ISSN 1883-9606

2014

Vol.129

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2013 ---- March 2014

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2013-March 2014

Introduction
This is volume 129 (the edition of year 2014) 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 more than 150 years ago. Since thenwe have consistently driven Japan’s progress in medical research, medical education, and clinicalcare, and in 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, 2014

i

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

1

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

2

Department of 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 ··················································

14

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

17

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

18

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

21

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

24

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

27

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

28

Department of Systems Pharmacology ·······································································

32

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

36

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

37

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

43

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

47

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

48

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

52

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

55

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

56

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

59

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

60

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

68

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

69

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

71

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

75

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

76

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

79

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

84

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

86

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

87

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

89

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

91

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

92

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

96

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

101

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

106

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

107

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

109

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

112

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

113

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

117

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

120

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

121

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

126

iii

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

130

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

136

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

137

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

142

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

147

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

151

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

155

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

159

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

161

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.447] )Department of Transfusion Medicine ·········································································

162

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

166

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

167

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

169

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

175

Department of Molecular and Cellular Reproductive Medicine ···········································

177

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

179

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

180

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

184

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

188

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

189

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

193

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

194

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

198

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

203

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

206

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

208

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

213

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

217

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

220

iv

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

222

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

223

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

227

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

231

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

235

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

241

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

247

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

251

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

253

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

254

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

257

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

261

Department of Health Sociology / Health Sociology and Health Education(See Departments of Health and Social Behavior / Health Education and Sociology [P.337] )Department of Mental Health ··················································································

262

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

266

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

271

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

274

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

275

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

278

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

281

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

284

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

285

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

289

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

292

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

296

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

302

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

303

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

309

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

313

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

314

v

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

317

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

320

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

324

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

326

Department of Biostatistics (See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.266])
Department of Social and Preventive Epidemiology ························································

327

Department of Clinical Epidemiology and Health Economics ··············································

330

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

333

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

336

Department of Mental Health(See Department of Mental Health [P.262] )Departments of Health and Social Behavior & Health Education and Sociology ····························· 337

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.271] )3. Health Services Sciences ·························································································

340

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.109] )Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.117] )Department of Clinical Information Engineering ····························································

341

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

343

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

344

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

347

Department of Vascular Regeneration (Daiichi Sankyo Co.,Ltd.)(See Department of Oral-Maxillofacial Surgery [P.231] )Department of Bone & Cartilage Regenerative Medicine(See Department of Orthopaedic Surgery [P.235] )Department of Cartilage & Bone Regeneration (Fujisoft)(See Department of Oral- Maxillofacial Surgery [P.231] )Department of Clinical Renal Regeneration(See Central Clinical Facilities Division of Tissue Engineering [P.493] )Department of Clinical Epidemiology and Systems ·························································

350

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

353

Science for joint reconstruction ( See Department of Orthopaedic Surgery [P.235] )Department of Molecular Neuroscience on Neurodegeneration (See Department of Neurology [P.96] )Department of Chronic Kidney Disease (CKD) ·····························································

357

vi

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

359

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

360

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

362

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

364

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

367

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

369

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

373

Department of Immunotherapy Management ································································

376

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

378

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

379

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

382

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

385

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

387

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

389

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

393

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

396

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

398

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

402

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

405

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

408

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

410

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

413

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

415

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

418

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

420

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

423

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

425

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

429

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

431

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

433

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

434

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

436

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

438

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

441

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

442

vii

University Hospital
Clinical Divisions ····································································································

445

Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.121] )Respiratory Medicine (See Department of Respiratory Medicine [P.126] )Gastroenterology (See Department of Gastroenterology [P.130] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.137] )Diabetes and Metabolic Diseases (See Department of Metabolic Diseases [P.142] )Hematology and Oncology (See Department of Hematology and Oncology [P.147] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.151] )Infectious Diseases (See Department of Infectious Diseases [P.155] )Neurology (See Department of Neurology [P.96] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.189] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.159] )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.206] )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.206] )Cardiovascular Surgery (See Department of Cardiothoracic Surgery [P.198] )Thoracic Surgery (See Department of Thoracic Surgery [P.194] )Neurosurgery (See Department of Neurosurgery [P.101] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.254] )Urology and Andrology (See Department of Urology [P.208] )Gynecologic Surgery (See Obstetrics and Gynecology [P.166] )Sensory and Motor System Medicine
Dermatology and Photolaser Medicine (See Department of Dermatology [P.223] )Ophthalmology and Vision Correction (See Department of Ophthalmology [P.241] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.235] )viii

Otorhinolaryngology, and Auditory and Voice Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.247] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.251] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.227] )Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.231] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.180] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.184] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.167, 169, 175] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.92] )Radiology
Radiology (See Department of Radiology [P.60] )Central Clinical Facilities ···························································································

446

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

447

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

451

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

455

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

457

Department of Emergency Services(See Department of Emergency and Critical Care Medicine [P.257] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.162] )Delivery Unit ·····································································································

461

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

462

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

464

Department of Intensive Care Unit
(See Department of Emergency and Critical Care Medicine [P.257] )Division of Diagnostic Pathology ··············································································

466

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

468

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

470

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

472

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

475

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

478

ix

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.52] )Department of Planning, Information, and Management(See Department of Medical Informatics and Economics [P.117] )University Hospital Medical Information Network (UMIN) Center ······································

484

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

487

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

489

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

493

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

497

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

500

Department of Pain and Palliative Medicine···································································

504

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

507

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

508

Department of Clinical Genomics, Medical Genome Center ···········································

510

Department of Genome Analysis, Medical Genome Center ············································

512

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

514

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

523

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

525

Department of Clinical Nutrition Therapy ····································································

526

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

530

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

531

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

534

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

537

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

539

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

543

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

546

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

548

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

551

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

554

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

556

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014x

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

1869
1871

Hospital).

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. 129, October 2014

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.

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014

xii

2000

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.

2013

Apr.

The International Research Center for Medical Education became a facility of the Graduate
School of medicine.

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014

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
Systems Pharmacology
Human Pathology and Diagnostic Pathology

Pathology

Molecular Pathology
Surgical Pathology

Microbiology
Pathology, Immunology
and Microbiology

Microbiology
Infection Control and Prevention

Immunology

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. 129, October 2014

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. 129, October 2014
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 Health 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

International ResearchCenter for Medical Education

Laboratory of Molecular Radiology

Section of Animal Research

Division of Research Resources and Support

Section of Radiation Biology

Department of Medical Education Studies

Section of Bioinformatics

Department of International Cooperation for
Medical Education

xvi

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014
Office of International Academic Affairs
Medical Library
Medical Scientist Training Program
Institution

Museum of Health and Medicine
Office for Research Ethics Support
Office for Life Science Research Equipment Supprt
Pharmacoepidemiology
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
Health Care Safety Management(Tokio Marine & Nichido)

Endowed Department

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
AXA Chair on Health and Human Security
Department of Advanced Translational Research and Medicine in Management of Pulmonary Hypertension
Department of Immunotherapy Management
Chronic Kidney Disease
General Affairs Office
Ubiquitous Health Informatics

Social Cooperation Program

Lipidomics
Functional Regulation of Adipocytes
Advanced Nursing Technology

Personnel Office
Research Support Office
Educational Affairs
Graduate Student Affairs

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014

xvii

Finance Office

Administrative officeContract Office
External Fund Management OfficeFinance Office
Faculty of Medicine
Graduate School of
Medicine

Facilities Office

Administrative Division

Acquisition 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. 129, October 2014

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 Esophageal 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. 129, October 2014
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
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
Department of Clinical Nutrition Therapy
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
Department of Personnel
Administration and Human
Resource Management
Department of Performance
Monitoring and Risk
Management

Organization of ClinicalManagement Support
Department of Education andStaff Development

Medical Specialists
Training Center
Office of Performance Monitoring
Medical Safety management
CenterInfection Control Center
Patient Help and Clinical
Ethics Center
General Education Center
Hospitality Center

Department of Hospital Planning and Management
Department of Research Support
Inpatient Services
Administration
Organization of ClinicalManagement

Outpatient Services
Administration
Central Clinical Services
Administration

Cancer Board
Inpatient Center

Vascular Board

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014xx

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

Chiho Watanabe

Director, Medical Library

Tsuyoshi Takato

Director General, University Hospital

Takashi Kadowaki

Director, Center for Disease Biology and Integrative Medicine

Masamitsu Iino

Director, International Research Center for Medical Education

Kazuhiko Yamamoto

Graduate School of Medicine
Molecular Cell Biology
Department of Cell Biology and Anatomy

Professor

Masahide Kikkawa

Professor

Shigeo Okabe

Professor

Noboru Mizushima

Professor

Hiroyuki Mano

Professor

Hiroki Kurihara

Professor

Yasushi Miyashita

Professor

Kensaku Mori

Professor

Masanobu Kano

Professor

Masamitsu Iino

Professor

Hiroki Ueda

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

Haruhiko Bito

Professor

Kenzo Hirose

Department of Biochemistry and Molecular Biology

Functional Biology
Department of Physiology

Department of Pharmacology

Pathology, Immunology and Microbiology
Department of Pathology

Department of Microbiology

Department of Immunology
Radiology and Biomedical Engineering

Neuroscience
Department of Basic Neuroscience

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014

xxi

Department of Integrative Medical Neuroscience
Department of Clinical Neuroscience

Professor

Kiyoto Kasai

Professor

Shoji Tsuji

Professor

Nobuhito Saito

Department of Occupational, Environmental and Preventive

Professor

Koji Matsushima

Medicine

Professor

Yasuki Kobayashi

Department of Forensic Medicine, and Medical Informatics

Professor

Kenichi Yoshida

and Economics

Professor

Kazuhiko Ohe

Professor

Issei Komuro

Professor

Takahide Nagase

Professor

Kazuhiko koike

Professor

Masaomi Nangaku

Professor

Takashi Kadowaki

Professor

Mineo Kurokawa

Professor

Kazuhiko Yamamoto

Professor

Yutaka Yatomi

Professor

Hitoshi Okazaki

Professor

Tomoyuki Fujii

Professor

Yutaka Osuga

Professor

Akira Oka

Professor

Tadashi Iwanaka

Professor

Masahiro Akishita

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

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II

Department of Clinical Laboratory Medicine and Pathology

Reproductive, Developmental and Aging Science
Department of Obstetrics and Gynecology

Department of Pediatric Science

Department of Aging Science
Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

xxii

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014

Department of Vital Care Medicine

Professor

Yoshitsugu Yamada

Professor

Naoki Yahagi

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

Hideo Yasunaga

Professor

Takahiro Kiuchi

Professor

Norito Kawakami

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Yasuki Kobayashi

Professor

Kazuhiko Ohe

Professor

Hiroshi Oyama

Professor

Kenichi Yoshida

Health Sciences and Nursing
Department of Health Sciences

Department of Preventive and Administrative Nursing

Department of Clinical Nursing

International Health
Department of International Social Medicine

Department of International Biomedical Sciences

School of Public Health
Department of Epidemiology and Health Sciences

Department of Behavioral Health Sciences

Department of Health Services Sciences

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014

xxiii

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

Professor

Toru Miyazaki

Laboratory of Structural Physiology

Professor

Haruo Kasai

Laboratory of Regenerative Medical Engineering

Professor

Takashi Ushida

Laboratory of Clinical Biotechnology

Professor

Kazunori Kataoka

Laboratory of Environmental Health Sciences

Professor

Chiharu Tohyama

Laboratory of Animal Resources

Professor

Atsu Aiba

Laboratory of Molecular Radiology

Professor

Kiyoshi Miyakawa

International Research Center for Medical Education

Professor

Kiyoshi Kitamura

Medical LibraryProfessor

Tsuyoshi Takato

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 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

Norio Hanafusa

Associate professor

Junichi Suzuki

Associate professor

Hiroshi Akazawa

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

Professor

Soichi Koike

Associate professor

Ryuichi Yamamoto

Associate professor

Naoto Hayashi

Associate professor

Kansei Uno

Associate professor

Takeharu Yoshikawa

Clinical Motor System Medicine

Associate professor

Toru Akune

Healthcare Safety Management (Tokio Marine & Nichido)

Professor

Yasushi Kodama

Molecular Cardiovascular Metabolism

Associate professor

Katsuyuki Ando

Integrated Molecular Science on Metabolic Diseases
Department of Advanced Clinical Science and Therapeutics

Computational Diagnostic Radiology and Preventive Medicine

xxiv

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014

The Department of Healthcare Quality Assessment

Associate professor

Hiroaki Miyata

Anti-Aging Medicine

Professor

Satoshi Inoue

Clinical Epidemiology and Systems

Associate professor

Daisuke Koide

Clinical Trial Data Manegement

Professor

Takuhiro Yamaguchi

Pharmacology and Pharmacokinetics

Associate professor

Akihiro Hisaka

Ubiquitous Preventive Medicine

Associate professor

Toru Suzuki

Science for joint reconstruction

Professor

Yoshio Takatori

Associate professor

Toru Moro

Department of Therapeutic Strategy for Heart Failure

Professor

Koichiro Kinugawa

Department of Molecular Neuroscience on Neurodegeneration

Associate professor

Atsushi Iwata

Department of Molecular Structure and Dynamics (JEOL/Zeiss)

Professor

Nobutaka Hirokawa

Department of Molecular Vascular Endocrinology

Associate professor

Masashi Isshiki

Department of Medical Genomics

Associate professor

Young Lim Choi

Associate professor

Yoshihiro Yamashita

Continence medicine

Professor

Yasuhiko Igawa

Department of Molecular Psychiatry

Associate professor

Kazuya Iwamoto

Department of Life Support Technology (Molten)

Associate professor

Taketoshi Mori

Department of Youth Mental Health

Associate professor

Tsuyoshi Araki

Department of Molecular Medicinal Sciences on Metabolic Regulation

Associate professor

Hiroaki Okazaki

Department of Advanced Nephrology and Regenerative Medicine Associate professor

Keiichi Hishikawa

Department of Sensory-recognition and Locomotive-function

Associate professor

Kimihiko Kameyama

AXA Chair on Health and Human Security

Professor

Manami Inoue

Department of Advanced Translational Research andAssociate professor

Eiki Takimoto

Department of Immunotherapy Management

Associate professor

Hiroko Kanda

Chronic kidney disease pathophysiology

Associate professor

Reiko Inagi

Department of Ubiquitous Health Informatics

Associate professor

Hideo Fujita

Department of Lipidomics

Professor

Takao Shimizu

Functional Regulation of Adipocytes

Associate professor

Hironori Waki

Advanced Nursing Technology

Associate professor

Ryoko Murayama

General Medicine

Head

Kazuhiko Koike

Cardiovascular Medicine

Head

Issei Komuro

Respiratory Medicine

Head

Takahide Nagase

Sciences in the Super-aged Society

Medicine in Management of Pulmonary Hypertension

Social Cooperation Program

University Hospital
Clinical Divisions

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014xxv

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

Masahiro Akishita

Psychosomatic Medicine

Head

Kazuhiro Yoshiuchi

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

HeadToshiaki Watanabe

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

Akira Oka

Pediatric Surgery

Head

Tadashi Iwanaka

Obstetrics and Gynecology

HeadTomoyuki Fujii

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Kuni Ohtomo

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Clinical Laboratory

Head

Yutaka Yatomi

Surgical Center

Head

Hiroshi Yasuhara

Imaging Center

Head

Kuni Ohtomo

Central Clinical Facilites

xxvi

The Tokyo Journal of Medical Sciences. Vol. 129, October 2014

Emergency Service

Head

Naoki Yahagi

Department of Blood Transfusion

Head

Hitoshi Okazaki

Perinatal Center

Head

Tomoyuki Fujii

Rehabilitation Center

Head

Nobuhiko Haga

Department of Medical Engineering

Head

Masahiko Sumitani

Central Supply Service

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoki Yahagi

Pathology

Head

Masashi Fukayama

Department of Corneal Transplantation

Head

Satoru Yamagami

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Department of Endoscopy and Endoscopic Surgery

Head

Mitsuhiro FujisiroDepartment of Hemodialysis and Apheresis

Head

Masaomi Nangaku

Medical Community Network and Discharge Planning

Head

Kiyoto Kasai

Infection Control and Prevention Service

Head

Kyoji Moriya

Department of Planning, Information and Management

Head

Kengo Miyo

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Organ Transplantation Service

Head

Norihiro Kokudo

Labor Safety and Health Management Office

HeadShin OnishiChild Psychiatry

Head

Yukiko Kano

Tissue Bank

Head

Sumihito Tamura

Epidemiology and Preventive Medicine

Head

Tsutomu Yamazaki

Cancer Resource Center

Head

Sachiyo Nomura

Center for Liaison and Public Relations

Head

Toshiaki Watanabe

Department of Chemotherapy

HeadNorihiro Kokudo

Department of Medical Record Management

Head

Toshiaki Watanabe

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

Sumihito Tamura

Department of Clinical Nutrition Therapy

Head

Yutaka Yatomi

Clinical Research Support Center

Head

Tsutomu Yamazaki

22nd Century Medical and Research Center

Head

Tuyoshi Takato

Department of Tissue Engineering

Head

Tsuyoshi Takato

Cooperative Unit of Medicine and Engineering Research

Head

Minoru Ono

Translational Research Center

Head

Mineo Kurokawa

Center for Genome Medicine

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.,

Lecturer and 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.

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. betatubulin mutation that cause severe neuropathies
disrupt axonal transport. EMBO J. 32:
1352-1364, 2013.
Chang Q., R. Nitta, S. Inoue, and N. Hirokawa.
Structural basis for ATP-induced isomerizationof kinesin. J. Mol. Biol. 425: 1869-1880,
2013.
Kanai Y., D. Wang, and N. Hirokawa. KIF 13b
enhances the endocytosis of LRP1 by recruiting
LRP1 to caveolae. J. Cell Biol. 204: 395-408,
2014.
Yang W., Y.Tanaka, M. Bundo, and N. Hirokawa.
Antioxidantsignaling
involvingthemicrotubulemotor KIF12 is an intracellular targetof nutrition excess in beta cells. Dev Cell inpress, 2014.

4

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

Lecturer
Toshiki Yagi, Ph.D.

Associate
Toshiyuki Oda, Ph. D.

Homepage

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

Introduction and Organization

Research activities

Our laboratory is one of the laboratories in
Department of Cell Biology and Anatomy. Since thereorganization of School of Medicine in 1997, the lab
was named as “Structural Biology”. The current lab
was established in 2009 when Masahide Kikkawa was
appointed as a professor.

Our lab focuses on the structure and function of
eukaryotic flagella/cilia. Flagella/cilia is both“propeller” and “antenna” of cells, whose
diameter is about 250 nm. From the recent
studies, it is becoming clear that flagella/cilia is
involved in various important cell functions.

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

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

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

Cryo-electron microscopy
One of our strength is in the high-resolution
cryo-electron microscopy (cryo-EM). This
techniqueenablespreserving
biologicalsamples by quickly freezing them and observes
the frozen samples without staining. Using
electron microscopy, we are able to obtainnano-meter resolution of macromolecularcomplexes such as axonemes. We have beendeveloping new techniques, such as asymmetrichelical reconstruction and Ruby-Helix software.
By using these new techniques, we are
currently studying dynein-microtubule complex,

5dynein stalk-microtubule complex to elucidate
the mechanism of dynein’s motor functions.
Model Organism
Our lab currently uses Chlamydomonas as amodel organism for studying flagella. To
identify molecules that are involved inregulating 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 themechanism of flagella regulation.

References
1. Oda T. and M. Kikkawa
Novel Structural
Labeling
Methodusing
Cryo-electron
Tomography and Biotin-Streptavidin System
Journal of Structural Biology, 183:305-11, 2013
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
as a Hub Controller for Axonemal Dynein
Activities” Current Biology, 23:656-64, 2013
4. Takarada O., N. Nishida, M. Kikkawa, and I.
Shimada “Backbone and side-chain 1H, 15N
and 13C resonance assignments of the
microtubule-binding domain of yeast cytoplasmic
dynein in the high and low-affinity states”
Biomolecular NMR Assignments, epub ahead of
print

6

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

Lecturer
Hirohide Iwasaki, Ph.D

Research Associate
Shinji Tanaka, Ph.D., Hiroaki Oshiro,

Homepage

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

Introduction and Organization

Research

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,

Education
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.

Okabe, S.
Fluorescence imaging of synapse formation andremodeling.
Microscopy(Oxf)., Feb;62(1):51-62., 2013
Shin, E., Kashiwagi, Y., Kuriu, T., Iwasaki, H.,
Tanaka, T., Koizumi, H., Gleeson, J.G. andOkabe, S.
Doublecortin-like kinase enhances dendritic
remodelling and negatively regulates synapse
maturation.
Nat Commun., 4:1440., 2013
Obashi, K. and Okabe, S.
Regulation of mitochondrial dynamics anddistribution by synapse position and neuronal
activity in the axon.
Eur J Neurosci., Aug;38(3):2350-63., 2013
Kondo, S. and Okabe, S.
In vivo two-photon microscopy of microglia.
Methods Mol Biol., 1041:319-35., 2013

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.
Professor Masami Muramatsu graduated from the
University of Tokyo Faculty of Medicine in 1955. He10began 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 throughinteraction with SNAP29 and VAMP8 (Itakura etal. 2012). We also found that STX17 interacts
with HOPS, which has been known to beimportant for the endosome-lysosome fusion, andshowed that HOPS also acts as a tethering
complex essential for the autophagosomelysosome fusion. We are further investigating the
spatiotemporal regulation of the autophagosomelysosome fusion.
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,
and 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
Autophagy is known to be partially selective. p62
protein and damaged mitochondria are selectively
degraded by autophagy. We have proposed thatthese selective substrates are recognized at two
steps (i) at the autophagosome formation site and11(ii) on the autophagosomal membrane. We arefurther characterizing the autophagosome
formation site and identifying selective substrates.
4. Physiological and pathological roles of
autophagy
In collaboration with Dr. Naomichi Matsumoto’s
group (Yokohama City University), we identifieddenovo
heterozygous
mutationsin
WDR45/WIPI4 gene, which encodes one of thehuman homolog of yeast Atg18, in patients with
Static encephalopathy of childhood withneurodegeneration in adulthood (SENDA). We
found that autophagy was indeed impaired inlymphoblastoid cell lines derived from SENDA
patients. We also found that autophagy is essential
for quality control of lens; lens-specificautophagy-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 ofcarbohydrates, amino acids, and nucleic acids are thetopics in our lectures. To graduate course students, themolecular biology course consisting of lectures andexperiments is provided.

Publication
1.

2.

3.

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.,

7.

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
independentof
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. 288:21074-21081 (2013).
Koyama-Honda, I., Itakura, E., Fujiwara, T.K.,
Mizushima, N. Temporal analysis of recruitmentof mammalian ATG proteins to the
autophagosome formation site. Autophagy
9:1491-1499 (2013).
Jiang, P., Nishimura, T., Sakamaki, Y., Itakura, E.,
Hatta, T., Natsume, T., Mizushima, N. The HOPS
complex mediates autophagosome-lysosome
fusion through interaction with syntaxin 17. Mol.
Biol. Cell. 25:8 1327-1337 (2014).

12

Department of Cellular Signaling
Professor
Hiroyuki Mano, M.D., Ph.D.

Associate Professor
Motonao Nakamura, Ph.D.

Assistant Professors
Manabu Soda, M.D., Ph.D., Toshihide Ueno, Ph.D.

Homepage

http://mano-lab.umin.jp/english/index.html

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.
We aim to discover essential growth driver genes
in cancer, and to develop reliable biomarkers andmolecular targeted therapies by using originalfunctional screening systems as well as genomics
approaches.
In addition to the members shown above, two
postdoctoral fellows, two research fellows, two
graduates, two undergraduates, five researchtechnicians and one secretary belong to ourdepartment. We are also in a tight collaboration with
Department of Medical Genomics.
Dr. Hiroyuki Mano joined Department of
Cellular Signaling at April 2013 as Professor. Drs.
Manabu Soda and Toshihide Ueno also joined thisDepartment at September 2013 as AssistantProfessors.

Teaching activities
We jointly take the responsibility for the lectures ofBiochemistry as well as training of biochemical

experiments. We accept students for Free Quarter andshort laboratory courses. We further deliver lecturesfor Graduate School of Medicine, and accept graduate
students.

Research activities
Department of Cellular Signaling tries to fulfill ourgoals mainly through two approaches.
(1) Functional screening with the use of retroviral
cDNA expression libraries.
The focus formation assay had been widely usedin 1980s and 1990s to identify oncogenes from humancancer. However, since this technology directly usescancer genome to transfer oncogenes into recipient
cells, expression of each gene is regulated by its 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.
(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13

NGS has enabled us to determine the full genome
sequence of a cancer specimen even in private
laboratories, it is still a demanding task to conduct
full-genome sequencing for a large number of samples.
Therefore, many laboratories now purify exonic
fragments from a sample genome, and determine theirsequences. However, since gene fusions usually takeplace at intronic regions, such sequencing approachwith captured exons fails to discover fusion genes.
Thus, we have developed a “cDNA-capturesystem”, in which exon capture is conducted on cDNA,
not genomic DNA. With this technology, a single
NGS experiment can detect point mutations,insertions/deletions and gene fusions simultaneously(Cancer Sci 103:131). We mainly use HiSeq2500 and
HiSeq2000 systems for NGS, and have developed
in-house computational pipelines for detecting
somatic
singlenucleotide
variations,insertions/deletions,andchromosomal
rearrangemetns.
By coupling such approaches, we have obtained
following findings this year.
CASP8 is a well-known proapoptotic factor, andhas somatic mutations in a wide range of humancancer. While such mutations have been believed toconfer loss-of-function in apoptosis and to contributeto carcinogenesis, we discovered that most of themconfer gain-of-function in NF-κB activity.
Likewise, we found that many somatic mutations
in
STK10
serine/threonine
kinases
provideNF-κB–inducing ability to this kinase.

References
1.

2.

Suzuki HI, Matsuyama H, Noguchi M, Yao T,
Komatsu N, Mano H, Sugimoto K, Miyazono K.
Computational dissection of distinct microRNA
activity signatures associated with peripheral T
cell lymphoma subtypes. Leukemia 2013:27:
2107-2111.
Ninomiya H, Kato M, Sanada M, Takeuchi K,
Inamura K, Motoi N, Nagano H, Nomura K,
Sakao Y, Okumura S, Mano H, Ogawa S,
Ishikawa Y. Allelotypes of lung adenocarcinomas
featuring ALK fusion demonstrate fewer oncoand suppressor gene changes. BMC Cancer
2013:13:8.

3.

4.

5.

6.

7.

8.

Miyanaga A, Shimizu K, Noro R, Seike M,
Kitamura K, Kosaihira S, Minegishi Y, Shukuya
T, Yoshimura A, Kawamoto M, Tsuchiya S,
Hagiwara K, Soda M, Takeuchi K, Yamamoto N,
Mano H, Ishikawa Y, Gemma A. Activity of
EGFR-tyrosine kinase and ALK inhibitors for
EML4-ALK-rearranged
non-small-celllungcancer harbored coexisting EGFR mutation. BMC
Cancer 2013:13:262.
Kawazu M, Ueno T, Kontani K, Ogita Y, Ando M,
Fukumura K, Yamato A, Soda M, Takeuchi K,
Miki Y, Yamaguchi H, Yasuda T, Naoe T,
Yamashita Y, Katada T, Choi YL, Mano H.
Transforming mutations of RAC guanosine
triphosphatases in human cancers. Proc Natl Acad
Sci U S A 2013:110:3029-3034.
Himpe E, Abdul Rahim SA, Verdood P, Mano H,
Kooijman R. Tec kinase stimulates cell survivalin transfected Hek293T cells and is regulated by
the anti-apoptotic growth factor IGF-I in humanneutrophils. Cell Signal 2013:25:666-673.
Fukumura K, Yamashita Y, Kawazu M, Sai E,
Fujiwara S, Nakamura N, Takeuchi K, Ando M,
Miyazono K, Ueno T, Ozawa K, Mano H. STK10
missense mutations associated with anti-apoptotic
function. Oncol Rep 2013:30:1542-1548.
Ando M, Kawazu M, Ueno T, Fukumura K,
Yamato A, Soda M, Yamashita Y, Choi YL,
Yamasoba T, Mano H. Cancer-associatedmissense mutations of caspase-8 activate nuclear
factor-kappaB signaling. Cancer Sci 2013:104:1002-1008.
Ando K, Tsushima H, Matsuo E, Horio K,
Tominaga-Sato S, Imanishi D, Imaizumi Y,
Iwanaga M, Itonaga H, Yoshida S, Hata T,
Moriuchi R, Kiyoi H, Nimer S, Mano H, Naoe T,
Tomonaga M, Miyazaki Y. Mutations in the
nucleolar
phosphoprotein,
nucleophosmin,
promote the expression of the oncogenictranscription factor MEF/ELF4 in leukemia cells
and potentiates transformation. J Biol Chem 2013:
288:9457-9467.

14

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

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kouichi Nishiyama, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html
Introduction and Organization

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 rolein the organogenesis of the kidney and lung as

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.

15

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,
Sobue G. Naratriptan mitigates
CGRP1-

7.

associated 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 inmacrophage
foam
cell
formationandatherosclerosis
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
resistance in 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.

16

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

18

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

Lecturer
Toshiyuki Hirabayashi, Ph.D.

Project Lecturer
Masaki Takeda, Ph.D., Yohei Ohashi, M.D., Ph.D.

Research Associate
Yusuke Adachi, Ph.D., Kenji Koyano, Ph.D., Keita Tamura, Ph.D.

Homepage

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 S. Nakanishi) take part in giving
lectures and laboratory courses to the undergraduate
students of the Medical School. The lectures are
aimed at providing a clear understanding of thehierarchical functional organizations of living systems.

The curriculum is updated every year. For example, a
new electrocardiogram 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. Some of these students
completed their own projects, and gave oralpresentations in international meetings and publishedoriginal papers in top-rank international 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 andstarted to study neurophysiology in our laboratory.
Furthermore, we accepted a Ph-D.-M.D course student
who enjoyed his Free-Quarter and decided to get into
the Ph-D.-M.D course. Thus the Free-Quarter system
has proved to provide an excellent basis for bringing
up M.D. researchers for future Japanese basic
medicine.
To facilitate communication among research groups
in our laboratory, a weekly conference is held for
discussing current research activities. We also have amonthly joint seminar with Department of Pharma-

19

cology, Department of Molecular Biology in Graduate
School of Pharmaceutical Sciences and Department ofChemical Pharmacology in Grauate School of
Pharmaceutical Sciences. As part of a teachingactivity for the graduate students, we have anotherweekly English seminar, in which the graduate
students learn how to give presentations and holddiscussions and debates in English.

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system :(1) higher functions of vision and memory, (2)non-invasive measurements of human brain activitiesand (3) non-invasive functional measurements ofmonkey brain activities that links above (1) and (2).
The results of such research have been published infirst-rate journals, as listed in the reference. A briefsummary of each topic follows:(1) In the primate, visual information processing in
the cerebral cortex proceeds along the neuralpathway originating from the primary visual areain the occipital lobe to the anterior part of thetemporal association cortex. Our laboratory
discovered several classes of important 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.

Hirabayashi, T., Takeuchi, D., Tamura, K., andMiyashita, Y.:
Microcircuits for Hierarchical Elaboration of Object
Coding Across Primate Temporal Areas.
Science 341, 191-195, 2013
Miyamoto, K., Osada, T., Adachi, Y., Matsui, T.,
Kimura, H.M., Miyashita, Y.:
Functional Differentiation of Memory Retrieval
Network in Macaque Posterior Parietal Cortex.
Neuron 77, 787-799, 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-state human brain networks.
Nat. Commun. 4:1370, 2013.
Yaguchi M., Ohashi Y., Tsubota T., Sato A.,
Koyano W.,K., Wang N., and Miyashita Y.:
Characterization of the Properties of Seven
Promoters in the Motor Cortex of Rats andMonkeys after Lentiviral Vector-Mediated Gene

20

Transfer.
Human Gene Therapy Methods 24, 333-344, 2013
5. Watanabe T, Abe O, Kuwabara H, Yahata N,
Takano Y, Iwashiro N, Natsubori T, Aoki Y, Takao
H, Kawakubo Y, Kamio Y, Kato N, Miyashita Y,
Kasai K, and Yamasue H. :Mitigation of Sociocommunicational Deficits ofAutism Through Oxytocin-Induced Recovery ofMedial Prefrontal Activity : A Randomized Trial.
JAMA Psychiatry (formerly Archives of General
Psychiatry). 71, 166-175, 2013
6. Watanabe T, Hanajima R, Shirota Y, Ohminami S,
Tsutsumi R, Terao Y, Ugawa Y, Hirose S,
Miyashita Y, Konishi S, Kunimatsu A, and Ohtomo
K. :Bidirectional
effects
oninter-hemisphericresting-state functional connectivity induced byexcitatory and inhibitory repetitive transcranial
magnetic stimulation.
Human Brain Mapping 35, 1896-1905, 2013
7. Tsubota,T., Ohashi, Y.,Tamura, K.:
Optogenetics in the cerebellum: Purkinjecell-specific approaches for understanding local
cerebellar functions.
Behavioural Brain Research 255, 226-34, 2013.
8. Hirabayashi, T., Takeuchi, D., Tamura, K., andMiyashita, Y. :Functional microcircuit recruited during retrieval of
object association memory in monkey perirhinal
cortex.
Neuron 77, 192-203, 2013.
9. Watanabe T., Hirose S., Wada H., Imai Y., MachidaT., Shirouzu I., Konishi S., Miyashita Y. andMasuda N.:
Energy landscapes of resting-state brain networks
Front. Neuroinform. 8: 12, 2014
10. Hirabayashi, T. and Miyashita, Y.:
Computational principles of microcircuits for visualobject processing in the macaque temporal cortex
Trends in Neurosci. 37, 178-187, 2014
11. Miyamoto, K., Adachi, Y., Osada, T., Watanabe, T.,
Kimura, H.M., Setsuie, R. and Miyashita, Y.:
Dissociable memory traces within the macaquemedial temporal lobe predict subsequent
recognition performance.
J. Neurosci. 34, 1988-1997, 201412. Hirabayashi, T., Tamura, K., Takeuchi, D., Takeda,
M., Koyano, W.,K., and Miyashita, Y.: Distinct
Neuronal Interactions in Anterior Inferotemporal
Areas of Macaque Monkeys during Retrieval of
Object Association Memory.
J. Neurosci. 34, 9377-9388, 2014
13. Watanabe, T., Takezawa, M., Nakawake, Y.,
Kunimatsu, A., Yamasue, H., Nakamura, M.,
Miyashita, Y. and Masuda N. :Two distinct neural mechanisms underlying indirect
reciprocity
Proc. Natl. Acad. Sci. U.S.A. 111, 3990-3995, 2014

21

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, 2
postdoctoral researchers, 1 visiting scientist, 3
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

22experience 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

23

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 (2013~)
1. 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. 110: 15931599 (2013)
2. Yamaguchi M, Manabe H, Murata K, and Mori K
Reorganization of neuronal circuits of the central
olfactory system during postprandial sleep Front.
Neural Circuits 7: 132 (2013)
3. Mori K, Manabe H, Narikiyo K, and Onisawa N
Olfactory consciousness and gamma oscillation
couplings across the olfactory bulb, olfactorycortex and orbitofrontal cortex
Front.
Psychology 4: 743 (2013)
4. Narikiyo K, Manabe H, and Mori K Sharp
wave-associated synchronized inputs from thepiriform cortex activate olfactory tubercle neurons
during slow-wave sleep
J Neurophysiol. 111:
72-81 (2014)
5. Mori K
Piriform Cortex and Olfactory
Tubercle
In: Mori K (Ed) The Olfactory
System, Springer, Tokyo, pp 161-176. (2014)
6. Nagayama S, Igarashi KM, Manabe H, and MoriK
Parallel Tufted Cell and Mitral Cell
Pathways from the Olfactory Bulb to theOlfactory Cortex
In: Mori K (Ed) The
Olfactory System, Springer, Tokyo, pp 133-160.
(2014)
7. Yamaguchi M
Interneurons in the Olfactory
Bulb: Roles in the Plasticity of Olfactory
Information Processing In: Mori K (Ed) The
Olfactory System, Springer, Tokyo, pp 97-132.
(2014)
8. Mori K Odor Maps in the Olfactory Bulb

In: Mori K (Ed)The Olfactory System,
Springer, Tokyo, pp 59-70. (2014)
9. Mori K and Manabe H Unique Characteristicsof the Olfactory System
In: Mori K (Ed) The
Olfactory System, Springer, Tokyo, pp 1-18.
(2014)
10. Sakamoto M, Ieki N, Miyoshi G, Mochimaru D,
Miyachi H, Imura T, Yamaguchi M, Fishell G,
Mori K, Kageyama R, Imayoshi I. Continuous
postnatal neurogenesis contributes to formation of
the olfactory bulb neural circuits and flexible
olfactory associative learning. J Neurosci. 34:
5788-99.(2014)
11. Yamaguchi M, Mori K. Critical periods in adultneurogenesis and possible clinical utilization of
new neurons Front. Neuroscience 8:177 (2014)
12. Komano-Inoue S., Manabe H., Ota M.,
Kusumoto-Yoshida I., Yokoyama T. K., Mori K.,
and Yamaguchi M. Top-down inputs from theolfactory cortex in the postprandial period
promote elimination of granule cells in theolfactory bulb Eur. J. Neurosci. (in press)

24

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, 8 graduate students,
2 undergraduate students and 6 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,

25morphology, 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(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminatedeventually with the progress of postnatal development,
and most Purkinje cells become innervated by single
climbing fibers by the end of the third postnatal weekin mice. We investigate the mechanisms how single
climbing fibers are selected and how the surplus
climbing fibers are eliminated.
(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an
activity-dependent manner, act retrogradely onto
presynaptic cannabinoid receptors and suppress
transmitter release. Since then, we have been
investigating the mechanisms of this retrograde
modulation. We are also interested in elucidating thephysiological significance of this phenomenon
including learning and memory, addiction, andanxiety.
(3) Synaptic integration in intact animals:
To understand the physiological function ofsynapses in vivo, we analyze synaptic transmission
and integration in single neurons in the intact brain byusing in vivo two-photon imaging and whole-cellrecording. We also develop new methods toimplement these experiments.

References(1) Ohtani Y, Miyata M, Hashimoto K, Tabata T,
Kishimoto K, Fukaya M, Kase D, Kassai H,

Nakao K, Hirata T, Watanabe M, Kano M, Aiba
A: The synaptic targeting of mGluR1 by its
carboxyl-terminal domain is crucial for
cerebellar function. J Neurosci 34: 2702-2712(2014).
(2) Horváth E, Woodhams SG, Nyilas R, Henstridge
CM, Kano M, Sakimura K, Watanabe M, Katona
I: Heterogeneous presynaptic distribution of
monoacylglycerol lipase, a multipotent regulatorof nociceptive circuits in the mouse spinal cord.
Eur J Neurosci 39: 419-434 (2014).
(3) Kamikubo, Y., Shimomura, T., Fujita, Y., Tabata,T., Kashiyama, T., Sakurai, T., Fukurotani, K. &
Kano,
M.:
Functional
cooperationofmetabotropic adenosine and glutamate receptors
regulates postsynaptic plasticity in the
cerebellum. J. Neurosci. 33: 18661-18671(2013).
(4) Kawamura, Y., Nakayama, H., Hashimoto, K.,
Sakimura, K., Kitamura, K. & Kano, M.: Spiketiming-dependent selective strengthening of
single climbing fiber inputs to Purkinje cells
during cerebellar development. Nature Commun.
4: 2732 (2013).
(5) Kitamura, K. & Kano, M.: Dendritic calcium
signaling in cerebellar Purkinje cell. Neural
Networks 47: 11-17 (2013).
(6) Hashizume, M., Miyazaki, T., Sakimura, K.,
Watanabe, M., Kitamura, K. & Kano, M.:
Disruption of cerebellar microzonal organizationin GluD2 (GluRδ2) knockout mouse. Front.
Neural Circuits 7: 130 (2013).
(7) Hashimotodani Y, Ohno-Shosaku T, Tanimura A,
Kita Y, Sano Y, Shimizu T, Di Marzo V, Kano M:
Acute inhibition of diacylglycerol lipase blocks
endocannabinoid-mediated retrograde synaptic
suppression:
evidenceforon-demandbiosynthesis of 2-arachidonoylglycerol.
J
Physiol (Lond) 591:4765-4776 (2013).
(8) Hashimoto K & Kano M.: Synapse elimination in
the developing cerebellum. Cell Mol. Life Sci.
24: 4667-4680 (2013).
(9) Kawashima T, Kitamura K, Suzuki K, Nonaka M,
Kamijo S, Takemoto-Kimura S, Kano M, Okuno
H, Ohki K, Bito H: Functional labeling of
neurons and their projections using a synthetic
activity-dependent promoter E-SARE. Nat. Meth.

26

10: 889-895 (2013).
(10) Keimpema, E, Alpar A, Howell F, Malenczyk K,
Hobbs C, Hurd Y.L, Watanabe M, Sakimura K,
Kano M, Doherty P & Harkany T: Diacylglycerol
lipase α manipulation reveals developmentalroles for intercellular endocannabinoid signaling.
Sci. Rep. 3: 2093 (2013).
(11) Mikuni T, Uesaka N, Okuno H, Hirai H,
Deisseroth K, Bito H & Kano M: Arc/Arg3.1 is a
postsynaptic mediator of activity-dependent
synapse elimination in the developing
cerebellum. Neuron 78: 1024-1035 (2013).
(12) Hoshina N, Tanimura A, Yamasaki M, Inoue T,
Fukabori R, Kuroda T, Yokoyama K, Tezuka T,
Sagara H, Hirano S, Kiyonari H, Takada M,
Kobayashi K, Watanabe M, Kano M, Nakazawa
T & Yamamoto T: Protocadherin 17 regulates
presynaptic
assemblyin
topographic
cortico-basal ganglia circuits. Neuron 78:
839-854 (2013).
(13) Fujii H, Inoue M, Okuno H, Sano Y,
Takemoto-Kimura S, Kitamura K, Kano M &Bito H: Nonlinear decoding and asymmetricrepresentation of neuronal input information by
CaMKIIα and calcineurin. Cell Rep. 3: 978-987(2013).

Functional Biology
2. Pharmacology

28

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

29

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 previously unrecognized cellularfunctions 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30

intracellular signals. We found that cells in contact
with neighbouring cells generate local transient
intracellular Ca2+ signals (Ca2+ lightning). Ca2+
lightning was exclusively observed near cell-cell
contact regions and was not observed in the central
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 in vitro. Furthermore, we recently showedthat IP3-Ca2+ signaling in cerebellar astrocytes(Bergmann glia) regulates glutamate transporter
levels in Bergman glial cells to maintain glutamate
clearance in the mature cerebellum.
In response to brain injury, astrocytes undergo
structural and functional changes (reactive
astrogliosis). We showed that injury-induced Ca2+
responses in astrocytes are important for reactive
astrogliosis and also for neuroprotection. We
studied the molecular mechanism involved in thisreaction, and found that a translational repressor
Pum2 is downregulated in a Ca2+-dependent
manner. We also identified that N-cadherin mRNA
is one of the target mRNAs of Pum2. Thus, Pum2
down-regulation induces reciprocal up-regulationof N-cadherin after brain injury. When the
N-cadherin gene is disrupted in astrocytes,
injury-induced astrogliosis and neuroprotection
were attenuated. These results clarified themolecular events that are responsible for the
astrogliosis and neuroprotection following brain
injury.
We have identified a new NO-dependent Ca2+
signaling mechanism in central neurons. We foundthat synaptically released NO S-nitrosylates theryanodine receptor (RyR) to activate Ca2+ releasethrough the Ca2+ release channel, which we referto as NO-induced Ca2+ release (NICR). NICR isrequired for the NO-dependent LTP at the parallel
fiber-Purkinje cell synapse described above.
Furthermore, NICR has a pathophysiological role,and seems to play an important role inNO-dependent neuronal cell death after brainischemia. This finding suggests that NICR can bea therapeutic target in certain forms of ischemic
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.

31

References
1.

2.

3.

4.

5.

6.

Kanemaru, K., Kubota, J., Sekiya, H., Hirose, K.,
Okubo, Y. and Iino, M. Calcium-dependentN-cadherin up-regulation mediates reactive
astrogliosis and neuroprotection after brain injury.
Proc Natl Acad Sci USA 110, 11612– 11617,
2013.
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. Nitricoxide-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.

32

Department of Systems
Pharmacology
Professor
Hiroki R. Ueda, M.D.,Ph.D.

Lecturer
Kazuki Tainaka, Ph.D.

Associate
Koji L. Ode, Ph.D., Etsuo A. Susaki, M.D., Ph.D.

Homepage http://sys-pharm.m.u-tokyo.ac.jp/
Teaching activities
Our Department, in collaboration with the
Department of Cellular and Molecular Pharmacology,
takes responsibility for lectures and laboratory courses
on pharmacology for the undergraduate students of theFaculty. There are some 39 lectures per year including
those given by six invited lectures to cover specialized
and currently highlighted fields in pharmacology. We
offer several laboratory courses, and all the membersof the Department participate in the courses to provide
close consultation for the students.
For the graduate students, there are series ofseminars on physiology and neuroscience. We also
have research seminars to discuss and stimulate theresearch activities of the graduate students in the
Department.

Research activities
With our members from different backgrounds, wewould like to realize experimental systems biology at
the organism level, leading to greater understanding
and even control of organismal pathophysiology. To
this end, we specifically focus on the cellular circuits
controlling the sleep/wake cycle and address thehourglass mechanism of sleep, a homeostatic- andcircadian-dependent regulation of sleep amount andtiming. Also we are planning multi-scale research
activities covering a series of length scales;
molecule-to-cell, cell-to-tissue, and tissue-to-organism
to envision such complicated underlying mechanism.
We are currently devoting our research to threetechnological challenges; 1) next-generation mouse
genetics, where we can produce genetically modified
mice in a high-throughput fashion, 2) system-level
identification and analysis of cellular circuits in thewhole-organ (especially, the whole-brain) andwhole-body, where we can identify individual cells or
cellular circuits in the whole-organ and whole-body,and 3) non-invasive observation/perturbation ofsystem dynamics, where we can observe or perturb the
specific cells or neurons in organisms in a
non-invasive manner. Combined with these techniques,
we investigate how the average (diurnality or
nocturnality), the dispersion (the length of sleepingtime), and the amount (insomniac or hypersomniac
responces) of sleep during circadian time aredetermined by environments and history of activities.
Additionally, we execute a comprehensive study to
examine dynamic properties of the biological system
inside cell-to-tissue scale, and their relations toorganism-level phenotypes.
1) Next-generation mouse genetics
In the conventional method for production ofgenetically-modified mice, a single line of

33gene-targeted ES cells is injected into host embryos(typically blastocysts) to generate chimera micecomprising a mixture of ES- and host-derived cells. In
addition, multiple mating procedures are needed togenerate the desired genetically modified mouse strain,
which typically takes from 9 months to several years.
To develop a high-throughput method of mouse
genetics (next-generation mouse genetics), we aretrying to 1) shorten the process by realizing F0
phenotyping with ~100% ES cell-derived mice (thesame generation at which chimeras are typically
produced) to skip the mating procedures, and 2)
parallelize the process by simultaneous preparation ofmultiple lines of ES cell clones. We aim to use thisnovel high-throughput method to produce hundreds ofstrains of genetically modified ~100% ES cell-derived
mice. Currently, we are developing high-throughput
TALENandCRISPER/Cas9-based
genomeengineering method.
2) System-level identification and analysis of cellular
circuits in the whole-organ and whole-body
To highlight the regulatory cellular networks in thesleep/wake rhythm, we facilitate an identification of
sleep/wake generating cells in the whole-brain in ahighly parallelized manner. A concerted effort has
been made especially in the brain, as scientists areaiming to clarify how neural activity is translated into
consciousness and other complex brain activities. One
example of the technologies needed is whole-brain
imaging at single-cell resolution. This imaging
normally involves preparing a highly transparent
sample that minimizes light scattering and thenimaging neurons tagged with fluorescent probes atdifferent slices to produce a 3D representation.
However, limitations in current methods prevent
comprehensive study of the relationship. A new
high-throughput method, CUBIC (Clear, Unobstructed
Brain Imaging Cocktails and Computational Analysis),published in Cell, is a great leap forward, as it offers
unprecedented rapid whole-brain imaging at single
cell resolution and a simple protocol to clear andtransparentize the brain sample based on the use ofaminoalcohols (Susaki et al., Cell, 2014). In
combination with light sheet fluorescence microscopy,
CUBIC was tested for rapid imaging of a number ofmammalian systems, such as mouse and primate,showing its scalability for brains of different size.
Additionally, it was used to acquire new
spatial-temporal details of gene expression patterns in
the hypothalamic circadian rhythm center. Moreover,by combining images taken from opposite directions,
CUBIC enables whole brain imaging and directcomparison of brains in different environmental
conditions. CUBIC overcomes a number of obstacles
compared with previous methods. One is the clearing
and transparency protocol, which involves seriallyimmersing fixed tissues into just two reagents for a
relatively short time. Second, CUBIC is compatible
with many fluorescent probes because of low
quenching, which allows for probes with longer
wavelengths and reduces concern for scattering when
whole brain imaging while at the same time inviting
multi-color imaging. Finally, it is highly reproducible
and scalable. While other methods have achieved
some of these qualities, CUBIC is the first to realize
all. CUBIC provides information on previously
unattainable 3D gene expression profiles and neuralnetworks at the systems level. Because of its rapid andhigh-throughput imaging, CUBIC offers extraordinary
opportunity to analyze localized effects of genomic
editing. It also is expected to identify neuralconnections at the whole brain level.
To comprehensively understand dynamic andcomplicated phenomena in organism-level, it is alsoessential to quantify the cellular dynamics with highly
time resolution. We are developing absolute,continuous, and highly sensitive quantification
methods of biomolecules secreted from specificregion in the brain. Currently, we have alreadysucceeded in the absolute quantification of peptides
and proteins even at the ato-mole level by using themass spectrometry. By further developing the method
such as on-line connection of microdialysis systemwith mass spectrometry, we address the establishmentof absolute quantification of various kinds of
biomolecules including neuropeptide, neurotransmitter,
and
other
unidentified
secretions
withacomprehensive, sensitive, and high time resolution
manner. Through these methods, we are also
developing clinical applications such as exploration ofnovel diagnostic markers.
3) Non-invasive observation/perturbation of system

34

dynamics
Currently, we have already developed anon-invasive sleep/wake analytical system based onhigh-sensitive
respiratory
analyzer
unlikeconventional electroencephalography (EEG) andelectromyogram (EMG), which are high-invasive,labor-intensive, and high cost phenotyping methods.
Furthermore, we have also devised automaticallystaging system to classify sleep and awake state fromlongitudinal data (Sunagawa et al, Genes to Cells
2013). Combined with these techniques, we achieved
automatic phenotyping of sleep and awake state only
by housing mice in the devised chamber for
respiratory analysis in a high-throughput fashion.
In another approach, we are developing
non-invasive quantification system of importantbiomolecules such as monoamine determining cellularstates in whole-brain scale. Although molecular
probes for monoamine detectable in MRI have beenreported, any groups have not succeeded in thevisualization of monoamine dynamics in the wholebrain by using molecular probe knock-in mice.
Through above mentioned next-generation mouse
genetics, we will construct mutant mice expressing
molecular probes in the whole-brain (or specifictissues), and establish non-invasive quantification
platform for biologically important molecules. As forcontactless perturbation of cellular state, we aredeveloping chemical genetics, where mutant miceexpressing foreign artificial receptor in neuron are
perturbed by the corresponding artificial ligand suchas DREADDs (designer receptors exclusively
activated by designer drugs) and PSAMs. For example,
we construct mutant mice expressing active hM3Dq
receptor or inactive hM4Di in specific neurons, andperturb the neurons without contact by oral
administration of triggering CNO. Alternatively, we
are also developing novel optogenetics where mutant
mice lacking all of photoreceptors but expressing
artificial infrared photoreceptors in specific neurons
could be perturbed by contactless infrared
photoirradiation (without implanting optical fibers inthe brain).
Understanding of hourglass mechanism of sleep, ahomeostatic dependent regulation of sleep amount andtimingIn the brain, there are multiple states such as awake,
NREM-sleep, and REM-sleep, and each state istransferred to each other without remaining in one
state. The underlying mechanism how these multiple
states are produced and what determine the amount ofeach state has been unknown yet. Initially, we are
identifying sleep-related molecules and genes throughthe next-generation mouse genetics. Especially, we arefocusing on wake-promoting genes such as
monoamine and acetylcholine (neural circuits
hypothesis), synaptic plasticity-related genes such as
receptors of glutamate and GABA, and modification
enzymes (synaptic plasticity hypothesis), andexcitatory genes determining membrane potential suchas ion pumps and ion channels (neural excitability
hypothesis). We elucidate what kinds of genes
determine the sleep amount and timing throughnon-invasive sleep/wake phenotyping system.
Furthermore, we clarify where sleep-regulating genes
are distributed in the brain and how neural circuits areconstructed through whole-brain imaging withsingle-cell resolution. We also elucidate how
parameters in dynamic homeostasis relating to thesleep amount and timing are determined throughnon-invasive perturbation system. Finally, we areaiming at our understanding of dynamic homeostasis
in the organism.

References
1. Susaki EA, Tainaka K, Perrin D, Kishino F,
Tawara T, Watanabe TM, Yokoyama C, Onoe H,
Eguchi M, Yamaguchi S, Abe T, Kiyonari H,
Shimizu Y, Miyawaki A, Yokota H, Ueda HR.
Whole-brain imaging with single-cell resolution
using chemical cocktails and computational
analysis. Cell 2014;157(3):726-39.
2. Ikeda S, Tainaka K, Matsumoto K, Shinohara Y,
Ode KL, Susaki EA, Ueda HR. Non-enzymaticDNA
cleavagereaction
inducedby
5-ethynyluracil in methylamine aqueous solution
and application to DNA concatenation. PLOS
ONE 2013:9(3):e92369.
3. Tsujino K, Narumi R, Masumoto KH, Susaki EA,
Shinohara Y, Abe T, Iigo M, Wada A, Nagano M,
Shigeyoshi Y, Ueda HR. Establishment of TSH
β real-time monitoring system in mammalian35

photoperiodism. Genes Cells 2013:18(7):575-88.
4. Sunagawa GA, Sei H, Shimba S, Urade Y, Ueda
HR. FASTER: an unsupervised fully automatedsleep staging method for mice. Genes Cells
2013:18(6):502-18.
5. Sasagawa Y, Nikaido I, Hayashi T, Danno H, Uno
KD, Imai T, Ueda HR. Quartz-Seq: a highly
reproducible and sensitive single-cell RNA-Seq
reveals non-genetic gene expression heterogeneity.
Genome Biology 2013:14(4):R31.

Pathology, Immunology andMicrobiology
1. Pathology

37

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

Associate Professor
Junji Shibahara, M.D., Ph.D., Tetsuo Ushiku, M.D., Ph.D.*
Takeshi Sasaki, M.D., Ph.D. (Telepathology & Remote Diagnosis Promotion Section)

Lecturer
Teppei Morikawa, M.D., Ph.D.*

Lecturer (Hospital)
Masako Ikemura, M.D., Ph.D.*

Associates
Akiko Kunita, Ph.D.,

Aya Shinozaki-Ushiku, M.D., Ph.D.,

Mariko Tanaka, M.D., Ph.D.,
Yukako Shintani, M.D., Ph.D.,

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

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

Hiroyuki Abe, M.D., Ph.D.*,

Ryu Miyagawa, Ph.D. (Cancer Professional Training 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
incorporating cutting-edge science and technology”.
Lecturer Dr. Takazawa moved as vice chairmanof Division of pathology, the Cancer Institute,Japanese Foundation of Cancer Research. Dr. Sasaki(Associate
Professor,
Yokohama
Municipal

University) took up a position, chief of Telepathology& Remote Diagnosis Promotion Section (TRD-PS). Dr.
Ushiku was promoted as Associate Professor, and Dr.
Morikawa as Lecturer, respectively. Dr. Ikemura
became Lecturer (Hospital), and Dr. Abe started his
career as one of Associates. Dr. Miyagawa is now
engaged in research of predicting the effect ofradiotherapy for cancer patients in our laboratory as
Associate of Cancer Professional Training Program.
Dr. Matsusaka moved to Department of Molecular
Oncology, Graduate School of Medicine, Chiba
University in October, and Dr. Shinozaki-Ushikuchanged her position to the hospital.

38

Three postgraduate students (Ichimura, Halimi,
and Hayashi) finished the course and received Ph.D.
In the new fiscal year, 2014, four new students willenter the postgraduate course, and there will be 16
postgraduates.
We are responsible for the pathology practice of
the University Hospital, and are carrying forward themorphology-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.

Clinical activities (diagnostic
pathology and autopsy)
Together with Division of Diagnostic Pathology, we
are responsible for the pathologic diagnosis andautopsy in the University Hospital. We set up
Telepathology & Remote Diagnosis Promotion
Section (TRD-PS), and started Outpatient Clinic of
Pathology (see the corresponding section of Divisionof 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 (Dr.
Shintani), and we also started e-learning programs forclinical residents to facilitate the understanding of the
CPC contents. (Dr. Ikemura). All of residents were
obligated to take the course for their training this year.
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(Dr. Shibahara).

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 Systemic Pathology for thesecond grade students are referred to the website.
Three students chose the clinical clerkship course for3rd grade medical students.
As for the free quarter program, we received two
students of M0 and four 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. Kunita,
Shinozaki-Ushiku, Matsusaka, and Abe). We arefocusing on abnormalities of microRNA moleculesand stem cell biology in the development andprogression of EBV-associated GC in addition to its
DNA methylation abnormality (ref.20). Professor
Fukayama presented the data as a keynote lecture of
8th Asian Pacific IAP (International Academy of
Pathology) Congress (September 5-8, Busan, Korea),
and as a lecture of 4th JCA-AACR Special Joint
Conference (December 16-18, Chiba, Japan). The year
2014 is the 50th anniversary of discovery of
Epstein-Barr virus, and Dr. Matsusaka had an honor topresent a paper as one of Young Investigators at the
memorial congress (March 23-25, 2014, Oxford, UK).
The second major theme is ‘traslational researchpathology’. We are engaged in search of target

39

molecules for cancer therapy by global analysis ofexpression profiles of various cancers, in collaboration
with Research Center for Advanced Science andTechnology (RCAST) (Dr. Morikawa).
The third theme is to re-evaluate the disease
entities and tumor entities from the standpoint ofclassical histopathology. Dr. Maeda reconstructed theclassification system of mucinous tumors of the ovary
with reference to claudin-18 expression (ref. 6). The
Ph.D. course student, Morita characterized the uniquesubgroup of lung cancer. high grade fetal
adenocarcinoma in collaboration with Department of
Pathology, National Cancer Center Hospital (ref. 19).
Dr. Ushiku, together with Prof. Lauwers (departmentof Pathology, MGH), investigated pathologicalfeatures of very well differentiated adenocarcinoma of
the stomach, and identified a subgroup, showing
co-existence of poorly differentiated type. Dr. Abeevaluated the cases of gastric cancer causing
pulmonary tumor thrombotic microangiopathy(PTTM), and found significant role of PDGFA
expression in the stomach cancer cells (ref. 1).
Dr. Maeda’s paper “Ovarian microcystic stromal
tumor – a new entity of ovarian tumor characterized
by beta catenin abnormalities’ was adopted as ahonorable paper (category B) at 59th autumn congressof Japanese Society of Pathology (November 21, 22,Kohu).
The research works closely related withpathology practice are described in Diagnostic
Pathology Division.

(3) Asada-Hirayama I, Ono S, Kodashima S, Niimi K,
Mochizuki

S,

Yamamichi

N,

Fujishiro

M,

Matsusaka K, Fukayama M, Koike K. Preoperative
iodine staining may complicate the demarcation ofesophageal carcinoma. Gut Liver. 2013 :7(4):492-6.
(4) Asada-Hirayama

I,

Kodashima

S,

Goto

O,

Yamamichi N, Ono S, Niimi K, Mochizuki S,
Konno-Shimizu M, Mikami-Matsuda R, Minatsuki
C, Takahashi Y, Matsusaka K, Ushiku T, Fukayama
M, Fujishiro M, Koike K. Factors predictive of
inaccurate determination of horizontal extent ofintestinal-type

earlygastric

cancers

duringendoscopic submucosal dissection: a retrospective
analysis. Dig Endosc. 2013;25(6):593-600.
(5) Fukushima Y, Oya S, Nakatomi H, Shibahara J,
Hanakita S, Tanaka S, Shin M, Kawai K, Fukayama
M, Saito N. Effect of dural detachment on
long-term tumor control for meningiomas treatedusing Simpson grade IV resection. J Neurosurg.
2013;119(6):1373-9.
(6) Halimi SA, Maeda D, Shinozaki-Ushiku A, Koso T,
Matsusaka K, Tanaka M, Arimoto T, Oda K,
Kawana K, Yano T, Fujii T, Fukayama M.
Claudin-18
mucinous

overexpression
borderline

tumourinintestinal-typeoftheovary.

Histopathology. 2013;63(4):534-44.
(7) Hangai S, Nakamura F, Kamikubo Y, Ichikawa M,
Suzuki H, Yoshida S, Yamada A, Takazawa Y,
Fukayama M, Koike K, Kurokawa M. Primary
gastrointestinal

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growth factor-A and vascular endothelial growthH, Watanabe T, Saito T, Kawahata S, Uchino R,

factor-C

ofHamada T, Miyabayashi K, Sasaki T, Kogure H,

pulmonary tumor thrombotic microangiopathy in

Yamamoto N, Sasahira N, Koike K, Fukayama M,

gastric cancer. Virchows Arch. 2013;462(5):523-31.

Sugawara Y, Kokudo N. Two cases with hepatic(2) Amano Y, Takai D, Ohishi N, Shinozaki-Ushiku A,

amyloidosis suspected of having primary sclerosing

contribute

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Fukayama M, Akahane M, Nakajima J, Nagase T.

cholangitis. Hepatol Res. 2013 Aug;43(8):911-6.

Successful Treatment of Mediastinal Unicentric(9) Hirasawa K, Sato C, Sasaki T, Koh R, Oka H,

Castleman's
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Morimoto M, Numata K, Kokawa A, Sasaki T,

Yoshinaga S, Kushima R, Nagahama R, Ohkura Y,

Nozawa A, Taguri M, Morita S, Maeda S, Tanaka K.

Tanaka S, Ajioka Y, Hirata I, Tanaka M, Hoshihara

Antithrombotic drugs are risk factors for delayed

Y, Kinoshita Y, Sasano H, Iwashita A, Tomita S,

postoperative bleeding after endoscopic submucosal

Hirota S, Yao T, Fujii S, Matsuda T, Ueno H,

dissection for gastric neoplasms. Gastrointest

Ishikawa Y, Takubo K, Fukushima N, Sugai T,

Endosc. 2013;78(3):476-83.

Iwafuchi M, Imura J, Manabe T, Fukayama M.

(17) Lochhead P, Kuchiba A, Imamura Y, Liao X,

Digestive disease management in Japan: a report on

Yamauchi M, Nishihara R, Qian ZR, Morikawa T,

The 6th Diagnostic Pathology Summer Fest in 2012.

Shen J, Meyerhardt JA, Fuchs CS, Ogino S.

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Fukayama M.

UBE2C is a marker of unfavorable

Kawana K, Nakagawa S, Fukayama M, Tetsu O,

prognosis in bladder cancer after radical cystectomy.

Fujii T, Yano T, Kozuma S. Cyclin D1 harboring

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Watanabe K, Ohishi N, Yatomi Y, Nakajima J,

Werner L, Kuchiba A, Yamauchi M, Hunter DJ,

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Shimono T, Fukayama M, Yamasoba T, Asakage T.

Koike K. Uninodular combined hepatocellular andPrognostic value of p16 expression and alcohol

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42

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2013;57(2):173-7.

rhabdomyosarcomas. Mod Pathol. 2013;26(6):(36) Uni M, Yoshimi A, Maki H, Maeda D, Nakazaki K,
Nakamura
Successful

F,

Fukayama
treatment

M,

Kurokawa

withM.

recombinant

thrombomodulin for B-cell lymphoma-associatedhemophagocytic

syndrome

complicatedbydisseminated intravascular coagulation. Int J Clin
Exp Pathol. 2013;6(6):1190-4.
(37) Uni M, Yoshimi A, Nakamura F, Takazawa Y,
Fukayama

M,

Kurokawa

M.

Successful

allogeneic stem cell transplantation for Lennert
lymphoma. Ann Hematol. 2013;92(6):859-60.
(38) Uni M, Nakamura F, Yoshimi A, Shinozaki-Ushiku
A, Hosoi A, Nakazaki K, Nannya Y, Fukayama M,
Kurokawa

M.

Transformationoffollicularlymphomaintheretroperitoneal

musclesdemonstrated by CT-guided needle biopsy of
FDG-avid lesions; case series. Int J Clin Exp Pathol.
2013;7(1):402-6.
(39) Ushiku T, Arnason T, Ban S, Hishima T, Shimizu M,
Fukayama M, Lauwers GY. Very well-differentiatedgastric carcinoma of intestinal type: analysis ofdiagnostic criteria. Mod Pathol. 2013;26(12):1620-31.
(40) Ushiku T, Moran CJ, Lauwers GY. Focallyenhanced gastritis in newly diagnosed pediatricinflammatory bowel disease. Am J Surg Pathol.
2013;37(12):1882-8.
(41) Watanabe K, Miyagawa R, Tomikawa C, Mizuno R,
Takahashi A, Hori H, Ijiri K. Degradation of
initiator tRNAMet by Xrn1/2 via its accumulationin the nucleus of heat-treated HeLa cells. Nucleic
Acids Res. 2013;41(8):4671-85.
(42) Yamauchi M, Lochhead P, Imamura Y, Kuchiba A,
Liao X, Qian ZR, Nishihara R, Morikawa T, Shima
K, Wu K, Giovannucci E, Meyerhardt JA, Fuchs
CS, Chan AT, Ogino S. Physical activity, tumor
PTGS2 expression, and survival in patients withcolorectal cancer. Cancer Epidemiol Biomarkers
Prev. 2013;22(6):1142-52.
(43) Yoshida A, Shibata T, Wakai S, Ushiku T, Tsuta K,

772-81.

lymphomakinasestatusin43

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

Associate Professor
Tetsuro Watabe, Ph.D. (until June 2013),
Daizo Koinuma, M.D., Ph.D. (from February 2014)

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 Professor of the Department of
Molecular Pathology from August 2000. In July 2013,
Dr. Tetsuro Watabe was promoted Professor of the
School of Life Sciences, Tokyo University of
Pharmacy and Life Sciences. Dr. Daizo Koinuma, aproject associate professor, was promoted Associate
Professor of the Department of Molecular Pathology
in February 2014. In March 2013, the Department
consists of a professor, an associate professor, two
assistant professors, a project assistant professor,
technical assistants, and some research fellows,
including 9 graduate students, 3 master course
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
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, weoffer several laboratory courses for students frommolecular 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.
Prof. Kohei Miyazono organized the 86th Annual
Meeting of the Japanese Biochemical Society as thechairman. The meeting was held from September 11 to
13 in Yokohama, and gathered more than 4,000
participants.
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

44

supported by the Core-to-Core Program “Cooperative
International Framework in TGF-β Family Signaling”
of Japan Society for the Promotion of Science (JSPS)(http://c2ctgfb.umin.jp/). We have annual TGF-β
meeting in Sweden or in the Netherlands every year,
and five graduate students participated in the TGF-β
meeting in Uppsala in 2013. At the 3rd internationalcore-to-core symposium held in Matsuyama, Ehime,
three researchers presented their data by oralpresentation, and 14 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 various
vascular endothelial cells and lymphatic endothelial
cells (LECs).
Lymphatic vessels play important roles in themaintenance of fluid homeostasis under physiologicalconditions, and inflammation and cancer metastasis
under pathological conditions. Mutations in ALK1, a
member of the TGF-β/BMP type I serine-threonine
kinase receptor family, have been shown to be
responsible for hereditary hemorrhagic telangiectasia(HHT), a human vascular disease. However, the rolesof ALK-1 signals in lymphangiogenesis remain to beelucidated. We found that ALK-1 signals inhibit
lymphatic vessel formation both in vitro and in vivo.
Lymphatic vessels were enlarged in various organs in
Alk1-knockout mice. The inhibitory effects of ALK-1
were induced by BMP-9, which decreased the numberof cultured LECs. Bmp9-knockout mouse embryos
displayed enlarged dermal lymphatic vessels by

increasing the number of Prox1-positive LECs.
BMP-9 also suppressed lymphatic vessel formation
during chronic inflammation in mice and in multiple
types of Bmp9-transduced tumors grafted toimmuno-compromised mice. BMP-9 suppressed theexpression of the transcription factor Prox1, which is
required to maintain LEC identity. Moreover,knockdown of Prox1 gene expression suppressed LEC
proliferation. Our findings thus revealed a novel
molecular basis for the roles of BMP-9/ALK-1 signals
in lymphatic vessel formation (Yoshimatsu et al., Proc
Natl Acad Sci USA 2013).
TGF-β shows both pro-apoptotic and anti-apoptotic
effects on epithelial cells and other cells in acontext-dependent fashion. The anti-apoptotic
functions of TGF-β are mediated by several regulatory
mechanisms, which may be related to thetumor-progressive phenotype of breast and othercancer cells. We performed RNA sequencing of mouse
mammary gland epithelial (NMuMG) cells, andidentified a long non-coding RNA (lncRNA), termed
lncRNA-Smad7 as a target of TGF-β. lncRNA-Smad7
is located in the proximity of the mouse Smad7 gene,and its expression is induced by TGF-β in mouse
mammary epithelial cells and breast cancer cells.
Inhibition of lncRNA-Smad7 expression attenuatedthe anti-apoptotic function of TGF-β in breast cancer
cells. In contrast, over-expression of lncRNA-Smad7
rescued the apoptosis induced by a TGF-β receptor
inhibitor SB431542 in the mouse breast cancer cellline JygMC(A). Knockdown of lncRNA-Smad7 failed
to alter the process of epithelial-mesenchymaltransition, phosphorylation of Smad2, or expression of
the Smad7 gene induced by TGF-β, suggesting thatthe effects of lncRNA-Smad7 on TGF-β functions
appears to be limited to apoptosis. Our findings may
thus provide an important information to elucidate acomplex mechanism for regulation of theanti-apoptotic effects of TGF-β signaling in normal
and transformed epithelial cells (Arase et al. Cancer
Sci 2014).

45

References
1. Suzuki, H.I., Mihira, H., Watabe, T., Sugimoto, K.,
and Miyazono, K. (2013) Widespread inference of
weighted microRNA-mediated gene regulation incancer transcriptome analysis. Nucleic Acids
Research 41 (5), e62.
2. Saito, A., Suzuki, H.I., Horie, M., Ohshima, M.,
Morishita, Y., Abiko, Y., and Nagase, T. (2013) An
integrated expression profiling reveals target
genes of TGF-β and TNF-α possibly mediated by
microRNAs in lung cancer cells. PLoS One 8 (2),e56587.
3. Kawabata, K.C., Ehata, S., Komuro, A., Takeuchi,K., and Miyazono, K. (2013) TGF-β-induced
apoptosis of B-cell lymphoma Ramos cells
through reduction of MS4A1/CD20. Oncogene 32(16), 2096-2106.
4. Saitoh, M., Shirakihara, T., Fukasawa, A.,
Horiguchi, K., Sakamoto, K., Sugiya, H., Beppu,
H., Fujita, Y., Morita, I., Miyazono, K., andMiyazawa, K. (2013) Basolateral BMP signaling
in polarized epithelial cells. PLoS One 8 (5),e62659.
5. Yamazaki, T., Suehiro, J.I., Miyazaki, H., Minami,T., Kodama, T., Miyazono, K., and Watabe, T.
(2013) The COUP-TFII variant lacking a
DNA-binding domain inhibits the activation of the
Cyp7a1 promoter through physical interaction
with COUP-TFII. Biochemical Journal 452 (2),345-357.
6. Konoeda, C., Koinuma, D., Morishita, Y., Sano,
A., Nagayama, K., Motomura, N., Kakimi, K.,
Miyazono, K., Nakajima, J., Nicolls, M.R., andMurakawa, T. (2013) Epithelial to mesenchymaltransition in murine tracheal allotransplantation:
an immunohistochemical observation. Transplantation Proceedings 45 (5), 1797-1801.
7. Motizuki, M., Isogaya, K., Miyake, K., Ikushima,
H., Kubota, T., Miyazono, K., Saitoh, M., andMiyazawa,
K.
(2013)
Oligodendrocytetranscription factor 1 (Olig1) is a Smad cofactor
involved in cell motility induced by transforming
growth factor-β. Journal of Biological Chemistry288 (26), 18911-18922.

8. Okita, Y., Kamoshida, A., Suzuki, H., Itoh, K.,
Motohashi, H., Igarashi, K., Yamamoto, M.,
Ogami, T., Koinuma, D., and Kato, M. (2013)
Transforming
growthfactor-βinducestranscription factors MafK and Bach1 to suppress
expression of the heme oxygenase-1 gene. Journalof Biological Chemistry 288 (28), 20658-20667.
9. Sundqvist, A., Zieba, A., Vasilaki, E., Herrera,
H.C., Söderberg, O., Koinuma, D., Miyazono, K.,
Heldin, C.-H., Landegren, U., ten Dijke, P., andvan Dam, H. (2013) Specific interactions between
Smad proteins and AP-1 components determine
TGF-β-induced breast cancer cell invasion.
Oncogene 32 (31), 3606-3615.
10. Shirakihara, T., Kawasaki, T., Fukagawa, A.,
Semba, K., Sakai, R., Miyazono, K., Miyazawa,K., and Saitoh, M. (2013) Identification of
integrin α3 as a molecular marker of cells
undergoing epithelial-mesenchymal transition andof cancer cells with aggressive phenotypes.
Cancer Science 104 (9), 1189-1197.
11. Suzuki, H.I., Matsuyama, H., Noguchi, M., Yao,
T., Komatsu, N., Mano, H., Sugimoto, K., andMiyazono, K. (2013) Computational dissection of
distinct microRNA activity signatures associatedwith peripheral T-cell lymphoma subtypes.
Leukemia 27 (10), 2107-2111.
12. Fukumura, K., Yamashita, Y., Kawazu, M., Sai, E.,
Fujiwara, S., Nakamura, N., Takeuchi, K., Ando,
M., Miyazono, K., Ueno, T., Ozawa, K., andMano, H. (2013) STK10 missense mutations
associated with anti-apoptotic function. Oncology
Reports 30 (4), 1542-1548.
13. Yoshimatsu, Y., Lee, Y.G., Akatsu, Y., Taguchi, L.,
Suzuki, H.I., Cunha, S.I., Maruyama, K., Suzuki,
Y., Yamazaki, T., Katsura, A., Oh, S.P.,
Zimmers,T.A., Lee, S.J., Pietras, K., Koh, G.Y.,
Miyazono, K., and Watabe, T. (2013) Bonemorphogenetic protein-9 inhibits lymphatic vessel
formation via activin receptor-like kinase 1 during
development and cancer progression. Proceedingsof the National Academy of Sciences of U.S.A. 110(47), 18940-18945.

46

14. Kikuchi, Y., Kunita, A., Iwata, C., Komura, D.,
Nishiyama, T., Shimazu, K., Takeshita, K.,
Shibahara, J., Kii, I., Morishita, Y., Yashiro, M.,
Hirakawa, K., Miyazono, K., Kudo, A., Fukayama,M., and Kashima, T.G.
(2014) The nichecomponent
periostinisproducedbycancer-associated fibroblasts, supporting growthof gastric cancer through ERK activation.
American Journal of Pathology 184(3), 859-870.
15. Suzuki, H.I., and Miyazono, K. (2013) p53
actions on microRNA expression and maturation
pathway. Methods in Molecular Biology 962,
165-181.
16. Morikawa, M., Koinuma, D., Miyazono, K., andHeldin, C.H. (2013) Genome-wide mechanisms of
Smad binding. Oncogene 32 (13), 1609-1615.
17. Ehata, S., Yokoyama, Y., Takahashi, K., andMiyazono, K. (2013) Bi-directional roles of bonemorphogenetic proteins in cancer: Anothermolecular Jekyll and Hyde? Pathology
International 63 (6), 287-296.
18. Kasuga, M., Ueki, K., Tajima, N., Noda, M.,
Ohashi, K., Noto, H., Goto, A., Ogawa, W., Sakai,R., Tsugane, S., Hamajima, N., Nakagama, H.,
Tajima, K., Miyazono, K., and Imai, K. (2013)
Report of the Japan Diabetes Society/JapaneseCancer Association Joint Committee on Diabetes
and Cancer. Cancer Science 104 (7), 965-976.

Pathology, Immunology andMicrobiology
2. Microbiology

48

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

Lecturer
Naoko Kamiya, Ph.D.

Associate
Yasuhiro Saito, Ph.D., Atsushi Takahashi, Ph.D.

Homepage

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

Introduction and Organization

6) Socioeconomic impact of microbial diseases

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. Saito and
Takahashi), 1 project assistant professor (Dr. Hayashi),
1 Post-doc (Dr. Takeda), 5 technical staffs (Drs. Fujii
andNishikawa,
Ms.
Kashiba,Kanemitsu,
Yamanouchi), 13 graduate school students (Ms. andMrs. Suzuki, Yanagiya, Kikuchi, Nagase, Saju, Senda,
Masoudi, Hashi, Bingo, Noda, Tajiri, Lin, Nojima),
and 1 research student (Mr. Ben).

Research activities

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

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 of

49

gastric cancer.
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.
Tyrosine-phosphorylated 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.
2. Regulation of nuclear SHP2 function by Hippo
signaling targets YAP/TAZ
Gain-of-function mutation of SHP2 tyrosine
phosphatase is a major cause of Noonan syndrome, acongenital malformation syndrome with cancer

predisposition, and is associated with a variety of
sporadic cancers. SHP2 is required for full activationof RAS-ERK signaling in the cytoplasm and is alsopresent in the nucleus, where it promotes Wnt target
gene activation through dephosphorylation ofparafibromin. However, molecular mechanisms
throughwhich
SHP2
undergoes
nucleartranslocalization remain poorly understood.
The mammalian Hippo pathway, a cascade ofserine/threonine kinases, controls cell proliferation andapoptosis by sensing high cell density. When the
Hippo signal is off, YAP (Yes-associated protein) andTAZ (transcriptional co-activator with PDZ-binding
motif) undergo nuclear translocalization. In the
nucleus, YAP/TAZ interact with the TEA-domain(TEAD) family of transcription factors and function astranscriptional coactivators of TEADs, causing
induction of TEAD-dependent genes that are involvedin promitogenic and prosurvival programs of cells.
Activation of the Hippo signal in response to high celldensity triggers a serine/threonine kinase cascade
comprising MST1/2 and LATS1/2, which results inthe phosphorylation of YAP/TAZ. Phosphorylated
YAP/TAZ are sequestered in the cytoplasm, where
they undergo proteasomal degradation, making
YAP/TAZ unavailable in the nucleus. Malfunctioningof the Hippo pathway abolishes contact inhibitionin vitro and organ size control in vivo, causing tissue
overgrowth and predisposition to cancer development
We found that SHP2 was distributed both to thecytoplasm and nucleus at low cell density but is
excluded from the nucleus at high cell density.
Furthermore, SHP2 physically interacted with
YAP/TAZ.
Throughtheinteraction,
nonphosphorylated YAP/TAZ promoted nuclear
translocalization of SHP2, which in turn stimulated
TCF/LEFand
TEAD-regulated
genes
via
parafibromindephosphorylation.
Conversely,
YAP/TAZ phosphorylated by Hippo signaling
sequestered SHP2 in the cytoplasm, thereby
preventing nuclear accumulation of SHP2. Hence,
YAP/TAZ serve as a rheostat for nuclear SHP2
function, which is switched off by the Hippo signal.
3. Elucidation of the three-dimensional structureof Helicobacter pylori CagA
Upon delivery into gastric epithelial cells, CagA

50

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
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-specificcaudal-related
homeobox
transcription factor, in gastric epithelial cells.
Furthermore, it was reported that ransgenic expressionof Cdx1 in mouse 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
CDX1-governed intestinal metaplasia, we establishedhuman gastric epithelial cell-derived stabletransfectant clones that inductively express CDX1
under a tet-off system. Expression microarray analysis
and ChIP-chip analysis revealed that CDX1 directly
activated stemness-associated reprogramming factors
SALL4 and KLF5 in gastric epithelial cells. In cultured
gastric epithelial cells, sustained expression of CDX1
gave rise to the induction of early intestinal-stemness
markers,
followedbytheexpressionofintestinal-differentiation markers. Furthermore, theinduction of these markers was suppressed byinhibiting either SALL4 or KLF5 expression. These
results indicated that CDX1-induced SALL4 andKLF5 converted gastric epithelial cells into tissue
stem-likeprogenitor
cells,
which
thentransdifferentiated into intestinal epithelial cells. Our
study places the stemness-related reprogramming
factors as critical components of CDX1-directedtranscriptional circuitries that promote intestinal
metaplasia.

References
1.

2.

3.

Bessède, E., Staedel, C., Acuña Amador, L.A.,
Nguyen, P.H., Chambonnier, L., Hatakeyama, M.,
Belleannée, G., Mégraud, F., Varon, C.
Helicobacter pylori generates cells with cancer
stem cell properties via epithelial-mesenchymaltransition-like changes. Oncogene 2013: doi:
10.1038/onc.2013.380.
Tsutsumi, R., Masoudi, M., Takahashi, A., Fujii,
Y., Hayashi, T., Kikuchi, I., Satou, Y., Taira, M.,
and Hatakeyama, M. YAP and TAZ, Hippo
signaling targets, act as a rheostat for nuclear
SHP2 function. Dev. Cell 2013:26:658-665.
Miura, K., Wakayama, Y., Tanino, M., Orba, Y.,
Sawa, H., Hatakeyama, M., Tanaka, S., Sabe, H.,
and Mochizuki, N. Involvement of EphA2-

51

4.

5.

mediated tyrosine phosphorylation of Shp2 in
Shp2-regulated activation of extracellular signalregulated kinase. Oncogene 2013:32:5292-5301.
Hayashi, T., Morohashi, M., and Hatakeyama, M.
Bacterial EPIYA effectors - Where do they comefrom? What are they? Where are they going? Cell.
Microbiol. 2013:15:377-385.
Yamahashi, Y., and Hatakeyama, M. PAR1b
takes the stage in the morphogenetic andmotogenetic activity of Helicobacter pylori CagA
oncoprotein. Cell Adh. Migr. 2013:7:11-17.

52

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53practical 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) Yotsuyanagi H, Ito K, Yamada N, Takahashi H,
Okuse C, Yasuda K, et al. High levels of hepatitis
B virus after the onset of disease lead to chronic
infection in patients with acute hepatitis B.
Clinical infectious diseases : an official
publication of the Infectious Diseases Society ofAmerica. 2013;57(7):935-42.
(2) Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K,
Yanagimoto S, Okugawa S, et al. Clostridium

difficile flagellin stimulates toll-like receptor 5,
and toxin B promotes flagellin-induced
chemokine production via TLR5. Life sciences.
2013;92(3):211-7.
(3) Yoshikawa T, Wada K, Lee JJ, Mitsuda T,
Kidouchi K, Kurosu H, et al. Incidence rate ofneedlestick and sharps injuries in 67 Japanesehospitals: a national surveillance study. PLoS
One. 2013;8(10):e77524.
(4) Yamazaki O, Yamada H, Suzuki M, Horita S,
Shirai A, Nakamura M, et al. Identification of
dominant negative effect of L522P mutation in
the electrogenic Na(+)-HCO(3)(-) cotransporter
NBCe1. Pflugers Archiv : European journal ofphysiology. 2013;465(9):1281-91.
(5) Uetera Y, Kishii K, Yasuhara H, Kumada N,
Moriya K, Saito R, et al. A 5 year longitudinal
study of water quality for final rinsing in the
single chamber washer-disinfector with a reverse
osmosis plant. PDA journal of pharmaceuticalscience and technology / PDA. 2013;67(4):399-411.
(6) Toya T, Shinohara A, Tatsuno K, Seo S, Nannya
Y, Ichikawa M, et al. A case of Schizophyllum
commune sinusitis following unrelated cord
blood transplantation for acute lymphoblastic
leukemia. Int J Hematol. 2013;98(2):261-3.
(7) Nukui Y, Hatakeyama S, Okamoto K, Yamamoto
T, Hisaka A, Suzuki H, et al. High plasma
linezolid concentration and impaired renal
function affect development of linezolid-induced
thrombocytopenia. The Journal of antimicrobial
chemotherapy. 2013;68(9):2128-33.
(8) Koyano S, Saito R, Nagai R, Tatsuno K,
Okugawa S, Okamura N, et al. Molecularcharacterization of carbapenemase-producing
clinical isolates of Enterobacteriaceae in ateaching hospital, Japan. Journal of medical
microbiology. 2013;62(Pt 3):446-50.
(9) Koya J, Nannya Y, Kobayashi H, Okugawa S,
Moriya K, Kurokawa M. Simultaneous increase
in 1,3-beta-D-glucan and procalcitonin levels in
Pseudomonas aeruginosa infection. The Journalof infection. 2013;67(2):164-6.
(10) Kataoka H, Ida T, Ishii Y, Tateda K, Oguri T,
Yoshida A, et al. Analysis of the influence ofdrug resistance factors on the efficacy of

54

combinations of antibiotics for multidrugresistant Pseudomonas aeruginosa isolated from
hospitals located in the suburbs of Kanto area,
Japan. Journal of Global Antimicrobial
Resistance. 2013;1(2):91-6.
(11) Horiuchi Y, Takagi A, Kobayashi N, Moriya O,
Nagai T, Moriya K, et al. Effect of the infectious
dose and the presence of hepatitis C virus coregene on mouse intrahepatic CD8 T cells.
Hepatology research : the official journal of theJapan Society of Hepatology. 2013.
(12) Higurashi Y, Tatsuno K, Fujimoto F, Kobayashi I,
Ida K, Seto Y, et al. Two cases of bacteremia
caused by Leptotrichia trevisanii in patients withfebrile neutropenia. Journal of infection andchemotherapy : official journal of the Japan
Society of Chemotherapy. 2013;19(6):1181-4.

Pathology, Immunology andMicrobiology
3. Immunology

56

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

Assistant Professor
Kazuo Okamoto, Ph.D.; Takako Negishi-Koga, 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).
On May 2012, Dr. Hiroshi Takayanagi started the
new laboratory aiming to shed light on two major
questions; First, why self-tolerance are broken in
autoimmune diseases? Second, what is the immune
network among multiple organs including bone andneuron?

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,
knowledge 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

57

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
post-menopausal
osteoporosis
andAlbers-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 activatedT cells c1 (NFATc1) as a master regulator for
osteoclast differentiation (Takayanagi et al., Dev
Cell. 2002; Asagiri et al., J. Exp. Med., 2005). We also
identified an ITAM-harboring co-receptor for RANK
(Koga et. al., Nature 2004) and the importance ofbridging signal cascade between RANK and ITAM via
Btk for RANK dependent osteoclastgenesis(Shinohara et al., Cell. 2008; Shinohara et al., Bone.
2014). We also studied in detail about cytosolic
calcium and identified Tmem64 as a key
transmembrane protein for osteoclastgenesis（Kim etal., Cell Metab., 2013. Furthermore, we revealed rolesof Semaphorin4D on osteoblast differentiation(Negishi-Koga et. al., Nature Med., 2011) andSemaphorin3A on inhibition of bone absorption as
well as promotion of bone formation (Hayashi et. al.,Nature 2012).

3) Development and regulation of lymphoid cells
Thymus is the primary lymphoid organ that
educates T cell and eliminates self-reacting T cells(negative selection). However, recently it became
clear that part of self-reactive T cells escape negative
selection in the thymus. This process is called“agonostic selection”. We uncovered importance ofcontinuous calcium influx into cytoplasm for agonistic
selection of T cells especially regulatory T cells(Oh-Hora et al., Immunity. 2013).
In the peripheral organs, mammals harbor large
numbers of lymphocytes such as T, B and recently
re-categorized innate lymphoid cells, which lackantigen receptors (Sawa et al., Science. 2010;
Furusawa et al., J Immunol. 2013). Focusing on the
nuclear hormone receptor RORγt expressing innate
lymphoid cell, we are trying to understand the cellularand molecular mechanisms that underlie maintenanceof the gut immune system in the steady state, and thepathogenicity of such innate lymphoid cells in the
inflammatory state.
4) Mechanism of autoimmune disease
The IL-17 producing helper T cell subset (Th17 cell)
plays critical roles in several autoimmune diseasemodels such as collagen induced arthritis (CIA) andexperimental encephalomyelitis (EAE). We haveidentified IκBζ as an indispensable transcription
factor for Th17 cell differentiation (Okamoto et al.,Nature. 2010). However, in both RA and EAE models,effector mechanisms of Th17 cells have been unclear.
Recently, we identified subset of Th17 cells robustly
produce IL-17 and RANKL and exacerbate bothinflammation and bone destruction in CIA mice.
Interestingly these Th17 cells are progeny of helper T
cells positive for Foxp3, a master regulator for
immunosuppressive Treg cells （ Komatsu et. al,,Nature Med., 2014）. Now we are keen to understandmolecular mechanism in which Foxp3+T cells convert
to Th17 lineage in inflammatory condition. Our final
goal in this project is to develop new therapeuticstrategies for human autoimmune diseases.

References
1. Komatsu N., Okamoto K., Sawa S., Nakashima T.,
Oh-Hora M., Kodama T., Tanaka, S., Bluestone,

58

2.

3.

4.
5.

6.

J.A., Takayanagi, H. Pathogenic conversion of
Foxp3+ T cells into TH17 cells in autoimmune
arthritis. Nat. Med. 20(1), 62-8. (2014)
Shinohara M., Chang BY., Buggy JJ., Nagai Y.,
Kodama T., Asahara H., Takayanagi H. The orally
available Btk inhibitor ibrutinib (PCI-32765)
protects against osteoclast-mediated bone loss.
Bone. 60, 8-15 (2014)
Furusawa JI., Moro K., Motomura Y., Okamoto K.,
Zhu J, Takayanagi H., Kubo M., Koyasu S.
Critical Role of p38 and GATA3 in Natural Helper
Cell Function. J Immunol. 191(4), 1818-26.
(2013)
Danks L., Takayanagi H. Immunology and bone. J
Biochem. 154(1), 29-39 (2013) ---Review
Oh-Hora M., Komatsu N., Pishyareh M., Feske S.,
Hori S., Taniguchi M., Rao A., Takayanagi H.
Agonist-Selected T Cell Development Requires
Strong T Cell Receptor Signaling andStore-Operated Calcium Entry. Immunity. 38(5),881-895 (2013)
Kim H., Kim T., Jeong B.C., Cho I.T., Han D.,
Takegahara N., Negishi-Koga T., Takayanagi H.,
Lee J.H., Sul J.Y., Prasad V., Lee S.H., Choi Y..
Tmem64 modulates calcium signaling during
RANKL-mediated osteoclast differentiation. Cell
Metab. 17(2), 249-60 (2013)

Radiology and Biomedical
Engineering
1. Radiology

60

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

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

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

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.,

Jiro Sato, M.D.,

Hidemasa Takao, MD.,

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

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

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

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

Shouhei Hanaoka, M.D., Ph.D.,

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

Masaki Katsura, 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

61

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 (Clinical Clerkship, CC) curriculum, small
groups of the fifth/sixth-year students are taking partin mini-lectures and practice to learn basics ofdiagnostic radiology, advanced medical techniques ofRadiation Oncology and Nuclear Medicine. They willlearn detailed principles of image constructions invarious 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
mobile tumors, represented by lung tumors is underinvestigation in collaboration with accelerator makers.

62

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.

3.

4.

5.

6.

7.

8.

References
1.

2.

Amemiya S, Kunimatsu A, Saito N, Ohtomo K.
Cerebral Hemodynamic Impairment: Assessmentwith Resting-State Functional MR Imaging.
Radiology 270(2): 548-55, 2014
Endo Y, Saito Y, Otsuki T, Takahashi A, Nakata Y,
Okada K, Hirozane M, Kaido T, Kaneko Y, Takada
E, Okazaki T, Enokizno T, Saito T, Komaki H,

9.

Nakagawa E, Sugai K, Sasaki M.
Persistent verbal and behavioral deficits after
resection of the left supplementary motor area inepilepsy surgery. Case Report.
Brain Dev 36(1): 74-9, 2014
Fujimaki Y, Tsunoda K, Ishimoto SI, Okada K,
Kinoshita M, Igaki H, Terahara A, Asakage T,
Yamasoba T.
Non-invasive objective evaluation of radiotherapyinduced dry mouth.
J Oral Pathol Med 43(2): 97-102, 2014
Furuta T, Yamaguchi M, Nakagami R, Akahane M,
Minami M, Ohtomo K, Moriyama N, Fujii H.
Delayed hepatic signal recovery on ferucarbotranenhanced magnetic resonance images: anexperimental study in rat livers with gadolinium
chloride-induced Kupffer cell damage.
MAGMA 26(3): 313-24, 2013
Gonoi W, Akai H, Hagiwara K, Akahane M,
Hayashi N, Maeda E, Yoshikawa T, Kiryu S, Tada
M, Uno K, Okura N, Koike K, Ohtomo K.
Santorinicele without pancreas divisum pathophysiology: Initial clinical and radiographic
investigations.
BMC Gastroenterol 13(1): 62, 2013
Gonoi W, Akahane M, Watanabe Y, Isono S, Maeda
E, Hagiwara K, Ohtomo K.
Visualization of bile movement using MRI
spin-labeling technique: preliminary results.
AJR Am J Roentgenol 201(1): 133-41, 2013
Goto M, Kunimatsu A, Shojima M, Abe O, Aoki S,
Hayashi N, Mori H, Ino K, Yano K, Saito N,
Ohtomo K.
A pitfall on the volume rendering method with 3D
time-of-flight MRA: a case of branching vessel at
the aneurysm neck.
Magn Reson Med Sci 12(1): 53-6, 2013
Goto M, Abe O, Aoki S, Hayashi N, Miyati T,
Takao H, Iwatsubo T, Yamashita F, Matsuda H,
Mori H, Kunimatsu A, Ino K, Yano K, Ohtomo K.
Diffeomorphic Anatomical Registration ThroughExponentiated Lie Algebra provides reduced effectof scanner for cortex volumetry with atlas-based
method in healthy subjects.
Neuroradiology 55(7): 869-75, 2013
Goto M, Abe O, Miyati T, Aoki S, Takao H,
Hayashi N, Mori H, Kunimatsu A, Ino K, Yano K,

63

Ohtomo K.
Association between iron content and gray matter
missegmentation with voxel-based morphometry inbasal ganglia.
J Magn Reson Imaging 38(4): 958-62, 2013
10. Goto M, Abe O, Aoki S, Takao H, Hayashi N,
Miyati T, Mori H, Kunimatsu A, Ino K, Yano K,
Ohtomo K.
Database of normal japanese gray matter volumes
in the default mode network.
J Magn Reson Imaging, 39(1): 132-42, 2014
11. 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 use of in-treatment linac
parameters.
Radiol Phys Technol 6(2): 335-42, 2013
12. Haga A, Magome T, Takenaka S, Imae T, Sakumi A,
Nomoto A, Igaki H, Shiraishi K, Yamashita H,
Ohtomo K, Nakagawa K.
Independent absorbed-dose calculation using theMonte Carlo algorithm in volumetric modulated arc
therapy.
Radiat Oncol 9(1): 75, 2014
13. Hanakita S, Koga T, Igaki H, Murakami N, Oya S,
Shin M, Saito N.
Role of Gamma Knife surgery for intracranial
atypical (WHO Grade II) meningiomas.
J Neurosurg 119(6): 1410-4, 2013
14. Hanakita S, Koga T, Shin M, Takayanagi S, Mukasa
A, Tago M, Igaki H, Saito N.
The long-term outcomes of radiosurgery for
intracranial hemangioblastomas.
Neuro Oncol 16(3): 429-33, 201415. Hayakawa YK, Kirino E, Shimoji K, Kamagata K,
Hori M, Ito K, Kunimatsu A, Abe O, Ohtomo K,
Aoki S.
Anterior cingulate abnormality as a neural correlateof mismatch negativity in schizophrenia.
Neuropsychobiology 68(4): 197-204, 2013
16. Hayakawa YK, Sasaki H, Takao H, Hayashi N,
Kunimatsu A, Ohtomo K, Aoki S.
Depressive symptoms and neuroanatomical
structures in community-dwelling women: A
combined voxel-based morphometry and diffusion
tensor imaging study with tract-based spatial

statisstics.
Neuroimage Clin 4(2014): 481-7, 201417. Hibi S, Yamaguchi Y, Umeda-Kameyama Y,
Takahashi M, Momose T, Akishita M, Ouchi Y.
Respiratory dysrhythmia in dementia with Lewy
bodies: a cross-sectional study.
BMJ Open 3(9): e002870, 2013
18. Ichikawa K, Kashio A, Mori H, Ochi A, Karino S,
Sakamoto T, Kakigi A, Yamasoba T.
A New computed tomography method to identify
meningitis-related cochlear ossification and fibrosis
before cochlear implantation.
Otolaryngol Head Neck Surg 150(4): 646-53, 2014
19. Igaki H, Onishi H, Nakagawa K, Dokiya T, Nemoto
K, Shigematsu N, Nishimura Y, Hiraoka M;
Japanese Society for Therapeutic Radiology andOncology Health Insurance Committee.
A newly introduced comprehensive consultation fee
in the national health insurance system in Japan: apromotive effect of multidisciplinary medical carein the field of radiation oncology--results from aquestionnaire survey.
Jpn J Clin Oncol 43(12): 1233-7, 2013
20. 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 37(5): 1072-6, 2013
21. Ito K, Mori E, Ishii K, Washimi Y, Asada T, Mori S,
Meguro K, Kitamura S, Hanyu H, Nakano S,
Matsuda H, Kuwabara Y, Hashikawa K, Momose T,
Uchida Y, Hatazawa J, Minoshima S, Kosaka K,
Yamada T, Yonekura Y; J-COSMIC Study Group.
Prediction of outcomes in MCI with 123I-IMP-CBF
SPECT: a multicenter prospective cohort study.
Ann Nucl Med 27(10): 898-906, 2013
22. Ito K, Sano T, Kamiya K, Nakata Y, Shigemoto Y,
Sato N, Oya Y, Matsuda H.
Massive accumulation of 11C-Pittsburg compound
B in the occipital lobes of a patient with early-onset
dementia accompanied by muscle weakness andhypertonicity.
Ann Nucl Med 27(10): 935-41, 2013
23. Kamiya K, Kunimatsu A, Mori H, Sato J, Akahane
M, Yamakawa T, Ohtomo K.
Preliminary report on virtual monochromatic
spectral imaging with fast kVp switching dual

64energy head CT: comparable image quality to thatof 120-kVp CT without increasing the radiation
dose.
Jpn J Radiol 31(4): 293-8, 2013
24. Kamiya K, Sato N, Ota M, Nakata Y, Ito K, KimuraY, Murata M, Mori H, Kunimatsu A, Ohtomo K.
Diffusion tensor tract-specific analysis of theuncinate fasciculus in patients with progressive
supranuclear palsy.
J Neuroradiol 40(2): 121-9, 2013
25. Kamiya K, Tanaka F, Ikeno M, Okumura A, Aoki S.
DTI tractography of lissencephaly caused by
TUBA1A mutation.
Neurol Sci 35(5): 801-3, 2014
26. Katsura M, Matsuda I, Akahane M, Yasaka K,
Hanaoka S, Akai H, Sato J, Kunimatsu A, Ohtomo
K.
Model-based iterative reconstruction technique forultralow-dose chest CT: comparison of pulmonary
nodule detectability with the adaptive statisticaliterative reconstruction technique.
Invest Radiol 48(4): 206-12, 2013
27. Kimura Y, Sato N, Sugai K, Maruyama S, Ota M,
Kamiya K, Ito K, Nakata Y, Sasaki M, Sugimoto H.
MRI, MR spectroscopy, and diffusion tensor
imaging findings in patient with static
encephalopathy of childhood with neurodegeneration in adulthood (SENDA).
Brain Dev 35(5): 458-61, 2013
28. Kobayashi R, Yamashita H, Okuma K, Shiraishi K,
Ohtomo K, Nakagawa K.
Salvage radiation therapy and chemoradiation
therapy for postoperative locoregional recurrence ofesophageal cancer.
Dis Esophagus 27(1): 72-8, 2014
29. Kusakabe M, Sasaki H, Sato J, Akahane M, Miyata
T, Ohtomo K.
Percutaneous transluminal renal angioplasty withstenting for stenotic venous bypass grafts: report oftwo cases.
Springerplus 2: 456, 2013
30. Maeda E, Yoshikawa T, Nakashima R, Kobayashi K,
Yokosawa K, Hayashi N, Masutani Y, Yoshioka N,
Akahane M, Ohtomo K.
Experimental system for measurement ofradiologists' performance by visual search task.
Springerplus 2: 607, 2013

31. Mashiko T, Mori H, Kato H, Doi K, Kuno S,
Kinoshita K, Kunimatsu A, Ohtomo K, Yoshimura
K.
Semipermanent volumization by an absorbablefiller: onlay injection technique to the bone.
American Society of Plastic Surgeons 1(1): 1-11,
2013
32. Matsuo Y, Onishi H, Nakagawa K, Nakamura M,
Ariji T, Kumazaki Y, Shimbo M, Tohyama N,
Nishio T, Okumura M, Shirato H, Hiraoka M; Japan
Conformal External Beam Radiotherapy Group;Japan Society of Medical Physics; Japan Society of
Medical Physics; Japanese Society of RadiologicalTechnology.
Guidelines for respiratory motion management inradiation therapy.
J Radiat Res 54(3): 561-8, 2013
33. Mitsuda M, Yamaguchi M, Nakagami R, Furuta T,
Sekine N, Niitsu M, Moriyama N, Fujii H.
Intensity correction method customized for
multi-animal abdominal MR imaging with 3T
clinical scanner and multi-array coil.
Magn Reson Med Sci 12(2): 95-103, 2013
34. Nakagawa K, Haga A, Sakumi A, Yamashita H,
Igaki H, Shiraki T, Ohtomo K, Iwai Y, Yoda K.
Impact of flattening-filter-free techniques ondelivery time for lung stereotactic volumetricmodulated arc therapy and image quality ofconcurrent kilovoltage cone-beam computed
tomography: a preliminary phantom study.
J Radiat Res 55(1): 200-2, 2014
35. Nakashima R, Kobayashi K, Maeda E, Yoshikawa T,
Yokosawa K.
Visual search of experts in medical image reading:the effect of training, target prevalence, and expert
knowledge.
Front Psychol 4: 166, 2013
36. Nakata Y, Sato N, Hattori A, Ito K, Kimura Y,
Kamiya K, Shigemoto Y, Nakagawa E, Sasaki M,
Ohtomo K.
Semi-automatic volumetry of cortical tubers intuberous sclerosis complex.
Jpn J Radiol 31(4): 253-61, 2013
37. Natsubori T, Inoue H, Abe O, Takano Y, Iwashiro N,
Aoki Y, Koike S, Yahata N, Katsura M, Gonoi W,
Sasaki H, Takao H, Kasai K, Yamasue H.
Reduced Frontal Glutamate + Glutamine and65

N-Acetylaspartate Levels in Patients With Chronic
Schizophrenia but not in Those at Clinical High
Risk for Psychosis or With First-Episode
Schizophrenia.
Schizophr Bull 47(10): 1383-8, 2013
38. Nemoto M, Yeernuer T, Masutani Y, Nomura Y,
Hanaoka S, MikiS, Yoshikawa T, Hayashi N,
Ohtomo K.
Development of Automatic Visceral Fat Volume
Calculation Software for CT Volume Data.
J Obes 2014: 495084, 2014
39. Numasaki H, Nishio M, Ikeda H, Sekiguchi K,
Kamikonya N, Koizumi M, Tago M, Ando Y,
Tsukamoto N, Terahara A, Nakamura K, Nishimura
T, Murakami M, Takahashi M, Teshima T; JapaneseSociety for Therapeutic Radiology and Oncology
Database Committee.
Japanese structure survey of radiation oncology in2009 with special reference to designated cancer
care hospitals.
Int J Clin Oncol 18(5): 775-83, 2013
40. Okuma H, Gonoi W, Ishida M, Shintani Y,
Takazawa Y, Fukayama M, Ohtomo K.
Heart Wall Is Thicker on Postmortem Computed
Tomography Than on Ante Mortem Computed
Tomography: The First Longitudinal Study.
PLoS One 8(9): e76026, 2013
41. Omori M, Yamashita H, Shinohara A, Kurokawa M,
Takita J, Hiwatari M, Nakagawa K.
Eleven secondary cancers after hematopoietic stem
cell transplantation using a total body irradiationbased regimen in 370 consecutive pediatric andadult patients.
Springerplus 2(1): 424, 2013
42. 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 54(4): 663-70, 2013
43. Ota M, Nakata Y, Ito K, Kamiya K, Ogawa M,
Murata M, Obu S, Kunugi H, Sato N.
Differential diagnosis tool for parkinsonian
syndrome using multiple structural brain measures.
Comput Math Methods Med 2013: 571289, 2013
44. Ota M, Sato N, Nakata Y, Ito K, Kamiya K,
Maikusa N, Ogawa M, Okamoto T, Obu S, Noda T,

Araki M, Yamamura T, Kunugi H.
Abnormalities of cerebral blood flow in multiple
sclerosis: A pseudocontinuous arterial spin labeling
MRI study.
Magn Reson Imaging 31(6): 990-5, 2013
45. Ota M, Ishikawa M, Sato N, Hori H, Sasayama D,
Hattori K, Teraishi T, Noda T, Obu S, Nakata Y,
Higuchi T, Kunugi H.
Discrimination between schizophrenia and major
depressive disorder by magnetic resonance imagingof the female brain.
J Psychiatr Res 47(10): 1383-8, 2013
46. Ota M, Hori H, Sato N, Sasayama D, Hattori K,
Teraishi T, Obu S, Nakata Y, Kunugi H.
Hypothalamic-pituitary-adrenal axis hyperactivity
and brain differences in healthy women.
Neuropsychobiology 68(4): 205-11, 2013
47. Shibata E, Ueda T, Akaike G, Saida Y.
CT findings of gastric and intestinal anisakiasis.
Abdom Imaging 39(2): 257?61, 2014
48. Shigemoto Y, Matsuda H, Kamiya K, Maikusa N,
Nakata Y, Ito K, Ota M, Matsunaga N, Sato N.
In vivo evaluation of gray and white matter volume
loss in the parkinsonian variant of multiple system
atrophy using SPM8 plus DARTEL for VBM.
Neuroimage Clin 2:491-6, 2013
49. Takanashi J, Osaka H, Saitsu H, Sasaki M, Mori H,
Shibayama H, Tanaka M, Nomura Y, Terao Y, Inoue
K, Matsumoto N, James Barkovich A.
Different patterns of cerebellar abnormality andhypomyelination between POLR3A and POLR3B
mutations.
Brain Dev 36(3): 259-63, 2014
50. Takahashi W, Yamashita H, Kida S, Masutani Y,
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 86(3): 426-31, 2013
51. Takahashi W, Yamashita H, Omori M, Kitagushi M,
Shibata-Kobayashi S, Sakumi A, Nakagawa K.
The feasibility and efficacy of stereotactic bodyradiotherapy for centrally-located lung tumors.
Anticancer Res 33(11): 4959-64, 2013
52. Takahashi W, Nakajima M, Yamamoto N, Yamada S,
Yamashita H, Nakagawa K, Tsuji H, Kamada T.

66

Carbon ion radiotherapy for oligo-recurrent lungmetastases from colorectal cancer: a feasibility
study.
Radiat Oncol 9(1): 68, 2014
53. Takao H, Hayashi N, Ohtomo K.
White matter microstructure asymmetry: effects ofvolume asymmetry on fractional anisotropy
asymmetry.
Neuroscience 231(2013): 1-12, 2013
54. Takao H, Hayashi N, Ohtomo K.
Effects of study design in multi-scanner
voxel-based morphometry studies.
Neuroimage 84(2014): 133-40, 2014
55. Takao H, Hayashi N, Ohtomo K.
Effects of the use of multiple scanners and of
scanner upgrade in longitudinal voxel-based
morphometry studies.
J Magn Reson Imaging 38(5): 1283-91, 2013
56. Tomizawa N, Maeda E, Akahane M, Torigoe R,
Kiryu S, Ohtomo K.
CoronaryCTangiography
using
the
second-generation 320-detector row CT: assessmentof image quality and radiation dose in various heart
rates compared with the first-generation scanner.
Int J Cardiovasc Imaging 29(7): 1613-8, 2013
57. Tsuchiya K, Aoki S, Shimoji K, Mori H, Kunimatsu
A.
Consecutive acquisition of time-resolved contrastenhanced MR angiography and perfusion MR
imaging with added dose of Gadolinium-based
contrast agent aids diagnosis of suspected brain
metastasis.
Magn Reson Med Sci 12(2): 87-93, 2013
58. Wang F, Akashi K, Murakami Y, Inoue Y, Furuta T,
Yamada H, Ohtomo K, and Kiryu S.
Detection of lung tumors in mice using a 1-Tesla
compact magneticresonance imaging system.
PLoS One 9(4): e94945, 2014
59. Watanabe T, Takezawa M, Nakawake Y, Kunimatsu
A, Yamasue H, Nakamura M, Miyashita Y, MasudaN.
Two distinct neural mechanisms underlying indirect
reciprocity.
Proc Natl Acad Sci U S A 111(11): 3990-5, 2014
60. Yamaguchi M, Mitsuda M, Ezawa K, Nakagami R,
Furuta T, Sekine N, Niitsu M, and Fujii H.
Artifact-reduced simultaneous MRI of multiple rats

with liver cancer using PROPELLER.
J Magn Reson Imaging 38(1): 225-30, 2013
61. Yamashita H, Niibe Y, Toita T, Kazumoto T,
Nishimura T, Kodaira T, Eto H, Kinoshita R,
Tsujino K, Onishi H, Takemoto M, Hayakawa K.
High-dose-rate
intra-cavitarybrachytherapy
combined with external beam radiation therapy forunder 40-year-old patients with invasive uterine
cervical carcinoma: clinical outcomes in 118
Patients in a Japanese multi-institutional study,
JASTRO.
Jpn J Clin Oncol 43(5): 547-52, 2013
62. Yamashita H, Omori M, Okuma K, Kobayashi R,
Igaki H, Nakagawa K.
Longitudinal Assessments of Quality of Life andLate Toxicities Before and After Definitive
Chemoradiation for Esophageal Cancer.
Jpn J Clin Oncol, 44(1): 78-84, 2014
63. Yamashita H, Okuma K, Nomoto A, Yamashita M,
Igaki H, Nakagawa K.
Extended cancer-free survival after palliative
chemoradiation for metastatic esophageal cancer.
World J Gastrointest Oncol 6(2): 52-4, 2014
64. Yamashita H, Yamashita M, Futaguchi M, Takenaka
R, Shibata S, Yamamoto K, Nomoto A, Sakumi A,
Kida S, Kaneko Y, Takenaka S, Shiraki T,
Nakagawa K.
Individually wide range of renal motion evaluatedby four-dimensional computed tomography.
Springerplus 3: 131, 2014
65. Yasaka K, Katsura M, Akahane M, Sato J, Matsuda
I, Ohtomo K.
Model-based iterative reconstruction for reductionof radiation dose in abdominopelvic CT: comparison to adaptive statistical iterative reconstruction.
Springerplus 2(1): 209, 2013
66. Yasaka K, Gonoi W, Akai H, Katsura M, Akahane
M, Kiryu S, Ohtomo K.
Differentiation of adrenal tumors in patients with
hepatocellular carcinoma: Adrenal adenoma versus
metastasis.
Eur J Radiol 82(8): 1213-8, 2013
67. Yoshikawa T, Hayashi N, Maeda E, Matsuda I,
Sasaki H, Ohtsu H, Ohtomo K.
Peritoneal fluid accumulation in healthy men andpostmenopausal women: evaluation on pelvic MRI.
AJR Am J Roentgenol 200(6): 1181-5, 2013

67

68. Yoshino M, Kin T, Saito T, Nakagawa D, Nakatomi
H, Kunimatsu A, Oyama H, Saito N.
Optimal setting of image bounding box can improveregistration accuracy of diffusion tensor tractography.
Int J Comput Assist Radiol Surg 9(2): 333-9, 2014

Radiology and Biomedical
Engineering
2. Biomedical Engineering

69

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
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, four PhD student, threemaster course students and one technician has joinedby the end of FY2013.

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. Our laboratory is also
accepting three under-graduate students (one in M2
and two in M1) as Medical Scientist Training Programin faculty of medicine. They are doing their own
research under the supervision of our staffs.

Research activities
1. Development of novel fluorescence probes
Two specialized rooms for chemical syntheses weresettled in our department, equipped with various
instruments for chemical syntheses, purification, andcharacterization, i.e., six chemical hoods, six
evaporators, two instruments for the purification ofcompounds based on different chromatographicalmechanisms, three HPLC systems, one HPLC systemfor bulk purification, 400 MHz NMR, ESI-TOF mass,and so on. UV-Vis spectrometers and fluorometers
were also settled in our laboratory. So now, molecular
design,chemical
syntheses,
purification,
characterization of novel probes can be done in our
department.
By using above instruments, we are now conducting
various projects of establishing novel bioimaging
techniques based on the development of new
fluorescence probes. So far, we have succeeded inestablishing rational design strategies of fluorescenceprobes based on photoinduced electron transfer andintramolecular spirocyclization mechanism. In 2013,
we have succeeded to develop various novel
fluorescence probes by utilizing the concept of bothmechanisms.
2. Live imaging of cellular functions and in vivo

70

tumors by precisely designed fluorescence probes
Various instruments for live imaging of cells andanimals were already settled in our laboratory, i.e.,
confocal fluorescence microscope equipped with awhite-light laser, 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. Yamashita S, Sakabe M, Ishizawa T, Hasegawa K,
Urano Y, Kokudo N: Visualization of the leakageof pancreatic juice using a chymotrypsin-activatedfluorescent probe. Br J Surg. 100(9): 1220-1228,
2013. doi: 10.1002/bjs.9185.
2. Terai T, Tomiyasu R, Ota T, Ueno T, Komatsu T,
Hanaoka K, Urano Y, Nagano T: TokyoGreen
derivatives as specific and practical fluorescentprobes for UDP-glucuronosyltransferase (UGT)
1A1.Chem Commun (Camb) 49(30): 3101-3103,
2013. doi: 10.1039/c3cc38810g.
3. Sakabe M, Asanuma D, Kamiya M, Iwatate JR,
Hanaoka K, Terai T, Nagano T, Urano Y:
Rational Design of Highly Sensitive Fluorescence
Probes For Protease and Glycosidase Based on
Precisely Controlled Spirocyclization. J. Am.
Chem. Soc. 135(1): 409-414, 2013. doi: 10.1021/
ja309688m.
4. 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, 2013. doi: 10.1002/anie.
201205151.

71

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 an associate professor, alecturer, a research fellow, 6 graduate students, aprofessor emeritus, 14 visiting researchers, a technicalstaff, and a 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 year medical students.
In systematic lectures, we teach introduction to theadvanced 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 knowledge, techniques andexperiences are acquired through the development andanimal experiment of the artificial hearts. In thepractice, we give the master course 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 their research bythemselves. The research subject of the doctor course
students is not limited to the field of the artificialorgans but is found from the wide area of advanced

72

medical engineering technologies.
Students must attend to the weekly meeting. They canlearn how to perform the research work and how toreport it through the meeting.
The education to train the leaders of medical
engineers and clinical engineers is another importantrole of our department.

Research activities
Our research field covers advanced diagnostic andtherapeutic medical engineering technologies forclinical medicine. The main subjects are artificialorgans (artificial hearts, assist circulations, artificial
lungs, artificial valves, tissue engineered artificialorgans, regenerative artificial organs, etc). Especially,
the artificial heart is our world famous research
project having a long history since 1959.
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 with high performance, goodanatomical fitting, high durability, high reliability,
high efficiency, good controllability, and excellent
biological compatibility, which can be implanted in
the body of small stature like Japanese. To meat the
purpose, we had been developing the TAH using
undulation pumps, named undulation pump TAH(UPTAH). The undulation pump is our original bloodpump invented in 1992. The UPTAH revealed to havean excellent performance and the goat whose heart
was replaced with the UPTAH survived for 153 days.
However, the UPTAH had a problem in the durabilityof the drive shaft mechanism. To improve the problemof the UPTAH, a new blood pump, named the helicalflow 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,
which can control venous pressure. 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 theoutput changed in accordance with a metabolic
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 animal experiment.
On the other hand, the 1/R control was applied to the
UPTAH and the HFTAH to perform a physiologicalstudy with a nonpulsatile TAH by changing the drivemode from pulsatile to nonpulsatile in a single goat.
The result showed that, for a short period, the 1/R
control could be promising not only with a pulsatilemode, but also with a nonpulsatile mode. The generalconditions and organ functions were not changed by
the application of the nonpulsatile mode. The cardiac
output and the arterial pressure changed with thecondition of the goat in the pulsatile and also
nonpulsatile modes, which seemed almost identical.
However, under the physiological atrial pressure, the73sucking effect of atria was more significant in the
nonpulsatile mode than the pulsatile mode. Therefore,
the nonpulsatile TAH with the 1/R control was
considered to be inadequate, unless some pulsatility
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 transportable heart
and/or lung assist device 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 one-month support. The wholesystem components will be packed in a case having
180 mm in diameter and 390 mm in length. The whole
weight will be about 20 kg.
Our research of the application of ICT (Informationand communication technology) to medicine has been
focused to the home medical care. The research anddevelopment for monitoring the condition of thepatients living at home has been performed utilizing
the miniaturized wireless ECG (electro cardiogram)unit with low power consumption. 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74respiratory frequency using the three-axis acceleration
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 thelaboratory of Prof. Mabuchi, Department ofInformation Physics and Computing, Graduate Schoolof Information Science and Technology.

References
1. Abe Y, Ishii K, Isoyama T, Saito I, Inoue Y, Sato M,
Hara S, Hosoda K, Ariyoshi K, Nakagawa H, Ono T,
Fukazawa K, Ishihara K, Imachi K. The helical flow
total artificial heart: implantation in goats. Proc 35th
Ann Intern Conf IEEE EMBS 2013: 2720-3
2. Isoyama T, Ariyoshi K, Nii K, Saito I, Fukunaga K,
Inoue Y, Ono T, Ishii K, Hara S, Imachi K, Takai M,
Abe Y. Emergency life support system aiming
preprimed oxygenator. Proc 35th Ann Intern Conf
IEEE EMBS 2013: 5731-4
3. Ishii K, Hosoda K, Isoyama T, Saito I, Ariyoshi K,
Inoue Y, Sato M, Hara S, lee X, Wu S, Ono T,
Nakagawa H, Imachi K, Abe Y. Pulsatile driving of
the helical flow pump. Proc 35th Ann Intern Conf
IEEE EMBS 2013: 2724-7
4. Wu S-Y, Saito I, Isoyama T, Inoue Y, Ishii K, Sato M,
Hara S, Hosoda K, Ariyoshi K, Li X, Nakagawa H,
Ono T, Abe Y. Relation between left atrial pressure
and the corresponding pulse pressure in the helicalflow total artificial heart. Proc 35th Ann Intern Conf
IEEE EMBS 2013: 671-4
5. Miura H, Saito I, Sato F, Shiraishi Y, Yambe T,
Matsuki H. A new control method depending on
primary phase angle of transcutaneous energy
transmission system for artificial heart. Proc 35th
Ann Intern Conf IEEE EMBS 2013: 5723-6

Neuroscience
1. Basic Neuroscience

76

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

Lecturer
Tadafumi Hashimoto, Ph.D.

Associate
Genta Ito, Ph.D.
Tomoko Wakabayashi, Ph.D.
Tomoki Kuwahara, Ph.D.

Homepage

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

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,
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

77

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
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 unique

78

subset 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). Knockout mice studies are confirming
the role of CLAC in neuromuscular development.
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.

Yuasa T, Sato N, Matsuda H, Iwatsubo T and theJapanese Alzheimer’s

DiseaseNeuroimaging

Initiative: A phantom-based geometrical distortion
correction method in MRI images for longitudinaland cross-sectional analysis with Alzheimer’s
disease and mild cognitive impairment. Medical
Physics 40:062303, 20135) Hoshi M, Ohki Y, Ito K, Tomita T, Iwatsubo T,

Ishimaru Y, Abe K, Asakura T: Experimental
detection of proteolytic activity in a signal peptide
peptidaseof

Arabidopsis

thaliana.

BMC

Biochemistry 14:16, 2013
6) Doody RS, Raman R, Farlow M, Iwatsubo T,

Vellas B, Joffe S, Kieburtz K, He F, Sun X,
Thomas RG, Aisen PS for the Alzheimer’s Disease
Cooperative Study Steering Committee; Siemers E,
Sethuraman G, Mohs R for the Semagacestat Study
Group: A phase 3 trial of semagacestat fortreatment of Alzheimer’s disease. N Engl J Med
369:341-350, 2013
7) Kamikawaji S, Ito G, Sano T, Iwatsubo T:

Differential

effectsoffamilial

Parkinson

mutations in LRRK2 revealed by a systematic
analysis of autophosphorylation. Biochemistry 52:

References

6052–6062, 20138) Ihara R, Matsukawa K, Nagata Y, Kunugi H, Tsuji

1) Takagi-Niidome

S, Tomita T, Iwatsubo T:

S, Chihara T, Kuranaga E, Miura M, Wakabayashi

Inhibition of γ-secretase activity by a monoclonal

T, Hashimoto T, Iwatsubo T: RNA binding

antibody against the extracellular hydrophilic loop

mediatesof presenilin 1. Biochemistry 52:61-69, 2013

Drosophila model of TDP-43 proteinopathy. Hum2) Imamura Y, Umezawa N, Osawa S, Iwatsubo T,

Kato N, Tomita T, Higuchi T: Effect of helicalconformation

andside-chain

structureonγ-secretase inhibition by β-peptide foldamers:
insight into substrate recognition. J Med Chem
56:1443-1454, 2013
3) Takasugi N, Sasaki T, Ebinuma I, Osawa S, Isshiki

H,

Takeo

K,

TomitaT,

Iwatsubo

T:

FTY720/Fingolimod, a sphingosine analogue,
reduces amyloid-β production in neurons. PLOS
One 8: e64050, 2013
4) Maikusa N, Yamashita F, Tanaka K, Abe O,

Kawaguchi A, Chiba S, Kasahara A, Kobayashi N,

neurotoxicity

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Mol Genet 22: 4474-4484, 2013

thetransgenic

79

Department of Neurochemistry
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
professor, four assistant professors, three postdoctoral

80

scholars, one technical staff member, five 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 that enables direct
exposure of Ph.D. graduate students and postdocs toboth young promising researchers and establishedinvestigators 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 ofcritical 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
also validated in long-term potentiation in the
hippocampus (Redondo et al., J Neurosci. 2010).
Furthermore,
CaMKIV-KO,
CaMKK-KOand81

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. The identification of SARE enables us tobuild 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(Kawashima et al. Nature Methods, 2013).
Inaddition to the transcriptional regulation, we are
currently investigating about the physiological
function and its molecular mechanism of Arc, which isthought to be a key player that contributes activity
dependent neuronal 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 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 inmost central neurons. Biochemical and cell biologicalstudies indicated a critical role for lipidification ofthis kinase to be properly sorted into specificlipid-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).
How do these multiple Ca2+-dependent signaling
molecules process each pattern of intracellular Ca2+
dynamics to induce a cellular response? Recently, we
have developed a method named dFOMA (dual FRET
imaging with optical manipulation) to simultaneously
measure activities of two distinct signaling moleculesin living neurons. Applying originally developed
FRET probes to dFOMA method enabled us tomeasure activities of CaMKII, calcineurin and Ca2+,

82

when a neuron received various frequencies ofsynaptic inputs. These experiments provided evidence
that CaMKIIα and calcineurin are fine-tuned to uniquebandwidths and compute input variables in an
asymmetric manner (Fujii et al., Cell Report 2013).
One further important topic that we have been
focusing for a number of years is the role of gene
expression in prolongation / consolidation of synapsespecific local changes. Neurons undergoing various
stimulus patterns have been followed up in time andthe amount of newly synthesized proteins and the
local distribution of induced gene products have beenmonitored. Using state-of-the-art multi-wavelength
fluorescence imaging techniques, we are now
quantitatively assessing how local distribution of these
newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature
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 ea 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).

83

While a true gradient in SDF-1α still remains to be
demonstrated in vivo, it is intriguing to note that mostactive axonal process formation and elongation
actually occur in the inner zone of EGL that is
opposite and most distant from the interface with the
pia mater (Bito, J. Biochem., 2003). Most strikingly,
we demonstrated that axon elongation could actively
occur in an intermediate Rho activity range thatenables ROCK to be weakened enough while allowing
another Rho effector mDia1 to actively mediate its
effect on actin nucleation and polymerization(Arakawa et al., J. Cell Biol., 2003).
Whether similar or distinct mechanisms also
operate during spinogenesis and spine maturation
remains to be determined, though a role for Rho andROCK has already been postulated in control of spinecomplexity and spine stability. However, multiple
small GTPase signaling cascades clearly seem tocontribute together, in a tightly coordinated manner, tospine regulation, since many distinct classes of GEFs
and GAPs have now been shown to be localized in 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 2013- December 2013)
1. Ageta-Ishihara N, Miyata T, Ohshima C, Watanabe
M, Sato Y, Hamamura Y, Higashiyama T,
Mazitschek R, Bito H, Kinoshita M. Septins
promote dendrite and axon development bynegatively regulating microtubule stability via
HDAC6-mediateddeacetylation.
NatureCommunications, 4: 2532, 2013.
2. Kawashima T, Kitamura K, Suzuki K, Nonaka M,
Kamijo S, Takemoto-Kimura S, Kano M, Okuno H,
Ohki K, Bito H. Functional labeling of neuronalensemble and axonal projections in vivo using a
synthetic activity-dependent promoter E-SARE.
Nature Methods, 10(9): 889-95, 2013.
3. Mikuni T, Uesaka N, Okuno H, Hirai H, Deisseroth
K, Bito H, Kano M. The immediate early gene
Arc/Arg3.1 is a postsynaptic mediator of activitydependent synapse elimination in the developing
cerebellum. Neuron, 78(6):1024-35, 2013.
4. Fujii H, Inoue M, Okuno H, Sano Y,
Takemoto-Kimura S, Kitamura K, Kano M, Bito H.
Nonlinear decoding and asymmetric representationof neuronal input information by CaMKIIα andcalcineurin. Cell Reports, 3(4): 978-87, 2013.

84

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.

853) 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. Kanemaru K, Kubota J, Sekiya H, Hirose K, Okubo
Y, Iino M. Calcium-dependent N-cadherin
up-regulation mediates reactive astrogliosis andneuroprotection after brain injury. Proc Natl Acad
Sci U S A. 110(28): 11612-7, 2013.

Neuroscience
2. Integrative Medical Neuroscience87

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?

88This 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.

89

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 2013, 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 2013 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

90References
1. 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 31(2): 89-95, 2013.
2. Kuwabara H, Yamasue H, Koike S, Inoue H,
Kawakubo Y, Kuroda M, Takano Y, Iwashiro N,
Natsubori T, Aoki Y, Kano Y, Kasai K. Altered
Metabolites in the Plasma of Autism Spectrum
Disorder: A Capillary Electrophoresis Time-ofFlight Mass Spectroscopy Study. PLoS One 8(9):e73814, 2013.
3. Kuwabara H, Araki T, Yamasaki S, Ando S, Kano Y,
Kasai K. Regional differences in post-traumaticstress symptoms among children after the 2011
tsunami in Higashi-Matsushima, Japan. Brain Dev
doi: 10.1016/j.braindev.2014.02.003., 2014.
4. Takizawa R, Fukuda M, Kawasaki S, Kasai K,
Mimura M, Pu S, Noda T, Niwa SI, Okazaki Y;
on behalf of the Joint Project for PsychiatricApplicationof
Near-Infrared
Spectroscopy(JPSY-NIRS)Group(Ishii-Takahashi
A).
Neuroimaging-aided differential diagnosis of thedepressive state. Neuroimage 85 Pt1: 498-507, 2014.
5. Sakakibara E, Takizawa R, Nishimura Y, Kawasaki
S, Satomura Y, Kinoshita A, Koike S, Marumo K,
Kono T, Kuwabara H, Ishii-Takahashi A, Kawakubo
Y, Kasai K. Genetic influences on prefrontal
activation during a verbal fluency task in adults: A
twin study based on multichannel near-infrared
spectroscopy. Neuroimage. 85 Pt1: 508-17, 2014.
6. Ishii-Takahashi A, Takizawa R, Nishimura Y,
Kawakubo Y, Matsubayashi J, Hamada K, Okuhata
S, Yahata N, Igarashi T, Kawasaki S, Yamasue H,
Kato N, Kasai K, Kano Y. Prefrontal activation
during inhibitory control measured by near-infrared
spectroscopy for differentiating between autism
spectrum disorders and attention deficit hyperactivity disorder in adults. Neuroimage Clin 4:
53-63, 2013.
7. Saito Y, Suga M, Tochigi M, Abe O, Yahata N,
Kawakubo Y, Liu X, Kawamura Y, Sasaki T, Kasai
K, Yamasue H. Neural correlate of autistic-like traits
and a common allele in the oxytocin receptor gene.
Soc Cogn Affect Neurosci doi: 10.1093/scan/nst136,

2013.
8. Kamio Y, Inada N, Moriwaki A, Kuroda M, Koyama
Y, Tsujii H, Kawakubo Y, Kuwabara H, Tsuchiya,
KJ, Uno Y. Quantitative autistic traits ascertained ina national survey of 22,529 Japanese schoolchildren.
Acta Psychiatr Scand 128(1): 45-53, 2013.
9. Kuroda, M, Kawakubo Y, Kuwabara H, Yokoyama
K, Kano Y, Kamio, Y. A Cognitive-Behavioral
Intervention for Emotion Regulation in Adults with
High-functioning Autism Spectrum Disorders: study
protocol for a randomized controlled trial. Trials 14:
231, 2013.
10. Kamio Y, Inada N, Koyama T, Inokuchi E, Tsuchiya
K, Kuroda M. Effectiveness of Using the Modified
Checklist for Autism in Toddlers in Two-Stage
Screening of Autism Spectrum Disorder at the
18-Month Health Check-Up in Japan. J Autism Dev
Disord 44(1): 194-203, 2013.
11. Marumo K, Takizawa R, Kinou M, Kawasaki S,
Kawakubo Y, Fukuda M, Kasai K. Functional
abnormalities in the left ventrolateral prefrontal
cortex during a semantic fluency task, and theirassociation with thought disorder in patients withschizophrenia. Neuroimage 85 Pt1: 518-26, 2014.
12. Watanabe T, Abe O, Kuwabara H, Yahata N, Takano
Y, Iwashiro N, Natsubori T, Aoki Y, Takao H,
Kawakubo Y, Kamio Y, Kato N, Miyashita Y, Kasai
K, Yamasue H: Mitigation of sociocommunicational
deficits of autism through oxytocin-induced
recovery of medial prefrontal activity: a randomized
trial. JAMA Psychiatry 71(2): 166-75, 2014.
13. Watanabe T, Yahata N, Kawakubo Y, Inoue H,
Takano Y, Iwashiro N, Natsubori T, Takao H, Sasaki
H, Gonoi W, Murakami M, Katsura M, Kunimatsu
A, Abe O, Kasai K, Yamasue H. Network structure
underlying resolution of conflicting nonverbal andverbal social information. Soc Cog Affect Neurosci
9(6): 767-75, 2014.
14. Sugano H, Nakanishi H, Nakajima M, Higo T,
Iimura Y, Tanaka K, Hosozawa M, Niijima S, Arai H.
Posterior quadrant disconnection surgery for
Sturge-Weber syndrome. Epilepsia doi: 10.1111/
epi.1254., 2014.
15. Shoji H, Hisata K, Hososawa M, Tanaka K, Shimizu
T. Oxidative stress early in infancy and neurodevelopmental outcome in very-low-birth-weight
infants. Pediatr Int doi: 10.1111/ped.12332. , 2014.

Neuroscience
3. Clinical Neuroscience92

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93rehabilitation 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.

Education
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
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) Iwashiro N, Yahata N, Kawamuro Y, Kasai K,
Yamasue H. Aberrant interference of auditory
negative words on attention in patients withschizophrenia. PLoS ONE. 2013; 8:e83201(2) Ishii-Takahashi A, Takizawa R, Nishimura Y,
Kawakubo Y, Kuwabara H, Matsubayashi J,
Hamada K, Okuhata S, Yahata N, Igarashi T,
Kawasaki S, Yamasue H, Kato N, Kasai K, Kano Y.
Prefrontal activation during inhibitory control
measured by near-infrared spectroscopy for
differentiating between autism spectrum disorders
and attention deficit hyperactivity disorder in adults.
Neuroimage Clin. 2013 4: 53-63(3) Koike S, Nishimura Y, Takizawa R, Yahata N, Kasai
K. Near-infrared spectroscopy in schizophrenia: A
possible biomarker for predicting clinical outcome
and treatment response. Front Psychiatry 2013 14
4:145.
(4) Nagai T, Tada M, Kirihara K, Araki T, Jinde S andKasai K. Mismatch negativity as a “translatable”
brain marker toward early intervention for
psychosis: a review. Front. Psychiatry 2013 4:115:
1-10.
(5) Kuwabara H, Yamasue H, Koike S, Inoue H,
Kawakubo Y, Kuroda M, Takano Y, Natsubori T,
Aoki Y, Kano Y, Kasai K Altered metabolites in theplasma of autism disorder: a capillaryelectrophoresis time-of-flight mass spectroscopy
study. PLoS ONE. 2013 8: e73814(6) Sumiyoshi C, Uetsuki M, Suga M, Kasai K,
Sumiyoshi T Development of brief versions of theWechsler Intelligence Scale for schizophrenia:
considerations of the structure and predictability ofintelligence. Psychiatry Res. 2013 210:773-779(7) Ando S, Nishida A, Koike S. A pilot retrospective
cohort study on the effectiveness of a

94

multidisciplinary team intervention for first-episodepsychosis in Japan. Psychiatr Serv. 2013 64(9):932-3.
(8) Natsubori T, Inoue H, Abe O, Takano Y, Iwashiro N,
Aoki Y, Koike S, Yahata N, Katsura M, Gonoi W,
Sasaki H, Takao H, Kasai K, Yamasue H Reduced
frontal glutamate+glutamine and N-acetylaspartatelevels in patients with chronic schizophrenia but notin those at clinical-high risk for psychosis or with
first-episode schizophrenia. Schizophr Bull. 2013
(9) Kinou M, Takizawa R, Marumo K, Kawasaki S,
Kawakubo Y, Fukuda M, Kasai K Differential
spatiotemporal characteristics of the prefrontal
hemodynamic response and their association withfunctional impairment in schizophrenia and major
depression. Schizophr Res. 2013 150:459-467(10) Nagai T, Tada M, Kirihara K, Yahata N, Hashimoto
R, Araki T, Kasai K Auditory mismatch and P3a inresonse to duration and frequency changes in theearly stages of psychosis. Schizophr Res. 2013 150:
547-554(11) Ikegame T, Bundo M, Sunaga E, Asai T, Nishimura
F, Yoshikawa A, Kawamura Y, Hibino H, Tochigi M,
Kakiuchi C, Sasaki T, Kato T, Kasai K, Iwamoto K
DNA methylation analysis of BDNF genepromoters in peripheral blood cells of schizophrenia
patients. Neurosci Res. 2013 77:208-214(12) Nishimura Y, Takizawa R, Koike S, Kinoshita A,
Satomura Y, Kawasaki S, Yamasue H, Tochigi M,
Kakiuchi C, Sasaki T, Iwayama Y, Yamada K,
Yoshikawa T, Kasai K Association of decreased
prefrontal hemodynamic response during a verbal
fluency task with EGR3 gene polymorphism inpatients with schizophrenia and in healthy
individuals. NeuroImage. 2013 85:527-534(13) Saito Y, Suga M, Tochigi M, Abe O, Yahata N,
Kawakubo Y, Liu X, Kawamura Y, Sasaki T, Kasai
K, Yamasue H Neural correlate of autistic-like traits
and a common allele in the oxygen receptor gene.
Soc Cogn Affect Neurosci. 2013(14) Ando S, Matsumoto T, Kanata S, Hojo A, Yasugi D,
Eto N, Kawanishi C, Asukai N, Kasai K One-year
follow up after admission to an emergency
department for drug overdose in Japan. Psychiatry
Clin Neurosci. 2013 67(6):441-450(15) 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. Int J Neuropsychopharmacol. 2013 16(10):2285-2294(16) Aoki Y, Inokuchi R, Nakao T, Yamasue H. Neuralbases of antisocial behavior: a voxel-based
meta-analysis. Soc Cogn Affect Neurosci. 2013(17) Sugawara H, Bundo M, Ishigooka J, Iwamoto K,
Kato T. Epigenetic regulation of serotonintransporter in psychiatric disorders. Journal of
Genetics and Genomics 2013 40:325-329(18) Ando S, Kasai K, Matamura M, Hasegawa Y,
Hirakawa H, Asukai N Psychosocial factors
associated with suicidal ideation in clinical patientswith depression. J Affect Disord. 2013 151(2):561-5(19) Aoki Y, Abe O, Nippashi Y, Yamasue H Comparisonof white matter integrity between autism spectrum
disorder subjects and typically developing
individuals: a meta-analysis of diffusion tensor
imaging tractography studies. Mol Autism. 2013 2;
4(1):25(20) Aoki Y, Inokuchi R, Suwa H Reduced
N-acetylaspartate in the hippocampus in patientswith fibromyalgia: a meta-analysis. Psychiatry Res.
2013 213(3):242-8(21) Brigman JL, Daut RA, Wright T, Gunduz-Cinar O,
Graybeal C, Davis MI, Jiang Z, Saksida LM, Jinde
S, Pease M, Bussey TJ, Lovinger DM, Nakazawa K,
Holmes A. GluN2B in corticostriatal circuits
governs choice learning and choice shifting. Nat
Neurosci. 2013 16:1101-1110(22) Noda Y, Nakamura M, Saeki T, Inouke M, Iwanari
H, Kasai K Potentiation of quantitativeelectroencephalograms
following
prefrontal
repetitive transcranial magnetic stimulation inpatients with major depression. Neurosci Res. 2013;
77:70-77(23) Sato H, Yahata N, Funane T, Takizawa R, Katura T,
Atsumori H, Nishimura Y, Kinoshita A, Kiguchi M,
Koizumi H, Fukuda M, Kasai K A NIRS–fMRI
investigation of prefrontal cortex activity during aworking memory task. Neuroimage. 2013 83:
158-173(24) Koike S, Takizawa R, Nishimura Y, Kinou M,
Kawasaki S, Kasai K Reduced but broader
prefrontal activity in patients with schizophrenia
during n-back working memory tasks: amulti-channel near-infrared spectroscopy study. J

95

Psychiatr Res. 2013 47(9):1240-1246(25) 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 2013 58:434-438.
(26) Aoki Y, Inokuchi R, Suwa H, Aoki A. Age-relatedchange of neurochemical abnormality inattention-deficit hyperactivity disorder: a metaanalysis. Neurosci Biobehav Rev. 2013 37(8):1692-701(27) Yamaguchi S, Wu SI, Biswas M, Yate M, Aoki Y,
Barley EA, Thornicroft G Effects of short-term
interventions to reduce mental health-related stigma
in university or college students: a systematic
review. J Nerv Ment Dis. 2013 201(6):490-503(28) Koike S, Sasaki R. Multi-modal brain imaging
showing brain damage to the orbitofrontal cortex
and left hemisphere, in a case of prolonged
hypoglycemia-induced
transienthemiplegia
followed by persistent encephalopathy. Psychiatry
Clin Neurosci. 2013 67(5):360-2.
(29) Aoki Y, Orikabe L, Takayanagi Y, Yahata N, Mozue
Y, Sudo Y, Ishii T, Itokawa M, Suzuki M, Kurachi
M, Okazaki Y, Kasai K, Yamasue H Volume
reductions in frontopolar and left perisylvian
cortices in methamphetamine induced psychosis.
Schizophr Res. 2013 147(2-3): 355-361(30) Furukawa M, Tochigi M, Otowa T, Arinami T, Inada
T, Ujike H, Watanabe Y, Iwata N, Itokawa M,
Kunugi H, Hashimoto R, Ozaki N, Kakiuchi C,
Kasai K, Sasaki T An association analysis of the
cardiomyopathy-associated 5 (CMYA5) gene withschizophrenia in a Japanese population. Psychiatr
Genet. 2013 23(4):179-180(31) Araki T, Niznikiewicz M, Kawashima T, Nestor PG,
Shenton ME, McCarley RW Disruption offunction-structure coupling in brain regions
sub-serving self monitoring in schizophrenia.
Schizophr Res 2013 146: 336-343(32) Takizawa R, Nishimura Y, Yamasue H, Kasai K
Anxiety and performance: the disparate roles ofprefrontal
subregions
under
maintained
psychological stress. Cereb Cortex. 2013(33) Jinde S, Zsiros V, Nakazawa K. Hilar mossy cell
circuitry controlling dentate granule cell excitability.
Front Neural Circuits. 7:14 2013(34) Ando S, Yamasaki S, Shimodera S, Sasaki T,

Oshima N, Furukawa TA, Asukai N, Kasai K, Mino
Y, Inoue S, Okazaki Y, Nishida A A greater numberof somatic pain sites is associated with poor mental
health in adolescents: a cross-sectional study. BMC
Psychiatry. 2013 13:30(35) 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. 2013 58(2):91-97"(36) Koike S, Takano Y, Iwashiro N, Satomura Y, Suga
M, Nagai T, Natsubori T, Tada M, Nishimura Y,
Yamasaki S, Takizawa R, Yahata N, Araki T,
Yamasue H, Kasai K A multimodal approach toinvestigate biomarkers for psychosis in a clinicalsetting: the integrative neuroimaging studies inschizophrenia targeting for early intervention andprevention (IN-STEP) project. Schizophr Res. 2013
143(1): 116-124(37) 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. 2013 31(2):89-95

96

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

Associate Professor
Jun Goto, M.D., Ph.D.

Lecturer
Jun Shimizu, M.D. , Ph.D.
Yasuo Terao, M.D.,Ph.D.

Associate
Yaeko Ichikawa, M.D.,Ph.D., Ritsuko Hanajima, M.D., Ph.D.,
Kaori Sakuishi, M.D., Ph.D., Masashi Hamada, M.D., Ph.D.,
Hiroyuki Ishiura, M.D., PhD.

Homepage http://square.umin.ac.jp/neurotky/
Introduction and Organization
The Department of Neurology was establishedby the founder Professor Yasuo Toyokura in 1964 as
one Department in the Brain Research Institute. The
Department of Neurology was succeeded byProfessors Toru Mannen and Ichiro Kanazawa. The
organization of the Brain Research Institute wasreorganized as the Division of Neuroscience of the
Graduate School of Medicine in 1997.

Clinical activities
We offer clinical services in the field of
Neurology. We are putting our effort to provide thepatients with highly advanced clinical practice as wellas on clinical activities connected to postgraduate
education of Neurology.
We have outpatient clinics covering the broad
fields of Neurology. Furthermore, we also provide
clinics specialized to movement disorders anddementia (Memory Clinic).
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.

Teaching activities
As for under-graduate education, our
Department takes a part in lectures of Neurology forthe 4th and 5th grade medical students, and clinicalclerkship for the 5th grade medical students.
In the clinical clerkship we include small group
lectures including neurophysiology, and stroke care.
We are also putting our effort for Free Quarters where
we offer various opportunities for medical students to
be involved in research activities, and 2-3 medical
students are conducting their research activities in thelaboratories.
In postgraduate education we offer the
integrated program including Neurology as the part ofthe program of Internal Medicine.
For training of board-certified Neurologists, weoffer the excellent program including patients’care,

97

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.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and toeventually develop new therapeutic strategies. Our
research activities include molecular genetics,
developmental biology, cell biology, pharmacology,
pathology, and physiology. We aim to integrate thesebroad research fields to better contribute to clinicalneurology.
In the filed of molecular genetics, we havedevelop Medical Genome Center, and introduced
next-generation sequencers to conduct comprehensive
genome analyses to elucidate molecular bases ofneurological diseases. Applying massively parallel
sequencing technologies, we found mutations in
COQ2 in familial as well as sporadic multiple system
atrophy. And also we discovered a new locus for ALS.
It is ALS19 that is caused by mutations in ERBB4.
Application of next generation sequencers formolecular diagnosis has been intensively investigated(Tsuji, S., Goto, J., Ichikawa, Y., Date, H., Suzuki, K.,
Mitsui, J., Ishiura, H., Matsukawa, T., Hatano, K.)
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 new therapeutic methods 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 (quadripulse stimulation). We have just started
a project to treat patients with movement disorders,intractable pain, epilepsy and so on using that newtreatment. (Terao, Y., Hanajima, R., Hamada, M.,
Okabe, S., Terada, S., Shirota, Y, Ohminami, S.,
Tsutumi, R., Matsuda, S., Shimizu, T., Tanaka, N., andTokushige, S.)
In the field of neuromuscular diseases, we
provide pathological diagnosis of biopsied materials
from patients with myopathy or neuropathy. We also
provide autoantibody testing for anti-gangliosideantibodies,musclespecific
antibodies
andparaneoplastic neurological antibodies. In research
field, using biopsied muscles and collected serum
samples, we have been studying the mechanisms ofinflammatory myopathies from the view points ofpathological changes, myositis specific autoantibodies,
serum cytokines, and expression profiling of muscle
samples. We aim to increase understanding of the
etiology and pathogenesis of neuromuscular diseases.
(Shimizu, J., Hida, A., and Maeda M.).
Department of Molecular Neuroscience on
Neurodegenerationisfundedby
JanssenPharmaceuticals. The main project is epigenetics
analysis in Alzheimer’s disease and we reported anaberrant epigenenome in Alzheimer’s disease.
Additional analysis is ongoing with other different
neurodegenerative disorders. MRI analysis of various
dementias are also ongoing. Participation in J-ADNI
project is almost completed. As a succession project,
we are now involved in J-ADNI2 study as a protocol
manager. We also conduceted several clinical trials
involving Eli-Lily’s florbetapir and the result is
submitted for publication. By using activity monitor,
we revealed that in female dementia patients, their
daily activity are significantly reduced, which could
be a new measure for monitoring the effect ofanti-dementia drugs．We also revealed that a classicalneurological sign Abadie’s phenomenon was useful indiagnosis of adrenoleukomyelopathy. We also
reported several interesting cases including adult onset
Huntington’s disease without chorea, cerebral
microbleeding in varicella zoster virus meningitis andprogressive apraxic agraphia with micrographia.
(Iwata, A., Hayashi, H.).

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Publication
1. 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. 72:739-49, 2012
2. Furubayashi T, Mochizuki H, Terao Y, Arai N,
Hanajima R, Hamada M, Matsumoto H,
Nakatani-Enomoto S, Okabe S, Yugeta A,
Inomata-Terada S, Ugawa Y. Cortical hemoglobin
concentration changes underneath the coil after
single-pulse transcranial magnetic stimulation: A
near-infrared spectroscopy (NIRS) study.
J.
Neurophysiol. 109:1626-37, 2013.
3. Higashihara M, Sonoo M, Yamamoto T,
Kawamura Y, Nagashima Y, Terao Y, Kaida K,
Kimura F, Ugawa Y, Tsuji S. Far-Field Potentials
in Hypothenar Motor Unit Number Estimation.
Muscle Nerve 48:191-7, 2013.
4. Ichikawa Y, Ishiura H, Mitsui J, Takahashi Y,
Kobayashi S, Takuma H, Kanazawa I, Doi K,
Yoshimura J, Morishita S, Goto J, Tsuji S. Exome
analysis reveals a Japanese family withspinocerebellar ataxia, autosomal recessive 1. J.
Neurol. Sci.331:158-60, 2013
5. Ihara R, Matsukawa K, Nagata Y, Kunugi H, Tsuji
S, Chihara T, Kuranaga R, Miura M, Wakabayashi
T, Hashimoto T and Iwatsubo T. RNA binding
mediates neurotoxicity in the transgenic
Drosophila model of TDP-43 proteinopathy. Hum.
Mol. Genet. 22:4474-84, 2013
6. Ishii A, Saito Y, Mitsui J, Ishiura H, Yoshimura J,
Arai H, Yamashita S, Kimura S, Oguni H,
Morishita S, Tsuji S, Sasaki M, Hirose S.
Identification of ATP1A3 mutations by exome
sequencing as the cause of alternating hemiplegia
of childhood in Japanese patients. PLOS One
8:e56120, 2013
7. Iwata A, Ishihara K, Tsuji S. Adult-onset
Huntington’s disease that presented without
chorea. Int Med 52, 2121-2, 2013
8. Iwata A, Iwatsubo T. Disease modifying therapy
for Alzheimer’s disease: Challenges and Hopes.
Neurol & Clin Neurosci 1: 49-53, 2013

9. Iwata A, Kowa H, Tsuji. Monitoring daily life
activity reveals less activity among female
dementia patients. Neurology and Clinical
Neuroscience 1, 91-95, 2013
10. Izumikawa T, Saigoh K, Shimizu J, Tsuji S,
Kusunoki S, Kitagawa H. A chondroitin
synthase-1 (ChSy-1) missense mutation in apatient with neuropathy impairs the elongation ofchondroitin sulfate chains initiated by chondroitin
N-acetylgalactosaminyltransferase- 1. Biochim.
Biphys. Acta 1830: 4806-4812, 2013
11. Kuzma-Kozakiewicz,
Berdy?ski,
Morita,Takahashi,
Kawata,Kaida,
Kazmierczak,
Lusakowska, Goto, Tsuji, Zekanowski C,
Kwiecinski H. Recurrent K3E mutation in Cu/Zn
superoxide dismutase gene associated withamyotrophic lateral sclerosis. Amyotrophic
LateralSclerosis
andFrontotemporal
Degeneration 14:608-14, 2013.
12. Kusunoki-Nakamoto F, Matsukawa T, Tanaka M,
Miyagawa T, Yamamoto T, Shimizu J, Ikemura M,
Shibahara J, Tsuji S. Successful treatment of anunresectable inflammatory myofibroblastic tumorof the frontal bone using a cyclooxygenase-2
inhibitor and methotrexate. Intern Med. 52:623-8.
2013
13. Landouré G, Toro C, Zhu P-P, Johnson JO,
Bricceno KV, Rinaldi C, Meilleur KG, Sangar? M,
Diallo O, Pierson TM, Ishiura H, Tsuji S, Hein N,
Fink JK, Stoll M, Nicholson G, Gonzalez M,
Z?chner S, D?rr A, Stevanin G, Biesecker LG,
Accardi J, Landis D, Gahl WA, Traynor BJ,
Blackstone C, Fischbeck KH, Burnett BG.
Hereditary spastic paraplegia type 43 (SPG43) iscaused by mutation in C19ORF12. Human
Mutation 34:1357-60, 2013
14. Matsumoto H, Hanajima R, Terao Y, Hashida H,
Ugawa Y. Neurophysiological analysis of thecauda equina in POEMS syndrome. Neurol Sci.
34: 121-2, 2013.
15. Matsumoto H, Tokushige SI, Hashida H,
Hanajima R, Terao Y, Ugawa Y. Focal lesion in
upper part of brachial plexus can be detected bymagnetic cervical motor root stimulation. Brain
Stimul. 6:538-40, 2013.
16. Matsumoto H, Konoma Y, Fujii K, Hanajima R,
Terao Y, Ugawa Y. A conduction block in sciatic

99

nerves can be detected by magnetic motor root
stimulation. J. Neurol. Sci. 331:174-6, 2013.
17. Matsumoto H, Hanajima R, Terao Y, Ugawa Y.
Magnetic-motor-root stimulation: Review. Clin.
Neurophysiol. 124:1055-67, 2013.
18. Mitsui J, Matsukawa T, Ishiura H, Fukuda Y,
Ichikawa Y, Date H, Ahsan B, Nakahara Y,
Momose Y, Takahashi Y, Iwata A, Goto J,
Yamamoto Y, Komata M, Shirahige K, Hara K,
Kakita A, Yamada M, Takahashi H, Onodera O,
Nishizawa M, Takashima H, Kuwano R,
Watanabe H, Ito M, Sobue G, Soma H, Yabe I,
Sasaki H, Aoki M, Ishikawa K, Mizusawa H,
Kanai K, Hattori T, Kuwabara S, Arai K, Koyano
S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K,
Nakashima K, Ito H, Izumi Y, Kaji R, Kato T,
Kusunoki S, Osaki Y, Horiuchi M, Kondo T,
Murayama S, Hattori N, Yamamoto M, Murata M,
Satake W, Toda T, Dürr A, Brice A, Filla A,
Klockgether T, Wüllner U, Nicholson G, Gilman
S, Shults CW, Tanner CM, Kukull WA, Lee V
M-Y, Masliah E, Low PA, Sandroni P,
Trojanowski JQ, Ozelius L, Foroud T, and Tsuji S.
Mutations of COQ2 in familial and sporadic
multiple system atrophy. New Engl. J. Med. 369:
233-44, 2013
19. Miyashita A, Koike A, Jun G, Wang L-S,
Takahashi S, Matsubara E, Kawarabayashi T,
Shoji M, Tomita N, Arai H, Asada T, Harigaya Y,
Ikeda M, Amari M, Hanyu H, Higuchi S, Ikeuchi
T, Nishizawa M, Suga M, Kawase Y, Akatsu H,
Kosaka K, Yamamoto T, Imagawa M, Hamaguchi
T, Yamada M, Moriaha T, Takeda M, Takao T,
Nakata K, Fujisawa Y, Sasaki K, Watanabe K,
Nakashima K, Urakami K, Ooya T, Takahashi M,
Yuzuriha T, Serikawa T, Yoshimoto S, Nakagawa
R, Kim J-W, Ki C-S, Won H-H, Na DL, Seo SW,
Mook-Jung I, The Alzheimer Disease Genetics
Consortium, St. George-Hyslop P, Mayeux R,
Haines JL, Pericak-Vance MA, Yoshida M,
Nishida N, Tokunaga K, Yamamoto K, Tsuji S,
Kanazawa I, Ihara Y, Schellenberg GD, Farrer LA.
and Kuwano R. SORL1 Is Genetically Associatedwith Late-Onset Alzheimer’s Disease in Japanese,
Koreans and Caucasians. PLoS ONE 8: e58618,
2013
20. Nakamura R, Atsuta N, Watanabe H, Hirakawa A,

Watanabe H, Ito M, Senda J, Katsuno M, Tanaka F,
Izumi Y, Kaji R, Morita M, Tomiyama H,
Taniguchi A, Aiba I, Mizoguchi K, Okamoto K,
Hasegawa K, Aoki M, Kawata A, Abe A,
Konagaya M, Imai T, Nakagawa M, Tsuji S,
Nakano I, Sobue G. Neck weakness is a potent
prognostic factor for sporadic amyotrophic lateralsclerosis patients. J Neurol Neurosurg Psych
84:1365-71, 2013
21. Naruse H, Nagashima Y, Maekawa R, Etoh T,
Hida A, Shimizu J, Kaida K, Shiio Y. Successfultreatment of infliximab-associated immunemediatedsensorypolyradiculopathy
withintravenous immunoglobulin. J Clin Neurosci.
20:1618-9, 2013
22. Sakurai Y, Ishii K, Sonoo M, Saito Y, Murayama
S, Iwata A, Hamada K, Sugimoto I, Tsuji S,
Mannen T. Progressive apraxic agraphia withmicrographia presenting as corticobasal syndromethat showed extensive Pittsburgh compound B
uptake. J Neurol 260, 1982-1991, 2013
23. Suzuki T, Shimoda M, Ito K, Hanai S, Aizawa H,
Kato T, Kawasaki K, Yamaguchi T, Ryoo HD,
Goto-Inoue N, Setou M, Tsuji S, Ishida N.
Expression of Human Gaucher Disease Gene
GBA Generates Neurodevelopmental Defects and
ER Stress in Drosophila Eye. PLoS One 8:
e69147. doi:10.1371/journal.pone.0069147
24. Takahashi T, Aoki M, Suzuki N, Tateyama M,
Yaginuma C, Sato H, Hayasaka M, Sugawara H,
Ito M, Abe-Kondo E, Shimakura N, Ibi T, Kuru S,
Wakayama T, Sobue G, Fujii N, Saito T,
Matsumura T, Funakawa I, Mukai, E, Kawanami
T, Morita M, Yamazaki M, Hasegawa T, Shimizu
J, Tsuji S, Kuzuhara S, Tanaka H, Yoshioka M,
Konno H, Onodera H and Itoyama Y. Clinicalfeatures and a mutation with late onset of limb
girdle muscular dystrophy 2B. J. Neurol.
Neurosurg. Psych. 84:433-40, 2013.
25. Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A,
Kurppa K, Moritoyo H, Belzil VV, Dion PA,
Higasa K, Doi K, Ishiura H, Mitsui J, Date H,
Ahsan B, Matsukawa T, Ichikawa Y, Moritoyo T,
Ikoma M, Hashimoto T, Kimura F, Murayama S,
Onodera O, Nishizawa N, Yoshida M, Atsuta N,
Sobue G, JaCALS, Fifita JA, Williams KL, Blair
IP, Nicholson GA, Gonzalez-Perez P, Brown,

100

Jr.RH, Nomoto M, Elenius K, Rouleau GA,
Fujiyama A, Morishita S, Goto J and Tsuji S.
ERBB4 Mutations that Disrupt the NeuregulinErbB4 Pathway Cause Amyotrophic Lateral
Sclerosis Type 19. Am J Hum Genet 93:900-5,
2013
26. Terao Y, Fukuda H, Shirota Y, Yugeta A, Yoshioka
M, Suzuki M, Hanajima R, Nomura Y, Segawa M,
Tsuji S, Ugawa Y. Deterioration of horizontal
saccades in progressive supranuclear palsy. Clin
Neurophysiol. 124: 354-63, 2013.
27. Terao Y, Fukuda H, Ugawa Y, Hikosaka O.
New perspectives on the pathophysiology ofParkinson's disease as assessed by saccade
performance:Aclinicalreview.
Clin.
Neurophysiol. 124:1491-506, 2013
28. Tsuji S. Neurogenomics view of neurologicaldiseases. Arch. Neurol. 70:689-94, 2013
29. 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 47:816-22, 2013
30. Yamashita T, Chai HL, Teramoto S, Tsuji S,
Shimazaki K, Muramatsu S, Kwak S. Rescue ofamyotrophic lateral sclerosis phenotype in amouse model by intravenous AAV9-ADAR2
delivery to motor neurons. EMBO Mol Med
5:1710-9, 2013

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

Associate Professor
Hirofumi Nakatomi, M.D., Ph.D.

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

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

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

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

Associate
Kazuhiko Ishii, M.D., Akihiro Ito, M.D., Ph.D., Takashi Ochi, M.D.
Shota Tanaka, M.D., Taichi Kin, M.D., Ph.D., Satoru Miyawaki, M.D., Ph.D.,
Naoto Kunii, M.D., Ph.D., Shunya Hanakita, 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 2013 to March 2014, 16,211 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 2012 and 2013, 881 and 866 patientswere admitted to the Neurosurgical Ward, respectively.
444 and 471 surgical procedures were performed with148 and 139 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102preserve 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 9 residents in 2014 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

103

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.

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Fujita N, Nakamura S, et al. Diagnosis and surgical104

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Buckner J, et al. Gliomatosis cerebri: clinicalcharacteristics, management, and outcomes. J
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Neurobiol Exp (Wars). 2013;73(2):304-11.
5. Fukushima Y, Oya S, Nakatomi H, Shibahara J,
Hanakita S, Tanaka S, et al. Effect of dural
detachment on long-term tumor control formeningiomas treated using Simpson grade IV
resection. J Neurosurg. 2013;119(6):1373-9.
6. Goto M, Kunimatsu A, Shojima M, Abe O, Aoki S,
Hayashi N, et al. A pitfall of the volume rendering
method with 3D time-of-flight MRA: a case of abranching vessel at the aneurysm neck. Magn
Reson Med Sci. 2013;12(1):53-6.
7. Hamaguchi T, Sakai K, Noguchi-Shinohara M,
Nozaki I, Takumi I, Sanjo N, et al. Insight into thefrequent occurrence of dura mater graft-associatedCreutzfeldt-Jakob disease in Japan. J Neurol
Neurosurg Psychiatry. 2013;84(10):1171-5.
8. Hanakita S, Koga T, Igaki H, Murakami N, Oya S,
Shin M, et al. Role of gamma knife surgery for
intracranial atypical (WHO grade II) meningiomas.
J Neurosurg. 2013;119(6):1410-4.
9. Hirohata T, Asano K, Ogawa Y, Takano S, Amano
K, Isozaki O, et al. DNA mismatch repair protein(MSH6) correlated with the responses of atypical
pituitary adenomas and pituitary carcinomas totemozolomide: the national cooperative study by
the Japan Society for Hypothalamic and Pituitary
Tumors. J Clin Endocrinol Metab. 2013;98(3):1130-6.
10. Hirohata T, Saito N, Takano K, Yamada S, Son JH,
Yamada SM, et al. Urinary growth hormone level
and insulin-like growth factor-1 standard deviation
score (IGF-SDS) can discriminate adult patientswith severe growth hormone deficiency. Endocr J.
2013;60(3):369-73.
11. Hirokazu T, Takayuki I, Yoshinori H, Kazunari K,
Akio A, Keiji K. Separation surgery of pygopagus
asymmetrical conjoined twins sharing U-shaped

12.

13.

14.

15.

16.

17.

18.

19.

20.

spinal cord: case report and literature review.
Childs Nerv Syst. 2013;29(4):699-706.
Inoue T, Ohwaki K, Tamura A, Tsutsumi K, Saito I,
Saito N. Subclinical ischemia verified bysomatosensory evoked potential amplitude
reduction during carotid endarterectomy: negative
effects on cognitive performance. J Neurosurg.
2013;118(5):1023-9.
Inoue T, Tamura A, Tsutsumi K, Saito I, Saito N.
Surgical embolectomy for large vessel occlusion ofanterior circulation. Br J Neurosurg. 2013;27(6):783-90.
Inoue T, Tsutsumi K, Ohwaki K, Tamura A, Ono H,
Saito I, et al. Stratification of intraoperative
ischemic impact by somatosensory evoked potential
monitoring, diffusion-weighted imaging andmagnetic resonance angiography in carotid
endarterectomy with routine shunt use. Acta
Neurochir (Wien). 2013;155(11):2085-96.
Koyama-Nasu R, Nasu-Nishimura Y, Todo T, Ino Y,
Saito N, Aburatani H, et al. The critical role ofcyclin D2 in cell cycle progression andtumorigenicity of glioblastoma stem cells.
Oncogene. 2013;32(33):3840-5.
Kunii N, Kamada K, Ota T, Greenblatt RE, Kawai
K, Saito N. The dynamics of language-related
high-gamma activity assessed on a spatiallynormalized brain. Clin Neurophysiol. 2013;124(1):91-100.
Kunii N, Kamada K, Ota T, Kawai K, Saito N.
Characteristic profiles of high gamma activity andblood oxygenation level-dependent responses invarious language areas. Neuroimage. 2013;65:
242-9.
Matsuo T, Kawai K, Uno T, Kunii N, Miyakawa N,
Usami K, et al. Simultaneous recording of
single-neuron activities and broad-area intracranialelectroencephalography: electrode design andimplantation procedure. Neurosurgery. 2013;73(2Suppl Operative):146-54.
Matsuo T, Kawasaki K, Kawai K, Majima K,
Masuda H, Murakami H, et al. Alternating Zones
Selective to Faces and Written Words in the Human
Ventral Occipitotemporal Cortex. Cereb Cortex.
2013.
Miyawaki S, Imai H, Shimizu M, Yagi S, Ono H,
Mukasa A, et al. Genetic variant RNF213

105

21.

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24.

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27.

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29.

c.14576G>A in various phenotypes of intracranial
major artery stenosis/occlusion. Stroke. 2013;
44(10):2894-7.
Ono H, Nakatomi H, Tsutsumi K, Inoue T, Teraoka
A, Yoshimoto Y, et al. Symptomatic recurrence of
intracranial arterial dissections: follow-up study of
143 consecutive casesand pathologicalinvestigation. Stroke. 2013;44(1):126-31.
Saito N, Kin T, Oyama H, Yoshino M, Nakagawa D,
Shojima M, et al. Surgical simulation of
cerebrovascular disease with multimodal fusion
3-dimensional computer graphics. Neurosurgery.
2013;60 Suppl 1:24-9.
Sakai K, Hamaguchi T, Noguchi-Shinohara M,
Nozaki I, Takumi I, Sanjo N, et al. Graft-relateddisease progression in dura mater graft-associatedCreutzfeldt-Jakob disease: a cross-sectional study.
BMJ Open. 2013;3(8):e003400.
Sato I, Higuchi A, Yanagisawa T, Mukasa A, Ida K,
Sawamura Y, et al. Factors influencing self- andparent-reporting health-related quality of life inchildren with brain tumors. Qual Life Res. 2013;22(1):185-201.
Shimizu M, Imai H, Kagoshima K, Umezawa E,
Shimizu T, Yoshimoto Y. Detection of compression
vessels in trigeminal neuralgia by surface-rendering
three-dimensional reconstruction of 1.5- and 3.0-T
magnetic resonance imaging. World Neurosurg.
2013;80(3-4):378-85.
Shinozaki M, Yasuda A, Nori S, Saito N, Toyama Y,
Okano H, et al. Novel method for analyzing
locomotor ability after spinal cord injury in rats:
technical note. Neurol Med Chir (Tokyo). 2013;53(12):907-13.
Shojima M, Morita A, Kimura T, Oshima M, Kin T,
Saito N. Computational Fluid Dynamic Simulationof a Giant Basilar Tip Aneurysm with Eventual
Rupture After Hunterian Ligation. World
Neurosurg. 2013.
Shojima M, Saito N. Translation of Computational
Fluid Dynamics Study to Neurosurgery. World
Neurosurg. 2013.
Takai K, Kin T, Oyama H, Shojima M, Saito N.
Three-dimensional angioarchitecture of spinal duralarteriovenous fistulas, with special reference to theintradural retrograde venous drainage system. J
Neurosurg Spine. 2013;18(4):398-408.

30. Takami H, Asai A, Ohshige H, Uesaka T, Takeda J,
Yoshimura K, et al. Fat necrosis appearing as
intraorbital tumour: Case report. Br J Neurosurg.
2013.
31. Takami H, Oshiro N, Hiraoka F, Murao M, Ide T.
Rapid resolution of a spontaneous large chronic
subdural haematoma in the posterior fossa underconservative treatment with platelet administration
to aplastic anaemia. Clin Neurol Neurosurg. 2013;
115(10):2236-9.
32. Takami H, Takasu Y, Ide T. Necklace-shaped
fusiform aneurysm on the primitive vertebral
communicating artery. Acta Neurochir (Wien).
2013;155(11):2127-8.
33. Tanaka M, Tsuno NH, Fujii T, Todo T, Saito N,
Takahashi K. Human umbilical vein endothelial cell
vaccine therapy in patients with recurrent
glioblastoma. Cancer Sci. 2013;104(2):200-5.
34. Tanaka S, Meyer FB, Buckner JC, Uhm JH, Yan ES,
Parney IF. Presentation, management, and outcomeof newly diagnosed glioblastoma in elderly patients.
J Neurosurg. 2013;118(4):786-98.
35. Tanaka S, Pollock BE, Stafford SL, Link MJ.
Stereotactic radiosurgery for trigeminal pain
secondary to benign skull base tumors. World
Neurosurg. 2013;80(3-4):371-7.
36. Tanaka S, Shin M, Mukasa A, Hanakita S, Saito K,
Koga T, et al. Stereotactic radiosurgery for
intracranial gliomas. Neurosurg Clin N Am. 2013;24(4):605-12.
37. Usami K, Kawai K, Sonoo M, Saito N.
Scalp-recorded evoked potentials as a marker for
afferent nerve impulse in clinical vagus nerve
stimulation. Brain Stimul. 2013;6(4):615-23.
38. Yoshino M, Kin T, Nakatomi H, Oyama H, Saito N.
Presurgical planning of feeder resection withrealistic three-dimensional virtual operation field inpatient with cerebellopontine angle meningioma.
Acta Neurochir (Wien). 2013;155(8):1391-9.
39. Yoshino M, Kin T, Saito T, Nakagawa D, Nakatomi
H, Kunimatsu A, et al. Optimal setting of image
bounding box can improve registration accuracy ofdiffusion tensor tractography. Int J Comput Assist
Radiol Surg. 2013.

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

107

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

Lecturer
Satoshi Ueha, Ph. D.

Assistant professor
Takeshi Shimaoka, Ph.D.,

Yuya Terashima, Ph.D.

Project Assistant professor
Etsuko Toda, Ph.D.

Homepage

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

Introduction and Organization
The Department of Molecular Preventive Medicine
was originally established in 1885. It was designed tooffer both a high level of hygienic education andfacilities for specialized research. At present, it is our
responsibility to give lectures, seminars and courses
for experiments and practical training on thepreventive medicine to the third grade medical
students. The professor, several invited lecturers(including adjunct staff), and research associates takepart in the education as well as research activities.
There are over twenty members in our department,
includingresearch
fellows,
graduate
andundergraduate 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 grade medical students. The course is consistedof lectures, seminars, experiments, and practicaltraining which are provided by our own staffs and also
by the experts outside: National Institute of Infectious
Diseases (Dr. Oishi), Kanazawa University (Dr.
Matsugo), Kyoto University (Dr. Koizumi), HealthService 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) Molecular and cellular bases of chronic
inflammation associated-organ fibrosis.
2) Establishment of ex-vivo differentiation system of
myofibroblast.
3) Elucidation of the cellular and molecularmechanisms that lead to Graft-Versus-Host
Disease.
4) Molecular analysis of chemokine receptor
signaling pathway and development of novel
therapeutic
drugs
againstcancerand108

inflammatory diseases.
5) Application of humanized anti-CD4 antibody forcancer.

References(1) 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, 183(3):758-73.
(2) 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 rationallyselected mixture of Clostridia strains from the humanmicrobiota. Nature. 2013, 500(7461):232-6.
(3) 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 acidreceptor agonist, ameliorates murine vasculitis throughthe suppression of neutrophil migration and activation.
Arthritis Rheum. 2013, 65 (2):503-12.
(4) Sekiguchi S, Kimura K, Chiyo T, Ohtsuki T, Tobita Y,
Tokunaga Y, Yasui F, Tsukiyama-Kohara K, Wakita T,
Tanaka T, Miyasaka M, Mizuno K, Hayashi Y,
Hishima T, Matsushima K, Kohara M. Immunization
with a recombinant vaccinia virus that encodes
nonstructural proteins of the hepatitis C virus
suppresses viral protein levels in mouse liver. PLoS
One. 2013, 7 (12):e51656.
(5) Hoshino A, Ueha S, Hanada S, Imai T, Ito M,
Yamamoto K, Matsushima K, Yamaguchi A, Iimura T.
Roles of chemokine receptor CX3CR1 in maintaining
murine bone homeostasis through the regulation ofboth osteoblasts and osteoclasts. J Cell Sci. 2013, 126(Pt 4):1032-45.
(6) 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 human CD45-/collagen1-positive cells under high glucose concentrations.
Clin Exp Nephrol. 2013, 17(6):793-804.
(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) Itakura M, Terashima Y, Shingyoji M, Yokoi S, Ohira
M, Kageyama H, Matui Y, Yoshida Y, Ashinuma H,
Moriya Y, Tamura H, Harigaya K, Matushima K,
Iizasa T, Nakagawara A, Kimura H. High CC
chemokine receptor 7 expression improves postoperative prognosis of lung adenocarcinoma patients.
Br J Cancer. 2013, 109(5):1100-8.

109

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

Associate Professor
Takahiro Higashi, M.D., Ph.D. (Until April, 2013)
Satoshi Toyokawa, M.S., Ph.D. (From December, 2013)

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

Associate
Fumiaki Nakamura, M.D., 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 2013, the Department
consists of four faculty members above listed, three
supporting staffs, 17 graduate students (13 in PhD
program and four in MPH program), 16 part-time
lecturers, and 18 visiting fellows.

110

Teaching activities
1) Undergraduate Program (Medical School)
In the winter term of the fourth grade in the Schoolof Medicine (M2), students are provided with thefollowing lectures; current issues of public health,preventive services, epidemiology, health economics,
community health and 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), an intensive courseof public health (e.g., health care systems, current
healthpolicy,occupational
medicineandenvironmental 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 prepar-

111

edness in local communities and healthcare facilities,(4) evaluation of the effectiveness of the Safe
Communities model for safety promotion, and (5)epidemiological study on incidence and survival rateof children with cerebral palsy.

References
1. Higashi T, Nakamura F, Saruki N, Takegami M,
Hosokawa T, Fukuhara S, Nakayama T, Sobue T:
Evaluation of newspaper articles for coverage of
public reporting data: a case study of unadjusted
cancer survival data. Japanese Journal of ClinicalOncology 43(1): 95-100, 2013.
2. Higashi T, Nakamura F, Saruki N, Sobue T:
Establishing a quality measurement system forcancer care in Japan. Japanese Journal of ClinicalOncology 43(3): 225-232, 2013.
3. Touyama M, Touyama J, Ochiai Y, Toyokawa S,
Kobayashi Y: Long-term survival of children withcerebral palsy in Okinawa, Japan. Developmental
Medicine & Child Neurology 55(5): 459-463,
2013.
4. Sugiyama T, Zingmond D, Lorenz KA, Diamant A,
Malley KO, Citko J, Gonzalez V, Wenger NS:
Implementing physician orders for life-sustaining
treatment in California hospitals: factors
associated with adoption. Journal of the American
Geriatrics Society 61(8): 1337-1344, 2013.
5. Tanihara S, Tomio J, Kobayashi Y: Using healthinsurance claim information for evacuee medical
support and reconstruction after the Great East
Japan Earthquake. Disaster Medicine & Public
Health Preparedness 7(4): 403-407, 2013.
6. Higashi T, Nakamura F, Shimada Y, Shinkai T,
MuranakaT, Kamiike W, Mekata E, Kondo K,
Wada Y, Sakai H, Ohtani M, Yamaguchi T,
Sugiura N, Higashide S, Haga Y, Kinoshita A,
Yamamoto T, Ezaki T, Hanada S, Makita F, Sobue
T, Okamura T: Quality of gastric cancer care in
designated cancer care hospitals in Japan.
International Journal of Quality and Health Care25(4): 418-428, 2013.
7. Kaneto C, Toyokawa S, Miyoshi Y, Suyama Y,
Kobayashi Y: Long-term weight change inadulthood and incident diabetes mellitus: MY
Health Up Study. Diabetes Research and Clinical

Practice 102(2): 138-146, 2013.
8. 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 18(6): 971-6, 2013.
9. Nakamura F, Hayashino Y, Nishiuchi T, Kakudate
N, Takegami M, Yamamoto Y, Yamazaki S,
Fukuhara S: Contribution of out-of-hospital
factors to a reduction in cardiac arrest mortality
after witnessed ventricular fibrillation or
tachycardia. Resuscitation 84(6): 747-51, 2013.
10. Nakahara S, Tomio J, Takahashi H, Ichikawa M,
Nishida M, Morimura N, Sakamoto T. Evaluationof pre-hospital administration of adrenaline(epinephrine) by emergency medical services forpatients with out of hospital cardiac arrest inJapan:
controlled
propensity
matchedretrospective cohort study. BMJ 347: f6829, 2013.
doi: 10.1136/bmj.f6829.

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

113

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://forensicmed.umin.jp

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.
Ken-ichi Yoshida has been directing our department
since 1999 as the 8th Professor and he has studied themechanism 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, four 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 of114

Tokyo every year. We have already autopsied morethan 11,423 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 corraboration 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 have

115

successfully developed an apparatus for the rat
model 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.

2.

3.

Saka K, Kudo K, Hayashida M, Kurisaki E, Niitsu
H, Terada M, Yamaguchi K, Yoshida K. Relationship between the matrix effect and the physicochemical properties of analytes in gas chromatography. Anal Bioanal Chem. 2013;405(30):9879-88.
Kiuchi T, Yoshida K, Kotani H, Tamaki K, Nagai H,
Harada K, Ishikawa H. Legal Medicine Information
System using CDISC ODM. Leg Med (Tokyo).
2013 ;15(6):332-4.
Kashima J, Shintani-Ishida K, Nakajima M, Maeda
H, Unuma K, Uchiyama Y, Yoshida K. Immunohistochemical study of the autophagy marker microtubule-associated protein 1 light chain 3 in nor-

116

mal and steatotic human livers. Hepatol Res.
2014 ;44(7):779-87.
4. Maeda H, Nagai H, Takemura G, Shintani-Ishida K,
Komatsu M, Ogura S, Aki T, Shirai M, Kuwahira I,
Yoshida K. Intermittent-hypoxia induced autophagy
attenuates contractile dysfunction and myocardial
injury in rat heart. Biochim Biophys Acta.
2013;1832(8):1159-66.
5. Unuma K, Aki T, Funakoshi T, Yoshida K, Uemura
K. Cobalt protoporphyrin accelerates TFEB activation and lysosome reformation during LPS-induced
septic insults in the rat heart. PLoS One.
2013;8(2):e56526.
6. Hirose I, Harada K, Kuroda R, Ishii Y, Nakajima M,
Kamei Y, Takazawa Y, Yoshida K. An autopsy report on a ruptured rudimentary horn (uterine anomaly) with ectopic pregnancy. Forensic Sci Int.
2013;224(1-3):e4-6.
7. Unuma K, Aki T, Matsuda S, Funakoshi T, Yoshida K, Uemura K. Inducer of heme oxygenase-1
cobalt protoporphyrin accelerates autophagy andsuppresses oxidative damages during lipopolysaccharide treatment in rat liver. Hepatol Res.
2013;43(1):91-6.
8. Unuma K, Aki T, Matsuda S, Funakoshi T, Yoshida K, Uemura K. Elimination and active extrusion of liver mitochondrial proteins during lipopolysaccharide administration in rat. Hepatol Res.
2013 May;43(5):526-34.
9. Hikiji W, Yamaguchi K, Saka K, Hayashida M,
Ohno Y, Fukunaga T. Acute fatal poisoning with
Tolfenpyrad. J Forensic Leg Med. 2013; 20:962-964.
10. Fujii Y, Funakoshi T, Uchida K, Watanabe M,
Saka K, Uemura K. An autopsy case of acutecarbon monoxide poisoning with fatal hypnotic
drugs in the blood. Int Med J. 2013; 20(5):587-588.
11. Kuroda R, Nakajima M, Nagai H, Maeda H,
Kashima J, Saka K, Shintani-Ishida K, Igarashi A,
Yoshida K. Small focal coagulation necrosis in
the myocardium of a young methamphetamineuser. Int J Cardiol. 2013; 164: e5-e6.

117Department of Medical
Informatics and Economics
Professor
Kazuhiko Ohe, M.D., Ph.D.

Homepage

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

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

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

118

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

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

Health Sciences with completion of required units
and passing a master’s thesis. In the doctoral course,
students will acquire Doctor of Health
Sciences(Ph.D.) with completion of required units
and passing a doctoral thesis.
3). 2-year M.P.H and 1-year M.P.H in the Department
of Health Informatics in the Shool of Public Health:
We offer 2-year Master of Publics Health (M.P.H)
course and the 1-year M.P.H program in the Schoolof Publics Health. See the homepage of the Shool of
Publics Health.
4). 2-year M.M.S in the Department of Health
Medical Informatics in the Medical Science
Graduate Program: Graduate School of Medicine,the University of Tokyo, offers the master course in
Medical Sciences. The course was established forstudents who graduate from faculties other than a
6-year program at Faculty of Medicine andeventually wish to advance to the Medical Sciences
doctoral course of the University of Tokyo.
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 andconcepts :119This research develops the methods to build thelarge scale medical ontology, which is a databasefor hundreds of thousand of clinical terms andconcepts and their relationships. It focuses on thedevelopment of basic methods for making andaccessing databases and will be applied for the
research.
2) Development of standardized IT infrastructure forclinical researches (Funding Program forWorld-Leading Innovative R&D on Science andTechnology: the FIRST program, 2010.3-2014.3)
This research develops autonomic, distributed,
real–time clinical support system. This project is apart of the FIRST program; ”Development ofMedical Technology for Treating Intractable
Cancers and Cardiovascular Diseases” supervised
by Professor Ryozo Nagai in the Department of
Cardiovascular Medicine.
3) A study on Natural Language Processing ofClinical Document (Industry-academia collaboration project with Fuji Xerox Limited, 2007-2012).
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.

2.

3.

4.

Koike S, Ide H, Kodama T, Matsumoto S,
Yasunaga H, Imamura T. Physician-scientists inJapan: attrition, retention, and implications forthe future. Acad Med. 2012 May;87(5):662-7.
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.
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.
Waki K, Fujita H, Uchimura Y, Aramaki E, Omae
K, Kadowaki T, Ohe K. DialBetics:
smartphone-based 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 Japanese Diagnosis 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
database system. 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 theFifth 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

121

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. (until the end of September, 2013)

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 also highly trained to be well knowledged
and expert in the most modern methods of diagnosis
and treatment. As a teaching and research hospital, we
also emphasize the development and incorporation of
new treatments if they may benefit the patient. From a
research standpoint, our interests range throughout all
fields of cardiovascular medicine ranging frommolecular biology to clinical research including
genomics. Importantly, our research interests are
aimed at making possible new diagnostics andtreatment of cardiovascular diseases. Finally, we havea particular interest in teaching not only for medical
students but also for residents which is important 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 2013, 1,782 patients were newly admitted to our
hospital ward of approximately 50 beds.
Cardiovascular angiograms were conducted in 1,802
patients, of which 610 cases were interventional
procedures. CT coronary angiography was examinedin 426 patients and cardiovascular MRI in 67. For
arrhythmias, there were 81 cases of implantation or
replacement of a pacemaker, 200 cases of catheter
ablation, and other specialized pacemaker devices
such as 20 cases of implantation or replacement of a
implantable cardioverter-defibrillator (ICD), and 17
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

122

were transplanted to 17 cases in 2013 (total 44 cases).
Duration of hospitalization is on average 14.3 days.
Out-patient clinics are available as part of the
Department of Medicine or as a specialized
department. The profile of diseases includes ischemic
heart disease, 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 238.8 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.

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 cardiovasculardiseases
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 (2013)
1. Akazawa
H,
YabumotoC,
Yano
M,
Kudo-Sakamoto Y, Komuro I. ARB and
Cardioprotection. Cardiovasc Drugs Ther 27:
155-160,2013
2. Ueda H, Yamada T, Masuda M, Morita T,
Furukawa Y, Tanaka K, Iwasaki Y, Okada T,
Kawasaki M, Kuramoto Y, Naito T, Fujimoto T,
Komuro I, Fukunami M. Kidney Enhancement on
X-Rays Following Emergency PercutaneousCoronary Procedure Predicts Poor Short- andLong-Term Clinical Outcomes. Circ J 77:982-987,
2013.
3. Watanabe S, Amiya E, Watanabe M, Takata M,
Ozeki A, Watanabe A, Kawarasaki S, Nakao T,
Hosoya Y, Omori K, Maemura K, Komuro I,
Nagai R. Simultaneous Heart Rate Variability
Monitoring Enhances the Predictive Value of
Flow-Mediated Dilation in Ischemic Heart
Disease. Circ J 77:1018-1025, 2013.
4. Kato N, Kinugawa K, Imamura T, Muraoka H,
Minatsuki S, Inaba T, Maki H, Shiga T, Hatano M,
Yao A, Komuro I, Nagai R. Trend of Clinical
Outcome and Surrogate Markers During Titrationof β-Blocker in Heart Failure Patients With
Reduced Ejection Fraction. Circ J 77:1001-1008,

123

2013.
5. Matsumoto S, Nakatani D, Sakata Y, Suna S,
Shimizu M, Usami M, Hara M, Sumitsuji S,
Nanto S, Sasaki T, Hamasaki T, Sato H, Hori M,
Komuro I; on Behalf of the Osaka Acute Coronary
Insufficiency Study (OACIS) Group. ElevatedSerum Heart-Type Fatty Acid- Binding Protein in
the Convalescent Stage Predicts Long-Term
Outcome in Patients Surviving Acute Myocardial
Infarction. Circ J 77:1026-1032, 2013.
6. Suna S, Sakata Y, Nakatani D, Okuda K, Shimizu
M, Usami M, Matsumoto S, Hara M, Ozaki K,
Mizuno H, Minamino T, Takashima S, Nishino M,
Matsumura Y, Takeda H, Tanaka T, Sato H, Hori
M, Komuro I. Decreased mortality associatedwith statin treatment in patients with acute
myocardial infarction and lymphotoxin-alpha
C804A polymorphism. Atherosclerosis 227:373-379, 2013.
7. Takahama H, Shigematsu H, Asai T, Matsuzaki T,
Sanada S, Fu HY, Okuda K, Yamato M, Asanuma
H, Asano Y, Asakura M, Oku N, Komuro I,
Kitakaze M, Minamino T. Liposomal Amiodarone
Augments Anti- arrhythmic Effects and Reduces
Hemodynamic Adverse Effects in an Ischemia/
Reperfusion Rat Model. Cardiovasc Drugs Ther
27:125-132, 2013.
8. Imamura T, Kinugawa K, Minatsuki S, Muraoka
H, Kato N, Inaba T, Maki H, Shiga T, Hatano M,
Yao A, Kyo S, Komuro I. Urine Osmolality
Estimated Using Urine Urea Nitrogen, Sodium
and Creatinine Can Effectively Predict Responseto Tolvaptan in Decompensated Heart Failure
Patients. Circ J 77:1208-1213, 2013.
9. 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 168:1429-1434, 2013.
10. Nakatani D, Sakata Y, Suna S, Usami M,
Matsumoto S, Shimizu M, Hara M, Uematsu M,
Fukunami M, Hamasaki T, Sato H, Hori M,
Komuro I; Osaka Acute Coronary Insufficiency
Study (OACIS) Investigators. Impact of Beta

Blockade Therapy on Long-Term Mortality After
ST-Segment
Elevation
Acute
Myocardial
Infarction in the Percutaneous Coronary Intervention Era. Am J Cardiol. 111:457-464, 2013.
11. Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Takata M, Ozeki A, Watanabe A,
Kawarasaki S , TaniguchiT, Ichimura Y, Toyama T,
Watanabe M, Hirata Y, Nagai R, Komuro I, Sato
S,Clinical correlation of brachial artery flowmediated dilation in patients with systemicsclerosis. Mod Rheumatol 24:106-111, 2014.
12. Amiya E, Watanabe M, Takata M, Watanabe S,
Ozeki A, Watanabe A, Kawarasaki S, Nakao T,
Hosoya Y, Omori K, Maemura K, Hirata Y, Nagai
R, Komuro I. Differences in Body Temperature
Variability Between Subjects With and Without
Diabetes and Predictive Value for Cardiovascular
Events. CircJ 77:1844-1853, 2013.
13. Takano H, Mizuma H, Kuwabara Y, Sato Y,
Shindo S, Kotooka N, Fujimatsu D, Kobayashi Y,
Inoue T, Node K, Komuro I; PEARL Study
Investigators Effects of pitavastatin in Japanesepatients with chronic heart failure. CircJ 77:917925, 2013.
14. Minamiguchi H, Sakata Y, Ohtani T, Mizote I,
Takeda Y, Mizuno H, Okuyama Y, Nakatani S,
Fujita M, Watanabe T, Uematsu M, Komuro I. Am
J Cardiol 168:1429-1434,2013.
15. Iwata Y, Fujimoto Y, Morino T, Sugimoto K,
Ohkubo K, Kadohira T, Fukushima K, Kitahara H,
Komuro I, Kobayashi Y. Effects of stem cell
mobilization by granulocyte colony-stimulating
factor on endothelial function after sirolimuseluting stent implantation: A double-blind,randomized, placebo-controlled clinical trial. Am
Heart J 165:408-414, 2013.
16. Ichibori Y, Nakatani D, Sakata Y, Tachibana K,
Akasaka T, Saito S, Fukushima N, Sawa Y, Nanto
S, Komuro I. Cardiac allograft vasculopathy
progression
associatedwithintraplaqueneovascularization. J Am Coll Cardiol 61:e149,
2013.
17. Imamura T, Kinugawa K, Kato N, Minatsuki S,
Muraoka H, Inaba T, Maki H, Shiga T, HatanoM,
Yao A, Kyo S, Ono M, Komuro I. Successful
conversion from thiazide to tolvaptan in a patientwith stage d heart failure and chronic kidney

124

disease before heart transplantation. Int Heart J
54:48-50,2013.
18. Tamai T, Yamaguchi O, Hikoso S, Takeda T,
Taneike M, Oka T, Oyabu J, Murakawa T,
Nakayama H, Uno Y, Horie K, Nishida K,
Sonenberg N, Shah AM, Takeda J, Komuro I,
Otsu K. Ras Homologue Enriched in Brain(Rheb)-dependent mTORC1 Activation BecomesIndispensable for Cardiac Hypertrophic Growth
after Early Postnatal Period. J Biol Chem
288:10176-10187, 2013.
19. Kimura K, Takenaka K, Ebihara A, Uno K,
Morita H, Nakajima T, Ozawa T, Aida I,
Yonemochi Y, Higuchi S, Motoyoshi Y, Mikata T,
Uchida I, Ishihara T, Komori T, Kitao R, Nagata T,
Takeda S, Yatomi Y, Nagai R, Komuro I.
Prognostic
impactofleftventricular
noncompaction in patients with Duchenne/Becker
muscular dystrophy - Prospective multicenter
cohort study. Int J Cardiol 168:1900-1904, 2013.
20. Sakamoto Y, Akazawa H, Komuro I. The Roles ofCalcium and Phosphorus in Cardiovascular
Diseases. The physiological and pathological
function of Ca(2+)-dependent cysteine protease(Calpain) Clin Calcium 23:519-525, 2013.
21. Taniguchi T, Ohtani T, Mizote I, Kanzaki M,
Ichibori Y, Minamiguchi H, Asano Y, Sakata Y,
Komuro I. Switching from carvedilol to bisoprololameliorates adverse effects in heart failure
patients with dizziness or hypotension. J Cardiol
61:417-422, 2013.
22. Akazawa
H,
YabumotoC,
Yano
M,
Kudo-Sakamoto Y, Komuro I. ARB and
Cardioprotection. Cardiovasc Drugs Ther 27:
155-160, 2013.
23. Nakatani D, Sakata Y, Suna S, Usami M,
Matsumoto S, Shimizu M, Hara M, Uematsu M,
Fukunami M, Hamasaki T, Sato H, Hori M,
Komuro I, Osaka Acute Coronary Insufficiency
Study I. Impact of beta blockade therapy on
long-term mortality after st-segment elevation
acute myocardial infarction in the percutaneous
coronary intervention era. Am J Cardiol 111:457-464, 2013.
24. Ueda H, Yamada T, Masuda M, Morita T,
Furukawa Y, Tanaka K, Iwasaki Y, Okada T,
Kawasaki M, Kuramoto Y, Naito T, Fujimoto T,

Komuro I, Fukunami M. Kidney Enhancement on
X-Rays Following Emergency PercutaneousCoronary Procedure Predicts Poor Short- andLong-Term Clinical Outcomes. Circ J 77:982-987,
2013.
25. Watanabe S, Amiya E, Watanabe M, Takata M,
Ozeki A, Watanabe A, Kawarasaki S, Nakao T,
Hosoya Y, Omori K, Maemura K, Komuro I,
Nagai R. Simultaneous Heart Rate Variability
Monitoring Enhances the Predictive Value of
Flow-Mediated Dilation in Ischemic Heart
Disease. Circ J 77:1018-1025, 2013.
26. Kato N, Kinugawa K, Imamura T, Muraoka H,
Minatsuki S, Inaba T, Maki H, Shiga T, Hatano M,
Yao A, Komuro I, Nagai R. Trend of Clinical
Outcome and Surrogate Markers During Titrationof β-Blocker in Heart Failure Patients With
Reduced Ejection Fraction. Circ J 77:1001-1008,
2013.
27. Matsumoto S, Nakatani D, Sakata Y, Suna S,
Shimizu M, Usami M, Hara M, Sumitsuji S,
Nanto S, Sasaki T, Hamasaki T, Sato H, Hori M,
Komuro I; on Behalf of the Osaka Acute Coronary
Insufficiency Study (OACIS) Group. ElevatedSerum Heart-Type Fatty Acid- Binding Protein in
the Convalescent Stage Predicts Long-Term
Outcome in Patients Surviving Acute Myocardial
Infarction. Circ J 77:1026-1032, 2013
28. Lee J, Kim KE, Choi DK, Jang JY, Jung JJ,
Kiyonari H, Shioi G, Chang W, Suda T,
Mochizuki N, Nakaoka Y, Komuro I, Yoo OJ, Koh
GY.
Angiopoietin-1
GuidesDirectional
Angiogenesis Through Integrin αvβ5 Signaling
for Recovery of Ischemic Retinopathy. Sci Transl
Med 5:203ra1271, 2013.
29. Tsukamoto Y, Mano T, Sakata Y, Ohtani T, Takeda
Y, Tamaki S, Omori Y, Ikeya Y, Saito Y, Ishii R,
Higashimori M, Kaneko M, Miwa T, Yamamoto K,
Komuro I. A Novel Heart Failure Mice Model ofHypertensive Heart Disease by Angiotensin II
Infusion, Nephrectomy, and Salt Loading. Am J
Physiol Heart Circ Physiol 305:1658-1657, 2013.
30. Nakaoka H, Nakagawa-Toyama Y, Nishida M,
Okada T, Kawase R, Yamashita T, Yuasa-Kawase
M, Nakatani K, Masuda D, Ohama T, Sonobe T,
Shirai M, Komuro I, Yamashita S. Correction:
Establishment of a Novel Murine Model of125

Ischemic Cardiomyopathy with Multiple Diffuse
Coronary Lesions. PLoS One 8:e70755, 2013.
31. Shen H, Eguchi K, Kono N, Fujiu K, Matsumoto
S, Shibata M, Oishi-Tanaka Y, Komuro I, Arai H,
Nagai R, Manabe I. Saturated Fatty Acid
Palmitate Aggravates Neointima Formation by
Promoting
SmoothMusclePhenotypic
Modulation. Arterioscler Thromb Vasc Biol
33:2596-2607, 2013.
32. 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 43:481-487, 2013.
33. Tamaki S, Mano T, Sakata Y, Ohtani T, Takeda Y,
Kamimura D, Omori Y, Tsukamoto Y, Ikeya Y,
Kawai M, Kumanogoh A, Hagihara K, Ishii R,
Higashimori M, Kaneko M, Hasuwa H, Miwa T,
Yamamoto K, Komuro I. Interleukin-16 promotes
cardiac fibrosis and myocardial stiffening in heart
failure with preserved ejection fraction. PLoS One
8:e68893, 2013.
34. Matsumoto S, Sakata Y, Suna S, Nakatani D,
Usami M, Hara M, Kitamura T, Hamasaki T,
Nanto S, Kawahara Y, Komuro I. Circulating
p53-responsive microRNAs are predictive
indicators of heart failure after acute myocardial
infarction. Circ Res 113:322-326, 2013.
35. Hara H, Yamashita H, Nakayama A, Hosoya Y,
Ando J, Iijima K, Hirata Y, Komuro I. A rare caseof anomalous origin of the left anterior
descending artery from the pulmonary artery. Int
J Cardiol 172:e66-e68, 2013.
36. Ashigaki N, Suzuki J, Aoyama N, Ogawa M,
Watanabe R, Kobayashi N, Komuro I, Izumi Y,
Isobe
M.
The
periodontal
pathogenaggregatibacter actinomycetemcomitans affects
experimental autoimmune myocarditis in mice.
Int Heart J 54: 412-416, 2013.
37. Nakaoka Y, Higuchi K, Arita Y, Otsuki M,
Yamamoto K, Hashimoto-Kataoka T, Yasui T,
Ikeoka K, Ohtani T, Sakata Y, Shima Y,
Kumanogoh A, Yamauchi-Takihara K, Tanaka T,
Kishimoto T, Komuro I. Tocilizumab for thetreatment of patients with refractory takayasu
arteritis. Int Heart J 54: 405-411, 2013.
38. Kato N, Kinugawa K, Nakayama E, Tsuji T,

Kumagai Y, Imamura T, Maki H, Shiga T, Hatano
M, Yao A, Miura C, Komuro I, Nagai R.
Insufficient self-care is an independent risk factor
for adverse clinical outcomes in Japanese patientswith heart failure. Int Heart J 54:382-389, 2013.
39. Imamura T, Kinugawa K, Minatsuki S, Muraoka
H, Kato N, Inaba T, Maki H, Hatano M, Yao A,
Komuro I. Tolvaptan can improve clinical course
in responders. Int Heart J 54:377-381, 2013.
40. Murakami M, Suzuki J, Yamazaki S, Ikezoe M,
Matsushima R, Ashigaki N, Aoyama N,
Kobayashi N, Wakayama K, Akazawa H, Komuro
I, Izumi Y, Isobe M. High incidence ofAggregatibacter actinomycetemcomitans infection
in patients with cerebral infarction and diabetic
renal failure: a cross-sectional study. BMC Infect
Dis 13:557, 2013.
41. Higashikuni Y, Tanaka K, Kato M, Nureki O,
Hirata Y, Nagai R, Komuro I, Sata M. Toll-likereceptor-2 mediates adaptive cardiac hypertrophy
in response to pressure overload throughinterleukin-1β upregulation via nuclear factor κB
activation. J Am Heart Assoc 2:e000267, 2013.
42. Watanabe R, Azuma RW, Suzuki J, Ogawa M, Itai
A, Hirata Y, Komuro I, Isobe M. Inhibition of
NF-κB activation by a novel IKK inhibitor
reduces the severity of experimental autoimmune
myocarditis via suppression of T-cell activation.
Am J Physiol Heart Circ Physiol 305: 1761-1771,
2013.
43. Imamura T, Kinugawa K, Kato N, Kagami Y,
Endo M, Kaneko N, Minatsuki S, Muraoka H,
Inaba T, Maki H, Hatano M, Doi K, Yao A,
Takazawa Y, Ono M, Kyo S, Komuro I.
Successfultreatmentofhemodynamic
compromise caused by antibody-mediated andcellular rejection in a recipient 12 years after hearttransplantation. Int Heart J 54:328-331, 2013.
44. Takeda Y, Sakata Y, Ohtani T, Tamaki S, Omori Y,
Tsukamoto Y, Aizawa Y, Shimamura K,
Shirakawa Y, Kuratani T, Sawa Y, Yamamoto K,
Mano T, Komuro I. Endovascular Aortic Repair
Increases Vascular Stiffness and Alters Cardiac
Structure and Function. Circ J 78:322-328, 2013.

126

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., 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., Yousuke Amano, 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 45 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,
interstitial pneumonia, respiratory infections, COPD,
pneumothorax and asthma. Many patients withprimary lung cancer also have interstitial pneumonia
or COPD as their back ground pulmonary diseases.
There are many emergency visits and admissions withpneumonia, respiratory failure due to exacerbation of
COPD or interstitial pneumonia, 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

127

together to make best diagnostic and therapeutic
approach to individual patients. This conference has
been highly appreciated as prototype of Cancer Boardof the University of Tokyo Hospital, and, is now held
as Respiratory Cancer Board. This conference is still
one of the most frequently held Cancer Board in our
hospital. Our department contributes to the pre- andpost-surgical evaluation of respiratory functions, andalso receives consultation about respiratorycomplications from almost every department in our
hospital
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,
the new developments and their remarkableeffectiveness of molecular-targeted therapies inprimary lung cancer attract much attention in thefields of both basic science and clinical practice.
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. Among respiratory diseases,
there are several disorders to which no effective
therapeutic modalities are currently available. For
example, ARDS is an acute lung injury and themortality rate for ARDS is extremely high despite ofintensive care using currently available tools.
Idiopathic pulmonary fibrosis is a progressive and fatal
inflammatory and fibrotic disorder of the lungparenchyma, while only a few medications are currently
available to treat the disease. We would like to makeevery effort to develop a novel and potential therapeutic
approach to these diseases.
Number of in-patients in 2013
1. Primary lung cancer
2. Interstitial pneumonia
3. Respiratory infection
4. COPD
5. Pneumothorax
6. Asthma

308
43
42
17
11
9

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, clinical clerkship for the 5thyear medical students, and clinical lectures for the 5th
and 6th year medical students. Elective 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 clinical clerkship, each student,
as a member of medical care team, has opportunities
to experience the daily clinical care with junior andsenior residents as well as with the Faculty. Eachstudent can learn how to make a medical interview,
check physical findings and make the actual plans forthe diagnosis and treatment. The respiratory
specialists provide lecture on fundamental chest
radiology as one of essential elements in clinicalclerkship and this lecture is highly appreciated by thestudents.
Elective clerkship at the 5th year of the educational
program is actively performed to facilitate theexposure to a wide range of clinical practice both at
the University of Tokyo Hospital and at one of theaffiliated hospitals for a relatively long period (eachfor two weeks). Several lectures on the specialized
theme on respiratory diseases are also provided.

128

As for post-graduate education, respiratory physicians(one senior resident and one associate) assemble ateam with one junior resident, and provide medical
cares for patients with various respiratory diseases.
Under these processes, residents are able to acquire
the knowledge and skills required for diagnosis andtreatment of respiratory diseases. Seminars on
important themes such as medical treatment of lungcancer, diagnostic chest imaging, and so on are held at
regular interval.

tion, 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.

Research Activities

1.

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 andelucidation of their pathophysiological roles in
respiratory diseases.
Analysis of disease-models using geneticallyengineered mice.
Analysis of DNA methylation, histone modificationand miRNA in primary lung cancer and their clinicalapplications.
Search for previously unidentified oncogenic driver
mutations in lung cancer and elucidation of resistantmechanisms against molecular-targeted dugs.
Analysis of functional alterations of airway epithelial
cells and fibloblasts in relation to tissue repair andremodeling, especially epithelial-mesenchymal transi-

Takahide Nagase is GOLD National Leader.

References

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Amano Y, Takai D, Ohishi N, Shinozaki-Ushiku
A, Fukayama M, Akahane M, Nakajima J,
Nagase T. Successful Treatment of Mediastinal
Unicentric
Castleman's
DiseaseUsing
Video-Assisted Thoracoscopic Surgery with
Preoperative Embolization. Case Rep Med. 2013;
354507.
Hiraishi Y, Goto Y, Ohishi N, Nagase T.
Infectious mediastinal lymphadenopathy after
repeated transbronchial needle aspiration. BMJ
Case Rep. 2013; 29.
Hirota N, Martin JG. Mechanisms of airway
remodeling. Chest. 2013; 144:1026-32.
Kawakami M, Morita S, Sunohara M, Amano Y,
Ishikawa R, Watanabe K, Hamano E, Ohishi N,
Nakajima J, Yatomi Y, Nagase T, Fukayama M,
Takai D. FER overexpression is associated withpoor postoperative prognosis and cancer-cellsurvival in non-small cell lung cancer. Int J Clin
Exp Pathol. 2013; 6:598-612.
Kawakami M, Ishikawa R, Amano Y, Sunohara
M, Watanabe K, Ohishi N, Yatomi Y, Nakajima J,
Fukayama M, Nagase T, Takai D. Detection ofnovel paraja ring finger 2-fer tyrosine kinase
mRNA chimeras is associated with poor
postoperative prognosis in non-small cell lungcancer. Cancer Sci. 2013; 104:1447-54.
Morita S, Yoshida A, Goto A, Ota S, Tsuta K,
Yokozawa K, Asamura H, Nakajima J, Takai D,
Mori M, Oka T, Tamaru J, Itoyama S, Furuta K,
Fukayama M, Tsuda H. High-grade lungadenocarcinoma with fetal lung-like morphology:
clinicopathologic, immunohistochemical, andmolecular analyses of 17 cases. Am J Surg Pathol.
2013; 37:924-32.
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Okashiro S, Nakahari T, Nakano T, Matsumura H,
Shimamoto C, Moriwaki Y, Misawa H,
Yamashita N, Nagase T, Kawashima K,
Yamashita N. Effect of secreted lymphocyte
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receptor-related peptide-1 (SLURP-1) on airway
epithelial cells. Biochem Biophys Res Commun.
2013; 438:175-9.
Noguchi S, Hamano E, Matsushita I, Hijikata M,
Ito H, Nagase T, Keicho N. Differential effects ofa common splice site polymorphism on thegeneration of OAS1 variants in human bronchial
epithelial cells. Hum Immunol. 2013; 74:
395-401.
Noguchi S, Hijikata M, Hamano E, Matsushita I,
Ito H, Ohashi J, Nagase T, Keicho N. MxAtranscripts with distinct first exons andmodulation of gene expression levels bysingle-nucleotide polymorphisms in humanbronchial epithelial cells. Immunogenetics. 2013;
65:107-14.
Saito A. EMT and EndMT: regulated in similar
ways? J Biochem. 2013; 153:493-5.
Saito A, Suzuki HI, Horie M, Ohshima M,
Morishita Y, Abiko Y, Nagase T. An integrated
expression profiling reveals target genes of
TGF-β and TNF-α possibly mediated by
microRNAs in lung cancer cells. PLoS One.
2013; 8:e56587.
Sasaki T, Isayama H, Nakai Y, Takahara N, SatohY, Takai D, Kogure H, Yamamoto N, Hirano K,
Tada M, Yatomi Y, Koike K. A pilot study ofsalvage irinotecan monotherapy for advanced
biliary tract cancer. Anticancer Res. 2013;33:2619-22.
Siddiqui S, Novali M, Tsuchiya K, Hirota N,
Geller BJ, McGovern TK, Risse PA, Jo T,
Zeroual MA, Martin JG. The modulation of large
airway smooth muscle phenotype and effects of
epidermal growth factor receptor inhibition in therepeatedly allergen-challenged rat. Am J Physiol
Lung Cell Mol Physiol. 2013; 304:L853-62.
Takahara N, Nakai Y, Isayama H, Sasaki T, SatohY, Takai D, Hamada T, Uchino R, Mizuno S,
Miyabayashi K, Mohri D, Kawakubo K, Kogure
H, Yamamoto N, Sasahira N, Hirano K, Ijichi H,
Tada M, Yatomi Y, Koike K. Uridine diphosphate

glucuronosyl transferase 1 family polypeptide A1
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Cancer Chemother Pharmacol. 2013; 71:85-92.
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Takai D, Saito A, Ono M, Takamoto S.
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Disruption of theexpression and function of microRNAs in lungcancer as a result of epigenetic changes. Front
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130

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

Associate Professor
Hiroyuki Isayama, M.D., Ph.D.

Lecturer
Minoru Tada, M.D., Ph.D.
Keisuke Tateishi, M.D., Ph.D.

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

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

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

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

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

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

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

Yasuo Tanaka, M.D., Ph.D.

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

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

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

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

Hideataka Fujinaga, M.D., Ph.D.

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

Masashi Izumiya, M.D., Ph.D.

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

Hayato Nakagaw, M.D., Ph.D.

Hiroshi Kogure, 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, an associate professor, 2lecturers, 20 associates, 15 fellows, 55 graduates andother visiting researchers including students fromabroad. A number of others are under a temporarytransfer in- and outside the country. The North andSouth wings on the 11th floor of Ward A haveprovided 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 90 inpatients on average, which are about
3,000 in total per year. We receive about 110 new
patients in and out of the hospital each week, with an

131average hospital stay of 12.3 days. Resident, juniorand senior staff members bear the responsibility for a
medical management of each inpatient, in collaboration with subspecialty groups concerned. The staff
members examine about 5,500 outpatients withvarious digestive diseases in a month. Professor’s
ward round is performed on Monday and Wednesday
mornings. Specialty and subspecialty clinical conferences are held on Monday evening.
Hepatocellular carcinoma is the most common
disease in patients who are admitted to the department(〜 750 cases in 2013). Number of treatments forhepatocellular carcinoma treatments, represented by
percutaneous radiofrequency ablation, exceeded 450
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. In addition, we aremaking efforts to develop an innovation for dailyclinical activities. For example, fibrosis progression inchronic liver disease is conventionally assessed byliver biopsy. Recently we can evaluate the stage ofliver fibrosis by Fibroscan®, newly developed
equipment that measures liver stiffness by ultrasound,which is useful for the evaluation of increasing
non-alcoholic steatohepatitis patients.
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 (250 patients a year). Nonexposedendoscopic wall-inversion surgery (news) was
developed and started to perform in the clinics.

Double-balloon endoscopy and capsule endoscopy
have been introduced recently, which enabled theexamination of whole small intestines (330 cases in2013). All those interventions are performed by themembers of the department, specially trained for eachtechnique. In addition, for the management strategy
against inoperative malignancies, we effectively
combine the interventional treatments with various
chemotherapy regimens using new moleculartargeting 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 of

132them 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.

2.

Research Activities
Both basic and clinical researchers are equallyencouraged, on condition that the results may
eventually contribute to the cure of gastroenterological disorders. The themes of our recent basic
researches include molecular elucidation 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.

3.

4.

5.

6.

References7.

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8.

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133

Yamamoto K, Asaoka Y, Ikenoue T, Tateishi K,
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Sugawara Y, Akahane M, Shibahara J, Yoshida H,
Koike K. Uninodular combined hepatocellularand cholangiocarcinoma with multiple nonneoplastic hypervascular lesions appearing in theliver of a patient with HIV and HCV coinfection.
J Clin Virol. 2013;57(2):173-7
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N, Hamada T, Ito Y, Takahara N, Uchino R,
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Kogure H, Hamada T, Miyabayashi K, Mizuno S,
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Yoshida H, Ono T, Aizawa K, Suzuki T, Yamazaki
T, Yatomi Y. Inverse correlations between serum
ADAMTS13 levels and systolic blood pressure,pulse pressure, and serum C-reactive protein
levels observed at a general health examination ina Japanese population: a cross-sectional study.
Clin Chim Acta. 2013 Jun 5;421:147-51.
13. Tateishi R, Shiina S, Akahane M, Sato J, Kondo Y,
Masuzaki R, Nakagawa H, Asaoka Y, Goto T,
Otomo K, Omata M, Yoshida H, Koike K.
Frequency, risk factors and survival associatedwith an intrasubsegmental recurrence after radiofrequency ablation for hepatocellular carcinoma.
PLoS One. 2013;8(4):e59040
14. Kinoshita H, Hirata Y, Nakagawa H, Sakamoto K,
Hayakawa Y, Takahashi R, Nakata W, Sakitani K,
Serizawa T, Hikiba Y, Akanuma M, Shibata W,
Maeda S, Koike K. Interleukin-6 mediates

epithelial-stromal interactions and promotes
gastric tumorigenesis. PLoS One. 2013 Apr 12;8(4):e60914.
15. Niikura R, Nagata N, Shimbo T, Akiyama J,
Uemura N. Colonoscopy can miss diverticula ofthe left colon identified by barium enema. World J
Gastroenterol. 2013 Apr 21;19(15):2362-7.
16. Sato M, Kato N, Tateishi R, Muroyama R,
Kowatari N, Li W, Goto K, Otsuka M, Shiina S,
Yoshida H, Omata M, Koike K IL28B minor
allele is associated with a younger age of onset of
hepatocellular carcinoma in patients with chronic
hepatitis C virus infection. J Gastroenterol 2013
17. Nakai Y, Isayama H, Ijichi H, Sasaki T, Takahara
N, Ito Y, Matsubara S, Uchino R, Yagioka H,
Arizumi T, Hamada T, Miyabayashi K, Mizuno S,
Yamamoto K, Kogure H, Yamamoto N, Hirano K,
Sasahira N, Tateishi K, Tada M, Koike K. A
multicenter phase II trial of gemcitabine andcandesartan combination therapy in patients withadvanced pancreatic cancer: GECA2. Invest New
Drugs. 2013 Oct;31(5):1294-9.
18. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Matsuda S, Fushimi K, Koike K.
Rarity of severe bleeding and perforation inendoscopic ultrasound-guided fine needle
aspiration for submucosal tumors. Dig Dis Sci.
2013 Sep;58(9):2634-8.
19. Yamamoto S, Tateishi K, Kudo Y, Yamamoto K,
Isagawa T, Nagae G, Nakatsuka T, Asaoka Y,
Ijichi H, Hirata Y, Otsuka M, Ikenoue T,
Aburatani H, Omata M, Koike K. Histone
demethylase KDM4C regulates sphere formation
by mediating the cross talk between Wnt andNotch pathways in colonic cancer cells.
Carcinogenesis. 2013 Oct;34(10):2380-8.
20. Mizuno S, Nakai Y, Isayama H, 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, Tada M, Koike K. Diabetes is a usefuldiagnostic clue to improve the prognosis ofpancreatic cancer. Pancreatology. 2013 May-Jun;
13(3):285-9.
21. Niikura R, Nagata N, Yamano K, Shimbo T,
Uemura N. High-dose barium impaction therapy
is useful for the initial hemostasis and for134

preventing the recurrence of colonic diverticular
bleeding unresponsive to endoscopic clipping.
Case Rep Gastrointest Med. 2013;2013:365954
22. Sato M, Tateishi R, Yasunaga H, Horiguchi H,
Yoshida H, Matsuda S, Fushimi K, Koike K Acuteliver disease in Japan: a nationwide analysis of theJapanese Diagnosis Procedure Combination
database. J Gastroenterol 2013 Jun 20.
23. Yamada A, Watabe H, Oka S, Kogure H, Imagawa
H, Kobayashi Y, Suzuki H, Watari I, Aoyama T,
Isayama H, Yamaji Y, Fujishiro M, Tanaka S,
Koike K. Feasibility of spiral enteroscopy inJapanese patients: study in two tertiary hospitals.
Dig Endosc. 2013 Jul;25(4):406-11.
24. Yamada A, Watabe H, Takano N, Togo G, Yamaji
Y, Yoshida H, Kawabe T, Omata M, Koike K.
Utility of single and double balloon endoscopy inpatients with difficult colonoscopy: a randomized
controlled trial. World J Gastroenterol. 2013 Aug
7;19(29):4732-6.
25. Takahara N, Isayama H, Nakai Y, Sasaki T,
Hamada T, Uchino R, Mizuno S, Miyabayashi K,
Kogure H, Yamamoto N, Sasahira N, Hirano K,
Ijichi H, Tateishi K, Tada M, Koike K. A
retrospective study of S-1 and oxaliplatin
combination chemotherapy in patients withrefractory pancreatic cancer. Cancer ChemotherPharmacol. 2013 Nov;72(5):985-90.
26. Sasaki T, Isayama H, Nakai Y, Takahara N,
Akiyama D, Yagioka H, Kogure H, Matsubara S,
Ito Y, Yamamoto N, Sasahira N, Hirano K, Toda N,
Tada M, Koike K. A retrospective study of
gemcitabine and cisplatin combination therapy as
second-line treatment for advanced biliary tract
cancer. Chemotherapy. 2013;59(2):106-11.
27. Sasahira N, Isayama H, Tokyokawa Y, Mizuno S,
Hirano K, Nakai Y, Sase R, Kogure H, Sasaki T,
Yamamoto N, Tada M, Koike K. A novel basket
catheter to facilitate endoscopic removal ofpancreatic stones (with video). Gastrointest
Endosc. 2013 Dec;78(6):925-9.
28. Hayakawa Y, Hirata Y, Kinoshita H, Sakitani K,
Nakagawa H, Nakata W, Takahashi R, Sakamoto
K, Maeda S, Koike K Differential roles of ASK1
and TAK1 in Helicobacter pylori-induced cellularresponses. Infect Immun. 2013 Dec;81(12):4551-60.

29. Fujiwara N, Tateishi R, Akahane M, Taguri M,
Minami T, Mikami S, Sato M, Uchino K, Enooku
K, Kondo Y, Asaoka Y, Yamashiki N, Goto T,
Shiina S, Yoshida H, Ohtomo K, Koike K.
Changes in risk of immediate adverse reactions toiodinated
contrastmedia
byrepeatedadministrations in patients with hepatocellular
carcinoma. PLoS One. 2013;8(10):e76018
30. He G, Dhar D, Nakagawa H, Font-Burgada J,
Ogata H, Jiang Y, Shalapour S, Seki E, Yost SE,
Jepsen K, Frazer KA, Harismendy O,
Hatziapostolou M, Iliopoulos D, Suetsugu A,
Hoffman RM, Tateishi R, Koike K, Karin M.
Identification of liver cancer progenitors whose
malignant progression depends on autocrine IL-6
signaling. Cell. 2013;155(2):384-96
31. Sato M, Kato N, Tateishi R, Muroyama R,
Kowatari N, Li W, Goto K, Otsuka M, Shiina S,
Yoshida H, Omata M, Koike K. The impact of
PNPLA3 polymorphisms on the development of
hepatocellular carcinoma in patients with chronic
hepatitis C virus Infection. Hepatol Res 2013
32. Inoue Y, Tomiya T, Nishikawa T, Ohtomo N,
Tanoue Y, Ikeda H, Koike K. Induction of
p53-dependent p21 limits proliferative activity of
rat hepatocytes in the presence of hepatocyte
growth factor. PLoS One, 2013; 8: e78346
33. Tsujino T, Isayama H, Nakai Y, Ito Y, Togawa O,
Toda N, Arizumi T, Kogure H, Yamamoto K,
Mizuno S, Yashima Y, Yagioka H, Sasaki T,
Matsubara S, Yamamoto N, Hirano K, Sasahira N,
Tada M, Koike K. The results of the Tokyo trial of
prevention of post-ERCP pancreatitis withrisperidone (Tokyo P3R): a multicenter,randomized, phase II, non-placebo-controlled trial.
J Gastroenterol. 2013 Aug;48(8):982-8.
34. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Fushimi K, Koike K. Japaneseseverity score for acute pancreatitis well predicts
in-hospital mortality: a nationwide survey of
17,901 cases. J Gastroenterol. 2013 Dec;48(12):1384-91.
35. Sasaki T, Isayama H, Nakai Y, Takahara N, SatohY, Takai D, Kogure H, Yamamoto N, Hirano K,
Tada M, Yatomi Y, Koike K. A pilot study ofsalvage irinotecan monotherapy for advanced
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36. Uchino R, Isayama H, Tsujino T, Sasahira N, Ito Y,
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Nakajima K, Akiyama D, Hamada T, Miyabayashi
K, Mizuno S, Kawakubo K, Kogure H, Sasaki T,
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Internal Medicine
2. Medicine Ⅱ137

Department of Nephrology and
Endocrinology
Professor
Masaomi Nangaku, M.D., Ph.D.

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

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

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

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

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

Hospital Lecturer
Takehiko Wada, M.D., Ph.D.

Associate
Katsutoshi Takahashi, M.D.

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

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

Megumi Fujita, M.D., Ph.D.,

Hideki Kato, M.D., Ph.D.,

Takahisa Kawakami, M.D., Ph.D.,

Nobuaki Ito, M.D., Ph.D.,

Motonobu Nakamura, M.D., Ph.D.,

Katsunori Manaka, M.D., Ph.D.,

Kenjiro Honda, M.D., Ph.D.,

Yoshifumi Hamasaki, M.D., Ph.D.

Homepage

http://www.todai-jinnai.com

Introduction and Organization
The Department 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 professors,
and the lecturers.

Clinical activities
The residents are in charge of up to 30 patients ofour department and supervised by associates andfaculty staffs. We have clinical conferences to discuss
the diagnosis 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 department, renal
biopsy is actively performed to give the real benefits

138of treatment to the patients. We also treat diabetic
patients with proteinuria and end-stage renal failure.
Each staff of our department also works at the
hemodialysis unit, thus we can manage patients inevery stage of renal diseases. 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 departments concerning disorders of water and mineral metabolism.

Education
We have responsibility for educating undergraduates, graduate students and residents. Our staffs
take part in several lectures for undergraduate andgraduate students. In addition, our members areactively involved in clinical clerkship forundergraduate 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 thewards, we are also educating residents during dailyclinical works and periodical lectures concerningkidney and endocrine diseases. Our department also
participates in Metabolism Research Course foreducating young clinical researchers and fellows incollaboration with Department of Diabetes andMetabolic Diseases, Department of Cardiology, andDepartment of Geriatric Medicine.

Research
In our department there are more than 30 studentsof the graduate school. We have research conferences
to discuss the results of the research with theProfessor and faculty members. As you see in thereferences below, our research topics are various andcover every field of nephrology, hypertension andendocrinology. We are also actively collaborating with
scientists outside the department and outside theUniversity including foreign countries. Achievementsof our researches are published in the world’s leading
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

139

quality of staff members.
2.
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]. “Apheresis Pocket Manual” hasbeen translated into Chinese and English, andthose translated versions have helped a number of
non-Japanese-speaking people to learn how to
perform apheresis.
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 transplant

3.
4.

5.
6.
7.
8.
9.

patients who 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.
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 their clinical significance in
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) Hamasaki Y, Doi K, Maeda-Mamiya R,
Ogasawara E, Katagiri D, Tanaka T, Yamamoto T,
Sugaya T, Nangaku M, Noiri E. A
5-hydroxytryptamine
receptor
antagonist,
sarpogrelate, reduces renal tubulointerstitial
fibrosis by suppressing PAI-1. Am J Physiol
Renal Physiol. 2013 Dec;305(12):F1796-803.
(2) Katagiri D, Hamasaki Y, Doi K, Okamoto K,
Negishi K, Nangaku M, Noiri E. Protection of
glucagon-like peptide-1 in cisplatin-induced
renal injury elucidates gut-kidney connection. J
Am Soc Nephrol. 2013 Dec;24(12):2034-43.
(3) Isshiki M, Nishimoto M, Mizuno R, Fujita T.
FRET-based sensor analysis reveals caveolae arespatially distinct Ca2+ stores in endothelial cells.
Cell Calcium. 2013 Dec;54(6):395-403.
(4) Kawarazaki
W,
FujitaT.
Aberrant
Rac1-mineralocorticoid receptor pathways insalt-sensitive hypertension. Clin Exp Pharmacol
Physiol. 2013 Dec;40(12):929-36.
(5) Doi K, Urata M, Katagiri D, Inamori M, Murata
S, Hisagi M, Ono M, Matsubara T, Ishii T,
Yahagi N, Nangaku M, Noiri E. Plasma
neutrophil gelatinase-associated lipocalin in140

acute kidney injury superimposed on chronic
kidney disease after cardiac surgery: amulticenter prospective study. Crit Care. 2013
Nov;17(6):R270(6) Inoue T, Nangaku M, Hinoshita F. Tuberculous
lymphadenitis in a dialysis patient diagnosed by
18-fluorodeoxyglucose
positronemission
tomography and IFN-γ release assay. Am J
Kidney Dis. 2013 Dec;62(6):1221.
(7) Inoue T, Nangaku M, Yamada K. Vitamin A
treatment for psoriasis vulgaris in a dialysis
patient. Am J Kidney Dis. 2013 Nov;62(5):1020-1.
(8) Oba S, Mizutani T, Suzuki E, Nishimatsu H,
Takahashi M, Ogawa Y, Kimura K, Hirata Y,
Fujita T. A useful method of identifying of
miRNAs which can down-regulate Zeb-2. BMC
Res Notes. 2013 Nov 18;6:470.
(9) Mimura I, Tanaka T, Nangaku M. Noveltherapeutic strategy with hypoxia-inducible
factors via reversible epigenetic regulation
mechanisms in progressive tubulointerstitial
fibrosis. Semin Nephrol. 2013 Jul;33(4):375-82.
(10) Mimura I, Kanki Y, Kodama T, Nangaku M.
Revolution of nephrology research by deep
sequencing: ChIP-seq and RNA-seq. Kidney Int.
2014 Jan;85(1):31-8.
(11) Nangaku M. Energy policy of the kidney: launchof AMPK as a novel therapeutic target. Am J
Physiol Renal Physiol. 2013 Oct 1;305(7):F977-8.
(12) 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-bloodtype
incompatible
livingrelatedrenaltransplantation. Transfus Apher Sci. 2013 Oct;49(2):254-8.
(13) Tanaka T, Yamaguchi J, Higashijima Y, Nangaku
M. Indoxyl sulfate signals for rapid mRNAstabilization of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal
domain 2 (CITED2) and suppresses theexpression of hypoxia-inducible genes inexperimental CKD and uremia. FASEB J. 2013
Oct;27(10):4059-75.

(14) Higashijima Y, Tanaka T, Nangaku M. Structurebased drug design for hypoxia-inducible factor
prolyl-hydroxylase inhibitors and its therapeuticpotential for the treatment of erythropoiesisstimulating agent-resistant anemia: raising
expectations for exploratory clinical trials. Expert
Opin Drug Discov. 2013 Aug;8(8):965-76.
(15) Wada T, Nangaku M. Novel roles of complement
in renal diseases and their therapeutic
consequences. Kidney Int. 2013 Sep;84(3):441-50.
(16) Shoji K, Murayama T, Mimura I, Wada T, Kume
H, Goto A, Ohse T, Tanaka T, Inagi R, van der
Hoorn FA, Manabe I, Homma Y, Fukayama M,
Sakurai T, Hasegawa T, Aburatani H, Kodama T,
Nangaku M. Sperm-associated antigen 4, a novel
hypoxia-inducible factor 1 target, regulates
cytokinesis, and its expression correlates with theprognosis of renal cell carcinoma. Am J Pathol.
2013 Jun;182(6):2191-203.
(17) Hanafusa N, Noiri E, Nangaku M. Differences in
reduction of coagulation factor XIII (F13)
between immunoadsorption plasmapheresis anddouble filtration plasmapheresis. Ther Apher Dial.
2013 Apr;17(2):241-2.
(18) Tanaka T, Nangaku M. Angiogenesis and hypoxia
in the kidney. Nat Rev Nephrol. 2013 Apr;9(4):211-22.
(19) Chiang CK, Nangaku M, Tanaka T, Iwawaki T,
Inagi R. Endoplasmic reticulum stress signal
impairs erythropoietin production: a role for
ATF4. Am J Physiol Cell Physiol. 2013 Feb 15;
304(4):C342-53.
(20) Nishi H, Shibagaki Y, Kido R, Tamura S,
Nangaku M, Sugawara Y, Fujita T. Chronic renal
outcome after living donor liver transplantation.
Clin Transplant. 2013 Jan-Feb;27(1):90-7.
(21) Horita S, Seki G, Yamada H, Suzuki M, Koike K,
Fujita T. Roles of renal proximal tubule transport
in the pathogenesis of hypertension. Curr
Hypertens Rev. 2013 May;9(2):148-55.
(22) 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: thestudy of assessment for kidney function by

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urinary microalbumin in randomized (SAKURA)
trial. Int J Med Sci. 2013 Jul 30;10(9):1209-16.
(23) Hayashi M, Tojo A, Shimosawa T, Fujita T. The
role of adrenomedullin in the renal NADPH
oxidase and (pro)renin in diabetic mice. J
Diabetes Res. 2013;2013:134395.
(24) Tanaka K, Hirohama D, Shirota M, Uetake Y,
Taguchi M, Takano K, Fukumoto S, Fujita T.
[Case report ; a case of Bardet-Biedl syndrome
with a pituitary tumor and growth hormone
deficiency]. Nihon Naika Gakkai Zasshi. 2013
Mar;102(3):704-7.
(25) Fujita M, Fujita T. The role of CNS in
salt-sensitive hypertension. Curr Hypertens Rep.
2013 Aug;15(4):390-4.
(26) Ogura S, Shimosawa T, Mu S, Sonobe T,
Kawakami-Mori F, Wang H, Uetake Y, Yoshida K,
Yatomi Y, Shirai M, Fujita T. Oxidative stressaugments pulmonary hypertension in chronically
hypoxic mice overexpressing the oxidized LDL
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Jul;305(2):H155-62.
(27) Hanamura K, Tojo A, Fujita T. Urinary andglomerular podocytes in patients with chronic
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(28) Nagase M, Fujita T. Role of Rac1mineralocorticoid-receptor signalling in renal andcardiac disease. Nat Rev Nephrol. 2013 Feb;9(2):86-98.

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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.,

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

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

Satoru Takase, M.D., Ph.D.,

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

URL http://dm.umin.jp/
Introduction and Organization
In 1998 the Department of Internal Medicine at the
University of Tokyo was reorganized to the morefunctional units based on clinical specialties. The
physicians specialized in diabetes and metabolic
diseases from 3 former departments of Internal
Medicine were unified to the Department of Metabolic
Diseases. The Department of Diabetes and Metabolic
Diseases is one of the major divisions in the
Department of Internal Medicine at the University ofTokyo, and covers diabetes mellitus and metabolic
diseases including obesity and dyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003) and Dr.
Toshiro Fujita (2003) and current professor Dr.
Takashi Kadowaki (2003-present), we have been

providing a wide-ranged clinical, teaching andresearch activities. 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 28 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 500 new inpatients per year. 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
Initiative (Project Associate Professor, Dr. Naoto
Kubota and Project Assistant Professor, Dr. Takayoshi

143

Sasako), Functional Regulation of Adipocytes (Project
Associate Professor, Dr. Hironori Waki and Project
Assistant Professor, Dr. Iseki Takamoto), Molecular
Medicinal Sciences on Metabolic Regulation (Project
Associate Professor, Dr. Hiroaki Okazaki and Project
Assistant Professor, Dr. Miki Okada-Iwabu), Divisionof Biophysics, Center for Disease Biology andIntegrative Medicine (Lecturer, Dr. Noriko Takahashi),Ubiquitous Health Informatics (Project AssistantProfessor, Dr. Kayo Waki), Clinical Epidemiology and
Systems (Project Assistant Professor, Dr. Mikio
Takanashi), and Division for Health Service
Promotion, The University of Tokyo (AssistantProfessor, Dr. Midori Kubota). With all these staffs,
we actively instruct and teach the residents andmedical school students; annual evaluation of theteaching skill by the students always rates ourdepartment within the three places of the top. In
addition, there are more than 20 students of Graduate
School in our division. With all these 66 members, we
enthusiastically work on the research activities, whichlead to the outstanding contributions in the field of
metabolism.

Clinical activities
Based on the update clinical evidences and with theexperienced skills, we provide patient-centered
medical services in the highest quality. We haveoutpatient clinics from Monday through Friday, andhave been following more than 180 patients per day(total 44,928 patients per year). On the inpatient ward,
we not only take care of around 30 patients in ourdivision as mentioned above, but also provide a
sophisticated management to all patients sufferingfrom metabolic diseases, especially diabetes mellitus.
Diabetes mellitus, metabolic syndrome, dyslipidemia
and obesity are becoming more prevalent in Japan,
and lead to complications including nephropathy,
retinopathy, neuropathy and cardiovascular diseases.
Thus, in collaboration with other departments, we
optimize the treatment of each patient.
We provide the educational classes to the patients
every day in the inpatient ward, and also give lectures
twice a week in the outpatient unit. In addition, in
collaboration with ancillary staffs of our hospital, we
provide patients well-reasoned instructions regarding

nutritional management, excise therapy and medical
therapy.
The weekly official activities of our department
consist of the pre-round case conference and the Ward
Round by the Professor on Monday. We also hold aweekly case conference by the consultation group
staffs.

Teaching activities
As for medical student education, our department
takes a part in systemic lectures for the 4th year
medical students, bed-side learning and clinicalclerkship for the 5th year medical students, andclinical lectures for the 6th year medical students.
In systemic lectures, comprehensive presentation for
the understanding of basic knowledge about theconcept, pathogenesis, diagnosis and treatment ofcommon metabolic diseases is performed.
In clinical lectures, we present clinical cases ofimportant diseases such as diabetes mellitus, and try
to discuss with the students several points forplanning the diagnosis and treatment in collaboration
with the faculties of the Departments of Nephrology,
Cardiology, and Ophthalmology.
During the period of bed-side learning, the students
have opportunities to experience the daily clinical carewith junior and senior residents as well as with theFaculty members. Each student can learn how to dohistory taking, perform physical examinations andmake the actual plans for the diagnosis and treatment.
Lectures that lead to profound understandings of themetabolic diseases are regularly provided by the staff
physicians.
In clinical clerkship, we arrange the program so thatthe students can experience the clinical practice andlearn the disease itself more profoundly. One faculty
and one senior-resident always instruct one student.
As for the post-graduate education, attending doctor(staff) and senior resident instruct the junior residents.
We provide advanced teaching through the seminars
and grand conference.

Research activities
There are several laboratories in our departments;
collaborating with each other or with other144

departments, we focus on the molecular mechanismsof the metabolic diseases and the establishment of thenovel therapeutics.
1) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, we are
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 andinter-tissue communication of glucose metabolism inobesity and type 2 diabetes. We believe that thesefindings will lead to novel therapeutic strategies fordiabetes 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.
3) Clinical trials and epidemiological studies
We are vigorously conducting clinical trials andepidemiological studies including “Japan Diabetes
Optimal Integrated Treatment study for 3 major risk
factors of cardiovascular diseases (J-DOIT3)”,“Longitudinal/cross-sectional studies to generate
evidence for diagnosis/management of metabolic
syndrome in governmental health checkup andguidance system (MHLW’s research project)”,
systematic reviews and meta-analyses with a focus on
important issues, and investigator initiated clinical
trials targeting for a new class of anti-diabetic agents.

References
1. Tajima N, Kadowaki T, Okamoto T, Sato A,
Okuyama K, Minamide T, Arjona Ferreira JC.
Sitagliptin added to voglibose monotherapy
improves glycemic control in patients with type 2
diabetes. J Diabetes Investig. 2013;4(6):595604.
2. Kadowaki T, Kondo K. Efficacy and safety ofteneligliptin in combination with pioglitazone inJapanese patients with type 2 diabetes mellitus.
J Diabetes Investig. 2013;4(6):576-84.
3. Kadowaki T, Tajima N, Odawara M, Nishii M,
Taniguchi T, Ferreira JC. Addition of sitagliptin toongoing metformin monotherapy improves
glycemic control in Japanese patients with type 2
diabetes over 52 weeks. J Diabetes Investig.
2013;4(2):174-81.
4. Imamura M, Iwata M, Maegawa H, Watada H,
Hirose H, Tanaka Y, Tobe K, Kaku K, Kashiwagi
A, Kadowaki T, Kawamori R, Maeda S.
Replication study for the association of rs391300
in SRR and rs17584499 in PTPRD with susceptibility to type 2 diabetes in a Japanese population.
J Diabetes Investig. 2013;4(2):168-73.
5. Kabeya Y, Goto A, Kato M, Takahashi Y,
Matsushita Y, Inoue M, Mizoue T, Tsugane S,
Kadowaki T, Noda M. History of having amacrosomic infant and the risk of diabetes: theJapan public health center-based prospective
diabetes study. PLoS One. 2013;8(12):e84542.
6. Nishimura S, Manabe I, Takaki S, Nagasaki M,
Otsu M, Yamashita H, Sugita J, Yoshimura K, Eto
K, Komuro I, Kadowaki T, Nagai R. Adipose
Natural Regulatory B Cells Negatively Control
Adipose Tissue Inflammation. Cell Metab. 2013:

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7. Kadowaki T. Ensuring success for J-NIH.
Science. 2013;342(6159):670.
8. Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T,
Hamagami K, Matsuda K, Yamaguchi M, Tanabe
H, Kimura-Someya T, Shirouzu M, Ogata H,
Tokuyama K, Ueki K, Nagano T, Tanaka A,
Yokoyama S, Kadowaki T. A small-molecule
AdipoR agonist for type 2 diabetes and short lifein obesity. Nature. 2013;503(7477):493-9.
9. Mori T, Nagase T, Takehara K, Oe M, Ohashi Y,
Amemiya A, Noguchi H, Ueki K, Kadowaki T,
Sanada H. Morphological pattern classification
system for plantar thermography of patients withdiabetes. J Diabetes Sci Technol. 2013;7(5):1102-12.
10. Wang J, Zhou Y, Koizumi N, Kubota N, Asano T,
Yuhashi K, Mitake T, Itani K, Takahashi T,
Takeishi S, Sasaki S, Kadowaki T, Sakuma I, Liao
H.
Automatic distance measurement of
abdominal aorta for ultrasonography-based
visceral fat estimation. Conf Proc IEEE Eng
Med Biol Soc. 2013;2013:6486-9.
11. Amemiya A, Noguchi H, Oe M, Takehara K,
Yamada A, Ohashi Y, Ueki K, Kadowaki T, Mori
T, Sanada H. Relationship between elevatedplantar pressure of toes and forefoot and gaitfeatures in diabetic patients. Conf Proc IEEEEng Med Biol Soc. 2013;2013:4633-6.
12. Yamada T, Hara K, Kadowaki T. Comment on:
Lin et al. Long-term changes in adiposity andglycemic control are associated with pastadenovirus infection. Diabetes Care 2013;36:
701-707. Diabetes Care. 2013;36(9):e161.
13. Yamada T, Hara K, Kadowaki T. Chewing betel
quid and the risk of metabolic disease,cardiovascular disease, and all-cause mortality: ameta-analysis. PLoS One. 2013;8(8):e70679.
14. Izumida Y, Yahagi N, Takeuchi Y, Nishi M,
Shikama A, Takarada A, Masuda Y, Kubota M,
Matsuzaka T, Nakagawa Y, Iizuka Y, Itaka K,
Kataoka K, Shioda S, Niijima A, Yamada T,
Katagiri H, Nagai R, Yamada N, Kadowaki T,
Shimano H. Glycogen shortage during fasting
triggers liver-brain-adipose neurocircuitry tofacilitate fat utilization. Nat Commun. 2013;4:2316.

15. Iwasaki Y, Shimomura K, Kohno D, Dezaki K,
Ayush EA, Nakabayashi H, Kubota N, Kadowaki
T, Kakei M, Nakata M, Yada T.
Insulin
Activates Vagal Afferent Neurons Including those
Innervating Pancreas via Insulin Cascade andCa(2+) Influx: Its Dysfunction in IRS2-KO Micewith Hyperphagic Obesity. PLoS One. 20136;
8(6):e67198.
16. Shirakawa J, Togashi Y, Sakamoto E, Kaji M,
Tajima K, Orime K, Inoue H, Kubota N,
Kadowaki T, Terauchi Y. Glucokinase activation
ameliorates ER stress-induced apoptosis inpancreatic
β-cells.
Diabetes. 2013;62(10):3448-58.
17. Nakaya K, Kubota N, Takamoto I, Kubota T,
Katsuyama H, Sato H, Tokuyama K, Hashimoto S,
Goto M, Jomori T, Ueki K, Kadowaki T.
Dipeptidyl peptidase-4 inhibitor anagliptin
ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet.
Metabolism. 2013;62(7):939-51.
18. 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. 2013;288(28):20692-701.
19. 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 isabundantly expressed in foam cells and is
involvedinatherosclerosis
development.
Arterioscler Thromb Vasc Biol. 2013;33(8):1986-93.
20. Iwashita M, Nakatsu Y, Sakoda H, Fujishiro M,
Kushiyama A, Fukushima T, Kumamoto S, Shinjo
T, Kamata H, Nishimura F, Asano T. Valsartan
restores inflammatory response by macrophagesin adipose and hepatic tissues of LPS-infused
mice. Adipocyte. 2013;2(1):28-32.

146

21. Kurano M, Tsukamoto K, Ohkawa R, Hara M,
Iino J, Kageyama Y, Ikeda H, Yatomi Y. Liverinvolvementin
sphingosine
1-phosphate
dynamism revealed by adenoviral hepatic overexpression of apolipoprotein M. Atherosclerosis.
2013;229(1):102-9.
22. Dohi T, Miyauchi K, Ohkawa R, Nakamura K,
Kurano M, Kishimoto T, Yanagisawa N, Ogita M,
Miyazaki T, Nishino A, Yaginuma K, Tamura H,
Kojima T, Yokoyama K, Kurata T, Shimada K,
Daida H, Yatomi Y. Increased lysophosphatidic
acid levels in culprit coronary arteries of patientswith acute coronary syndrome. Atherosclerosis.
2013;229(1):192-7.
23. Kubota T, Kubota N, Kadowaki T. The role ofendothelial insulin signaling in the regulation of
glucose metabolism. Rev Endocr Metab Disord.
2013 ;14(2):207-16.
24. Yamada T, Hara K, Umematsu H, Kadowaki T.
Male pattern baldness and its association withcoronary heart disease: a meta-analysis. BMJ
Open. 2013;3(4). doi:pii: e002537.
25. Otani Y, Nakatsu Y, Sakoda H, Fukushima T,
Fujishiro M, Kushiyama A, Okubo H, Tsuchiya Y,
Ohno H, Takahashi S, Nishimura F, Kamata H,
Katagiri H, Asano T. Integrator complex plays anessential role in adipose differentiation. Biochem
Biophys Res Commun. 2013 ;434(2):197-202.
26. Enooku K, Kato R, Ikeda H, Kurano M, Kume Y,
Yoshida H, Ono T, Aizawa K, Suzuki T, Yamazaki
T, Yatomi Y. Inverse correlations between serum
ADAMTS13 levels and systolic blood pressure,pulse pressure, and serum C-reactive protein
levels observed at a general health examination ina Japanese population: a cross-sectional study.
Clin Chim Acta. 2013;421:147-51.
27. Nabeno M, Akahoshi F, Kishida H, Miyaguchi I,
Tanaka Y, Ishii S, Kadowaki T.
A comparative
study of the binding modes of recently launcheddipeptidyl peptidase IV inhibitors in the activesite. Biochem Biophys Res Commun. 2013;
434(2):191-6.
28. Takase S, Osuga J, 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 rarevariant in the APOC2 gene. J Atheroscler
Thromb. 2013;20(5):481-93.
29. Ono Y, Kurano M, Ohkawa R, Yokota H, Igarashi
K, Aoki J, Tozuka M, Yatomi Y. Sphingosine
1-phosphate release from platelets during clot
formation: close correlation between platelet
count and serum sphingosine 1-phosphateconcentration. Lipids Health Dis. 2013;12:20.
30. Yamauchi T, Kadowaki T. Adiponectin receptor asa key player in healthy longevity and obesityrelated diseases. Cell Metab. 2013 ;17(2):185-96.
31. 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, Ng DP, 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 to type 2
diabetes susceptibility in Sikhs of Punjabi origin
from India. Diabetes. 2013;62(5):1746-55.
32. Matsumoto T, Nagase Y, Hirose J, Tokuyama N,
Yasui T, Kadono Y, Ueki K, Kadowaki T,
Nakamura K, Tanaka S. Regulation of bone
resorption and sealing zone formation in
osteoclasts occurs through protein kinase
B-mediated microtubule stabilization. J Bone
Miner Res. 2013 ;28(5):1191-202.
33. Waki K, Sugawara Y, Mizuta K, Taniguchi M,
Ozawa M, Hirata M, Nozawa M, Kaneko J,
Takahashi K, Kadowaki T, Terasaki PI, Kokudo N.
Predicting operational tolerance in pediatricliving-donor liver transplantation by absence of
HLA antibodies. Transplantation. 2013;95(1):177-83.
34. 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.

147

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

Lecturer
Yasuhito Nannya, M.D., Ph.D.

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

Special Lecturer (Hospital)
Fumihiko Nakamura, M.D., Ph.D.

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

Assistant Professor
Kumi Nakazaki, M.D., Ph.D.,

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

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

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

Hiroki Asano, M.D., Ph.D.,

Yuki Kagoya, M.D., Ph.D.

Homepage

http://www.u-tokyo-hemat.com/

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, andeducation of undergraduate as well as graduate
students. We are also engaged in continuous educationof post-graduate doctors who develop into
sophisticated hematologists of eminent distinction.
These activities are performed by the united efforts ofall 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. That is, three
doctors (a junior resident, a senior resident, and an
assistant professor) are assigned to one patient. Since
clinical issues are highly related to hematopoietic stem
cell transplantation especially for patients withhematological diseases, a substantial portion of ourclinical conferences are shared with staff members ofDepartment of Cell Therapy and Transplantation
Medicine and Department of Pediatrics (Hematology/
Oncology). A number of clinical problems involved in
the patient management are discussed in the morning
clinical conference held thrice a week. Diagnostic andtherapeutic issues as well as pathological aspects ofthought-provoking cases are also discussed twice permonth in clinical conferences, 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 60-65 patients visit our
outpatient clinic every weekday. One of our final

148

goals in the clinical activities is to cure all patientswith hematological malignancies.
We perform various kinds of genetic or molecularanalyses to detect, characterize, and monitor
malignant cells and make use of them for diagnosis
and planning of treatments.
Here are some technical aspects on the treatment
strategy:
1. High-dose chemotherapy with or without
autologous stem cell support: Adequate high-dose
chemotherapy is administered for the treatment ofmalignant disease. For the autologous stem cell
support, peripheral blood stem cell is usually
selected as a source of stem cells.
2. Allogeneic hematopoietic stem cell transplantation: Bone marrow cells are operatively
harvested and infused without preservation. For
peripheral blood stem cell transplantation,
leukapheresis is performed with the use of an
automated continuous flow blood cell separator,and harvested cells are preserved in cooperation
with Department of Transfusion Medicine.
Recently, transplantation conditioned with reduced
intensity regimen (RIST, reduced-intensity stem
cell transplantation) is commonly performed forthe elderly patients and patients with organ
impairment. The development of this strategy
expands the eligibility of transplant recipients.
Allogeneic hematopoietic stem cell transplantation
for the elderly are performed under the admissionof ethical committee of the Faculty of Medicine.
Cord blood cells are also used as the sources ofhematopoietic 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 physicalexamination, interpretation of laboratory tests, andpractical 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. Goyama S, Schibler J, Cunningham L, Zhang Y,
Rao Y, Nishimoto N, Nakagawa M, Olsson A,

149

Wunderlich M, Link KA, Mizukawa B, Grimes
HL, Kurokawa M, Liu PP, Huang G, Mulloy JC.
Transcription factor RUNX1 promotes survival of
acute myeloid leukemia cells. J Clin Invest 2013;
123: 3876-88.
2. Hangai S, Nakamura F, Kamikubo Y, Honda A,
Arai S, Nakagawa M, Ichikawa M, Kurokawa M.
Erythroleukemia showing early erythroid andcytogenetic responses to azacitidine therapy. Ann
Hematol 2013; 92: 707-9.
3. Hangai S, Nakamura F, Kamikubo Y, Ichikawa M,
Suzuki H, Yoshida S, Yamada A, Takazawa Y,
Fukayama M, Koike K, Kurokawa M. Primary
gastrointestinal
follicularlymphomawithhistological transformation. Ann Hematol 2013;
92: 993-4.
4. Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto
N, Watanabe-Okochi N, Kurokawa M. A role for
RUNX1 in hematopoiesis and myeloid leukemia.
Int J Hematol 2013; 97: 726-34.
5. Kobayashi T, Ichikawa M, Kamikubo Y,
Kurokawa M. Acute myeloid leukemia withcryptic CBFB-MYH11 type D. Int J Clin Exp
Pathol 2013; 6: 110-2.
6. Kobayashi T, Hangaishi A, Yamamoto G,
Shinohara A, Morikawa T, Takazawa Y, Ota S,
Imai Y, Nakamura F, Kurokawa M. Successfultreatment of secondary NK/T-cell lymphoma of
the testis. Ann Hematol 2013; 92: 997-8.
7. Kobayashi T, Ichikawa M, Nannya Y, Kurokawa
M. The effect of decreased-dose idarubicin for
elderly patients with acute myeloid leukemia. Jpn
J Clin Oncol 2013; 43: 1047-51.
8. Koya J, Nannya Y, Kobayashi H, Okugawa S,
Moriya K, Kurokawa M. Simultaneous increase in
1,3-β-D-glucan and procalcitonin levels in
Pseudomonas aeruginosa infection. J Infect 2013;
67: 164-6.
9. Kumano K, Arai S, Kurokawa M. Generation of
iPS cells from normal and malignant
hematopoietic cells. Int J Hematol 2013; 98:
145-52.
10. Morita K, Nannya Y, Yoshizato T, Kurokawa M.
Simple but powerful prognostic scoring model for
MALT lymphoma: a retrospective study. Ann
Hematol 2013; 92: 421-3.
11. Morita K, Yoshimi A, Masuda A, Ichikawa M,

Yatomi Y, Kurokawa M. Unique association of
Waldenström macroglobulinemia with optic
neuritis and monoclonal T cell expansion. Int J
Hematol 2013; 98: 247-9.
12. Shinohara A, Yoshiki Y, Masamoto Y, Hangaishi
A, Nannya Y, Kurokawa M. Moxifloxacin is more
effective than tosufloxacin in reducing
chemotherapy-induced febrile neutropneia inpatients with hematological malignancies. Leuk
Lymphoma 2013; 54; 794-8.
13. Toya T, Shinohara A, Tatsuno K, Seo S, Nannya Y,
Ichikawa M, Makimura K, Moriya K, Kurokawa
M. A case of Schizophyllum commune sinusitis
following unrelated cord blood transplantation for
acute lymphoblastic leukemia. Int J Hematol
2013; 98: 261-3.
14. Uni M, Yoshimi A, Nakamura F, Takazawa Y,
Fukayama M, Kurokawa M. Successful allogeneic
stem cell transplantation for Lennert lymphoma.
Ann Hematol 2013; 92; 859-60.
15. Uni M, Yoshimi A, Maki H, Maeda D, Nakazaki
K, Nakamura F, Fukayama M, Kurokawa M.
Successfultreatment
withrecombinant
thrombomodulin for B-cell lymphoma-associatedhemophagocytic syndrome complicated bydisseminated intravascular coagulation. Int J Clin
Exp Pathol 2013; 6: 1190-4.
16. UniM,
NakamuraF,
YoshimiA,
Shinozaki-Ushiku A, Hosoi A, Nakazaki K,
Nannya Y, Fukayama M, Kurokawa M.
Transformation of follicular lymphoma in the
retroperitoneal
musclesdemonstratedbyCT-guided needle biopsy of FDG-avid lesions;case series. Int J Clin Exp Pathol 2013; 15: 402-6.
17. Watanabe-Okochi N, Yoshimi A, Sato T, Ikeda T,
Kumano K, Taoka K, Satoh Y, Shinohara A,
Tsuruta T, Masuda A, Yokota H, Yatomi Y,
Takahashi K, Kitaura J, Kitamura T, Kurokawa M.
The shortest isoform of C/EBPβ, liver inhibitory
protein (LIP), collaborates with Evi1 to induce
AML in a mouse BMT model. Blood 2013; 121:4142-55.
18. Yoshizato T, Nannya Y, Imai Y, Ichikawa M,
Kurokawa
M.
Clinicalsignificanceof
serum-soluble interleukin-2 receptor in patientswith follicular lymphoma. Clin Lymphoma
Myeloma Leuk 2013; 13: 410-6.

150

19. Yoshizato T, Watanabe-Okochi N, Nannya Y,
Ichikawa M, Takahashi T, Sato T, Masuda A,
Yatomi Y, Tsuno NH, Kurokawa M, Takahashi K.
Prediction model for CD34 positive cell yield in
peripheral blood stem cell collection on the fourth
day after G-CSF administration in healthy donors.
Int J Hematol 2013; 98: 56-65.

151

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

Lecturer
Fujio Takeuchi, M.D., Ph.D. (Rheumatology)
Kimito Kawahata, M.D., Ph.D. (Rheumatology)
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. (Rheumatology)
Yukiko Iwasaki，M.D., Ph.D. (Rheumatology)
Hiroaki Harada, M.D., Ph.D. (Allergology)
Ou Sasaki, M.D., Ph.D. (Allergology)

Project Associate professor
Hiroko Kanda, M.D., Ph.D. (Rheumatology)

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

The Department of Allergy and Rheumatology
presently consists of 14 staffs mentioned above, who
preside over 3 medical staff, 17graduate students for"Doctor of Medical Science" and 1 staff studying
abroad. The outpatient facilities are situated on the
2nd floor of the Outpatient Clinic. The inpatient
facility is mainly located on the 13th floor of the
Hospital Ward A. The physician's office is situated in
the East Hospital Ward and the research rooms arelocated in the East Hospital Ward, the Central Wardand the Internal Medicine Research Ward.

Education
In regard to undergraduate education, theDepartment is in charge of internal medicine
diagnosis and systemic lectures for M2 students andclinical lectures and bedside education for M3 and M4
students in cooperation with other departments ofinternal medicine. The systemic lectures and clinicallectures covers clinical immunology, connective tissue
diseases and allergy. Bedside education provides
students with a good opportunity to learn about
patients as well as practical knowledge through152

numerous seminars.
For postgraduate education, internal medicine
trainees are accepted on rotation basis and trained asinternist. Our department accepts students for "Doctorof Medical Science". Our 4-year education covers
clinicalimmunology,
molecular
immunology,
rheumatology and allergology.

Medical Care
General and special outpatient clinics are opened from
Monday to Friday. Special outpatients clinics include
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 5 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

2013

1. Kanzaki T, Kawahata K, Kanda H, Fujio K, Kubo
K, Akahira L, Michishita K, Eri T, Yamamoto K.
Long-term therapeutic effects and safety oftacrolimus added to methotrexate in patients withrheumatoid arthritis. Rheumatol Int. 33(4):871-7.
2013
2. Ishiguro N, Yamamoto K, Katayama K, Kondo M,
Sumida T, Mimori T, Soen S, Nagai K,
Yamaguchi T, Hara M; Iguratimod-Clinical Study
Group. Concomitant iguratimod therapy inpatients with active rheumatoid arthritis despite
stable doses of methotrexate: a randomized,
double-blind, placebo-controlled trial. Mod
Rheumatol. 23(3):430-9. 2013
3. Nagafuchi Y, Shoda H, Fujio K, Ishii S, Sugiyama
H, Yamamoto K. Tuberculous pleurisy diagnosed
by medical thoracoscopy in an adalimumabtreated rheumatoid arthritis patient after treatmentof latent tuberculosis infection. Mod Rheumatol.
23(5):1013-7. 2013
4. Takeuchi T, Harigai M, Tanaka Y, Yamanaka H,
Ishiguro N, Yamamoto K, Miyasaka N, Koike T,
Kanazawa M, Oba T, Yoshinari T, Baker D;
GO-MONO study group. Golimumab monotherapy in Japanese patients with active
rheumatoid arthritis despite prior treatment withdisease-modifying antirheumatic drugs: results ofthe phase 2/3, multicentre, randomised, doubleblind, placebo-controlled GO-MONO study
through 24 weeks. Ann Rheum Dis. 72(9):148895. 2013
5. Shoda H, Morita K, Kanda H, Fujio K, Yamamoto
K. An elderly woman with peripheral spondyloarthritis with aortitis. Mod Rheumatol. 2012.
[Epub ahead of print]

153

6. Terao C, Ohmura K, Kawaguchi Y, Nishimoto T,
Kawasaki A, Takehara K, Furukawa H, Kochi Y,
Ota Y, Ikari K, Sato S, Tohma S, Yamada R,
Yamamoto K, Kubo M, Yamanaka H, Kuwana M,
Tsuchiya N, Matsuda F, Mimori T. PLD4 as anovel susceptibility gene for systemic sclerosis ina Japanese population. Arthritis Rheum. 65(2):472-80. 2013
7. Fujio K, Okamura T, Sumitomo S, Yamamoto K.
Regulatory cell subsets in the control of
autoantibody production related to systemic
autoimmunity. Ann Rheum Dis. 72 Suppl 2:ii85-9.
2013
8. Tanaka Y, Kawai S, Takeuchi T, Yamamoto K,
Miyasaka N. Prevention of joint destruction bytacrolimus in patients with early rheumatoid
arthritis: a post hoc analysis of a double-blind,randomized, placebo-controlled study. Mod
Rheumatol. 23(6):1045-52.2013
9. Iwasaki Y, Fujio K, Okamura T, Yanai A,
Sumitomo S, Shoda H, Tamura T, Yoshida H,
Charnay P, Yamamoto K. Egr-2 transcription
factor is required for Blimp-1-mediated IL-10
production in IL-27-stimulated CD4+ T cells. Eur
J Immunol. 43(4):1063-73. 2013
10. Shimane K, Kochi Y, Suzuki A, Okada Y, Ishii T,
Horita T, Saito K, Okamoto A, Nishimoto N,
Myouzen K, Kubo M, Hirakata Nakamura Y,
Kamatani N, Yamamoto K.An association
analysis of HLA-DRB1 with systemic lupus
erythematosus and rheumatoid arthritis in a
Japanese population: effects of *09:01 allele ondisease phenotypes. Rheumatology (Oxford).
52(7):1172-82. 2013
11. Nagafuchi Y, Sumitomo S, Soroida Y, Kanzaki T,
Iwasaki Y, Michishita K, Iwai T, Ikeda H, Fujio K,
Yamamoto K. The power Doppler twinkling
artefact associated with periarticular calcificationinduced by intra-articular corticosteroid injection
in patients with rheumatoid arthritis. Ann Rheum
Dis. 72(7):1267-9. 2013
12. Takeuchi T, Kawai S, Yamamoto K, Harigai M,
IshidaK,
Miyasaka
N.
Post-marketingsurveillance of the safety and effectiveness oftacrolimus in 3,267 Japanese patients withrheumatoid arthritis. Mod Rheumatol. 2013.
[Epub ahead of print]

13. Sumitomo S, Fujio K, Okamura T, Morita K,
Ishigaki K, Suzukawa K, Kanaya K, Kondo K,
Yamasoba T, Furukawa A, Kitahara N, Shoda H,
Shibuya M, Okamoto A, Yamamoto K.
Transcription factor early growth response 3 isassociated with the TGF-β1 expression and theregulatory activity of CD4-positive T cells in vivo.
J Immunol. 191(5):2351-9. 2013
14. Sasaki O, Imamura M, Yamazumi Y, Harada H,
Matsumoto T, Okunishi K, Nakagome K, Tanaka
R, Akiyama T, Yamamoto K, Dohi M.
Alendronate attenuates eosinophilic airway
inflammation associated with suppression of Th2
cytokines, Th17 cytokines, and eotaxin-2. J
Immunol. 191(6):2879-89. 201315. Sumitomo S, Fujio K, Okamura T, Yamamoto K.
Egr2 and Egr3 are the unique regulators for
systemic autoimmunity. JAKSTAT. 2(2):e23952.
2013
16. Nakashima K, Arai1 S, Suzuki A, Nariai Y, Urano
T, Nakayama M, Ohara O, Yamamura K,
Yamamoto K, Miyazaki1 T. PAD4 regulates
proliferation of multipotent hematopoietic cells bycontrollingc-myc
expression.
NatureCommunications. 1836.2013
17. 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 FceRIcrosslinking stimulation enhances basophil
mediator release. Int Arch Allergy Immunol.
161(Suppl 2):23-31.2013
18. Ohshima
M,
Kanda
H,
Kubo
K,
Yonezumi-Hayashi A, Tateishi S, Yamamoto K.:
Characterization of 5C11-positive activatedinterferon-producing cells in patients withsystemic lupus erythematosus. Lupus. 22:44-51.
2013
19. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K,
Kochi Y, Ohmura K, Suzuki A, Yoshida S,
Graham RR, Manoharan A, Ortmann W, Bhangale
T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD,
Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su
DF, Yang J, Xie G, Keystone E, Westra HJ, Esko T,
Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA,
Diogo D, Cui J, Liao K, Guo MH, Myouzen K,
Kawaguchi T, Coenen MJ, van Riel PL, van de154

Laar MA, Guchelaar HJ, Huizinga TW, Dieudé P,
Mariette X, Bridges SL Jr, Zhernakova A, Toes
RE, Tak PP, Miceli-Richard C, Bang SY, Lee HS,
Martin J, Gonzalez-Gay MA, RodriguezRodriguez L, Rantapää-Dahlqvist S, Arlestig L,
Choi HK, Kamatani Y, Galan P, Lathrop M; RACI
consortium; GARNET consortium, Eyre S, Bowes
J, Barton A, de Vries N, Moreland LW, Criswell
LA, Karlson EW, Taniguchi A, Yamada R, Kubo
M, Liu JS, Bae SC, Worthington J, Padyukov L,
Klareskog L, Gregersen PK, Raychaudhuri S,
Stranger BE, De Jager PL, Franke L, Visscher PM,
Brown MA, Yamanaka H, Mimori T, Takahashi A,
Xu H, Behrens TW, Siminovitch KA, Momohara
S, Matsuda F, Yamamoto K, Plenge RM..
Genetics of rheumatoid arthritis contributes tobiology and drug discovery. Nature. 506(7488):376-381. 2014
20. Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro
N, Tanaka Y, Eguchi K, Watanabe A, Origasa H,
Iwai K, Sakamaki Y, van der Heijde D, Miyasaka
N, Koike T. Efficacy and safety of certolizumab
pegol without methotrexate co-administration in
Japanese patients with active rheumatoid arthritis:the HIKARI randomized, placebo-controlled trial.
Mod Rheumatol. 2013 Nov 1. [Epub ahead ofprint]
21. Chihara Y, Egawa H, Oga T, Tsuboi T, Handa T,
Yagi S, Iida T, Yoshizawa A, Yamamoto K,
Mishima M, Tanaka K, Uemoto S, Chin K.
Predictive Factors for Reintubation following
Noninvasive Ventilation in Patients with
Respiratory Complications after Living Donor
Liver Transplantation. PLoS One. 8(12):e81417.
2013
22. Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro
N, Tanaka Y, Eguchi K, Watanabe A, Origasa H,
Shoji, T,Sakamaki Y, van der Heijde D, Miyasaka
N, Koike T.Efficacy and safety of certolizumab
pegol plus methotrexate in Japanese rheumatoid
arthritis patients with an inadequate response tomethotrexate: the J-RAPID randomized, placebocontrolled trial. Mod Rheumatol. 2013 Dec 9.
[Epub ahead of print]
23. Kimura E, Kanzaki T, Tahara K, Hayashi H,
Hashimoto S, Suzuki A, Yamada R, Yamamoto K,
Sawada T. Identification of. citrullinated cellularfibronectin in synovial fluid from patients withrheumatoid arthritis. Mod Rheumatol.2014 Feb
5.[Epub ahead of print]

155

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-

156

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)

2)

3)

4)

5)

6)

7)

Nukui Y, Hatakeyama S, Okamoto K, Yamamoto T,
Hisaka A, Suzuki H, Yata N, Yotsuyanagi H,
Moriya K. High plasma linezolid concentration andimpaired renal function affect development oflinezolid-induced thrombocytopenia. J Antimicrob
Chemother. 2013;68:2128-33.
Tanaka S, Nagata N, Mine S, Igari T, Kobayashi T,
Sugihara J, Honda H, Teruya K, Kikuchi Y, Oka S,
Uemura N. Endoscopic appearance of AIDS-related
gastrointestinal
lymphoma
withc-MYC
rearrangements: case report and literature review.
World J Gastroenterol. 2013;19:4827-31.
Nagata N, Shimbo T, Sekine K, Tanaka S, Niikura
R, Mezaki K, Morino E, Yazaki H, Igari T,
Ohmagari N, Akiyama J, Oka S, Uemura N.
Alcohol and smoking affect risk of uncomplicatedcolonic diverticulosis in Japan. PLoS One. 2013;10:
e81137.
Okamoto K, Brown JD. Hepatosplenic schistosomiasis presenting as spontaneous hemoperitoneumin a Filipino immigrant. Am J Med Sci. 2013;346:
334-7.
Thomas BS, Okamoto K, Bankowski MJ, Seto TB.
A lethalcase of Pseudomonas putida bacteremia due
to soft tissue infection. Infect Dis Clin Pract.
2013;21:147-213.
Yamaguchi Y, Nukui Y, Kotaki A, Sawabe K, Saijo
M, Watanabe H, Kurane I, Takasaki T, Tajima S.
Characterization of a serine-to-asparagine substitution at position 123 in the Japanese encephalitis.
J Gen Virol. 2013; 94: 90-96.
Nagata N, Shimbo T, Sekine K, Tanaka S, Niikura

157

R, Mezaki K, Morino E, Yazaki H, Igari T,
Ohmagari N, Akiyama J, Oka S, Uemura N.
Combined endoscopy, aspiration, and biopsy
analysis for identifying infectious colitis in patientswith ileocecal ulcers. Clin Gastroenterol Hepatol.
2013; 11: 673-80.
8) 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.
9) 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.
10) Saito N, Hida A, Koide Y, Ichikawa Y, Shimizu J,
Mukasa A, Nakatomi H, Hatakeyama S, Ooka T,
Hayashi T, Tsuji S. Culture-negative brain abscesses
with Streptococcus intermedius infection whose
diagnosis was established by direct analysis of 16s
ribosomal DNA fragments. Intern Med. 2012;51:
211-6.
11) Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K,
Yanagimoto S, Okugawa S, Ota Y, Yotsuyanagi H.
Clinical features of Bacteroides bacteremia andtheir association with colorectal carcinoma.
Infection. Infection. 2012;40:63-7.
12) Kitazawa T, Yoshino Y, Tatsuno K, Ota Y,
Yotsuyanagi H. Changes in the mean plateletvolume levels after bloodstream infection haveprognostic value. Intern Med. 2013;52:1487-93.
13) Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K,
Yanagimoto S, Okugawa S, Yotsuyanagi H, Ota Y.
Clostridium difficile flagellin stimulates toll-likereceptor 5, and toxin B promotes flagellin-induced
chemokine production via TLR5. Life Sci. 2013;
92:211-7.
14) Yotsuyanagi H, Ito K, Yamada N, Takahashi H,
Okuse C, Yasuda K, Suzuki M, Moriya K,
Mizokami M, Miyakawa Y, Koike K. High levels of
hepatitis B virus after the onset of disease lead tochronic infection in patients with acute hepatitis B.
Clin Infect Dis. 2013;57:935-42.
15) 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;42:1236-40.
16) 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. 2013;51:e17-8.
17) 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.
18) 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;51:1779-82.
19) 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.
20) Okazaki T, Yamazaki K, Iwasaki T, Okano T,
Kurosaki Y, Nakamura K, Fujioka T, Yotsuyanagi H.
α2-HS glycoprotein is an essential component ofcryoglobulin associ¬ated with chronic hepatitis C.
Clin Chem Lab Med. 2012 Jul 27.
doi:pii:/j/cclm.ahead-of-print/cclm-2012-0293/cclm-2012-0293.xml.10.1515/cclm-2012-0293. [Epubahead of print]21) 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 ofprint]
22) 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158

low-titer hepatitis B surface antigen. Hepatol Res.
2012;42:1236-1240.
23) Nukui Y, Hatakeyama S, Kitazawa T, Mahira T,
Shintani Y, Moriya K. Pandemic 2009 influenza A(H1N1) virus among Japanese healthcare workers:
sero¬prevalence and risk factors. Infect Control
Hosp Epidemiol. 2012; 33: 58-62
24) 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 1025) 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.
26) Koyano S, Saito R, Nagai R, Tastuno K, Okugawa
S, Okamura N, Moriya K. J Med Microbiol. 2012
Nov 15. [Epub ahead of print]27) 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]28) Okugawa S, Moayeri M, Pomerantsev AP, Sastalla I,
Crown D, Gupta PK, Leppla SH. Lipoprotein
biosynthesis by prolipoprotein diacylglyceryltransferase is required for efficient spore
germination and full virulence of Bacillus anthracis.
Mol Microbiol. 2012;83:96-109.

159

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.
Mami Kayano, 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
associate professor, two associates, and 5 adjunctprofessors, and other members are 2 senior residents,
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 2013 January to 2013 December, 1425 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
2013 January to 2013 December, the numbers of the
new outpatients and of the overall outpatients in our
department were 108 and 2625, 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.

160

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

References
1. Ishikawa Y, Fukui S, Saito T, Fujita J, Watanabe
M, Yoshiuchi K. Family preference for place ofdeath mediates the relationship between patient

preference and actual place of death:
A nationwide retrospective cross-sectional study.
PLoS ONE 8 : e56848,2013
2. Fukui S, Fujita J, Yoshiuchi K. Associations
between Japanese people’s concern about family
caregiver burden and preference for end-of-lifecare location. Journal of Palliative Care 29:
22-28,2013
3. Fukui M, Iwase S, Sakata N, Kuroda Y, Yoshiuchi
K, Nakagawa K, Quinn K, Hudson PL.
Effectiveness of using clinical guidelines for
conducting palliative care family meetings inJapan. Supportive Care in Cancer 21:53-58,2013

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

162

Department of Transfusion
Medicine
Professor
Hitoshi Okazaki, 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

1631) 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) 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 5 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 (red cells,
platelets, leukocytes) and their importance intransfusion medicine and in transplantation (bonemarrow and organ);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) Introduction to the preventive measures of bloodborne viral transmission, especially focusing on
the NAT test and the look-back survey.
7) Acquisition of informed consents related to bloodtransfusion, using the role playing method.
8) The indications and techniques of autologous
blood collection and preservation;9) The techniques for peripheral blood stem cells(PBSCs) collection and preservation, as well as
their clinical application;10) The immunotherapy of cancer patients;
11) 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”.
12) 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. Development of a new methodology for plateletcross-match.

164

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

References
1. Shimizu M, Nakajima F, Okazaki H, Satake M,
Tadokoro K: Two novel null HLA-A alleles withidentical exon 4 nonsense mutations: HLA-A*24:
183N and A*02:356N. Tissue Antigens 82:136137, 2013
2. Nogawa M, Naito Y, Chatani M, Onodera H,
Shiba M, Okazaki H, Matsuzaki K, Satake M,
Nakajima K, Tadokoro K: Parallel comparison ofapheresis-collected platelet concentrates stored infour different additive solutions. Vox Sang 105:305-12 2013
3. Yoshizato T, Watanabe-Okochi N, Nannya Y,
Ichikawa M, Takahashi T, Sato T, Masuda A,
Yatomi Y, Tsuno NH, Kurokawa M, Takahashi K.
Prediction model for CD34 positive cell yield in
peripheral blood stem cell collection on the fourth
day after G-CSF administration in healthy donors.
Int J Hematol. 2013; 98(1):56-65.
4. Matsuhashi M, Tsuno NH, Ikeda T, Mishima Y,
Watanabe-Okochi N, Santoso S, Tozuka M,
Takahashi K. The frequencies of SLC44A2 alleles
among the Japanese population. Tissue Antigens.
2013; 81(4):227-8.
5. Tsuno NH, Nagura Y, Kawabata M, Matsuhashi M,
Sone S, Ikeda T, Okochi N, Takahashi K. The
current status of autologous blood transfusion in
Japan--the importance of pre-deposit autologous
blood donation program and the needs to achieve
patient blood management. Transfus Apher Sci.
2013; 49(3):673-80.
6. Nagura Y, Tsuno NH, Tanaka M, Matsuhashi M,
Takahashi K. The effect of pre-storage wholeblood leukocyte reduction on cytokines/
chemokines levels in autologous CPDA-1 whole

blood. Transfus Apher Sci. 2013; 49(2):223-30.
7. Nagura Y, Tsuno NH, Ohkawa R, Nojiri T,
Tokuhara Y, Matsuhashi M, Yatomi Y, Takahashi
K. Inhibition of lysophosphatidic acid increase byprestorage whole blood leukoreduction in
autologous CPDA-1 whole blood. Transfusion.
2013; 53(12):3139-48.
8. Murono K, Kawai K, Kazama S, Tsuno NH,
Sunami E, Kitayama J, Watanabe T. Colorectal
cancer with multiple metachronous metastasis
achieving complete remission 14 years after
surgical resection: report of a case. Int Surg. 2013;
98(1):49-54.
9. Hiyoshi M, Kitayama J, Kazama S, Taketomi Y,
Murakami M, Tsuno NH, Hongo K, Kaneko M,
Sunami E, Watanabe T. The expression ofphospholipase A2 group X is inversely associatedwith metastasis in colorectal cancer. Oncol Lett.
2013; 5(2):533-538.
10. Murono K, Kitayama J, Tsuno NH, Nozawa H,
Kawai K, Sunami E, Akahane M, Watanabe T.
Hepatic steatosis is associated with lower
incidence of liver metastasis from colorectal
cancer. Int J Colorectal Dis. 2013; 28(8):1065-72.
11. Tanaka M, Tsuno NH, Fujii T, Todo T, Saito N,
Takahashi K. Human umbilical vein endothelial
cell vaccine therapy in patients with recurrent
glioblastoma. Cancer Sci. 2013; 104(2):200-5.
12. Kawai K, Kitayama J, Tsuno NH, Sunami E,
Watanabe T. Thrombocytosis before pre-operative
chemoradiotherapy predicts poor response andshorter local recurrence-free survival in rectal
cancer. Int J Colorectal Dis. 2013; 28(4):527-35.
13. Hongo K, Tsuno NH, Kawai K, Sasaki K, Kaneko
M, Hiyoshi M, Murono K, Tada N, Nirei T,
Sunami E, Takahashi K, Nagawa H, Kitayama J,
Watanabe T. Hypoxia enhances colon cancer
migration and invasion through promotion ofepithelial-mesenchymal transition. J Surg Res.
2013; 182(1):75-84.
14. 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.

165

J Biol Chem. 2013 Apr 5;288(14):9924-32.
15. Kan A, Ikeda T, Fukai A, Nakagawa T, Nakamura
K, Chung UI, Kawaguchi H, Tabin CJ. SOX11
contributes to the regulation of GDF5 in joint
maintenance. BMC Dev Biol. 2013; 13:4. doi:
10.1186/1471-213X-13-4.
16. 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. 2013; 72(5):748-53.
17. Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto
N, Watanabe-Okochi N, Kurokawa M. A role for
RUNX1 in hematopoiesis and myeloid leukemia.
Int J Hematol. 2013; 97(6):726-34.
18. Watanabe-Okochi N, Yoshimi A, Sato T, Ikeda T,
Kumano K, Taoka K, Satoh Y, Shinohara A,
Tsuruta T, Masuda A, Yokota H, Yatomi Y,
Takahashi K, Kitaura J, Kitamura T, Kurokawa M.
The shortest isoform of C/EBPβ, liver inhibitory
protein (LIP), collaborates with Evi1 to induce
AML in a mouse BMT model. Blood. 2013;
121(20):4142-55.

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

167

Department of
Reproductive Endocrinology
Professor
Tomoyuki Fujii

Associate Professor
Kei Kawana

Lecturer
Osamu Hiraike

Kaori Koga

Tetsuya Hirata

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

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases, genetic
counseling and assisted reproductive technologies(ART).
We 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 300 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 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 2013
(1) Harada M, et.al. Predictive factors forrecurrence of ovarian mature cystic teratomas
after surgical excision. Eur J Obstet Gynecol
Reprod Biol. 2013 Dec; 171(2): 325-8.
(2) Akiyama I, et.al. Follistatin is induced by IL-1β
and TNF-α in stromal cells from endometrioma.

168

Reprod Sci. 2013 Jun; 20(6):675-9.
(3) Takemura Y, et.al. Increased risk of placenta
previa is associated with endometriosis andtubal 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
treated with 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 canoccur in uterine artery pseudoaneurysm after
laparoscopically assisted myomectomy. J Obstet
Gynaecol Res. 2013; 39(2): 598-602.
(6) Urata Y, et.al. Interleukin-4 and prostaglandin
E2 synergistically up-regulate 3β-hydroxysteroid
dehydrogenase type 2 in endometrioma stromalcells. J Clin Endocrinol Metab 2013; 98(4):1583-90.
(7) Yoshida M, et.al. Reliability and validity of theJapanese version of the pelvic floor distressinventory-short form 20. Int Urogynecol J. 2013;24(6): 1039-46.
(8) Zhao Y, et.al. Cyclic stretch augments productionofneutrophil
chemokines
andmatrix
metalloproteinase-1 in human uterine smoothmuscle cells. Am J Reprod Immunol. 2013 Mar;69(3): 240-7.
(9) Zhao Y, et.al. Cyclic stretch augments productionofneutrophil
chemokines
andmatrix
metalloproteinases-1 (MMP-1) from humandecidual cells, and the production was reduced
by progesterone. Am J Reprod Immunol. 2013
May; 69(5): 454-62.
(10) Tanaka E, et.al. Burden of menstrual symptoms
in Japanese women - an analysis of medical
care-seeking behavior from a survey-based
study. Int J Womens Health. 2013 Dec 17; 6:
11-23.
(11) Tanaka E, et.al. Burden of menstrual symptoms
in Japanese women: results from a survey-based
study. J Med Econ. 2013 Nov; 16(11): 1255-66.
(12) Koga K, et.al. Recurrence of endometrioma
after laparoscopic excision and its prevention by
medical management. Front Biosci (Elite Ed).
2013 Jan 1; 5: 676-83.

(13) Fujimoto A, et.al. Laparoendoscopic single- siteconcomitant surgery for gallstones and a giant
ovarian teratoma. Asian J Endosc Surg. 2013
Aug; 6(3): 223-5.
(14) Hasegawa A, et.al. Laparoscopic ovariansparing surgery for a young woman with an
exophytic ovarian fibroma. J Obstet Gynaecol
Res. 2013 Dec; 39(12): 1610-3.
(15) Tokura Y, et.al. The significance of serumanti-Müllerian hormone (AMH) levels inpatients over age 40 in first IVF treatment. J
Assist Reprod Genet. 2013 Jun; 30(6): 821-5.

169

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 19
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

170

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

173

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

174(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 2013
(1) Nagasaka K, et.al. PDZ domains and viral
infection: versatile potentials of HPV-PDZ
interactions in relation to malignancy. Biomed
Res Int. 2013; 2013: 369712.
(2) Tomio K, et.al. Omega-3 polyunsaturated Fatty
acids suppress the cystic lesion formation of
peritoneal endometriosis in transgenic mousemodels. PLoS One. 2013 Sep 10; 8(9): e73085.
(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) Halimi SA, et.al. Claudin-18 overexpression in
intestinal-type mucinous borderline tumour of theovary. Histopathology. 2013 Oct; 63(4): 534-44.
(6) Ikeda Y, et.al. Cyclin D1 harboring the T286I
mutation promotes oncogenic activation in

endometrial cancer. Oncol Rep. 2013 Aug; 30(2):584-8.
(7) Kojima S, et.al. The prevalence of cervicalregulatory T cells in HPV-related cervicalintraepithelial neoplasia (CIN) correlates
inversely with 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) Ichinose M, et.al. The influence of infertility
treatment on the prognosis of endometrial cancer
and atypical complex endometrial hyperplasia.
Int J Gynecol Cancer 2013; 23(2): 288-93.
(10)Nagasaka K, et.al. A novel interaction between
hScrib and PP1γ downregulates ERK signaling
and suppresses oncogene- induced celltransformation. PLoS One. 2013; 8(1): e53752.

175

Department of Perinatal Medicine
Professor
Tomoyuki Fujii

Associate Professor
Takahiro Yamashita

LecturerTakeshi Nagamatsu

Homepage

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

Organization
The Department of Perinatal Medicine is organized
by one professor, one associate professor and one
lecturer, being directed practically by Professor
Tomoyuki Fujii, the chairman of the Department of
Obstetrics and Gynecology. All the staff members aretaking part in both the clinical and research activities,
as well as the teaching activities, with 19 associates of
the University of Tokyo Hospital. For the clinicalaspect, they are engaged with in-patient andout-patient care including the activities in the delivery
units.

Activities
The clinical service for perinatology in the
University of Tokyo Hospital consists of out-patient
clinic and the Delivery Unit. [See Delivery Unit of the
University of Tokyo Hospital]
By the advance of the techniques for prenatal
diagnosis of fetal growth and congenital malformations, the area of fetal medicine is enlarging.
Strict measurement of fetal growth during pregnancy
has made possible the accurate diagnosis of fetal
growth restriction. New techniques like fetal blood
sampling and three-dimensional ultrasonography havebeen introduced into clinical service. The subjects ofstudies were focused on “fetus” and “ultrasound” inperinatology and medical engineering research group.

Fetal behavior, particularly breathing movements andsleep-wakefulness cycle were studied with ultrasoundin human fetuses. Studies were done to investigate
mechanism of fetal brain damage by repeated cord
occlusion in sheep. The effect of brain damage on
fetal behavior was also studied.
Recurrent spontaneous abortion (RSA) is diagnosed
by a history of three times or more spontaneousabortions in the first trimester. Our “RSA clinic”
opens once a week. About 200 new couples with RSA
visit our hospital in a year. The patients are checked
several risk factors of RSA, such as anatomical,
chromosomal, hormonal, biological, or autoimmune
factors. To RSA patients with autoimmune factors,
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%.

176

References published in 2013
(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(2) Yamashita A, et.al. Increased tissue levels ofomega-3 polyunsaturated fatty acids prevents
pathological preterm birth. Sci Rep. 2013 Nov 1;
3: 3113.
(3) Nagai M, et.al. Characterization of transplacental
transfer of paroxetine in perfused human placenta:
development of a pharmacokinetic model toevaluate tapered dosing. Drug Metab Dispos.
2013 Dec; 41(12): 2124-32.
(4) Sayama S, et.al. Human decidual macrophages
suppress IFN-γ production by T cells throughcostimulatory B7-H1: PD-1 signaling in earlypregnancy. J Reprod Immunol. 2013 Dec; 100(2):109-17.
(5) Hosoya Y, et.al. Cardiac magnetic resonanceimaging in a patient with amniotic fluid embolism
associatedwithseverecardiopulmonary
complications. Int Heart J. 2013; 54(2): 119-22.

177

Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Lecturer
Osamu Hiraike

Kaori Koga

Tetsuya Hirata

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.

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases andgenetic counseling. We also perform minimal accesssurgery for endometriosis, uterine fibroid, benign
tumor and so on.
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 cystectomy 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 for peri/post-menopausal women is
becoming more important. We have alreadyestablished the primary care system for womenfocusing on climacteric syndrome and osteoporosis.

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

References published in 2013
(1) Harada M, et.al. Predictive factors forrecurrence of ovarian mature cystic teratomas
after surgical excision. Eur J Obstet Gynecol
Reprod Biol. 2013 Dec; 171(2): 325-8.
(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 andtubal 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
treated with laparoscopy and diagnosed using
immunohistology. J Obstet Gynaecol Res. 2013
Jan; 39(1): 430-3.

178(5) Oishi H, et.al. Spontaneous cessation andrecurrence of massive uterine bleeding canoccur in uterine artery pseudoaneurysm after
laparoscopically assisted myomectomy. J Obstet
Gynaecol Res. 2013; 39(2): 598-602.
(6) Urata Y, et.al. Interleukin-4 and prostaglandin
E2 synergistically up-regulate 3β-hydroxysteroid
dehydrogenase type 2 in endometrioma stromalcells. J Clin Endocrinol Metab 2013; 98(4):1583-90.
(7) Yoshida M, et.al. Reliability and validity of theJapanese version of the pelvic floor distressinventory-short form 20. Int Urogynecol J. 2013;24(6): 1039-46.
(8) Zhao Y, et.al. Cyclic stretch augments productionofneutrophil
chemokines
andmatrix
metalloproteinase-1 in human uterine smoothmuscle cells. Am J Reprod Immunol. 2013 Mar;69(3): 240-7.
(9) Zhao Y, et.al. Cyclic stretch augments productionofneutrophil
chemokines
andmatrix
metalloproteinases-1 (MMP-1) from humandecidual cells, and the production was reduced
by progesterone. Am J Reprod Immunol. 2013
May; 69(5): 454-62.
(10) Tanaka E, et.al. Burden of menstrual symptoms
in Japanese women - an analysis of medical
care-seeking behavior from a survey-based
study. Int J Womens Health. 2013 Dec 17; 6:
11-23.
(11) Tanaka E, et.al. Burden of menstrual symptoms
in Japanese women: results from a survey-based
study. J Med Econ. 2013 Nov; 16(11): 1255-66.
(12) Koga K, et.al. Recurrence of endometrioma
after laparoscopic excision and its prevention by
medical management. Front Biosci (Elite Ed).
2013 Jan 1; 5: 676-83.
(13) Fujimoto A, et.al. Laparoendoscopic single- siteconcomitant surgery for gallstones and a giant
ovarian teratoma. Asian J Endosc Surg. 2013
Aug; 6(3): 223-5.
(14) Hasegawa A, et.al. Laparoscopic ovariansparing surgery for a young woman with an
exophytic ovarian fibroma. J Obstet Gynaecol
Res. 2013 Dec; 39(12): 1610-3.
(15) Tokura Y, et.al. The significance of serumanti-Müllerian hormone (AMH) levels inpatients over age 40 in first IVF treatment. J
Assist Reprod Genet. 2013 Jun; 30(6): 821-5.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

180

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)
Junko Takita, M.D., Ph.D.

Lecturer
Shinya Tsuchida, M.D., Ph.D., Masakazu Mimaki, M.D., Ph.D., Yutaka Harita, M.D., Ph.D.,
Ryo Inuzuka, M.D., PhD.,
Motohiro Kato, M.D., Ph.D., (Department of Cell Therapy and Transplantation Medicine)

Associate
Nobutaka Shimizu, M.D., Ph.D., Ken-ichirou Miura, M.D., Haruko Tsurumi, M.D.,Ph.D.,
Mitsuteru Hiwatari, M.D., Ph.D., Hiroyuki Iwasaki, M.D., Hiroki Yasudo M.D., Ph.D.,
Tsuyoshi Isojima, M.D., Youichirou Hirata, M.D., Ph.D., Takahiro Shindo,M.D., Taiyu
Hayashi, M.D., Nagahisa Takahashi, M.D., Konomi Shimoda, M.D., Yoshinori Aoki, M.D.,
Ryosuke Shiozawa, M.D., Sayaka Ohta, M.D., Atsushi Itoh, M.D., Yoshihiko Shidara, M.D.,
Kentarou Watanabe, M.D.
(As of March 31, 2014)

Homepage

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

Introduction and Organization
The former Department of Pediatrics developed into
Department of Pediatrics and Department ofDevelopmental Pediatrics, which comprise subgroupsof the Group of Reproductive, Developmental andAging Medicines, Graduate School of Medicine, The
University of Tokyo.
Our staff consists of 1 professor, 3 associate
professors, 5 lecturers, 18 associate professors, 14senior residents, 2 research fellow, and 18 graduate

students on March 31, 2014.
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.

181

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

182

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.

2.

3.

4.

5.

6.

7.

8.

Referencess
1. Hayashi T, Inuzuka R, Shiozawa Y, Shindo T,
Shimizu N, Katori T: Treatment strategy andlong-term prognosis for patients withesophageal atresia and congenital heart diseases.

9.

Pediatr Cardiol 34: 64-69, 2013
Hirata Y, Kurobe H, Higashida M, Fukuda D,
Shimabukuro M, Tanaka K, Higashikuni Y,
Kitagawa T, Sata M: HMGB1 plays a criticalrole in vascular inflammation and lesion
formation
via
toll-likereceptor
9.
Atherosclerosis 231: 227-233, 2013
Hirata Y, Kurobe H, Nishio C, Tanaka K,
Fukuda D, Uematsu E, Nishimoto S, Soeki T,
Harada N, Sakaue H, Kitagawa T, Shimabukuro
M, Nakaya N, Sata M: Exendin-4, a
glucagon-like peptide-1 receptor agonist,
attenuates neointimal hyperplasia after vascular
injury. Eur J Pharmacol 699: 106-111, 2013
Hirata Y, Kurobe H, Uematsu E, Yagi S, Soeki T,
Yamada H, Fukuda D, Shimabukuro M,
Nakayama M, Matsumoto K, Sakai Y, Kitagawa
T, Sata M: Beneficial effect of a synthetic
prostacyclin agonist, ONO-1301, in rat
autoimmune myocarditis model. Eur J
Pharmacol 699: 81-87, 2013
Inuzuka R, Seki M, Sugimoto M, Saiki H,
Masutani S, Senzaki H: Pulmonary arterial wall
stiffness and its impact on right ventricularafterload in patients with repaired tetralogy of
Fallot. Ann Thorac Surg 96: 1435-1441, 2013
Isojima T, Harita Y, Furuyama M, Sugawara N,
Ishizuka K, Horita S, Kajiho Y, Miura K,
Igarashi T, Hattori M, Kitanaka S: LMX1B
mutation with residual transcriptional activity
as a cause of isolated glomerulopathy. Nephrol
Dial Transplant 29: 81-88, 2013
Ito N, Ito K, Koshimichi H, Hisaka A, Honma
M, Igarashi T, Suzuki H: Contribution ofprotein binding, lipid partitioning, andasymmetrical transport to drug transfer into
milk in mouse versus human. Pharm Res 30(9):2410-2422, 2013
Kato M, Koh, K, Oshima K, Oguma E, Uchida
H, Kishimoto H, Kikuchi A. Hanada R: A
long-term survivor of relapsed stage IV
malignant rhabdoid tumor of the kidney.
Pediatrics International 55: 245-248, 2013
Kato M, Matsumoto K, Suzuki R, Yabe H,
Inoue M, Kigasawa H, Inagaki J, Koh K, Hashii
Y, Tauchi H, Suminoe A, Kikuta A, Sakamaki H,
Kawa K, Kato K, Fukuda T. Salvage allogeneic

183

hematopoietic SCT for primary graft failure inchildren. Bone Marrow Transplant 48: 11731178, 2013
10. Kato M, Takahashi Y, Tomizawa D, Okamoto Y,
Inagaki J, Koh K, Ogawa A, Okada K, Cho Y,
Takita J, Goto H, Sakamaki H, Yabe H, Kawa K,
Suzuki R, Kudo K, Kato K: Comparison of
intravenous with oral busulfan in allogeneic
hematopoietic stem cell transplantation withmyeloablative conditioning regimens forpediatric acute leukemia. Biol Blood Marrow
Transplant 19: 1690-1694, 2013
11. Kato M, Yasui N, Seki M, Kishimoto H,
Sato-Otsubo A, Hasegawa D, Kiyokawa N,
Hanada R, Ogawa S, Manabe A, Takita J, Koh
K: Aggressive transformation of juvenile
myelomonocytic leukemia associated with
duplication of oncogenic KRAS in consequenceof acquired uniparental disomy. J Pediatr 162:
1285-1288, 2013
12. Kim KS, 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 130:11-12, 2013
13. Miura K, Kurihara H, Horita S, Chikamoto H,
Hattori M, Harita Y, Tsurumi H, Kajiho Y,
Sawada Y, Sasaki S, Igarashi T, Kunishima S,
Sekine T: Podocyte expression of nonmuscle
myosin heavy chain-IIA decreases in idiopathic
nephrotic syndrome, especially in focal
segmental glomerulosclerosis. Nephrol Dial
Transplant 28: 2993-3003, 2013
14. Miura K, Sekine T, Takahashi K, Takita J,
Harita Y, Ohki K, Park MJ, Hayashi Y, Tajima A,
Ishihara M, Hisano M, Murai M, Igarashi T:
Mutational analyses of the ATP6V1B1 and
ATP6V0A4 genes in patients with primary
distal renal tubular acidosis. Nephrol Dial
Transplant 28: 2123-2130, 2013
15. Nishimura R, Takita J, Sato-Otsubo A, Kato M
Koh K, Hanada R, Tanaka Y, Kato K, Maeda D,
Fukayama M, Sanada M, Hayashi Y, Ogawa S:
Characterization of genetic lesions in
rhabdomyosarcoma using a high-density single

nucleotide polymorphism array. Cancer Sci.
104: 856-864, 2013
16. Seki M, Koh K, Inoue T, Tomita Y, Kato M,
Shimizu M, Morishita E, Hanada R:
Prophylactic administration of prothrombin
complexconcentrates
forcongenital
prothrombin deficiency with a novel frameshift
mutation, prothrombin saitama. Pediatr Blood
Cancer 60: 503-505, 201317. Shiozawa Y, Inuzuka R, Harita Y, Kagawa J:
Age-related differences in the course of theacute phase symptoms of Kawasaki disease.
Pediatr Infect Dis J 32: e365-369, 2013
18. Takeuchi M, Oda Y, Suzuki I: Maculopapularrash in the convalescent phase of Kawasaki
disease: case series and literature review. Eur J
Pediatr 172: 405-407, 2013
19. Takeuchi M, Shiozawa R, Hangai M, Takita J,
Kitanaka S. Cephalhematoma and petechialrashes associated with acute parvovirus B19
infection: a case report. BMC Infect Dis. 13:
465, 2013
20. Taniguchi R, Koyano S, Suzutani T, Goishi K,
Ito Y, Morioka I, Oka A, Nakamura H, Yamada
H, Igarashi T, Inoue N: Polymorphisms in
TLR-2 are associated with congenital
cytomegalovirus (CMV) infection but not withcongenital CMV disease. Int J Infect Dis
17(12): e1092-1097, 2013

184

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

Lecturer
Mari Arai, M.D. Ph.D.

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

Research Associate
Masahiko Sugiyama, M.D.,

Tetsuya Ishimaru, M.D., Ph.D.

Mariko Yoshida, 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,
2 lecturers, 3 research associates. More than 20
members of our department shoulder the clinical workas pediatric surgeons.

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

185

careful 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
and blood samples.

References
1. Yoshida M, Matsuoka K, Nakazawa A, Yoshida M,
Inoue T, Kishimoto H, et al. Sacrococcygeal yolk

186

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sac tumor developing after teratoma: aclinicopathological
studyofpediatric
crococcygeal germ cell tumors and a proposal of
the pathogenesis of sacrococcygeal yolk sactumors. 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.
Komura M, Komura H, Otani Y, Kanamori Y,
Iwanaka T, Hoshi K, Takato T, Tabata Y: Thejunction between hyaline cartilage and engineered
cartilage in rabbits. Laryngoscope 123: 1547-1551,
2013.
Tanaka Y, Uchida H, Kawashima H, Sato K,
Takazawa S, Jimbo T, et al. Successful two-stage
thoracoscopic repair of long-gap esophageal
atresia using simple internal traction and delayed
primary anastomosis in a neonate: report of a case.
Surg Today. 2013; 43(8):906-9.
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
Technol. 2013; 22(1):9-16.
Takazawa S, Uchida H, Kawashima H, Tanaka Y,
Sato K, Jimbo T, Deie K, Koiwai K, Nomura K,
Iwanaka T: Massive hemorrhage after Kasai
portoenterostomy in a patient with a congenital
extrahepatic portosystemic shunt, malrotation anda double aortic arch: report of a case. Surg Today.
2013 May 9. [Epub ahead of print]
Takahashi M, Kanamori Y, Takahashi M, Momose
T, Iwanaka T: Detection of a metastatic lesion andtiny yolk sac tumors in two teenage patients by
FDG-PET: report of two cases. Surg Today. 2013
Jun 26. [Epub ahead of print]
Takazawa S, Uchida H, Kawashima H, Tanaka Y,
Sato, Takahiro Jimbo T, Masuko T, Deie K,
Iwanaka T, Successful left thoracoscopic
esophagectomy for congenital esophageal stenosis
with a useful adjunct of preoperative endoscopic
marking, J Laparoendosc Adv Surg Tech B
Videoscopy. 2013
Ishimaru T, Takazawa S, Uchida H, Kawashima H,
Fujii M, Harada K, Sugita N, Mitsuishi M,

Iwanaka T: Development of a needle driver withmultiple degrees of freedom for neonatal
laparoscopic surgery. J Laparoendosc Adv Surg
Tech 23: 644-648, 2013
10. Takazawa S, Ishimaru T, Fujii M, Harada K,
Sugita N, Mitsuishi M, Iwanaka T: Assessment ofsuturing in the vertical plane shows the efficacy ofthe multi-degree-of-freedom needle driver forneonatal laparoscopy.
Pediatr Surg Int 29:
1177-82. 2013
11. Takazawa S, Uchida H, Kawashima H, Tanaka Y,
Masuko T, Deie K, Nagase Y, Iwanaka T: Externalstabilization for severe tracheobronchomalacia
using separated ring-reinforced ePTFE grafts is
effective and safe on a long-term basis. Pediatr
Surg Int. 29: 1165-1169,2013
12. Iwanaka T, Taguchi T, Kitagawa H, Yamataka A.:
Editorial Pediatr Surg Int 2013 epub
13. Yonekura T, Ueno S, Iwanaka T: Care of children
in a natural disaster: lessons learned from theGreat East Japan earthquake and tsunami. Pediatr
Surg Int ;29(10) :1047-51. 2013
14. Hanazaki K, Tominaga R, Nio M, Iwanaka T,
Okoshi K, Kaneko K, Nagano H, Nishida T,
Nishida H, Hoshino K, Maehara T, Masuda M,
Matsufuji H, Yanaga K, Tabayashi K, Satomi S,
Kokudo N: Report from the committee for
improving the work environment of Japanesesurgeons: survey on effects of the fee revision for
medical services provided by surgeons. Surg
Today online-first, 2013
15. Yoshida M, Tanaka M, Gomi K, Iwanaka T,
Dehner LP, Tanaka Y: Fetal lung interstitial tumor:
The first Japanese case report and a comparison
with fetal lung tissue and congenital cystic
adenomatoid malformation/congenital pulmonary
airway malformation type 3. Pathol Int. 63:506-9,
2013
16. Masuko T, Uchida H, Kawashima h, Tanaka Y,
Deie K, Iwanaka T: Laparoscopic Excision of
Urachal Remnents Is a Safe and Effective
Alternative to Open Surgery in Children. J
Laparoendosc Adv Surg Tech A. 2013 Sep 28.
[Epub ahead of print]
17. Tanaka Y, Uchida H, Kawashima H, Sato K,
Takazawa S, Masuko T, Deie K, Iwanaka T:
Complete thoracoscopic versus video-assisted

187

thoracoscopic resection of congenital lung lesions.
J Laparoendosc Adv Surg Tech A. 2013 Aug;23:719-22, 2013
18. Japanese multicenter study group on male highimperforate anus (equal contribution): Multicenter
retrospective comparative study of laparoscopically assisted and conventional anorectoplasty for male infants with rectoprostatic
urethral fistula. J Pediatr Surg 48: 2383-2388,
2013
19. Websky Mv, Fujishiro J, Ohsawa I, Praktiknjo M,
Wehner S, Abu-Elmagd K, Kitamura K, Kalff JC,
Schaefer N, Pech T. The novel guanylhydrazone
CPSI-2364 ameliorates ischemia reperfusion
injury after experimental small bowel transplantation.Transplantation.2013 Jun 15; 95(11):1315-23.
20. Fujishiro J, Masumoto K, Urita Y, Shinkai T,
Gotoh C. Pancreatic complications in pediatriccholedochal cysts. J Pediatr Surg.2013 48(9):1897-902.
21. Deie K, Uchida H, Kawashima H, Tanaka Y,
Masuko T, Takazawa S. Single-incision
laparoscopic-assisted appendectomy in children:
exteriorization of the appendix is a key
componentof a simple and cost-effective
surgical technique. J Pediatr Surg Int. 2013 Nov;
29 (11)1187-91
22. Watanabe E, Tanaka K, Takeda N, Takayasu H,
Yokota K, Watanabe M: Surgical technique toprevent spillage of cyst fluid during operation for
cystic ovarian tumors. Pediatr Surg Int. 2013
Jun;29(6):645-9
23. Yoneda A, Usui N, Taguchi T, Kitano Y, Sago H,
Kanamori Y, Nakamura T, Nosaka S, Oba MS:
Impact of the histological type on the prognosis ofpatients with prenatally diagnosed sacrococcygeal
teratomas: the results of a nationwide Japanesesurvey. Pediatr Surg Int. 2013 Nov;29(11):1119-25
24. Watanabe Y, Kanamori Y, Uchida K, Taguchi T.
Isolated hypoganglionosis: results of a nationwide
survey in Japan. Pediatr Surg Int. 2013 Nov;
29(11):1127-30.
25. Watanabe T, Takahashi M, Amari S, Ohno M,
Sato K, Tanaka H, Miyasaka M, Fuchimoto Y, Ito
Y, Kanamori Y: Olive oil enema in a pre-term

infant with milk curd syndrome. PediatrInt. 2013
Aug;55(4):e93-5
26. Takahashi M, Kanamori Y, Takahashi M, Momose
T, Iwanaka T: Detection of a metastatic lesion andtiny yolk sac tumors in two teenage patients by
FDG-PET: report of two cases. Surg Today. 2013
Jun 26. [Epub ahead of print]
27. Nagata K, Usui N, Kanamori Y, Takahashi S,
Hayakawa M, Okuyama H, Inamura N, Fujino Y,
Taguchi T: The current profile and outcome ofcongenital diaphragmatic hernia: a nationwide
survey in Japan. J Pediatr Surg. 2013 Apr;48(4):738-44
28. Takahashi S, Sago H, Kanamori Y, Hayakawa M,
Okuyama H, Inamura N, Fujino Y, Usui N,
Taguchi T: The junction between hyaline cartilage
and engineered cartilage in rabbits. Pediatr Int.
2013 Aug;55(4):492-7.
29. 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 Feb;48(2):e29-31.
30. Yamada K, Kanamori Y, Tanaka H, Fujino A,
Watanabe T, Takeda N, Takahashi M, Yamada W,
Ishihama H: Plasma citrulline may be a goodmarker of intestinal functions in intestinal
dysfunction. Surg Today. 2013 Nov; 43(11):1330-2.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

189

Department of Geriatric Medicine
Department of Aging Research
Professor
Masahiro Akishita, MD, PhD.

Associate Professor
Sumito Ogawa, MD, PhD.

Lecturer
Yasuhiro Yamaguchi, MD., PhD.

Tomohiko Urano, MD, PhD.

Research Associate
Hidetaka Ota, MD, PhD.

Taro Kojima, MD.

Yumi Kameyama, MD, PhD.

Shinya Ishii, MD.

Kenichi Takayama, MD, PhD

Masaki Ishii, MD, PhD

Homepage

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

Introduction and Organization
The Department of Geriatric Medicine wasestablished in 1962, as the first geriatric department inJapan.
Since elderly patients usually have multiple organ
disorders, these patients should be taken cared as awhole from multiple points of view. In addition,
symptoms, signs and responses to the treatment in theelderly patients could be quite different from theyounger counterparts. Specific knowledge on thephysiological and metabolic changes with aging isnecessary when these elderly patients are treated.
Quality of life of the patients is another point of viewwhich should be emphasized. The department belongs
to the division of Internal Medicine. The staff includes
one professor, one associate professor, two lecturers,
and 6 assistant professors.
Our sub-specialty includes respirology, cardiology,
neurology, hematology, endocrinology, and bonemetabolism, besides the general geriatric internal
medicine.
The main objective of our research is to elucidate

the pathophysiology of aging process and understandelderly patients from viewpoints of basic aging
science using molecular biology technique andclinical aspects using the recent advancement oftechnology and geriatric assessment.

Clinical activities
In the clinical ward, there are approximately 25
patients who are taken care of by junior, senior andchief 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. 352 newand a total of 18,528 patients visited the out-patient
clinic in the last fiscal year.

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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 physicalexamination, 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.

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
disorderResearch

Publications

Various studies have been done over a wide rangeof field, such as clinical observational studies orbasic molecular studies.
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

1. Akishita M, Ishii S, Kojima T, Kozaki K, Kuzuya
M, Arai H, Arai H, Eto M, Takahashi R, Endo H,
Horie S, Ezawa K, Kawai S, Takehisa Y, Mikami
H, Takegawa S, Morita A, Kamata M, Ouchi Y,
Toba K. Priorities of Health Care Outcomes for
the Elderly. J Am Med Dir Assoc 14:479-484,
2013.
2. Azuma K, Tsukui T, Ikeda K, Shiba S, Nakagawa
K, Okano T, Urano T, Horie-Inoue K, Ouchi Y,
Ikawa M, Inoue S: Liver-specific γ-glutamyl
carboxylase-1 deficient mice display bleeding
diathesis and short life span. PLoS ONE 9,e88643, 2014.
3. Chen LK, Liu LK, Woo J, Assantachai P, Auyeung
TW, Bahyah KS, Chou MY, Chen LY, Hsu PS,
Krairit O, Lee JS, Lee WJ, Lee Y, Liang CK,
Limpawattana P, Lin CS, Peng LN, Satake S,
Suzuki T, Won CW, Wu CH, Wu SN, Zhang T,
Zeng P, Akishita M, Arai H. Sarcopenia in Asia:
consensus report of the asian working group forsarcopenia.. J Am Med Dir Assoc 15:95-101,
2014.
4. Greendale GA, Ishii S, Huang MH, Karlamangla
AS. Predicting the Timeline to the Final
Menstrual Period: the Study of Women’s HealthAcross the Nation. J Clin Endocrinol Metab.
98:1483-1491, 2013
5. Hibi S, Yamaguchi Y, Umeda-Kameyama Y,
Iijima K, Takahashi M, Momose T, Akishita M,
Ouchi Y: Respiratory dysrhythmia in dementia
with Lewy bodies: a cross-sectional study. BMJ
open 3:e002870, 2013
6. Ikeda K, Shiba S, Horie-Inoue K, Shimokata K,

191

Inoue S: A stabilizing factor for mitochondrial
respiratory supercomplex assembly regulates
energy metabolism in muscle. Nat Commun 4,
2147, 2013.
7. Ishii S, Cauley JA, Greendale GA, Crandall CJ,
Huang MH, Danielson ME, Karlamangla AS.
Trajectories of Femoral Neck Strength in Relation
to the Final Menstrual Period in a Multi-Ethnic
Cohort. Osteoporosis Int 24:2471-2481, 2013
8. Ishii S, Cauley JA, Greendale GA, Crandall CJ,
Danielson ME, Ouchi Y, Karlamangla AS.
C-Reactive Protein, Bone Strength, and 9-year
Fracture Risk: Data from The Study of Women's
Health Across the Nation (SWAN). J Bone Miner
Res. 28:1688-1698, 2013
9. Ishii S, Miyao M, Mizuno Y, Tanaka-Ishikawa M,
Akishita M, Ouchi Y. Association between serum
uric acid and lumbar spine bone mineral densityin peri- and postmenopausal Japanese women.
Osteoporosis Int 25:1099-105, 2014.
10. Ishii S, Tanaka T, Shibasaki K, Ouchi Y, Kikutani
T, Higashiguchi T, Obuchi S, Ishikawa-Tanaka K,
Hirano H, Kawai H, Tsuji T, Iijima K.
Development of a simple screening test forsarcopenia in older adults. Geriatrics andGerontology International. Suppl 1:93-101,2014
11. Mori T, Ishii S, Greendale GA, Cauley JA,
Sternfeld B, Crandall CJ, Han W, Karlamangla AS.
Physical Activity as Determinant of Femoral Neck
Strength Relative to Load in Adult Women.
Findings from the Hip Strength Across the
Menopause Transition Study. Osteoporosis Int.
25:265-272. 2014
12. Nagai K, Shibata S, Akishita M, Sudoh N, Obara
T, Toba K, Kozaki K. Efficacy of combined use of
three non-invasive atherosclerosis tests to predict
vascular events in the elderly; carotid
intima-media thickness, flow-mediated dilation ofbrachial artery and pulse wave velocity.
Atherosclerosis. 231:365-370, 2013.
13. Ota H, Akishita M, Tani H, Tatefuji T, Ogawa S,
Iijima K, Eto M, Shirasawa T, Ouchi Y.
trans-Resveratrol in Gnetum gnemon protects
againstoxidative-stress-induced
endothelial
senescence. J Nat Prod. 76:1242-1247,2013
14. Shibasaki K, Ogawa S, Yamada S, Iijima K, Eto
M, Kozaki K, Toba K, Akishita M, Ouchi Y.

Association of decreased sympathetic nervous
activity with mortality of older adults in long-termcare. Geriatr Gerontol Int.14:159-66, 2014.
15. Son BK, Akishita M, Iijima K, Ogawa S, Arai T,
Ishii H, Maemura K, Aburatani H, Eto M, Ouchi Y.
Thrombomodulin, a novel molecule regulating
inorganic phosphate-induced vascular smoothmuscle cell calcification. J Mol Cell Cardiol
56:72-80, 2013
16. Tani H, Hikami S, Iizuna S, Yoshimatsu M,
Asama T, Ota H, Kimura Y, Tatefuji T, Hashimoto
K, Higaki K. Pharmacokinetics and safety of
resveratrol derivatives in humans after oral
administration of melinjo (Gnetum gnemon L.)
seed extract powder. J Agric Food Chem.
62:1999-2007, 201417. Oneyama C, Kito Y, Asai R, Ikeda J, Yoshida T,
Okuzaki D, Kokuda R, Kakumoto K, Takayama K,
Inoue S, Morii E, Okada M: MiR-424/
503-mediated Rictor upregulation promotes tumor
progression. PLoS ONE 8, e80300, 2013.
18. Takayama K, Horie-Inoue K, Katayama S, Suzuki
T, Tsutsumi S, Ikeda K, Urano T, Fujimura T,
Takagi K, Takahashi S, Homma Y, Ouchi Y,
Aburatani H, Hayashizaki Y, Inoue S: Androgenresponsive long noncoding RNA CTBP1-AS
promotes prostate cancer. EMBO J 32, 1665-1680,
2013.
19. Yamada Y, Fujimura T, Takahashi S, Takayama K,
Urano T, Murata T, Obinata D, Ouchi Y, Homma
Y, Inoue S: Clinical significance of amyloid
precursor protein in patients with testicular germ
cell tumor. Adv Urol 2013, 348438, 2013.
20. Yamaga R, Ikeda K, Horie-Inoue K, Ouchi Y,
Suzuki Y, Inoue S: RNA-sequencing of MCF-7
breast cancer cells identifies novel estrogenresponsive genes with functional estrogen
receptor-binding sites in the vicinity of theirtranscription start sites. Horm Cancer 4, 222-232,
2013.
21. Gotanda H, Kameyama Y, Yamaguchi Y, Ishii M,
Hanaoka Y, Yamamoto H, Ogawa S, Iijima K,
Akishita M, Ouchi Y: Acute exogenous lipoid
pneumonia caused by accidental kerosene
ingestion in an elderly patient with dementia: acase report. Geriatr Gerontol Int. 13:222-225,
2013

192

22. Ishii M, Yamaguchi Y, Yakabe M, Ohike Y, Eto M,
Izutsu K, Hangaishi A, Akishita M, Kurokawa M,
Ouchi Y: Intravascular large B-cell lymphomawith symptoms resembling progressive dementia:
a clinical case report. J Am Geriatr Soc 61:
303-304,2013
23. Yonenaga A, Ota H, Honda M, Koshiyama D,
Yagi T, Hanaoka Y, Yamamoto H, Yamaguchi Y,
Iijima K, Akishita M, Ouchi Y: Marked
improvement of elderly postprandial hypotension
by dipeptidyl peptidase IV inhibitor. Geriatr
Gerontol Int 13:227-229,2013

Surgical Sciences
1. Surgery

194

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Murakawa, Tomohiro

StaffsAnraku, Masaki
Nitadori, Jun-ichi
Nagayama, Kazuhiro
Kitano, Kentaro

Homepage

http://ctstokyo.umin.ne.jp/

History
Clinical works and basic research of the thoracic
surgery have been performed since the prewar era inthis university, when Professor Tsuduki, Masao
adopted the modified Coryllos’s thoracoplasty for thetreatment of the pulmonary tuberculosis in 1934. They
initiated thoracoscopy for the treatment of the
tuberculosis in our country. After the successful
application of the 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). Nakajima, Jun has taken overthe mission of the department since April 2011.

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 clinicalresearch, and education of the medical students,
postgraduates, and the surgical residents in our
university.

Clinical activities
Six staffs (Nakajima J, Murakawa T, Anraku M,
Nitadori J, Nagayama K, 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 2012 was approximately 370 thousand195

out of 1.26 million total deaths in Japan. Of them, 72
thousand people were killed by tracheal, bronchial 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. More than 300
thoracic surgeries are performed in our department in2013.
We have performed the modern-style thoracoscopy
for the diagnosis and treatment of the thoracic
diseases with less surgical invasiveness since 1992.
We currently conduct a standard surgery for clinicalstage
IA
NSCLC,
i.e.
lobectomy
andlymphadenectomy through thoracoscopy: In 2013,
85% of patients with NSCLC was the candidate forthoracoscopic surgery in our department. Researches
on less-invasiveness, oncological advantage of thethoracoscopic 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 hosted the annual meeting ofJapan Association for Research on Thymus (JART)
this year, and we are now actively participating a
multiinstitutional study on malignant thymic epithelial
neoplasms database led by JART.
We are now preparing for clinical lungtransplantation for the patients suffering fromadvanced stage of diffuse lung diseases that are
refractory to conventional treatments. Our hospital iscertified as a lung transplant centers this fiscal year.
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 for

196

the treatment of the patients with unresectable orrecurrent NSCLC.
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) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(4) Application of new fluorescent agents fordiagnosis of lung cancer.
(5) Immunotherapy for lung cancer and malignant
mesothelioma.
(6) Single and multi-institutional studies on thymic
epithelial malignant neoplasms.
(7) Single and multi-institutional studies on surgicaltherapeutics for pulmonary metastasis.
(8) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea after
allogeneic transplantation.
(9) Research on donor lung preservation.

Selected publications
1. Murakawa T, Konoeda C, Ito T, Inoue Y, Sano A,
Nagayama K, Nakajima J. The ground glass
opacity component can be eliminated from the
T-factor assessment of lung adenocarcinoma. Eur
J Cardiothorac Surg. 2013;43(5):925-32
2. Iida T, Nomori H, Shiba M, Nakajima J, Okumura
S, Horio H, Matsuguma H, Ikeda N, Yoshino I,
Ozeki Y, Takagi K, Goya T, Kawamura M,
Hamada C, Kobayashi K; Metastatic Lung Tumor
Study Group of Japan. Prognostic factors after
pulmonary metastasectomy for colorectal cancer
andrationalefordetermining
surgicalindications: a retrospective analysis. Ann Surg.
2013;257(6):1059-64
3. Shiono S, Sato T, Horio H, Chida M, Matsuguma
H, Ozeki Y, Nakajima J, Okumura S; Metastatic
Lung Tumor Study Group of Japan. Outcomesand prognostic factors of survival after
pulmonary resection for metastatic gastric cancer.
Eur J Cardiothorac Surg. 2013;43(1):e13-6.
4. 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;15(4):481-91.
5. Sano A, Fukami T, Murakawa T, Nakajima J.
Recurrent Pneumothorax Related to Swyer-James
Syndrome. Ann Thorac Cardiovasc Surg. 2013
Feb 15. [Epub ahead of print]
6. Sano A, Murakawa T, Nakajima J. Chronic
tension empyema. Asian Cardiovasc Thorac Ann.
2013;21(1):93-6
7. Yoshida Y, Ota S, Murakawa T, Takai D,
Nakajima
J.
Combined
Large
Cell
Neuroendocrine Carcinoma and Adenocarcinoma
with Epidermal Growth Factor Receptor Mutation
in a Female Patient Who Never Smoked. Ann
Thorac Cardiovasc Surg. 2013 Mar 22. [Epubahead of print]
8. Kawakami M, Morita S, Sunohara M, Amano Y,
Ishikawa R, Watanabe K, Hamano E, Ohishi N,
Nakajima J, Yatomi Y, Nagase T, Fukayama M,
Takai D. FER overexpression is associated withpoor postoperative prognosis and cancer-cellsurvival in non-small cell lung cancer. Int J Clin
Exp Pathol. 2013;6(4):598-612
9. Morita S, Yoshida A, Goto A, Ota S, Tsuta K,
Yokozawa K, Asamura H, Nakajima J, Takai D,
Mori M, Oka T, Tamaru J, Itoyama S, Furuta K,
Fukayama M, Tsuda H. High-grade lungadenocarcinoma with fetal lung-like morphology:
clinicopathologic, immunohistochemical, andmolecular analyses of 17 cases. Am J Surg Pathol.
2013;37(6):924-32
10. 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 bygadolinium-neutron capture therapy using
gadolinium-entrapped liposome as gadolinium
delivery agent. Biomed Pharmacother. Biomed
Pharmacother. 2013;67(6):451-7
11. Konoeda C, Koinuma D, Morishita Y, Sano A,
Nagayama K, Motomura N, Kakimi K, Miyazono
K, Nakajima J, Nicolls MR, Murakawa T.
Epithelial to mesenchymal transition in murine
tracheal allotransplantation: an immunohisto-

197

chemical observation. Transplant Proc. 2013;
45(5):1797-801
12. Kawakami M, Ishikawa R, Amano Y, Sunohara M,
Watanabe K, Ohishi N, Yatomi Y, Nakajima J,
Fukayama M, Nagase T, Takai D. Detection ofnovel paraja ring finger 2-fer tyrosine kinase
mRNA chimeras is associated with poor
postoperative prognosis in non-small cell lungcancer. Cancer Sci. 2013;104(11):1447-54.
13. Amano Y, Takai D, Ohishi N, Shinozaki-Ushiku
A, Fukayama M, Akahane M, Nakajima J, Nagase
T.
Successful Treatment of Mediastinal
Unicentric
Castleman's
DiseaseUsing
Video-Assisted Thoracoscopic Surgery with
Preoperative Embolization.
Case Rep Med.
2013;2013:35.
14. Saita K, Murakawa T, Kawano H, Sano A,
Nagayama K, Nakajima J. Chest wall deformity
found in patients with primary spontaneous
pneumothorax. Asian Cardiovasc Thorac Ann.
2013;21(5):582-7.
15. Huang H, Peng X, Nakajima J. Advances in the
study of biomarkers of idiopathic pulmonary
fibrosis in Japan. Biosci Trends. 2013; 7(4):172-177
16. Nitadori J, Bograd AJ, Morales EA, Rizk NP,
Dunphy MP, Sima CS, Rusch VW, Adusumilli PS.
Preoperative consolidation-to-tumor ratio andSUVmax stratify the risk of recurrence in patients
undergoing
limitedresectionforlungadenocarcinoma ≤2 cm. Ann Surg Oncol. 2013;20(13):4282-8.
17. Nitadori J, Bograd AJ, Kadota K, Sima CS, Rizk
NP, Morales EA, Rusch VW, Travis WD,
Adusumilli PS. Impact of micropapillary
histologic subtype in selecting limited resection
vs lobectomy for lung adenocarcinoma of 2cm orsmaller. J Natl Cancer Inst. 2013; 105(16):1212-20.
18. Nitadori J, Colovos C, Kadota K, Sima CS,
Sarkaria IS, Rizk NP, Rusch VW, Travis WD,
Adusumilli PS. Visceral pleural invasion does notaffect recurrence or overall survival among
patients with lung adenocarcinoma ≤ 2 cm: aproposal to reclassify T1 lung adenocarcinoma.
Chest. 2013;144(5):1622-31.
19. Kadota K, Nitadori J, Adusumilli PS. Prognostic

value of the immune microenvironment in lungadenocarcinoma. Oncoimmunology. 2013; 2(5):e24036.
20. Suzuki K, Kadota K, Sima CS, Nitadori J, Rusch
VW, Travis WD, Sadelain M, Adusumilli
PS.Clinical impact of immune microenvironment
in stage I lung adenocarcinoma: tumor
interleukin-12 receptor β2 (IL-12Rβ2), IL-7R,
and stromal FoxP3/CD3 ratio are independent
predictors of recurrence. J Clin Oncol. 2013;31(4):490-8.
21. Kadota K, Nitadori J, Sarkaria IS, Sima CS, Jia X,
Yoshizawa A, Rusch VW, Travis WD, Adusumilli
PS. Thyroid transcription factor-1 expression isan independent predictor of recurrence andcorrelates with the IASLC/ATS/ERS histologic
classification in patients with stage I lungadenocarcinoma. Cancer. 2013;119(5): 931-8
22. Vogl UM, Nagayama K, Bojic M, Hoda MA,
Klepetko W, Jaksch P, Dekan S, Siersch V,
Mitterbauer M, Schellongowski P, Greinix HT,Petkov V, Schulenburg A, Kalhs P, Rabitsch W.
Lung transplantation for bronchiolitis obliterans
after allogeneic hematopoietic stem celltransplantation: a single-center experience.
Transplantation. 2013; 95(4):623-8

198

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

Associate Professor
Noboru Motomura, M.D.

Lecturer
Yasutaka Hirata, M.D., Aya Saito, M.D., Mitsutoshi Kimura , M.D.

Associate
Tetsuhiro Takaoka, 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 anincreasing number of patients who require ventricularassist device treatment. Present staffs are one Chief

199

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 2014, 47 cases ofheart transplantation and more than 140 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) development of a newly-designed surgical robotic system,4) application of regenerative medicine to end-stage

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heart failure, 5) mechanism analysis of right heart
failure and development of effective pharmacologicaltherapy, 6) development of versatile suture device, 7)
development of new drug for spinal cord ischemia .

References(1) Kyo S, Minami T, Nishimura T, Gojo S, Ono M:
New era for therapeutic strategy for heart failure:
Destination therapy by left ventricular assist
device. J Cardiol 2012, 59: 101-9(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
Implantation of Left Ventricular Assist Device.
Circ J 2013; 77, 96-104(3) Yamauchi H, Motomura N, Chung UI, Sata M,
Takai D, Saito A, Ono M, Takamoto S: Growthassociated hyperphosphatemia in young recipients
accelerates aortic allograft calcification in a rat
model. J Thorac Cardiovasc Surg 2013; 145:
522-30(4) Imamura T, Kinugawa K, Kato N, Minatsuki S,
Muraoka H, Inaba T, Maki H, Shiga T, Hatano M,
Yao A, Kyo S, Ono M, Komuro I: Successful
conversion from thiazide to tolvaptan in a patientwith stage D heart failure and chronic kidneydisease before heart transplantation. Int Heart J
2013; 54: 48-50(5) Koyama S, Itatani K, Kyo S, Aoyama R,
Ishiyama T, Harada K, Ono M: Subacute
Presentation of Right Ventricular Perforation afterPacemaker Implantation. Ann Thorac Cardiovasc
Surg 2013; 19: 73-75(6) Imamura T, Kinugawa K, Hatano M, Kato N,
Minatsuki S, Muraoka H, Inaba T, Maki H, Shiga
T, Yao A, Kyo S, Ono M, Nagai R: Bosentan
improved persistent pulmonary hypertension in acase after implantation of a left ventricular assist
device. J Artif Organ 2013; 101-104(7) 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 2013; 77:995-1000(8) Yamakawa M, Kyo S, Yamakawa S, Ono M,
Kinugawa K, Nishimura T: Destination therapy:
the new gold standard treatment for heart failure
patients with left ventricular assist devices. Gen
Thorac Cardiovasc Surg 2013; 61: 111-117(9) Imamura T, Kinugawa K, Kato N, Minatsuki S,
Muraoka H, Inaba T, Maki H, Shiga T, Hatano M,
Hosoya Y, Takahashi M, Yao A, Kyo S, Ono, M,
Komuro I: A case of recovery of response totolvaptan associated with remission of acutekidney injury and increased urine osmolality. Int
Heart J 2013; 54: 115-118 PMID
(10) Hiroyoshi J, Saito A, Panthee N, Imai Y,
Kawashima D, Motomura N, Ono M: Aortic
Valve Replacement for Aortic Stenosis Caused by
Alkaptonuria. Ann Thorac Surg 2013; 95:
1076-1079(11) 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
continuous-flow LVAD with cardiac beatsynchronizing system in acute ischemic heart
failure models. J Artif Organs 2013; 16: 119-128(12) Imamura T, Kinugawa K, Hatano M, Kato N,
Minatsuki S, Muraoka H, Inaba T, Maki H,
Kimura M, Kinoshita O, Shiga T, Yao A, Kyo S,
Ono M, Komuro I: Acute pulmonary
vasoreactivity test with sildenafil or nitricmonoxide before left ventricular assist device
implantation. J Artif Organs 2013; 16: 389-392(13) Imamura T, Kinugawa K, Ono M, Kagami Y,
Endo M, Minatsuki S, Muraoka H, Kato N, Inaba
T, Maki H, Hatano M, Yao A, Kyo S, Komuro I:
Everolimus-incorporated
immune-suppressantstrategy improves renal dysfunction while
maintaining low rejection rates after hearttransplantation in Japanese patients. Int Heart J
2013; 54: 222-227(14) Imamura T, Kinugawa K, Kato N, Kagami Y,
Endo M, Kaneko N, Minatsuki S, Muraoka H,
Inaba T, Maki H, Hatano M, Doi K, Yao A,
Takazawa Y, Ono M, Kyo S, Komuro I:
Successfultreatmentof
Hemodynamic

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compromise caused by antibody-mediated andcellular rejection in a recipient 12 years after
heart transplantation. Int Heart J 2013; 54:
328-331(15) 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 bygadolinium-neutron capture therapy using
gadolinium- entrapped liposome as gadolinium
delivery agent. Biomed Pharmacother 2013; 67:
451-457(16) Saito A, Miyata H, Motomura N, Ono M,
Takamoto S: Japan Cardiovascular Surgery
Database
Organization.
Propensity-matchedanalysis of bilateral internal mammary artery vssingle internal mammary artery in 7702 cases ofisolated coronary artery bypass grafting. Eur J
Cardiothorac Surg 2013; 44: 711-7(17) Tabata M, Kasegawa H, Suzuki T, Watanabe H,
Fukui T, Takanashi S, Ono M: Long-term
outcomes of early surgery for asymptomatic
severe chronic mitral regurgitation. J Heart Valve
Dis 2013: 22, 354-360(18) Kubota H, Miyata H, Motomura N, Ono M,
Takamoto S, Harii K, Oura H, Hirabayashi S, Kyo
S: Deep sternal wound infection after cardiac
surgery. J CardioThorac Surg 2013; 8: 132. doi:
10.1186/1749-8090-8-132(19) Ando T, Kawashima D, Kim H, Joung S, Liao H,
Kobayashi E, Gojo S, Kyo S, Ono M, Sakuma I.
Directminimal-invasive
intraoperativeelectrophysiological mapping of the heart. Minim
Invasive Ther Allied Technol 2013; 22: 372-380(20) Inoue T, Nishimura T, Murakami A, Kinoshita O,
Kyo S, Ono M: Four-year paracorporeal left
ventricular assist device (LVAD) support for heart
failure after Rastelli operation. J Artif Organs
2013; 16: 501-503(21) Ono M, Nishimura T, Kinoshita O, Shiga T,
Kinugawa K , Nagai R, Kyo S: Improved survival
in patients with continuous-flow ventricular assist
device for bridge to heart transplantation.
Transplant Proc 2013; 45:2017-2018(22) Fukushima N, Ono M, Saito S, Saiki Y, Kubota S,
Tanoue Y, Minami M, Konaka S, Ashikari J:

Japanese strategies to maximize heart and lungavailabilities: experience from 100 consecutive
brain-dead donors. Transplant Proc 2013; 45:
2871-2874(23) Fukushima N, Ono M, Saiki Y, Minami M,
Konaka S, Ashikari J: Donor Evaluation andManagement System (Medical Consultant
System) in Japan: Experience From 200
Consecutive Brain-Dead Organ Donation.
Transplant Proc 2013; 45:1327-1330(24) Kimura M, Kinoshita O, Nishimura T, Imamura T,
Shiga T, Kashiwa K, Kinugawa K, Kyo S, Ono
M: Successful weaning from the DuraHeart witha low left ventricular ejection fraction. J Artif
Organs 2013: 16: 504-507(25) Doi K, Urata M, Katagiri D, Inamori M, Murata S,
Hisagi M, Ono M, Matsubara T, Ishii T, Yahagi N,
Nangaku M, Noiri E: Plasma neutrophil
gelatinase-associated lipocalin in acute kidney
injury superimposed on chronic kidney disease
after cardiac surgery: a multicenter prospective
study. Crit Care. 2013; 17: R270
(26) Takeda K, Miyata H, Motomura N, Yamauchi T,
Toda K, Sawa Y, Takamoto S. Contemporary
perioperative results of heart valve replacement indialysis patients: analysis of 1,616 patients fromthe Japan adult cardiovascular surgery database.J
Heart Valve Dis. 2013; 22: 850-888(27) Miyairi T, Miyata H, Taketani T, Sawaki D,
Suzuki T, Hirata Y, Shimizu H, Motomura N,
Takamoto S; Japan Adult Cardiovascular
Database
Organization.
Risk
model
of
cardiovascular surgery in 845 Marfan patientsusing the Japan adult cardiovascular surgery
database. Int Heart J. 2013; 54: 401-404(28) Tokuda Y, Miyata H, Motomura N, Araki Y,
Oshima H, Usui A, Takamoto S; Japan Adult
Cardiovascular Database Organization. Outcomeof pericardiectomy for constrictive pericarditis inJapan: a nationwide outcome study. Ann Thorac
Surg. 2013; 96: 571-6(29) Okamoto Y, Motomura N, Murashima S,
Takamoto S. Anxiety and depression after
thoracic aortic surgery or coronary artery bypass.
Asian Cardiovasc Thorac Ann. 2013; 21: 22-30(30) Kaminishi Y, Misawa Y, Kobayashi J, Konishi H,
Miyata H, Motomura N, Takamoto S; Japan

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Cardiovascular Surgery Database Organization.
Patient-prosthesis mismatch in patients withaortic valve replacement. Gen Thorac Cardiovasc
Surg. 2013; 61: 274-9.
(31) Inoue T, Kitamura T, Torii S, Hanayama N, Oka
N, Itatani K, Tomoyasu T, Irisawa Y, Shibata M,
Hayashi H, Ono M, Miyaji K: Five-week use of amonopivot centrifugal blood pump as a rightventricular assist device in severe dilated
cardiomyopathy. J Artif Organs. 2014; 17: 95-98(32) Ozaki S, Saito A, Nakaminami H, Ono M,
Noguchi N, Motomura N: Comprehensive
evaluation of fibrin glue as a local drug-delivery
system-efficacy and safety of sustained release ofvancomycin by fibrin glue against local
methicillin-resistant
Staphylococcus
aureusinfection. J Artif Organs 2014; 17: 42-49

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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.

Takashi Kiyokawa MD. PhD

Asami Tanabe MD.

Tomoki Deguchi 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. And, hernia surgery isusually perfomed, also. All residents and medical
personnel work many extra hours with highmotivation whenever it is necessary for the good of
the patients.

References
1. Aikou S, Aida J, Takubo K, Yamagata Y, Seto Y,
Kaminishi M, Nomura S. Columnar metaplasia ina surgical mouse model of gastro-esophageal
reflux disease is not derived from bone

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2.

3.

4.

5.

6.

7.

8.

9.

marrow-derived cell. Cancer Sci 104(9):1154-61,
2013
Motoyama S, Mori K, Kamei T, Miura M, Hinai Y,
Sato Y, Yoshino K, Sasaki T, Miyata G, Seto Y,
Ogawa J. Evaluation of the risk of lymph nodemetastasis using CRP 1846C>T genetic
polymorphism in submucosal thoracic esophageal
squamous cell carcinoma. Ann Surg Oncol 20(6):1978-84,2013
Nashimoto A, Akazawa K, Isobe Y, Miyashiro I,
Katai H, Kodera Y, Tsujitani S, Seto Y, Furukawa
H, Oda I, Ono H, Tanabe S, Kaminishi M. Gastriccancer treated in 2002 in Japan: 2009 annual
report of the JGCA nationwide registry. Gastric
Cancer. 16(1):1-27,2013
Nomura S, Terao S, Adachi K, Kato T, Ida K,
Watanabe H, Shimbo T; Research Group for
Establishment of Endoscopic Diagnosis of
Chronic Gastritis. Endoscopic diagnosis of gastricmucosal activity and inflammation. Dig Endosc
25(2): 136-46, 2013
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.
Hepato- gastroenterology 60(124): 751-5, 2013
Mitsui T, Goto O, Shimizu N, Hatao F, Wada I,
Niimi K, Asada-Hirayama I, Fujishiro M, Koike
K, Seto Y.Novel Technique for Full-Thickness
Resection of Gastric Malignancy: Feasibility ofNonexposed Endoscopic Wall-Inversion Surgery(NEWS) in Porcine Models.Surg Laparosc
Endosc Percutan Tech 23(6): e217-21,2013
Mori K, Yamagata Y, Wada I, Shimizu N,
Nomura S, Seto Y.Robotic-assisted totallytranshiatal lymphadenectomy in the middle
mediastinum for esophageal cancer. J Robot Surg
7:385-387,2013
Mitsui T, Fukatsu K, Yanagawa M, Amenomori S,
Ogawa E, Fukuda T, Murakoshi S, Moriya T,
Yasuhara H, Seto Y.Truncal vagotomy
temporarily
decreases
theproandanti-inflammatory cytokine levels in the small
intestine. Surg Today. 2013
Shimoyama S. Diabetes mellitus carries a risk ofgastric cancer: a meta-analysis. World J
Gastroenterol 19(40): 6902-10, 2013

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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

207

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 (2013)
1. Kokudo T, Hasegawa K, Sugawara Y, et al. Pitfallof right lateral sector graft procurement:
supraportal right posterior hepatic artery.
Transplantation 2013; 27:89-91.
2. Mise Y, Sakamoto Y, Ishizawa T, et al. A
worldwide survey of the current daily practice inliver surgery. Liver Cancer 2013; 2:55-66.
3. Takemura N, Saiura A, Koga R, et al. Repeat
hepatectomy for recurrent liver metastasis fromgastric carcinoma. World J Surg 2013; 37:
2667-70.
4. Yamashita S, Sakabe M, Ishizawa T, et al.
Visualization of the leakage of pancreatic juice
using a chymotrypsin-activated fluorescent probe.
Br J Surg 2013; 100:1220-8.
5. Kawaguchi Y, Sugawara Y, Ishizawa T, et al.
Identification of veno-occlusive regions in a right
liver graft after reconstruction of vein segments 5
and 8: application of indocyanine green fluorescence imaging. Liver Transpl 2013; 19:778-9.
6. Kaneko J, Sugawara Y, Tamura S, et al. De novo
malignancies after adult-to-adult living-donorliver transplantation with a malignancy surveillance program: comparison with a Japanese

population-based study. Transplantation 2013; 15:1142-7.
7. Sakamoto Y, Nara S, Kishi Y, et al. Is extended
hemihepatectomy plus pancreaticoduodenectomy
justified for advanced bile duct cancer andgallbladder cancer? Surgery 2013; 153:794-800.
8. Kawaguchi Y, Sugawara Y, Yamashiki N, et al.
Role of 6-month abstinence rule in living donorliver transplantation for patients with alcoholic
liver disease. Hepatol Res 2013; 43:1169-74.
9. Togashi J, Sugawara Y, Akamatsu N, et al. Qualityof life after adult living donor livertransplantation: A longitudinal prospective
follow-up study. Hepatol Res 2013; 43:1052-63.
10. Yamashita S, Hasegawa K, Takahashi M, et al.
One-stage hepatectomy following portal vein
embolization for colorectal liver metastasis.
World J Surg 2013; 37:622-8.
11. Shindoh J, Andreou A, Aloia TA, et al.
Microvascular invasion does not predict
long-term survival in hepatocellular carcinoma up
to 2 cm: reappraisal of the staging system forsolitary tumors. Ann Surg Oncol 2013; 20:1223-9.
12. Hasegawa K, Kokudo N, Makuuchi M, et al.
Comparison of resection and ablation forhepatocellular carcinoma: a cohort study based ona Japanese nationwide survey. J Hepatol 2013;
58:724-9.
13. Tamura S, Sugawara Y, Kokudo N. Virtual liverresection: computer-assisted operation planning
using a three-dimensional liver representation.
Liver Transpl 2013; 19:238.
14. Mise Y, Tani K, Aoki T, Sakamoto Y, et al. Virtual
liver resection: computer-assisted operation
planning using a three-dimensional liver representation. J Hepatobiliary Pancreat Sci 2013; 20:
157-64.
15. Shindoh J, Hasegawa K, Matsuyama Y, et al. Low
hepatitis C viral load predicts better long-term
outcomes in patients undergoing resection ofhepatocellular carcinoma irrespective of serologic
eradication of hepatitis C virus. J Clin Oncol
2013; 31: 766-73.
16. Kawaguchi Y, Ishizawa T, Miyata Y, et al. Portal
uptake function in veno-occlusive regions
evaluated by real-time fluorescent imaging using
indocyanine green. J Hepatol 2013; 58:247-53.

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

Associate Professor
Haruki Kume, M.D., Ph.D.,

Hioraki Nishimatsu, M.D., Ph.D.

Lecturer
Tohru Nakagawa, M.D., Ph.D.,

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

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

Motohumi 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.

Jinpei Miyakawa, 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 1,300 from January 2013 to December 2013.
Elective operations are performed on Tuesday,
Wednesday and Thursday. 1,382 operations were
performed in 2013. The numbers of main operations

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are adrenalectomy 14, nephrectomy 35, partial
nephrectomy 38, nephroureterectomy 22, radical
cystectomy 21, radical prostatectomy 92, transurethralresection of the bladder tumor (TUR-Bt) 162,transurethral resection of the prostate (TUR-P) 17,
laparoscopic surgery 60, and Robot assisted surgery
89.
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 28,700 patientdays from January 2013 to December 2013.

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

References
1.

2.

3.

4.

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.

5.

6.

Research activities

7.

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

8.

9.

Aizawa N, Homma Y, Igawa Y: Characteristics ofLower Urinary Tract Dysfunction and Bladder
Afferent Nerve Properties in Type 2 Diabetic
Goto-Kakizaki rats. J Urol 2013; 189, 1580-7.
Aizawa N, Homma Y, and Igawa Y: Influence ofhigh fat diet feeding for 20 weeks on lower
urinary tract function in mice. LUTS 2013; 5,
101-8.
Azuma T, Matayoshi Y, Odani K, Sato Y, Sato Y,
Nagase Y, Oshi M: Preoperative NeutrophilLymphocyte Ratio as an Independent Prognostic
Marker for Patients With Upper Urinary Tract
Urothelial Carcinoma. Clin Genitourin Cancer
2013; 11, 337-41.
Azuma T, Nagase Y, Oshi M: Pyuria Predicts
Poor Prognosis in Patients With Non-MuscleInvasive Bladder Cancer.
Clin Genitourin
Cancer 2013; 11, 331-6.
Azuma T, Nagase Y, Oshi M: Prognostic marker
for patients with malignant ureter obstruction.
Clin Genitourin Cancer 2013; 11, 353-6.
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
type incompatible living related renal transplantation. Transfus Apher Sci 2013; 49, 254-8.
Hara T, Nakanishi H, Nakagawa T, Komiyama M,
Kawahara T, Manabe T, Miyake M, Arai E, Kanai
Y, Fujimoto H: Ability of preoperative 3.0-Tesla
magnetic resonance imaging to predict theabsence of side-specific extracapsular extensionof prostate cancer. Int J Urol 2013; 20, 993-9.
Homma Y, Fujimura T: Linguistic validation of
the English version of the Overactive Bladder
Symptom Score. Int J Urol 2013, Epub.
Homma Y, Nomiya A, Tagaya M, Oyama T,
Takagaki K, Nishimatsu H, Igawa Y: Increased

210

10.

11.

12.

13.

14.

15.

16.

17.

mRNA expression of genes involved inpronociceptive inflammatory reactions in bladdertissue of interstitial cystitis. J Urol 2013; 190,
1925-31.
Hosaka K, Yang Y, Seki T, Nakamura M,
Andersson P, Rouhi P, Yang X, Jensen L, Lim S,
Feng N, Xue Y, Li X, Larsson O, Ohhashi T, and
Cao Y: Tumour PDGF-BB expression levels
determine dual effects of anti-PDGF drugs on
vascular remodeling and metastasis.
Nat
Commun 2013; 4, 2129.
Igawa Y, Kumano S, Aizawa N, Saito Y, Ito H,
Watanabe S, Takahashi N, Tajimi M, Nishimatsu
H, Homma Y: Changes in the function andexpression of T-type and N-type calcium
channels in the rat bladder after bladder outlet
obstruction. J Urol 2013, Epub.
Iizuka T, Sawabe M, Takubo K, Liu M, Homma Y,
Suzuki M, Arai T: hTERT Promoter
Polymorphism, -1327C>T, is Associated with the
Risk of Epithelial Cancer. Springer Plus 2013;
2, 249.
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 2013; 32, 652-6.
Jeong SJ, Homma Y, and Oh SJ: Reproducibility
study of Overactive Bladder Symptom Score
questionnaire and its response to treatment(RESORT) in Korean population with overactive
bladder symptoms. Qual Life Res 2013, Epub.
Kamei J, Nishimatsu H, Nakagawa T, Suzuki M,
Fujimura T, Fukuhara H, Igawa Y, Kume H,
Homma Y: Risk factors for septic shock in acuteobstructive pyelonephritis requiring emergency
drainage of the upper urinary tract. Int Urol
Nephrol 2013; 46: 493-7.
Kawai T, Enomoto Y, Morikawa T, Matsushita H,
Kume H, Fukayama M, Yamaguchi H, Kakimi K,
and Homma Y: High expression of Heat Shock
Protein 105 predicts a favorable prognosis forpatients with urinary bladder cancer treated byradical cystectomy. Mol Clin Onc 2013, Epub.
Kojima T, Imai Y, Tsushima K, Uno K, Fujiu K,
Iiri T, Nishimatsu H, Suzuki T, Sugiyama H,
Asada K, Nakao T, Yamashita H, Hirata Y, Nagai

18.

19.

20.

21.

22.

23.

24.

25.

R. Temporary Dual-Chamber Pacing Can
Stabilize Hemodynamics During Noncardiac
Surgery in a Patient With Left Ventricular
Hypertrophy and Outflow Obstruction.
J
Cardiothorac Vasc Anesth 2013, Epub.
Kumagai J, Hofland J, Erkens-Schulze S, Dits NF,
Steenbergen J, Jenster G, Homma Y, de Jong FH,
van Weerden WM: Intratumoral conversion ofadrenal androgen precursors drives androgen
receptor-activated cell growth in prostate cancer
more potently than de novo steroidogenesis.
Prostate 2013; 73, 1636-50.
Minagawa T, Aizawa N, Igawa Y, Wyndaele JJ:
The role of transient receptor potential ankyrin 1(TRPA1) channel in activation of single unit
mechanosensitive bladder afferent activities in
the rat. Neurourol Urodyn 2013, Epub.
Minagawa T, Wyndaele M, Aizawa N, Igawa Y,
Wyndaele JJ: Mechanisms of Pelvic Organ Cross
Talk: 2. Impact of Colorectal Distention on
Afferent Nerve Activity of the Rat Bladder. J
Urol 2013; 190, 1123-30.
Morikawa T, Kawai T, Abe H, Kume H, Homma
Y, Fukayama M:
UBE2C is a marker ofunfavorable prognosis in bladder cancer afterradical cystectomy. Int J Clin Exp Pathol 2013;
6, 1367-74.
Nagata M, Matsumura T, Kami M: How do
Weekly Magazines Provide Information on
Urogenital Cancer to the Public in Aged
Societies? Open J Urol 2013; 3, 246-7.
Nagata M, Takita M, Kishi Y, Kodama Y,
Matsumura T, Murashige N, Homma Y, Kami M:
Cancer Articles in Weekly Magazines: UsefulMedia to Deliver Cancer Information to the
Public? Jpn J Clin Oncol 2013; 43, 426-30.
Nakagawa T, Hara T, Kawahara T, Ogata Y,
Nakanishi H, Komiyama M, Arai E, Kanai Y,
Fujimoto H: Prognostic risk stratification ofpatients with urothelial carcinoma of the bladderwith recurrence after radical cystectomy. J Urol
2013; 189, 1275-81.
Nakamura M, Yasunaga H, Haraguchi T, Ando S,
Sugihara T, Horiguchi H, Ohe K, Matsuda S,
Fushimi K: Length of mechanical restraint
following haloperidol injections versus oral
atypical antipsychotics for the initial treatment of

211

26.

27.

28.

29.

30.

31.

32.

33.

acute schizophrenia: A propensity-matchedanalysis from the Japanese diagnosis procedure
combination database. Psychiatry Res 2013; 30,
412-6.
Nishimatsu H, Kitamura T, Yamada D, Nomiya A,
Niimi A, Suzuki M, Fujimura T, Fukuhara H,
Nakagawa T, Enomoto Y, Kume H, Igawa Y,
Homma Y: Improvement of symptoms of aging inmales by a preparation LEOPIN ROYAL(R)containing aged garlic extract and other 5 ofnatural medicines-Comparison with traditional
herbal medicines (Kampo). Aging Male 2013,
Epub.
Nishimatsu H, Suzuki E, Nomiya A, Niimi A,
Suzuki M, Fujimura T, Fukuhara H, Kume H,
Homma Y: Adrenomedullin and Angiopoietin-1
Additively Restore Erectile Function in Diabetic
Rats: Comparison with the Combination Therapyof Vascular Endothelial Growth Factor andAngiopoietin-1. J Sex Med 2013; 10, 1707-19.
Nomiya A, Naruse T, Niimi A, Nishimatsu H,
Kume H, Igawa Y, Homma Y: On- and posttreatment symptom relief by repeated instillationsof heparin and alkalized lidocaine in interstitial
cystitis. Int J Urol 2013; 20, 1118-22.
Oba S, Mizutani T, Suzuki E, Nishimatsu H,
Takahashi M, Ogawa Y, Kimura K, Hirata Y,
Fujita T: A useful method of identifying of
miRNAs which can down-regulate Zeb-2. BMC
Res Notes 2013; 6, 470.
Ochiai A, Okihara K, Kamoi K, Oikawa T,
Shimazui T, Murayama S, Tomita K, Umekawa T,
Uemura H, Miki T: Clinical utility of the prostatecancer gene 3 (PCA3) urine assay in Japanese
men undergoing prostate biopsy. BJU Int 2013;
111, 928-33.
Okamura K, Takei M, Nojiri Y, Otsuka A,
Takamoto H, Maeda Y, Fujimura T, Yokoyama T,
Gotoh M, Homma Y: Twelve months follow-up
injection of Onabotulinumtoxin A into vesicalsubmucosa for refractory non-neurogenic
overactive bladder. LUTS 2013; 5, 55-9.
Sato T, Ishikawa A, Homma Y: Effect of Reduced
Form of Coenzyme Q10 on Cyclosporine
Nephrotoxicity. Exp Clin Transplant 2013; 11,
17-20.
Sato Y, Yoshizato T, Shiraishi Y, Maekawa S,

34.

35.

36.

37.

38.

39.

Okuno Y, Kamura T, Shimamura T, Sato-Otsubo
A, Nagae G, Suzuki H, Nagata Y, Yoshida K, Kon
A, Suzuki Y, Chiba K, Tanaka H, Niida A,
Fujimoto A, Tsunoda T, Morikawa T, Maeda D,
Kume H, Sugano S, Fukayama M, Aburatani H,
Sanada M, Miyano S, Homma Y, Ogawa S:
Integrated molecular analysis of clear-cell renal
cell carcinoma. Nat Genet 2013; 45, 860-7.
Shiraishi Y, Sato Y, Chiba K, Okuno Y, Nagata Y,
Yoshida K, Shiba N, Hayashi Y, Kume H,
Homma Y, Sanada M, Ogawa S, Miyano S: An
empirical Bayesian framework for somatic mutation detection from cancer genome sequencing
data. Nucleic Acids Res 2013; 41, e89.
Shoji K, Murayama T, Mimura I, Wada T, Kume
H, Goto A, Ohse T, Tanaka T, Inagi R, van der
Hoorn FA, Manabe I, Homma Y, Fukayama M,
Sakurai T, Hasegawa T, Aburatani H, Kodama T,
Nangaku M: Sperm-associated antigen 4, a novel
hypoxia-inducible factor 1 target, regulates
cytokinesis, and its expression correlates with theprognosis of renal cell carcinoma. Am J Pathol
2013; 182, 2191-203.
Sugihara T, Kattan MW: Prostate cancer: Does
genetic score justify early prostate biopsy? Nat
Rev Urol 2013, Epub.
Sugihara T, Yasunaga H, Horiguchi H, Fujimura
T, Nishimatsu H, Kume H, Ohe K, Matsuda S,
Fushimi K, and Homma Y: Longer operative time
is associated with higher risk of severe
complications after percutaneous nephrolithotomy: Analysis of 1511 cases from aJapanese nationwide database. Int J Urol 2013;
20, 1193-8.
Sugihara T, Yasunaga H, Horiguchi H, Fujimura
T, Nishimatsu H, Kume H, Ohe K, Matsuda S,
Fushimi K, and Homma Y: Is mechanical bowel
preparation in laparoscopic radical prostatectomy
beneficial? An analysis of a Japanese national
database. BJU Int 2013; 112, E76-81.
Sugihara T, Yasunaga H, Horiguchi H, Fujimura
T, Nishimatsu H, Ohe K, Matsuda S, Fushimi K,
Kattan MW, Homma Y: Does Mechanical Bowel
Preparation Improve Quality of Laparoscopic
Nephrectomy?
Propensity
Score-matched
Analysis in Japanese Series. Urology 2013; 81,
74-9.

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40. Sugihara T, Yasunaga H, Horiguchi H, Fujimura
T, Nishimatsu H, Tsuru N, Kazuo S, Ohe K,
Fushimi K, Homma Y: Regional, institutional andindividual factors affecting selection ofminimally invasive nephroureterectomy in Japan:
A national database analysis. Int J Urol 2013;
20, 695-700.
41. Sugihara T, Yasunaga H, Horiguchi H, Matsuda S,
Fushimi K, Kattan MW, and Homma Y: Does
mechanical bowel preparation ameliorate damage
from rectal injury in radical prostatectomy?
Analysis of 151 rectal injury cases. Int J Urol
2013, Epub.
42. 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; 111, 459-66.

213

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.,

Soichiro Ishihara, M.D., Ph.D.

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

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

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

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

Tomomichi Kiyomatsu M.D., Ph.D.

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

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

Satomi Yoneyama 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 515
surgically treated inpatients in the year of 2013. On
Monday, Wednesday and Friday mornings, pre- andpost-surgery conferences are held, and the Professor's
Round takes place after the conference every
Wednesday. Operating days are Monday, Tuesday andThursday. In addition to the clinical conferences,
research conferences are held every Monday morning.
Each research unit holds its own conference every
week. Over 1200 colonoscopies are performed for ayear. The newest technologies are introduced for214diagnosis 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 2013, 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.

2)
3)
4)
5)
6)

Cancer surveillance in ulcerative colitis
Carcinogenesis in ulcerative colitis
Laparoscopically assisted colon surgery
Local immunity in colorectal cancer
Genetic analysis of colorectal cancer andadenoma
7) Prognostic factor of early colorectal cancer8) Surveillance program following colectomy forcolorectal cancer
9) The mechanism of liver metastasis of colorectal
cancer10) Dendritic cell Immunotherapy for advanced
cancer11) Cancer Immunotherapy targeting to the tumor
vessels12) Role of LPA S1P and productive enzymes intumor metastasis
13) Lipid metabolism in carcinogenesis and tumor
progression14) Role of peripheral nerve on the growth og
gastrointestinal cancer15) Genetic 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)

Research activities

References

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

1.

Emoto S, Yamaguchi H, Kamei T, Ishigami H,
Suhara T, Suzuki Y, Ito T, Kitayama J, Watanabe
T. Intraperitoneal administration of cisplatin via
an in situ cross-linkable hyaluronic acid-based

215

2.

3.

4.

5.

6.

7.

8.

9.

hydrogel for peritoneal dissemination of gastriccancer. Surg Today. Epub ahead of print.
Hiyoshi M, Kitayama J, Kazama S, Taketomi Y,
Murakami M, Tsuno NH, Hongo K, Kaneko M,
Sunami E, Watanabe T. The expression ofphosphor- lipase A2 group X is inversely
associated with metastasis in colorectal cancer.
Oncology letters. 5(2):533-538.2013.
Ishihara S, Watanabe T, Fukushima Y, Akahane T,
Horiuchi A, Shimada R, Nakamura K, Hayama T,
Yamada H, Nozawa K, Matsuda K, Hashiguchi Y.
Safety and factors contributing to the difficulty oflaparoscopic surgery for rectal cancer treatedwith preoperative chemoradiotherapy. TechColoproctol. Epub ahead of print.
Kawai K, Kitayama J, Tsuno NH, Sunami E,
WatanabeT.
Thrombocytosis
beforepre-operative chemoradiotherapy predicts poor
response and shorter local recurrence-freesurvival in rectal cancer. Int J Colorectal Dis.
28(4): 527-535. 2013.
Kawai K, Watanabe T. Colorectal cancer andhypercoagulability. Surg Today. Epub ahead ofprint.
Kitayama J, Emoto S, Yamaguchi H, Isigami H,
Kamei T, Yamashita H, Seto Y, Matsuzaki K,
Watanabe T. Flow cytometric quantification of
intra- peritoneal free tumor cells (FTC) inpatients with peritoneal metastasis. Cytometry B
clin Cytom. Epub ahead of print.
Kitayama J, Emoto S, Yamaguchi H, Isigami H,
Watanabe T. CD90(+) mesothelial-like cells inperitoneal fluid promote peritoneal metastasis byforming a tumor permissive microenvironment.
PloS One. In press.
Kitayama J, Ishigami H, Yamaguchi H,
Yamashita H, Emoto S, Kaisaki S, Watanabe T.
Salvage gastrectomy after intravenous andintraperitoneal paclitaxel (PTX) administration
with oral S-1 for peritoneal dissemination ofadvanced gastric cancer with malignant ascites.
Ann Surg Oncol. Epub ahead of print.
Murono K, Kawai K, Kazama S, Tsuno NH,
Sunami E, Kitayama J, Watanabe T. Colorectal
cancer with multiple metachronous metastasis
achieving complete remission 14 years after
surgical resection: report of a case. Int Surg.

10.

11.

12.

13.

14.

15.

16.

17.

18.

98(1):49-54. 2013.
Murono K, Kitayama J, Tsuno NH, Nozawa H,
Kawai K, Sunami E, Akahane M, Watanabe T.
Hepatic steatosis is associated with lower
incidence of liver metastasis from colorectal
cancer. Int J Colorectal Dis. 28(8):1065-72. 2013.
Nishikawa T, Takei Y, Teshima S, Deie K, Takano
Y, Tsuno NH, Maeda M. A Hypervascular
Malignant Solitary Fibrous Tumor in the
Mesentery of the Rectum with Good Response to
Preoperative Radiation Therapy: Case Report. Int
Canc Conf J. 2(1):30-35. 2013.
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. 23(7):675-82. 2013.
Sasaki S, Miura E, Nakayama H, Watanabe T.
Incisional
bladderherniafollowing
appendectomy: Report of a case. Surg Today.
Epub ahead of print.
Sasaki S, Watanabe T, Nakayama H. Analysis of
the mRNA expression of chemotherapy-related
genes in colorectal carcinoma using the
Danenberg tumor profile method. J Oncol. Epubahead of print.
Tada N, Tsuno NH, Kawai K, Murono K, Nirei T,
Ishihara S, Sunami E, Kitayama J, Watanabe T.
Changes in the plasma levels of cytokines/
chemokines for predicting the response to
chemoradiation therapy in the rectal cancer
patients. Oncol Rep. 31(1):463-71. 2013.
Watanabe T. Biomarker for high-risk patientswith stage II colon cancer. Lancet Oncol.
14(13):1247-8. 2013.
Watanabe T, Yoshino T, Uetake H, Yamazaki K,
Ishiguro M, Kurokawa T, Saijo N, Ohashi Y,
Sugihara K. KRAS mutational status in Japanesepatients with colorectal cancer: results from anationwide, multicenter, cross-sectional study.
Jpn J Clin Oncol. 43(7):706-12. 2013.
Watanabe T, Kobunai T, Akiyoshi T, Matsuda K,
Ishihara S, Nozawa K. Prediction of response topreoperative chemoradiotherapy in rectal cancer
by using reverse transcriptase polymerase chain
reaction analysis of four genes. Dis Colon

216

Rectum. Epub ahead of print.
19. Yamaguchi H, Kitayama J, Ishigami H, Emoto S,
Yamashita H, Watanabe T. A phase 2 trial of
intravenous and intraperitoneal paclitaxel
combined with S-1 for treatment of gastric cancer
with macroscopic peritoneal metastasis. Cancer.
119(18):3354-3358. 2013.

217

Department of Vascular Surgery
Professor
Toshiaki Watanabe, M.D., Ph.D.

Lecturer
Kunihiro Shigematsu, M.D., Ph.D.

Associate
Katsuyuki Hoshina, M.D., Ph.D.,

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

Takuya Hashimoto, 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 Professor, one Associate Professor, andfour Associates. The outpatient office is located on thethird floor of the Outpatient Building. The ward issituated on the eighth floor of the Ward Building. The
administrative office and research laboratories arelocated in the Administration and Research Building.
Current activities of the Department of Vascular
Surgery in clinical practice, education, and research
are summarized as follows.

Clinical activities
The Department of Vascular Surgery has anextensive clinical program in both primary and tertiarycare for vascular problems, and manages patients with
peripheral arterial occlusion, abdominal and thoracoabdominal aortic aneurysms, peripheral aneurysm,
visceral arterial occlusion, carotid artery disease andcommon disorders of the venous circulation such asvaricose veins and venous leg ulcers. State-of-the-art
techniques of percutaneous transluminal angioplasty,
angioscopy and intraoperative ultrasonography areavailable for the treatment of peripheral arterial
disease. And endovascular aneurysm repair was alsoavailable for the treatment of abdominal aortic
aneurysm. The outpatient clinic is open from Monday
through Friday, and twenty-four-hour consultation isavailable for urgent or emergency problems.
Included in the department is the non-invasive
Clinical Vascular Laboratory, which sees over 500
patients per year, with broad reaching expertise inperipheral vascular diagnostic modalities. Also thedepartment has an active angiography program, which
encompasses all aspects of diagnostic and therapeuticintervention in over 500 patients per year and a fullrange of other support and collaborative services.
On Monday, Wednesday and Friday mornings, preand post-surgery conferences are held. Operating days
are Monday, Tuesday and Thursday. The vascularclinical conference is held every Tuesday evening.

Teaching activities
The Department of Vascular Surgery also offers afellowship in vascular surgery for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in vascularsurgery. The Department of Vascular Surgery has a
Vascular Surgery Training Program and provides
broad reaching experience in technical aspects ofvascular surgery, development of surgical judgment,

218

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
month on Saturday morning. The following are themajor 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.
18) Modeling of saccular aneurysm with thecomputational simulation.

References
1. Hoshina K, Nemoto M, Hashimoto T, Miura S,
Urabe G, Nakazawa T, Hosaka A, Kato M,
Ohkubo N, Miyairi T, Okamoto H, Shigematsu K,
Miyata T. Study design of PROCEDURE study. A
randomized comparison of the dose-dependent
effect of pitavastatin in patients with abdominal
aortic aneurysm with massive aortic atheroma:
prevention of cholesterol embolization during
endovascular and open aneurysm repair. Ann Vasc
Dis. 2013;6;62-66.
2. Hoshina K, Akai T, Takayama T, Kato M,
Nakazawa T, Okamoto H, Shigematsu K, Miyata
T. Outcomes and morphologic changes after
endovascular repair for abdominal aortic
aneurysms with a severely angulated neck: A
device-specific analysis. Circ J. 2013;77:
1996-2002.
3. Yamamoto K, Taniguchi R, Hosaka A, Hoshina K,
Okamoto H, Shigematsu K, Miyata T. Fate of theasymptomatic contralateral limb after initialintervention for ipsilateral critical limb ischemia.
Int Angiol. 2013;32:526-31.

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4. Yamamoto S, Hoshina K, Takazawa Y, Okamoto
H, Shigematsu K, Miyata T, Watanabe T.. Aortic
dissectin occurring 18 months after successful
endovascular repair in an anatomical difficult caseof abdominal aortic aneurysm. Case Report Vasc
Med 2013.
5. Hosaka A, Miyata T, Hoshina K, Okamoto H,
Shigematsu K. Surgical management of a primaryexternal iliac venous aneurysm causing
pulmonary thromboembolism: report of a case.
Surg Today 2013 Epub ahead of print.
6. Nishiyama A, Hoshina K, Hosaka A, Okamoto H,
Shigematsu K, Miyata T. Treatment strategy for apancreaticoduodenal artery aneurysm with orwithout a celiac trunk occlusive lesion. Ann Vasc
Dis. 2013;6:725-9.
7. Nemoto M, Hoshina K, Takayama T, Miura S,
Nakazawa T, Kato M, Shigematsu K, Miyata T,
Watanabe T. Statins reduce extensive aortic
atheromas in patients with abdominal aortic
aneurysms. Ann 711-7.
8. Hoshina K, Shigematsu K, Hosaka A, Okamoto H,
Miyata T, Watanabe T. The effect of recombinanthuman soluble thrombomodulin on disseminatedintravascular coagulation in an abdominal aortic
aneurysm. Blood Coagul Fibrinolysis. 2013;25:
389-91.
9. Yamamoto K, Li X, Shu C, Miyata T, Dardik A.
Technical aspects of the mouse aortocaval fistula.
J Vis Exp 2013;11: e50449.
10. Shirasu T, Hosaka A, Okamoto H, Shigematsu K,
Takeda Y, Miyata T, Watanabe T. Bowel necrosis
following endovascular revascularization forchronic mesenteric ischemia: a case report andreview of the literature. BMC Gastroenterol.
2013;19:118.
11. Akai A, Okamoto H, Shigematsu K, Miyata T,
Watanabe T. Revascularization surgery for penile
calciphylaxis. J Vasc Surg. 2013 Dec;58(6):1665-7.

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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

Yasuko Kikuchi MD. PhD

Takako Wakeda 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 250
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.

2.

3.

4.
The focus of our research is “surgical metabolism
and nutrition” and “the body’s adaptive responses
during postoperative recovery”. In addition, we havebeen engaged in the project of chemo-sensitivity ofbreast cancer and of treatment for breast tumors byhigh-energy ultrasound. Research details follow.
1) Mechanisms of cross tolerance among different
stresses (endotoxin - hypoxia/ hypoxia - hypoxia)
after surgery
2) Role of 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. 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 thebreast show more rapid telomere shortening than5.

myoepithelial cells and fibroblasts. Human Pathol
39:1647-1655,2008.
Ogawa T, Tsuji E, Shirakawa K, Hayashibara N,
Kurabayashi R, Terada K, Kikuchi Y, Kanauchi H,
Sakatani T Primary non-Hodgkin’s lymphoma of
the breast treated nonsurgically:report of threecases. Breast Cancer 18:68-72,2011.
Kikuyama M, Takeshima H, Kinoshita T,
Okochi-Takeda E, Wakabayashi M, AkashiTanaka S, Ogawa T, Seto Y, Ushijima T.
Development of a novel approach, theepigenome-based outlier approach, to identify
tumorsuppressor genes silenced by abrrent DNA
methylation. Cancer Let 322:204-212,2012.
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.
International journal of radiation oncology,
biology, physics. 84:331-5(2012). Epub 2012/03/
23.
Okubo M, Tada K, Niwa T, Nishioka K, Tsuji E,
Ogawa T, Seto Y. A case of breast cancer in theaxillary tail of Spence - enhanced magnetic
resonance imaging and positron emission
tomography for diagnostic differentiation andpreoperative treatment decision. World journal ofsurgical oncology. 11:217(2013).

Surgical Sciences
2. Sensory and Motor System Medicine

223

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

Tomomitsu Miyagaki, M.D., Ph.D.

Rei Watanabe, M.D., Ph.D.

Hospital Lecturer
Zenshiro Tamaki, M.D., Ph.D.

Yuri Masui, M.D., Ph.D

Associate
Mayuko Araki, M.D.

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

Soshi Morimura, M.D., Ph.D.

Ayumu Yoshizaki, M.D., Ph.D.

Takuya Miyagawa, M.D.

Minami Maru, 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 with 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-eight doctors
who basically belong to our department are currently
out in affiliated hospitals mainly engaged in clinicalworks there. Additionally, six 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 sixteen dermatologists who are studying in
the postgraduate course under the guidance of staff
members of our department.

224

In addition to series of lectures, clinical education
is provided for fifth- and sixth- grade medical students,
which aims at giving a general introduction for how tomake 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 out-patient
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.

Zhang S, Fujita H, Mitsui H, Fuentes-Duculan J,
Yanofsky VR, Pettersen JS, Suárez-Fariñas M,
Gonzalez J, Wang QF, Bruce MJ, Krueger JG,
Felsen D, Carucci JA: Increased Tc22 andTreg/CD8 ratio contribute to aggressive growth oftransplant associated squamous cell carcinoma.
PLOS ONE. (5):e62154, 2013.
2. Suga H, Sugaya M, Miyagaki T, Ohmatsu H,
Okochi H, Sato S: CXCR3 Deficiency Prolongs
Th1-Type Contact Hypersensitivity. J Immunol.
190(12):6059-70, 2013.
3. Kimura T, Sugaya M, Blauvelt A, Okochi H, Sato
S: Delayed wound healing due to increased
interleukin-10 expression in mice with lymphatic
dysfunction. J Leukoc Biol. 94(1):137-45, 2013
4. Saeki H, Hirota T, Nakagawa H, Tsunemi Y, Kato
T, Shibata S, Sugaya M, Sato S, Doi S, Miyatake
A, Ebe K, Noguchi E, Ebihara T, Amagai M,
Esaki H, Takeuchi S, Furue M, Nakamura Y,
Tamari M: Genetic polymorphisms in the IL22
gene are associated with psoriasis vulgaris in a

Japanese population. J Dermatol Sci. 71(2):14850, 2013.
5. Hikichi T, Matoba R, Ikeda T, Watanabe A,
Yamamoto T, Yoshitake S, Tamura-Nakano M,
Kimura T, Kamon M, Shimura M, Kawakami K,
Okuda A, Okochi H, Inoue T, Suzuki A, Masui S:
Transcription
factors
interferingwithdedifferentiation induce cell type-specifictranscriptional profiles. Proc Natl Acad Sci U S A.
110(16):6412-7, 2013.
6. Asano Y, Trojanowska M: Fli1 represses
transcription of the human alpha2(I) collagengene by recruitment of the HDAC1/p300 complex.
PLOS ONE. 8(9):e74930, 2013.
7. Shibata S, Asano Y, Sato S: Cutaneouspolyarteritis nodosa localized to the arm receiving
infusion of abatacept. Eur J Dermatol. 23(5):7389, 2013.
8. Suga H, Sugaya M, Miyagaki T, Kawaguchi M,
Morimura S, Kai H, Kagami S, Ohmatsu H, Fujita
H, Asano Y, Tada Y, Kadono T, Sato S: Serumvisfatin levels in patients with atopic dermatitis
and cutaneous T-cell lymphoma. Eur J Dermatol.
23(5):629-35, 2013.
9. Fujita H: The role of IL-22 and Th22 cells inhuman skin diseases. J Dermatol Sci. 72(1):3-8,
2013.
10. Yanaba K, Kamata M, Ishiura N, Shibata S, Asano
Y, Tada Y, Sugaya M, Kadono T, Tedder TF, Sato
S: Regulatory B cells suppress imiquimodinduced psoriasis-like skin inflammation. J
Leukoc Biol. 94(4):563-73, 2013.
11. Kagami S, Kuwano Y, Shibata S, Uwajima Y,
Yamada D, Miyamoto A, Miyagawa T, Araki M,
Takahashi K, Isomura S, Aozasa N, Masui Y,
Yamamoto M, Inuzuka R, Katori T, Sato S:
Propranolol is more effective than pulsed dyelaser and cryosurgery for infantile hemangiomas.
Eur J Pediatr. 172(11):1521-6, 2013.
12. Takekoshi T, Wu X, Mitsui H, Tada Y, Kao MC,
Sato S, Dwinell MB, Hwang ST: CXCR4
negatively regulates keratinocyte proliferation in
IL-23-mediated psoriasiform dermatitis. J Invest
Dermatol. 133(11):2530-7, 2013.
13. Kimura T, Sugaya M, Yokobayashi H, Tamaki T:
A case of tuberculosis cutis miliaris withepithelioid cell granuloma. J Dermatol. 40(12):225

1062-3, 2013.
14. Asano Y, Sato S: Animal models of scleroderma:current state and recent development. Curr
Rheumatol Rep. 15(12):382, 2013.
15. Kamata M, Tada Y, Mitsui A, Shibata A,
Miyagaki T, Asano Y, Sugaya M, Kadono T, Sato
S: ICAM-1 deficiency exacerbates sarcoid-likegranulomatosis induced by Propionibacterium
acnes through impaired IL-10 production by
regulatory T cells. Am J Pathol. 183(6):1731-9,
2013.
16. Kamata M, Fujita H, Hamanaka T, Takahashi1 K,
Koga H, Hashimoto T, Sato S: Anti-laminin γ1
pemphigoid accompanied by autoantibodies tolaminin α3 and γ2 subunits of laminin-332. JAMA
Dermatol. 149(12):1437-9, 2013.
17. Yanaba K, Yoshizaki A, Muroi E, Ogawa F,
Shimizu K, Sato S: Increased circulating solublevascular adhesion protein-1 levels in systemicsclerosis: association with lower frequency andseverity of interstitial lung disease. Int J Rheum
Dis. 16(4):442-7, 2013.
18. Suga H, Sugaya M, Yamamoto M, Miyagaki T,
Ohmatsu H, Hoashi T, Sato S: Peripheral T cell
lymphoma, not otherwise specified, showing
multiple ulcers on the extremities. Int J Dermatol.
52(9):1147-9, 2013.
19. Takehara K, Ihn H, Sato S: A randomized, doubleblind, placebo-controlled trial: intravenous
immunoglobulin treatment in patients with diffuse
cutaneous systemic sclerosis. Clin Exp
Rheumatol. 31(2 Suppl 76):151-6, 2013.
20. Suga H, Sugaya M, Tamaki Z, Yamamoto M, Tada
Y, Sato S: Varicella-like generalized pustulosis
induced by adalimumab. Int J Dermatol. 52(7):890-2, 2013.
21. Yanaba K, Kamata M, Asano Y, Tada Y, Sugaya
M, Kadono T, Tedder TF, Sato S:
CD19
expression in B cells regulates atopic dermatitis ina mouse model. Am J Pathol. 182(6):2214-22,
2013.
22. Akamata K, Asano Y, Noda S, Taniguchi T,
Takahashi T, Ichimura Y, Toyama T, Sumida H,
Kuwano Y, Yanaba K, Tada Y, Sugaya M,
Kadono T, Sato S: An inverse correlation ofserum angiogenin levels with estimatedglomerular filtration rate in systemic sclerosis

patients with renal dysfunction, Eur J Dermatol.
23(2):269-70, 2013.
23. Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Takata M, Ozeki A, Watanabe A,
Kawarasaki S, Taniguchi T, Ichimura Y, Toyama T,
Watanabe M, Hirata Y, Nagai R, Komuro I, Sato
S: Clinical correlation of brachial artery flowmediated dilation in patients with systemicsclerosis. Mod Rheumatol. Mar 30, 2013. [Epubahead of print]
24. Hau CS, Kanda N, Noda S, Tatsuta A, Kamata M,
Shibata S, Asano Y, Sato S, Watanabe S, Tada Y:
Visfatin enhances the production of cathelicidin
antimicrobial peptide, human β-defensin-2,
human β-defensin-3, and S100A7 in humankeratinocytes and their orthologs in murine
imiquimod-induced psoriatic skin. Am J Pathol.
182(5):1705-17, 2013.
25. Morimura S, Sugaya M, Sato S: Interaction
between CX3CL1 and CX3CR1 regulates
vasculitis induced by immune complex deposition.
Am J Pathol. 182(5):1640-7, 2013.
26. Masui Y, Asano Y, Shibata S, Noda S, Akamata K,
Aozasa N, Taniguchi T, Takahashi T, Ichimura Y,
Toyama T, Sumida H, Yanaba K, Tada Y, Sugaya
M, Sato S, Kadono T: A possible contribution of
visfatin to the resolution of skin sclerosis npatients with diffuse cutaneous systemic sclerosis
via a direct anti-fibrotic effect on dermal
fibroblasts and Th1 polarization of the immune
response. Rheumatology (Oxford). 52(7):1239-44,
2013.
27. Kagami S, Sugaya M, Suga H, Morimura S, Kai
H, Ohmatsu H, Fujita H, Tsunemi Y, Sato S:
Serum gastrin-releasing peptide levels correlatewith pruritus in patients with atopic dermatitis. J
Invest Dermatol. 133(6):1673-5, 2013.
28. Miyagaki T, Sugaya M, Suga H, Ohmatsu H,
Fujita H, Asano Y, Tada Y, Kadono T, Sato S:
Serum-soluble herpes virus entry mediator levels
reflect disease severity and Th2 environment incutaneous T-cell lymphoma. Acta Derm Venereol.
93(4):465-7, 2013.
29. Noda S, Asano Y, Takahashi T, Akamata K,
Aozasa N, Taniguchi T, Ichimura Y, Toyama T,
Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya
M, Kadono T, Sato S: Decreased cathepsin V

226

expression due to Fli1 deficiency contributes tothe development of dermal fibrosis andproliferative vasculopathy in systemic sclerosis.
Rheumatology (Oxford). 52(5):790-9, 2013.
30. Noda S, Asano Y, Aozasa N, Akamata K,
Taniguchi T, Takahashi T, Ichimura Y, Toyama T,
Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya
M, Kadono T, Sato S: Clinical significance ofserum soluble Tie1 levels in patients withsystemic sclerosis. Arch Dermatol Res. 305(4):325-31, 2013.
31. Hasegawa M, Asano Y, Endo H, Fujimoto M,
Goto D, Ihn H, Inoue K, Ishikawa O, Kawaguchi
Y, Kuwana M, Ogawa F, Takahashi H, Tanaka S,
Sato S, Takehara K: Serum chemokine levels as
prognostic markers in patients with early systemicsclerosis: a multicenter, prospective, observational study. Mod Rheumatol. 23(6):1076-84,
2013.
32. Sumida H, Nakamura K, Yanagida K, Ohkawa R,
Asano Y, Kadono T, Tamaki K, Igarashi K, Aoki
J, Sato S, Ishii S, Shimizu T, Yatomi Y: Decreasein circulating autotaxin by oral administration of
prednisolone. Clin Chim Acta. 415:74-80, 2013.
33. 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: Increased production of soluble
inducible costimulator in patients with diffuse
cutaneous systemic sclerosis. Arch Dermatol Res.
305(1):17-23, 2013.
34. Takahashi T, Asano Y, Akamata K, Aozasa N,
Taniguchi T, Noda S, Masui Y, Ichimura Y,
Toyama T, Tamaki Z, Tada Y, Sugaya M, Kadono
T, Sato S: Dynamics of serum angiopoietin-2
levels correlate with efficacy of intravenous pulse
cyclophosphamide therapy for interstitial lungdisease associated with systemic sclerosis, Mod
Rheumatol. 23(5):884-90, 2013.
35. Shibata S, Tada Y, Asano Y, Yanaba K, Sugaya
M, Kadono T, Kanda N, Watanabe S, Sato S:
IL-27 activates Th1-mediated responses inimiquimod-induced psoriasis-like skin lesions.
J Invest Dermatol. 133(2):479-88, 2013.
36. Suga H, Sugaya M, Miyagaki T, Ohmatsu H,
Fujita H, Kagami S, Asano Y, Tada Y, Kadono T,
Sato S: Association of nerve growth factor,

chemokine (C-C motif) ligands and immunoglobulin E with pruritus in cutaneous T-cell
lymphoma. Acta Derm Venereol. 27;93(2):144-9,
2013.
37. Masui Y, Asano Y, Takahashi T, Shibata S,
Akamata K, Aozasa N, Noda S, Taniguchi T,
Ichimura Y, Toyama T, Tamaki Z, Sumida H,
Yanaba K, Tada Y, Sugaya M, Sato S, Kadono T:
Clinical significance of monitoring serum
adiponectin levels during intravenous pulse
cyclophosphamide therapy in interstitial lungdisease associated with systemic sclerosis. Mod
Rheumatol. 23(2):323-9, 2013.

227

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

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

Project Lecturer
Takuya Iida, M.D., Ph.D.

Mitsunaga Narushima, M.D.

Associate
Makoto Mihara, M.D.

Takeshi Todokoro, M.D.

Takumi Yamamoto, M.D.

Hisako Hara, M.D.

Kensuke Tashiro, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/plastic/english/index.html

Organization
The present faculty of the Department of Plastic
and Reconstructive Surgery consists of 1 professor, 1
associate professor, 1 lecturer, 2 project lecturer, 5associates, 6 physicians, and 4 residents. There areabout 100 doctors in the department, but most areserving in rotation at affiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 20 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 the lectures
include general concepts of plastic surgery, woundhealing, congenital malformations, skin grafts andflaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine.
In the bed side practice the students have the228

opportunity of seeing various diseases and disorders in
the field of plastic surgery and attending outpatient
clinics, surgical operations and clinical lectures byfaculty members. For graduate school students,
microsurgical training program is undertaken in thelaboratory room. In the postgraduate course, after
completing the 6-year training program, a trainee cansit for the board examination of the Japan Society of
Plastic and Reconstructive Surgery. In addition, we
accepted 31 observers from foreign countries including
China, United Kingdom, United States, Korea,
Thailand, Spain, Belgium, Taiwan, Canada, India andAustralia.

extraction of a fluid from continuous suction
drainage.
15) Studies on mechanism of biological effects ofretinoids on epidermis and dermis.
16) Studies on regeneration of peripheral nerves.

References (2013)1.

Research Activities
2.
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

3.

4.

5.

6.

7.

出版物等(2013)
Hara H, Mihara M, Seki Y, Todokoro T, Iida T,
Koshima I. Comparison of indocyanine green
lymphographic findings with the conditions ofcollecting lymphatic vessels of limbs in patientswith lymphedema Plast Reconstr Surg. 2013 Dec;
132(6):1612-8.
Kisu I, Mihara M, Banno K, Umene K, Araki J,
Hara H, Suganuma N, Aoki D. Risks for donors
in uterus transplantation. Reprod Sci. 2013 Dec;
20(12):1406-15
Hara H, Mihara M, Seki Y, Koshima I.
Lymphoedema caused by idiopathic lymphatic
thrombus. J Plast Reconstr Aesthet Surg. 2013
Dec;66(12):1780-3.
Mihara M, Hara H, Araki J, Narushima M, Iida T,
Koshima I. Treatment of hand lymphedema withfree flap transfer and lymphangiogenesis analysis
after hand replantation using indocyanine green(ICG) lymphography and histological analysis.
J Plast Reconstr Aesthet Surg. 2013 Nov;66(11):e338-40
Todokoro T, Furniss D, Oda K, Kawana K,
Narushima M, Mihara M, Kikuchi K, Hara H,
Yano T, Koshima I. Effective treatment of pelvic
lymphocele by lymphaticovenular anastomosis.
Gynecol Oncol. 2013 Feb;128(2):209-14
Doi K, Tanaka S, Iida H, Eto H, Kato H, Aoi N,
Kuno S, Hirohi T, Yoshimura K.
Stromalvascular fraction isolated from lipo-aspirates
using an automated processing system: bench andbed analysis J Tissue Eng Regen Med. 2013;
7(11): 864-70
Yamamoto T, Narushima M, Yoshimatsu H,
Yamamoto N, Oka A, Seki Y, Todokoro T, Iida T,
Koshima I. Indocyanine green velocity: lymphtransportation capacity deterioration with progression of lymphedema. Ann Plast Surg. 2013 Nov;
71(5):591-4. doi: 10.1097/SAP.0b013e318255168a.

229

8. Yamamoto T, Yoshimatsu H, Narushima M,
Yamamoto N, Koshima I. Split intravascular
stentsforside-to-end
lymphaticovenular
anastomosis. Ann Plast Surg. 2013 Nov;71(5):538-40. doi: 10.1097/SAP.0b013e318250f0a0.
9. Iida T, Narushima M, Yoshimatsu H, Yamamoto T,
Araki J, Koshima I. A free vascularised iliacbone flap based on superficial circumflex iliac
perforators for head and neck reconstruction. J
Plast Reconstr Aesthet Surg. 2013 Nov;66(11):1596-9. doi: 10.1016/j.bjps.2013.03.031. Epub
2013 Apr 19.
10. Narushima M, Iida T, Kadono T, Hara H,
Yamamoto Y, Todokoro T, Mihara M, Koshima I.
Free concha flap for sensitive nasal reconstruction
using the infraorbital artery and nerve as arecipient vessel and a recipient nerve. Microsurgery. 2013 May;33(4):311-4. doi: 10.1002/micr.
22091. Epub 2013 Apr 9.
11. Yamamoto T, Yoshimatsu H, Yamamoto N,
Narushima M, Iida T, Koshima I. Side-to-end
Lymphaticovenular anastomosis through temporary lymphatic expansion. LoS One. 2013;8(3):e59523. doi: 10.1371/journal.pone.0059523. Epub
2013 Mar 25.
12. Yamamoto T, Yamamoto N, Azuma S, Todokoro T,
Koshima I. Handy thermography for bedsideevaluation of pressure ulcer. J Plast Reconstr
Aesthet Surg. 2013 Jul; 66(7): e205-6. doi:
10.1016/j.bjps.2013.02.005. Epub 2013 Mar 6. No
abstract available
13. Azuma S, Yamamoto T, Koshima I. Donor-site
lymphatic function after microvascular lymph
node transfer should be followed using
indocyanine green lymphography.
Plast
Reconstr Surg. 2013 Mar ;131(3): 443e-4e. doi:
10.1097/PRS.0b013e31827c7194. No abstract
available.
14. Tashiro K, Mihara M, Todokoro T, Narushima M,
Yamamoto T, Iida T, Araki J, Iwamoto T, Koshima
I. Christmas tree background for supermicrosurgical anastomosis with the presence of avertical interval. J Reconstr Microsurg. 2013
Mar;29(3):205-8. doi: 10.1055/s-0032-1331145.
Epub 2013 Jan 2. No abstract available.
15. Yamamoto T, Yamamoto N, Yoshimatsu H,
Narushima M, Koshima I.
LEC score: ajudgment tool for indication of indocyanine green
lymphography. Ann Plast Surg. 2013 Feb;70(2):227-30. doi: 10.1097/SAP.0b013e3182380861.
16. Yamamoto T, Yoshimatsu H, Narushima M, Seki
Y, Yamamoto N, Shim TW, Koshima I. A
modified side-to-end lymphaticovenular anastomosis.
Microsurgery. 2013 Feb;33(2):130-3.
doi: 10.1002/micr.22040. Epub 2012 Sep 14.
17. Iida T, Mihara M, Yoshimatsu H, Narushima M,
Koshima I.
Reconstruction of the external
auditory canal using a super-thin superficial
circumflex iliac perforator flap after tumour
resection. J Plast Reconstr Aesthet Surg. 2013
Mar;66(3):430-3. doi: 10.1016/j.bjps.2012.08.005.
Epub 2012 Sep 10
18. Iida T, Mihara M, Narushima M, Todokoro T,
Hara H, Yoshimatu H, Koshima I, Kadono T.
Dynamic reconstruction of full-thickness abdominal wall defects using free innervated vastus
lateralis muscle flap combined with free anterolateral thigh flap. Ann Plast Surg. 2013 Mar;70(3):331-4. doi: 10.1097/SAP.0b013e3182321b64.
19. Yamamoto T, Yamamoto N, Hara H, Mihara M,
Narushima M, Koshima I. Upper extremity
lymphedema index: a simple method for severity
evaluation of upper extremity lymphedema. Ann
Plast Surg. 2013 Jan;70(1):47-9. doi: 10.1097/
SAP.0b013e3182275d23.
20. Eto H, Ishimine H, Kinoshita K, Watanabe-Susaki
K, Kato H, Doi K, Kuno S, Kurisaki A,
Yoshimura K.
Characterization of humanadipose tissue-resident hematopoietic cell populations reveals a novel macrophage subpopulation
with CD34 expression and mesenchymal
multipotency. Stem Cell Dev 22: 985-997, 2013.
21. Inoue K, Yoshimura K.
Isolation andcharacterization of human hair follicle epithelial
cells. Methods Mol Biol 946: 411-421, 2013.
22. Mashiko T, Mori H, Kato H, Doi K, Kuno S,
Kinoshita K, Kunimatsu A, Ohtomo K, YoshimuraK.
Semi-permanent volumization by anabsorbable filler: Onlay injection technique to thebone. Plast Reconstr Surg Glob Open 1: e4,
2013.
23. Bourin P, Bunnell BA, Casteilla L, Domonici M,
Katz AJ, March KL, Redl H, Rubin JP, Yoshimura
K, Gimble JM. Stromal cells from the adipose

230

tissue derived stromal vascular fraction (SVF) andculture expanded adipose-derived stromal/stem
cells (ASC): a joint statement of IFATS and ISCT.
Cytotherapy 15: 641-648, 2013.
24. Inoue K, Yoshimura K.
Skin stem cells.
Methods Mol Biol 989: 305-313, 2013.
25. Yang S, Eto H, Kato H, Doi K, Kuno S, Kinoshita
K, Ma H, Tsai CH, Chou WT, Yoshimura K.
Comparative characterization of stromal vascular
cells derived from three types of vascular wall andadipose tissue. Tissue Eng Part A 19:2724-2734,
2013.
26. Ishimine H, Yamakawa N, Sasao M, Tadokoro M,
Kami D, Komazaki S, Tokuhara M, Takada H, Ito
Y, Kuno S, Yoshimura K, Umezawa A, Ohgushi H,
Asashima M, Kurisaki A. N-Cadherin is a
prospective cell surface marker of humanmesenchymal stem cells that have high ability for
cardiomyocyte
differentiation.
Biochem
Biophys Res Commun 438: 753-759, 2013

231

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.

232

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)2336) 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. 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 mousemesenchymal cell line C3H10T1/2 by modulatingbone morphogenetic protein (BMP) signaling. J
Cell Physiol. 2013 Jan;228(1):163-71.
2. Yano F, Saito T, Ogata N, Yamazawa T, Iino M,
Chung UI, Kawaguchi H. Arthritis Rheum. 2013
Feb;65(2):429-35. β-catenin regulates parathyroid
hormone/parathyroid hormone-related protein
receptor signals and chondrocyte hypertrophy
through binding to the intracellular C-terminal
region of the receptor. Arthritis Rheum. 2013 Feb;
65(2):429-35.
3. 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. 2013 Apr 5;288(14):9924-32.
4. Komiyama Y, Ohba S, Shimohata N, Nakajima K,
Hojo H, Yano F, Takato T, Docheva D, Shukunami
C, Hiraki Y, Chung UI. Tenomodulin expression
in the periodontal ligament enhances cellularadhesion. PLoS One. 2013 Apr 10;8(4):e60203.
5. 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
disease-modifying osteoarthritis drug candidate
targeting Runx1.Ann Rheum Dis. 2013 May;
72(5):748-53
6. Suenaga H, Hoang Tran H, Liao H, Masamune K,
Dohi T, Hoshi K, Mori Y, Takato T. Real-time insitu three-dimensional integral videography andsurgical navigation using augmented reality: apilot study. Int J Oral Sci. 2013 Jun;5(2):98-102.
7. Yano F, Hojo H, Ohba S, Saito T, Honnami M,
Mochizuki M, Takato T, Kawaguchi H, Chung UI.
Cell-sheet technology combined with athienoindazole derivative small compound TD198946 for cartilage regeneration. Biomaterials.
2013 Jul;34(22):5581-7.
8. Maeda Y, Hojo H, Shimohata N, Choi S,
Yamamoto K, Takato T, Chung UI, Ohba S. Bonehealing by sterilizable calcium phosphate tetrapods eluting osteogenic molecules. Biomaterials.
2013 Jul;34(22):5530-7.
9. Maeda Y, Suenaga H, Sugiyama M, Saijo H,
Hoshi K, Mori Y, Takato T. Clinical presentationof epignathus teratoma with cleft palate; andduplication of cranial base, tongue, mandible, andpituitary gland. J Craniofac Surg. 2013 Jul;24(4):1486-91.
10. 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.2013
Jul;50(4):381-7.
11. Kobayashi H, Terada D, Yokoyama Y, Moon DW,

234

Yasuda Y, Koyama H, Takato T.Vascular-inducing
poly(glycolic acid)-collagen nanocomposite-fiber
scaffold. J Biomed Nanotechnol. 2013 Aug;9(8):1318-26.
12. Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M,
Eto K, Nakauchi H, Tanaka S, Chung UI,Kawaguchi H. Generation of Col2a1-EGFP iPS
cells for monitoring chondrogenic differentiation.
PLoS One. 2013 Sep 16;8(9):e74137.
13. Susami T, Okayasu M, Inokuchi T, Ohkubo K,
Uchino N, Uwatoko K,Takahashi-Ichikawa N,
Nagahama K, Takato T. Maxillary Protraction in
Patients With Cleft Lip and Palate in Mixed
Dentition: Cephalometric Evaluation After
Completion of Growth. Cleft Palate Craniofac J.
2013 Sep 6.
14. Hong J, Zhang H, Kawase-Koga Y, Sun T.
MicroRNA function is required forneurite
outgrowth of mature neurons in the mousepostnatal cerebral cortex. Front Cell Neurosci.
2013 Sep 13;7:151.
15. Wang J, Suenaga H, Yang L, Liao H, Kobayashi
E, Takato T, Sakuma I. Real-time marker-freepatient registration and image-based navigation
using stereo vision for dental surgery. Lecture
Notes in Computer Science. 2013 Sep;8090:9-18.
16. 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. 2013 Oct;18(5):1563-71
17. Matsuyama M, Fujihara Y, Inaki R, Nishizawa S,
Nagata S, Takato T, Hoshi K. Evaluation of invivo migration of chondrocytes from tissueengineered cartilage that was subcutaneouslytransplanted in mouse model. OJRM. 2013 Oct;2(4):93-8.
18. Kawase-Koga Y, Mori Y, Hoshi K, Takato T. A
novel technique for preventing skin pressure sores
using a rubber tube during surgical treatment ofmandibular condyle fractures. J Craniofac Surg.
2013 Nov;24(6):e604-6.
19. Komatsu N, Kawase-Koga Y, Mori Y, Kamikubo
Y, Mineo Kurokawa M, Takato T. Human
immunodeficiency
virus-associatedBurkittlymphoma in a Japanese patient with earlysubmandibular swelling: a case report. BMC Res
Notes. 2013 Dec;6:557.

20. Mori Y, Hoshi K, Takato T, Takahashi M , Hirano
Y, Kanno Y, Ohkubo K , Saijo H. Submucous
cleft palate: variations in bony defects of the hardpalate. Br J Oral Maxillofac Surg 2013 Dec;51(8):e220-3.
21. Mori Y, Kanazawa S, Watanabe M, Suenaga H,
Nagata S, Fujihara Y, Takato T, Hoshi K.
Usefulness of agarose mold as a storage container
for three-dimensional tissue-engineered cartilage.
Mater Sci Appl. 2013;4(8):73-8.
22. Mori Y, Watanabe M, Nakagawa S, Asawa Y,
Nishizawa S, Saijo H, Nagata S, Fujihara Y,
Takato T, Hoshi K. Hollow fiber module applied
for effective proliferation and harvest of cultured
chondrocytes. Mater Sci Appl. 2013;4(8):62-7.
23. Uto S, Nishizawa S, Takasawa Y, Asawa Y,
Fujihara Y, Takato T, Hoshi K. Bone and cartilage
repair by transplantation of induced pluripotent
stem cells in murine joint defect model. Biomed
Res. 2013; 34(6):281-8.
24. Kawase-Koga Y, Mori Y, Saijo H, Hoshi K,
Takato T. Reconstruction of a complex midface
defect from excision of a squamous cell
carcinoma, according to regional aesthetic units.
Oral Surg Oral Med Oral Pathol Oral Radiol.（inpress）
25. Fujihara Y, Takato T, Hoshi K. Macrophageinducing fasl on chondrocytes forms immune
privilege in cartilage tissue engineering,enhancing in vivo regeneration. Stem Cells. (inpress)
26. Wang J, Suenaga H, Hoshi K, Yang L, Kobayashi
E, Sakuma I, Liao H. Augmented Reality
Navigation With Automatic Marker-Free Image
Registration Using 3D Image Overlay for Dental
Surgery. IEEE Trans Biomed Eng. (in press)
27. Suenaga H, Unami M, Hoshi K, Mori Y, Takato T.
Ectopic complex odontoma of the nasal cavity: A
rare case. J Oral Maxillofac Surg Med Pathol. (inpress)
28. Suenaga H, Saijo H, Hoshi K, Mori Y, Takato T.
Diclofenac sodium induced Stevens-Johnson
Syndrome in a hospitalized patient during
treatment of splenic injury and mandibular
fracture. J Oral Maxillofac Surg Med Pathol. (inpress)

235

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

Associate Professors
Katsushi Takeshita, M.D., Ph.D.,

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

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

Yuho Kadono, M.D., Ph.D.

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

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

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

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

Shuji Taketomi, M.D.

Hiroshi Inui, M.D.

Yutaka Morizaki, M.D.

Yuki Taniguchi, M.D., Ph.D.

Takeyuki Tanaka, M.D.

Koki Sanada, M.D.

Yasushi Takamoto, M.D.

Kazuya Isawa, M.D.

Shigeyuki Tanaka, M.D.

Jun-ichi Oya, M.D.,

Kazuhito Soma, M.D.

Homepage

http://www.u-tokyo-ortho.jp/

Introduction and Organization
In 1906 our department was established as the firsteducational institute of orthopedic surgery in Japan,
by the first professor Yoshinori Tashiro who hadlearned orthopedic surgery in Germany and Austria.
Initially, the department treated patients with
infectious disorders and congenital malformations,such as poliomyelitis, tuberculosis of the spine,congenital clubfoot and hip dislocation. The numberof outpatients visiting our department in 1910 was
estimated to be no more than 3.3% of that of the twosurgical departments in the University of Tokyo
Hospital.
The number and characteristics of the patients,
however, have changed dramatically in these 100

years. This is because our department addressed theacute needs of society from the beginning. Prof.
Tashiro believed that trauma should be treated byorthopedists, so he provided his pupils with thistraining. Since 1950’s, the department has
increasingly been involved in the treatment of traffic
and industrial accident victims. Prof. Tashiro and his
successor professor Kenji Takagi devoted themselvesto the establishment of an institute for children withdisabilities. The arthroscopy was developed by Prof.
Takagi, and is now considered to represent a
breakthrough in the development of minimallyinvasive surgery. We have recently been conducting
many studies related to the ossification of spinal
ligaments (OPLL), rheumatoid arthritis, biomechanics,
and the degenerative skeletal disorders such as236

osteoporosis and osteoarthritis in response to theprogressive aging of our society.
Our department is now adept in the entire field of
medical science and medical practice related to thehuman locomotor system, the importance of which is
now clearly recognized not only in Japan, but also all
over the world. To meet the expanding needs ofsociety, we have been conducting the teaching,clinical, and research activities described below.
Faculty members of the department are one
professor, two associate professors, two lecturers, 15
associates, 9 medical staff members, 8 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, clinicalclerkship programs to 5th year students and elective
clinical clerkship programs 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 3-week period of clinical clerkshipprogram, students have opportunities to join one ofclinical teams and experience patient care andorthopaedic practice with residents and faculty
members. We have developed an original text for the
students to learn on-site orthopedics effectively. They
are encouraged to participate in clinical conferences
and surgeries. They are also required to submit
reports on the cases they are involved in. They learn

how to conduct a medical interview, check physicalfindings and draw up actual plans for a diagnosis andtreatment including surgery.
Elective clinical clerkship provides 4 weeks ofmore intensive exposure to the clinical practice. The
students are attached to a clinical team and are
involved in most of the clinical activities performedby the team.
For postgraduate education, junior residents join
our department for 1-8 months. In 14
doctors-in-training completed our program during
this fiscal year. Since the training period is short,they are encouraged to experience emergency cases asoften as possible to learn primary care. For seniorresidents, 1-year clinical programs were conducted incoorporation with our affiliated hospitals. 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 38,034 patients
visited the outpatient clinic in 2013.
The ward has approximately 55 to 65 beds available
and is divided into the subgroups above. The members
are on duty for daily patient care under the supervisionof faculty members. The weekly official activities ofour department include ward rounds by the professor
on Tuesday. Post- and preoperative case conferences
are held on Monday evening, Tuesday morning andThursday evening.
1,357 operations were performed in 2013. These
include 300 spine surgeries (including 73 cervicalspine surgeries,111 thoracolumbar spine surgeries, and
59 scoliosis surgeries),81 surgeries for rheumatoid
arthritis patients, 134 hip surgeries,262 knee surgeries(including 47 computer-assisted ACL reconstruction,
47 computer-assisted TKA,48 UKA), 3 shoulder

237

surgeries, 253 hand surgeries, 5 limb lengthening andreconstruction surgeries using external fixators, 106
surgeries for bone and soft tissue tumor and 191
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 spine group is now converting open surgeries
to minimum invasive surgeries using endoscopic
technique.
The scoliosis group used the navigation systemespecially for patients with complex deformity. In
addition to the conventional correction surgery,
growth-assist techniques such as dual growing rods
are utilized.
Main operations performed by the rheumatoid
arthritis clinic group were total joint arthroplasty.
They are using image-free navigation system in total
knee arthroplasty operation, which is useful for theaccurate placement of the implants.
The hip surgery group treated mainly acetabular
dysplasia and osteoarthritis of the hip joint. They
performed not only total hip replacements, but also
several osteotomies including rotational acetabularosteotomy (RAO). The RAO was originated andestablished in our department. They conducted aclinical trial for a new artificial hip joint using the
MPC polymer in collaboration with the Department ofMaterials Engineering in Tokyo University.
The knee clinic group developed a new anterior
cruciate ligament reconstruction technique using thenavigation
systembasedonintraoperative
three-dimensional fluoroscopic image to realize ideal
graft placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
The tumor group managed multidisciplinary
treatment for musculoskeletal sarcoma including

chemotherapy, limb sparing surgery and radiotherapy
in coorporation with other departments.
Limb reconstruction operations using external
fixators included non-union, leg lengthening anddeformity correction. One of the main interests of thisgroup is the development of a system to analyze themechanical properties of a skeletal system. During
this period of analysis, the mechanical properties ofthe fracture site in vivo are to be evaluated bymonitoring the motion of a dynamic pin clamp during
simulated walking.

Research activities
Our research activities cover the full range of themusculoskeletal system medicine, using the in-depthsciences of biology and technology. Especially in thefield of molecular biology of bone and cartilage
metabolism, we are regarded as being on the leadingedge in the world. Basic research is performed under
the supervision of the faculty staff members. Four
endowment departments take an active role inresearch activities in close collaboration with ourdepartment. 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 resorption, we have been
researching and released some important reports aboutbone metabolism, especially in differentiation,
activation and apoptosis of osteoclast.

238

Recently we have been getting achievement in the
new research topics such as “Osteoimmunology”, a
new research field studying on signaling cross-talkbetween bone metabolism and immunology, or“Epigenetics”, new research concept in spotlight using
comprehensive analysis technique.
As for research of cartilage, we have researchedmolecular biology of cartilage with the students of 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 2013, we reported
RelA, NF-κB family member is a potent transcriptional activator of ADAMTS5, aggrecanases-2 inchondrocytes during osteoarthritis development. We
are continuously researching the roles of HIF-1, HIF-2,
Notch and NF-κB signaling in chondrocytes.
Our clinical groups also take part in many
multicenter clinical studies conducted by Japan
Musculoskeletal Oncology Group (JMOG), National
Database of Rheumatic Diseases by iR-net in Japan(NinJa), and other multicenter groups

References
1. Kanazawa T, Nishino J, Tohma S, Tanaka S.
Analysis of the affected joints in rheumatoid
arthritis patients in a large Japanese cohort. Mod
Rheumatol 23(1):44-49, 2013 Jan
2. JJujo Y, Yasui T, Nagase Y, Kadono Y, Oka H,
Tanaka S. Patellar fracture after total knee
arthroplastyforrheumatoid
arthritis.
J
Arthroplasty 28(1):40-43, 2013 Jan
3. 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 population-based cohort study ofJapanese men and women: the ROAD Study.
Bone 52(1):516-523, 2013 Jan
4. Fujii T, Matsudaira K, Yoshimura N, Hirai M,
Tanaka S. Associations between neck andshoulder discomfort (Katakori) and job demand,
job control, and worksite support. Mod
Rheumatol. 2013 Jan 22. [Epub ahead of print]
5. Tanaka S. Regulation of bone destruction inrheumatoid arthritis through RANKL-RANK
pathways. World J Orthop 4(1):1-6, 2013 Jan 18
6. Chikuda H, Yasunaga H, Takeshita K, Horiguchi
H, Kawaguchi H, Ohe K, Fushimi K, Tanaka S:
Mortality and morbidity after high-dose
methylprednisolone treatment in patients with
acute
cervicalspinalcord
injury:apropensity-matched analysis using a nationwide
administrative database. Emerg Med J. 2013 Feb
28. [Epub ahead of print]
7. Ono K, Ohashi S, Tanaka S: Rheumatoid arthritis
and bone -periarticular and systemic bone loss-].
Clin Calcium 23(2):249-255, 2013 Feb
8. Inui H, Taketomi S, Nakamura K, Sanada T,
Tanaka S, Nakagawa T. An additional reference
axis improves femoral rotation alignment inimage-free computer navigation assisted total
knee arthroplasty. J Arthroplasty 28(5):766-771,
2013 May [Epub 2013 Mar 15 ]9. Muraki S, Akune T, En-Yo Y, Yoshida M, Tanaka
S, Kawaguchi H, Nakamura K, Oka H, Yoshimura
N. Association of dietary intake with joint space
narrowing and osteophytosis at the knee inJapanese men and women: the ROAD study. Mod
Rheumatol. 2013 Mar 16. [Epub ahead of print]
10. Moro T, Kyomoto M, Ishihara K, Saiga K,
Hashimoto M, Tanaka S, Ito H, Tanaka T, Oshima
H, Kawaguchi H, Takatori Y. Grafting of poly
(2-methacryloyloxyethyl phosphorylcholine) on
polyethylene liner in artificial hip joints reduces
production of wear particles. J Mech Behav
Biomed Mater. 2013 Apr 17.
11. Matsumoto T, Nagase Y, Hirose J, Tokuyama N,
Yasui T, Kadono Y, Ueki K, Kadowaki T,
Nakamura K, Tanaka S. Regulation of bone
resorption and sealing zone formation in
osteoclasts occurs through protein kinase
B-mediated microtubule stabilization. J Bone
Miner Res. 2013 May;28(5):1191-202.
12. Inui H, Taketomi S, Nakamura K, Takei S, Takeda
H, Tanaka S, Nakagawa T. Influence of navigation
system updates on total knee arthroplasty. BMC
Sports Sci Med Rehabil. 2013 May 2;5(1):10.
13. Chikuda H, Yasunaga H, Horiguchi H, Takeshita
K, Sugita S, Taketomi S, Fushimi K, Tanaka S.
Impact of age and comorbidity burden on
mortality and major complications in older adults

239

undergoing orthopaedic surgery: an analysis using
the Japanese diagnosis procedure combination
database. BMC Musculoskelet Disord. 2013 May
28;14(1):173. [Epub ahead of print]
14. Sugita S, Chikuda H, Ohya J, Taniguchi Y,
Takeshita K, Haga N, Ushiku T, Tanaka S.
Cervical canal stenosis caused by progressive
fusion and enlargement of cervical vertebrae withfeatures of Proteus syndrome and Klippel-Feilsyndrome. Skeletal Radiol. 2013 Jun 13. [Epubahead of print]
15. Ono K, Ohashi S, Tanaka S, Matsumoto T. [Bonestructure in rheumatoid arthritis]. Clin Calcium.
2013 Jul;23(7):983-91.
16. Oka H, Akune T, Muraki S, Tanaka S, Kawaguchi
H, Nakamura K, Yoshimura N. The mid-term
efficacy of intra-articular hyaluronic acidinjections on joint structure: a nested case control
study. Mod Rheumatol. 2013 Jul;23(4):722-8.
17. Taketomi S, Inui H, Hirota J, Nakamura K,
Sanada T, Masuda H, Tanaka S, Nakagawa T.
Iliotibial band irritation caused by the EndoButton
after anatomic double-bundle anterior cruciate
ligament reconstruction: report of two cases. Knee.
2013 Aug;20(4):291-4.
18. Ono K, Ohashi S, Tanaka S. [Secondary
Osteoporosis or Secondary Contributors to Bone
Loss in Fracture. Therapeutic intervention ofrheumatoid arthritis bone loss]. Clin Calcium.
2013 Sep; 23(9): 1345-52
19. Taketomi S, Inui H, Nakamura K, Hirota J,
Sanada T, Masuda H, Takeda H, Tanaka S,
Nakagawa T: Clinical outcome of anatomic
double-bundle ACL reconstruction and 3D CT
model-based validation of femoral socket aperture
position. Knee Surg Sports Traumatol Arthrosc.
2013 Oct 2. [Epub ahead of print]
20. Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M,
Eto K, Nakauchi H, Tanaka S, Chung UI,Kawaguchi H: Generation of Col2a1-EGFP iPS
Cells
for
Monitoring
Chondrogenic
Differentiation. PLoS One. 2013 Sep 16;8(9)21. Ogura K, Yasunaga H, Horiguchi H, Ohe K,
Shinoda Y, Tanaka S, Kawano H: Impact of
hospital volume on postoperative complications
and in-hospital mortality after musculoskeletal
tumor surgery: analysis of a national

administrative database. J Bone Joint Surg Am.
2013 Sep 18;95(18):1684-91.
22. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N: Incidence of certified need of carein the long-term care insurance system and its risk
factors in the elderly of Japanese populationbased cohorts: The ROAD study.
GeriatrGerontol Int. 2013 Sep 11. [Epub ahead of print]
23. Sugita S, Chikuda H, Ohya J, Taniguchi Y,
Takeshita K, Haga N, Ushiku T, Tanaka S:
Cervical canal stenosis caused by progressive
fusion and enlargement of cervical vertebrae withfeatures of Proteus syndrome and Klippel-Feilsyndrome. Skeletal Radiol. 2013 Jun 13. [Epubahead of print]
24. Taketomi S, Inui H, Hirota J, Nakamura K,
Sanada T, Masuda H, Tanaka S, Nakagawa T:
Iliotibial band irritation caused by the EndoButton
after anatomic double-bundle anterior cruciate
ligament reconstruction: report of two cases.
Knee. 2013 Aug;20(4):291-4..knee.2013.03.013.
25. Kawata M, Inui H, Taketomi S, Nakamura K,
Nakagawa T, Tanaka S: Recurrent hemarthrosis
after total knee arthroplasty caused by theimpingement of a remnant lateral meniscus: A
case report. Knee. 2013 Oct 31.
26. Miyamoto H, Miura T, Morizaki Y, Uehara K,
Ohe T, Tanaka S: Comparative study on the
stiffness of transverse carpal ligament between
normal subjects and carpal tunnel syndrome
patients. Hand Surg. 2013;18(2):209-14.
27. Matsubayashi Y, Takeshita K, Sumitani M,
Oshima Y, Tonosu J, Kato S, Ohya J, Oichi T,
Okamoto N, Tanaka S: Validity and reliability of
the Japanese version of the painDETECT
questionnaire: a multicenter observational study.
PLoS One. 2013 Sep 30;8(9)28. Omata Y, Hagiwara F, Nishino J, Matsudaira K,
Kadono Y, Juji T, Mori T, Nakayama H, Nagase Y,
Hirose J, Yasui T, Matsumoto T, Matsui T, Tohma
S, Tanaka S: Vertebral fractures affect functional
status in postmenopausal rheumatoid arthritis
patients.J Bone Miner Metab. 2013 Dec 21. [Epubahead of print]
29. Muraki S, Yoshimura N, Akune T, Tanaka S,
Takahashi I, Fujiwara S: Prevalence, incidence

240

and progression of lumbar spondylosis by genderand age strata. Mod Rheumatol. 2013 Nov 5.
[Epub ahead of print]
30. Uehara K, Chikuda H, Higurashi Y, Ohkusu K,
Takeshita K, Seichi A, Tanaka S: Pyogenic discitis
due to Abiotrophia adiacens. Int J Surg Case Rep.
2013;4(12):1107-9.
31. Ogura K, Yasunaga H, Horiguchi H, Ohe K,
Kawano H.: Incidence and Risk Factors for
Pulmonary
Embolism
After
Primary
Musculoskeletal Tumor Surgery. Clin Orthop
Relat Res. 2013 May 21.
32. Tsuda Y, Goto T, Ikegami M, Yamada N,
Yamakawa K, Hozumi T, Kawano H, Takaki Y,
Kitahara Y.: Incidence of, and risk factors for,postoperative venous thromboembolism inpatients with benign or malignant musculoskeletal
tumors. J Orthop Sci. 2013 Jul;18(4):613-7.
33. Yamamoto Y, Yoshizawa T, Fukuda T,
Shirode-Fukuda Y, Yu T, Sekine K, Sato T,
Kawano H, Aihara K, Nakamichi Y, Watanabe T,
Shindo M, Inoue K, Inoue E, Tsuji N, Hoshino M,
Karsenty G, Metzger D, Chambon P, Kato S, Imai
Y. :Vitamin D receptor in osteoblasts is a negative
regulator of bone mass control. Endocrinology.
2013 Mar;154(3):1008-20.
34. Ogura K, Goto T, Imanishi J, Shinoda Y, Okuma T,
Tsuda Y, Kobayashi H, Akiyama T, Hirata M,
Yamamoto A, Kawano H.: Neoadjuvant andadjuvant chemotherapy with modified mesna,
adriamycin, ifosfamide, and decarbazine (MAID)
regimen for adult high-grade non-small round cellsoft tissue sarcomas. Int J Clin Oncol. 2013
Feb;18(1):170-6

241

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.,

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., Hiromasa Sawamura, M.D., Ph.D., Takashi Ueta,M.D.,Ph.D.,
Kazuyoshi Otomo,M.D., Taku Toyama,M.D., Fumiyuki Araki,M.D.,Ph.D.,
Rie Tanaka.M.D.

Homepage

http://www.todaiganka.jp/

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242

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 Y, Azumi A, Furuta M, Goto H, Hamaoka
S, Hayashi K, Hayashi N, Kase S, Kashima T,
Katori N, Konno K, Kubota T, Obata H, Oguchi Y,
Ohshima K, Oyama T, Shikishima K, Sogabe Y,
Sugiyama K, Takahira M, Tsuji H, Ueda S,
Yoshikawa H: A prevalence study of IgG4-related
ophthalmic disease in Japan. Jpn J Ophthalmol
57:573-579, 2013
2. Aihara M, Oshima H, Araie M: EXTraKT study
group: Effects of SofZia-preserved travoprost andbenzalkonium chloride-preserved latanoprost on
the ocular surface a multicentre randomized
single-masked study. Acta Ophthalmol 91: e7-e14,
2013
3. Arita R: Validity of noninvasive meibographysystems: noncontact meibography equipped with aslit-lamp and a mobile pen-shaped meibograph.
Cornea 1:S65-S70, 2013
4. Arita R, Itoh K, Maeda S, Maeda K, Amano S: A
newly developed noninvasive and mobile
pen-shaped meibography system. Cornea 32:
242-247, 2013
5. Arita R, Shirakawa R, Maeda S, Yamaguchi M,
Ohashi Y, Amano S: Decreased surface
temperature of tarsal conjunctiva in patients withmeibomian gland dysfunction. JAMA Ophthalmol
131:818-819, 2013
6. Arita R, Suehiro J, Haraguchi T, Maeda S, Maeda
K, Tokoro H, Amano S: Topical diquafosol forpatients with obstructive meibomian gland
dysfunction. Br J Ophthalmol 97:725-729, 2013
7. Asaoka R: Measuring visual field progression in
the central 10 degrees using additional
information from central 24 degrees visual fields
and ‘Lasso Regression’. PloS One 8:e72199, 2013
8. Asaoka R: The relationship between visual acuity
and central visual field sensitivity in advanced
glaucoma. Br J Ophthalmol 97:1355-1356, 2013
9. Asaoka R, Russell RA, Malik R, Garway-Heath
DF, Crabb DP: Five-year forecasts of the Visual
Field Index (VFI) with binocular and monocularvisual fields. Graefes Arch Clin Exp Ophthalmol
251:1335-1341, 2013
10. Dimitrova G, Kato S, Nagahara M: Body postureduring colour Doppler imaging of the eye and243orbit. Acta Ophthalmologica 91:406, 2013
11. Fujimura S, Ueta T, Takahashi H, Obata R, Smith
RT, Yanagi Y: Characteristics of fundus
autofluorescence and drusen in the fellow eyes ofJapanese patients with exudative age-related
macular degeneration. Graefes Arch Clin Exp
Ophthalmol 251:1-9, 2013
12. Fukuda R, Usui T, Miyai T, Mori Y, Miyata K,
Amano S: Corneal thickness and volume
measurements by swept source anterior segment
optical coherence tomography in normal subjects.
Curr Eye Res 38:531-536, 2013
13. Fukuda R, Usui T, Miyai T, Yamagami S, Amano
S: Tear meniscus evaluation by anterior segment
swept-source optical coherence tomography. Am J
Ophthalmol 155:620-624, 2013
14. Fukushima S, Nakagami T, Suto C, Hirose A,
Uchigata Y: Prevalence of retinopathy and its risk
factors in a Japanese population. J Diabetes Invest
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15. Hiraoka T, Miyata K, Nakamura Y, Miyai T,
Ogata M, Okamoto F, Oshika T: Influences ofcycloplegia with topical atropine on ocularhigher-order aberrations. Ophthalmology 120:
8-13, 2013
16. Hirasawa H, Araie M, Tomidokoro A, Saito H,
Iwase A, Ohkubo S, Sugiyama K, Ootani T, Kishi
S, Matsushita K, Maeda N, Hangai M, Yoshimura
N: Reproducibility of thickness measurements ofmacular inner retinal layers using SD-OCT withor without correction of ocular rotation. Invest
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17. Hirose A, Furushima D, Yamaguchi N, Kitano S,
Uchigata Y: Prediction of retinopathy at 20 years
after onset in younger-onset type 1 diabetes using
mean metabolic memory-free HbA1c values: theimportance of using HbA1c data of total, notpartial, diabetes duration. Diabetes Care. 36:
3812-3814, 2013
18. Inaba K, Ito Y, Suzuki S, Sekii S, Takahashi K,
Kuroda Y, Murakami N, Morota M, Mayahara H,
Sumi M, Uno T, Itami J: Results of radical
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19. Inoue K, Shiokawa M, Wakakura M, Tomita G:
Deepening of the upper eyelid sulcus caused by 5
types of prostaglandin analogs. J Glaucoma 22:

626-631, 2013
20. Inoue K, Tanaka A, Tomita G: Effects of
tafluprost treatment for 3 years in patients withnormal-tension glaucoma. Clin Ophthalmol 7:
1411-1416, 2013
21. Iriyama A, Aihara Y, Yanagi Y: Outer retinal
tubulation in inherited retinal degenerative disease.
Retina 33:1462-1465, 2013
22. Iwahashi-Shima C, Azumi A, Ohguro N, Okada
AA, Kaburaki T, Goto H, Sonoda KH, Namba K,
Mizuki N, Mochizuki M: Acute retinal necrosis:
factors associated with anatomic and visual
outcomes. Jpn J Ophthalmol 57:98-103, 2013
23. Joko T, Shiraishi A, Akune Y, Tokumaru S,
Kobayashi T, Miyata K, Ohashi Y: Involvement of
P38MAPK in human corneal endothelial cell
migration induced by TGF-β2. Exp Eye Res 108:
23-32, 2013
24. Kaburaki T, Zhang Q, Jin X, Uchiyama M, Fujino
Y, Nakahara H, Takamoto M, Otomo K, Niimi M:
Effects of Japanese herbal medicine Sairei-to on
murine experimental autoimmune uveitis. Graefes
Arch Clin Exp Ophthalmol 251:2733-2739, 2013
25. Kadonosono K, Yamane S, Arakawa A, Inoue M,
Yamakawa T, Uchio E, Yanagi Y, Amano S:
Endovascular cannulation with a microneedle forcentral retinal vein occlusion. JAMA Ophthalmol
131:783-786, 2013
26. Karakawa A, Murata H, Hirasawa H, Mayama C,
Asaoka R: Detection of progression ofglaucomatous visual field damage using thepoint-wise method with the binomial test. PLoS
One 8:e78630, 2013
27. Kawasaki S, Misawa H, Tamura Y, Kondo Y,
Satoh S, Hasegawa O, Kato S, Terauchi Y:
Relationship between coronary artery disease andretinopathy in patients with type 2 diabetes
mellitus. Intern Med 52:2483-2487, 2013
28. Kimakura M, Sakai O, Nakagawa S, Yoshida J,
Shirakawa R, Toyono T, Yokoo S, Amano S:
Stromal bed quality and endothelial damage after
femtosecond laser cuts into the deep corneal
stroma. Br J Ophthalmol 97:1404-1409, 2013
29. Lamparter J, Russell RA, Zhu H, Asaoka R,
Yamashita T, Ho T, Garway-Heath DF: The
influence of intersubject variability in ocular
anatomical variables on the mapping of retinal

244

locations to the retinal nerve fiber layer and optic
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30. Liang ZH, Tomioka R, Murata H, Asaoka R,
Yamanishi K: Quantitative prediction of visual
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31. Matsuda J, Kaburaki T, Kobayashi S, Numaga J:
Treatment of recurrent anterior uveitis withinfliximab in patient with ankylosing spondylitis.
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32. Mayama C, Araie M: Effects of antiglaucoma
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2013
33. Mayama C, Saito H, Hirasawa H, Konno S,
Tomidokoro A, Araie M, Iwase A, Ohkubo S,
Sugiyama K, Otani T, Kishi S, Matsushita K,
Maeda N, Hangai M, Yoshimura N: Circle- andgrid-wise analyses of peripapillary nerve fiber
layers by spectral domain optical coherence
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34. Mimura T: Bilateral eyelid erythema associatedwith false eyelash glue. Cutan Ocul Toxicol
32:89-90, 2013
35. Mimura T, Usui T, Yamagami S, MiyaiT, Amano
S: Relationship between total tear IgE andspecific serum IgE in autumnal allergic
conjunctivitis. Cornea 32:14-19, 2013
36. Mimura T, Yamagami S, Kamei Y, Goto M,
Matsubara M: Influence of axial length on
conjunctivochalasis. Cornea 32:1126-1130, 2013
37. Mimura T, Yamagami S, Kamei Y, Goto M,
Matsubara M: Specific IgE in tear fluid andfeatures of allergic conjunctivitis. Curr Eye Res
38:917-925, 2013
38. Mishima K, Tomidokoro A, Suramethakul P,
Mataki N, Kurita N, Mayama C, Araie M:
Iridotrabecular contact observed using anterior
segment three-dimensional OCT in eyes with ashallow peripheral anterior chamber. Invest
Ophthalmol Vis Sci 54:4628-4635, 2013
39. Miyashita H, Yokoo S, Yoshida S, Kawakita T,
Yamagami S, Tsubota K, Shimmura S. Long-term

maintenance of limbal epithelial progenitor cells
using rho kinase inhibitor and keratinocyte growth
factor. Stem Cells Transl Med. 2:758-65, 2013
40. Miyata K, Otani S, Honbou M, Minami K: Use ofscheimpflug corneal anterior-posterior imaging in
ray-tracing intraocular lens power calculation.
Acta Ophthalmol 91:e546-e549, 2013
41. Murata H, Hirasawa H, Aoyama Y, Sugisaki K,
Araie M, Mayama C, Aihara M, Asaoka R:
Identifying areas of the visual field important for
quality of life in patients with glaucoma. PLoS
One 8:e58695, 2013
42. Noda Y, Ida Y, Tanaka S, Toyama T, Roggia MF,
Tamaki Y, Sugita N, Mitsuishi M, Ueta T: Impactof robotic assistance on precision of vitreoretinal
surgical procedures. PLoS One 8:e54116, 2013
43. Noma H, Funatsu H, Mimura T: Changes ofinflammatory factors after intravitreal triamcinolone acetonide for macular edema with central
retinal vein occlusion. J Ocul Pharmacol Ther 29:
363-365, 2013
44. Noma H, Funatsu H, Shimada K, Mimura T:
Influence of pars plana vitrectomy on macularsensitivity and morphology in patients with
branch retinal vein occlusion and serous retinal
detachment. Ophthalmic Surg Lasers Imaging
Retina 44:160-167, 2013
45. Noma H, Mimura T: Aqueous soluble vascularendothelial growth factor receptor-2 in macularedema with branch retinal vein occlusion. Curr
Eye Res 38:1288-1290, 2013
46. Noma H, Mimura T, Eguchi S: Association of
inflammatory factors with macular edema inbranch retinal vein occlusion. JAMA Ophthalmol
131:160-165, 2013
47. Noma H, Mimura T, Shimada K: Retinal function
and morphology in central retinal vein occlusion
with macular oedema. Curr Eye Res 38:143-149,
2013
48. Noma H, Mimura T, Shimada K: Changes ofmacular sensitivity and morphology after pars
plana vitrectomy for macular edema with central
retinal vein occlusion: a case series. BMC
Ophthalmol 13:2, 2013
49. Noma H, Mimura T, Tatsugawa M, Shimada K:
Aqueous flare and inflammatory factors inmacular edema with central retinal vein occlusion:

245

a case series. BMC Ophthalmol 13:78, 2013
50. Noma H, Shimada K, Mimura T: Influence ofretinal ischemia on macular function after pars
plana vitrectomy for macular edema with branchretinal vein occlusion. Int Ophthalmol 33:677-686,
2013
51. Noma H, Shimada K, Mimura T: Visual function
after pars plana vitrectomy in macular edema with
branch retinal vein occlusion. Int Ophthalmol
33:227-236, 2013
52. Noma H, Shimizu H, Mimura T: Unilateralmacular edema with central retinal vein occlusion
in systemic lupus erythematosus: a case report.
Clin Ophthalmol 7:865-867, 2013
53. Obata R, Takahashi H, Ueta T, Yuda K, Kure K,
Yanagi Y: Tomographic and angiographic
characteristics of eyes with macular focal
choroidal excavation. Retina 33:1201-1210, 2013
54. Ohno H, Nagano M, Inoue K: Spatula knife for
25-gauge vitrectomy. Retina 33:447-448, 2013
55. Ohtomo K, Ueta T, Toyama T, Nagahara M:
Predisposing factors for primary acquired
nasolacrimal duct obstruction. Graefes Arch Clin
Exp Ophthalmol 251:1835-1839, 2013
56. Sakata R, Aihara M, Murata H, Mayama C,
Tomidokoro A, Iwase A, Araie M: Contributing
factors for progression of visual field loss innormal-tension glaucoma patients with medical
treatment. J Glaucoma 22:250-254, 2013
57. Sakata R, Aihara M, Murata H, Saito H, Iwase A,
Yasuda N, Araie M: Intraocular pressure changeover a habitual 24-hour period after changing
posture or drinking water and related factors innormal tension glaucoma. Invest Ophthalmol Vis
Sci 54:5313-5320, 2013
58. Sakata R, Shirato S, Miyata K, Aihara M:
Recovery from deepening of the upper eyelid
sulcus after switching from bimatoprost tolatanoprost. Jpn J Ophthalmol 57:179-184, 2013
59. Seki G, Horita S, Suzuki M, Yamazaki O, Usui T,
Nakamura M, Yamada H: Molecular mechanismof renal and extrarenal manifestations caused byinactivation of the electrogenic Na+-HCO3cotransporter NBCe1. Front Physiol 4:270-277,
2013
60. Shiibashi M, Yoshimoto M, Shigeeda T, Kitano S,
Kato S: Experience using the heidelberg retina

angiograph 2 with a wide-field contact lenssystem in diabetic retinopathy cases. OpenOphthalmol J 7:54-57, 2013
61. Shirakawa R, Arita R, Amano S: Meibomian
gland morphology in Japanese infants, children,
and adults observed using a mobile pen-shaped
infrared meibography device. Am J Ophthalmol
155:1099-1110, 2013
62. Sugahara M, Fujimoto T, Shidara K, Inoue K,
Wakakura M: A case of anterior ischemic optic
neuropathy associated with uveitis. Clin
Ophthalmol 7:1023-1026, 2013
63. Sugimoto K, Murata H, Hirasawa H, Aihara M,
Mayama C, Asaoka R: Cross-sectional study:
Does combining optical coherence tomographymeasurements using the 'Random Forest' decision
tree classifier improve the prediction of thepresence of perimetric deterioration in glaucoma
suspects? BMJ Open 3:e003114, 2013
64. Sugita Y, Miura K, Araki F, Furukawa T, Kawano
K. Contributions of retinal direction-selective
ganglion cells to optokinetic responses in mice.
Eur J Neurosci 38:2823-2831, 2013
65. Tan X, Aoki A, Yanagi Y: Color vision
abnormality as an initial presentation of thecomplete type of congenital stationary night
blindness. Clin Ophthalmol 7:1587-1590, 2013
66. Toyono T, Usui T, Yokoo S, Kimakura M,
Nakagawa S, Yamagami S, Miyata K, Oike Y,
Amano S: Angiopoietin-like protein 2 is a potent
hemangiogenic and lymphangiogenic factor incorneal inflammation. Invest Ophthalmol Vis Sci
54:4278-4285, 2013
67. Yamamoto K, Takahashi H, Kanno M, Noda Y,
Fujino Y: Changes in parafoveal retinal thickness
and subfoveal choroidal thickness in a patientwith dengue fever-associated maculopathy. J
Ophthalmic Inflamm Infect 3:63, 2013
68. Yamashita T, Asaoka R, Tanaka M, Kii Y,
Yamashita T, Nakao K, Sakamoto T: Relationshipbetween position of peak retinal nerve fiber layer
thickness and retinal arteries on sectoral retinal
nerve fiber layer thickness. Invest Ophthalmol Vis
Sci 54:5481-5488, 2013
69. Yashiro S, Fujino Y, Tachikawa N, Inamochi K,
Oka S: Long-term control of CMV retinitis in apatient with idiopathic CD4+T lymphocytopenia.

246

J Infect Chemother 19:316-320, 2013
70. Yotsumoto S, Meguro A, Ishihara M, Uemoto R,
Ota M, Morimoto S, Kaburaki T, Ando Y,
Takenaka S, Ohno S, Inoko H, Mizuki N:
Investigation of the association between Toll-likereceptor 9 gene polymorphisms and sarcoidosis inJapanese patients. Ocul Immunol Inflamm 21:
234-236, 2013

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．

Mizuo Ando, M.D., Ph.D.

Research Associate
Naoya Egami, M.D.

Yu Matsumoto, M.D., Ph.D.

Akinori Kashio, M.D.

Yuki Saito, M.D.

Chisato Fujimoto, M.D, Ph.D

Shu Kikuta, M.D., Ph.D.

Hironori Nisihijima, M.D.

Rumi Ueha、M.D.

Go Omura、M.D.

Homepage

http://www.h.u-tokyo.ac.jp/orl /Introduction and Organization
The Department of Otorhinolaryngology was
founded in 1899 by Prof. Waichiro Okada who studiedin Germany. This is the first department ofotorhinolaryngology of the national university inJapan. Our department 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. Moreover 14
Japanese graduate students and one Chinese foreign
graduate student participate in basic research.
Weekly preoperative and postoperative conferences
are held to discuss surgical cases in detail. Special
lectures on leading research activities are presented byinvited guests on a regular basis. A weekly journal
club is held to introduce current research papers.

248

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 300 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.
10) Vestibular myogenic evoked potentials in cochlear
implant and inner ear anomaly.
11) Hair cell physiology in the vestibular end organ.
12) Newborn hearing screening and language
development in deaf children.

24913) 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. Yamauchi A, Imagawa H, Sakakibara KI,
Yokonishi H, Nito T, Yamasoba T, Tayama N.
Phase difference of vocally healthy subjects inhigh-speed digital imaging analyzed withlaryngotopography. Journal of Voice. 2013;27:
39-45.
2. Jin Y, Kondo K, Ushio M, Kaga K, Ryan AF,
Yamasoba T. Developmental changes in the
responsiveness of rat spiral ganglion neurons toneurotrophic factors in dissociated culture:differential responses for survival, neuritogenesis
and neuronal morphology. Cell and Tissue
Research 2013;351:15-27
3. Sugasawa K, Iwasaki S, Fujimoto C, Kinoshita M,
Inoue A, Egami N, Ushio M, Chihara Y,
Yamasoba T. Diagnostic usefulness of multifrequency tympanometry for Ménière's disease.
Audiology and Neurootology 2013;18: 152-160.
4. Inoue A, Iwasaki S, Ushio M, Chihara Y,
Fujimoto C, Egami N, Yamasoba T. Effect ofvestibular dysfunction on the development ofgross motor function in children with profoundhearing loss. Audiology and Neurootology 2013;
18: 143-151.
5. Kagoya R, Shinogami M, Kohno M, Yamasoba T.
Distortion-product otoacoustic emission tests
evaluate cochlear function and differentiate cochlear and vestibular schwannoma. Otolaryngology- Head and Neck Surgery 2013;148:267-271
6. Kikuta S, Fletcher ML, Homma,R, Yamasoba T,
Nagayama1 S. Odorant response properties ofindividual neurons in an olfactory glomerular
module. Neuron 2013;77:1122-1135
7. Makizumi Y, Kashio A, Sakamoto T, Karino S,
Kakigi A, Iwasaki S, Yamasoba T. Cochlear
implantation in a patient with osteogenesis

imperfecta. Auris Nasus Larynx. 2013;40:510-3.
8. Fujimoto C, Murofushi T, Chihara Y, Ushio M,
Suzuki M, Yamaguchi T, Yamasoba T, Iwasaki S.
Effect of severity of vestibular dysfunction on
postural instability in idiopathic bilateral vestibulopathy. Acta Oto-Laryngologica (Stockholm)
2013;133:454-61
9. Saito Y, Yoshida M, Ushiku T, Omura G, Ebihara
Y, Shimono T, Fukayama M, Yamasoba T,
Asakage T. Prognostic value of p16 expression
and alcohol consumption in Japanese patientswith oropharyngeal squamous cell carcinoma.
Cancer. 2013; 119:2005-11
10. Narushima M, Yamasoba T, Iida T, Sakamoto T,
Kashio A, Karino S, Yamamoto T, Kikuchi K,
Mihara M, Koshima I. Supermicrosurgicalreconstruction for congenital aural atresia using apure skin perforator flap: concept and long-term
results. Plastic and Reconstructive Surgery. 2013;
131: 1359-66
11. Iwasaki S, Egami N, Inoue A, Kinoshita M,
Fujimoto C, Murofushi T, Yamasoba T. Ocularvestibular evoked myogenic potential elicitedfrom binaural air-conducted stimulations: clinicalfeasibility in patients with peripheral vestibular
dysfunction.
Acta
OtoLaryngologica(Stockholm). 2013;133: 708-13
12. Kinoshita M, Iwasaki S, Fujimoto C, Inoue A,
Egami N, Chihara Y, Ushio M, Yamasoba T.
Ocular vestibular evoked myogenic potentials in
response to air-conducted sound and boneconducted vibration in vestibular schwannoma.
Otology and Neurotology. 2013;34: 1342-1348.
13. Sumitomo S, Fujio K, Okamura T, Morita K,
Ishigaki K, Suzukawa K, Kanaya K, Kondo K,
Yamasoba T, Furukawa A, Kitahara N, Shoda H,
Shibuya M, Okamoto A, Yamamoto K.
Transcription factor early growth response 3 isassociated with the TGF-β1 expression and theregulatory activity of CD4-positive T cells in vivo.
Journal of Immunology. 2013; 191:2351-9.
14. Ando M, Kawazu M, Ueno T, Fukumura K,
Yamato A, Soda M, Yamashita Y, Choi YL,
Yamasoba T, Mano H. Cancer- associatedmissense mutations of caspase-8 activate nuclear
factor-κB signaling. Cancer Science. 2013;104:1002-8

250

15. Kakigi A, Takubo Y, Egami N, Kashio A, Ushio M,
Sakamoto T, Yamashita S, Yamasoba T.
Evaluation of the internal structure of normal andpathological guinea pig cochleae using opticalcoherence
tomography.
Audiology
and
Neurootology 2013;18:335–343
16. Egami N, Kakigi A, Sakamoto T, Takeda T,
Hyodo M, Yamasoba T. Morphological andfunctional changes in a new animal model of
Ménière's disease. Laboratory Investigation.
2013;93:1001-11
17. Nakanishi W, Yamaguchi S, Matsuda A,
Suzukawa M, Shibui A, Nambu A, Suto H, Saito
H, Matsumoto K, Yamasoba T, Nakae S. IL-33,
but not IL-25, is crucial for the development ofhouse dust mite antigen-induced allergic rhinitis.
Plos One 2013;8:e78099
18. Egami N, Ushio M, Yamasoba T, Yamaguchi T,
Murofushi T, Iwasaki S. The diagnostic value ofvestibular evoked myogenic potentials in patientswith Meniere's disease. Journal of Vestibular
Research 2013;23:249-57.
19. Fujimaki Y, Tsunoda K, Ishimoto SI, Okada K,
Kinoshita M, Igaki H, Terahara A, Asakage T,
Yamasoba T. Non-invasive objective evaluation ofradiotherapy- induced dry mouth. Journal of Oral
Pathology and Medicine. 2014 ;43:97-102
20. Fujimoto C, Egami N, Kinoshita M, Sugasawa K,
Yamasoba T, Iwasaki S. Postural stability investibular neuritis: Age, disease duration andresidual vestibular function. Laryngoscope. 2014;
124:974-979
21. Fujimoto C, Egami N, Kinoshita M, Sugasawa K,
Yamasoba T, Iwasaki S. Factors affecting postural
instability in Meniere's disease. Otolaryngol Head
Neck Surg. 2013;149:759-65
22. Yamasoba T, Lin FR, Someya S, Kashio A,
Sakamoto T, Kondo K.Current concepts inage-related hearing loss: epidemiology and mechanistic pathways. Hearing Research 2013;303:
30-38.
23. Matsumoto Y, Nomoto T, Toh K, Cabral H,
Murakami M, Christie RJ, Kim HJ, Ogura T,
Miyata K, Nishiyama N, Yamasoba T, Kataoka K.
Intravital Real-Time Confocal Laser Scanning
Microscopy for the In Situ Evaluation of
Nanocarriers. You Han Bae, Randall J. Mrsny,

Kinam Park (Eds). Cancer Targeted Drug Delivery.
Springer 2013 pp 607-620.

251

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. Sixteen students haveentered the graduate school by 2013, and twelve ofthem were granted Ph.D.

Clinical activities
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The
Rehabilitation Center and the Department of
Rehabilitation Medicine are united and engage inclinical practice. We have at present no charged ward,
and treat about 3,000 new referrals annually fromalmost all the departments of the university hospital.
We always take charge of 250-300 patients
corresponding about 25-30% of the whole number of
inpatients. We also see 30 people per day at theoutpatient rehabilitation setting. The numerical ratioof outpatient is being reduced in order to give priority
to the clinical service corresponding to needs
expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year

252

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-calledclinical clerkship for 5th year students from
Wednesday to Friday every week. They experience a
few patients and learn how to take a patients’ history,
physical findings, functional evaluation, and how toplan rehabilitation programs. We have introduced a
few of elective students for elective clinical clerkshipto our collaborating hospitals with specialized
rehabilitation ward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

dysplasias
8) Analysis of musculo-skeletal involvement incongenital insensitivity to pain

References
1.

2.

3.

4.

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 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
7) Disabilities and handicaps in patients with skeletal

6.

7.

8.

Haga N, Kubota M, Miwa Z: Epidemiology ofhereditary sensory and autonomic neuropathy
type IV and V in Japan. Am J Med Genet A
161A: 871-874, 2013
Haga N, Kosaki K, Takikawa K, Tanaka H,
Okada K, Nakahara Y, Ogata N: Education andrelated support from medical specialists forJapanese patients with major skeletal dysplasias.
Disabil Health J 6: 399-404, 2013
Jiao S, Zhang Y, Ma W, Haga N: FOP in China
and Japan: an overview from domestic literatures.
Am J Med Genet Part A 161A: 892-893, 2013
Jiao S, Tsutani K, Haga N*: Review of Cochranereviews on acupuncture: how Chinese resources
contribute to Cochrane reviews. J AlternComplement Med 19(7): 613-621, 2013
Zhang Y, Ogata N, Yozu A, Haga N:
Two-dimensional video gait analyses in patientswith congenital insensitivity to pain. Dev
Neurorehabil 16(4): 266-270, 2013
Tojima M, Ogata N, Yozu A, Sumitani M, Haga
N*: Novel three-dimensional motion analysis
method for measuring the lumbar spine range of
motion: Repeatability and reliability comparedwith an electrogoniometer. Spine 38: E1327E1333, 2013
Sugita S, Chikuda H, Ohya J, Taniguchi Y,
Takeshita K, Haga N, Tanaka S: Cervical canalstenosis caused by progressive fusion andenlargement of cervical vertebrae with features ofProteus syndrome and Klippel-Feil syndrome.
Skeletal Radiol 42: 1743-1746, 2013
Nakahara Y, Katagiri T, Ogata N, Haga N*:
ACVR1 (587T>C) mutation in a variant form offibrodysplasia ossificans progressive -second
report. Am J Med Genet Part A 164A: 220-224,
2014

Surgical Sciences
3. Vital Care Medicine

254

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 2013 toApril 2014, 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.

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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) Sumitani M, Kogure T, Nakamura M, Shibata M,
Yozu A, Otake Y, Yamada Y. Classification of thepain nature of CRPS type 1, based on patientcomplaints,
into
neuropathic
painandnociceptive/inflammatory pain, using the McGill
Pain Questionnaire. Journal of Anesthesia andClinical Research 2013;4(8);1-5(2) Sumitani M, Yasunaga H, Uchida K, Horiguchi H,
Nakamura M, Ohe K, Fushimi K, Matsuda S,
Yamada Y. Perioperative factors affecting theoccurrence of acute complex regional pain
syndrome following limb bone fracture surgery:
Data from the Japanese Diagnosis Procedure
Combination database. Rheumatology (Oxford).
2013 Dec 24. [Epub ahead of print]

256(3) Matsubayashi Y, Takeshita K, Sumitani M, Kato
S, Ohya J, Oichi T, Okamoto N, Tanaka S.
Validity and reliability of the Japanese version of
the painDETECT Questionnaire: a multicenter
observational study. PLoS One. 2013 Sep 30;
8(9):e68013.
(4) Chikuda H, Ohtsu H, Ogata T, Sugita S, Sumitani
M, Koyama Y, Matsumoto M, Toyama Y, the
OSCIS. Optimal treatment for spinal cord injury
associated with cervical canal stenosis (OSCIS):
A study protocol for a randomized controlled trial
comparing early versus delayed surgery. Trials.
2013 Aug 7;14:245.
(5) Uchida T, Ohno N, Asahara M, Yamada Y,
Yamaguchi O, Tomita M, Makita K. Soluble
isoform of the receptor for advanced glycation
end products as a biomarker for postoperative
respiratory failure after cardiac surgery. PLoS
One. 2013 Jul 23;8(7):e70200.
(6) Sato K, Kitamura T, Kawamura G, Mori Y, Sato R,
Araki Y, Yamada Y. Glucose use in fasted rats
under sevoflurane anesthesia and propofol
anesthesia. Anesth Analg. 2013 Sep;117(3):627-33(7) Kawamura G, Kitamura T, Sato K, Sato R, Mori Y,
Araki Y, Yamada Y. Glucose administration
during volume resuscitation using dextran-40
from hemorrhagic shock ameliorates acid/baseimbalance in fasted rats under sevoflurane
anesthesia. Biosci Trends. 2013 Jun;7(3):138-43.
(8) Tojima M, Ogata N, Honda M, Yozu A, Sumitani
M, Haga N. A novel three-dimensional motion
analysis method for measuring the lumbar spine
range of motion: Repeatability and reliability
compared with an electrogoniometer. Spine 2013
Oct 1;38(21):E1327-33.
(9) Suka M, Odajima T, Kasai M, Igarashi A,
Ishikawa H, Kusama M, Nakayama T, Sumitani
M, Sugimori H. The 14-item health literacy scale
for Japanese adults (HLS-14). Environ HealthPrev Med. 2013 Sep;18(5):407-15(10) Yozu A, Haga N, Tojima M, Zhang Y, Sumitani
M, Otake Y Vertical peak ground force inhuman infant crawling. Gait Posture. 2013 Feb;
37(2):293-5.

257

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.

Masataka Gunshin, M.D.

Takehiro Matsubara, M.D.

Shinji Matsuse, M.D.

Yoshihiro Ueda, M.D.

Rei Ito, M.D.

Kanae Nagatomo, M.D.

Masahiro Nishida, M.D.

Taro Kasai, M.D.

Naoko Ohashi, M.D.

Toshifumi Asada,M.D.

Kent Doi, M.D.

Associate

Staff
Yusuke Komiyama, D.D.S. Tomohiro Sonoo, M.D.

Hiroaki Kobayashi, M.D.

Kazuma Oshima, M.D.

Hiromi Matsuda M.D.

Akinori Maeda, M.D.

Michiko Nomori, 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 andcardiac resuscitation rooms complete with STAT
X-ray and full monitoring and resuscitation equipment.
There are 9 treatment spaces including space fororthpedics, gynecology, and Optho-ENT evaluations.
10 overnight-stay monitored beds, X-ray, rapid spiralCT, ultrasound, angiography and STAT Lab arelocated adjacent 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.

258

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 clinicaldepartments of the Medical School. The university ofTokyo hospital was officially designated as emergency
medical care center in December 2010.

Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only
tertiary emergency but also primary and secondary
emergency care on 24-hour-a-day basis. In the 2006,
we had about 6,000 ambulance patients out of total
20,300 ER outpatients.
The new ER, four times the size of the present
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation
rooms for dentistry, ophthalmology, otorhinolaryngology and gynecology, 2 resuscitation bays, 1
operating room and 4 observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery,
surgery, neurosurgery or anesthesiology create “thesemi-closed ICU” model. We are responsible for theentire care of the critically ill patients (i.e. patientswith respiratory insufficiency such as ARDS, withsepsis, with MOF, with shock), post-operative
patients, and tertiary emergency patients, placing anemphasis on evidence-based medical therapy. We
had 2,700 ICU/CCU patients in the 2007. In 2007,
the number of beds in ICU/CCU increased to 16
and the facility included the 24 beds for the highcare ICU2.
3) Bed management
The objective of bed management services is toprovide a timely and appropriate bed allocation for
all the patients. In our hospital, patients areallocated to three types of wards, that is, generalward, ICU2 and ICU/CCU in accordance with theircritical condition. The ICU2 undertakes the leading
bed management in the hospital to ensure maximum
performance as an acute hospital.
4) Risk management
It is split into two categories – in-hospital andout-hospital disasters. In regard to in-hospital risk
management, including “code blue emergency”, weare responsible for patient safety on 24-hour/365day basis. And in regard to out-hospital risk
management, our hospital has been authorized by
the Tokyo Metropolitan Government as a disasterbase hospital, and also the Government hasrequested the formation of Disaster Medical
Assistant Team (DMAT) from us. We are now
proceeding with a drastic revision of in-hospitalmanual for disaster control, holding seminars on
disaster medicine, and enforcing the disastertraining. We have oxygen and medical suction
equipment on the passageways in the new ER since2006 fiscal year in case treating the large number ofdisaster patients.

Teaching activities
1) Six hours of lecture for the 2nd year medical
student, the topics include the prehospitalemergency care, the initial evaluation of emergency
patients, disaster medicine, serious infections
disease, and medical equipment. Four hours ofsimulation training of Basic Life Support.
2) One month of clinical clerkship and 1 week of
bed-side training for the 3rd year. ACLS Basiccourse (ICLS) is held for the participants in theclinical clerkship program, and successful
completion of this course will enable students to be
ICLS certified.
3) Clinical integrated lecture for the 4th year students
includes diagnosis and treatment of serious patientsusing case studies of shock, conscious disorder,
trauma, intoxication, infections disease, burns,
hypothermia, and convulsion. After learning a
ACLS course, students experience the real practiceof emergency medicine as fellow passengers in theambulance and as 2.5-day trainees in affiliated259

hospitals’ emergency centers.
In conformity with the guideline by Ministry of
Health, Labour and Welfare, all residents learn andpractice emergency medicine and primary care at
every level, primary, secondary and tertiary. The
residents are trained in the ACLS Basic (ICLS)
during resident year to obtain the knowledge andskills in CPR.
Junior residents are also assigned to ICU services
to gain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
In the senior resident program in 2006, we willtrain the new residents to be skilled in advanced
critical care medicine including primary caretrauma, MOF, shock, and equipment support.
As medical aspects of disaster management, we
provide the residents with lectures based on
MIMMS (Major Incident Medical Management 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.

2.

3.

4.

5.

Research activities
We investigate the pathophysiology of sepsis andsepsis-related conditions including ARDS by using
several different animal models (cecal lingation andpuncture, histone injection, etc).
Several clinical studies that evaluated the utility of
new biomarkers in ICU population have been
conducted. In addition, we performed health care cost
analysis on out-of-hospital cardiopulmonary arrest byusing the Japanese Diagnosis Procedure Combination
database, which is the largest clinical database inJapan.

6.

7.

References8.
1. Fukuda T, Ohashi N, Matsubara T, Doi K,
Gunshin M, Ishii T, Kitsuta Y, Nakajima S, Yahagi
N. Applicability of the prehospital termination ofresuscitation rule in an area dense with hospitalsin Tokyo: a single-center, retrospective,
observational study: is the pre hospital TOR rule
applicable in Tokyo? Am J Emerg Med. 2014 Feb;

9.

32(2):144-9.
Doi K, Urata M, Katagiri D, Inamori M, Murata S,
Hisagi M, Ono M, Matsubara T, Ishii T, Yahagi N,
Nangaku M, Noiri E. Plasma neutrophil
gelatinase-associated lipocalin in acute kidney
injury superimposed on chronic kidney disease
after cardiac surgery: a multicenter prospective
study. Crit Care. 2013 Nov 12;17(6):R270.
Doi K, Noiri E, Nangaku M, Yahagi N, Jayakumar
C, Ramesh G. Repulsive guidance cue semaphorin
3A in urine predicts the progression of acutekidney injury in adult patients from a mixed
intensive care unit. Nephrol Dial Transplant. 2014
Jan;29(1):73-80.
Inokuchi R, Sato H, Nanjo Y, Echigo M, Tanaka A,
Ishii T, Matsubara T, Doi K, Gunshin M, Hiruma
T, Nakamura K, Shinohara K, Kitsuta Y,
Nakajima S, Umezu M, Yahagi N. The proportionof clinically relevant alarms decreases as patient
clinical severity decreases in intensive care units:a pilot study. BMJ Open. 2013 Sep 10; 3(9):e003354.
Qian K, Ando T, Nakamura K, Liao H, Kobayashi
E, Yahagi N, Sakuma I. Ultrasound imaging
method for internal jugular vein measurement andestimation of circulating blood volume. Int J
Comput Assist Radiol Surg. 2014 Mar;9(2):231-9.
Nakamura K, Doi K, Okamoto K, Arai S, Ueha S,
Matsushima K, Nakajima S, Yahagi N, Noiri E.
Specific antibody in IV immunoglobulin forpostsplenectomy sepsis. Crit Care Med. 2013
Aug;41(8):e163-70.
Inamori S, Shirai M, Yahagi N, Pearson JT, Fujii
Y, Umetani K, Kobayashi Y, Okura Y, Yakehiro M,
Minamiyama M. A comparative study of cerebral
microcirculation during pulsatile and nonpulsatile
selective cerebral perfusion: assessment bysynchrotron radiation microangiography. ASAIO J.
2013 Jul-Aug;59(4):374-9.
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 Oct;28(5):564-70.
Fukuda T, Yasunaga H, Horiguchi H, Ohe K,
Fushimi K, Matsubara T, Yahagi N. Health care

260

costs related to out-of-hospital cardiopulmonaryarrest in Japan. Resuscitation. 2013 Jul; 84(7):964-9.
10. Inokuchi R, Sato H, Nakajima S, Shinohara K,
Nakamura K, Gunshin M, Hiruma T, Ishii T,
Matsubara T, Kitsuta Y, Yahagi N. Developmentof information systems and clinical decision
support systems for emergency departments: along road ahead for Japan. Emerg Med J. 2013
Nov;30(11):914-7.
11. Hiruma T, Nakamura K, Inokuchi R, Kurata H,
Gunshin M, Matsubara T, Ishii T, Nakajima S,
Yahagi N, Shinohara K. Tsunami lungaccompanied by multiple disorders. Am J Respir
Crit Care Med. 2013 Jan 1;187(1):110-1.
12. Sonoo T, Gunshin M, Son D, Nakajima S,
Kitamura K, Yahagi N, Wong JG. Cerebral venous
thrombosis and "Dense Triangle Sign" onunenhanced head computed tomographic scan.
Am J Emerg Med. 2014 Feb;32(2):192.e3-4.
13. Inokuchi R, Ishida T, Maeda J, Nakajima S,
Yahagi N, Matsumoto A. Anaerobiospirillum
succiniciproducens-induced bacteremia in ahealthy man. Am J Emerg Med. 2014
Jul;32(7):812.e1-3.
14. Inokuchi R, Nakamura K, Mizuno N, Sato H,
Shinohara K, Matsubara T, Doi K, Ishii T,
Gunshin M, Nakajima S, Yahagi N. Adult-onset
seizures in a patient with Down syndrome andportosystemic shunt. Brain Dev. 2014 Aug; 36(7):626-9.
15. Nakamura K, Yamane K, Shinohara K, Doi K,
Inokuchi R, Hiruma T, Nakajima S, Noiri E,
Yahagi N. Hyperammonemia in idiopathic
epileptic seizure. Am J Emerg Med. 2013 Oct;31(10):1486-9.
16. Okada M, Inokuchi R, Shinohara K, Matsumoto A,
Ono Y, Narita M, Ishida T, Kazuki C, Nakajima S,
Yahagi N. Chromobacterium haemolyticuminduced bacteremia in a healthy young man. BMC
Infect Dis. 2013 Sep 3;13(1):406.
17. Ohashi N, Nakamura K, Inokuchi R, Sato H,
Tokunaga K, Fukuda T, Nakajima S, Yahagi N.
EDTA-dependent pseudothrombocytopenia complicated by eosinophilic pneumonia. Am J Emerg
Med. 2013 Jul;31(7):1157.e5-7.
18. Tanaka K, Inokuchi R, Namai Y, Yahagi N.

Retropharyngeal cellulitis in adolescence. BMJ
Case Rep. 2013 May 17;2013.
19. Sonoo T, Wada T, Inokuchi R, Nakamura K,
Nakajima S, Yahagi N. Putamen hemorrhage
occurred simultaneously with Stanford type A
acute aortic dissection: a case report. Am J Emerg
Med. 2013 Jun;31(6):995.e3-4.

Health Sciences and Nursing
1. Health Sciences

262

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 2013.
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,

263

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, work-life balance, and CREW (Civility,
Respect and Engagement at Work)) are also actively
investigated. Furthermore, research in the department
includes various other topics, such as psychiatricrehabilitation, clinical psychology, psychotherapy,
child and adolescent psychiatry; and developmental
disorders. Most of the research has been conducted ina close collaboration with researchers in otherdomestic and foreign institutions/universities.

5.

6.

7.

References (Jan.-Dec., 2013)
1.

2.

3.

4.

Kido Y, Kawakami N, Miyamoto Y, Chiba R,
Tsuchiya M. Social Capital and Stigma Toward
People with Mental Illness in Tokyo, Japan.
Community mental health journal 2013;49(2):243-247.
Takaoka Y, Kawakami N. Fruit and vegetableconsumption in adolescence and health in early
adulthood: a longitudinal analysis of the Statistics
Canada's National Population Health Survey. BMC
Public Health 2013;13:1206
Stein DJ, Aguilar-Gaxiola S, Alonso J, Bruffaerts R,
de Jonge P, Liu Z, Miguel Caldas-de-Almeida J,
O'Neill S, Viana MC, Al-Hamzawi AO,
Angermeyer MC, Benjet C, de Graaf R, Ferry F,
Kovess-Masfety V, Levinson D, de Girolamo G,
Florescu S, Hu C, Kawakami N, Maria Haro J,
Piazza M, Posada-Villa J, Wojtyniak BJ, Xavier M,
Lim CC, Kessler RC, Scott KM. Associations
between mental disorders and subsequent onset of
hypertension. Gen Hosp Psychiatry (in press)
Karam EG, Friedman MJ, Hill ED, Kessler RC,
McLaughlin KA, Petukhova M, Sampson L, Shahly
V, Angermeyer MC, Bromet EJ, de Girolamo G, deGraaf R, Demyttenaere K, Ferry F, Florescu SE,
Haro JM, He Y, Karam AN, Kawakami N,
Kovess-Masfety V, Medina- Mora ME, Browne
MA, Posada-Villa JA, Shalev AY, Stein DJ, Viana

8.

9.

10.

11.

12.

13.

MC, Zarkov Z, Koenen KC. Cumulative traumas
and risk thresholds: 12-month PTSD in the World
Mental Health (WMH) Surveys. Depress Anxiety(in press)
Park J, Kitayama S, Markus HR, Coe CL,
Miyamoto Y, Karasawa M, Curhan KB, Love GD,
Kawakami N, Boylan JM, Ryff CD. Social status
and anger expression: The cultural moderation
hypothesis. Emotion. 2013 Dec;13(6):1122-31.
Miyamoto Y, Boylan JM, Coe CL, Curhan KB,
Levine CS, Markus HR, Park J, Kitayama S,
Kawakami N, Karasawa M, Love GD, Ryff CD.
Negative emotions predict elevated interleukin-6 in
the United States but not in Japan. Brain Behav
Immun. 2013 Nov;34:79-85.
Sugimoto T, Shinozaki T, Miyamoto Y Aftershocks
Associated With Impaired Health Caused by theGreat East Japan Disaster Among Youth AcrossJapan: A National Cross-Sectional Survey Interact J
Med Res 2013;2(2):e31(link)
Nakagawa Y, Inoue A, Kawakami N, Tsuno K,
Tomioka K, Nakanishi M, Mafune K, Hiro H.
Effect modification by coping strategies on theassociation of organizational justice withpsychological distress in Japanese workers. J Occup
Health (in press)
Demerouti E, Shimazu A, Bakker A, Shimada K,
Kawakami N. Work-self balance: A longitudinal
study on the effects of job demands and resourceson personal functioning in Japanese working
parents. Work Stress 2013; 27: 223-243.
Shimazu A, Kawakami N, Kubota K, Inoue A,
Kurioka S, Miyaki K, Takahashi M, Tsutsumi A.
Psychosocial mechanisms of psychological healthdisparity in Japanese workers. Ind Health 2013; 51:
472-481.
Matsumoto T, Tachimori H, Tanibuchi Y, Takano A,
Wada K. Clinical features of patients with designer
drugs-related disorder in Japan: A comparison withpatients with methamphetamine- and hypnotic/
anxiolytic-related disorders. Psychiatry Clin
Neurosci. (in press)
Oshio T, Umeda M, Fujii M. The association of life
satisfaction and self-rated health with income
dynamics among male employees in Japan: Japan& The World Economy 2013; 28:143-150.
Oshio T, Umeda M, Kawakami N. The impact of

264

14.

15.

16.

17.

18.

19.

20.

interpersonal childhood adversity on adult mental
health: How much is mediated by social supportand socioeconomic status in Japan? Public Health2013; 127(8):754-760
Shimoda H, Inoue A, Kawakami N, Tsuno K.
One-year test-retest reliability of a Japanese webbased version of the WHO Composite International
Diagnostic Interview (CIDI) for major depression
in a working population. Int J Methods Psychiatr
Res (in press)
Kurioka S, Inoue A, Tsutsumi A. Optimum cut-off
point of the Japanese short version of theEffort-Reward Imbalance Questionnaire. J Occup
Health 2013; 55(5): 340-8.
Suzuki T, Miyaki K, Tsutsumi A, Hashimoto H,
Kawakami N, Takahashi M, Shimazu A, Inoue A,
Kurioka S, Kakehashi M, Sasaki Y, Shimbo T.
Japanese dietary pattern consistently relates to low
depressive symptoms and it is modified by job
strain and worksite supports. J Affect Disord 2013;
150(2): 490-8.
Kubota K, Inoue A, Shimizu Y, Kagata S, Yong R,
Hirama Y, Shiga M, Kawazoe T. Health-Related
Problems after the Great East Japan Earthquake: An
Evaluation Based on the Annual Health Examination. J Nurs Care 2013, 2: 134. doi: 10.4172/
2167-1168.1000134. (web-site)(pdf)
Matsudaira K, Shimazu A, Fujii T, Kubota K,
Sawada T, Kikuchi N, Takahashi M. Workaholism
as a risk factor for depression, disabling back pain,
and sickness absence among Japanese workers.
PLoS ONE 8(9): e75140: 2013. doi:10.1371/journal.
pone.0075140(PLoS ONE)
Karam EG, Friedman MJ, Hill ED, Kessler RC,
McLaughlin KA, Petukhova M, Sampson L, Shahly
V, Angermeyer MC, Bromet EJ, de Girolamo G, deGraaf R, Demyttenaere K, Ferry F, Florescu S,
Haro JM, He Y, Karam AN, Kawakami N,
Kovess-Masfety V, Medina-Mora ME, Oakley
Browne MA, Posada-Villa JA, Shalev AY, Stein DJ,
Viana MC, Zarkov Z, Koenen KC. Cumulative
traumas and risk thresholds: 12-month PTSD in theWorld Mental Health (WMH) Surveys Depression
and Anxiety (in press)
Shimazu A, Kubota K, Bakker AB, Demerouti E,
Shimada K, Kawakami N. Dual experiences ofwork-to-family conflict and family-to-work con-

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

flict: A spillover-crossover perspective. J Occup
Health 2013; 55: 234-243.
Okamoto M, Kawakami N, Kido Y, Sakurai K.
Social capital and suicide: an ecological study inTokyo, Japan. Environ Health Prev Med. 2013l;
18(4):306-12.(PMID: 23180068)
吉村健佑, 川上憲人, 堤 明純, 井上彰臣, 小林
由佳, 竹内文乃, 福田敬. 職場におけるメンタ
ルヘルスの第一次予防対策に関する費用便益
分析. 産業衛生学雑誌 2013; 55(1): 11-24.
Chiba R, Miyamoto Y, Kawakami N, Harada N.
Effectiveness of the program to facilitate recovery
for people with long term mental illness in Japan.
Nursing & Health Siences. (in press)
Ishizaki M, Kawakami N, Honda R, Yamada Y,
Nakagawa H, Morikawa Y. A Prospective Study ofPsychosocial Work Characteristics and Long Sick
Leave of Japanese Male Employees in Multiple
Workplaces. Ind Health. 2013 May 2. [Epub aheadof print]
Inoue A, Kawakami N, Tsuno K, Shimazu A,
Tomioka K, Nakanishi M. Job demands, job
resources, and work engagement of Japaneseemployees: a prospective cohort study. Int Arch
Occup Environ Health 2013; 86(4): 441-9.
Inoue A, Kawakami N, Tsuno K, Tomioka K,
Nakanishi M. Organizational justice andpsychological distress among permanent andnon-permanent employees in Japan: a prospective
cohort study. Int J Behav Med 2013; 20(2): 265-76.
Inoue A, Kawakami N, Tsuno K, Tomioka K,
Nakanishi M. Organizational justice and major
depressive episode in Japanese employees: across-sectional study. J Occup Health 2013; 55(2):47-55.
Pando M, Aranda C, Tsuno K, Inoue A, Kawakami
N. Assessing psychological violence andharassment at work: reliability and validity of theJapanese version of the Inventory of Violence andPsychological Harassment (IVAPT) comparing
NAQ-R and LIPT. J Occup Health 2013; 55(2):108-19.
Kubo, T., Takahashi, M., Togo, F., Liu, X., Shimazu,A., Tanaka, K., Takaya, M. Effects on employees ofcontrolling working hours and working schedules.
Occup Med. 2013; 63: 148-51.
Lasalvia A, Zoppei S, Van Bortel T, Bonetto C,

265

31.

32.

33.

34.

35.

Cristofalo D, Wahlbeck K, Bacle SV, Van
Audenhove C, van Weeghel J, Reneses B,
Germanavicius A, Economou M, Lanfredi M, Ando
S, Sartorius N, Lopez-Ibor JJ, Thornicroft G; the
ASPEN/INDIGO Study Group. Global pattern ofexperienced and anticipated discrimination reported
by people with major depressive disorder: across-sectional survey. Lancet. 2013;381(9860):
55-62. doi: 10.1016/S0140-6736(12)61379-8.
Miyaki K, Song Y, Taneichi S, Tsutsumi A,
Hashimoto H, Kawakami N, Takahashi M, Shimazu
A, Inoue A, Kurioka S, Shimbo T. Socioeconomic
Status is Significantly Associated with Dietary Salt
Intakes and Blood Pressure in Japanese Workers(J-HOPE Study). Int J Environ Res Public Health.
2013 Mar 11;10(3):980-93.
Honjo K, Kawakami N, Tsuchiya M, Sakurai K,
WMH-J 2002-2006 Survey Group. Association ofsubjective and objective socioeconomic status withsubjective mental health and mental disorders
among Japanese men and women. Int J Behav Med(in press)
Demerouti E, Shimazu A, Bakker A, Shimada K,
Kawakami N. Balancing between work, family andthe self: A longitudinal study among Japaneseworking parents. Work & Stress (in press)
Kido Y, Kawakami N, WHO World Mental HealthJapan Survey Group. Sociodemographic determinants of attitudinal barriers in the use of mental
health services in Japan: Findings from the World
Mental Health Japan Survey 2002–2006. Psychiatry
and Clinical Neurosciences. 2013;67(2):101–109.
(link)
Miyaki K, Song Y, Taneichi S, Tsutsumi A,
Hashimoto H, Kawakami N, Takahashi M, Shimazu
A, Inoue A, Kurioka S, Shimbo T. Socioeconomic
Status Is Significantly Associated with the Dietary
Intakes of Folate and Depression Scales in Japanese
Workers (J-HOPE Study). Nutrients. 2013 Feb 18;
5(2):565-78.

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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267

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.

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’

4.

5.

6.

Published articles
1. Tanaka S, Yoshimura Y, Kamada C, Tanaka S,
Horikawa C, Okumura R, Ito H, Ohashi Y,
Akanuma Y, Yamada N, Sone H; Japan Diabetes
Complications Study Group. Intakes of dietaryfiber, vegetables, and fruits and incidence of
cardiovascular disease in Japanese patients with
type 2 diabetes. Diabetes Care. 2013;36(12):3916-22.
2. Oba K, Paoletti X, Alberts S, Bang YJ, Benedetti
J, Bleiberg H, Catalano P, Lordick F, Michiels S,

7.

8.

Morita S, Ohashi Y, Pignon JP, Rougier P, Sasako
M, Sakamoto J, Sargent D, Shitara K, Cutsem EV,
Buyse M, Burzykowski T; GASTRIC group.
Disease-free survival as a surrogate for overall
survival in adjuvant trials of gastric cancer: ameta-analysis. J Natl Cancer Inst. 2013;105(21):1600-7.
Paoletti X, Oba K, Bang YJ, Bleiberg H, Boku N,
Bouché O, Catalano P, Fuse N, Michiels S,
Moehler M, Morita S, Ohashi Y, Ohtsu A, Roth A,
Rougier P, Sakamoto J, Sargent D, Sasako M,
Shitara K, Thuss-Patience P, Van Cutsem E,
Burzykowski T, Buyse M; GASTRIC group.
Progression-free survival as a surrogate foroverall survival in advanced/recurrent gastriccancer trials: a meta-analysis. J Natl Cancer Inst.
2013;105(21):1667-70.
Kaga C, Takagi A, Kano M, Kado S, Kato I, Sakai
M, Miyazaki K, Nanno M, Ishikawa F, Ohashi Y,
Toi M. Lactobacillus casei Shirota enhances thepreventive efficacy of soymilk in chemicallyinduced breast cancer. Cancer Sci. 2013;104(11):1508-14.
Umemoto S, Ogihara T, Rakugi H, Matsumoto M,
Kitagawa K, Shimada K, Higaki J, Ito S, Suzuki
H, Ohashi Y, Saruta T, Matsuzaki M;
Combination Therapy of Hypertension to Prevent
Cardiovascular. Effects of a benidipine-based
combination therapy on the risk of stroke
according to stroke subtype: the COPE trial.
Hypertens Res. 2013;36(12):1088-95.
Toi M, Hirota S, Tomotaki A, Sato N, Hozumi Y,
Anan K, Nagashima T, Tokuda Y, Masuda N,
Ohsumi S, Ohno S, Takahashi M, Hayashi H,
Yamamoto S, Ohashi Y. Probiotic Beverage withSoy Isoflavone Consumption for Breast Cancer
Prevention: A Case-control Study. Curr Nutr Food
Sci. 2013;9(3):194-200.
Sakane Y, Yamaguchi M, Yokoi N, Uchino M,
Dogru M, Oishi T, Ohashi Y, Ohashi Y.
Development and validation of the Dry
Eye-Related Quality-of-Life Score questionnaire.
JAMA Ophthalmol. 2013 Oct;131(10):1331-8.
Rakugi H, Ogihara T, Umemoto S, Matsuzaki M,
Matsuoka H, Shimada K, Higaki J, Ito S, Kamiya
A, Suzuki H, Ohashi Y, Shimamoto K, Saruta T;
Combination Therapy of Hypertension to Prevent268

Cardiovascular Events Trial Group. Combination
therapy for hypertension in patients with CKD: asubanalysis of the Combination Therapy ofHypertension to Prevent Cardiovascular Events
trial. Hypertens Res. 2013;36(11):947-58.
9. Tanaka S, Miyazaki T, Uemura Y, Kuroda T,
Miyakawa N, Nakamura T, Fukunaga M, Ohashi
Y, Ohta H, Mori S, Hagino H, Hosoi T, Sugimoto
T, Itoi E, Orimo H, Shiraki M. Design of arandomized clinical trial of concurrent treatment
with vitamin K2 and risedronate compared to
risedronate alone in osteoporotic patients:
Japanese Osteoporosis Intervention Trial-03(JOINT-03). J Bone Miner Metab. 2014;32(3):298-304.
10. Ishikura K, Uemura O, Ito S, Wada N, Hattori M,
Ohashi Y, Hamasaki Y, Tanaka R, Nakanishi K,
Kaneko T, Honda M; Pediatric CKD Study Group;Japan Committee of Measures for Pediatric CKDof the Japanese Society of Pediatric Nephrology.
Pre-dialysis chronic kidney disease in children:
results of a nationwide survey in Japan. Nephrol
Dial Transplant. 2013;28(9):2345-55.
11. Watanabe T, Yoshino T, Uetake H, Yamazaki K,
Ishiguro M, Kurokawa T, Saijo N, Ohashi Y,
Sugihara K. KRAS mutational status in Japanesepatients with colorectal cancer: results from anationwide, multicenter, cross-sectional study. Jpn
J Clin Oncol. 2013;43(7):706-12.
12. Sato Y, Fujimoto S, Konta T, Iseki K, Moriyama T,
Yamagata K, Tsuruya K, Yoshida H, Asahi K,
Kurahashi I, Ohashi Y, Watanabe T. U-shaped
association between body mass index andproteinuria in a large Japanese general population
sample. Clin Exp Nephrol. 2014;18(1):75-86.
13. Moriya T, Tanaka S, Kawasaki R, Ohashi Y,
Akanuma Y, Yamada N, Sone H, Yamashita H,
Katayama S; Japan Diabetes Complications Study
Group. Diabetic retinopathy and microalbuminuria can predict macroalbuminuria andrenal function decline in Japanese type 2 diabetic
patients: Japan Diabetes Complications Study.
Diabetes Care. 2013;36(9):2803-9.
14. Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto
H, Boku N, Fukutomi A, Sugimori K, Baba H,
Yamao K, Shimamura T, Sho M, Kitano M, Cheng
AL, Mizumoto K, Chen JS, Furuse J, Funakoshi A,

Hatori T, Yamaguchi T, Egawa S, Sato A, Ohashi
Y, Okusaka T, Tanaka M. Randomized phase III
study of gemcitabine plus S-1, S-1 alone, or
gemcitabine alone in patients with locallyadvanced and metastatic pancreatic cancer inJapan and Taiwan: GEST study. J Clin Oncol.
2013;31(13):1640-8.
15. Hagino H, Shiraki M, Fukunaga M, Nakano T,
Takaoka K, Ohashi Y, Nakamura T, Matsumoto T.
Number and severity of prevalent vertebral
fractures and the risk of subsequent vertebral
fractures in Japanese women with osteoporosis:
results from the minodronate trial. J Bone Miner
Metab. 2013;31(5):544-50.
16. Kanda Y, Oshima K, Kako S, Fukuda T, Uchida N,
Miyamura K, Kondo Y, Nakao S, Nagafuji K,
Miyamoto T, Kurokawa M, Okoshi Y, Chiba S,
Ohashi Y, Takaue Y, Taniguchi S. In vivo T-cell
depletion with alemtuzumab in allogeneic hematopoietic stem cell transplantation: Combined
results of two studies on aplastic anemia andHLA-mismatched haploidentical transplantation.
Am J Hematol. 2013;88(4):294-300.
17. Iimuro S, Imai E, Watanabe T, Nitta K, Akizawa T,
Matsuo S, Makino H, Ohashi Y, Hishida A;
Chronic Kidney Disease Japan Cohort Study
Group. Clinical correlates of ambulatory BP
monitoring among patients with CKD. Clin J Am
Soc Nephrol. 2013;8(5):721-30.
18. Tanaka S, Tanaka S, Iimuro S, Yamashita H,
Katayama S, Akanuma Y, Yamada N, Araki A, Ito
H, Sone H, Ohashi Y; Japan Diabetes
Complications Study Group; Japanese Elderly
Diabetes Intervention Trial Group. Predicting
macro- and microvascular complications in type 2
diabetes: the Japan Diabetes Complications
Study/the Japanese Elderly Diabetes Intervention
Trial risk engine. Diabetes Care. 2013;36(5):1193-9.
19. Heianza Y, Arase Y, Saito K, Hsieh SD, Tsuji H,
Kodama S, Tanaka S, Ohashi Y, Shimano H,
Yamada N, Hara S, Sone H. Development of ascreening score for undiagnosed diabetes and its
application in estimating absolute risk of future
type 2 diabetes in Japan: Toranomon Hospital
Health Management Center Study 10 (TOPICS
10). J Clin Endocrinol Metab. 2013;98(3):269

1051-60.
20. GASTRIC (Global Advanced/Adjuvant Stomach
Tumor Research International Collaboration)
Group, Oba K, Paoletti X, Bang YJ, Bleiberg H,
Burzykowski T, Fuse N, Michiels S, Morita S,
Ohashi Y, Pignon JP, Rougier P, Sakamoto J,
Sargent D, Sasako M, Shitara K, Tsuburaya A,
Van Cutsem E, Buyse M. Role of chemotherapy
for advanced/recurrent gastric cancer: an
individual-patient-data meta-analysis. Eur J
Cancer. 2013;49(7):1565-77.
21. Kodama S, Tanaka S, Heianza Y, Fujihara K,
Horikawa C, Shimano H, Saito K, Yamada N,
Ohashi Y, Sone H. Association between physicalactivity and risk of all-cause mortality andcardiovascular disease in patients with diabetes: ameta-analysis. Diabetes Care. 2013;36(2):471-9.
22. Tanaka S, Yoshimura Y, Kawasaki R, Kamada C,
Tanaka S, Horikawa C, Ohashi Y, Araki A, Ito H,
Akanuma Y, Yamada N, Yamashita H, Sone H;
Japan Diabetes Complications Study Group. Fruit
intake and incident diabetic retinopathy with type2 diabetes. Epidemiology. 2013;24(2):204-11.
23. Ohashi Y, Uemura Y, Fujisaka Y, Sugiyama T,
Ohmatsu H, Katsumata N, Okamoto R, Saijo N,
Hotta T. Meta-analysis of epoetin beta anddarbepoetin alfa treatment for chemotherapyinduced anemia and mortality: Individual patient
data from Japanese randomized, placebocontrolled trials. Cancer Sci. 2013;104(4):481-5.
24. Nitta K, Iimuro S, Imai E, Matsuo S, Makino H,
Akizawa T, Watanabe T, Ohashi Y, Hishida A.
Risk factors for increased left ventricular
hypertrophy in patients with chronic kidneydisease. Clin Exp Nephrol. 2013;17(5):730-42.
25. Nishiwaki M, Ikewaki K, Ayaori M, Mizuno K,
Ohashi Y, Ohsuzu F, Ishikawa T, Nakamura H;
MEGA Study Group. Risk reductions for
cardiovascular disease with pravastatin treatment
by dyslipidemia phenotype: a post hoc analysis of
the MEGA Study. J Cardiol. 2013;61(3):196-200.
26. Okamoto H, Hori M, Matsuzaki M, Tsutsui H,
Yamazaki T, Nagai R, Yoshikawa T, Fujio Y,
Nonen S, Azuma J, Izumi T, Ohashi Y, Kitabatake
A; J-CHF Investigators.
Minimal dose for
effective clinical outcome and predictive factors
for responsiveness to carvedilol: Japanese chronic

heart failure (J-CHF) study. Int J Cardiol. 2013;
164(2):238-44.
27. Kawasaki R, Tanaka S, Tanaka S, Abe S, Sone H,
Yokote K, Ishibashi S, Katayama S, Ohashi Y,
Akanuma Y, Yamada N, Yamashita H; Japan
Diabetes Complications Study Group. Risk ofcardiovascular diseases is increased even withmild diabetic retinopathy: the Japan Diabetes
Complications Study. Ophthalmology. 2013;
120(3):574-82.
28. Mizuno K, Tajima N, Ohashi Y, Nakamura H.
Is the risk of new-onset diabetes by statinsassociated with diet adherence? Int J Cardiol.
2013;166(1):277.
29. Iwagami S, Baba Y, Watanabe M, Shigaki H,
Miyake K, Ishimoto T, Iwatsuki M, Sakamaki K,
Ohashi Y, Baba H. LINE-1 hypomethylation isassociated with a poor prognosis among patientswith curatively resected esophageal squamous cell
carcinoma. Ann Surg. 2013;257(3):449-55.
30. Kato H, Nakagami G, Iwahira Y, Otani R, Nagase
T, Iizaka S, Tamai N, Matsuyama Y, Sanada H.
Risk factors and risk scoring tool for infection
during tissue expansion in tissue expander andimplant breast reconstruction. Breast J. 2013;19(6):618-26.
31. Taguri M, Matsuyama Y. Comments on 'An
information criterion for marginal structuralmodels' by R. W. Platt, M. A. Brookhart, S. R.
Cole, D. Westreich, and E. F. Schisterman. Stat
Med. 2013;32(20):3590-1.
32. Fujita R, Iimuro S, Shinozaki T, Sakamaki K,
Uemura Y, Takeuchi A, Matsuyama Y, Ohashi Y.
Decreased duration of acute upper respiratory
tract infections with daily intake of fermented
milk: a multicenter, double-blinded, randomized
comparative study in users of day care facilities
for the elderly population. Am J Infect Control.
2013;41(12):1231-5.
33. Utsunomiya T, Shimada M, Kudo M, Ichida T,
Matsui O, Izumi N, Matsuyama Y, Sakamoto M,
Nakashima O, Ku Y, Kokudo N, Makuuchi M;
Liver Cancer Study Group of Japan. Nationwide
study of 4741 patients with non-B non-C
hepatocellular carcinoma with special reference tothe therapeutic impact. Ann Surg. 2014;259(2):336-45.

270

34. Ohki T, Tateishi R, Akahane M, Mikami S, Sato
M, Uchino K, Arano T, Enooku K, Kondo Y,
Yamashiki N, Goto T, Shiina S, Yoshida H,
Matsuyama Y, Omata M, Ohtomo K, Koike K.
CT with hepatic arterioportography as apretreatment examination for hepatocellular
carcinoma patients: a randomized controlled trial.
Am J Gastroenterol. 2013;108(8):1305-13.
35. Hasegawa K, Makuuchi M, Kokudo N, Izumi N,
Ichida T, Kudo M, Ku Y, Sakamoto M,
Nakashima O, Matsui O, Matsuyama Y; Liver
Cancer Study Group of Japan. Impact ofhistologically confirmed lymph node metastases
on patient survival after surgical resection forhepatocellular carcinoma: report of a Japanesenationwide survey. Ann Surg. 2014;259(1):166-70.
36. Aoki T, Kokudo N, Matsuyama Y, Izumi N,
Ichida T, Kudo M, Ku Y, Sakamoto M,
Nakashima O, Matsui O, Makuuchi M; Liver
Cancer Study Group of Japan. Prognostic impactof spontaneous tumor rupture in patients with
hepatocellular carcinoma: an analysis of 1160
cases from a nationwide survey. Ann Surg. 2014;
259(3):532-42.
37. Takayasu K, Arii S, Sakamoto M, Matsuyama Y,
Kudo M, Ichida T, Nakashima O, Matsui O, Izumi
N, Ku Y, Kokudo N, Makuuchi M; Liver Cancer
Study Group of Japan. Clinical implication ofhypovascular hepatocellular carcinoma studied in
4,474 patients with solitary tumour equal or lessthan 3 cm. Liver Int. 2013;33(5):762-70.
38. Hasegawa K, Kokudo N, Makuuchi M, Izumi N,
Ichida T, Kudo M, Ku Y, Sakamoto M,
Nakashima O, Matsui O, Matsuyama Y.
Comparison of resection and ablation forhepatocellular carcinoma: a cohort study based ona Japanese nationwide survey. J epatol. 2013;
58(4):724-9.
39. Seyama Y, Imamura H, Inagaki Y, Matsuyama Y,
Tang W, Makuuchi M, Kokudo N. Intermittent
clamping is superior to ischemic preconditioning
and its effect is more marked with shorter
clamping cycles in the rat liver. J Gastroenterol.
2013;48(1):115-24.
40. Sugimoto T, Shinozaki T, Miyamoto Y.
Aftershocks associated with impaired healthcaused by the great East Japan disaster among
youth across Japan: a national cross-sectional
survey. Interact J Med Res. 2013;2(2):e31.
41. Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando J,
Takahashi M, Yamamoto M, Shinozaki T,
Miyauchi K, Nagao K, Hirayama A, Yoshimura M,
Komuro I, Nagai R, Daida H. Significance ofimbalance in the ratio of serum n-3 to n-6
polyunsaturated fatty acids in patients with acutecoronary syndrome. Am J Cardiol. 2014;113(3):441-5.
42. Nishizaki Y, Daimon M, Miyazaki S, Suzuki H,
Kawata T, Miyauchi K, Chiang SJ, Makinae H,
Shinozaki T, Daida H. Clinical factors associatedwith classical symptoms of aortic valve stenosis. J
Heart Valve Dis. 2013;22(3):287-94.
43. Manabe S, Kasegawa H, Fukui T, Tabata M,
Shinozaki T, Shimokawa T, Takanashi S. Do
semi-rigid prosthetic rings affect left ventricularfunction after mitral valve repair? Circ J. 2013;
77(8):2038-42.

271

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.
We have eleven department graduate students.
All of them are doctoral program students.

272

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. Sixteen bachelor theses, twenty mastertheses, and eight doctoral dissertations werecompleted between April 2004 and March 2014. 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273

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
Akabayashi A. (ed.) The Future of Bioethics:
International Dialogues. Oxford University Press,
2014.
2. 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 18:368–376. 2013.
1.

3. Miyazaki Y, Hayashi K, Mizunuma H, Lee JS,
Katanoda K, Imazeki S, Suzuki S. Smoking habits
in relation to reproductive events among Japanesewomen: findings of the Japanese Nurses' HealthStudy. Prev Med 57:729–731. 2013.
4. Tajima M, Lee JS, Watanabe E, Park JS, Tsuchiya
R, Fukahori A, Mori K, Kawakubo K. Association
between the changes of twelve lifestyle behaviors
and the development of metabolic syndromeduring one year among workers in the Tokyo
metropolitan area. Cir J 2014; in press
5. Takimoto Y, Yoshiuchi K, Shimodaira S,
Akabayashi A: Diamine oxidase activity levels inanorexia nervosa. Int J Eat Disord 47:203–5.
2014.
6. Nakazawa
E.
Commentary:
Regenerative
Madicine and Science Literacy. The Future of
Bioethics: International Dialogues. Akabayashi A.
(ed.) Oxford University Press, 31–34, 2014.
7. Kodama S, Takashima K. Commentary: The
Bioplitics and Bioehics Surrounding Chimeric
Embryo Research in Japan: A Comment on
Jonathan Moreno’s “Chimera in Bioethics andBiopolitics”.
The
Futureof
Bioethics:
International Dialogues. Akabayashi A. (ed.)
Oxford University Press, 394-398, 2014.
8. Yamamoto K. Commentary: What is ‘Substantive
Public Health Ethics’? The Future of Bioethics:
International Dialogues. Akabayashi A. (ed.)
Oxford University Press, 539-542, 2014.

Health Sciences and Nursing
2. Preventive and Administrative Nursing

275

Department of
Nursing Administration /Advanced Clinical Nursing
Professor
Noriko Yamamoto-Mitani, Ph.D., R.N.

Lecturer
Makoto Tanaka, Ph.D., R.N.

Assistant Professor
Kimie Takehara, Ph.D., R.N.
Nami Saito, M.S.N., R.N.

Homepage

http://nurs-adm.umin.jp/

Introduction and Organization
The Department of Nursing Administration/
Advanced Clinical Nursing has 60 years of history andtradition. It was firstly established as Department ofFundamental Nursing in School of Health Care andNursing in 1954. The School of Health Care andNursing composed of two basic medical departments
and six nursing departments. When the School of
Health Care and Nursing was reorganized as the
School of Health Sciences in 1965, only one nursing
department remained so the department was re-named
as Department of Nursing, responsible for all nursing
education. In 1992, as School of Health Sciences
became The School of Health Sciences and Nursing,two new departments of nursing was established, so
the Department of Nursing became once again
Department of Fundamental Nursing. As the result ofshift to the chair system of the Graduate School of
Medicine in 1996, two departments were established,
Department of Nursing Administration and
Department of Advanced Clinical Nursing. Our
department is responsible for the Fundamental
Nursing education for undergraduate students. This

year, Dr. Noriko Yamamoto-Mitani, the department
chair in the Department of Adult Health, held
responsibility concurrently.

Teaching activities
Undergraduate Courses
In the undergraduate program, our department is incharge of the lectures and clinical practicums for
Fundamental Nursing I, Fundamental Nursing II,
Fundamental Nursing III, Nursing Administration andFirst Aid & CPR.
Fundamental Nursing 1 (2 credits, Lectures)This course offers fundamental knowledge ofnursing, such as history and theory in nursing,concepts of professional nursing practice, nursing
service and care delivery systems, nursing
administration, and nursing education. We invite
nursing professionals, who are active players invarious fields, to learn clinical application andutilization of this knowledge and discuss roles andactivities of nursing.
Fundamental Nursing 2 (2 credits, Lectures)This course offers fundamentals in understanding276

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 course prepares students for 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 nursing administrative practicum inunits or divisions in hospitals. Students will learn caredelivery systems such as staffing and patientclassification systems, nursing informatics, andbudgetary issues including cost effectiveness andquality improvement.
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), AED (automatedexternal defibrillator).

Graduate courses
This year, our department did not open thegraduate course lectures.
We obliged to educate individual graduate students
in the research. We have the department seminar incollaboration with the Department of Adult Nursing
every week, where members provide the actual plans
for their own research and discuss the topic.

Research activities
Development of Nursing Care Skills to Improve
Patient Care Environment
We have been examining self-management support
for patients with chronic disease, nursing care systemin outpatient and long-term facilities for older adults,
and development of innovative nursing care skills. We
also conducted cross-cultural comparison of nursing
practice and nursing education to clarify the current
status and issues in order to better understand the stateof individual patient.

References
1. Kosaka S, Tanaka M, Sakai T, Tomikawa S,
Yoshida K, Chikaraishi T, Kazuma K.
Development of self-management scale for kidneytransplant recipients, including management of
post-transplantation chronic kidney disease. ISRN
Transplantation. 2013; Article ID 619754,
http://dx.doi.org/10.5402/2013/619754.
2. Nakagami G, Kimura N, Takehara K, Nakamura
T, Kawashima M, Tsunemi Y, Sanada H.
Relationship between activity of daily living andasteatosis in the lower legs among elderly
residents in long-term care institutions: a crosssectional study. Int Wound J. 2013; doi: 10.1111/
iwj.12169.
3. Tsunemi Y, Takehara K, Miura Y, Nakagami G,
Sanada H, Kawashima M. Screening for tinea
unguium by dermatophyte test strip. Br J
Dermatol. 2013;170(2):328-31.

277

4. Mori T, Nagase T, Takehara K, Oe M, Ohashi Y,
Amemiya A, Sanada H. Morphological patternclassification system for plantar thermography ofpatients with diabetes. J Diabetes Sci Technol.
2013;7(5):1102–12.
5. 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
related to moisture-associated dermatitis surrounding malignant wounds in breast cancer
patients. Eur J Oncol Nurs. 2013;17(5):673-80.
6. Nakagami G, Takehara K, Kanazawa T, Miura Y,
Nakamura T, Kawashima M, Tsunemi Y, Sanada
H. The prevalence of skin eruptions and mycosesof the buttocks and feet in aged care facility
residents: A cross-sectional study. Arch Gerontol
Geriatr. 2013;58(2):201-4.

278

Department of Family Nursing
Professor
Kiyoko Kamibeppu, Ph.D., R.N., P.H.N.

Assistant Professors
Mari Ikeda, Ph.D., R.N., P.H.N.
Iori Sato, Ph.D., R.N., P.H.N.
Rieko Fukuzawa, Ph.D., R.N., M.W., P.H.N.

Homepage:

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

Introduction and Organization

Research

This department was established in 1992. In 1994,
we founded the Japanese Association for Research in
Family Nursing. Four faculty members currently serve
the department: a professor and three assistantprofessors. Enrolled at present are 7 doctoral students,
13 master’s students, 1 undergraduate student, 2
research students, and 24 visiting researchers.

In our department, research topics span a variety of
topics, focusing on both healthy families and thoseaffected by health problems, and including diverse
developmental stages such as perinatal and later-life
periods. Our on-going research projects include thefollowing:
1. Mitigation of postpartum depression andprevention of child abuse and neglect;
2. Development of a Pediatric Quality of Life (QOL)
Inventory for children with chronic illness andtheir parents;
3. Late effects of treatment and posttraumatic stressdisorder in children with cancer;
4. Support for mothers with mental illness and theiroffspring;
5. Roles and competencies of nursing staff in childday-care centers;
6. Caregiving burden and utilization of respite careservices in families of severely disabled children;
7. Support for dying patients and their families(QOL and family functioning);
8. Nurses’ attitudes toward family nursing.

Education
1. Graduate Courses, School of Health Sciences andNursing (credit hours)
Advanced Family Nursing I (2)Advanced Family Nursing II (2)Laboratory and/or Field Work on Family Nursing(16)
Practicum in Translational Research Nursing (2)2. Undergraduate Courses for Students in the Schoolof Integrated Health Sciences (credit hours)
Family Nursing (2)Clinical Immunology (1)3. Undergraduate Courses for Nursing Students in the
School of Integrated Health Sciences (credit hours)
Pediatric and Child Health Nursing (2)Clinical Practicum in Pediatric and Child HealthNursing (3)In particular, through our research project titled,“Establishment of family nursing skills anddevelopment of a medical collaboration system model
for child abuse prevention from the perinatal period”,
we are developing a perinatal mental health and child279

care support system, in collaboration with the
University of Tokyo Hospital and community-based
networks.
Since 2013, under the Health Labour Sciences
Research Grant and as part of a new research project
titled, “Situation analysis and quality improvement
study on sick and convalescent child day-careservices”, we have also been investigating the
distribution and role of day-care nursing staff inserving sick and convalescing children
Further studies on “Late effects in pediatric cancer
survivors” and “Supporting pediatric cancer survivors’
reentry to school” have been ongoing, in collaboration
with pediatric cancer researchers and a variety offamily support organizations across the country.
Funding for these research projects was granted
through a 2004-2006 Ministry of Education, Culture,
Sports, Science and Technology Grant-in-Aid for
Scientific Research and currently through a Cancer
Research-specific Health Labour Sciences Research
Grant.
Additionally, based on the department’s richcollective research experiences, we founded theCenter for Quality of Life Research in April 2012 to
study QOL across wide developmental stages andhealth conditions. Using this platform, we aim to
accumulate, integrate, and disseminate scientificresearch and knowledge on QOL in a more systematicmanner.
Most recently, newly initiated research studies bydepartment members are exploring the various
experiences of children with cancer and their families
who were extensively affected by the Tohoku
Earthquake of 2011.
In addition to our research activities, we holdbimonthly Family Care Group Supervisions , whereby
deeper understanding of family nursing practices is
promoted. In this we aim to enhance the quality ofclinical practice and research in family nursing andcontribute to the establishment of the science offamily nursing.

Publications
4. Ikeda M, Kamibeppu K. Measuring the risk
factors for postpartum depression: development of
the Japanese version of the Postpartum

Depression Predictors Inventory-Revised (PDPIR-J). BMC Pregnancy and Childbirth. 2013; 13:112.
5. Sato I, Higuchi A, Yanagisawa T, Mukasa A, Ida
K, Sawamura Y, Sugiyama K, Saito N, Kumabe T,
Terasaki M, Nishikawa R, Ishida Y, Kamibeppu K.
Factors influencing self- and parent-reporting
health-related quality of life in children with brain
tumors. Quality of Life Research. 2013; 22(1):185-201.
6. Sugishita K, Kurihara K, Murayama S,
Kamibeppu K. Approach to perinatal mental
health and child abuse prevention in Japanese
prefectural health centers. Health. 2013; 5(4):735-42.
7. Toyama N, Kurihara K, Muranaka M, Kamibeppu
K. Factors influencing self-efficacy in breastfeeding support among public health nurses inJapan. Health. 2013; 5(12): 2051-8.
8. Ikeda M, Nishigaki K, Kamibeppu K. A
qualitative study of “pregnancy experiences” andthe significance of sharing them with one’s
spouse: from an attachment perspective. Journalof Japanese Clinical Psychology. 2013; 31(2):312-7.
9. Sugishita K, Kamibeppu K. Relationship between
prepartum and postpartum depression to use
EPDS. Japanese Journal of Maternal Health.
2013; 53(4): 444-50.
10. Mitsui C, Yamazaki A, Maeda N, Horibe K,
Asami K, Hara J, Ida K, Koh K, Ozawa M,
Manabe A, Kamibeppu K. Quality of life anddisclosure about illness among adolescents withcancer. The Japanese Journal of PediatricHematology/Oncology. 2013; 50(1): 79-84.
11. Kamibeppu K. Enlightenment activities on‘nursing the understanding of a family’. Japanese
Journal of Family Therapy. 2013; 30(3): 66-9.
12. Kamibeppu K, Setoyama A, Mizukosi M, Ikeda M.
Parenting support system and midwifery carestarting from the pregnancy period for child abuse
prevention. BIRTH Perinatal Nursing. 2013;
2(2): 64-7.
13. Kamibeppu K, Ishibashi A. Resilience of and carefor pediatric cancer survivors and their families.
The Japanese Journal of Child Nursing. 2013;36(8): 1007-12.

280

14. Kamibeppu K. Theory to support recovery:
Resilience and its surroundings. President’s
speech at the 19th Annual Conference of Japanese
Association for research in Family Nursing.
Japanese Journal of Research in Family Nursing.
2013; 18(2): 119-26.
15. Ikeda M, Kamibeppu K. Case conferences innursing. Japanese Journal of Psychotherapy. 2013;
39(5): 726-30.
16. Sato I, Kamibeppu K. Malignant brain tumor
treatment and evaluation tools for QOL. Clinical
Neuroscience. 2013; 31(10): 1154-5.
17. Toju K, Kamibeppu K. Development of trust
relationships between nurses and children andtheir family. (Special topic: Children withleukemia – latest knowledge and basic care –support for children with leukemia and theirfamily. Specific care and support after
hospitalization). The Japanese Journal of Child
Nursing. 2013; 36(8): 1013-9.

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Department ofCommunity Health Nursing /Public Health Nursing
Associate Professor
Satoko Nagata, Ph.D., R.N., P.H.N.

Research Associate
Takashi Naruse, Ph.D., R.N., P.H.N.
Masako Kageyama, Ph.D., R.N., P.H.N.
Shinji Iizaka, Ph.D., R.N., P.H.N.

Homepage

http://park.itc.u-tokyo.ac.jp/chn/

Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. At present,
there are three faculty members introduced above and
11 graduate course students (5 in master course, 6 indoctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

Education
1. Undergraduate program, in the School of Integrated Health Sciences
1) Home Health Nursing (4 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.
2) 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.
3) 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.
4) Home Health Nursing Practice (2 credit, practice)This program offers opportunities to learn thebasis of home nursing and understand the life ofhome care patients and their family at home-visit
nursing station and hospital’s department ofdischarge planning. Basic techniques and the roleof nursing through collaboration with otherprofession are mastered.
5) 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. In addition,
students will visit various working sites for nurses

282

to deepen their knowledge of multiple healthrelated resources, and learn the actual skills of
health guidance towards individuals/ families/
groups through experience.
2. Graduate program, in the Graduate School of
Health Sciences and Nursing
1) Advanced Community Health Nursing I(2 credits, lectures)This program is to study the health at thecommunity-level and theory and application of thecommunity organization.
2) Advanced Community Health Nursing II(2 credits, lectures)This program is to study the research issues onhome care and methodology of qualitative
research for community health nursing.
3) Advanced 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, and evaluating the capacity of discharge-planning nurses inreal-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 the elderly 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
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

283

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, 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, 10(2), 242–254,
2013.
(2) 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 Science, 10(2), 267–272, 2013.
(3) Mahiro Sakai, Takashi Naruse, Satoko Nagata.
Home visiting nurses' attitudes toward caring fordying patients and related workplace factors: across-sectional study. International Journal of
Palliative Nursing, 19(4), 195-204, 2013.
(4) 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, 16(3), 228–235, 2013.
(5) Atsuko Taguchi, Takashi Naruse, Yuki Kuwahara,
Satoko Nagata Sachiyo Murashima. Home
visiting nurse agencies for community dwellingelderly at nighttime in Japan. Home Health CareManagement & Practice, 25(6), 256–263, 2013.
(6) Masako Kageyama, Atsuko Taguchi. Childraising Support Skills Provided by Public Health
Nurses for Mothers with Serious Mental Illness :Balancing the Mother's Condition and Childraising. Journal of Japan Academy ofCommunity Health Nursing, 16(2), 47-54, 2013.
(7) Takashi Naruse, Atsuko Taguchi, Satoko Nagata,
Yuki Kuwahara, Sachiyo Murashima. The
prevalence and characteristics of long term careinsurance clients who are judged to needfrequent home visiting service by their caremanagers. Japanese Journal of Public Health,60(6), 370-376, 2013.
(8) Sachi Sakata, Takashi Naruse, Atsuko Taguchi,
Sachiyo Murashima. Mothers' difficulty inchildrearing classified in terms of their children's
behavioral characteristics. Japanese Journal of
Public Health, 61(1), 3-15, 2014.
(9) Naoko Horikoshi, Yuki Kuwahara, Atsuko
Taguchi, Satoko Nagata, Sachiyo Murashima.
Home care and place of death for elderly people
living in the remote islands of Japan : An
examination on the presence of inpatient
facilities ． Japanese Journal of Public Health.
60(7), 412-421, 2013.
(10) Naoko Horikoshi, Yuki Kuwahara, Atsuko
Taguchi, Takashi Ozawa, Satoko Nagata,
Sachiyo Murashima. Home care and place ofdeath for elderly people living in the remoteislands of Japan. An examination on the presenceof inpatient facilities. Journal of Health andWelfare Statistics, 60(6), 9-14, 2013.
(11) Takashi Naruse, Mahiro Sakai (Cotranslator).
Edited by Arnold B. Bakker, Michael P. Leiter.
Translated by Akiomi Inoue, Yasumasa Otsuka,
Akihito Shimazu, Kotaro Taneichi. WorkEngagement: A Handbook of Essential Theory
and Research. Tokyo: Seiwa Shoten Inc, 2014.

Health Sciences and Nursing
3. Clinical Nursing

285

Department of Adult HealthNursing/Palliative Care Nursing
Professor
Noriko Yamamoto-Mitani, Ph.D., R.N.

Assistant Professor (Senior)
Masakazu Nishigaki, Ph.D., R.N., C.G.C. (~Feb. 2014)
Yukari Takai, Ph.D., R.N. (Oct. 2013~)

Assistant Professor (Junior)
Miho Suzuki, Ph.D., ANP-BC, R.N.
Ayumi Igarashi, Ph.D., R.N.

Project Assistant Professor
Reiko Yamahana, MS, R.N. (Jan. 2014~)

Homepage

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

Introduction 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. Noriko
Yamamoto-Mitani has been responsible for administration as a department chair since 2012.

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.
Developing new nursing knowledge grounded onJapanese culture, as needed in tomorrow’s aged
society, is a major agenda of our department.

Research
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,

Faculty members conduct studies on various topics
in the field of adult and gerontological nursing.
Yamamoto-Mitani’s main interest is quality management and improvement in long-term care and homecare nursing. We have been examining systems thatenable quality nursing care provided by homecare
nurses and in long-term facilities. The issue of nursing
care quality to meet diverse needs of clients at homeor long-term care facilities will increase its
importance in coming years given the limited financial

286

resources and shortage of human resources in theseareas of practice.
Takai has mainly worked on the topic of chronic
pain and its management. She has examined thecurrent status of care for chronic pain, has beendeveloping effective care protocols for chronic pain,and examining effective mechanisms to educate
clinical nurses and care workers on effective carestrategies for pain management. She aims to establish
a new standard of care for persons in chronic pain in
the community and long-term care facilities,
particularly older adults including persons withdementia. Pain among older adults tends to beoverlooked by healthcare providers; it is important tomaintain and improve their physical function andquality 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 main research projects that we
conducted in 2013. Details of our publications andfunding are shown in our department website andannual report.
1) Developing an educational program for quality
improvement in care of chronic pain at
long-termcarefacilities
forelderly(Yamamoto-Mitani)In this project, it has been aimed at improving
quality in care of chronic pain; the following studies
are to be conducted: developing a care protocol forchronic pain in long-term care facilities in Japan,

elucidating barriers to quality improvement andsearching for effective ways to overcoming thesebarriers, and developing an educational program fornurses working at long-term care facilities andmini-trial.
This year we have reviewed literature and visitedseveral long-term care facilities in and out of Japan.
We also reviewed literature on care of chronic pain,
care of pain among persons with dementia, and theissue of care quality improvement in long-term carefacilities. Multiple articles have reported thatinterventions to chronic pain using multidisciplinary
approach have reduced pain level; treatments such as
medication, physical exercise, or social support wereeffective. Effective treatment to pain in persons withdementia included cognitive behavioral therapy;
multiple methods for quality improvement in care oflong-term care facilities have been reported withpossible facilitators/barriers to quality improvement.
We visited a nursing home affiliated to University ofMissouri School of Nursing and some long-term carefacilities in Japan. A literature review was presented at
the Annual Scientific Meeting of Japan GerontologicalNursing Society, and another review will be presented
at the Annual Congress of the Gerotnological Societyof America. The review papers were currently underreview/ in preparation.
2) Development of nursing care standards forolder people with chronic pain (Takai)
In order to develop better pain management systems,
especially for older people with chronic pain andpeople with dementia, we have developed chronic
pain management standards for older residents at thelong-term care facilities. In 2013, we conducted afeasibility study of the developed standards. We asked
nurses and care workers at the long-term care facilities
to use the standards and collected their opinions. As aresult, the developed standards demonstrated someevidences of usability. Educational supports may benecessary to facilitate appropriate usage of thestandards. We have also explored experience andself-care among older people with chronic pain using
grounded theory approaches. We will present findingsof the studies at 15th World Congress on Pain andother conferences.

2873) Establishment of support system for the elderlyin the integrated community care (Suzuki,
Igarashi)In the Japanese aged society, it is an urgent problem
to establish a local structure supporting the life of theelderly persons by the community. As one of themeasures to solve the problem, the evaluation of theappropriateness of the public services in thecommunity is necessary. We have been examined what
combination of services the elderly persons are using
and what its related factors are. We will also examine
the outcomes affected by the combination of the used
services.
In addition, in the integrated community care, theutilization of the local resources, including
nongovernmental services, is demanded. We havediscussed the possibility of utilizing convenience
stores, which exist closely in local communities inJapan, as a hub of the elderly support. We have started
descriptive studies to explore the convenience stores’
support for the elderly persons as the first step.

Publications
1. Igarashi A, Miyashita M, Morita T, Akizuki N,
Akiyama M, Shirahige Y, Eguchi K. A
population-based survey on perceptions of opioid
treatment and palliative care units: OPTIM Study.
Am J Hosp Palliat Med. 2014;31:155-60.
2. Takai Y, Yamamoto-Mitani N, Ko A. Prevalenceof and factors related to pain among elderly
Japanese residents in long-term healthcare
facilities. Geriat Gerontol Int. 2014;14(2):481-9.
3. Takai Y, Yamamoto-Mitani N, Ko A, Heilemann
MV. Differences in pain measures by Mini-Mental
State Examination scores of residents in aged carefacilities: examining the usability of the Abbey
Pain Scale- Japanese version. Pain Manag Nurs.
2014;15(1):236-45.
4. Watanabe M, Yamamoto-Mitani N, Nishigaki M,
Okamoto Y, Igarashi A, Suzuki M. Caremanagers’ confidence in managing home-based
end-of-life care: a cross-sectional study. BMC
Geriatr. 2013 Jul 1;13(1):67.
5. Takai Y, Yamamoto-Mitani N, Chiba Y, Nishikawa
Y, Sugai Y, Hayashi K. Prevalence of pain amongresidents in Japanese nursing homes: a descriptive

study. Pain Manag Nurs. 2013 Jun;14(2):e1-9.
6. Takai Y, Yamamoto-Mitani N, Suzuki M, Furuta Y,
Sato A, Fujimaki Y. Developing and validating a
Japanese version of the Assessment of Pain in
Elderly People with Communication Impairment.
Arch Gerontol Geriat. 2013;57(3):403-10.
7. Takai Y, Yamamoto-Mitani N, Fukahori H,
Kobayashi S, Chiba Y. Nursing ward managers'
perceptions of pain prevalence at the aged-carefacilities in Japan: a nationwide survey. PainManag Nurs. 2013 Sep;14(3):e59-66.
8. 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.
Gastroenterol Res. 2013;6(2):49-55.
9. 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. J Adv Nurs. 2013;
69(12):2675-85.
10. 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. J Nurs Educ. 2013;
52(5): 283-9.
11. Tokunaga-Nakawatase Y, Nishigaki M, Taru C,
Miyawaki I, Nishida J, Kosaka S, Sanada H,
Kazuma K. Computer-supported indirect-form
lifestyle-modification support program using
Lifestyle Intervention Support Software for
Diabetes Prevention (LISS-DP) for people with afamily history of type 2 diabetes in a medical
checkup setting: a randomized controlled trial.
Prim Care Diabetes. Epub 2014 Feb 12. pii:
S1751-9918(14)00008-4.
12. Nishigaki M, Tokunaga-Nakawatase Y, Nishida J,
Kazuma K. The effect of genetic counseling for
adult offspring of patients with type 2 diabetes on
attitudes toward diabetes and its heredity: arandomized controlled trial. J Genet Couns. Epub
2014 Jan 8.
13. 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288

randomized controlled trial. Pain Manag Nurs.
Epub 2013 Mar 5.
14. 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. 2013
Sep;48(9):1006-15.

289

Department ofMidwifery and Women's Health
Associate Professor
Megumi Haruna, Ph.D., R.N.M., P.H.N.

Lecturer
Masayo Matsuzaki, Ph.D., R.N.M., P.H.N.

Research associate
Mie Shiraishi, Ph.D., R.N.M., P.H.N.

Homepage

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

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 (5 in master course, 4 indoctoral course) and a visiting researcher.

Teaching activities
We have graduate and undergraduate courses for
midwifery and maternal care, and women's health.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health I(2 credits, lectures)
2) Advanced Midwifery and Women’s Health II(2 credits, lectures)
2. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternal-Newborn Nursing(2 credits, lectures)
2) Clinical Practicum in Maternal-Newborn
Nursing (2 credits, practices)
3. Undergraduate Advanced Courses for Midwifery,
School of Health Sciences and Nursing1) Midwifery I (1 credit, lectures)

2) Midwifery II (1 credit, lectures)
3) Midwifery III (2 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)

Research activities
Our research activities focus on maternal and childhealth with emphasis on the promotion of women's
health and their quality of life at every stage of theirlives.
We conduct the following research projects.
1. Collecting evidence for health guidance during
pregnancy• Adequate maternal nutrition and weight
management
This study examines maternal body composition,
lipid metabolic biomarkers and nutritional intake
to optimize weight management and a healthy
lifestyle during pregnancy to prevent low birthweight. Based on our investigations into the290

optimal maternal nutritional status and gestational
weight gain, we propose health guidance that canhelp pregnant women lower the risk of pregnancy
complications and adverse birth outcomes.
• The effect of exercise during pregnancy
This study investigates the effect of exercise on
mental and physical health among pregnant
women.
• 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.
• Development of effective skin care intervention toprevent neonatal skin trouble.
This study investigates the effect of moisturizing
skin care on improvement of skin barrier functions
among healthy neonates.
2. 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• Promotion of women's healthcare after delivery
This study examines the relationship between
maternal body composition and lifestyle factors
among postpartum women, including breastfeeding.
3. Development of a support system for women's
mental health during the perinatal period• "Fear of childbirth" and psychosocial factors
among pregnant Japanese womenThis study aims to translate the Wijma Delivery
Expectancy/Experience Questionnaire into Japanese and examine its validity and reliability, and to
identify the psychosocial risk factors of intense
fear of childbirth.

Publications
1.

2.

3.

4.

5.

6.

7.

8.

Haruna, M., Watanabe, E., Matsuzaki, M., Ota, E.,
Shiraishi, M., Murayama, R., Yoshida, M., Yeo, S.
(2013). The effects of an exercise program on
health-related quality of life in postpartum
mothers: A randomized controlled trial. Health,5(3): 432-9.
Shiraishi, M., Haruna, M., Matsuzaki, M.,
Murayama, R., Kitanaka, S., Sasaki, S. (2013).
Validity of a self-administered diet history
questionnaire for estimating vitamin D intakes ofJapanese pregnant women. Maternal and Child
Nutrition. (in press)
Shiraishi, M., Haruna, M., Matsuzaki, M.,
Murayama, R., Yatsuki, Y., Sasaki, S. (2013).
Estimation of eicosapentaenoic acid anddocosahexaenoic acid intakes in pregnant
Japanese women without nausea by using aself-administered diet history questionnaire.
Nutrition Research, 33, 473-8.
Shiraishi, M., Haruna, M., Matsuzaki, M.,
Murayama, R., Sasaki, S. (2013). Validity of adiet history questionnaire estimating β-carotene,
vitamin C and α-tocopherol intakes in Japanesepregnant women. International Journal of Food
Sciences and Nutrition, 64, 694-9.
Murayama, R., Tsuda, M., Haruna, M., Matsuzaki,
M., Aoki, K. (2013). Relationship between
perceived sleep posture and subjective sleep
quality: Changes related to progression ofpregnancy. Journal of Society Nursing Practice,25(1): 49-57.
Kitamura, T., Ohashi, Y., Kita, S., Haruna, M.,
Kubo, R. (2013). Depressive mood, bonding
failure, abusive parenting among mothers withthree-month old babies in a Japanese community.
Open Journal of Psychiatry, 3: 1-7.
Takegata, T., Haruna, M., Matsuzaki, M.,
Shiraishi, M., Murayama, R., Okano, T., &Severinsson E. (2013). Translation and validationof the Japanese version of the Wijma Delivery
Expectancy/Experience Questionnaire version A.
Nursing & Health Sciences, 15, 326-32.
Yoshida, M., Murayama, R., Nakata, M., Haruna,M., Matsuzaki, M., Shiraishi, M., Sanada, H.
(2013). Pelvic floor function and advanced

291

maternal age at first vaginal delivery. Open
Journal of Obstetrics and Gynecology, 3(4A):
28-34, DOI: 10.4236/ojog.2013.34A005.
9. Yoshida, M., Murayama, R., Haruna, M.,
Matsuzaki, M., Yoshimura, K., Murashima, S.,
Kozuma, S. (2013). Longitudinal comparison
study of pelvic floor function between womenwith and without stress urinary incontinence aftervaginal delivery. Journal of Medical Ultrasonics,
40(2): 125-31.

292

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, 6
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293caregiver burden in family caregivers; behavioral andpsychological symptoms of dementia; patient satisfaction with psychiatric services; and reducing the useof seclusion and restraint. We are conducting studies
in collaboration with researchers in other institutions
and universities.

References
1. Kido Y, Kawakami N, Miyamoto Y, Chiba R,
Tsuchiya M. Social Capital and Stigma Toward
People with Mental Illness in Tokyo, Japan.
Community mental health journal 2013;49(2):243-247.
2. Takaoka Y, Kawakami N. Fruit and vegetableconsumption in adolescence and health in early
adulthood: a longitudinal analysis of the Statistics
Canada's National Population Health Survey.
BMC Public Health 2013;13:1206
3. Stein DJ, Aguilar-Gaxiola S, Alonso J, Bruffaerts
R, de Jonge P, Liu Z, Miguel Caldas-de-Almeida J,
O'Neill S, Viana MC, Al-Hamzawi AO,
Angermeyer MC, Benjet C, de Graaf R, Ferry F,
Kovess-Masfety V, Levinson D, de Girolamo G,
Florescu S, Hu C, Kawakami N, Maria Haro J,
Piazza M, Posada-Villa J, Wojtyniak BJ, Xavier
M, Lim CC, Kessler RC, Scott KM. Associations
between mental disorders and subsequent onset of
hypertension. Gen Hosp Psychiatry (in press)
4. Karam EG, Friedman MJ, Hill ED, Kessler RC,
McLaughlin KA, Petukhova M, Sampson L,
Shahly V, Angermeyer MC, Bromet EJ, deGirolamo G, de Graaf R, Demyttenaere K, Ferry F,
Florescu SE, Haro JM, He Y, Karam AN,
Kawakami N, Kovess-Masfety V, Medina- MoraME, Browne MA, Posada-Villa JA, Shalev AY,
Stein DJ, Viana MC, Zarkov Z, Koenen KC.
Cumulative traumas and risk thresholds:
12-month PTSD in the World Mental Health(WMH) Surveys. Depress Anxiety (in press)
5. Park J, Kitayama S, Markus HR, Coe CL,
Miyamoto Y, Karasawa M, Curhan KB, Love GD,
Kawakami N, Boylan JM, Ryff CD. Social status
and anger expression: The cultural moderation
hypothesis. Emotion. 2013 Dec;13(6):1122-31.
6. Miyamoto Y, Boylan JM, Coe CL, Curhan KB,
Levine CS, Markus HR, Park J, Kitayama S,

Kawakami N, Karasawa M, Love GD, Ryff CD.
Negative emotions predict elevated interleukin-6
in the United States but not in Japan. Brain Behav
Immun. 2013 Nov;34:79-85.
7. Sugimoto T, Shinozaki T, Miyamoto Y
Aftershocks Associated With Impaired Health
Caused by the Great East Japan Disaster Among
Youth Across Japan: A National Cross-Sectional
Survey Interact J Med Res 2013;2(2):e31(link)
8. Nakagawa Y, Inoue A, Kawakami N, Tsuno K,
Tomioka K, Nakanishi M, Mafune K, Hiro H.
Effect modification by coping strategies on theassociation of organizational justice with psychological distress in Japanese workers. J Occup
Health (in press)
9. Demerouti E, Shimazu A, Bakker A, Shimada K,
Kawakami N. Work-self balance: A longitudinal
study on the effects of job demands and resourceson personal functioning in Japanese working
parents. Work Stress 2013; 27: 223-243.
10. Shimazu A, Kawakami N, Kubota K, Inoue A,
Kurioka S, Miyaki K, Takahashi M, Tsutsumi A.
Psychosocial mechanisms of psychological healthdisparity in Japanese workers. Ind Health 2013;
51: 472-481.
11. Takano A, Kawakami N, Miyamoto Y, Matsumoto
T. Busshitsu shiyou shougai kanja nitaisuru ninchi
koudou ryouhou proguramu wo teikyousuru
iryoujuujisha no taido no henka [Improvement in
the therapeutic attitudes of health care
professionals who offer cognitive behavioral
therapy towards substance abusers]. (in Japanese)
Nihon Arukoru Yakubutsu Igakkai Zasshi.
(Japanese journal of alcohol studies & drug
dependence) (in press)
12. Matsumoto T, Tachimori H, Tanibuchi Y, Takano
A, Wada K. Clinical features of patients withdesigner drugs-related disorder in Japan: A comparison with patients with methamphetamine- andhypnotic/anxiolytic-related disorders. Psychiatry
Clin Neurosci. (in press)
13. Tanibuchi Y, Matsumoto T, Tachimori H, Takano
A, Wada K. Dappou Doraggu ranyou izon kanjano
rinshouteki tokuchou: ranyousuru seihin no keijou
niyoru hikaku. (in Japanese) Seishinka
chiryougaku (Japanese journal of psychiatrictreatment) (in press)

294

14. Oshio T, Umeda M, Kawakami N. The impact ofinterpersonal childhood adversity on adult mental
health: How much is mediated by social supportand socioeconomic status in Japan? Public Health2013; 127(8):754-760
15. Shimoda H, Inoue A, Kawakami N, Tsuno K.
One-year test-retest reliability of a Japanese
web-based version of the WHO Composite
International Diagnostic Interview (CIDI) for
major depression in a working population. Int J
Methods Psychiatr Res (in press)
16. Suzuki T, Miyaki K, Tsutsumi A, Hashimoto H,
Kawakami N, Takahashi M, Shimazu A, Inoue A,
Kurioka S, Kakehashi M, Sasaki Y, Shimbo T.
Japanese dietary pattern consistently relates tolow depressive symptoms and it is modified byjob strain and worksite supports. J Affect Disord
2013; 150(2): 490-8.
17. Karam EG, Friedman MJ, Hill ED, Kessler RC,
McLaughlin KA, Petukhova M, Sampson L,
Shahly V, Angermeyer MC, Bromet EJ, deGirolamo G, de Graaf R, Demyttenaere K, Ferry F,
Florescu S, Haro JM, He Y, Karam AN,
Kawakami N, Kovess-Masfety V, Medina-Mora
ME, Oakley Browne MA, Posada-Villa JA,
Shalev AY, Stein DJ, Viana MC, Zarkov Z,
Koenen KC. Cumulative traumas and risk
thresholds: 12-month PTSD in the World Mental
Health (WMH) Surveys Depression and Anxiety(in press)
18. Shimazu A, Kubota K, Bakker AB, Demerouti E,
Shimada K, Kawakami N. Dual experiences ofwork-to-family conflict and family-to-work
conflict: A spillover-crossover perspective. J
Occup Health 2013; 55: 234-243.
19. Okamoto M, Kawakami N, Kido Y, Sakurai K.
Social capital and suicide: an ecological study inTokyo, Japan. Environ Health Prev Med.
2013l;18(4):306-12.(PMID: 23180068)
20. Yoshimura K, Kawakami N, Tsutsumi A, Inoue A,
Kobayashi Y, Takeuchi A, Fukuda T. Shokuba ni
okeru mentaruherusu no daiichiji yobou taisaku
nikansuru hiyou benneki bunseki. [Cost-benefit
analysis of primary prevention programs formental health at the workplace in Japan]. (inJapanese) Sangyo Eiseigaku Zasshi (Journal ofoccupational health) 2013; 55(1): 11-24.

21. Chiba R, Miyamoto Y, Kawakami N, Harada N.
Effectiveness of the program to facilitate recovery
for people with long term mental illness in Japan.
Nursing & Health Siences. (in press)
22. Ishizaki M, Kawakami N, Honda R, Yamada Y,
Nakagawa H, Morikawa Y. A Prospective Studyof Psychosocial Work Characteristics and Long
Sick Leave of Japanese Male Employees inMultiple Workplaces. Ind Health. 2013 May 2.
[Epub ahead of print]
23. Inoue A, Kawakami N, Tsuno K, Shimazu A,
Tomioka K, Nakanishi M. Job demands, job
resources, and work engagement of Japaneseemployees: a prospective cohort study. Int Arch
Occup Environ Health 2013; 86(4): 441-9.
24. Inoue A, Kawakami N, Tsuno K, Tomioka K,
Nakanishi M. Organizational justice andpsychological distress among permanent andnon-permanent employees in Japan: a prospective
cohort study. Int J Behav Med 2013; 20(2):265-76.
25. Inoue A, Kawakami N, Tsuno K, Tomioka K,
Nakanishi M. Organizational justice and major
depressive episode in Japanese employees: across-sectional study. J Occup Health 2013; 55(2):47-55.
26. Pando M, Aranda C, Tsuno K, Inoue A,
Kawakami N. Assessing psychological violenceand harassment at work: reliability and validity of
the Japanese version of the Inventory of Violence
andPsychological
Harassment(IVAPT)
comparing NAQ-R and LIPT. J Occup Health2013; 55(2): 108-19.
27. Miyamoto Y. Hito to hito tono kankeisei torikabari- wo kangaeru: intentional peer support
kara mananda mono. [Relationship and recovery:
What we learned from Intentional Peer Support](in Japanese). Buriifu saikoserapii kenkyu(Japanese Journal of Brief Psychoterapy) 2013;22(1): 1-13.
28. Lasalvia A, Zoppei S, Van Bortel T, Bonetto C,
Cristofalo D, Wahlbeck K, Bacle SV, Van
Audenhove C, van Weeghel J, Reneses
B,Germanavicius A, Economou M, Lanfredi M,
Ando S, Sartorius N, Lopez-Ibor JJ, Thornicroft
G; the ASPEN/INDIGO Study Group. Global
patternofexperienced
andanticipated295

discrimination reported by people with major
depressive disorder: a cross-sectional survey.
Lancet. 2013; 381(9860): 55-62. doi: 10.1016/
S0140-6736(12)61379-8.
29. Miyaki K, Song Y, Taneichi S, Tsutsumi A,
Hashimoto H, Kawakami N, Takahashi M,
Shimazu A, Inoue A, Kurioka S, Shimbo T.
Socioeconomic Status is Significantly Associatedwith Dietary Salt Intakes and Blood Pressure in
Japanese Workers (J-HOPE Study). Int J Environ
Res Public Health. 2013 Mar 11;10(3):980-93.
30. Honjo K, Kawakami N, Tsuchiya M, Sakurai K,
WMH-J 2002-2006 Survey Group. Association ofsubjective and objective socioeconomic status
with subjective mental health and mental
disorders among Japanese men and women. Int J
Behav Med (in press)
31. Demerouti E, Shimazu A, Bakker A, Shimada K,
Kawakami N. Balancing between work, family
and the self: A longitudinal study among Japaneseworking parents. Work & Stress (in press)
32. Kido Y, Kawakami N, WHO World Mental HealthJapan Survey Group. Sociodemographic determinants of attitudinal barriers in the use of mental
health services in Japan: Findings from the World
Mental Health Japan Survey 2002–2006.
Psychiatry and Clinical Neurosciences. 2013;
67(2):101–109.(link)
33. Miyaki K, Song Y, Taneichi S, Tsutsumi A,
Hashimoto H, Kawakami N, Takahashi M,
Shimazu A, Inoue A, Kurioka S, Shimbo T.
Socioeconomic Status Is Significantly Associatedwith the Dietary Intakes of Folate and Depression
Scales in Japanese Workers (J-HOPE Study).
Nutrients. 2013 Feb 18;5(2):565-78.

296

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
Takeo Minematsu, Ph.D.

Research Associate
Nao Tamai, R.N., Ph.D.,

Shinji Iizaka, R.N., P.H.N., Ph.D.,

Megumi Funakubo, R.N., P.H.N., Ph.D** by August 2013

Homepage

http://www.rounenkango.m.u-tokyo.ac.jp/english/index-e.html

Introduction and Organization
The Department of Gerontological Nursing wasestablished in June 2003, followed by theestablishment of the Department of Wound CareManagement in April 2006. These two departments
are currently headed by 1 professor and assisted by 1
lecturer, 1 project lecturer, 3 research associate, and 2
part-time lecturers for undergraduate course and 6
part-time lecturers for graduate course. The student
consists of 8 doctoral course students and 10 mastercourse students. The goal of our department is toachieve “Evidence-based practice and development ofgerontological nursing 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 2013 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, in
continence malnutrition, infection, dementia andpressure 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 2013 contents were as follows;a) Age-related changes in the physiologic system,
Aging and dementiab) Aging and osteoporosis, aging and respiratory297

disorders.
c) Aging and cardiovascular disorders, aging andrenal 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/ 2 credits)
The aim of this practicum is to learn present situationof gerontological nursing through practicing in thelong-term care facility. The program in 2013 was
supported by the long-term care facility owned by
Medical Corporation Tatsuoka.
3) Bachelor’s thesis
There was no undergraduate student in 2013.
2. Graduate course
1) Gerontological Nursing I(Summer course/ 2 credits)
The main theme of Gerontological Nursing I in 2013
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, engineering, and clinicalnursing research. Recent research papers wereselected from these three fields and criticallyevaluated.
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 understand and learn
scientific ways of thinking for gerontologicalconsiderations of the future Japanese community. The
main themes in 2013 were as follows;a) Continence management in elderly peopleb) Nursing translational research, a new approach todevelop advanced technologies by academiahospital collaborationc) Geriatric syndrome and health promotiond) Dementia care focusing on patients withearly-onset dementia and their family.
e) Measurement and analysis of motor function andevaluation of interventionf) Energy metabolism of skeletal muscleg) Metabolic variation caused by invasion andinflammationh) Past, present, and future perspective of pressure
ulcer management in long-term medical facilities
3) Wound Care Management I(Summer course/ 2 credits)
The main topic of Wound Care Management I in 2013
was learning of basic knowledge (basic biology,
clinical research, and engineering) which is necessary
to understand the wound management studies.
The topics were as follows.
a) Basis of skin and wound healingb) Basic knowledge of pressure ulcers and nursing
approachc) Basis of clinical nursing researchd) Basis of engineering researche) Basis of molecular and cellular biologicalresearch
4) Wound Care Management II(Winter course/ 2 credits)
The main theme of Wound Care Management II in2013 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) Advanced wound care provided by wound,ostomy, and continence nursesb) Basic and advanced wound healing fromdermatological aspectc) Basic and advanced knowledge for support
surfaced) Basic knowledge and clinical application ofultrasonographye) Establishing skin care strategy for obesity people
with skin disorders

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f)

Research and development for value innovation

5) Master’s thesis
The followings were research themes in 2013;“Thrombosis―HIF-1 cycle involving PAI-1 incompressed mouse skin: A new aspect of pressure
ulcer development mechanisms”“Prediction of healing progress of pressure ulcers bywound blotting: Distribution analysis of peroxidase
activity on necrotic tissue”“Development of an anomaly detection method inhome monitoring system for the elderly using
financial theories”“Development and evaluation of a system to assess
the effect of footwear on the in-shoe plantar pressure
and shear during gait”“Development and clinical evaluation of air mattresswith independent control of air cell pressure
depending on interface pressure distribution”“Process of determination for making therapeutic
footwear for diabetic patients and continuation of
footwear use (in Japanese)”5) Doctor’s thesis
The followings were research themes in 2013;“Development of biomarkers for the Wound Fluid
RT-PCR method to detect critically colonized andinfected wounds”

Research activities
1. Activity policy
Our gerontological nursing research focuses on
elderly people suffering from 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 wounds.
The majority of our clinical research has been
conducted at The University of Tokyo Hospital. We
have been participating at pressure ulcer multidisciplinary team rounds. We also attend the Foot Care
Outpatient Clinic held by the Department ofMetabolic Diseases and the Stoma Outpatient Clinic
held by the Departments of Urology and Colorectal
Surgery. In addition, we support the Department ofAdvanced Nursing Technology which was establishedin December 2012 as a social cooperation program topromote team nursing intervention and research
involving the clinical division, the nursing department,
and the nursing departments of Graduate school of
Medicine. Through this program, nurses canscientifically study the subject of nursing, including
research in epidemiologic surveys and molecular- andgene-level topics in cooperation. Furthermore, thetechnology and medical equipment developed bycompanies can be evaluated in the hospital, offering
new nursing technology suitable for needs in clinicalsites.
In 2013, we have proposed a new research
diagram “Bioengineering Nursing” which consists ofnursing biology that investigates the detailed
mechanism of the target phenomenon, nursing
engineering that develops technologies for the
clarified target, and nursing translational research that
evaluates the technologies in the clinical filed andfurthermore explores the new clinical problems. We
organized introductory seminar for bioengineering
nursing research supported by JSPS Grant-in-Aid for
Scientific Research (A). We had many nursing
researchers and clinical nurses from intra- andextramural ways. We furthermore organized advanced
hands-on seminar of bioengineering nursing researchmethodologies for those who attended the introductory seminar and are interested in this researchframework. Furthermore, we have edited Bioengineering Nursing: New Horizons of Nursing
Research. Nova Science Pub Inc, which will be
published in April, 2014.
In this year, the Society for Nursing Science andEngineering was established. This society was formed
from the forum for nursing science and engineering
which have been working as an assemblage toenhance collaboration between nursing science andbasic sciences to form the basic grounds for this newly
emerged academic discipline. Professor Sanada
assumed the first position of the president of thissociety. In accordance with new establishment of thissociety, 1st annual conference was held which wasorganized by Project Associate Professor Taketoshi
Mori from Life Support Technology (Molten)
Department. This conference was held at Hongo
campus from October 4th to 5th, 2013.

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The multidisciplinary pressure ulcer team round isa unique opportunity to contribute to the pressure
ulcer management in the university hospital. This
activity was highly recognized across the globe and
JWC2013 Innovation Award was given from Journalof Wound Care, which is one of the high impact
academic journals in wound research filed.
Regarding international activities, Professor
Sanada was invited in several domestic or international conferences. Professor Sanada has given
invited lecture at the 1st Borneo International
Nursing Conference 2013 in Seoul. She attended the20th IAGG World Congress of Gerontology andGeriatrics and 5th Congress of Asia PacificEnterostomal Therapy Nurses Association in
Conjunction with Korean Society of Coloproctology
as a lecturer. She acted as an executive committee
member at 17th East Asia Forum of Nursing Scholars.
The research team headed by Professor Sanada
visited to Curtin University, School of Nursing andMidwifery, Australia to have a meeting regarding
skin tear research with Professor Keryln Carville tofacilitate international collaboration. Professor
Sanada has been working as Secretary for World
Union of Wound Healing Societies and an
International Board of Directors for International
Lymphoedema Framework.
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 blotting for analyzing physiological status of
the skin・ 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 insole-type simultaneous measurement system of plantar pressure and shear
force during gait3) Clinical studies
・ Novel assessment technologies for pressure
ulcers・ 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
・ Survey and international comparison oflymphoedema (collaboration with International
Lymphoedema Framework)
・ Methods for predicting skin tear development
・ 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.
・ JWC2013 Innovation Award・ Research Award from 43rd Conference of theJapanese Society for Wound Healing“Gene expression changes in mouse skin tissues
induced by acylated homoserine lactone”
・ Research Award from 1st Conference of Nursing
Science and Engineering“Thermographic assessment for extravasation
during intravenous infusion”“Extraction of ultrasonographic features ofaspiration by image process focusing on tracheal
wall and aspirated bolus”
・ The 20th IAGG Congress of Gerontology andGeriatrics Best Poster Award“Visual and morphological evaluation of
peristomal skin under the ceramide-containing
adhesive”
・ Research Award from 22nd Conference ofJapanese Society of Wound, Ostomy, andContinence Management“Prediction of pressure ulcer prognosis by

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thermographic and wound blotting assessment”
・ “Exploring molecular markers for detecting
pressure-induced delayed wound healing inpressure ulcers”“Factors associated with wound related pain inpatients with malignant wounds from breast
cancer”・ Best research article award from 22nd Conferenceof Japanese Society of Wound, Ostomy, andContinence Management“Evaluation of foot ulcer risk in diabetic patientsat a university hospital based on the risk
categorization system of the International
Consensus on the diabetic foot”
・ Prize for research article 22nd Conference ofJapanese Society of Wound, Ostomy, andContinence Management“Evaluation of skin temperature, humidity, andcomfort of two types of absorbent products forurinary incontinence”
・ Ohura Award from Japanese Society of Pressure
Ulcers“Combination of thermographic and ultrasonographic assessments for early detection ofdeep tissue injury”

References
1. Noguchi H, Handa M, Fukui R, Shimosaka M,
Mori T, Sato T, Sanada H. Measurement of dense
static point cloud and online behavior recognition
using horizontal LIDAR and pan rotation ofvertical LIDAR with mirrors. SICE JCMSI. 2014;
7(1):12-20.
2. Ichikawa-Shigeta Y, Sugama J, Sanada H,
Nakatani T, Konya C, Nakagami G, Minematsu T,
Yusuf S, Mugita Y. Physiological and appearance
characteristics of skin maceration in elderly
women with incontinence. J Wound Care. 2014;23(1):18- 30.
3. Watanabe Y, Oe M, Takemura Y, Sasaki M, Onishi
M, Kanda K, Sanada H. Four factor Research
Awareness Scale for Nurses in Japanese:
Instrument development study. Jpn J Nurs Sci.
2013;10(2):232-41.
4. Okajima S, Hirota A, Kimura E, Inagaki M, Tamai
N, Iizaka S, Nakagami G, Mori T, Sugama J,

Sanada H. Health-related quality of life andassociated factors in patients with primary
lymphedema. Jpn J Nurs Sci. 2013; 10(2):202-11.
5. Nakagami G, Sanada H, Sugama J. Development
and evaluation of a self-regulating alternatingpressure air cushion. Disabil Rehabil Assist
Technol. 2013. doi: 10.3109/17483107.2013.
867371.
6. Kaitani T, Nakagami G, Sanada H. Costeffectiveness of conservative sharp wounddebridement for pressure ulcers offered by wound,ostomy and continence nurses: A propensity scorematching analysis. J Wound Technol. 2013;21:
6-10.
7. Nakagami G, Takehara K, Kanazawa T, Miura Y,
Nakamura T, Kawashima M, Tsunemi Y, Sanada
H. The prevalence of skin eruptions and mycosesof the buttocks and feet in aged care facility
residents: A cross-sectional study. Arch Gerontol
Geriatr. 2014;58(2):201-4.
8. Minematsu T, Nishijima Y, Huang L, Nakagami G,
Ohta Y, Kurata S, Sanada H. HSL Attenuates theFollicular Oxidative Stress and Enhances the Hair
Growth in ob/ob Mice. Plast Reconstr Surg Global Open. 2013;1(7):e60.
9. Gregg MF, Sanada H, Yamamoto A,
Yamamoto-Mitani N. (Committee of International
Affairs, Japan Association of Nursing Programs in
Universities): Quality in doctoral nursing
education in Japan, Official journal of theinternational network for doctoral education innursing (IDEN). 2013;1(2):4-8
10. Tsunemi Y, Takehara K, Miura Y, Nakagami G,
Sanada H, Kawashima M. Screening for tinea
unguium by dermatophyte test strip. Br J
Dermatol. 2014;170(2):328-31.
11. Mori T, Nagase T, Takehara K, Oe M, Ohashi Y,
Amemiya A, Sanada H. Morphological patternclassification system for plantar thermography ofpatients with diabetes. J Diabetes Sci Technol.
2013;7(5):1102–12.
12. Nakagami G, Kimura N, Takehara K, Nakamura T,
Kawashima M, Tsunemi Y, Sanada H.
Relationship between activity of daily living andasteatosis in the lower legs among elderly
residents in long-term care institutions: across-sectional study. Int Wound J. 2013. doi:

301

10.1111/iwj.12169.
13. Mugita Y, Minematsu T, Huang L, Sugama J,
Ichikawa Y, Nakagami G, Nagase T, Oe M,
Noguchi H, Mori T, Sanada H. A convenient andhighly sensitive method for quantification ofceramide in tape-stripping samples by dot-blot
analysis as a skin barrier assessment technique inmurine macerated skin. J Jpn WOCM. 2013;17(3):201-12.
14. Ogawa Y, Mori T, Noguchi H, Nakagami G,
Sanada H. Development and evaluation of an air
mattress structure and function for reducing
discomfort when elevating the head-of-bed.
Disabil Rehabil Assist Technol. 2013. doi: 10.
3109/17483107.2013.836689.
15. Mori T, Nagase T, Takehara K, Oe M, Ohashi Y,
Amemiya A, Noguchi H, Ueki K, Kadowaki T,
Sanada H. Morphological pattern classification
system for plantar thermography of patients withdiabetes. J Diabetes Sci Technol. 2013; 7(5):1102-12.
16. Kato H, Nakagami G, Iwahira Y, Otani R, Nagase
T, Iizaka S, Tamai N, Matsuyama Y, Sanada H.
Risk factors and risk scoring tool for infection
during tissue expansion in tissue expander andimplant breast reconstruction. Breast J. 2013;19(6):618-26.
17. Yamane T, Nakagami G, Yoshino S, Muramatsu A,
Matsui S, Oishi Y, Kanazawa T, Minematsu T,
Sanada H. Hydrocellular foam dressing promotes
wound healing along with increases in
Hyaluronan Synthase 3 and PPARα gene
expression in epidermis. PLoS One. 2013;8(8):e73988.
18. Matsumoto M. Sugama J, Okuwa M, Dai M,
Matsuo J, Sanada H. Non-invasive monitoring ofcore body temperature rhythms over 72 h in 10
bedridden elderly patients with disorders ofconsciousness in a Japanese hospital: A pilot study.
Arch Gerontol Geriatr. 2013;57(3):428-32.
19. 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 malignantwounds in breast cancer
patients. Eur J Oncol Nurs. 2013;17(5):673-80.

20. Kimura N, Nakagami G, Takehara K, Miura Y,
Nakamura T, Kawashima M, Tsunemi Y, Sanada
H. Prevalence of asteatosis and asteatotic eczema
among elderly residents in facilities covered bylong-term care insurance. J Dermatol. 2013;40(9):770-1.
21. Yoshida M, Murayama R, Nakata M, Haruna M,
Matsuzaki M, Shiraishi M, Sanada H. Pelvic floor
function and advanced maternal age at firstvaginal delivery. Open J Obstet Gynecol. 2013;
3(4A): 28-34.
22. Nagase T, Iizaka S, Kato H, Nakagami G, Kaitani
T, Machida M, Oshima H, Ochiai H, Bito S,
Sanada H; ASPU Group. Undermining incisionand healing of deep pressure ulcers: A prospective
cohort study of pressure ulcers by the Japanese
National Hospital Organization. Wound Repair
Regen. 2013;21(4):512-9.
23. Masaki N, Sugama J, Okuwa M, Inagaki M,
Matsuo J, Nakatani T, Sanada H. Heel blood flow
during loading and off-loading in bedridden older
adults with low and normal ankle-brachialpressure index: a quasi- experimental study. Biol
Res Nurs. 2013;15(3):285-91.
24. Yoshida M, Murayama R, Ota E, Nakata M,
Kozuma S, Homma Y. Reliability and validityof the Japanese version of the pelvic floor distressinventory-short form 20. Int Urogynecol J. 2013;24(6):1039-46.
25. Yoshida M, Murayama R, Haruna M, Matsuzaki
M, Yoshimura K, Murashima S, Kozuma S.
Longitudinal comparison study of pelvic floor
function between women with and without stressurinary incontinence after vaginal delivery. J Med
Ultrasonics. 2013;40(2):125-31.
26. Nakagami G, Yoshida S, Matsumoto M, Koyano Y,
Yamamoto Y, Sugama J, Sanada H. A new
objective evaluation method for PU cleansing
using a rapid bacteria counting system. J Wound
Care. 2013;22(5):278-81.
27. 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
rat model for deep tissue injury deterioration. Int
Wound J. 2013. doi: 10.1111/iwj.12082.

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
Hiroshi Nishiura, MD, PhD
Mariko Gakiya, MA, EdD
Stuart Gilmour, MPH, MStat
Shinji Nakaoka, MEng, PhD
Makoto Kawakami, MBA
Hirofumi Yokoi, MBA
Yasutaka Saeki, MA

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 the provision of the best possible information and rigorous
monitoring and evaluation. The department's members
generate knowledge and ideas through their research,strengthen technical and leadership skills througheducational programs, and enhance national capacities
through collaborative projects, especially in thedeveloping world. As of March 2014 the department,
headed by Professor Kenji Shibuya, included thefollowing staff complement: one project professor(Minami Inoue); one associate professor (Hiroshi
Nishiura); one project lecturer (Mariko Gakiya); twoassistant professors (Stuart Gilmour and Shinji
Nakaoka); three project assistant professors (Makoto
Kawakami, Hirofumi Yokoi and Yasutaka Saeki); fourpost-doctoral fellows; 12 adjunct lecturers; eight
doctoral students; and five 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 generations 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.

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Furthermore, through the Global Leadership Program(GLP) students are able to develop skills andexperience to become future leaders in global health.
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 followings are the topics covered in the academic
year 2013:- Global health policy- Global health governance- Health-related MDG and post-MDG priorities- Universal health coverage- Global 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 assessment of the burden of diseasein Japan. Ministry of Education, Culture, Sports,
Science and Technology, Grants-in-Aid for Scientific
Research (A). 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 Research on Life-Style Related Diseases
Including Cardiovascular Diseases and Diabetes
Mellitus: Projection of disease burden and economic
burden allowing for change in population structure,socioeconomic status, and lifestyles in Japan. Ministry of
Health, Labour, and Welfare Health and Labour Science
Research Grants. PI: Manami Inoue.

305

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, Scienceand 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

Developing a policy decision system for immunization
programs. Toyota Physical and Chemical ResearchInstitute, research grant program. PI: Hiroshi
Nishiura.
Epidemiological modeling of pandemics using severe
fractions of cases. Nakajima Foundation, research
grant program. PI: Hiroshi Nishiura.
Classification and estimation of the biological effectsof vaccination. St. Luke’s Life Science Institute,research grant program. PI: Hiroshi Nishiura
Quantifying transmission dynamics using illness onset
data. Ministry of Education, Culture, Sports, Scienceand Technology, Grants-in-aid for young scientists. PI:
Hiroshi Nishiura
Estimation of the number of HIV-infected individuals
to understand the epidemiological dynamics. Ministryof Health, Labour and Welfare Research Grants. PI:
Hiroshi Nishiura.

Integrated research of social and health science toinvestigate the pathogenesis of cardiovascular diseases
attributable to social and psychological factors. Ministryof Education, Culture, Sports, Science and Technology,
Grants-in-Aid for Scientific Research (C). CI: Manami
Inoue

Mathematical epidemiologic studies for infectious
disease control and immunization. Ministry of Health,Labour and Welfare Research Grants. PI: Hiroshi
Nishiura.

Real-time estimation of the minimum doses ofvaccination. The Health Care Science Institute,research grant program. PI: Hiroshi Nishiura.

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.

Estimating the effectiveness of case isolation.
Sumitomo Electrical Engineering Group, Basic
research funding program. PI: Hiroshi Nishiura.
Mathematical identification of the reservoir host of
trypanosomiasis. Oyama Health Organization,
research grant program. PI: Hiroshi Nishiura.

Multi-scale modeling of dynamical immune
responses: toward understandings of skininflammatory diseases. Ministry of Education,
Culture,Sports,ScienceandTechnology,
Grants-in-aid for young scientists. PI: Shinji Nakaoka.

Publications
Optimization of immunization programs using amathematical model. Ministry of Education, Culture,
Sports, Science and Technology, Grants-in-Aid for
Challenging Exploratory Research. PI: Hiroshi
Nishiura.

1. Danaei G, Singh GM, Paciorek CJ, Lin CJK,
Cowan MJ, et al. The global cardiovascular risk
transition: association of four metabolic risk
factors with national income, urbanization, andWestern diet in 1980 and 2008. Circulation. 2013;

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127:1483-1502.
2. Tsubokura M, Kato S, Nihei M, Sakuna Y,
Furutani T, et al. Limited internal radiation
exposure associated with resettlements to aradiation-contaminated homeland after the
Fukushima daiichi nuclear disaster. PLOS ONE.
2013; 8(12):e81909
3. Hisashige A, Sasako M, Nakajima T.
Cost-effectiveness of adjuvant chemotherapy for
curatively resected gastric cancer with S-1. BMC
Cancer. 2013; 13:443.
4. Okamoto N, Hisashige A, Tanak Y, Kurumatani N.
Development of the Japanese 15D instrument ofhealth-related quality of life: Verification ofreliability and validity among elderly people.
PLOS ONE. 2013; 8(4): e61721.
5. Suzuki R, Iwasaki M, Hara A, Inoue M, Sasakui S,
et al. Fruit and vegetable intake and breast cancer
risk defined by estrogen and progesterone
receptor status: the Japan Public HealthCenter-based Prospective Study. Cancer Causes
and Control. 2013; 24(12): 2117-28.
6. Nanri A, Mizoue T, Poudel-Tandukar N, Noda M,
Kato M, et al. Dietary patterns and suicide inJapanese adults: health centre-based prospective
study. British Journal of Psychiatry. 2013; 203:
422-7.
7. Michikawa T, Inoue M, Sawada N, Sasazuki S,
Tanaka Y, et al. Plasma levels of adiponectin andprimary liver cancer risk in middle-aged Japanese
adults with hepatitis virus infection: A nested
case-control
study.
Cancerepidemiology,
biomarkers and prevention. 2013; 22(12): 2250-7.
8. Kurotani K, Nanri A, Goto A, Mizoue T, Noda M,
et al. Vegetable and fruit intake and risk of type 2
diabetes: Japan Public Health Center-based
Prospective Study. British Journal of Nutrition.
2013;109(4); 709-717.
9. Zhou Y, Lau E, Ip D, Nishiura H, Leung G, et al.
Years of life lost in the first wave of the 2009
influenza A (H1N1) pandemic in Hong Kong.
American Journal of Epidemiology. 2013; 178(8):1313-8.
10. Sasazuki S, Charvat H, Hara A, Wakai K,
Nakamura K, et al. Diabetes mellitus and cancer
risk: pooled analysis of eight cohort studies inJapan. Cancer Science. 2013; 104(11): 1499-1507.

11. Chen Y, Copeland W, Vedanathan R, Grant E, Lee
J, et al. Association between body mass index andcardiovascular disease in east Asians and south
Asians: pooled analysis of prospective data fromthe Asia Cohort Consortium. British Medical
Journal. 2013; 347: f5446.
12. Tsubokura M, Shibuya K, Kato S, Oikawa T,
Kanazawa Y. Acute intake of radionuclides
immediately after the incident as the main
contributor of the internal radiation exposure after
Fukushima daiichi nuclear disaster. JAMA
Pediatrics. 2013;167(12):1169-70.
13. Tanimoto T, Kami M, Shibuya K. Research
misconduct and scientific integrity: a call for a
global forum. The Lancet. 2013; 382(9896):940.
14. Gilmour S, Kanda M, Kusumi E, Tanimoto T,
Kami M, Shibuya K. HPV vaccination
programme in Japan. The Lancet. 2013; 382(9894):768.
15. Tsubokura M, Nihei M, Sato K, Masaki S,
Sakuma Y, et al. Measurement of internalradiation exposure among decontamination
workers in villages near the crippled Fukushima
daiichi nuclear power plant. Health Physics. 2013;
105(4):379-381.
16. Sugimoto A, Nomura S, Tsubokura M, Matsumura
T, Muto K, et al. The relationship between media
consumption and health-related anxieties after the
Fukushima daiichi nuclear disaster. PLOS ONE.
2013; 8(8):e65331.
17. Atker S, Jesmin S, Rahman MM, Islam MM,
Khatun MT, et al. Higher gravidity and parity areassociated with increased prevalence of metabolic
syndrome among rural Bangladeshi women.
PLOS ONE. 2013; 8(8):e68319.
18. Ganchimeg T, Mori R, Ota E, Koyanagi A,
Gilmour S, et al. Maternal and perinatal outcomesamong nulliparous adolescents in low- andmiddle-income countries: a multi-country study.
BJOG. 2013;120(13):1622-30.
19. Degenhardt L, Gilmour S, Shand F, Bruno R,
Campbell G, et al. estimating the proportion ofprescription opioids that is consumed by people
who inject drugs in Australia. Drug and alcohol
review. 2013;32(5):468-474.
20. Bilano V, Borja M, Cruz E, Tan A, Mortera L,
Reganit P. Smoking-attributable burden of lung

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cancer in the Philippines: a comparative risk
assessment. The Lancet. 2013; 381(S15).
21. Mori J, Tsubokura M, Sugimoto A, Tanimoto T,
Kami M, et al. Increased incidence of dog-bite
injuries after the Fukushima nuclear accident.
Preventive Medicine. 2013;57(4):363-5.
22. Cowling BJ, Ip DK, Fang VJ, Suntarattiwong P,
Olsen SJ, et al. Aerosol transmission is an
important mode of influenza A virus spread.
Nature Communications. 2013;4:1935.
23. Ejima K, Aihara K, Nishiura H. Modeling theobesity epidemic: Social contagion and its
implications for control. Theoretical biology andmedical modeling. 2013;3:10-17.
24. Mizumoto K, Yamamoto T, Nishiura H. Contact
behavior of children and parental employment
behavior during school closures against the
pandemic influenza A (H1N1-2009) in Japan.
Journal of international medical research. 2013;41(3):716-24.
25. Rahman MM, Gilmour S, Saito E, Sultana P,
Shibuya K. Self-reported illness and household
strategies for coping with health-care payments in
Bangladesh. Bulletin of the World HealthOrganization. 2013;91:449-458.
26. Abe SK, Stickley A, Roberts B, Richardson E,
Abbott P, et al. Changing patterns of fruit andvegetable intake in countries of the former Soviet
Union. Public Health Nutrition. 2013;23:1-9.
27. Kokubo Y, Iso H, Saito I, Yamagishi K, Yasuya H,
et al. The impact of green tea and coffee consumption on the reduced risk of stroke incidence
in Japanese population: the Japan public healthcenter-based study cohort. Stroke. 2013;44(5):1369-74.
28. Ysauya H, Iso H, Yamagishi K, Kokubo Y, Saito I,
et al. Development of a point-based prediction
model for the incidence of total stroke: Japan
public health center study. Stroke. 2013; 44(5):1295-302.
29. Yamagishi K, Iso H, Kokubo Y, Saito I, Yatsuya H,
et al. Dietary intake of saturated fatty acids andincident stroke and coronary heart disease inJapanese communities: the JPHC study. European
Heart Journal. 2013; 34(16):1225-32.
30. Ikeda A, Kawachi I, Iso H, Iwasaki M, Inoue M,
Tsugane S. Social support and cancer incidence

and mortality: The JPHC study cohort II. Cancer
Causes and Control. 2013;24(5):847-60.
31. Nishiura H, Mizumoto K, Ejima K. How tointerpret the transmissibility of novel influenza
A(H7N9): an analysis of initial epidemiological
data of human cases from China. Theoretical
Biology and Medical Modeling. 2013;10:30.
32. Gilmour S, Hamakawa T, Shibuya K. Cashtransfer programmes in developing countries. The
Lancet. 2013; 381(9874):1254-1255.
33. Ejima K, Aihara K, Nishiura H. The impact ofmodel building on the transmission dynamics
under vaccination: observable (symptom-based)versus unobservable (contagiousness-dependent)
approaches. PLOS ONE. 2013; 8(4): e62062.
34. Wong JY, Wu P, Nishiura H, Goldstein E, Lau
EHY, et al. Infection fatality risk of the pandemicA(H1N1) virus in Hong Kong in 2009. American
Journal of Epidemiology. 2013; 177(8): 834-40.
35. Lau LL, Ip DK, Nishiura H, Fang VJ, Chan KH,
et al. Heterogeneity in virus shedding among
medically-attended influenza A virus infections.
Journal of infectious diseases. 2013; 207(8):1281-5.
36. Ikeda N, Irie Y, Shibuya K. Determinants ofreduced child stunting in Cambodia: analysis ofpooled data from three Demographic and Health
Surveys. Bulletin of the World HealthOrganization. 2013;91:341-349.
37. Eshak E, Iso H, Mizoue T, Inoue M, Noda M,
Tsugane S. Soft drink, 100% fruit juice, andvegetable juice intakes and risk of diabetes
mellitus. Clinical Nutrition. 2013; 32:300-8.
38. Lin Y, Fu R, Grant E, Chen Y, Lee JE, et al.
Association of body mass index and risk of deathfrom pancreas cancer in Asians: findings from theAsia Cohort Consortium. European Journal ofCancer Prevention. 2013; 22:244-50.
39. Nomura S, Gilmour S, Tsubokura M, Yoneoka D,
Sugimoto A, Oikawa T, et al. Mortality risk
amongst nursing home residents evacuated after
the Fukushima nuclear accident: a retrospective
cohort study. PLOS ONE. 2013;8(3):e60192.
40. Perera HK, Wickramasinghe G, Cheung CL,
Nishiura H, Smith DK, et al. Swine influenza in
Sri Lanka. Emerging Infectious Diseases. 2013;19(3):481-4.

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41. Murray C, Richards M, Newton J, Fenton K,
Anderson H, et al. UK health performance:
findings of the Global Burden of Disease Study
2010. The Lancet. 2013; 381(9871):997-1020.
42. Nishiwaki Y, Michikawa T, Takebayashi T, Nitta
H, Iso H, et al. Long-term explosure to particularmatter in relation to mortality and incidence of
cardiovascular disease: the JPHC study. Journal of
Atherosclerosis and Thrombiosis. 2013; 20:296309.
43. Rahman MM, Gilmour S, Saito E, Sultana P,
Shibuya K. Health-related financial catastrophe,
inequality and chronic illness in Bangladesh.
PLOS ONE. 2013;8(2): e568973.
44. Balogun O, Hirayama F, Wariki W, Koyanagi A,
Mori R. Interventions for improving outcomes for
pregnant women who have experienced genital
cutting. Cochrane Database of Systematic
Reviews. 2013;2.
45. Tobe R, Mori R, Huang L, Xu L, Han D, Shibuya
K. Cost-effectiveness analysis of a national
neonatal hearing screening program in China:
Conditions for the scale-up. PLOS ONE. 2013;
8(1): e51990.
46. Di Cesare M, Khang YH, Asaria P, Blakely T,
Cowan MJ et al. Inequalities in noncommunicable diseases and effective responses.
The Lancet. 2013; 381: 585-597.
47. Nishiura H, Mizumoto K. Epidemiologicaldeterminants of successful vaccine development.
International Journal of Medical Science. 2013;10(4):382-4.
48. Mizumoto K, Ejima K, Yamamoto T, Nishiura H.
Vaccination and clinical severity: Is theeffectiveness of contact tracing and case isolation
hampered by past vaccination? International
Journal of Environmental Research and Public
Health. 2013; 10(3): 816-829.
49. Mizumoto K, Yamamoto T, Nishiura H.
Age-dependent estimates o the epidemiologicalimpact of pandemic influenza (H1N1-2009) inJapan. Computational and Mathematical Methods
in Medicine. 2013;2013:637064.
50. Jesmin S, Akter S, Rahman MM, Islam MM,
Islam AM, et al. Disruption of components ofvascular endothelial growth factor angiogenic
signaling system in metabolic syndrome. Findings

from a study conducted in rural Bangladeshi
women. Thrombosis and Haemostasis. 2013; 381(9865).
51. Koyanagi A, Zhang J, Dagvadorj A, Hirayama F,
Shibuya K, et al. Macrosomia in 23 developing
countries: an analysis of a multicountry, facilitybased, cross-sectional survey. Lancet. 2013; 381(9865): 476-483.
52. Jung S, Spiegelman D, Baglietto L, Bernstein L,
Boggs DA, et al. Fruit and vegetable intake andrisk of breast cancer by hormone receptor status.
Journal of the National Cancer Institute. 2013;
105:219-36.
53. Mizumoto K, Nishiura H, Yamamoto T.
Effectiveness of antiviral prophylaxis coupledwith contact tracing in reducing the transmissionof the influenza A (H1N1-2009): A systematic
review. Theoretical Biology and Medical
Modeling. 2013; 10-4.
54. Nishiura H, Yen HL, Cowling BJ. Sample size
considerations for one-to-one animal transmission
studies of the influenz A virus. PLOS ONE. 2013;
8(1): e55358.
55. Nanri A, Shimazu T, Takachi R, Ishihara J,
Mizoue T, et al. Dietary patterns and type 2
diabetes in Japanese men and women: the Japan
Public Health Center-based Prospective Study.
European Journal of Clinical Nutrition. 2013; 67:
18-24.

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Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH

Assistant Professors
Junko Yasuoka, DSc, MPH
Keiko Nanishi, MD
Akira Shibanuma, MID

Specially-Appointed Assistant Professor
Kimiyo Kikuchi, PhD, MHSc

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
and social justice in health within and across nations.
To achieve this, we aim toward:
1. Investigating how to improve the health status of
the most vulnerable people, in particular, indeveloping countries;
2. Undertaking research on the influence of
globalization on health and social development;
3. Investigating mechanisms to reduce inequalities
between and within nations on health anddevelopment.
Our research focuses on how to activate
community-based activities and how to link abottom-up approach to national and international
policy. The department currently consists of: 1

department chair and professor, 3 assistant professors,
1 specially-appointed assistant professor, 10 visiting
lecturers, 24 PhD course students, 16 master’s course
students, 1 research students, and 28 visiting
researchers.
About 65% of the students areinternational 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. We are
currently making an international guideline as a partof our activities.
In addition, we contributed to develop a WHO’s
guideline on human resource for health as well as to
the Asia Pacific Action Alliance on Human Resources
for Health.
Furthermore, we carry out a research project onmaternal and child health in Ghana in collaboration
with JICA and the Ministry of Health, Ghana.

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Teaching Activities
The main objectives of our teaching activities are
the following two:1) To cultivate researchers who understandactivities of practitioners in the field;
2) To cultivate practitioners who understandresearch.
The graduate school curriculum is composed
mainly of community and global health advanced
courses, exercises and practical work. All curriculum
focus on community health. Our main educational
activities other than curriculum include technicalassistance in writing master’s and doctoral theses. We
always encourage students to publish their theses ininternational journals. In addition, we urge students togain experiences in the field and learn about real
global health from their experiences.
Because we have many international students, alllectures, practices, and discussions are carried out inEnglish. For those who don’t have health/medical
background, we provide a wide variety of curriculumfrom basics to advanced level.
We also provide trainings to young leaders fromoverseas run by the JICA and lectures in different
universities.

Research Activities
The major objectives of our research activities are
the following two:1)

To promote research which has a significant
impact on global and local societies;2) To promote research which contributes toendogenous development.
We aim at demonstrating research findings basedon community-based data directly collected from thefield. Therefore, we place high importance onfieldwork. At the same time, our department aims tocontribute to policy making and promoting actions forbetter health by making the best use ofcommunity-based research. We carry out research byworking in tandem with different research institutes,
international organizations, JICA, NGOs, anduniversities in developing countries. We conduct
research mainly in developing countries, but we also

are involved in research in Japan.
The major directions of current research haveencompassed 1) health, nutrition, and development,2) health, human rights and human security, 3)
ecological approach in infectious disease control, 4)
health promotion, 5) disaster and health, 6) humanresources for health worldwide, and 7) maternal andchild health.
Our research has been conducted in various
countries, including Nepal, Myanmar, Thailand,
Bangladesh, Viet Nam, Lao PDR, Cambodia, Ghana,Tanzania, Kenya, Zambia, and Peru.

References
1. Sunguya BF, Poudel KC, Mlunde LB, Urassa DP,
Yasuoka J, Jimba M. Nutrition Training Improves
Health Workers' Nutrition Knowledge andCompetence to Manage Child Undernutrition: A
Systematic Review. Front Public Health. 2013
Sep 24;1:37.
2. Saw YM, Yasuoka J, Saw TN, Poudel KC, Tun S,
Jimba M. What are the factors associated withHIV testing among male injecting andnon-injecting drug users in Lashio, Myanmar: across-sectional study. BMJ Open. 2013 Jun 20;3(6).
3. Saw YM, Win KL, Shiao LW, Thandar MM,
Amiya RM, Shibanuma A, Tun S, Jimba M.
Taking stock of Myanmar's progress toward thehealth-related Millennium Development Goals:
current roadblocks, paths ahead. Int J Equity
Health. 2013 Sep 11;12:78.
4. Poudel KC, Palmer PH, Jimba M, Mizoue T,
Kobayashi J, Poudel-Tandukar K. Coinfection of
Hepatitis C Virus among HIV-Positive People in
the Kathmandu Valley, Nepal. J Int Assoc Provid
AIDS Care. 2014 May-Jun;13(3):277-83
5. Hasegawa A, Yasuoka J, Ly P, Nguon C, Jimba M.
Integrating child health services into malaria
control services of village malaria workers inremote Cambodia: service utilization andknowledge of malaria management of caregivers.
Malar J. 2013 Aug 23;12(1):292.
6. Takanashi K, Quyen DT, Le Hoa NT, Khan NC,
Yasuoka J, Jimba M. Long-term impact ofcommunity-based information, education and311

communication activities on food hygiene andfood safety behaviors in Vietnam: a longitudinal
study. PLoS One. 2013 Aug 12;8(8):e70654.
7. Rodriguez-Fernandez R, Siopa M, Simpson SJ,
Amiya RM, Breda J, Cappuccio FP. Current salt
reduction
policies
acrossgradientsofinequality- adjusted human development in the
WHO European region: minding the gaps. Public
Health Nutr. 2013 Aug 8:1-11.
8. Matsubara C, Green J, Astorga LT, Daya EL,
Jervoso HC, Gonzaga EM, Jimba M. Reliability
tests and validation tests of the client satisfaction
questionnaire (CSQ-8) as an index of satisfaction
with childbirth-related care among Filipino
women BMC Pregnancy Childbirth. 2013 Dec
17;13:235.
9. Seyfi F, Poudel KC, Yasuoka J, Otsuka K, Jimba
M. Intention to seek professional psychologicalhelp among college students in Turkey: influenceof help-seeking attitudes. BMC Res Notes. 2013
Dec 6;6:519.
10. Hongo H, Green J, Otsuka K, Jimba M.
Development and psychometric testing of theJapanese version of the maternal breastfeeding
evaluation scale. J Hum Lact. 2013 Nov; 29(4):611-9.
11. Matsumoto-Takahashi EL, Tongol-Rivera P,
Villacorte EA, Angluben RU, Yasuoka J, Kano S,
Jimba M. Determining the active role ofmicroscopists in community awareness-raising
activities
formalariaprevention:across- sectional study in Palawan, the Philippines.
Malar J. 2013 Nov 1;12:384.
12. 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. 2013 Nov;22(6):389-94.
13. Sunguya BF, Poudel KC, Mlunde LB, Urassa DP,
Jimba M, Yasuoka J. Efficacy of in-service
nutrition training for mid-level providers to
improve feeding practices among HIV-positive
children in Tanga, Tanzania: study protocol for acluster randomized controlled trial. Trials. 2013
Oct 25;14:352.
14. Sunguya BF, Poudel KC, Mlunde LB, Shakya P,
Urassa DP, Jimba M, Yasuoka J. Effectiveness ofnutrition training of health workers toward
improving caregivers' feeding practices forchildren aged six months to two years: asystematic review. Nutr J. 2013 May 20;12:66.
15. Dhital R, Otsuka K, Poudel KC, Yasuoka J,
Dangal G, Jimba M. Improved quality of life after
surgery for pelvic organ prolapse in Nepalesewomen. BMC Womens Health. 2013 May 9;
13:22.
16. Akiyama T, Win T, Maung C, Ray P, Sakisaka K,
Tanabe A, Kobayashi J, Jimba M. Mental healthstatus among Burmese adolescent students living
in boarding houses in Thailand: a cross-sectional
study. BMC Public Health. 2013 Apr 12;13:337.
17. Shrestha RM, Otsuka K, Poudel KC, Yasuoka J,
Lamichhane M, Jimba M. Better learning inschools to improve attitudes toward abstinence
and intentions for safer sex among adolescents inurban Nepal. BMC Public Health. 2013 Mar 20;
13:22.
18. Saito J, Nonaka D, Mizoue T, Kobayashi J,
Jayatilleke AC, Shrestha S, Kikuchi K, Haque SE,
Yi S, Ayi I, Jimba M. Limited potential of school
textbooks to prevent tobacco use among students
grade 1-9 across multiple developing countries: acontent analysis study. BMJ Open. 2013 Feb 21;3(2).
19. Syed EH, Melkonian S, Poudel KC, Yasuoka J,
Otsuka K, Ahmed A, Islam T, Parvez F,
Slavkovich V, Graziano JH, Ahsan H, Jimba M.
Arsenic Exposure and Oral Cavity Lesions in
Bangladesh.
J
Occup
EnvironMed.
2013;55(1):59-66.
20. N, Poudel KC, Jimba M. Health-related quality oflife, depression, and self-esteem in adolescentswith leprosy-affected parents: results of across-sectional study in Nepal. BMC Public
Health. 2013 Jan 10;13:22.
21. Kitamura T, Obara H, Takashima Y, Takahashi K,
Inaoka K, Nagai M, Endo H, Jimba M, Sugiura Y.
World Health Assembly Agendas and trends ofinternational health issues for the last 43 years:
Analysis of World Health Assembly Agendas
between 1970 and 2012. Health Policy. 2013
May;110(2-3):198-206.
22. Poudel-Tandukar K, Poudel KC., Jimba M,
Kobayashi J, Johnson AC, Palmer PH. Serum312

25-hydroxyvitamin D levels and C-reactive
protein in persons with Human Immunodeficiency Virus Infection. AIDS Res Hum
Retroviruses. 2013 Mar;29(3):528-34.
23. 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.
24. Son DT, Yasuoka J, Poudel KC, Otsuka K, Jimba
M. Massively multiplayer online role-playing
games (MMORPG): association between its
addiction, self-control and mental disorders
among young people in Vietnam. Int J Soc
Psychiatry. 2013 Sep;59(6):570-7.
25. 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. 2013 Nov; 22(6):389-94.
26. 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. 2013 Jun;28(2):223-32.

International Health
2. International Biomedical Sciences

314

Department of Human Genetics
Professor
Katsushi Tokunaga, Ph.D.

Associate Professor
Akihiko Mabuchi, M.D., Ph.D.

Research Associate
Taku Miyagawa, Ph.D.,

Yuki Hitomi, Ph.D.

Project Research Associate
Hiroko Miyadera, Ph.D.,

Homepage

Hiromi Sawai, Ph.D.

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

Introduction and Organization
The Department of Human Genetics wasestablished in 1992. Currently, the department has 1
professor, 1 associate professor, 4 research associates,
11 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, aswell 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 HLAassociated autoimmune and infectious disorders, byprotein functional studies.
5) Genetic analyses combined with epidemiologicalstudies for bone and joint diseases. This study
focuses on the elucidation of genetic susceptibility

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to those, based on four cohorts established inJapan.

References
1. Kurosaki M, Tanaka Y, Nishida N, Sakamoto N,
Enomoto N, Matsuura K, Asahina Y, Nakagawa M,
Watanabe M, Sakamoto M, Maekawa S, Tokunaga
K, Mizokami M, and Izumi N: Model
incorporating the ITPA genotype identifies
patients at high risk of anemia and treatment
failure with pegylated-interferon plus ribavirin
therapy for chronic hepatitis C. J Med Virol.
85(3): 449-58, 2013.
2. Miyagawa T, Kawamura H, Obuchi M, Ikesaki A,
Ozaki A, Tokunaga K, Inoue Y, and Honda M:
Effects of oral L-carnitine administration in
narcolepsy patients: a randomized, double-blind,cross-over and placebo-controlled trial. PLoS
ONE. 8(1): e53707, 2013.
3. Khor S-S, Miyagawa T, Toyoda H, Yamasaki M,
Kawamura Y, Tanii H, Okazaki Y, Sasaki T, Lin L,
Faraco J, Rico T, Honda Y, Honda M, Mignot E,
and Tokunaga K: Genome-wide association studyof HLA-DQB1*06:02 negative essential hypersomnia. PeerJ 1: e66, 2013.
4. Miyashita A, Koike A, Jun G, Wang LS, Takahashi
S, Matsubara E, Kawarabayashi T, Shoji M,
Tomita N, Arai H, Asada T, Harigaya Y, Ikeda M,
Amari M, Hanyu H, Higuchi S, Ikeuchi T,
Nishizawa M, Suga M, Kawase Y, Akatsu H,
Kosaka K, Yamamoto T, Imagawa M, Hamaguchi
T, Yamada M, Moriaha T, Takeda M, Takao T,
Nakata K, Fujisawa Y, Sasaki K, Watanabe K,
Nakashima K, Urakami K, Ooya T, Takahashi M,
Yuzuriha T, Serikawa K, Yoshimoto S, Nakagawa
R, Kim JW, Ki CS, Won HH, Na DL, Seo SW,
Mook-Jung I; Alzheimer Disease Genetics
Consortium, St George-Hyslop P, Mayeux R,
Haines JL, Pericak-Vance MA, Yoshida M,
Nishida N, Tokunaga K, Yamamoto K, Tsuji S,
Kanazawa I, Ihara Y, Schellenberg GD, Farrer LA,
and Kuwano R: SORL1 Is Genetically Associatedwith Late-Onset Alzheimer's Disease in Japanese,
Koreans and Caucasians. PLoS ONE. 8(4):e538618, 2013.
5. Jinam TA, Phipps ME, Saitou N; HUGO

Pan-Asian SNP Consortium: Admixture patterns
and genetic differentiation in Negrito groups from
West Malaysia estimated from genome-wide SNP
data. Hum. Biol. 85(1-3): 173-188, 2013.
6. Kawamura Y, Takahashi T, Liu X, Nishida N,
Tokunaga K, Ukawa K, Noda Y, Yoshikawa A,
Shimada T, Umekage T, and Sasak T: DNApolymorphism in the FKBP5 gene affects
impulsivity in intertemporal choice. Asia-PacificPsychiatry. 5(1): 31-38, 2013.
7. Kanazawa T, Ikeda M, Glatt SJ, Tsutsumi A,
Kikuyama H, Kawamura Y, Nishida N, Miyagawa
T, Hashimoto R, Takeda M, Sasaki T, Tokunaga K,
Koh J, Iwata N, and Yoneda H: Genome-wide
association study of atypical psychosis. Am. J.
Med. Genet. B Neuropsychiatr. Genet. 162(7):679-686, 2013.
8. Isogai H, Miyadera H, Ueta M, Sotozono C,
Kinoshita S, Tokunaga K, and Hirayama N:
In silico risk assessment of HLA-A*02:06associated Stevens-Johnson syndrome and toxic
epidermal necrolysis (SJS/TEN) caused by cold
medicine ingredients. J. Toxicol. 2013: e514068,
2013.
9. Ikeda M, Okahisa Y, Aleksic B, Won M, Kondo N,
Naruse N, Aoyama-Uehara K, Sora I, Iyo M,
Hashimoto R, Kawamura Y, Nishida N,
Miyagawa T, Takeda M, Sasaki T, Tokunaga K,
Ozaki N, Ujike H, and Iwata N: Evidence forshared genetic risk between methamphetamineinduced psychosis and schizophrenia. Neuropsychopharmacology. 38(10):1864-1870, 2013.
10. Nishida N, Tokunaga K, and Mizokami M:
Genome-wide association study reveals hostgenetic factors for liver diseases. J. Clin. Translat.
Hepatol. 1: 45-50, 2013.
11. Ruzzo EK, Capo-Chichi JM, Ben-Zeev B,
Chitayat T, Mao H, Pappas AL, Hitomi Y, Mao H,
Lu Y, Yao X, Hamdan FF, Pelak K, Reznik-Wolf
H, Bar-Joseph I, Oz-Levi D, Lev D,
Lerman-Sagie T, Leshinsky-Silver E, Anikster Y,
Ben-Asher E, Olender T, Colleaux L, Decarie JC,
Blaser S, Banwell B, Joshi RB, He XP, Patry L,
Silver RJ, Dobrzeniecka S, Islam M, Hasnat A,
Aryal DK, Rodriguiz RM, Wetsel WC, McNamara
JO, Rouleau GA, Silver DL, Lancet D, Pras E,
Mitchell GA, Michaud JL, and Goldstein DB:

316

Deficiency of asparagine synthetase causes
congenital microcephaly and a progressive formof encephalopathy. Neuron 80: 429-441, 2013.
12. Hitomi Y, Heinzen EL, Donatello S, Dahl HH,
Damiano JA, Berkovic SF, Scheffer IE, Legros B,
Rai M, Pandolfo M, Goldstein DB, Van Bogaert P,
and Depondt C: Mutations in TNK2 in severe
autosomal recessive infantile-onset epilepsy. Ann.
Neurol. 74: 495-501, 2013.
13. Epi4K Consortium; Epilepsy Phenome/Genome
Project, Allen AS, Berkovic SF, Cossette P,
Delanty N, Dlugos D, Eichler EE, Epstein MP,
Glauser T, Goldstein DB, Han Y, Heinzen EL,
Hitomi Y, Howell KB, Johnson MR, Kuzniecky R,
Lowenstein DH, Lu YF, Madou MR, Marson AG,
Mefford HC, Esmaeeli Nieh S, O'Brien TJ,
Ottman R, Petrovski S, Poduri A, Ruzzo EK,
Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil
B, Alldredge BK, Bautista JF, Berkovic SF, BoroA, Cascino GD, Consalvo D, Crumrine P,
Devinsky O, Dlugos D, Epstein MP, Fiol M,
Fountain NB, French J, Friedman D, Geller EB,
Glauser T, Glynn S, Haut SR, Hayward J,
Helmers SL, Joshi S, Kanner A, Kirsch HE,
Knowlton RC, Kossoff EH, Kuperman R,
Kuzniecky R, Lowenstein DH, McGuire SM,
Motika PV, Novotny EJ, Ottman R, Paolicchi JM,
Parent JM, Park K, Poduri A, Scheffer IE,
Shellhaas RA, Sherr EH, Shih JJ, Singh R, Sirven
J, Smith MC, Sullivan J, Lin Thio L, Venkat A,
Vining EP, Von Allmen GK, Weisenberg JL,
Widdess-Walsh P, and Winawer MR: De novo
mutations in epileptic encephalopathies. Nature
501(7466):217-221, 2013.

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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, Italy, Greece, China, Taiwan,
Korea, Thailand, Viet Nam, Laos, Malaysia, Indonesia,
Bangladesh, Pakistan, Sri Lanka and Australia, inorder to promote the mothers’ and children’s health allover 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 health8) Introduction to General Health Science
2. Graduate course, the Graduate School of Medicine,318

School of International Health Sciences
In addition to lectures and laboratory courses by ourown staff, special lectures are given by experts both
inside and outside the University.

References
1.

Research activities
2.

(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 andEllis-van Creveld 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.

3.

4.

5.

6.

7.

8.

9.

Iwasa M, Yamagata T, Mizuguchi M, Itoh M,
Matsumoto A, Hironaka M, Honda A, Momoi MY,
Shimozawa N. Contiguous ABCD1 DXS1357E
deletion syndrome: Report of an autopsy case.
Neuropathology 2013; 33(3): 292-298.
Kakiuchi S, Nonoyama S, Wakamatsu H, Kogawa K,
Wang L, Kinoshita-Yamaguchi H, Takayama-Ito M,
Lim CK, Inoue N, Mizuguchi M, Igarashi T, Saijo
M. Neonatal herpes encephalitis caused by avirologically confirmed acyclovir-resistant herpes
simplex virus 1 strain. Journal of ClinicalMicrobiology 2013; 51(1): 356-359.
Miyazaki C, Saitoh M, Itoh M, Yamashita S,
Miyagishi M, Takashima S, Moser AB, Iwamori M,
Mizuguchi M. Altered phospholipid molecularspecies and glycolipid composition in brain, liverand fibroblasts of Zellweger syndrome. Neuroscience Letters 2013; 552(1): 71-75.
Mizuguchi M. Influenza encephalopathy and related
neuropsychiatric syndromes. Influenza and Other
Respiratory Viruses 2013; 7(Suppl 3): 67-71.
Ohsawa M, Kobayashi T, Okura H, Igarashi T,
Mizuguchi M, Hino O. TSC1 Controls Distributionof Actin fibers through its effect on function of Rho
family of small GTPases and regulates cell migration and polarity. PLoS One 2013; 8(1): e54503.
Okitsu S, Khamrin P, Thongprachum A, Kongkaew
A, Maneekarn N, Mizuguchi M, Hayakawa S,
Ushijima H. Whole-genomic analysis of G3P[23],G9P[23] and G3P[13] rotavirus strains isolated frompiglets with diarrhea in Thailand, 2006-2008.
Infection, Genetics and Evolution 2013; 18C: 74-86.
Sakai E, Yamanaka G, Kawashima H, Morishima Y,
Ishida Y, Oana S, Miyajima T, Shinohara M, Saitoh
M, Mizuguchi M. A case of recurrent acuteencephalopathy with febrile convulsive statusepilepticus with carnitine palmitoyltransferase IIvariation. Neuropediatrics 2013; 44(4): 218-221.
Sakakibara A, Ando R, Sapir T, Tanaka T.
Microtubule dynamics in neuronal morphogenesis.
Open Biology 2013; 3(7): 130061
Shin E, Kashiwagi Y, Kuriu T, Iwasaki H, Tanaka T,
Koizumi H, Gleeson JG, Okabe S. Doublecortin-likekinase enhances dendritic remodelling andnegatively regulates synapse maturation. Nature

319

Communications 2013; 4: 1440.
10. Shinohara M, Saitoh M, Nishizawa D, Ikeda K,
Hirose S, Takanashi JI, Takita J, Kikuchi K, Kubota
M, Yamanaka G, Shiihara T, Kumakura A, Kikuchi
M, Toyoshima M, Goto T, Yamanouchi H,
Mizuguchi M. ADORA2A polymorphism predisposes children to encephalopathy with febrile
status epilepticus. Neurology 2013; 80(17): 1571
-1576.
11. Thongprachum A, Chan-It W, Khamrin P, Okitsu S,
Nishimura S, Kikuta H, Yamamoto A, Sugita K,
Baba T, Mizuguchi M, Maneekarn N, Hayakawa S,
Ushijima H. Reemergence of new variant G3
rotavirus in Japanese pediatric patients, 2009-2011.
Infection, Genetics and Evolution 2013; 13: 168174.
12. Thongprachum A, Khamrin P, Chan-It W, Malasao
R, Chaimongkol N, Okitsu S, Mizuguchi M,
Maneekarn N, Hayakawa S, Ushijima H. Emergenceof norovirus GII/4 2006a and 2006b variants in
hospitalized children with acute gastroenteritis in
Thailand. Clinical Laboratory 2013; 59(3-4): 271276.
13. Tumurkhuu M, Saitoh M, Takita J, Mizuno Y,
Mizuguchi M. A novel SOS1 mutation in
Costello/CFC syndrome affects signaling in both
RAS and PI3K pathways. Journal of Receptors andSignal Transduction Research 2013; 33(2): 124-128.
14. Tran DN, Pham TM, Ha MT, Tran TT, Dang TK,
Yoshida LM, Okitsu S, Hayakawa S, Mizuguchi M,
Ushijima H. Molecular epidemiology and disease
severity of human respiratory syncytial virus in
Vietnam. PLoS One 2013; 8(1): e45436.

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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)
Shinya YASUMOTO, Ph.D. (GRENE project)

Homepage

http://www.humeco.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
We had eight research/teaching faculties in FY2013,
including two working for the “Global 30” program,taught in English, two for “NEXT” program, and one
for “GRENE” program. Apart from the faculty staffs,
two supporting staffs, three doctoral candidates (oneforeign student), six master course students (including
three foreign students), and one research student are
working in the department. There are ten
extra-university lecturers delivering lectures in either
graduate or undergraduate course. Prof. Watanabeholds additional roles in the Transdisciplinary
Initiative for Global Sustainability (TIGS) as well as
in the Earth Observation Data Integration & Fusion
Research Initiative (EDITORIA).

Teaching activities
The department is one of the six departments of the
School of International Health. Human Ecology

Special Lecture I focused on the basic components of
Human Ecology such as demography, nutrition, andenvironment. In “Human Ecology Special Lecture II”,emphases were on recent topics and ongoing
researches in the field of Human Ecology and relatedareas. With these classes for the Graduate Students,
we tried to describe Human Ecology as a basic
component of International Health, and gave examplesof the recent issues that have been dealt with andapproaches used in this field. The lectures for the
Graduate Course were given in English.
In the undergraduate course, the department is incharge of a part of the School of Integrated Health
Sciences, providing the lectures on “Human Ecology”,“Environmental Health”, “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

321

explosion, food security, and environmental issues inrelation to the problems that Asia-Pacific region(including Japan) has been facing. Another emphasis
was on the relation between human activities andchemical contamination of the environment.
In addition to these “regular” courses, we have beenin charge of two education programs associated withinternational activities, both of them involves entire ora part of the School of International Health (SIH).
The first one, Global30, has ended in this fiscal year;
we have offered a course providing the information on
basic study/research tools in the field of international
health. The second one is, in collaboration with the
Graduate School of Engineering of UTokyo, “Urban
Engineering and Health in Asia” (UEHAS), which
been adopted as one of the MEXT-funding“Re-inventing Japan” project (PI= Prof. Takizawa,
Dept. of Urban Engineering). UEHAS is an
educational program at the graduate level entailing
credit exchange between UTokyo and six universities
in ASEAN countries. Our department has been in
charge of coordinating the program from SIH side.

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.

322

3. Subsistence transition and adaptation:
In many Asian and Oceania countries, various typesof developmental projects have been undertaken
aiming at economic development, procurement of
natural resources, or accelerating tourism. Attempts todescribe such changes from the viewpoint of political
ecology were made in China as well as Papua New
Guinea.
4. Role of selenium in a population highly exposed
to methylmercury through fish consumption:
Relatively high concentration of methylmercury(MeHg) can be found in some predator fish species
through food chain, and health risks associated withexcessive consumption of such seafood items havebeen debated long time. On the other hand, fish isvery important source of some nutrients including
protein, polyunsaturated fatty acids, and minerals, andsome of these nutrients might interfere with MeHg
toxicity. Thus, net risk/benefit of eating fish are notimmediately clear. We examined the nutritional statusof selenium, a micronutrient for which fish provide
substantial amount.
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. Use of “earth-observation” data in the field ofhealth science through the Data Integration andAnalysis System (DIAS):
This project has been conducted as one of the
program under “Green Network of Excellence –environmental information” (GRENE-ei) project, inwhich various kinds of earth-observation data, stored
or modified in/through DIAS, would be utilized invarious scientific fields (so called Social Benefit Area).

We have been running an “Eco-health” program, inwhich we tried to connect environmental andhealth-related information in the framework of“human” ecology and tried to identify newly emerging
health risks due to climate change andsocio-demographical change. In this project, we havebeen collaborating with other Schools in UTokyo, a
couple of Japanese universities and institutions, aswell as many overseas universities, governmental
agencies, etc. Namely, we are trying to address theissue of heat and air pollution, urban water issues, andtropical infectious diseases associated with humanland use.
7. Utilization of the downscaled simulation models
for predicting health impacts of heat and 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.
This program was conducted under “Seamless
Chemical Assimilation System and its Application for
Atmospheric Environmental Materials (SALSA: PI
Prof. Nakajima, AORI at UTokyo), which in turn run
under the MEXT-funded “Research Program on
Climate Change Adaptation” (RECCA). In thisscheme, we, in collaboration with National Institutefor Environmental Studies (NIES), are in charge ofpredict the future impact of heat as well as air
pollution (mainly PM2.5) on various health events.

References
1. Soli KW., Kas M., Maure T., Umezaki M., Morita
A., Siba PM., Greenhill AR., Horwood PF. (2013)
Evaluation of colorimetric detection methods for
Shigella, Salmonella and Vibrio cholerae by loopmediated isothermal amplification. Diagnostic
Microbiology and Infectious Disease 77(4): 321323
2. Vengiau G., Umezaki M., Phuanukoonnon S., Siba
P., Watanabe C. (2013) Associations of socioeconomic status with diet and physical activity in
migrant Bougainvilleans in Port Moresby, Papua
New Guinea. Ecology of Food and Nutrition (inpress)

323

3. 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.
4. 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 Health38(5): 834-837.
5. 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.
6. 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.
7. 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.
8. Zhou R., Li Y., Umezaki M., Ding Y., Jiang H.W.,
Comber A., Fu H. (2013) Association between
physical activity and neighborhood environment
among middle-age adults in Shanghai. Journal ofEnvironmental and Public Health. Articile ID:
239595. doi.org/10.1155/2013/239595.
9. 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 Developing Rat Cerebrum. Environ Sci Technol. 47(6):2862-8.
10. 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.

324

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,

325

gene knockout)
III. Parasitic protozoa (Plasmodium falciparum,
Trypanosoma
brucei,
Trypanosoma
cruzi,
Cryptosporidium)1) characterization of mitochondria as a target forthe chemotherapy2) molecular biology of mitochondrial DNA3) structure based drug design (SBDD)
IV. Protein synthesis
1) Mitochondrial protein synthesis
2) Biogenesis of cytoplasmic ribosomes

References
1. Synergy of ferrous ion on 5-aminolevulinic acidmediated growth inhibition of Plasmodium
falciparum. Komatsuya K, Hata M, Balogun E. O,
Hikosaka K, Suzuki S, Takahashi K, Tanaka T,
Nakajima M, Ogura S-I, Sato S, Kita K. (2013) J.
Biochem. 154, 501–504.
2. Intron and RNA splicing in archaea. Watanabe Y.,
Yoshinari S. (2013) Viva Origino 41, 12-12
3. Cryopreservation of nematode Caenorhabditis
elegans in the adult stage. (2013) Hayashi, M.,
Amino, H., Kita, K. and Murase, N. Cryo Lett. 34,
388-395
4. Diversity of parasite complex II. (2013) Harada, S.,
Inaoka, D. K. Ohmori, J. and Kita, K. Biochem.
Biophys. Acta (Bioenergetics) 1827, 968-667
5. Structural characteristics of the alternative oxidase.
(2013) Moore, A. L., Shiba, T., Young, L., Harada,
S., Kita, K. and Ito, K. Ann. Rev. Plant Biol. 64,
637-663
6. Identification and characterization of sialidase-like
activity in the developmental stage of Amblyomma
variegatum. (2013) Natala, A. J., Balogun, E. O.,
Balogun, J. A. B., Inuwa, H. M., Andrew, J. N.,
Shiba, T., Harada, S., Kita, K., Agbede, R. I. S. andEsievo, K. A. N. J. Med. Entomol. 50, 85-93
7. Pharmacophore identification of ascofuranone,
potent inhibitor of cyanide-insensive alternativeoxidase of Trypanosoma brucei. (2013) Saimoto,H., Kido, Y., Haga, Y., Sakamoto, K. and Kita, K. J.
Biochem. 153, 267-273

8. Cloning and characterization of hypoxia-inducible
factor-1 subunits from Ascaris suum - a parasitic
nematode highly adapted to changes of oxygen
conditions during its life cycles. (2013) Goto, M.,
Amino, H., Nakajima, M., Tsuji, N., Sakamoto, K.
and Kita, K. Gene 516, 39-47
9. Structure of the trypanosome cyanide-insensitive
alternative oxidase, a promising drug target. (2013)
Shiba, T., Kido, Y., Sakamoto, K., Inaoka, D. K.,
Tsuge, C., Tatsumi, R., Takahashi, G., Balogun, E.
O., Nara, T., Aoki, T., Honma, T., Tanaka, A., Inoue,M., Matsuoka, S., Saimoto, H., Moore, M. L.,
Harada, S. and Kita, K. Proc. Natl. Acad. Sci. USA
110, 4580-4585
10. Cyanide-insensitive Quinol Oxidase (CIO) from
Gluconobacter oxydans is a unique terminal
oxidase subfamily of cytochrome bd. (2013) Miura,
H., Mogi, T., Ano, Y., Migita, C. T., Matsutani, M.,
Yakushi, T., Kita, K. and Matsushita, K. J.
Biochem. 153, 535-454
11. Biochemical characterization of highly active
Trypanosoma brucei gambiense glycerol kinase, apromising drug target. (2013) Balogun, E. O.,
Inaoka, D. K., Shiba, T., Kido, Y., Nara, T., Aoki,
T., Honma, T., Tanaka, A., Inoue, M., Matsuoka, S.,
Michels, P. A. M., Harada, S. and Kita, K. J.
Biochem. 154, 77-84
12. High-throughput RNA sequencing profiles andtranscriptional evidence of aerobic respiratory
enzymes in sporulating oocytes and sporozoites ofEimeria tenella. (2013) Matsubayashi, M., Hatta, T.,
Miyoshi, T., Anisuzzaman, Sasaki, K., Shimura, K.,
Isobe, T., Kita, K. and Tsuji, N.S Infect. Genet.
Evol. 18, 269-276
13. Type II Fp of human mitochondrial respiratorycomplex II and its role in adaptation to hypoxia andnutrition-deprived conditions. (2013) Sakai, C.,
Tomitsuka, E., Miyagishi, M., Harada, S. and Kita,
K. Mitochondrion 13, 602-609

School of Public Health
1. Epidemiology and Health Sciences

327

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 was established at thesame 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 thisresearch field, we conduct many multi-center studies

328with 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. Fukumoto A, Asakura K, Murakami K, Sasaki S,
Okubo H, Hirota N, Notsu A, Todoriki H, Miura A,
Fukui M, Date C. Within-and between-individual
variation in energy and nutrient intake in Japanese
adults: effect of age and sex difference on groupsize and number of records required for adequate
dietary assessment. J Epidemiol 2013; 23(3):178-86.
2. Goto M, Morita A, Goto A, Deura K, Sasaki S,
Aiba N,Shimbo T, Terauchi Y, Miyachi M, Noda
M, Watanabe S, for the SCOP Study Group.
Reduction in adiposity, β-cell function, insulin
sensitivity, and cardiovascular risk factors: aprospective study among Japanese with obesity.
PLoS One 2013; 8(3): e57964.
3. Tanaka E, Yatsuya H, Uemura M, Murata C,
Otsuka R, Toyoshima H, Tamakoshi K, Sasaki S,
Kawaguchi L, Aoyama A. Associations of protein,fat, and carbohydrate intakes with insomnia
symptoms among middle-aged Japanese workers.
J Epidemiol 2013; 23(2): 132-8.
4. Takezawa J, Yamada K, Miyachi M, Morita A,
Aiba N, Sasaki S, Watanabe S. Preproghrelin gene
polymorphisms in obese Japanese women. Minorhomozygotes are light eaters, do not prefer protein
or fat, and apparently have a poor appetite.
Appetite 2013; 63: 105-11.
5. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Arakawa M. Fish and fat intake and prevalence ofdepressive symptoms during pregnancy in Japan:
Baseline data from the Kyushu Okinawa Maternaland Child Health Study. J Psychiatr Res 2013;
47(5): 572-8.
6. Miyajima I, Kawaguchi T, Fukami A, Nagao Y,
Adachi H, Sasaki S, Imaizumi T, Sata M. Chronic
HCV infection was associated with severe insulin
resistance and mild atherosclerosis: a population-

based study in an HCV hyperendemic area. J
Gastroenterol 2013; 48(1): 93-100.
7. Goto A, Morita A,Goto M, Sasaki S, Miyachi M,
Aiba N, Kato M, Terauchi Y, Noda M, Watanabe S,
for the Saku cohort Study Group. Validity of
diabetes self-reports in the Saku Diabetes Study. J
Epidemiol 2013; 23(4): 295-300.
8. Sasaki S. Dietary reference intakes for Japanese
2010: Basic theories for the development. J Nutr
Sci Vitaminol 2013; 59: S9-S17.
9. Sasaki S. Dietary reference intakes for Japanese
2010: Basic concepts for application J Nutr Sci
Vitaminol 2013; 59: S18-S25.
10. Horiguchi H, Oguma E, Sasaki S, Okubo H,
Murakami K, Miyamoto K, Hosoi Y, Murata K,
Kayama F. Age-relevant renal effects of cadmium
exposure through consumption of home-harvested
rice in female Japanese farmers. Environ Int 2013;
56: 1-9.
11. Murakami K, Sasaki S, Uenishi K,Japan Dietetic
Students Study for Nutrition and Biomarkers
Group. Serum adiponectin concentration in
relation to macronutrient and food intake in young
Japanese women. Nutrition 2013; 29(11-12):1315-20.
12. Hiratsuka C, Fukuwatari T, Sano M, Saito K,
Sasaki S, Shibata K. Supplementing healthy
women with up to 5.0 g/d of L-Tryptophan has noadverse effects. J Nutr 2013; 143(6): 859-66.
13. Suga H, Murakami K, Sasaki S. Development ofan amino acid composition database andestimation of amino acid intake in Japanese adults.
Asia Pac J Clin Nutr 2013; 22: 188-99.
14. Kato M, Goto A, Tanaka T, Sasaki S, Igata A,
Noda M. Effects of walking on medical cost: A
quantitative evaluation by simulation focusing on
diabetes. J Diabetes Investig 2013; 4(6): 667-72.
15. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Validity of a diet history
questionnaire estimating beta-carotene, vitamin C
and alpha-tocopherol intakes in Japanese pregnant
women. Int J Food Sci Nutr 2013; 64(6): 694-9.
16. Tanaka K, Miyake Y, Sasaki S, Hirota Y. Infant
feeding practices and risk of dental caries inJapan: The Osaka Maternal and Child HealthStudy. Pediatric Dentistry 2013; 35: 267-71.

329

17. Murakami K, Sasaki S, Uenishi K; Japan Dietetic
Students’ Study for Nutrition and Biomarkers
Group. Higher intake of vitamin B-6 and dairy
products and lower intake of green and oolong tea
are independently associated with lower serum
homocysteine concentration in young Japanesewomen. Nutr Res 2013; 33(8): 653-60.
18. Kiyohara C, Miyake Y, Koyanagi M, Fujimoto T,
Shirasawa S, Tanaka K, Fukushima W, Sasaki S,
Tsuboi Y, Yamada T, Oeda T, Shimada H,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M; Fukuoka Kinki Parkinson's Disease
Study Group. MDR1 C3435T polymorphism andinteraction with environmental factors in risk of
Parkinson's disease: a case-control study in Japan.
Drug Metab Pharmacokinet. 2013; 28: 138-43.
19. Kaino W, Daimon M, Sasaki S, Karasawa S,
Takase K, Tada K, Wada K, Kameda W, Susa S,
Oizumi T, Fukao A, Kubota I, Kayama T, Kato T.
Lower physical activity is a risk factor for aclustering of metabolic risk factors in non-obese
and obese Japanese subjects: The Takahata study.
Endocr J 2013; 60: 617-28.
20. Sakurai M, Nakamura K, Miura K, Takamura T,
Yoshita K, Sasaki S, Nagasawa S, Morikawa Y,
Ishizaki M, Kido T, Naruse Y, Suwazono Y and
Nakagawa H. Family history of diabetes, lifestylefactors, and the 7-year incident risk of type 2
diabetes mellitus in middle-aged Japanese men
and women. Journal of Diabetes Investigation
2013; 4: 261-8.
21. Shibata K, Fukuwatari T, Sasaki S, Sano M,
Suzuki K, Hiratsuka C, Aoki A, Nagai C. Urinary
excretion levels of water-soluble vitamins in
pregnant and lactating women in Japan. J Nutr Sci
Vitaminol 2013; 59: 178-86.
22. Yaguchi-Tanaka Y, Kawagoshi Y, Sasaki S, Fukao
A. Cross-Sectional Study of Possible Association
between Rapid Eating and High Body Fat Rates
among Female Japanese College Students. J Nutr
Sci Vitaminol (Tokyo) 2013; 59: 243-9.
23. Hara M, Yakushiji Y, Nannri H, Sasaki S, Noguchi
T, Nishiyama M, Hirotsu T, Nakajima J, Hara H.
Joint effect of hypertension and lifestyle-related
risk factors on the risk of brain microbleeds inhealthy individuals. Hypertens Res 2013; 36: 78994.

24. Shibata K, Fukuwatari T, Sasaki S. Nutritional
Status of Water-soluble Vitamins Did not Differ
According to Intake Levels of Wheat and Wheat
Alternatives and Rice and Rice Alternatives as aStaple Food in Pregnant Japanese Women.
Nutrition and Metabolic Insights 2013; 6: 51-7.
25. Shibata K, Tachiki A, Mukaeda K, Fukuwatari T,
Sasaki S, Jinno Y. Changes in Plasma Pyridoxal
5'-Phosphate Concentration during Pregnancy
Stages in Japanese Women. J Nutr Sci Vitaminol
2013; 59: 343-6.
26. Shin MN, Lee KH, Lee HS, Sasaki S, Oh HY, Lyu
ES, Kim MK. Maternal and grandmaternal obesityand environmental factors as determinants ofdaughter's obesity. Nutr Res Pract 2013; 7: 400-8.
27. Kobayashi S, Asakura K, Suga H, Sasaki S. Highprotein intake is associated with low prevalenceof frailty among old Japanese women: amulticenter cross-sectional study Nutr J 2013; 12:
164-73.
28. Fujii H, Iwase M, Ohkuma T, Ogata-Kaizu S, Ide
H, Kikuchi Y, Idewaki Y, Joudai T, Hirakawa Y,
Uchida K, Sasaki S, Nakamura U, Kitazono T.
Impact of dietary fiber intake on glycemic control,
cardiovascular risk factors and chronic kidneydisease in Japanese patients with type 2 diabetes
mellitus: the Fukuoka Diabetes Registry. Nutr J
2013; 12: 159.
29. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Arakawa M. Maternal fat intake during pregnancy
and wheeze and eczema in Japanese infants: theKyushu Okinawa Maternal and Child HealthStudy. Ann Epidemiol 2013; 23(11): 674-80.
30. Ilmiawati C, Ogawa M, Sasaki S, Watanabe T,
Kayama F. Urinary arsenic excretion profiles andassociated dietary in Japanese women from acoastal area in Chiba Prefecture. Jichi Medical
University Journal 2013; 36: 1-11.

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Department of Clinical
Epidemiology and Health
Economics
Professor
Hideo Yasunaga, MD, PhD.

Assistant Professor
Hiroki Matsui, MPH.

Homepage

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

Introduction and Organization
The Department of Clinical Epidemiology and Health
Economics 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 clinical practice, health caresystem/policy for further improvement of the qualityof health care. For this purpose, the Department puts aunique emphasis on quantitative analytic methods andinter-disciplinary theories across clinical epidemiology, health service research, health economics andhealth policy.

Teaching activities
Under the MPH program, the Department is
responsible for 6 courses, one on introduction toclinical medicine for non-MD students, two on
clinical epidemiology, two on health economics, andone 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.
Health economics course provides an intermediatelevel of micro-economics and health economics
theories of consumer choice, insurance, and humancapital, and enhances discussion to apply these
theories to behaviors of providers and consumers. The
3-day intensive course offers students an opportunity
for hands-on training of actual cost-effectivenessanalysis of health care and technologies.
The course on health care organization management
provides basics of financial accounting, andmanagement frameworks on human resource, strategy,
information, and risk, helping the students deepen theknowledge through in-class discussion over real-casescenarios.
The Department accepted 6 master students for the
fiscal years of 2013.

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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, and hospital administration and quality
assurance.
The Department 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.

References
1.

2.

3.

4.

5.

Yasunaga H, Horiguchi H, Kuwabara K, Matsuda S,
Fushimi K, Hashimoto H, Ayanian JZ. Outcomes
After Laparoscopic or Open Distal Gastrectomy for
Early-stage Gastric Cancer: A Propensity-matched
Analysis. Ann Surg 2013;257(4):640-6
Yasunaga H, Horiguchi H, Matsuda S, Fushimi K,
Hashimoto H, Ayanian JZ. Body mass index andoutcomes following gastrointestinal cancer surgery
in Japan: A retrospective cohort study. Brit J Surg
2013;100:1335–43
Yasunaga H, Horiguchi H, Hashimoto H, Matsuda S,
Fushimi K. Effect and Cost of Treatment for Acute
Pancreatitis With or Without Gabexate Mesylate: A
Propensity Score Analysis Using a Nationwide
Administrative Database. Pancreas 2013; 42(2):260-4Akahane M, Tanabe S, Ogawa T, Koike S,
Horiguchi H, Yasunaga H, Imamura T.
Characteristics and Outcomes of PediatricOut-of-Hospital Cardiac Arrest by Scholastic Age
Category. Pediatric Critical Care Medicine 2013;14(2):130-6
Akiyama T, Chikuda H, Yasunaga H, Horiguchi H,
Fushimi K, Saita K. Incidence and Risk Factors for
Mortality of Vertebral Osteomyelitis: A Retrospective Analysis Using the Japanese Diagnosis

Procedure Combination Database. BMJ Open 2013;
3:e002412.
6. Chikuda H, Yasunaga H, Horiguchi H, Takeshita K,
Sugita S, Taketomi S, Fushimi K, Tanaka S. Impact
of Age and Comorbidity Burden on Mortality and
Major Complications in Older Adults Undergoing
Orthopaedic Surgery: An Analysis Using theJapanese
Diagnosis
Procedure
Combination
Database. BMC Musculoskeletal Disorders 2013;
14(1):173
7. 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 ;84(7):964-9.
8. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Matsuda S, Fushimi K, Koike K.
Rarity of severe bleeding and perforation inendoscopic ultrasound-guided fine needle aspiration
for submucosal tumors. Digestive Diseases Science
2013;58:2634-8.
9. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Matsuda S, Fushimi K, Koike K.
Continuous regional arterial infusion for acutepancreatitis: A propensity score analysis using anationwide administrative database. Critical Care2013;17(5):R214.
10. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Fushimi K, Ohe K, Koike K. Japanese
Severity Score for Acute Pancreatitis Well Predicts
In-hospital Mortality: A Nationwide Survey of
17,901 Cases. Journal of Gastroenterology 2013;
48(12):1384–91
11. Nakamura M, Yasunaga H, Ando S, Haraguchi T,
Sugihara T, Horiguchi H, Ohe K, Matsuda S,
Fushimi K. Length of mechanical restraint following
haloperidol injections versus oral atypicalantipsychotics for the initial treatment of acuteschizophrenia: A Propensity-Matched Analysis fromthe Japanese Diagnosis Procedure Combination
Database. Psychiatry Research 2013;209:412-6
12. Nakamura M, Yasunaga H, Shimada T, Horiguchi H,
Matsuda S, Fushimi K. Body mass index andin-hospital mortality in anorexia nervosa: data fromthe Japanese Diagnosis Procedure Combination
Database. Eating and Weight Disorders 2013;18(4):437-9.

332

13. Ogura K, Yasunaga H, Horiguchi H, Ohe K,
Shinoda Y, Tanaka S, Kawano H. Incidence and risk
factors for postoperative pulmonary embolism
following primary musculoskeletal tumor surgery:
Analysis of a national administrative database. Clin
Orthop Relat Res 2013;471:3310-6.
14. Ogura K, Yasunaga H, Horiguchi H, Ohe K,
Shinoda Y, Tanaka S, Kawano H. Impact of
Hospital Volume on Postoperative Complications
and In-hospital Mortality after Musculoskeletal
Tumor Surgery: Analysis of a National Administrative Database. J Bone Joint Surg Am 2013;
95(18):1684-91.
15. Sone M, Mizunuma K, Nakajima Y, Yasunaga H,
Ohtomo K. Job satisfaction, income, workload,
workplace, and demographics of Japaneseradiologists in the 2008 survey. Japanese Journal ofRadiology 2013;31:364-70.
16. 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: 12,372 Patients inJapanese National Series. BJU Int 2013;111(3):459-66
17. Sugihara T, Yasunaga H, Horiguchi H, Fujimura T,
Nishimatsu H, Kume H, Ohe K, Matsuda S, Fushimi
K, Homma Y. Is mechanical bowel preparation inlaparoscopic radical prostatectomy beneficial? Ananalysis of a Japanese national database. BJU Int
2013;112(2):E76-81.
18. Sugihara T, Yasunaga H, Horiguchi H, Fujimura T,
Nishimatsu H, Tsuru N, Kazuo S, Ohe K, Fushimi K,
Homma Y. Regional, institutional and individual
factors affecting selection of minimally invasive
nephroureterectomy in Japan: A national database
analysis. Int J Urol 2013 ;81(1):74-9
19. Sugihara T, Yasunaga H, Horiguchi H, Tsuru N,
Ihara H, Fujimura T, Nishimatsu H, Ohe K, Fushimi
K, Homma Y. Comparisons of perioperative
outcomes and costs between open and laparoscopic
radical prostatectomy: a propensity-score matching
analysis based on the Japanese Diagnosis Procedure
Combination database. Int J Urol 2013;20:349-53.
20. Sugihara T, Yasunaga H, Horiguchi H, Fujimura T,
Nishimatsu H, Ohe K, Matsuda S, Fushimi K,
Kattan MW, Homma Y. Does Mechanical Bowel
Preparation Improve Quality of Laparoscopic

Nephrectomy? Propensity Score-matched Analysis
in Japanese Series. Urology 2013;81(1):74-9.
21. Sugihara T, Yasunaga H, Horiguchi H, Tsuru N,
Fujimura T, Nishimatsu H, Kume H, Ohe K,
Matsuda S, Fushimi K, Homma Y. Wide Range andVariations in Minimally Invasive Surgery For Renal
Malignancy in Japan: A Population Based Analysis.
Int J Clin Oncol 2013;18:1070–1077.
22. Takeuchi M, Yasunaga H, Horiguchi H, Hashimoto
H, Matsuda S. Pyloromyotomy versus intravenous
atropine therapy for the treatment of infantile pyloric
stenosis: an analysis using nationwide hospitaldischarge database. Pediatrics International 2013;
55(4):488-91
23. Takeuchi M, Yasunaga H, Horiguchi H, Matsuda S.
The Burden of Epiglottitis Among JapaneseChildren Before the Vaccination Era: an Analysis
Using a Nationwide Administrative Database.
Journal of Infection and Chemotherapy 2013;19:876-9.
24. Tanabe S, Ogawa T, Akahane M, Koike S,
Horiguchi H, Yasunaga H, Mizoguchi T, Hatanaka T,
Yokota H, Imamura T. Comparison of Neurological
Outcome between Tracheal Intubation andSupraglottic Airway Device Insertion of Out-ofhospital Cardiac Arrest Patients: A Nationwide,
Population-based, Observational Study. Journal of
Emergency Medicine 2013;44(2)389-397.
25. Tsugawa Y, Kumamaru H, Yasunaga H, Hashimoto
H, Horiguchi H, Ayanian JZ. The Association of
Hospital Volume with Mortality and Costs of Carefor Acute Stroke in Japan. Medical Care 2013;
51:782–8.

333

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)
4. Mass communication: Press conference
5. Internet communication (1)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.”

334

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.

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References
1. Tang W., Fukuzawa M., Ishikawa H., Tsutani K.,
Kiuchi T. Review of the registration of clinical
trials in UMIN-CTR from 2 June 2005 to 1 June2010 - focus on Japan domestic, academic clinical
trials. Trials. 2013; 14(1): 333.
2. Kiuchi T, Yoshida K, Kotani H, Tamaki K, Nagai
H, Harada K, Ishikawa H. Legal Medicine
Information System using CDISC ODM. Legal
Medicine. 2013; 15(6): 332-334.
3. Ono N., Kiuchi T., Ishikawa H. Development andpilot testing of a novel education method fortraining medical interpreters. Patient Education &Counseling. 2013; 93: 604-611.
4. Ishikawa H., Hashimoto H., Kiuchi T. The
evolving concept of "patient-centeredness" inpatient-physician communication research. Social
Science & Medicine. 2013; 96: 147-153.
5. Anazawa R., Ishikawa H., Kuchi T. Evaluation of
online machine translation by nursing users.
Computers, Informatics, Nursing. 2013; 31(8):382-387.
6. Park MJ., Green J., Ishikawa H., Yamazaki Y.,
Kitagawa A., Ono M., Yasukata F., Kiuchi T.
Decay of Impact after Self-Management
Education for People with Chronic Illnesses:
Changes in Anxiety and Depression over One
Year. PLoS ONE. 2013; 8(6): e65316.
7. Lai AY., Ishikawa, H., Kiuchi, T., Mooppil, N.,
Griva, K. Communicative and Critical Health
Literacy, and Self-management Behaviors in
End-Stage Renal Disease Patients with Diabetes
on Hemodialysis. Patient Education andCounseling. 2013; 91: 221-227.
8. Anazawa R., Ishikawa H., Kiuchi T. Use of online
machine translation for nursing literature - A
questionnaire-based survey. The Open Nursing
Journal. 2013; 7: 22-28.
9. Suka M., Odajima T., Kasai M., Igarashi A.,
Ishikawa H., Kusama M., Nakayama T., Sumitani
M., Sugimori H. The 14-item health literacy scale
for Japanese adults (HLS-14). Environmental
Health and Preventive Medicine. 2013; 18(5):407-415.
10. Anazawa, R., Ishikawa, H., Park, MJ., Kiuchi, T.
Online Machine Translation Use with Nursing

Literature: Evaluation Method and Usability.
Computers, Informatics, Nursing. 2013; 31(2):59-65.

School of Public Health
2. Behavioral Health Sciences

337

Departments ofHealth and Social Behavior &Health Education and Sociology
Professor in health and social behavior
Hideki Hashimoto, M.D., D.PH.

Associate Professor in health sociology and health education
Naoki Kondo, MD, PhD.

Lecturer

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 former 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 four 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 I & II: The course highlights
the significance of social determinants of health(SDH) as a key exposure causing social gradientof health. A series of omnibus lectures, each ofwhich focusing a specific topic of SDH (e.g.

338

income distribution, gender, job stress, anddiscrimination), are provided by invited lecturers
specialized in the field. The course is followedby course II which offers application of concepts
into practice through in-class discussion andgroup works.
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.
3) Health Sociology; Sociology in medicine andsociology applied to health issues are treated in
the systemic course of lectures, covering social
model of health, medical gaze and socializationof health professionals, phenomenology ofchronic ills, and culture and health.
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:3) Health education: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.
Dr. Kondo also is an active and leading coreresearcher in another large cohort for social epidemiology in gerontology, called Japan Gerontological
Evaluation Study (JAGES) that covers more than 23
municipalities and 200000 participating old people inthe community. The project purports to reveal social
relationship and its impact on health in later life.

339

References
1. Furuya Y, Kondo N, Yamagata Z, Hashimoto H.
Health literacy, socioeconomic status and selfrated health in Japan. Health Promot Int. 2013 Oct
2. Ishikawa H, Hashimoto H, Kiuchi T. The evolving
concept of "patient-centeredness" in patientphysician communication research. Soc Sci Med.
2013 Nov;96:147-53. doi: 10.1016/j.socscimed.
2013.07.026.
3. Tsugawa Y, Kumamaru H, Yasunaga H, Hashimoto
H, Horiguchi H, Ayanian JZ. The association of
hospital volume with mortality and costs of carefor stroke inJapan. Med Care. 2013 Sep; 51(9):782-8. doi: 10.1097/MLR.0b013e31829c8b70.
4. Suzuki T, Miyaki K, Tsutsumi A, Hashimoto H,
Kawakami N, Takahashi M, Shimazu A, Inoue A,
Kurioka S, Kakehashi M, Sasaki Y, Shimbo T;
J-HOPE study group (the Japanese study ofHealth, Occupation, and Psychosocial factors
related Equity).
Japanese dietary patternconsistently relates to low depressive symptoms
and it is modified by job strain and worksite
supports. J Affect Disord. 2013 Sep5;150(2):490-8. doi: 10.1016/j.jad.2013.04.044.
5. Enari T, Hashimoto H. Does salary affect the
choice of residency in non-university teaching
hospitals? A panel analysis of Japan Residency
Matching Programme data. Hum Resour Health.
2013 Mar 8;11(1):12. doi: 10.1186/1478-4491-1112.
6. Miyaki K, Song Y, Taneichi S, Tsutsumi A,
Hashimoto H, Kawakami N, Takahashi M,
Shimazu A, Inoue A, Kurioka S, Shimbo T.
Socioeconomic status is significantly associatedwith dietary salt intakes and blood pressure in
Japanese workers (J-HOPE Study). Int J Environ
Res Public Health. 2013 Mar 11;10(3):980-93.
doi:10.3390/ijerph10030980.
7. Miyaki K, Song Y, Taneichi S, Tsutsumi A,
Hashimoto H, Kawakami N, Takahashi M,
Shimazu A, Inoue A, Kurioka S, Shimbo T.
Socioeconomic status is significantly associatedwith the dietary intakes of folate and depression
scales in Japanese workers (J-HOPE Study).
Nutrients. 2013 Feb 18;5(2):565-78. doi: 10.3390/
nu5020565.

8. 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. doi: 10.1186/1472-6947-12-151.
9. Tokunaga M, Hashimoto H. Factors affecting theentry of for-profit providers into a price regulated
market for formal long-term care services: a casestudy from Japan. Soc Sci Med. 2013 Jan; 76(1):143-9. doi:10.1016/j.socscimed.
10. Yasuda T, Ojima T, Nakamura M, Nagai A,
Tanaka T, Kondo N, Suzuki K, Yamagata Z.
Postpartum smoking relapse among women who
quit during pregnancy: cross-sectional study inJapan. J Obstet Gynaecol Res. 2013 Nov; 39(11):1505-12.doi: 10.1111/jog.12098.
11. Shrestha S, Aihara Y, Yoden K, Yamagata Z,
Nishida K, Kondo N. Access to improved waterand its relationship with diarrhoea in Kathmandu
Valley, Nepal: a cross-sectional study. BMJ Open.
2013 Jun 28;3(6). pii: e002264. doi: 10.1136/
bmjopen-2012-002264.
12. Suzuki K, Sato M, Ando D, Kondo N, Yamagata Z.
Differences in the effect of maternal smoking
during pregnancy for childhood overweight before
and after 5 years of age. J Obstet Gynaecol Res.
2013 May;39(5):914-21. doi: 10.1111/jog.12025.
13. Takagi D, Kondo K, Kondo N, Cable N, Ikeda K,
Kawachi I. Socialdisorganization/social fragmentation and risk of depression among older people
in Japan: multilevel investigation of indices ofsocial distance. Soc Sci Med. 2013 Apr;83:81-9.
doi: 10.1016/j.socscimed.2013.01.001.
14. Aida J, Kondo K, Kawachi I, Subramanian SV,
Ichida Y, Hirai H, Kondo N, Osaka K, Sheiham A,
Tsakos G, Watt RG. Does social capital affect theincidence of functional disability in older
Japanese? A prospective population-based cohort
study. J Epidemiol Community Health. 2013 Jan;67(1):42-7. doi: 10.1136/jech-2011-200307.

School of Public Health
3. Health Services Sciences

341

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Research Associate
Toki Saito, 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 have

342

given 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.

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. Yoshino M, Kin T, Saito T, Nakagawa D,
Nakatomi H, Kunimatsu A, Oyama H, Saito N.
Optimal setting of image bounding box can
improve registration accuracy of diffusion tensor
tractography. Int J Comput Assist Radiol Surg.
2013 Aug 20.
2. Saito N, Kin T, Oyama H, Yoshino M, Nakagawa
D, Shojima M, Imai H, Nakatomi H. Surgicalsimulation of cerebrovascular disease withmultimodal fusion 3-dimensional computer
graphics. Neurosurgery. 2013 Aug; 60 Suppl 1:
24-9.
3. Yoshino M, Kin T, Nakatomi H, Oyama H, Saito
N. Presurgical planning of feeder resection withrealistic three-dimensional virtual operation fieldin patient with cerebellopontine angle meningioma. Acta Neurochir (Wien). 2013 Aug; 155(8):1391-9.
4. Takai K, Kin T, Oyama H, Shojima M, Saito N.
Three-dimensional angioarchitecture of spinal
dural arteriovenous fistulas, with special reference
to the intradural retrograde venous drainage
system. J Neurosurg Spine. 2013 Apr; 18(4):398-408.

Endowed Department

344

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

345

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 for pharmacoepidemiologic 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,346

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.

347

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 thisuniversity as an essential study. The lectures have been
served by this department. For postgraduate education,
seminars of traditional medicine have been held at theuniversity.
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.

348

The diagnosis is made by the western medicine using
blood examinations and imaging studies. After thescientific diagnosis, patients are diagnosed based on
the instructions of the traditional herbal medicine, andtreated mainly with the medicinal herbs.

Teaching activities
As for under-graduate student education, ourdepartment takes a part in systemic lectures for the 4thyear medical students. In systemic lectures,comprehensive presentation for the understanding ofbasic knowledge about the concept, pathogenesis,
pathology, diagnosis and treatment is performed.
In systemic lectures, we also present clinical cases ofrepresentative cases, and try to discuss with thestudents several points for planning the diagnosis andtreatment. Demonstration of some herbs and typical
recipes is also served during the lectures.
Free seminars “traditional medicine as a life science”
are served, in which we analyze and translate thescientific data into the traditional medicine and also
try to integrate the idea from both medicines.
For international experimental educations, a special
lecture on traditional herbal medicine and demonstration of acupuncture were given for foreign students
from over 40 countries at Harvard Project for Asianand International Relations Tokyo Conference.
Postgraduate students are served with scientificeducation of molecular cell biology and biophysics.
As for the post-graduate clinical education, we provide
clinical lectures regularly on the use of traditional
herbal medicine.

Research activities
Our research field covers from clinical, pharmacological, biological, and biophysical activities of
traditional medicinal herbs. We focus on the molecularmechanisms of cell functions and intracellularsignaling pathways.
Traditional medicinal herbs such as Ginseng has long
been used as an anti-aging agent in Asian countries.
Our laboratory studies molecular mechanisms ofaction by such anti-aging herbs. Ginsenoside Rb1, amajor constituent of Ginseng has been demonstrated
to exert the biological action as a phytoandrogen.

Endocrinological activities of anti-aging herbs areinvestigated using various molecular cell biologicalapproaches including biochemistry, immunochemistry,
molecular biology, molecular genetics such as genetargeting and transgenic mouse approaches, molecularbiophysics.
Much current interest is focused on the therapeuticpotential of hormone replacement therapy (HRT).
However, one of the major adverse reactions of HRT
is considered to promote cancer growth. It is urgent
for us to elucidate the mechanisms of action by theanti-aging herbs and to compare them with those ofhormones. Subsequently, we compare the biologicalactivities of the anti-aging herbs and their counterpart
hormones. We have demonstrated ginsenoside Rb1
and icariin exert the biological activity through its
non-genomic action on androgen receptors. Recently,
we have demonstrated that cinnamaldehyde, a major
constituent of cinnamon selectively stimulates progesterone secretion in human adrenal cells. Our studies
are focused on endocrinological actions of anti-aging
herbs which are exerted through their genomic or
non-genomic actions of steroid hormones.
The spinocerebellar ataxias (SCAs) are clinically andgenetically a heterogeneous group of neurodegenerative disorders. At present, we have noeffective therapeutic tools. SCA6 has been
demonstrated to be an autosomal dominant cerebellar
ataxia associated with small polyglutamine-dependent
expansions in the alpha 1A-voltage calcium channel.
Long-term remission of this genetic disease has been
attained with medicinal herbs. The findings of ourstudy imply the therapeutic potential of herbal
medicine for this hereditary neurodegenerative
disorder. Extensive investigations are under way toclarify the mechanisms. It has been also demonstrated
that some herbs are effective against multiple sclerosis,
neuromyelitis optica, glaucoma, epilepsy, Parkinson’s
disease or depression 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

349

herbal medicine are 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. Wieland LS, Manheimer E, Sampson M, Barnabas
JP, Bouter LM, Cho K, Lee MS, Li X, Liu J,
Moher D, Okabe T, Pienaar ED, Shin BC,
Tharyan P, Tsutani K, van der Windt DA, Berman
BM. Bibliometric and content analysis of the
Cochrane Complementary Medicine Field
specialized register of controlled trials. Syst Rev.
2013 Jul 4;2:51. doi: 10.1186/2046-4053-2-51.

350

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
DepartmentofPlanning,
Information
andManagement, the University Hospital Medical
Information
Network(UMIN)
Center,theDepartments of Epidemiology and Biostatistics, andthe Department of 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

351

of Diabetes and Metabolic Medicine (Professor
Takashi Kadowaki) since then. And associate
Takanashi and Researcher Yoshiko Mizuno became amember of this department and the Center for
Epidemiology and Preventive Medicine. In 2013, thedepartment of Cardiovascular Medicine (Professor
Issei Komuro) became the parental department again.
In addition to that, the Clinical Research Support
Center (Professor Tsutomu Yamazaki) joined as theparental 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.

Teaching activities
On behalf of Professor Yamazaki, Associate
Professor Koide gave a lecture for junior students ofIntegrated Health Sciences, Faculty of Medicine, theUniversity of Tokyo. The title of the lecture was“Clinical research and genetic analysis in the field ofcardiovascular diseases and life-style related diseases”
in the series of "pharmacology and toxicology" at theroom number N101, in the 3rd Building of Medicine
on May 14 in 2013. And associate professor, Koide
gave a lecture which was entitled "Pharmacoepidemiology and Pharmacovigilance by using
database" in the series of medical common lectures
XXXIII, at the 6th seminar room on 13F of medical
and education research building, on Nov 19th in 2013.
Furthermore, associate Takanashi gave a lecture on
lipid as a part of clinical training for the 5th and 6th
grade's students of Medicine, the University of Tokyo.
Also, the basic lectures of Medical Writing took
place as an intensive course on September 12-13 in2013, 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.

With the department of Pharmacoepidemiology,
associate professor Koide gave a lecture which wasentitled "possibility of record-linkage in Japan" on
November 9-10 in 2013. .
In addition, associate professor Koide gave a
special lecture regarding "E-learning system forclinical research and trial in the 9th of clinicalresearch seminar at the large hall in the education andresearch building in Jichi Medical University, on April
23 in 2013. Also he gave a lecture as “-ClinicalPharmacology-, Evaluation of Drug Efficacy and
Safety" (3) Pharmacoepidemiology”, which was given
to the sixth-grade students at Tokyo University ofpharmacy and Sciences on July 4 in 2013.
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 andprofession" for three years since 2012. As the 2nd yearof it, the e-learning system has been implemented in
UMIN. Therefore, we expand our scope of humanresource development for not only clinicalepidemiology, but also clinical research and trial.

Research 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. 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 2013. In the future, this systeminfrastructure will be available with other medical
institutions for clinical epidemiology2) Improving Quality of Health Care
As a member of the quality improvement andassessment committee, clinical pathway committee,
and a chair of the committee for quality care at ouruniversity hospital, associate professor Koide

352

contributes to assess our quality care and improvement.
3) Standardization
Epidemiology

ofInformationinClinical

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.
4) 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 therapeutic targets to combat obesity-related disorders.
5) Preventive Medicine for Cardiovascular Disease
In collaboration with the Center for Epidemiology
and Preventive Medicine, we conduct epidemiologicalresearch not only focusing on cardiovascular field but
also covering numerous diseases related to otherorgans. In light of the need for novel approaches, wesought to elucidate mechanisms of atherosclerosis bycarrying out comprehensive research targeting healthy
subjects. One of our recent findings regarding

oxidative stress suggests that excessive state of serumiron levels in healthy patients can be associated with
subclinical atherosclerosis. Currently, we are studying
the impact of thyroid dysfunction on atherosclerosis,
which could contribute to preventive cardiology.

References
1. Yamazaki T, Kohro T, Chujo M, Ishigaki M,
Hashimoto T.: The occurrence rate of
cerebrovascular and cardiac events in patients
receiving antihypertensive therapy from thepost-marketing surveillance data for valsartan inJapan (J-VALID). Hyperten Res.36:140-150, 2013.

353

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, theDepartment of Ubiquitous Preventive Medicine wasinaugurated in August 1st, 2007 (Heisei 19), with adonation from three pharmaceutical companies,
Toa-Eiyo Ltd., Shionogi & Co., Ltd. and NEC
Corporation to the University (since August 2010,
from Shionogi & Co.). Its predecessor is theClinical Bio-Informatics Research Unit in the
Graduate School of Medicine of the University ofTokyo (Director: Ryozo Nagai) which wasestablished in 2002 (Heisei 14) as a governmentfunded program (Bio-Informatics Training Programsupported by the Ministry of Education, Culture,
Sports, Science and Technology [MEXT] throughSpecial Coordination Funds for Promoting Scienceand Technology). When the Clinical BioInformatics Research Unit completed its program
tenure in 2007, its academic mission and services
were continued by the Department of Ubiquitous
Preventive Medicine and the Department of Clinical
Epidemiology and Systems, both affiliated with 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 forprevention and early detection of disease. For thispurpose, advanced and highly efficient techniquesof proteome analysis are used with potential clinicalapplication to preventive medicine. We are also
committed to developing surrogate biomarkers forthe discovery of drugs used in the treatment ofcardiovascular diseases as well as the optimizationof their efficacy, and to develop information
infrastructuretechnologies
foradvancingpersonalized medicine by clinically applying thetechniques of proteome analysis in an effort topromote preventive medicine for health promotion.
Our mission is to ultimately establish the academicbasis for Ubiquitous Preventive Medicine.
Our department provides diagnostic/therapeutic
as well as academic support for the Department of
Epidemiology and Preventive Medicine establishedin 2007 within the University of Tokyo Hospital. In
collaboration with our department, the Departmentof Clinical Epidemiology and Systems also support
the management of the Department of Epidemiology and Preventive Medicine.

Research Activities
The principal objectives of our research are todevelop diagnostic technologies for prevention and354

early detection of disease by using advanced andhighly efficient techniques of proteome analysis,
focusing on the development of diagnostic
biomarkers and diagnostic/therapeutic systems, andto promote translational research which connects
basic scientific findings such as defined diseasemechanism to tangible clinical application. A
typical example is that we are in the process ofdeveloping methods for the measurement of protein
modifications in cardiovascular diseases and othernew bio-tools for early detection of lifestyle-relateddiseases.
One of the achievements we have made is theworld first biomarker detecting system for ischemic
heart disease, which is a collaborative work by Toru
Suzuki and Shimadzu Corporation. This systemallows to detect conformational change ordegradation of proteins which are important in
cardiovascular pathologies such as ischemic heartdisease and heart failure. This system consists of
two major parts, mass spectrometry analysis whichenables qualitative and quantitative evaluation ofprocessed degradation products or post-transcriptional modification of specific proteins, andimmunoprecipitation. We have already confirmed
and published its utility in clinical practice (Clin
Chem, in press), further, issued press-release fromthe 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 ispursued on an ongoing basis with its main research
projects being Medical Equipment Development
Research Project from 2011 to 2013 under the
Ministry of Health, Labour and Welfare andAcademic-Industrial Research Collaboration (joint
research with Shimadzu Corporation).
In addition to the development of proteomicsbased diagnostic methods, we also are developing
information
infrastructuretechnologies
foradvancing personalized medicine by clinically
applying these methods to preventive medicine, as
in comprehensive medical examinations. In this way,
Ubiquitous Preventive Medicine is an appliedscience, based on which a comprehensive system is

to be developed in an effort to promote preventive
and participatory medicine for health promotion,and translational research which refines basic
findings to clinical application.

Clinical activities
The Department of Ubiquitous Preventive
Medicine is involved in the management of the
Department of Epidemiology and Preventive
Medicine in the University of Tokyo Hospital andprovides diagnostic/therapeutic as well as academic
support for the department.

Teaching activities
The Department of Ubiquitous Preventive
Medicine offers education and research supervision
to graduate students and post-doctoral fellows in theaffiliate Department of Cardiovascular Medicine.

References
Academic Papers in English
1. 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): 385390.
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.

355

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,
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 acuteaortic dissection; (from the International Registryof Acute Aortic Dissection [IRAD]). Am J
Cardiol. 2012, 109: 122-127.

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

2.

3.

4.

5.

6.

7.

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
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 andOutcomes in Patients 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-Complicated AcuteType 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

356

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
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

357

Department of Chronic Kidney
Disease (CKD)
Associate Professor
Miki Nagase, M.D., Ph.D.

Associate
Shigetaka Yoshida, M.D., Ph.D.

Homepage http://plaza.umin.ac.jp/~kid-endo/07-lab/18-nagaselab/nagaselabtop.html
Introduction and Organization

Research activities

The Department of Chronic Kidney Disease (CKD)
was established in January 2009 by a donation fromJapan Boehringer Ingelheim Co., Ltd., in cooperation
with the Department of Nephrology and
Endocrinology (Prof. Toshiro Fujita) and Department
of Urology (Prof. Yukio Homma).
Chronic kidney disease (CKD) is a disease entity
advocated by National Kidney Foundation in 2002.
CKD is regarded as one of the highest priority medical
issues at present. CKD patients, if untreated, willdevelop end-stage renal disease requiring artificial
dialysis. They are also high risk group of
cardiovascular disease (CVD).
The main research objects of this department are to
elucidate the molecular mechanisms by whichmetabolic syndrome increases the risk of CKD or bywhich CKD promotes CVD, to identify novel
therapeutic target molecules, and to develop new
diagnostic and treatment strategies, and to constructexperimental evidence that can be applied to the CKD
treatment.
We cooperate with Department of Nephrology and
Endocrinology, Department of Urology, and otherresearch groups having abundant clinical resources
and analytical strategies, and perform basic research
as well as translational and clinical researches. We
hope that our department will become the center of
excellence for CKD research.

In our department, we investigate the roles ofaldosterone/mineralocorticoid receptor (MR) system,
salt, adipokines, oxidative stress, inflammation caused
by immune cells in the processes linking metabolic
syndrome to CKD, especially focusing on glomerular
podocyte injury, a major cause of proteinuria.
Aldosterone has recently been recognized as animportant mediator of target organ damage, in
addition to its role in salt and blood pressure
homeostasis. Recent epidemic of obesity and high salt
diet in our modern society are postulated to cause
inappropriate activation of the aldosterone/mineralocorticoid receptor (MR) system, leading tocardiovascular and renal disease. We demonstrated
that metabolic syndrome rat is susceptible to renal
injury, especially when fed a high salt diet, due toinappropriate aldosterone/MR activation. Adipocytederived aldosterone-releasing factors (ARF) may
account for aldosterone excess in this model. We
further identified small GTPase Rac1 as a novel
activator of MR, and reported that the ligandindependent MR activation by Rac1 contributes to thenephropathy of several CKD models.
We have several ongoing projects, such as basic
research focusing on “cross-talk between Rac1 andMR”, and translational research to verify the clinicalsignificance of Rac1/MR activation and to develop
epoch-making diagnostic and therapeutic strategies.

358(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 humangenes for both renin and angiotensinogen.
Angiotensin coverting enzyme inhibitor (ACE-I)
significantly increases their plasma angiotensin I,
and therefore it is inferior to renin inhibitor inangiotensin 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 in renoprotective effect in high salt loaded
Tsukuba hypertensive mice. We are aldo
submitting a paper on 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.

359

Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Project Associate
Ryo Nitta, M.D.,

Homepage

Tadayuki Ogawa, Ph. D.

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

Teaching activities
We are involved in teaching medical students andMaster course and Ph. D. course students in thefollowing lectures and laboratory courses together
with the Department of Cell Biology and Anatomy.
I.
1) Lecture on Cell Bilogy, Developmental Biology,
Histology and Neurocytology.
2) Lecture on Gross Anatomy and Neuroanatomy. to
medical students and students of other facultiesII.
1) Laboratory course of Gross Anatomy and
Neuroanatomy.
2) Laboratory course of Histology and Histology of
the Cenrtral Nervous System.
to medical students and students of other faculties.
In addition we offer a special training course (freequarter) of various kinds of molecular cell biology
techniques such as immunocytochemistry, electron
microscopy, biochemistry, molecular biology, biophysics, and cellular and molecular neurobiology
technique to medical students.
Especially we devote ourselves for the teaching of the
cutting edge approaches of new light microscopy suchas the Photoactivated Localization Microscopy (PALM),
cryo-electron microscopy and X-ray crystallography.

Research activities
Our laboratory studies molecular motors and rail
microtubules and the mechanisms of intracellulartransport. To study these molecular mechanisms we
use new molecular cell biological approaches
including cutting edge light microscopies, cryoelectron microscopy of molecular resolution, X-ray
crystallography, biophysics, molecular biology andmolecular genetics. We aim to study the structure anddynamics of the molecular motors in vitro and in vivo
at the highest special and temporal resolution and onthese bases try to elucidate functions of molecularmotors in vivo combining molecular genetics.

References
1. 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.
2. Niwa S., H. Takahashi, and N. Hirokawa. betatubulin mutation that cause severe neuropathies
disrupt axonal transport. EMBO J. 32: 1352-1364,
2013.
3. Chang Q., R. Nitta, S. Inoue, and N. Hirokawa.
Structural basis for ATP-induced isomerization ofkinesin. J. Mol. Biol. 425: 1869-1880, 2013.
4. Kanai Y., D. Wang, and N. Hirokawa. KIF 13b
enhances the endocytosis of LRP1 by recruiting
LRP1 to caveolae. J. Cell Biol. 204: 395-408,
2014.
5. Yang W., Y. Tanaka, M. Bundo, and N. Hirokawa.
Antioxidant signaling involving the microtubulemotor KIF12 is an intracellular target of nutrition
excess in beta cells. Dev Cell in press, 2014.

360

Department of Molecular Vascular
Endocrinology
Associate Professor
Masashi Isshiki, M.D, Ph.D.

Associate
Risuke Mizuno, 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. Lifestylerelated illnesses such as high blood pressure are
known to cause abnormalities in the blood vessels and,as a result, to cause disorders of important organs likethe heart, kidneys, and brain. Various vasoactive
substances and signal transduction in cells forming thevascular structure are thought to be involved in thisprocess. This department conducts research with theaim of understanding the molecular mechanisms andpathophysiology of vascular disorders brought about
by lifestyle-related illnesses and accumulatingknowledge that can be applied to the treatment ofcardiovascular diseases.

Research activities
1. Understanding vascular endothelial function
regulatory mechanisms by intracellular Ca2+
signaling
The vasoregulator that we are particularly interested inis calcium signaling in vascular endothelial cells.
Calcium ions are extremely important signaling

factors that are involved in many vital phenomena. An
important feature of calcium signaling is that it
enables diverse cellular functions through spatiotemporal regulation. We have observed a number ofextremely interesting phenomena using confocal laser
microscope imaging systems. We have reported that,when cultured endothelial cells are stimulated with anagonist such as ATP, the increase in intracellular
calcium spreads to the entire cell in the form ofcalcium waves, starting from the cell edges where
caveolae are abundant (Isshiki et al., PNAS 1998).
Caveloae are invaginations with a diameter of about
100 nm in the cell membrane, and their function has
attracted attention in recent years due to the presenceof a variety of signaling transduction molecules thatare 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 is triggered, contain
substances that accumulate on the upstream side of theflow caused by shear stress and on the opposite side in
the direction of travel during cell migration (Isshiki etal., J Cell Sci 2002). One candidate that has been
proposed as a shear stress sensor is P2x4 receptors on
the cell membrane, and experimental data indicatingthat they are coupled with the production of nitricoxide (NO) in endothelial cells has also been obtained(Yamamoto, Isshiki, et al., Nat Med, 2006). Recently,
we have also been involved in an investigation of therelationship between intracellular calcium dynamics

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and endothelial cell function using Fluorescence
Resonance Energy Transfer (FRET). For example,
when the amount of calcium in the intracellular
calcium store decreases, there is an effect called
SOCE (store-operated calcium entry) whereby
calcium flows into the cell from outside; we haveshown 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 and antiarteriosclerosis; therefore, thispathway is related to the pathology of high bloodpressure and arteriosclerosis, and research in this area
may identify treatment targets. In addition, we havealso been analyzing the relationship between
calcium-dependent molecular regulation and calcium
dynamics directly under the cell membrane, which
may not be obtainable with conventional calcium
indicators, depending on the extracellular calcium
concentration (Isshiki et al., Circ Res 2004).
2. Understanding the pathophysiology of andvasoregulation by STIM1, a new Ca2+ regulatory
molecule
Recently, the important role played by a molecule
called STIM1, which is present in the ER Ca2+ store,
in SOCE control has been discovered, and we havealso been looking at STIM1 in our laboratory toinvestigate its role in endothelial cells.
A study is now underway to investigate STIM1's
relationship with the pathophysiology of vasculardisorders associated with arteriosclerosis and highblood pressure by preparing endothelial-cell-specific
STIM1 knockout mice and analyzing STIM1's effects
on endothelial performance and blood pressure.
3. Searching for new and existing vasoactive
substances and understanding new vasoactive
mechanisms
We are also interested in searching for new vasoactive
substances and understanding new action mechanismsof existing substances. For example, the influence ofaldosterone on vascular endothelial function, which is
not mediated by transcription mechanisms, hasrecently been investigated in cultured cells and by
tonus measurements in rat aortic ring (Muto et al.,Hypertens Res 2008). Also, we have reported thateplerenone, which is a selective aldosterone antagonist,
improves endothelial function by suppressing theexpression of caveolin, which is an eNOS inhibitor(Muto et al., AHA 2008). Recently, we have also been
examining the effects H2S on vascular function,
which is of physiological and pharmacologicalinterest.
4. Physiological investigation of the contribution oflymphatic vessel function in the pathology ofsalt-sensitive hypertension
Recently, it has been reported that lymph capillary
regeneration in the skin, which is caused by saltloading, is related to the pathology of salt-sensitive
hypertension. However, the effects of salt loading on
the regulatory control mechanism of lymphatic
circulation are not yet sufficiently understood.
Research is currently underway to look at the effectsof salt on changes to the functional properties ofcollecting lymphatic vessels that are mainly involvedin the propulsion of lymph, using animal models.

References
Academic Conferences and Lectures
International Conferences
1. Nishimoto, M. Mizuno, R., Isshiki, M. and Fujita
T. Stim1 regulates blood pressure via NO
production in vascular endothelial cells. The 18th
International Vascular Biology Meeting, Apr.
2013, Kyoto
2. Mizuno, R. and Isshiki, M. A high salt dietstrengthens chronotropic effects of lymphaticmechanical activities in mice. Vascular Biology
Oct 20-24, 2013, Hyannis MA, USA362

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

Clinical activities

Our department has been established as anendowment department supported by Astellas Pharma
Inc. in close collaboration with the Department ofUrology on July 1st 2010 to facilitate researches
specially focusing on continence medicine. Since July,
2013, this department has been received kind
donations from six pharmaceutical companies(Astellas Pharma Inc., Asahi-kasei Pharma Corp., Ono
Pharmaceutical Co., Ltd, Kissei Pharmaceutical Co.,
Ltd, Kyorin Pharmaceutical Co., Ltd, and Taiho
Pharmaceutical Co., Ltd).
The aim of our department is to contribute to theadvancement of continence medicine through basic
and clinical researches on regulation mechanisms oflower
urinarytract(LUT)
functionandpathphysiology of LUT dysfunction, as well asfunction/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.

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.

Teaching activities
We take part in providing systematic urologicallectures for second year medical students, and bed
side teaching for third and fourth year medical
students.

Research activities
We are currently investigating regulation mechanisms of lower urinary tract (LUT) function, andpathophysiological 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

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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

Publications
1. Aizawa N, Homma Y, Igawa Y. Characteristics
of lower urinary tract dysfunction and bladderafferent nerve properties in type 2 diabetic
goto-kakizaki rats. J Urol. 2013 Apr; 189(4):1580-7.
2. Aizawa N, Homma Y, Igawa Y. Influence of highfat diet feeding for 20 weeks on lower urinary
tract function in mice. LUTS 2013, 5(2):101–8.
3. Igawa Y, Michel MC. Pharmacological profile ofβ3-adrenoceptor agonists in clinical development
for the treatment of overactive bladder syndrome.
Naunynschmiedebergs Arch Pharmacol. 2013
Mar; 386(3):177-83.
4. Nomiya A, Naruse T, Niimi A, Nishimatsu H,
Kume H, Igawa Y, Homma Y. On- andpost-treatment symptom relief by repeatedinstillations of heparin and alkalized lidocaine ininterstitial cystitis. Int J Urol. 2013 Nov;
20(11):1118-22.
5. Minagawa T, Wyndaele M, Aizawa N, Igawa Y,
Wyndaele JJ. Mechanisms of pelvic organcross-talk: 2. Impact of colorectal distention onafferent nerve activity of the rat bladder. J Urol.
2013 Sep;190(3):1123-30.
6. Homma Y, Nomiya A, Tagaya M, Oyama T,
Takagaki K, Nishimatsu H, Igawa Y. IncreasedmRNA expression of genes involved inpronociceptive inflammatory reactions in bladdertissue of interstitial cystitis. J Urol. 2013 Nov;
190(5):1925-31.
7. Minagawa T, Aizawa N, Igawa Y, Wyndaele JJ.
The role of transient receptor potential ankyrin 1(TRPA1) channel in activation of single unit
mechanosensitive bladder afferent activities in therat. Neurourol Urodyn, 2013 Jun 19. doi:10.1002/
nau.22449. [Epub ahead of print]
8. Aizawa N, Ogawa S, Sugiyama R, Homma Y,
Igawa Y. Influence of urethane-anesthesia on theeffect of resiniferatoxin treatment on bladderfunction in rats with spinal cord injury. Neurourol
Urodyn. 2013 Dec 28. doi: 10.1002/nau.22549.
[Epub ahead of print]

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Department of Medical Genomics
Associate Professors
Yoshihiro Yamashita, M.D., Ph.D., Young Lim Choi, M.D., Ph.D.

Lecturer
Masahito Kawazu M.D., Ph.D.

Homepage

http://mano-lab.umin.jp/english/genome.html

Introduction and Organization

graduate students of the Graduate School of Medicine.

Department of Medical Genomics was established in
September 2009 with the goal to identify essential
growth drivers in every cancer, by taking advantage ofour functional screening system coupled with the next
generation sequencing technologies. Department ofMedical Genomics had been settled by the tightsupport from Department of Molecular Pathology(Professor Kohei Miyazono) and by the donation from
Astellas Pharma Inc. and Illumina, Inc. Starting as of
September 2012, Department of Medical Genomics
has been run only by the donation from Astellas
Pharma Inc. Since April 2013, Department of Cellular
Signaling (Professor Hiroyuki Mano) co-supported
this Department. Dr. Yoshihiro Yamashita joined thisDepartment at September 2013 as an Associate
Professor.
The Department of Medical Genomics enjoys awide range of research collaboration with many
academic institutes within Japan and also from abroad.
Especially, this Department is under an intimate
collaboration with Division of Functional Genomics,
Institute of Molecular Medicine, Jichi Medical
University.

Research activities

Teaching activities
We jointly take the responsibility for the lectures ofBiochemistry as wells as training of Biochemical
Experiments for the undergraduate students of the
School of Medicine. We also deliver training for

Department of Medical Genomics tries to fulfill ourgoals mainly through two approaches.
(1) Functional screening with the use of retroviral
cDNA expression libraries.
The focus formation assay had been widely usedin 1980s and 1990s to identify oncogenes from humancancer. However, since this technology directly usescancer genome to transfer oncogenes into recipient
cells, expression of each gene is regulated by its 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 of365

different 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.
We examined gene copy number of
EML4-ALK–positive tumors in a genome-wide manner,and found that copy number alterations in oncogenes
and tumor-suppressor genes are significantly lessfrequent in tumors harboring EML4-ALK that those
without it.
(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)
We 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).
Interestingly, RAC1(N92I), but not NRAS(Q61K),
was shown to be an essential growth driver to whichcancer cells are addicted.

References
1. Suzuki HI, Matsuyama H, Noguchi M, Yao T,
Komatsu N, Mano H, Sugimoto K, Miyazono K.
Computational dissection of distinct microRNA
activity signatures associated with peripheral T cell
lymphoma subtypes. Leukemia 2013:27:21072111.
2. Ninomiya H, Kato M, Sanada M, Takeuchi K,
Inamura K, Motoi N, Nagano H, Nomura K, Sakao
Y, Okumura S, Mano H, Ogawa S, Ishikawa Y.
Allelotypes of lung adenocarcinomas featuring
ALK fusion demonstrate fewer onco- andsuppressor gene changes. BMC Cancer 2013:13:8.
3. Miyanaga A, Shimizu K, Noro R, Seike M,
Kitamura K, Kosaihira S, Minegishi Y, Shukuya T,
Yoshimura A, Kawamoto M, Tsuchiya S,
Hagiwara K, Soda M, Takeuchi K, Yamamoto N,
Mano H, Ishikawa Y, Gemma A. Activity of
EGFR-tyrosine kinase and ALK inhibitors for
EML4-ALK-rearranged non-small-cell lung cancer
harbored coexisting EGFR mutation. BMC Cancer
2013:13:262.
4. Kawazu M, Ueno T, Kontani K, Ogita Y, Ando M,
Fukumura K, Yamato A, Soda M, Takeuchi K,
Miki Y, Yamaguchi H, Yasuda T, Naoe T,
Yamashita Y, Katada T, Choi YL, Mano H.
Transforming mutations of RAC guanosine
triphosphatases in human cancers. Proc Natl Acad
Sci U S A 2013:110:3029-3034.
5. Himpe E, Abdul Rahim SA, Verdood P, Mano H,
Kooijman R. Tec kinase stimulates cell survival intransfected Hek293T cells and is regulated by theanti-apoptotic growth factor IGF-I in humanneutrophils. Cell Signal 2013:25:666-673.
6. Fukumura K, Yamashita Y, Kawazu M, Sai E,
Fujiwara S, Nakamura N, Takeuchi K, Ando M,
Miyazono K, Ueno T, Ozawa K, Mano H. STK10
missense mutations associated with anti-apoptotic
function. Oncol Rep 2013:30:1542-1548.
7. Ando M, Kawazu M, Ueno T, Fukumura K,
Yamato A, Soda M, Yamashita Y, Choi YL,
Yamasoba T, Mano H. Cancer-associated missense
mutations of caspase-8 activate nuclear factor-

366

kappaB signaling. Cancer Sci 2013:104:10021008.
8. Ando K, Tsushima H, Matsuo E, Horio K,
Tominaga-Sato S, Imanishi D, Imaizumi Y,
Iwanaga M, Itonaga H, Yoshida S, Hata T,
Moriuchi R, Kiyoi H, Nimer S, Mano H, Naoe T,
Tomonaga M, Miyazaki Y. Mutations in the
nucleolar
phosphoprotein,
nucleophosmin,
promote the expression of the oncogenictranscription factor MEF/ELF4 in leukemia cells
and potentiates transformation. J Biol Chem 2013:
288:9457-9467.

367

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. Ikegame T, Bundo M, Sunaga F, Asai T,
Nishimura F, Yoshikawa A, Kawamura Y, Hibino
H, Tochigi M, Kakiuchi C, Sasaki T, Kato T,
Kasai K, Iwamoto K. DNA methylation analysis
of BDNF gene promoters in peripheral blood cellsof schizophrenia patients. Neuroscience Research
2013,77:208-214.
2. 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 methylationin human neuroblastoma cells. International
Journal of Neuropsychopharmacology 2013,16:2285-2294.
3. 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.
International
JournalofDevelopmental
Neuroscience 2013,31:89-95.
4. Nishioka M, Bundo M, Koike S, Takizawa R,
Kakiuchi C, Araki T, Kasai K, Iwamoto K.
Comprehensive DNA methylation analysis ofperipheral blood cells derived from patients with
first-episode schizophrenia. Journal of Human
Genetics 2013,58:91-97.

368

5. Ikegame T, Bundo M, Murata Y, Kasai K, Kato T,
Iwamoto K. DNA methylation of the BDNF geneand its relevance to psychiatric disorders. Journalof Human Genetics 2013,58:434-438.
6. Sugawara H, Bundo M, Ishigooka J, Iwamoto K,
Kato T. Epigenetic regulation of serotonintransporter in psychiatric disorders. Journal of
Genetics and Genomics 2013,40:325-329.

369

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.

Our department contributed to establishment of thesociety for nursing science and engineering from 2012.
The first annual meeting of nursing science andengineering was hold at 5th Oct 2013. Our department
played a great important role for management of themeeting as a host.
Current members include a project associate projector
and two project assistant professors. We accept
students from Division of Health Science and Nursing.
Accepted two master course students were graduatedat the end of 2013. 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 electricengineering, which is closely related to developmentof medical and nursing devices. Hiroshi Noguchitaught measurement engineering. We invited Prof.
Yuji Ota, Ochanomizu University to lecture for
Wound Care Management II, and Ryuji Kajiwara
Molten Corp. to lecture for Wound Care Nursing II.

370

In a part of Gerontological Nursing I for graduate
course, the members in the department lectured thefeatures and reading method of journal papers ofengineering research based on typical publications.
In 2013, the staffs in our department supported two
master course students. Their master thesis themes are“Development of an anomaly detection method inhome monitoring system for the elderly using
financial theories” and “Development and evaluationof a system to assess the effect of footwear on thein-shoe plantar pressure and shear during gait”
The members in our department supported the mastercourse student of the Department of GerontologicalNursing / Wound Care Management. The master thesis
theme of the student is “Development and clinicalevaluation of air mattress with independent control of
air cell pressure depending on interface pressure
distribution.”
As for the other education activity, our department
supported management of the first seminar for nursing
science and engineering. The staffs in our department
had engineering-related lectures and introduction ofresearch using ultrasonography. In addition, practicaltraining was conducted using Labview, which is afamous software for measurement.

Research activities
Our research themes are to investigate causes of
diseases and/or wounds due to daily life activity, andto develop instrument for effective monitoring andpreventing diseases and/or wounds. We study scienceand technology of natural human monitoring, nursing
engineering, and human behavior sensing thoroughly.
We are seeking a new interdisciplinary researchdomain between engineering and nursing, and willing
to realize comfortable daily life through theseresearches.
We are developing the methodology to support healthy
and comfortable daily life by 1) monitoring daily life
naturally, 2) understanding the typical behaviors, and

3) predicting diseases, injuries, and accidents using
various sensing technology.
Main themes of our department are the following:a) Development of monitoring systems for patient on
a bed and vital sign measurement system using
mattressb) Construction of behavior measurement in dailyliving environment using simple sensors andalgorithm for typical behavior pattern extraction
and transition estimation of human behavior
patternc) Three dimensional leg movement measurement
and spatiotemporal 3D leg state measurement for
prevention of foot ulcerd) Human position measurement and behavior
estimation using laser range scannerse) Design and construction of human behavior
database
As for the clinical field, we attend the Foot Care
Outpatient Clinic held by Department of Metabolic
Diseases.
As for the mimamori engineering, which is a main
theme in our department, a new technique for anomaly
detection from activity data from monitoring sensor
was developed. We focus attention on the similarity ofthe sensor data to the financial data, and apply themethod in the financial area into the anomaly
detection from the sensor data. Our method separates
the sequential activity data into trend and volatility.
Based on the trend and the volatility, the activity
patterns were divided into two four types. The method
switch the formulation according to the identified
activity pattern. Our method achieved detection of
anomaly from sensor data collected in the elderly
people.
As for measurement system of shear force during
walking for diabetic patients, the system was
improved. The previous system requires a special
shoes for measurement, which restricts themeasurement condition. To resolve this problem, thethin sheet involving shear sensor is attached on thefoot plantar directly. The approach frees the systemfrom the special shoes. Thus, our system can measure

371

the shear force using the patient’s own shoes. The
reliability and validity were already validated by thenormal participants.
We achieved collaborative work between engineeringand nursing with the Department of GerontologicalNursing/Wound Care Management. The work wasdevelopment of air mattress with independent controlof air cell pressure depending on interface pressure.
The air mattress monitors always the interfacepressure distribution using the embedded sensor. Oncethe mattress detects the locally high pressure region,
the mattress reduce the inner air cell pressure related
to the high pressure area. This function is achieved by
combination of pressure distribution sensor andindependent air cell control. Our engineeringknowledge assists to develop this new measurement
system.
We achieved the prize about the following
presentation.
1. Yuka Miura. Presentation Award of the first annual
meeting of nursing science and engineering.
(Domestic conference)
Yuka Miura, Gojiro Nakagami, Haruka Tohara,
Koichi Yabunaka, Hiroshi Noguchi, Taketoshi Mori,
Hiromi Sanada. “Detection Method of aspiration fromultrasonography image using image recognition
technique focusing on tracheal wall and bolus” Inproceedings of the first annual meeting of nursing
science and engineering. 2013;21.
2. Hiroshi Noguchi, Best Presentation Award of IIP
section in mechanical engineering. (Domestic
conference)
Hiroshi Noguchi, Manabu Takano, Ayumi Amemiya,
Makoto Oe, and Taketoshi Mori, “Measurement
System for Shear Force Generated on Plantar Surface
at Push Off Phase”, In proceeding of mechanicalengineering, J241034, 2013.

References
1. Yoshida M, Murayama R, Ota E, Nakata M,
Kozuma S, Homma Y. Reliability and validity of
the Japanese version of the pelvic floor distress

2.

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inventory-short form 20. Int Urogynecol J. 2013;24(6):1039-46.
Yoshida M, Murayama R, Haruna M, Matsuzaki
M, Yoshimura K, Murashima S, Kozuma S.
Longitudinal comparison study of pelvic floor
function between women with and without stressurinary incontinence after vaginal delivery. J Med
Ultrasonics. 2013;40(2):125-31.
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
rat model for deep tissue injury deterioration. Int
Wound J. 2013 May 7. doi: 10.1111/iwj.12082.
Yoshida M, Murayama R, Nakata M, Haruna M,
Matsuzaki M, Shiraishi M, Sanada H. Pelvic floor
function and advanced maternal age at firstvaginal delivery. Open Journal of Obstetrics andGynecology. Vol.3No. 4A, 28-34, Pub. Date:
June 18, 2013. DOI: 10.4236/ojog.2013.34A005
Mori T, Nagase T, Takehara K, Oe M, Ohashi Y,
Amemiya A, Noguchi H, Ueki K, Kadowaki T,
andSanadaH.
Morphological
Pattern
Classification System for Plantar Thermographyof Patients with Diabetes. Journal of Diabetes
Science and Technology, Volume 7, Issue 5,
pp.1102-1112, September 2013. (2013 h5-index
31, h5-median 41)
Ogawa Y, Mori T, Noguchi H, Nakagami G,
Sanada H., Development and evaluation of an air
mattress structure and function for reducing
discomfort when elevating the head-of-bed.
Disabil Rehabil Assist Technol. 2013 Sep 20.
[Epub ahead of print]
Mugita Y. Minematsu T. Huang L. Sugama J.
Ichikawa Y. Nakagami G. Nagase T. Oe M.
Noguchi H. Mori T. Sanada H. A convenient andhighly sensitive method for quantification ofceramide in tape-stripping samples by dot-blot
analysis as a skin barrier assessment technique inmurine macerated skin. J Jpn WOCM.2013;17(3):201-212.
Noguchi H, Fukada H, Mori T, Sanada H, Sato T,
Objectand
Human
Localization
withZigBee-Based Sensor Devices in a Living
Environment. Radio Frequency Identificationfrom System to Applications. Edited by Mamun
Bin Ibne, ISBN 978-953-51-1143-6, InTech, 6372

2013. Edited by Mamun Bin Ibne, ISBN
978-953-51-1143-6, InTech, 6 2013. DOI:
10.5772/53366.
http://www.intechopen.com/books/radio-frequenc
y-identification-from-system-to-applications/obje
ct-and-human-localization-with-zigbee-based-sen
sor-devices-in-a-living-environment
9. 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
Scan Data, Journal of Robotics and Mechatronics,
Vol. 25, No. 1, pp. 5-15, 2013.

373

Department of Youth Mental
HealthAssociate Professor
Tsuyoshi Araki, M.D., Ph.D.

Lecturer
Noriaki Yahata, 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.

374

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.

References
1. Natsubori T, Inoue H, Abe O, Takano Y, Iwashiro
N, Aoki Y, Koike S, Yahata N, Katsura M, Gonoi
W, Sasaki H, Takao H, Kasai K. & Yamasue H.
Reduced Frontal Glutamate + Glutamine and
N-Acetylaspartate Levels in Patients With
Chronic Schizophrenia but not in Those at
Clinical High Risk for Psychosis or With
First-Episode Schizophrenia. Schizophr Bull.
2013 (in press).
2. Nagai T, Tada M, Kirihara K, Yahata N,
Hashimoto R, Araki T and Kasai K: Auditory
mismatch negativity and P3a in response to
duration and frequency changes in the early stagesof psychosis. Schizophr Res, 2013 DOI 10.1016/
j.schres.2013.08.005
3. Saito Y, Suga M, Tochigi M, Abe O, Yahata N,
Kawakubo Y, Liu X, Kawamura Y, Sasaki T,
Kasai K & Yamasue H: Neural correlate ofautistic-like traits and a common allele in theoxytocin receptor gene.
Soc Cogn Affect
Neurosci. 2013 (in press).
4. Sato H, Yahata N, Funane T, Takizawa R, Katura
T, Atsumori H, Nishimura Y, Kinoshita A,
Kiguchi M, Koizumi H, Fukuda M & Kasai, K: A
NIRS-fMRI investigation of prefrontal cortex
activity during a working memory task.
Neuroimage. 83C, 158-173 (2013).
5. Sakakibara E, Takizawa R, Nishimura Y,
Kawasaki S, Satomura Y, Kinoshita A, Koike S,
Marumo K, Kinou M, Tochigi M, Nishida N,
Tokunaga K, Eguchi S, Yamasaki S, Natsubori T,
Iwashiro N, Inoue H, Takano Y, Takei K, Suga M,
Yamasue H, Matsubayashi J, Kohata K, Shimojo
C, Okuhata S, Kono T, Kuwabara H,
Ishii-Takahashi A, Kawakubo Y, Kasai K: Genetic
influences on prefrontal activation during a verbal
fluency task in adults: A twin study based on

multichannel near-infrared spectroscopy. Neuroimage. 2013 Apr 2. [Epub ahead of print]
6. Aoki Y, Orikabe L, Takayanagi Y, Yahata N,
Mozue Y, Sudo Y, Ishii T, Itokawa M, Suzuki M,
Kurachi M, Okazaki Y, Kasai K & Yamasue H:
Volume reductions in frontopolar and left
perisylvian cortices in methamphetamine induced
psychosis.
Schizophr Res. 147(2-3), 355-61(2013).
7. Watanabe T, Yahata N, Kawakubo Y, Inoue H,
Takano Y, Iwashiro N, Natsubori T, Takao H,
Sasaki H, Gonoi W, Murakami M, Katsura M,
Kunimatsu A, Abe O, Kasai K & Yamasue H:
Network structure underlying resolution of
conflicting nonverbal and verbal social information. Soc Cogn Affect Neurosci. 2013 (in press).
8. Nagai T, Tada M, Kirihara K, Araki T, Jinde S andKasai K: Mismatch negativity as a “translatable”
brain marker toward early intervention for
psychosis: a review. Front. Psychiatry 4:115,
2013 DOI 10.3389/fpsyt.2013.00115
9. Aoki Y, Abe O, Yahata N, Kuwabara H, Natsubori
T, 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 K. J., Kato N, Kasai K & Yamasue H:
Absence of age-related prefrontal NAA change inadults with autism spectrum disorders. Transl
Psychiatry. 2, e178. (2013).
10. Takizawa R, Nishimura Y, Yamasue H, Kasai K:
Anxiety and Performance: The Disparate Roles ofPrefrontal
Subregions
Under
Maintained
Psychological Stress. Cereb Cortex. 2013 Feb 20.
[Epub ahead of print]
11. Araki T, Niznikiewicz M, Kawashima T, Nestor
PG, Shenton ME, McCarley RW: Disruption offunction-structure coupling in brain regions
sub-serving self monitoring in schizophrenia.
Schizophr Res 146: 336-343, 2013 DOI 10.
1016/j.schres.2013.02.028.
12. Nishioka M, Bundo M, Koike S, Takizawa R,
Kakiuchi C, Araki T, Kasai K, Iwamoto K.:
Comprehensive DNA methylation analysis ofperipheral blood cells derived from patients with
first-episode schizophrenia. J Hum Genet 58: 91-7,
2013 DOI 10.1038/jhg.2012.140.

375

13. Koike S, Takano Y, Iwashiro N, Satomura Y, Suga
M, Nagai T, Natsubori T, Tada M, Nishimura Y,
Yamasaki S, Takizawa R, Yahata N, Araki T,
Yamasue H, Kasai K: A multimodal approach toinvestigate biomarkers for psychosis in a clinicalsetting: The integrative neuroimaging studies inschizophrenia targeting for early intervention andprevention (IN-STEP) project. Schizophr Res
143: 113-24, 2013 DOI 10.1016/j.schres.2012.
11.012.

376

Department of Immunotherapy
Management
Project Associate Professor
Hiroko Kanda, M.D., Ph.D.

Project Associate
Shoko Tateishi, M.D., PhD

Homepage http://ryumachi.umin.jp/immu.html
Introduction and Organization

Clinical activities

Recently, biologic agents which target cytokines orcell surface molecules have been developed and play
an important role in the treatment of autoimmune
diseases. In Japan, biologic agents are available forthe treatment of rheumatoid arthritis, psoriasis, Behcet
disease and inflammatory bowel diseases. Thesediseases are treated in the Department of Allergy &Rheumatology, Dermatology, Gastroenterology, Surgical oncology & Vascular surgery, and Ophthalmology.
The Department of Immunotherapy Management wasestablished in April 2013 through donations from six
pharmaceuticalcompanies(Mitsubishi-Tanabe,
Bristol-Myers, Chugai, Janssen pharma, Abbvie,
Eisai). The Department of Allergy & Rheumatology,
Dermatology, and Orthopedics work in collaboration.
Not only biologic agents but also small molecules
have been developed in succession. However, it isdifficult to predict the efficacy and toxicity of theseagents by the background characteristics of patientswith rheumatoid arthritis. The aims of this department
are to propose an optimal treatment strategy for eachpatient and to establish a platform to investigate novel
biologics through analyses of immunological changes
by biologics treatments and the relationship between
biologics response and biomarkers or genetic
information.

We established a new booth for outpatients withrheumatoid arthritis who are receiving biologic agents
which is available every morning from Monday to
Friday. We focus on total rheumatoid arthritis carewith biologic agents. Moreover, we examine outpatients with psoriasis before biologics treatment andjudge whether biologics treatments can be used safely.

Teaching activities
As for education, we take part in providing
information of biologic agents for patients who are thecandidates to receive biologics, including necessity,
benefits, safety, complications, procedures and costs.
Every time when a new biologic agent becomes
available for prescription, we provide information of
the agent for medical staffs. Moreover, we are giving
lectures about biologics treatment for medical students
at bed-side learning programs or at systematic lecture
courses.

Research activities
As for research, we are investigating novel biologics
through analyses of immunological changes by
biologics treatments and the relationship between
biologics response and biomarkers or genetic
information.

377

References
1. Shibuya M, Fujio K, Morita K, Harada H, Kanda
H, Yamamoto K.: Successful treatment withtocilizumab in a case of Cogan's syndrome
complicated with aortitis. Mod Rheumatol. 23(3):577-81. 2013
2. Kanzaki T, Kawahata K, Kanda H, Fujio K, Kubo
K, Akahira L, Michishita K, Eri T, Yamamoto K.:
Long-term therapeutic effects and safety oftacrolimus added to methotrexate in patients withrheumatoid arthritis. Rheumatol Int. 33(4): 871-7,
2013
3. Ohshima M, Kanda H, Kubo K, YonezumiHayashi A, Tateishi S, Yamamoto K.: Characterization of 5C11-positive activated interferonproducing cells in patients with systemic lupus
erythematosus. Lupus. 22:44-51. 2013
4. Kanda H, Koya A, Uozaki H, Tateishi S, Sato K,
Hagino N, Sawada T, Yamamoto K.: Membranous
nephropathy with repeated flares in IgG4-relateddisease. Clin Kidney J. 6(2): 204-7, 2013

Endowed Department(22nd Century Medical and Research Center)379

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
clinical materials derived from patients withagreement and approval of both the patients and theethics committee of the University Hospital. Also, in
cooperation with outpatient clinics and hospitals
outside, we are collecting and analyzing the clinicaldata on metabolic syndrome from an epidemiologicalstandpoint with the aim of returning the fruitful resultsof the translational research to the clinical practicedepartments.

380

Teaching activities
Our department belongs to the Graduate School of
Medicine and Faculty of Medicine, the University ofTokyo. We are constantly instructing several
postgraduate students and supervising them in order tosucceed in obtaining the medical doctor degrees of the
University of Tokyo. We also contribute to
examination of the applicants for the doctor degrees,and make several lectures for the students in the
Faculty of Medicine at the University of Tokyo as
well.

Research activities
Our research field of interest covers the followings.
 Identification and isolation of novel susceptible
genes and related factors to metabolic syndrome
through systemic molecular and biologicalanalysis on human and rodent animal models of
metabolic syndrome.
 Performance of clinical and epidemiologicalanalysis with regard to metabolic syndrome.
 Development of novel diagnostic method for risk
factors of cardiovascular diseases.
 Contribution to the development of preventive
and therapeutic novel agents to treat patients withmetabolic syndrome.
 Exploration of novel mechanisms of action ofavailable pharmaceutical agents to treat patientswith cardiovascular diseases.
First of all, with regard to analysis on metabolic
syndrome, we analyzed clinical and epidemiological
data in the Japanese population by means of factor
analysis focusing on metabolic syndrome. The results
indicated that, even in the Japanese population where
severe insulin resistance can hardly be seen andcommon, the presence of insulin resistance is a crucial
factor underlying the clustering of risk factors related
to metabolic syndrome.
Recently, through the genetic analysis of animalmodel of metabolic syndrome, we have successfully
isolated and identified a novel gene underlying
visceral fat accumulation, a hallmark of metabolic
syndrome. Its characterization is described below indetail.
The spontaneously hypertensive rat (SHR) is an

important genetic animal model of hypertension,
dyslipidemia, and insulin resistance closely related tometabolic syndrome. We previously reported thegenetic heterogeneity among SHR strains, mostimportantly, the fact that SHR strains could be divided
into two separate groups according to the presence orabsence of genetic null mutation at the CD36 gene.
Representatively, the SHR/NCrj strain lacks CD36
due to the mutation while the SHR/Izm strain has
normal CD36. Although these two strains are quite
different in terms of visceral fat accumulation, insulin
secretion capacity, kidney weight and proteinuria,
very interestingly, these differences could not beascribed to the CD36 gene mutation, indicating thepresence of another important genetic abnormality. By
performing the so-called QTL (quantitative trait
locus ) analysis on the F2 cross population between
the two SHR strains, we have identified a QTL linked
significantly to epididymal fat weights and bloodpressure located near D1Wox28 on rat chromosome 1.
Next, as the result of a systematic screening of genes
located within the candidate QTL region by means ofgene expression analysis with a Gene-chip microarray,
we have identified the SLC22A18 gene located at thepeak of the QTL region. Interestingly, SHR/NCrj has apoint mutation at the donor splice site of an intron of
the SLC22A18 gene, while SHR/Izm lacking themutation found in SHR/Izm has wild-type SLC22A18,
The SLC22A18 gene is most abundantly expressed inliver and kidney, and it is also expressed ubiquitously,
for example, in the adipose tissue and pancreatic islet
cells. While the physiological function of SLC22A18
remains largely unknown, it is postulated as amembranous protein that would be possibly involvedin the membranous transport. It is also predicted thatthe donor splice site mutation found in SHR/NCrj
should cause the skipping of a single exon encoding
34 amino acids that would be crucial for normal
function of SLC22A18. In fact, the kinetic analysis
using a radio-labeled chemical agent that is postulated
to be an exogenous substrate for SLC22A18 on
isolated adipocytes clearly demonstrated that the
adipocytes derived from SHR/NCrj with the
SLC22A18 defect have significantly altered functionin terms of uptake of the substrate into adipocytes ascompared with those from SHR/Izm, establishing thefunctional significance of the mutation.

381

Based upon these observations, we hypothesized thatthe genetic and functional abnormality of SLC22A18
could cause visceral fat accumulation, kidney
impairment, hypertension and impaired insulin
secretion. To test this hypothesis, we have establishedcell lines that either overexpress or underexpress
SLC22A18, and also overexpressed in vivo with useof adenovirus vectors. We are also trying to establish
genetically-engineered mice such as transgenic miceoverexpressing rat SLC22A18 and knockout mice
deficient in the SLC22A18 gene. By analyzing thephenotypes of those genetically-engineered mice, weplan to explore the clue to the etiological mechanismof visceral fat accumulation. Interestingly, since thefunction of SLC22A18 can possibly be regulated bysome synthetic exogenous substrate, verification of
the above hypothesis may open a new way to develop
a novel pharmaceutical agent to treat metabolic
syndrome focusing on SLC22A18 as a new target.
As another important approach to metabolic syndrome,
we have also generated knockout mice deficient in thegene for KAT-1 (kynurenine aminotransferase-1),
which we previously identified a promising candidate
gene of hypertension in SHR. Interestingly, thosehomozygous knockout mice developed hypertension
and manifested insulin resistance, sympathetic
hyperactivity, resistance to diet-induced obesity, anddiabetic insipidus. These observations may serve todevelop a novel pharmaceutical agent to treat
metabolic syndrome focusing on KAT-1 as a newtarget as well.
Finally, we also carry out a series of researchexperiments aiming at exploration of novel
mechanisms of action of available pharmaceuticalagents to treat patients with cardiovascular diseases.

Reference
1. 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
HDL-cholesterol in Japan. J Atheroscler Thromb.
2012;19:207-1

382

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:

383

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

Dendritic cell therapy
2. 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
3. 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
4. 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
5. 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
6. 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.
7. UMIN registration number ： UMIN000001419
active, not recruiting
IRB number：2120-(1)The efficacy and safety of autologous γδ T celltransfer therapy for esophageal cancer
8. UMIN registration number ： UMIN000004130
active, not recruiting
IRB number：P201019-11Z
Intraperitoneal autologous γδ T cell therapy forrefractory gastric cancer with ascites

9. 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
10. 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

Teaching activities
Research guidance in molecular immunology isprovided to postgraduate students. Because knowledge
and techniques for evaluation of immune response areimportant for clinicians and medical researchers, we
also provide many opportunities to postgraduate
students to learn how to analyze in vivo immune
responses by means of experiments using animalmodels and by the immunological monitoring of thepatients themselves in clinical research.

Research activities
All of our research activities are directed 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384

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. Kawai T, Enomoto Y, Morikawa T, Matsushita H,
Kume H, Fukayama M, Yamaguchi H, Kakimi K,
Homma Y. High expression of heat shock protein
105 predicts a favorable prognosis for patientswith urinary bladder cancer treated with radical
cystectomy. Mol Clin Oncol. 2014 Jan;2(1):38-42.
2. Isogawa M, Chung J, Murata Y, Kakimi K, Chisari
FV. CD40 activation rescues antiviral CD8⁺ T
cells from PD-1-mediated exhaustion. PLoS
Pathog. 2013;9(7):e1003490.
3. Konoeda C, Koinuma D, Morishita Y, Sano A,
Nagayama K, Motomura N, Kakimi K, Miyazono
K, Nakajima J, Nicolls MR, Murakawa T.
Epithelial to mesenchymal transition in murine
tracheal allotransplantation: an immunohistochemical observation. Transplant Proc. 2013 Jun;45(5):1797-801.
4. 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. 2013 Jul;67(6):451-7.
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.

385

Division of Total Renal Care
Medicine
Project Associate Professor
Norio Hanafusa, 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 310 thousands of patients receive dialysis
treatment due to end-stage renal disease in Japan.
These dialysis therapies comprise hemodialysis andperitoneal dialysis. However, the majority ofend-stage renal disease (ESRD) population receives
hemodialysis as their renal replacement therapies,
while only limited population receives peritoneal
dialysis currently.
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.

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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, Maeda-Mamiya R,
Ogasawara E, Katagiri D, Tanaka T, Yamamoto T,
Sugaya T, Nangaku M, Noiri E. A
5-hydroxytryptamine
receptor
antagonist,
sarpogrelate, reduces renal tubulointerstitial
fibrosis by suppressing PAI-1. Am J Physiol Renal
Physiol. 2013 Dec 15;305(12):F1796-803.
2. Doi K, Ishizu T, Tsukamoto-Sumida M, Hiruma T,
Yamashita T, Ogasawara E, Hamasaki Y, Yahagi N,
Nangaku M, Noiri E. The high-mobility groupprotein B1-Toll-like receptor 4 pathway
contributes to the acute lung injury induced bybilateral nephrectomy. Kidney Int. 2014 Mar 19.
doi: 10.1038/ki.2014.62.
3. Katagiri D, Hamasaki Y, Doi K, Okamoto K,
Negishi K, Nangaku M, Noiri E. Protection of
glucagon-like peptide-1 in cisplatin-induced renal
injury elucidates gut-kidney connection. J Am Soc
Nephrol. 2013 Dec;24(12):2034-43.
4. 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 Oct;49(2):254-8.
5. Torato T, Doi K, Negishi K, Hamasaki Y,
Satonaka H, Hanafusa N, Noiri E. Efficacy ofvitamin E-bonded polysulfone dialyzer andpolysulfone dialyzer on a series of nonanticoagulant hemodialysis. ASAIO J. 2013 MayJun;59(3):284-5.
6. 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 Oct;28(5):564-70.

7. Ito T, Hanafusa N, Fukui M, Yamamoto H,
Watanabe Y, Noiri E, Iwase S, Miyagawa K,
Fujita T, Nangaku M. Single center experience ofcell-free and concentrated ascites reinfusion
therapy in malignancy related ascites. Ther Apher
Dial. 2014 Feb;18(1):87-92.
8. Nakai S, Watanabe Y, Masakane I, Wada A, Shoji
T, Hasegawa T, Nakamoto H, Yamagata K,
Kazama JJ, Fujii N, Itami N, Shinoda T,
Shigematsu T, Marubayashi S, Morita O,
Hashimoto S, Suzuki K, Kimata N, Hanafusa N,
Wakai K, Hamano T, Ogata S, Tsuchida K,
Taniguchi M, Nishi H, Iseki K, Tsubakihara Y.
Overview of regular dialysis treatment in Japan(as of 31 December 2011). Ther Apher Dial. 2013
Dec;17(6):567-611.
9. Hanafusa N, Noiri E, Nangaku M. Differences in
reduction of coagulation factor XIII (F13)
between immunoadsorption plasmapheresis anddouble filtration plasmapheresis. Ther Apher Dial.
2013 Apr;17(2):241-2.

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Department of Integrated
Molecular Science on Metabolic
Diseases
Project Associate Professor
Kazuo Hara, M.D., Ph.D.

( ~ August 2013)

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.

388

Research activities
The DIMSMD Research Laboratory aims to elucidate
the molecular mechanisms of lifestyle-related diseases
such as the metabolic syndrome, diabetes andcardiovascular disease associated with obesity and to
put relevant molecular targets identified in the process
to effective use in the treatment of these diseases. Of
note, the DIMSMD Research Laboratory has animpressive track record in research in this area,
including identification of multiple “key molecules”
implicated in lifestyle-related diseases, such as
adiponectin receptors, which led to an elucidation ofsome of the processes through which lifestyle-relateddiseases develop and progress, based on functional
analyses that tap into developmental engineering and
RNA engineering. The DIMSMD ResearchLaboratory has also been credited with discoveringthat adiponectin is highly active in its high molecularweight form as a ligand to the adiponectin receptors
and that its quantitative measurement is useful in the
diagnosis of insulin resistance and the metabolic
syndrome. Not only that, the DIMSMD ResearchLaboratory has found that, via the adiponectin
receptors, the plant-derived peptide osmotin activates
the AMPK pathway which has a critical role inprotecting against lifestyle-related diseases. Currently,
the DIMSMD Research Laboratory is proactively
engaged in the development of definitive treatments
for lifestyle-related diseases that draw on ligands
specific for the adiponectin receptors.

References(1) Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T,
Hamagami K, Matsuda K, Yamaguchi M, Tanabe
H, Kimura-Someya T, Shirouzu M, Ogata H,
Tokuyama K, Ueki K, Nagano T, Tanaka A,
Yokoyama S, Kadowaki T.: A small-molecule
AdipoR agonist for type 2 diabetes and short lifein obesity. Nature 503, 493-499 (2013)(2) Yamada T, Hara K, Umematsu H, Kadowaki T.:
Male pattern baldness and its association withcoronary heart disease: a meta-analysis. BMJ
Open 3, e002537 (2013)(3) Yamada T, Hara K, Kadowaki T.: Chewing betel
quid and the risk of metabolic disease,cardiovascular disease, and all-cause mortality: ameta-analysis. PLoS One 8, e70679 (2013)(4) Hara K, Fujita H, Johnson TA, Yamauchi T,
Yasuda K, Horikoshi M, Peng C, Hu C, Ma RC,
Imamura M, Iwata M, Tsunoda T, Morizono T,
Shojima N, So WY, Leung TF, Kwan P, Zhang R,
Wang J, Yu W, Maegawa H, Hirose H; DIAGRAM
consortium, Kaku K, Ito C, Watada H, Tanaka Y,
Tobe K, Kashiwagi A, Kawamori R, Jia W, Chan
JC, Teo YY, Shyong TE, Kamatani N, Kubo M,
Maeda S, Kadowaki T.: Genome-wide association
study identifies three novel loci for type 2 diabetes.
Hum. Mol. Genet. 23, 239-246 (2014)(5) Yamada T, Hara K, Kadowaki T.: Comment on:
Lin et al. Long-term changes in adiposity andglycemic control are associated with pastadenovirus infection. Diabetes Care 36, 701-707(2013)(6) Yamauchi T, Iwabu M, Okada-Iwabu M,
Kadowaki T.: Adiponectin receptors: A review of
their structure, function and how they work. Best
Pract. Res. Clin. Endocrinol. Metab. 1, 15-23(2014)(7) Kadowaki T, Yamauchi T, Okada-Iwabu M, Iwabu
M.: Adiponectin and its receptors: Implications for
reduction of obesity-associated diseases andprolongation of longevity. The Lancet Diabetes
and Endocrinology 2, 8-9 (2014)

389

Department of Advanced Clinical
Science and Therapeutics
Project Associate Professor
Hiroshi Akazawa, 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.

390

References
1. Ozasa Y, Akazawa H, Qin Y, Tateno K, Ito K,
Kudo-Sakamoto Y, Yano M, Yabumoto C, Naito
AT, Oka T, Lee JK, Minamino T, Nagai T,
Kobayashi Y, Komuro I. Notch activation
mediatesangiotensin
II-induced
vascularremodeling by promoting the proliferation andmigration of vascular smooth muscle cells.
Hypertens Res. 36: 859-65, 2013.
2. Yoshizawa T, Sakurai T, Kamiyoshi A,
Ichikawa-Shindo Y, Kawate H, Iesato Y, Koyama
T, Uetake R, Yang,L, Yamauchi A, Tanaka M,
Toriyama Y, Igarashi K, Nakada T, Kashihara T,
Yamada M, Kawakami H, Nakanishi H, Taguchi
R, Nakanishi T, Akazawa H, Shindo T. Novel
regulation of cardiac metabolism and homeostasis
bytheadrenomedullin-receptor
activitymodifying protein 2 system. Hypertension. 61:
341-351, 2013.
3. 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 of neutrophil migration and activation.
Arthritis Rheum 65: 503-12, 2013.
4. Ashigaki N, Suzuki J, 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 304: H740-8, 2013.
5. Aoyama N, Suzuki J, Ogawa M, Watanabe R,
Kobayashi N, Hanatani T, Ashigaki N, Sekinishi
A, Izumi Y, Isobe M. Toll-like receptor-2 plays afundamental role in the periodontal bacteriaaccelerated abdominal aortic aneurysms. Circ J
77: 1565–73, 2013.
6. Kanno Y, Watanabe R, Zempo H, Ogawa M,
Suzuki J, Isobe M. Chlorogenic acid attenuates
ventricular remodeling after myocardial infarction
in mice. Int Heart J 54: 176-80, 2013.
7. Tada Y, Uto K, Wada H, Sakakura K, Suzuki J,
Nishikawa T, Ako J, Momomura S. A case offulminant myocarditis with preceding repeatedepisodes of congestive heart failure. Cardiol Res.
4: 78-81, 2013.
8. Masumura M, Watanabe R, Nagashima A, Ogawa
M, Suzuki J, Shichiri M, Komuro I, Isobe M.
Anti-salusin-β antibody enhances angiogenesis
after myocardial ischemia reperfusion injury.
Expert Opin Ther Targets. 17: 1003-9, 2013.
9. Hamaya R, Ogawa M, Suzuki J, Kobayashi N,
Hirata Y, Nagai R, Komuro I, Isobe M. A selective
peroxisome proliferator activated receptor-β/δ
agonist attenuates neointimal hyperplasia afterwire-mediated arterial injury. Expert Opin
Investig Drugs. 22: 1095-106, 2013.
10. Ashigaki N, Suzuki J, Ogawa M, Watanabe R,
Aoyama N, Kobayashi N, Hirata Y, Komuro I,
Izumi Y, Isobe M. Periodontal bacteria aggravatechronic renal failure induced by subtotal
nephrectomy in mice. Immun Endoc Metab
Agents in Med Chem 13: 206-213: 2013.
11. Ashigaki N, Suzuki J, Aoyama N, Ogawa M,
Watanabe R, Kobayashi N, Komuro I, Izumi Y,
Isobe M. A periodontal pathogen, Aggregatibacter
actinomycetemcomitans, affects experimental
autoimmune myocarditis in mice. Int Heart J
54:412-6, 2013.
12. Zempo H, Suzuki J, Ogawa M, Watanabe R, Tada
Y, Takamura C, Isobe M. Chlorogenic acidsuppresses a cell adhesion molecule inexperimental autoimmune myocarditis in mice.
Immun Endoc Metab Agents in Med Chem 13:
232-236, 2013.
13. Watanabe R, Wakizono Azuma R, Suzuki J,
Ogawa M, Itai A, Hirata Y, Komuro I, Isobe M.
Inhibition of NF-kappaB activation by a novel
IKK inhibitor reduces the severity of experimental
autoimmune myocarditis via suppression of T-cell
activation. Am J Physiol Heart Circ Physiol. 305:
H1761-71, 2013.
14. Ogawa M, Suzuki J, Isobe M. An angiotensin
converting enzyme inhibitor suppresses contrast
media induced renal dysfunction via bradykinin
pathway in a murine model of subtotal
nephrectomy. Immun Endoc Metab Agents in
Med Chem 13: 176-184, 2013.
15. Murakami M, Suzuki J, Yamazaki S, Ikezoe M,
Matsushima R, Ashigaki N, Aoyama N, Kobayashi

391

N, Wakayama K, Akazawa H, Komuro I, Izumi Y,
Isobe M. High incidence of Aggregatibacter
actinomycetemcomitans infection in patients withcerebral infarction and diabetic renal failure: A
cross-sectional study. BMC Infect Dis. 13: 557,
2013.
16. Shimamura M, Nakagami H, Sata M, Takaoka M,
Azuma J, Kiomy Osako M, Koriyama H,
Kurinami H, Wakayama K, Miyake T, Morishita
R. Unique remodeling processes after vascular
injury in intracranial arteries: analysis using anovel mouse model. J Cereb Blood Flow Metab.
33: 1153-9, 2013.
17. Higashikuni Y, Tanaka K, Kato M, Nureki O,
Hirata Y, Nagai R, Komuro I, Sata M. Toll-likereceptor-2 mediates adaptive cardiac hypertrophy
in response to pressure overload throughinterleukin-1β upregulation via nuclear factor κB
activation. J Am Heart Assoc. 2: e000267, 2013.
18. Rakugi H, Ogihara T, Umemoto S, Matsuzaki M,
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 patients with CKD: asubanalysis of the Combination Therapy ofHypertension to Prevent Cardiovascular Events
trial. Hypertens Res. 36: 947-58, 2013.
19. Nakayama A, Takahashi M, Hina K, Fujiu K,
Sugiyama H, Kojima T, Ando J, Imai Y, Hirata Y,
Nagai R. Radiofrequency catheter ablation of theaccessory pathway adversely affected the left
ventricular outflow tract pressure gradient in apatient with hypertrophic obstructive cardiomyopathy. Int Heart J. 54:111-4, 2013.
20. Amiya E, Watanabe M, Takata M, Watanabe S,
Ozeki A, Watanabe A, Kawarasaki S, Nakao T,
Hosoya Y, Omori K, Maemura K, Hirata Y, Nagai
R, Komuro I. Differences in body temperature
variability between subjects with and without
diabetes and predictive value for cardiovascular
events. Circ J. 77: 1844-53, 2013.
21. Ogawa N, Imai Y, Nishimura H, Kato M, Takeda
N, Nawata K, Taketani T, Morota T, Takamoto S,
Nagai R, Hirata Y. Circulating transforming
growth factor β-1 level in Japanese patients with
Marfan syndrome. Int Heart J. 54: 23-6, 2013.

22. 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. 168: 1429-34, 2013.
23. 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
assessmentofventricles
inpulmonary
hypertension on 3-dimensional echocardiography.
Circ J. 77: 198-206, 2013.
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.
Preoperative levels of bilirubin or creatinine
adjusted by age can predict their reversibility after
implantation of left ventricular assist device. Circ
J. 77:96-104, 2013.
25. Miyairi T, Miyata H, Taketani T, Sawaki D,
Suzuki T, Hirata Y, Shimizu H, Motomura N,
Takamoto S; Japan Adult Cardiovascular
Database Organization. Risk model of cardiovascular surgery in 845 marfan patients using theJapan adult cardiovascular surgery database. Int
Heart J. 54: 401-4, 2013.
26. Takahashi M, Suzuki E, Kumano S, Oba S, Sato T,
Nishimatsu H, Kimura K, Nagano T, Hirata Y.
Angiopoietin-1 mediates adipose tissue-derived
stem cell-induced inhibition of neointimal
formation in rat femoral artery. Circ J. 77: 157484, 2013.
27. Oba S, Mizutani T, Suzuki E, Nishimatsu H,
Takahashi M, Ogawa Y, Kimura K, Hirata Y,
Fujita T. A useful method of identifying of
miRNAs which can down-regulate Zeb-2. BMC
Res Notes. 18: 470, 2013.
28. Hara H, Yamashita H, Nakayama A, Hosoya Y,
Ando J, Iijima K, Hirata Y, Komuro I. A rare caseof anomalous origin of the left anterior
descending artery from the pulmonary artery. Int J
Cardiol. 2013 Dec 27. [Epub ahead of print]
29. Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Takata M, Ozeki A, Watanabe A,

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Kawarasaki S, Taniguchi T, Ichimura Y, Toyama
T, Watanabe M, Hirata Y, Nagai R, Komuro I,
Sato S. Clinical correlation of brachial arteryflow-mediated dilation in patients with systemicsclerosis. Mod Rheumatol. 2013 Mar 30. [Epubahead of print]
30. Takata M, Amiya E, Watanabe M, Omori K, ImaiY, Fujita D, Nishimura H, Kato M, Morota T,
Nawata K, Ozeki A, Watanabe A, Kawarasaki S,
Hosoya Y, Nakao T, Maemura K, Nagai R, Hirata
Y, Komuro I. Impairment of flow-mediateddilation correlates with aortic dilation in patientswith Marfan syndrome. Heart Vessels. 2013 Jul
14. [Epub ahead of print]
31. Sahara M, Ikutomi M, Morita T, Minami Y,
Nakajima T, Hirata Y, Nagai R, Sata M. Deletionof angiotensin-converting enzyme 2 promotes thedevelopment of atherosclerosis and arterial
neointima formation. Cardiovasc Res. 2013 Nov 4.
[Epub ahead of print]
32. Tajima M, Hiroi Y, Takazawa Y, Muraoka H,
Iwata H, Yamashita H, Hirata Y, Nagai R.
Immunoglobulin G4-related multiple systemic
aneurysms and splenic aneurysm rupture during
steroid therapy. Hum Pathol. 2013 Oct 15. [Epubahead of print]
33. Kojima T, Imai Y, Tsushima K, Uno K, Fujiu K,
Iiri T, Nishimatsu H, Suzuki T, Sugiyama H,
Asada K, Nakao T, Yamashita H, Hirata Y, Nagai
R. Temporary dual-chamber pacing can stabilize
hemodynamics during noncardiac surgery in apatient with left ventricular hypertrophy andoutflow obstruction. J Cardiothorac Vasc Anesth.
2013 Aug 26. [Epub ahead of print]
34. Tada Y, Ogawa M, Watanabe R, Zempo H,
Takamura C, Suzuki J, Dan T, Miyata T, Isobe M,
Komuro I. Neovascularization induced by hypoxia
inducible transcription factor is associated with
the improvement of cardiac dysfunction inexperimental autoimmune myocarditis. Expert
Opin Investig Drugs. 2013 Nov 11. [Epub aheadof print]
35. Kobayashi N, Suzuki J, Ogawa M, Aoyama N,
Komuro I, Izumi Y, Isobe M. Porphyromonas
gingivalis promotes neointimal formation afterarterial injury through toll-like receptor 2

signaling. Heart Vessels. 2013 Sep 4. [Epub aheadof print]
36. Suzuki J, Imai Y, Aoki M, Fujita D, Aoyama N,
Tada Y, Akazawa H, Izumi Y, Isobe M, Komuro I,
Nagai R, Hirata Y. High incidence and severity of
periodontitis in Marfan syndrome patients inJapan. Heart Vessels 2013 Nov 8. [Epub ahead ofprint]English Review
1. Akazawa H, Yano M, Yabumoto C,
Kudo-Sakamoto Y, Komuro I. Angiotensin II type
1 and type 2 receptor-induced cell signaling. Curr
Pharm Des. 19: 2988-95, 2013.
2. Akazawa H, Yabumoto C, Yano M, KudoSakamoto Y, Komuro I. ARB and cardioprotection. Cardiovasc Drugs Ther. 227:155-60,
2013.

393

Department of Ischemic
Circulatory Physiology,
KAATSU training
Associate Professor
Toshiaki Nakajima, M.D., Ph.D.

Assistant Professor
Tomohiro Yasuda, Ph.D.

Research Associate
Taira Fukuda, M.D., Ph.D.

Fellow Researcher
Toshihiro Morita, M.D., Ph.D.

Home page

http://kaatsu.umin.jp/

Introduction of this chair
We investigate the clinical usefulness and basic
mechanisms of KAATSU training for rehabilitation inpatients with various diseases. Especially, the
KAATSU training is applied for muscle training inpatients with cardiovascular, orthostatic dysregulation(OD) and respiratory (COPD) diseases. In addition,
we have examined the clinical benefits of KAATSU
training on cardiac rehabilitation. The KAATSU
training also may be able to be applied to various
kinds of fields such as the muscle training for
astronauts, and severe patients with marked muscle
atrophy in long-term bed rest.

Contents of our study
The KAATSU training is a unique technique of
performing low-load exercises such as resistance
exercises and treadmill with restricted muscle bloodflow that results in an increase of muscle mass andmuscular strength comparable to high-intensity
training. Additionally, the KAATSU trainings canpromote endocrine activities such as growth hormone(GH) secretion. Therefore, KAATSU training may be
an epoch-making rehabilitation training for patientswith various kinds of diseases and old-aged patients.
Also, since KAATSU femoral blood flow restriction
induces the retention of blood flow in lower
extremities, it reduces venous return, and induces
subsequent hemodynamic changes like lower body
negative pressure (LBNP). Thus, KAATSU may partly
provide an orthostatic stimulus, and an effective
countermeasure for cardiovascular deconditioning inweightlessness like LBNP. In our laboratory, we havebeen studying the clinical usefulness of the KAATSU
training and comparing it with the ordinary
rehabilitation. The main targets of our study are as
follows: (1) Clinical usefulness of the KAATSU
training in cardiac rehabilitation. There are many
severe patients with muscle atrophy, especially inintensive care units (ICU) and high-intensive care unit
(HCU), and in our cardiovascular ward. We haveexamined the possibility of KAATSU training formuscle training and early ambulation of these patients.
(2) Clinical usefulness of this training in patients with394

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) 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.
2) Yasuda T, Fukumura K, Fukuda T, Iida H, Imuta
H, Sato Y, Yamasoba T, Nakajima T. Effects of
low-intensity, elastic band resistance exercise
combined with blood flow restriction on muscle
activation. Scandinavian Journal of Medicine andScience in Sports 2014, 24(1); 55-61.
3) Madarame H, Kurano M, Fukumura K, Fukuda T,
Nakajima T. Hemostatic and inflammatory
responses to blood flow-restricted exercise inpatients with ischemic heart diseases: a pilot study.
Clin Physiol Funct Imaging. 2013; 33: 11-7.
4) 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):14-19.
5) 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)
6) 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
2013 Sep;54(3):213-225.
7) 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. 2013 Jul;43(7):481-487.
8) Eshima H, Tanaka Y, Sonobe T, Inagaki T,
Nakajima T, Poole DC, Kano Y. In vivo imaging
of intracellular Ca2+ after muscle contractions
and direct Ca2+ injection in rat skeletal muscle indiabetes. American Journal of Physiology Regulatory,Integrative
andComparative
Physiology 2013 Sep 15;305(6):R610-618.
9) Sahara M, Ikutomi M, Morita T, Minami Y,
Nakajima T, Hirata Y, Nagai R, Sata M. Deletionof Angiotensin-converting Enzyme 2 Promotes
the Development of Atherosclerosis and Arterial
Neointima Formation. Cardiovasc Res. 2013 Nov
4. [Epub ahead of print]
10) Fukuda T, Yasuda T, Fukumura K, Iida H, Morita
T, Sato Y, Nakajima T. Low-intensity kaatsu
resistance exercise using an lelastic band
enhances muscle activation in patients withcardiovascular diseases. Int J KAATSU Training
Res 2013; 9: 1-5.
11) Inoue A, Iwasaki S, Fujimori C, Nakajima T,
Yamasoba T. Developmental changes in theprotective effect of exogenous brain-derived

395

neurotrophic factor and neurotrophin-3 against
ototoxic drugs in cultured rat vestibular ganglion
neurons. Cell and Tissue Res (in press)
12) Yasuda T, Fukumura K, Sato Y, Yamasoba T,
Nakajima T. Effects of detraining after blood flow
restricted low-intensity training on muscle sizeand strength in older adults. Aging Clinical andExperimental Research (in press)
13) Tsutsumi T, Okamoto Y, Takano NK, Wakatsuki D,
Suzuki H, Sezaki T, Iwasawa K, Nakajima T.
Time-frequency analysis of the QRS complex inpatients with ischemic cardiomyopathy andmyocardial infarction. International Jouranal of
Cardiology (in press)
14) Yasuda T, Fykumura K, Uchida Y, Koshi H, Iida
H, Masamune K, Yamasoba T, Sato Y, Nakajima T.
Effects of low-load, elastic band resistancetraining combined with blood flow restriction on
muscle size and arterial stiffness in older adults.
Journal of Gerontology: Biological Sciences (inpress)

396

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.

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 the clinicalinformation database to the better one and put that into
practical use in developing the clinical research.
Our department belongs to the 22nd century medical
center in the University of Tokyo Hospital, which was
founded as the front line of university-industry
partnerships. As our research foothold is located in thehospital, we could keep the close connection with thebedside. Our department is thought to be suited for
obtaining the maximum output in clinical research.

Research activities
The onset and progression of the disease are thought
to be caused by the environmental and/or genetic
factors. What is the best way to identify thepathogenesis and the factors predicting the prognosis?

The answer should be the filing of the clinicalinformation.
We are constructing the effective framework to makethe relevant clinical data available for research andperforming the investigation to resolve the clinicalquestions, followed by the translation of its fruits tothe bedside.
Another mission is to confer the explicit scientificre-evaluation on the health issues (e.g. eating habits,
exercise, lifestyle) which have been believed to be
empirically effective. This mission has to be followedby the prompt publicity of the “accurate” data led byour re-evaluation.
The realization of these missions above could becompleted in a close collaboration with the academic
groups and private enterprises. In this regard, we areready to discuss and think together with anybody
anytime.
In summary, our research field covers the issues asfollows;
1. Development of information analysis system andsystematization of clinical information
2. Clinical and/or genomic research utilizing theclinical information analysis system
3. Scientific verification of eating habits, exercise
and lifestyle
4. Analysis on the current state of the medical
system
5. Spread of accurate medical information to society
utilizing the information technology

397

Research Grants
A Grant from the Ministry of Health, Labour andWelfare (2013-2017) (to Morita H)
A Grant from the Ministry of Education, Culture,
Sports, Science and Technology (2012-2016) (toMorita H)

References
1. Morita H.
Human genomics in cardiovascular medicine;
implications and perspectives.
Circ J. 77: 876-885, 2013
2. Nakayama A, Morita H, Ando J, Fujita H, Ohtsu H,
Nagai R.
Adverse cardiovascular outcomes associated withconcurrent use of clopidogrel or ticlopidine andproton-pump inhibitors in patients undergoing
percutaneous coronary intervention.
Heart Vessels. 28: 292-300, 2013
3. Nakao T, Morita H, Maemura K, Amiya E, Inajima
T, Saito Y, Watanabe M, Manabe I, Kurabayashi M,
Nagai R, Komuro I.
Melatonin ameliorates Angiotensin II-induced
vascular endothelial damage via its antioxidative
properties.
J Pineal Res. 55: 287-293, 2013
4. Kimura K, Takenaka K, Ebihara A, Uno K, Morita
H, Nakajima T, Ozawa T, Aida I, Yonemochi Y,
Higuchi S, Motoyoshi Y, Mikata T, Uchida I,
Ishihara T, Komori T, Kitao R, Nagata T, Takeda S,
Yatomi Y, Nagai R, Komuro I.
Prognostic
impactofleftventricular
noncompaction in patients with Duchenne/Becker
musculardystrophy-prospective
multicenter
cohort study-.
Int J Cardiol. 168: 1900-1904, 2013
5. Morita H, Komuro I.
A novel channelopathy in pulmonary arterial
hypertension.
New England Journal of Medicine 369: 2161-2162,
2013
6. Morita H.
Genetic variants and dilated cardiomyopathy – To
be or not to be causative: Is that the question? –Circ J. 77: 2879-2880, 2013

398

Department of Joint Disease
Research
Project Associate Professor
Noriko Yosihmura, M.D., Ph.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 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 in 2005-2007,
then 2nd and 3rd follow-ups were performed in 20082010, and 2012-13, respectively. A 4th comprehensive
clinic visit is planned from 2015.

References
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 the prevalence and incidence of OA and OP
as well as pain and disability in the Japanese
population. It is difficiult to design rational clinicaland public health approaches for the diagnosis,
evaluation, and prevention of OA and OP without such
epidemiological data.
We therefore established a large-scale nationwide
osteoarthritis/osteoporosis cohort study called ROAD

1. Nishizawa Y, Ohta H, Miura M, Inaba M,
Ichimura S, Shiraki M, Takada J, Chaki O, Hagino
H, Fujiwara S, Fukunaga M, Miki T, Yoshimura N,
for the Committee on the Guidelines for the Useof Biochemical Markers of Bone Turnover in
Osteoporosis, Japan Osteoporosis Society
Committee organization: Guidelines for the use ofbone metabolic markers in the diagnosis andtreatment of osteoporosis (2012 Edition), J Bone
Miner Metab 31: 1-15, 2013
2. Muraki S, Oka H, Akune T, Ishimoto Y, Nagata K,
Yoshida M, Tokimura F, Nakamura K, Kawaguchi
H, Yoshimura N: Physical performance, bone andjoint diseases, and incidence of falls in Japanese
men and women: A longitudinal cohort study.
Osteoporos Int 24: 459-466, 2013
3. 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 population-based cohort study of

399

4.

5.

6.

7.

8.

9.

Japanese men and women: The ROAD Study.
Bone 52: 516-523, 2013
Ishimoto Y, Yoshida M, Nagata K, Yamada H,
Hashizume H, Yoshimura N: Consuming
breakfast and exercising longer during highschool increases bone mineral density in young
Japanese men. J Bone Miner Metab 31: 329-336,
2013
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, Masood 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, Kelsall HL, Hoe VC, Urquhart DM, Derrett S,
McBride D, Herbison P, Gray A: Disablingmusculoskeletal pain in working populations: Is it
the job, the person or the culture? Pain 154:856-863, 2013 doi: 10.1016/j.pain.2013.02.008.
Mithal A, Boonen S, Bonjour J-P, Burckhardt P,
Degens H, Hajj Fuleihan G El, Josse R, Lips P,
Morales Torres J, Rizzoli R, Yoshimura N, Wahl
DA, Cooper C, Dawson-Hughes B for the IOF
CSA Nutrition Working Group: Impact ofnutrition on muscle mass, strength, andperformance in older adults. Osteoporos Int 24:
1555-1566, 2013
Tsutsui S, Yoshimura N, Watanuki A, Yamada H,
Nagata K, Ishimoto Y, Enyo Y, Yoshida M: Risk
factors and natural history of de novo
degenerative lumbar scoliosis in a communitybased cohort: The Miyama Study. Spine deformity
1: 287-292, 2013
Fujii T, Matsudaira K, Yoshimura N, Hirai M,
Tanaka S: Associations between neck andshoulder discomfort (Katakori) and job demand,
job control, and worksite support. Mod
Rheumatol 23: 1198-1204, 2013
Oka H, Akune T, Muraki S, Tanaka S, Kawaguchi
H, Nakamura K, Yoshimura N: The mid-term

efficacy of intra-articular hyaluronic acidinjections on joint structure: A nested case-control
study. Mod Rheumatol 23: 722-728, 2013
10. 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: Associations between radiographic
lumbar spinal stenosis and clinical symptoms in
the general population: The Wakayama Spine
Study. Osteoarthritis Cartilage 21: 783-788, 2013
doi: 10.1016/j.joca.2013.02.656
11. Yoshimura N, Muraki S, Oka H, Morita M,
Yamada H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T: Profiles of vitamin D insufficiency anddeficiency in Japanese men and women:
association with biological, environmental, andnutritional factors and coexisting disorders: theROAD study. Osteoporos Int 24: 2775-2787, 2013
doi: 10.1007/s00198-013-2372-z
12. Coggon D, Ntani G, Vargas-Prada S, Martinez JM,
Serra C, Benavides FG, Palmer KT and othermembers of the CUPID Collaborators (Felli VE,
Harari R, Barrero LH, Felknor SA, Gimeno D,
Cattrell A, Bonzini M, Solidaki E, Merisalu E,
Habib RR, Sadeghian F, Kadir MM,
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, Vega EJ, Harris EC,
Delclos G, 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, Kelsall HL,
Hoe VC, Urquhart DM, Derrett S, McBride D,
Herbison P, Gray A: International variation inabsence from work attributed to musculoskeletal
illness: findings from the CUPID study. Occup
Environ Med 70: 575-584, 2013
13. Coggon D, Ntani G, Palmer KT, Felli VE, Harari
R, Barrero LH, Felknor SA, Gimeno D, Cattrell A,
Vargas-Prada S, Bonzini M, Solidaki E, Merisalu
E, Habib RR, Sadeghian F, Masood 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,
Clare Harris E, Serra C, Miguel Martinez J,

400Delclos 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, Rajitha Wickremasinghe A,
Yoshimura N, Kelsall HL, Hoe VC, Urquhart DM,
Derrett S, McBride D, Herbison P, Gray A:
Patterns of multi-site pain and associations withrisk factors. Pain 154: 1769-1777, 2013
14. Kanis JA, Adachi JD, Cooper C, Clark P,
Cummings SR, Diaz-Curiel M, Harvey N,
Hiligsmann M, Papaioannou A, Pierroz DD,
Silverman SL, Szulc P; Epidemiology and Qualityof Life Working Group of IOF (Kanis JA, Cooper
C, Adachi J, Borgström F, Clark P, Cummings S,
Diaz-Perez M, Dimai HP, Hiligsmann M, Lau E,
Lips P, Lewiecki M, Lorenc R, McCloskey E,
Papioannou A, Ortolani S, Silverman S, Szulc P,
Yoshimura N, Sosa M, Harvey N): Standardising
the descriptive epidemiology of osteoporosis:
recommendations from the Epidemiology andQuality of Life Working Group of IOF.
Osteoporos Int 24: 2763-2764, 2013.
15. Inoue I, Kato J, Yoshimura N, Maeda Y, Moribata
K, Shingaki N, Deguchi H, Enomoto S, Maekita T,
Ueda K, Iguchi M, Tamai H, Fujishiro M,
Uamamichi N, Takeshita T, Ichinose M: Elevatedrisk of recurrent colorectal neoplasia with
Helicobacter pylori‑associated chronic atrophic
gastritis: A follow ‑ up study of patients withendoscopically resected colorectal neoplasia. Mol
Clin Oncol 1: 75-82, 2013
16. Teraguchi M, Yoshimura N, Hashizume H,
Muraki S, Yamada H, Minamide A, Oka H,
Ishimoto Y, Nagata K, Kagotani R, Takiguchi N,
Akune T, Kawaguchi H, Nakamura K, Yoshida M:
Prevalence and distribution of intervertebral discdegeneration over the entire spine in a
population-based cohort: the Wakayama Spine
Study. Osteoarthritis Cartilage 22: 104-110, 2014
17. Yoshida T, Kato J, Inoue I, Yoshimura N, Deguchi
H, Mukoubayashi C, Oka M, Watanabe M,
Enomoto S, Niwa T, Maekita T, Iguchi M, Tamai
H, Utsunomiya H, Yamamichi N, Fujishiro M,
Iwane M, Takeshita T, Ushijima T, Ichinose M:
Cancer development based on chronic active
gastritis and resulting gastric atrophy as assessedby serum levels of pepsinogen and Helicobacter

pylori antibody titer. Int J Cancer 134: 1445-1457,
2014
18. Johansson H, Kanis JA, Odén A, McCloskey E,
Chapurlat RD, Christiansen C, Cummings SR,
Diez-Perez A, Eisman JA, Fujiwara S, Glüer CC,
Goltzman D, Hans D, Khaw KT, Krieg MA,
Kröger H, Lacroix AZ, Lau E, Leslie WD,
Mellström D, Melton LJ 3rd, O'Neill TW, Pasco
JA, Prior JC, Reid DM, Rivadeneira F, van Staa T,
Yoshimura N, Zillikens MC: A meta-analysis of
the association of fracture risk and body massindex in women. J Bone Miner Res 29: 223-233,
2014
19. Inoue I, Kato J, Tamai H, Iguchi M, Maekita T,
Yoshimura N, Ichinose M: Helicobacter pylori-related chronic gastritis as a risk factor forcolonic neoplasms. World J Gastroenterol 20:
1485-1492, 2014
20. Kanis JA, Johansson H, Oden A, Cooper C,
McCloskey EV; Epidemiology and Quality of Life
Working Group of IOF (Kanis JA, Cooper C,
Adachi J, Borgström F, Clark P, Cummings S,
Diaz-Curiel M, Dimai HP, Harvey N, Hiligsmann
M, Lau E, Lewiecki M, Lips P, Lorenc R,
McCloskey E, Ortolani S, Papioannou A,
Silverman S, Sosa M, Szulc P, Yoshimura N).
Worldwide uptake of FRAX. Arch Osteoporos 9:166, 2014
21. Yoshimura N, Nagata K, Muraki S, Oka H,
Yoshida M, Enyo Y, Kagotani R, Hashizume H,
Yamada H, Ishimoto Y, Teraguchi M, Tanaka S,
Kawaguchi H, Toyama Y, Nakamura K, Akune T:
Prevalence and progression of the radiographic
ossification of posterior longitudinal ligament andits associated factors in the Japanese populations:
A 3-year follow-up of the ROAD study.
Osteoporos Int 25: 1089-1098, 2014
22. Muraki S, Oka H, Akune T, En-yo Y, Yoshida M,
Sasaki S, Nakamura K, Kawaguchi H, Yoshimura
N: Association of dietary intake with joint space
narrowing and osteophytosis at the knee inJapanese men and women: The ROAD Study.
Mod Rheumatol 24: 236-242, 2014
23. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Nakamura K, Yoshimura N: Exercise habitsduring middle age are associated with lower

401

prevalence of sarcopenia: the ROAD study.
Osteoporos Int 25: 1081-1088, 2014
24. Muraki S, Yoshimura N, Akune T, Takahashi I,
Fujiwara S: Prevalence, incidence, andprogression of lumbar spondylosis by gender andage strata. Mod Rheumatol 24: 657-661, 201425. Hashizume H, Yoshimura N, Nagata K, Miyazaki
N, Ishimoto Y, Nishiyama R, Yamada H, Yoshida
M: Development and evaluation of a video
exercise program for locomotive syndrome in theelderly. Mod Rheumatol 24: 250-257, 2014
26. Nagata K, Yoshida M, Ishimoto Y, Hashizume H,
Yamada H, Yoshimura N: Skipping breakfast andless exercise are risk factors for bone loss ofJapanese young adults: a 3-year follow-up for
medical students. J Bone Miner Metab 32: 420427, 2014
27. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N: Incidence of certified need of carein the long-term care insurance system and its risk
factors in the elderly of Japanese populationbased cohorts: The ROAD study. Geriatr Gerontol
Int 14: 695-701, 2014
28. Akune T, Muraki S, Oka H, Tanaka S, Kawaguchi
H, Tokimura F, Yoshida H, Suzuki T, Nakamura K,
Yoshimura N: Association of physical activities ofdaily living with the incidence of certified need ofcare in the long-term care insurance system ofJapan: the ROAD study. J Orthop Sci 19: 489-496,
2014
29. Yoshimura N, Akune T, Fujiwara S, Nishiwaki Y,
Shimizu Y, Yoshida H, Sudo A, Omori G, Yoshida
M, Shimokata H, Suzuki T, Muraki S, Oka H,
Nakamura K: Prevalence of knee pain, lumbar
pain and its co-existence in Japanese men andwomen: The Longitudinal Cohorts of Motor
System Organ (LOCOMO) study. J Bone Miner
Meta, in press
30. Tanaka S, Kuroda T, Yamazaki Y, Shiraki Y,
YoshimuraN,
ShirakiM:Serum
25-hydroxyvitamin D below 25 ng/mL is a risk
factor for long bone fracture comparable to bonemineral density in Japanese postmenopausal
women. J Bone Miner Metab, in press
31. Muraki S, Akune T, Nagata K, Ishimoto Y,
Yoshida M, Tokimura F, Tanaka S, Oka H,

Kawaguchi H, Nakamura K, Yoshimura N:
Association of knee osteoarthritis with onset andresolution of pain and physical functional
disability: The ROAD Study. Mod Rheumatol, inpress
32. Yoshimura N, Akune T, Fujiwara S, Shimizu Y,
Yoshida H, Nishiwaki Y, Sudo A, Omori G,
Yoshida M, Shimokata H, Suzuki T, Muraki S,
Oka H, Nakamura K: Incidence of disability andits associated factors in Japanese men and women:
The Longitudinal Cohorts of Motor System Organ(LOCOMO) study. J Bone Miner Metab, in press
33. Kagotani R, Yoshida M, Muraki S, Oka H,
Hashizume H, Yamada H, Enyo Y, Nagata K,
Ishimoto Y, Teraguchi M, Tanaka S, Nakamura K,
Kawaguchi H, Akune T, Yoshimura N: Prevalenceof diffuse idiopathic skeletal hyperostosis (DISH)
of whole spine and its association with lumbar
spondylosis and knee osteoarthritis: The ROAD
Study. J Bone Miner Metab, in press
34. Nagata K, Yoshimura N, Hashizume H, Muraki S,
Ishimoto Y, Yamada H, Takiguchi N, Nakagawa Y,
Minamide A, Oka H, Kawaguchi H, Nakamura K,
Akune T, Yoshida M: The prevalence of cervicalmyelopathy among subjects with narrow cervicalspinal canal in a population-based magnetic
resonance imaging study: the Wakayama Spine
Study. Spine J, in press
35. Muraki S, Akune T, Ishimoto Y, Nagata K,
Yoshida M, Tokimura F, Tanaka S, Oka H,
Kawaguchi H, Nakamura K, Yoshimura N: Does
osteophytosis at the knee predict health-related
quality of life decline? A 3-year follow-up of the
ROAD study. Clin Rheumatol, in press
36. Yoshimura N, Muraki S, Oka H, Nakamura K,
Kawaguchi H, Tanaka S, Akune T: Serum levelsof 25-hydroxyvitamin D and occurrence ofmusculoskeletal diseases, such as osteoporosis,
knee osteoarthritis and lumbar spondylosis: A
three-year follow-up of the ROAD study.
Osteoporos Int, in press

402

Department of Health Management
and Policy
Project Professor
Soichi Koike, M.D., Ph.D., M.P.H., M.B.A.

Project Associate Professor
Ryuichi Yamamoto, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/hmp/

Introduction and Organization

Research activities

The Department of Health Management and Policy
is an endowed department affiliated with the “22ndCentury Medical and Research Center,” which is a
center of industry-academia collaboration establishedby the University of Tokyo Hospital. Since its
establishment in 2005, the department has established
a complex research infrastructure of clinicalepidemiology and clinical economics, medical policy
studies,
andmedicalmanagement
studies;academically utilized medical information network
covering multicenter; and provided interdisciplinary
researches and policy recommendations to achieve
improvement of the quality and efficiency of healthcare in higher dimension.
With donations from Nissay Information
Technology Co., Ltd., the Department launched its
first courses on April 1, 2005. As of March of 2014,
donations have been made to the Department from thefollowing six companies: Nissay Information
Technology Co., Ltd., Chugai Pharmaceutical Co.,
Ltd., Shionogi & Co., Ltd., Asahi Kasei Pharma
Corporation, CRECON Research & Consulting Inc.,and Otsuka Pharmaceutical Co., Ltd. The cooperative
departments are the Department of Medical
Informatics and Economics, Division of Social
Medicine, Graduate School of Medicine, theDepartment of Clinical Epidemiology and Health
Economics, School of Public Health, and theDepartment of Biostatistics, School of Public Health.

We are working on the following activities, widely
contributing to the health of the people by utilizing
medical care information.
1) Health policy researches utilizing official statistics
data.
Since health policy researches utilizing official
statistical survey data can be performed rapidly andcost effectively as compared to conducting a new
survey, remarkable contribution can be expected to thepromotion of the evidence based health policy.
In this department, in particular, by performing ananalysis of the official statistics data of the Ministry of
Health, Labour and Welfare such as medical doctors,
dentists and pharmacists investigation, medical
facilities survey, and the patient survey, we perform
health policy researches regarding evaluation of initialclinical training system, regional and departmentspecific distribution of medical doctors, career path of
medical doctors and the medical specialist system.
2) Researches on the use of medical information andthe protection of personal information.
The progression sheet of the "new information andcommunications technology strategy" which thegovernment was determined in June 2010 mentions
the study on the development of guidelines and how toprovide not only for the provision of the receipt
information database to third parties but also third403

party provision of DPC data.
In this department, along with the research on theuse of medical information and the protection of
personal information, Dr. Yamamoto is involved
actively in the development process of the healthpolicy as the Chair of "Experts meeting for theprovision of receipt information" of the Ministry of
Health, Labour and Welfare and as a member of
personal data review meeting of the Cabinet
Secretariat.
3) We have also put the following research into
practice.
- Regional and departmental disparities in the supplyof doctors.
- Relationship between the volume and outcomes ofsurgical operations.
- Economic evaluation of healthcare services.
- Policy evaluation study of occupational health, suchas prevention of death from overwork.
- Research on systems that contribute to medical
safety.
- Research for the sustainable development ofregional healthcare systems.
- Research on nationwide public-access defibrillatorsand improvement of outcomes after out-of-hospital
cardiac arrests.

References
1. Koike S, Furui Y. Long-term care-service use andincreases in care-need level among home-based
elderly people in a Japanese urban area. Healthpolicy. 2013 Apr;110(1):94-100.
2. Yasunaga H, Horiguchi H, Kuwabara K, Matsuda
S, Fushimi K, Hashimoto H, et al. Outcomes after
laparoscopic or open distal gastrectomy forearly-stage gastric cancer: a propensity-matchedanalysis. Annals of surgery. 2013 Apr;257(4):640-6.
3. Yasunaga H, Horiguchi H, Matsuda S, Fushimi K,
Hashimoto H, Ayanian JZ. Body mass index andoutcomes following gastrointestinal cancer
surgery in Japan. The British journal of surgery.
2013 Sep;100(10):1335-43.
4. Yasunaga H, Horiguchi H, Hashimoto H, Matsuda
S, Fushimi K. Effect and cost of treatment for

acute pancreatitis with or without gabexate
mesylate: a propensity score analysis using anationwide administrative database. Pancreas.
2013 Mar;42(2):260-4.
5. Akahane M, Tanabe S, Ogawa T, Koike S,
Horiguchi H, Yasunaga H, et al. Characteristics
and outcomes of pediatric out-of-hospital cardiac
arrest by scholastic age category. Pediatric criticalcare medicine : a journal of the Society of Critical
Care Medicine and the World Federation of
Pediatric Intensive and Critical Care Societies.
2013 Feb;14(2):130-6.
6. Akiyama T, Chikuda H, Yasunaga H, Horiguchi H,
Fushimi K, Saita K. Incidence and risk factors for
mortality of vertebral osteomyelitis: a retrospective analysis using the Japanese diagnosis
procedure combination database. BMJ open.
2013;3(3).
7. Chikuda H, Yasunaga H, Horiguchi H, Takeshita
K, Sugita S, Taketomi S, et al. Impact of age andcomorbidity burden on mortality and majorcomplications in older adults undergoing orthopaedic surgery: an analysis using the Japanesediagnosis procedure combination database. BMC
musculoskeletal disorders. 2013;14(1):173.
8. Fukuda T, Yasunaga H, Horiguchi H, Ohe K,
Fushimi K, Matsubara T, et al. Health care costs
related to out-of-hospital cardiopulmonary arrestin Japan. Resuscitation. 2013 Jul;84(7):964-9.
9. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Matsuda S, et al. Rarity of severe
bleeding and perforation in endoscopic
ultrasound-guided fine needle aspiration for
submucosal tumors. Digestive diseases andsciences. 2013 Sep;58(9):2634-8.
10. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Matsuda S, et al. Continuous
regional arterial infusion for acute pancreatitis: apropensity score analysis using a nationwide
administrative database. Critical care. 2013 Oct
2;17(5):R214.
11. Hamada T, Yasunaga H, Nakai Y, Isayama H,
Horiguchi H, Fushimi K, et al. Japanese severity
score for acute pancreatitis well predicts
in-hospital mortality: a nationwide survey of
17,901 cases. Journal of gastroenterology. 2013
Dec;48(12):1384-91.

404

12. Nakamura M, Yasunaga H, Haraguchi T, Ando S,
Sugihara T, Horiguchi H, et al. Length ofmechanical restraint following haloperidol
injections versus oral atypical antipsychotics forthe initial treatment of acute schizophrenia: apropensity-matched analysis from the Japanesediagnosis procedure combination database.
Psychiatry research. 2013 Oct 30;209(3):412-6.
13. Nakamura M, Yasunaga H, Shimada T, Horiguchi
H, Matsuda S, Fushimi K. Body mass index andin-hospital mortality in anorexia nervosa: datafrom the Japanese Diagnosis Procedure
Combination database. Eating and weight
disorders: EWD. 2013 Dec;18(4):437-9.
14. Ogura K, Yasunaga H, Horiguchi H, Ohe K,
Kawano H. Incidence and risk factors for
pulmonary embolism after primary musculoskeletal tumor surgery. Clinical orthopaedics andrelated research. 2013 Oct;471(10):3310-6.
15. Ogura K, Yasunaga H, Horiguchi H, Ohe K,
Shinoda Y, Tanaka S, et al. Impact of hospital
volume on postoperative complications andin-hospital mortality after musculoskeletal tumor
surgery: analysis of a national administrative
database. The Journal of bone and joint surgery
American volume. 2013 Sep 18;95(18):1684-91.
16. Sugihara T, Yasunaga H, Horiguchi H, Nishimatsu
H, Kume H, Ohe K, et al. A nomogram predicting
severe adverse events after ureteroscopic
lithotripsy: 12 372 patients in a Japanese national
series. BJU international. 2013 Mar; 111(3):459-66.
17. Sugihara T, Yasunaga H, Horiguchi H, Fujimura T,
Nishimatsu H, Kume H, et al. Is mechanicalbowel preparation in laparoscopic radical prostatectomy beneficial? An analysis of a Japanesenational database. BJU international. 2013 Jul;
112(2):E76-81.
18. Sugihara T, Yasunaga H, Horiguchi H, Fujimura T,
Nishimatsu H, Tsuru N, et al. Regional,
institutional and individual factors affecting
selection of minimally invasive nephroureterectomy in Japan: a national database analysis.
International journal of urology : official journalof the Japanese Urological Association. 2013 Jul;
20(7):695-700.

19. Sugihara T, Yasunaga H, Horiguchi H, Tsuru N,
Ihara H, Fujimura T, et al. Comparisons ofperioperative outcomes and costs between open
and laparoscopic radical prostatectomy: apropensity-score matching analysis based on theJapanese Diagnosis Procedure Combination
database. International journal of urology : official
journal of the Japanese Urological Association.
2013 Mar;20(3):349-53.
20. Sugihara T, Yasunaga H, Horiguchi H, Fujimura T,
Nishimatsu H, Ohe K, et al. Does mechanicalbowel preparation improve quality of laparoscopic
nephrectomy? Propensity score-matched analysis
in Japanese series. Urology. 2013 Jan;81(1):74-9.
21. Sugihara T, Yasunaga H, Horiguchi H, Tsuru N,
Fujimura T, Nishimatsu H, et al. Wide range andvariation in minimally invasive surgery for renalmalignancy in Japan: a population-based analysis.
International journal of clinical oncology. 2013
Dec;18(6):1070-7.
22. Takeuchi M, Yasunaga H, Horiguchi H,
Hashimoto H, Matsuda S. Pyloromyotomy versus
i.v. atropine therapy for the treatment of infantile
pyloric stenosis: nationwide hospital discharge
database analysis. Pediatrics international: official
journal of the Japan Pediatric Society. 2013 Aug;55(4):488-91.
23. Takeuchi M, Yasunaga H, Horiguchi H, Fushimi
K. The burden of epiglottitis among Japanesechildren before the Haemophilus influenzae type b
vaccination era: an analysis using a nationwide
administrative database. Journal of infection andchemotherapy: official journal of the Japan
Society of Chemotherapy. 2013 Oct;19(5):876-9.
24. Tanabe S, Ogawa T, Akahane M, Koike S,
Horiguchi H, Yasunaga H, et al. Comparison ofneurological outcome between tracheal intubationand supraglottic airway device insertion ofout-of-hospital cardiac arrest patients: anationwide, population-based, observational study.
The Journal of emergency medicine. 2013 Feb;
44(2):389-97.
25. Tsugawa Y, Kumamaru H, Yasunaga H,
Hashimoto H, Horiguchi H, Ayanian JZ. The
association of hospital volume with mortality andcosts of care for stroke in Japan. Medical care.
2013 Sep;51(9):782-8.

405

Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Associate Professor
Naoto Hayashi, MD, PhD, Kansei Uno, MD, PhD, Takeharu Yoshikawa, MD, PhD

Project Research Associate
Mika Nagasaki, MD, PhD, Kensuke Asaba, MD, PhD, Eriko Maeda, MD, PhD, Aya
Watanabe, MD, PhD, Soichiro Miki, MD, PhD

Project researcher
Yukihiro Nomura, PhD, Mitsutaka Nemoto, PhD

Homepage http://www.h.u-tokyo.ac.jp/research/center22/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 three project associate
professors, five project research associates and two
project researchers, along with a medical staff ofapproximately 50 employees in the health-screening
center.

Clinical Activities
CDRPM is responsible for the clinical activities in the
CDRPM Health Screening Center. The following

diagnostic imaging modalities are installed tofacilitate high level of diagnostic accuracy: positronemission computed tomography/X-ray computed
tomography (PET/CT), 3-tesla magnetic resonanceimaging (3T-MRI) system, ultrasound imaging system,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 system406

is 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.
2) 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 of software, andepidemiological 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) Amiya E, Takata M, Watanabe M, Takahashi T,
Asano Y, Hatano M, Ozeki A, Watanabe A,
Kawarasaki S, Tamaki Z, Taniguchi T, Ichimura
Y, Toyama T, Nagai R, Sato S, Komuro I.
Presence of desaturated hemoglobin enhances thecontribution of blood cells to flow-mediateddilation in subjects with systemic sclerosis.
Int.J.Cardiol. ;168(3):3125-3127 2013.
(2) Amiya E, Watanabe M, Takata M, Watanabe S,
Ozeki A, Watanabe A, Kawarasaki S, Nakao T,
Hosoya Y, Omori K, Maemura K, Hirata Y,
Nagai R, Komuro I. Differences in bodytemperature variability between subjects with andwithout diabetes and predictive value for cardiovascular events. Circ.J. ;77(7):1844-1853 2013.
(3) Gonoi W, Akahane M, Watanabe Y, Isono S,
Maeda E, Hagiwara K, Ohtomo K. Visualizationof bile movement using MRI spin-labelingtechnique: preliminary results. AJR Am.J.
Roentgenol.; 201(1):133-141 2013.
(4) Gonoi W, Akai H, Hagiwara K, Akahane M,
Hayashi N, Maeda E, Yoshikawa T, Kiryu S,
Tada M, Uno K, Okura N, Koike K, Ohtomo K.
Santorinicele without pancreas divisum pathophysiology: Initial clinical and radiographic
investigations. BMC Gastroenterol.; 13(1):62
2013.
(5) Goto M, Abe O, Aoki S, Hayashi N, Miyati T,
Takao H, Iwatsubo T, Yamashita F, Matsuda H,
Mori H, Kunimatsu A, Ino K, Yano K, Ohtomo K,
Japanese Alzheimer's Disease Neuroimaging
Initiative. Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra
provides reduced effect of scanner for cortex
volumetry with atlas-based method in healthy
subjects. Neuroradiology; 55(7):869-875 2013.
(6) 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;
55(2):245-250 2013.
(7) 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; 38(4):958-962 2013.
(8) Goto M, Kunimatsu A, Shojima M, Abe O, Aoki
S, Hayashi N, Mori H, Ino K, Yano K, Saito N,
Ohtomo K. A pitfall of the volume rendering
method with 3D time-of-flight MRA: a case of abranching vessel at the aneurysm neck. Magn.
Reson.Med.Sci.; 12(1):53-56 2013.
(9) Hayakawa YK, Sasaki H, Takao H, Mori H,
Hayashi N, Kunimatsu A, Aoki S, Ohtomo K.
Structural brain abnormalities in women with
subclinical depression, as revealed by voxelbased morphometry and diffusion tensor imaging.
J.Affect.Disord.; 144(3):263-268 2013.
(10) Inano S, Takao H, Hayashi N, Yoshioka N, MoriH, Kunimatsu A, Abe O, Ohtomo K. Effects ofage and gender on neuroanatomical volumes.
J.Magn.Reson.Imaging; 37(5):1072-1076 2013.

407(11) Kimura K, Takenaka K, Ebihara A, Uno K,
Morita H, Nakajima T, Ozawa T, Aida I,
Yonemochi Y, Higuchi S, Motoyoshi Y, Mikata
T, Uchida I, Ishihara T, Komori T, Kitao R,
Nagata T, Takeda S, Yatomi Y, Nagai R,
Komuro I. Prognostic impact of left ventricular
noncompaction in patients with Duchenne/Becker
muscular dystrophy--prospective multicenter
cohort study. Int.J.Cardiol.; 168(3):1900-1904
2013.
(12) Maeda E, Katsura M, Gonoi W, Yoshikawa T,
Hayashi N, Ohtsu H, Ohtomo K. Abnormal
signal intensities of the seminal vesicles in ascreening population. J.Magn.Reson.Imaging
2013.
(13) Maeda E, Yoshikawa T, Nakashima R,
Kobayashi K, Yokosawa K, Hayashi N, Masutani
Y, Yoshioka N, Akahane M, Ohtomo K.
Experimental system for measurement ofradiologists' performance by visual search task.
Springerplus; 2:607-1801-2-607. eCollection2013 2013.
(14) Nakashima R, Kobayashi K, Maeda E,
Yoshikawa T, Yokosawa K. Visual search ofexperts in medical image reading: the effect oftraining, tar get prevalence, and expert
knowledge. Front Psychol; 4:166 2013.
(15) Nishimura S, Manabe I, Takaki S, Nagasaki M,
Otsu M, Yamashita H, Sugita J, Yoshimura K,
Eto K, Komuro I, Kadowaki T, Nagai R. Adipose
Natural Regulatory B Cells Negatively Control
Adipose Tissue Inflammation. Cell.Metab. 2013.
(16) Takahashi T, Asano Y, Amiya E, Hatano M,
Tamaki Z, Takata M, Ozeki A, Watanabe A,
Kawarasaki S, Taniguchi T, Ichimura Y, Toyama
T, Watanabe M, Hirata Y, Nagai R, Komuro I,
Sato S. Clinical correlation of brachial arteryflow-mediated dilation in patients with systemicsclerosis. Mod.Rheumatol. 2013.
(17) Takao H, Hayashi N, Ohtomo K. White matter
microstructure asymmetry: Effects of volume
asymmetry on fractional anisotropy asymmetry.
Neuroscience; 231:1-12 2013.
(18) Takao H, Hayashi N, Ohtomo K. Sex
dimorphism in the white matter: Fractional
anisotropy and brain size. J.Magn.Reson.Imaging
2013.

(19) Takao H, Hayashi N, Ohtomo K. Effects of theuse of multiple scanners and of scanner upgradein longitudinal voxel-based morphometry studies.
J.Magn.Reson.Imaging; 38(5):1283-1291 2013.
(20) Takata M, Amiya E, Watanabe M, Omori K, ImaiY, Fujita D, Nishimura H, Kato M, Morota T,
Nawata K, Ozeki A, Watanabe A, Kawarasaki S,
Hosoya Y, Nakao T, Maemura K, Nagai R,
Hirata Y, Komuro I. Impairment of flowmediated dilation correlates with aortic dilationin patients with Marfan syndrome. Heart Vessels
2013.
(21) Tomizawa N, Maeda E, Akahane M, Torigoe R,
Kiryu S, Ohtomo K. Coronary CT angiographyusing the second-generation 320-detector row
CT: assessment of image quality and radiationdose in various heart rates compared with thefirst-generation scanner. Int J Cardiovasc
Imaging; 29(7):1613-1618 2013.
(22) Watanabe S, Amiya E, Watanabe M, Takata M,
Ozeki A, Watanabe A, Kawarasaki S, Nakao T,
Hosoya Y, Omori K, Maemura K, Komuro I,
Nagai R. Simultaneous heart rate variability
monitoring enhances the predictive value offlow-mediated dilation in ischemic heart disease.
Circ.J.; 77(4):1018-1025 2013.
(23) Yoshikawa T, Hayashi N, Maeda E, Matsuda I,
Sasaki H, Ohtsu H, Ohtomo K. Peritoneal fluid
accumulation in healthy men and postmenopausal
women: evaluation on pelvic MRI. AJR Am.J.
Roentgenol.; 200(6):1181-1185 2013.

408

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/research/center22/contribute/rinsyo_undouki.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 epidemiology
and main target diseases are osteoarthritis, spondylosis
and osteoporosis. Osteoarthritis and osteoporosis aremajor public health issues in the elderly that cause
impairment of ADL/QOL. The number of patientswith 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 etiological evidence. We have to datecreated a baseline database with detailed clinical andgenomic information on three population-based
cohorts with total 3,040 participants in urban,
mountainous and seacoast communities of Japan.
Recruitment and baseline visits began in October 2005

and were completed over a 1.5-year period, with thelast visit in March 2007. A third comprehensive clinic
visit have been already completed in 2013.

References
1. Muraki S, Akune T, Oka H, Ishimoto Y, Nagata K,
Yoshida M, Tokimura F, Nakamura K, Kawaguchi
H, Yoshimura N. Physical Performance, Bone andJoint Diseases, and Incidence of Falls in Japanese
Men and Women: A Longitudinal Cohort Study.
Osteoporos Int 2013;24:459-466.
2. 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 population-based cohort study ofJapanese men and women: The ROAD Study
Bone 2013;52:516-23.
3. Oka H, Akune T, Muraki S, Tanaka S, Kawaguchi
H, Nakamura K, Yoshimura N. The mid-term
efficacy of intra-articular hyaluronic acidinjections on joint structure: A nested case-control
study. Modern Rheum 2013;23:722-8.
4. 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 2012;
2:pii: e001520. doi: 10.1136/bmjopen-2012001520.

409

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. Associations between radiographic
lumbar spinal stenosis and clinical symptoms in
the general population: The Wakayama Spine
Study Osteoarthritis Cartilage 2013;21:783-8.
6. Yoshimura N, Muraki S, Oka H, Morita M,
Yamada H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T. Profiles of vitamin D insufficiency
and deficiency in Japanese men and women:
Association with biological, environmental, andnutritional factors and coexisting disorders: The
ROAD study Osteoporos Int 2013;24:2775-87.

410

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. (until 31st May, 2013)
Shoko Ogawa, M.D. (since 16th September, 2013)

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/research/center22/contribute/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 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

411

the ideal ways to build a better legal system. Together
therewith, making the best use of the experience of astate-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.

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).

References
Papers
1. Yasushi Kodama. “Healthcare ADR”(Japanese)
Nippon Hyoron Sha Co., Ltd. “Horitsu Jiho” Vol.

85 No. 4 2013, 33 - 38, April 1, 2013
2. Yasushi Kodama, “Legal problems related tocontraindicated matters”(Japanese) Igaku-ShoinLtd. “JIM” Vol. 23 No. 5, 376 - 378, May 15,
2013
3. Yasushi Kodama, “Aiming for further improvements in investigations into the cause of death”
The Japanese Society of Internal Medicine“Journal of the Japanese Society of Internal
Medicine” Vol. 102 No. 9, 2347 - 2349,
September 10, 2013
Books
1. Takahashi editor and author Takase, Oguchi,
Yasuhara, Yasushi Kodama et al authors, “Court
practice series 5 The actual practice of a medicalcase”(Japanese) Shojihomu Co., Ltd., 57 - 78,
July 5, 2013 issue
Conference Presentations
Domestic Meetings (in Japanese)
1. Yasushi Kodama. Panel Discussion Aiming for
Further Improvement of Cause of Death
Investigations “Towards the Establishment of theFoundation of a Cause of Death Investigation
System ~ From the Standpoint of a Lawyer”
110th The Japanese Society of Internal Medicine Annual Lecture Meeting Panel Discussion, April
14, 2013
2. Yasushi Kodama. “The Way of Thinking ofMedical Care Safety and Medical Practice
Disputes” National Hospital Organization
Hospital Director Workshop Lecture, May 16,
2013
3. Yasushi Kodama.
Concerning Medical Practice
Disputes” National Hospital Organization
Deputy Hospital Director Workshop Lecture, May
30, 2013
4. Yasushi Kodama. “Legal Basic Knowledge
concerning Medical Care Disputes - Medical Care
Safety” Japan Hospital Association Medical
Care Safety Manager Training Class, June 8, 2013
5. Yasushi
Kodama.
“LegalRelationships
Surrounding Doctors - Dentists” Ministry of
Health, Labor and Welfare
PhysicianRe-education Group Study, June 29, 2013
6. Yasushi Kodama. “Considering the Basics of Risk

412Management”
National Social Welfare
Corporation Manager Conference
Social
Welfare Corporation Manager Course (first halfterm) Lecture, July 22, 2013
7. Yasushi Kodama. “Medical Care ADR” Tokyo
Tama Tachikawa Health Care Center Medical
Care Safety Workshop Lecture, July 26, 2013
8. Yasushi Kodama. “Legal Basic Knowledge
concerning Medical Care Disputes - Medical Care
Safety” Japanese Nursing Association Medical
Care Safety Manager Training Workshop Lecture,
July 29, 2013
9. Yasushi Kodama. “Legal Basic Knowledge
concerning Medical Care Disputes - Medical Care
Safety” Japanese Society for Quality and Safety
in Medical Care Medical Care Safety Manager
Training Workshop Lecture, August 2, 2013
10. Yasushi Kodama. “Risk Management in Medical
Care ~ Law and Economics of Compensation”
Institute for Health Economics and Policy
Lecture, September 4, 2013
11. Yasushi
Kodama.
“The
Way
Accident
Investigations Should Be -- From the Standpointof Legal Theory” 61st Japanese College of
Cardiology Annual Meeting Lecture, September
20, 2013
12. Yasushi
Kodama.
“LegalRelationships
Surrounding Doctors - Dentists” Ministry of
Health, Labor and Welfare
PhysicianRe-education Group Study, September 28, 2013
13. Yasushi Kodama. “Risk Management in Medical
Care ~ Law and Economics of Compensation”
University of Tokyo Graduate School of Public
Policy Medical Care Policy Practicing Community (H-PAC) Lecture, November 13, 2013
14. Yasushi Kodama. “Recent Trend of Medical Care
Disputes”
Municipal Hospital Medical Care
Accident Prevention Countermeasures Committee,
November 22, 2013
15. Yasushi Kodama. “Risk Management Introduction
I” National Social Welfare Facility Manager
Conference
Beginning level Risk Manager
Training Course (first half term) Lecture,
December 3, 2013
16. Yasushi Kodama. “Medical Care DisputeHandling and the Legal System” Japanese Society
for Quality and Safety in Healthcare Medical

Care Safety Manager Training Workshop Lecture,
December 12, 2013
17. Tomoko Matsuura. “How information sharing
between patients and healthcare professionals willchange medical society - producing medical
information with patients (workshop open to the
public)”, Japanese Society for Quality and Safety
in Healthcare 8th annual scientific meeting. Nov.
23-24, 2013
18. Maiko Mizuki, Tomoko Matsuura, Reiko Segawa,Shinji Nagakawa, Shoko Ogawa, Yasushi Kodama.
“Practical Approach for Coordination between
Consultation Offices in hospitals and outside
hospitals.” Japanese Society for Quality and
Safety in Healthcare 8th annual scientific meeting.
Nov. 23-24, 2013
19. Chieko Ishida, Maiko Mizuki. “Practical Reportof Structural Patient Support in the hospital.”,Japanese Society for Quality and Safety in
Healthcare 8th annual scientific meeting. Nov.
23-24, 2013
20. Reiko Segawa, Shinji Nagakawa, Tomoko
Matsuura, Maiko Mizuki, Shoko Ogawa, Yasushi
Kodama. “Consultation staffs’ feelings ofdifficulty with management of patients support
office in hospitals.”, Japanese Society for Quality
and Safety in Healthcare 8th annual scientificmeeting. Nov. 23-24, 2013
International Meetings
1. Yasushi Kodama, “Alternative Dispute Resolution
New Dawn for Asia New Development of ADR in
Japan”, 26th LAWASIA Annual Conference, The
Law Society of Singapore, October 28, 2013
2. Reiko Segawa, Ayako Nagata, Tomohiro
Shinozaki, and Katsuya Kanda. “The Association
between Nurses’ Changes in Practice andResponses of Colleagues to their Medical Errors
in Japan.” International Society for Quality in
Healthcare 30th International Conference in
Edinburgh. Oct. 13-16, 2013.
3. Reiko Segawa, Ayako Nagata, Mami onishi,
Satoko Nagai, and Katsuya Kanda. “Factors
Predictive of Nurses’ Negative Change in Practiceafter Their Error: A Classification and Regression
Tree Approach.” East Asian Forum of Nursing
Scholars 17th in Manila. Feb. 20-21, 2014

413

Division of Molecular
Cardiovascular Metabolism(Daiichi-Sankyo Company, Limited)
Research Associate Professor
Katsuyuki Ando, M.D., Ph.D.

Research Associate
Megumi Fujita, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/~kid-endo/a-3-13.html

Introduction and Organization
In order to investigate common diseases such as
hypertension
and
their
reno-cardiovascularcomplication, which is induced by deflective lifestyle(salt excess, obesity, and so on), the Division of
Molecular Cardiovascular Metabolism was started
with donation of Daiichi-Sankyo Company Limited
and supported by the Department of Nephrology and
Endocrinology, in April 1, 2006. This division consistsof the above-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. The division was
finished in March 2014.

Teaching activities
In March of 2007, 2008, and 2010, 2012 total fivegraduate fellows took the medical degree.

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, and chronic
kidney disease-associated hypertension. This finding
suggests that sympathoexcitation by ROS in the brain is
a common and important mechanism for pathophysiology of many types of hypertensive disease due
to defective lifestyle. In these illnesses, it is well known
that RAAS also plays an important role and aldosterone
has been suggested to contribute to progress of cardiac
and renal injury. Thus, we examined the role ofaldosterone in oxidative stress-induced sympathoexcitation in the brain of hypertension with salt excess
and obesity and showed interesting 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
injury compared with high salt intake in adulthood

414

probably 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. 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
2. 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
MicroalbumininRandomized(SAKURA) Trial. Internat J Med Sci. 2013; 10(9):1209-1216.
3. Ando K, Kawarazaki H, Miura K, Matsuura H,
Watanabe Y, Yoshita K, Kawamura M, Kusaka M,
Kai H, Tsuchihashi T, Kawano Y. [ScientificStatement] Report of the Salt Reduction
Committee of the Japanese Society of Hypertension (1) Role of salt in hypertension andcardiovascular diseases. Hypertens Res. 2013;36(12): 1009-1019.
4. Miura K, Ando K, Tsuchihashi T, Yoshita K,
Watanabe Y, Kawarazaki H, Matsuura H, Kusaka
M, Kai H, Kawamura M, Kawano Y. [ScientificStatement] Report of the Salt Reduction
Committee of the Japanese Society of Hypertension (2) Goal and strategies of dietary salt
reduction in the management of hypertension.
Hypertens Res. 2013; 36(12):1020-1025.

5. Tsuchihashi T, Kai H, Kusaka M, Kawamura M,
Matsuura H, Miura K, Ando K, Maruyama S,
Hayabuchi H, Takagi Y, Nakahigashi N, Sato T,
Kawano Y. [Scientific Statement] Report of theSalt Reduction Committee of the Japanese Societyof Hypertension (3) Assessment and application ofsalt intake in the management of hypertension.
Hypertens Res. 2013; 36(12):1026-1031.
6. Shimamoto K, Ando K, Fujita T, Hasebe N,
Higaki J, Horiuchi zm, Imai Y, Imaizumi T,
Ishimitsu T, Ito M, Ito S, Itoh H, Iwao H, Kai H,
Kario K, Kashihara N, Kawano Y, KimMitsuyama S, kimura G, Kohara K, Komuro I,
Kumagai H, Matsuura H, Miura K, Morishita R,
Naruse M, Node K, Ohya Y, Rakugi H, Saito I,
Saitoh S, Shimada K, Shimosawa T, Suzuki H,
Tamura K, Tanahashi N, Tsuchihashi T, Uchiyama
M, Ueda S, Umemura S, on behalf of The
Japanese Society of Hypertension Committee for
Guidelines for Management of Hypertension. The
Japanese Society of Hypertension Guidelines forManagement of Hypertension (JSH 2014).
Hypertens Res. 2014; 37(4): 253-392.
7. Ando K: L-/N-type calcium channel blockers andproteinuria. Cur Hypertens Rev. 2014;9:210-218.
8. Ando K, Nitta K, Rakugi H, Nishizawa Y,
Yokoyama H, Nakanishi T, Kashihara N, Tomita
K, Nangaku M, Takahashi K, Isshiki M,
Shimosawa T, Fujita T. Comparison of theantialbuminuirc effects of benidipine andhydrochlorthiazide in renin-angiotensin system(RAS) inhibitor-treated hypertensive patients with
albuminuira: the COSMO-CKD (COmbination
Strategy on renal function of benidipine ordiuretics treatMent with RAS inhibitOrs in a
Chronic Kidney Disease hypertensive population)
study. Int J Med Sci 2014; 11(9): 897-904.

415

Department of Healthcare Quality
Assessment
Associate Professor
Hiroaki Miyata, Ph.D.

Assistant Professor
Ai Tomotaki, R.N., M.S.

Researcher
Hiroki Nogawa, M.D., Ph.D.

Researcher
Norimichi Hirahara, Ph.D.

Researcher
Junichi Okubo

Clerical Staff
Arata Takanashi

Clerical Staff
Chieko Fujimura

Clerical Staff (Secretary)
Nanayo Kyogoku

Homepage

http://hqa.umin.jp/

Introduction and Organization
The Department of Healthcare Quality Assessment(HQA) was established in 2006 and has been engaging
in research 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 since 2009 and with the
Department of Pediatric Surgery since 2010. In 2012,
the Department of Health and Social Behavior joinedin the collaboration circle, replacing with the
Department of Health Economics and Epidemiology
Research.

Health care reform should focus on improving
physical health and healthcare value for patients. As
only medical teams can improve the quality ofhealthcare services in its strict sense, HQA has beencollaborating with various healthcare professional
committees. HQA supports them with systematic datacollection, data management, practical analysis anduseful feedback. Our benchmarking projects are basedon clinical database and they drive quality
improvement in each related field. With such
positive-sum competition, patients will receive better
healthcare service, physicians will be rewarded fortheir excellence, and healthcare costs will becontained. Three principles should guide thistransformation: (a) the goal is to meet patients’ values,

416(b) medical practice should be organized aroundmedical conditions and care cycles, and (c) results —risk-adjusted outcomes and costs — must be measured.
HQA has already developed risk models and provided
several practical tools for medical professionals
through joint research projects with Japan
Cardiovascular Surgery Database (JCVSD). One ofthe practical tools is JapanSCORE which allows
doctors to calculate a patient’s risk of mortality andmorbidities. JapanSCORE incorporates JCVSD risk
models that are designed to serve as statistical tools toaccount for the impact of the patient risk factors on
the operative mortality and morbidity. HQA also has
conducted policy analysis and clinical research which
can contribute to healthcare quality improvement
throughout Japan. Value-based competition on the
results have paved the way for a reform thatrecognizes the role of healthcare professionals at theheart of the system.

Research activities
For healthcare quality improvement, a) healthcare
quality must be clearly identified and b) quality
indicators must be set and monitored carefully in eachhealthcare region. A well-designed database systemthat continuously collects clinical data in reliable andvalidated manners is mandatory to identify thehealthcare quality, monitor the quality indicators, andimprove the quality of healthcare services. HQA has
designed and managed nationwide database system incollaboration with the Japan Surgical Society, theJapanese Society for Cardiovascular Surgery, theJapanese Society of Gastroenterological Surgery, andother medical professional societies.
Severity-adjusted indicators must be used forinvestigating clinical outcomes and exploring thesystems that provide the best practices for patients.
HQA has developed risk models and conducted
outcome analyses based on the systematic datacollection. These analyses enable risk assessment andprognosis prediction of cardiovascular surgeries andbenchmarking of the participating facilities in the
database project. This information is useful for
discussion in pre-surgery conference, patients’ better
understanding of treatment as well as promotion ofhealthcare quality improvement.
Also, a new project in collaboration with National
Clinical Database (NCD) has started since 2011.
Today more than 4,100 hospital departments fromaround Japan participate in NCD activities. The
database collects more than 1,300,000 surgical cases
per year.

References
1. Kobayashi H, Miyata H, Gotoh M, Baba H,
Kimura W, Kitagawa Y, Nakagoe T, Shimada M,
Tomita N, Sugihara K, Mori M. Risk model forright hemicolectomy based on 19,070 Japanesepatients in the National Clinical Database. Journalof Gastroenterology: 2013; July.
2. Kuno T, Numasawa Y, Miyata H, Takahashi T,
Sueyoshi K, Ohki T, Negishi K, Kawamura A,
Kohsaka S, Fukuda K. Impact of coronary
dominance on in-hospital outcomes after
percutaneous coronary intervention in patientswith acute coronary syndrome. PLOS ONE,2013;8(8):e72672.
3. Saito A, Miyata H, Motomura N, Ono M,
Takamoto S and Japan Cardiovascular Surgery
Database
Organization.
Propensity-matchedanalysis of bilateral internal mammary artery
versus single internal mammary artery in 7702
cases of isolated coronary artery bypass grafting;
European Journal of Cardiothoracic Surgery, Eur J
Cardiothorac Surg. Eur J Cardiothorac Surg.
2013;44(4):711-7.
4. Ohno Y, Maekawa Y, Miyata H, Inoue S, Ishikawa
S, Sueyoshi K, Noma S, Kawamura A, Kohsaka S,
Fukuda K. Impact of periprocedural bleeding on
incidence of contrast- Induced acute kidney injury
in patients treated with percutaneous coronary
intervention. J Am Coll Cardiol. 2013;62(14):1260-6.
5. Tokuda Y, Miyata H, Motomura N, Araki Y,
Oshima H, Usui A, Takamoto S; The Japan Adult
Cardiovascular Database Organization. Outcomeof pericardiectomy for constrictive pericarditis inJapan: A nationwide outcome study. Ann Thorac
Surg. 2013;96(2):571-6.
6. Kubota H, Miyata H, Motomura N, Ono M,

417

Takamoto S, Harii K, Oura N, Hirabayashi S, Kyo
S. Deep sternal wound infection after cardiac
surgery. J Cardiothorac Surg. 2013 May 20;8:132.
7. Kaminishi Y, Misawa Y, Kobayashi J, Konishi H,
Miyata H, Motomura N, Takamoto S; Japan
Cardiovascular Surgery Database Organization.
Patient-prosthesis mismatch in patients with aortic
valve replacement. Gen Thorac Cardiovasc Surg.
2013 May;61(5):274-9.
8. Endo A, Kohsaka S, Miyata H, Kawamura A,
Noma S, Suzuki M, Koyama T, Ishikawa S,
Momiyama Y, Nakagawa S, Sueyoshi K, Takagi S,
Takahashi T, Sato Y, Ogawa S, Fukuda K.
Disparity in the application of guideline-based
medical therapy after percutaneous coronary
intervention: analysis from the Japaneseprospective multicenter registry. Am J Cardiovasc
Drugs. 2013 Apr;13(2):103-12.
9. Numasawa Y, Kohsaka S, Miyata H, Kawamura A,
Noma S, Suzuki M, Nakagawa S, Momiyama Y,
Takahashi T, Sato Y, Fukuda K. Use ofthrombolysis in myocardial infarction risk score
to predict bleeding complications in patients withunstable angina and non-ST elevation myocardial
infarction undergoing percutaneous coronary
intervention. Cardiovasc Interv Ther. 2013 Jan 30.
10. Kodaira M, Kawamura A, Miyata H, Noma S,
Suzuki M, Ishikawa S, Momiyama Y, Nakagawa S,
Sueyoshi K, Takahashi T, Takamoto S, Ogawa S,
Sato Y, Kohsaka S, Fukuda K; For JCD-KICS
investigators. Door to balloon time: How short isenough under highly accessible nationwide
insurance coverage? Analysis from the Japanesemulticenter registry. Int J Cardiol. 2013; 168(1):534-6.
11. Numasawa Y, Kohsaka S, Miyata H, Kawamura A,
Noma S, Suzuki M, Nakagawa S, Momiyama Y,
Sato Y, Fukuda K. Safety of transradial approachfor percutaneous coronary intervention in relation
to body mass index: A report from a Japanesemulticenter registry. Cardiovasc Interv Ther.
2013;28(3):242-9.
12. Arai T, Yuasa S, Miyata H, Kawamura A,
Maekawa Y, Ishikawa S, Noma S, Inoue S, Sato Y,
KohsakaS,
FukudaK.
Incidenceof
periprocedural myocardial infarction and cardiac
biomarker testing after percutaneous coronary

intervention in Japan: Results from a multicenter
registry. Heart Vessels. 2013;28(6):714-9.

418

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

419

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. Hiroi H, Momoeda M, Watanabe T, Ito M, Ikeda
K, Tsutsumi R, Hosokawa Y, Koizumi M,
Nakazawa F, Osuga Y, Muramatsu M, Taketani Y,
Inoue S: Expression and regulation of transient
receptor potential cation channel, subfamily M,
member 2 (TRPM2) in human endometrium. Mol
Cell Endocrinol 365, 146-152, 2013.
2. Zhao Y, Koga K, Osuga Y, Izumi G, Takamura M,
Harada M, Hirata T, Hirota Y, Yoshino O, Inoue
S, Fujii T, Kozuma S: Cyclic Stretch Augments
Production of Neutrophil Chemokines and Matrix
Metalloproteinases-1 (MMP-1) from Human
Decidual Cells, and the Production was Reduced
by Progesterone. Am J Reprod Immunol 69,
454-462, 2013.
3. Takayama K, Horie-Inoue K, Katayama S, Suzuki
T, Tsutsumi S, Ikeda K, Urano T, Fujimura T,
Takagi K, Takahashi S, Homma Y, Ouchi Y,
Aburatani H, Hayashizaki Y, Inoue S: Androgen-

4.

5.

6.

7.

8.

9.

responsive long noncoding RNA CTBP1-AS
promotes prostate cancer. EMBO J 32, 1665-1680,
2013.
Yamaga R, Ikeda K, Horie-Inoue K, Ouchi Y,
Suzuki Y, Inoue S: RNA-sequencing of MCF-7
breast cancer cells identifies novel estrogenresponsive genes with functional estrogen
receptor-binding sites in the vicinity of theirtranscription start sites. Horm Cancer 4, 222-232,
2013.
Ikeda K, Shiba S, Horie-Inoue K, Shimokata K,
Inoue S: A stabilizing factor for mitochondrial
respiratory supercomplex assembly regulates
energy metabolism in muscle. Nat Commun 4,
2147, 2013.
Yamada Y, Fujimura T, Takahashi S, Takayama
K, Urano T, Murata T, Obinata D, Ouchi Y,
Homma Y, Inoue S: Clinical significance ofamyloid precursor protein in patients withtesticular germ cell tumor. Adv Urol 2013,
348438, 2013.
Oneyama C, Kito Y, Asai R, Ikeda J, Yoshida T,
Okuzaki D, Kokuda R, Kakumoto K, Takayama K,
Inoue S, Morii E, Okada M: MiR-424/503mediated Rictor upregulation promotes tumor
progression. PLoS ONE 8, e80300, 2013.
Ijichi N, Shigekawa T, Ikeda K, Miyazaki T,
Horie-Inoue K, Shimizu C, Saji S, Aogi K, Tsuda
H, Osaki S, Saeki T, Inoue S: Association of
positive EBAG9 immunoreactivity with unfavorable prognosis in breast cancer patientstreated with tamoxifen. Clin Breast Cancer 13,
465-470, 2013.
Takagi K, Ito S, Miyazaki T, Miki Y, Shibahara Y,
Ishida T, Watanabe M, Inoue S, Sasano H, Suzuki
T: Amyloid precursor protein (APP) in humanbreast cancer: an androgen-induced geneassociated with cell proliferation. Cancer Sci 104,
1532-1538, 2013.

420

Department of Clinical Trial DataManagement
Project Professor
Takuhiro Yamaguchi, Ph.D.

Project Assistant Professor
Tempei Miyaji, M.S.

Project Researcher
Hiroshi Ohtsu, M.S.

Homepage

http://ctdm.umin.jp/

Introduction and Organization
Why we discuss Clinical Data Management (CDM)?
The reason why the concept of CDM is important has
not been fully discussed and educated in Japan. Our
department was established to answer this question.
The Department of Clinical Trial Data Management
was established in 2007 and carries out educationaland research activities on CDM in collaboration withThe Department of Biostatistics and The ClinicalResearch 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
the world.

Teaching activities
1. Development of systematic educational programsof CDM and holding of seminars, which include; Design of clinical trials
 CDM
 Protocol development
 Regulatory science Ethics
 IT
 Safety information and PMS
 Translational research methodology
 …
2. Acceptance of clinical trial staffs from other sites,that is, conducting an on-the-job training (OJT)
3. Support to clinical researchers, especially those in
the University of Tokyo Hospital, in collaboration
with the Clinical Research Support Center and theDepartment of Clinical Epidemiology and Systems;
 Consultation works on medical statistics andresearch methodology
 Data center is working at our department andstuffs are included as a biostatistician or a421

clinical data manager

Research activities
In addition to activities described above, we aredeveloping 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 related areas of healthcare and we are challenging to convert several academic clinical trial data to CDISC Standards formats.
We are also supporting several clinical studies which
are conducting in the University of Tokyo Hospital.
For example our department functions as a data centerfor “A replication-competent, recombinant herpes
simplex virus type 1 (G47delta) in patients with
progressive glioblastoma” and “A clinical study of an
oncolytic herpes simplex type 1 (HSV-1) G47delta forpatients with castration resistant prostate cancer”
which are conducted at Translational Research Center(TRAC) and Department of Urology in the Universityof Tokyo Hospital respectively. Moreover, we havecollaborative works with several departments which
belong to 22nd Century Medical and Research Centerin the Hospital and are responsible for Biostatistics
Division of The Clinical Research Support Center(CresCent) in the Hospital.

3.

4.

5.

6.

References7.

1. Tsugihashi Y, Kakudate N, Yokoyama Y,
Yamamoto Y, Mishina H, Fukumori N, Nakamura
F, Takegami M, Ohno S, Wakita T, Watanabe K,
Yamaguchi T, Fukuhara S. A novel Internetbased blended learning programme providing corecompetency in clinical research. Journal of
Evaluation Clinical Practice 2013; 19(2): 250-5.
2. Fujimoto C, Murofushi T, Chihara Y, Ushio M,
Suzuki M, Yamaguchi T, Yamasoba T, Iwasaki S.
Effect of severity of vestibular dysfunction on
postural instability in idiopathic bilateral

8.

vestibulopathy. Acta Oto-Laryngologica 2013;
133(5): 454-61.
Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M,
Tochigi T, Kawamura S, Aoki H, Numata I,
Takeda A, Namiki S, Namima T, Ikeda Y, Kambe
K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi
H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y.
Prospective Randomized Phase II Trial of a Single
Early Intravesical Instillation of Pirarubicin(THP) in the Prevention of Bladder Recurrence
After Nephroureterectomy for Upper Urinary
Tract
Urothelial
Carcinoma:
The
THP
Monotherapy Study Group Trial. Journal of
Clinical Oncology 2013; 31(11): 1422-7.
Otsuka K, Taguri M, Dennis CL, Wakutani K,
Awano M, Yamaguchi T, Jimba M. Effectivenessof a Breastfeeding Self-efficacy Intervention: Do
Hospital Practices Make a Difference? MaternalChild Health Journal 2013 Apr 18. [Epub ahead ofprint]
Kawaguchi T, Azuma K, Yamaguchi T, Soeda H,
Sekine Y, Koinuma M, Takeuchi H, Akashi T,
Unezaki S. Development and validation of theJapanese version of the Decisional Conflict Scaleto investigate the value of pharmacists' information: a before and after study. BMC medical
informatics and decision making 2013; 13(1): 50.
Hidaka H, Yamaguchi T, Miyazaki H, Nomura K,
Kobayashi T. Congenital cholesteatoma ispredominantly found in the posterior-superior
quadrant in the Asian population: systematic
review and meta-analysis, including our clinicalexperience. Otology & neurotology 2013; 34(4):630-8.
Morita T, Miyashita M, Yamagishi A, Akiyama M,
Akizuki N, Hirai K, Imura C, Kato M, Kizawa Y,
Shirahige Y, Yamaguchi T, Eguchi K. Effects of aprogramme of interventions on regional comprehensive palliative care for patients with cancer: amixed-methods study. Lancet Oncology 2013;14(7): 638-46.
Kurosawa S, Miyawaki S, Yamaguchi T,
Kanamori H, Sakura T, Moriuchi Y, Sano F,
Kobayashi T, Yasumoto A, Hatanaka K, Yanada M,
Nawa Y, Takeuchi J, Nakamura Y, Fujisawa S,
Shibayama H, Miura I, Fukuda T. Prognosis ofpatients with core binding factor acute myeloid

422

leukemia after first relapse. Haematologica 2013;
98(10): 1525-31.
9. Mitsuzuka K, Koie T, Narita S, Kaiho Y,
Yoneyama T, Tsuchiya N, Kakoi N, Kawamura S,
Tochigi T, Ohyama C, Habuchi T, Yamaguchi T,
Arai Y. Changes in indications and oncologicaloutcomes of radical prostatectomy after 2000-data from 1268 Japanese patients treated withradical prostatectomy between 2000 and 2009.
Japanese Journal of Clinical Oncology 2013;
43(8): 821-6.
10. Ooba N, Setoguchi S, Ando T, Sato T, Yamaguchi
T, Mochizuki M, Kubota K. Claims-based definition of death in Japanese claims database: validity
and implications. PLoS One 2013; 8(5): e66116.
11. Jinzaki M, Hirano M, Hara K, Suzuki T,
Yamashina A, Ikari Y, Iino M, Yamaguchi T,
Kuribayashi S. A randomized, double-blind,placebo-controlled, phase II dose-finding study ofthe short acting β1-blocker, landiolol hydrochloride, in patients with suspected ischemic
cardiac disease. International journal of cardiovascular imaging 2013; 29(s1): 7-20.
12. Hangai S, Iwase S, Kawaguchi T, Kogure Y,
Miyaji T, Matsunaga T, Nagumo Y, Yamaguchi T.
Effect of Active Hexose-Correlated Compound in
Women Receiving Adjuvant Chemotherapy for
Breast Cancer: A Retrospective Study. Journal of
alternative and complementary medicine 2013 Jul
5. [Epub ahead of print]
13. Takahashi M, Omodaka K, Maruyama K,
Yamaguchi T, Himori N, Shiga Y, Ryu M,
Kunikata H, Nakazawa T. Simulated Visual Fields
Produced from Macular RNFLT Data in Patientswith Glaucoma. Current eye research 2013;38(11): 1133-41.
14. Nagai H, Kitano T, Nishimura T, Yasuda H,
Nakata K, Takashima S, Kanai M, Matsumoto S,
Mori Y, Kakudo Y, Sato H, Yamaguchi T,
Kameno K, Kim YH, Mishima M, Yanagihara K.
Use of glucose solution for the alleviation of
gemcitabine-induced vascular pain: a doubleblindrandomized crossover study. Support Care
Cancer 2013 Jul 23. [Epub ahead of print]
15. Ito A, Shintaku I, Satoh M, Ioritani N, Tochigi T,
Numata I, Namima T, Kambe K, Kyan A, Ueno S,
Katoh S, Adachi H, Yamashita S, Yamaguchi T,

Arai Y; on behalf of the Tohoku Urological EBM
Study Group.
16. Intravesical Seeding of Upper Urinary Tract
Urothelial Carcinoma Cells During Nephroureterectomy: An Exploratory Analysis from the
THPMG Trial. Japanese Journal of ClinicalOncology 2013 Sep 4. [Epub ahead of print]
17. Takano T, Niikura H, Ito K, Nagase S,
Utsunomiya H, Otsuki T, Toyoshima M, Tokunaga
H, Kaiho-Sakuma M, Shiga N, Nagai T, Tanaka S,
Otsuki A, Kurosawa H, Shigeta S, Tsuji K,
Yamaguchi T, Yaegashi N. Feasibility study of
gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiatedendometrial sarcoma in Japan.
International
Journal of Clinical Oncology 2013 Oct 24. [Epubahead of print]
18. Yamaguchi T, Iwase S, Goto Y, Tsuboi M,
Yamamoto D, Odagiri H, Tsubota Y, Iioka Y,
Kawaguchi T, Anzai N, Miyaji T, Hamaguchi T,
Takatsu Y, Shimada Y, Mitchell S, Basch E.
Development Program for the Japanese Version of
the PRO−CTCAE. Japanese pharmacology &therapeutics 2013; 41(s2): s79-82.
19. Chikuda H, Ohtsu H, Ogata T, Sugita S, Sumitani
M, Koyama Y, Matsumoto M, Toyama Y; OSCIS
investigators. Optimal treatment for spinal cord
injury associated with cervical canal stenosis(OSCIS): a study protocol for a randomized
controlled trial comparing early versus delayed
surgery. Trials. 2013 Aug 7; 14: 245.
20. Yoshikawa T, Hayashi N, Maeda E, Matsuda I,
Sasaki H, Ohtsu H, Ohtomo K. Peritoneal fluid
accumulation in healthy men and postmenopausal
women: evaluation on pelvic MRI. AJR Am J
Roentgenol. 2013 Jun; 200(6): 1181-5.
21. Shirota Y, Ohtsu H, Hamada M, Enomoto H,
Ugawa Y; Research Committee on rTMS
Treatment of Parkinson's Disease. Supplementary
motor area stimulation for Parkinson disease: arandomized controlled study. Neurology. 2013
Apr 9; 80(15): 1400-5.
22. 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. 2013 Jun; 47(6): 816-22.

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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 the faculty of pharmaceuticalsciences. It lists more than 300 drugs which areclassified by both clearance pathway and degree of
DDI, and is published in a journal which is distributed
to all pharmacies and relating facilities in Japan forfree. The list is used for inspection of prescriptions
in pharmacies, and in addition, for various 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. Honma M, Ikebuchi Y, Kariya Y, Hayashi M,
Hayashi N, Aoki S, Suzuki H. Rankl subcellulartrafficking and regulatory mechanisms inosteocytes. J Bone Miner Res. 28:1936-49, 2013.
2. Ito N, Ito K, Koshimichi H, Hisaka A, Honma M,
Igarashi T, Suzuki H. Contribution of protein
binding, lipid partitioning, and asymmetricaltransport to drug transfer into milk in mouseversus human. Pharm Res. 30:2410-22, 2013.
3. Kudo T, Hisaka A, Sugiyama Y, Ito K. Analysis of
the repaglinide concentration increase produced
by gemfibrozil and itraconazole based on theinhibition of the hepatic uptake transporter andmetabolic enzymes. Drug Metab Dispos. 41:
362-71, 2013.
4. Nukui Y, Hatakeyama S, Okamoto K, Yamamoto
T, Hisaka A, Suzuki H, Yata N, Yotsuyanagi H,
Moriya K. High plasma linezolid concentrationand impaired renal function affect development oflinezolid-induced thrombocytopenia. J Antimicrob
Chemother. 68:2128-33, 2013.
5. Yamashita F, Sasa Y, Yoshida S, Hisaka A, Asai Y,
Kitano H, Hashida M, Suzuki H. Modeling ofrifampicin-induced cyp3a4 activation dynamics
for the prediction of clinical drug-druginteractions from in vitro data. PLoS One.
8:e70330, 2013.

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Department of
Therapeutic Strategy forHeart Failure
Project Professor
Koichiro Kinugawa, M.D.

Project Research Assosiate
Mitsutoshi Kimura, M.D

Project Researcher
Shunei Kyo, M.D.
Takashi Nishimura,M.D
Naoko Kato

Project Academic Support Specialist
Kumiko Kakuya
Ikuko Funayama

Homepage

http: http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization
The Department of Therapeutic Strategy for Heart
Failure (TSHF) in the University of Tokyo Hospital
was established by the support of the Department of
Cardiac Surgery (Professor Shinichi Takamoto) andthe Department of Cardiology (Professor Ryozo
Nagai) of the University of Tokyo Hospital in May
2008. The purpose to establish the department of
TSHF is to promote surgical and medical innovative
treatment for end-stage heart failure in the Universityof Tokyo Hospital, which includes heart transplant,
pediatric heart transplant, ventricular assist device,
and regenerative therapy. The Department has been
also supported by thirteen companies,

Clinical Activities
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.
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

426

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
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

427

and insurance reimbursement was obtained this April.
Other two LVAD will be approved within this year.

References
1. Yamakawa M, Kyo S, Yamakawa S, Ono M,
Kinugawa K, Nishimura T. Destination therapy:
the new gold standard treatment for heart failure
patients with left ventricular assist devices. Gen
Thorac Cardiovasc Surg. 2013; 61(3):111-7. doi:
10.1007/s11748-012-0181-5. Epub 2012 Dec 21.
2. Ono M, Nishimura T, Kinoshita O, Shiga T,
Kinugawa K, Nagai R, et al. Improved survival inpatients with continuous-flow ventricular assist
device for bridge to heart transplantation.
Transplant Proc. 2013; 45(5):2017-8. doi: 10.
1016/j.transproceed.2013.01.005.
3. Nagai R, Kinugawa K, Inoue H, Atarashi H, Seino
Y, Yamashita T, et al. Urgent Management of
Rapid Heart Rate in Patients with Atrial
Fibrillation/Flutter
andLeft
Ventricular
Dysfunction – Comparison of the Ultra-ShortActing β1-Selective Blocker Landiolol with
Digoxin (J-Land Study) –. Circ J. 2013; 77:908-16.
4. Kinugawa K, Imamura T, Komuro I. Experienceof a Vasopressin Receptor Antagonist, Tolvaptan
under the Unique Indication in Japanese Heart
Failure Patients. Clin Pharmacol Ther. 2013; 94:449-51.
5. Kimura M, Kinoshita O, Nishimura T, Imamura T,
Shiga T, Kashiwa K, et al. Successful weaningfrom the DuraHeart with a low left ventricularejection fraction. J Artif Organs. 2013;16:504-7.
6. Kato N, Kinugawa K, Nakayama E, Tsuji T,
Kumagai Y, imamura T, et al. Insufficient selfcare is an independent risk factor for adverse
clinical outcomes in Japanese patients with heart
failure. Int Heart J. 2013;54:382-9.
7. Kato N, Kinugawa K, Nakayama E, Hatakeyama
A, Tsuji T, Kumagai Y, et al. Development andPsychometric Properties of the Japanese Heart
Failure Knowledge Scale. Int Heart J. 2013; 54:
228-33.
8. Kato N, Kinugawa K, Imamura T, Muraoka H,
Minatsuki S, Inaba T, et al. Trend of Clinical
Outcomes and Surrogate Markers during Titrating

β-blocker in Heart Failure Patients with Reduced
Ejection Fraction: the Relevance of Achieved
Heart Rate and β-blocker Dose. Circ J. 2013;
77:1001-8.
9. Inaba T, Yao A, Nakao T, Hatano M, Maki H,
Imamura T, et al. Volumetric and Functional
Assessment of Ventricles in Pulmonary Hypertension on 3-Dimensional Echocardiography. Circ
J. 2013;77:198-206.
10. Imamura T, Kinugawa K, Shiga T, Kato N,
Muraoka H, Minatsuki S, et al. Novel Criteria of
Urine Osmolality Effectively Predict Response to
Tolvaptan in Decompensated Heart Failure
Patients. Circ J. 2013;77:96-104.
11. Imamura T, Kinugawa K, Shiga T, Endo M, Kato
N, Inaba T, et al. Preoperative levels of bilirubinor creatinine adjusted by age can predict theirreversibility after implantation of left ventricularassist device. Circ J. 2013;77(1):96-104. .
12. Imamura T, Kinugawa K, Ono M, Kagami Y,
Endo M, Minatsuki S, et al. EverolimusIncorporated
Immunosuppressant
Strategy
Improves Renal Dysfunction Maintaining Low
Rejection Rates After Heart Transplantation in
Japanese Patients. Int Heart J. 2013;54:222-7.
13. Imamura T, Kinugawa K, Minatsuki S, Muraoka
H, Kato N, Inaba T, et al. Urine Osmolality
Estimated by Urine Urea Nitrogen, Sodium andCreatinine can Effectively Predict Responses toTolvaptan in Decompensated Heart Failure
Patients. Circ J. 2013;77:397-404.
14. Imamura T, Kinugawa K, Minatsuki S, Muraoka
H, Kato N, Inaba T, et al. Tolvaptan can Improve
Clinical Course in Responders -Validation
Analysis for the Definition of Responsiveness by
Urine Volume. Int Heart J. 2013;54:377-81.
15. Imamura T, Kinugawa K, Kato N, Minatsuki S,
Muraoka H, Inaba T, et al. Successful Conversion
to Tolvaptan in Stage D Heart Failure Patient with
Chronic Kidney Disease Before Heart Transplantation. Int Heart J. 2013;54:48-50.
16. Imamura T, Kinugawa K, Kato N, Minatsuki S,
Muraoka H, Inaba T, et al. A Case with Recovery
of Response to Tolvaptan Associated with
Remission of Acute Kidney Injury and Increased
Urine Osmolality. Int Heart J. 2013;54(2):115-8.
17. Imamura T, Kinugawa K, Kato N, Kagami Y,

428

Endo M, Minatsuki S, et al. Successful Treatment
of Hemodynamic Compromise Caused by
Antibody-Mediated and Cellular Rejection in arecipient 12 years after Heart Transplantation. Int
Heart J. 2013;54:328-31.
18. Imamura T, Kinugawa K, Hatano M, Kato N,
Minatsuki S, Muraoka H, et al. Bosentan
improved persistent pulmonary hypertension in acase after implantation of a left ventricular assist
device. J Artif Organs. 2013;16(1):101-4. doi:
10.1007/s10047-012-0662-4. Epub 2012 Sep 27.
19. Imamura T, Kinugawa K, Hatano M, Kato N,
Minatsuki S, Muraoka H, et al. Acute pulmonary
vasoreactivity test with sildenafil or nitricmonoxide before left ventricular assist device
implantation. J Artif Organs. 2013;16:389-92.

429

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 based on heterotrophic
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 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 seems likely that the globally
standardized procedures help to attract many patientsfrom abroad in the medical tourism.
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.
Water quality has been studied twice a year over 5
years in the washer-disinfector with a reverse osmosis
plant installed in our surgical center. Incidentally,
ISO/TC 150 on the joint prostheses discusses thestandards on the remaining amount of endotoxin per
an implant.
Uetera is the domestic convener of ISO/TC 198 in
Japan. He is also a member of the Advisory Editorial
Board for the journal “Zentralsterilisation.” It is the430

official publication of the German Society for Sterile
Supply and the European Society for Hospital Sterile
Supply.
There are some legal regulations on the pressurized
vessels and ethylene oxide sterilization in Japan.
Autoclaves should undergo the annual inspection by
the Labour Standards Inspection Office. Whenethylene oxide sterilizers are used, the safety ofworking 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. Uetera
reported that cleaning 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 test
methods for evaluating cleaning efficacy.
(2) Evaluation of water quality in the washerdisinfector:
Water quality has been evaluated in our washerdisinfector with a reverse osmosis (RO) plantaccording to AAMI TIR34: 2007 Water for the
reprocessing of medical devices. Tap water or
hot-supply water was used for cleaning andintermediate 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 washerdisinfectors. The authors have reported that thesystematic method using the Ishikawa fishbone
diagram, a famous diagram for the quality control in
the industry, will also help to improve the water
quality for final rinsing in the washer-disinfectors
employed in 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.: Reverting colour change ofBowie-Dick test indicator caused by an air leakinto the chamber of prevacuum autoclave.
Zentralsterilisation 21(5): 357–63, 2013.

431

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.

Introduction and Organization
Diabetes is currently estimated to affect some 9.5
million patients or 20.5 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 andlifestyle-related diseases but include their relateddiseases, such as cancer and Alzheimer’s disease,which evidence from Japan and overseas suggests
represent potential targets for novel drug development,

432

to make research contributions that help advance
healthcare toward the next century.

References(1) Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T,
Hamagami K, Matsuda K, Yamaguchi M, Tanabe
H, Kimura-Someya T, Shirouzu M, Ogata H,
Tokuyama K, Ueki K, Nagano T, Tanaka A,
Yokoyama S, Kadowaki T.: A small-molecule
AdipoR agonist for type 2 diabetes and short lifein obesity. Nature 503, 493-499 (2013)(2) Takase S, Osuga J, 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 rarevariant in the APOC2 gene. J. Atheroscler.
Thromb. 20, 481-493 (2013)(3) Yamauchi T, Iwabu M, Okada-Iwabu M,
Kadowaki T.: Adiponectin receptors: A review of
their structure, function and how they work. Best
Pract. Res. Clin. Endocrinol. Metab. 1, 15-23(2014)(4) Kadowaki T, Yamauchi T, Okada-Iwabu M, Iwabu
M.: Adiponectin and its receptors: Implications for
reduction of obesity-associated diseases andprolongation of longevity. The Lancet Diabetes
and Endocrinology 2, 8-9 (2014)

Social Cooperation Program434

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, Dr. Kita gives lectures on “Proteome andmetabolome”. For doctor-course students, Dr. Kita
delivers a lecture on “Principles and Applications ofMass Spectrometry”.

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.
Methods for clinical samples
Clinical samples such as blood, urine, feces, andtissue biopsies vary much as compared with controlled435

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. Quantification of eicosanoids
by mass spectrometry. Idenshi Igaku Mook, 24,
63-70 (2013) (Japanese)
2. Hashimotodani Y, Ohno-Shosaku T, Tanimura A,
Kita Y, Sano Y, Shimizu T, Di Marzo V, Kano M.
Acute inhibition of diacylglycerol lipase blocks
endocannabinoid-mediated retrograde signalling:evidenceforon-demandbiosynthesisof2-arachidonoylglycerol. J. Physiol., 591, 4765-4776(2013)
3. Tokuoka M S, Kita Y, Shindou H, Shimizu T.
Alkylglycerol monooxygenase as a potential
modulator for PAF synthesis in macrophages.
Biochem. Biophys. Res. Commun., 436, 306-312(2013)
4. Yoshikawa K, Kita Y, Furukawa A, Kawamura N,
Hasegawa-Ishii S, Chiba Y, Takei S, Maruyama K,
Shimizu T, Shimada A. Excitotoxicity-induced
immediate surge in hippocampal prostanoid
production has latent effects that promote chronic
progressive neuronal death. Prostaglandins Leukot.
Essent. Fatty Acids, 88, 373-381 (2013)

436

Functional Regulation of
Adipocytes
Associate Professor
Hironori Waki, M.D., Ph.D.

Assistant Professor
Iseki Takamoto, 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.

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.

Research activities(1) Epigenetic analyses of adipocytes by using
next-generation sequencer (NGS)NGS is one of breakthrough technologies in genome
science. NGS technologies have revolutionized how
we study the epigenome and transcriptional regulation

437

of 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 inhealth and disease state and aim to elucidate themolecular mechanisms underlying the transcriptional
regulatory network. On the other hand, to investigate
roles of disease-susceptible genes identified ingenome-wide association studies (GWASs) of type 2
diabetes, we generated transgenic mice thatoverexpress the dominant-negative form of TCF7L2
in the pancreatic beta cells. We have reported that themice exhibit reduction in the amount of the pancreatic
beta cells, insulin secretion (Diabetologia. 2014
Mar;57(3): 542-53.). We also investigated effects of a
DPP4 inhibitor treatment on systemic glucose andlipid metabolism in glucokinase heterozygous
knockout mice and show that the treatment increase
the amount of the pancreatic beta cells and insulin
secretion. Our ultimate goal is to propel our research
focusing on
mechanisms of obesity, type 2 diabetes and themetabolic syndrome by using comprehensive
epigenomic, genomic, biochemical and genetic
engineering approaches.

References
1. Takamoto I, Kubota N, Nakaya K, Kumagai K,
Hashimoto S, Kubota T, Inoue M,Kajiwara E,
Katsuyama H, Obata A, Sakurai Y, Iwamoto M,
Kitamura T, Ueki K, Kadowaki T. TCF7L2 inmouse pancreatic beta cells plays a crucial role inglucose homeostasis by regulating beta cell mass.
Diabetologia. 2014 Mar; 57(3): 542-53. doi: 10.
1007/s00125-013-3131-6. Epub 2013 Dec 8.
PubMed PMID: 24317852.
2. Nakaya K, Kubota N, Takamoto I, Kubota T,
Katsuyama H, Sato H, Tokuyama K, Hashimoto S,
Goto M, Jomori T, Ueki K, Kadowaki T.
Dipeptidyl peptidase-4 inhibitor anagliptin
ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet.
Metabolism. 2013 Jul; 62(7): 939-51. doi:10.
1016/j.metabol.2013.01.010. Epub 2013 Feb 8.
PubMed PMID: 23790528.

438

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., Rika Arai, 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 andRika Arai (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 involved inproviding lectures such as Gerontological Nursing,439

Gerontological Nursing I and Gerontological Nursing
II, for undergraduates, master course students, or
PhD course students with the Department ofGerontological Nursing/Wound Care management.

•••

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.

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 and an interview
survey of nurses at the University of Tokyo hospitalwere therefore conducted to identify clinical needs inthe clinical setting. This survey was conducted as acollaborative research with the Department of nursing(University of Tokyo hospital), and is ongoing.
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 2013
• 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.

References
1. Miura Y, Nakagami G, Yabunaka K, Tohara H,
Murayama R, Noguchi H, Mori T, Sanada H.
Method for detecting aspiration based on image
prosessing-assisted
B-modevideo
ultrasonography. Journal of Nursing Science andEngineering. 2014;1(1):12-20.
2. Matsuzaki M, Haruna M, Nakayama K, Shiraishi
M, Ota E, Murayama R, Murashima S, Yeo S.
Adapting the Pregnancy Physical Activity
Questionnaire for Japanese pregnant women. J
Obstet Gynecol Neonatal Nurs. 2014 Jan-Feb;
43(1):107-16.
3. Watanabe Y, Oe M, Takemura Y, Sasaki M, Onishi
M, Kanda K, Sanada H. Four factor Research
Awareness Scale for Nurses in Japanese:
Instrument development study. Jpn J Nurs Sci.
2013;10(2):232-41.doi:10.1111/jjns.12009.
4. Mugita Y, Minematsu T, Huang L, Sugama J,
Ichikawa Y, Nakagami G, Nagase T, Oe M,
Noguchi H, Mori T, Sanada H. A convenient andhighly sensitive method for quantification ofceramide in tape-stripping samples by dot-blot
analysis as a skin barrier assessment technique inmurine macerated skin. J Jpn WOCM. 2013;17(3):201-12.
5. Mori T, Nagase T, Takehara K, Oe M, Ohashi Y,
Amemiya A, Noguchi H, Ueki K, Kadowaki T,
Sanada H. Morphological pattern classification
system for plantar thermography of patients withdiabetes. Journal of Diabetes Science andTechnology. 2013;7(5):1102-12.
6. 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
related to moisture-associated dermatitis surrounding malignant wounds in breast cancer
patients. Eur J Oncol Nurs. 2013. doi:10.1016/
j.ejon.

440

7. 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. Int Urogynecol J.2013;24(6):1039-46.
8. Yoshida M, Murayama R, Haruna M, Matsuzaki
M, Yoshimura K, Murashima S, Kozuma S.
Longitudinal comparison study of pelvic floor
function between women with and witout stressurinary incontinence after vaginal delivery. J Med
Ultrasonics. 2013;40(2):125-31.
9. 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 mother: A
randomized controlled trial. Health. 2013; 5(3):432-439.
10. 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
rat model for deep tissue infury deterioration. Int
Wound J.2013 May 7.doi:10.1111/iwj.12082.
11. 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
12. Nakagami G, Iizaka S, Murayama R. Chapter 5.
Nursing Translational Research. Bioengineering
Nursing:New Horizons of Nursing Research.
Nova Science Publishers. 97-144, 2014.
13. Oe M, Tamai N, Yoshida M, Yabunaka K. Chapter
7. Typical Bioengineering Nursing Research.
Bioengineering Nursing: New Horizons of
Nursing Research. Nova Science Publishers.
167-202, 2014.

Social Cooperation Program(22nd Century Medical and Research Center)442

Department of Ubiquitous Health
Informatics
Associate Professor
Hideo Fujita, M.D., Ph.D.

Assistant Professor
Waki Kayo, M.D., Ph.D.

Homepage

http://uhi.umin.jp

Introduction and Organization
Our mission is to promote research and developmentof a novel integration system where pieces of patients
healthcare information are virtually combined together
that are stored separately in diverse medical/
healthcare facilities. Recently developed mobile
information
communication
technologies
in
conjunction with cloud computing provide sturdy
environment to build a “virtual ubiquitous healthinformation space”. We particularly focus on better
clinical outcomes, as well as efficacy, safety, andsecurity matters achieved by those innovative systems
in the various medical/healthcare fields.

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“Mobile Cloud-based ECG (MCECG)” as a clinicallyvalid approach to this problem. We have developed acloud computing system with wirelessly transmission
ECG units, potentially clinical usefulness due to thecloud-based server built. Ongoing studies include
practical usage of mobile cloud ECG in the clinicalsettings of emergency care. We are collaborating withKitasato University, Oita University, and Hokuto
hospital. Clinical studies provide clinical evidence
that MCECG is significantly effective for better
prognostic outcome.
2. DialBetics: A novel smartphone-based selfmanagement support system for type 2 diabetic
patients
It is fundamentally important for diabetic patients tomaintain appropriate balance of diet and exercise,although the clear solution for it has not yet been
established. We have developed a novel smartphonebased self-management support system for type 2
diabetic patients. This new system has an automaticfunction of stratifying daily patient's biometric
information such as blood glucose, blood pressure,and food intake retrieved by the home sensor and443

router according to medical risk evaluation.
Stratification engine feedback the risk level and raw
data to the patients, as well as to the administrator
only if the risk level indicates extremely high so thathe/she can urge the patient to see or consult his healthprofessionals as soon as possible. It has long been
pointed out that introduction of telemedicine canproblematically increase the burden of healthcare
workers, even if its efficacy may be ascertained,suggesting the difficulties to maintain and promote thesystem. We are also struggling to develop a new
system to overcome this kind of apprehension by
developing a new algorithm to reduce the burden ofhealth care workers. We conducted clinical studies
including 56 diabetics patients in accordance with thereviewed protocol of the ethics committee. Safety andefficacy aspects of DialBetics were reported in the
Journal of Diabetes Science and Technology as a full
paper. Besides we promote the evolutional algorithm
in collaboration with a specific research laboratory inFaculty of Engineering. We plan to conduct a newclinical study this year.
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. Fujimoto H, Suzuki T, Aizawa K, Sawaki D,
Ishida J, Ando J, Fujita H, Komuro I, Nagai R
Processed B-type natriuretic peptide is abiomarker of postinterventional restenosis in
ischemic heart disease. Clin Chem. 2013 Sep;
59(9):1330-7.
2. 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.
3. 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. 2013 May;28(3):292-300.
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.

444

5. 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.
6. 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
7. 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.
8. 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 May; 222(1):278-83.
9. 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.
2012 Apr;29(4):404-10.
10. 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 Mar; 221(1):148-53.
11. 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.
12. 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.
13. Ohe H, Waki K, Yoshitomi M, Morimoto T,
Nafady-Hego H, Satoda N, Li Y, Zhao X,
Sakaguchi S, Uemoto S, Bishop GA, Koshiba T
Factors affecting operational tolerance after
pediatric living-donor liver transplantation:
impact of early post-transplant events and HLA
match. Transpl Int. 2012 Jan;25(1):97-106.
14. Waki K, Sugawara Y, Kokudo N, Kadowaki T
Long-term pancreas allograft survival insimultaneous pancreas-kidney trans- plantation byera. Clin Transpl. 2012:13-22.

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

447

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
Tomoko Nakao, M.D., Makoto Kaneko, M.D., Akiko Masuda, M.D., Makoto Kurano, M.D.

Chief Technologist
Shigeo Okubo, 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
2013, 245,894 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2013, over 5,076,461

serum enzyme tests (such as AST and ALT), and799,492 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2013, 1,131,451 samples were examined forcomplete blood cell counts, cell surface marker
analysis, prothrombin time, fibrinogen, glucose, andHbA1C tests, and 244,555 urine samples were
examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2013, 48,366 ECG, 23,324
pulmonary function tests, 10,861 echocardiography
tests, 14,894 abdominal echography tests, and 10,819
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448

section is going to be further expanded since there isso much demand from clinical doctors.
3.

Teaching activities
Lectures are given to the fourth and fifth grade
medical students on clinical tests including
hematology, chemistry, endocrinology, immunology,
bacteriology, cardiology, and pulmonary function.
The reversed CPC program is presented to the fifthand sixth grade students. Laboratory practice teachingis provided for the fifth year medical students, insmall groups of 6-7 students for one-week duration.
In this course, students learn clinical and practicalknowledge and techniques on various laboratory tests.
Students from professional schools also study
laboratory medicine under the guidance of members inClinical Laboratory Center.

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.

4.

5.

6.

7.

References
Original article:
1. Arano, T., Nakagawa, H., Ikeda, H., and Koike, K.
Adiponectin in chronic hepatitis C. Clin. J.
Gastroenterol. 6: 259-263, 2013.
2. Chen, M.J., Chen, K.Y., Chiang, S.J., Daimon, M.,
and Lee, S.J. The Telehealth Care Service Model

8.

of Hypertensive Treatmen. J Telemed Telecare.
19: 238-41, 2013.
Dohi, T., Miyauchi, K., Ohkawa, R., Nakamura,K., Kurano, M., Kishimoto, T., Yanagisawa, N.,
Ogita, M., Miyazaki, T., Nishino, A., Yaginuma,
K., Tamura, H., Kojima, T., Yokoyama, K., Kurata,T., Shimada, K., Daida, H., and Yatomi, Y.
Increased lysophosphatidic acid levels in culprit
coronary arteries of patients with acute coronary
syndrome. Atherosclerosis 229: 192-197, 2013.
Enooku, K., Kato, R., Ikeda, H., Kurano, M.,
Kume, Y., Yoshida, H., Ono, T., Aizawa, K.,
Suzuki, T., Yamazaki, T., Yatomi, Y. Inverse
correlations between serum ADAMTS13 levels
and systolic blood pressure, pulse pressure, andserum C-reactive protein levels observed at a
general health examination in a Japanese
population: a cross-sectional study. Clin. Chim.
Acta 421: 147-151, 2013.
Gotoh, H., Enooku, K., Soroida, Y., Sato, M.,
Hikita, H., Suzuki, A., Iwai, T., Yokota, H.,
Yamazaki, T, Koike, K., Yatomi, Y., and Ikeda, H.
Perihepatic lymph node enlargement observed at a
general health examination: a cross-sectional
study. Hepatol. Res. 43: 906-910, 2013.
Hikita, H., Nakagawa, H., Tateishi, R., Masuzaki,
R., Enooku, K., Yoshida, H., Omata, M., Soroida,Y., Sato, M., Gotoh, H., Suzuki, A., Iwai, T.,
Yokota, H., Koike, K., Yatomi, Y., and Ikeda, H.
Perihepatic lymph node enlargement is a negative
predictor of liver cancer development in chronic
hepatitis C patients. J. Gastroenterology 48:
366-373, 2013.
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., and 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. 43: 1005-1012, 2013.
Ichikawa, R., Daimon, M., Miyazaki, T., Kawata,T., Miyazaki, S., Maruyama, M., Chiang, SJ.,
Suzuki, H., Ito, C., Sato, F., Watada, H., andDaida, H.
Influencing factors on cardiac
structure and function beyond glycemic control in449

patients with type 2 diabetes mellitus. Cardiovasc
Diabetol. 12: e38, 2013.
9. Ikeda, H., Enooku, K., Ohkawa, R., Koike, K.,
and Yatomi, Y. Plasma lysophosphatidic acidlevels and hepatocellular carcinoma. Hepatology.
57: 417-418, 2013.
10. Inoue, Y., Tomiya, T., Nishikawa, T., Ohtomo, N.,
Tanoue, Y., Ikeda, H., and Koike, K. Induction of
p53-dependent p21 limits proliferative activity of
rat hepatocytes in the presence of hepatocyte
growth factor. PLoS ONE 8: e78346, 2013.
11. Ito, S., Iwaki, S., Koike, K., Yuda, Y., Nagasaki,A., Ohkawa, R., Yatomi, Y., Furumoto, T., Tsutsui,
H., Sobel, B.E., Fujii, S. Increased plasma
sphingosine-1-phosphate in obese individuals andits capacity to increase the expression ofplasminogen activator inhibitor-1 in adipocytes.
Coron. Artery Dis. 24: 642-650, 2013.
12. Kanno, N., Kaneko, M., Suzuki ,A., Yatomi ,Y.
Evaluation of Factor XIII Activity Using
Berichrom FXIII Chromogenic Assay on the
Fully-Automated Coagulation Analyzer CS-2000i- Based on Comparisons with Universal
Biochemical Analyzer and Antigen Method-Sysmex Journal International Vol. 23 No. 1(2013) Sysmex Journal International Web HP(https://sysmex-success.com/cs/)
13. Kawakami, M., Morita, S., Sunohara, M., Amano,Y., Ishikawa, R., Watanabe, K., Hamano, E.,
Ohishi, N., Nakajima, J., Yatomi, Y., Nagase, T.,
Fukayama, M., Takai, D. FER overexpression isassociated with poor postoperative prognosis andcancer-cell survival in non-small cell lung cancer.
Int. J. Clin. Exp. Pathol. 6: 598-612, 2013.
14. Kawakami, M., Ishikawa, R., Amano, Y.,
Sunohara, M., Watanabe, K., Ohishi, N., Yatomi,Y., Nakajima, J., Fukayama, M., Nagase, T., Takai,
D. Detection of novel paraja ring finger 2-fer
tyrosine kinase mRNA chimeras is associated withpoor postoperative prognosis in non-small celllung cancer. Cancer Sci.104: 1447-1454, 2013.
15. Kawata, T., Daimon, M., Hasegawa, R., Toyoda,T., Sekine, S., Himi, T., Uchida, D., Miyazaki, S.,
Hirose, K., Ichikawa, R., Maruyama, M., Suzuki,
H., and Daida, H. Prognostic value of coronary
flow reserve assessed by transthoracic Doppler
echocardiography on long-term outcome inasymptomatic patients with type 2 diabetes
without overt coronary artery disease. Cardiovasc
Diabetol. 12: e121, 2013.
16. Kimura, K., Takenaka, K., Ebihara, A., Uno, K.,
Morita, H., Nakajima, T., Ozawa, T., Aida, I.,
Yonemochi, Y., Higuchi, S., Motoyoshi, Y.,
Mikata, T., Uchida, I., Ishihara, T., Komori, T.,
Kitao, R., Nagata, T., Takeda, S., Yatomi, Y.,
Nagai, R., and Komuro, I. Prognostic impact ofleft ventricular noncompaction in patients with
Duchenne/Becker
musculardystrophy
Prospective multicenter cohort study. Int. J.
Cardiol. 168: 1900-1904, 2013.
17. Kurano, M., Tsukamoto, K., Ohkawa, R., Hara,
M., Iino, J., Kageyama, Y., Ikeda, H., Yatomi, Y.
Liver involvement in sphingosine 1-phosphate
dynamism revealed by adenoviral hepatic
overexpression of apolipoprotein M. Atherosclerosis 229: 102-109, 2013.
18. Makinae, H., Numata, N., Kitaoka, H., Daimon,
M., Yamamoto, T., and Amano, A. Use ofpacemaker programmers for disaster victim
identification. Forensic Sci Med Pathol. 9: 551553, 2013
19. Miyabe, Y., Miyabe, C., Iwai, Y., Takayasu, A.,
Fukuda, S., Yokoyama, W., Nagai, J., Jona, M.,
Tokuhara, Y., Ohkawa, R., Albers, H.M., Ovaa, H.,
Aoki, J., Chun, J., Yatomi, Y., Ueda, H., Miyasaka,M., Miyasaka, N., and Nanki, T. Lysophosphatidic
acid receptor LPA is essential for development ofarthritis.Arthritis. Rheum. 65: 2037-2047, 2013.
20. Morita, K., Yoshimi, A., Masuda, A., Ichikawa,M., Yatomi, Y., Kurokawa, M. Unique associationof Waldenström macroglobulinemia with optic
neuritis and monoclonal T cell expansion. Int J.
Hematol. 98: 247-249, 2013.
21. Nagafuchi, Y., Sumitomo, S., Soroida, Y., Kanzaki,
T., Iwasaki, Y., Michishita, K., Iwai ,T., Ikeda, H.,
Fujio, K., and Yamamoto,K. The power Doppler
twinkling artefact associated with periarticular
calcification induced by intra-articular corticosteroid injection in patients with rheumatoid
arthritis. Ann. Rheum Dis. 72: 1267-1269, 2013.
22. Nagura, Y., Tsuno, N.H., Ohkawa, R., Nojiri, T.,
Tokuhara, Y., Matsuhashi, M., Yatomi, Y., andTakahashi, K. Inhibition of Lysophosphatidic Acid
(LPA) Increase by Pre-storage Whole-Blood

450

Leukocyte Reduction in Autologous CPDA-1
Whole Blood. Transfusion 53: 3139-48, 2013.
23. Nakao T, Morita H, Maemura K, Amiya E,
Inajima T, Saito Y, Watanabe M, Manabe I,
Kurabayashi M, Nagai R, Komuro I. Melatoninameliorates angiotensin II-induced vascularendothelial damage via its antioxidative properties.
J Pineal Res. 55(3):287-93, 2013.
24. Nikitenko L.L, Shimosawa, T., Henderson, S.,
Mäkinen, T., Shimosawa, H., Qureshi U., Pedley
B.,Rees M.C.P., Fujita, T., and Boshoff C.
Adrenomedullin Haploinsufficiency Predisposes
to Secondary Lymphedema. J. Invest Dermatol.
133: 1768-1776, 2013.
25. Nishizaki, Y., Daimon, M., Miyazaki, S., Suzuki,
H., Kawata, T., Miyauchi, K., Chiang, SJ.,
Makinae, H., Shinozaki, T., and Daida, H.
Clinical Factors Associated with ClassicalSymptoms of Aortic Valve Stenosis. J Heart
Valve Dis. 22: 287-294, 2013.
26. Ogura,S., Shimosawa, T., Mu,S. Sonobe, T.,
Kawakami-Mori, F., Wang, H.,Uetake, Y. ,Yoshida, K., Yatomi,Y., Shirai,M., and Fujita, T.
Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing oxidized LDL receptor. Am. J. Physiol.
Heart Circ. Physiol.305: H155-162, 2013.
27. Ono, Y., Kurano, M., Ohkawa, R., Yokota, H.,
Igarashi, K., Aoki, J., Tozuka, M., Yatomi, Y.
Sphingosine 1-phosphate release from platelets
during clot formation: close correlation between
platelet count and serum sphingosine 1-phosphateconcentration. Lipids Health Dis. 12: 20, 2013.
28. Sasaki ,T,. Isayama, H., Nakai, Y., Takahara, N.,
Satoh, Y., Takai, D., Kogure, H., Yamamoto, N.,
Hirano, K., Tada, M., Yatomi, Y., Koike, K. A
pilot study of salvage irinotecan monotherapy foradvanced biliary tract cancer.Anticancer Res. 33:
2619-2622, 2013.
29. Sumida., H., Nakamura, K., Yanagida, K.,
Ohkawa, R., Asano, Y., Kadono, T., Tamaki, K.,
Igarashi, K., Aoki, J., Sato, S., Ishii, S., Shimizu,T., Yatomi, Y. Decrease in circulating autotaxin byoral administration of prednisolone.Clin. Chim.
Acta. 415: 74-80, 2013.
30. Takahara, N., Nakai, Y., Isayama, H., Sasaki, T.,
Satoh, Y., Takai, D., Hamada, T., Uchino, R.,

Mizuno, S., Miyabayashi, K., Mohri, D.,
Kawakubo, K., Kogure, H., Yamamoto, N.,
Sasahira, N., Hirano, K., Ijichi, H., Tada, M.,
Yatomi, Y., Koike, K. Uridine diphosphate
glucuronosyl transferase 1 family polypeptide A1
gene (UGT1A1) polymorphisms are associatedwith toxicity and efficacy in irinotecan
monotherapy for refractory pancreatic cancer.
Cancer Chemother. Pharmacol. 71: 85-92, 2013.
31. Watanabe-Okochi, N., Yoshimi, A., Sato, T., Ikeda,
T., Kumano, K., Taoka, K., Satoh, Y., Shinohara,A., Tsuruta, T., Masuda, A., Yokota, H., Yatomi,Y., Takahashi, K., Kitaura, J., Kitamura, T.,
Kurokawa, M. The shortest isoform of C/EBPβ,
Liver inhibitory protein (LIP), collaborates with
Evi1 to induce AML in a mouse BMT model.
Blood. 121: 4142-4155, 2013.
32. Yang, B., Daimon, M., Ishii, K., Kawata, T.,
Miyazaki, S., Hirose, K., Ichikawa, R., Chiang,
SJ., Suzuki, H., Miyauchi, K., and Daida, H.
Prediction of Coronary Artery Stenosis at Rest in
Patients with Normal Left Ventricular Wall
Motion: Segmental Analyses Using Strain
Imaging Diastolic Index. Int Heart J. 54:266-272,
2013.
33. Yoshizato, T., Watanabe-Okochi, N., Nannya, Y.,
Ichikawa, M., Takahashi, T., Sato, T., Masuda, A.,
Yatomi, Y., Tsuno, NH., Kurokawa, M., Takahashi,
K. Prediction model for CD34 positive cell yieldin peripheral blood stem cell collection on the
fourth day after G-CSF administration in healthy
donors.Int. J. Hematol. 98: 56-65, 2013.
Review article:
1. Takuwa, Y., Ikeda, H., Okamoto, Y., Takuwa, N.,
Yoshida, K. Sphingosine 1-phosphate as amediator involved in development of fibrotic
diseases. Biochim Biophys Acta. 1831: 185-192,
2013.
Book:
1. Yatomi, Y., Igarashi, K., Nakamura, K., Ohkawa,R., Masuda, A., Suzuki, A., Kishimoto, T., Ikeda,
H., and Aoki, J. Clinical introduction of lysophosphatidic acid (LPA) and autotaxin assays.
Lysophospholipid Receptors: Signaling and Biochemistry (eds., J. Chun, T. Hla, W. Moolenaar,
and S. Spiegel) pp. 709-735. John Wiley & Sons,
Inc., Hoboken. 2013.

451

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
The centralized management of operating rooms(OR) first began at the University of Tokyo Hospitalin July 1955. The office, so called the 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 surgicalcenter had 14 ORs including one bio-clean room. The
administrative staff included 4 doctors, 75 nurses, 6technical officials, 5 part-time employees. The
surgical center became to provide managerial servicesof the OR to 18 surgical departments after moving
into the new office building. The total volume ofoperations remained to be below 6,300 a year between
1999 and 2000 because of the number of ORs andnurses.
In July 2001, the branch hospital in Mejiro area wasmerged with the University of Tokyo Hospital in
Hongo area, which opened a new Ward B Building in
October 2001. After the merger, the number ofelective operations markedly increased and becameover 7,300. The two additional ORs were began to be
used tentatively to accommodate an abrupt increase in

the number of elective operations. The one OR was set
up on the ICU/CCU/HCU floor in the new Ward A
Building and the other was in the Outpatient Clinic
Building. The outpatient OR orthopedic outpatientswas diverted for the general OR, which was used forthe short-stay and day surgery.
Until September 2001, the elective operations had
been performed in 9 ORs. After October 2001, 12 ORs
began to be used. In the year 2007, the Central
Clinical Service Building 2, which had 11 ORs, wascompleted to solve the shortage of the number of ORs.
As a result, the total number of ORs became 23, andthen the number of operations has dramaticallyincreased.
A total of 8,485, 9,550, 9921, 9,944, 10,394,
10,170, 10,752 and 11,235 operations were performed
in 2006, 2007, 2008, 2009 2010, 2011, 2012 and 2013
fiscal year, respectively. The number of operationsin 2013 fiscal year counts for approximately 1.8 times
comparing to that in 2001.
These days more and more patients undergo theoperation, using endoscopic technique, such as
laparoscopic/thoracoscopic operation. There is also anapparent increase in the number of patients who are at452high risk with critical morbidity or with positive test
for the particular types of 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 planning of operation schedule to theeducation of the medical students and research on
healthcare practices.

Planning of Operation Schedule
All operations of in-patients are performed in 23
ORs at the surgical center. Computer system has beenutilized in order to handle the information related tothe operation. In May 1999, the on-line system wasintroduced to order the elective and urgent/emergent
operations through the computer terminal in the wards.
The input of postoperative patient information started
from March in 2000.
The present status of the operation process began to
be seen through the computer monitor from May in1997. This system also enabled the medical staff toknow the availability of the ORs of the next day. From
November in 2000, the medical staff can see theoperation schedule through the hospital computer
network. The photographs of surgical sites, resectedorgans and live video image began to be delivered tothe clinical departments from February in 1997.
The SPD system and the progressive patient caresystem started in the Ward A Building and Central
Clinical Service Building 2 in order to improve theworkflow of hospital in October 2001. In the surgicalcenter, this SPD system has been available since
September in 2002.
Recently, the number of complicated and long
surgical procedures using advanced technology has
dramatically increased. In addition, more and morepatients tend to undergo surgery using artificial
implant, joint prosthesis or intraocular lenses. Thoseoperations include organ transplantation, microvascular surgery, cardiovascular surgery, minimallyinvasive surgery and navigation-guided orthopedic/
neurosurgical surgery and stent grafting for theabdominal or thoracic aortic aneurysms. Organtransplantation and intraoperative three-dimensional
echo-guided surgery are also frequently performed.
Minimally invasive surgery is another recent trend of
the operation. Those include MIDCAB operations for
CABG and endovascular treatment for heart
anomalies such as ASD and VSD. More recently, therobotic surgery has started at the surgical center.
Healthcare-Associated infections (HAI) are criticalissues in the surgical center. It is mandatory to educate
how to prevent HAI and occupational infections. As
the number of operation of the patients withemergence and re-emergence infectious diseases suchas HIV and tuberculosis has increased, all health carestaff in the surgical center are required to adhere to theprinciples of standard precautions and transmissionbased precautions.

Teaching Activities
The following lectures or seminar are given to theundergraduates and postgraduates medical students:
aseptic techniques, sterilization/disinfection methods,
prevention of perioperative infections, humoral andcellular responses to trauma and shock, training ofscrubbing and gown techniques. The curriculum is
updated each year. Introductory course for disinfection,sterilization and preservation of surgical instruments
and medical devices was added in the training courses
in 1998, which gained more interest and popularity
among 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 robotic surgery.
As a result, the education related to the assist for thosesurgical procedure has become most important
activities in the surgical center. The lectures ofadvanced technologies are in the curriculum for thesurgeons, the nursing staff and clinical engineers sothat they can understand how to use them in a proper
way.
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,

453

prevention of perioperative infections, and on-sitetraining of scrubbing and gown techniques as wall as
aseptic preparation of surgical instruments in the OR.
An advanced course is prepared to the experienced
nurses as well. The purpose of this course is toupgrade their perioperative nursing skills so that they
can demonstrate full nursing skills even in thecomplicated and long 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 given lectures on
aseptic techniques, sterilization/disinfection methods,
preventionofperioperative
infections,andmaintenance of reusable surgical instruments such as
forceps, scissors and clamps. These subjects are
summarized and stated in the manual. Lectures arealso given to the senior technical officers andtemporary employees to promote their technicalknowledge and skills.

Research Activitiesl) Safety management and safe surgery
2) Introduction of IT technology in the advanced
surgery3) Improvement of cost-effectiveness in the surgicaltreatment
4) International comparison of cost-effectiveness inthe surgical treatment
5) Maintain of the surgical environment in the OR,
including aseptic conditions, air conditioning andsurgical 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 reusable surgical instruments11) Recording and delivery of the live video images ofthe surgical field
12) Improvement of minimally invasive surgery andinflammatory responses
13) Perioperative management of nutrition
14) Others

References（2011-2013）
1. Fukatsu K, Kudsk KA. Nutrition and gut
immunity. Surg Clin North Am. 2011; 91(4):755-70.
2. 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-associated lymphoid tissue. JPEN. 2011;34:616-24, 2011.
3. Murakoshi S, Fukatsu K, Omata J, Moriya T,
Noguchi M, Saitoh D, Koyama I. Effects ofadding butyric acid to PN on gut-associatedlymphoid tissue and mucosal immunoglobulin A
levels. JPEN. 2011; 35:465-72.
4. Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg
Res. 2012: 172:83-4.
5. 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. 2011; 30:513-6.
6. Fukatsu K. Nutrition and gut immunity. Surg Clin
North Am. 2011; 91(4):755-70.
7. Yasuhara H, Fukatsu K, Komatsu T, Obayashi T,
Saito Y, Uetera Y. Prevention of medical accidents
caused by defective surgical instruments. Surgery.
2012; 151(2):153-61.
8. Fukatsu K. The long road to optimizing theparenteral provision of nutrients. JPEN J Parenter
Enteral Nutr. 2012; 36(2):157-8.

454

9. 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; 151(5):745-55.
10. Yasuhara H, Fukatsu K, Komatsu T, Obayashi T,
Saito Y, Uetera Y. Prevention of medical accidents
caused by defective surgical instruments. Surgery.
2012; 151(2):153-61.
11. Fukatsu K. Friend or foe? Linkage between
hormonal response and innate immunity. J Surg
Res. 2012; 172(1):83-4.
12. 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;
174(2):334-8.
13. Uetera Y, Kishii K, Yasuhara H, Kumada N,
Moriya K, Saito R, Okazaki M, Misawa Y,
Kawamura K. A 5 year longitudinal study of waterfor final rising in the single chamber
washerdisinfector with a reverse osmosis plant.
PDA J Pharm Sci Technol. 2013; 67(4):399-411.
14. 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. 2013; 258(6):1059-64.
15. Uetera Y, Kishii K, Yasuhara H, Kumada N,
Moriya K, Kumada N, Tannno H. Reverting
colour change of Bowie-Dick test indicator
caused by an air leak into the chamber ofprevacuum autoclave. Zentralsterilization. 2013;21(5):357-363

455

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, 73 radiological
technicians and 1 technical official of the radiation
control. The staff members of the Department ofRadiology (teachers, the graduate school students,
medical staffs, and the clinical trainees) join this. In
addition, the doctors of other departments and thenurses cooperate and are also engaged in the clinicalradiology 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: Ongoing collaborative 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456

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.

457

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Lecturer
Tappei Takada, Ph.D.

Research Associate
Yoshiyuki Ohno, Ph.D.,

Yoshiaki Kariya, Ph.D.,

Kazuo Takayama,

Masashi Honma,

Tomoko Mayuzumi,

Yoshitsugu Yanagihara, Ph.D.,

Takehito Yamamoto,

Yoshihide Yamanashi, Ph.D.,

Homepage

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

Introduction and Organization
We have 10 faculty members, 66 pharmacy staffs,
and 7 graduate students and 6 undergraduate students
from the faculty of pharmaceutical sciences and 2
graduate students from the faculty of medicine (as ofDecember 1st, 2013). 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 contra-

indications 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.
4) Drug matters and drug management section
Drug matter section manages the adoption of
medical supplies (in-hospital and out-hospital),
periodically reconsiders the adopted medicines,

458

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(2,416 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 2013)
Number of items on in-hospital formulary: 2,416
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
449,529 ps.
(outside :359,506 ps.)(inside :90,023 ps.)out-patient chemotherapy:
11,218 ps.
in-patients :237,565 ps.
injection drugs:
214,741 ps.
IVH:
6,817 ps.
chemotherapy:
10,813 pp.
TDM consultations (annual) :17,109 pp.
Numbers of hospital pharmaceutical cares (annual):
11,304 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
charge of “Special Lecture Basic Pharmaceutical
Science IV”, “Special Lecture Clinical Science”,“Advanced Course of Medical Pharmacy" as acooperator of the Clinical Pharmacokinetics. Recent
trends of the medical pharmacy as well as the practical459

developments 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
2013, 16 pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

Research
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“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.

Publications(1) Honma M, Ikebuchi Y, Kariya Y, Hayashi M,

Hayashi N, Aoki S, Suzuki H. Rankl subcellulartrafficking and regulatory mechanisms in osteocytes.
J Bone Miner Res. 28:1936-49, 2013.
(2) Ito M, Yamanashi Y, Toyoda Y, Izumi-Nakaseko H,

Oda S, Sugiyama A, Kuroda M, Suzuki H, Takada T,
Adachi-Akahane S. Disruption of stard10 genealters the pparalpha-mediated bile acid homeostasis.
Biochim Biophys Acta. 1831:459-68, 2013.
(3) Ito N, Ito K, Koshimichi H, Hisaka A, Honma M,

Igarashi T, Suzuki H. Contribution of protein
binding,lipid

partitioning,

andasymmetricaltransport to drug transfer into milk in mouse versus
human. Pharm Res. 30:2410-22, 2013.
(4) Kariya Y, Honma M, Suzuki H. Systems-based

understanding of pharmacological responses with

460

combinations of multidisciplinary methodologies.

Results of the tokyo trial of prevention of post-ercp

Biopharm Drug Dispos. 34:489-507, 2013.

pancreatitis with risperidone-2: A multicenter,(5) Magdy T, Arlanov R, Winter S, Lang T, Klein K,

randomized, placebo-controlled, double-blind clini-

Toyoda Y, Ishikawa T, Schwab M, Zanger UM.

cal trial. Gastrointest Endosc. 78:842-50, 2013.

Abcc11/mrp8 polymorphisms affect 5-fluorouracil-(11) Yamashita F, Sasa Y, Yoshida S, Hisaka A, Asai Y,

induced severe toxicity and hepatic expression.

Kitano H, Hashida M, Suzuki H. Modeling ofPharmacogenomics. 14:1433-48, 2013.

rifampicin-induced cyp3a4 activation dynamics for(6) Matsuo H, Ichida K, Takada T, Nakayama A,

the prediction of clinical drug-drug interactions

Nakashima H, Nakamura T, Kawamura Y, Takada Y,

from in vitro data. PLoS One. 8:e70330, 2013.

Yamamoto K, Inoue H, Oikawa Y, Naito M, Hishida(12) Yoshikado T, Takada T, Yamamoto H, Tan JK, Ito K,

A, Wakai K, Okada C, Shimizu S, Sakiyama M,

Santa T, Suzuki H. Ticlopidine, a cholestatic liver

Chiba T, Ogata H, Niwa K, Hosoyamada M, Mori A,

injury-inducible drug, causes dysfunction of bile

Hamajima N, Suzuki H, Kanai Y, Sakurai Y, Hosoya

formation via diminished biliary secretion ofT, Shimizu T, Shinomiya N. Common dysfunctional

phospholipids: Involvement of biliary-excreted

variants in abcg2 are a major cause of early-onset

glutathione-conjugated ticlopidine metabolites. Mol

gout. Sci Rep. 3:2014, 2013.

Pharmacol. 83:552-62, 2013.

(7) Nakayama A, Matsuo H, Shimizu T, Ogata H,

Takada Y, Nakashima H, Nakamura T, Shimizu S,
Chiba T, Sakiyama M, Ushiyama C, Takada T,
Inoue K, Kawai S, Hishida A, Wakai K, Hamajima
N, Ichida K, Sakurai Y, Kato Y, Shimizu T,
Shinomiya N. Common missense variant of
monocarboxylate transporter 9 (mct9/slc16a9) geneis associated with renal overload gout, but not withall gout susceptibility. Hum Cell. 26:133-6, 2013.
(8) Nukui Y, Hatakeyama S, Okamoto K, Yamamoto T,

Hisaka A, Suzuki H, Yata N, Yotsuyanagi H, Moriya
K. High plasma linezolid concentration andimpaired renal function affect development oflinezolid-induced thrombocytopenia. J Antimicrob
Chemother. 68:2128-33, 2013.
(9) Takeuchi K, Ohishi M, Ota S, Suzumura K,

Naraoka H, Ohata T, Seki J, Miyamae Y, Honma M,
Soga T. Metabolic profiling to identify potential
serum biomarkers for gastric ulceration induced by
nonsteroid anti-inflammatory drugs. J Proteome Res.
12:1399-407, 2013.
(10) Uchino R, Isayama H, Tsujino T, Sasahira N, Ito Y,

Matsubara S, Takahara N, Arizumi T, Toda N,
Mohri D, Togawa O, Yagioka H, Yanagihara Y,
Nakajima K, Akiyama D, Hamada T, Miyabayashi
K, Mizuno S, Kawakubo K, Kogure H, Sasaki T,
Yamamoto N, Nakai Y, Hirano K, Tada M, Koike K.

461

Delivery Unit
Professor
Tomoyuki Fujii

Associate Professor
Takahiro Yamashita

LecturerTakeshi Nagamatsu

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, one lecturer and about 10 fellows. All thestaff members are taking part in research activities ofreproductive endocrinology, gynecologic oncology, or
perinatal medicine, as well as being engaged within-patient and out-patient care for pregnant women
including the activities in the delivery units.

Activities
Total number of delivery cases was 847 in 2013.
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.]

462

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Lecturer

Naoshi Ogata, M.D.

Associate
Yauo Nakahara, M.D., Motomu Suga, M.D., Sayaka Fujiwara, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The physical therapy service started in 1963 at the
University of Tokyo Hospital, and then expanded toinclude occupational therapy and social work section.
In 1966 this service was converted to the central
rehabilitation service department as a part of theCentral Diagnostic and Therapeutic Service
Department. The Central Rehabilitation Service
became an independent unit in 1970. After the
reorganization of the University of Tokyo Hospital
according to major organic classification in 1998,
outpatient clinic as rehabilitation medicine wasinstalled. The formal title of our unit was changed
from the Physical Therapy Department to the
Rehabilitation Department by the budget measures in
the fiscal year 2001, and we integrated the related
personnel categories, which belonged to theorthopedic surgery department and the physicalmedicine department.
At the present time our department consists of four
sections. Rehabilitation physicians’ section includes
five 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. Eighteen
physical therapists are working in the physical therapy
section. In the occupational therapy section, five
occupational therapists work for the generalrehabilitation service and the other four 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
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The
Rehabilitation Center and the Department of
Rehabilitation Medicine are united and engage inclinical practice. We have at present no charged ward,
and treat about 3,000 new referrals annually fromalmost all the departments of the university hospital.
We always take charge of 250-300 patients
corresponding about 25-30% of the whole number of
inpatients. We also see 30 people per day at theoutpatient rehabilitation setting. The numerical ratioof outpatient is being reduced in order to give priority
to the clinical service corresponding to needs
expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year

463

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-calledclinical clerkship for 5th year students from
Wednesday to Friday every week. They experience a
few patients and learn how to take a patients’ history,
physical findings, functional evaluation, and how toplan rehabilitation programs. We have introduced a
few of elective students for elective clinical clerkshipto our collaborating hospitals with specialized
rehabilitation ward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with otherdepartments in our hospital, other faculties in our
university, and institutions outside the University ofTokyo. The ongoing and scheduled projects are as
follows.
1) Motion analysis of patients with joint disorders
in the lower extremities
2) Motion analysis of motor development inchildren
3) Early detection, diagnosis, and progression
prevention of musculoskeletal disorders in theelderly4) Rehabilitation approaches for patients withhemophilia
5) Rehabilitation approaches for patients with spina
bifida6)7)8)Treatment 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. Haga N, Kubota M, Miwa Z: Epidemiology ofhereditary sensory and autonomic neuropathy typeIV and V in Japan. Am J Med Genet A 161A:
871-874, 2013
2. Haga N, Kosaki K, Takikawa K, Tanaka H, Okada
K, Nakahara Y, Ogata N: Education and related
support from medical specialists for Japanesepatients with major skeletal dysplasias. Disabil
Health J 6: 399-404, 2013
3. Jiao S, Zhang Y, Ma W, Haga N: FOP in China
and Japan: an overview from domestic literatures.
Am J Med Genet Part A 161A: 892-893, 2013
4. Jiao S, Tsutani K, Haga N*: Review of Cochranereviews on acupuncture: how Chinese resources
contribute to Cochrane reviews. J AlternComplement Med 19(7): 613-621, 2013
5. Zhang Y, Ogata N, Yozu A, Haga N:
Two-dimensional video gait analyses in patientswith congenital insensitivity to pain. Dev
Neurorehabil 16(4): 266-270, 2013
6. Tojima M, Ogata N, Yozu A, Sumitani M, Haga
N*: Novel three-dimensional motion analysis
method for measuring the lumbar spine range of
motion: Repeatability and reliability comparedwith an electrogoniometer. Spine 38: E1327E1333, 2013
7. Sugita S, Chikuda H, Ohya J, Taniguchi Y,
Takeshita K, Haga N, Tanaka S: Cervical canalstenosis caused by progressive fusion andenlargement of cervical vertebrae with features ofProteus syndrome and Klippel-Feil syndrome.
Skeletal Radiol 42: 1743-1746, 2013
8. Nakahara Y, Katagiri T, Ogata N, Haga N*:
ACVR1 (587T>C) mutation in a variant form offibrodysplasia ossificans progressive -second
report. Am J Med Genet Part A 164A: 220-224,
2014

464

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 in thehospital for cleaning and sterilization of previously
used devices. All re-usable devices are transported
to our division via automated guided vehicle systemfrom surgical center, ward and outpatient 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.

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.

Facilities

Research activities

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.

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.

Activities

References

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

1. 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

465

2.

3.

4.

5.

6.

Underlying Increased Postoperative Infectious
Complications During Parenteral Nutrition. Ann
Surg. 2013 Dec;258(6):1059-64
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.

466

Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D., Ph.D.*

Associate Professor (Deputy Director)
Junji Shibahara, M.D., Ph.D.*
Takeshi Sasaki, M.D., Ph.D. (Telepathology & Remote Diagnosis Promotion Section)

Associate Professor
Tetsuo Ushiku, M.D., Ph.D.*

Lecturer
Teppei Morikawa, M.D., Ph.D.,

Lecturer (Hospital)
Masako Ikemura, M.D., Ph.D.

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

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

Keisuke Matsusaka, M.D., Ph.D., Hiroyuki Abe, M.D., Ph.D.,
Aya Shinozaki-Ushiku, M.D., Ph.D. *Mariko Tanaka, M.D., Ph.D. *Clinical Fellow
Akihiro Kawabe, M.D.,

Homepage

Kensuke Ohigata, M.D.,

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology(*) and Division of Diagnostic Pathology of
University Hospital have been organized to function
as a unit.
The proper staffs in the Division of Diagnostic
Pathology include a lecturer, five associates, and two
clinical staffs.
We set up Telepathology & Remote Diagnosis
Promotion Section (TRD-PS), and Dr. Sasaki(Associate
Professor,
Yokohama
Municipal
University) took up a position, chief of Telepathology& Remote Diagnosis Promotion Section (TRD-PS)（ see www.h.u-tokyo.ac.jp/vcms_lf/dayori79.pdf ） .
We also started Outpatient Clinic of Pathology, and Dr.
Sasaki explained the detail of cancer pathology to thepatients with breast cancer.

Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2013
fiscal year consisted of 16,811 cases of histologicalexamination (23,272 specimens), 19,896 cases ofcytology, 790 of frozen histology, 486 of
intra-operative cytology, 53 casees of autopsy (16.1%of the autopsy rate), and 1 autopsy case from other467

hospitals.
Clinico-pathological conferences (CPCs) for thetwo autopsy cases are held every month in the hospital.
Furthermore, the following surgical pathology
conferences are regularly held with each clinicaldivision for the cases of various tumors of organs;thoracic organs (Dr. Shinozaki-Ushiku in charge),
liver and pancreato-biliary tract (Drs. Shibahara andTanaka), male genitourinary (Dr. Morikawa) andfemale genital tracts (Dr. Maeda), breast (Dr. Ikemura),
and bone and soft tissues (Dr. Ushiku). Biopsy
conferences are also held in the cases of kidney (Dr.
Shintani in charge), skin (Dr. Maeda) 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.
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 clinical residents (juniorcourse) to submit a report of CPC case as an
obligatory requirement of their medical training foreach of them. We have made out the digest version of
CPC slides open in the hospital (Dr. Shintani), andalso started e-learning program for interns to solve theproblems in CPC by themselves, therby facilitating
their understanding (Dr. T Ikemura). All of residents
were obligated to take the course for their training thisyear.

The Division of Diagnostic Pathology received
eight junior residents (total 26 months) in 2011 fortheir second year program of the internship.

Research activities
Dr. Sasaki is in charge of the research to evaluate
feasibility of telepathology for daily practice ofdiagnostic pathology.
We continue the study to investigate theusefulness of post mortem CT images for hospital
autopsy (Drs. Shintani and Abe). We obtain
postmortem images with a CT apparatus in the
autopsy-assisting CT room, and compare the resultswith those of autopsy in order to understand thepatients’ pathophysiology (Ref. 26 in Department of
Pathology and Diagnostic Pathology).
We continue the pathological studies ofneoplastic diseases on the basis of surgical pathology
conferences (see the pages of Department of
Pathology and Diagnostic Pathology). We are also
developing a new antibody-based in vivo-imaging andtherapy in collaboration with Department of Upper GI
tract surgery, and Genome Science Division, ResearchCenter for Advanced Science and Technology, theUniversity of Tokyo. We are evaluating the feasibilityof antibody panels for immunohistochemistry todetect the metastasis in the sentinel lymph nodes of
the gastric cancer, by constructing the tissue array ofprimary and metastatic cancers (Drs. Ushiku,
Matsusaka, and Abe). We also cooperate with projects
developing PET and in vivo imaging of cancers with
Departments of Upper GI tract Surgery andHepato-biliary & Pancreas Surgery.

References
See the corresponding section of Department of
Pathology and Diagnostic Pathology

468

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 89 corneal transplantations were performed in
2013. In addition to the full-thickness corneal transplantation, we have successfully performed corneal
endothelial transplantation for patients with bullous
keratopathy, the most common disease of corneal
transplantation. Generally, corneal transplantation is
performed as emergency operation, because we needto 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 tocorneal diseases. In patients with chemical burn of469

ocular 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 results in corneal
transplantation.

References
1. Mimura T, Yamagami S, Amano S. Corneal
endothelial regeneration and tissue engineering.
Prog Retin Eye Res. 35:1-17, 2013.
2. Miyashita H, Yokoo S, Yoshida S, Kawakita T,
Yamagami S, Tsubota K, Shimmura S. Long-term
maintenance of limbal epithelial progenitor cells
using rho kinase inhibitor and keratinocyte growth
factor. Stem Cells Transl Med. 2:758-65, 2013.
3. Mimura T, Usui T, Yamagami S, Miyai T, Amano
S. Relationship between total tear IgE and specificserum IgE in autumnal allergic conjunctivitis.
Cornea. 32:14-9, 2013.
4. Fukuda R, Usui T, Miyai T, Yamagami S, Amano
S. Tear meniscus evaluation by anterior segment
swept-source optical coherence tomography. Am
J Ophthalmol. 155:620-4, 2013.
5. Mimura T, Yamagami S, Kamei Y, Goto M,
Matsubara M. Influence of axial length on
conjunctivochalasis. Cornea. 32:1126-30, 2013.
6. Toyono T, Usui T, Yokoo S, Kimakura M,
Nakagawa S, Yamagami S, Miyata K, Oike Y,
Amano S. Angiopoietin-like protein 2 is a potent
hemangiogenic and lymphangiogenic factor incorneal inflammation. Invest Ophthalmol Vis Sci.
54:4278-85, 2013.
7. Mimura T, Yamagami S, Kamei Y, Goto M,
Matsubara M. Specific IgE in tear fluid andfeatures of allergic conjunctivitis. Curr Eye Res.
38:917-25, 2013.

470

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Motohiro Kato, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Assistant Professor
Akihide Yoshimi, M.D., Ph.D. (Hematology-Oncology)

Homepage

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

Introduction and Organization
Department of Cell Therapy and Transplantation
Medicine was institutionally established in 1995, 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 800 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 2013, 37 patients received HSCTs. We cooperatewith the members of Department of Hematology andOncology, Hematology/Oncology group in the
Department of Pediatrics, and Department ofTransfusion 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.
Clinical conference for hematopoietic stem celltransplantation: The conference is held monthly. The
members of Department of Hematology and Oncology,

471

Hematology/Oncology group in Department ofPediatrics, and Department of Transfusion Medicine
join the conference and discuss on HSCT recipients.

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. Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto
N, Watanabe-Okochi N, Kurokawa M. A role for
RUNX1 in hematopoiesis and myeloid leukemia.
Int J Hematol 2013; 97: 726-34.
2. Kumano K, Arai S, Kurokawa M. Generation of
iPS cells from normal and malignant hematopoietic cells. Int J Hematol 2013; 98: 145-52.
3. Toya T, Shinohara A, Tatsuno K, Seo S, Nannya Y,
Ichikawa M, Makimura K, Moriya K, Kurokawa
M. A case of Schizophyllum commune sinusitis
following unrelated cord blood transplantation for
acute lymphoblastic leukemia. Int J Hematol

6.

7.

8.

2013; 98: 261-3.
Uni M, Yoshimi A, Nakamura F, Takazawa Y,
Fukayama M, Kurokawa M. Successful allogeneic
stem cell transplantation for Lennert lymphoma.
Ann Hematol 2013; 92; 859-60.
Watanabe-Okochi N, Yoshimi A, Sato T, Ikeda T,
Kumano K, Taoka K, Satoh Y, Shinohara A,
Tsuruta T, Masuda A, Yokota H, Yatomi Y,
Takahashi K, Kitaura J, Kitamura T, Kurokawa M.
The shortest isoform of C/EBPβ, liver inhibitory
protein (LIP), collaborates with Evi1 to induce
AML in a mouse BMT model. Blood 2013; 121:4142-55.
Yoshizato T, Watanabe-Okochi N, Nannya Y,
Ichikawa M, Takahashi T, Sato T, Masuda A,
Yatomi Y, Tsuno NH, Kurokawa M, Takahashi K.
Prediction model for CD34 positive cell yield in
peripheral blood stem cell collection on the fourth
day after G-CSF administration in healthy donors.
Int J Hematol 2013; 98: 56-65.
Kato M, Takahashi Y, Tomizawa D, Okamoto Y,
Inagaki J, Koh K, Ogawa A, Okada K, Cho Y,
Takita J, Goto H, Sakamaki H, Yabe H, Kawa K,
Suzuki R, Kudo K, Kato K. Comparison of
intravenous with oral busulfan in allogeneic
hematopoietic stem cell transplantation withmyeloablative conditioning regimens for pediatricacute leukemia. Biol Blood Marrow Transplant
2013; 19:1690-4.
Kato M, Matsumoto K, Suzuki R, Yabe H, Inoue
M, Kigasawa H, Inagaki J, Koh K, Hashii Y,
Tauchi H, Suminoe A, Kikuta A, Sakamaki H,
Kawa K, Kato K, Fukuda T. Salvage allogeneic
hematopoietic SCT for primary graft failure inchildren. Bone Marrow Transplant 2013;
48:1173-1178.

472

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Mitsuhiro Fujishiro, M.D., Ph.D.

Associate
Shuntaro Yoshida, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kogaku/index.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.

473

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2004

2005

2006

2007

2008

2009

EGD*
Colonoscopy
Bronchoscopy
EUS**Enteroscopy
Laryngoscopy
Colposcopy

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

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

2013
11840
6000
169
763
375
128
404
19679

*Esophagogastroduodenoscopy, **Endoscopic ultrasonography

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

References(1) Sakamoto A, Fujishiro M, Koike K, Nagai R,
Ishizaka N. The prevalence of malignant
neoplastic and non-malignant gastrointestinal
lesions in cardiology inpatients. J Cardiol. 61:
181–185, 2013
(2) Fujishiro M, Sugita N. Animal feasibility study ofan innovated splash-needle for endoscopic
submucosal dissection in the upper gastrointestinal tract. Dig Endosc. 25: 7–12, 2013
(3) Fujishiro M, Chiu PW, Wang HP. Role ofantisecretory agents for gastric endoscopic
submucosal dissection. Dig Endosc. 25 Suppl 1:
86–93, 2013
(4) Konno-Shimizu M, Yamamichi N, Inada K,
Kageyama-Yahara N, Shiogama K, Takahashi Y,
Asada-Hirayama I, Yamamichi-Nishina M,
Nakayama C, Ono S, Kodashima S, Fujishiro M,
Tsutsumi Y, Ichinose M, Koike K. Cathepsin e isa marker of gastric differentiation and signet-ringcell carcinoma of stomach: a novel suggestion on
gastric tumorigenesis. PLoS One. 8:e56766, 2013
(5) Asada-Hirayama I, Kodashima S, Fujishiro M,
Ono S, Niimi K, Mochizuki S, Konno-Shimizu M,
Mikami-Matsuda R, Minatsuki C, Nakayama C,
Takahashi Y, Yamamichi N, Koike K. Narrow
band imaging with magnification can pick up
esophageal squamous cell carcinoma more

efficiently than lugol chromoendoscopy inpatients after chemoradiotherapy. Diagn Ther
Endosc. 2013:256439, 2013
(6) Asada-Hirayama I, Kodashima S, Goto O,
Yamamichi N, Ono S, Niimi K, Mochizuki S,
Konno-Shimizu
M,
Mikami-Matsuda
R,
Minatsuki C, Takahashi Y, Matsusaka K, Ushiku
T, Fukayama M, Fujishiro M, Koike K. Factors
predictive of inaccurate determination of horizontal extent of intestinal-type early gastric cancers
during endoscopic submucosal dissection: A
retrospective analysis. Dig Endosc. 25:593-600,
2013(7) Goda K, Singh R, Oda I, Omae M, Takahashi A,
Koike T, Uedo N, Hirasawa D, Fujishiro M,
Hirasawa K, Morita Y, Ho LK, Ajioka Y.
Current status of endoscopic diagnosis andtreatment of superficial Barrett's adenocarcinoma
in Asia-Pacific region. Dig Endosc. 25 Suppl
2:146-50, 2013(8) Singh R, Shahzad MA, Tam W, Goda K, Yu LH,
Fujishiro M, Uedo N, Ruszkiewicz A. Preliminary
feasibility study using a novel narrow-band
imaging system with dual focus magnification
capability in Barrett's esophagus: Is the time ripe
to abandon random biopsies? Dig Endosc. 25
Suppl 2:151-6, 2013(9) Sakaguchi Y, Ono S, Fujishiro M, Yamamichi N,
Koike K.
Invasion of poorly differentiatedadenocarcinoma to the deep muscularis mucosae
may be an indicator of lymph node metastasis in
Barrett's esophageal cancer. Dig Endosc. 25 Suppl
2:168-72, 2013

474(10) Shimamoto T, Yamamichi N, Kodashima S,
Takahashi Y, Fujishiro M, Oka M, Mitsushima T,
Koike K. No association of coffee consumption
with gastric ulcer, duodenal ulcer, reflux
esophagitis, and non-erosive reflux disease: across-sectional study of 8,013 healthy subjects inJapan. PLoS One. 8:e65996, 2013(11) Yoshida S, Watabe H, Isayama H, Kogure H,
Nakai Y, Yamamoto N, Sasaki T, Kawakubo K,
Hamada T, Ito Y, Yashima Y, Sasahira N, Hirano
K, Yamaji Y, Tada M, Omata M, Koike K.
Feasibility of a new self-expandable metallic stentfor patients with malignant colorectal obstruction.
Dig Endosc. 25:160-6, 2013(12) Yamada A, Watabe H, Oka S, Kogure H,
Imagawa H, Kobayashi Y, Suzuki H, Watari I,
Aoyama T, Isayama H, Yamaji Y, Fujishiro M,
Tanaka S, Koike K. Feasibility of spiralenteroscopy in Japanese patients: Study in two
tertiary hospitals. Dig Endosc. 25:406-11, 2013(13) Ono S, Niimi K, Fujishiro M, Nakao T, Suzuki K,
Ohike Y, Kodashima S, Yamamichi N, Yamazaki
T, Koike K Ultrathin endoscope flexibility can
predict discomfort associated with unsedated
transnasal esophagogastroduodenoscopy.World J
Gastrointest Endosc. 5:346-51, 2013(14) Asada-Hirayama I, Ono S, Kodashima S, Niimi K,
Mochizuki S, Yamamichi N, Fujishiro M,
Matsusaka K, Fukayama M, Koike K.
Preoperative iodine staining may complicate thedemarcation of esophageal carcinoma. Gut Liver.
7:492-6, 2013(15) Minatsuki C, Yamamichi N, Shimamoto T,
Kakimoto H, Takahashi Y, Fujishiro M,
Sakaguchi Y, Nakayama C, Konno-Shimizu M,
Matsuda R, Mochizuki S, Asada-Hirayama I,
Tsuji Y, Kodashima S, Ono S, Niimi K,
Mitsushima T, Koike K. Background factors of
reflux esophagitis and non-erosive reflux disease:a cross-sectional study of 10,837 subjects in Japan.
PLoS One. 8:e69891, 2013(16) Hangai S, Nakamura F, Kamikubo Y, Ichikawa M,
Suzuki H, Yoshida S, Yamada A, Takazawa Y,
Fukayama M, Koike K, Kurokawa M. Primary
gastrointestinal
follicularlymphomawithhistological transformation. Ann Hematol.
92:993-4, 2013

475

Department of Hemodialysis andApheresis
Professor
Masaomi Nangaku, M.D.,Ph.D.

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

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

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
Center for Hemodialysis was further renovated andstarted operations in Fall of 2006. This new Center for
Hemodialysis is equipped with one pressure control
unit in addition to 12 hemodialysis machines under astate-of-the-art hemodialysis control system. Ourconcept of a hemodialysis controlling system is a hub
to transfer all digital and analog data from patients andto monitor machines, including blood purification
machines, to the host computer in our hospital,
centralizing all data and administering medical coding
and billing robustly. Blood purification machines in
the ICU are also connectable to this system, which
was developed collaboratively with Nihon Kohden
Corp. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.

2.

3.
4.

5.
6.
7.

Teaching activities
1.

2.
3.

Clinical activities

4.

1.

5.

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.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to
second year residents on request.
Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010

476

6.

[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 clinical actionability 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
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,

477

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

478

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
Tetsuya Ueda, M.D., Ph.D.
Satoshi Iimuro, M.D., Ph.D.
Shuichi Kawarasaki, M.D., Ph.D.

Project Research Associate
Akiko Kishi Svensson, 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. Institutional guidelines, forms andtemplates for investigator-initiated clinical trials wereprepared in 2002 according to the principle of the
ICH-GCP and made available to the public on our
website, aiming at the contribution to the improvement of clinical trials in Japan. The support wasprovided to the investigators mainly in terms ofprotocol development and protection of research
participants.
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

479

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 Operation Division, Biostatistics
Division, Data Management Division, Monitoring
Division and Safety Information Division. Activitiesof these Divisions include protocol formulation,
project management, study design/statistical analysis,
data management, monitoring and assistance withsafety information reporting, respectively.
The Center was selected in 2011 as an MHLWfunded center of excellence for early stage andexploratory clinical trials of drugs for psychiatric andneurological diseases, enabling the Center to reinforce
the staff and to be equipped with phase 1 facilities.
Thus, the third unit, i.e., Phase 1 unit (P1 unit) wasestablished in May 2012 with 13 beds exclusively
used for clinical trials. It is featured as an integrated
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 2014, the Center staff includes aprofessor, an associate professor, a project associate
professor, 3 assistant professors, a project assistantprofessor, 14 pharmacists, 19.5 nurses (full-time
equivalent, FTE), 8 laboratory technicians (FTE), 3
clinical psychologists, 6 project specialists and 5
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.
<Site Coordinating Unit>
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 of industrysponsored clinical trials to IRB, we hold a preliminary
hearing system (named as “protocol presentation”)
before IRB.
The items processed by the Center as the IRB
secretariat in fiscal 2013 included, as for industrysponsored trials for marketing approval, 58 new
protocol applications, 76 study extension applications,506 protocol amendment applications, 1009
SAE/safety information reports, 41 study closure or
termination reports. As for investigator-initiatedclinical research, the Center processed 67 new
protocols (including 13 applications for compassionate use of unapproved drugs), 226 applications for
protocol amendment, 222 SAE/safety information
reports, 60 reports for study closure or termination.
Protocol presentations of industry-sponsored trials
prior to application to IRB totaled 14 applications.
Preliminary
consultation
andguidanceforinvestigator-initiated research application including
cases of compassionate totaled 59 and 20 applications,
respectively.
Clinical Research Support Center managed
drug/device inventory for 127 clinical trials forregulatory approval, 3 postmarketing trials, 2 trials ofdevices, 32 investigator-initiated clinical trials, andone case of compassionate use in fiscal 2013. The
number of prescriptions processed was 1074 for trials
for approval and postmarketing trials combined, 1106
for investigator-initiated clinical trials. We are
currently managing trial drugs centrally for 2
multicenter trials. We masked investigational drugs
for one double-blind placebo controlled trial. We arealso in charge 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-initiated480

trials have been employed as needed. The number oftrial participants that CRCs interacted with seemed to
be on the increase: 3776 in 2010, 3604 in 2011, 4785
in 2012 and 5329 in 2013. The number of monitoring
visits was 827 in 2013.
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.
<Central Coordinating Unit>
At Central Coordinating Unit, which wasestablished in the Center in 2010, 21 projects as ofMarch 2014 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 the second
investigator-initiated registered clinical trial, that wasa first-in-human study, a clinical trial notification was
submitted to the regulatory authority, PMDA, in
December 2012 and the trial finished in March 2014.
<P1 Unit>
After the P1 Unit was established in May 2012, wearranged for starting clinical trials the preparation of
SOPs, manuals and forms, the establishment of
in-house collaboration system, the on-the-job trainingof the staff and the recruitment system of healthy
volunteers. The practical use of P1 unit started withthe first clinical trial in October 2012. In 2013, we
conducted the first-in-human clinical trials for ourown compound that are expected to modify thedisease progression of Alzheimer’s disease. The trials
were placebo-controlled dose escalation studies andconducted for healthy elderly volunteers aged between
65 and 80 years. They consisted of 4 dose cohorts ofsingle administration studies with 11-day observation
periods in hospital and 4 dose cohorts of multiple

administration (once daily, 16 days) studies with
26-day period observation in hospital.
< University Hospital Clinical Trial Alliance>
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. From April 2014 on, another special grant
was given to the collaborative activities among theuniversities in translational research and training
programs of investigators and staff in clinicalresearch.
Until the end of March 2014, 68 protocols wereintroduced to the Alliance including 38 multinational
trials. The Alliance helped to assess feasibility in 14
trials and to select the participating sites in 42.
Cooperative protocol presentation (hearing) sessions
were held for 37 protocols. Based on the data of 20
trials, industry sponsors applied for drug approval
from Ministry of Health, Labour and Welfare and 19
drugs have been so far approved.
As part of the Alliance activities we developed a481

clinical research support system, UHCT ACReSS, tosupport glass-root clinical researchers in the quality
and project management. UHCT ACReSS is a
Web-based participant-allocation and data collection
system, which is easily customized by researchers.
The system is being used practically by 31 projects asof March 2014, and also commercially available withthe brand name ‘eACReSS’ of Fujitsu Corporation.
<National University Hospital Clinical Research
Initiative>
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 and the second meeting washeld for two days in February 2014 in The Universityof Tokyo.

Teaching Activities
From 2013 on, the Center takes charge of a two-day
training course in ‘Clinical Clerkship’ for each groupof medical students. Three resident physicians got
training for a month in the Center as part of the M.D.
residency-training program.
Annual CRC training course for national, public
and private university hospitals in 2013 was held
under the auspices of Tokyo University Hospital for 5days, in which 95 trainees from university hospitals all
across the country participated.
“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.
The 13th University of Tokyo Hospital Clinical
Trial Seminar was held on March 28, 2014
cosponsored with the UHCT Alliance and the Centerof excellence for early and exploratory clinical trials
program with ca. 250 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 andbiostatistics focused on practical application to trials.
The Center was involved in 28 presentations inscientific meetings, of which 14 were as presenters,and 37 invited lectures in fiscal 2013 and 42 publishedpapers in 2013.

Publications
1) Okamoto H, Hori M, Matsuzaki M, Tsutsui H,
Yamazaki T, Nagai R, Yoshikawa T, Fujio Y,
Nonen S, Azuma J, Izumi T, Ohashi Y, Kitabatake
A.; On behalf of all J-Chf Investigators. Minimaldose for effective clinical outcome and predictive
factors for responsiveness to carvedilol: Japanesechronic heart failure (J-CHF) study.
Int J
Cardiol. 2013;164(2):238-244.
2) Yamazaki T, Kohro T, Chujo M, Ishigaki M,
Hashimoto T.: The occurrence rate of cerebrovascular and cardiac events in patients receiving
antihypertensive therapy from the post-marketingsurveillance data for valsartan in Japan (J-VALID).
Hyperten Res 2013;36:140-150.
3) Kohro T, Yamazaki T, Sato H, Ohe K, Nagai R.:
The impact of a change in hypertension
management guidelines on diuretic use in Japan:
trends in antihypertensive drug prescriptions from2005 to 2011. Hypertens Res 2013;36(6):559-563.
4) Yamazaki T, Nohara R, Daida H, Hata M, Kaku K,
Kawamori R, Kishimoto J, Kurabayashi M,
Masuda I, Sakuma I, Yokoi H, Yoshida M, for the
Justification for Atherosclerosis for Regression
Treatment (JART) Investigators: Intensive Lipidlowering therapy for slowing progression as wellas inducing regression of atherosclerosis inJapanese patients subanalysis of the JART study.
Int Heart J 2013;54(1):33-39.
5) Nohara R, Daida H, Hata M, Kaku K, Kawamori
R, Kishimoto J, Kurabayashi M, Masuda I,
Sakuma I, Yamazaki T, Yokoi H, Yoshida M, for
the Justification for Atherosclerosis for482

Regression Treatment (JART) Investigators:
Effect of long-term intensive lipid-lowering
therapy with rosuvastatin on progression of
carotid intima-media thickness - Justification for
Atherosclerosis for Regression Treatment (JART)
Extension Study-. Circ J 2013;77(6):1526-1533.
6) Enooku K, Kato R, Ikeda H, Kurano M, Kume Y,
Yoshida H, Ono T, Aizawa K, Suzuki T, Yamazaki
T, Yatomi Y.: Inverse correlations between serum
ADAMTS13 levels and systolic blood pressure,pulse pressure, and serum C-reactive protein
levels observed at a general health examination ina Japanese population: A cross-sectional study.
Clinica Chimica Acta 2013;421:147-151.
7) JCS Joint Working Group: Guidelines for Elective
Percutaneous Coronary Intervention in Patients
With Stable Coronary Artery Disease (JCS 2011)
Published in 2012 -Digest Version-. Circ J 2013;
77(6):1590-1607.
8) JCS Joint Working Group: Guidelines for theClinical Application of Bypass Grafts and theSurgical Techniques (JCS 2011) Published in2012 -Digest Version-. Circ J 2013; 77(6):16081641.
9) Yamamoto M, Watanabe E, Suzuki T, Yamazaki T,
Ohtsu H, Ozaki Y, Ogawa S, Yamashita T.
J-RHYTHM II Investigators.; Association
between the quality of life and asymptomatic
episodes of paroxysmal atrial fibrillation in the
J-RHYTHM II study. J Cardiol. 2013; doi:10.
1016/j.jjcc.
10) Inazawa T, Sakamoto K, Kohro T, Iijima R,
Kitazawa T, Hirano T, Kawamura M, Tagami M,
Tanaka A, Mori Y, Yamazaki T, Shiba T.;
RESEARCH Study Group. RESEARCH (Recognized effect of Statin and ezetimibe therapy forachieving LDL-C Goal), a randomized, doctororiented, multicenter trial to compare the effects
of higher-dose statin versus ezetimibe-plus-statinon the serum LDL-C concentration of Japanese
type-2 diabetes patients design and rationale.
Lipids Health Dis. 2013; doi:10.1186/1476-511X12-142.
11) Ono S, Niimi K, Fujishiro M, Nakao T, Suzuki K,
Ohike Y, Kodashima S, Yamamichi N, Yamazaki
T, Koike K.: Ultrathin endoscope flexibility can
predict discomfort associated with unsedated

transnasal esophagogastroduodenoscopy. World J
Gastrointest Endosc 2013;5(7):346-51.
12) Kohro T, Yamazaki T, Sato H, Harada K, Ohe K,
Komuro I, Nagai R.: Trends in antidiabetic
prescription patterns in Japan from 2005 to 2011.
Int Heart J. 2013;54(2):93-7.
13) Fukuda S, Shimada K, Fujita M, Yoshiyama M,
Yoshikawa J, Kohro T, Hayashi D, Yamazaki T,
Nagai R.: Changes in serum cholesterol levels
determine future risk of cardiovascular events inpatients with acute coronary syndrome in theJapanese Coronary Artery Disease (JCAD) Study.
J Cardiol. 2013;61(6):387-92.
14) Gotoh H, Enooku K, Soroida Y, Sato M, Hikita H,
Suzuki A, Iwai T, Yokota H, Yamazaki T, Koike K,
Yatomi Y, Ikeda H.: Perihepatic lymph nodeenlargement observed at a general healthexamination: A cross-sectional study. Hepatol Res.
2013;43(8):906-10.
15) Kohro T, Yamazaki T.: Will diagnosing
polyvascular disease in coronary heart disease
patients improve their outcomes? Circ J. 2013;
77(1):43-4.
16) Thiri Kyaw W, Nishikawa N, Moritoyo T, Tsujii T,
Iwaki H, Nomoto M.: Evaluating the driving
ability in patients with Parkinson's disease using adriving simulator. Intern. Med. 2013;52:871-876.
17) Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A,
Kurppa K., Moritoyo H, Belzil V.V, Dion P.A,
Higasa K, Doi K, Ishiura H, Mitsui J, Date H,
Ahsan B, Matsukawa T, Ichikawa Y, Moritoyo T,
Ikoma M, Hashimoto T, Kimura F, Murayama S,
Onodera O, Nishizawa M, Yoshida M, Atsuta N,
Sobue G.; JaCALS, Fifita JA, Williams KL, Blair
IP, Nicholson GA, Gonzalez-Perez P, Brown R.H.
Jr, Nomoto M, Elenius K, Rouleau GA, Fujiyama
A, Morishita S, Goto J, Tsuji S. ERBB4 mutations
that disrupt the neuregulin-ErbB4 pathway cause
amyotrophic lateral sclerosis type 19. Am. J. Hum.
Genet. 2013;7;93:900-905.
18) Iimuro S, Imai E, Watanabe T, Nitta K, Akizawa T,
Matsuo S, Makino H, Ohashi Y, Hishida A;
Chronic Kidney Disease Japan Cohort Study
Group; Clinical correlates of ambulatory BP
monitoring among patients with CKD. Clin J Am
Soc Nephrol. 2013 May;8(5):721-30.
19) Nitta K, Iimuro S, Imai E, Matsuo S, Makino H,

483

Akizawa T, Watanabe T, Ohashi Y, Hishida A.:
Risk factors for increased left ventricular hypertrophy in patients with chronic kidney disease.
Clin Exp Nephrol. 2013 Oct; 17(5):730-42.
20) Fujita R, Iimuro S, Shinozaki T, Sakamaki K,
Uemura Y, Takeuchi A, Matsuyama Y, Ohashi Y.:
Decreased duration of acute upper respiratory
tract infections with daily intake of fermented
milk: a multicenter, double-blinded, randomized
comparative study in users of day care facilities
for the elderly population. Am J Infect Control.
2013 Dec;41(12):1231-5.
21) Tanaka S, Tanaka S, Iimuro S, Yamashita H,
Katayama S, Akanuma Y, Yamada N, Araki A, Ito
H, Sone H, Ohashi Y; Japan Diabetes
Complications Study Group; Japanese Elderly
Diabetes Intervention Trial Group. Predicting
macro- and microvascular complications in type 2
diabetes: the Japan Diabetes Complications
Study/the Japanese Elderly Diabetes Intervention
Trial risk engine. Diabetes Care. 2013 May;36(5):1193-9.

484

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485

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 410,000
registrants, and approximately 93,000,000 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

486

•

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

487

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 heart transplantation and deceased donor liver transplantation.

References (2013)
1. Kokudo T, Hasegawa K, Sugawara Y, et al. Pitfall ofright lateral sector graft procurement: supraportalright posterior hepatic artery. Transplantation 2013;
27:89-91.
2. Mise Y, Sakamoto Y, Ishizawa T, et al. A worldwide
survey of the current daily practice in liver surgery.
Liver Cancer 2013; 2:55-66.
3. Takemura N, Saiura A, Koga R, et al. Repeat
hepatectomy for recurrent liver metastasis fromgastric carcinoma. World J Surg 2013; 37:2667-70.
4. Yamashita S, Sakabe M, Ishizawa T, et al.
Visualization of the leakage of pancreatic juice using
a chymotrypsin-activated fluorescent probe. Br J
Surg 2013; 100:1220-8.
5. Kawaguchi Y, Sugawara Y, Ishizawa T, et al.
Identification of veno-occlusive regions in a right
liver graft after reconstruction of vein segments 5
and 8: application of indocyanine green fluorescenceimaging. Liver Transpl 2013; 19:778-9.
6. Kaneko J, Sugawara Y, Tamura S, et al. De novo
malignancies after adult-to-adult living-donor livertransplantation with a malignancy surveillance
program: comparison with a Japanese populationbased study. Transplantation 2013; 15:1142-7.
7. Sakamoto Y, Nara S, Kishi Y, et al. Is extended
hemihepatectomy plus pancreaticoduodenectomy
justified for advanced bile duct cancer andgallbladder cancer? Surgery 2013; 153:794-800.
8. Kawaguchi Y, Sugawara Y, Yamashiki N, et al. Roleof 6-month abstinence rule in living donor livertransplantation for patients with alcoholic liverdisease. Hepatol Res 2013; 43:1169-74.
9. Togashi J, Sugawara Y, Akamatsu N, et al. Qualityof life after adult living donor liver transplantation:
A longitudinal prospective follow-up study. Hepatol
Res 2013; 43:1052-63.
10. Yamashita S, Hasegawa K, Takahashi M, et al.
One-stage hepatectomy following portal vein
embolization for colorectal liver metastasis. World J
Surg 2013; 37:622-8.
11. Shindoh J, Andreou A, Aloia TA, et al.
Microvascular invasion does not predict long-term
survival in hepatocellular carcinoma up to 2 cm:
reappraisal of the staging system for solitary tumors.
Ann Surg Oncol 2013; 20:1223-9.
12. Hasegawa K, Kokudo N, Makuuchi M, et al.
Comparison of resection and ablation forhepatocellular carcinoma: a cohort study based on a
Japanese nationwide survey. J Hepatol 2013; 58:
724-9.
13. Tamura S, Sugawara Y, Kokudo N. Virtual liverresection: computer-assisted operation planning
using a three-dimensional liver representation. Liver
Transpl 2013; 19:238.
14. Mise Y, Tani K, Aoki T, Sakamoto Y, et al. Virtual
liver resection: computer-assisted operation planning using a three-dimensional liver representation.

488

J Hepatobiliary Pancreat Sci 2013; 20:157-64.
15. Shindoh J, Hasegawa K, Matsuyama Y, et al. Low
hepatitis C viral load predicts better long-term
outcomes in patients undergoing resection ofhepatocellular carcinoma irrespective of serologic
eradication of hepatitis C virus. J Clin Oncol 2013;
31: 766-73.
16. Kawaguchi Y, Ishizawa T, Miyata Y, et al. Portal
uptake function in veno-occlusive regions evaluatedby real-time fluorescent imaging using indocyanine
green. J Hepatol 2013; 58:247-53.

489

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., Lumine Matsumoto, M.D., Ph.D. ,Atsuko Ozeki, 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490

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) 2013from April 1, to March 31,
2014, the total number of examinees (who had basic
examinations and optional examinations) was 6,827,
including 2,373 in basic examinations, 461 incomplete cardiovascular examinations, 14 in home
blood pressure screening, 647 in complete cerebrovascular examinations, 97 in check up dementia,
378in colorectal cancer screening, 408 in uterine
cancer screening, 472 in breast cancer screening,
588in lung cancer screening, 868 in tumor marker
diagnosis, 485 in estimation of gastric cancer risk, 8 inupper gastrointestinal endoscopy (later), and 61 inoral/dental examinations.
When examinees visit other departments in our
hospital for a work-up or treatment, we write a letterof referral by request. In the FY 2013, we issued 833
letters of referral to other departments in our hospitaland 50 to other hospitals.
We have expanded our public relations efforts andduring the FY 2013 15,000 brochure were delivered.

491

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) Okamoto H., Hori M., Matsuzaki M., Tsutsui H.,
Yamazaki T., Nagai R., Yoshikawa T., Fujio Y.,
Nonen S., Azuma J., Izumi T., Ohashi Y.,
Kitabatake A.; On behalf of all J-Chf
Investigators. Minimal dose for effective clinicaloutcomeandpredictive
factorsfor
responsiveness to carvedilol: Japanese chronic
heart failure (J-CHF) study. Int J Cardiol.
164(2):238-244,2013(2) Yamazaki T., Kohro T., Chujo M., Ishigaki M.,
Hashimoto T.: The occurrence rate of cerebrovascular and cardiac events in patients receiving
antihypertensive therapy from the post-marketingsurveillance data for valsartan in Japan(J-VALID). Hyperten Res 36:140-150,2013(3) Kohro T., Yamazaki T., Sato H., Ohe K., Nagai
R.: The impact of a change in hypertension
management guidelines on diuretic use in Japan:
trends in antihypertensive drug prescriptions
from 2005 to 2011. Hypertens Res doi:10.1038/
hr.2012.216. 2013
(4) Yamazaki T., Nohara R., Daida H., Hata M.,
Kaku K., Kawamori R., Kishimoto J.,
Kurabayashi M., Masuda I., Sakuma I., Yokoi H.,
Yoshida M., for the Justification for
Atherosclerosis for Regression
Treatment(JART) Investigators: Intensive Lipid-lowering
therapy for slowing progression as well as
inducing regression of atherosclerosis inJapanese patients subanalysis of the JART study.
Int Heart J 54(1):33-39,2013(5) Nohara R., Daida H., Hata M., Kaku K.,
Kawamori R., Kishimoto J., Kurabayashi M.,
Masuda I., Sakuma I., Yamazaki T., Yokoi H.,
Yoshida M., for the Justification for
Atherosclerosis for Regression Treatment (JART)
Investigators: Effect of long-term intensive
lipid-lowering therapy with rosuvastatin on

progression of carotid intima-media thickness Justification for Atherosclerosis for Regression
Treatment (JART) Extension Study-. Circ J
doi:10.1253/circj.CJ-12-1149,2013(6) Enooku K., Kato R., Ikeda H., Kurano M., Kume
Y., Yoshida H., Ono T., Aizawa K., Suzuki T.,
Yamazaki T., Yatomi Y.: Inverse correlations
between serum ADAMTS13 levels and systolicblood pressure, pulse pressure, and serum
C-reactive protein levels observed at a general
health examination in a Japanese population : A
cross-sectional study. Clinica Chimica Acta
421:147-151,2013(7) Bossone E, Corteville DC, Harris KM, Suzuki T,
Fattori R, Hutchison S, Ehrlich MP, Pyeritz RE,
Steg PG, Greason K, Evangelista A, Kline-Rogers
E, Montgomery DG, Isselbacher EM, Nienaber
CA, Eagle KA. Stroke and outcomes in patientswith acute type A aortic dissection. Circulation.
2013, 128: S175-9.
(8) Larsen M, Bartnes K, Tsai TT, Eagle KA,
Evangelista A, Nienaber CA, Suzuki T, Fattori R,
Froehlich JB, Hutchison S, Sundt TM, Januzzi JL,
Isselbacher EM, Montgomery DG, Myrmel T.
Extent of preoperative false lumen thrombosis
does not influence long-term survival in patientswith acute type a aortic dissection. J Am Heart
Assoc. 2013, 2 : e000112.
(9) Miyairi T, Miyata H, Taketani T, Sawaki D,
Suzuki T, Hirata Y, Shimizu H, Motomura N,
Takamoto S. Risk model of cardiovascularsurgery in 845 marfan patients using the Japan
adult cardiovascular surgery database. Int HeartJ. 2013, 54: 401-4.
(10) Fujimoto H, Suzuki T, Aizawa K, Sawaki D,
Ishida J, Ando J, Fujita H, Komuro I, Nagai R.
Processed B-Type Natriuretic Peptide Is a
Biomarker of Postinterventional Restenosis in
Ischemic Heart Disease. Clin Chem.2013, 59:
1330-1337.
(11) Enooku K, Kato R, Ikeda H, Kurano M, Kume Y,
Yoshida H, Ono T, Aizawa K, Suzuki T,
Yamazaki T, Yatomi Y. Inverse correlations
between serum ADAMTS13 levels and systolicblood pressure, pulse pressure, and serum
C-reactive protein levels observed at a general
health examination in a Japanese population: A492

cross-sectional study Clin Chim Acta. 2013,
421: 147-151.
(12) Sawaki D, Suzuki T. Targeting Transforming
Growth Factor-β Signaling in Aortopathies in
Marfan Syndrome. Circ J. 2013, 77(4): 898899.
(13) Bechmann LP, Vetter D, Ishida J, Hannivoort RA,
Lang UE, Kocabayoglu P, Isabel Fiel M, Muñoz
U, Patman GL, Ge F, Yakar S, Li X, Agius L, Lee
YM, Zhang W, Yiu Hui K, Televantou D,
Schwartz GJ, Leroith D, Berk PD, Nagai R,
Suzuki T, Reeves HL, Friedman SL.
Post-transcriptional activation of PPAR alpha by
KLF6 in hepatic steatosis. J Hepatol. 2013,
58(5): 1000-1006(14) Aizawa K, Suzuki T.
Takotsubo Cardiomyopathy: Japanese Perspective. Heart Failure
Clin. 2013, 9(2): 243-247.
(15) Bossone E, Suzuki T, Eagle KA, Weinsaft JW.
Diagnosis of Acute Aortic Syndromes - Imaging
and Beyond. Herz. 2013, 38(3): 269-276.
(16) Suzuki T, Bossone E, Sawaki D, Jánosi RA,
Erbel R, Eagle K, Nagai R. Biomarkers ofaortic diseases. Am Heart J, 2013, 165(1):15-25(17) Ono S, Niimi K, Fujishiro M, Nakao T, Suzuki K,
Ohike Y, Kodashima S, Yamamichi N, Yamazaki
T, Koike K. Ultrathin endoscope flexibility can
predict discomfort associated with unsedated
transnasal esophagogastroduodenoscopy. WorldJ Gastrointest Endosc. 2013 Jul 16;5(7):346-51.
doi: 10.4253/wjge.v5.i7.346.
(18) Ono S, Tsuji Y, Fujishiro M, Kodashima S,
Yamamichi N, Koike K. An effective techniquefor delivery of polyglycolic acid sheet afterendoscopic submucosal dissection of the esophagus: the clip and pull method. Endoscopy
2013; 45: E1–E2(in press).
(19) 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. 2013 Mar 7

International Conferences(1) American Heart Association (Dallas U.S.A:
2013/11/16)
・Lee S., Daimon M., Kimura K., Hatano M.,
Inaba T., Kohro T., Iimuro S., Mizuno Y., Maki H.,
Koide D., Yao A., Kinugawa K., Yamazaki T.,
Komuro I.
A Diagnostic Algorithm to Exclude Elevated
Right Atrial Pressure Using Echocardiographic
Measurements of Inferior Vena Cava
(2) American college of cardiology scientific session
2013 (San Francisco, CA, USA: 2013/3/9-11)
William T. Froehlich, Jip L. Tolenaar, Toru Suzuki,
Artur Evangelista Masip, Alan Braverman, Linda
Pape, Matthias Voehringer, Patrick O'Gara,
Alberto Forteza, Kevin Greason, Philippe Steg,
Eric Isselbacher, Christoph Nienaber, Kim Eagle,
Santi Trimarchi,
Predictors of Death in Type B Acute Aortic
Dissection Patients: An Analysis from theInternational Registry of Acute Aortic Dissection(IRAD)
Artur Evangelista Masip, Reed Pyeritz, Matthias
Voehringer, Truls Myrmel, Marek P. Ehrlich,Mark Peterson, Linda Pape, Toru Suzuki,
Guillaume Jondeau, Andrea Ballotta, Daniel
Montgomery,
Eric
Isselbacher,
Christoph
Nienaber, Kim Eagle, Patrick O'Gara,
Influence of Family History on Acute Aortic
Dissection: An Analysis from the International
Registry of Acute Aortic Dissection (IRAD)(3) 2013 Gordon Research Conferences; Mammalian
DNA Repair (Ventura, CA, USA: 2013/2/10-15)
Hong Zhan, Toru Suzuki, Kenichi Aizawa, Daigo
Sawaki, Junichi Ishida, Bo-Kyung Son, Kiyoshi
Miyagawa, Issei komuro, Ryozo Nagai
Ataxia Telangiectasia Mutated (ATM)-mediatedDNA Damage Response in Cardiac Fibroblasts
Plays an Important Role in Modulating
Doxorubicin-induced Cardiotoxicity

493

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D.

Vice Director
Kazuto Hoshi, M.D., Ph.D.

Project Associate Professors
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.,

Yoko Hosaka, M.D., Ph.D.,

Seiichi Yokoo, Ph.D.

Homepage

http://square.umin.ac.jp/t-e/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped
800 m2 laboratory on the 8th floor of the In-patient
Ward 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 a special medical office in the Universityof Tokyo Hospital.
June, 2002 Department of Corneal Tissue
Engineering founded by a donation from HOYA healthcare CO., Ltd.
July, 2002 Department of Vascular Regeneration
founded by a donation from Daiichi Pharmaceutical

494

Co., Ltd.
July, 2002 Department of Bone & Cartilage
Regenerative 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 In-patient 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 Co., 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.

495

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, and we have conducted 3 cases of the clinicalstudy according to our original plan. As stated above,
we are proceeding translational research aiming at
clinical application of tissue engineering andregenerative medicine.

496

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.

2.

3.

4.

5.

6.

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 mousemesenchymal cell line C3H10T1/2 by modulatingbone morphogenetic protein (BMP) signaling. J
Cell Physiol. 2013 Jan;228(1):163-71.
Yano F, Saito T, Ogata N, Yamazawa T, Iino M,
Chung UI, Kawaguchi H. β-catenin regulatesparathyroid hormone/parathyroid hormone-related
protein receptor signals and chondrocyte
hypertrophy through binding to the intracellular
C-terminal region of the receptor. Arthritis Rheum.
2013 Feb; 65(2):429-35.
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. 2013 Apr 5;288(14):9924-32.
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. 2013 May;72(5):748-53
Yano F, Hojo H, Ohba S, Saito T, Honnami M,
Mochizuki M, Takato T, Kawaguchi H, Chung UI.
Cell-sheet technology combined with athienoindazole derivative small compound
TD-198946
for
cartilage
regeneration.
Biomaterials. 2013 Jul;34(22):5581-7.
Maeda Y, Hojo H, Shimohata N, Choi S,

Yamamoto K, Takato T, Chung UI, Ohba S. Bonehealing by sterilizable calcium phosphate
tetrapods
eluting
osteogenic
molecules.
Biomaterials. 2013 Jul;34(22):5530-7.
7. Kobayashi H, Terada D, Yokoyama Y, Moon DW,
Yasuda Y, Koyama H, Takato T.Vascular-inducing
poly(glycolic acid)-collagen nanocomposite-fiber
scaffold. J Biomed Nanotechnol. 2013 Aug;9(8):1318-26.
8. Saito T, Yano F, Mori D, Ohba S, Hojo H, Otsu M,
Eto K, Nakauchi H, Tanaka S, Chung UI,Kawaguchi H. Generation of Col2a1-EGFP iPS
cells for monitoring chondrogenic differentiation.
PLoS One. 2013 Sep 16;8(9):e74137.
9. Uto S, Nishizawa S, Takasawa Y, Asawa Y,
Fujihara Y, Takato T, Hoshi K. Bone and cartilage
repair by transplantation of induced pluripotent
stem cells in murine joint defect model. Biomed
Res. 2013 Dec; 34(6):281-8.
10. Mori Y, Hoshi K, Takato T, Takahashi M, Hirano
Y, Kanno Y, Ohkubo K, Saijo H. Submucous cleft
palate: variations in bony defects of the hardpalate. 2013 Dec;51(8):e220-3.

497

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- andlong-term plans. Following is a list of hospitalmanagement achievements in which Hospital
Planning and Management was deeply involved.
・ “22nd Century Medical Center” launched・ new central hospital building launched
・ Enhanced functions in the inpatient ward
(expansion of ICU/CCU, increase in number ofbeds in the Psychiatry Department, GCU and498

MFICU, expansion of GCU)
・ To reduce the average length of hospital stays,
and improve the bed occupancy rate・ To achieve reduce drug costs and costs for
medical materials
・ Critical Care Center launched
In addition to these achievements, the division
has also strived to improve innovative patient
services, such as introducing a credit card forpatients, attracting commercial stores in thehospital, and illuminating the hospitalbuildings. At the same time, the division has
worked to develop an environment in which
medical care staff can provide high-quality andsafe medical treatment in a more composed
fashion.
(3) Medical policy recommendations
The division is not just restricted to the
management of the University of Tokyo Hospital.
It also actively implements policy recommendations aimed at improving the medical system inJapan and at deregulating medical care.
Furthermore, we point out issues related toJapan’s medical insurance system based onevidence, and we constantly issue messages fortheir improvement.

Teaching activities
Turning to postgraduate education, the division
accepts 2 research students from the Department ofMedical Informatics and Economics at the Graduate
School of Medicine.
Postgraduate students and research students pursue
their own research projects, not just from the researchareas of healthcare management and hospitalmanagement, but also from such areas as healthcare
economics and healthcare policy. The students review
previous literature and materials, and they are actively
engaged in developing research designs and thecollection of data. The students present regularresearch progress reports, they are given thoroughinstruction on writing academic papers, and they also
follow a rigid schedule of academic presentations.

Research activities
The research activities of the division are notlimited to merely healthcare management and hospitalmanagement, but cover a broader area, including
health policy and health economics.
(1) Research in healthcare management
In the past, the division analyzed the impact thata prospective payment system, which is based on
Diagnosis Procedure Combination (DPC), has on
the healthcare workplace, and it conducted
research to estimate the effects that this system
has on the length of hospital stays. The divisionalso conducted research related to the efficientuse of medical facilities, by studying therelationship between the running of operatingrooms and the number of hospital beds.
In an attempt to systemize healthcare management,
the division edited a standard textbook.
(2) Research in healthcare policy
The division undertook comparative studies
between medical systems in Japan and otherdeveloped countries. Empirical studies related tothe disparity in domestic and imported prices of
medical materials among multi countries, andstudies into the career paths of medical doctors
and health workers’ migration are ongoing.
The division carried out assessments related toJapan’s medical insurance system, and inparticular, conducted research into improvements
to the prospective payment system based on DPC,
and the effectiveness of such improvements.
(3) Research in healthcare economics
In cooperation with hospitals providing cares for
HIV/AIDS patients, the division is conducting
cost-accounting study in HIV/AIDS care.
Recently, we began cost-effectiveness analysis
for hepatitis B prevention strategies.
(4) Other research topic
The division commits a research project
regarding socio-economic impacts on childhood
obesity using a large panel data set, with otherresearch institutes

499

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 and outcomes ofout-of-hospital cardiopulmonary arrest: a nationwide observational study. Critical Care 2011:15(3);R120.

500

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. Outof the 3 psychologists, 2 promoted from part-timeones to full-time ones for a definite term. A new
post of psychiatric social worker working mainly
for the Department of Child Psychiatry was createdin 2013 also.

Clinical activities
In the year 2013, the Department of Child
Psychiatry consisted of 12 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 2013 was 252 and thesame as that in 2012. 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-eight patients were aged 6-10 years

501

old and 34 patients were older than 20 years old,suggesting that needs for assessment and treatmentof adults with developmental disorders are
increasing.
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. For general psychiatrists including senior residents of the Departmentof Neuropsychiatry, round for developmental
disorders and an inpatient program of assessment
about developmental disorders are provided asopportunity to get knowledge and experience ofdevelopmental disorders.
In response to the increasing interest to adults
with developmental disorders, a seminar ofdevelopmental disorders was held in June 2013, andover 190 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

502

addition, research related specifically to the clinicalactivities in the Department of Child Psychiatry iscurrently being investigated.

Functional MRI study of adults with ADHD andadults with Tourette syndrome by delayed rewardtask is in process.

Clinical evaluation and treatment
Effectiveness study of early intervention for
autistic
preschoolers
comparingindividual
treatment and “group therapy” is being undertaken.
Effectiveness of a program of group cognitive
behavior therapy for adults with high-functioning
ASD the revised program is investigated in arandomized 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.

References

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
As we are interested in gene-environment
interaction, we are examining influence of age ofparents and assisted reproduction technologies on
emergence of ASD. We are analyzing samples ofindividuals from a multiplex family of ASD byexome sequencing also. We are beginning genetic
analysis of Tourette syndrome 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.

1. 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 31(2): 89-95,
2013.
2. Kuwabara H, Yamasue H, Koike S, Inoue H,
Kawakubo Y, Kuroda M, Takano Y, Iwashiro N,
Natsubori T, Aoki Y, Kano Y, Kasai K. Altered
Metabolites in the Plasma of Autism Spectrum
Disorder: A Capillary Electrophoresis Time-ofFlight Mass Spectroscopy Study. PLoS One
8(9):e73814, 2013.
3. Kuwabara H, Araki T, Yamasaki S, Ando S,
Kano Y, Kasai K. Regional differences inpost-traumatic stress symptoms among children
after the 2011 tsunami in Higashi-Matsushima,
Japan. Brain Dev doi: 10.1016/j.braindev.2014.
02.003., 2014.
4. Takizawa R, Fukuda M, Kawasaki S, Kasai K,
Mimura M, Pu S, Noda T, Niwa SI, Okazaki Y;
on behalf of the Joint Project for PsychiatricApplication of Near-Infrared Spectroscopy(JPSY-NIRS) Group (Ishii-Takahashi A).
Neuroimaging-aided differential diagnosis of
the depressive state. Neuroimage 85 Pt1: 498507, 2014.
5. Sakakibara E, Takizawa R, Nishimura Y,
Kawasaki S, Satomura Y, Kinoshita A, Koike S,
Marumo K, Kono T, Kuwabara H, IshiiTakahashi A, Kawakubo Y, Kasai K. Genetic
influences on prefrontal activation during averbal fluency task in adults: A twin study
based on multichannel near-infrared spectroscopy. Neuroimage. 85 Pt1: 508-17, 2014.
6. Ishii-Takahashi A, Takizawa R, Nishimura Y,
Kawakubo Y, Matsubayashi J, Hamada K,
Okuhata S, Yahata N, Igarashi T, Kawasaki S,
Yamasue H, Kato N, Kasai K, Kano Y.
Prefrontal activation during inhibitory control
measured by near-infrared spectroscopy for503

differentiating between autism spectrum
disorders and attention deficit hyperactivity
disorder in adults. Neuroimage Clin 4: 53-63,
2013.
7. Saito Y, Suga M, Tochigi M, Abe O, Yahata N,
Kawakubo Y, Liu X, Kawamura Y, Sasaki T,
Kasai K, Yamasue H. Neural correlate ofautistic-like traits and a common allele in theoxytocin receptor gene. Soc Cogn Affect
Neurosci doi: 10.1093/scan/nst136, 2013.
8. Kamio Y, Inada N, Moriwaki A, Kuroda M,
Koyama Y, Tsujii H, Kawakubo Y, Kuwabara H,
Tsuchiya, KJ, Uno Y. Quantitative autistic traits
ascertained in a national survey of 22,529
Japanese schoolchildren. Acta Psychiatr Scand
128(1): 45-53, 2013.
9. Kuroda, M, Kawakubo Y, Kuwabara H,
Yokoyama K, Kano Y, Kamio, Y. A
Cognitive-Behavioral Intervention for Emotion
Regulation in Adults with High-functioning
Autism Spectrum Disorders: study protocol fora randomized controlled trial. Trials 14: 231,
2013.
10. Kamio Y, Inada N, Koyama T, Inokuchi E,
Tsuchiya K, Kuroda M. Effectiveness of Using
the Modified Checklist for Autism in Toddlers
in Two-Stage Screening of Autism Spectrum
Disorder at the 18-Month Health Check-Up in
Japan. J Autism Dev Disord 44(1): 194-203,
2013.
11. Marumo K, Takizawa R, Kinou M, Kawasaki S,
Kawakubo Y, Fukuda M, Kasai K. Functional
abnormalities in the left ventrolateral prefrontal
cortex during a semantic fluency task, and theirassociation with thought disorder in patientswith schizophrenia. Neuroimage 85 Pt1: 518-26,
2014.
12. Watanabe T, Abe O, Kuwabara H, Yahata N,
Takano Y, Iwashiro N, Natsubori T, Aoki Y,
Takao H, Kawakubo Y, Kamio Y, Kato N,
Miyashita Y, Kasai K, Yamasue H: Mitigationof sociocommunicational deficits of autism
through oxytocin-induced recovery of medial
prefrontal activity: a randomized trial. JAMA
Psychiatry 71(2): 166-75, 2014.
13. Watanabe T, Yahata N, Kawakubo Y, Inoue H,
Takano Y, Iwashiro N, Natsubori T, Takao H,

Sasaki H, Gonoi W, Murakami M, Katsura M,
Kunimatsu A, Abe O, Kasai K, Yamasue H.
Network structure underlying resolution of
conflicting nonverbal and verbal social
information. Soc Cog Affect Neurosci 9(6):767-75, 2014.
14. Sugano H, Nakanishi H, Nakajima M, Higo T,
Iimura Y, Tanaka K, Hosozawa M, Niijima S,
Arai H. Posterior quadrant disconnection
surgery for Sturge-Weber syndrome. Epilepsia
doi: 10.1111/epi.1254., 2014.
15. Shoji H, Hisata K, Hososawa M, Tanaka K,
Shimizu T. Oxidative stress early in infancy andneurodevelopmental outcome in very-lowbirth-weight infants. Pediatr Int doi: 10.1111/
ped.12332. , 2014.

504

Department of Pain and Palliative
Medicine
Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/pailiative/

History and outline of organization
About a half of the cancer patients die by cancer
though of the recent innovations of anti-cancer
treatments. It mainly depends on the efficacy of thefirst-line strategies whether cancer is curable or not.
Almost all the cancer patients whose initial treatment
was unsuccessful die after the distressing struggle
against their disease within several years. It is clear
for such patients that both sufficient anti-cancer
treatments and appropriate approaches to improvetheir quality of life (QOL) are simultaneously
indispensable.
However in our nation, most attention has been
entirely paid to the improvement of cure rate andsurvival time of cancer patients. On the other hand, we
have to consider 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 their cancer does or does not
respond to anti-cancer 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 Pain and Palliative Medicine of The
University of Tokyo Hospital, we pain and palliative
care team takes a leading role not only to control
physical symptoms of cancer patients but also to carefor the mental and social support at the same time, andto improve the overall QOL of patients. Moreover, we
also promote the education, research and innovationof pain and palliative medicine of our hospital anduniversity.
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 pain andpalliative care team are composed of many kinds ofspecialists containing three full-time staff doctors, twofull-time doctors, and two certificated cancer andhospice care nurses who take an initiative in thismultidisciplinary team. We visit to bedsides,
consultation rooms and everywhere in the hospital,and offer palliative care to cancer patients who havereceived cancer care in cooperation with patients’attending doctors, ward staff, therapists ofrehabilitation, social workers and every kind of
professionals.
The annual number of consultation by our pain andpalliative care team is getting increased. In 2013, thenumber achieved to more than total 500 cases. To date
we have 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 Pain and Palliative Medicine,junior residents of the first and second year can learn

505

the basic knowledge and practice of palliative care by
selecting an optional subject for one, two, four oreight months. And then they can participate in the pain
and palliative care team and attend the daily
team-conference on weekdays.
1) 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 pain and palliative carespecialists.
2) CurriculumContents of training･ All junior residents are assigned to the pain andpalliative care team. They chiefly participate inpalliative care practice 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 thepain and palliative care team treats is often in an
end stage, and his or her condition changes
physically and mentally day by day. Residents
should input the clinical data about palliative careof such patients concisely to the database. Theyacquire the outline of data management of thepalliative care connected directly to a clinicalresearch.

･ 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 (pain and palliative care team)that contains medical instructors. We pain andpalliative care team take charge of about 40-50
inpatients usually.
･ Multidisciplinary conference: Psychiatrists, pain
clinicians/Anesthesiologists,
orthopaedicians,
pharmacists, medical social workers and others
participate in the daily or weekly conference
besides the regular member of the pain andpalliative care team. Residents can discuss actively
the multidisciplinary palliative care plans which our506

team should carry out. Participants from each
occupation also guide the care plans from their
viewpoints of experts.

4.

Research
The clinical information accumulated from thepalliative care consultation is input to the concise
database simultaneously and utilized for various kindsof 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 pain
and palliative care team2) Development of the scale to measure thedesirability of the death and bereavement and its
application to the nationwide survey3) Investigating cognitive dysfunction by pain4) Synergistic influence between sleep disorder andpain5) Assessment of neuropathic pain
6) Relationships among our university hospital andlocal hospitals and clinics
7) Palliative care supporting metastatic breast cancer
patient6) In palliative medicine field, clinical researchesand questionnaires

Publications
1. Kogure T, Sumitani M, Suka M, Ishikawa H,
Odajima T, Igarashi A, Kusama M, Okamoto M,
Sugimori H, Kawahara K. Validity and Reliabilityof the Japanese version of the Newest Vital Sign:
a preliminary study. Plos One 2014; 9: e94582
2. Suka M, Odajima T, Kasai M, Igarashi A,
Ishikawa H, Kusama M, Nakayama T, Sumitani
M, Sugimori H. The 14-item health literacy scale
for Japanese adults (HLS-14). Environ HealthPrev Med 2013; 18: 407-15
3. Yozu A, Haga N, Tojima M, Zhang Y, Sumitani M,
Otake Y. Vertical peak ground force in human

5.

6.

7.

8.

9.

infant crawling. Gait and Posture 2013; 37: 293-5
Matsubayashi Y, Takeshita K, Sumitani M, Kato S,
Ohya J, Oichi T, Okamoto N, Tanaka S. Validity
and reliability of the Japanese version of thepainDETECT Questionnaire: a multicenter
observational study. Plos One 2013; 8: e68013
Tojima M, Ogata N, Honda M, Yozu A, Sumitani
M, Haga N. A novel three-dimensional motion
analysis method for measuring the lumbar spine
range of motion: Repeatability and reliability
compared with an electrogoniometer. Spine 2013;
38: e1327-33
Chikuda H, Ohtsu H, Ogata T, Sugita S, Sumitani
M, Koyama Y, Matsumoto M, Toyama Y, the
OSCIS investigators. Optimal treatment for spinal
cord injury associated with cervical canal stenosis(OSCIS): A study protocol for a randomized
controlled trial comparing early versus delayed
surgery. Trials 2013; 14: 245
Sumitani M, Kogure T, Nakamura M, Shibata M,
Yozu A, Otake Y, Yamada Y. Classification of thepain nature of CRPS type 1, based on patientcomplaints, into neuropathic pain and nociceptive/
inflammatory pain, using the McGill Pain
Questionnaire. Journal of Anesthesia and ClinicalResearch 2013; 4: 8
Murasawa T, Fujiu K, Yokota J, Iwazaki K,
Tanimoto H, Miyazaki S, Asada K, Kojima T,
Imai Y, Sumitani M, Komuro I. Continuous
cardiac stroke volume monitoring leads to early
detection of cardiac tamponade in the percutaneous intracardiac intervention. J Hypertension 2013; 2: 3-8
Matsumoto Y, Yoshikawa M, Wakita Y, Sumitani
M, Miyao M, Ishiguro H. Impression of androidfor communication support in hospitals andelderly facilities. Field and Service Robotics [11],Eds. Yoshida K; Springer, 2013; p.159-73(And, more than 60 Japanese articles)

507

Cancer Resource Center
Associate Professor
Sachiyo Nomura, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/cancer_support/index.html

Introduction and Organization
As part of national efforts to address cancer, thegovernment has been establishing a network of“cancer care hub hospitals”. In response to its being
designated as a regional cancer care hub hospital in2008, the University of Tokyo Hospital established theCancer Resource Center to provide consultations tocancer patients and their families as well as residents
in neighboring communities with aim of leading them
to appropriate departments and facilities.
The Center consists of a chief of the center, and two
consultant nurses. In addition, staff from the Cancer
Board, an in-hospital interdisciplinary cancer
treatment team, may join consultations depending on
issues to be discussed.

when receiving treatment, such as medical
expenses, how to get along after being discharged
from hospital, and nursing services. The Center
provides patients with advice and support, so thatthey can resolve such worries.
3. Provision of information on second opinion
The Center provides information on how to get asecond opinion and on facilities that provide
second opinions.
4. Provision of general information and advice on
cancer
The Center sends out and provides information topeople who do not have cancer but who want tofind out about cancer, for instance, the treatment
and screening for it.

Scope
Clinical activities
1. Provision of information if patient contracts
cancer
If a person gets cancer, the first thing they need to
do is collect information on cancer. This Center
provides information and booklets on different
types of cancer. Furthermore, in order to select thebest treatment for oneself from among thetherapies presented by doctors, the person needs
to accurately understand the doctors’ explanations.
At the Center, we explain difficult medical terms
in simple language, and we help patients
understand their doctors’ advice.
2. Various kinds of advice on the medical care ofcancer
If a person contracts cancer, besides the medical
problem of what kind of treatment to undergo andwhere, there are also issues related to medical care

We are going to meet patients and their families not
only of our patients but also from all over Japan. We
will make effort to have many patients receive goodtherapies with their satisfy.

508

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
abnormalityoferythrocytes,
issignificantly and independently associated withadverse outcomes after percutaneous coronary
intervention (aHR of cardiac death: 3.45, 95%CI:
1.22-9.80, P=0.019) and (2) serum concentrations of509

IgG4 and sIL-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 bygenetic mutations of FBN1 gene. We performed mutational analysis using a high-throughput microarraybased 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 requirement of
insulin injections among Japanese individuals.
Diabetes Care 35:1763-70, 2012
2. Kodama K, Horikoshi M, Toda K, Yamada S,
Hara K, Irie J, Sirota M, Morgan AA, Chen R,
Ohtsu H, Maeda S, Kadowaki T, Butte AJ.
Expression-based genome-wide association study
links the receptor CD44 in adipose tissue with
type 2 diabetes. Proc Natl Acad Sci U S A. 109:7049-54, 2012
3. Imamura M, Maeda S, Yamauchi T, Hara K,
Yasuda K, Morizono T, Takahashi A, Horikoshi
M, Nakamura M, Fujita H, Tsunoda T, Kubo M,
Watada H, Maegawa H, Okada-Iwabu M, Iwabu
M, Shojima N, Ohshige T, Omori S, Iwata M,
Hirose H, Kaku K, Ito C, Tanaka Y, Tobe K,
Kashiwagi A, Kawamori R, Kasuga M, Kamatani
N; Diabetes Genetics Replication and 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 ofmacrocytosis on adverse outcomes after coronary
intervention. Atherosclerosis 2012;221:148-53
Ogawa N, Imai Y, Takahashi Y, Nawata K, HaraK, Nishimura H, Kato M, Takeda N, Kohro T,
Morita H, Taketani T, Morota T, Yamazaki T,
Goto J, Tsuji S, Takamoto S, Nagai R, Hirata Y.
Evaluating Japanese patients with the Marfan
syndrome using high-throughput microarraybased mutational analysis of fibrillin-1 gene. Am
J Cardiol 2011;108: 1801-7.

510

Department of Clinical Genomics,
Medical Genome Center
Director & Professor
Shoji Tsuji, M.D., Ph.D.

Vice-director & Associate Professor
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), surgeons, and staffs
of the Departments of Clinical Laboratory Medicine,
Human Genetics and Nursing Science.

Activities
The exclusive consultation room (Room 200) is
allocated in the outpatient clinic. Consultation andcounseling is performed by a team of medical doctor
and non-M.D. staffs. All cases are reviewed anddiscussed at the conference which is held on the 1st
Monday every month.
Counseling of participants in researches including
genome or gene analysis is a duty with which thehospital and the faculty charge the department.
To build suitable clinical systems including
modern genomic medicine we are cooperating withother departments. We are participating in Marfan’sSyndrome Clinic which is managed collaboratively by
the Departments of Cardiovascular Surgery, Cardiovascular Medicine, Pediatrics, Spinal Surgery 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.

Publications
1. Ichikawa Y, Ishiura H, Mitsui J, Takahashi Y,
Kobayashi S, Takuma H, Kanazawa I, Doi K,
Yoshimura J, Morishita S, Goto J, Tsuji S. Exome
analysis reveals a Japanese family with spinocerebellar ataxia, autosomal recessive 1. J. Neurol.
Sci.331:158-60, 2013
2. Izumikawa T, Saigoh K, Shimizu J, Tsuji S,
Kusunoki S, Kitagawa H. A chondroitin
synthase-1 (ChSy-1) missense mutation in apatient with neuropathy impairs the elongation ofchondroitin sulfate chains initiated by chondroitin
N-acetylgalactosaminyltransferase- 1. Biochim.
Biphys. Acta 1830: 4806-4812, 2013
3. Kuźma-Kozakiewicz M, Berdyński M, Morita M,
Takahashi Y, Kawata A, Kaida K, Kaźmierczak B,
Lusakowska A, Goto J, Tsuji S, Zekanowski C,
Kwieciński H. Recurrent K3E mutation in Cu/Zn
superoxide dismutase gene associated with amyotrophic lateral sclerosis. Amyotrophic Lateral
Sclerosis and Frontotemporal Degeneration 14:608-14, 2013.
4. Mitsui J, Matsukawa T, Ishiura H, Fukuda Y,
Ichikawa Y, Date H, Ahsan B, Nakahara Y,
Momose Y, Takahashi Y, Iwata A, Goto J,

511

Yamamoto Y, Komata M, Shirahige K, Hara K,
Kakita A, Yamada M, Takahashi H, Onodera O,
Nishizawa M, Takashima H, Kuwano R,
Watanabe H, Ito M, Sobue G, Soma H, Yabe I,
Sasaki H, Aoki M, Ishikawa K, Mizusawa H,
Kanai K, Hattori T, Kuwabara S, Arai K, Koyano
S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K,
Nakashima K, Ito H, Izumi Y, Kaji R, Kato T,
Kusunoki S, Osaki Y, Horiuchi M, Kondo T,
Murayama S, Hattori N, Yamamoto M, Murata M,
Satake W, Toda T, Dürr A, Brice A, Filla A,
Klockgether T, Wüllner U, Nicholson G, Gilman S,
Shults CW, Tanner CM, Kukull WA, Lee V M-Y,
Masliah E, Low PA, Sandroni P, Trojanowski JQ,
Ozelius L, Foroud T, and Tsuji S. Mutations of
COQ2 in familial and sporadic multiple system
atrophy. New Engl. J. Med. 369:233-44, 2013
5. Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A,
Kurppa K, Moritoyo H, Belzil VV, Dion PA,
Higasa K, Doi K, Ishiura H, Mitsui J, Date H,
Ahsan B, Matsukawa T, Ichikawa Y, Moritoyo T,
Ikoma M, Hashimoto T, Kimura F, Murayama S,
Onodera O, Nishizawa N, Yoshida M, Atsuta N,
Sobue G, JaCALS, Fifita JA, Williams KL, Blair
IP, Nicholson GA, Gonzalez-Perez P, Brown,
Jr.RH, Nomoto M, Elenius K, Rouleau GA,
Fujiyama A, Morishita S, Goto J and Tsuji S.
ERBB4 Mutations that Disrupt the NeuregulinErbB4 Pathway Cause Amyotrophic Lateral
Sclerosis Type 19. Am J Hum Genet 93:900-5,
2013
6. Tsuji S. Neurogenomics view of neurologicaldiseases. Arch. Neurol. 70:689-94, 2013

512

Department of Genome Analysis,
Medical Genome Center,
Director & Professor
Shoji Tsuji, M.D., Ph.D.

The Department of Genome Analysis started as acore facility at the University of Tokyo Hospital in
2011. Next generation sequencers (NGSs), which havebeen installed until now, include two Illumina
HiSeq2500s ， one Pacific Bioscience RS II, one
Illumina MiSeq, one Life Technologies 5500xl, and
one Roche GS Junior. Robotics for preparation ofsamples has also been installed. Computer servers forprocessing of massive amount of genome data havebeen installed in the server room, which are connected
to NGs via network system isolated from the internet.

Activities
The core facility offers genome sequencing
employing NGSs for other laboratories in the
University of Tokyo Hospital as well as for the
in-house projects. The core facility further offers
genome sequencing employing NGSs for laboratories
outside of the University of Tokyo. Starting in 2011,
exome and target sequencing of 5,030 samples (3,552
samples for the in-house project) and whole genome
sequencing of 88 samples (23 samples for the in-houseprojects) have been accomplished.

Research Accomplishments
Multiple system atrophy (MSA) is the mostcommon sporadic spinocerebellar degeneration.
Although MSA is generally a sporadic disease, wehave identified multiplex families where siblings areaffected with MSA. Employing a pipeline software forthe linkage analysis, SNP HiTLink, we conducted
detailed linkage analyses on the six multiplex MSA
families, and narrowed down the candidate region to80 Mbp. Whole genome resequencing of the proband
in one of the multiplex families was conducted, which
revealed COQ2 as the putative gene for MSA. The
patients were shown to carry homozygous orcompound heterozygous mutations of COQ2 in two of
the six families. Furthermore, we demonstrated thatheterozygous functionally deleterious mutations of
COQ2 confer a risk for developing MSA in sporadic
MSA (New Engl. J. Med. 369:233-44, 2013).
We applied detailed linkage analyses and wholegenome resequencing to a family with amyotrophic
lateral sclerosis with an autosomal dominant
inheritance. Whole genome resequencing revealed anovel mutation of ERBB4. Furthermore, mutations of
ERBB4 was further shown in a Canadian ALS family
and in a sporadic patient as a de novo mutation,
confirming that ERBB4 is the causative gene for ALS(ALS19) (Am J Hum Genet 93:900-5, 2013)．

Publications
1. Ichikawa Y, Ishiura H, Mitsui J, Takahashi Y,
Kobayashi S, Takuma H, Kanazawa I, Doi K,
Yoshimura J, Morishita S, Goto J, Tsuji S. Exome
analysis reveals a Japanese family with spinocerebellar ataxia, autosomal recessive 1. J. Neurol.
Sci. 331:158-60, 2013
2. Izumikawa T, Saigoh K, Shimizu J, Tsuji S,
Kusunoki S, Kitagawa H. A chondroitin
synthase-1 (ChSy-1) missense mutation in apatient with neuropathy impairs the elongation ofchondroitin sulfate chains initiated by chondroitin
N-acetylgalactosaminyltransferase- 1. Biochim.
Biphys. Acta 1830: 4806-4812, 2013

513

3. Kuźma-Kozakiewicz M, Berdyński M, Morita M,
Takahashi Y, Kawata A, Kaida K, Kaźmierczak B,
Lusakowska A, Goto J, Tsuji S, Zekanowski C,
Kwieciński H.. Recurrent K3E mutation in Cu/Zn
superoxide dismutase gene associated with amyotrophic lateral sclerosis. Amyotrophic Lateral
Sclerosis and Frontotemporal Degeneration 14:608-14, 2013.
4. Mitsui J, Matsukawa T, Ishiura H, Fukuda Y,
Ichikawa Y, Date H, Ahsan B, Nakahara Y,
Momose Y, Takahashi Y, Iwata A, Goto J,
Yamamoto Y, Komata M, Shirahige K, Hara K,
Kakita A, Yamada M, Takahashi H, Onodera O,
Nishizawa M, Takashima H, Kuwano R,
Watanabe H, Ito M, Sobue G, Soma H, Yabe I,
Sasaki H, Aoki M, Ishikawa K, Mizusawa H,
Kanai K, Hattori T, Kuwabara S, Arai K, Koyano
S, Kuroiwa Y, Hasegawa K, Yuasa T, Yasui K,
Nakashima K, Ito H, Izumi Y, Kaji R, Kato T,
Kusunoki S, Osaki Y, Horiuchi M, Kondo T,
Murayama S, Hattori N, Yamamoto M, Murata M,
Satake W, Toda T, Dürr A, Brice A, Filla A,
Klockgether T, Wüllner U, Nicholson G, Gilman S,
Shults CW, Tanner CM, Kukull WA, Lee V M-Y,
Masliah E, Low PA, Sandroni P, Trojanowski JQ,
Ozelius L, Foroud T, and Tsuji S. Mutations of
COQ2 in familial and sporadic multiple system
atrophy. New Engl. J. Med. 369:233-44, 2013
5. Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A,
Kurppa K, Moritoyo H, Belzil VV, Dion PA,
Higasa K, Doi K, Ishiura H, Mitsui J, Date H,
Ahsan B, Matsukawa T, Ichikawa Y, Moritoyo T,
Ikoma M, Hashimoto T, Kimura F, Murayama S,
Onodera O, Nishizawa N, Yoshida M, Atsuta N,
Sobue G, JaCALS, Fifita JA, Williams KL, Blair
IP, Nicholson GA, Gonzalez-Perez P, Brown,
Jr.RH, Nomoto M, Elenius K, Rouleau GA,
Fujiyama A, Morishita S, Goto J and Tsuji S.
ERBB4 Mutations that Disrupt the NeuregulinErbB4 Pathway Cause Amyotrophic Lateral
Sclerosis Type 19. Am J Hum Genet 93:900-5,
2013
6. Tsuji S. Neurogenomics view of neurologicaldiseases. Arch. Neurol. 70:689-94, 2013

514

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, 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 a decisionof the following basic principles; recruitment for theparticipation to this unit should be, as a general rule,
an open call for a joint project of clinical department
and engineering or pharmaceutical research group in
The University of Tokyo, an equipment/administration
expense of a laboratory should be a responsibility of
the user, and a basic participation period to this unit
should be three years and for the continued
participation in the unit, a review and approve of thesteering committee is indispensable.
2002 October. An open call for participants to thisunit started. There were 18 applications and thesteering committee approved all projects after review.
A liaison conference of Cooperative Unit of Medicine
and Engineering Research was organized by arepresentative member of each project. Configurationof each project in a space of 554.4m2 that is consisted

515

of 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
2014 January 24. Development forum of advanced
medical seeds took place

Research activities
Development of Advanced Stereotactic Radiation
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, thecenter-of-mass motion of the tumor and thetwo-dimensional projection images for lung cancer
patients have been predicted by a multi-channel
singular spectrum analysis. This system will remove adelay problem during the real-time tumor-tracking
radiation therapy, and will provide a safer radiation
therapy than the current ones because this will be able
to detect an irregular breathing motion of the tumor. In
the prediction using movie, the tumor deformation is
involved in the evaluation. In addition, thein-treatment 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.

516

Research and development of micro-neurosurgicalrobotic systems
Department of Neurosurgery, The University of Tokyo
Hospital
Mitsuishi-Sugita
Laboratory,
DepartmentofMechanical Engineering, School of Engineering
Development of micro-neurosurgical robotic systems
and advanced microscopic image processing forautomated surgical task recognition.
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 Cardiothoracic Surgery, Graduate /School of Medicine
Department of Radiology, University of Tokyo
Hospital
Department of Nuclear Engineering and Management,

517

School of Engineering
Endowment Department, Department of Immunotherapeutics (Medinet)
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (BNCT) using
small neutron accelerator equipped to hospital andalso develop more effective immumotherapeutic
approaches.
Molecular Imaging Laboratory, Cooperative Unitof Medicine, Engineering and Pharmaceutical
Research
Laboratory of Chemistry and Biology, Graduate
School of Pharmaceutical Sciences
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
Division of Science for Joint Reconstruction,
Graduate School 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 of518

heart diseases by the synergistic effort of cellularphysiology and computational mechanics. For
collecting quantitative data for the simulator,
mechanical analysis of cardiomyocytes is performed.
Laboratory of Hard-Tissue Nanomedicine
Kataoka & Yamasaki Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Department of Cartilage & Bone Regeneration,
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
andchondrocytic
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 regenerationand 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.
Development of intraoperative navigation system
during rectal cancer surgery
Department of Surgical Oncology
Department of Precision Engineering, Bio-Medical
Precision Engineering Laboratory
Recently, less invasive laparoscopic surgery has
played a central part even in the field of pelvic surgery
including rectal surgery. Therefore, safer and more
effective surgical modalities are needed. In thisresearch department, we aim to develop theintraoperative tracking system corresponding topostural change, and to establish the intraoperative
real-time 3D display system which will enable
surgeons to recognize the location of the forceps
during rectal surgery through the use of preoperative
image information.

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22. Lee S, Matsuno R, Ishihara K, Takai M. Electrontransfer with enzymes on nanofiliform titaniumoxide films with electron-transport ability.
Biosens Bioelectron 40: 289-293, 2013.
23. Lin X, Konno T, Takai M, Ishihara K. Redox
phospholipid polymer microparticles as doubly
functional polymer support for immobilization of
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24. Mitsuishi M, Morita A, Sugita N, Sora S,
Mochizuki R, Tanimoto K, Baek YM, Takahashi
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25. Kurose Y, Baek YM, Kamei Y, Tanaka S, Harada
K, Sora S, Morita A, Sugita N, and Mitsuishi M.
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Gwangju, Korea, October 20-23, 2013.
26. Yuya K, Harada K, Tanaka S, Kurose Y, Baek YM,
Sora S, Morita A, Sugita N, Mitsuishi M, Mastermanipulator with high usability designed for
microsurgical robotic system. IMMRCAS, (8),suppl.1, S127, 2013.
27. Chang Ho, Seo, Heonuk Jeong, Katsuko S.
Furukawa, Yuji Suzuki, Takashi Ushida,The
switching of focal adhesion maturation sites andactin filament activation for MSCs by topographyof well-defined micropatterned surfaces, Biomaterials 34 1764-1771 8 (2013)
28. Asaoka T, Ohtake S, Furukawa KS, Tamura A,
Ushida T., Development of bioactive porous
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29. Takayuki Akimoto, Kanako, Okuhira, Katsuji
Aizawa, Shogo Wada, Hiroaki Honda, Toru
Fukubayashi, Takashi Ushida, Skeletal muscle
adaptation in response to mechanical stress in
p130Cas−/−mice. Am J Physiol Cell Physiol,
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30. Takahashi, H., Mitsuya, Y., Fujiwara, T., Fushie T.,
Development of a glass GEM, Nuclear
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and Associated Equipment, vol. 724, pp. 1-4, OCT
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Yasuaki; et al, Time over threshold based
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32. Nakamura, Y.; Shimazoe, K.; Takahashi, H.,
Design and fabrication of endoscope-type
Compton camera, Nuclear Instruments & Methods
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33. Shimazoe, K., Takahashi, H., Yeom, J.Y. ,Furumiya, T., Ohi, J., Multi-channel Waveform
Sampling ASIC for radiation detection andmeasurement, Radiation Measurements, vol. 55,
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H., et al., Development of a scintillating G-GEM
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35. Mitsuya, Y., Fujiwara, T., Takahashi, H.,
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Takahashi, et al., Development of Hard X-Ray
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37. Yamazaki T, Kohro T, Chujo M, Ishigaki M,
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50. Takahiro Egawa, Kazuhisa Hirabayashi, Yuichiro
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Kamiya, Ryu Iwatate, Kenjiro Hanaoka, Takuya
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Chem. Soc., 135, 409-414 (2013).
54. Takehiro Ando, Dai Kawashima, Hongho Kim,
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523

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

524

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.

525

International Medical Center
Director and Associate Professor
Sumihito Tamura, M.D.,Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/english/international-patients/index.html

Introduction and Organization
One of the University of Tokyo’s significant
challenges is globalization. The International Medical
Center was launched in November, 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, andoffering solutions to financial challenges, so that eachdepartment 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.
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.

526

Department of Clinical Nutrition
Therapy
Head of the Department
Naoto Kubota (Associate Professor)

Assistant Head of the Department
Kazuhiko Fukatsu (Associate Professor, Surgical Center)
Rie Sekine

Lectuer
Hideaki IjichiHomepage

http://www.h.u-tokyo.ac.jp/patient/depts/eiyoukanri/index.html

Introduction and Organization

head dietitians, which primarily conducted its
activities at the University of Tokyo, was realized, andthe managerial dietitian system was established by apartial revision of the Nutritionists Act. In 1972,
nutritional guidance was actively provided to
inpatients and outpatients with the aim of obtaining
approval to charge fees, and in 1978 a medical dietcharge and nutrition guidance charge were established.
In 1988, a timely tray service achieved by using hot
and cold food-tray carts was instituted in order todispel the “too early, cold, unappetizing” reputation of
hospital meals.
In 1991, the name of the food service section waschanged to the “Department of Nutrition Management”, a change that had a long been sought bynationwide national-university-hospital managerial
dietitian staff members. At the same time, the nutrition
sections of the main hospital and branch hospital wereconsolidated, and the head of the Department of
Nutrition Management, who was a managerial
dietitian, assumed the section manager post to form asystem composed of 5 managerial dietitians at themain hospital and 3 managerial dietitians at the branchhospital.
In 1994, as a result of a partial revision of the
National Health Insurance Act, the standard foodservice approval system was abolished, and a dietIn 1922, a stall in the outpatient department of thehospital and hospital ward shop sold milk, baked
goods, cider and ice cream. In 1925, a service contract
between the hospital and the Kojinkai Foundation
resulted in the start of a patient food service. In 1936,
a “special therapeutic diet” approach for newborn
infants, diabetes, nephropathy in which a physician
prescribed the food composition individually for eachpatient was instituted for the first time in Japan. In
1950, a national-hospital complete food service
system was announced, and the nutrient content
provided was standardized. The nutrient content
provision for patient meals at the time was 2400
kcal/day. In 1952, the inpatient meal service wasofficially outsourced to a foundation.
In 1957, the first nationwide meeting of nationaluniversity-hospital head dietitians was held at the
University of Tokyo with the aim of improving
patients’ diets.
In 1958, the complete food service was abolished.
Implementation of a standard food service and staffing
with a dietitian became required conditions, and thefood service section was staffed by a part-time section
chief and a dietitian. In 1962, a request from thenationwide meeting of national-university-hospital
526

527

dietitians, and nurses was improved.
In 2013, the Department of Nutrition Management
was reorganized as the Department of ClinicalNutrition Therapy. A physician (Professor, the head of
the Central Clinical Services Administration) assumed
the concurrent post of head of the Department, and thehead of the Department of Nutrition Management
assumed the post of Assistant Head of the Department;
they undertook responsibility for managing the foodservice, maintaining activities of the NST, andstrengthening its functions. In 2014, with the adventof a full-time department head, improvements weremade to NST activities and to the nutrition therapy,
education, and research system. As a result of amanagerial strategic personnel distribution, 5 newmanagerial dietitians (full-time) have been assigned
this fiscal year.

therapy notification system on admission was set up.
An on-admission nutrition guidance fee was alsoestablished.
In 1998, the first diet therapy exhibit organized by
the Department of Nutrition Management was
conducted as part of the diabetes week events that theTokyo Diabetes Association held to the side of the freespace in the vestibule of the outpatient department. In
the first year there were 3527 visitors a week.
In 2001, integration of the branch hospital with themain hospital resulted in an 8-managerial- dietitiansystem. In 2004, the Department of Nutrition
Management was separated from the medical service
division. In 2005, the introduction of the self-pay
system for inpatient meals meant that inpatients began
to be charged for their meals. During the same year
one managerial dietitian (limited-term employment)
was added to the staff.
In 2006, charges for the performance of nutrition
management were newly established, and that meant
providing nutrition management for all patients. The
increase in work was accompanied by the addition of
one managerial dietitian (limited-term employment) to
the staff. Team care was introduced the same year, andin-hospital activity in the form of an all-department
nutrition support team (NST) was inaugurated. Eachhospital ward was staffed with a physician, managerial
dietitian, and nurse in charge of an NST, andwhenever necessary members from other fields(pharmacists,
medicaltechnologists,
physicaltherapists) joined, and they held a hospital ward
meeting once a week. In 2010, an NST committee wascreated as a result of the establishment of charges for
NSTs. The NST director up until that time became amember of the committee and played an active role as
the center of in-hospital NST activities. The additionof one managerial dietitian to the staff (full time) as afull-time employee to calculate the billing charges for
the NST was approved. In 2011, the inauguration of anutritional guidance service for recipients of healthcheckups in the Department of Epidemiology andPreventive Medicine was accompanied by the additionof one managerial dietitian (limited-term employment)
to the staff. In 2012, charges for conducting nutrition
management were abolished. They were incorporated
into the basic hospital-admission fee, and the nutrition
management system by physicians, managerial

Clinical Activities
The Department is proactively conducting
nutritional guidance in regard to metabolic diseases,
including diabetes, chronic kidney disease,dyslipidemia, and obesity, perioperative guidance,
including in regard to postgastrectomy diets,
hepatobiliary and pancreatic disease diets, and cardiac
disease diets, etc., mothers’ classes, etc.
The records of achievements in 2013 show that
there were 2176 instances of inpatient nutritional
guidance (354 without charge) and 3268 instances of
outpatient nutritional guidance (166 without charge).
The results for group nutritional guidance showed thatduring the year there had been 438 outpatient diabetes
classes and 254 inpatient diabetes classes (for some ofwhich there was a charge), and that there had been 156
best-weight classes, classes after gastric cancer
operations for 115 patients, and mother’s classes for
208 mothers.
In July 2012, a physician, managerial dietitian, andnurse formed a dialysis prevention team, and began
calculating fees for diabetes and dialysis prevention
guidance and management in the outpatient clinic. The
managerial dietitian and nurse provide guidance on
Wednesday and Thursday afternoons, and in 2013
there were 199 guidance sessions.

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528

Teaching Activities
The Department accepts managerial dietitian
clinical trainees. In 2013, the department accepted 39
trainees from 7 training schools: Ochanomizu
University, Tokyo Kasei University, Otsuma Women’s
University, Kagawa Education Institute of Nutrition,
Jissen Women’s Educational Institute, Japan Women’s
University, and Wayo Women’s University.
In 2011, the Department began accepting NST
trainees. From 1 to 4 or 5 terms are conducted ayear (5 days/week/term). Participants are mainly
managerial dietitians, pharmacists, nurses, medical
technologists, and physical therapists, and candidates
are trainees whose aim is acquiring the qualifications
certified by academic societies or to become afull-time employee to calculate the billing charges for
the NST. There were 15 participants in 2013.

3.

4.

5.

Research

6.

・Joint research with the Department of Stomach andEsophageal Surgery
Research topic: “Evaluation of nutrition indexes
after proximal gastrectomy”
・Research topic: “Multi-center randomized controlled
study of the effects of early post-gastrectomy oral
feeding support”
・Joint research with the Department of Hepatobiliaryand Pancreatic Surgery
Research topic: “Assessment of perioperative
improvement in nutrition status by an open trial of
an immune-enhancing diet in patients who haveundergone pancreatoduodenectomy”

7.

8.

standpoint of the presence or absence ofpotassium correction, The 58th Congress of theJapanese Society for Dialysis Therapy, 2013.6.
Kinoshita E, Sakurai M, Sekine R: Nutrition
approach to obese patients whose intake cannot be
evaluated, The 31st Congress of the JapaneseSociety for Treatment of Obesity, 2013.6.
Sekine R: NST medical staff session (introductory
edition) Complications of enteral nutrition andcountermeasures (in hospitals), The 17th Annual
Meeting of the Japan Society of Metabolism andClinical Nutrition, 2014.1.11.
Sekine R: Special program 1 “The role of thespecialist in clinical nutrition therapy at the
University of Tokyo Hospital”, the role of thespecialist in clinical nutrition therapy in clinicalpractice and future prospects, The 17th Annual
Meeting of the Japan Society of Metabolism andClinical Nutrition, 2014.1.12.
Sekine R: Diabetes TV Symposium “Nutritional
guidance in clinical practice; AstraZeneca (Corp.),2014.1.31.
Sekine R: Research engaged in by managerial
dietitians, 3. University of Tokyo Nursing
Research Symposium -Aiming for collaboration
among physicians, nurses, and researchers-,
Graduate School of Medicine and Faculty of
Medicine, The University of Tokyo, Research
Building, 14F, Tetsumon Memorial Hall. 2014.2.1
Sekine R: Hospital unit managerial dietitianstaffing, current status of hospital ward staffing at
the University of Tokyo Hospital, The 56th
Meeting of the Nutrition Research Group of theTokyo Branch of the Japan Hospital Association.
2014.03.14
Sekine R, Sawada M, Uehata Y, et al.: Effect of an
ONS (oral nutritional supplement) on the loss ofskeletal muscle mass after stomach cancer surgery,86th Annual Meeting of the Japanese Gastric
Cancer Association, 2014.03.22

References

9.

<Academic meeting presentations, etc.>
1. Sekine R, Sasaki S, Nanjo Y: Luncheon Seminar“Total management of fecal incontinence
according to a University of Tokyo carealgorithm”, The 22nd Meeting of the JapaneseSociety of Wound, Ostomy and ContinenceManagement, 2013.5.24.
2. Togashi H, Hanafusa N, Nangaku M, Sekine R:
Background factors of patients who requiredietary potassium management from the<Publications>
1. Sekine R, Sasaki S, Nanjo Y: Special issue “Total
management of fecal incontinence (diarrhea)”,
Expert Nurse, Oct issue, Vol.29, No.12.2013.
2. Sekine R, Ogawa S （ eds. ） : 24 Points aboutsarcopenia, Fuji Medical Publishing, 2013.11.18
528

529

3. Sekine R: Special issue. Nutrition management
designed to improve the QOL of decubitus ulcer
patients “Key points in carbohydrate setting andadministration”：WOC Nursing,Vol.1.No.3.2013.
4. Kinoshita E: Need for an approach by managerial
dietitians to the psychosocial aspects of morbidly
obese patients -Experience with patients with low
self-esteem who refuse to disclose their foodrecords-： Prospects for Obesity Therapeutics, No.
2:3-3.2014.1

529

Center for Disease Biology andIntegrative Medicine

531

Laboratory of Molecular
Biomedicine for Pathogenesis
Professor
Toru Miyazaki, M.D., Ph.D.

Lecturer
Satoko Arai, Ph.D.

Official Website:

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

Research
Our laboratory focuses 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, wegive 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 researchers. 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 the following two
major projects.
1. AIM (Apoptosis Inhibitor of Macrophage) as amaster switch to various modern diseases.
The rapid change in lifestyles and eating habits intoday’s society are thought to be the cause of various
disorders; metabolic syndrome and lifestyle-relateddiseases increase the risk of developing obesity,
diabetes, and cardiovascular disease; a fatty liver leads

to NASH and liver disease, may result in liver cancer;
autoimmune disease followed by obesity, chronic
renal failure, and Alzheimer’s disease are considered
as well. We hypothesize that such various modern
disorders, seemingly unrelated at first sight, share thecommon underlying pathological condition andmechanism, and the group of molecules exists as themaster 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 an 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 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 ofobesity, 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 differentiates the532

outcome and the risk of getting various diseases.
Finding the mechanism on the regulation of AIM
activity will shed light on 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
Joint Meeting in Taipei
Nearly forty participants from three labs at National
Taiwan University, National Yang-Ming University,
and The University of Tokyo gathered in Taipei,
Taiwan for our first joint meeting from Apr 24 to 27,

2013. Its venue being set up at National Taiwan
University Hospital (NTUH) International Convention
Center, we had oral/poster presentations on our latest
research findings, mainly delivered by juniorresearchers and students of each lab, followed bydebates all together. The highly content-richpresentations and vigorous question-and-answer
sessions in English became a stimulating experience
for us all.
The observation tour to NTUH, dinners andget-together parties at the end of each day and otherirreplaceable activities made our joint meeting still
more successful. We greatly appreciate Professor Lin
and her lab members’ efforts on the arrangements forthis meeting. We are all looking forward to having thetwo labs as our guests next time in Japan.
List of labs:
Prof. Wan-Wan Lin’s Laboratory, National Taiwan
University
Prof. Shie-Liang Hsieh’s Laboratory, National
Yang-ming University
Prof. Toru Miyazaki’s Laboratory, The University ofTokyo
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-EXTRA
This is a lecture series on the latest experimental
techniques for medical research, founded as anextension of DBELS. We offer monthly lecture series,
each of which convenes twice to four times a month,aiming mostly at graduate students and juniorresearchers.
This series provides lectures by experts fromcompanies, universities and research institutions
specializing in a wide range of areas such as
molecular biology, cellular biology, genetics,
immunology and others.

533

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 Science
On Jun 6, 2006, to commemorate the foundation of
our lab, we organized an invited recital by Mr Maestro
Krystian Zimerman, a world-famous pianist, followed
by a debate session on music and science between Mr.
Zimerman and Professor Miyazaki at Yasuda
Auditorium with more than 800 audiences.
Visiting Professors
We welcomed Prof. Wakeland from Southwestern
Medical Center at The University of Texas in fiscal
2006, and Prof. D. Mathis and Prof. C. Benoist(immunology) from Harvard University in fiscal 2007,
all of whom belonged to our lab as a guest professor
for three months respectively.

4.

5.

6.

Publications
7.
1. Uramatsu, T., Nishino, T., Obata, Y., Sato, Y.,
Furusu, A., Koji, T., Miyazaki, T. & Kohno, S.
Involvementof
Apoptosis
InhibitorofMacrophages in a Rat Hypertension Model with
Nephrosclerosis: Possible Mechanisms of Actionof Olmesartan and Azelnidipine- Biol Pharm Bull.
36, 1271-1277 (2013).
2. A-Gonzalez, N., Guillen, J. A., Gallardo, G., Diaz,
M., de la Rosa, J. V., Hernandez, I. H.,
Casanova-Acebes, M., Lopez, F. Tabraue, C.,
Beceiro, S., Hong, C., Lara, P. C., Andujar, M.,
Arai, S., Miyazaki, T., Li, S., Corbi, A. L.,
Tontonoz, P., Hidalgo, A. & Castrillo, A. The
Nuclear Receptor LXRα controls the functional
specialization of splenic macrophages- Nat.
Immunol. 14, 831-839 (2013).
3. Nakashima, K., Arai, S., Suzuki, A., Nariai, Y.,
Urano, T., Nakayama, M., Ohara, O., Yamamura,K., Yamamoto, K. & Miyazaki, T. PAD4 regulates
proliferation of multipotent haematopoietic cellsby controlling c-myc expression- Nat. Commun.
4, 1836 (2013).
Arai, S., Maehara, N., Iwamura, Y., Honda, S.,
Nakashima, K., Kai, T., Ogishi, M.,Morita, K.,
Kurokawa, J., Mori, M., Motoi, Y., Miyake, K.,
Matsuhashi, N., Yamamura, K., Ohara, O.,
Shibuya, A., Wakeland, E. K., Li, Q. Z. &Miyazaki, T. Obesity-associated autoantibody
production requires AIM to retain IgM immune
complex on follicular dendritic cells- Cell Rep. 3,
1187-1198 (2013).
Kojima, J., Araya, J., Hara, H., Ito, S., Takasaka,N., Kobayashi, K., Fujii, S., Tsurushige, C.,
Numata, T., Ishikawa, T., Shimizu, K., Kawaishi,
M., Saito, K., Kamiya, N., Hirano, J., Odaka, M.,
Morikawa, T., Hano, H., Arai, S., Miyazaki, T.,
Kaneko, Y., Nakayama, K. & Kuwano, K.
Apoptosis inhibitor of macrophage (AIM)
expression in alveolar macrophages in COPDRespir. Res. 14, 30 (2013).
Geng, S., Matsushima, H., Okamoto, T., Yao, Y.,
Lu, R., Page, K., Blumenthal, R. M., Ward, N. L.,
Miyazaki, T. & Takashima, A. Emergence, origin,and function of neutrophil-dendritic cell hybrids
in experimentally induced inflammatory lesions in
mice- Blood 121, 1690-1700 (2013).
Matsushima, H., Geng, S., Lu, R., Okamoto, T.,
Yao, Y., Mayuzumi, N., Kotol, P. F., Chojnacki, B.
J., Miyazaki, T., Gallo, R. L. & Takashima, A.
Neutrophil differentiation into a unique hybrid
population exhibiting dual phenotype andfunctionality of neutrophils and dendritic cellsBlood 121, 1677-1689 (2013).

534

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Lecturer
Noriko Takahashi, M.D., Ph.D.

Research Associates
Jun Noguchi, Ph.D., Akiko Hayashi, M.D., Ph.D.
Satoshi Watanabe, Ph.D., Sho Yagishita, M.D. Ph.D.

Homepage

http://www.bm2.m.u-tokyo.ac.jp/

Introduction and Organization

Research activities

The Center for Disease Biology and Integrative
Medicine (CDBIM) has been established in 2003, andelected Dr. Kasai as the professor of the Division of
Basic Medical Sciences (2) of CDBIM in July of 2004.
Dr. Kasai was in the National Institute forPhysiological Sciences, and officially took office inthe University of Tokyo in November, 2005. The
Kasai laboratory has moved to the first building ofFaculty of Medicine in January, 2006. It belongs to theSection of Functional Biology in the Graduate Schoolof Medicine. Its name has been changed from
Division of Biophysics to Laboratory of Structural
Physiology in the April, 2008.

Functional imaging is a central theme in modern
biology and medicine. All biological functions involvea multitude of interactions at the molecular, cellular,
and system levels, and it is ultimately desirable toperform molecular and cellular imaging in intact
preparations in which the original in vivo functions
are preserved. We have been exploring two-photon
excitation microscopy with a new type of laser, an
infrared femtosecond-pulse laser, as a means toachieve this goal. The two-photon microscope has theability to penetrate deep into tissues and is the only
imaging instrument that allows investigations of intact
tissues at the cellular and molecular levels. 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.

Teaching activities
We have 2 master course and 3 doctor course
students in 2013. We were also responsible forundergraduate education of physiology, and organized
all lectures, student experiments and examinations.
We gave all together 7 lectures of physiology forundergraduate students, and 4 lectures of physiology
and neuroscience for master course students. Twoundergraduate students join the activity of ourlaboratory for free quarter (FQ).

535

1)

2)

Activity-dependent competition of synapses
plays a key role in neural organization and is often
promoted by GABA; however, its cellular bases arepoorly understood. Excitatory synapses of corticalpyramidal neurons are formed on small protrusions
known as dendritic spines, which exhibit structural
plasticity. We used two-color uncaging of glutamate
and GABA in rat hippocampal CA1 pyramidal
neurons and found that spine shrinkage andelimination were markedly promoted by theactivation of GABA receptors shortly before action
potentials. GABAergic inhibition suppressed bulk
increases in cytosolic Ca concentrations, whereas itÄb0preserved the Ca nanodomains generated by
NMDA-type receptors, both of which werenecessary for spine shrinkage. Unlike Äb0spine
enlargement, spine shrinkage spread to neighboring
spines (<15 nm) and competed with theirenlargement, and this Äb0process involved theactin-depolymerizing factor ADF/cofilin. Thus,
GABAergic inhibition directly suppresses local
dendritic Ca transients and strongly promotes thecompetitive selection of dendritic spines (Ref. 4).
Drug discovery in psychiatry has been limited tochemical modifications of compounds originallydiscovered serendipitously. Therefore, moremechanism-oriented strategies of drug discovery formental disorders are awaited. Schizophrenia is adevastating mental disorder with synaptic
disconnectivity involved in its pathophysiology.
Reduction in the dendritic spine density is a majoralteration that has been reproducibly reported in the
cerebral cortex of patients with schizophrenia.
Disrupted-in-Schizophrenia-1 (DISC1), a factor that
influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders,has a regulatory role in the postsynaptic density inassociation with the NMDA-type glutamate
receptor, Kalirin-7, and Rac1. Prolonged knockdown of DISC1 leads to synaptic deterioration,
reminiscent of the synaptic pathology ofschizophrenia. Thus, we tested the effects of novel
inhibitors to p21-activated kinases (PAKs), major
targets of Rac1, on synaptic deterioration elicitedby knockdown expression of DISC1. These
compounds not only significantly ameliorated thesynaptic deterioration triggered by DISC1
knockdown but also partially reversed the size ofdeteriorated synapses in culture. One of these PAK
inhibitors
prevented
progressive
synaptic
deterioration in adolescence as shown by in vivo
two-photon imaging and ameliorated a behavioral
deficit in prepulse inhibition in adulthood in a
DISC1 knockdown mouse model. The efficacy of
PAK inhibitors may have implications in drug
discovery
forschizophrenia
andrelatedneuropsychiatric disorders in general (Ref. 8).

References
1. Lam, P.*, Ohno, M.*, Subhankar, D.*, He, Y., Qin,
T., Lian, T., Zhu, D., Kang, Y., Liu, Y., Kauppi, M.,
Xie, L., Wan, W., Bin, N., Sugita, S., Olkkonen, V.,
Takahashi, N., Kasai, H.CA & Gaisano, H.Y.CA(2013). Munc18b is a major mediator of insulin
exocytosis in rat pancreatic β-cells. Diabetes.
62:2416-2428. (CACorresponding authors.)
2. Hira, R., Ohkubo, F., Ozawa, K., Isomura, Y.,
Kitamura, K., Kano, M., Kasai, H., & Matsuzaki,
M. (2013). Spatial and temporal reconfigurationof microcircuitry activity in the motor cortex forvoluntary movement. J. Neurosci. 33:1377-1390.
3. Hira, R., Ohkubo, F., Tanaka, Y.R., Masamizu, Y.,
Augustine, G.J., Kasai, H. & Matsuzaki, M.
(2013). In vivo optogenetic tracing of functional
corticocortical connections between motor
forelimb areas. Frontier in Neural Circuits 7:55.
4. Hayama, T., Noguchi, J., Watanabe, S., EllisDavies, 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. 16:1409-1416.
5. Nuriya,M, Momotake, A, Kimura, Y., Yasui, M.,
Kasai, H. & Arai, T. (2013) Evaluation of
dialkylaminofluorene-based hemicyanine dyes forsecond harmonic generation imaging by the directcomparison approach. Bull. Chemical Soc. Jpn.
86:1190-1192.
6. Asrican, B, Augustine, G.J., Berglund, K., Chen,
S., Chow, N. Deisseroth, K., Feng, G., Gloss, B.
Hira, R., Hoffman, C., Kasai, K., Katarya, M.,

536

Jinsook, K., Kudolo, J., Lee, L., Qiang Lo, S.,
Mancuso, J., Matsuzaki, M., Nakajima, R., Qiu,
L., Tan, T., Tang, Y., Ting, J.T., Tsuda, S. & Wen,
L. (2013). Next-generation transgenic mice for
optogenetic analysis of neural circuits. Frontier in
Neural Circuits 7:160.
7. Takehara, H., Nagaoka, A., Noguchi, J., Akagi, T.,
Sakai, T., Chung, U., Kasai, H. & Ichiki, T.
(2013). Implementation of tetra-poly (ethylene
glycol) hydrogel with high mechanical strength
into microfluidic device technology. Biomicrofluidics 7, 054109.
8. Hayashi-Takagi, A., Araki, Y., Nakamura, M.,
Vollrath, B., Duron, S.G., Yan, Z., Kasai, H.,
Huganir, R.L., Campbell, D.A., Sawa, A. (2014)
PAKs inhibitors ameliorate schizophreniaassociated dendritic spine deterioration in vitro
and in vivo during late adolescence. Proc. Natl.
Acad. Sci. U.S.A. 111, 6461-6.

537

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
Research activities
The Division is composed of two laboratories, Ushidalaboratory and Ito 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. Prof. Ito charged at Department of Chemical
System Engineering. The current laboratory members
include one JSPS postdoctoral fellow, and 12 graduate
students from Department of Chemical System
Engineering, Graduate School of Engineering.

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, separation
technology, and biotechnology at the Chemical
System Engineering course and Bioengineering course
at Graduate School of Engineering School.

Prof. Ushida’s laboratory aims to establish key
technologies for regenerative medicine. One of the
projects of our research targets the hard tissue
regeneration, such as cartilage or bone by tissue
engineering technology. Hard tissue engineering
requires the control of its shape in addition to the cell
accumulation and scaffold play a key role in meeting
this requirement. We focus on the development of
biocompatible materials such as synthetic polymer orinorganic materials combined with stem cellbiotechnology. Secondly, we try to elucidate
mechanisms of cellular responses to physicalstimulations such as hydrostatic pressure, shear stress,
stretch, through observing intracellular signaling, andto adopt those effects to tissue engineering.
1) Tissue engineering of cartilage or bone defect- Design and development of biocompatible materials
for cartilage or bone using synthetic polymer,
inorganic materials or those combination.
- Development of osteoinductive biomaterials
hybridized with bioactive substances.
- Order made shaping of scaffolds by router system
according to the graphical images of tissue defects- Establishment of vascular rich graft bed bybiomaterials that spur new blood vessel growth.

5382) 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) Biomaterials- 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- Hemostat by hydrogels
3) Tissue engineering- Hydrogel scaffolds to control cell development andvascular network constraction- Development of oxygen carriers by membraneemulsification

References
1. Chang Ho Seo, Heonuk Jeong, Katsuko S.
Furukawa, Yuji Suzuki, Takashi Ushida,The
switching of focal adhesion maturation sites andactin filament activation for MSCs by topography ofwell-defined micropatterned surfaces, Biomaterials
34 1764-1771 8 (2013)

2. Asaoka T, Ohtake S, Furukawa KS, Tamura A,
Ushida T., Development of bioactive porous
α-TCP/HAp beads for bone tissue engineering. J
Biomed Mater Res A. Nov; 101(11):3295-3300(2013)
3. Takayuki Akimoto, Kanako Okuhira, Katsuji
Aizawa, Shogo Wada, Hiroaki Honda, Toru
Fukubayashi, Takashi Ushida, Skeletal muscle
adaptation in response to mechanical stress in
p130Cas−/− mice. Am J Physiol Cell Physiol, Mar;
304(6):C541-547 (2013)
4. Akira Takahashi, Yukimitsu Suzuki, Takashi Suhara,
Kiyohiko Omichi, Atsushi Shimizu, Kiyoshi
Hasegawa, Norihiro Kokudo, Seiichi Ohta,
Taichi Ito, An in situ cross-linkable hydrogel of
hyaluronan produced via copper-free click chemistry.
Biomacromolecules, 2013 (10)3581- 3588
5. Yao-Tong Lai, Seiichi Ohta, Kazuki Akamatsu,
Shin-ichi Nakao, Yasuyuki Sakai, Taichi Ito,
Preparation of uniform-sized poly [methacryloxypropyl tris(trimethylsiloxy)silane] microspheres
via Shirasu porous glass membrane emulsification
technique. Journal of Chemical Engineering ofJapan, 2013(46) 777-784
6. Taichi Ito, Hidenori Ohashi, Takanori Tamaki, Takeo
Yamaguchi, Mathematical Modeling of Molecular
Recognition by an Ion-Gating Membrane Oscillator,
Journal of Membrane Science, 2013(448) 231-239

539

Laboratory of Clinical
Biotechnology
Professor
Kazunori Kataoka, Ph.D.

Associate Professor
Kanjiro Miyata, Ph.D.

Research Associate Professor
Keiji Itaka, M.D., Ph.D.

Assistant Professor
Yutaka Miura, 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
Laboratory of Clinical Biotechnology in Center for
Disease Biology and Integrative Medicine (CDBIM)
was established in April 2003. This laboratory wishes
to contribute to the development of nanomedicine.
Our laboratory actively collaborates with Graduate
School of Engineering at The University of Tokyo andDivision of Tissue Engineering at The University ofTokyo Hospital. Our laboratory also participates in the
Graduate Program for Leaders in Life Innovation,
which started in 2012, for novel medicine-engineeringinterdisciplinary communication, and tries to produce
medical ventures by promoting liaison with theindustrial sector, and further, professionals who
understand both advanced medicine and nanotechnology. Our laboratory consists of one professor,
two associate professors, one assistant professor, andseveral project staff members.
Our laboratory 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. Nanomachines, which
are constructed by integrating materials and systems
on a nanometer 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, nanomachines are
expected to become an important interface between
basic biomedical science and clinical medicine byfacilitating the translation of basic achievements into
clinical applications. Our laboratory wishes to produce
innovative medical nanomachines 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 with

540

increased complexity, and thus scholars in both areasfind it hard to understand each other. This situation
prevents the effective development of revolutionary
medical diagnostic and therapeutic inventions. Ourlaboratory 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
nanomachines 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 less than 100 nm, in aqueous media. The
core of the micelles behaves as a nanoreservoir for
drugs, while the coronal shell providing thebiocompatible surface. Polymeric micelles can
incorporate a variety of drugs including hydrophobic
drugs, metal complex drugs, and macromolecular
drugs such as proteins and DNA, and release them in asustained manner or in response to environmental
changes such as pH. The site-specific drug delivery
can be achieved by conjugation of the pilot moleculeson the surface of polymeric micelles. Thus, polymeric
micelles behave as smart chemical nanomachines forthe 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

paclitaxel, cisplatin (CDDP), and oxaliplatin bypolymeric micelles, and observed enhanced antitumor
activity with reduced side effects. These micellar
formulations are currently being tested in clinical
trials.
Recently, plasmid DNA (pDNA), messenger RNA(mRNA), and small interfering RNA (siRNA) arehighlighted as promising tools for the treatment ofgenetic and intractable diseases. One of the major
requirements for therapeutic use of pDNA, mRNA,and siRNA is the development of nanovectors, which
can safely and effectively deliver them into specificcells and regulate their expressions. Recently, we have
prepared polymeric micelles incorporating siRNAthrough the electrostatic interaction between siRNAand positively charged block copolymers. The
polymeric micelles protected the loaded siRNA fromdegradation by nuclease attack and showed efficientgene silencing in a variety of cells. Also, various
smart functionalities, such as targeting ability andenvironmental sensitivity, can be integrated intopolymeric micelles, providing the opportunities todevelop effective synthetic nanovectors resemblingviruses. Thus, polymeric micelles are expected as
useful nanocarriers of nucleic acid drugs for in vivo
application.

References
1. Y. Miura, T. Takenaka, K. Toh, S. Wu, H.
Nishihara, M. R. Kano, Y. Ino, T. Nomoto, Y.
Matsumoto, H. Koyama, H. Cabral, N. Nishiyama,
K. Kataoka, Cyclic RGD-linked polymeric
micelles for targeted delivery of platinum
anticancer drugs to glioblastoma through theblood-brain tumor barrier. ACS Nano 7 (10) 85838592 (2013)
2. S. Deshayes, H. Cabral, T. Ishii, Y. Miura, S.
Kobayashi, T. Yamashita, A. Matsumoto, Y.
Miyahara,
N.
Nishiyama,K.
Kataoka,
Phenylboronic acid-installed polymeric micelles
for targeting sialylated epitopes in solid tumors. J.
Am. Chem. Soc. 135 (41) 15501-15507 (2013)
3. K. Kusumoto, H. Akita, T. Ishitsuka, Y.
Matsumoto, T. Nomoto, R. Furukawa, A.
El-Sayed, H. Hatakeyama, K. Kajimoto, Y.
Yamada, K. Kataoka, H. Harashima, A lipid

541

envelope-type nano particle incorporating a
multifunctional peptide for the systemic siRNAdelivery to the pulmonary endothelium. ACS
Nano 7 (9) 754-7541 (2013)
4. H. Cabral, M. Murakami, H. Hojo, Y. Terada, M.
R. Kano, U. -I. Chung, N. Nishiyama, K. Kataoka,
Targeted therapy of spontaneous murine
pancreatic tumors by polymeric micelles prolongs
survival and prevents peritoneal metastasis. Proc.
Natl. Acad. Sci. USA. 110 (28) 11397-11402(2013)
5. T. A. Tockary, K. Osada, Q. Chen, K. Machitani,
A. Dirisala, S. Uchida, T. Nomoto, K. Toh, Y.
Matsumoto, K. Itaka, K. Nitta, K. Nagayama, K.
Kataoka, Tethered PEG crowdedness determining
shape and blood circulation profile of polyplex
micelle gene carriers. Macromolecules 46 (16)6585-6592 (2013)
6. Y. Izumida, N. Yahagi, Y. Takeuchi, M. Nishi, A.
Shikama, A. Takarada, Y. Masuda, M. Kubota, T.
Matsuzaka, Y. Nakagawa, Y. Iizuka, K. Itaka, K.
Kataoka, S. Shioda, A. Niijima, T. Yamada, H.
Katagiri, R. Nagai, N. Yamada, T. Kadowaki, H.
Shimano, Glycogen shortage during fasting
triggers liver-brain-adipose neurocircuitry tofacilitate fat utilization. Nat. Commun. 4 2316
(2013)
7. D. Kokuryo, Y. Anraku, A. Kishimura, S. Tanaka,
M. R. Kano, J. Kershaw, N. Nishiyama, T. Saga, I.
Aoki, K. Kataoka, SPIO-PICsome: Developmentof a highly sensitive and stealth-capable MRI
nano-agent for tumor detection using SPIO-loaded
unilamellar polyion complex vesicles (PICsomes).
J. Control. Release 169 (3) 220-227 (2013)
8. S. Biswas, K. Kinbara, T. Niwa, H. Taguchi, N.
Ishii, S. Watanabe, K. Miyata, K. Kataoka, T.
Aida, Biomolecular robotics for chemomechanically driven guest delivery fuelled byintracellular ATP. Nat. Chem. 5 613-620 (2013)
9. H. Oana, M. Morinaga, A. Kishimura, K. Kataoka,
M. Washizu, Direct formation of giant unilamellar
vesicles from microparticles of polyion complexes
and investigation of their properties using a
microfluidic chamber. Soft Matter 9 5448-5458(2013)
10. H. Takemoto, K. Miyata, S. Hattori, T. Ishii, T.
Suma, S. Uchida, N. Nishiyama, K. Kataoka,

Acidic pH-responsive siRNA conjugate forreversible carrier stability and accelerated
endosomal escape with reduced IFNα-associatedimmune response. Angew. Chem. Int. Ed. 52 (24)6218-6221 (2013)
11. Y. Matsumoto, Y. Zhang, T. Azuma, K.
Yoshinaka, K. Osada, K. Kataoka, S. Takagi, Sizeeffect of complexed plasmid DNA to genetransfection efficiency of microbubble-mediatedsonoporation. POMA. 19 075068-075074 (2013)
12. M. Ohgidani, K. Furugaki, K. Shinkai, Y.
Kunisawa, K. Itaka, K. Kataoka, K. Nakano,
Block/homo polyplex micelle-based GM-CSF
gene therapy via intraperitoneal administration
elicits antitumor immunity against peritoneal
dissemination and exhibits safety potentials inmice and cynomolgus monkeys. J. Control.
Release 167 (3) 238-247 (2013)
13. S. Wu, V. Kasim, M. R. Kano, S. Tanaka, S. Ohba,
Y. Miura, K. Miyata, X. Liu, A. Matsuhashi, U. -l.
Chung, K. Kataoka, N. Nishiyama, M. Miyagishi,
Transcription factor YY1 contributes to tumor
growth by stabilizing hypoxia factor HIF-1α in a
p53-independent manner. Cancer Res. 73 (6)1787-1799 (2013)
14. K. Endo, T. Ueno, S. Kondo, N. Wakisaka, S.
Murono, M. Ito, K. Kataoka, Y. Kato, T.
Yoshizaki, Tumor-targeted chemotherapy with thenanopolymer-based drug NC-6004 for oral
squamous cell carcinoma. Cancer Sci. 104 (3)369-374 (2013)15. S. Uchida, K. Itaka, H. Uchida, K. Hayakawa, T.
Ogata, T. Ishii, S. Fukushima, K. Osada, K.
Kataoka, In vivo messenger RNA introduction
into the central nervous system using polyplex
nanomicelle. PLoS One 8 (2) e56220 (2013)
16. A. Kasuya, S. Hirakawa, K. Liu, A. Kishimura, Y.
Anraku, K. Kataoka, M. Ogawa, S. Mori, H. K.
Takahashi, J. Sakabe, Y. Tomono, M. Nishibori,
Y. Tokura, Anti-HMGB1 antibody attenuates
vascular hyperpermeability and promotes woundhealing during ischemia-reperfusion injury modelin mouse skin. J. Dermatol. Sci. 69 (2) e59 (2013)
17. Y. Anraku, A. Kishimura, Y. Yamasaki, K.
Kataoka, Living unimodal growth of polyion
complex vesicles via 2D supramolecular542

polymerization. J. Am. Chem. Soc. 135 (4) 14231429 (2013)
18. A. Vollrath, A. Schallon, C. Pietsch, S. Schubert,
T. Nomoto, Y. Matsumoto, K. Kataoka, U. S.
Schubert, A toolbox of differently sized andlabeled PMMA nanoparticles for cellular uptake
investigations. Soft Matter 9 (1) 99-108 (2013)
19. P. Mi, H. Cabral, D. Kokuryo, M. Rafi, Y. Terada,
I. Aoki, T. Saga, T. Ishii, N. Nishiyama, K.
Kataoka,
Gd-DTPA-loaded
polymer-metal
complex micelles with high relaxivity for MR
cancer imaging. Biomaterials 34 (2) 492-500(2013)
20. N. Gouda, K. Miyata, R. J. Christie, T. Suma, A.
Kishimura, S. Fukushima, T. Nomoto, X. Liu, N.
Nishiyama, K. Kataoka, Silica nanogelling ofenvironment-responsive PEGylated polyplexes forenhanced stability and intracellular delivery ofsiRNA. Biomaterials 34 (2) 562-570 (2013)
21. Y. Matsumoto, T. Nomoto, K. Toh, H. Cabral, M.
Murakami, R. J. Christie, H. -J. Kim, T. Ogura, K.
Miyata, N. Nishiyama, T. Yamasoba, K. Kataoka,
Intravital real-time confocal laser scanningmicroscopy for the in situ evaluation of
nanocarriers, in Cancer targeted drug delivery:
An elusive dream, Eds., Y. -H. Bae, R. J. Mrsny,
K. Park, Springer, New York, USA, 2013, 607620.
22. K. Miyata, R. J. Christie, T. Suma, H. Takemoto,H. Uchida, N. Nishiyama, K. Kataoka,
Fine-tuning of repeating aminoethyelene units
in poly(aspartamide) side chains for enhanced
siRNA delivery, in Tailored Polymer Architectures for Pharmaceutical and Biomedical
Applications (ACS Symposium Series, Vol. 1135),
Eds., C. Scholz, J. Kressler, American Chemical
Society, Washington, D.C., USA, 2013, Chapter
11, 189-196.
23. F. Pittella, K. Kataoka, Polymeric micelles for
siRNA delivery, in RNA Interference from
Biology to Therapeutics (Advances in Delivery
Science and Technology), Ed., K. A. Howard,
Springer, New York, USA, 2013, 161-184.

543

Laboratory of Environmental
Health Sciences
Professor
Chiharu Tohyama, Ph.D., Dr.Med.Sci.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Assistant Professor
Eiki Kimura, 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 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’,(2) elucidating epigenetic mechanisms that alter thesusceptibility to chemicals, i.e., ‘epigenetic
mechanism, and (3) clarifying effects of chemicals on
the learning/memory, emotion and sociality of therodents, i.e, behavioral and cognitive toxicology.
Our research efforts are further directed to develop
methodologies for evaluating behavioral toxicities invivo and to establish in vitro toxicity techniques atcellular and molecular levels. In addition to thesebasic approaches to the environmental toxicology, we
aim to provide data for obtaining the safety standard
in environmental factors and food, and to contribute to
the development of research in life and clinicalsciences.
Among a variety of potentially toxic substances inthe environment, we focus especially on dioxin and its
related-compounds and heavy metals which react withspecific receptors and proteins.
As to a major study on the ‘molecular target
toxicology’, we have been studying how lactational
exposure to dioxin induces hydronephrosis. It has
been established that aryl hydrocarbon receptor (AhR)
is required to elicit the majority of dioxin toxicity.
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544

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)
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)

545

Publications
1. Kakeyama M, Endo T, Yan Zhang, Miyazaki W,
Tohyama C. Disruption of paired-associatelearning in rat offspring perinatally exposed todioxins. Archives of Toxicology. 88(3):789-98,
2014.
2. Sugai E, Yoshioka W, Kakeyama M, Ohsako S,
Tohyama C. In utero and lactational exposure
to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates
dysregulation of the lipid metabolism in mouseoffspring fed a high-calorie diet. Journal Applied
Toxicology. 34(3):296-306, 2014.
3. Kurita H, Ohsako S, Hashimoto S, Yoshinaga J,
Tohyama C. Prenatal zinc deficiency-dependent
epigenetic alterations of mouse metallothionein2gene. J Nutr Biochem. 24(1):256-266, 2013.
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.
66(2):208-16, 2013.
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. 133(2):197-208, 2013.

546

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 was completed and the accommodation 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, a project
acadmic support specialist, 5 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, mice,and marmosets. The number of registered users of ourfacility was 740 at the end of academic year 2013.
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

547

models for human genetic diseases. We have alsoestablished new gene targeting technology using the
CRISPR/Cas system.
1. Selective activation of mTORC1 signaling in
the brain
Mammalian target of rapamycin (mTOR) has been
implicated in human neurological diseases such as
tuberous sclerosis complex (TSC), neurodegeneration
and autism. However, little is known as to when andhow mTOR involved in pathogenesis of these diseases
because of a lack of animal models that directly
increase mTOR activity.
Here we generated
transgenic mice expressing a gain-of-function mutant
of mTOR in forebrain in a temporally controlledmanner.
Selective activation of mTORC1 inembryonic stage induced cortical atrophy caused byprominent apoptosis of neuronal progenitors,
associated with upregulation of HIF-1α. In striking
contrast, activation of mTORC1 pathway in adulthood
resulted in cortical hypertrophy with fatal epileptic
seizure that recapitulates human TSC. ActivatedmTORC1 in adult cortex also promoted rapid
accumulation of cytoplasmic inclusions and activationof microglial cells, indicative of progressive
neurodegeneration. Our findings demonstrate thatmTORC1 plays different roles between developmental
and adult stages, and contributes to humanneurological diseases.
2. Generation of mutant mice by CRISPR/Cas
systemGeneration of C57BL/6 inbred mutant mice isimportant for neuroscience research. However, mutant
generation using embryonic stem cells derived frominbred strains is time consuming and laborious. Here,
we show a rapid and efficient method to generatemutant mice by microinjection of mRNAs for
CRISPR-associated (Cas) nuclease and exonuclease 1(Exo1) and single-guide (sg) RNAs into C57BL/6
embryos. The sgRNAs were targeted to mGluR1 geneencoding the metabotropic glutamate receptor subtype
1 which is essential for cerebellar function. Injectionof Cas9 mRNAs/sgRNAs and/or Exo1 mRNAs
generated mGluR1 mutant mice with efficiencies of
22.2 to 58.5%. We found that co-injection of Exo1
mRNAs improved the efficiency of mutant mice

generation by CRISPR/Cas system. Among themGluR1 mutants, a homozygous mutant had
cerebellar ataxia and expressed no detectable mGluR1
protein in the cerebellum. This study showed that
CRISPR/Cas system with Exo1 can be applied tocomprehensive analysis of multiple gene functions invivo on C57BL/6 genetic background.

References
1. Asahara S, Shibutani Y, Teruyama K, Inoue HY,
Kawada Y, Etoh H, Matsuda T, Kimura- Koyanagi
M, Hashimoto N, Sakahara M, Fujimoto W,
Takahashi H, Ueda S, Hosooka T, Satoh T, Inoue
H, Matsumoto M, Aiba A, Kasuga M, Kido Y.
Ras-related C3 botulinum toxin substrate 1(RAC1) regulates glucose-stimulated insulin
secretion via modulation of F-actin. Diabetologia.
2013 May; 56(5): 1088-1097
2. Torigoe M, Yamauchi K, Tamada A, Matsuda I,
Aiba A, Castellani V, Murakami F. Role ofneuropilin-2 in the ipsilateral growth of midbrain
dopaminergic axons. Eur J Neurosci. 2013 May;
37(10): 1573-1583.

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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 in
integrated health sciences. Radiation protection isemphasized in this 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549

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. Genet SC, Fujii Y, Maeda J, Kaneko M, Genet
MD, Miyagawa K, Kato TA: Hyperthermia
inhibits homologous recombination repair andsensitizes cells to ionizing radiation in a time- andtemperature-dependent manner. J Cell Physiol
228:1473-1481, 2013
2. Fujii Y, Genet MD, Roybal EJ, Kubota N,
Okayasu R, Miyagawa K, Fujimori A, Kato TA:
Comparison of the bromodeoxyuridine-mediatedsensitization effects between low-LET andhigh-LET ionizing radiation on DNA doublestrand breaks. Oncol Rep 29:2133-2139, 2013
3. Enomoto A, Fukasawa T, Takamatsu N, Ito M,
Morita A, Hosoi Y, Miyagawa K: The HSP90
inhibitor 17-allylamino-17-demethoxygeldanamycin
modulates radiosensitivity by downregulating

550

serine/threonine kinase 38 via Sp1 inhibition. Eur
J Cancer 49:3547-3558, 2013
4. Morita A, Ariyasu S, Ohya S, Takahashi I, Wang
B, Tanaka K, Uchida T, Okazaki H, Hanaya K,
Enomoto A, Nenoi M, Ikekita M, Aoki S, Hosoi
Y: Evaluation of Zinc (II) chelators for inhibiting
p53-mediated apoptosis. Oncotarget 4:2439-50,
2013

551

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 Faculty of
Medicine. Its three most important roles, as defined by
the Committee on International Academic Affairs, arei) international educational exchange, ii) international
contacts in research and scientific fields, and iii)
international cooperation in health care and medicine.

Activities
This document reports on the office's activities inthese areas over the academic year 2013 (April 1, 2013
through March 31, 2014).

1. International Educational Exchange
1.1 Student counseling about education and research
In 2013, there were 110 foreign students (38countries) officially registered in the Graduate Schoolof Medicine. Many inquiries were received during thisperiod from prospective applicants for foreign student
and trainee status: responses were sent to 58 suchinquiries.
Many currently enrolled foreign students received
counseling at this office concerning their studies andlife at the University of Tokyo and the requirements for
obtaining scholarships and degrees.

In addition, a large number of University of Tokyo
students wish to supplement their training with basic
clinical experience overseas before graduation, as wellas the type of short-term training (1-3 months)
frequently called clinical electives overseas. Inquiries
from these students were either answered by this officeor 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 gettogether of foreign students and University of Tokyo
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 2013, 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 2013 Contest
foreign students gave oral presentations based on theirresearch 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 ofTokyo was renewed in May 2004. Since that time,
twelve University of Tokyo students have taken
research electives at the University of Pennsylvania,
and two students from the University of Pennsylvania

552

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 four University of Tokyo students visited toattend clinical electives at Johns Hopkins University,and four students from Johns Hopkins University havetaken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the University of Michigan
Medical School in January 2005. Since the start of the
program in 2005, fifteen University of Tokyo students
have attended clinical electives at the University ofMichigan Medical School, and five 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,
eleven University of Tokyo students visited to attend
research electives at Munich University, and five
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,
four University of Tokyo students visited to attend
clinical electives at Taipei Medical University and eightstudents from Taipei Medical 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 Mahidol University in
September 2006. Since the start of the program in 2006,

five University of Tokyo students visited to attend
research electives at Mahidol University, and sevenstudents from Mahidol University have taken clinicalelectives 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 58 requests from students forcounseling regarding pre-graduation or post-graduation
studies abroad are received by the Office ofInternational Academic Affairs. The office responds tothese requests by providing information, advice, andletters of recommendation.

2. 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 in English
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, Yamazaki Y,
Kitagawa A, et al. (2013) Decay of Impact afterSelf-Management Education for People with
Chronic Illnesses: Changes in Anxiety andDepression over One Year. PLoS ONE 8(6):e65316. doi:10.1371/journal.pone.0065316
2. Hongo H, Green J, Otsuka K, Jimba M.
Development and psychometric testing of theJapanese version of the maternal breastfeeding
evaluation scale. J Hum Lact. 2013 Nov; 29(4):611-9. doi: 10.1177/0890334413491142. Epub
2013 Jun 18.
3. Matsubara C, Green J, Astorga LT, Daya EL,
Jervoso HC, Gonzaga EM, Jimba M. Reliability

553

tests and validation tests of the client satisfaction
questionnaire (CSQ-8) as an index of satisfaction
with childbirth-related care among Filipino women.
BMC Pregnancy and Childbirth 2013 13:235.
4. Fukuhara S, Wakita T, Yamada M, Hiratsuka Y,
Green J, et al. (2013) Development of a Short
Version of the Visual Function Questionnaire Using
Item- Response Theory. PLoS ONE 8(9): e73084.
doi:10.1371/journal.pone.0073084

554

Museum of Health and Medicine
Director
Kazuhiko Ohe

Specially-appointed technical expert
Atsushi Kitade

Homepage

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

History and overview
The origins of the School of Medicine and the
University of Tokyo Hospital can be traced back to theestablishment of the Kanda Otamaga-Ike Vaccination
Center in 1858. In 2008, it celebrated its 150th
anniversary. The Museum of Health and Medicine wasplanned as part of commemorative projects tocelebrate the 150th anniversary of the founding of the
School and the Hospital, and was opened on January
20, 2011. One of the themes for the commemorative
projects marking the 150th anniversary was the“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”, the fifth “Locomotive syndrome” , andthe sixth “Diabetes Mellitus” followed.
Since the opening of the Museum, more than
56,024 people had visited by the end of FY2013.

555

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.

556

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., Ph.D.

Homepage

http://www.ircme.m.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 ofInternational Cooperative Study in Medical Education,
and Planning & Cooperation for International
Cooperative Projects and Information on Medical
Education. Names of two new departments are
Department of Medical Education Studies andDepartment of International 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

557

education). As the studies of medical education
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 2013, we welcomed a visiting faculty:
Dr. Joyce Pickering (16 Oct 2013 – 28 Mar 2014),
Associate Professor, Vice Chair, Education,

Department of Medicine, Faculty of Medicine,
McGill University, Canada

Publication
1. Dwi Tyastuti, Hirotaka Onishi, Fika Ekayanti,
Kiyoshi Kitamura. An educational intervention ofinterprofessional learning in community based
health care in Indonesia: what did we learn fromthe pilot study? Journal of Education and Practice4(25): online, 2013
2. Alan Schwartz, Kimihiko Yamagishi, Norimichi
Hirahara, Hirotaka Onishi, James Barnes IV,
Adam Rosman, Maggie Garcia, Sam Lee,
Shoshana Butler. Risk perception and risk
attitudes in Tokyo: A report of the first administration of DOSPERT+M in Japan. Judgment and
Decision Making 8(6): 691-699, 2013
3. Samy A. Azer1, Michelle Mclean, Hirotaka
Onishi, Masami Tagawa, Albert Scherpbier.
Cracks in problem-based learning: What is youraction plan?. Medical Teacher 35(10): 806-814,
2013
4. Hirotaka Onishi. Help students redefine failure asa learning experience, pp22-24. Monitor yourprogress, pp165-167. Samy A. Azer (ed). Making
sense of clinical teaching: a hands-on guide tosuccess. CRC Press. Boca Raton, 2013