the-art treatment in variety offields. One of the roles of the International Medical
Center is to establish a system through which we
provide medical expertise to patients from overseas.
In the past, some foreign patients have successfullyreceived treatment thanks to the support of individual
departments. However, from henceforth, theInternational Medical Center will cater to the various
requirements that must be met when accepting
overseas patients, including travel assistance,
multilingual support, translation of medical
documents, and offering solutions to financial
challenges, so that each department can focus solely
on providing sophisticated treatment to those patients.
As well as receiving patients, another important
aspect is the globalization of clinical education. We
hope to establish a system in which non-Japanese
doctors accepted for residencies, or those who come toreceive cutting-edge medical training can carry out
operations, interventions or demonstrations without
being hindered by their nationality. Similarly, we hopeto establish a system through which overseas doctors

can learn new techniques alongside Japanese doctors,
and to provide an environment where doctors fromvarious countries can mingle with young doctors
working at our hospital, as well as student physiciansin participatory clinical training.
International accreditation is unavoidable if theseachievements are to be accepted on a global scale. We
expect this process to involve both human andfinancial resources equaling or surpassing thoserequired for the hospital function assessment. We hope
to hold further discussions with the hospital as awhole, in order to make this a reality in the near
future.
Lastly, heightening the capability of physicians andmedical staff to cater to international needs is an
important factor in globalizing The University ofTokyo Hospital. To this end, the International Medical
Center will attempt to cultivate personnel by hosting
various international exchanges and language-training
programs so as to further develop the hospital’s
capabilities to become an international hub in thefield.

Center for Disease Biology andIntegrative Medicine

521

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. Mainly, we focus on following two
major projects.

1. AIM (Apoptosis Inhibitor of Macrophage) as amaster switch to various modern diseases.
The rapid change in the living style and dietary
pattern in today’s modern society are thought to be thecause of various disorders; metabolic syndrome andlife style related disease increase the risk ofdeveloping obesity, diabetes, and cardiovasculardisease; a fatty liver leads to NASH and liver disease,
may result in liver cancer; autoimmune disease
followed by obesity, chronic renal failure, andAlzheimer’s disease are considered as well. We
hypothesize that such various modern disorders,seemingly unrelated at first sight, share the common
underlying pathological condition and mechanism,and the group of molecules exists as the master switch,
regulating the varied conditions.
We found a soluble apoptosis inhibitor factor largely
produced by tissue macrophage, named AIM (apoptosis
inhibitor of macrophage). Our recent studies showedthat AIM plays important role in regulating thepathological condition of the modern diseases.
AIM is produced by macrophage and largely
presents in bloodstream as a soluble molecule. Once
AIM is incorporated (absorbed?) into adipose tissue, it
decomposes fatty droplets resulting in controlling the
progression of obesity. However, when this process
undergoes effectively and excessively under the obese
condition, oppositely to control the progression of

522

obesity, chronic inflammation of adipose tissue andinsulin resistance are triggered and Type II diabetes
and atherosclerosis are worsen.
Moreover, because AIM binds to IgM inbloodstream, it leads to production of various
autoantibodies, especially under the obese condition.
This suggests that the obesity is the cause of
autoimmune disease. Other studies showed that liverdisease, cancer, and kidney disease worsen under low
concentration of AIM. It is suggested that theconcentration of AIM in bloodstream differ theoutcome and the risk of getting various diseases.
Finding the mechanism on the regulation of AIM
activity will shed the light of developing a diagnostics
and potential treatments to modern diseases. We will
focus on the details of involvement of AIM to thevarious diseases by generating a mouse model. Also,
cohort study is carried out using and analyzing thehuman specimen, aiming to develop a novel drug
treatment.
2. Finding new mechanisms of infertility
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. DEDD molecules regulate the speed ofcell division by sensing the concentration of ribosomal
DNA and its proteins, causing to determine the size ofcell. Also, DEDD molecules seem to function as asensory system of nutrient level, affecting directly tothe cell division activity level.
Due to the fact that DEDD knockout mice (♀)
results in 100% infertility, we focused on finding its
pathological mechanism. We found that female micelacking DEDD are infertile owing to unsuccessful
decidualization: The uterine decidua, which differentiates from stromal cells after implantation in a process
known as decidualization, plays essential role insupporting embryonic growth before establishment of
the placenta. In human, the cause of 25% of infertility
is unknown. It can be suggested that malfunction of
DEDD molecules may be the factor causing infertility
in human; so we now seek the involvement of DEDD
molecules in human fertility.
Since our recent
studies suggest DEDD molecules also have an effecton permeability of blood vessel in uterine, we try
creating a new model mice to further understand themechanism of infertility and to develop a treatment.

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.

523

Publications
1. Iwamura, Y., Mori, M., Nakashima, K., Mikami,T., Murayama, K., Arai, S. & Miyazaki, T.
Apoptosis inhibitor of macrophage (AIM)diminishes lipid droplet-coating proteins leading
to lipolysis in adipocytes. Biochem. Biophys. Res.
Commun. 422, 476-481 (2012)
2. Mori, M., Kimura, H., Iwamura, Y., Arai, S. &Miyazaki, T. Modification of N-glycosylation
modulates the secretion and lipolytic function of
apoptosis inhibitor of macrophage (AIM).
FEBSLett. 586, 3569-3574 (2012)
3. 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)
4. 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)
5. Mori, M., Kitazume, M., Ose, R., Kurokawa, J.,
Osuga, Y., Arai, S. & Miyazaki, T. Deatheffector domain-containing protein (DEDD) isrequired for uterine decidualization during earlypregnancy in mice. J Clin Invest 121: 318-327(2011)
6. 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)
7. 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)
8. Bhatia, H., Hallock, J.L., Sterner, L.S., Karkashon,S., Miyazaki, T., Dean, A., & Little, J.A. A short-chain fatty acid mediated reversed globin geneswitch in primary definitive erythroid cells. Blood
113: 6440-8 (2009)
9. 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)
10. 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).
11. 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).
12. 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).
13. 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).
14. 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).
15. 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).
16. Haks, M.C., Lefebvre, J.M., Lauritsen, J.P.H.,
Carleton, M., Rhodes, M., Miyazaki, T., Kappes,

524

D.J. & Wiest, D.L. Attenuation of γδTCRsignaling efficiently diverts thymocytes to the αβlineage. Immunity 22: 595-606 (2005).
17. 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).
18. 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).
19. 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).
20. 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).
21. Miyazaki, T., Ohura, T., Kobayashi, M.,
Shigematsu, Y., Yamaguchi, S., Suzuki, Y., Hata,
I., Aoki, Y., Yang, X., Minjares, C., Haruta, I., Uto,
H., Ito, Y. & Muller, U. Fatal propionic acidemia
in mice lacking propionyl-CoA carboxylase andits rescue by postnatal, liver-specific supplementation via a transgene. J. Biol. Chem. 276:
35995-35999 (2001).
22. 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).
23. 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).
24. Miyazaki, T. & Lemonnier, F.A. Modulation ofthymic selection by expression of an immediate-

early gene, early growth response 1 (Egr-1). J.
Exp. Med. 188:715-723 (1998).
25. 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).
26. Miyazaki, T., Müller, U. & Campbell, K.S.
Normal development but differentially alteredproliferative responses of lymphocytes in micelacking CD81. EMBO. J. 16: 4217-4225. (1997).
27. 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).
28. Miyazaki, T., Dierich, A., Benoist, C. & Mathis D.
Independentmodesofnaturalkilling
distinguished in mice lacking Lag3. Science 272:405-408 (1996).
29. 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).
30. 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).

525

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 5 doctor course students in 2012. We werealso responsible for undergraduate education ofphysiology, and organized all lectures, student
experiments and examinations. We were also
responsible for an introductory lecture of physiology,
and 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 two
representative works of this year in some detail.
1) Competitive selection of synaptic connections plays a
key role in the refinement of neuronal networks during
development,
learning
andmemory.
Cellular526

mechanisms mediating such competition are poorly
understood. In the pyramidal neurons of the cerebral
cortex, excitatory synapses are formed on small
protrusions of dendrite known as dendritic spines.
Competitive selection of dendritic spines should beachieved by their structural plasticity, as the enlargement
and shrinkage of spines is associated with long-term
potentiation (LTP) and depression (LTD), respectively.
We used two-color uncaging of glutamate and GABA in
rat hippocampal slice preparations, and found that
although spine enlargement was confined to thestimulated spine, spine shrinkage spread intoneighboring spines over 10 µm, even when only one
spine was stimulated. Spine shrinkage was markedly
promoted by the activation of GABAA receptors, andwas mediated by the dephosphorylation and activation ofactin depolymerising factors, ADF/cofilin, which
effectively spread along dendrites. This spread ofshrinkage enabled competitive interaction with the spine
enlargement that was induced by the accumulation ofphosphorylated cofilin in the stimulated spines. Thus,
GABAergic inhibition promotes synaptic competition byfacilitating spine shrinkage and elimination.
2) The dynamics of exocytosis are diverse and have been
optimized for the functions of synapses and a wide
variety of cell types. For example, the kinetics of
exocytosis varies by more than five orders of magnitude
between ultrafast exocytosis in synaptic vesicles andslow exocytosis in large dense-core vesicles. However,in all cases, exocytosis is mediated by the same
fundamental mechanism, i.e., the assembly of soluble
N-ethylmaleimide-sensitive factor attachment protein
receptor (SNARE) proteins. It is often assumed thatvesicles need to be docked at the plasma membrane and
SNARE proteins must be preassembled before
exocytosis is triggered. However, this model cannot
account for the dynamics of exocytosis recently reported
in synapses and other cells. For example, vesicles
undergo exocytosis without pre-stimulus docking during
tonic exocytosis of synaptic vesicles in the active zone.
In addition, epithelial and hematopoietic cells utilize
cAMP and kinases to trigger slow exocytosis of
non-docked vesicles. In this review, we summarize themanner in which the diversity of exocytosis reflects theinitial configurations of SNARE assembly, includingtransSNARE, binary-SNARE, unitary-SNARE, andcisSNARE configurations. The initial SNARE
configurations depend on the particular SNARE subtype(syntaxin, SNAP25 or VAMP), priming proteins(Munc18, Munc13, CAPS, complexin, or snapin),
triggering proteins (synaptotagmins, Doc2, and various
protein kinases) and the sub-membraneous cytomatrix,
and they are the key to determining the kinetics ofsubsequent exocytosis. These distinct initialconfigurations will help us clarify the common SNARE
assembly processes underlying exocytosis and membranetrafficking in eukaryotic cells.

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 of dense corevesicles 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 ofglutamate revealing the structure-function relationships o f dendritic spines in the neocortex of adultmice. 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 the dendrites 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 and Konnerth).
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 neuronalproperties with single-cell resolution in the living
rodent brain. Mol. Cell. Neurosci., 48, 246-257.

527

6. Kimura, Y., Momotake, A., Takahashi, N., Kasai, H.
& Arai, T. (2012)
Polarity-dependent photophysical properties ofhemicyanine dyes and their application in 2-photon
microscopy biological imaging. Chemistry Letters
41, 528-530.
7. Ogata, S., Miki, T., Seino, S., Tamai, S., Kasai, H. &Nemoto, T. (2012). A novel function of Noc2 inagonist-induced intracellular Ca2+ increase during
zymogen-granule exocytosis in pancreatic acinar
cells. PLoS ONE 7: e37048.
8. Kasai, H., Takahashi, N. & Tokumaru, H. (2012).
Distinct initial SNARE configurations underlying
the diversity of exocytosis. Physiol. Rev., 92:19151964.
9. Hayama, T., Noguchi, J., Watanabe, S., Ellis-Davies,
G.C.R., Hayashi, A. Takahashi, N., Matsuzaki, M. &Kasai, H. (2013). GABA promotes the competitive
selection of dendritic spines by controlling local
Ca2+ signaling. Nature Neurosci. In press.

528

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.

529- Order made shaping of scaffolds by router system
according to the graphical images of tissue defects- Establishment of vascular rich graft bed by biomaterials that spur new blood vessel growth.
2) Cellular signal transduction induced by physicalstimulations- Hydrostatic pressure loading to chondrocytes orarticular cartilage- Shear stress loading to endothelial cells- Stretch loading to endothelial cells, smooth muscle
cells
Biomaterials are one of important keys in medicine
and medical engineering. In the field of tissue
engineering, scaffold materials are extremely
important. In the drug delivery field, drugs areencapsulated in various materials which achieve ideal
release kinetics. The functions of these biomaterials
and phenomena inside and outside biomaterials invivo are complicated both in terms of chemistry andbiology. Ito Laboratory is trying to design and develop
novel biomaterials for tissue engineering and drugdelivery by the combination of medicine and chemicalsystem engineering. Especially we focus 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. R. Horiuchi, T. Akimoto, Z. Hong, T. Ushida.
Mechanical stretch maintains Nanog expression
through PI3K/Akt signals in mouse embryonic stem
cells. Exp Cell Res, 318(14), 1726-1732 (2012)
2. Ryo TACHIKAWA, Akira Tsukamoto, Keiichi

NAKAGAWA, Tatsuhiko ARAFUNE, Hongen
LIAO, Etsuko KOBAYASHI, Takashi USHIDA,
Ichiro SAKUMA, Development of an Expansion
Wave Generator for Shock Wave Therapy,
Advanced Biomedical Engineering, 1: 68-73 (2012)
3. Masako Yokoi, Koji Hattori, Koichi Narikawa,
Hajime Ohgushi, Mika Tadokoro, Kazuto Hoshi,
Tsuyoshi Takato, Akira Myoui, Katsuhiko Nanno,
Yukio Kato, Masami Kanawa, Katsura Sugawara,
Tomoko Kobo and Takashi Ushida., Feasibility andlimitations of round robin test for assessment ofevaluation protocols in tissue-engineered medical
product. Journal of Tissue Engineering andRegenerative Medicine, 6; 550-558 (2012)
4. Yusuke MITSUOKA, Akira TSUKAMOTO,
Shunsuke IWAYOSHI, Katsuko S. FURUKAWA
and Takashi USHIDA, High Time Resolution
Time-Lapse Imaging Reveals Continuous Existence
and Rotation of Stress Fibers under Cyclic Stretch in
HUVEC, J Biomech Sci & Eng 7, (2), 188-198(2012)
5. Yuuki Sugawara, Hidenori Kuroki, Takanori Tamaki,
Hidenori Ohashi, Taichi Ito, Takeo Yamaguchi,“Conversion of a molecular signal into a visual color
based on the permeation of nanoparticles through abiomolecule-recognition gating membrane” Anal.
Methods, 4(9), 2635-2637 (2012)

530

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/english/research/04.php
http://www.bmw.t.u-tokyo.ac.jp/english/index.html

Introduction and Organization
Division of Clinical Biotechnology in Center for
Disease Biology and Integrative Medicine (CDBIM)
was established in April 2003. This division wishes tocontribute to the development of nanomedicine. Our
division actively collaborates with Graduate School ofEngineering at The University of Tokyo and Divisionof Tissue Engineering at The University of Tokyo
Hospital. Our division also plays a major role in the
Global COE (GCOE) program, which started in 2008,
for novel medicine-engineering interdisciplinary
communication, and tries to produce medical venturesby promoting liaison with the industrial sector, andfurther, professionals who understand both advanced
medicine and nanotechnology. Our division consistsof one professor, two associate professors, one
assistant professor, and several project staff members.
Our division particularly focuses on thedevelopment of nanomedicine. Nanotechnology,
which has been attracting tremendous attention as aleading scientific field in the 21st century, attempts toprocess and assemble materials with precision at theatomic/molecular level to produce units withsophisticated functionalities. Nanodevices, which areconstructed by integrating materials and systems on ananometer scale, hold the key to realizing thefuturistic medical system that can fulfill the needed
function at the right time and the right place withminimal invasiveness. Furthermore, nanodevices are
expected to become an important interface between
basic biomedical science and clinical medicine byfacilitating the translation of basic achievements into
clinical applications. Our division wishes to produce
innovative medical nanodevices based on nanotechnology, spreading the idea of "Nanomedicine"
intranationally and internationally.

Teaching activities
Traditional medicine-engineering interdisciplinary
programs have focused on the exchange of researchers
and the promotion of collaborative researches between
these two different academic areas. However, the next
generation of medicine, such as "minimum-invasive
diagnosis-treatment" and "targeting medical treatment",
and also nanotechnologies are developing rapidly withincreased complexity, and thus scholars in both areas

531

find it hard to understand each other. This situation
prevents the effective development of revolutionary
medical diagnostic and therapeutic inventions. Our
division intends to provide an optimal milieu where
undergraduate and graduate students from both fieldsof medicine and engineering can study their fusionarea with respect to each other's background in orderto achieve the ultimate goal of developing smart
nanodevices for the futuristic medical system.

Research activities
Drug delivery to the target site of action is strongly
desired to enhance the drug function and minimize theside effects. In this regard, drug delivery systems
based on self-assemblies of block copolymers (i.e.,
polymeric micelles) have drawn much attention as oneof the medical applications of the nanotechnology.
Block copolymers spontaneously form polymeric
micelles, which consist of the core-shell structure withthe size of ~100 nm, in aqueous media. The core of
the micelles behaves as a nanoreservoir for drugs,
while the coronal shell providing the biocompatible
surface. Polymeric micelles can incorporate a varietyof drugs including hydrophobic drugs, metal complex
drugs, and macromolecular drugs such as proteins andDNA, and release them in a sustained manner or in
response to environmental changes such as pH. The
site-specific drug delivery can be achieved by
conjugation of the pilot molecules on the surface ofpolymeric micelles. Thus, polymeric micelles behave
as smart chemical nanomachines for the drug
targeting.
The long-circulation of drug carriers is a requisite
for the successful drug targeting. The major 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 evade fromthose barriers in the body, resulting in stable blood
circulation. Another advantage of using polymeric
micelles is their preferential accumulation in solid
tumors, probably due to microvascular hyperpermeability and immature lymphatic system in tumor
tissues. We have succeeded in the tumor-selective
delivery of several antitumor drugs including
adriamycin (ADR), cisplatin (CDDP), and oxaliplatinby polymeric micelles, and observed enhanced
antitumor activity with reduced side effects. These
micellar formulations are currently being tested inclinical trials.
Recently, plasmid DNA (pDNA) and siRNA are
highlighted as promising tools for the treatment ofgenetic and intractable diseases. One of the major
requirements for therapeutic use of pDNA and siRNAis the development of gene vectors, which can safely
and effectively deliver them into specific cells andregulate their expressions. Recently, we have preparedpolymeric micelles incorporating pDNA through theelectrostatic interaction between pDNA and positively
charged block copolymers. The polymeric micelles
protected the loaded pDNA from degradation by
nuclease attack and showed efficient gene transfer to avariety of cells. Also, various smart functionalities,
such as targeting ability and environmental sensitivity,
can be integrated into polymeric micelles, providing
the opportunities to develop effective synthetic
vectors resembling viruses. Thus, polymeric micelles
are expected as useful nanocarriers of pDNA andsiRNA for in vivo application.

References
1. M. Naito, T. Ishii, A. Matsumoto, K. Miyata, Y.
Miyahara, K. Kataoka, A phenylboronatefunctionalized polyion complex micelle for ATPtriggered release of siRNA. Angew. Chem. Int. Ed.
51 (43) 10751-10755 (2012)
2. T. Endo, K. Itaka, M. Shioyama, S. Uchida, K.
Kataoka, Gene transfection to spheroid culture
system on micropatterned culture plate by polyplex
nanomicelle: A novel platform of geneticallymodified cell transplantation. Drug Deliv. Transl.
Res. 2 (5) 398-405 (2012)
3. M. Sanjoh, K. Miyata, R. J. Christie, T. Ishii, Y.
Maeda, F. Pittella, S. Hiki, N. Nishiyama, K.
Kataoka, Dual environment-responsive polyplex
carriers for enhanced intracellular delivery ofplasmid DNA. Biomacromolecules 13 (11) 36413649 (2012)
4. Y. Maeyoshi, A. Saeki, S. Suwa, M. Omichi, H.
Marui, A. Asano, S. Tsukuda, M. Sugimoto, A.
Kishimura, K. Kataoka, S. Seki, Fullerene

532

nanowires as a versatile platform for organic
electronics. Sci. Rep. 2 (600) (2012)
5. T. Suma, K. Miyata, Y. Anraku, S. Watanabe, R. J.
Christie, H. Takemoto, M. Shioyama, N. Gouda, T.
Ishii, N. Nishiyama, K. Kataoka, Smart
multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica, endosomedisrupting polycation, and detachable PEG. ACS
Nano 6 (8) 6693-6705 (2012)
6. F. Pittella, K. Miyata, Y. Maeda, T. Suma, S.
Watanabe, Q. Chen, R. J. Christie, K. Osada, N.
Nishiyama, K. Kataoka, Pancreatic cancer therapy
by systemic administration of VEGF siRNAcontained in calcium phosphate/charge-conversional
polymer hybrid nanoparticles. J. Control. Release
161 (3) 868-874 (2012)
7. K. Osada, H. Cabral, Y. Mochida, S. -E. Lee, K.
Nagata, T. Matsuura, M. Yamamoto, Y. Anraku, A.
Kishimura, N. Nishiyama, K. Kataoka, Bioactive
polymeric metallosomes self-assembled throughblock copolymer-metal complexation. J. Am. Chem.
Soc. 134 (32) 13172-13175 (2012)
8. S. Murayama, B. Su, K. Okabe, A. Kishimura, K.
Osada, M. Miura, T. Funatsu, K. Kataoka, M. Kato,
NanoPARCEL: A method for controlling cellularbehavior with external light. Chem. Commun. 48(67) 8380-8382 (2012)
9. H. Takemoto, K. Miyata, T. Ishii, S. Hattori, S.
Osawa, N. Nishiyama, K. Kataoka, Accelerated
polymer-polymer click conjugation by freeze-thaw
treatment. Bioconjugate Chem. 23 (8) 1503-1506(2012)
10. Y. Zhang, R. Tachibana, A. Okamoto, T. Azuma,
A. Sasaki, K. Yoshinaka, K. Osada, K. Kataoka, S.
Takagi, Y. Matsumoto, Ultrasound-mediated genetransfection in vitro: Enhanced efficiency bycomplexation of plasmid DNA. Jpn. J. Appl. Phys.
51 (7) 07GF29-07GF29-5 (2012)
11. K. Miyazaki, Y. Morimoto, N. Nishiyama, Y.
Maekawa, W. -Z. Hu, K. Nakatate, K. Kaneda, N.
Shinomiya, K. Kataoka, A novel homogeneous
irradiation fiber probe for whole bladder wall
photodynamic therapy. Lasers Surg. Med. 44 (5)413-420 (2012)
12. M. Kumagai, S. Shimoda, R. Wakabayashi, Y.
Kunisawa, T. Ishii, K. Osada, K. Itaka, N.
Nishiyama, K. Kataoka, K. Nakano, Effective

transgene expression without toxicity by intraperitoneal administration of PEG-detachable
polyplex micelles in mice with peritoneal dissemination. J. Control. Release 160 (3) 542-551 (2012)
13. R. J. Christie, Y. Matsumoto, K. Miyata, T.
Nomoto, S. Fukushima, K. Osada, J. Halnaut, F.
Pittella, H. -J. Kim, N. Nishiyama, K. Kataoka,
Targeted polymeric micelles for siRNA treatmentof experimental cancer by intravenous injection.
ACS Nano 6 (6) 5174-5189 (2012)
14. Q. Chen, K. Osada, T. Ishii, M. Oba, S. Uchida, T.
A. Tockary, T. Endo, Z. Ge, H. Kinoh, M. R. Kano,
K. Itaka, K. Kataoka, Homo-catiomer integration
into PEGylated polyplex micelle from blockcatiomer for systemic antiangiogenic gene therapy
for fibrotic pancreatic tumors. Biomaterials 33 (18)4722-4730 (2012)15. S. Uchida, K. Itaka, Q. Chen, K. Osada, T. Ishii, M.
A. Shibata, M. Harada-Shiba, K. Kataoka,
PEGylated polyplex with optimized PEG shielding
enhances gene introduction in lungs by minimizing
inflammatory responses. Mol. Ther. 20 (6) 11961203 (2012)
16. M. Rafi, H. Cabral, M. R. Kano, P. Mi, C. Iwata,
M. Yashiro, K. Hirakawa, K. Miyazono, N.
Nishiyama, K. Kataoka, Polymeric micelles
incorporating (1,2-diaminocyclohexane)platinum(II) suppress the growth of orthotopic scirrhous
gastric tumors and their lymph node metastasis. J.
Control. Release 159 (2) 189-196 (2012)
17. Y. Yamada, M. Hashida, T. Nomura, H. Harashima,
Y. Yamasaki, K. Kataoka, A. Yamashita, R.
Katoono, N. Yui, Different mechanisms fornanoparticle formation between pDNA and siRNAusing polyrotaxane as the polycation. ChemPhys
Chem 13 (5) 1161-1165 (2012)
18. T. Suma, K. Miyata, T. Ishii, S. Uchida, H. Uchida,
K. Itaka, N. Nishiyama, K. Kataoka, Enhanced
stability and gene silencing ability ofsiRNA-loaded polyion complexes formulated frompolyaspartamide derivatives with a repetitive arrayof amino groups in the side chain. Biomaterials 33(9) 2770-2779 (2012)19. 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 three-533

dimensional model to investigate nanoparticle
delivery. Biochem. Biophys. Res. Commun. 419 (1)32-37 (2012)
20. J. -H. Kim, E. Lee, J. -S. Park, K. Kataoka, W. -D.
Jang, Dual stimuli-responsive dendritic-linear
block copolymers. Chem. Commun. 48 (30) 36623664 (2012)
21. 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)
22. 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)
23. K. Osada, T. Shiotani, T. A. Tockary, D.
Kobayashi, H. Oshima, S. Ikeda, K. Itaka, K.
Kataoka, Enhanced gene expression promoted by
the quantized folding of pDNA within polyplex
micelles. Biomaterials 33 (1) 325-332 (2012)
24. 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)
25. H. -J. Kim, M. Oba, F. Pittella, T. Nomoto, H.
Cabral, Y. Matsumoto, K. Miyata, N. Nishiyama,
K. Kataoka, PEG-detachable cationic polyaspartamide derivatives bearing stearoyl moieties
for systemic siRNA delivery toward subcutaneous
BxPC3 pancreatic tumor. J. Drug Target. 20 (1)33-42 (2012)
26. 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)
27. Y. Lee, K. Kataoka, Delivery of nucleic acid drugs.
Adv. Polym. Sci. 249 95-134 (2012)
28. K. Miyata, N. Nishiyama, K. Kataoka, Rational
design of smart supramolecular assemblies forgene delivery: Chemical challenges in the creationof artificial viruses. Chem. Soc. Rev. 41 (7) 25622574 (2012)

534

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 was
newly established as a department of the Center for
Disease Biology and Integrative medicine in 2005
when Dr. Tohyama was transferred to the professor.
Since then, the laboratory activity in the research andeducation I in the environmental toxicology has beenstimulated with approximately 25 laboratory members
including staff, 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

535

been established that aryl hydrocarbon receptor (AhR)
is required to elicit the majority of dioxin toxicity.
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, the observation of which is thought to loosen the chromatinstricter. In another study, we found that low zincstatus during gestation affect the gene regulation of
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 Themes
1. Elucidation of mechanisms involved in the
manifestation of toxicity at the molecular andcellular level due to exposure to environmental
pollutants, such as dioxin/PCBs and heavy metals.
2. Clarification of epigenetic mechanisms that altersusceptibility to environmental chemicals.
3. 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.
4. 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 charge of ‘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)536

Master Course in the School of Public Health:Environmental Health Medicine (Lecture)
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. Endo T, Kakeyama M, Uemura Y, Haijima A,
Okuno H, Bito H, Tohyama C. ExecutiveFunction
Deficits and Social-Behavioral Abnormality inMice Exposed to a Low Dose of Dioxin In Uteroand via Lactation. PLoS One. 2012;7(12):e50741.
doi: 10.1371/journal.pone.0050741.
2. Yoshioka W, Endo N, Kurashige A, Haijima A,
Endo T, Shibata T, Nishiyama R, Kakeyama M,
Tohyama C. Fluorescence laser microdissection
reveals a distinct pattern of gene activation in themouse hippocampal region. Scientific Reports
2:783; DOI:10.1038/srep00783, 2012. [3. Yoshioka W, Aida-Yasuoka K, Fujisawa N,
Kawaguchi T, Ohsako S, Hara S, Uematsu S, Akira
S, Tohyama C. Critical role of microsomal
prostaglandin E synthase-1 in the hydronephrosis
caused by lactational exposure to dixin in mice.
Toxicol Sci. 127(2): 547-554, 2012 doi:10.1093/
toxsci/kfs115
4. Dourson ML, Gadagbui B, Griffin S, GarabrantDH, Haws LC, Kirman C, Tohyama C. The
importance of problem formulations in risk
assessment: A case study involving dioxincontaminated soil.Regul Toxicol Pharmacol. 2013:
66(2):208-16. doi: 10.1016/j.yrtph.2013.03.010.
5. Van den Berg M, Denison MS, Birnbaum LS,
Devito MJ, Fiedler H, Falandysz J, Rose M,
Schrenk D, Safe S, Tohyama C, Tritscher A,
Tysklind M, Peterson RE. PolybrominatedDibenzo-p-Dioxins, Dibenzofurans, and Biphenys:
Inclusion in the Toxicity Equivalency Factor
Concept for Dioxin-Like Compounds. Toxicol Sci.
2013: 133(2):197-208. doi: 10.1093/toxsci/kft070.

537

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, 6 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 670
at the end of academic year 2012.
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

538

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. We established theprobasin-Cre transgenic mice that express Cre
specifically in the prostate.
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 currently generated severaltransgenic mouse lines carrying mGluR1 mutant genes.
We found that a new transgenic line expressing wild
type mGluR1 in melanocyte produces melanoma. We
are currently examining the tumor formation in themGluR1 mutant transgenic mice.

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-Kik-

GR/+ 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. Moreover, we generated a new mutant
mouse strain using same targeting vector. And we
confirmed same phenotype as obesity. Recently, weare generating R26-H2B-Kik-GR transgenic mice by
DNA injection into pronuclear.

References
1. Aizawa R, Yamada A, Suzuki D, Iimura T, Kassai H,
Harada T, et al. Cdc42 is required for chondrogenesis and interdigital programmed cell death
during limb development. Mech Dev. 2012 Mar-Jun;
129(1-4): 38-50.
2. Hirata T, Kumada T, Kawasaki T, Furukawa T,
Aiba A, Conquet F, Saga Y, Fukuda A. Guidepost
neurons for the lateral olfactory tract: Expressionof metabotropic glutamate receptor 1 andinnervation by glutamatergic olfactory bulb axons.
Dev Neurobiol. 2012 Apr; 72(12): 1559-1576.
3. Kato HK, Kassai H, Watabe AM, Aiba A,
Manabe T. Functional coupling of the metabotropic glutamate receptor, InsP3 receptor andL-type Ca2+ channel in mouse CA1 pyramidalcells. J Physiol. 2012 Jul; 590(13): 3019-3034.

539

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

540

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.

References
1. Hosoya N, Okajima M, Kinomura A, Fujii Y,
Hiyama T, Sun J, Tashiro S, Miyagawa K.
Synaptonemal complex protein SYCP3 impairs
mitotic recombination by interfering with BRCA2.
EMBO Rep. 2012;13(1):44-51.
2. Enomoto A, Kido N, Ito M, Takamatsu N,
Miyagawa K. Serine-threonine kinase 38 isregulated by glycogen synthase kinase-3 andmodulates oxidative stress-induced cell death.
Free Radic Biol Med. 2012;52(2):507-515.
3. Furusawa Y, Fujiwara Y, Hassan MA, Tabuchi Y,
Morita A, Enomoto A, Kondo T. Inhibition of
DNA-dependent
proteinkinasepromotes
ultrasound-induced cell death including apoptosis
in human leukemia cells. Cancer Lett. 2012;322(1):107-112.

541

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 2012 (April 1,2012 through March 31, 2013).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2012, there were 122 foreign students (32countries) 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 62 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 60 people attended in 2012, 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 2012
Contest foreign students gave oral presentations basedon their research papers to interested fellow students
and faculty, and the five best speakers were given
awards.
A formal agreement for academic exchange
between the University of Pennsylvania and the
University of Tokyo was renewed in May 2004. Since

542

that time, eleven University of Tokyo students havetaken research electives at the University ofPennsylvania, 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, twenty two University of Tokyo students visited
to attend clinical electives at Johns Hopkins
University, and four students from Johns Hopkins
University have taken clinical electives at the
University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the University of Michigan
Medical School in January 2005. Since the start of the
program in 2005, thirteen University of Tokyo
students have attended clinical electives at the
University of Michigan 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,
nine University of Tokyo students visited to attend
research electives at Munich University, and four
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 eight students from Taipei Medical University

have taken clinical electives at the University ofTokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and 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 34 requests from students forcounselingregarding
pre-graduationor
post-graduation studies abroad are received by the
Office of International Academic Affairs. The office
responds to these requests by providing information,
advice, and letters of recommendation.
2. 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 withregard to the importance of the activities of graduate
students and postdoctoral fellows.
(4) They should observe how teaching assistants
contribute in education and research, and how
teaching assistants are trained to become leaders andmentors.

543

In 2012, five young researchers from the Graduate
School of Medicine at the University of Tokyo havebeen studying at the partner institutions in the USA.
3. Education and research
3.1 Education
In 2012, 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 2012, 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, Green J, Ishikawa H, Kiuchi T. Hidden
decay of impact after education for selfmanagement of chronic illnesses: hypotheses.
Chronic Illness. 2013 9: 73 originally published
online 9 July 2012
DOI: 10.1177/1742395312453351
2. Kreiter CD, Green J, Lenoch S, Saiki T. The
overall impact of testing on medical student
learning: quantitative estimation of consequential
validity. Adv Health Sci Educ Theory Pract. 2012
Aug 11. [Accepted on 31 July 2012, Epub ahead ofprint]
DOI 10.1007/s10459-012-9395-7

544Museum 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“development of communication between healthscience and care and 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
students studying medicine, health care services andrelated areas, (3) research the history of medicine andhealth care through archives, instruments andtechnology, and (4) preserve and investigate 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 inmedical science and health care. Planning andsupervision of the permanent exhibition and special
exhibition is done with the cooperation of the various
research units within the School and the Hospital,
other departments 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 by its graduates since the Meiji
era (1868-1912), and the latest knowledge about
infectious diseases. The second was “the Secret of
Vessel System”, which introduced the circulatory
system. The third “diagnosis of cancer”, the fourth“Our brain”, and the fifth “Locomotive syndrome”
followed.
Since the opening of the Museum, more than38,111 people had visited by the end of FY2011.

545

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.

546

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
International Research Center for Medical
Education (IRCME), established in 2000, hadfunctioned as a center for the whole university andkept relations with Graduate School of Medicine invarious ways. IRCME became an affiliated center for
education and research under the control of Graduate
School of Medicine since April 2013. IRCME previously consisted of two departments of International
Cooperative Study in Medical Education, andPlanning & Cooperation for International Cooperative
Projects and Information on Medical Education.
Names of two new departments are Department ofMedical Education Studies and Department ofInternational Cooperation for Medical Education.
The mission of IRCME includes promotion of
medical education not only in Faculty of Medicine of
the University of Tokyo but also of the whole country,
and international cooperation in medical education
area in developing countries. Specific contents are as
follows:(1) Research in medical education and dissemination
within and outside of the University
Medical and health professions education needs tocontinue revisions to meet health care needs of thecountry or the region. However, since every country
or region has different culture or social system,
experiences to apply updated evidences to the realsettings to revise the system.
(2) Research in international cooperation in medical
education area
To find a generalizable methodology for international
cooperation in medical education area we contributeto international cooperation for improvement ofundergraduate and postgraduate education in thecontext of status quo of each developing country.
(3) Support to undergraduate and postgraduate
education in the University
Through the support to education in Faculty of
Medicine and Its University Hospital, we show theeffective ness of such teaching practice and apply it toother medical schools in Japan for future reform.

Activities of Each Department
1. Medical Education Studies
This department promotes research related to
medical education field (including health professions
education). As the studies of medical education

547

develop very rapidly all over the world, thedepartment expands research to construct theories andemphasizes activities of educational practice or
improvement.
In the University, this department provides
information and member(s) as to the education ofFaculty of Medicine in such as academic affair
committee, medical education reform working group,and clinical clerkship managers’ meeting. Moreover,the department offers direct educational activities suchas PBL (problem-based learning) and clinical skill
practical training. Medical students are welcomed forfree quarter for practical work for research. The
department supervises CAT-OSCE (common achievement test-objective structured clinical examination)and gives advices from expert perspectives.
Medical education seminars of the University ofTokyo and basic courses of medical education aremonthly held. The department also runs and manages“Tsutsuji no kai” under the consortium with Tokyo
Medical Dental University to develop standardized
patients indispensable for education of medical
interview.
2. International
Cooperation
for
Medical
Education
This department participates in international
cooperation projects and practically works for the
research and educational developments in medical
education field (undergraduate and postgraduate
education in medicine, dentistry, pharmacy, nursing,public health, rehabilitation, etc. in countries mainlyin Asia. Furthermore, the department collects information and exchanges human relations for international
cooperation in medical education areas domesticallyand internationally, and supports projects related to
medical education.
IRCME invites international experts distinguishedin medical education practices or research as visiting
faculty members approximately six months per year.
Such faculty advises and teaches for planning andimplementing the activities of IRCME, and promotes
collaborative research.
In 2012, we welcomed a visiting professor:
Dr. Jeffrey G. Wong (1 Oct 2012 – 29 Mar 2013),
Professor, Internal Medicine, Medical University ofSouth Carolina, USA