ISSN 0285-6131I

東 京 医 学
THE TOKYO JOURNAL OF MEDICAL SCIENCES
October

2006

Vol. 113

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2004 ― March 2006

共同編集

東京医学会・東京大学医師会・東京大学医学部
JOINTLY EDITED BY

THE
THE

TOKYO

SOCIETY

UNIVERSITY OF

THE UNIVERSITY OF

OF MEDICAL

TOKYO

TOKYO

SCIENCES

MEDICAL

SOCIETY

FACULTY OF

MEDICINE

東
学術刊行物

京

医

学

Tokyo J. Med. Sci.

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2004-March 2006

Introduction
This is the report of the University of Tokyo’s Faculty of Medicine and Graduate School of Medicine
for the years 2004 and 2005. Here we document each department’s research and educational activities.
The University of Tokyo has an historically unique role as the leading force in medicine within Japan. It
is only natural to expect that we will also be in the forefront of medicine worldwide. We take it as our
mission to be an internationally recognized source of important research results, and a center for training
outstanding medical scientists and clinicians.
Throughout the 20th century medicine was dominated by the West, but we are confident that in the 21st
century much greater contributions will come from Asia. In that context the role of Japan, and in particularthat of the Graduate School of Medicine at the University of Tokyo, will become even more important.
Always conscious of our mission, we should continue pursuing our educational and scientific interests
enthusiastically.
As we create the future, let us strive to achieve the best in medical research and teaching.
Nobutaka Hirokawa
Dean, Faculty of Medicine and Graduate School of Medicine
The University of Tokyo
March, 2006

i

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

1
2

2. Biochemistry and Molecular Biology ·················································································
Department of Molecular Biology ······················································································
Department of Cellular Signaling ·······················································································
Department of Physiological Chemistry and Metabolism ··················································

5
6
9
13

Functional Biology
1. Physiology ···························································································································
Department of Integrative Physiology ················································································
Department of Cellular and Molecular Physiology ·····························································
Department of Neurophysiology ·························································································

17
18
21
24

2. Pharmacology ······················································································································
Department of Cellular and Molecular Pharmacology ·······················································
Department of Molecular Neurobiology ·············································································

27
28
31

Pathology, Immunology and Microbiology
1. Pathology ·····························································································································
Department of Human Pathology and Diagnostic Pathology ·············································
Department of Molecular Pathology ···················································································

35
36
42

2. Microbiology ·······················································································································
Department of Microbiology ·······························································································
Department of Infection Control and Prevention ································································
3. Immunology ························································································································
Department of Immunology ································································································

47
48
51
55
56

ii

Radiology and Biomedical Engineering
1. Radiology ····························································································································
Department of Radiology ····································································································

59
60

2. Biomedical Engineering ······································································································
Department of System Physiology ······················································································
Department of Bioimaging and Biomagnetics ····································································
Department of Biosystem Construction & Control ·····························································

67
68
71
75

Neuroscience
1. Basic Neuroscience ·············································································································
Department of Neuropathology ···························································································
Department of Neurochemistry ···························································································

79
80
83

2. Speech and Cognitive Sciences ···························································································
Department of Speech Science ····························································································
Department of Speech Physiology ······················································································

89
90
92

3. Clinical Neuroscience ·········································································································
Department of Neuropsychiatry ··························································································
Department of Neurology ····································································································
Department of Neurosurgery ·······························································································

95
96
102
108

Social Medicine
1. Occupational, Environmental and Preventive Medicine ·····················································
Department of Molecular Preventive Medicine ··································································
Department of Public Health ·······························································································
Department of Radiological Health ·····················································································

113
114
118
122

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

125
126
130

Internal Medicine
1. Medicine I ·····························································································································
Department of Cardiovascular Medicine ············································································
Department of Respiratory Medicine ··················································································

135
136
142

iii

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

147

2. Medicine II ····························································································································
Department of Nephrology and Endocrinology ··································································
Department of Metabolic Disease ·······················································································
Department of Hematology and Oncology ·········································································
Department of Allergy and Rheumatology ·········································································
Department of Infectious Diseases ······················································································
Department of Stress Science and Psychosomatic Medicine ··············································

159
160
164
172
177
181
185

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

189

Department of Clinical Laboratory Medicine (See Clinical Laboratory Center)
Department of Transfusion Medicine and Immunohematology ·········································

190

Reproductive, Developmental and Aging Sciences
1. Obstetrics and Gynecology ·································································································
Department of Reproductive Endocrinology ······································································
Department of Gynecologic Oncology ···············································································
Department of Perinatal Medicine ······················································································

193
194
197
202

2. Pediatric Sciences··················································································································
Department of Pediatrics, Department of Developmental Pediatrics ·································
Department of Pediatric Surgery ·························································································
Department of Pediatric Oncology ······················································································

205
206
212
216

3. Aging Sciences ····················································································································
Department of Geriatric Medicine, Department of Aging Research ···································

219
220

Surgical Sciences
1. Surgery ································································································································
Department of Thoracic Surgery ·························································································
Department of Cardiothoracic Surgery ···············································································
Department of Gastrointestinal Surgery ··············································································
Department of Hepatobiliary Pancreatic Surgery and Department of Artificial
Organ and Transplantation Surgery ·····················································································
Department of Urology ·······································································································
Department of Surgical Oncology ·······················································································
Department of Vascular Surgrry ··························································································
Department of Metabolic Care and Endocrine Surgery ······················································

225
226
229
233
238
244
249
253
256

iv

2. Sensory and Motor System Medicine ·················································································
Department of Dermatology ································································································
Department of Plastic and Reconstructive Surgery ·····························································
Department of Oral-Maxillofacial Surgery ·········································································
Department of Orthopaedic Surgery ···················································································
Department of Ophthalmology ····························································································
Department of Otorhinolaryngology and Head & Neck Surgery ·······································
Department of Rehabilitation Medicine ··············································································

259
260
265
268
272
281
287
292

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

295

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

296
301

Health Sciences and Nursing
1. Health Sciences ···················································································································
Department of Health Sociology ·························································································
Department of Mental Health ······························································································
Department of Biostatistics / Epidemiology and Preventive Health Sciences ····················
Department of Social Gerontology ·····················································································
Department of Biomedical Ethics & Department of Health Promotion Sciences ················

305
306
309
312
317
320

2. Nursing Sciences ·················································································································
Department of Nursing Administration/ Advanced Clinical Nursing ·································
Department of Adult Nursing / Terminal and Long-term Care Nursing ·····························
Department of Family Nursing ···························································································
Department of Community Health Nursing ········································································
Department of Psychiatric Nursing ·····················································································
Department of Midwifery and Women’s Health ·································································
Department of Gerontological Nursing ···············································································

325
326
329
334
336
339
342
344

International Health
1. International Social Medicine ·····························································································
Department of Health Policy and Planning ·········································································
Department of International Community Health ································································

347
348
351

2. International Biomedical Sciences ······················································································
Department of Human Genetics ··························································································
Department of Developmental Medical Sciences ·······························································

355
356
361

v

Department of Human Ecology ···························································································
Department of Biomedical Chemistry ·················································································

366
370

University Hospital
Clinical Divisions ······················································································································
General Medicine ················································································································
Cardiovascular Medicine (See Department of Cardiovascular Medicine)
Respiratory Medicine (See Department of Respiratory Medicine)
Gastroenterology (See Department of Gastroenterology)
Nephrology and Endocrinology

373
374

(See Department of Nephrology and Endocrinology)
Metabolic Diseases (See Department of Metabolic Diseases)
Hematology and Oncology (See Department of Hematology and Oncology)
Allergy and Rheumatology (See Department of Allergy and Rheumatology)
Infectious Diseases (See Department of
Neurology (See Department of Infectious Diseases)
Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research)
Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine)
General Surgery ···················································································································
Stomach and Eophagus Surgery (See Department of Gastrointestinal Surgery)
Colon and Rectal Surgery (See Department of Surgical Oncology)
Hepatobiliary Pancreatic Surgery(See Department of Hepatobiliary Pancreatic Surgery)
Vascular Surgery (See Department of Vascular Surgery)
Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery)
Artificial Organ and Transplantation Surgery(See Department of Artificial Organ and Transplantation Surgery)
Cardiovascular Surgery (See Department of Cardiothoracic Surgery)
Thoracic Surgery (See Department of Thoracic Surgery)
Neurosurgery (See Department of Neurosurgery)
Anesthesiology and Pain Relief Center (See Department of Anesthesiology)
Urology and Andrology (See Department of Urology)
Gynecologic Surgery (See Department of Obstetrics and Gynecology)
Dermatology and Photolaser Medicine (See Department of Dermatology)
Ophthalmology and Vision Collection (See Department of Ophthalmology)

375

vi

Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery)
Otorhinolaryngology, and Auditory and Voices Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery)
Rehabilitation Medicine (See Department of Rehabilitation Medicine)
Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery)
Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery)
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics)
Pediatrics Surgery (See Department of Pediatrics Surgery)
Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of ynecologic Oncology /Department of Perinatal Medicine)
Neuropsychiatry (See Department of Neuropsychiatry)Radiology (See Department of Radiology)
Central Clinical Facilities ··········································································································
Clinical Laboratory Center ··································································································
Surgical Center ····················································································································
Department of Clinical Radiology ······················································································
Department of Emergency Services(See Department of Clinical Emergency and Critical Care Medicine)
Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine and Immunohematology)
Delivery Unit ·······················································································································
Central Rehabilitation Service ····························································································
Department of Intensive Care Unit
(See Department of Clinical Emergency and Critical Care Medicine)
Division of Diagnostic Pathology ·······················································································
Department of Corneal Transplantation ··············································································
University Hospital Medical Information Network (UMIN) Center ··································
Organ Transplantation Service ····························································································
Department of Cell Therapy and Transplantation Medicine ···············································
Department of Infection Control and Prevention(See Department of Infection Control and Prevention)
Department of Endoscopy and Endoscopic Surgery ···························································
Clinical Research Center ·····································································································

377
378
383
387

390
391

393
395
399
402
403

407
410

vii

Division of Tissue Engineering ···························································································
Hospital Planning and Management ···················································································
Department of Child Psychiatry ··························································································
Clinical Geonomics ·············································································································
Cooperative Unit of Medicine and Engineering Research ··················································

413
419
423
426
427

Pharmaceutical Service ·············································································································
Department of Pharmacy ·····································································································

441
442

Center for Disease Biology and Integrative Medicine ······························································
Division of Basic Medical Sciences (2) ···············································································

447
448

Division of Biomedical Materials and Systems ··································································
Division of Clinical Biotechnology ····················································································
Division of Environmental Health Sciences ·······································································

451
456
460

Section of Animal Research, Division of Research Resources and Support ······················
Section of Radiation Biology ······························································································
Section of Bioinformatics ····································································································

463
466
469

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

470

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

473

編集後記

viii

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

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

Nobutaka Hirokawa(Dean, Faculty of Medicine)
Chairman, School of Health Sciences and Nursing

Kai Ichiro

Director, Medical Library

Ouchi Yasuyoshi

Director General, University Hospital

Ryozo Nagai

Director, Center for Disease Biology and Integrative Medicine

Takao Shimizu

The director of the International Research Center for

Kimitaka Kaga

Medical Education.
Graduate School of Medicine
Molecular Cell Biology
Department of Cell Biology and Anatomy

professor

Nobutaka Hirokawa

Department of Biochemistry and Molecular Biology

professor

Hiroto Okayama

professor

Takao Shimizu

professor

Hiroki Kurihara

professor

Yasushi Miyashita

professor

Kensaku Mori

professor

Tomoyuki Takahashi

professor

Masamitsu Iino

professor

Masayoshi Mishina

professor

Masashi Fukayama

professor

Kohei Miyazono

professor

Akio Nomoto

professor

Kazuhiko Koike

professor

Tadatsugu Taniguchi

Department of Radiology

professor

Kuni Otomo

Department of Biomedical Engineering

professor

Joji Andoprofessor

Shogo Ueno

professor

Yasuo Ihara

professor

Nobumasa Kato

professor

Shoji Tsuji

Functional Biology
Department of Physiology

Department of Pharmacology
Pathology, Immunology and Microbiology
Department of Pathology
Department of Microbiology
Department of Immunology
Radiology and Biomedical Engineering

Neuroscience
Department of Basic Neuroscience
Department of Speech and Cognitive Sciences
Department of Clinical Neuroscience

ix

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

professor

Norito Saito

Department of Occupational, Environmental and Preventive

professor

Koji Matsushima

Medicine

professor

Yasuki Kobayashi

Department of Forensic Medicine, and Medical Informatics

professor

Kenichi Yoshida

and Economics

professor

Kazuhiko Ohe

professor

Ryozo Nagai

professor

Takahide Nagase

professor

Masao Omata

professor

Takashi Kadowaki

professor

Mineo Kurokawa

professor

Kazuhiko Yamamoto

professor

Kazuhiko Koike

professor

Akira Akabayashi

professor

Yutaka Yatomi

professor

Koki Takahashi

professor

Yuji Taketani

professor

Osamu Tsutsumi

professor

Takashi Igarashi

professor

Kouhei Hashizume

professor

Yasuyoshi Ouchi

professor

Shinichi Takamoto

professor

Michio Kaminishi

professor

Masatoshi Makuuchi

professor

Tadaichi Kitamura

professor

Hirokazu Nagawa

professor

Kunihiko Tamaki

professor

Isao Koshima

professor

Tsuyoshi Takato

professor

Kozo Nakamura

professor

Makoto Araie

professor

Kimitaka Kaga

professor

Naoki Yahagi

professor

Yasuo Ohashi

professor

Ichiro Kai

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II professor Toshiro Fujita

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

Department of Vital Care Medicine
Health Sciences and Nursing
Department of Health Sciences

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006x

professor

Akira Akabayashi

professor

Katsuya Kanda

professor

Keiko Kazuma

professor

Sachiyo Murashima

professor

Hiromi Sanada

Department of International Social Medicine

professor

Susumu Wakai

Department of International Biomedical Sciences

professor

Katsushi Tokunaga

professor

Hiroshi Ushijima

professor

Chiho Watanabe

professor

Kiyoshi Kita

professor

Kazuhiko Yamamoto

Associate professor

Kiyoshi Kubota

Associate professor

Tetsuro Okabe

Associate professor

Satoru Yamagami

Department of Nursing Sciences

International HealthInternational Academic Affairs
Faculty of Medicine
Endowed Departments
Department of Pharmacoepidemiology
Department of Integrated Traditional Medicine(Tsumura)
Department of Corneal Tissue Regeneration (Amniotec Inc.)

Department of Clinical Vascular Regeneration(Daiichi Pharmaceutical Co.)
Associate professor

Hiroyuki Koyama

Associate professor

Chung, Ung-il

Associate professor

Seishi Ogawa

Associate professor

Kazuto Hoshi

Associate professor

Keiichi Hishikawa

professor

Hiroshi Suzuki

professor

Ryo Taguchi

Associate professor

Yoshiya Oda

Department of Systematic Clinical Oncology

Associate professor

Shin Sasaki

Hospital Logistics by Sagawa Express Co.,Ltd.

professor

Hirohito Kuse

Associate professor

Takanari Gotoba

Associate professor

Kazuhiro Kakimi

Associate professor

Shinya Oku

Associate professor

Shinya Kaname

Associate professor

Toshimasa Yamauti

Department of Bone & Cartilage Regenerative Medicine
Department of Hematopoietic Regeneration
Department of “Menicon” Cartilage of Bone Regeneration

Department of Clinical Renal Regeneration
Department of Developmental and Medical Technology(Sankyo)
Department of Metabolome

Clinical Molecular Epidemiology(Tanabe Seiyaku Co., Ltd.)
Immunotherapeutics (Medinet)
Healthcare Related Informatics (NTT DATA CORPORATION)
Division of Total Renal Care Medicine
Integrated Molecular Science on Metabolic Diseases

xi

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

Department of Advanced Clinical Science and Therapeutics
Associate professor

Koji Kawakami,
Masataka Sata

Sato Sports Plaza Co., Ltd Kaatsu Training

Associate professor

Toshiaki Nakajima

Department of Sleep Disorder Research(Alfresa)

Associate professor

Takashi Ebisawa

Associate professor

Dobun Hayashi

Department of Joint Disease Research

Associate professor

Noriko Yoshimura

Health Care Management and Policy

professor

Hideki Hashimoto

Associate professor

Naoto Hayashi

Associate professor

Hoshio Uehara,

Translational Research Based on the Clinical Database

Computational Diagnostic Radiology and Preventive Medicine
Helth Service Center

Tsukasa Sasaki,
Yasushi Okubo
International Research Center for Medical Education Director Kimitaka Kaga
professor Kiyoshi Kitamura

Associate professor

Junji Ohtaki

General Medicine

Head

Yasuyoshi Ouchi

Cardiovascular Medicine

Head

Ryozo Nagai

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Masao Omata

Nephrology and Endocrinology

HeadToshiro Fujita

Metabolic Diseases

Head

Takashi Kadowaki

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Kazuhiko Yamamoto

Infectious Diseases

Head

Kazuhiko Koike

Neurology

Head

Shoji Tsuji

Geriatric Medicine

Head

Yasuyosi Ouchi

Psychosomatic Medicine

Head

Akira Akabayashi

General Surgery

Head

Masatoshi Makuuchi

Stomach and Esophagus Surgery

HeadMichio KaminishiColon and Rectal Surgery

Head

Hirokazu Nagawa

Hepatobiliary Pancreatic Surgery

Head

Masatoshi Makuuchi

Vascular Surgery

Head

Hirokazu Nagawa

Breast and Endocrine Surgery

HeadMichio Kaminishi

Artificial organ and Transplantation Surgery

Head

Masatoshi Makuuchi

Cardiovascular Surgery

HeadShinichi Takamoto

Thoracic Surgery

HeadShinichi Takamoto

Anesthesiology and Pain Relief Center Urology and Andrology

Head

Tadaichi Kitamura

Gynecologic Surgery

HeadOsamu Tsutsumi

University Hospital
Clinical Divisions

Neurosurgery

xii

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

Dermatology and Photolaser Medicine

Head

Kunihiko Tamaki

Ophthalmology and Vision Collection

Head

Makoto Araie

Orthopaedic and Spinal Surgery

Head

Kouzo Nakamura

Otorhinolaryngology and Auditory and Voice Surgery

Head

Kimitaka Kaga

Plastic, Reconstructive and Aesthetic Surgery

Head

Isao Koshima

Oral-Maxillofacial Surgery, Dentistry and Orthodontics

Head

Tsuyoshi Takato

Pediatrics

Head

Takashi Igarashi

Pediatric Surgery

Head

Kohei Hashizume

Obstetrics and Gynecology

Head

Yuji Taketani

Neuropsychiatry

Head

Nobumasa KatoRadiology

Head

Kuni Ohtomo

Head

Yutaka Yatomi

Radiological Center

Head

Kuni Ohtomo

Emergency Services

Head

Naoki Yahagi

Transfusion Medicine and Immunohematology

HeadKoki Takahashi

Delivery Unit

Head

Yuji Taketani

Intensive Care Unit

Head

Naoki Yahagi

Intensive Pathology

Head

Masashi Fukayama

Corneal Transplantation

Head

Shiro Amano

Infection Control and Prevention

Head

Kazuhiko Koike

Department of Endoscopy and Endoscopic Surgery

Head

Takao Kawabe

Center for Hemodialysis and Apheresis

Head

Toshiro Fujita

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Cell Therapy and Transplantation Medicine

Head

Shigeru Chiba

Clinical Research Center(tentative name)Head

Masao Omata

Department of Medical Social Service and Welfare

Head

Yasuyoshi Ouchi

Department of Planning, Infomation and Management

Head

Kazuhiko Ohe

Department of Organ Transplantation Service

Head

Masatoshi Makuuchi

Pharmaceutical Department

Head

Hiroshi Suzuki

Rehabilitation Medicine

Central Clinical Facilites
Clinical Laboratory Center
Surgical Center

Rehabilitation Service
Medical Engineering (tentative name)Supply Center (tentative name)

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

xiii

Organization Chart
Cell Biology
Cell Biology and Anatomy

Structural Biology
Structural Cell Biology

Molecular Cell Biology

Cellular Neurobiology
Molecular Biology
Biochemistry and Molecular Biology

Cellular Signaling
Physiological Chemistry andMetabolism
Integrative Physiology

Physiology
Functional Biology

Cellular and Molecular Physiology
Neurophysiology

Pharmacology

Cellular and Molecular Pharmacology
Molecular Neurobiology
Human Pathology and Diagnostic Pathology

Pathology

Molecular Pathology

Microbiology

Microbiology

Surgical Pathology
Pathology, Immunology
and Microbiology

Infection Control and Prevention
Immunology

Molecular Immunology
Clinical Immunology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

Radiation Oncology/Experimental
Radiology
System Physiology
Bioimaging and Biomagnetics
Biomedical Engineering

Biosystem Construction and Control
Biomechanics
Medical Optics
Clinical Engineering
Neuropathology

Basic Neuroscience
Graduate School of
Medicine

Neurochemistry
Neurobiology
Speech Science

Neuroscience

Speech and Cognitive Neuroscienes

Cognitive Neuroscience
Speech Physiology
Sensory and Motor Neuroscience
Neuropsychiatry

Clinical Neuroscience

Neurology
Neurosurgery
Molecular Preventive Medicine

Social Medicine

Occupational, Environmental andPreventive Medicine

Public HealthRadiological Health

xiv

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006
Forensic Medicine, and Medical
Informatics and Economics

Forensic Medicine
Medical Informatics and Economics
Cardiovascular Medicine
Vascular Biology

Medicine I

Respiratory Medicine
Gastroenterology
Nephrology
Endocrinology

Internal Medicine

Nutrition and Metabolism
Medicine II

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

Clinical Laboratory Medicine
and Pathology

Diagnostic Pathology
Transfusion Medicine
Reproductive Endocrinology

Obstetrics and Gynecology

Gynecological Oncology
Perinatal Medicine
Molecular Reproductive Medicine
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. 113, October 2006
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
Adult Nursing
Nursing Sciences

Palliative Care Nursing
Family Nursing
Community Health Nursing
Psychiatric Nursing
Gerontological Nursing
Midwifery and Woman’s HealthInternational Social Medicine
International Health

Health Policy and Planning
International Community Health
Human Genetics Cell Biology

International Biomedical
Sciences

Developmental Medical Sciences
Human Ecology
Biomedical ChemistryCenter for Disease Biology
and Integrative medicine

Division of Basic Medical Sciences (1)Division of Basic Medical Sciences (2)Division of Biomedical Materials and Systems
Division of Clinical Biotechnology
Division of Environmental Health Sciences
Division of Research Resources and Support

Section of Animal Research
Section of Radiation Biology
Section of Bioinformatics

Faculty of Medicine
Graduate School of Medicine
Administrative Division

Administrative Office
Cell Biology and Anatomy
Biochemistry and Molecular Biology
Physiology
Pharmacology
Pathology
Microbiology
Immunology
Radiology
Biomedical Engineering
Basic Neuroscience
Speech and Cognitive Sciences
Clinical NeuroscienceCell Biology

School of Medicine

Occupational, Environmental and Preventive Medicine
Medical Principles and Medical Ethics

xvi

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006
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
Family Nursing
School of Health Sciences
and Nursing

Comunity Health Nursing
Fundamental Nursing
Adult Health and Nursing
Mental Health and Nursing
Health Sociology
Health Administration
Epidemiology and Biostatistics
Human Ecology
Biochemistry and Nutrition
Maternal and Child HealthFaculty of
Medicine

Endowed Department

Pharmacoepidemiology
Integrated Traditional Medicine (Tsumura)
Corneal Tissue Regeneration (Amniotec inc.)
Clinical Vascular Regeneration (Daiichi Pharmaceutical Co.)
Bone & Cartilage Regenerative Medicine
Hematopoietic Regeneration“Menicon”Caartilage of Bone Regeneration
Clinical Renal Regeneration
Developmental nd Medical Technology(Sankyo)
Metabolome
Systematic Clinical Oncology
Hospital Logistics by Sagawa Express Co. Ltd.
Clinical Molecular Epidemiology (Tanabe Seiyaku Co. Ltd.)
Immunotherapeutics (Medinet)
Healthcare Related Informatics (NTT DATA CORPORATION)
Total Renal Care Medicine
Integrated Molecular Science on Metabolic Diseases
Advanced Clinical Science and Therapeutics
Sato Sports Plaza Co.Ltd. Kaatsu Training
Sleep Disorder Research (Alfresa)
Translational Research Based on the Clinical Database
Joint Disease Research
Health Care Management and Policy
Computational Diagnostic Radiology and Preventive Medicine

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

xvii

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

Metabolic Diseases
Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases
Neurology

ClinicalDivisions

Geriatric Medicine
Psychosomatic Medicine
General Surgery
Stomach and Esophageal Surgery

Universit
Hospital

Colon and Rectal Surgery
Hepato Biliary and Pancreatic Surgery
Vascular Surgery
Breast and Endocrine Surgery
Surgery

Artificial organ and Transplantation Surgery
Cardiovascular Surgery
Thoracic Surgery
Neurosurgery
Anesthesiology and Pain Relief Cente
Urology and Andrology
Gynecologic Surgery
GDermatology 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
Clinical Laboratory Center
Surgical Center
Radiological Center
Emergency Services
Transfusion Medicine
Delivery Unit

Central Clinical Facilities

Rehabilitation Service
Medial Engineering Supply CenterxviiiThe Tokyo Journal of Medical Sciences. Vol. 113, October 2006

Intensive Care Unit
Pathology
Sectin of Corneal Transplantation
Department of Cell and Gene Therapy
Department of Endoscopy and Endoscopic Surgery
Department of Hemodialysis and Apheresis
Hospital Computer Center
Department of Medical Social Service and Welfare
Clinical Research Center
Infection Control and Prevention
University Hospital Hospital Medical Information
Network Center
Organ Transplantation Service
Department of Nutrition
Labor Safety and Health Management Office
Project Team For Hospital Development
Department of Clinical and Genetic Informatics
The Clinical Training Center
Department of Palliative Medicine
Public Relations Office
Department of Clinical Genomics
Cooperative Unit of Medicine and Engineering Research
Pharmaceutical Department
Nursing Department
Administration Office

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

xix

History
1858

May
Nov

1859
1860
1861

Sep.
Oct.
Oct.

1863
1868

Feb.
Jul.

1869
1871

Feb.
Dec.
Jul.

1872

Aug.

1874
1876
1877

May.
Nov.
Apr.

1886

Mar.

1897
1917

Jun.
Aug.

1919
1931
1936

Apr.
Feb.
Jan.
Nov.
Oct.
Apr.
Apr.
Jul.
Apr.
Apr.
May.
Mar.
Apr.
Apr.

1947
1950
1953
1956
1958
1961
1965

82 practitioners trained in Dutch (European) medicine in Edo (Tokyo) laid out money and establishedat Kanda Mitamagaike Vaccination station called the Shutojyo (vaccination center).
The Shutojyo burned by a fire which emerged from Kanda Aioicho, continued its operationat
othersites such as a residence of Ito Genboku.
The Shutojyo was moved to and reconstructed at Shitaya Izumibashi Dohri.
TheShutojyo became an official medical institution of the Shogunate Government.
The Shutojyo was renamed as Seiyo Igaku-syo (Institute of Western Medicine) and offered courses
ofWestern medicine in the fields of education, autopsy, and vaccination.
The Seiyo Igaku-sho was renamed as Igaku-sho (Institute of Medicine).
The Igaku-sho, affiliated with the Military hospital which was moved from Yokohama to Todo
residence in Shitaya, was renamed as Daibyoin (the Great Hospital).
The Daibyoin renamed as Igakko-ken-byoin (Medical School and Hospital).
Igakko-ken-byoin was renamed as Daigaku-Higashiko (University East Building).
Ministry of Education was established and Daigaku-Higashiko
was renamed as Higashiko (EastBuilding).
School System was established, renaming Higashiko as Daiichi-daigaku-ku-igakko (The1stUniversity
District Medical School).
Daiichi-daigaku-ku-igakko was renamed as Tokyo-igakko (Tokyo Medical School).
Tokyo-Igakko was moved to Hongo.
Tokyo-Igakko, affiliated with Tokyo-Kaisei School, renamed as The University of Tokyo.Tokyo
Medical School was renamed as The University of Tokyo Faculty of Medicine.
The University of Tokyo was renamed as Imperial University, and University of Tokyo FacultyofMedicine renamed as Imperial University Medical college. Graduate School was established.
The Imperial University was renamed as Tokyo Imperial University.
Eiraku Hospital affiliated with Ministry of Education Medical Practice License Examination, moved toTokyo Imperial University and renamed as Koishikawa hospital affiliated to Tokyo Imperial University
Medical College.
Faculty system was established renaming Medical College as Faculty of Medicine.
The first building of the Faculty of Medicine was constructed.
Brain research office donated by Mr. Horikoshi Hisasaburo.
The second building of the Faculty of Medicine (main building) was constructed.
Tokyo Imperial University renamed as The University of Tokyo.
Institute of Nursing renamed as University Nursing School.
School of Health Care and Nursing founded.
Graduate School of the new system founded, Division of Biological Science Dr. Med.of Medicine.
Midwives School established.
Division of Pharmaceutical Sciences became independent Faculty.
Celebrated centennial of The University of Tokyo Faculty of Medicine.
Medical Library was built in memorial of the centenary.
Institute of Medical Electronics established.
Research Institute of Logopedics and Poniatrics was established.
School of Health Care and Nursing reorganized as the School of Health Sciences.
Graduate School of The University of Tokyo Reorganized and Division of Biological Science. Dr.Med.
Science course became Medical Science Division.
Health Science Course was established in Medical Science Division.

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

xx

1966
1971
1973
1983
1985
1987
1992

Sep.
Apr.
Mar.
Jan.
Sep.
Apr.
Apr.

1995

Jul.
Apr.

1996

Apr.

1997

Apr.

1999

Apr.

2000

Apr.

2001
2003

Apr.
Apr.

The third building of Faculty of Medicine was constructed.
Laboratory for Animal Experiments was established.
Animal Center for Biomedical Research was constructed.
Annex of the third building of the Faculty of Medicine was constructed.
Medical and International Academic Affairs established.
Graduate School specialized course was changed to major.
School of Health Sciences became The School of Health Science and Nursing.
School of International Health was established in Medical Science Division.
Radiation Research Institute was established.
As the result of the shift to the chair system of the Graduate School of Medicine, four divisions wereabolished, Third Basic Medicine, Social Medicine, Third Clinical Medicine and Fourth Clinical
Medicine. Instead, four divisions were established, Pathology, Immunology and Microbiology, Social
Medicine, Reproductive, Developmental and Aging Science and Surgery.
As the result of the shift to the chair system of the Graduate School of Medicine, three divisions wereabolished, First Clinical Medicine, Health Science and International Health. Instead, three divisions
were established, Internal Medicine, Health Science and Nursing and International Health.
As the result of the shift to the chair system of the Graduate School of Medicine, three divisions wereabolished, First Basic Medicine, Second Basic Medicine and Second Clinical Medicine. Instead four
divisions were established. Molecular Cell Biology, Functional Biology, Radiology and Biomedical
Engineering and Neuroscience.
As the result of above mentioned reorganization, three institutes were abolished, Institute of Brain
Research, Institute of Medical Electronics and Institute of Logopedics and Phoniatrics.
Master Course of Medical Science was established in Graduate School of Medicine.
This course accepts graduates of all faculties except those from Schools of Medicine, Dentistry, andVeterinary Medicine.
The International Research Center for Medical Education was established.
(The shared facility for education and research)
University Branch Hospital was united to University Hospital.
The Center for Disease Biology and Integrative Medicine was established.

The University of Tokyo,
Graduate School of Medicine①

Molecular Cell Biology
1. Cell Biology and Anatomy②

2

Department of Cell Biology andAnatomyProfessor
Nobutaka Hirokawa, M.D.

Associate Professor
Yoshimitsu Kanai, M. D.,
Sen Takeda, M. D.

Takao Nakata, M. D.,

Yosuke Takei, M. D.,

Lecturer
Yasuko Noda, M. D.,

Sumio Terada, M. D.

Associate
Yasushi Okada, M. D.,
Ryo Nitta, M. D.,
Hiroaki Yajima, Ph. D.

Yosuke Tanaka, M. D.,
Noriko Homma, Ph. D.,

Masahiko Kawagishi, M. 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, Histology and Neurocytology.
2) Lecture on Gross Anatomy and Neuroanatomy. to
medical students and students of other facultiesII.
1) Laboratory course of Gross Anatomy and Neuroanatomy.
2) Laboratory course of Histology and Histology of
the Cenrtral Nervous System.
to medical students and students of other faculties.
In addition we offer a special training course (freequarter) of various kinds of molecular cell biology
techniques such as immunocytochemistry, electron
microscopy, biochemistry, molecular biology, biophysics, and cellular and molecular neurobiology
technique to medical students.

Research activities
Our research field covers the molecular cell biologyof the cytoskeleton. We focus on the molecularmechanisms of cell morphogenesis and intracellulartransports.
Our laboratory studies molecular architecture, dynamics and function of the neuronal cytoskeleton using various new molecular cell biological approaches
including new electron microscopy such as the quick
freeze deep etch electron microscopy, cryoelectron
microscopy at atomic resolution, and cryoultramicrotomy, biochemistry, immunocytochemistry, molecularbiology, molecular genetics such as gene targeting andtransgenic mouse approaches, molecular biophysics
and structure biology including X ray crystallography
and cryoelectron microscopy.
In this way we can study structure, dynamics andfunctions of cytoskeleton from gene to cell, tissue andwhole body.
Nerve cells as units of complicated neuronal networks in the brain develop very polarized morphology

3composed of dendrites, cell body and a long axon
along the direction of impulse propagation. The neuronal cytoskeleton plays three major important roles.
1) It provides dynamic frameworks for neurite extension and maintenance.
2) It provides structural bases for organelle transports
in the cells. Namely it works as rails and motor molecules to transport materials from cell center to periphery and from periphery to cell center.
3) It very importantly regulates release processes oftransmitters and also contributes to anchor receptors at
the postsynaptic sites.
Our laboratory studies molecular architecture, dynamics and function of the cytoskeleton focusing onthese three major roles.
To study these molecular mechanisms we use newmolecular cell biological approaches including electron microscopy of molecular resolution, biochemistry,
biophysics, molecular biology and molecular genetics
and X-ray crystallography.

References
1. Ogawa, T., R. Nitta, Y. Okada, and N. Hirokawa.
A common mechanism for microtubule destabilizers - M-type kinesins stabilize curling of the
protofilament using the class-specific neck andloops. Cell 116: 591-602, 2004.
2. Nitta, R., M. Kikkawa, Y. Okada, and N. Hirokawa.
KIF1A alternately uses two loops to bind microtubules. Science 305: 678-683, 2004.
3. Kanai, Y., N. Dohmae, and N. Hirokawa. Kinesintransports RNA: isolation and characterization of
an RNA-transporting granule. Neuron 43: 513525, 2004.
4. Mizuno, N., S. Toba, M. Edamatsu, J. Watai-Nisni,
N. Hirokawa, Y. Toyoshima, and M. Kikkawa.
Dynein and kinesin share an overlapping microtubule-binding site. EMBO J 23: 2459-2467,
2004.
5. Hirokawa, N. and R. Takemura. Molecular motors
in neuronal development, intracellular transportand diseases. Curr Opin Neurobiol 14: 564-573,
2004.
6. Hirokawa, N. and R. Takemura. Kinesin superfamily proteins and their various functions anddynamics. Exp Cell Res 301: 50-59, 2004.

7. Hirokawa, N. Microtubule-Associated Proteins.
Encycl Biol Chem 2:676-682, 2004.
8. Hirokawa, N. and R. Takemura. Kinesin superfamily proteins. Encycl Biol Chem 2: 508-516,
2004.
9. Hirokawa, N. and R. Takemura. Molecular motors
and mechanisms of directional transport in neurons. Nature Rev Neurosci 6: 201-214, 2005.
10. Teng J., T. Rai, Y. Tanaka, Y. Takei, T. Nakata, M.
Hirasawa, A. B. Kulkarni, and N. Hirokawa. The
KIF3 motor transports N-cadherin and organizes
the developing neuroepithelium. Nature Cell Biol
7: 474-482, 2005.
11. Tanaka, Y., Y. Okada, and N. Hirokawa. FGF-induced
vesicular release of Sonic hedgehog and retinoic
acid in leftward nodal flow is critical for left-rightdetermination. Nature 435: 172-177, 2005.
12. Okada, Y., S. Takeda, Y. Tanaka, J.-C. I. Belmonteand N. Hirokawa. Mechanism of nodal flow: aconserved symmetry breaking event in left-rightaxis determination. Cell 121: 633-644, 2005.
13. Miki. H., Y. Okada, and N. Hirokawa. Analysis of
the kinesin superfamily: insights into structureand function. Trend Cell Biol 15: 467-476, 2005.

Molecular Cell Biology
2. Biochemistry and Molecular Biology③

6

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

Associate Professor
Shigeki Jinno, Ph.D.

Associate
Hanako Yamamoto, Ph.D.,

Kenji Ito, Ph.D.

Homepage http://www.cellcycle.m.u-tokyo.ac.jp/
Introduction and Organization
This Department was established in 1893 initiallyas a part of Department of Physiology, but in 1897
became independent. In 1927, it was renamed Department of Biochemistry, in 1974 First Department ofBiochemistry and in 1997 Department of Molecular
Biology, according to the creation of new related departments and the reorganization of Faculty of Medicine. This Department has been headed by 7 professors, who made great contributions to the developmentof biochemistry, nutrition and molecular biology inJapan.
Professor Muneo Kumagawa, who headed
this first Biochemistry or Medical Chemistry
Department established in this country, graduatedin 1882 The University of Tokyo Faculty of
Medicine. In 1884 he went to Department of
Pathology, The University of Berlin headed by
Rudolf Virchow and under the supervision of
Ernst Salkowski. After returning to Japan, he
was promoted to Lecture and Professor of thisDepartment. In 1908, He discovered lack ofglycogenecity in lipids, which has been firmly
established besides some exceptions, and succeeded in purification of vitamin B1, which was
discovered by C. Eijikman in 1906. He educatedmany including Masahiro Sakaguchi, who developed a world-famous colorimetric method forarginine and Takaoki Sasaki, who first succeeded in generating liver cancer with chemicals.
Professor Samuro Kakiuchi graduated The
Imperial University of Tokyo Faculty of Medicine in 1906 and studied under Professor Kumagawa. After studies in US, he come back andsucceeded late Kumagawa. He published Journal of Biochemistry and founded the JapaneseSociety of Biochemistry. His students included
Professors Kodama and Shimazono.
Professor Keizo Kodama graduated the Imperial University of Tokyo in 1918. Taking positions of lecturer and Associate Professor andmaking studies at Cambridge University, hebecame Professor of Biochemistry Kyushu Imperial University and succeeded Professor Kodama in 1933. He studied oxidation and reduction and nutrition.
Professor Norio Shimazono graduated The
Imperial University of Tokyo Faculty of Medicine in 1928, followed by taking positions asassociate, lecturer, professor at Niigata Medical
School. In 1952 he succeeded Professor Kodama.
He studied vitamin B1/ cocarboxylase, ketoacid
metabolism and hexose metabolism.
Professor Tamio Yamakawa graduated The
Imperial University of Tokyo Faculty of Medicine and began studies at The Institute for In-

7fectious Diseases, The University of Tokyo. After becoming Associate Professor and Professor,
he succeeded Professor Shimazono. He was apioneer in glycolipid research and discovered
the involvement of sialic acid in the ABO blood
type antigens.
Professor Masami Muramatsu graduated The
University of Tokyo Faculty of Medicine in 1955.
He began studies in Department of Internal
Medicine, went to Baylor Collage of Medicine to
study under H. Busch, and after coming back,took a position at Cancer Institute and professorship at Tokushima University School of
Medicine. In 1982, he succeeded Professor Yamakawa. He studied ribosomal RNA and cloned
interferon and p450 genes.
Professor Hiroto Okayama graduated Kumamoto University School of Medicine in 1973.
After taking a Ph.D. degree at Kyoto University
School of Medicine, he went to Stanford University to study under P. Berg. Taking a position at NIH US, he became Professor of Molecular Genetics, Osaka University Institute for
Infectious Diseases. In 1993 he succeeded Professor Muramatsu. At Stanford and NIH, hestudied gene cloning and developed a fulllength cDNA cloning method and a cDNA expression cloning vector system. After return toJapan, he has been studying cell cycle control
and cancer.

Research Activities
Our current study focuses on the understanding of
the molecular mechanism enabling the anchorage-independent S phase onset, which is the universal
property of cancer cells. All the members of our laboratory are participating in this study.
1. Molecular Mechanism for anchorage loss- induced Cdc6 degradation.
In 2002, we reported that anchorage deprivation
led to termination of expression of Cdc6, a factor
essential for the assembly of Pre-RC, via
Rb-independent transcriptional repression andpapain family protease-led degradation. We now
have identified the protease as lysosomal cathepsins, released from low cholesterol-content ly-

sosomes upon anchorage deprivation. We further
found that the PI3-kinase-mTOR signal was essential for blocking the release of cathepsins fromthe lysosomes and that anchorage loss disrupted
this signaling, thereby inducing cathepsin release
and Cdc6 degradation.
2. Transcriptional control of the cdc6 gene
It has been known that the E2F-DP-Rb transcriptional factor complex regulates transcription of
the cdc6 gene. We have discovered that a transcriptional activator to be identified is criticallyinvolved in activation of this promoter during
growth stimulation and that this factor is activatedby Cdk4. This finding provides a critical clue tosolve the long recognized paradox that functionally similar Cdk4 and Cdk6 are expressed in cells
and both can activate E2F-DP-Rb, yet Cdk4 is
uniquely required for S phase onset.
3. Mechanism controlling recovery from DNA
damage-induced S phase arrest
It has been known that after receiving severe DNA
damage, cells are delayed in recovery and resumption of S phase progression long after DNA
damage repair is completed. We found that Cdc6
protein plays a critical role in determining thetiming of recovery. Enforced expression of Cdc6
drastically accelerates recovery with similarly accelerated reactivation of Cdk2. Thus Cdc6 plays ahighly important role in S phase progression evenafter the assembly of Pre-RC is completed.

Education
To medical students, we give lectures on DNA andrelated. DNA replication, transcription, nuclear export
of mRNA, translation, gene engineering and mobile
DNA are the topics covered by the lectures.
To graduate course students, the genetic engineeringcourse consisting of lectures and experiments is provided.

References
1. Isobe, H., Nakanishi, W., Tomita, N., Jinno S.,
Okayama, H. and Nakamura, E. 2006, Nonviral

8gene delivery by aminofullerene. Mol Pharm 3,
124-134.
2. Moro, T., Ogasawara, T., Chikuda, H., Ikeda, T.,
Ogata, N., Maruyama, Z., Komori, T., Hoshi, K.,
Chung, U.I., Nakamura, K., Okayama, H., andKawaguchi H. 2005, Inhibition of Cdk6 expression through p38 MAP kinase is involved in differentiation of mouse prechondrocyte ATDC5. J.
Cell Physiol.204, 927-933.
3. Ogasawara, T., Kawaguchi, H., Jinno, S., Hoshi,
K., Itaka, K., Takato, T., Nakamura, K., and Okayama, H.; Bone morphogenetic protein-2-induced
osteoblast differentiation requires Smad-mediateddown-regulation of Cdk6. 2004, Mol. Cell. Biol.
24, 6560-6568.
4. Ogasawara, T., Katagiri, M., Yamamoto, A., Hoshi,K., Takato, T., Nakamura, K., Tanaka, S., Okayama, H., Kawaguchi, H.; Osteoclast differentiation by RANKL requires NF-kappaB-mediateddownregulation of cyclin-dependent kinase 6(Cdk6). 2004, J. Bone Miner. Res. 19, 11281136.

9Department of Cellular Signaling
Professor
Takao Shimizu, M,D., Ph.D.

Associate Professor
Takehiko Yokomizo, M.D., Ph.D.

Lecturer
Satoshi Ishii, Ph.D.

Associate
Yoshihiro Kita, Ph.D.,

Hideo Shindou, Ph.D.

Homepage http://biochem2.umin.jp/index.html
Introduction and Organization

Research activities

In addition to the above 5 faculty members, we have
15 graduate students (14 doctor course students including 2 PhD-MD course students and 1 master course
student), and 1 undergraduate medical student (Free
Quarter). Several clinical scientists and a research fellow from pharmaceutical company are also our members. Ms Toshie Takahashi (Associate) belongs to the
Dean of the Faculty and is in charge of maintenanceand education of various instruments for common use.

1. Roles and cellular signaling of lipid mediators.
Oxygenated products of arachidonic acid (prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids) as well as bioactive phospholipids(platelet-activating factor and other related phospholipids) activate cellular signaling pathways invarious cells. These lipid mediators, working together with other bioactive substances such asneurotransmitters and cytokines, are now considered to play significant roles in neuronal plasticity
and self-defense systems. To identify the roles oflipid mediators in the living systems, principally
three approaches are ongoing with different strategies; (1) isolation of enzymes involved in syntheses
and degradation of lipid mediators, cloning of
cDNAs and genes, elucidation of enzyme regulation at transcriptional and posttranscriptional levels.
(2) cloning of G-protein-coupled receptors for lipid
mediators and clarification of intracellular signaling mechanisms; and (3) target disruption or overexpression of the gene of interest in mice, andidentification of the in vivo role of each moleculeby examining phenotypes of these mice. In the last
several years we have cloned several key enzymesof phospholipid metabolism and receptors for lipid

Teaching activities
For about 100 undergraduate students from the Faculty of Medicine, and about 5 students from Faculty of
Science (Department of Anthropology), we deliver
about 80 lectures, small-group seminars, and laboratory
course for a couple of weeks. Our laboratory is accepting Free Quarter students every year, and the total
number from 2003 to 2005 is around 10. For graduate
course students, we have three-month lecture series(biochemistry and genetic engineering), and aneight-week laboratory course for clinical scientists.

10

mediators. Several lines of transgenic mice andknock-out mice were established and their phenotypes were analyzed. We found that these mediators
are involved in inflammation, allergy, and neuronal
functions.

machines and instruction for the beginners. As her
own projects, she is identifying peptide sequencesof various proteins by HPLC-MS, and identification of small-molecular weight compounds by
GC-MS and HPLC-MS.

2. Metabolomics analyses of lipid mediators.
Lipid mediators are produced through cascade
pathways. In the cascade known as “arachidonate
cascade”, several key enzymes such as cytosolic
phospholipase A2, cyclooxygenases, and lipoxygenases function as common regulators in combination with various terminal synthases that produce
specific lipid mediator molecular species. For acomprehensive analysis of lipid mediators, a simultaneous quantitation method with sensitivity
and reliability is necessary. Thus, we have recently
developed a quantitation system for multiplex lipid
mediators by column-switching HPLC–tandem
mass spectrometry. When optimized, the systemenables the rapid analysis of 14 lipid mediatorswith a throughput of 96 samples/24 h, lower limitsof quantitation of 5 pg on column, and linear calibration ranges up to 2000–5000 pg. Indeed, we
successfully detected dynamic changes in a seriesof lipid mediators in some pathologic tissues of rodents.

5. Internet Web site
To see our research activities in more detail, pleaserefer to our web site (http://biochem2.umin.jp/index_j.
html). In this homepage, you will also find our experimental protocols useful for the molecular andcellular biology studies. Drs. Kimura and Kita are
responsible for the homepage.

3. Research on membrane biogenesis and surfactant
production.
Membrane phospholipids and pulmonary surfactants are produced by a family of lysophospholipid
acyltransferases. We recently isolated a gene encoding lysophosphatidylcholine acyltransferases,
which might be involved in production of pulmonary surfactant.
4. Various instrumental analyses.
The Faculty of Medicine has various analytical andpreparative instruments for the common use, which
include mass spectrometers (JEOL HX 110, Hitachi
M-80 and Finnigan MAT TSQ 7000 [ThermoQuest]) equipped with gas chromatographs or
HPLC, PerkinElmer peptide sequencers, FUJI BAS
2000 image analyzer, BD FACScan, and Beckman
capillary electrophoresis system (P/ACE 2000). Ms.
Takahashi is in charge of the maintenance of these

6. Collaboration with Department of Metabolome
In 2003, a new laboratory, Department of Metabolome was established by the donation of Shimadzu Co., Ltd, and Ono Pharmaceutical Co. Professor Ryo Taguchi and Associate Professor Yoshiya Oda are worldwide leading researchers onproteomics and metabolomics. In collaboration
with them, we are searching for novel lipid mediators that bind to orphan G-protein-coupled receptors, lacking identified cognate ligands.

References
1. Ando K, Tsuji E, Ando Y, Kunitomo J, Yamashita
M, Ohta S, et al. Preparation of 2- and 4(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxybenzo[b]furans having potent antagonistic activity
against human leukotriene B4 BLT1 and/or BLT2
receptors. Org Biomol Chem. 2004;2:3427-31.
2. Angeli V, Llodra J, Rong JX, Satoh K, Ishii S,
Shimizu T, et al. Dyslipidemia associated withatherosclerotic disease systemically alters dendritic
cell mobilization. Immunity. 2004;21:561-74.
3. Branger J, Wieland CW, Florquin S, Maris NA,
Pater JM, Speelman P, et al. Platelet-activating
factor receptor-deficient mice show an unalteredclearance of nontypeable Haemophilus influenzae
from their respiratory tract. Shock. 2004;22:543-7.
4. Brink C, Dahlen SE, Drazen J, Evans JF, Hay DW,
Rovati GE, et al. International Union of Pharmacology XLIV. Nomenclature for the oxoeicosanoid
receptor. Pharmacol Rev. 2004;56:149-57.
5. Hikiji H, Ishii S, Shindou H, Takato T, Shimizu T.

11Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy. J Clin Invest. 2004;114:85-93.
6. Hirabayashi T, Murayama T, Shimizu T. Regulatory
mechanism and physiological role of cytosolic
phospholipase A2. Biol Pharm Bull. 2004;27:116873.
7. Hori T, Yokomizo T, Ago H, Sugahara M, Ueno G,
Yamamoto M, et al. Structural basis of leukotriene
B412-hydroxydehydrogenase/15-Oxo-prostaglandin
13-reductase catalytic mechanism and a possible
Src homology 3 domain binding loop. J Biol Chem.
2004;279:22615-23.
8. Houjou T, Yamatani K, Nakanishi H, Imagawa M,
Shimizu T, Taguchi R. Rapid and selective identification of molecular species in phosphatidylcholine and sphingomyelin by conditional neutral loss
scanning and MS3. Rapid Commun Mass Spectrom.
2004;18:3123-30.
9. Ishii S, Nagase T, Shindou H, Takizawa H, Ouchi Y,
Shimizu T. Platelet-activating factor receptor develops airway hyperresponsiveness independentlyof airway inflammation in a murine asthma model.
J Immunol. 2004;172:7095-102.
10. Ishikawa S, Uozumi N, Shiibashi T, Izumi T, Fukayama M, Shimizu T, et al. Short report: Lethal
malaria in cytosolic phospholipase A2- and phospholipase A2IIA-deficient mice. Am J Trop Med
Hyg. 2004;70:645-50.
11. Lu DP, Chandrakanthan V, Cahana A, Ishii S,
O'Neill C. Trophic signals acting via phosphatidylinositol-3 kinase are required for normal
pre-implantation mouse embryo development. J
Cell Sci. 2004;117:1567-76.
12. Murakami N, Yokomizo T, Okuno T, Shimizu T.
G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine. J Biol
Chem. 2004;279:42484-91.
13. Rijneveld AW, Weijer S, Florquin S, Speelman P,
Shimizu T, Ishii S, et al. Improved host defense
against pneumococcal pneumonia in platelet-activating factor receptor-deficient mice. J Infect Dis. 2004;189:711-6.
14. Takai D, Nagase T, Shimizu T. New therapeutic key
for cystic fibrosis: a role for lipoxins. Nat Immunol.
2004;5:357-8.

15. Taniguchi M, Shimizu T. Characterization of anovel member of murine semaphorin family. Biochem Biophys Res Commun. 2004;314:242-8.
16. Tashiro S, Sumi T, Uozumi N, Shimizu T, Nakamura T. B-Myb-dependent regulation of c-Myc expression by cytosolic phospholipase A2. J Biol
Chem. 2004;279:17715-22.
17. Ando K, Tsuji E, Ando Y, Kunitomo J, Kobayashi
R, Yokomizo T, et al. Synthesis of 2-, 4- and5-(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxyben
zo[b]furans and their leukotriene B4 receptor antagonistic activity. Org Biomol Chem. 2005;3:2129-39.
18. Fahy E, Subramaniam S, Brown HA, Glass CK,
Merrill AH, Jr., Murphy RC, et al. A comprehensive classification system for lipids. J Lipid Res.
2005;46:839-61.
19. Houjou T, Yamatani K, Imagawa M, Shimizu T,
Taguchi R. A shotgun tandem mass spectrometricanalysis of phospholipids with normal-phase and/or
reverse-phase liquid chromatography/electrosprayionization mass spectrometry. Rapid Commun
Mass Spectrom. 2005;19:654-66.
20. Iizuka Y, Yokomizo T, Terawaki K, Komine M,
Tamaki K, Shimizu T. Characterization of a mousesecond leukotriene B4 receptor, mBLT2: BLT2dependent ERK activation and cell migration ofprimary mouse keratinocytes. J Biol Chem. 2005;
280:24816-23.
21. Ishii S, Kihara Y, Shimizu T. Identification of T cell
death-associated gene 8 (TDAG8) as a novel acidsensing G-protein-coupled receptor. J Biol Chem.
2005;280:9083-7.
22. Kihara Y, Ishii S, Kita Y, Toda A, Shimada A, Shimizu T. Dual phase regulation of experimental allergic encephalomyelitis by platelet-activating factor. J Exp Med. 2005;202:853-63.
23. Kita Y, Takahashi T, Uozumi N, Nallan L, Gelb
MH, Shimizu T. Pathway-oriented profiling of lipid
mediators in macrophages. Biochem Biophys Res
Commun. 2005;330:898-906.
24. Kita Y, Takahashi T, Uozumi N, Shimizu T. A multiplex quantitation method for eicosanoids andplatelet-activating factor using column-switching
reversed-phase liquid chromatography-tandem mass
spectrometry. Anal Biochem. 2005;342:134- 43.
25. Lang PA, Kempe DS, Tanneur V, Eisele K, Klarl

12BA, Myssina S, et al. Stimulation of erythrocyte
ceramide formation by platelet-activating factor. J
Cell Sci. 2005;118:1233-43.
26. Marusic S, Leach MW, Pelker JW, Azoitei ML,
Uozumi N, Cui J, et al. Cytosolic phospholipase
A2α-deficient mice are resistant to experimental
autoimmune encephalomyelitis. J Exp Med.
2005;202:841-51.
27. Ohto T, Uozumi N, Hirabayashi T, Shimizu T.
Identification of novel cytosolic phospholipase A2s,
murine cPLA2δ, ε, and ζ, which form a gene cluster with cPLA2β. J Biol Chem. 2005;280:2457683.
28. Oikawa Y, Yamato E, Tashiro F, Yamamoto M,
Uozumi N, Shimada A, et al. Protective role forcytosolic phospholipase A2α in autoimmune diabetes of mice. FEBS Lett. 2005;579:3975-8.
29. Okuno T, Yokomizo T, Hori T, Miyano M, Shimizu
T. Leukotriene B4 receptor and the function of its
helix 8. J Biol Chem. 2005;280:32049-52.
30. Saiga A, Uozumi N, Ono T, Seno K, Ishimoto Y,
Arita H, et al. Group X secretory phospholipase A2
can induce arachidonic acid release and eicosanoid
production without activation of cytosolic phospholipase A2α. Prostaglandins Other Lipid Mediat.
2005;75:79-89.
31. Shimada A, Satoh M, Chiba Y, Saitoh Y,
Kawamura N, Keino H, et al. Highly selective localization of leukotriene C4 synthase in hypothalamic and extrahypothalamic vasopressin systems
of mouse brain. Neuroscience. 2005;131:683-9.
32. Shindou H, Ishii S, Yamamoto M, Takeda K, Akira
S, Shimizu T. Priming effect of lipopolysaccharide
on acetyl-coenzyme A:lyso-platelet-activating factor acetyltransferase is MyD88 and TRIF independent. J Immunol. 2005;175:1177-83.
33. Taguchi R, Houjou T, Nakanishi H, Yamazaki T,
Ishida M, Imagawa M, et al. Focused lipidomics bytandem mass spectrometry. J Chromatogr B Analyt
Technol Biomed Life Sci. 2005;823:26-36.
34. Taniguchi M, Masuda T, Fukaya M, Kataoka H,
Mishina M, Yaginuma H, et al. Identification andcharacterization of a novel member of murine
semaphorin family. Genes Cells. 2005;10:785-92.
35. Terawaki K, Yokomizo T, Nagase T, Toda A, Taniguchi M, Hashizume K, et al. Absence of leukotriene B4 receptor 1 confers resistance to airway

hyperresponsiveness and Th2-type immune responses. J Immunol. 2005;175:4217-25.
36. Toyo-Oka K, Sasaki S, Yano Y, Mori D, Kobayashi
T, Toyoshima YY, et al. Recruitment of katanin p60
by phosphorylated NDEL1, an LIS1 interacting
protein, is essential for mitotic cell division andneuronal migration. Hum Mol Genet. 2005;14:
3113-28.
37. Zhang Q, Mousdicas N, Yi Q, Al-Hassani M, Billings SD, Perkins SM, et al. Staphylococcal lipoteichoic acid inhibits delayed-type hypersensitivity
reactions via the platelet-activating factor receptor.
J Clin Invest. 2005;115:2855-61.

13

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

Associate Professor
Tomoichiro Asano, M.D.

Associate
Yukiko Kurihara, M.D.,

Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html
Introduction and Organization
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, 1 visiting scientist, 10
graduate students (8 doctoral course, 2 master’scourse). We are also working together with the Endowment Department of Developmental and Medical
Technology (Sankyo) in research and education.

Teaching Activities
We give a series of lectures and laboratory courses
on biochemistry and molecular biology for undergraduate students from Faculty of Medicine and Faculty of Science. We also accept undergraduate students taking “Free Quarter” and “Early-Exposure-to-Medicine” courses every year. Several students are staying 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.

Research Activities
1. Development
To clarify the molecular mechanism underlying the morphogenesis and organogenesis in
the craniofacial and cardiovascular region, weinvestigated the phenotype of endothelin-1(ET-1) knockout mice and identified theET-1/Dlx5/6 pathway involved in neuralcrest-driven branchial arch patterning. We are
now studying the intracellular signaling pathway involved and the function of downstream
molecules including Calpain6. We further
identified TAZ as a protein that binds to andcoactivates Pax3, a key transcription factor inneural crest development and are analyzing its
function in vivo.
To further understand the mechanisms of celldifferentiation, we are studying how the DNA
methylation status is controlled in preimplantation development and how reprogramming
occurs after nuclear transfer. We are getting
new findings about the mechanism of maintenance methylation during preimplantation de-14velopment.
In addition, we are investigating the organogenesis and cell differentiation of the vessel, lung and inner ear, aiming at their regeneration. Recently, we found that Id1 confers invivo angiogenic property to human vascularendothelial cells via angiopoietin-1 upregulation, which may give a clue to novel strategy fortherapeutic angiogenesis.
2. Metabolism
Regarding the research for metabolism, we
identified a novel protein which specificallyassociates with Akt, a key molecule for insulin–mediated metabolism. This protein enhances
the phosphorylation state as well as the kinase
activity of Akt, and thus, we termed it as APE(Akt Phosphorylation Enhancer). APE is very
likely to be involved in the suppression of
apoptosis and regulation of cell cycle, and interestingly, APE overexpression was observedin the approximately half of the cancer celllines tested.
In addition, we found that resistin likemolecule β (RELMβ) secreted from gut is increased by high-fat diet or in the obese condition. RELMβ activates ERK and JNK, andthereby induces insulin resistance. Indeed, it
was demonstrated that RELMβ transgenic mice
exhibited hyperglycemia, hyperlipidemia andfatty liver. Thus, we speculate that RELMβ canbe a diagnostic marker for judging insulin resistance, or also be a good candidate as a target
molecule for the therapy of insulin resistance.
We are currently investigating the effects of
RELMβ on vascular function and an involvement on atherosclerosis, and also attempting toconstruct a system for measuring human
RELMβ.

References (2004-2006)
1. Murakami M, Tominaga J, Makita R, Uchijima Y, Kurihara Y, Nakagawa O, Asano T,
Kurihara H. Transcriptional activity of Pax3
is co-activated by TAZ. Biochem. Biophys.
Res. Commun. 339:533-539, 2006.

2. Kushiyama, A., Shojima, N., Ogihara, T., Inukai,K., Sakoda, H., Fujishiro, M., Fukushima, Y., Anai,
M., Ono, H., Horike, N., Viana, A., Uchijima, Y.,
Nishiyama, K., Shimosawa, T., Fujita, T., Katagiri,
H., Oka, Y., Kurihara, H. and Asano, T. Resistin
like moleculeβactivates MAPKs, suppresses insulin signaling in hepatocytes and induces diabetes,
hyperlipidemia and fatty liver in transgenic miceon a high-fat diet. J. Biol. Chem. 280:42016-25,
2005.
3. Nishiyama K, Takaji K, Kataoka K, Kurihara Y, Yoshimura M, Kato A, Ogawa H,
Kurihara H. Id1 gene transfer confers angiogenic property on fully differentiatedendothelial cells and contributes to therapeutic angiogenesis. Circulation 112:28402850, 2005.
4. Sakoda, H., Fujishiro, M., Shojima, N., Ogihara,T., Kushiyama, A., Fukushima, Y., Anai, M., Ono,
H., Kikuchi, M., Horike, N., Viana, A., Uchijima,Y., Kurihara, H. and Asano, T. Glycogendebranching enzyme association with β-subunit
enhances AMP-activated protein kinase activity.
Am J Physiol Endocrinol Metab 289:E474-81,
2005
5. Anai, M., Shojima, N., Katagiri, H., Ogihara, T.,
Sakoda, H., Onishi, Y., Ono, H., Fujishiro, M.,
Fukushima, Y., Horike, N., Viana, A., Kikuchi, M.,
Noguchi, N., Takahashi, SI., Takata, K., Oka, Y.,
Uchijima, Y., Kurihara, H. and Asano, T. A novel
PKB/AKT-binding protein enhanced PKB kinase
activity and regulates DNA synthesis J. Biol.
Chem. 280:18525-35, 2005
6. Shojima, N., Ogihara, T., Inukai, K., Fujishiro, M.,
Sakoda, H., Kushiyama, A., Katagiri, H., Anai, M.,
Ono, H., Fukushima, Y., Horike, N., Viana, A.,
Uchijima, Y., Kurihara, H. and Asano, T. Serum
concentrations of RELMb and g are elevated inhigh-fat diet fed and obese db/db mice, with increased productions in intestinal tract and bonemarrow. Diabetologia 48(5): 984-92, 2005
7. Abell, K., Bilancio, A., Clarkson, R.W.E., Tiffen,
P.G., Altaparmakov, A., Burdon, T.G., Asano, T.,
Vanhaesebroek, B., and Watson, C.J. Stat3 induced apoptosis requires a molecular switch inPI(3)K subunit composition. Nat Cell Biol.
7:392-8, 2005

15

8. Ishigaki, Y., Katagiri, H., Yamada, T., Ogihara, T.,
Imai, J., Uno, K., Hasegawa, Y., Gao, J., Ishihara,
H., Shimosegawa, T., Sakoda, H., Asano, T., andOka, Y. Dissipating excess energy stored in theliver is a potential treatment strategy for diabetes
associated with obesity. Diabetes. 54:322-332,
2005
9. Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y.,
Ogihara, T., Uno, K., Hasegawa, Y., Gao, J., Ishihara, H., Sasano, H., Mizuguchi, H., Asano, T.,
and Oka, Y. Constitutively active PDX1 induced
efficient insulin production in adult murine liver.
Biochem. Biophys. Res. Commun. 326:402-409,
2005.
10. Sasaoka, T., Fukui, K., Wada, T., Murakami, S.,
Kawahara, J., Ishihara, H., Funaki, M., Asano, T.,
and Kobayashi, M. Inhibition of endogenous
SHIP2 ameliorates insulin resistance caused bychronic insulin treatment in 3T3-L1 adipocytes.
Diabetologia 48:336-44, 2005
11. Nelson-Degrave, VL., Wickenheisser, JK., Hendricks,
KL., Asano, T., Fujishiro, M., Legro, RS., Kimball,SR., Strauss, JF. 3rd, and McAllister, JM. Alterations in MEK and ERK Signaling in Theca Cells
Contribute to Excessive Androgen Production in
Polycystic Ovary Syndrome (PCOS). Mol Endocrinol. 19:379-90, 2005
12. Morita H, Saito Y, Ohashi N, Yoshikawa M,
Katoh M, Ashida T, Kurihara H, Nakamura
T, Kurabayashi M, Nagai R. Fluvastatinameliorates the hyperhomocysteinemia-induced
endothelial dysfunction: the antioxidative
properties of fluvastatin. Circ. J. 69:475-480,
2005.
13. Inoue K, Arai Y, Kurihara H, Kita T, Sawamura T. Overexpression of lectin-like
oxidized low-density lipoprotein receptor-1
induces intramyocardial vasculopathy inapolipoprotein E-null mice. Circ. Res. 97:
176-184, 2005.
14. Shozu M, Minami N, Yokoyama H, Inoue M,
Kurihara H, Matsushima K, Kuno K.
ADAMTS-1 is involved in normal folliculardevelopment, ovulatory process and organization of the medullary vascular network in the ovary. J. Mol. Endocrinol. 35:
343-55, 2005

15. Igata, M., Motoshima, H., Tsuruzoe, K., Kojima,K., Matsumura, T., Kondo, T., Taguchi, T., Nakamura, K., Yano, M., Kukidome, D., Matsumoto,K., Toyonaga, T., Asano, T., Nishikaa, T., andAraki, E. Adenosine Monophosphate-ActivatedProtein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of
Cell Cycle Progression Circ. Res. 97:837-44,
2005
16. Ieda M, Fukuda K, Hisaka Y, Kimura K, Kawaguchi H, Fujita J, Shimoda K, Takeshita E, Okano
H, Kurihara Y, Kurihara H, Ishida J, Fukamizu A,
Federoff HJ, Ogawa S, Endothelin-1 regulates
cardiac sympathetic innervation in the rodent
heart by controlling nerve growth factor expression. J. Clin. Invest. 113:876-884, 2004.
17. Ozeki H, Kurihara Y, Tonami K, Watatani S,
Kurihara H. Endothelin-1 regulates the
dorsoventral branchial arch patterning in
mice. Mech.Dev. 121:387-395, 2004.
18. Fukuhara S, Kurihara Y, Arima Y, Yamada
N, Kurihara H.Temporal requirement ofsignaling cascade involving endothelin-1/
endothelin A receptor in branchial arch development. Mech.Dev. 121:1223- 1233, 2004.
19. Murakami M, Kataoka K, Fukuhara S,
Nakagawa O, Kurihara H. Akt-dependent
phosphorylation negatively regulates thetranscriptional activity of dHAND by inhibiting the DNA binding activity. Eur. J.
Biochem. 271:3330-3339, 2004.
20. Murakami M, Kataoka K, Tominaga J,
Nakagawa O, Kurihara H. Differential cooperation between dHAND and three different E-proteins. Biochem. Biophys. Res.
Commun. 323:168-174, 2004.
21. Asano, T., Saito, Y., Kawakami, M., Yamada, N.,
Sekino, H., Hasegawa, S., and Fidarestat ClinicalPharmacology Study Group Erythrocytic sorbitol
contents in diabetic patients correlate with blood
aldose reductase protein contents and plasma
glucose levels, and are normalized by the potent
aldose reductase inhibitor fidarestat (SNK-860). J.
Diabetes and its Complications 18: 336-342, 2004
22. Okamoto, T., Namikawa, K., Asano, T., Takaoka,
K., and Kiyama, H. Differential regulation of theregulatory subunits for phosphatidylinositol 3-kinase

16

in response to motor nerve injury. Mol. Brain Res.
131:119-25, 2004
23. Fukushima, Y., Matsui, T., Saitoh, T., Ichinose, M.,
Tateishi, K., Shindo, T., Fujishiro, M., Sakoda, H.,
Shojima, N., Kushiyama, A., Fukuda, S., Anai, M.,
Ono, H., Oka, M., Shimizu, Y., Kurihara, H., Nagai, R., Ishikawa, T., Asano, T., and Omata, M.
Unique roles of G protein-coupled histamine H(2)and gastrin receptors in growth and differentiationof gastric mucosa. Eur J Pharmacol. 502:243-52,
2004
24. Xing, G., Shimosawa, T., Ogihara, T., Matsui, H.,
Itakura, K., Qingyou, X., Asano, T., Ando, K., andFujita, T. Angiotensin II-induced insulin resistance is enhanced in adrenomedullin-deficientmice. Endocrinology. 145:3647-51, 2004
25. Asano, T., Ogihara, T., Katagiri, H., Sakoda, H.,
Ono, H., Fujishiro, M., Anai, M., Kurihara, H.,
and Uchijima, Y. Glucose transporter and Na+/
glucose Cotransporter as Molecular Targets ofAnti-Diabetic Drugs. Current Medicinal Chemistry 11:763-771, 2004
26. Ogihara, T., Sakoda, H., Katagiri, H., Anai, M.,
Shojima, N., Kushiyama, A., Fujishiro, M., Ono,
H., Kikuchi, M., Fujita, T., and Asano, T. Molecular mechanisms of insulin resistance associated with hypertension and oxidative stress. Recent Res. Devel. Biophys. Biochem. 4:1-19, 2004
27. Asano, T., Anai, M., Sakoda, H., Fujishiro, M.,
Ono, H., Kurihara, H., and Uchijima, Y. SGLT asa therapeutic target. Drugs of the Future 29(5):461-466, 2004
28. Obara, S., Nakata, M., Takeshima, H., Katagiri,
H., Asano, T., Oka, Y., Maruyama, I., and Kuratsu,
J. Integrin-linked kinase (ILK) regulation of thecell viability in PTEN mutant glioblastoma and invitro inhibition by the specific COX-2 inhibitor
NS-398. Cancer Lett. 208:115-22, 2004
29. Ogihara. T., Asano, T., Katagiri, H., Sakoda, H.,
Anai, M., Shojima, N., Ono, H., Fujishiro, M.,
Kushiyama, A., Fukushima, Y., Kikuchi, M., Noguchi, N., Aburatani, H., Gotoh, Y., Komuro, I.,
and Fujita, T. Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B
pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia. 47:794-805, 2004.

Functional Biology
1. Physiology④

18

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

Associate Professor
Seiki Konishi,

M.D., Ph.D.

Lecturer
Kiyoshi Nakahara, Ph.D.

Associate
Tetsuya Fukushima, M.D., Ph.D.,
Masaki Takeda, Ph.D.

Toshiyuki Hirabayashi,

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, in teachingactivities for undergraduate courses and the nursing
school. The fields in which our laboratory specializes
span the entire spectrum of animal functions 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, K. Honma and I. Hasegawa) 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 the hierarchical functional organiza-

tions of living systems. The curriculum is updated
every year. For example, a new electrocardiogram
experiment in humans was introduced to the laboratory course, which gained popularity and interest
among students. We accept Free-Quarter students
every year. Usually these students' activities are notlimited to one Quarter, and 3 students (M0, M2 andM3) continued to enjoy their research from 2004
through 2005. Some of these students completed theirown projects, and gave oral presentations in international meetings and published original papers in
top-rank international journals.
To facilitate communication among research groups
in our laboratory, a weekly conference is held for discussing current research activities. We also have amonthly joint seminar with Department of Pharmacology, Department of Psychology in Faculty of Letters and Department of Biophysics in Faculty of Science. As part of a teaching activity for the graduate
students, we have another weekly English seminar, inwhich the graduate students learn how to give presentations and hold discussions and debates in English.

19

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. Recently many functional subfields have been identified in the occipito-temporal cortex. Our laboratory discovered
several classes of important memory-neurons
electrophysiologically in the temporal lobe of themonkey. 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 thatthe backward signal from the medial temporal
lobe to the inferotemporal cortex mediates formation of the mnemonic neural circuits for the association. Recently we also found that the top-down
signal from the prefrontal cortex to the inferotemporal cortex plays a central role in retrieval ofthe mnemonic associative neural code stored in
the inferotemporal cortex. Since association is abasic mechanism for constructing the humanmemory-based knowledge system, our finding
provides a key to understanding the basic organization of the primate cerebral cortex.
(2) The recent explosion of new technologies fornoninvasive measurements of human brain activities, especially of functional magnetic resonance imaging (fMRI), allows us to observe parallel activation of functional brain modules inhumans engaged in various mental tasks. In particular, fMRI with the echo-planar magnetic
resonance sequence provides a powerful noninvasive method that is superior to conventional
PET imaging in both spatial and temporal resolution. FMRI is completely noninvasive and appro-

priate for use with normal volunteers. We developed a new method called “event-related fMRI”,
which enables to utilize the time resolution of
fMRI. We applied this “event-related fMRI”
method to the analysis of human cognition, andidentified several functional centers in the humanprefrontal cortex in cognitive tasks such as the
Wisconsin Card Sorting Task.
(3) Recently, we successfully applied fMRI method
to macaque monkeys performing highly intelligent cognitive tasks. These fMRI studies weredone in ultra-high field MRI scanner at 4.7 Tesler,
successfully providing much higher spatial resolution than in a conventional clinical MRI scanner.
This approach provides us a new approach thatbridges a gap between the human non-invasive
studies and the various invasive studies in animals, including intra-cortical electrical microstimulation and reversible functional inactivation with GABA agonist drug injections.

References (2004-2005)
1. Miyashita, Y. : Cognitive memory: cellular andnetwork machineries and their top-down control.
Science 306, 435-440, 2004.
2. Koyama, M., Hasegawa, I., Osada, T., Adachi, Y.,
Nakahara, K. and Miyashita, Y. : Functional
magnetic resonance imaging of macaque monkeys
performing visually guided saccade tasks: comparison of cortical eye fields with humans. Neuron 41, 795-807, 2004.
3. Jimura, K., Konishi, S. and Miyashita, Y. : Dissociable concurrent activity of lateral and medial
frontal lobe during negative feedback processing.
NeuroImage 22, 1578-1586, 2004.
4. Fukushima, T., Hasegawa, I. and Miyashita, Y. :Prefrontal neuronal activity encodes spatial target
representations sequentially updated following
nonspatial target-shift cues.
J. Neurophysiol. 91, 1367-1380, 2004.
5. Kikyo, H. and Miyashita, Y. : Temporal lobe activations of “feeling-of-knowing” induced by
face-name associations. NeuroImage 23, 13481357, 2004.
6. Nakahara, K. and Miyashita, Y. : Understanding
intentions: through the looking glass. Science 308,20

644-645, 2005.
7. Konishi, S., Chikazoe, J., Jimura, K., Asari, T.
and Miyashita, Y. : Neural mechanism in anterior
prefrontal cortex for release from inhibition of
prolonged set interference.
Proc. Natl. Acad. Sci. USA 102, 12584-12588,
2005.
8. Koyano, K., Tokuyama, W. and Miyashita,
Y. :Deeply located granule cells and mitralcells undergo apoptosis after transection of
the central connections of the main olfactory bulb in the adult rat. Neuroscience 131,
293-302, 2005.
9. Asari, T., Jimura, K., Konishi, S. and Miyashita,
Y. : Multiple components of lateral posterior parietal activation associated with cognitive set
shifting. NeuroImage 26, 694-702, 2005.
10. Takeda, M., Naya, Y., Fujimichi, R., Takeuchi, D.
and Miyashita, Y. : Active maintenance of associative mnemonic signal in monkey inferior temporal cortex. Neuron 48, 839-848, 2005.
11. Hirabayashi, T. and Miyashita, Y. : Dynamicallymodulated spike correlation in monkey inferior
temporal cortex depending on the feature configuration within a whole object.
J. Neurosci. 25, 10299-10307, 2005.

21

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

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

Associate
Hiroshi Nagao, Ph.D.,

Hideki Kashiwadani, Ph.D.

Homepage http:// morilab.m.u-tokyo.ac.jp/
Education

topics.

The department provides lectures and practice inphysiology for undergraduate students. The department provides also lectures and instructions for laboratory research for graduate and undergraduate students in the fields of sensory physiology and molecular and cellular neurobiology. Seminars, progress reports, and journal club for graduate students are routinely provided. Monthly joint seminars (Functional
Biology Seminars and RIKEN BSI Group Seminars)
are also provided for graduate students.

(1) Analysis of the functional neuronal circuits in thecentral olfactory system.
We are studying the ‘odor maps’ in the olfactory
bulb and olfactory cortex to understand the logic
employed by the olfactory system for discrimination among numerous odor molecules and perception of the olfactory image of objects. Recently
we demonstrated a powerful state-dependent gating of odor information flow within olfactorycortex that works in synchrony with the gating ofother sensory systems. Our findings suggest astate-dependent switchover of signal processing
modes in olfactory cortex, and open the way toanalyzing the gating in olfactory system.

Research
Using multidisciplinary approaches including electrophysiology, optical imaging, molecular and cellularbiology, and molecular genetics, we at the Department
of Cellular and Molecular Physiology aim at understanding neuronal mechanism for the perception of
sensory inputs and for the emotional states induced by
the sensory inputs.
We have been investigating also the functions ofcell adhesion molecules in the development of synapses and neuronal circuits as well as in the contact-mediated interactions between neurons and immune cells.
Currently we are focusing on the following four(2) Cellular and molecular mechanisms for the contact-mediated interactions between neurons andimmune cells in physiological and pathologicalconditions.
We are currently focusing on telecncephalon-specific cell adhesion molecule, telencephalin.
We found that damage on hippocampal CA1 area
caused by local injection of kainic acid increased
density and area of contacts between activatedmicroglia and the dendrites of CA1 pyramidal
neurons. We are further investigating the telen-

22

cephalin-mediated signals between neurons andimmune cells during recovery from the neuronaldamage.
(3) Neurogenesis and neuron-elimination in the adultbrain.
The olfactory system is chosen as a model systemwith which to study the recruitment of
newly-generated neurons in the adult neuronal
circuit. We are studying cellular and molecularmechanisms that segregate the fate of new neurons between successful incorporation and apoptotic elimination into/from the neuronal circuit.
We are also focusing on the heterogeneity of local
interneurons in the olfactory bulb. We are trying
to reveal the functional differentiation of subtypesof interneurons in odor information processing,and address the question how they are recruited
into the adult neuronal circuit and contribute to
the plasticity of adult olfactory system.
(4) Molecular and cellular mechanisms for the formation and plasticity of specific neuronal connections.
Olfactory system has precise projection of olfactory axons onto specific glomeruli and distinct
neuronal circuit with laminar specific synaptic
connections. We found that a leucine rich repeat
membrane protein, 5T4, was expressed by a specific subset of granule cells, whose dendrites project selectively to the superficial sublamina of theexternal plexiform layer. The results suggest that
5T4-positive granule cells preferentially interact
with tufted cells. We will expand the investigation
to the other candidate molecules already found by
the proteomics approach.

Publications (2004-2006)
1. Mori K, Takahashi YK, Igarashi KM, Yamaguchi
M. Maps of odorant molecular features in the
mammalian olfactory bulb. Physiological Reviews
86:409-433 (2006)
2. Imamura F, Nagao H, Naritsuka H, Murata Y, Taniguchi H, Mori K. A leucine-rich repeat membrane protein 5T4 is expressed by a subtype of
granule cells with dendritic arbor in specific strataof the mouse olfactory bulb. J. Comp. Neurol.
495:754-768 (2006)
3. Xu Y, Kitada M, Yamaguchi M, Dezawa M, Ide C.
Increase in bFGF-responsive neural progenitor
population following contusion injury of the adultrodent spinal cord. Neurosci. Lett. 397:174-179(2006)
4. Kunze A, Grass S, Witte OW, Yamaguchi M,
Kempermann G, Redecker C. Proliferative response of distinct hippocampal progenitor cell
populations after cortical infarcts in the adultbrain. Neurobiol. Dis. 21:324-332 (2006)
5. Matsuno H, Okabe S, Mishina M, Yanagida T,
Mori K, Yoshihara Y. Telencephalin slows spine
maturation. J. Neurosci. 26:1776-1786 (2006)
6. Mitsui S, Saito M, Mori K, Yoshihara Y. A transcription enhancer that directs telencephalon-specific transgene expression in mouse brain.
Cerebral Cortex (in press)
7. Yamaguchi M, Mori K. Critical period for sensory
experience-dependent survival of newly-generated
granule cells in the adult mouse olfactory bulb.
Proc. Natl. Acad. Sci. USA 102:9697-9702 (2005)
8. Murakami M, Kashiwadani H, Kirino Y, Mori K.
State-dependent sensory gating in olfactory cortex.
Neuron 46:285-296 (2005)
9. Mitsui S, Saito M, Hayashi K, Mori K, Yoshihara
Y. A novel phenylalanine-based targeting signal
directs telencephalin to neuronal dendrites. J.
Neurosci. 25:1122-1131 (2005)
10. Igarashi KM, Mori K. Spatial representation ofhydrocarbon odorants in the ventrolateral zones of
the rat olfactory bulb. J. Neurophysiol. 93:10071019 (2005)
11. Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H,
Toyokuni S, Yamaguchi M, Takeda J, Seino Y.
Nestin-positive cells in adult pancreas express
amylase and endocrine precursor cells. Pancreas
31:126-131 (2005)
12. Yamaguchi M. Analysis of neurogenesis usingtransgenic mice expressing GFP with nestin gene
regulatory regions. Chemical Senses Suppl.
1:i117-i118 (2005)
13. Yamamoto K, Yamaguchi M, Okabe S. Direct
visualization of cell movement in the embryonicolfactory bulb using green fluorescent protein

23transgenic mice: evidence for rapid tangential migration of neural cell precursors. Neuroscience
Research 51:199-214 (2005)
14. Takahashi YK, Nagayama S, Mori K. Detection
and masking of spoiled food smells by odor maps
in the olfactory bulb. J. Neurosci. 24:8690-8694(2004)
15. Takahashi YK, Kurosaki M, Hirono S, Mori K.
Topographic representation of odorant molecularfeatures in the rat olfactory bulb. J. Neurophysiol.
92:2413-2427 (2004)
16. Hasegawa S, Yamaguchi M, Nagao H, Yoshihara
Y, Mori K. Activated natural killer cells adhere tocultured hippocampal neurons and affect the dendritic morphology. J. Neuroimmunol. 151:126136 (2004)
17. Nagayama S, Takahashi YK, Yoshihara Y, Mori K.
Mitral and tufted cells differ in the decoding
manner of odor maps in the rat olfactory bulb. J.
Neurophysiol. 91:2532-2540 (2004)
18. Lopez IA, Zhao PM, Yamaguchi M, Vellis Jd,
Espinosa-Jeffrey A. Stem/progenitor cells in the
postnatal inner ear of the GFP-nestin transgenic
mouse. Int. J. Dev. Neurosci. 22:205-213 (2004)

24

Department of Neurophysiology
Professor
Tomoyuki Takahashi, M.D., Ph.D.

Lecturer
Tetsuhiro Tsujimoto, M.D., Ph.D.

Naoto Saitoh, Ph.D.

Associate
Tetsuya Hori, Ph.D.

Home page http://square.umin.ac.jp/nphystky
Introduction and organization
Our laboratory was founded in 1953 as Departmentof Neurophysiology, Institute for Brain Research. In
1996 it was integrated into Graduate School of Medicine. We teach neurophysiology for medical undergraduates and for students in the Master and Ph.D.
courses. Our research is aimed at elucidating cellularand molecular mechanisms underlying synaptictransmission.

slices. In this course, students learn how electricalsignals are made of ion channel currents. In separate
set-ups, students record field synaptic potentials fromhippocampal slices and learn how to induce short-termand long-term Ph.D.synaptic plasticities. Trainings for
the Master and Ph.D. course students are made regularly on Monday in the forms of progress reports andjournal clubs, where students and staffs summarize
topics and also classics in physiology and neuroscience.

Teaching activities

Research Activities

We teach medical undergraduates in lectures and apractical course. Lectures are designed for students tolearn basic mechanisms underlying electrical signals,
how they are generated and propagated through nerve
fibers and across synapses. Students also learn dynamic aspects of synaptic efficacy underlying diverse
brain functions such as memory and consciousness. A
couple of months before lectures students in 20 groups
are given key words with references to prepare asummary sheet, upon which each group presents a
short talk in a class. Their talks are followed by discussions and supplementary lectures by a professor.
During the procedure of preparing summary sheets,
students make discussions with a professor. In practicalcourse, students are encouraged to make patch-clamp
recordings from neurons visually identified in brain

In mammalian CNS, after synaptic contacts areformed in fetal period, synapses undergo morphological, functional and molecular changes during postnatal
development, toward establishment of mature synapses differentiated into various neuronal functions.
Our research aim is to clarify causal molecular-functional relationship, for elucidating molecularmechanisms underlying synaptic transmission andmodulation. In brainstem slices of rodents, a giant
nerve terminal, called the calyx of Held, can be visually identified. We make simultaneous presynaptic andpostsynaptic whole-cell recordings from the calyces
and target cells in developing rodents, and make analyses on synaptic transmission. With these recordings
we combine (i) presynaptic capacitance measurements
for assessing synaptic vesicle exo/endocytosis, (ii)25

infusion of drugs or inhibitor proteins into the terminal, (iii) Ca measurements. In addition we make (iv)
immunocytochemical examinations for protein expressions in the calyceal terminals, (v) use knockout
mice to establish causal molecular-function relationships, and (vi) make bilateral cochlear ablations toinvestigate whether newly found developmental
change depends upon hearing input activity. Ourpresent subjects of research are clarifications ofmechanisms underlying (1) vesicle recycling and reuse, (2) transmitter release probability, (3) facilitationof transmitter release, (3) high-fidelity synaptictransmission.

References (2004-2005)
1. Kaneko M. & Takahashi T. (2004). Presynaptic
mechanism underlying cAMP-dependent synaptic
potentiation. J Neurosci. 24, 5202-5208.
2. Sedej S., Tsujimoto T., ZXorec R. & Rupnik M.
(2004). Voltage-activated Ca2+ channels and theirrole in the endocrine function of the pituitary
gland in newborn and adult mice. J. Physiol. 555,
769-782.
3. Takahashi T., Kajikawa Y., Kimura M., Saito N. &Tsujimoto T. (2004). Presynaptic mechanism underlying regulation of transmitter replase by Gprotein coupled receptors. Kor. J. Physiol. Pharmacol. 8, 69-76.
4. Ishikawa T., Kaneko M., H-S Shin & Takahashi T.
(2005). Presynaptic N-type and P/Q-type Ca2+
channels mediating synaptic transmission at thecalyx of Held of mice. J. Physiol. 568, 199-209.
5. Takago H., Nakamura Y. & Takahashi T. (2005).
G protein-dependent presynaptic inhibition mediated by AMPA receptors at the calyx of Held. Proc.
Natl. Acad. Sci. U.S.A. 102, 7368-7373.
6. Yamashita T., Hige T. & Takahashi T. (2005).
Vesicle endocytosis requires dynamin-dependent
GTP hydrolysis at a fast CNS synapse. Science
307, 124-127.
7. Koike-Tani M., Saitoh N. & Takahashi T. (2005).
Mechanisms underlying developmental speedingin AMPA-EPSC decay time at the calyx of Held. J.
Neurosci. 25, 199-207.
8. Takahashi T. (2005). Postsynaptic receptor

mechanisms underlying developmental speedingof synaptic transmission. Neuroscience Research
53, 229-240.
9. Takahashi T. (2005). Dynamic aspects of presynaptic calcium currents mediating synaptictransmission. Cell Calcium 37, 507-511.

Functional Biology
2. Pharmacology⑤

28

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

Associate Professor
Kenzo Hirose, M.D., Ph.D.

Associate
Toshiko Yamazawa, Ph. D.,

Sho Kakizawa, Ph. D.

Homepage http://calcium.cmp.m.u-tokyo.ac.jp/
Introduction and Organization
Our department was founded in 1885 and collaborates with the Department of Molecular Neurobiology
and Pharmacology in the education of undergraduate
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
seven outside expert lecturers to cover rapidly developing fields in pharmacology and related medical
sciences. The laboratory courses include both traditional and advanced pharmacological experiments. A
new intensive laboratory course for medical students
started in the year 2001, and we participated in 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 to function as a molecular switch in almost every importantcell function including muscle contraction, exocytosis,
cell proliferation, immune responses and regulation ofsynaptic functions. This is the reason why this field is
expanding rapidly and our research activity is now
diversifying. We are particularly interested in Ca2+
signalling in central neurons.
Ca2+ signals show very dynamic, temporal and spatial changes. This property allows the calcium signal
to be an extremely versatile cellular switch regulating
diverse cell functions. One of the most notable spatiotemporal patterns of Ca2+ signals is the oscillatorychange in intracellular 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 these questions. First,
we studied inositol 1,4,5-trisphosphate (IP3)- induced
Ca2+ release mechanism, which is one of the mostimportant Ca2+ mobilizing mechanisms in many typesof 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 andshowed that the positive feedback regulation of IP3R
via the Ca2+ sensor of IP3R indeed plays an essential
role in regulating the Ca2+ signal dynamics including

29

Ca2+ oscillation. These results provide a clue to themechanism 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 cellular functions that are
regulated by the Ca2+ oscillation frequency. NFAT isdephosphorylated by Ca2+-dependent phosphatase,calcineurin, and translocates from the cytoplasm to the
nucleus to initiate transcription. We analyzed the kinetics of the 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 the mechanism that decodes the Ca2+ oscillation frequency. We also showedthat Ca2+ oscillation is more 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.
Our study on Ca2+ signalling made us realize theimportance of visualization of signalling molecules
within living cells. Thus, our laboratory has been involved in the generation of new indicators of signalling molecules upstream 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 todetect the phosphorylation of myosin regulatory lightchain. The indicator allowed us to image phosphorylation state of myosin light chain in living cells. Recently, we generated a nitric oxide (NO) indicator
based on the heme-binding domain of soluble
guanylyl cyclase. This indicator was successfully usedin cerebellar slice preparations to image NO signals in
response to parallel fiber (PF) stimulation. We foundthat the NO signal intensity decreases steeply with
distance form the activated synapse and generate
synapse-specific long-term potentiation (LTP) of
PF-Purkinje cell synapses. We also showed that theNO 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 the central nervous system.

The RNA interference technique is an extremely
useful method to knock down target mRNA to study
the function of the protein in question. We generated a
new method for enzymatic production of libraries ofsmall interfering RNA. In addition, in collaboration
with outside research groups, we looked into the molecular mechanism of circadian rhythm.

References
1. Uchino M, Sakai N, Kashiwagi K, Shirai Y, Shinohara Y, Hirose K, Iino M, Yamamura T, Saito N.
Isoform-specific phosphorylation of metabotropic
glutamate receptor 5 by protein kinase C (PKC)
blocks Ca2+ oscillation and oscillatory translocation of Ca2+-dependent PKC. J Biol Chem 2004;
279:2254-61.
2. Shirane D, Sugao K, Namiki S, Tanabe M, Iino M,
Hirose K. Enzymatic production of RNAi libraries
from cDNAs. Nat Genet 2004;36:190-6.
3. Ueda HR, Hayashi S, Matsuyama S, Yomo T,
Hashimoto S, Kay SA, Hogenesch JB, Iino M.
Universality and flexibility in gene expression
from bacteria to human. Proc Nat Acad Sci USA
2004;101:3765-9.
4. Ueda HR, Chen W, Minami Y, Honma S, Honma
K, Iino M, Hashimoto S. Molecular-timetable
methods for detection of body time and rhythm
disorders from single-time-point genome-wide
expression profiles. Proc Nat Acad Sci USA
2004;101:11227-32.
5. Yogo T, Kikuchi K, Inoue T, Hirose K, Iino M,
Nagano T. Modification of intracellular Ca2+ dynamics by laser inactivation of inositol 1,4,5trisphosphate receptor using membrane-permeant
probes. Chem Biol 2004;11:1053- 8.
6. Okubo Y, Kakizawa S, Hirose K, Iino M. Cross
talk between metabotropic and ionotropic glutamate receptor-mediated signaling in parallel fiber-induced inositol 1,4,5-trisphosphate production in cerebellar Purkinje cells. J Neurosci
2004;24:9513-20.
7. Yamada A, Hirose K, Hashimoto A, Iino M.
Real-time imaging of myosin II regulatory lightchain phosphorylation using a new protein biosensor. Biochem J 2005;385:589-94.
8. Ueda HR, Hayashi S, Chen W, Sano M, Machida30

M, Shigeyoshi Y, Iino M, Hashimoto S. System-level identification of transcriptional circuits
underlying mammalian circadian clocks. Nat
Genet 2005;37:187-92.
9. Hayakawa Y, Nemoto T, Iino M, Kasai H. Rapid
Ca2+-dependent increase in oxygen consumption
by mitochondria in single mammalian central neurons. Cell Calcium 2005;37:359-70.
10. Hashimoto A, Hirose K, Iino M. BAD detects coincidence of G2/M Phase and growth factor deprivation to regulate apoptosis. J Biol Chem
2005;280:26225-32.
11. Namiki S, Kakizawa S, Hirose K, Iino M. NO
signalling decodes frequency of neuronal activity
and generates synapse-specific plasticity in mouse
cerebellum. J Physiol, 2005;566:849-863.
12. Kakizawa S, Miyazaki T, Yanagihara D, Iino M,
Watanabe M, Kano M. Maintenance of presynaptic function by AMPA receptor-mediated excitatory postsynaptic activity in adult brain. Proc Nat
Acad Sci USA 2005;102:19180-5.

31Department of
Molecular Neurobiology
Professor
Masayoshi Mishina, Ph.D.

Associate
Tomonori Takeuchi, Ph.D.,
Takashi Uemura, Ph.D.,

Tomoyuki Yoshida, Ph.D.,
Kazuto Nakao, Ph.D.

Homepage http://www.pharmacol2.m.u-tokyo.ac.jp/
Teaching activities
Our Department, in collaboration with the Department of Cellular and Molecular Pharmacology, takes
responsibility for lectures and laboratory courses on
pharmacology for the undergraduate students of theFaculty. There are some 41 lectures per year including
those given by seven invited lectures to cover specialized and currently highlighted fields in pharmacology.
We offer several laboratory courses, and all the members of the Department participate in the courses toprovide close consultation for the students.
For the graduate students, there are series of seminars on molecular biology and neuroscience. We also
have research seminars to discuss and stimulate theresearch activities of the graduate students in the Department.

Research activities
Current research activities are focused on the molecular basis of learning and memory. As an initialstep, we have elucidated the molecular diversity of the
NMDA-type glutamate receptor (GluR) channel thatplays a key role in synaptic plasticity as a molecularcoincidence detector. Combination of the GluRε and
GluRζ subunit families is essential for the formation
NMDA-type GluR channels. The four glutamatebinding GluRε subunits are distinct in distribution,functional properties and regulation. Thus, multiple
GluRε subunits are major determinants of the NMDA
receptor channel diversity, and the molecular compositions and functional properties of NMDA receptor
channels are different depending on the brain regions
and developmental stages. We generated mutant mice
defective in respective GluRε subunits by gene targeting. We have shown that disruption of the GluRε1
subunit results in the increase of thresholds for bothhippocampal LTP and contextual learning. The
GluRε2 subunit mutant mice showed the impairmentof the formation of the whisker-related neuronal barrelette structure in the brainstem trigeminal nucleus.
We found the GluRδ subunit family, a novel memberof the GluR channel family, by cloning. The GluRδ2
subunit is selectively localized in cerebellar Purkinjecells. Analyses of the GluRδ2 mutant mice reveal thatthe δ2 subunit plays important roles in the motor coordination, the formation of parallel fiber-Purkinje cell
synapses and climbing fiber-Purkinje cell synapses,and the long-term depression of parallel fiber-Purkinje
cell synaptic transmission. These findings have led
our current hypothesis that the activity-dependent
synapse refinement during neural development and thelearning and memory in adult brain share the common
molecular mechanism.
To verify this proposal, we are employing two approaches. One is the forward genetic approach in zebrafish to systematically screen the key molecules of

32

the formation and dynamic changes of synapses. We
developed a highly efficient deletion mutagenesis inzebrafish and isolated mutant zebrafish with defects inneural development. Current efforts are on the efficient cloning of the mutant genes. The other approachis the reverse genetics with mice. To examine thefunctional roles of developmentally important molecules in higher brain functions and to seek for engram,
we are developing the stage- and brain region-specificconditional targeting. The wealth of knowledge on theneural circuits makes the cerebellum an ideal system
to study the molecular mechanism of brain function.
To develop a cell type-specific and temporal regulation system of gene targeting in the cerebellum, we
employed the NMDA-type glutamate receptor GluRε3
subunit gene and Cre recombinase-progesterone receptor fusion (CrePR) gene in combination. Injectionof the CrePR fusion gene placed under the control of
the 10 kb 5’ region of the GluRε3 gene into C57BL/6
eggs yielded the ECP25 line that strongly expressed
the CrePR mRNA selectively in the granule cells of
the cerebellum. Using a transgenic mouse carrying areporter gene for Cre-mediated recombination, we
showed that antiprogestins could induce the recombinase activity of CrePR fusion protein in the cerebellar
granule cells of the ECP25 line. Thus, the establishedmouse line will provide a valuable tool to investigate
the mechanism of cerebellar function by manipulating
molecules in the temporally regulated and granulecell-specific manner

References
1. Matsuda N, Mishina M. Identification of chaperonin CCT γ subunit as a determinant of retinotectal development by whole-genome subtraction
cloning from zebrafish no tectal neuron mutant.
Development. 2004;131:1913-1925.
2. Uemura T, Mori H, Mishina M. Direct interactionof GluRδ2 with Shank scaffold proteins in cerebellar Purkinje cells. Mol Cell Neurosci. 2004;26:
330-341.
3. Fuse T, Kanai Y, Kanai-Azuma M, Suzuki M,
Nakamura K, Mori H, Hayashi Y, Mishina M.
Conditional activation of RhoA suppresses theepithelial to mesenchymal transition at the primitive streak during mouse gastrulation. Biochem

Biophys Res Commun. 2004;318:665-672.
4. Kitano T, Matsumura S, Seki T, Hikida T, Sakimura K, Nagano T, Mishina M, Nakanishi S, Ito S.
Characterization of N-methyl-D-aspartate receptor
subunits involved in acute ammonia toxicity.
Neurochem Int. 2004;44:83-90.
5. Miyamoto Y, Yamada K, Nagai T, Mori H,
Mishina M, Furukawa H, Noda Y, Nabeshima T.
Behavioral adaptations to addictive drugs in micelacking the NMDA receptor ε1 subunit. Eur J
Neurosci. 2004;19:151-158.
6. Murai N, Tsuji J, Ito J, Mishina M, Hirano T. Vestibular compensation in glutamate receptor delta-2
subunit knockout mice: dynamic property of vestibulo-ocular reflex. Eur Arch Oto-Rhino-Laryngol. 2004;261:82-86.
7. Yoshida T, Katoh A, Ohtsuki G, Mishina M, Hirano T. Oscillating Purkinje neuron activity causing involuntary movement in a mutant mouse deficient in the glutamate receptor δ2 subunit. J
Neurosci. 2004;24:2440-2448.
8. Sato Y, Kobayashi E, Hakamata Y, Kobahashi M,
Wainai T, Murayama T, Mishina M, Seo N.
Chronopharmacological studies of ketamine innormal and NMDA ε1 receptor knockout mice.
Brit J Anaesth. 2004;92:859-864.
9. Takehara K, Kawahara S, Munemoto Y, Kuriyama
H, Mori H, Mishina M, Kirino Y. The NMDA receptor GluRε2 is important for delay and trace
eyeblink conditioning in mice. Neurosci Lett.
2004;364:43-47.
10. Kawakami K, Takeda H, Kawakami N, Kobayashi
M, Matsuda N, Mishina M. A transposon-mediatedgene trap approach identifies developmentally
regulated genes in zebrafish. Dev Cell. 2004;7:
133-144.
11. Abe M, Fukaya M, Yagi T, Mishina M, Watanabe
M, Sakimura K. NMDA receptor GluRε/NR2
subunits are essential for postsynaptic localizationand protein stability of GluRζ1/NR1 subunit. J
Neurosci. 2004;24:9292-9304 .
12. Mikami Y, Yoshida T, Matsuda N, Mishina M.
Expression of zebrafish glutamate receptor δ2 inneurons with cerebellum-like wiring. Biochem
Biophys Res Commun. 2004;322:168-176.
13. Nishimura W, Muratani T, Tatsumi S, Sakimura K,
Mishina M, Minami T, Ito S. Characterization of

33

N-methyl-D-aspartate receptor subunits responsible for postoperative pain. Eur J Pharmacol.
2004;503:71-75.
14. Ohtsuki G, Kawaguchi S, Mishina M, Hirano T.
Enhanced inhibitory synaptic transmission in the
cerebellar molecular layer of the GluRδ2 knockout mouse. J Neurosci. 2004;24:10900-10907.
15. Hirai H, Miyazaki T, Kakegawa W, Matsuda S,
Mishina M, Watanabe M, Yuzaki M. Rescue ofabnormal phenotypes of the δ2 glutamate receptor-null mice by mutant δ2 transgenes. EMBO
Report. 2005;6:90-95.
16. Takeuchi T, Miyazaki T, Watanabe M, Mori H,
Sakimura K, Mishina M. Control of synaptic
connection by glutamate receptor δ2 in the adult
cerebellum. J Neurosci. 2005;25:2146-2156.
17. Yoshida T, Mishina M. Distinct roles of calcineurin-nuclear factor of activated T-cells andprotein kinase A-cAMP response element binding
protein signaling in presynaptic differentiation. J
Neurosci. 2005;25:3067-3079.
18. Sakamoto T, Takatsuki K, Kawahara S, Kirino Y,
Niki H, Mishina M. Role of hippocampal NMDA
receptors in trace eyeblink conditioning. Brain
Res. 2005;1039:130-136.
19. Katoh A, Yoshida T, Himeshima Y, Mishina M,
Hirano T. Defective control and adaptation of reflex eye movements in mutant mice deficient ineither the glutamate receptor δ2 subunit or Purkinje cells. Eur J Neurosci. 2005;21:1315-1326.
20. Sato Y, Kobayashi E, Murayama T, Mishina M,
Seo N. Effect of N-methyl-D-aspartate receptor ε1
subunit gene disruption of the action of generalanesthetic drugs in mice. Anesthesiology. 2005;
102:557-561.
21. Takahashi Y, Mori H, Mishina M, Watanabe M,
Kondo N, Shimomura J, Kubota Y, Matsuda K,
Fukushima K, Shiroma N, Akasaka N, Nishida H,
Imamura A, Watanabe H, Sugiyama N, Ikezawa
M, Fujiwara T. Autoantibodies and cell-mediatedautoimmunity to NMDA-type GluRε2 in patientswith Rasmussen’s encephalitis and chronic progressive epilepsia partialis continua. Epilepsia.
2005;46 (Suppl 5):152-158.
22. Taniguchi M, Masuda T, Fukaya M, Kataoka H,
Mishina M, Yaginuma H, Watanabe M, Shimizu T.
Identification and characterization of a novel

member of murine semaphorin family. Genes
Cells. 2005;10:785-792.
23. Weitlauf C, Honse Y, Auberson YP, Mishina M,
Lovinger DM, Winder DG. Activation of
NR2A-containing NMDA receptors is not obligatory for NMDA-receptor dependent long-term
potentiation. J Neurosci. 2005;25:8386-8390.
24. Abe T, Matsumura S, Katano T, Mabuchi T, Takagi K, Xu L, Yamamoto A, Hattori K, Yagi T,
Watanabe M, Nakazawa T, Yamamoto T, Sasaki Y,
Suzuki M, Mishina M, Nakai Y, Ito S.
Fyn-kinase-mediated phosphorylation of NMDA
receptor NR2B subunit at Tyr 1472 is essential for
maintenance of neuropathic pain. Eur J Neurosci.
2005;22:1445-1454.
25. Wu Y, Kawakami R, Fukaya M, Sakimura K,
Mishina M, Watanabe M, Ito I, Shigemoto R.
Target-cell-specific left-right asymmetry of NMDA
receptor content in Schaffer collateral synapses in
ε1/NR2A knockout mice. J Neurosci. 2005;25:
9213-9226.
26. Yamashita T, Miyagi Y, Ono M, Ito H, Watanabe
K, Sonoda T, Tsuzuki K, Ozawa S, Aoki I, Okuda
K, Mishina M, Kawamoto S. Identification andcharacterization of a novel Delphilin variant withan alternative N-terminus. Mol Brain Res.
2005;141:83-95.
27. Kato Y, Takatsuki K, Kawahara S, Fukunaga S,
Mori H, Mishina M, Kirino Y. N-methylD-aspartate receptors play important roles in acquisition and expression of the eyeblink conditioned response in glutamate receptor subunit δ2mutant mice. Neuroscience. 2005;135:1017-1023.
28. Takatsuki K, Kawahara S, Mishina M, Kirino Y.
Characterization of hippocampal theta rhythm inwild-type mice and glutamate receptor subunit δ2mutant mice during eyeblink conditioning with ashort trace interval. Brain Res. 2005;1063:159167.
29. Matsuno H, Okabe S, Mishina M, Yanagida T,
Mori K, Yoshihara Y. Telencephalin slows spine
maturation. J Neurosci. 2006;26:1776-1786.

Pathology, Immunology andMicrobiology
1. Pathology⑥

36

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

Associate Professor
Toshiro Niki, M.D.,Ph.D. (Professor, Jichi Medical School),
Ken-ichi Ohashi, M.D.,Ph.D.(Toranomon Hospital)

Lecturer
Noriyoshi Fukushima, M.D., Ph.D., Hiroshi Uozaki, M.D., Ph.D.
Ja-Mun Chong, M.D., Ph.D. (visiting researcher, USA),
Hisako Endo, M.D., Ph.D. (Division of Diagnostic Pathology)

Lecturer (Hospital)
Kenji Kashima, M.D., Ph.D.,
Yutaka Takazawa, M.D., Ph.D.
Toru Motoi, M.D., Ph.D. (visiting researcher, USA)

Associate
Satoshi Ota, M.D., Ph.D.,
Tateru Ishida, M.D., Ph.D.
Akiteru Goto, M.D., Ph.D.,
Junji Shibahara, M.D., Ph.D.,
Tetsuo Ushiku, M.D., Ph.D.
Yasunori Ota, M.D., Ph.D. (Toranomon Hospital)

Technical Support Specialist
Takamichi Natsuzaka,

Yasuyuki Morishita, M.T.,

Shinichi Harada

Homepage http://pathol.umin.ac.jp/
Introduction and Organization
The Department of Human Pathology united
the Department of Diagnostic Pathology, andhas started as a new department, the Department of Human Pathology and Diagnostic Pathology in 2003. It is responsible for the practice of diagnostic pathology, education, and research in conjunction with Division of Diagnostic Pathology of the University Hospital.
The unification is also expected to facilitate thenext-generation pathology.

We cerebrated the 30th memorial year of theDivision of Diagnostic Pathology, and publishedcommemorative issues in 2005. We also hosted
the 51st autumn scientific meeting of Japanese
Academy of Pathology at Yasuda MemorialHall.
The staffs in 2004 consisted of a professor,(MF), two associate professors (TN, KO), four
associates (KK, AG, JS, TU) and three technicalsupport specialists (TN, YM, SH). The staffs ofDivision of Diagnostic Pathology (DDP) were
one lecturer (HE), and four associates (TM, HU,

37

YT, YO). In 2005, the associate professor, Dr. T
Niki was invited as the professor by Jichi
Medical School. Dr. K Ohashi moved to Toranomon Hospital as the Director of Department of Pathology, and Dr. Y Ota also moved to
the Toranomon Hospital. Lecturer Dr. N Fukushima came from Tokyo Medical School, andDr. H Uozaki was promoted to a Lecturer. Dr. S
Ota came from Division of Pathology, Hokkaido
University Hospital, and Dr. T Ishida from
Department of Hematology, Juntendo University. Dr. H Endo will complete her term of officeat the end of this fiscal year.
Two graduates received PhD in 2004 and six
in 2005. Twelve postgraduate students (onefrom other university and three from abroad)are now studying in the department.
We are responsible for the surgical pathology
and autopsy in the University Hospital. The
research is based on morphology, targeting
human diseases. On the other hand. we takecharge of Systemic Pathology course, ClinicalClerkship, and Bedside-learning for 2nd –4th
grade students. We also take part in the General Pathology course in conjunction with Department of Molecular Pathology.

Clinical activities
The surgical pathology practice and autopsy
services are our duties. We are now engaged in
the technical and systemic development of
rapid diagnosis, utilizing the rapid tissue processing system.
Autopsy conference on two cases each isregularly held every month. CPC is also held
periodically for surgical pathology including
tumors of thoracic organs and upper gastrointestinal tract, brain, liver, pancreatobiliary
tract, urology, gynecology, bone- and soft tissue,
and biopsy of various disease of liver, kidney, &dermatology.

Teaching activities
We take part in the General Pathology course,
especially in its morphological aspects for the

1st grade of undergraduate students. The course
program and lecture notes are available in UTOpen Course Ware（http://ocw.u-tokyo.ac.jp/）.
Classes of Systemic Pathology course andexercises are now held every week in parallelwith those of Systemic Medical course. Such an
integrated classes are expected to promote thestudents’ understanding. We have prepared thepathology lectures for ophthalmology, oral surgery, and otolaryngology. Pathology exercisesfor brain tumors, dermatology, and infectious
diseases are also included. We have adopted theslide-projected examination since 2003, and thequestions and answers are available on our
website.
In BSL course, a pair of students is required
to inspect and analyze the one teaching case of
autopsy. Students are also required to examine
surgical materials of popular Carcinomas. Onemonth course of Clinical Clerkship has been
introduced since 2003. Seven students took thecourse from January to March in 2004, and thesame in 2005.
The past graduate examinations of Diagnostic Pathology are also referred on the web. We
owe the development and maintenance of our
web-site to Dr. Uozaki.

Research activities
Armed with the morphology, we are engaged
in the investigation of the relationship between
chronic inflammation and neoplasm:
1. Epstein-Barr virus associated neoplasms,
such as gastric carcinoma and lymphomas. .
2. Lung carcinomas and scar formation.
We are also searching the candidates for theantibody drug by global analysis of expression
profiles of various cancers in collaboration with
Research Center for Advanced Science andTechnology, the University of Tokyo.
Our research lab has moved to the newbuilding in December, 2005. Although the research style of human pathology is a ranch-type,
rather than a factory-type, the standard research facilities of molecular biology and molecular pathology are indispensable. Dr. Ka-

38shima devoted himself to set up our laboratory.

References
2004
1. Fukayama M, Hishima T, Fujii T, Zettl A,
Shimosato Y: Squamous cell carcinoma. In
Tumours of the Lung, Pleura, Thymus andHeart. Travis T, Brambilla E, Muller-Hermelink
HK, Harris CC (eds), IARC press, Lyon,
2004, p172-174
2. Hata K, Watanabe T, Motoi T, Nagawa H.
Pitfalls of pit pattern diagnosis in ulcerative
colitis-associated dysplasia. Gastroenterology. 2004 Jan;126(1):374-6.
3. Goto T, Motoi N, Motoi T, Okuma T, Kawano H, Yamamoto A, Nakamura K. Spindle cell lipoma of the knee: a case report. J
Orthop Sci. 2004;9(1):86-9.
4. Shimoyama S, Aoki F, Kawahara M, Yahagi
N, Motoi T, Kuramoto S, Kaminishi M.
Early gastric cancer development in a familial adenomatous polyposis patient. Dig
Dis Sci. 2004 Feb;49(2):260-5.
5. Koshiishi N, Chong JM, Fukasawa T, Ikeno
R, Hayashi Y, Funata N, Nagai H, Miyaki M,
Matsumoto Y, Fukayama M. p300 gene alterations in intestinal and diffuse types ofgastric carcinoma.Gastric Cancer. 2004;7(2):85-90.
6. Sudo M, Chong JM, Sakuma K, Ushiku T,
Uozaki H, Nagai H, Funata N, Matsumoto Y,
Fukayama M. Promoter hypermethylationof E-cadherin and its abnormal expression
in Epstein-Barr virus-associated gastriccarcinoma. Int J Cancer. 2004 Mar 20;109(2):194-9.
7. Akiyama K, Numaga J, Kagaya F, Takazawa Y, Suzuki S, Koseki N, Kato S, Kaburaki T, Kawashima H. Case of optic nerve
involvement in metastasis of a gastrointestinal stromal tumor. Jpn J Ophthalmol.
2004 Mar-Apr; 8(2):166-8.
8. Uemura K, Nakajima M, Yamauchi N, Fukayama M, Yoshida K. Sudden death of apatient with primary hypereosiophilia, colon tumours, and pulmonary emboli. J Clin

Pathol. 2004 May;57(5):541-3.
9. Konishi T, Watanabe T, Kitayama J, Shibahara J, Hiramatsu T, Hara K, Kuriki K,
Nagawa H. Successfully treated idiopathic
rectosigmoid perforation 7 years after renaltransplantation.J Gastroenterol. 2004;39(5):484-9.
10. Shibahara J, Goto A, Niki T, Tanaka M,
Nakajima J, Fukayama M. Primary pulmonary paraganglioma: report of a functioning case with immunohistochemical andultrastructural study. Am J Surg Pathol.
2004 Jun;28(6):825-9.
11. Ishikawa S, Uozumi N, Shiibashi T, Izumi
T, Fukayama M, Shimizu T, Watanabe J,
Nogami S. Short report: Lethal malaria in
cytosolic phospholipase A2- and phospholipase A2IIA-deficient mice. Am J Trop Med
Hyg. 2004 Jun;70(6):645-50
12. Inoue T, Kawahara N, Shibahara J, Masumoto T, Usami K, Kirino T. Extraduralneurenteric cyst of the cerebellopontine angle. Case report. J Neurosurg. 2004 Jun;100(6):1091-3
13. Goto T, Kawano H, Yamamoto A, Yokokura
S, Iijima T, Motoi T, Nakamura K. Simple
curettage without bone grafting for enchondromas of the foot. Arch Orthop Trauma
Surg. 2004 Jun;124(5):301-5.
14. Koketsu S, Watanabe T, Hori N, Umetani N,
Takazawa Y, Nagawa H. Hemophagocytic
syndrome caused by fulminant ulcerative
colitis and cytomegalovirus infection: reportof a case. Dis Colon Rectum. 2004 Jul;47(7):1250-3.
15. Dobashi Y, Goto A, Fukayama M, Abe A,
Ooi A. Overexpression of cdk4/cyclin D1, apossible mediator of apoptosis and an indicator of prognosis in human primary lungcarcinoma. Int J Cancer. 2004 Jul 1;110(4):532-41.
16. Goto A, Niki T, Moriyama S, Funata N,
Moriyama H, Nishimura Y, Tsuchida R,
Kato JY, Fukayama M. Immunohistochemical
study of Skp2 and Jab1, two key moleculesin the degradation of P27, in lung adenocarcinoma. Pathol Int. 2004 Sep;54(9): 675-

39

81.
17. Shibahara J, Todo T, Morita A, Mori H,
Aoki S, Fukayama M. Papillary neuroepithelial tumor of the pineal region. A casereport. Acta Neuropathol (Berl). 2004 Oct;108(4):337-40.
18. Sakurai S, Hasegawa T, Sakuma Y, Takazawa Y, Motegi A, Nakajima T, Saito K,
Fukayama M, Shimoda T. Myxoid epithelioid
gastrointestinal stromal tumor (GIST) withmast cell infiltrations: a subtype of GIST
with mutations of platelet-derived growth
factor receptor alpha gene. Hum Pathol.
2004 Oct;35(10):1223-30.
19. Goto A, Niki T, Terado Y, Fukushima J,
Fukayama M. Prevalence of CD99 protein
expression in pancreatic endocrine tumours(PETs). Histopathology. 2004 Oct;45(4): 38492.
20. Sakuma K, Chong JM, Sudo M, Ushiku T,
Inoue Y, Shibahara J, Uozaki H, Nagai H,
Fukayama M. High-density methylation of
p14ARF and p16INK4A in Epstein-Barrvirus-associated gastric carcinoma. Int J
Cancer. 2004 Nov 1;112(2):273-8.
2005
1. Goto A, Nakajima J, Hara K, Niki T, Fukayama M. Lung adenocarcinoma associated with familial adenomatous polyposis.
Clear cell carcinoma with beta-catenin accumulation accompanied by atypical adenomatous hyperplasia. Virchows Arch. 2005
Jan;446 (1): 73-7
2. Yoshino M, Morita A, Shibahara J, Kirino T.
Radiation-induced spinal cord cavernous
malformation. Case report. Neurosurg. 2005
Jan;102(1 Suppl):101-4.
3. Oya S, Kawahara N, Aoki S, Hayashi N,
Shibahara J, Izumi M, Kirino T. Intracranial extracerebral glioneuronal heterotopia.
Case report and review of the literature. J
Neurosurg. 2005 Jan;102(1 Suppl):105-12.
4. Konishi T, Watanabe T, Kitayama J, Shibahara J, Nagawa H. Endoscopic andhistopathologic findings after formalin application for hemorrhage caused by chronic

radiation- induced proctitis. Gastrointest
Endosc. 2005 Jan;61(1):161-4.
5. Kobayashi T, Makuuchi M, Sano K, Koyama
K, Motoi T. Repeated obstructive jaundice
and acute pancreatitis caused by metastatic
liver tumor: an unusual case. Hepatogastroenterology. 2005 Jan-Feb;52(61): 220-2.
6. Yuge T, Nibu K, Kondo K, Shibahara J,
Tayama N, Sugasawa M. Loss of FHIT expression in squamous cell carcinoma andpremalignant lesions of the larynx. Ann
Otol Rhinol Laryngol. 2005 Feb;114(2): 12731.
7. Sakamoto T, Uozaki H, Kondo K, Imauchi Y,
Yamasoba T, Sugasawa M, Kaga K. Cyclooxygenase-2 regulates the degree of apoptosis bymodulating bcl-2 protein in pleomorphic
adenoma and mucoepidermoid carcinoma of
the parotid gland. Acta Otolaryngol. 2005
Feb;125(2):191-5.
8. Fukumoto S, Yamauchi N, Moriguchi H,
Hippo Y, Watanabe A, Shibahara J, Taniguchi H, Ishikawa S, Ito H, Yamamoto S,
Iwanari H, Hironaka M, Ishikawa Y, Niki T,
Sohara Y, Kodama T, Nishimura M, Fukayama M, Dosaka-Akita H, Aburatani H.
Overexpression of the aldo-keto reductase
family protein AKR1B10 is highly correlated with smokers' non-small cell lungcarcinomas. Clin Cancer Res. 2005 Mar
1;11(5):1776-85.
9. Takahashi Y, Endo H, Tange T, Kurabayashi R, Nomura S, Kaminishi M, Tange T.
Des-gamma carboxy prothrombin (PIVKAII)- and alpha-fetoprotein (AFP)- producing
gastric cancer. J Gastroenterol. 2005 Apr;
40(4):432-3.
10. Shimamura T, Ito H, Shibahara J, Watanabe A, Hippo Y, Taniguchi H, Chen Y, Kashima T, Ohtomo T, Tanioka F, Iwanari H,
Kodama T, Kazui T, Sugimura H, Fukayama M, Aburatani H. Overexpression of
MUC13 is associated with intestinal-type
gastric cancer. Cancer Sci. 2005 May;96(5):265-73.
11. Seto E, Yang L, Middeldorp J, Sheen TS,
Chen JY, Fukayama M, Eizuru Y, Ooka T,

40

Takada K. Epstein-Barr virus (EBV)-encoded BARF1 gene is expressed in nasopharyngeal carcinoma and EBV-associatedgastric carcinoma tissues in the absence oflytic gene expression. J Med Virol. 2005
May;76(1):82-8.
12. Sakuma K, Uozaki H, Chong JM, Hironaka
M, Sudo M, Ushiku T, Nagai H, Fukayama
M. Cancer risk to the gastric corpus in
Japanese, its correlation with interleukin1beta gene polymorphism (+3953*T) and
Epstein-Barr virus infection. Int J Cancer.
2005 May 20;115(1):93-7.
13. Inamura K, Satoh Y, Okumura S, Nakagawa K, Tsuchiya E, Fukayama M, Ishikawa Y. Pulmonary adenocarcinomas withenteric differentiation: histologic and immunohistochemical characteristics comparedwith metastatic colorectal cancers and usual
pulmonary adenocarcinomas. Am J Surg
Pathol. 2005 May;29(5):660-5.
14. Takazawa Y, Sakurai S, Sakuma Y, Ikeda T,
Yamaguchi J, Hashizume Y, Yokoyama S,
Motegi A, Fukayama M. Gastrointestinal
stromal tumors of neurofibromatosis type I(von Recklinghausen's disease). Am J Surg
Pathol. 2005 Jun;29(6):755-63.
15. Kaizaki Y, Hosokawa O, Sakurai S, Fukayama M. Epstein-Barr virus-associatedgastric carcinoma in the remnant stomach:de novo and metachronous gastric remnant
carcinoma. J Gastroenterol. 2005 Jun;40(6):570-7.
16. Ishiguro N, Motoi T, Osaki M, Araki N,
Minamizaki T, Moriyama M, Ito H, Yoshida
H. Immunohistochemical analysis of amuscle ankyrin-repeat protein, Arpp, inparaffin-embedded tumors: evaluation of
Arpp as a tumor marker for rhabdomyosarcoma. Hum Pathol. 2005 Jun;36(6):6205.
17. Ikegaya H, Iwase H, Zheng HY, Nakajima
M, Sakurada K, Takatori T, Fukayama M,
Kitamura T, Yogo Y. JC virus genotyping
using formalin-fixed, paraffin-embedded renal
tissues. J Virol Methods. 2005 Jun; 126(1-2):37-43.

18. Tanaka Y, Yokoo H, Komori T, Makita Y,
Ishizawa T, Hirose T, Ebato M, Shibahara J,
Tsukayama C, Shibuya M, Nakazato Y. A
distinct pattern of Olig2-positive cellular
distribution in papillary glioneuronal tumors: a manifestation of the oligodendroglial phenotype? Acta Neuropathol (Berl).
2005 Jul;110(1):39-47.
19. Takahashi Y, Fukushima J, Fukusato T,
Shiga J, Tanaka F, Imamura T, Fukayama
M, Inoue T, Shimizu S, Mori S. Prevalenceof ischemic enterocolitis in patients withacute pancreatitis. J Gastroenterol. 2005
Aug;40(8):827-32.
20. Motoi T, Ishida T, Kawato A, Motoi N, Fukayama M. Pigmented neurofibroma: review of Japanese patients with an analysisof melanogenesis demonstrating coexpression of c-met protooncogene and microphthalmia- associated transcription factor. Hum Pathol. 2005 Aug;36(8):871-7.
21. Maruyama K, Morita A, Shibahara J, Nakazato Y, Kirino T. Multifocal pilocytic astrocytomas with ependymal differentiationin the bilateral medial temporal lobes: casereport. Neurol Med Chir (Tokyo). 2005
Aug;45(8):411-4.
22. Goto A, Niki T, Li C-P, Matsubara D, Murakami Y, Funata N, Fukayama M. Loss of
TSLC1 expression in lung adenocarcinoma:
relationships with histological subtypes, sex
and prognostic significance. Cancer Sci.
2005 Aug;96(8):480-6.
23. Shibahara J, Fukayama M. Secondary
glioblastoma with advanced neuronal immunophenotype. Virchows Arch. 2005 Sep;
447(3):665-8.
24. Kanamori Y, Hashizume K, Sugiyama M,
Motoi T, Fukayama M, Ida K, Igarashi T.
Intrapulmonary solitary fibrous tumor inan eight-year-old male. Pediatr Pulmonol.
2005 Sep;40(3):261-4.
25. Uozaki H, Chong JM, Fujimoto E, Itoh M,
Saito M, Sakuma K, Sudo M, Ushiku T,
Niki T, Nagai H, Takada K, Fukayama M.
Soft and hard keratin expression in Epstein-Barr- virus-associated gastric carci-

41

noma. Anticancer Res. 2005 Sep-Oct;25(5):3183-90.
26. Inamura K, Fujiwara T, Hoshida Y, Isagawa
T, Jones MH, Virtanen C, Shimane M,
Satoh Y, Okumura S, Nakagawa K, Tsuchiya E, Ishikawa S, Aburatani H, Nomura
H, Ishikawa Y. Two subclasses of lungsquamous cell carcinoma with different
gene expression profiles and prognosis
identified by hierarchical clustering andnon-negative matrix factorization. Oncogene. 2005 Oct 27;24(47): 7105-13.
27. Yamashita H, Nakagawa K, Tago M, Nakamura N, Shiraishi K, Yamauchi N, Ohtomo K Pathological changes after radiotherapy for primary pituitary carcinoma: acase report. J Neurooncol. 2005 Nov;75(2):209-14.
28. Monzen K, Hosoda T, Hayashi D, Imai Y,
Okawa Y, Kohro T, Uozaki H, Nishiyama T,
Fukayama M, Nagai R. The use of a supercooling refrigerator improves the preservation of organ grafts. Biochem Biophys Res
Commun. 2005 Nov 18;337(2):534-9.
29. Katoh H, Shibata T, Kokubu A, Ojima H,
Loukopoulos P, Kanai Y, Kosuge T, Fukayama M, Kondo T, Sakamoto M, Hosoda F,
Ohki M, Imoto I, Inazawa J, Hirohashi S.
Genetic profile of hepatocellular carcinoma
revealed by array-based comparative genomic hybridization: identification of genetic indicators to predict patient outcome.
J Hepatol. 2005 Nov;43(5):863-74.
30. Yamauchi N, Watanabe A, Hishinuma M,
Ohashi K, Midorikawa Y, Morishita Y, Niki
T, Shibahara J, Mori M, Makuuchi M,
Hippo Y, Kodama T, Iwanari H, Aburatani
H, Fukayama M. The glypican 3 oncofetal
protein is a promising diagnostic marker forhepatocellular carcinoma. Mod Pathol. 2005
Dec;18(12): 1591-8
31. Satoh Y, Ishikawa Y, Inamura K, Okumura
S, Nakagawa K, Tsuchiya E. Classificationof parietal pleural invasion at adhesion
sites with surgical specimens of lung cancer
and implications for prognosis. VirchowsArch. 2005 Dec;447(6):984-9.

32. Saito Y, Motoyoshi Y, Kashima T,
Izumiyama-Shimomura N, Toda T, Nakano
I, Hasegawa M, Murayama S. Uniquetauopathy in Fukuyama-type congenital
muscular dystrophy. J Neuropathol Exp
Neurol. 2005 Dec;64(12):1118-26.
33. Matsubara D, Niki T, Ishikawa S, Goto A,
Ohara E, Yokomizo T, Heizmann CW, Aburatani H, Moriyama S, Moriyama H, Nishimura Y, Funata N, Fukayama M. Differential expression of S100A2 and S100A4in lung adenocarcinomas: clinicopathological significance, relationship to p53 andidentification of their target genes. Cancer
Sci. 2005 Dec;96(12):844-57.
34. Uozaki H, Fukayama M, Nakagawa K,
Ishikawa T, Misawa S, Doi M, Maekawa K.
The pathology of multi-organ involvement:
two autopsy cases from the Tokai-mura
criticality accident. BJR Suppl. 2005;
27:13-6
35. Chong JM, Uozaki H, Fukayama M. Epstein-Barr virus-associated gastric carcinoma. In The Diversity of Gastric Carcinoma. Pathogenesis, Diagnosis, and Therapy. Kaminishi M, Takubo K, Mafune K(eds.), Springer-Verlag, Tokyo, 2005, pp127138

42

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

Associate Professor
Keiji Miyazawa, Ph.D.

Associate
Masao Saitoh, D.D.S.

Tetsuro Watabe, 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 started to work as the professor of the Department of Molecular Pathology inAugust 2000. Now, the Department consists of aprofessor, an associate professor, two associates, 4technicians, and several research fellows, including
6 graduate students, 5 master course students, 2
post-doctoral fellows, and a research fellow from
France.

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

We also supervise research activities of thegraduate students of the Department. Our laboratory
is located at the 11th floor at the Research Buildingof Graduate School of Medicine. The laboratory isvery convenient for doing research, since most of
the experiments can be done at this floor. We have
“Progress Meeting” twice a month, “Journal Club”
every Friday, and “Monday Seminar” once a monthin collaboration with the Department of Biochemistry at the Cancer Institute of the Japanese Foundation for Cancer Research.
We have been doing collaboration with the
Ludwig Institute for Cancer Research, Uppsala,Sweden for more than 10 years. We have annual
TGF-β meeting in Sweden every spring, and somegraduate students participate in the meeting andorally present their results.
Graduate students also present data at various
meetings, including Annual Meetings of the Japanese Cancer Association, and Annual Meeting of
the Molecular Biology Society of Japan. At the corridor of our laboratory, posters of our graduate students reported at these meetings are presented.

Research activities
Our major research interest is to elucidate how

43members of the TGF (transforming growth factor)-βsuperfamily transduce signals, and how they regulate growth, differentiation, and apoptosis of various cells. We are also interested in the regulation ofangiogenesis and lymphangiogenesis using embryonic stem (ES) cell-derived vascular progenitor
cells and other endothelial cells.
Since TGF-β is a potent inhibitor of various cells,
perturbations of TGF-β signaling result in progression of cancer. On the other hand, TGF-β accelerates growth and metastasis of certain cancers in advanced stages. Thus, studies on the mechanisms of
TGF-β signaling is important to understand theroles of TGF-β in various cancers. We are currently
interested in mechanisms of the action of inhibitory
Smad (Smad7) and transcriptional co-repressor
c-Ski in TGF-β signaling. We have found that theactivity of Smad7 is positively regulated by ubiquitin ligases Smurf1/2 and WWP1, whereas anotherubiquitin ligase Arkadia negatively regulates theaction of Smad7. We have also shown that transferof the Smad7 gene results in prevention of metastasis of murine breast cancer. BMPs are members of
the TGF-β superfamily. We have reported that
BMP-4 induces apoptosis of myeloma and B-cellhybridoma cells by dysfunction of the endoplasmic
reticulum.
While lymphatic systems play important roles inphysiological conditions and pathological processes
such as cancer metastasis, molecular mechanismsthat govern lymphangiogenesis remain largely unknown. We have found that homeobox transcription
factor Prox1 induces expression of VEGF receptor-2, PDGF receptor-β, and Angiopoietin-2 in endothelial cells, resulting in enhancement of motility
and migration of endothelial cells. Prox1 thus acts
as a master regulator of lymphangiogenesis, andconfers the characteristics of lymphatic endothelial
cells to vascular endothelial cells by modulating
multiple signaling cascades.

References
1. Takeda, M., Mizuide, M., Oka, M., Watabe, T.,
Inoue, H., Suzuki, H., Fujita, T., Imamura, T.,
Miyazono, K., and Miyazawa, K. (2004) Interaction with Smad4 is indispensable for suppressionof BMP signaling by c-Ski. Mol. Biol. Cell 15 (3),963-972.
2. Ijichi, H., Otsuka, M., Tateishi, K., Ikenoue, T.,
Kawakami, T., Kanai, F., Arakawa, Y., Seki, N.,
Shimizu, K., Miyazono, K., Kawabe, T., andOmata, M. (2004) Smad4-independent regulationof p21/WAF1 by transforming growth factor-β.
Oncogene 23 (5), 1043-1051.
3. Kahata, K., Hayashi, M., Asaka, M., Hellman, U.,
Kitagawa, H., Yanagisawa, J., Kato, S., Imamura,T., and Miyazono, K. (2004) Regulation of transforming growth factor-β and bone morphogenetic
protein signaling by transcriptional co-activator
GCN5. Genes Cells 9 (2), 143-151.
4. Maeda, S., Hayashi, M., Komiya, S., Imamura, T.,
and Miyazono, K. (2004) Endogenous TGF-βsignaling suppresses maturation of osteoblastic
mesenchymal cells. EMBO J. 23 (3), 552-563.
5. Kondo, M., Suzuki, H., Takehara, K., Miyazono,
K., and Kato, M. (2004) Transforming growth
factor-β signaling is differentially inhibited by
Smad2D450E and Smad3D407E. Cancer Sci. 95(1), 12-17.
6. Yanagita, M., Oka, M., Watabe, T., Iguchi, H.,
Niida, A., Takahashi, S., Akiyama, T., Miyazono,
K., Yanagisawa, M., and Sakurai, T. (2004)
USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the kidney. Biochem.
Biophys. Res. Commun. 316 (2), 490-500.
7. Miyazono, K., Ishikawa, F., Winterhager, E.,
Deppert, W., and Rajewsky, M.F. (2004) NinthJapanese-German workshop on molecular andcellular aspects of carcinogenesis, Essen, Germany, 18-20 September, 2003. Cancer Sci. 95 (3),276-281.
8. Usui, M., Yoshida, Y., Tsuji, K., Oikawa, K., Miyazono, K., Ishikawa, I., Yamamoto, T., Nifuji, A.,
and Noda, M. (2004) Tob-deficiency super-enhances osteoblastic activity after ovariectomy to block estrogen deficiency- induced osteoporosis. Proc. Natl. Acad. Sci. USA 101 (17),6653-6658.
9. Miyazono, K., Maeda, S., and Imamura, T. (2004)
Coordinate regulation of cell growth and differentiation by TGF-β superfamily and Runx proteins.
Oncogene 23 (24), 4232-4237.
10. Horiki, M., Imamura, T., Okamoto, M., Hayashi,

44M., Murai, J., Myoui, A., Ochi, T., Miyazono, K.,
Yoshikawa, H., and Tsumaki, N. (2004) Smad6/
Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism withosteopenia. J. Cell Biol. 165 (3), 433-445.
11. Mochizuki, T., Miyazaki, H., Hara, T., Furuya, T.,
Imamura, T., Watabe, T., and Miyazono, K. (2004)
Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-β
superfamily signaling. J. Biol. Chem. 279 (30),31568-31574.
12. Kondo, M., Cubillo, E., Tobiume, K., Fukuda, N.,
Suzuki, H., Takehara, K., Cano, A., Saitoh, M.,
and Miyazono, K. (2004) A role for Id in theregulation of TGF-β-induced epithelial- mesenchymal transdifferentiation. Cell Death Differ. 11(10), 1092-1101.
13. Suzuki, H., Yagi, K., Kondo, M., Kato, M., Miyazono, K., and Miyazawa, K. (2004) c-Ski inhibits the TGF-β signaling pathway through stabilization of inactive Smad complexes on Smadbinding elements. Oncogene 23 (29), 5068-5076.
14. Komuro, A., Imamura, T., Saitoh, M., Yoshida, Y.,
Yamori, T., Miyazono, K., and Miyazawa, K.
(2004) Negative regulation of transforming
growth factor-β (TGF-β) signaling by WW domain-containing protein 1 (WWP1). Oncogene 23(41), 6914-6923.
15. Brederlau, A., Faigle, R., Elmi, M., Zarebski, A.,
Sjoberg, S., Fujii, M., Miyazono, K., and Funa, K.
(2004) The bone morphogenetic protein type Ib
receptor is a major mediator of glial differentiation and cell survival in adult hippocampal progenitor cell culture. Mol. Biol. Cell 15 (8), 38633875.
16. Ikeda, Y., Imai, Y., Kumagai, H., Nosaka, T.,
Morikawa, Y., Hisaoka, T., Manabe, I., Maemura,K., Nakaoka, T., Imamura, T., Miyazono, K.,
Komuro, I., Nagai, R., and Kitamura, T. (2004)
Vasorin, a transforming growth factor beta-binding protein expressed in vascular smooth muscle
cells, modulates the arterial response to injury invivo. Proc. Natl. Acad. Sci. USA. 101 (29), 1073210737.
17. Miyazaki, H., Watabe, T., Kitamura, T., and Miyazono, K. (2004) BMP signals inhibit proliferation and in vivo tumor growth of andro-

gen-insensitive prostate carcinoma cells. Oncogene 23 (58), 9326-9335.
18. Beppu, H., Ichinose, F., Kawai, N., Jones, R.C.,
Yu, P.B., Zapol, W.M., Miyazono, K., Li, E., andBloch, K.D. (2004) BMPR-II heterozygous mice
have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to
prolonged hypoxia. Am. J. Physiol. Lung Cell Mol.
Physiol. 287 (6), L1241-1247.
19. Kuratomi, G., Komuro, A., Goto, K., Shinozaki,M., Miyazawa, K., Miyazono, K,., and Imamura,T. (2004) Neural precursor cell expressed, developmentally down-regulated 4-2 (NEDD4-2) negatively regulates transforming growth factor-β(TGF-β) signaling by inducing ubiquitin-mediateddegradation of Smad2 and TGF-β type I receptor.
Biochem. J. 386 (3), 461-470.
20. Yamamoto, K., Sokabe, T., Watabe, T., Miyazono,
K., Yamashita, J.K., Obi, S., Ohura, N., Matsushita, A., Kamiya, A., and Ando, J. (2005) Fluid
shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro. Am. J. Physiol. Heart Circ.
Physiol. 288 (4), H1915- 1924.
21. Suzuki, H., Watabe, T., Kato, M., Miyazawa, K.,
and Miyazono K. (2005) Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived
vascular progenitor cells into endothelial cells.
Blood 105 (6), 2372-2379.
22. Kawazu, M., Asai, T., Ichikawa, M., Yamamoto,G., Saito, T., Goyama, S., Mitani, K., Miyazono,
K., Chiba, S., Ogawa, S., Kurokawa, M., andHirai, H. (2005) Functional domains of Runx1 aredifferentially required for CD4 repression, TCRβ
expression, and CD4/8 double-negative to CD4/8
double-positive transition in thymocyte development. J. Immunol. 174 (6), 3526-3533.
23. Moren, A., Imamura, T., Miyazono, K., Heldin,
C.-H., and Moustakas, A. (2005) Degradation of
the tumor suppressor Smad4 by WW and
HECT-domain ubiquitin ligases. J. Biol. Chem.
280 (23), 22115-22123.
24. Kano, M.R., Morishita, Y., Iwata, C., Iwasaka, S.,
Watabe, T., Ouchi, Y., Miyazono, K., and Miyazawa, K. (2005) VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhance-

45

ment of endogenous PDGF-B/ PDGFRβ signaling.
J. Cell Sci. 118 (16), 3759-3768.
25. Tojo, M., Hamashima, Y., Hanyu, A., Kajimoto,T., Saitoh, M., Miyazono, K., Node, M., andImamura, T. (2005) The ALK-5 Inhibitor A-83-01
inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-β.
Cancer Sci. 96 (11), 791-800.
26. Azuma, H., Ehata, S., Miyazaki, H., Watabe, T.,
Maruyama, O., Imamura, T., Sakamoto, T., Kiyama, S., Kiyama, Y., Ubai, T., Inamoto, T., Takahara, S., Itoh, Y., Otsuki, Y., Katsuoka, Y., Miyazono, K., and Horie, S. (2005) Effect of Smad7
expression on metastasis of mouse mammary carcinoma JygMC(A) cells. J. Natl. Cancer Inst. 97(23), 1734-1746.
27. Miyazono, K., Maeda, S., and Imamura, T. (2005)
BMP receptor signaling: transcriptional targets,regulation of signals, and signaling cross-talk.
Cytokine Growth Factor Rev. 16 (3), 251-263.

Pathology, Immunology andMicrobiology
2. Microbiology⑦

48

Department of Microbiology
Professor
Akio Nomoto, Ph.D.

Associate Professor
Tetsuro Matano, M.D., Ph.D.

Associate
Takeshi Yamada, Ph.D.,

Tsubasa Munakata, Ph.D.,

Seii Ohka, Ph.D.

Homepage http://microbiology.m.u-tokyo.ac.jp/
Introduction and Organization
Microbial disease has been recognized as the major
threat to human health throughout the history. Despite
the development of preventive and therapeutic interventions against some pathogenic microbes, infectious
disease is still one of the most significant medical
problems. On the other hand, microbial organisms
have served as a useful model as well for elucidating
the molecular mechanisms of a variety of biologicalevents, providing useful insights into life science. Recently, efforts have also been initiated by a number of
research groups to utilize animal viruses as a tool forhuman gene therapy. In order to familiarize students
with these issues, importance of microbiology inmedical education is increasing more rapidly than ever.
To fulfill this requirement, our department, as the only
basic microbiology unit in the Faculty, currently assumes a responsibility for teaching bacteriology, mycology, and virology to medical undergraduates.

Teaching Activities
Undergraduate Course, Faculty of Medicine
In a series of lectures (totally 60 hr) and laboratory
courses (30 hr), the following subjects are covered.
1) Molecular biology of bacteria, phages, and animalviruses2) Mechanisms of microbial diseases

3) Laboratory diagnosis of pathogenic microbes
4) Infection control and biosafety
5) Application of microbial organisms for biotechnology
6) Socioeconomic impact of microbial diseases
In addition to the staff of our department, experts
from the National Institutes of Infectious Diseases (Dr.
Shimada), Dokkyo Medical University (Dr. Masuda),
Teikyo University (Dr. Kawana), Faculty of Agriculture (Dr. Onodera), and Institute of Medical Science(Dr. Sasakawa, Dr. Kawaoka, Dr. Iwamoto, and Dr.
Saito) contribute to the teaching activities.

Research Activities
1. IRES (internal ribosome entry site)-dependent
virus tropism
Ohka, S., Azuma, A., Murakami, K., Fujimaki, T.,
Munakata, T., Honaga, T., Yanagiya, A., and Nomoto, A.
2. Poliovirus entry via PVR (poliovirus receptor)
Ohka, S., Matsuda, N., and Nomoto, A.
3. Effect of viral infection on cell metabolism
Matsuda, N., Yanagiya, A., Ohka, S., and Nomoto,A.
4. Blood brain barrier permeation of poliovirus
Sakai, M., Ohka, S., and Nomoto, A.
5. HCV (hepatitis C virus) genome as an RNA
replicon

49

6.
7.

8.

9.

Yamada, T., Shigenobu, F., and Nomoto, A.
Molecular basis for HCV pathogenesis
Yamada, T., Murayama, A., and Nomoto, A.
Molecular basis for retroviral pathogenesis
Kawada, M., Kusuki, K., Shoto, S., Sasaki, Y.,
Seki, S., Takeda, A., Igarashi, H., and Matano, T.
Virus-specific immune responses
Tsukamoto, T., Kawada, M., Kobayashi, M., Takeda, A., Igarashi, H., and Matano, T.
Development of AIDS vaccine
Yamamoto, H., Moriya, C., Kato, M., Takeda, A.,
Igarashi, H., and Matano, T.

References
1. Fujiyuki T, Takeuchi H, Ono M, Ohka S, Sasaski
T, Nomoto A, Kubo T. A novel insect picorna-likevirus identified in the brain of aggressive worker
honeybees. J Virol. 2004;78(3):1093-100.
2. Nagata N, Iwasaki T, Ami Y, Sato Y, Hatano I,
Harashima A, Suzaki Y, Yoshii T, Hashikawa T,
Sata T, Horiuchi Y, Koike S, Kurata T, Nomoto A.
A poliomyelitis model through mucosal infection
in transgenic mice bearing human poliovirus receptor, TgPVR21. Virol. 2004;321: 87-100.
3. Ohka S, Matsuda N, Tohyama K, Oda T, Morikawa M, Kuge S, Nomoto A. Receptor (CD155)dependent endocytosis of poliovirus and retrograde axonal transport of the endosome. J Virol.
2004; 78(13):7186-98.
4. Hanaki K, Ohka S, Yamamoto K, Nomoto A, Yoshikura H. Oligo (dA-dT) dependent signal amplification for the detection of proteins in cells. Bio
Techniques. 2004;36(5):1-6.
5. Oda T, Ohka S, Nomoto A. Ligand stimulation of
CD155α inhibits cell adhesion and enhances cell
migration in fibroblasts. Biochem. Biophys. Res.
Commun. 2004;319:1253-64.
6. Ogino T, Fukuda H, Imajoh-Ohmi S, Kohara M,
Nomoto A. Membrane binding properties andterminal residues of the mature hepatitis C Virus
capsid protein in insect cells. J Virol. 2004;78(21):11766- 77.
7. Fujiyuki T, Takeuchi H, Ono M, Ohka S, Sasaki T,
Nomoto A, Kubo T. Kakugo virus from brains of
aggressive worker honeybees. Adv. Vir. Res.
2005;65:1-27.

8. Yanagiya A, Jia Q, Ohka S, Horie H, Nomoto A.
Blockade of poliovirus-induced cytopathic effectin neural cells by monoclonal antibody against
poliovirus or human poliovirus receptor. J Virol.
2005; 79(3):1523-32.
9. Tomasec P, Wang ECY, Davidson AJ, Vojtesek B,
Armstrong M, Griffin C, McSharry BP, Rickards
RJ, Nomoto A, Sinzger C, Wilkinson GWG.
Down-regulation of NK cell activating ligand
CD155 by human cytomegalovirus UL141. Nature Immunol. 2005;6(2): 81-8.
10. Matano T, Kobayashi M, Igarashi H, Takeda A,
Nakamura H, Kano M, Sugimoto C, Mori K, Iida
A, Hirata T, Hasegawa M, Yuasa T, Miyazawa M,
Takahashi Y, Yasunami M, Kimura A, O'Connor
DH, Watkins DI, Nagai Y. Cytotoxic T lymphocyte-based control of simian immunodeficiency
virus replication in a preclinical AIDS vaccine
trial. J Exp Med. 2004;199:1709-18.
11. Lun WH, Takeda A, Nakamura H, Kano M, MoriK, Sata T, Nagai Y, Matano T. Loss of virus-specific CD4+ T cells with increases in viralloads in the chronic phase after vaccine-based
partial control of primary simian immunodeficiency virus replication in macaques. J Gen Virol.
2004;85:1955-63.
12. Kato M, Igarashi H, Takeda A, Horie S, Higashihara E, Matano T. Stimulation of virus-specific T
cell responses by dendritic cell vaccination in thechronic phase of simian AIDS models. Jpn J Infect Dis. 2004;57:220-3.
13. Kato M, Igarashi H, Takeda A, Sasaki Y, Nakamura H, Kano M, Sata T, Iida A, Hasegawa M,
Horie S, Higashihara E, Nagai Y, Matano T. Induction of Gag-specific T-cell responses by
therapeutic immunization with a Gag-expressing
Sendai virus vector in macaques chronically infected with simian-human immunodeficiency virus. Vaccine. 2005;23:3166-73.
14. Mori K, Sugimoto C, Ohgimoto S, Shioda T, Kusagawa S, Takebe Y, Kano M, Matano T, Yuasa T,
Kitaguchi D, Miyazawa M, Takahashi Y, Yasunami M, Kimura A, Yamamoto N, Szuki Y, Nagai
Y. Influence of glycosylation on the efficacy of an
Env-based vaccine against SIVmac239 in a macaque AIDS model. J Virol. 2005;79:10386-96.
15. Kobayashi M, Igarashi H, Takeda A, Kato M,

50

Matano T. Reversion in vivo after inoculation of amolecular proviral DNA clone of simian immunodeficiency virus with a cytotoxic-T-lymphocyte
escape mutation. J Virol. 2005;79:11529-32.
16. Kawada M, Igarashi H, Takeda A, Tsukamoto T,
Yamamoto H, Dohki S, Takiguchi M, Matano T.
Involvement of multiple epitope-specific cytotoxic T-lymphocyte responses in vaccine-based
control of simian immunodeficiency virus replication in rhesus macaques. J Virol. 2006;80:194958.

51

Department of
Infection Control and Prevention
Professor
Kazuhiko Koike, M.D., Ph.D.

Lecturer
Kyoji Moriya, M.D., Ph.D.
Hiroshi Yotsuyanagi, M.D., Ph.D.

Associate
Yoshizumi Shintani, M.D.,

Shu Okugawa, M.D., Ph.D.

Homepage http://www.cc.h.u-tokyo.ac.jp/mulins/kansen/index.html (inside thehospital only)
Introduction and Organization
The Department of Infection Control and Prevention
started at first as the Division of Hospital Infection
Control Services on January 23, 1991. This divisiondeveloped into the Division of Infection Control andPrevention on September l, 1993 and the present department on June 4, 1994. Currently, our faculty consists of one professor, two lecturers, 6 guest lecturers,
two associates, one research student, 12 laboratory
technicians, and two office assistants. For isolation andidentification of microorganisms from clinical specimens, we amalgamated the microbiology unit from the
Department of Clinical Laboratory in 2001.

Clinical activities
Our daily activities are as follows:
1) Surveillance and control of hospital-acquired infection, such as infection or colonization of methicillin-resistant Staphylococcus aureus and otherdrug-resistant microbes.
2) Investigation of trends in weekly bases andmonthly reports to all departments; Screening of

3)
4)
5)
6)

colonization; monitoring of appropriate use of antibiotics such as mupirocin and vancomycin.
Microbiological investigation of wards and environment (at request or need).
Detection, investigation, intervention and control of
the hospital infection outbreak.
Offering of information and advice on HIV-infectedpatients’ management.
Direct inquiries and advises on management ofpatients with various infections through ward
rounds every week.

Teaching activities
We have been charged for education of undergraduate students on the course of medicine (lectures andpractical exercises on the infection control for the 3rd
and 4th grade students and lectures on infectious diseases for the 4th grade students), the course of healthscience (lectures on microbiology), and the school ofnursing (lectures and practical exercises on microbiology). These lectures and exercises contain subjects not
only on the hospital infection but also on clinical microbiology. We are also engaged in the education of

52

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:
1) Development of preemptive strategies for the control of healthcare-associated infection2) Development of new methods in infection control
and treatment of viral hepatitis
3) Molecular pathogenesis of hepatocellular 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 of opportunistic cytomegaloviral infection10) Mechanism of multi-drug resistant microorganisms

References
1) Miyoshi H, Fujie H, Moriya K, Shintani Y, Tsutsumi
T, Makuuchi M, Kimura S, Koike K. Methylation
status of suppressor of cytokine signaling-1 gene inhepatocellular carcinoma. J Gastroenterol 2004;
39:563-569.
2) Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Kimura S, Moriya K, Koike K. Hepatitis C virus anddiabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology
2004;126:840-848.
3) Koike K, Fujie H, Shintani Y, Miyoshi H, Moriya
K. Hepatitis C and Diabetes Mellitus: what is themetabolic pathway? Gastroenterology 2004;127:
1280-1281.
4) Yano M, Hayashi H, Yoshioka K, Kohgo Y, Saito H,
Niitsu Y, Kato J, Iino S, Yotsuyanagi H, Kobayashi
Y, Kawamura K, Kakumu S, Kaito M, Ikoma J,

Wakusawa S, Okanoue T, Sumida Y, Kimura F, Kajiwara E, Sata M, Ogata K. A significant reduction
in serum alanine aminotransferase levels after
3-month iron reduction therapy for chronic hepatitis C: a multicenter, prospective, randomized, controlled trial in Japan. J Gastroenterol. 39: 570-574,
2004.
5) Yotsuyanagi H, Hashidume K, Suzuki M, Maeyama S, Takayama T, Uchikoshi T. Role of hepatitis B virus in hepatocarcinogenesis in alcoholics.
Alcohol Clin Exp Res. 28(Suppl):181S, 2004.
6) Fukuda Y, Yotsuyanagi H, Ooka S, Sekine T, Koike
J, Takano T, Suzuki M, Itoh F, Nishioka K, Kato T.
Identification of a new autoantibody in patientswith chronic hepatitis. Hum Immunol. 65:1530,
2004.
7) Nakayama K, Okugawa S, Yanagimoto S, Kitazawa T, Tsukada K, Kawada M, Kimura
S, Hirai K, Takagaki Y, Ota Y. Involvement of
IRAK-M in peptidoglycan-induced tolerance inmacrophages. J Biol Chem. 2004 Feb 20;279(8):6629-34.
8) Koike K, Moriya K. Metabolic aspects of hepatitis
C: steatohepatitis resembling but distinct from
NASH. J Gastroenterol 2005;40:329-336.
9) Hatakeyama S, Moriya K, Saijo M, Morisawa Y,
Kurane I, Koike K, Kimura S, Morikawa S. Persisting humoral anti-smallpox immunity among
current Japanese population after the discontinuation in 1976 of routine smallpox vaccinations. Clin
Diagn Lab Immun 2005;12:520-524.
10) Koike K. Steatosis in chronic hepatitis C: fuel for
overproduction of oxidative stress? J Gastroenterol 2005;40:664-665.
11) Miyoshi H, Fujie H, Shintani Y, Tsutsumi T, Shinzawa S, Makuuchi M, Kokudo N, Matsuura Y, Suzuki T, Miyamura T, Moriya K, Koike K. Hepatitis
C virus core protein exerts an inhibitory effect on
suppressor of cytokine signaling (SOCS)-1 gene
expression. J Hepatol 2005;43:757-763.
12) Koike K. Hepatitis C as a metabolic disease: implication for the pathogenesis of NASH. Hepatol
Res 2005;33:145-150.
13) Koike K. Molecular basis of hepatitis C virus-associated hepatocarcinogenesis: lessons fromanimal model studies. Clin Gastroenterol Hepatol
2005;3:S132-S135.

5314) Saito R, Misawa Y, Moriya K, Koike K, Ubukata
K, Okamura N. Development and evaluation of aloop-mediated isothermal amplification assay for
rapid detection of Mycoplasma pneumoniae. J
Med Microbiol 2005;54:1037-1041.
15) Orita M, Masuko-Hongo K, Yotsuyanagi H, Matsui
T, Suzuki-Kurokawa M, Nishioka K, Kato T. Molecular transplantation: delivery of membranous
proteins onto live cells. Anal Biochem. 340:184186, 2005.
16) Katakura Y, Yotsuyanagi H, Hashizume K, Okuse
C, Okuse N, Nishikawa K, Suzuki M, Iino S, Itoh F.
Pancreatic involvement in chronic viral hepatitis.
World J Gastroenterol. 11: 3508, 2005.
17) Yotsuyanagi H, Okuse C, Yasuda K, Orito E, Nishiguchi S, Toyoda J, Tomita E, Hino K, Okita K,
Murashima S, Sata M, Hoshino H, Miyakawa Y,
Iino S; Japanese Acute Hepatitis B Group. Distinct
geographic distributions of hepatitis B virus genotypes in patients with acute infection in Japan. J
Med Virol. 77: 39-46, 2005.
18) Koike K. Hepatitis C virus infection presenting
with metabolic disease by inducing insulin resistance. Intervirology 2006;49:51-57.
19) Koike K, Miyoshi H. Oxidative stress and hepatitis
C viral infection. Hepatol Res 2006;34:65-76.
20) Nukui Y, Tajima S, Kotaki A, Ito M, Takasaki T,
Koike K, Kurane I. Novel dengue virus type 1 fromtravelers to Yap State, Micronesia. Emerg Infect
Dis 2006;12(2): 343-346.
21) Koike K. Oxidative stress and apoptosis in hepatitis
C: the core issue. J Gastroenterology 2006 inpress.
22) Matsuoka-Aizawa S, Gatanaga H, Sato H, Koike K,
Kimura K, Oka S. Gag substitutions responsible for
nelfinavir-dependent enhancement of precursor
cleavage and human immunodeficiency virus
type-1 replication. Virus Res 2006 Feb 3; [Epubahead of print]23) Koike K. Pathogenesis of HCV-associated HCC:
dual-pass carcinogenesis through the activation ofoxidative stress and intracellular signaling. Hepatol Res 2006 in press.
24) Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol
Hepatol 2006 in press.

25) Okuse C, Yotsuyanagi H, Nagase Y, Kobayashi Y,
Yasuda Y, Koike K, Iino S, Suzuki M, Itoh F. Risk
Factors for Retinopathy Associated with Interferon
Alpha-2b and Ribavirin Combination Therapy inPatients with Chronic Hepatitis C. World J Gastroenterol 2006 in press.

Pathology, Immunology andMicrobiology
3. Immunology⑧

56

Department of Immunology
Professor
Tadatsugu Taniguchi,Ph.D.

Lecturer
Akinori Takaoka, M.D., Ph.D.

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

Hideyuki Yanai, Ph.D.

Homepage http://www.m.u-tokyo.ac.jp/mcm/
Introduction and Organization
The Department of Immunology was formerly called the Department of Serology, which
has a history going back to 1918. The department was changed to its present name, when Dr.
Tomio Tada, now Professor Emeritus of The
University of Tokyo, took his position in 1977
as the professor and chair of the department. Dr.
Tada has made great contributions that madethis department world-renowned, through hisinnovative research as well as his great contributions to the international community of immunologists. After his retirement in 1994, webasically followed the tradition of the department established by Dr. Tada and tried to improve it further, in terms of providing highstandard education to students and cutting-edge
research in immunology worldwide. Research
projects currently being conducted began withthe original identification of two cytokine genes
and their characterization between the late1970s and the early 1980s, namely, the genes
encoding human fibroblast interferon (nowknown as IFN- ) and interleukin-2 (IL-2).
These initial studies have led us to further
characterization of these cytokine systems in
the context of the regulation of immunity andoncogenesis. One of our major contributions isthe discovery and characterization of a new
family of transcription factors, termed interferon regulatory factors (IRFs). Our current research interests are aimed at clarifying thefunction and regulation of the IRF family oftranscription factors in oncogenesis and immunity. As a part of our scientific and educational
activities, we organize many seminars by inviting distinguished scientists from all over theworld..

Teaching activities
Our teaching responsibility is to provide lectures on immunobiology, immunochemistry andmolecular immunology to the undergraduate
students of the faculty. It is also our responsibility to provide laboratory courses on basic
immunology to students. In addition to lecturesand laboratory courses provided by our own
staff members, special lectures are also given
by guest experts. We also offer a special training course (called ‘free quarter’) of basic andadvanced biological and immunological techniques to medical students. The education of
graduate students is based on weekly conferences during which the students present the
progress of their own research projects anddiscuss on their future directions. Lectures on

57leading research activities are given by active
researchers from overseas whenever they visit
our department. The students may gain a profound interest in the field through these lectures.

Research activities
Our research field includes cellular and molecular immunology in general. Once an immune response is initiated by an antigenic
stimulus, the magnitude of the response is controlled by the complex mechanisms. We havebeen extensively analyzing mechanisms thatfunction in the regulation of gene expression
and signal transduction in host defense systems.
In particular, we focus on the molecularmechanisms underlying host defense against
viral and bacterial infections. Among thesemechanisms, the interferon (IFN) system is themost powerful and important for the control ofsuch infections. During the course of the study,
we have identified the interferon regulatory
factor (IRF) family, which play critical roles in
immunity. Most notably, studies of IRFs haverevealed their remarkable functional diversity
in regulating the immune systems, in particular,
as the key regulators of the TLR-induced immune response. We showed that the transcription factor IRF-7 is essential for both the virus-activated MyD88-independent pathway as
well as the TLR-activated MyD88-dependent
pathway of IFN-α/βgene induction. Furthermore, we found that the MyD88-dependent IFN
induction pathway activated in plasmacytoid
dendritic cells (pDCs) by the TLR9 family isentirely IRF-7-dependent and this MyD88IRF-7 pathway is critical to the induction of
CD8+ T cell response in vivo. The highIFN-α/β production in plasmacytoid dendritic
cells (pDCs) induced by the stimulation of the
TLR9 subfamily is dependent on the MyD88IRF-7 signalling pathway; however, it remained
unknown until recently how and why pDCs, but
not other cell types such as conventional DCs(cDCs), achieve the activation of this pathway.
We found that the endosomal persistence of

MyD88-IRF-7 signalling critically determines
the unique ability of pDCs to produce large
amounts of IFN-α/β. This ingenious spatial
regulation of signalling in pDCs represents a
distinct response to pathogen-associated nucleic
acids that could be exploited for the manipulation of immune responses.
We also found that RF-5 is essential for the
MyD88-dependent gene induction program,which is commonly activated by TLRs. IRF-5
interacts with and is activated by MyD88 and
TRAF6, and that TLR activation results in the
nuclear translocation of IRF-5 to activate cytokine gene transcription. Thus, our study identified IRF-5 as a new, principal downstream
regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses.
More recently, we found that IRF-4 functions
as a negative regulator of IRF-5 by competingwith IRF-5 for MyD88 interaction. Work is inprogress to elucidate further the mechanism ofactivation of IRF-5, as well as its role inanti-tumor immune responses.

References
1. Honda, K., Yanai, H., Takaoka, A., and Taniguchi,T.; Regulation of the type I IFN induction: a current view. (2005) Int Immunol, Nov; 17(11):136778. Epub 2005 Oct 7.
2. Negishi, H., Ohba, Y., Yanai, H., Takaoka, A.,
Honma, K., Yui, K., Matsuyama, T., Taniguchi, T.,
and Honda, K.; Negative regulation of Tolllike-receptor signaling by IRF-4. (2005) Proc Natl
Acad Sci U S A., Nov 1; 102(44): 15989-94.
3. Takayanagi, H., Sato, K., Takaoka, A., and Taniguchi, T.; Interplay between interferon and othercytokine systems in bone metabolism. (2005)
Immunol Rev, 181-93.
4. Honda, K., Ohba, Y., Yanai, H., Negishi, H., Mizutani, T., Takaoka, A., Taya, C., and Taniguchi,T.; Spatiotemporal regulation of MmyD88-IRF-7
signalling for robust type I interferon induction.
(2005) Nature, 434, 1035-1040.
5. Honda, K., Yanai, H., Negishi, H., Asagiri, M.,

58

Sato, M., Mizutani, T., Shimada, N., Ohba, Y.,
Takaoka, A., Yoshida, N., and Taniguchi, T.;
IRF-7 is the master regulator of type-I interferon-dependent immune responses. (2005) Nature 434, 772–777.
6. Takaoka, A., Yanai, H., Kondo, S., Duncan, G.,
Negishi, H., Mizutani, T., Kano, S., Honda, K.,
Ohba, Y., Mak, T.M., and Taniguchi, T.; Integralrole of IRF-5 in the gene induction programme
activated by Toll-like receptors. (2005) Nature,434, 243-249.
7. Taniguchi, T., and Takaoka, A.; Type I interferonsystem and IRF family of transcription factors inhost defense regulation. (2005) Proc. Jpn. Acad.
81, 1-13.
8. Honda, K., Mizutani, T., and Taniguchi, T.; Negative regulation of IFN-α/β signaling by IFN regulator factor 2 for homeostatic development ofdendritic cells. (2004) Proc.Natl. Acad. Sci. USA,101, 2416-2421.

Radiology and Biomedical
Engineering
1. Radiology⑨

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.

Shigeki Aoki, M.D.,Ph.D.,

Lecturer
Osamu Abe, M.D.,Ph.D.,
Masaaki Akahane, M.D.,

Masao Tago, M.D.,Ph.D.
Yoshitaka Masutani, Ph.D.

Associate
Hisao Koga, M.D.,
Hiroshi Igaki, M.D.,Ph.D,
Nobuyuki Kato, M.D.,

Haruyasu Yamada, M.D.,Ph.D.,
Harushi Mori, M.D.,
Naoki Nakamura, M.D.

Homepage http://www.m.u-tokyo.ac.jp/mcm/
Introduction and Organization
Department of Radiology was established in 1932.
Radiology covers three major fields that are, Diagnostic Radiology (imaging and intervention), Radiation
Oncology (radiotherapy) and Nuclear Medicine. The
clinical, educational and research activities of our department are being carried out in cooperation with
Department of Radiology in The Research Institute ofMedical Science, which has three (1 associate professor, 1 lecturer, and 1 associate) positions. In addition,
Department of Radiology 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 by diagnostic radiologists. Diagnostic radiologists, gastro-

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

61

Teaching activities
Lectures are given to the fourth-, fifth- andsixth-year students to provide fundamental knowledgeof diagnostic radiology, radiation oncology and nuclear 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 bedside-learning (BSL) curriculum, sixteen small groupsof the fifth-year students are taking part in mini-lectures and practice to learn basics of diagnostic radiology for one week. For the sixth-year students, another week of small group training and mini-lectures
are prepared to learn 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 of radiology according to their interests.

Research activities
Research activities in our department include clinical research, animal experiments and development of
instruments as well as computer-based new technology. Diagnostic Radiology group in the department
promotes research activities aiming at efficacy improvement of diagnostic imaging and expansion of its
application. Multi-row detector helical computed tomography (MDCT) enables us to take tomographic
images in three-dimensional (3D) fashion. Using thedata acquired by MDCT various kinds of diseases inalmost all parts of the body, from cerebral diseases tomusculoskeletal diseases, can be displayed in 3D images. New 3D software developed in 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 the Faculty of Engineering,
the University of Tokyo. This section will contributeto development of novel softwares to abstract clinically useful information from the 3D imaging data
more sophisticatedly. In the field of magnetic reso-

nance (MR) imaging, MR digital subtraction angiography, perfusion imaging, and diffusion tensor
imaging are the foci of research. These techniques areaggressively applied to the investigation of vascularand neoplastic diseases of the brain. Application of an
open-type MR imaging unit to interventional radiology is another field of clinical research. In our section,
MR imaging is specifically used to the treatment ofvascular malformation. Basic animal experiments arealso in progress in the field of functional MR imaging
and diffusion and perfusion MR techniques.
Radiation oncology group promotes research projects in two major fields, one is physical engineering
aspect of radiotherapy and the other is reduction of
injuries due to radiation exposure. With the purpose ofachieving precise external irradiation, a new linear
accelerator with C-arm and multileaf collimator systems was developed and installed, which is utilized
mainly for non-coplanar radiation therapy in many
patients especially with brain tumor or head and necktumor. Dynamic conical conformal radiotherapy (Dyconic therapy) for metastatic brain tumors using theaccelerator is under evaluation. In addition to gamma
knife radiosurgery, this new accelerator based stereotactic radiotherapy for brain diseases has been undergone, and stereotactic radiotherapy for body tumors,such as lung and liver tumors, has been investigated. A
new technology to track mobile tumors, represented
by lung tumors is under investigation in collaboration
with accelerator makers. Novel approach to terminal
care of patients with various cancers has been investigated and implemented as the palliative care team incooperation with expert nurses. The relationship between terminal condition and cytokines, and newly
developed scoring system of quality of life are being
evaluated. The gustatory injury due to radiotherapy
has been investigated through animal experiments incombination with the laboratory of biological function,
Graduate School of Agricultural and Life Sciences,
University of Tokyo, and through taste tests inclinical setting. Radiation injuries in many tissues in
the critically accident in Tokai-mura were also investigated.
Nuclear Medicine group promote clinical researchon images of function by the application of radioisotope-labeled tracer technology. In particular, emission
tomography (PET and SPECT) is applied for the62evaluation of cerebral blood flow and metabolism inpatients with dementia, epilepsy, and cerebrovasculardiseases. Cerebral blood flow, glucose metabolism andneural synaptic functions are measured for the understanding of normal and pathophysiological states of
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 and [C-11] raclopride. The study of 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 for investigation. At present, whole body FDG-PET is one of
the most effective tool for exploring metastatic lesionsof cancer patients. Combination display of SPECT/PET with XCT/MRI would be a routine job andanatomo-functional images would play an importantrole in the clinical management of the patients.

References
1) Abe O, Masutani Y, Aoki S, Yamasue H, Yamada
H, Kasai K, Mori H, Hayashi N, Masumoto T,
Ohtomo K.
Topography of the human corpus callosum using
diffusion tensor tractography. Journal of Computer Assisted Tomography 28(4): 533-539, 2004
2) Abe O, Mori H, Aoki S, Kunimatsu A, Hayashi N,
Masumoto T, Yamada H, Masutani Y, Kabasawa
H, Ohtomo K. Periodically rotated overlapping
parallel lines with enhanced reconstruction-based
diffusion tensor imaging: comparison with echo
planar imaging-based diffusion tensor imaging.
Journal of Computer Assisted Tomography 28(5):654-660, 2004

3) Abe O, Yamada H, Masutani Y, Aoki S, Kunimatsu A, Yamasue H, Fukuda R, Kasai K, Hayashi N, Masumoto T, Mori H, Soma T, Ohtomo
K.Amyotrophic lateral sclerosis: diffusion tensor
tractography and voxel-based analysis. NMR in
Biomedicine 17(6): 411-416, 2004
4) Akahane M, Koga H, Kato N, Yamada H, Uozumi
K, Tateishi R, Teratani T, Shiina S, Ohtomo K.
Complications of percutaneous radiofrequency
ablation for hepatocellular carcinoma: imaging
spectrum and management. Radiographics, 25(supplment 1): 57-68, 2005
5) Chiba T, Tokuuye K, Matsuzaki Y, Sugahara S,
Chuganji Y, Kagei K, Shoda J, Hata M, Abei M,
Igaki H, Tanaka N, Akine Y. Proton beam therapy
for hepatocellular carcinoma: a retrospective review of 162 patients. Clinal Cancer Research11(10): 3799-3805, 2005
6) Furuya K, Kawahara N, Morita A, Momose T,
Aoki S, Kirino T. Focal hyperperfusion after superficial temporal artery-middle cerebral arteryanastomosis in a patient with moyamoya disease.
Journal of Neurosurgery 100(1): 128-132, 2004
7) Hanajiri K, Mitsui H, Maruyama T, Kondo Y,
Shiina S, Omata M, Nakagawa K. 18F-FDG PET
for hepatocellular carcinoma presenting with portal vein tumor thrombus. Journal of Gastroenterology 40(10): 1005-1006, 2005
8) Hasegawa K, Imamura H, Akahane M, Miura Y,
Kiryu S, Ohtomo K, Makuuchi M. Administrationof iodized oil resulted in impaired liver function
due to enhanced portosystemic shunting. Cardiovascular and Interventional Radiology 27(3):282-284, 2004
9) Hata M, Tokuuye K, Sugahara S, Kagei K, Igaki
H, Hashimoto T, Ohara K, Matsuzaki Y, Tanaka N,
Akine Y. Proton beam therapy for hepatocellular
carcinoma with portal vein tumor thrombus. Cancer 104(4): 794-801, 2005
10) Hayashi N, Watanabe Y, Masumoto T, Mori H,
Ohtomo K, Okitsu O, Takahashi T. Utilization of
low-field MR scanners. Magnetic Resonance in
Medical Science 3(1): 27-38, 2004
11) Hosoi Y, Watanabe T, Nakagawa K, Matsumoto Y,
Enomoto A, Morita A, Nagawa H, Suzuki N.
Up-regulation of DNA-dependent protein kinase
activity and Sp1 in colorectal cancer. International

63

Journal of Oncology 25(2): 461-468, 2004
12) Igaki H, Tokuuye K, Okumura T, Sugahara S,
Kagei K, Hata M, Ohara K, Hashimoto T, Tsuboi
K, Takano S, Matsumura A, Akine Y. Clinical results of proton beam therapy for skull base chordoma. International Journal of Radiation Oncology, Biology and Physics 60(4): 1120-1126, 2004
13) Igaki H, Karasawa K, Sakamaki H, Saito H, Nakagawa K, Ohtomo K, Tanaka Y. Renal dysfunction after total-body irradiation significance of
selective renal shielding blocks. Strahlentherapie
und Onkologie 181(11): 704-708, 2005
14) Inoue T, Kawahara N, Shibahara J, Masumoto T,
Usami K, Kirino T. Extradural neurenteric cyst of
the cerebellopontine angle. Case report. Journal of
Neurosurgery 100(6): 1091-1093, 2004
15) Inoue Y, Kurimoto S, Kameyama S, Ohta N,
Akahane M, Yoshikawa K, Yokoyama I, Minami
M, Ohtomo K, Kitamura T. Prolonged renal parenchymal retention of 99mTc-MAG3 after nephronsparing surgery. Nuclear Medicine Communications 25(5): 509-513, 2004
16) Inoue Y, Minami M, Ohtomo K. Isotopic scan for
diagnosis of renal disease. Saudi Journal of Kidney Diseases and Trans-plantation 15: 257-264,
200417) Inoue Y, Shirouzu I, Machida T, Yoshizawa Y,
Akita F, Minami M, Ohtomo K. Collimator choicein cardiac SPECT with I-123-labeled tracers.
Journal of Nuclear Cardiology 11(4): 433-439,
200418) Inoue Y, Nomura Y, Nakaoka T, Watanabe M,
Kiryu S, Okubo T, Ohtomo K. Effect of temporal
resolution on the estimation of left ventricularfunction by cardiac MR imaging. Magnetic
Resonance Imaging 23(5): 641-645, 200519) Ito K, Momose T, Oku S, Ishimoto S, Yamasoba T,
Sugasawa M, Kaga K. Cortical activation shortly
after cochlear implantation. Audiology and
Neuro-Otology 9(5): 282-293, 200420) Iwase S, Murakami T, Saito Y, Nakagawa K.
Steep elevation of blood interleukin-6 (IL-6) associated only with late stages of cachexia in cancer patients. European Cytokine Network 15(4):312-316, 2004
21) Kaga K, Nakamura M, Takayama Y, Momose T. A
case of cortical deafness and anarthria. Acta

Oto-Laryngologica 124(2): 201-205, 2004
22) Kamada K, Todo T, Masutani Y, Aoki S, Ino K,
Takano T, Kirino T, Kawahara N, Morita A. Combined use of tractography-integrated functional
neuronavigation and direct fiber stimulation.
Journal of Neurosurgery 102(4): 664-672, 200523) Kanda Y, Komatsu Y, Akahane M, Kojima S,
Asano-Mori Y, Tada M, Oshima K, Isayama H,
Ogawa S, Motokura T, Chiba S, Ohtomo K,
Omata M, Hirai H. Graft-versus-tumor effectagainst advanced pancreatic cancer after allogeneic reduced-intensity stem cell transplantation.
Transplantation 79(7): 821-827, 200524) Karino S, Hayashi N, Aoki S, Ohtomo K, Yamasoba T. New method of using reconstructed
images for assessment of patency of intracochlear
spaces for cochlear implant candidates.The Laryngoscope 114(7): 1253-1258, 2004
25) Kashiwagi K, Okubo T, Tsukahara S. Associationof magnetic resonance imaging of anterior optic
pathway with glaucomatous visual field damage
and optic disc cupping. Journal of Glaucoma
13(3): 189-195, 2004
26) Kazama Y, Watanabe T, Akahane M, Yoshioka N,
Ohtomo K, Nagawa H. Crohn's disease withlife-threatening hemorrhage from terminal ileum:
successful control by superselective arterial embolization. Journal of Gastroenterology 40(12):1155-1157, 200527) Koga K, Osuga Y, Harada M, Hirota Y, Yamada H,
Akahane M, Kugu K, Taketani Y. Sciatic endometriosis diagnosed by computerized tomography-guided biopsy and CD10 immunohistochemical staining. Fertility and Sterility 84(5):1508, 200528) Koike A, Hashimoto M, Nagayama O, Tajima A,
Kubozono T, Oikawa K, Uejima T, Momose T,
Aizawa T, Fu LT, Ito H. Cerebral oxygenation
during exercise and exercise recovery in patientswith idiopathic dilated cardiomyopathy. The
American Journal of Cardiology 94(6): 821-824,
200429) Komiyama S, Taniguchi S, Matsumoto Y, Tsunoda
E, Ohto T, Suzuki Y, Yin HL, Tomita M, Enomoto
A, Morita A, Suzuki T, Ohtomo K, Hosoi Y, Suzuki N. Potentiality of DNA-dependent protein
kinase to phosphorylate Ser46 of human p53.

64

BBRC. Biochemical and Biophysical ResearchCommunication 323(3): 816-822, 200430) Kunimatsu A, Aoki S, Masutani Y, Abe O, Hayashi N, Mori H, Masumoto T, Ohtomo K. The optimal trackability threshold of fractional anisotropy for diffusion tensor tractography of the corticospinal tract. Magnetic Resonance in Medical
Sciences 3(1): 11-17, 200431) Kunimatsu N, Kunimatsu A, Kojima K, Hirabayasi Y, Ohtomo K. A Case of Renal Angioleiomyoma with Rapid Growing: CT Findings with
Histopathological Correlation. Radiation Medicine 22(6): 437-441, 200432) Maeda E, Akahane M, Inoue Y, Watadani T, Jo D,
Kato J, Minami M, Ohtomo K. An unusual enhancing pelvic lesion. European Radiology 15(9):2041-2042, 200533) Maeda E, Akahane M, Inoue Y, Watadani T, Jo D,
Kato J, Minami M, Ohtomo K. Delayed enhancement of pelvic lymphangiomyoma associated with lymphangioleiomyomatosis on MR imaging (2005: 9b). European Radiology 15(12):2528-2531, 200534) Maruyama K, Kamada K, Shin M, Itoh D, Aoki S,
Masutani Y, Tago M, Kirino T. Integration of
three-dimensional corticospinal tractography into
the treatment planning in gamma knife radiosurgery. Technical note. Journal of Neurosurgery
102(4): 673-677, 200535) Mayahara H, Oda Y, Kawaguchi A, Kagawa K,
Murakami M, Hishikawa Y, Igaki H, Tokuuye K,
Abe M. A case of hepatocellular carcinoma initially treated by carbon ions, followed by protons
for marginal recurrence with portal thrombus. Radiation Medicine 23(7): 513-519, 200536) Mori H, Aoki S, Abe O, Hayashi N, Masumoto T,
Yoshikawa T, Ohtomo K, Hirakawa N, Ugawa Y.
Non-homogeneous increased intensity of the cortex on PROPELLER DW MRI in CreutzfeldtJakob disease.
Rivista di Neuroradiologia 17(1): 13-16, 200437) Mori H, Masutani Y, Abe O, Aoki S, Hayashi N,
Masumoto T, Yoshikawa K, Yamada H, Ohtomo K.
Visualization of central nervous system nerve
communications using diffusion tensor imaging.
Rivista di Neuroradiologia 17(2): 135-144, 200438) Mori H, Aoki S, Ohtomo K. Mortion artifact

mimicking the pulvinar sing. Rivista di Neuroradiologia 17(5): 659-660, 200439) Mori H, Aoki S, Abe O, Hayashi N, Masutani Y,
Ohtomo K, Oya S, Morita A. Diffusion property
following
functional
hemispherectomy inhemimegalencephaly. Acta Radiologica 45(7):778-781, 2004
40) Nakagawa K. Current status and future prospectsof radiation therapy and medical accelerator. Proceedings of the 1st annual meeting of particle accelerator society of Japan and the 29th linear accelerator meeting of Japan: 25-29, 2004
41) Nakagawa K, Fukuhara N, Kawakami H. A
packed building-block compensator (TETRIS-RT)
and feasibility for IMRT delivery. Medical Physics 32(7): 2231-2235, 200542) Nakagawa K, Koyanagi H, Shiraki T, Saegusa S,
Sasaki K, Oritate T, Mima K, Miyazawa M, Ishidoya T, Ohtomo K, Yoda K. A radiophotoluminescent glass plate system for medium-sized field
dosimetry. Review of Scientific Instruments
76(10): 106104(4pages), 2005
43) Nakagawa K, Yamashita H, Shiraishi K, Nakamura N, Tago M, Igaki H, Hosoi Y, Shiina S,
Omata M, Makuuchi M, Ohtomo K. Radiation
therapy for portal venous invasion by hepatocellular carcinoma. World Journal of Gastroenterology 11(46): 7237-7241, 200544) Nakagawa S, Yano T, Nakagawa K, Tanizawa S,
Suzuki Y, Yasugi T, Huibregtse J, Taketani Y.
Analysis of the expression and localization of a
LAP protein, human scribble, in the normal andneoplatic epithelium of uterine cervix. British
Journal of Cancer 90(1): 194-199, 200445) Ohara K, Tanaka YO, Tsunoda H, Oki A, Satoh T,
Onishi K, Kagei K, Sugahara S, Hata M, Igaki H,
Tokuuye K, Akine Y, Yoshikawa H. Preliminary
estimation of treatment effect on uterine cervicalsquamous cell carcinoma in terms of tumor regression rate: comparison between chemoradiotherapy and radiotherapy alone. Radiation Medicine 23(1): 25-29, 200546) Omura K, Tsukamoto T, Kotani Y, Ohgami Y,
Minami M, Inoue Y. Different mechanisms involved in interhemispheric transfer of visuomotor
information. NeuroReport 15(18): 2707-2711,
2004

65

47) Sakai M, Inoue Y, Oba H, Ishiguro A, Sekiguchi
K, Tsykune T, Mitomo M. Age-dependence ofdiffusion-weighted magnetic resonance imaging
findings in maple syrup urine disease encephalopathy. Journal of Computer Assisted Tomography
29(4): 524-527, 2005
48) Sato S, Shiratori Y, Imamura M, Obi S, Shiina S,
Akahane M, Ohtomo K, Omata M. Re-appearanceof power Doppler signals in the tumor nodules ofhepatocellular carcinoma after transarterial embolization reflects residual viable tumor cells:
histological confirmation. Hepato- Gastroenterology
51(55): 56-61, 200449) Sekino M, Inoue Y, Ueno S. Magnetic resonanceimaging of electrical conductivity in the humanbrain. IEEE Transactions on Magnetics 41(10):4203-4205, 2005
50) Shibahara J, Todo T, Morita A, Mori H, Aoki S,
Fukayama M. Papillary neuroepithelial tumor of
the pineal region. A case report. Acta Neuropathologica 108(4): 337-340, 2004
51) Shin M, Maruyama K, Kurita H, Kawamoto S,
Tago M, Terahara A, Morita A, Ueki K, Takakura
K, Kirino T. Analysis of nidus obliteration rates
after gamma knife surgery for arteriovenous malformations based on long-term follow-up data: theUniversity of Tokyo experience. Journal of Neurosurgery 101(1): 18-24, 2004
52) Shin M, Kawahara N, Maruyama K, Tago M,
Ueki K, Kirino T. Risk of hemorrhage from an arteriovenous malformation confirmed to have been
obliterated on angiography after stereotactic radiosurgery. Journal of Neurosurgery 102(5): 842846, 200553) Shinohara K, Nakano H, Miyazaki N, Tago M,
Kodama R. Effects of single-pulse (< 1 ps) X-rays
from laser-produced plasmas on mammalian cells.
Journal of Radiation Research 45(4): 509-514,
200454) Suzuki J, Tomidokoro A, Araie M, Tomita G, Yamagami J, Okubo T, Masumoto T. Visual fielddamage in normal-tension glaucoma patients withor without ischemic changes in cerebral magnetic
resonance imaging. Japanese Journal of Ophthalmology 48(4): 340-344, 2004
55) Takahashi M, Momose T, Kameyama M, Mizuno
S, Kumakura Y, Ohtomo K. Detection of cerebro-

spinal fluid leakage in intracranial hypotension
with radionuclide cisternography and blood activity monitoring. Annals of Nuclear Medicine 19(4):339-343, 2005
56) Takao H, Momose T, Ohtomo K. Methionine andglucose metabolism of central neurocytomq: a
PET study. Clinical Nuclear Medicine 29(12):838-839, 2004
57) Tanaka M, Ino Y, Nakagawa K, Tago M, Todo T.
High-dose conformal radiotherapy for supratentorial malignant glioma: a historical comparison.
The Lancet Oncology 6(12): 953-960, 200558) Tani K, Azuma M, Nakazaki Y, Oyaizu N, Hase H,
Ohata J, Takahashi K, OiwaMonna M, Hanazawa
K, Wakumoto Y, Kawai K, Noguchi M, Soda Y,
Kunisaki R, Watari K, Takahashi S, Machida U,
Satoh N, Tojo A, Maekawa T, Eriguchi M, Tomikawa S, Tahara H, Inoue Y, Yoshikawa H, Yamada
Y, Iwamoto A, Hamada H, Yamashita N, Okumura
K, Kakizoe T, Akaza H, Fujime M, Clift S, Ando
D, Mulligan R, Asano S. Phase I study of autologous tumor vaccines transduced with the GM-CSF
gene in four patients with stage IV renal cell cancer in Japan: clinical and immunological findings.
Molecular Therapy 10(4): 799-816, 2004
59) Toda N, Akahane M, Kiryu S, Matsubara Y, Yamaji Y, Okamoto M, Minagawa N, Ohgi K, Komatsu Y, Yahagi N, Yoshida H, Kawabe T, Ohtomo K, Omata M. Pancreas duct abnormalities inpatients with ulcerative colitis: a magnetic resonance pancreatography study. Inflammatory
Bowel Disease, 11(10): 903-908, 2005
60) Uozaki H, Fukayama M, Nakagawa K, Ishikawa T,
Misawa S, Doi M, Maekawa K. The pathology ofmulti-organ involvement: two autopsy cases fromthe Tokai-mura criticality accident. The Britishi
Journal of Radiology 78(supplment 27): 13-16,
200561) Yamamoto K, Komiyama T, Miyata T, Kitagawa T,
Momose T, Shigemtsu H, Nagawa H. Contralateral stenosis as a risk factor for carotid endoarterectomy measured by near infrared spectroscopy.
International Angiology 23(4): 388-93, 2004
62) Yamashita H, Nakagawa K, Tago M, Shiraishi K,
Nakamura N, Ohtomo K, Oda K, Nakagawa S,
Yasugi T, Taketani Y. Comparison between conventional surgery and radiotherapy for FIGO stage

66

I-II cervical carcinoma: a retrospective Japanesestudy. Gynecologic Oncology 97(3): 834-839,
200563) Yamashita H, Nakagawa K, Tago M, Nakamura N,
Shiraishi K, Ohtomo K.Salvage radiotherapy for
postoperative loco-regional recurrence of esophageal cancer. Diseases of the Esophagus 18(4):215-220, 2005
64) Yamashita H, Nakagawa K, Tago M, Shiraishi K,
Nakamura N, Ohtomo K. Treatment results andprognostic analysis of radical radiotherapy for locally advanced cancer of the uterine cervix. British Journal of Radiology 78(933): 821-826, 2005
65) Yamashita H, Nakagawa K, Tago M, Nakamura N,
Shiraishi K, Yamauchi N, Ohtomo K. Pathologicalchanges after radiotherapy for primary pituitarycarcinoma: a case report. Journal of Neurooncology 75(2): 209-214, 2005
66) Yamashita H, Nakagawa K, Tago M, Igaki H,
Nakamura N, Shiraishi K, Sasano N, Ohtomo K.
The experience of concurrent chemoradiation forJapanese patients with superficial esophageal
squamous cell carcinoma: a retrospective study.
American Journal of Clinical Oncology 28(6):555-559, 2005
67) Yamasue H, Yamada H, Yumoto M, Kamio S,
Kudo N, Uetsuki M, Abe O, Fukuda R, Aoki S,
Ohtomo K, Iwanami A, Kato N, Kasai K. Abnormal association between reduced magnetic mismatch field to speech sounds and smaller left
planum temporale volume in schizophrenia.
NeuroImage 22(2): 720-727, 2004
68) Yamasue H, Iwanami A, Hirayasu Y, Yamada H,
Abe O, Kuroki N, Fukuda R, Tsujii K, Aoki S,
Ohtomo K, Kato N, Kasai K. Localized volume
reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study. Psychiatry Research:Neuroimaging
131(3): 195-207, 2004
69) Yin HL, Suzuki Y, Matsumoto Y, Tomita M, Furusawa Y, Enomoto A, Morita A, Aoki M, YatagaiF, Suzuki T, Hosoi Y, Ohtomo K, Suzuki N. Radiosensitization by hyperthermia in the chicken
B-lymphocyte cell line DT40 and its derivatives
lacking nonhomologous end joining and/or homologous recombination pathways of DNA double-strand break repair. Radiation Research 162(4): 433-441, 2004
70) Yokoyama I, Inoue Y, Moritan T, Ohtomo K, Nagai R. Impaired myocardial vasodilatation duringhyperaemic stress is improved by simvastatin but
not by pravastatin in patients with hypercholesterolaemia. European Heart Journal 25(8): 671679, 2004
71) Yoshikawa K, Inoue Y, Shimada M, Akahane M,
Itoh S, Seno A, Hayashi S. Contrast-enhanced MR
angiography in rats with hepatobiliary contrast
agents. Magnetic Resonance Imaging 22(7): 937942, 2004

Radiology and Biomedical
Engineering
2. Biomedical Engineering⑩

68

Department of
System Physiology
Professor
Joji Ando, M.D.,Ph.D.

Lecturer
Masahiro Shibata, Ph.D.,

Kimiko Yamamoto, M.D.,Ph.D.

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

Research activities

Our department originated from the Institute ofMedical Electronics, established in 1961. In 1997, as aresult of the shift to the chair system of the Graduate
School of Medicine, the Institute was replaced withthree departments of Biomedical Engineering: System
Physiology, Bioimaging and Biomagnetics, and Biosystem Construction and Control. The Department of
System Physiology consists of one professor and two
lecturers.

This laboratory has been pursuing the study of biomechanics dealing with mechanical phenomena in thehuman body, especially focusing on cellular sensing
and response mechanisms to mechanical stimuli. The
main theme of our work is the relationships between
shear stress, a mechanical force generated by blood
flow, and its target cells, vascular endothelial cells. This
would be of benefit not only to understanding blood
flow-mediated regulation of vascular functions but also
to the elucidation of clinically important problems suchas angiogenesis, vascular remodeling and atherogenesis
which occur in a blood flow-dependent manner.
Original biomedical engineering methods have been
applied, in which cultured endothelial cells are exposed
to controlled levels of shear stress in a fluid–dynamic
flow apparatus and whose responses are analyzed at thecellular and molecular levels. Microcirculatory hemodynamics and oxygen transport are studied by employing opto-electronics technology. The results of theseexperiments are listed below.

Teaching activities
We provide lectures of “Early Exposure to Medicine”
for second year students, “Basic Principles of Biomedical Engineering” for second and third year students, “Introduction to Biomedical Engineering” forpostgraduate students in the faculty of Medicine, and“Principles of Medicine” for postgraduate students inthe faculty of Engineering. We offer practical trainingof biomedical engineering research to third and fourthyear medical students. A weekly seminar is held in ourlaboratory bringing together staff, postgraduate students
and research fellows to discuss journal articles and give
updates on experiments. Our aim is to enhance the research skills of students.

1. Cell responses to shear stress
2. Shear stress-mediated gene regulation
3. Shear stress signal transduction
4. Oxygen dynamics and microvascular energetics

69

1. Cell responses to shear stress
Our studies have demonstrated that endothelial cells
have functional responses to shear stress. When a cultured endothelial cell monolayer was partially denuded,
surrounding cells migrated and proliferated in the denuded area, and covered the denuded area. Shear stressenhanced the regenerative functions of endothelial cells(Microvasc Res 1987, Biorheology, 1990). Shear stressincreased the production of nitric oxide, a potent vasodilator, in endothelial cells in a dose-dependent manner(BBRC 1994). Shear stress also increased the expression of thrombomodulin, an antithrombotic molecule,in endothelial cells (BBRC 1994). In contrast, it decreased the expression of vascular cell adhesion, whichleads to the inhibition of leukocyte adhesion to vascularcell adhesion molecule-1 (VCAM-1; BBRC 1993, Am J
Physiol 1994). A collaborative study showed that shear
stress increases the levels of adrenomedulin and C-typenatriuretic peptide mRNA which have vasodilating effects in addition to nitric oxide (Hypertension 1997),
and that it also augmented the expression of lectin likelow density lipoprotein receptor (LOX-1) at the protein
and mRNA level (Circ Res 1998). Recently, we revealed that endothelial progenitor cells (EPCs) circulating in human peripheral blood proliferate and differentiate into mature endothelial cells in response to shear
stress, thereby forming tube-like structures in collagengel (J Appl Physiol 2003). We also found that shear
stress induces the differentiation of murine embryonicstem cells (ES cells) into endothelial cells in vitro (AmJ Physiol 2005). Based on these findings, in a collaborative study, a new type of artificial blood vessel, in
which ES cells were cultured in polymer tubes and exposed to pulsatile shear stress, was developed (J Artif
Organs 2005).
2. Shear stress-mediated gene regulation
We have demonstrated that shear stress regulates endothelial gene expression transcriptionally and/or posttranscriptionally. Shear stress downregulates VCAM-1
gene transcription via the double AP-1 binding element(TGACTCA) in the promoter which functions as ashear stress-responsive element (Am J Physiol 1997).
Shear stress has also been shown to increase the levelof granulocyte/macrophase-colony stimulating factor(GM-CSF) via mRNA stabilization (Circ Res 1988).
Differential display analysis showed that around 600

known and unknown transcripts were up- or
down-regulated in human umbilical vein endothelial
cells exposed to a shear stress of 15 dynes/cm2 for 6 h(BBRC 1996). From these shear stress-responsive
genes, a cDNA encoding an unknown G-protein coupled receptor was cloned (BBRC 1997). We showedthat the transcription factor SP1 is involved in the shear
stress-induced down-regulation of P2X4 (an ATP-gatedcation channel) gene expression in endothelial cells(Am J Physiol 2001). DNA microarray analysis revealed that approximately 3% of the all endothelial
genes, which corresponds to about 600 genes, respondto shear stress (J Athero Thromb 2003). Recently, we
revealed that endothelial genes are differentially regulated by laminar and turbulent shear stress. Laminarshear stress decreases the gene expression of urokinase
plasminogen activator (uPA), which plays a role in fibrinolysis and vascular remodeling, via both
GATA6-mediated down-regulation of gene transcription
and an acceleration of mRNA degradation, while turbulent shear stress increases the uPA gene expression
through mRNA stabilization (Am J Physiol 2004).
3. Shear stress signal transduction
We first showed that Ca2+ signalling plays an important role in the mechanism by which endothelial cells
recognize the shear stress signal and transmit it into thecell interior（In Vitro Cell Dev Biol 1988. Strong
shearing forces induced by dragging endothelial cellswith a balloon causes an increase in cytoplasmic Ca2+
concentrations (Biorheology 1994). A relatively weak
shearing force like shear stress generated by fluid flowneeds the presence of extracellular ATP to induce Ca2+
response, and at several hundred nanomolar of ATP,intracellular Ca2+ concentrations increase in a shear
stress-dependent manner (BBRC 1991, 1993). Generally, flow-induced Ca2+ responses are initiated at a locus at the cell edge and propagate throughout the entire
cell in the form of a Ca2+ wave. The initiation locus
corresponded precisely to caveolae rich cell edges (Proc
Natl Acad Sci 1998). We found that a subtype of
ATP-gated cation channel, the P2X4 receptor, is expressed in human vascular endothelial cells (Am J
Physiol 2000) and that P2X4 receptors play a crucialrole in the shear stress-dependent Ca2+ response (Circ
Res 2000). Endogeneously released ATP by shear stressis involved in the P2X4-mediated Ca2+ responses (Am J

70

Physiol 2003). Recently, we produced P2X4-deficient
mice and observed that the P2X4-deficent mice have
impaired flow-dependent control of vascular tone andremodeling, indicating that shear stress signal transduction via P2X4 plays a critical role in the regulation of
circulatory functions (Nat Med 2006).
4.Oxygen dynamics and microvascular energetics
For nearly 100 years, the capillary is believed to be
the sole source of oxygen supply to surrounding tissue.
By using an originally developed laser microscopic
system (Med Biol Eng Comput 1999), we found a significant downstream drop in the arteriolar oxygen level(J Appl Physiol 2001), and clarified that this drop in
oxygen was caused by oxygen supply to tissue fromarterioles (Eur J Appl Physiol 2005). Furthermore, wehave examined the effect of vessel wall oxygen consumption on the oxygen drop in arterioles. We foundthat the vascular wall oxygen consumption in functional
arterioles was more than 100 times greater than thevalues reported in in vitro experiments, and the oxygen
consumption depends on the total amount of workloadof vascular smooth muscle (Am J Physiol 2005a). We
have also studied the relationship between the endothelium derived nitric oxide and oxygen transport to tissue,and clarified the physiological role of nitric oxide as amodulator of tissue oxygenation by reducing oxygen
consumption by vessel walls (Am J Physiol 2005b).

References
1. Yamamoto K, Sokabe T, Matsumoto T, Yoshimura
K, Shibata M, Ohura N, Fukuda T, Sato T, Sekine
K, Kato S, Isshiki M, Fujita T, Kobayashi M,
Kawamura K, Masuda H, Kamiya A, Ando J. Impaired flow- dependent control of vascular tone andremodeling in P2X4-deficient mice. Nat Med.
2006;12:133-137.
2. Yamamoto K, Sokabe T, Watabe T, Miyzono K,
Yamashita JK, Obi S, Ohura N, Matsushita A,
Kamiya A, Ando J. Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells
into vascular endothelial cells in vitro. Am J
Physiol Heart Circ Physiol. 2005;288:H1915H1924.
3. Huang H, Nakayama Y, Qin K, Yamamoto K, AndoJ, Yamashita JK, Itoh H, Kanda K, Yaku H, Oka-

moto Y, Nemoto Y. Differentiation from embryonicstem cells to vascular wall cells under in vitro pulsatile flow loading. J Artif Organs. 2005;8:
110-118.
4. Chen YM, Shiraishi N, Satokawa H, Kakugo A,
Narita T, Gong JP, Osada Y, Yamamoto K, Ando J.
Cultivation of endothelial cells on adhesive protein-free synthetic polymer gels. Biomaterials.
2005;26:4588-4596.
5. Shibata M, Ichioka S, Ando J, Togawa T, Kamiya A.
Non-linear regulation of capillary perfusion in relation to ambient pO2 changes in skeletal muscle. Eur
J Appl Physiol. 2005;94:352-355.
6. Shibata M, Ichioka S, Kamiya A. Estimating oxygen consumption rates of arteriolar walls underphysiological conditions in rat skeletal muscle. Am
J Physiol Heart Circ Physiol. 2005;289:H295H300.
7. Shibata M, Ichioka S, Kamiya A. Nitric oxide
modulates oxygen consumption by arteriolar walls
in rat skeletal muscle. Am J Physiol Heart Circ
Physiol. 2005;289:H2673-H2679.
8. Ohura N, Ichioka S, Nakatsuka T, Shibata M.
Evaluating dressing materials for the prevention ofshear force in the treatment of pressure ulcers. J
Wound Care. 2005;14:401-404.
9. Asano Y, Ichioka S, Shibata M, Ando J, Nakatsuka
T. Sprouting from arteriovenous shunt vessels withincreased flow. Med Biol Eng Comput. 2005;43:
126-130.
10. Warabi E, Wada Y, Kajiwara H, Kobayashi M, Koshiba N, Hisada T, Shibata M, Ando J, Tsuchiya M,
Kodama T, Noguchi N. Effect on endothelial cellgene expression of shear stress, oxygen concentration, and low-density lipoprotein as studied by anovel flow cell culture system. Free Radic Biol
Med 2004;37:682-694.
11. Sokabe T, Yamamoto K, Ohura N, Nakatsuka H,
Qin K, Obi S, Kamiya A, Ando J. Differential
regulation of urokinase-type plasminogen activator
expression by fluid shear stress in human coronary
artery endothelial cells. Am J Physiol Heart Circ
Physiol. 2004; 287:H2027- H2034.
12. Ichioka S, Kudo S, Shibata M, Ando J, Sekiya N,
Nakatsuka T. Bone marrow cell implantation improves flap viability after ischemia-reperfusion injury. Ann Plast Surg 2004;52:414-418.

71

Department of
Bioimaging and Biomagnetics
Professor
Shoogo Ueno, Ph.D.

Associate
Masaki Sekino, Ph.D.

Homepage http://medes.m.u-tokyo.ac.jp/
Introduction and Organization
Since its establishment in 1974, the Department of
Bioimaging and Biomagnetics has been engaged in research on engineering science in medicine and biology.
We promote interaction with the international biomedical research community by hosting and collaboratingwith distinguished scientists and by participating indomestic and international conferences.

Teaching activities
The faculty and staff of the Department strive to provide the highest quality of education and research opportunities for our students. We are responsible for alecture on the fundamental engineering principles for
medical students, as well as for a lecture on biologicalengineering for engineering students at the graduatelevel. In addition to our weekly lectures, the Department has several special lectureships on biomagnetism.

Research activities
Our laboratory specializes in biomagnetic research,which includes the measurement of biomagnetic fields,
magnetic stimulation of the brain, and the effects ofmagnetic fields on biological systems. We develop, integrate, and apply new ideas through innovative interdisciplinary research approaches. Our research topics
cover wide areas in medical and biological engineering,

including technology for measurement, information
processing, and modeling in the following fields.
1. Magnetic stimulation of biological systems:• Noninvasive focal and vectorial transcranial magnetic stimulation of the human brain and nervous
system.
• Functional mapping of the human cortex by transcranial magnetic stimulation (TMS).
• Calculation and imaging of induced electric fields
and currents in the head.
• Modulation of gene expression, such as downor-up regulation of messenger RNA from repetitive
magnetic stimulation.
• Application of repetitive transcranial magnetic
stimulation (rTMS) for the treatment of central
nervous system diseases and mental illnesses.
2. Measurement of biomagnetic fields:• Utilization of superconducting quantum interference device (SQUID) to measure the very weakmagnetic fields of the brain.
• Source estimation from magnetoencphalographic(MEG) data.
• Studies of higher brain functions, such as memory,
cognition, emotion and learning, using MEG, EEG
and functional magnetic resonance imaging (fMRI).
• Source modeling of MEG and EEG activities.
3. Effects of magnetic and electromagnetic fields on
biological systems and materials:• Effects of intense magnetic fields on biologicalmaterials such as diamagnetic water, fibrin, colla-

72

gen and paramagnetic oxygen.
• Effects of magnetic and extremely low frequency(ELF) electromagnetic fields on living systems
such as developing embryos, genetic systems andintracellular signal transduction.
• Effects of pulsed and electromagnetic fields on living systems such as blood brain barrier, neuronal
information processes and carcinogenesis.
• Effects of magnetic fields on biochemical andchemical reactions.
• Applications in tissue engineering.
4. Imaging of Electrical Information Based on Magnetic Resonance Imaging (MRI):• Impedance MRI• Direct Neuronal Current MRI
In the past 2 years, our research focused on the development of functional brain dynamics imaging withhigh time resolution and high spatial resolution. The
main techniques employed were TMS (transcranial
magnetic stimulation), MEG (magnetoencephalogram),
EEG (electroencephalogram), electric current imaging
by MRI, and impedance imaging by MRI. These techniques are noninvasive and very useful for studying
higher brain functions of humans such as memory andcognition.
• Conventional MRI does not reveal information
about the electrical properties of the body. We developed new methods to visualize neuronal current
distribution and electrical-impedance distribution.
The basic principle is to erase the effects of BOLD
(blood oxygenation level dependent) by subtracting
MRI signals with different polarities of gradientmagnetic fields. Measurements were made with anecho planar imaging (EPI) sequence at 1.5 T. MRI
mapping of the neuronal currents in the brain during middle finger and thumb tapping was clearlyobserved. The basic idea of impedance imaging is
to use the shielding effects of induced eddy currents on spin precession.
• We compared current density distributions in electroconvulsive therapy (ECT) and TMS using the finite element method. In the ECT model, electric
currents were applied through electrodes with avoltage of 100 V. In the TMS model, an alternating
current was applied to a figure-eight coil so that thepeak magnetic flux density at the coil center was
0.6 T. The maximum current densities inside thebrain in ECT and TMS were 234 A/m2 and 322
A/m2, respectively. While the skull significantly
affected current distributions in ECT, TMS efficiently induced eddy currents in the brain. Our results will support clinical investigations to determine the electrode and coil positions that maximize
efficacy.
• We developed an EEG measurement system thatcombined TMS. We were able to non-invasively
evaluate the cortical reactivity and functional connections between different brain areas. We used
TMS to investigate memory encoding and retrieval,particularly the role of the dorsolateral prefrontal
cortex in associative memory for visual patterns.
TMS disrupts associative learning for abstract patterns over the right frontal area, and suggest thatthe participating cortical networks may be lateralized in accordance with classic concepts of hemispheric specialization.
• To investigate the safety aspects of TMS on thebrain, functional and anatomical changes in thebrain were investigated. Our initial experimental
results revealed that TMS does not affect the fEPSP(field excitatory post synaptic potential) of the rat
hippocampus.
We also investigated the effects of strong magnetic
fields (8T, 14T) on the structure, organization, andfunction of biological systems and materials, and thepossible medical and therapeutic applications of magnetic fields.
• Animal experimental results. (1) We investigatedthe cleavage patterns of Xenopus laevis eggs in theearly stages of development. We observed a declined third cleavage line after exposure to a horizontal strong magnetic field of 14 T. (2) The bodytemperature of rat decreased by 1 K during magnetic field exposure at 8 T. (3) Near infrared lightabsorption measurements of a rat brain understrong magnetic fields indicated an increased
population of oxygenated hemoglobin. (4) In frog
sciatic nerve experiments, nerve conduction velocity was decelerated by magnetic fields of up to 8 T.
• The effects of 14 T strong static magnetic fields onthe functional properties of biological materials,
such as proteins, oxygen molecules and water, werealso investigated. (1) A spectrum profile of hemoglobin inside red blood cells indicated conforma-

73•

tional changes depending on the magnetic flux
density. (2) Magnetic field exposure initiated platelet aggregation with the aid of collagen and accelerated the aggregation of platelets and fibrin. (3)Leukemia cell proliferation was decreased by an 8
T magnetic field, as a result of behavioural changesof dissolved oxygen during exposure. (4) Magnetic
fields inhibited bioluminescence of luciferin andluciferease in both in vitro and in vivo experiments.
Possible applications of magnetic fields for thecontrol of biochemical reactions were suggested.
We explored the possible medical applications ofmagnetically oriented collagen. Magnetically oriented collagen fibers were used to control the specific orientation of smooth muscle cells (A7r5),
bone cells (MC3T3) and nerve cells (PC12). Further experiments, however, demonstrated the magnetic orientation of adherent cells without collagenguidance after long-term exposure to static magnetic fields. Further studies must be carried our toclarify the detailed mechanisms which include thediamagnetic properties of the cells. Our findings
may lead to a clinically viable treatment of bone
fractures and bone defects.

References
1. Sekino M, Ueno S. Numerical calculation of eddy
currents in transcranial magnetic stimulation for
psychiatric treatment. Neurol Clin Neurophysiol.
2004; 88: 1-5.
2. Sekino M, Inoue Y, Ueno S. Magnetic resonanceimaging of mean values and anisotropy of electricalconductivity in the human brain. Neurol Clin Neurophysiol. 2004; 55: 1-5.
3. Nakagawa S, Imada T, Ueno S, Tonoike M. Spatiotemporal source imaging of brain magnetic fields
associated with short-term memory by linear andnonlinear optimization methods. IEEE Trans Magn.
2004; 40(2): 635-638.
4. Iramina K, Maeno T, Ueno S. Topography of EEG
responses evoked by transcranial magnetic stimulation to the cerebellum. IEEE Trans Magn. 2004;
40(4): 2982-2984.
5. Takeuchi M, Sekino M, Iriguchi N, Ueno S.
Spin-spin relaxation and apparent diffusion coefficient of magnetically oriented collagen gels. IEEE

Trans Magn. 2004;40(4): 2976-2978.
6. Ogiue-Ikeda M Ueno S. Magnetic cell orientation
depends on cell type and cell density. IEEE Trans
Magn. 2004; 40(4): 3024-3026.
7. Ogiue-Ikeda M, Sato Y, Ueno S. Destruction oftargeted cancer cells using magnetizable beads andpulsed magnetic force. IEEE Trans Magn. 2004;
40(4): 3018-3020.
8. Yamaguchi S, Ogiue-Ikeda M, Sekino M, Ueno S.
The effect of repetitive magnetic stimulation on thetumor development. IEEE Trans Magn. 2004; 40(4): 3021-3023.
9. Sekino M, Ueno S. FEM based determination of
optimum current distribution in transcranial magnetic stimulation as an alternative to electroconvulsive therapy. IEEE Trans Magn. 2004; 40(4):2167-2169.
10. Sekino M, Matsumoto T, Yamaguchi K, Iriguchi N,
Ueno S. A method for NMR imaging of a magnetic
field generated by electric current. IEEE Trans
Magn. 2004; 40(4): 2188-2190.
11. Sekino M, Yamaguchi K, Wada H, Hamakubo T,
Kodama T, Ueno S, High-resolution magnetic
resonance angiography of the rat brain: detection of
cerebral vasospasms in subarachnoid hemorrhage
models. IEEE Trans Magn. 2004; 40(4): 29732975.
12. Takashima Y, Miyakoshi J, Ikehata M, Iwasaka M,
Ueno S, Koana T. Genotoxic effects of strong static
magnetic fields in DNA-repair defective mutants ofdrosphila melanogaster. J Radiat Res.2004; 45(3):393-397.
13. Kowatari Y, Yamamoto M, Takahashi T, Kansaku K,
Kitazawa S, Ueno S, Yamane S. Dominance of theleft oblique view in activating the cortical networkfor face recognition. Neurosci Res. 2004; 50(4):475-480.
14. Funamizu H, Ogiue-Ikeda M, Mukai H, Kawato S,
Ueno S. Acute repetitive transcranial magnetic
stimulation reactivates dopaminergic system in lesion rats. Neurosci Letter (in press).
15. Hatada T, Sekino M, Ueno S. Detection of weakmagnetic fields induced by electrical currents with
MRI: theoretical and practical limits of sensitivity.
Magn Reson Med Sci. 2004; 3: 159-163.
16. Iwasaka M, Ikehata M, Miyakoshi J, Ueno S.
Strong static magnetic field effects on yeast prolif-

74eration and distribution. Bioelectrochem. 2004;
65(1): 59-68.
17. Takeuchi M, Sekino M, Iriguchi N, Ueno S. Dependence of the spin-spin relaxation time of collagen gels on collagen fiber directions. Magn Reson
Medical Sci. 2004; 3: 153-157.
18. Iwasaka M. Magnetic-field parallel motion of living cells. J Appl Phys. 2005; 97: 10Q907.
19. Hatada T, Sekino M, Ueno S. FEM-based calculation of the theoretical limit of sensitivity for detecting weak magnetic fields in the human brain
using magnetic resonance imaging. J Appl Phys.
2005; 97: 10E109.
20. Mihara H, Sekino M, Iriguchi N, Ueno S. A novel
method for an accurate T1 relaxation time measurement compensating B1 fields inhomogeneity in
MR imaging. J Appl Phys. 2005; 97: 10E107.
21. Mihara H, Iriguchi N, Ueno S. Imaging of the dielectric resonance effect in high field MRI. J Appl
Phys. 2005; 97: 10R305.
22. Sekino M, Mihara H, Iriguchi N, Ueno S. Dielectric resonance in magnetic resonance imaging: signal inhomogeneities in samples of high permittivity . J Appl Phys. 2005; 97: 10R303.
23. Kimura T, Sato Y, Kimura F, Iwasaka M, Ueno S.
Micropatterning of cells using modulated magnetic
fields. Langmuir. 2005; 21(3): 830-832.
24. Hata K, Yamaguchi H, Tsurita G, Watanabe S,
Waka K, Taki M, Ueno S, Nagawa H. Short term
exposure to 1439 Mhz pulsed TDMA field does notalter melatonin synthesis in rats. Bioelectromagnetics. 2005; 26(1): 49-53.
25. Yamamoto M, Kowatari Y, Ueno S, Yamane S, Kitazawa S. Accelerated recognition of left oblique
views of faces. Exp Brain Res. 2005; 161(1):27-33.
26. Ogiue-Ikeda M, Kawato S Ueno S. Acquisition ofischemic tolerance by repetitive transcranial magnetic stimulation in the rat hippocampus. Brain Res.
2005; 1037: 7-11.
27. Iriguchi N, Matsuda H, Migita M, Ogawa K, Sekino M, Mihara H, Ueno S. Novel circularly polarized slotted tube resonator (CPSTR) for magnetic
resonance signal detection. Information. 2005; 8:
301-305.
28. Gjini K, Maeno T, Iramina K, Ueno S. Short-term
episodic memory encoding in the human brain: a

MEG and EEG study. IEEE Trans Magn. 2005;
41(10): 4149 - 4151.

75

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

Lecturer
Takashi Isoyama, Ph.D.

Associate
Shuichi Mochizuki, M.D, Ph.D.

Homepage http://www.bme.rcast.u-tokyo.ac.jp/
Introduction and Organization

searches with us.

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 was started in1964 for the purpose of research and development of
the advanced diagnostic and therapeutic instruments
for the clinical medicine and their related technologies.
To date, medical engineering is not only a very important academic discipline but also a very importantmeans for the clinical medicine. The name of the department and institute has been changed as shown
above since April 1, 1997 with the structural reform ofFaculty of Medicine.
As the research field covers interdisciplinary andcomprehensive researches based on the medical andengineering technique for clinical medicine, we arecooperating with various laboratories. Especially, Research Center for Advanced Science and Technology(RCAST) presided by Associate Prof. Chinzei, Department of Information Physics and Computing (IPC),
Graduate School of Information Science and Technology presided by Prof. Mabuchi, and Tohoku University Biomedical Engineering Research Organization (TUBERO) presided by Prof. Imachi have beenclosely contacting and performing cooperative re-Teaching activities
As for under-graduate education, our department
takes a part in systematic lectures for the 2nd and 3rdyear medical students, provides guidance and practicein the small group seminar for the 1st year medical
students and in the free quarter course and othershort-term course for the 3rd and 4th year medical
students. In systematic lectures, basic knowledge
about the advanced diagnostic and therapeutic medical
engineered technologies and artificial organ technologies are presented. The basic lecture of clinical engineering is included.
As for post-graduate education, our department takes
a part in series of lectures for doctor course and mastercourse students. In the lectures, philosophy, methodology and basic and special knowledge about medical
engineering for basic and clinical medicine are presented.
The educational practice of the post-graduate students is performed mainly by on-the-job training
method in the daily research works. Especially,
pre-operative management, anesthesia, surgery,post-operative management, measurement, data processing, ethical factor, and so on are learned through76

the animal experiment of artificial heart. As for the
subject of research, students find it by themselvesfrom not only the field of artificial organs but also thewide area of medical engineering field. On the other
hand, the education to train the leaders of biomedical
engineer and clinical engineer is another importantrole. Other than the medical students, many students
come from engineering department of our university
and other university such as Waseda University andKitasato University. Students must attend to weekly
meeting. They can learn how to proceed the research
work and how to report it through this meeting.

Research activities
Our research field covers artificial organs (especiallyartificial heart and assist circulation), biomaterials, laser
surgery and medicine, thermology, measurement instruments, nerve interface, micromachine andnanomedicine, and these involved in the advanced diagnostic and therapeutic instruments and technologies.
The artificial heart (AH) study is world famous research project having a long history since 1959. Almost
all the researchs such as driving mechanism, blood
pump, artificial valve, materials, measurement, control
method, circulatory physiology and pathophysiology
have been studied. Almost all the stuffs and students
join to this research. In 1995, we succeeded to survive agoat with the total artificial heart (TAH) for 532 days,
which is still the longest survival record of TAH animals in the world.
To date, two main AH projects are being performed.
One is the implantable TAH research and the other isthe multi-institutional comprehensive project to develop
a totally implantable ventricular assist device for clinical use. We invented a small blood pump with highperformance, named undulation pump (UP). We aredeveloping an undulation pump total artificial heart(UPTAH) which is the most compact implantable total
artificial heart in the world. To date, we succeeded tosurvive a goat for 63 days with UPTAH. Using thetechnology of the UPTAH, 5-year project to develop a
totally implantabe ventricular assist device for clinicaluse have been performed since 2002 in cooperation
with Hokkaido University, Hokkaido Tokai University,
Tohoku University, Waseda University, Kyusyu University and several companies.

Physiological study how to control the output of
TAH is another big interest. We have developed ouroriginal control method, named 1/R control, in which
the cardiac output is controlled by the cardiovascular
center through the feedback mechanism using changes
in total peripheral resistance and arterial pressure. To
date, the 1/R control is the single method to realize aphysiological control of the output of TAH, in which
the particular problems of TAH such as venous hypertension, slight anemia, low thyroid hormone level, andso on, are not occurred and the output is changed inaccordance with metabolic condition of the animal. The
1/R control was installed in the UPTAH and the pathphysiological study is being performed.
Concerning the biomaterials, the mechanism ofthrombus formation and calcification on the medical
polymer surfaces, especially in artificial heart and onpolymer valve have been studied. The evaluation of
biocompatibility of many biomaterials is also importanttask.
In the field of laser surgery and medicine, the influence of various kinds of laser on tissues and organs has
been studied since 1964, and laser scalpels and coagulators have been developed. The applications of laser tothe minimally invasive surgery have been studied.
Coronary laser angioplasty, laser revasculerization of
the ventricle, laser nucleotomy for lumbar disc herniation were research outcome under the cooperation withseveral universities and hospitals. Recently, handy typelaser coagulator using a high power semiconductor laser was developed.
Thermology is one of the original works of our department in Japan. Development of instrument and basic physiological studies have been performed. Recently, imaging of effectiveness in alternative andcomprehensive medicine is under the basic study.
Implantable probe for observation of microcirculation is under the development using CCD chip. This
device is expected to progress the physiology of the
microcirculation with the combination of the artificial
heart.
Nerve interface will be very important to control theartificial organs. The basic study to develop a multiple
interface array to single nerve fibers is being studiedusing micromachine technique.
Micromachine and nanomedicine technologies arealso important for the next generation artificial organs.

77

Cell culture in the small hole with diameter of 100
micron and 320 micron depth was succeeded for constructing complex organ with tissue engineering technique.

References
1. Baba A, Dobsak P, Saito I, Isoyama T, Takiura K,
Abe Y, Chinzei T, Vasku J, Imachi K. Microcirculation of the bulbar conjunctiva in the goat implanted with a total artificial heart: effects of pulsatile and nonpulsatile flow. ASAIO J. 2004;50(4):321-27.
2. Takiura K, Chinzei T, Abe Y, Isoyama T, Saito I,
Mochizuki S, Imachi K. A temporal and spatial
analysis of cavitation on mechanical heart valves
by observing faint light emission. ASAIO J.
2004;50(3):285-90, Erratum in: ASAIO J. 2004;
50(4):402.
3. Okamoto E, Inoue T, Hashimoto T, Saito I, Abe Y,
Chinzei T, Isoyama T, Imachi K, Mitamura Y.
Development of an electro-stethoscope systemand design of an optimum filter based on tissue
sound transmission for noninvasive early diagnosis of malfunction of an implanted mechanical total artificial heart. Artificial Organs. 2004;28(2):226-29.
4. Abe Y, Wakamatsu K, Goto S. Development of ahandy-type laser surgical unit. SPIE. 2004; 5967:
59670E1-E5.
5. Takeuchi S, Suzuki T, Mabuchi K, Fujita H. 3D
flexible multichannel neural probe array. J Micromech and Microeng. 2004;14(1):104-107.
6. Saito I, Abe Y, Chinzei T, Isoyama T, Ono T, Nishitani Y, Nemoto I, Inoue Y, Watanabe N, Asao H,
Miura H, Kakubari Y, Arai S, Iwasaki K, Makino
T, Okamoto E, Sato F, Mochizuki S, Kouno A,
Funamizu H, Nakagawa H, Mitsui M, Taniguchi
N, Mitsumune N, Sugino A, Ono M, Takiura K,
Mitamura Y, Matsuki H, Umezu M, Takamoto S,
Imachi K. Implantation of the undulation pumpventricular assist system. Proceeding of 6th
Asia-Pacific Conference on Medical & BiologicalEngineering. 2005;91-7.
7. Takeuchi S, Ziegler D, Yoshida Y, Mabuchi K,
SuzukiT. Parylene flexible neural probe with micro fluidic channel. Lab on a Chip. 2005;5: 519-

523.
8. Takiura K, Fukuta Y, Funamizu H, Mochizuki S,
Nakagawa H, Saito I, Suzuki T, Fujita H, Chinzei
T. Novel cell culturing system with micromachined template for the realization of a complex organ. IFMBE Proceedings. 2005;11:385457.
9. Mitsui M, Suzuki T, Mabuchi K, Takiura K, Saito
I, Chinzei T, Mochizuki S, Isoyama T, Abe Y,
Imachi K. Development of a Novel Intrafascicular
Nerve Electrode. ASAIO J. 2005;51(6):692-95.

Neuroscience
1. Basic Neuroscience⑪

80

Department of Neuropathology
Professor
Yasuo Ihara, M.D.

Associate Professor
Lecturer
Maho Morishima-Kawashima, Ph.D.

Associate
Satoru Funamoto, Ph.D.,

Tomohiro Miyasaka, Ph.D.

Homepage
Introduction and Organization

Teaching activities

The Institute for Brain Research to which Department of Neuropathology originally belonged is dated
back to 1935, when three laboratories were set to start
brain research within the Department of Psychiatry. The
first lab was headed by Dr. Teizo Ogawa, the second by
Dr. Shufu Yoshimasu, and the third by Dr. Katsumi
Kakeda. In 1953, the Institute for Brain Research wasformally established, which consisted of six departments, namely Departments of Neuropathology, Neuroanatomy, Neurophysiology, Neurochemistry, andPsychology. In 1959, Dr. Hirotsugu Shiraki promoted to
the first professor of Neuopathology, followed by Drs.
Tatsuya Yamamoto and Masanori Tomonaga. In 1991,
Dr. Yasuo Ihara succeeded the professorship, and became the fourth professor of Neuropathology. In 1997,
the Institute was closed as the Faculty of Medicine,
University of Tokyo was promoted to the Graduate
School of Medicine. By extensive reorganization, Department of Neuropathology now makes up the Neuroscience Division, together with Departments of Neurochemistry, Neurobiology (formerly Psychology), Neurology, Neurosurgery, and Psychiatry, and three departments from the Institute for Phonetics.

As we belonged to the research institute in the past,
we have not been heavily involved in the teaching activities. What we are presently involved are to provide
lectures on Alzheimer’s disease and neuroanatomy topremedical students, and master course students. For
these five years intensive neuroanatomy course has
been provided towards doctoral and master students
every January for a period of seven days.

Research activities
The long-term goal of the research in our department
is to determine the molecular events that lead to thedevelopment of Alzheimer's disease (AD).

Current goals include:
1 Characterization of γ-secretase—Senile plaques, oneof the neuropathological hallmarks of Alzheimer’s disease (AD), are composed of a small ~40-residue protein
called amyloid β-protein (Aβ). Aβ is produced from
β-amyloid precursor protein (APP), through sequential
cleavages by two membrane proteases referred to as βand γ-secretases. β-Secretase is a membrane-bound as-

81partyl protease, and cleaves APP in its luminal portion,
generating a 99-residue-fragment called βC-terminal
fragment (βCTF). βCTF in turn is cleaved by
γ-secretase in the middle of its transmembrane domain,
generating Aβ which is finally secreted into the extracellular space. While the most predominant productis Aβ40, a two-residue longer species, Aβ42, is believed to be the species initially deposited in the brain
and predominates in senile plaques. Thus far, threecausative genes for familial AD, APP, presenilin (PS) 1,
and PS2, have been identified, and the FAD mutations
found in these genes lead to increased production ofAβ42, strongly suggesting that Aβ42 is a real culprit forAD.
The mechanism of intramembrane cleavages at theAβ40 and Aβ42 sites by γ-secretase has remained an
enigma. Accumulating evidence suggests that γ-secretaseis also an aspartyl protease with its catalytic site(s) sitting within the membrane. Active γ-secretase is assumed to take the form of a high-molecular-weightmultiprotein complex consisting of at least four integral
membrane proteins, PS, Aph-1, nicastrin, and Pen-2, allof which are essential for the emergence of fullγ-secretase activity. PS1/2 appear to compose the catalytic core of γ-secretase.
γ-Secretase cleaves APP in the middle of the transmembrane domain (γ-cleavage), releasing Aβ, and near
the membrane-cytoplasm boundary (ε-cleavage), producing APP intracellular domain (AICD). ε-Cleavage
generates AICD50-99, a major product, and AICD4999, a minor product. Although the relationship between
γ- and ε-cleavages is still not well understood, our previous study showed that some correlations exist between the major counterparts, Aβ40 vs. AICD50-99,
and between the minor counterparts, Aβ42 vs. AICD4999.
We have identified several longer Aβs within cells
and in the brain, including Aβ43, Aβ45, Aβ46, andAβ48. In contrast, only two species of AICD49-99 and50-99 were identified in the newly established solubilized assay system. Thus, it is likely that βCTF undergoes first ε-cleavage, followed by γ-cleavages at multiple sites within its transmemebrane domain. Thesecleavage sites are aligned on the α-helical surface ofthe transmembrane domain, and we speculate that
βCTF is processed at every third residue from its
C-terminus by γ-secretase.

2 Tau and neuronal cell deathMicrotubule-binding protein tau, which promotes
tubulin polymerization and stabilizes microtubules, wasidentified as the major component of the framework ofneurofibrillary tangles (NFT) found in the brain affected by so called tauopathy, the conditions such as
Alzheimer’s disease (AD) and frontotemporal dementia
with parkinsonism linked to chromosome 17(FTDP-17). Patients affected by FTDP-17 develop
execution problems, behavioral abnormalities, often
parkinsonism, and finally dementia. More than 25 exonic and intronic mutations in the tau gene in FTDP-17
families are currently found, strongly suggesting that
tau is directly involved in the neurodegeneration andneuronal loss.
Those animal models so far made provide both invaluable information about the nature of neurodegeneration caused by tauopathy. However, detailed picturesof neurodegeneration have remained unknown largely
because of the complexity of the nervous system. We
thus generated transgenic nematode expressing human
WT tau or two kinds of FTDP-17 mutant tau (P301L
and R406W) in six mechanosensory neurons, ALML/R,
AVM, PLML/R, and PVM. They can be readily traced
to their fine neuronal processes under microscopy, acondition which is difficult to obtain in other models.
These neurons are characterized by distinct microtubules of a larger diameter that consist of 15 protofilaments (instead of 11), and by expression of MEC-12
and MEC-7, and distinct types of α and β-tubulin.
Decreases in the touch response are associated withvarious types of neuritic abnormalities. The greater
these alterations are, the more the response is decreased.
Various abnormal neuritic characteristics could be interpreted as derived from generation of aberrant neurites during development. These observations would
suggest that dysfunction, a decrease in the touch response, is not due to neuronal loss, but may be due tothe formation of abnormally generated neurites, presumably leading to the formation of abnormal neuronal
circuits and resulting in null response. There appear to
be two types of neurodegeneration, tau-accumulating
and tau-nonaccumulating degeneration, in the affected
worms. This view was previously proposed for the
neocortical neurons affected by AD, based on unbiased
stereological observations. Even if tau does not accu-

82

mulate in the cell bodies, their neuronal processes are
already abnormal, suggesting that even a trace amountof tau, especially of mutant tau, can be toxic to touchneurons. We do not currently know why these two typesof neurodegeneration can happen. One possibility
would be that tau accumulation is a late event during
the course of neurodegeneration, and the rate of accumulation varies for individual cells. In rapidly degenerating neurons, tau may not be produced sufficiently toaccumulate, leading to tau-negative degeneration. In
contrast, in slowly degenerating neurons, tau exists insufficient amounts to accumulate, leading to tau-positive
degeneration. This strongly suggests that tau accumulation (or formation of tau inclusions) is not required forthe toxic effect of mutant tau.

References
1. Watanabe N, Araki W, Chui DH, Makifuchi T,
Ihara Y, Tabira T: Glypican-1 as an Aß binding
HSPG in the human brain: Its localization in DIG
domains and possible roles in the pathogenesis of
Alzheimer's disease. FASEB J 18: 1013-1015, 2004
2. Oyama F, Kotliarova S, Harada A, Ito M, Miyazaki
H, Ueyama Y, Hirokawa N, Nukina N, Ihara Y:
Gem GTPase and tau: morphological changes induced by Gem GTPase in CHO cells are antagonized by tau. J Biol Chem 279: 27272-27277, 2004
3. Watanabe A, Hong W-K, Dohmae N, Takio K,
Morishima-Kawashima M, Ihara Y: Molecular aging of tau: disulfide-independent aggregation andnonenzymatic degradation in vitro and in vivo. J
Neurochem 90: 1302-1311, 2004
4. Funamoto S, Morishima-Kawashima M, Tanimura
Y, Hirotani N, Saido TC and Ihara Y: Truncatedcarboxyl terminal fragments of ß-amyloid precursor protein are processed to amyloid ß-proteins 40
and 42. Biochemistry 43:13532-13540, 2004
5. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Hirotani N, Horikoshi Y, Maeda M, Saido
TC, Ihara Y: Longer forms of amyloid ß-protein:
implications for the mechanism of intramembranous cleavage by γ-secretase. J Neurosci 25:436445, 2005
6. Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S,
Yamashita N, Nakamura F, Takei K, Ihara Y,
Mikoshiba K, Kolattukudy P, Honnorat J, Goshima

Y: Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of
CRMP2: implication of common phosphorylating
mechanism underlying axon guidance and Alzheimer's disease. Genes Cells 10: 165-179, 2005
7. Katsuno T, Morishima-Kawashima M, Saito Y,
Yamanouchi H, Ishiura S, Murayama S, Ihara Y:
Independent accumulations of tau and amyloid
β-protein in the human entorhinal cortex. Neurology 64: 687-692, 2005
8. Nakaya Y, Yamane T, Shiraishi H, Wang HQ, Matsubara E, Sato T, Dolios G, Wang R, De Strooper
B, Shoji M, Komano H, Yanagisawa K, Ihara Y,
Fraser P, St George-Hyslop P, Nishimura M: Random mutagenesis of presenilin 1 identifies novel
mutants exclusively generating long amyloid beta
peptides. J Biol Chem 280:19070-19077, 2005
9. Sato T, Tanimura Y, Hirotani N, Saido TC, Morishima-Kawasdhima M, Ihara Y: Blocking thecleavage at midportion between γ- and ε-sites remarkably suppresses the generation of amyloid β-protein. FEBS Lett 579: 2907-2912, 2005
10. Miyasaka T, Watanabe A, Saito Y, Murayama S,
Mann DMA, Yamazaki M, Ravid R, MorishimaKawashima M, Nagashima K, Ihara Y: Visualization of newly deposited tau in neurofibrillary tangles and neuropil threads. J Neuropathol Exp Neurol 64: 665-674, 2005
11. Miyasaka T, Ding Z, Gengyo-Ando K, Oue M,
Yamaguchi H, Mitani S, Ihara Y: Progressive neurodegeneration in C. elegans model of tauopathy.
Neurobiol Dis 20: 372-383, 2005
12. Yagishita S, Morishima-Kawashima M, Tanimura Y,
Ishiura S, Ihara Y: DAPT-induced intracellular accumulations of longer amyloid β-proteins: further
implications for the mechanism of intramembranecleavage by γ-secretase. Biochemistry 45: 3952
-3960, 2006

83

Department of Neurochemistry
Associate Professor and Head
Haruhiko Bito, M.D., Ph.D.
Assistant Professors
Hiroyuki Okuno, Ph.D.
Sayaka Takemoto-Kimura, M.D., Ph.D.

Homepage http://www.neurochem.m.u-tokyo.ac.jp/Homepage.html
Introduction and Organization
Our Department’s primary goal is to elucidate thebasic signal transduction mechanisms which mediate
key processes underlying various brain functions, suchas learning, memory or emotion. A fundamental question is how an ensemble behavior of 10~100 billion
neurons can possibly give rise to a coherent and integrated “brain” that controls the whole human organism
for a period of more than eighty years. Our central
nervous system is physically wired and organized basedon evolutionary and developmental principles that areprimarily encoded into the genome and that are highly
conserved in mammals from rodents to primates. This
neural network, however, is able to recognize andmemorize 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 and affective valence,
while also unconsciously facilitating coordinated body
responses.
Neurochemistry once used to be a relatively dull discipline consisting of analyzing substances that form thebrain. However, it has recently become a field of excitement where we are now (almost) able to measurechanges in cellular messengers or modifications in signaling molecules in critical parts of the neurons such as
the dendritic spines or the axon terminals, as the neurons summate synaptic potentials or fire action poten-

tials.
What are the precise nature and the whole spectrumof the molecular changes in the neurons that undergo
heavy or patterned electrical activity? What are themolecular rules that govern these local and globalchanges, both electrical and chemical? How are these
events, in turn, converted into more profound modifications of the synaptic wiring mechanisms? And finallydo these alterations genuinely underlie certain kinds ofinformation 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 signaling from synapse-to-nucleus, and back from nucleus-to-synapses.
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sides ofthe 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 andthen 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

84

building of the Medical School. The Department currently enrolls one associate professor, two assistantprofessors, one postdoctoral scholar, one technical staff
member, three Ph.D. and one M.S. 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 Biology- Nutrition” core curriculum (two hours);3) Introductory Molecular and Cellular Neuroscience,
and Basic Neurochemistry lectures to first-year
master degree students (three hours);
4) Organization of the lecture course: “Basic Neuroscience” (Molecular and Cellular Neuroscience) (alecture series with fifteen lectures from outstanding
neuroscientists from all over Japan).
Additionally, Neurochemistry Seminars are frequently and regularly organized under the auspices ofthe 21st Century Center of Excellence Program Grant“Center for Integrated Brain Medical Science”. This
enables direct exposure of Ph.D. graduate students andpostdocs to both young promising researchers and established investigators from all over the world.

Research activities
The Department of Neurochemistry currently focuses
its resources into two core projects:
1) Molecular investigation (including identification,
characterization and real-time visualization) of signaling molecules involved in calcium-dependent synaptic
modification, especially during signaling from synapse-to-nucleus, and back from nucleus-to-synapses.
Changes in efficacy of synaptic transmission havebeen shown to strongly correlate with functional plasticity of many brain circuits including the hippocampus,
the amygdala, the striatum, the neocortex, the cerebellum or the spinal cord. An early phase of long-term

synaptic plasticity is induced by virtue of specific postand/or presynaptic modifications of the biochemicalmachinery dedicated to synaptic release and neurotransmitter recognition. It then is expressed by bistablemechanisms that are strongly governed and dictated by
the pattern of synaptic calcium influxes experienced
during the initial conditioning period. While the molecular identity of the involved synaptic proteins is now(almost) being solved (or is becoming much less controversial than before), several essential questions remain unanswered.
The “Old” question was: What are the molecular determinants that enable these plastic changes to be induced and maintained locally?
Yet, related issues of critical importance that still remain wide open questions are:1) What are the full-range of calcium-triggered molecular signaling cascades which are activated atand near the potentiated/depressed synapses? And
how do they influence plasticity per se?
2) What is the contribution of activity-dependent gene
expression in prolongation and consolidation ofsuch synapse-restricted changes?
In order to begin to address these issues, we havebeen investigating in particular the role of several calcium-calmodulin dependent protein kinases.
We previously showed the critical importance of a
CaMKK/CaMKIV cascade in triggering synaptically-stimulated nuclear CREB phosphorylation in
hippocampal neurons. The extreme biochemical efficacy and the relative poor frequency-dependence of thissignaling cascade, in combination with the robust correlation between prolonged pCREB response anddownstream gene expression led us to propose that
CaMKK/CaMKIV/pCREB cascade was likely to act asa critical temporal integrator for activity-dependent
gene expression in excitatory neurons (Bito et al., Cell,
1996; Bito et al., Curr. Opin. Neurobiol., 1997; Bito,
Cell Calcium, 1998). This hypothesis has now been
critically tested in various brain systems and indeed
pCREB immunofluorescence is now considered as auniversal marker for integrated synaptic activity that ismore sensitive than that of c-Fos. Furthermore, CaMKIV-KO, CaMKK-KO and CaMKIV-dominant negative transgenic studies by many laboratories have confirmed the critical role for CaMKIV as synaptic activity-triggered CREB kinase.

85

We subsequently also showed that CaMKIV in the
cerebellar granule cells played a critical role in tuning
the pCREB response necessary for depolarization-mediated neuronal survival, and that in fact CaMKIV stability was actively maintained by depolarization.
Loss of depolarizing signal led to a caspase-mediatedproteolytic 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 toprevent 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 many neurodegenerative disorders such as hereditary polyglutamine diseases. We
thus speculated that if CREB-opathies (or various defects in CREB-mediated gene activation mechanisms)
were critical determinants in exacerbating neurodegeneration, certain disease forms may actually accompany
deficit in CaMKIV / pCREB signaling (Bito and Takemoto-Kimura, Cell Calcium 2003). This hypothesis is
now being tested.
One parallel branch of CaMK signaling that has notbeen widely studied is the CaMKK/CaMKI pathway.
During the search for potential CaMKIV-like CREB
regulatory kinases (CLICKs), we identified a novel
CaMKI isoform that contained a C-terminal CAAX
lipid modification motif (Takemoto-Kimura et al., J.
Biol. Chem., 2003). This novel membrane-bound
CaMK (CLICK-III/CaMKIγ) is most expressed in thecentral nucleus of the amygdala and in the ventral medial hypothalamus, while also being present at a much
weaker amount in most central neurons. Ongoing biochemical and cell biological studies indicate a criticalrole for lipidification of this kinase to be properly
sorted into specific lipid-restricted membrane microdomains. The function played by this lipidified, membrane-inserted CaMK in synapse circuitry formationand maturation is now being scrutinized. Furthermore,
we recently identified the critical lipid-modifying enzyme that controls lipid-anchoring of this kinase.
One further important topic that we have been focusing for a number of years is the role of gene expression in prolongation / consolidation of synapse-specificlocal changes. Neurons undergoing various stimulus

patterns have been followed up in time and the amountof newly synthesized proteins and the local distributionof induced gene products have been monitored. Usingstate-of-the-art multi-wavelength fluorescence imaging
techniques, we are now quantitatively assessing how
local distribution of these newly synthesized geneproducts affect synaptic protein complexes.
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sides ofthe synapses, in the dendritic spines and in axon terminals.
Both synaptic maturation and synaptic plasticity havebeen shown to include a morphological component thatis directed by the dynamics of actin cytoskeleton, amajor cytoskeletal component both in the dendritic
spines and at the very proximity of boutons in the axon
terminals. Few studies in the past, however, had directly
addressed what molecular determinants regulate actin
dynamics in living central neurons undergoing synaptic
activity. This was in part because actin filament assembly and disassembly were classically studied mostly at
the moving edges of lamellipodia of large growth cones
in large-size neurons from either mollusc or peripheral
nerve cells. Such visualization turned out to be much
more difficult 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 reorganized by exposure to synaptic activity. In our dissociated culture
system, virtually all spines contained a high amount of
GFP-actin and most of them with few exceptions wereapposed to FM4-64-positive active presynaptic termini.
In these cultures, increases in synaptic glutamatergictransmission by repeated bursts of high-frequency synaptic activity clearly induced several distinct kinds ofactivity-dependent actin mobilization, including a slow
but sustained synaptic delivery of GFP-actin in a
non-negligible number of activated spines and a massive but transient enhancement in cortical actin at thesomatic periphery. The former was entirely dependent
on NMDA-dependent 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 com-86

plex spatially segretated patterns of actin cytoskeletal
reorganization, with variable impact on either neuronalmorphology and/or synaptic protein assembly (Furuyashiki et al., PNAS, 2002).
Similar studies are now ongoing in cerebellar Purkinje neurons, where spinogenesis is also subject tocomplex 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 the context of developmentally regulated neuronal morphogenesis. We first established in a model cell line
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, inaddition to its essential role in regulating growth cone
motility, Rho/ROCK activity in fact acted as a negativegate that tightly controls the timing with which the firstprocesses are initiated out from the round cell soma
(Bito et al., Neuron, 2000). Disruption of Rho/ROCK
activity was sufficient to immediately initiate neuritogenesis. This indicated that endogenous Rho activators,
by titrating ROCK activity, continuously antagonizedprocess/ branch formation and that local gradient of
Rho activators might play a crucial role in shaping thetiming and the extent of process formation (Bito, J.
Biochem., 2003). Consistent with this idea, we foundthat in cerebellar granule cells, a chemokine SDF-1αreleased from the pia mater was likely to be a predominant Rho activator via stimulation of a cognate andspecific GPCR CXCR4 (Arakawa et al., J. Cell Biol.,
2003). While a true gradient in SDF-1α still remains to
be demonstrated in vivo, it is intriguing to note thatmost active 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 anintermediate Rho activity range that enables ROCK to
be weakened enough while allowing another Rho effector mDia1 to actively mediate its effect on actin nucleation and polymerization (Arakawa et al., J. Cell
Biol., 2003).
Whether similar or distinct mechanisms also operate

during spinogenesis and spine maturation remains to be
determined, though a role for Rho and ROCK has already been postulated in control of spine complexity
and spine stability. However, multiple small GTPasesignaling cascades clearly seem to contribute together,in a tightly coordinated manner, to spine regulation,
since many distinct classes of GEFs and GAPs havenow been shown to be localized in the dendritic spines.
We ourselves initially reported the first two direct examples for PSD localization for such Rho small
GTPases interacting proteins, Citron (Furuyashiki et al.,J. Neurosci., 1999) and Cupidin/Homer2 (Shiraishi etal., J. Neurosci., 1999).

Publications by lab members (April
2004 - March 2006)
1. Nemoto, T.., Kojima, T.., Oshima, A., Bito, H.,
Kasai, H. Stabilization of exocytosis by dynamic
F-actin coating of zymogen granules in pancreaticacini. J. Biol. Chem. 279, 37544-37550 (2004)
2. Suga, H., Takeda, S., Haga, T., Okamura, M.,
Takao, K., and Takemoto, K. Stimulation of increases in intracellular calcium and prostaglandin
E2 generation in Chinese hamster ovary cells expressing receptor-Gα16 fusion proteins. J. Biochem.
135, 605-613 (2004).
3. Takeda, S., Okada, T., Okamura, M., Haga, T.,
Isoyama-Tanaka, J., Kuwahara, H., and Minamino,
N. The receptor-Gα fusion protein as a tool for
ligand screening: A model study using a nociceptin
receptor-Gαi2 fusion protein. J. Biochem. 135,597-604 (2004).
4. Zhang, Q., Okamura, M., Guo, Z.-D., Niwa, S.,
and Haga, T. Effects of partial agonists and Mg2+
ions on the interactions of M2 muscarinic acetylcholine receptor and G protein Gαi1 subunit in the
M2-Gαi1 fusion protein. J. Biochem. 135, 589-596(2004).
5. Fuse, T., Kanai, Y., Kanai-Azuma, M., Suzuki, M.,
Nakamura, K., Mori, H., Hayashi, Y., Mishina, M.
Conditional activation of RhoA suppresses theepithelial to mesenchymal transition at the primitive streak during mouse gastrulation. Biochem
Biophys Res Commun. 318, 665-672 (2004).
6. Moriyoshi, K., Iijima, K., Fujii, H., Ito, H., Cho, Y.,
Nakanishi, S. Seven in absentia homolog 1A medi-

87

ates ubiquitination and degradation of group 1 metabotropic glutamate receptors. Proc Natl Acad Sci
U S A. 101, 8614-8619 (2004).
7. Hoshino, M., Nakamura, S., Mori, K., Kawauchi,T., Terao, M., Nishimura, Y.V., Fukuda, A., Fuse,
T., Matsuo, N., Sone, M., Watanabe, M., Bito, H.,
Terashima, T., Wright, C.V.E., Kawaguchi, Y., Nakao, K., and Nabeshima, Y. Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fatesin cerebellum. Neuron 47, 201-213 (2005).
8. Matsuoka, Y., Furuyashiki, T., Yamada, K., Nagai,T., Bito, H., Tanaka, Y., Kitaoka, S., Ushikubi, F.,
Nabeshima, T., Narumiya, S. Prostaglandin E receptor EP1 controls impulsive behavior understress. Proc. Natl. Acad. Sci. USA 102, 1606616071 (2005).
9. Iki, J., Inoue, A., Bito, H., Okabe, S. Bidirectional
regulation of postsynaptic cortactin distribution by
BDNF and NMDA receptor activity. Eur. J. Neurosci. 22, 2985-2994 (2005).
10. Okuno, H. and Bito H. CREB1.
AfCS/Nature Molecule Pages, doi:10.1038/ mp.
a000690.01 (2006).
11. Nonaka, M., Doi, T., Fujiyoshi, Y., TakemotoKimura, S., Bito, H. Essential contribution of theligand-binding βB-βC loop of PDZ1 and PDZ2 in
the regulation of postsynaptic clustering, scaffolding and localization of PSD-95, J. Neurosci. 26:
763-774 (2006).

Neuroscience
2. Speech and Cognitive Sciences⑫

90

Department of Speech Science
Associate Professor
Yoshihiro Takayama, M.D.

AssociateKenji Itoh, Ph.D.,

Michiru Makuuchi, Ph.D.

Homepage
Introduction and Organization

Research activities

Speech and language are the most prominent cognitive functions distinguishing human being from nonhuman animals. The Department of Speech Scienceaims at basic, interdisciplinary studies on the humanspeech and language communication. The research area
ranges from physical and physiological processes inspeech production and perception, developmental aswell as adult cognitive processes in speech and nonverbal communication to medical application of speechand hearing support technologies. Many studies are
conducted in cooperation with other departments, faculties and universities such as in the field of engineering, linguistics, psychology, education and clinicalneuroscience.

1. Brain mechanisms on spoken language production,
comprehension and their linkage in human communication
2. Physical, physiological and computational modeling studies on verbal and nonverbal temporal behaviors of Japanese and others
3. Cognitive process in acquisition of native speech,
language and communication skills in infants andchildren
4. Learning mechanisms of second language andworld knowledge in adults with established first
language
5. Objective and quantitative assessment of normal aswell as pathological speech, language and social
skills
6. Technological developments of aids for the hearing,speech, language and mentally handicapped

Teaching activities
1. Graduate Course
Speech Science and Language Communication
Pathophysiology of Higher Brain Functions(for School of Humanities and Sociology)
2. Undergraduate Course
Introduction to Medical Data
Speech and Language Communication* The lectures are conducted in collaboration with the
Departments of Speech Physiology, Cognitive Scienceand Sensory and Motor Neuroscience.

References
1. Karino S, Yumoto M, Itoh K, Yamakawa K, Mizuochi T, Kaga K. A modified parallel paradigm forclinical evaluation of auditory echoic memory. Int
Congr Ser. 2004;1270: 169-72.
2. Kawakubo Y, Maekawa H, Itoh K, Hashimoto O,
Iwanami A. Spatial attention in individuals with
pervasive developmental disorders using the gap
overlap task. Psychiatry Res. 2004; 125:269-75.
3. Yumoto M, Uno A, Itoh K, Matsuda M, Karino S,
Kaga K. Spatiotemporal neuromagnetic activities

91

during pitch processing in musicians. Int Congr Ser.
2004;1270:173-6.
4. Araki T, Kasai K, Nakagome K, Fukuda M, Itoh K,
Koshida I, Kato N, Iwanami A. Brain electric activity for active inhibition of auditory irrelevant information. Neurosci Lett. 2005;374:11-6.
5. Karino S, Yumoto M, Itoh K, Yamakawa K, Mizuochi T, Kaga K. A modified parallel paradigm forclinical evaluation of auditory echoic memory.
Neuroreport. 2005;16:683-7.
6. Kasai K, Hashimoto O, Kawakubo Y, Yumoto M,
Kamio S, Itoh K, Koshida I, Iwanami A, Nakagome
K, Fukuda M, Yamasue H, Yamada H, Abe O, Aoki
S, Kato N. Delayed automatic detection of change
in speech sounds in adults with autism: A MEG
study. Clin Neurophysiol. 2005;116:1655-64.
7. Mizuochi T, Yumoto M, Karino S, Itoh K, Yamakawa K, Kaga K. Effect of the spectral envelopeon the auditory evoked N100m. Int Congr Ser.
2005;1278:247-50.
8. Mizuochi T, Yumoto M, Karino S, Itoh K, Kaga K.
Perceptual categorization of sound spectral envelopes reflected in auditory evoked N1m. Neuroreport. 2005;16:555-8.
9. Yumoto M, Uno A, Itoh K, Matsuda M, Karino S,
Saitoh O, Kaneko Y, Yatomi Y, Kaga K. Spatiotemporal neuromagnetic activities during pitch
processing in musicians. Neuroreport. 2005;16:1175-8.
10. Yumoto M, Uno A, Itoh K, Karino S, Saitoh O,
Kaneko Y, Yatomi Y, Kaga K. Audiovisual phonological mismatch produces early negativity inauditory cortex. Neuroreport. 2005;16:803-6.

92

Department of Speech Physiology
Associate Professor
Yoshihiro Takayama, M.D., Ph.D.

Associate
Kimihiro Nakamura, M.D., Ph.D.

Michiru Makuuchi, Ph.D.

Homepage
Introduction and Organization

Research activities

The Department of Speech Physiology is one of
the three departments composing the Speech
and Cognitive Science Section. Research in thelaboratory is currently aimed at understanding
the functional architecture of the language andcognitive system.

1. Clinical Neuropsychology:
By studying patients with disorders resulting frombrain damage, we can make inferences about thekinds of cognitive representations and processes
that constitute the normal system. Recent researchin the field of clinical neuropsychology focused on
1.Neuropsychological sequels of acute andchronic stroke, 2.neuropsychological deficits associated with degenerative diseases, 3.short and longterm neuropsychological deficits in patients withepilepsy.
2. Cognitive Psychology:
Using behavioral measures such as reaction time,answer fine-grained questions about the structure of
representations and the time course of processing,
we are doing studies of unimpaired individuals'
performance on language tasks to reveal the ways
in which the brain represents and accesses knowledge about a word's meaning, sound structure andwritten form.
3. Functional Neuroimaging:
We have recently begun to use functional magnetic
resonance imaging (fMRI) to identify brain regionsthat subserve various components of language.
We are performing fMRI studies to establsh
more appropriate description of the functionof Broca's area using both language andnon-language tasks.

Clinical activities
Assessment for aphasia, amnesia, apraxia,
agnosia and dementia are conducted in collaboration with the Department of Neurology andthe Department of Neurosurgery.

Teaching activities
1. Graduate School of Medicine
Speech Science and Language Communiction.
Pathophysiology of Speech and Language Communication*.
Introduction to Neuroscience.
2. Master Course, Faculty of Medicine
Cognitive Neuroscience*
3. Graduate School of Literature
Physiology and Pathophysiology of Higher Brain
Function*
4. Undergraduate School of Medicine
Speech and Language Communication*(* Jointly organized with the Department of Cognitive
Neuroscience and the Department of Speech Science)

93

References
1. Takayama Y, Kinomoto K, Nakamura K. Selective
impairment of the auditory-verbal short-term
memory due to a lesion of the superior temporalgyrus. Eur Neurol. 2004; 51(2):115-7.
2. Kaga K, Nakamura M, Takayama Y, Momose H. A case of cortical deafness andanarthria. Acta Otolaryngol 2004; 124: 2025.
3. Thuy DH, Matsuo K, Nakamura K, Toma K, Oga T,
Nakai T, Shibasaki H, Fukuyama H. Implicit andexplicit processing of kanji and kana words andnon-words studied with fMRI. Neuroimage. 2004;
23(3):878-89.
4. Kinomoto K, Takayama Y, Abe M, Nakamura K,
Akiguchi I. A compensatory mechanism in unilateral akinetic-rigid syndrome: an fMRI study. Clin
Neurol Neurosurg. 2004; 106(4):330-4.
5. Abe M, Kondo T, Takayama Y. An HLA-B54 positive case of "encephalo-mucocutaneous syndrome".
J Neurol. 2004;251(9):1151-3.
6. Dong Y, Nakamura K, Okada T, Hanakawa T, Fukuyama H, Mazziotta JC, Shibasaki H. Neuralmechanisms underlying the processing of Chinese
words: an fMRI study. Neurosci Res. 2005 Jun;52(2):139-45.
7. Michiru Makuuchi, Tatsuro Kaminaga, Morihiro
Sugishita. Brain activation during ideomotor praxis:
imitation and movements executed by verbal command J Neurol Neurosurg Psychiatry 2005; 76:12533.
8. Michiru Makuuchi. Is Broca's area a crucial cortex
for imitation? Cereb Cortex 2005; 15:563-570.
9. Nakamura K, Dehaene S, Jobert A, Le Bihan D,
Kouider S. Subliminal convergence of Kanji andKana words: further evidence for functional parcellation of the posterior temporal cortex in visual
word perception. J Cogn Neurosci 2005;17:954-68.
10. Nakamura K, Oga T, Okada T, Sadato N, Takayama
Y, Wydell T, Yonekura Y, Fukuyama H. Hemispheric asymmetry emerges at distinct parts of theoccipitotemporal cortex for objects, logograms andphonograms: a functional MRI study. Neuroimage.
2005;28(3):521-8.

Neuroscience
3. Clinical Neuroscience⑬

96

Department of Neuropsychiatry
Professor
Nobumasa Kato, M.D., Ph.D.

Associate Professor
Nobuo Nakayasu, M.D., Ph.D.,

Koichi Tsunashima, M.D., Ph.D.

Lecturer
Nagafumi Doi, M.D., Ph.D.,

Masatoshi Shibayama, M.D., Ph.D.,

Mieko Chinzei, M.D., Ph.D.,

Kiyoto Kasai, M.D., Ph.D.

Associate
Masuhiro Sakata, M.D.,

Tatsuo Samejima, M.D.,

Kotaro Kudo, M.D., Ph.D.,

Yuka Obi, M.D.,

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

Yasushi Nomura, M.D.

Homepage http://npsy.umin.ac.jp/
Introduction and Organization
The Department of Neuropsychiatry is Japan's oldest
psychiatric department which was established in 1886.
"Anti-Psychiatry" movement for the last 3 decades had
highly negative effects on the progress in all aspects of
our activities. However, since 1994, our department has
been normalized and restarted to play a leading role inpsychiatry in Japan. Now the Department of Neuropsychiatry provides a wide-ranged clinical, training,
and research services. Since May 2002, we have beenworking in the new closed ward (34 beds) and in the
open ward (20 beds). Moreover, since 2000, we havebeen supported by a government grant for basic andclinical neuroscience in stress-related disorders including posttraumatic stress disorder (PTSD). Since 2005,
we have begun to focus on basic and clinical neuroscience in pervasive developmental disorders (PDDs).

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

psychiatrists, 4 clinical psychologists, 2 trained nurses,
and 1 psychiatric social worker. Approximately 1200
new patients visited yearly (2005), and the total visits
per year was about 35,000 (140 per day).
The secluded ward has 34 beds including 3 seclusion
rooms. We also have 20 beds for psychiatric use in a
general ward. Approximately 350 patients with various
psychiatric disorders were admitted in a year (2005),
about one-third of whom were referred from the emergency unit. Occupational therapy, recreational therapy,
group therapy, and art therapy are performed.
We established Japan’s first child psychiatry day careunit in national university hospitals in 1967. As children
with Down’s syndrome began to be accepted into nurseries and kindergartens around the year 1975, the focusof this division shifted to the psychological pedagogyof autism. Treatment of autism changed along with theunderstanding of the clinical condition, from behavioral
therapy to cognitive development based therapy. Since
1997, our division was reduced in size and an improved
therapy system, “developmental psychology outpatient
clinic” was established. This outpatient clinic encom-

97

passes individual treatment and psychological counseling by clinical psychologists under the supervision of
psychiatrists. Our staff includes 1 full-time psychiatrists,
4 part-time psychiatrists, and 3 clinical psychologists.
We provide care for 260 autistic or developmentallydisabled children per year. Since 2000, a short term
therapy group program has started. Parents participatedin the treatment program alongside the staff members.
This not only emphasizes the therapy of the child, but
assesses their developmental level from many directions. The purpose of the therapy program is to help
parents gain a better understanding of children’s disability and to help them to acquire a more supportiverole for their children in the home environment. Since
2005, we have established clinical and educational center for developmental disorders, and provided clinicaland educational activities in pervasive developmental
disorders.

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

Research activities
Stress- It is well accepted that neuropeptide Y (NPY)
is involved in anxiolytic-like effects and anti-stress effects. Pharmacological and behavioral studies haveconsistently indicated that these effects are mainly mediated through an activation of NPY Y1 receptor in thebrain. To further elucidate the functional role of Y1 receptor, we have evaluated the histological and behavioral changes in Y1 receptor-deficient mice, after an
exposure to 2h of restraint stress. Trimethyltin (TMT), a
neurotoxic organotin, has been shown to cause selective
loss of pyramidal neurons in the rat hippocampus,
similar to stress-induced hippocampal changes. Several
recent studies in animal models of brain ischemia revealed the neuroprotective properties of tacrolimus(FK506), a potent immunosuppressant used in organtransplants. Therefore, we have investigated the effectof FK-506 on the neuronal death and apoptosis in the
hippocampus after TMT intoxication, using immunohistochemistry and TUNEL method.
Epilepsy- Systemic injection of kainic acid in rat
causes severe convulsions, increased seizure susceptibility and seizure-induced neuronal death. Since precise
mechanisms of various anticonvulsants are still unclear,
we have investigated to elucidate whether these anticonvulsants demonstrate neuroprotective effects on
kainic acid-induced neuronal death in the hippocampus.
Environmental endocrine disrupter- Bisphenol-A(BPA), one of environmental endocrine disrupters, isreleased from polycarbonate plastics, and is known to
mimic oestrogens in their action. Recent studies reported that prenatal and neonatal exposure to low-dose
bisphenol-A modulates the sexual differentiation of
behavior and the central dopaminargic effects in vivo
and in vitro. We examine the effects of BPA on the behavior, memory and the expression of estrogen-alphareceptor in the brain of rats exposed to BPA during thefetal and suckling periods at a dosage far less than the
no-observed-adverse-effect level.
Genetic Research- The Genetic Research Group of
the department is investigating genetic as well as environmental mechanism of psychiatric disorders. A major
focus of the studies is exploration of susceptibility
genes of the disorders including schizophrenia, infantile
autism, their spectrum disorders and anxiety disorder(mainly panic disorder). A number of candidates of thesusceptible genes are studied using case-control and
TDT (transmission disequilibrium test) designs. We areat present achieving most interesting results in the investigations of DISC1, Neuregulin1 and other candidate
genes in schizophrenia and the chromosome 7 genes in
infantile autism. Another focus is investigation of genesthat affect the development of personality.
Neuroimaging- Our group plays a leading role inpsychiatric neuroimaging in Japan. Our research aims
at multi-modality neuroimaging (structural and functional MRI, MR spectroscopy, EEG, MEG, near-infrared spectroscopy (NIRS), PET) in schizophrenia, mooddisorders, pervasive developmental disorders, and posttraumatic stress disorder (PTSD).
Clinical Pharmacology- The atypical neuroleptics
have been widely prescribed in our country. They con-

98

tribute to the reduction of uncomfortable side effects
and the improvement of the patient’s QOL. But the
typical neuroleptics still have been used because of
their sedative effects particularly in acute state of
Schizophrenia. We have been investigating a voluntary
clinical research, which contain the practical evaluation
to the treatment of atypical neuroleptics for acute psychotic state in Schizophrenia.
Recently the abnormal glucose tolerance induced byatypical neuroleptics had been reported and some accidental hyperglycemia had happened in our country, too.
Though there are many reports involving to this problem in foreign country, few detailed investigation was
performed in Japan until now. We are preparing to examine the glucose tolerance of inpatients that aretreated by neuroleptics in collaboration with many hospitals and expect that the frequency of risk and someactual factors will be revealed.
Neuropathological study of dementias- Our interest is
neuropathological background of dementia, especially
NFT-predominant form of dementia (NFTD). NFTD isa sporadic subset of dementia pathologically characterized by abundant and almost exclusive appearance of
NFTs in the limbic areas with scarcity of senile plaques.
Our study suggests that pathogenetic background of
NFTD may be different from that of AD and cognitive
decline in NFT-SC may be affected not only by severityof NFT pathology but also by coexisting vascular lesions and/or argyrophilic grains.

References
1. Abe O, Masutani Y, Aoki S, Yamasue H, Yamada H,
Kasai K, Mori H, Hayashi N, Masumoto T, Ohtomo K: Topography of the human corpus callosum
using diffusion tensor tractography. Journal ofComputer Assisted Tomography 28:533-539,2004
2. Abe O, Yamada H, Masutani Y, Aoki S, Kunimatsu
A, Yamasue H, Fukuda R, Kasai K, Hayashi N,
Msumoto T, Mori H, Soma T, Ohtomo K: Amyotrophic lateral sclerosis: diffusion tensor tractography and voxel-based analysis. NMR in Biomedicine17:411-416,2004
3. Yoshinaga C, Kadomoto I, Otani T, Sasaki T, Kato
N: Prevalence of post-traumatic stress disorder inincarcerated juvenile delinquents in Japan. Psychiatry and Clinical Neurosciences 58:383-388,

2004
4. Hamakawa H, Murashita J, Yamada N, Inubushi T,
Kato N, Kato T: Reduced intracellular pH in thebasal ganglia and whole brain measured by
31P-MRS in bipolar disorder.
Psychiatry and Clinical Neurosciences 58:82-88,
2004
5. Kakiuchi C, Ishiwata M, Umekage T, Tochigi M,
Kohda K, Sasaki T, Kato T: Association of the
XBPI-116C/G polymorphism with schizophrenia in
the Japanese population. Psychiatry and Clinical
Neurosciences 58:438-440,2004
6. Kasai K, McCarley RW, Salisbury DF, Onitsuka T,
Memeo S, Yurgelum-Todd D, Kikinis R, Jolesz FA,
Shenton ME: Cavum septipellucidi in parients with
first-episode schizophrenia and firstepisode affective psychosis. Schizophrenia Research 71: 65-76,
2004
7. Kato C, Umekage T, Tochigi M, Otowa K, Hibino
H, Ohtani T, Kohda K, Kato N, Sasaki T: Mitochondrial DNA polymorphisms and extraversion.
American Journal of Medical Genetics 128:76-79,
2004
8. Kudo N, Nakagome K, Kasai K, Araki T, Fukuda
M, Kato N, Iwanami A: Effects of corollary discharge on event-related potentials during selective
attention task in healthy men and women. Neuroscience Research 48:59-64,2004
9. Liu Y, Imai H, Sadamatsu M, Tsunashima K, Kato
N: Cytokines participate in neuronal death inducedby trimethyltin in the rat hippocampus via type II
glucocorticoid receptors. Neuroscience Research
50:209-217,2004
10. Marui T, Hashimoto O, Nanba E, Kato C, Tochigi
M, Umekage T, Ishijima M, Kohda K, Kato N, Sasaki T: An association between the neurofibromatosis-1(NF1)locus and autism in the Japanese
population. American Journal of Medical Genetics
13:43-47,2004
11. Marui T, Hashimoto O, Nanba E, Kato C, Tochigi
M, Umekage T, Kato M, Sasaki T: Gastrin-releasing peptide receptor(GRPG) locus in
Japanese subjects with autism. Brain and Development 26:5-7,2004
12. Matsuo K, Watanabe A, OnoderaY, Kato N, Kato T:
Prefrontal hemodynamic response to verbal fluency
task and hyperventilation in bipolar disorder meas-

99

ured by multi-channel near-infrared spectroscopy.
Journal of Affective Disorders 82: 85-92,2004
13. Ohtani T, Iwanami A, Kasai K, Yamasue H, Kato T,
Sasaki T, Kato N: PTSD symptoms in victims ofTokyo subway attack. Psychiatry and Clinical
Neurosciences 58 :624-9,2004
14. Onitsuka T, Shenton ME, Salisbury DF, Dickey CC,
Kasai K, Toner SK, Frumin M, Kikinis R, Jolesz
FA, McCarley RW: Middle and inferior temporalgyrus gray matter volume abnormalities in chronic
schizophrenia: an MRI study. American Journal of
Psychiatry 161:1603-1611,2004
15. Rogers M, Kasai K, Matsuo K, Fukuda R, Iwanami
A, Nakagome K, Fukuda M, Kato N: Executive
and prefrontal dysfunction in depression: a reviewof neuropsychological and imaging evidence. Neuroscience Research 50:1-11,2004
16. Tochigi M, Marumo K, Hibino H, Otowa T, Kato C,
Marui T, Araki T, Otani T, Umekage T, Kato N,
Sasaki T: Season of birth effect on personality in a
general population. Neuroscience Letters 365:120123,2004
17. Tochigi M, Okazaki Y, Kato N, Sasaki T: Whatcauses the seasonality of birth in schizophrenia?
Neuroscience Research 48:1-11,2004
18. Tochigi M, Zhang X, Umekage T, Ohashi J, Kato C,
Marui T, Otowa T, Hibino H, Otani T, Kohda K,
Liu S, Kato N, Tokunaga K, Sasaki T: Associationof six polymorphisms of the NOTCH4 gene withschizophrenia in the Japanese population. American
Journal of Medical Genetics 128:37-40, 2004
19. Watanabe A, Matsuo K, Kato N, Kato T: Cerebrovascular response to cognitive tasks and hyperventilation measured by multi-channel near-infrared spectroscopy. The Journal of Neuropsychiatry
and Clinical Neurosciences 15:442-449,2004
20. Yamasue H, Iwanami A, Hirayasu Y, Yamada H,
Abe O, Kuroki N, Fukuda R, Tsujii K, Aoki S, Ohtomo K, Kato N, Kasai K: Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: An MRI parcellation
study. Psychiatry Research Neuroimaging 131:195207,2004
21. Yamasue H, Yamada H, Yumoto M, Kamio S, Kudo
N, Uetsuki M, Abe O, Fukuda R, Aoki S, Ohtomo
K, Iwanami A, Kato N, Kasai K: Abnormal association between reduced magnetic mismatch field

to speech sounds and smaller left planum temporale
volume in schizophrenia. Neuroimage 22:720727,2004
22. Yoshinaga C, Kadomoto I, Otani T, Sasaki T, Kato
N: Prevalence of PTSD in incarcerated juvenile delinquents in Japan. Psychiatric and Clinical Neurosciences 58:383-388,2004
23. Araki T, Kasai K, Nakagome K, Fukuda M, Itoh K,
Koshida I, Kato N, Iwanami A: Brain electric activity for active inhibition of auditory irrelevant information. Neuroscience Letters 374:11-6, 2005
24. Araki T, Kasai K, Yamasue H, Kato N, Kudo N,
Ohtani T, Nakagome K, Kirihara K, Yamada H,
Abe O, Iwanami A: Association between lower
P300 amplitude and smaller anterior cingulate cortex volume in patients with posttraumatic stressdisorder: a study of victims of Tokyo subway sarin
attack. Neuroimage 25:43-50, 2005
25. Araki T, Kasai K, Nakagome K, Fukuda M, Itoh K,
Koshida I, Kato N, Iwanami A: Brain electric activity for active inhibition of auditory irrelevant information. Neuroscience Letters 374:11-16, 2005
26. Araki T, Yamasue H, Sumiyoshi T, Kuwabara H,
Suga M, Iwanami A, Kato N, Kasai K: Perospirone
in the treatment of schizophrenia: Effect on verbal
memory organization. Progress in Neuropsychopharmacology and Biological Psychiatry, in press
27. Fujimura Y, Ikoma Y, Yasuno F, Suhara T, Ota M,
Matsumoto R, Nozaki S, Takano A, Kosaka J,
Zhang M.-R, Nakao R, Suzuki K, Kato N, Ito H:
Quantitative analyses of [18F]FEDAA1106 binding
to peripheral benzodiazepine receptors in living
human brain. Journal of Nuclear Medicine, in press
28. Ishijima M, Watanabe K, Kasai K, Kato N, Sasaki
T: No association of FOXP2 and PTPRZ1 on 7q31
with autism from the Japanese population. Neuroscience Research 53:91-94, 2005
29. Kaiya H, Umekage T, Harada S, Okazaki Y, Sasaki
T: Factors associated with the development ofpanic attack and panic disorder: a survey in theJapanese population. Psychiatry and Clinical Neurosciences 59:177-82, 2005
30. Kakiuchi C, Ishiwata M, Nanko S, Kunugi H, Minabe Y, Nakamura K, Mori N, Fujii K, Umekage T,
Tochigi M, Kohda K, Sasaki T, Yamada K, Yoshikawa T, Kato T: Functional polymorphisms of
HSPA5: Possible association with bipolar disorder.

100

Biochemical and Biophysical Research Communications 336:1136-1143, 2005
31. Kasai K, Hashimoto O, Kawakubo Y, Yumoto M,
Kamio S, Itoh K, Koshida I, Iwanami A, Nakagome K, Fukuda M, Yamasue H, Yamada H, Abe O,
Aoki S, Kato N: Delayed automatic detection ofchange in speech sounds in adults with autism: amagnetoencephalographic study. Clinical Neurophysiology 116:1655-1664, 2005
32. Kato C, Kakiuchi C, Umekage T, Tochigi M, Kato
N, Kato T, Sasaki T: The XBP1 gene polymorphism and personality. American Journal of Medicine Genetics 136B:103-105, 2005
33. Kazuno AA, Munakata K, Mori K, Tanaka M,
Nanko S, Kunugi H, Umekage T, Tochigi M,
Kohda K, Sasaki T, Akiyama T, Washizuka S, Kato
N, Kato T: Mitochondrial DNA sequence analysis
of patients with 'atypical psychosis'. Psychiatry andClinical Neurosciences 59:497-503, 2005
34. Kirihara K, Araki T, Kasai K, Maeda K, Hata A,
Uetsuki M, Yamasue H, Rogers MA, Kato N, Iwanami A: Confirmation of a relationship between
reduced auditory P300 amplitude and thought disorder in schizophrenia. Schizophrenia Research, inpress
35. Kohda K, Jinde S, Iwamoto K, Bundo M, Kato N,
Kato T: Maternal separation stress drastically decreases expression of transthyretin in the brains ofadult rat offspring. The International Journal of
Neuropsychopharmacology 9:1-8, 2005
36. Kudo N, Kasai K, Itoh K, Koshida I, Yumoto M,
Kato M, Kamio S, Araki T, Nakagome K, Fukuda
M, Yamasue H, Yamada H, Abe O, Kato N, Iwanami A: Comparison between mismatch negativity
amplitude and magnetic mismatch field strength innormal adults. Biological Psychology, in press
37. Maeda K, Nakagome K, Kasai K, Ikebuchi E, Iwanami A, Kudo N, Araki T, Fukuda M: Electrophysiological indices associated with social functioning outcome in schizophrenia: a 5-year follow
up study. Neuroscience Research 51:215-218, 2005
38. Matsumoto S, Akiyama T, Tsuda H, Miyake Y,
Kawamura Y, Akiskal KK, Akiskal HS: Reliability
and validity of TEMPS-A in a Japanese nonclinicalpopulation:Application to unipolar and bipolar depressives. Journal of Affective Disorders, in press
39. Matsuo K, Onodera Y, Hamamoto T, Muraki K,

Kato N, Kato T: Hypofrontality and microvascular
dysregulation in remitted late-onset depression assessed by functional near-infrared spectroscopy.
Neuroimage 26:234-242, 2005
40. Sakamoto H, Fukuda R, Okuaki T, Machida T, Shirouzu I, Kasai K, Yamasue H, Akiyama T, Kato N:
Parahippocampal activation evoked by masked
traumatic images in posttraumatic stress disorder: afunctional MRI study. Neuroimage 26:813-821,
2005
41. Nishimura T, Schwarzer C.,Gasser N.,Kato
N,Vezzani A.,Sperk G: Altered expression of
GABAa and GABAb receptor submit mRNAs in
the hippocampus after kindling and electrically induced status epilepticus. Neuroscience
134:691-704, 2005
42. Ohtani T, Matsuo K, Kasai K, Kato T, Kato N:
Hemodynamic response to emotional memory recall with eye movement. Neuroscience Letters
380:75-79, 2005
43. Onitsuka T, Nestor PG, Gurrera RJ, Shenton ME,
Kasai K, Frumin M, Niznikiewicz MA, McCarley
RW: Association between reduced extraversion andright posterior fusiform gyrus gray matter reduction
in chronic schizophrenia. American Journal of
Psychiatry 162:559-601, 2005
44. Paraguison RC.,Higaki K, Sakamoto Y, Hashimoto
O, Miyake N, Matsumoto H, Yamamoto K, Sasaki
T, Kato N, Nanba E: Polyhistidine Tract Expansions in HOXA1 Result in Intranuclear Aggregation and Increased Cell Death. Biochemical andBiophysical Research Communications, in press
45. Takemura N: Evidence for neurogenesis within thewhite matter beneath the temporal neocortex of theadult rat brain. Neuroscience 134:121-32, 2005
46. Tochigi M, Onai T, Narita K, Hibino H, Rogers M,
Umekage T, Kohda K, Otani T, Kanamori R, Kato
N, Sasaki T: Seasonality of schizophrenia births in
the Japanese population: increased winter births
possibly confined to the north area. Schizophrenia
Research 75:433-438, 2005
47. Tochigi M, Umekage T, Kato C, Marui T, Otowa T,
Hibino H, Otani T, Kohda K, Kato N, Sasaki T:
Serotonin 2A receptor gene polymorphism andpersonality traits: no evidence for significant association. Psychiatric Genetics 15: 67-69, 2005
48. Tochigi M, Otani T, Yamasue H, Kasai K, Kato T,

101

Iwanami A, Kato N, Sasaki T: Support for relationship between serum cholinesterase and posttraumatic stress disorder: 5-year follow-ups of victims of the Tokyo subway sarin poisoning. Neuroscience Research 52:129-131, 2005
49. Tochigi M, Otowa T, Hibino H, Kato C, Otani T,
Umekage T, Utsumi T, Kato N, Sasaki T: Combined Analysis of Association between personality
Traits and Three Functional Polymorphisms in the
Tyrosine Hydroxylase, Monoamine Oxidase A, andCatechol-O-methyltransferase Genes. Neuroscience
Research, in press
50. Yamasue H, Ishijima M, Abe O, Sasaki T, Yamada
H, Suga M, Rogers M, Minowa I, Someya R, Kurita H, Aoki S, Kato N, Kasai K: Neuroanatomy inmonozygotic twins with Asperger disorder discordant for comorbid depression. Neurology 65:491492, 2005
51. Yoshikawa E, Matsuoka Y, Yamasue H, Inagaki M,
Nakano T, Akechi T, Kobayakawa M, Fujimori M,
Nakaya N, Akizuki N, Imoto S, Murakami K, Kasai K, Uchitomi Y: Prefrontal cortex and amygdalavolume in first minor or major depressive episodeafter cancer diagnosis. Biological Psychiatry, inpress
52. Zhang X, Tochigi M, Ohashi J, Maeda K, Kato T,
Okazaki Y, Kato N, Tokunaga K, Sawa A, Sasaki T:
Association study of the DISC1/TRAX locus withschizophrenia in a Japanese population. Schizophrenia Research, in press

102

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

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

Lecturer
Yoshikazu Ugawwa, M.D., Ph.D.
Jun Goto, M.D., Ph.D.

Associate
Jun Shimizu, M.D.,Ph.D.,

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

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

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

Yuji Takahashi, M.D.,PhD.

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

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

In the in patient ward, we offer programs for postgraduate education including the program for the firststage postgraduate education. We also offer the excellent training program with the goal to get the board of
Neurologist. In 2005, we initiated deep brain stimulation for the treatment of movement disorders in cooperation with Department of Neurosurgery. Clinical trials
including that for polyglutamine disease and that basedon vestibular nerve stimulation are being conducted.

Teaching activities
As for under-graduate education, our department
takes a part in lectures of Neurology for the 4th and 5th
grade medical students, and bed-side learning for the
5th grade medical students, and clinical clerkship forthe 6th grade medical students.
In the bed-side learning we include small group lectures covering neurological examination, neurophysiology, neuroradiology, neuropathology, neuropsychology, neuroimmunology, and neurogenetics. We are also
putting our effort for Free Quarters where we offer

103

various opportunities for medical students to be involved in research activities, and 2-3 medical students
are conducting their research activities in the laboratories.
In postgraduate education we offer the integrated
program including Neurology as the part of the program of Internal Medicine.
For training of board-certified Neurologists, we offer
the excellent program including patients’care, training
in Neurophysiology and Neuropathology, consultation
for Neurology, and supervising of junior trainees. This
program is integrated with clinical practice at the affiliated hospitals where rich experience is obtained fornumerous cases in Clinical Neurology.
In Graduate School, we offer highly advanced research activities based on the interest of graduate students. In 2003, 21st Century COE program started in
the Neuroscience Division, and we are putting our effort to establish excellent Institution for Neuroscience
integrating basic and clinical neuroscience fields.

Research activities
Our research field covers broad fields related to neurological diseases, with the goals to elucidate themechanisms of neurological diseases, and to eventuallydevelop new therapeutic strategies. Our research activities include molecular genetics, developmental biology,
cell biology, pharmacology, pathology, and physiology.
We aim to integrate these broad research fields to better
contribute to clinical neurology.
In the filed of molecular genetics, we have develop ahigh throughput DNA-microarray-based diagnostic
system. This system provides comprehensive analysesof genes including those for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and familial spastic paraplegia. We have initiated multicenter-based consortium for multiple system atrophy. A
large-scale genome-wide analyses are being conducted
to identify disease susceptibility genes. We have established excellent animal models for dentatorubral-pallidoluysian atrophy, and conducting studies fordevelopment of therapeutics. As the new protein degradation pathway, the role of autophagy was investigated. The molecular mechanisms of neurodegenerationin SCA17, another polyglutamine disease, were investigated. (Tsuji, S., Goto, J., Shimizu, J., Nakamura, K.,

Takahashi, Y., Momose, Y., Date, H., Iwata, A., Jin, Y.,
Zhou, J., , Ruberu, R.P.T., Ruberu, N.N., Suzuki, K.,
Nakahara, Y., Seki, N., Deoka, K.)
We have demonstrated that RNA editing of glutamate
receptor subunit GluR2 was significantly reduced in
motor neurons in sporadic ALS patients in a neuronalclass-selective and disease-specific manner. Since thismolecular change is the primary causes of neuronal
death, research work on elucidation of the underlying
molecular mechanism and development of specifictherapy for sporadic ALS is undergoing. We have been
investigating to what extent the vestibular nerve stimulation is beneficial for alleviating parkinsonism andorthostatic hypotension in patients with Parkinson disease and Shy-Drager syndrome. Validity of a wearable
accelerometer in evaluating anti-parkinsonism medication in outpatient clinic has been also under investigation. (Kwak S., Kawahara. Y., Sun, H., Pan, W.D.,
Hideyama, T.,Nishimoto, Y., Ito, K.)
The human neurophysiology section has been studying normal function of the human brain and pathophysiology for neurological disorders using several
non-invasive physiological methods, such as TMS, EEG,
MEG, fMRI, NIRS. Our final goal is to develop a new
therapeutic method for intractable disorders. One ofthem is deep brain stimulation (DBS) which has been
partly established. We began a physiological approachto elucidate the mechanisms for DBS in the patients.
We have also recently developed a new, highly effective
TMS method to induce a long term effects on the human brain using repetitive, monophasic magnetic stimuli. We have just stared a project to treat patients withmovement disorders, intractable pain, epilepsy and soon using that new treatment. (Ugawa, Y., Terao, Y.,
Hanajima, R., Okabe, S., Arai, N., Terada, S., Yugeta, A.,
Hamada, M., Furubayashi, T., Mizuno, Y., Shirasawa,
H., Machii, K.)
In the field of neuromuscular diseases, we provide
diagnosis of neuromuscular pathology (muscle andnerve biopsies) and autoantibody testing. Our neuromuscular pathology service evaluates approximately
100 neuromuscular biopsy specimens each year. In research field, we focus on exploring the mechanism of
inflammatory myopathies and immune mediated neuropathies. We also focus on establishing improved
methods of diagnosis and treatment of these diseases.
Using clinical, pathological and molecular techniques,

104

we aim to increase understanding of the etiology andpathogenesis of neuromuscular diseases. (Shimizu, J.,
Kowa, H., Mikata, T., Sugimoto, I., Kano, S., Uchinokura, A., Tokimura, N., Tajiri, M., Mashiko, R.)

References
1. Date H, Igarashi S, Sano Y, Takahashi T, Takahashi
T, Takano H, Tsuji S, Nishizawa M, Onodera O.
The FHA domain of aprataxin interacts with the
C-terminal region of XRCC1. Biochem Biophys
Res Commun 2004;325 (4):1279-85.
2. Hara K, Fukushima T, Suzuki T, Shimohata T,
Oyake M, Ishiguro H, Hirota K, Miyashita A, Kuwano R, Kurisaki H, Yomono H, Goto J, Kanazawa
I, Tsuji S. Japanese SCA families with an unusual
phenotype linked to a locus overlapping with
SCA15 locus. Neurology 2004;62(4):648-51.
3. Hayashi T, Ohnishi T, Okabe S, Teramoto N,
Nonaka Y, Watabe H, Imabayashi E, Ohta Y, Jino H,
Ejima N, Sawada T, Iida H, Matsuda H, Ugawa Y.
Long-term effect of motor cortical repetitive transcranial magnetic stimulation. Ann Neurol 2004;56(1):77-85.
4. Hitoshi S, Seaberg RM, Koscik C, Alexson T, Kusunoki S, Kanazawa I, Tsuji S, van der Kooy D.
Primitive neural stem cells from the mammalian
epiblast differentiate to definitive neural stem cells
under the control of Notch signaling. Genes Dev
2004;18(15):1806-11.
5. Iwata NK, Hanajima R, Furubayashi T, Terao Y,
Uesugi H, Shiio Y, Enomoto H, Mochizuki H, Kanazawa I, Ugawa Y. Facilitatory effect on the motor
cortex by electrical stimulation over the cerebellumin humans. Exp Brain Res 2004;159(4):418-24.
6. Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I,
Kwak S. Glutamate receptors: RNA editing anddeath of motor neurons. Nature 2004;427(6977):
801.
7. Kawahara Y, Ito K, Sun H, Ito M, Kanazawa I,
Kwak S. Regulation of glutamate receptor RNA
editing and ADAR mRNA expression in developing human normal and Down's syndrome brains.
Brain Res Dev Brain Res 2004;148(1):151-5.
8. Kawahara Y, Ito K, Sun H, Ito M, Kanazawa I,
Kwak S: GluR4c, an alternative splicing isoform of
GluR4 is abundantly expressed in adult humanbrain. Mol Brain Res 127：150-155, 2004.
9. Kowa H, Sakakura T, Matsuura Y, Wakabayashi T,
Mann DM, Duff K, Tsuji S, Hashimoto T, Iwatsubo
T. Mostly separate distributions of CLAC- versus
Abeta40- or thioflavin S-reactivities in senile
plaques reveal two distinct subpopulations ofbeta-amyloid deposits. Am J Pathol 2004;165(1):273-81.
10. Margolis RL, Holmes SE, Rosenblatt A, Gourley L,
O'Hearn E, Ross CA, Seltzer WK, Walker RH,
Ashizawa T, Rasmussen A, Hayden M, Almqvist
EW, Harris J, Fahn S, MacDonald ME, Mysore J,
Shimohata T, Tsuji S, Potter N, Nakaso K, Adachi
Y, Nakashima K, Bird T, Krause A, Greenstein P.
Huntington's Disease-like 2 (HDL2) in North
America and Japan. Ann Neurol 2004;56(5):670-4.
11. Matsumoto M, Yada M, Hatakeyama S, Ishimoto H,
Tanimura T, Tsuji S, Kakizuka A, Kitagawa M,
Nakayama KI. Molecular clearance of ataxin-3 isregulated by a mammalian E4. EMBO J 2004;23(3):659-69.
12. Mochizuki H, Terao Y, Okabe S, Furubayashi T,
Arai N, Iwata NK, Hanajima R, Kamakura K, Motoyoshi K, Ugawa Y. Effects of motor corticalstimulation on the excitability of contralateral motor and sensory cortices. Exp Brain Res 2004;158(4):519-26.
13. Ohnishi T, Matsuda H, Imabayashi E, Okabe S,
Takano H, Arai N, Ugawa Y. rCBF changes elicitedby rTMS over DLPFC in humans. Suppl Clin
Neurophysiol 2004;57:715-20.
14. Ohtake H, Limprasert P, Fan Y, Onodera O, Kakita
A, Takahashi H, Bonner LT, Tsuang DW, Murray
IV, Lee VM, Trojanowski JQ, Ishikawa A, Idezuka
J, Murata M, Toda T, Bird TD, Leverenz JB, Tsuji
S, La Spada AR. Beta-synuclein gene alterations indementia with Lewy bodies. Neurology 2004;63(5): 805-11.
15. Ohtake H, Shimohata T, Terajima K, Kimura T, Jo
R, Kaseda R, Iizuka O, Takano M, Akaiwa Y, Goto
H, Kobayashi H, Sugai T, Muratake T, Hosoki T,
Shioiri T, Okamoto K, Onodera O, Tanaka K,
Someya T, Nakada T, Tsuji S. Adult-onset leukoencephalopathy with vanishing white matter witha missense mutation in EIF2B5. Neurology 2004;
62 (9):1601-3.
16. Sano Y, Date H, Igarashi S, Onodera O, Oyake M,

105

Takahashi T, Hayashi S, Morimatsu M, Takahashi
H, Makifuchi T, Fukuhara N, Tsuji S. Aprataxin,
the causative protein for EAOH is a nuclear proteinwith a potential role as a DNA repair protein. Ann
Neurol 2004;55(2):241-9.
17. Struzik ZR, Hayano J, Sakata S, Kwak S, and Yamamoto Y:1/f scaling in heart rate requires antagonistic autonomic control. Physical Review E 70:
050901(R)-1-4, 2004.
18. Tamura Y, Hoshiyama M, Inui K, Nakata H, Qiu Y,
Ugawa Y, Inoue K, Kakigi R. Facilitation ofA[delta]-fiber-mediated acute pain by repetitivetranscranial magnetic stimulation. Neurology 2004;
62(12):2176-81.
19. Tamura Y, Okabe S, Ohnishi T, N Saito D, Arai N,
Mochio S, Inoue K, Ugawa Y. Effects of 1-Hz repetitive transcranial magnetic stimulation on acutepain induced by capsaicin. Pain 2004;107(1-2):
107-15.
20. Tan CF, Piao YS, Hayashi S, Obata H, Umeda Y,
Sato M, Fukushima T, Nakano R, Tsuji S, Takahashi H. Familial amyotrophic lateral sclerosis withbulbar onset and a novel Asp101Tyr Cu/Zn superoxide dismutase gene mutation. Acta Neuropathol(Berl) 2004;108(4):332-6.
21. Tanaka E, Ishii K, Akagi T, Hirai K, Motelica-Heino I, Katayama Y, Higashi H, Hashikawa
T, Tsuji S. A new cytochemical method for ultrastructural localization of Co2+ in rat hippocampal
CA1 pyramidal neurons in vitro. J Neurosci Methods 2004;135(1-2):1-8.
22. Taniguchi M, Utsugi T, Oyama K, Mannen H, Kobayashi M, Tanabe Y, Ogino A, Tsuji S. Genotype
of stearoyl-coA desaturase is associated with fatty
acid composition in Japanese Black cattle. Mamm
Genome 2004;15(2):142-8.
23. Tomimitsu H, Shimizu J, Ishikawa K, Ohkoshi N,
Kanazawa I, Mizusawa H. Distal myopathy withrimmed vacuoles (DMRV): new GNE mutations
and splice variant. Neurology 2004;62(9):1607-10.
24. Toyoshima Y, Yamada M, Onodera O, Shimohata
M, Inenaga C, Fujita N, Morita M, Tsuji S, Takahashi H. SCA17 homozygote showing Huntington's
disease-like phenotype. Ann Neurol 2004;55(2):281-6.
25. Tsuji S. Spinocerebellar ataxia type 17: latest
member of polyglutamine disease group highlights

unanswered questions. Arch Neurol 2004;61(2):183-4.
26. Tsuji S. DNA vaccination may open up a new avenue for treatment of Alzheimer disease. Arch Neurol 2004;61(12):1832.
27. Yamada M, Tan CF, Inenaga C, Tsuji S, Takahashi
H. Sharing of polyglutamine localization by theneuronal nucleus and cytoplasm in CAG-repeat
diseases. Neuropathol Appl Neurobiol 2004;30(6):665-75.
28. Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M,
Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schröder JM, Vance JM,
Battologlu E. Mutations in the mitochondrial
GTPase mitofusin 2 cause Charcot-Marie-Tooth
neuropathy type 2A. Nat Genet 2004;36 (5):44951.
29. Aoki S, Iwata NK, Masutani Y, Yoshida M, Abe O,
Ugawa Y, Masumoto T, Mori H, Hayashi N, Kabasawa H, Kwak S, Takahashi S, Tsuji S, Ohtomo
K. Quantitative evaluation of the pyramidal tract
segmented by diffusion tensor tractography: feasibility study in patients with amyotrophic lateralsclerosis. Radiat Med 2005;23(3):195-9.
30. Arai N, Okabe S, Furubayashi T, Terao Y, Yuasa K,
Ugawa Y. Comparison between short train, monophasic and biphasic repetitive transcranial magnetic
stimulation (rTMS) of the human motor cortex.
Clin Neurophysiol 2005;116 (3):605-13.
31. Funayama M, Hasegawa K, Ohta E, Kawashima N,
Komiyama M, Kowa H, Tsuji S, Obata F. An
LRRK2 mutation as a cause for the parkinsonism
in the original PARK8 family. Ann Neurol
2005;57(6):918-21.
32. Gardner RJ, Knight MA, Hara K, Tsuji S, Forrest
SM, Storey E. Spinocerebellar ataxia type 15.
Cerebellum 2005;4(1):47-50.
33. Hirakawa M, Morita D, Tsuji S, Kusunoki S. Effects of phospholipids on antiganglioside antibody
reactivity in GBS. J Neuroimmunol 2005;159(1-2):
129-32.
34. Iwata NK, Ugawa Y. The effects of cerebellar
stimulation on the motor cortical excitability inneurological disorders: a review. Cerebellum

106

2005;4(4):218-23.
35. Kawahara Y, Ito K, Ito M, Tsuji S, Kwak S. Novel
splice variants of human ADAR2 mRNA: skippingof the exon encoding the dsRNA-binding domains,and multiple C-terminal splice sites. Gene 2005;
363: 193-201.
36. Kawahara Y, Kwak S. Excitotoxicity and ALS:
what is unique about the AMPA receptors expressed on spinal motor neurons? Amyotroph Lateral Scler Other Motor Neuron Disord 2005;6(3):131-44.
37. Kwak S, Kawahara Y: Deficient RNA editing of
GluR2 and neuronal death in ALS, J Mol Med
83:110-120, 2005
38. Miyashita T, Tabuchi A, Fukuchi M, Hara D, Kisukeda T, Shimohata T, Tsuji S, Tsuda M. Interference with activity-dependent transcriptional activation of BDNF gene depending upon the expanded
polyglutamines in neurons. Biochem Biophys Res
Commun 2005;333(4):1241-8.
39. Mochizuki H, Masaki T, Matsushita S, Ugawa Y,
Kamakura K, Arai H, Motoyoshi K, Higuchi S.
Cognitive impairment and diffuse white matter atrophy in alcoholics. Clin Neurophysiol 2005;116(1):223-8.
40. Mochizuki H, Ugawa Y. High-frequency oscillations in somatosensory system. Clin EEG Neurosci
2005;36(4):278-84.
41. Sakuishi K, Hanajima R, Kanazawa I, Ugawa Y.
Periodic motor cortical excitability changes associated with PSDs of EEG in Creutzfeldt-Jakob disease (CJD). Clin Neurophysiol 2005;116(5):1222-6.
42. Shimohata M, Shimohata T, Igarashi S, Naruse S,
Tsuji S. Interference of CREB-dependent transcriptional activation by expanded polyglutamine
stretches--augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases. J Neurochem 2005;93(3):654-63.
43. Sun H, Kawahara Y, Ito K, Kanazawa I, Kwak S:
Expression profile of AMPA receptor subunit
mRNA in single adult rat brain and spinal cord
neurons in situ, Neurosci Res 52:228-234, 2005.
44. Suzuki Y, Takemoto Y, Shimozawa N, Imanaka T,
Kato S, Furuya H, Kaga M, Kato K, Hashimoto N,
Onodera O, Tsuji S. Natural history of X-linked
adrenoleukodystrophy in Japan. Brain Dev 2005;27(5):353-7.
45. Takahashi T, Nozaki K, Tsuji S, Nishizawa M,
Onodera O. Polyglutamine represses cAMP-responsive-element-mediated transcription without
aggregate formation. Neuroreport 2005;16(3):2959.
46. Terao Y, Furubayashi T, Okabe S, Arai N, Mochizuki H, Kobayashi S, Yumoto M, Nishikawa M,
Iwata NK, Ugawa Y. Interhemispheric transmissionof visuomotor information for motor implementation. Cereb Cortex 2005;15(7):1025-36.
47. Yamamoto Y, Struzik ZR, Soma R, Ohashi K,
Kwak S. Noisy vestibular stimulation improvesautonomic and motor responsiveness in central
neurodegenerative disorders. Ann Neurol 2005;58(2):175-81.
48. Kawahara Y, Sun H, Ito K, Hideyama T, Aoki M,
Sobue G, Tsuji S, Kwak S. Underediting of GluR2
mRNA, a neuronal death inducing molecularchange in sporadic ALS, does not occur in motor
neurons in ALS1 or SBMA. Neurosci Res
2006;54(1):11-4.
49. Mitsui J, Saito Y, Momose T, Shimizu J, Arai N,
Shibahara J, Ugawa Y, Kanazawa I, Tsuji S, Murayama S. Pathology of the sympathetic nervous system corresponding to the decreased cardiac uptakein (123)I-metaiodo- benzylguanidine (MIBG) scintigraphy in a patient with Parkinson disease. J
Neurol Sci 2006;243(1-2):101-4.
50. Mochizuki H, Ugawa Y, Terao Y, Sakai KL. Cortical hemoglobin-concentration changes under thecoil induced by single-pulse TMS in humans: a simultaneous recording with near-infrared spectroscopy. Exp Brain Res 2006;169(3):302-10.
51. Struzik ZR, Hayano J, Soma R, Kwak S, Yamamoto Y: Aging of complex heart rate dynamics.
IEEE Transaction of Biomedical Engineering53:
89-94, 2006
52. Terao Y, Mizuno T, Shindoh M, Sakurai Y, Ugawa
Y, Kobayashi S, Nagai C, Furubayashi T, Arai N,
Okabe S, Mochizuki H, Hanajima R, Tsuji S. Vocal
amusia in a professional tango singer due to a rightsuperior temporal cortex infarction. Neuropsychologia 2006;44(3):479-88.
53. Yuasa K, Arai N, Okabe S, Tarusawa Y, Nojima T,
Hanajima R, Terao Y, Ugawa Y. Effects of thirty
minutes mobile phone use on the human sensory

107

cortex. Clin Neurophysiol 2006;117 (4):900-5.

108

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

Associate Professor
Akio Morita, M.D., Ph.D.,

Nobutaka Kawahara, M.D., Ph.D.

Lecturer
Tomoki Todo, M.D., Ph.D.,

Kensuke Kawai, M.D., Ph.D.,

Yasushi Ino, M.D., Ph.D.

Associate
Akira Iijima, M.D.,

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

Jyunichi Tanaka , M.D.,

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

Hirofumi Nakatami, M.D., Ph.D., Keisuke Maruyama, M.D., Ph.D.,

Shigeo Sora, M.D.,
Keisuke Takai, M.D.

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

Clinical activities

The Department of Neurosurgery at the Universityof Tokyo Hospital consists of 14 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research and education. The staffs include
a professor/chairman, two associate professors, threelecturers and nine associates.
Clinical ward for Neurosurgery in our university
hospital was founded in 1951 as the first Neurosurgical clinic in Japan. Dr. Keiji Sano, as the founding
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.

General and specialized outpatient clinics are open
three days a week (Monday, Wednesday and Friday).
New patient are accepted two days a week (Tuesday
and Thursday). Specialized outpatient clinics are open
for patient with brain tumors, pituitary disease, spinal
disease, cerebrovascular disease, epilepsy, and gamma
knife treatment. From April 2004 through March 2005,
12263 patients were treated at the outpatient clinics.
The Neurosurgery Ward has about 40 beds on theseventh floor of the New Hospital Building opened in
Sept. 2001. In 2004 and 2005, 567 and 600 patientswere admitted to the Neurosurgical Ward, respectively.
Three hundred and forty eight and 322 surgical procedures were performed with 126 and 140 gamma
knife precedures in each year. Our practice covers awide variety of neurosurgical diseases including malignant and benign brain tumors, hemorrhagic and occlusive cerebrovascular diseases, spinal disorders,
epilepsy, pain and movement disorders.

109

Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used to preserve brain function as much as possible. Stateof-the-art techniques including intraoperative computer-aided navigation and intravascular procedures
help our continuous effort to increase the safety ofsurgical treatment.
Our department is affiliated with 42 neurosurgicalinstitutions in and around the city of Tokyo including
15 university medical centers, where our residents andstudents are exposed to various pathologies. Surgicalcase volume in all hospitals exceeds 4000cases.

Teaching activities
Medical students take lectures of clinical neurosurgery in their second year. Clinical case studies andbedside teaching are scheduled in the third and fourthyears. The lecturers introduce general Neurosurgery as
well as the state-of-art Neurosurgical practice to thestudents. At the bedside teaching and clinical clerkship,
they are offered opportunities to learn clinical management of Neurosurgical patients in the hands-on
style, and also are exposed to practice in various subspecialties in neurosurgery through special seminars
given by experts in the fields.
We accept 5 residents in 2006 as a new residency
program. These residents are trained in the university
hospital and affiliated hospitals to experience every
aspects of neurosurgical practice for five years in average. Our residency training is finalized after thesixth year, when the finishing residents serve as seniorresident at the university hospital for 6 months. Academic training is provided through numerous intramural clinical and research conference, journal clubs
seminars as well as quarterly regional meeting 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 schoolof Medicine, University of Tokyo, to be involved inadvanced basic research activities for 4 year. Aftercomplete training, our graduates stay in the department to be an associate in our or other university hospitals or become clinical staff in our affiliated hospi-

tals.

Research activities
Clinical research in these two years have mainly
focused on treatment of acoustic neurinoma techniques of skull base surgery, treatment of malignant
brain tumors, radiosurgery and epilepsy surgery. The
results were presented at domestic and international
meetings including Annual Meetings of the Japan
Neurosurgical Society and Annual Meetings ofAmerican 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 isto regenerate 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 byadministration of growth factors. We also succeeded in regeneration of striatal neurons. Molecular mechanisms of adult neurogenesis are
currently investigated using various models toenhance post-ischemic regeneration. By extending
the research into primate model, we are pursuingclinical 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 havenot improved for decades. We develop a new
strategy by using replication-competent herpes
simplex viruses (HSV) that are genetically engineered to replicate in and kill tumor cells but notnormal cells. Using a third-generation oncolytic
HSV, we currently prepare a clinical trial on patients with progressive glioblastoma. Using our
HSV vector construction system, we further create
and test various oncolytic HSV vectors “armed”
with immunostimulatory genes.
We also practice “tailor-made” chemotherapy

110

based on the results of genetic analyses routinely
performed on tumor specimens obtained fromglioma patients. Currently, using polymeric micelles, we develop a new mode of chemo- therapeutic drug delivery system for brain tumors.
3) Traslational research with Department of Engineering
We have developed Slave-Master type micro- surgical robotic system in our medico-engineeringlaboratory. The prototype of our system enabled
micro-anastomosis of very fine arteries in thedepth of 12cm. Also, our system showed very steplearning curve in performing micro-procedures.
The prototype system was demonstrated at EXPO
2005 in Aichi in June 2005, and our basic result
has been presented in international meetings andpublished in following journals.
In the other project, we are developing new drugdelivery system, which can be effectively concentrated to the malignant brain tumors and deliver
effective therapeutic agents.
4) Gamma knife radiosurgery
Our department is the first to introduce gamma
knife radiosurgery in Japan to treat various kindsof intracranial lesions including skull base tumors
or deep-seated brain arteriovenous malformations
with successful clinical result. We have particularly excellent achievement on treatment of brain
arteriovenous malformations; not only imaging
result but also effect on the risk of hemorrhage
was analyzed and reported in NEJM 352:146-53.
Moreover, the integration of diffusion-tensor tractography into gamma knife treatment enabled us
to confirm the dose to the critical white matter fibers inside the brain, which can be performed only
in our department among the world and can leadto safer treatment.
5) Clinical applications of the functional brain imaging for neurosurgery
Our department intensively utilizes various kindsof functional imaging modalities including magnetoencephalography, functional MRI and diffusion tensor imaging-based tractography for presurgical brain mapping. Combining the results ofthe multi-modalities enables to visualize all corti-

cal and subcortical networks of the motor, language and other cognitive 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.
The electrophysiological monitoring such as electrical cortical and subcortical stimulations, anddirect recording of the cortical potentials are simultaneously performed to develop highly reliable
non-invasive techniques of the functional brain
mapping, validating the combined results. Thisclinical research gives favorable potentials to preserve the eloquent brain functions and improve thepatients’ quality of life.
6) Prospective National registry of Unruptured Cerebral Aneurysms: Unruptured Cerebral Aneurysm
Study In Japan (UCAS Japan)
Since 2001, UCAS Japan has been conducted inour department. This is a national study to identify
1)natural course of unruptured cerebral aneurysms
in Japanese population and 2)risks associated withmanagement of unruptured aneurysm in Japaneseinstitutions. Currently we enrolled more than 7000
patients with unruptured cerebral aneurysm foundin 404 institutions and prospective follow-up has
been conducted using on-line registry system.
Since January 2006, UCAS II; prospective Qualityof Life analysis of patients with unruptured cerebral aneurysms has also been started.

References
1. Shojima M, Oshima M, Takagi K, Torii R, Hayakawa M, Katada K, Morita A, Kirino T. Magnitude and role of wall shear stress on cerebral aneurysm: computational fluid dynamic study of 20
middle cerebral artery aneurysms. Stroke. 2004;35(11):2500-5.
2. Maruyama K, Shin M, Kurita H, Kawahara N,
Morita A, Kirino T. Proposed treatment strategy
for cavernous sinus meningiomas: a prospective
study. Neurosurgery. 2004;55(5):1068-75.
3. Morita A, Okada Y, Kitano M, Hori T, Taneda M,
Kirino T. Development of hybrid integrated en-

111

doscope-holder system for endoscopic microneurosurgery. Neurosurgery. 2004;55(4): 926-31.
4. Nikaido H, Tsunoda H, Nishimura Y, Kirino T,
Tanaka T. Potential role for heat shock protein 72
in antagonizing cerebral vasospasm after rat subarachnoid hemorrhage. Circulation. 2004; 110(13):1839-46.
5. Shin M, Maruyama K, Kurita H, Kawamoto S,
Tago M, Terahara A, Morita A, UekiK, Takakura
K, Kirino T. Analysis of nidus obliteration rates
after gamma knife surgery for arteriovenous malformations based on long-term follow-up data: theUniversity of Tokyo experience. J Neurosurg.
2004;101(1): 18-24.
6. Mukasa A, Ueki K, Ge X, Ishikawa S, Ide T, Fujimaki T, Nishikawa R, Asai A, Kirino T, Aburatani H. Selective expression of a subset of neuronal genes in oligodendroglioma with chromosome 1p loss. Brain Pathol. 2004;14(1): 34-42.
7. Kawahara N, Wang Y, Mukasa A, Furuya K, Shimizu T, Hamakubo T, Aburatani H, Kodama T,
Kirino T. Genome-wide gene expression analysis
for induced ischemic tolerance and delayed neuronal death following transient global ischemia inrats. J Cereb Blood Flow Metab. 2004;24(2):21223.
8. Yonekura I, Kawahara N, Nakatomi H, Furuya K,
Kirino T. A model of global cerebral ischemia in
C57 BL/6 mice. J Cereb Blood Flow Metab.
2004;24(2):151-8.
9. Furuya K, Kawahara N, Kawai K, Toyoda T,
Maeda K, Kirino T. Proximal occlusion of the
middle cerebral artery in C57Black6 mice: relationship of patency of the posterior communicating artery, infarct evolution, and animal survival. J
Neurosurg. 2004;100(1): 97-105.
10. Furuya K, Zhu L, Kawahara N, Abe O, Kirino T.
Differences in infarct evolution between
lipopolysaccharide-induced tolerant and nontolerant conditions to focal cerebral ischemia. J
Neurosurg. 2005;103(4):715-23.
11. Morita A, Sora S, Mitsuishi M, Warisawa S, Suruman K, Asai D, Arata J, BabaS, Takahashi H,
Mochizuki R, Kirino T. Microsurgical robotic
system for the deep surgical field: development of

aprototype and feasibility studies in animal andcadaveric models. J Neurosurg. 2005;103(2):3207.
12. Shojima M, Oshima M, Takagi K, Torii R, Nagata
K, Shirouzu I, Morita A, Kirino T. Role of thebloodstream impacting force and the local pressure elevation in therupture of cerebral aneurysms.
Stroke. 2005;36(9):1933-8.
13. Shin M, Kawahara N, Maruyama K, Tago M,
Ueki K, Kirino T. Risk of hemorrhage from an arteriovenous malformation confirmed to have been
obliterated on angiography after stereotactic radiosurgery. J Neurosurg. 2005; 102(5):842-6.
14. Maruyama K, Kamada K, Shin M, Itoh D, Aoki S,
Masutani Y, Tago M, Kirino T. Integration of
three-dimensional corticospinal tractography into
treatment planning for gamma knife surgery. J
Neurosurg. 2005;102(4):673-7.
15. Kamada K, Todo T, Masutani Y, Aoki S, Ino K,
Takano T, Kirino T, Kawahara N, Morita
A.Combined use of tractography-integrated functional neuronavigation and direct fiber stimulation.
J Neurosurg. 2005;102(4):664-72.
16. Morita A, Fujiwara S, Hashi K, Ohtsu H, Kirino T.
Risk of rupture associated with intact cerebral
aneurysms in the Japanese population: a systematic review of the literature from Japan. J Neurosurg. 2005;102(4):601-6.
17. Maruyama K, Kawahara N, Shin M, Tago M, Kishimoto J, Kurita H, Kawamoto S, Morita A, Kirino T. The risk of hemorrhage after radiosurgery
for cerebral arteriovenous malformations. N Engl
J Med. 2005 13;352(2): 146-53.
18. Shimizu T, Imai H, Seki K, Tomizawa S, Nakamura M,. Honda F, Kawahara N, Saito N: Cyclophilin C-associated protein and cyclophilin C
mRNA are upregulated in penumbral neurons andmicroglia after focal cerebral ischemia. J Cereb
Blood Flow Metab 2005;25:325-37,
19. Tanaka M, Ino Y, Nakagawa K, Tago M, Todo T:
High-dose conformal radiotherapy for supratentorial malignant glioma: a historical comparison.
Lancet Oncology 2005;6(12): 953-60.
20. Iijima A, Piotin M, Mounayer C, Spelle L, Weill A,
Moret J. Endovascular treatment with coils of 149

112

middle cerebral artery berry aneurysms. Radiology. 2005;237(2):611-9.

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

⑭

114

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

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

Associate
Shinichi Hashimoto, Ph.D.,

Makoto Haino, M.D., Ph.D.

Nobuyuki Yamazaki,

Takeshi Shimaoka, Ph.D.

Homepage http://www.prevent.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Molecular Preventive Medicine
was established in 1885. It was designed to offer both ahigh level of hygienic education and facilities for specialized research. At present, it is our responsibility togive lectures, seminars and courses for experiments andpractical training on the preventive medicine to thethird grade medical students. The professor, several
invited lecturers (including adjunct staffs) and four research associates take part in the education as well as
research activities. There are over thirty members including research fellows, graduate students and guest
researchers in our department.

Teaching activities
The field of our department covers the wide area of
preventive medicine. The main scope of 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 health and environment. The
education is provided for the third grade medical students. The course is consisted of lectures, seminars,
experiments, and practical training are provided by ourown staffs and also by the experts outside: National
Institute of Infectious Diseases (Dr. Takebe), Yamanashi University (Dr. Matsugo), Mie University (Dr. Kawanishi), Environmental Science Center of The University of Tokyo (Dr. Karima), Health Service Center of
The University of Tokyo (Dr. Okubo), Toyama Medical
and Pharmaceutical University (Dr. Inadera), Kyoto
Prefectural University of Medicine (Dr. Sakai), Shinshu
University (Dr. Fukushima).

Research activities
We focus on several research fields as follows;
1) Establishment of pathophysiological roles ofchemokines and dendritic cells in vivo in various
animal disease models.
2) Molecular analysis of chemokine receptor signaling pathway.
3) Serial analysis of gene expression in various typesof cells and tissues in normal as well as diseasestate4) Development of vaccines against pathogenic microorganisms and cancer5) Establishment of a novel bio-monitoring systemfor environmental chemicals.

115

References
1. Fujimura T, Aiba S, Yoshino Y, Kuroki S, Kimura Y,
Kikuchi K, et al. CCR4 Expression by atypical T
cells in systemic pilotropic lymphoma: its behavior
under treatment with interferon gamma, topical
PUVA and systemic retinoid. Dermatology. 2004;
208(3):221-6.
2. Hashimoto S, Suzuki Y, Kasai Y, Morohoshi K,
Yamada T, Sese J, et al. 5'-end SAGE for the analysis of transcriptional start sites. Nat Biotechnol.
2004 Sep;22(9):1146-9.
3. Hontsu S, Yoneyama H, Ueha S, Terashima Y, Kitabatake M, Nakano A, et al. Visualization of naturally occurring Foxp3+ regulatory T cells in normal
and tumor-bearing mice. Int Immunopharmacol.
2004 Dec 20;4(14):1785-93.
4. Inoue T, Fujishima S, Ikeda E, Yoshie O, Tsukamoto N, Aiso S, et al. CCL22 and CCL17 in rat radiation pneumonitis and in human idiopathic pulmonary fibrosis. Eur Respir J. 2004 Jul;24(1):4956.
5. Ito T, Ishikawa S, Sato T, Akadegawa K, Yurino H,
Kitabatake M, et al. Defective B1 cell homing to
the peritoneal cavity and preferential recruitment of
B1 cells in the target organs in a murine model forsystemic lupus erythematosus. J Immunol. 2004
Mar 15;172(6):3628-34.
6. Kamohara H, Matsuyama W, Shimozato O, Abe K,
Galligan C, Hashimoto S, et al. Regulation of tumour necrosis factor-related apoptosis-inducing
ligand (TRAIL) and TRAIL receptor expression inhuman neutrophils. Immunology. 2004 Feb;111(2):186-94.
7. Katoh S, Matsumoto N, Matsumoto K, Tokojima M,
Ashitani J, Nakamura-Uchiyama F, et al. A possible
role of TARC in antigen-specific Th2-dominant
responses in patients with Paragonimiasis westermani. Int Arch Allergy Immunol. 2004 Jul;134(3):248-52.
8. Kitagawa K, Wada T, Furuichi K, Hashimoto H,
Ishiwata Y, Asano M, et al. Blockade of CCR2
ameliorates progressive fibrosis in kidney. Am J
Pathol. 2004 Jul;165(1):237-46.
9. Kotani M, Kotani T, Ishizaka A, Fujishima S, Koh
H, Tasaka S, et al. Neutrophil depletion attenuatesinterleukin-8 production in mild-overstretch venti-

lated normal rabbit lung. Crit Care Med. 2004
Feb;32(2):514-9.
10. Kuno K, Bannai K, Hakozaki M, Matsushima K,
Hirose K. The carboxyl-terminal half region of
ADAMTS-1 suppresses both tumorigenicity andexperimental tumor metastatic potential. Biochem
Biophys Res Commun. 2004 Jul 9;319(4):1327-33.
11. Matsui M, Araya SI, Wang HY, Matsushima K,
Saida T. Immunomonitoring measures in relapsing-remitting multiple sclerosis. J Neuroimmunol.
2004 Mar;148(1-2):192-9.
12. Morimoto J, Yoneyama H, Shimada A, Shigihara T,
Yamada S, Oikawa Y, et al. CXC chemokine ligand
10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced
beta cell proliferation without affecting insulitis. J
Immunol. 2004 Dec 1;173(11):7017-24.
13. Motomura K, Toyoda N, Oishi K, Sato H, Nagai S,
Hashimoto S, et al. Identification of a host genesubset related to disease prognosis of HIV-1 infected individuals. Int Immunopharmacol. 2004
Dec 20;4(14):1829-36.
14. Nishiwaki T, Yoneyama H, Eishi Y, Matsuo N, Tatsumi K, Kimura H, et al. Indigenous pulmonary
Propionibacterium acnes primes the host in the development of sarcoid-like pulmonary granulomatosis in mice. Am J Pathol. 2004 Aug;165(2):631-9.
15. Niwa R, Shoji-Hosaka E, Sakurada M, Shinkawa T,
Uchida K, Nakamura K, et al. Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 withenhanced antibody-dependent cellular cytotoxicity
shows potent therapeutic activity to T-cell leukemia
and lymphoma. Cancer Res. 2004 Mar 15;64(6):2127-33.
16. Sato T, Ishikawa S, Akadegawa K, Ito T, Yurino H,
Kitabatake M, et al. Aberrant B1 cell migration into
the thymus results in activation of CD4 T cells
through its potent antigen-presenting activity in thedevelopment of murine lupus. Eur J Immunol. 2004
Dec;34(12):3346-58.
17. Wada T, Furuichi K, Sakai N, Iwata Y, Kitagawa K,
Ishida Y, et al. Gene therapy via blockade ofmonocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol. 2004 Apr;15(4):940-8.
18. Yanaba K, Mukaida N, Matsushima K, Murphy PM,
Takehara K, Sato S. Role of C-C chemokine receptors 1 and 5 and CCL3/macrophage inflamma-116

tory protein-1alpha in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects
by compensatory chemokine production. Eur J
Immunol. 2004 Dec;34(12):3553-61.
19. Yoneyama H, Matsuno K, Zhang Y, Nishiwaki T,
Kitabatake M, Ueha S, et al. Evidence for recruitment of plasmacytoid dendritic cell precursors to
inflamed lymph nodes through high endothelial
venules. Int Immunol. 2004 Jul;16(7):915-28.
20. Yoshimura-Uchiyama C, Iikura M, Yamaguchi M,
Nagase H, Ishii A, Matsushima K, et al. Differential modulation of human basophil functions throughprostaglandin D2 receptors DP and chemoattractant
receptor-homologous molecule expressed on Th2
cells/DP2. Clin Exp Allergy. 2004 Aug;34(8):1283-90.
21. Yurino H, Ishikawa S, Sato T, Akadegawa K, Ito T,
Ueha S, et al. Endocrine disruptors (environmental
estrogens) enhance autoantibody production by B1
cells. Toxicol Sci. 2004 Sep;81(1):139-47.
22. Zhang Y, Yoneyama H, Wang Y, Ishikawa S,
Hashimoto S, Gao JL, et al. Mobilization of dendritic cell precursors into the circulation by administration of MIP-1alpha in mice. J Natl Cancer
Inst. 2004 Feb 4;96(3):201-9.
23. Akadegawa K, Ishikawa S, Sato T, Suzuki J, Yurino
H, Kitabatake M, et al. Breakdown of mucosal
immunity in the gut and resultant systemic sensitization by oral antigens in a murine model for systemic lupus erythematosus. J Immunol. 2005 May
1;174(9):5499-506.
24. Hashida N, Ohguro N, Nakai K, Kobashi-Hashida
M, Hashimoto S, Matsushima K, et al. Microarray
analysis of cytokine and chemokine gene expression after prednisolone treatment in murine experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4224-34.
25. Iizasa H, Yoneyama H, Mukaida N, Katakoka Y,
Naito M, Yoshida N, et al. Exacerbation of granuloma formation in IL-1 receptor antagonist- deficient mice with impaired dendritic cell maturation
associated with Th2 cytokine production. J Immunol. 2005 Mar 15;174(6):3273-80.
26. Kasai Y, Hashimoto S, Yamada T, Sese J, Sugano S,
Matsushima K, et al. 5'SAGE: 5'-end Serial Analysis of Gene Expression database. Nucleic Acids
Res. 2005 Jan 1;33(Database issue):D550-2.

27. Matsui M, Araya S, Wang HY, Matsushima K,
Saida T. Differences in systemic and central nervous system cellular immunity relevant to relapsing-remitting multiple sclerosis. J Neurol. 2005
Aug;252(8):908-15.
28. Matsuzaki Y, Hashimoto S, Fujita T, Suzuki T,
Sakurai T, Matsushima K, et al. Systematic identification of human melanoma antigens using serial
analysis of gene expression (SAGE). J Immunother.
2005 Jan-Feb;28(1):10-9.
29. Niwa R, Sakurada M, Kobayashi Y, Uehara A, Matsushima K, Ueda R, et al. Enhanced natural killer
cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellularcytotoxicity induction at lower antigen density.
Clin Cancer Res. 2005 Mar 15;11(6):2327-36.
30. Shigihara T, Shimada A, Oikawa Y, Yoneyama H,
Kanazawa Y, Okubo Y, et al. CXCL10 DNA vaccination prevents spontaneous diabetes throughenhanced beta cell proliferation in NOD mice. J
Immunol. 2005 Dec 15;175(12):8401-8.
31. Shozu M, Minami N, Yokoyama H, Inoue M, Kurihara H, Matsushima K, et al. ADAMTS-1 is involved in normal follicular development, ovulatory
process and organization of the medullary vascular
network in the ovary. J Mol Endocrinol. 2005
Oct;35(2):343-55.
32. Takeuchi A, Usui Y, Takeuchi M, Hattori T, Kezuka
T, Suzuki J, et al. CCR5-deficient mice develop
experimental autoimmune uveoretinitis in the context of a deviant effector response. Invest Ophthalmol Vis Sci. 2005 Oct;46(10):3753-60.
33. Terashima Y, Onai N, Murai M, Enomoto M,
Poonpiriya V, Hamada T, et al. Pivotal function forcytoplasmic protein FROUNT in CCR2-mediatedmonocyte chemotaxis. Nat Immunol. 2005 Aug;6(8):827-35.
34. Tokuyama H, Ueha S, Kurachi M, Matsushima K,
Moriyasu F, Blumberg RS, et al. The simultaneous
blockade of chemokine receptors CCR2, CCR5 andCXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated colitis. Int Immunol. 2005 Aug;17(8):1023-34.
35. Yoneyama H, Matsuno K, Toda E, Nishiwaki T,
Matsuo N, Nakano A, et al. Plasmacytoid DCs help
lymph node DCs to induce anti-HSV CTLs. J Exp

117

Med. 2005 Aug 1;202(3):425-35.

118

Department of Public HealthProfessor
Yasuki Kobayashi, M.D.,Ph.D.

Associate Professor
Kazuo Inoue, M.D., Ph.D.

Lecturer
Hajime Sato, M.D., M.P.H., Ph.D., D.P.H.

Associate
Satoshi Toyokawa, Ph.D.

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

Teaching activities

Public health departments in medical schools in Japan were introduced after the World War II, following
the model of the U.S. systems for public health andmedical education. The Department of Public Healthwas established in 1947, in the Faculty of Medicine, theUniversity of Tokyo. In 1995, the Department became apart of the Division of Social Medicine, Graduate
School of Medicine, as the result of the shift to a
graduate school system in the University of Tokyo.
The objectives of the Department are both education
and research of public health. The Department trains
graduate and undergraduate students through lectures,
seminars, field practice, and laboratory work in publichealth and occupational medicine, for the degrees ofMedical Doctor (MD), Master of Medical Sciences(MSc), and Doctor of Medical Sciences (equivalent to
Ph.D.).
The Department has conducted research on a wide
variety of public health issues, including health policy
and economics, occupational medicine, community andclinical epidemiology, and so on. In addition, the staff
members of the Department have offered public andoccupational health services to the governments, industries, and local communities.

1) Graduate Program
The Department offers special lectures, seminars,
field practice, and laboratory work on public health andoccupational medicine to graduate students. In thesetraining, special emphasis has been placed on the following points: (1) how to conduct epidemiologicalstudies, (2) how to use epidemiological and statisticalmethods, (3) how to use economic concepts and methods in the health fields, (4) how to establish the collaboration with health professionals in the various fields,and (5) how to read and write original papers.
Part of the seminars described above has been formally open to all students in the Graduate School of
Medicine as an intensive practice course on study
methods in public health. At the same time, the Department has provided the students enrolling in the
Master of Medical Science program with a short course
on public health.
2) Undergraduate Program
In the winter term of the second year in the School of
Medicine (M2), students are provided with the following lectures: (1) current issues in the field of publichealth, (2) preventive services, (3) epidemiology, (4)119health economics, (5) community health (6) occupational and environmental health, (7) infection and tuberculosis control, (8) behavioral medicine, (9) international health, and (10) health policy in Japan. Similarly,
in the fourth year (M4), a concentration course of public health (e.g., health care systems, occupational medicine, and community health practice) is provided. All
the above lectures are given by faculty members andpart-time lectures including governmental officials.
Field practice and laboratory work in public health isdue in the spring term of M3, which is jointly provided
by Department of Molecular Preventive Medicine andthe other departments related to public health fields.
Averagely four to five students (small group) are assigned to one special topic group with a tutor (a faculty
member or part-time lecturer). Each group conducts
field practice, review work, or laboratory work andwrites a report in the style of original or review paper.
The reports submitted are bound and made available tothose students in subsequent years.
The Department also provides those lectures related
to public health and occupational medicine for undergraduate students in the School of Health Sciences andNursing, and the Faculty of Engineering.

Research activities
1) Health policy and economics
We are interested in the topics of health care systemand economics in general. We have performed and published those studies related to supply and demand sidesof health services in Japan; such as supply and distribution of physicians, the separation of pharmaceuticaldispensing and prescribing in medical practice, coststudies of outpatient and inpatient services, and the efficiency and equity issues of the Japan's health insurance system. We have also carried on several policy
studies from international comparative perspectives,
especially tobacco smoking control, and patient isolation policy for Hansen’s disease. These studies havebeen published in some international policy journals.
Recently, we started a collaborative study on a system
of HIV/AIDS care with the introduction of highly active anti-retroviral therapy (HAART) in developing
countries, since such a system involves medical, behavioral, social, and economic factors, and would inevitably become an important health policy issue.

2) Occupational health
We have tackled the issues of health effects of leadand other heavy metals and solvents, and health effectsof pesticides in developing countries as part of the Alliance for Global Sustainability project. We have also
been interested in epidemiology and prevention oflife-style diseases and mental problems among workers
in various occupational settings.
3) Community and clinical epidemiology
We have done several epidemiological studies incommunity, such as active life expectancy for thecommunity elderly, as well as those studies in clinicalepidemiology. Most of these studies have been carriedon in collaboration with local communities or clinicaldepartments.
In relation to the above activities, two events should
be noted: (1) Dr. Kazuo Inoue hosted the 9th Academic
Meeting of Emergency Medicine for Rural Areas andRemote Islands in 2005, and (2) Dr. Hajime Sato wasawarded the 2005 Walter Beach Award jointly by the
Policy Study Organization (Washington D.C.) and theSouthern Political Science Association (Georgia) in the
United States.

References
1. Ogata Y, Kobayashi Y, Fukuda T, Mori K, Hashimoto M, Otosaka K. Measuring relative work values for home care nursing services in Japan. Nursing Research 2004; 53: 145-153.
2. Tanihara S, Kobayashi Y. Sequential evaluation of
the national medical expenditures for asthma carein Japan. Journal of Epidemiology 2004; 14: 100103.
3. Ueno S, Yokoyama K, Okuno M, Wang RS, Fujioka Y, Kobayashi Y. Effects of static load on theweight and protein content in the leg muscles of themouse: a simulation of prolonged standing in theworkplace. Industrial Health 2004; 42: 401-407.
4. Inoue K, Matsumoto M. Japan’s new postgraduate
medical training system. Clinical Teacher 2004; 1:
39-41.
5. Kobayashi Y. Japan’s new postgraduate training
system. Clinical Teacher 2004; 1: 107-108.
6. Ishizaki T, Kai I, Kobayashi Y, Matsuyama Y,

120

Imanaka Y. The effect of aging on functional decline among older Japanese living in a community:
a 5-year longitudinal data analysis. Aging Clinicaland Experimental Research 2004; 16: 233-239.
7. Inoue K. Highly pathogenic Avian Flu, Japan.
Emerging Infectious Disease 2004; 10: 1327- 1328.
8. Matsumoto M, Okayama M, Inoue K, Kajii E.
High-tech rural clinics and hospitals in Japan: acomparison to the Japanese average. Australian
Journal of Rural Health 2004; 12: 215-219.
9. Matsumoto M, Inoue K. Innovative research from arural practice: a blue dahlia? Australian Journal of
Rural Health 2004; 12: 224-225.
10. Miyairi T, Takamoto S, Kotsuka Y, Takeuchi A,
Yamanaka K, Sato H. Neurocognitive outcome after retrograde cerebral perfusion. Annals of Thoracic Surgery 2004; 77: 1630-1635.
11. Miyaji K, Murakami A, Sato H, Takamoto S. The
limiting factors for transxiphoid approach in congenital cardiac surgery. Heart Surgery Forum 2004;
7: E250-253.
12. Chei C, Toyokawa S, Kano K. Gender differencesin obesity among preschool children in Ibaraki
prefecture. Japanese Journal of Health and Human
Ecology 2004; 70: 77-83.
13. Nakata A, Haratani T, Takahashi M, Kawakami N,
Arito H, Kobayashi F, Fujioka Y, Fukui S, Araki S.
Association of sickness absence with poor sleep
and depressive symptoms in shift workers. Chronobiology International 2004; 21: 899-912.
14. Sakami S, Maeda M, Maruoka T, Nakata A, Komaki G, Kawamura N. Positive coping up-and
down-regulates in vitro cytokine productions fromT cells dependent on stress levels. Psychother Psychosom 2004; 73: 243-251.
15. Matsumoto M, Okayama M, Inoue K, Kajii E.
Factors associated with rural doctors' intention tocontinue a rural career: a survey of 3072 doctors inJapan. Australian Journal of Rural Health 2005; 13:219-225.
16. Osuga Y, Hayashi K, Kobayashi Y, Toyokawa S,
Momoeda M, Koga K, Yoshino O, Tsusmi O, Hoshida H, Terakawa N, Taketani Y. Dysmenorrhea inJapanese women. International Journal of Gynecology & Obstetrics. 2005; 88: 82-83.
17. Inoue K, Kobayashi Y, Hanamura H, Toyokawa S.
Association of periodontitis with increased whiteblood cell count and blood pressure. Blood Pressure 2005; 14: 53-58.
18. Waza K, Antonnette G, Stephen Z, Inoue K, Sasaki
M, Okajima Y, Ishibashi Y. A pilot study on using
patient health questionnaire in the primary care setting in Japan. General Medicine 2005; 6 : 9-15.
19. Nakata A, Ikeda T, Takahashi M, Haratani T, Fujioka Y, Fukui S, Swanson NG, Hojou M, Araki S.
Sleep-related risk of occupational injuries in Japanese small and medium-scale enterprises. Industrial
Health 2005; 43: 89–97.
20. Sato H, Akabayashi A, Kai I. Public appraisal ofgovernment efforts and participation intent in medico-ethical policymaking in Japan: the case of brain
death and organ transplant. BMC Medical Ethics
2005; 6: 1-12.
21. Sato H, Akabayashi A. Bioethical policymaking on
advanced medical technologies: Institutional characteristics and citizen participation in eight OECD
countries. Review of Policy Research 2005; 22:571-587.
22. Sato H, Frantz JE. Termination of the leprosy isolation policy in the US and Japan - science, policychanges, and the garbage can model. BMC International Health and Human Rights 2005; 5: 1-16.
23. Frantz JE, Sato H. The fertile soil of policy learning: Hansen's disease policy in US and Japan. Policy Sciences 2005; 38: 159-176.
24. Kimura K, Yokoyama K, Sato H, Nordin RB, Naing L, Kimura S, Okabe S, Maeno T, Kobayashi Y,
Kitamura F, Araki S. Effects of pesticides on peripheral and central nervous system functions intobacco farmers in Malaysia - studies on peripheral
nerve conduction, brain-evoked potentials andcomputerized tomography. Industrial Health 2005;
43: 285-294.
25. Kitajima T, Kobayashi Y, Chaipah W, Sato H,
Toyokawa S, Chadbunchachai W, Thuennadee W.
Access to antiretroviral therapy among HIV/AIDS
patients in Khon Kaen province, Thailand. AIDS
Care 2005; 17: 359-366.
26. Miyairi T, Takamoto S, Kotsuka Y, Takeuchi
A,Yamanaka K, Sato H. Comparison of neurocognitive results after coronary artery bypass grafting
and thoracic aortic surgery using retrograde cerebral perfusion. European Journal of Cardio-Thoracic Surgery 2005; 28: 97-103.

121

27. Nakajima J, Sato H, Takamoto S. Is preoperativetransbronchial biopsy worsen the postsurgicalprognosis of lung cancer? - a propensity score-adjusted analysis. Chest 2005; 128: 3512- 3518.
28. Toyokawa S, Kobayashi Y, Ohmori M. A refined
method for estimating medical expenditures forliver disease using the patient survey and claim
data in Japan. Japanese Journal of Public Health
2005; 52: 957-961.
29. Maeno T, Ohta A, Hayashi K, Kobayashi Y, Mizunuma H, Nakai S, Ohashi Y, Suzuki S. Impact ofreproductive experience on women’s smoking behaviour in Japanese nurses. Public Health 2005;
119: 816-824.

122

Department of Radiological Health
Associate
Akinori Morita, Ph.D.

Homepage http://plaza.umin.ac.jp/~uthouki/index.html
Introduction and Organization
The Department of Radiological Health was originally established in 1961 as a joint department of university’s central institution for education & research ofpeaceful use of atomic energy. The research fields ofthis department are fundamental and applied radiological protection and safety. After the retirement of Professor Yoshiro Aoki, Professor Norio Suzuki of the Department of Radiation Oncology concurrently held theprofessorship of the Department from 2000 to his retirement in March 2003. Since 2000, the Department
has been in collaboration with the Department of Radiation Oncology at the same working place. In April
2003, Department of Radiation Oncology and Radiation
Research Institute were integrated into Section of Radiation Biology as a division of Center for Disease Biology and Integrative Medicine. Thus, the Departmentof Radiological Health is now in collaboration with theSection of Radiation Biology.

Teaching activities
Education for the second- and forth-year medical students was provided as courses of the biological effectsof radiation, the radiological protection and the radiological health. Each course consisted of lectures andexperiments, through which the students learned theconcept of radiological protection and the practicaltechniques of radiological safety for workers and clinical patients. The third-year students of health science
course were also provided with a course of radiation
hygiene, which consisted of lectures and experiments.
The students learned the concepts of radiological protection, techniques of risk assessments of radiation andpractical technique of radiation safety for workers andthe public. The students learned the concepts of radiation safety and hygiene for vocational and medical use.
The department provided the special lectures on theradioecology, the environmental radiation risk assessment and radiological protection for post-graduatedstudents. After the retirement of Professor Suzuki, theSection of Radiation Biology has covered these teaching activities.

Research activities
The experimental researches in the Department hadcovered many fields such as biological effects, risk assessment, computer simulation of biological effects andbio-kinetics, and risk management. The main focuses ofresearch activities had been the following categories;
1) Radiological protection for patients and workers inmedical field.
2) Risk assessment and risk perception of low doseradiation.
3) Radiation-induced carcinogenesis.
4) The combined effects of radiation and chemical
agents on embryos/fetuses.
5) Bio-kinetics of radionuclides in fetus body anddose estimation of internal exposure to fetuses.
6) The embryonic and fetal effects of non-ionizing
radiation.
7) Estimation of body compositions with whole body
gamma counter.
8) Medical emergency plans for workers in nuclear
accidents.
9) Means of health care for victims of atomic explosions in Hiroshima and Nagasaki.
10) The methods of health control of workers of nu-

123clear power plants.
Current research activities are focused on development of a new method of radiation protection based on
regulation of p53.

References (April 2004-March 2006)
1. Morita A, Zhu J, Suzuki N, Enomoto A, Matsumoto Y, Tomita M, Suzuki T, Ohtomo K, Hosoi Y.
Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis byinactivating p53. Cell Death Differ. 2006; 13: 499511.
2. Li Z, Hosoi Y, Cai K, Tanno Y, Matsumoto Y,
Enomoto A, Morita A, Nakagawa K, Miyagawa. K.
Src tyrosine kinase inhibitor PP2 suppresses
ERK1/2 activation and epidermal growth factor receptor transactivation by X-irradiation. Biochem.
Biophys. Res. Commun. 2006; 341: 363-68.
3. Komiyama S, Taniguchi S, Matsumoto Y, Tsunoda
E, Ohto T, Suzuki Y, Yin H-L, Tomita M, Enomoto
A, Morita A, Suzuki T, Ohtomo K, Hosoi Y, Suzuki
N. Potentiality of DNA-dependent protein kinase tophosphorylate Ser46 of human p53. Biochem.
Biophys. Res. Commun. 2004; 323: 816-22.
4. Yin H-L, Suzuki Y, Matsumoto Y, Tomita M, Furusawa Y, Enomoto A, Morita A, Aoki M, Yatagai Y,
Suzuki T, Hosoi Y, Suzuki N. Hyperthermic radiosensitization in chiken B lymphocyte cell line
DT40 lacking non-homologous end-joining and/or
homologous recombination pathways of DNA double-strand break repair. Radiat. Res. 2004; 162:
433-41.
5. Hosoi Y, Matsumoto Y, Enomoto A, Morita A,
Green J, Nakagawa K, Naruse K, Suzuki N. Suramin sensitizes cells to ionizing radiation by inactivating DNA-dependent protein kinase. Radiat. Res.
2004; 162: 308-14.

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

⑮

126

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

Lecturer
Koichi Uemura, M.D., Ph.D.

Associate
Kaori Shintani, Ph.D.,

Kou Takahashi, M.D, Ph.D.

Homepage http://plaza.umin.ac.jp/~forensic/
Introduction and Organization
Our department was founded as the first departmentof forensic medicine in Japan in 1888. Actually Associate Professor Kuniyoshi Katayama had already lectured
in “judicial medicine” to students in University of Tokyo in 1882. Professor Katayama insisted that theyshould merely study judicial medicine as well as trial
relations in depth on the legislation, so he renamed “judicial medicine” to “forensic medicine” in 1891. Professor Katayama was the first professor in our department, and he held additional post of neuropsychiatry
professor.
Professor Sadanori Mita was famous as a serologist,
and he was founded the serological department (thedepartment of Immunology) in University of Tokyo. He
discovered the antigen-antibody reaction and complement fixation reaction.
Professor Tanemoto Furuhata was the first person of
an ABO blood group system study, and he contributed
the development of criminology. He autopsied somecases to be left in criminology, too.
Professor Shokichi Ueno studied serelogy, he wasdiscovered the complex III. In the time of Professor
Ueno, the first national detective examiner class was
performed.
In the time of Professor Toshiyuki Miki, he was notable to autopsy for University of Tokyo dispute for four
years. However, he left many achievements in a studyof a blood type and performed a paternity test.
Profssor Ikuo Ishiyama contributed to forensic pathology. He introduced DNA fingerprint and PCR technique into forensic medicine.
Professor Takehiko Takatori studied the formation of
adipocere biochemically. He dissected the sarin subway
attacks in Tokyo and specified the cause of death wassarin.(?)
Now Professor Ken-ichi Yoshida studied the cause ofdeath investigation system of a medical malpractice, adissection system as well as heart-related sudden death.
He performs a medical care-related death model trialfrom 2005.
The staff of our department consists of one professor,
one lecturer, two associate, one special technician, one
technician, five postgraduate students and one researcher.

Forensic autopsy
The determination of precise cause of death is themost important work in our department. So we autopsy
80-90 criminal cases in eastern part of Tokyo every year.
We have already autopsied more than 10000 cases since1889. Some of these cases are very famous in criminology in Japan.
In forensic autopsy, we examine the pathological,
drinking, toxicological and blood type testing of eachcase, too. Finally, forensic pathologists in our depart-

127

ment diagnose the cause of death. Official documents
written in our forensic judgments are so precious that
we keep them since first autopsy case in 1889. We haveserious responsibility in the determination of cause ofdeath.
Recently, we are often confronted with various problems such as medical accidents and malpractice.
In our department, we provide detective examiners opportunities to learn forensic autopsy, they will conduct
on the first line of crime investigation in Japan.

2) Forensic practices are associated with various legal
or social problems of medicine, and so our doctor
course students who graduated from the faculty oflaw conduct attitude surveys of “unusual death”,
information disclosure after autopsy on the legal
and social issues associated with medical acts.

References1.

Teaching activities
As for under-graduate education, our department
takes a part in systemic lectures for the 6th year medical students, Free Quarter training course for the 3-4thyear medical students, and Clinical Clerkship learning
for the 5th year medical students.
In systemic lectures, comprehensive presentation for
the understanding of basic knowledge about the forensic medicine, the detail exposition of forensic cases isperformed.
Clinical clerkship at the 5th year of the educational
program is the early exposure to the forensic practice,several lectures about body phenomenon, injury, asphyxia, internal sudden death, disturbance from abnormal circumstances, poisoning, forensic odontology,
object inspection and forensic training are provided fora relatively long period (for one month). In Free Quarter training course for the 3-4th year medical students,
they have opportunities to experience forensic duty
works for 2 weeks.

4.

Research activities

6.

Our research is wide ranged from social issues tomolecular biology. Main research interest in our department is as follows:
1) More than two thirds of the causes of unusual death
are ischemic heart disease. Psychic stress from accidents, assaults, overwork and physical restriction
often trigger off these deaths.
So our laboratory specializes in myocardial andnerve cell disorders after ischemia, and the roles ofmolecular mechanism of cell death. We also study
differences of cell response, change of cytoskeleton
after ischemia or stress

2.

3.

5.

7.

8.

9.

Yoshida K, Uemura K, Shintani-Ishida K. Calpain in
myocardial ischemia-reperfusion and related diseases.
Molecular Mechanism of Heart Diseases. 2005; 149165.
Uemura K. Fujimiya T, Ohbora Y, Yasuhara M, Yoshida K. Individual differences in the kinetics of alcohol absorption and elimination: A human study. Forensic Sci Med Pathol 20051: 27-30.
Uemura K, Adachi-Akahane S, Shintani-Ishida K,
Yoshida K. Carbon monoxide protects cardiomyogenic cells against ischemic death through L-type
Ca2+ channel inhibition. Biochem Biophys Res
Commun 2005 334(2): 661-668.
Uemura K, Saka K, Kikuchi Y, Shintani-Ishida K,
Yoshida K. An autopsy case of strangulation with fatal
blood concentration of pentobarbital: simultaneous
drug analyses by GC/MS and LC/MS. Res Prac
Forens Med 2005 48:225-30.
Hoshino S, Kikuchi Y, Nakajima M, Kimura H, Takenaka S, Uemura K, Yoshida K. Endothelial NO
synthase (eNOS) phosphorylation regulates coronary
diameter during ischemia-reperfusion in association
with oxidative stress. Free Radic Res. 2005 39:481489.
Ikegaya H, ZhengH-Y, Saukko PJ, Varesmaa-KorhoneL, Hpvi T, Vesikari T, Takasaka T, Sugitomo C, Kitamura T, Yogo Y. Genetic Deversity of JC Virus in the
Saami and the Finns: Inplications for their Population
History. Am. J. Physical Anthropol. 2005 128(1): 185193.
Ikegaya H, Iwase H, Zheng H-Y, Nakajima M, Sakurada K, Takatori T, Fukayama M, Yogo Y. JC Virusgenotyping using formalin-fixed, paraffin-embedded
renal tissues. J Virol Methods. 2005 126: 37-43.
Ikegaya H, Kato A, Kumatno S, Tomonaga T. Correlation between age and the efficacy of ESWL. BJU Int.
2005 96(7): 1145
Sakurada K, Sakai I, Sekiguchi L, Shiraishi T, Ike-

128

gaya H, Yoshida K. Usefulness of a latex agglutination assay for FDP D-dimer to demonstrate the presence of postmortem blood. Int J Legal Med.2005
119(3): 167-171.
10. Ohnishi ST, Ohnishi T, Muranaka S, Fujita H, Kimura
H, Uemura K, Yoshida K, Utsumi K. A possible siteof superoxide generation in the complex I segment of
rat heart mitochondria. J Bioenerg Biomembr.2005
37(1): 1-15.
11. Zheng HY, Kojima K, Ikegaya H, Takasaka T, Kitamura T, Yogo Y. JC Virus genotyping suggests a closeaffinity between Greenland Inuit and other circumartic populations. Anthoropological Science. 2005
113: 291-293.
12. Zheng HY, Takasaka T, Noda K, Kanazawa A, Mori H,
Kabuki T, Joh T, Oh-ishi T, Ikegaya H, Nagashima K,
Hall WW, Kitamura T, Yogo Y. New sequence polymorphisms in the outer loops of the JC polymavirus
major capsid protein (VP1) possibly associated with
progressive multifocal leukoencephalopathy. J Gen.Virol.
2005 86: 2035-2045.
13. Zheng JY, Ikegaya H, Takasaka T, Matsushima-Ohno
T, Sakurai M, Kanazawa I, Kishida S, Nagashima K,
Kitamura T. Characterization of the VP1 loop mutations widespread among JC virus polyomavirus isolates associated with progressive multifocal leukoencephalopathy. Biochem Biophys Res Commun. 2005
333: 996-1002.
14. Zheng JY, Kojima H, Ikegaya H, Takasaka T, Kitamura T, Yogo Y. JC Virus genotyping suggests a closeaffinity between Greenland Inuit and other circumartic populations. Anthoropological Science. 2005
113: 291-293.
15. Yoshioka N, Adachi J, Ueno Y, Yoshida K. Oxysterols
increase in diabetic rats. Free Radic Res.2005 39(3):299-304.
16. Kimura H, Liu S, Yamada S, Uchida U, Matsumoto K,
Yoshida K. Rapid increase in serum lipid peroxide
4-hydroxynoneal (HNE) in early endo-toxemia. Free
Radic Res.2005: 845-851.
17. Nishio H, Takai S, Miyazaki M, Horiuchi H, Osawa
M,Uemura K, Yoshida K, Mukaida M, Ueno Y, Suzuki K. Usefulness of serum mast cell-specific chymase levels for postmortem diagnosis of anaphylaxis.
Int J Legal Med.2005 119(6): 331-334.
18. Sakurada K. Ikegaya H, Motani H, Iwase H, Sekiguch
K, alutsu T, Yoshino M, Takatori T, Sakai I. JC virus

genotyping can be used to narrow down the native
place of persons from urine stains. Jpn. J. Forensic
Sci.Tech. 2005 10(2): 111-117.
19. Kikuchi Y, Iwase H, Nakajima M, Uemura K, Ikegaya
H, Shintani K, Takeichi H, Nakamura M, Yoshida
K.Utility of the Method of Injecting Poster Color
Pigment Solution for Detection of Vascular Injury
Sites in Forensic Autopsy. Res. Pract. Forens. Med.
2005 48: 135-141.
20. Uemura K, Nakajima M, Yamauchi U, Fukayama M,
Yoshida K. Sudden death of a patient with primary
hypereosinophilia, colon tumours, and pulmonary
emboli. J Clin Pathol 2004 57(5): 541-543.
21. Ikegaya H, Heino J, Laaksonen H, Toivonen S, Kalimo H, Saukko P. Accumulation of plasma proteinsin Purkinje cells as an indicator of blood-brain barrier
breakdown. Forensic Sci Int 2004 146:121-4.
22. Hatanaka K, Kawata H, Toyofuku T, Yoshida K.
Down-regulation of connexin43 in early myocardialischemia and protective effect by ischemic preconditioning in rat hearts in vivo. Jpn Heart J 2004 45(6):1007-19.
23. Mizukami Y, Iwamatsu A, Aki T, Kimura M, Nakamura K, Nao T, Okusa T, Matsuzaki M, Yoshida K,
Kobayashi S. ERK1/2 regulates intracellular ATP
levels through alpha-enolase expression in cardiomyocytes exposed to ischemic hypoxia and reoxygenation. J Biol Chem 2004 279(48): 50120-31.
24. Morimoto K, Kurahashi Y, Shintani-Ishida K,
Kawamura N, Miyashita M, Uji M, Tan N, Yoshida K.
Estrogen replacement suppresses stress-induced cardiovascular responses in ovariectomized rats. Am J
Physiol Heart Circ Physiol 2004 287(5): H1950-6.
25. Fujimoto H, Ohno M, Ayabe S, Kobayashi H, Ishizaka N, Kimura H, Yoshida K, Nagai R. Carbon
monoxide protects against cardiac ischemia-reperfusion
injury in vivo via MAPK and Akt-eNOS pathways.
Arterioscler Thromb Vasc Biol 2004 24(10): 1848-53.
26. Kuzumoto N, Kitagawa Y, Uemura K, Ueyama T,
Yoshida K, Furuya H, Takaki M. A brief regional
ischemic-reperfusion enhances propofol-induced depression in left ventricular function of in situ rat
hearts. Anesthesiology 2004 101(4): 879-87.

27. Zheng HY, Zhao P, Suganami H, Ohasi Y, Ikegaya H,
Kim JC, Sugimoto C, Takasaka T, Kitamura T, Yogo
Y. Regional distribution of two related Northeast
Asian genotypes of JC virus, CY-a and -b: Implica-

129

tions for the dispersal of Northeast Asians. Microbes
Infect 2004 6: 596-603.

130

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

Homepage http://www.m.u-tokyo.ac.jp/medinfo/
Introduction and Organization
The Department of Medical Informatics and Economics aims to reform medical systems and make social contribution by applying information technology to
medical field such as medical economics and hospitalmanagement. The department develops basic methods
that are applicable to medical information systems inthe 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, next-generation electronic health record systems, virtual health care environment, computer representations and standardizationof medical concepts, ontology, medical knowledge engineering, hospital epidemiology, quality assessment ofhealthcare, clinical and bioinformatics engineering,privacy protection and encryption, analysis of hospitalmanagement, safety management in healthcare.
The professor of the department also holds the postof director of the department planning, information andmanagement (DPIM) in the University of Tokyo Hospital. DPIM is the department that deals with information analyses and future planning for the University ofTokyo Hospital by using information systems as well as
the planning, design, development, and operation of
information systems for the whole hospital. The DPIM
was newly established on April 1, 2003, after integration of the Hospital Computer Center and the project
team for hospital development, which separately ex-

isted 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 are promoted together with DPIM activities. Only one professor is the official faculty member of the Department ofMedical Informatics and Economics, however, facultyoutside the department participates as teaching staffs ofthe graduate course: Assoc. prof. T. Imamura and Lecturer. K. Miyo from DPIM, Prof. T. Kiuchi from UMIN
center, Visiting assoc. prof. S. Oku from the Department of Healthcare Related Informatics that is the affiliated department (April 2004 - ), Visiting assoc. Prof.
H. Hashimoto from the Department of Health Management and Policy that is also the affiliated department(Oct. 2005 - ), Assoc. Prof. R.Yamamoto from Interfaculty Initiative in Information Studies, Graduate Schoolof Interdisciplinary Information Studies, and Prof. H.
Oyama and Assoc. Prof. Y. Onogi from Division ofClinical and Bioinformatics Engineering, Departmentof Clinical Bioinformatics, Graduate School of Medicine.
The origin of the Department of Medical Informatics
and Economics dates back to 1983 when the hospitalcomputer center was officially approved as one of thecentral clinical service facilities in the hospital. At thesame time, the doctor’s course for medical informatics
was established. In accordance with the reform to theuniversity with graduate school curriculum in the university of Tokyo, the Department of Medical Informatics and economics was established in present divisionof social medicine in 1997. Then, one professor and one

131

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

Teaching activities
The department offers the Medical Science Doctoral
course (4-year program). The eligibility for admission
is open to those who graduate from a 6-year undergraduate program at the School of Medicine and those
who have master’s degrees either in the University ofTokyo or any other institutions. It does not need to havea medical license to apply for admission. Students will
receive Doctor’s degree in Medical Science with completion of required units and passing a doctoral thesis.
The department is collaborating with the health informatics course in the division of Health Sciences andNursing at the Graduate School of Medicine. Although
the department formally belongs to the Division of Social Medicine, it offers the course of health informatics
for students in the division of Health Sciences andNursing. Therefore most faculty members in this department also supervise the students in the Health Informatics course. The Health Informatics course offers
2-year master’s course program and 3-year doctoral
course program. Completing required units and passing
thesis, the master’s course students will receive Master’s degree in Health Science and the doctoral course
student will receive Doctor’s degree in Health Science.
Furthermore our department accepts the students inthe master’s course of Medical Science. The purpose ofthis course is to foster research and technical professionals who did not graduate from 6-year undergraduate
program but has wishes to take the doctoral course of
Medical Science in the university of Tokyo. It is required for students in the master’s course of Medical

Science to pass the interview examination in order toenroll the doctoral course.
In this master’s course, all students spend the first
four months on the planned coursework, then will decide which department they wish to be enrolled. Afterassignment of each department, students conduct theirresearches and complete master’s thesis over remaining
one and half year. Completing the required units andpassing the thesis, they will receive the Master’s degree
in Medical Science.
The enrolled students in FY2004 are seven in doctor’s course for Medical Informatics and Economics,
two in master’s course for Health Informatics, and two
in master’s course for Medical Science. The students in
FY2005 are six in doctor’s course for Medical Informatics and Economics, one in doctor’s course of Health
Informatics, one in master’s course of Health Informatics, and one for master’s course of Medical Science.
The students’ researches cover various topics. The
main ones are the analysis of medical cost for the DPC
Classification”, development of method for mapping
Japanese standard terminology of disease Names toEnglish SNOMED-CT, a study on the Reference Functional Model for standard EHR systems, a study on thecommunication model for healthcare institution, a study
on methods for healthcare safety control, and medical
support by electronic description format of chemical
therapy regimen and inference mechanism.

Research activities
Our main research domains are 1) application studies
on developments of clinical information systems as
typified by hospital information system and electronic
health records system, 2) studies on medical safetycontrol systems, 3)medical knowledge discovery andanalysis of medical economics indicators by using databases of hospital information system and electronic
health records system, 4) structured representations andstandardization of medical terms and concepts, 5) privacy protection and security in healthcare information
systems, 6) information analysis on food safety, 7)
analysis of various issues on DPC, 8) application ofvirtual environment for healthcare.
In these domains, major research topics are as listed
below.

1321) The development of information model ofbasic functions required for Standardized
Electronic Health Records (EHR) Systems(Research on Health Technology Assessment
H15-IRYOU-046 from Health and Labour
Sciences Research Grants, 2003-2004)
This research surveys the required functions for
EHR systems. Based on the survey result, the functional model for standard EHR systems is constructed. The standardization of function provided
by various EHR systems is expected to be promoted.
2) A study on satisfaction of medical informationneeds and the protection of personal information in
EHR (Gran-in-Aid for Scientific Research on Priority Areas (2) No.16016227 from Ministry of
Education, Culture, Sports, Science and Technology, 2003-2005)
In the age that EHR is widely used, it will increase
the possibility that clinical information in EHR
may be accessed and referred by more clinicalstaffs than that in paper-base health records. Although it has some advantages, the disadvantagethat clinical information is accessed by the staff
that has no need to refer the information exists.
This research discusses how to control the unnecessary access by analyzing system log.
3) A study on development methods for large scale
ontology databases of medical terms and concepts(Grant-in-Aid for Scientific Research (A)(2)
No.16200039 from Ministry of Education, Culture,
Sports, Science and Technology, 2004-2007)
This research develops the methods to build thelarge scale medical ontology, which is a databasefor hundreds of thousand of clinical terms and concepts and their relationships. It focuses on the development of basic methods for making and accessing databases and will be applied for the research described in 6).
4) A study on a bedside system for automatic security
surveillance (H16-IRYOU-026 from Researchon Health Technology Assessment, Healthand Labour Sciences Research Grants, 20042006)
Existing bedside system for security control is justchecking the barcodes or IC tags of medical prod-ucts, patients and staffs. This control depends on
conscious and active acts of staffs. This research,however, develops a method to achieve automatic
detection of approaching objects by applying various information engineering methods. It is expected that the mix ups of objects are prevented
before they occur.
5) A study on the development of a patient-oriented,
event-driven, and intellectual clinical support subsystem (Industry – academia - government collaboration project with Fujitsu Limited, 2004-2008)
This research develops autonomic, distributed,
real–time clinical support system. This system will
be tested by being incorporated in the information
system of the university of Tokyo Hospital.
6) Construction of Clinical and Medical Ontology
Database (Industry – academia - government collaboration project with the Japan Anatomy Laboratory, Co, Ltd., 2004-2008)
This research aims the construction of actuallyavailable clinical and medical ontology with approximately 200,000 terms. It also develops application tools for the ontology.

References
1. Matsuya S, Onogi Y, Shinohara N, Yamaguchi I,
Watanabe H, et al. Physician order entry of ultrasound examination with handheld wireless terminal.
Proceedings of SPIE Medical Imaging 2004: PACS
and Imaging Informatics; 2004 Feb 17-19; San
Diego; USA. Bellingham: SPIE Society of
Photo-Optical Instrumentation Engineer, Inc; 2004.
p.43-51,
2. Onogi Y, Ohe K, Tanaka M, Nozoe A, Sakurai T,
Sato M, et al. Mapping Japanese Medical Terms to
UMLS Metathesaurus. Proceedings of Medinfo
2004; 2004 Sep 7-11 San Francisco, USA. Amsterdam: IOS Press; 2004;11(Pt 1):406-10.
3. Kuroda Y, Nakao M, Kuroda T, Oyama H, Yoshihara H. Haptic Rendering Method of Friction
Forces for Indirect Shape Perception. Proceedingsof VSMM 2004; 2004 Nov 17-19; Gifu Japan.
2004. p.232-8.
4. Nakao M, Kuroda T, Komori M, Oyama H, Komeda M. Physics-based preoperative approachplanning using hybrid virtual bodies. Stud Health133Technol Inform. 2004;98:262-4.
5. Kuroda Y, Nakao M, Kuroda T, Oyama H, Komori
M, Matsuda T. FEM-based interaction model between elastic objects for indirect palpation simulator. Stud Health Technol Inform. 2004;98:183-9.
6. Nakao M, Imanishi K, Kuroda T, Oyama H ．
Practical Haptic Navigation with Clickable 3D Region Input Interface for Supporting Master-Slave
Type Robotic Surgery. Medicine Meets Virtual Reality. 2004;12:265-71.
7. Yasunaga H, Ide H, Imamura T, Ohe K. Impact of
the Japanese Diagnosis Procedure Combination-based Payment System on Cardiovascular
Medicine-related Costs. Int. Heart J. 2005;46(5):855-66.
8. Shinohara N, Oyama H, Matsuya S, OHE K. A
Computational Method for Identifying Medical
Complications based on Hospital Information System Data. Proceedings of CJK-MI Conference
2005, 2005 Nov 11; Shenzhen. 2005. p.133-4.
9. Aramaki E., Imai T, Kashiwagi M, Kajino M, Miyo
K, Ohe K.: Toward Medical Ontology via Natural
Language Processing. International Joint Conference on Natural Language Processing (IJCNLP)
workshop OntoLex2005, 2005 Oct 15; Jeju Island,South Korea. 2005. p.53-8.
10. Uenotsuchi T, Nakayama J, Asahi M, Kohro M,
Akimoto T, Muto M, et al. Dermatological manifestations in Yusho:correlation between skin symptoms and blood leavels of dioxins, such as polychlorinated dibenzofurans(PCDFs) and polychlorinated biphenyls(PCBs). J of Dermatolo Sci Suppl.
2005;1(1):S73-80.
11. Nishio N, Imamura T. Smoking Prevalence among
Dentists in Hyogo, Japan. Japanese J of Dental
Practice Administration. 2005; 40(3):170-5.
12. Uenotsuchi T, .Lio Y, Tadakuma A, Haraduka R,
Kanagawa Y, Imamura T, et al. Sex ratio in thechildren of Yusho patients. Journal of Dermatolo
Sci Suppl. 2005;1(1):S81-3.
13. Nakao M, Imanishi K, Kuroda T, Oyama H. Practical haptic navigation with clickable 3D region
input interface for supporting master-slave typerobotic surgery. Stud Health Technol Inform, 2005;
111:273-6.

Internal Medicine
1. Medicine Ⅰ

⑯

136

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

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

Lecturer
Yoshinori Seko, M.D., Ph.D.,

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

Hospital Lecturer
Nobukazu Ishizaka, Ph.D.,

Homepage

Koji Maemura, Ph.D.

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

Introduction and Organization
The Department of Cardiovascular Medicine is actively involved in clinical medicine, basic research andteaching. In line with the rapidly evolving and progressing nature of modern treatment of cardiovasculardiseases, our department has changed dynamically during the recent years. Not only do we have the mosthighly advanced equipment and facilities (e.g. 24-hourcardiac care unit), but are personnel are also highly
trained to be well knowledged and expert in the mostmodern methods of diagnosis and treatment. As ateaching and research hospital, we also emphasize thedevelopment and incorporation of new treatments ifthey may benefit the patient. From a research standpoint, our interests range throughout all fields of cardiovascular medicine ranging from molecular biology
to clinical research including genomics. Importantly,
our research interests are aimed at making possible new
diagnostics and treatment of cardiovascular diseases.
Finally, we have a particular interest in teaching not
only for medical students but also for residents which isimportant for the future of cardiovascular medicine.

Outline of department
Staff: one professor (Ryozo Nagai), 1 associate professor (Yasunobu Hirata), 2 assistant professors (outpatient
clinic Yoshinori Seko and hospital ward Hiroshi Yamashita), 15 research associates, 9 staff members, 30
graduate school students, 6 researchers, 1 members onleave and 2 members studying abroad.

Clinical activities
In 2004, 1,107 patients were admitted to our hospitalward of which 80% were due to ischemic heart disease. Diagnostic tests reached large numbers including
about 7,000 echocardiography exams, 1,500 Holter
24-hour electrocardiogram exams and 1,300 treadmill
exams. Cardiovascular angiograms were conducted in
1,450 patients, of which 491 cases received coronary
angioplasty. Other interventional procedures such as
catheter ablation were also performed frequently(catheter ablation 31, pacemaker implantation 56).
There are about 50 beds for our division in the hospitalward. The bed occupancy rate is 95%. Duration of
hospitalization is shortest among departments at an average of 13.0 days.
Out-patient clinics are available as part of the De-

137partment of Medicine or as a specialized department.
Patient numbers are increasing each year to 43,612 in
2004. The profile of diseases includes ischemic heartdisease in main in addition to hypertension and peripheral artery disease. Out-patient clinics are open bothmornings and afternoons from Monday to Friday. Approximately 160 patients visit each day. Acute casesof coronary heart disease and aortic disease are also a
focus of the department, as emergent catheterization isavailable 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 are courses
available at the medical school. For bedside teaching,
two students are placed under the guidance of one research associate allowing for teaching in small groups.
Specialized groups provide lectures. As forpost-graduate education, residents are educated throughspecialized group conferences, chart rounds, grandrounds and clinical conferences.

Research activities
Areas of interest are as follows:
1. Regulated expression of smooth muscle myosin
heavy chain
2. Mouse genetic models of cardiovascular diseases
and vascular development
3. Differentiation of smooth muscle cells
4. Genetic risk analysis of atherosclerosis
5. Mechanism of post-PTCA restenosis
6. MRI in cardiovascular diseases
7. Gene expression and regulation in cardiomyocytes
8. Nitric oxide and endothelial function
9. Aerobic threshold and cardiac rehabilitation
10. Molecular analysis of myosin light chain mutations
in familial hypertrophic cardiomyopathy
11. Clock gene in cardiovascular diseases
12. Early diagnosis of ischemic heart disease using
visualization techniques of coronary arteries
13. Immunological basis of myocarditis and dilated
cardiomyopathy
14. Anti-arrhythmia therapy using catheter ablation
15. New treatment for pulmonary hypertension

16. Development of drug eluting stent
17. Clinical application of vasoactive substances for
cardiorenal insufficiency
18. Bone marrow-derived cells in atherosclerosis
19. Regeneration therapy for cardiovascular disease

References
1. Aizawa K, Suzuki T, Kada N, Ishihara, A,
Kawai-Kowase K, Matsumura T, Sasaki K, Munemasa Y, Manabe I, Kurabayashi M, Collins T, Nagai R. Regulation of platelet-derived growth factor-A chain by Krüppel-like factor 5: new pathway
of cooperative activation with nuclear factor-kappaB. J Biol Chem. 279: 70-6, 2004
2. Amaki T, Suzuki T, Nakamura F, Hayashi D, Imai
Y, Morita H, Fukino K, Nojiri T, Kitano S, Hibi N,
Yamazaki T, Nagai R. Circulating malondialdehyde-modified LDL is a biochemical risk marker
for coronary artery disease. Heart. 90:1211-3, 2004
3. Eto Y, Koike A, Matsumoto A, Momomura S, Tajima A, Aizawa T, Fu LT, Itoh H. Early aerobic
training increases end-tidal CO2 pressure during
exercise in patients after acute myocardial infarction. Circ J. 68:778-83, 2004
4. Fujimoto H, Ohno M, Ayabe S, Kobayashi H, Ishizaka N, Kimura H, Yoshida K, Nagai R. Carbon
monoxide protects against cardiac ischemia-reperfusion injury in vivo via MAPK and
Akt--eNOS pathways. Arterioscler Thromb Vasc
Biol. 24: 1848-53, 2004
5. Hayashi D, Kudoh S, Shiojima I, Zou Y, Harada K,
Shimoyama M, Imai Y, Monzen K, Yamazaki T,
Yazaki Y, Nagai R, Komuro I. Atrial natriuretic
peptide inhibits cardiomyocyte hypertrophy throughmitogen-activated protein kinase phosphatase-1.
Biochem Biophys Res Commun. 322: 310-9, 2004
6. Hiroi Y, Fujiu K, Komatsu S, Sonoda M, Sakomura
Y, Imai Y, Oishi Y, Nakamura F, Ajiki K, Hayami N,
Murakawa Y, Ohno M, Hirata Y, Ohtomo K, Nagai
R. Carvedilol therapy improved left ventricularfunction in a patient with arrhythmogenic rightventricular cardiomyopathy. Jpn Heart J. 45:169-77,
2004
7. Iimuro S, Shindo T, Moriyama N, Amaki T, Niu P,
Takeda N, Iwata H, Zhang Y, Ebihara A, Nagai R.
Angiogenic effects of adrenomedullin in ischemia

138

and tumor growth. Circ Res. 95: 415-23, 2004
8. Ikeda Y, Imai Y, Kumagai H, Nosaka T, Morikawa
Y, Hisaoka T, Manabe I, Maemura K, Nakaoka T,
Imamura T, Miyazono K, Komuro I, Nagai R, Kitamura T. Vasorin, a transforming growth factor
beta-binding protein expressed in vascular smoothmuscle cells, modulates the arterial response to injury in vivo. Proc Natl Acad Sci U S A. 101:
10732-7, 2004
9. Ishizaka N, Saito K, Noiri E, Sat M, Mori I, Ohno
M, Nagai R. Iron dextran causes renal iron deposition but not renal dysfunction in angiotensin Ⅱtreated and untreated rats Nephron Physiology.
98:107-13, 2004
10. Kamijo A, Kimura K, Sugaya T, Yamanouchi M,
Hikawa A, Hirano N, Hirata Y, Goto A, Omata M.
Urinary fatty acid-binding protein as a new clinicalmarker of the progression of chronic renal disease.
J Lab Clin Med. 143:23-30, 2004
11. Kamijo A, Sugaya T, Hikawa A, Okada M, Okumura F, Yamanouchi M, Honda A, Okabe M, Fujino T, Hirata Y, Omata M, Kaneko R, Fujii H, Fukamizu A, Kimura K. Urinary excretion of fatty
acid-binding protein reflects stress overload on theproximal tubules. Am J Pathol. 165:1243-55, 2004
12. Kasai H, Yao A, Oyama T, Hasegawa H, Akazawa
H, Toko H, Nagai T, Kinugawa K, Kohmoto O,
Maruyama K, Takahashi T, Nagai R, Miyawaki A,
Komuro I. Direct measurement of Ca2+ concentration in the SR of living cardiac myocytes. Biochem
Biophys Res Commun. 314: 1014-20, 2004
13. Katoh M, Matsumoto A, Nakajima T, Hirose K,
Iwasawa K, Takenaka K, Yamashita H, Sugiura S,
Hirata Y, Nagai R. Amlodipine increases nitric oxide production in exhaled air during exercise in patients with essential hypertension. Am J Hypertens.
17:729-33, 2004
14. Kawanami D, Maemura K, Takeda N, Harada T,
Nojiri T, Imai Y, Manabe I, Utsunomiya K, Nagai R.
Direct reciprocal effects of resistin and adiponectin
on vascular endothelial cells: a new insight into
adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun. 314: 415-9, 2004
15. Ma J, Iida H, Jo T, Takano H, Oonuma H, Morita T,
Toyo-Oka T, Omata M, Nagai R, Okuda Y, Yamada
N, Nakajima T. Ursodeoxycholic acid inhibits endothelin-1 production in human vascular endothe-lial cells. Eur J Pharmacol. 28:67-74, 2004
16. Morita H, Nagai R. Recurrent venous thromboembolism in men and women. N Engl J Med. 351:
2015-8, 2004
17. Morita H, Nagai R. Mutation of perinatal myosin
heavy chain. N Engl J Med. 351: 2556-8, 2004
18. Muto S, Senda M, Adachi N, Suzuki T, Nagai R,
Horikoshi M. Purification crystallization and preliminary X-ray diffraction analysis of human oncoprotein SET/TAF-1β. Acta Crystallogr D Biol
Crystallogr. 60:712-4, 2004
19. Nagata D, Takeda R, Satonaka H, Sata M, Suzuki E,
Nagano T, Hirata Y. AMP-activated protein kinase
inhibits angiotensin II- stimulated vascular smoothmuscle cells proliferation. Circulation 110:444-51,
2004
20. Nishimura S, Yasuda S, Katoh M, Yamada KP, Yamashita H, Saeki Y, Sunagawa K, Nagai R, HisadaT, Sugiura S. Single cell mechanics of rat cardiomyocytes under isometric, unloaded and physiologically loaded conditions. Am J Physiol.
287:H196-202, 2004
21. Niu P, Shindo T, Iwata H, Iimuro S, Takeda N,
Zhang Y, Ebihara A, Suematsu Y, Kangawa K, Hirata Y, Nagai R. Protective effects of endogenous
adrenomedullin on cardiac hypertrophy, fibrosis,
and renal damage. Circulation. 109:1789-94, 2004
22. Sahara M, Kirigaya H, Oikawa Y, Yajima J, Nagashima K, Hara H, Ogasawara K, Aizawa T. Softplaque detected on intravascular ultrasound is thestrongest predictor of in-stent restenosis: an intravascular ultrasound study. Eur Heart J. 25:
2026-33, 2004
23. Saito K,Ishizaka N, Aizawa T, Sata M, Iso-o N,
Noiri E, Ohno M, Nagai R. Role of aberrant ironhomeostasis in the upregulation of TGF-β1 in thekidney of angiotensin Ⅱ-induced hypertensive rat.
Hypertens Res. 27:599-607, 2004
24. Sakurai S, Takenaka K, Shiojima I, Sonoda M, Uno
K, Nakahara K, Nagai R. Close physical contact of
the heart with diaphragm causes pseudo-asynergyof left ventricular inferior wall in normal subjects.
Echocardiography. 21: 573-9, 2004
25. Sata M, Nagai R. Origin of neointimal cells in
autologous vein graft. Arterioscler Thromb Vasc
Biol. 24: 1147-9, 2004
26. Sata M, Nishimatsu H, Osuga JI, Tanaka K, Ishi-

139zaka N, Ishibashi S, Hirata Y, Nagai R. Statins
augment collateral growth in response to ischemia
but they do not promote cancer and atherosclerosis.
Hypertension. 43:1214-20, 2004
27. Sata M, Nagai R. Mouse models of vein graft
Arterioscler Thromb Vasc Biol. 24: e185-e187,
2004
28. Sata M, Nagai R. Inflammation, angiogenesis, andendothelial progenitor cells: how do endothelial
progenitor cells find their place? J Mol Cell Cardiol.
36: 459-63, 2004
29. Satonaka H, Suzuki E, Nishimatsu H, Takeda R,
Goto A, Fujita T, Nagai R, Hirata Y. Calcineurin
promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates
vascular inflammation. Circ Res. 94:693-700, 2004
30. Seko Y, Fukuda S, Nagai R. Serum levels of endostatin, vascular endothelial growth factor(VEGF), and hepatocyte growth factor (HGF) inpatients with acute myocardial infarction undergoing early reperfusion therapy. Clin Sci. 106:439-42,
2004
31. Seko Y, Fujimura T, Taka H, Mineki R, Murayama
K, Nagai R. Hypoxia followed by reoxygenationinduces secretion of cyclophilin A (CyPA) from
cultured rat cardiac myocytes. Biochem Biophys
Res Commun. 317:162-8, 2004
32. Sonoda M, Yonekura K, Yokoyama I, Takenaka K,
Nagai R, Aoyagi T. Common carotid intima-media
thickness is correlated with myocardial flow reserve in patients with coronary artery disease: auseful non-invasive indicator of coronary atherosclerosis. Int J Cardiol. 93: 131-6, 2004
33. Suzuki E, Satonaka H, Nishimatsu H, Oba S, Takeda R, Omata M, Fujita T, Nagai R, Hirata Y.
Myocyte enhancer factor 2 mediates vascular inflammation via the p38-dependent pathway. Circ
Res. 95:42-9, 2004
34. Takeda N, Maemura K, Imai Y, Harada T, Kawanami D, Nojiri T, Manabe I, Nagai R. Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascularendothelial growth factor and its receptor, Flt-1.
Circ Res. 95:146-53, 2004
35. Watanabe M, Feinberg MW, Lebedeva MA, Depina
AS, Hanai J, Mammoto T, Frederick JP, Wang X-F,
Sukhatme VP, and Jain MK. Transforming growth

factor-beta 1 inhibition of vascular smooth muscle
cell activationis mediated via Smad3. J Biol Chem.
279:16388-93, 2004
36. Yamashita H, Sugiura S, Fujita H, Yasuda S, Nagai
R, Saeki Y, Sugi H. Myosin heavy chain isoforms
modulate motor function of cardiac myosin bychanging crossbridge kinetics. Pathophysiology ofcardiovascular disease. Edited by Dhalla NS, Rupp
H, Angel A, Pierce GN. Kluwer Academic Publishers, Boston, 35-49, 2004
37. Yokoyama I, Inoue Y, Morita T, Ohtomo K, Nagai
R. Impaired myocardial vasodilatation during hyperaemic stress is improved by simvastatin but notby pravastatin in patients with hypercholesterolaemia. Eur Heart J. 25: 671-9, 2004
38. Amiya E, Ishizaka N, Watanabe A, Endo Y, Itou R,
Yoshida S, Nangaku M, Nagai R. A case of retroperitoneal fibrosis with periaortic and pericardial
involvement. Circ J. 69:760-762, 2005
39. Fujiu K, Manabe I, Ishihara A, Oishi Y, Iwata H,
Nishimura G, Shindo T, Maemura K, Kagechika H,
Shudo K, Nagai R. Synthetic retinoid Am80 suppresses smooth muscle phenotypic modulation andin-stent neointima formation by inhibiting KLF5.
Circ Res. 97: 1132-41,2005
40. Fukuda D, Sata M, Tanaka K, Nagai R. Potent inhibitory effect of sirolimus on circulating vascularprogenitor cells. Circulation. 111: 926-31,2005
41. Higashikuni Y, Sata M, Nagai R. Reversible left
ventricular hypertrophy after Tako-Tsubo-like cardiomyopathy. Acta Cardiol. 60: 77-9,2005
42. Iida H, Jo T, Iwasawa K, Morita T, Hikiji H, Takato
T, Toyo-oka T, Nagai R, Nakajima T. Molecularand pharmacological characteristics of transient
voltage-dependent K+ currents in cultured humanpulmonary arterial smooth muscle cells. Br J
Pharmacol. 46:49-59,2005
43. Imai Y, Taketani T, Maemura K, Takeda N, Harada
T, Nojiri T, Kawanami D, Monzen K, Hayashi D,
Murakawa Y, Ohno M, Hirata Y, Yamazaki T, Takamoto S, Nagai R. Genetic analysis in a patientwith recurrent cardiac myxoma and endocrinopathy.
Circ J. 69:994-5, 2005
44. Ishizaka N, Ishizaka Y, Toda E, Hashimoto H, Nagai R, Yamakado M. Hypertension is the mostcommon component of metabolic syndrome andthe greatest contributor to carotid arteriosclerosis in140

apparently healthy japanese individuals. Hypertens
Res. 28:27-34, 2005
45. Ishizaka N, Saito K, Noiri , Sata M, Ikeda H, Ohno,
J, Ando A, Mori I, Ohno M, Nagai R. Administration of angiotensin II induces iron deposition andupregulation of TGF-β1 mRNA in the rat liver. Am
J Physiol Regul Integr Comp Physiol. 288:R106370, 2005
46. Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado
M. Association between serum uric acid, metabolic
syndrome, and carotid atherosclerosis in japaneseindividuals. Arterioscler Thromb Vasc Biol. 25:
1038-44, 2005
47. Ishizaka N, Saito K, Mori I, Matsuzaki G, Ohno M,
Nagai R. iron chelation suppresses the ferritin
upregulation and attenuates vascular dysfunction in
the aorta of angiotensin II-infused rats. Arterioscler
Thromb Vasc Biol. 25:2282-8, 2005
48. Kamijo A, Sugaya T, Hikawa A, Yamanouchi M,
Hirata Y, Ishimitsu T, Numabe A, Takagi M, Hayakawa H, Tabei F, Sugimoto T, Mise N, Kimura K.
Clinical evaluation of urinary excretion ofliver-type fatty acid-binding protein as a marker forthe monitoring of chronic kidney disease: a multicenter trial. J Lab Clin Med. 145:125-33, 2005
49. Kono S, Kushiro T, Hirata Y, Hamada C, Takahashi
A, Yoshida Y. Class of antihypertensive drugs,
blood pressure status, and risk of cardiovasculardisease in hypertensive patients: a case-control
study in Japan. Hypertens Res. 28: 811-7, 2005
50. Matsumoto S, Miyagishi M, Akashi H, Nagai R,
Taira K. Analysis of double-stranded RNA-induced
apoptosis pathways using interferon-response noninducible small interfering RNA expression vector
library. J Biol Chem. 280: 25687-96, 2005
51. Matsumura T, Suzuki T, Aizawa K, Munemasa Y,
Muto S, Horikoshi M, Nagai R. The deacetylase
HDAC1 negatively regulates the cardiovasculartranscription factor Kruppel-like factor 5 throughdirect interaction. J Biol Chem. 280:12123-9, 2005
52. Monzen K, Hosoda T, Hayashi D, Imai Y, Okawa Y,
Kohro T, Uozaki H, Nishiyama T, Fukayama M,
Nagai R. The use of a supercooling refrigerator
improves the preservation of organ grafts. Biochem
Biophys Res Commun. 337:534-9, 2005
53. Morita H, Nagai R. Family history. N Engl J Med.
352:732-3, 2005

54. Morita H, Nagai R. Prostanoid DP receptor variants
and asthma. N Engl J Med. 352: 837-8, 2005
55. Nagai R, Suzuki T, Aizawa K, Shindo T, Manabe I.
Significance of the transcription factor KLF5 in
cardiovascular remodeling. J Thromb Haemost. 3:
1569-76, 2005
56. Nishimatsu H, Suzuki E, Satonaka H, Takeda R,
Omata M, Fujita T, Nagai R, Kitamura T, Hirata Y:
Endothelial dysfunction and hypercontractility ofvascular myocytes are ameliorated by fluvastatin inobese Zucker rats. Am J Physiol Heart Circ Physiol
288:H1770-6, 2005
57. Nishimura S, Yamashita H, Katoh M, Yamada KP,
Sunagawa K, Saeki Y, Ohnuki Y, Nagai R, Sugiura
S. Contractile dysfunction of cardiomyopathic
hamster myocytes is pronounced under high loadconditions. J Mol Cell Cardiol. 39: 231-9, 2005
58. Oishi Y, Manabe I, Tobe K, Tsushima K, Shindo T,
Fujiu K, Nishimura G, Maemura K, Yamauchi T,
Kubota N, Suzuki R, Kitamura T, Akira S,
Kadowaki T, Nagai R. Kruppel-like transcription
factor KLF5 is a key regulator of adipocyte differentiation. Cell Metabolism. 1:27-39, 2005
59. Sahara M, Sata M, Matsuzaki Y, Tanaka K, Morita
T, Hirata Y, Okano H, Nagai R. Comparison ofvarious bone marrow fractions in the ability to participate in vascular remodeling after mechanicalinjury. Stem Cells. 23:874-8, 2005
60. Saito K, Ishizaka N, Hara M, Matsuzaki G, Sata M,
Mori, I , Ohno M and Nagai R. Lipid accumulation
and TGF-β upregulation in the kidneys of rats thatwere administered angiotensin II. Hypertension.
46:1180-85, 2005
61. Saito K, Ishizaka N, Aizawa T, Sata M, Iso-o N,
Noiri E, Mori I, Ohno M, Nagai R. Iron chelation
and a free radical scavenger suppress angiotensin
II-induced upregulation of TGF-β1 in the heart. Am
J Physiol Heart Circ Physiol. 288:H1836-43, 2005
62. Sasaki E, Kojima H, Nishimatsu H, Urano Y, Kikuchi K, Hirata Y, Nagano T. Highly sensitivenear-infrared fluorescence probes for nitric oxide
and their application to isolated organs. J Am Chem
Soc. 127:3684-5, 2005
63. Sata M, Fukuda F, Tanaka K, Kaneda Y, Yashiro H,
Shirakawa I. The role of circulating precursors invascular repair and lesion formation. J Cell Mol
Med. 9: 557-568, 2005

141

64. Sata M, Tanaka K, Nagai R. Circulating osteoblast-lineage cells. N Engl J Med. 353: 737-8,
2005
65. Satonaka H, Suzuki E, Hayakawa H, Nishimatsu H,
Nagata D, Oba S, Kamijo A, Takeda R, Takahashi
M, Yamamoto Y, Kimura K, Hirata Y. Long-term
effect of imidapril hydrochloride compared withdilazep hydrochloride administration on bloodpressure and renal function in patients with chronic
glomerulonephritis. Int Heart J. 46:701-10, 2005
66. Suzuki T, Aizawa K, Matsumura T, Nagai R. vascular implications of the kruppel-like family oftranscription factors. Arterioscler Thromb Vasc
Biol. 25: 1135-41, 2005
67. Takano H, Morita T, Iida H, Asada K, Kato M, Uno
K, Hirose K, Matsumoto A, Takenaka K, Hirata Y,
Eto F, Nagai R, Sato Y, Nakajima T. Hemodynamic
and hormonal responses to a short-term low-intensity resistance exercise with the reduction of muscle blood flow. Eur J Appl Physiol. 95, 65-73,2005
68. Takeda R, Suzuki E, Satonaka H, Oba S, Nishimatsu H, Omata M, Fujita T, Nagai R, Hirata Y.
Blockade of endogenous cytokines mitigates neointimal formation in obese Zucker rats. Circulation.
111: 1398-406,2005
69. Tanaka K, Sata M, Fukuda D, Suematsu Y, Motomura N, Takamoto S, Hirata Y, Nagai R. Age-associated Aortic Stenosis in ApoE-deficient Mice. J
Am Coll Cardiol. 46. 134-41,2005

142

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

Associate Professor
Hajime Takizawa, M.D.,Ph.D.

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

Associate
Taiji Nagata, M.D.,Ph.D.,
Masashi Desaki, M.D.,Ph.D.,
Taisuke Jo, M.D.,Ph.D.,
Hiroshi Kitagawa, M.D.,Ph.D.

Tadashi Kohyama, M.D.,Ph.D.,
Hidehiko Mizuguchi, M.D.,
Hiroyuki Takahashi, M.D.,Ph.D.,

Homepage http://kokyuki.umin.jp/
Introduction and Organization
The staff of the Department of the Respiratory Medicine, Graduate School of Medicine, University of Tokyo, consists of 1 professor, 1 associate professor, 1lecturer, and 7 assistant professors. In the University ofTokyo, affiliated hospitals and foreign institutions, approximately 50 members belong to the Department. In
the University of Tokyo Hospital, 20 respiratory physicians are doing clinical works.
The Department of the Respiratory Medicine wasestablished in April 1998, and chaired by Professor
Kazuhiko Yamamoto. In June 2003, Takahide Nagase
was appointed to Professor and since then chairs the
Department.
Based on the fact that a number of patients with respiratory diseases including lung cancer and COPD istremendously increasing, fruitful results of respiratory
research are more and more expected in the 21st century.
In this era, we are conducting basic and clinical researches for wide variety of respiratory disorders including lung cancer, asthma and COPD. Especially, we

have been intensively studying the molecular mechanisms underlying the pathogenesis of lung disorders.
Our research goal is to develop novel therapeutic tools
to manage these pulmonary diseases.

Clinical Activities
The Department of Respiratory Medicine is responsible for the out-patient care as well as the diagnosis
and treatment of in-patients (40 cases on average). Our
practice is performed by the three-member system of ajunior resident, a senior resident and an experienced
associate.
Main diseases of in-patients are bronchogenic carcinoma, pneumonia, chronic obstructive pulmonary disease (COPD), interstitial lung diseases, asthma, andother respiratory failure. Our department contributes tothe pre- and post-operational evaluation of respiratory
functions, and also receives consultation from otherdepartments.
In respiratory diseases, there are several disorders towhich no pharmaceutical agents are currently effective.

143

For example, acute respiratory distress syndrome (ARDS)
is an acute lung injury and the mortality rate for ARDS isextremely high despite of intensive care using currently
available drugs. Idiopathic pulmonary fibrosis (IPF) is a
progressive and fatal disorder of the lung parenchyma,
while no useful drugs are currently available to treat IPF.
However, their mechanisms still remain to be elucidated.
We would like to make every effort to develop a noveland potential therapeutic approach to these diseases.
Number of in-patients in 2004
1. Lung cancer
2. Respiratory infection
3. COPD
4. Interstitial pneumonia
5. Malignacy (except for lung cancer)

221
60
41
33
24

A weekly chart round and professor’s round arescheduled for Tuesday afternoon. A specialized clinicalconference is held, together with respiratory surgeons
and radiologists, where radiographic diagnosis, indication of thoracoscopic biopsy, CT-guided biopsy, andsurgical and radiological treatment are discussed.

Teaching Activities
As for under-graduate education, our department
takes part in systemic lectures and specific learning for
diagnosis of respiratory diseases for the 4th year medical students, bed-side learning for the 5th year medical
students, and clinical lectures for the 5th and 6th year
medical students. Clinical Clerkship for the 5th year
students is actively performed in collaboration withexpert doctors from several leading hospitals.
In systemic lectures, comprehensive presentation for
the understanding of basic knowledge about the concept,
pathogenesis, pathology, diagnosis and treatment ofcommon respiratory diseases is performed.
In clinical lectures, we present clinical cases of important diseases such as lung cancer, and try to discusswith the students several points for planning the diagnosis and treatment in collaboration with the Faculty of
the Department of Respiratory Surgery.
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 the Faculty. Each student can learn how to make a medical

interview, check physical findings and make the actual
plans for the diagnosis and treatment. Several lectures
about the specific topics important in respiratory medicine such as fundamental chest radiology, treatment ofasthma and COPD, and oxygen therapy are provided by
the respiratory specialists.
Clinical clerkship at the 5th year of the educational
program is actively performed to facilitate the early
exposure to the clinical practice for a relatively long
period ( for one month ), and, in general, is very highly
appreciated by the students.
As for the post-graduate education, 7 to 8 junior residents join the Department of General Medicine on the
13th floor simultaneously for one month, and are expected to experience respiratory as well as other diseases. Since the training period is short, the residents
are expected to experience emergency cases as often as
possible.

Research Activities
Our department is conducting basic and clinical researches for many respiratory disorders including lungcancer, asthma, COPD, diffuse panbronchiolitis (DPB),
interstitial lung diseases, pulmonary vascular diseases
and others. We have also been studying the effects of
air pollutants such as diesel exhausts. Epidemiological,
clinical, cellular and molecular techniques are utilized
for the elucidation of novel findings in respiratory
medicine. Postgraduate students as well as the Faculty
members make considerable studies about chemokines/cytokines, prostanoids, airway epithelial cells,smooth muscle cells and eosinophils. Genetic studies
about asthma, diffuse panbronchiolitis, and lung cancer
have also been fruitful. These results have been presented and/or published in the Scientific Meeting and/or
peer-review Journals. Our main research projects are as
follows.
Clinical studies of lung cancer, COPD, bronchialasthma and pulmonary fibrosis
Epidemiological studies of diffuse panbronchiolitis(DPB) and interstitial lung disease
Molecular mechanisms underlying the pathogenesis ofacute lung injury or ARDS
Molecular mechanisms underlying the pathogenesis of
pulmonary fibrosis

144

Analysis of disease models using genetically- engineered mice
Effects of air pollutants such as diesel exhausts on airway hyperresponsiveness Roles of chemokines/ cytokines and eicosanoids on airway epithelial cells, smoothmuscle cells and eosinophils.
DNA methylation and lung cancer
Establishment of conditional vectors for hairpin siRNAknockdowns
Establishment of CpG island searcher
Hajime Takizawa is an Associate Editor of American
Journal of Respiratory Cell and Molecular Biology, an
official Journal of American Thoracic Society. Takahide
Nagase is an Associate Editor of Respirology and an
Editorial Board Member of American Journal of Physiology.

References
1. Tanaka G, Matsushita I, Ohashi J, Tsuchiya N,
Ikushima S, Oritsu M, Hijikata M, Nagata T,
Yamamoto K, Tokunaga K, Keicho N. Evaluationof microsatellite markers in association studies: asearch for an immune-related susceptibility gene insarcoidosis. Immunogenetics 2005;56:861-70.
2. Kamio K, Matsushita I, Hijikata M, Kobashi Y,
Tanaka G, Nakata K, Ishida T, Tokunaga K, Taguchi Y, Homma S, Nakata K, Azuma A, Kudoh S,
Keicho N. Promoter Analysis and Aberrant Expression of MUC5B gene in Diffuse Panbronchiolitis.
Am J Respir Crit Care Med 2005;171:949-57.
3. Kamio K, Matsushita I, Tanaka G, Ohashi J, Hijikata M, Nakata K, Tokunaga K, Azuma A, Kudoh S,
Keicho N. Direct determination of MUC5B promoter haplotypes based on the method of single-strand conformation polymorphism and theirstatistical estimation. Genomics 2004;84:613-22.
4. Iida H, Jo T, Iwasawa K, Morita T, Hikiji H, Takato
T, Toyo-Oka T, Nagai R, Nakajima T. Molecularand pharmacological characteristics of transient
voltage-dependent K(+) currents in cultured humanpulmonary arterial smooth muscle cells. Br J
Pharmacol 2005;146:49-59.
5. Jo T, Iida H, Kishida S, Imuta H, Oonuma H, Nagata T, Hara H, Iwasawa K, Soma M, Sato Y, Nagase T, Nagai R, Nakajima T. Acute and chronic

effects of eicosapentaenoic acid on voltage-gatedsodium channel expressed in cultured humanbronchial smooth muscle cells. Biochem Biophys
Res Commun 2005;331:1452-9.
6. Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J,
Hara K, Omata M, Nagai R, Takizawa H, Nagase T,
Nakajima T. Voltage-gated sodium channel expressed in cultured human smooth muscle cells:
involvement of SCN9A. FEBS Lett 2004;567:33943.
7. Ma J, Iida H, Jo T, Takano H, Oonuma H, Morita T,
Toyo-Oka T, Omata M, Nagai R, Okuda Y, Yamada
N, Nakajima T. Ursodeoxycholic acid inhibits endothelin-1 production in human vascular endothelial cells. Eur J Pharmacol 2004;505:67-74.
8. Iida H, Takano H, Meguro K, Asada K, Oonuma H,
Morita T, Kurano M, Sakagami F, Uno K, Hirose K,
Nagata T, Takenaka K, Suzuki J, Hirata Y, Furuichi
T, Eto F, Nagai R, Sato Y, Nakajima T. Hemodynamic and autonomic nervous responses to the restriction of femoral blood flow by KAATSU. Int J
KAATSU Training Res 2005;1:57-64.
9. Nishi H, Shibagaki Y, Hatakeyama S, Ito T, Nagata
T, Ohno M, Tojo A, Nangaku M, Fujita T. Metastatic intracranial empyema from renal cyst infection
in autosomal dominant polycystic kidney disease.
Nephrol Dial Transplant 2005;20:2820-3.
10. Sugimoto K, Makihara T, Saito A, Ohishi N, Nagase T, Takai D. Betaine improved restriction digestion. Biochem Biophys Res Commun 2005;337:
1027-9.
11. Liang G, Lin JC, Wei V, Yoo C, Cheng JC, Nguyen
CT, Weisenberger DJ, Egger G, Takai D, Gonzales
FA, Jones PA. Distinct localization of histone H3
acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proc Natl
Acad Sci USA 2004;101:7357-62.
12. Takai D, Nagase T, Shimizu T. New therapeutic key
for cystic fibrosis: a role for lipoxins (Editorial).
Nature Immunol 2004;5:357-8.
13. Takai D, Jones PA. Origins of bidirectional promoters: computational analyses of intergenic distance in the human genome, Mol Biol Evol
2004;21:463-7.
14. Yamauchi Y, Okazaki H, Desaki M, Kohyama T,
Kawasaki S, Yamamoto K, Takizawa H. Methotrexate induces interleukin-8 production by human

145

bronchial and alveolar epithelial cells. Clin Sci(Lond) 2004;106:619-25.
15. Lazarowski ER, Tarran R, Grubb B, van Heusden
CA, Okada S, Boucher RC. Nucleotide releaseprovides a mechanism for airway surface liquid
homeostasis. J Biol Chem 2004;79:36855-64.
16. Okada SF, O'Neal WK, Huang P, Nicholas RA,
Ostrowski LE, Craigen WJ, Lazarowski ER,
Boucher RC. Voltage-dependent anion channel-1(VDAC-1) contributes to ATP release and cellvolume regulation in murine cells. J Gen Physiol
2004;24:513-26.
17. Kobayashi T, Liu X, Wen FQ, Fang Q, Abe S,
Wang XQ, Hashimoto M, Shen L, Kawasaki S,
Kim HJ, Kohyama T, Rennard SI. Smad3 mediates
TGF-beta1 induction of VEGF production in lungfibroblasts. Biochem Biophys Res Commun 2005;
327:393-8.
18. Shibuya H, Hirohata S. Differential effects of
IFN-α on the expression of various Th2 cytokines
in human CD4+ T cells. J Allergy Clin Immunol
2005;116:205-12.
19. Takahashi H, Shibuya M. The vascular endothelial
growth factor (VEGF)-VEGF receptor system andits role under physiological and pathological conditions. Clin Sci (Lond) 2005;109:227-41.
20. Takahashi H, Hattori S, Iwamatsu A, Takizawa H,
Shibuya M. A novel snake venom vascular endothelial growth factor (VEGF) predominantly induces vascular permeability through preferential
signaling via VEGF receptor-1. J Biol Chem 2004;
279:46304-14.
21. Takahashi H, Shibuya M. Molecular targetingtherapy for tumor angiogenesis. Experimental
Medicine 2004;22:1980-1986.
22. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms ofanti-inflammatory action of erythromycin in humanbronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor- kappaB activation. Antimicrob Agents Chemother
2004;48:1581-5.
23. Kato J, Kohyama T, Okazaki H, Desaki M, Nagase
T, Rennard SI, Takizawa H. Leukotriene D4 potentiates fibronectin-induced migration of human lungfibroblasts. Clin Immunol 2005;117:177-81.
24. Fang Q, Liu X, Abe S, Kobayashi T, Wang XQ,

Kohyama T, Hashimoto M, Wyatt T, Rennard SI.
Thrombin induces collagen gel contraction partiallythrough PAR1 activation and PKC-epsilon. Eur
Respir J 2004;24:918-24.
25. Kim H, Liu X, Kobayashi T, Conner H, Kohyama T,
Wen FQ, Fang Q, Abe S, Bitterman P, Rennard SI.
Reversible cigarette smoke extract-induced DNA
damage in human lung fibroblasts. Am J Respir
Cell Mol Biol 2004;31:483-90.
26. Kohyama T, Liu X, Wen FQ, Kobayashi T, Fang Q,
Abe S, Cieslinski L, Barnette MS, Rennard SI. Cytokines modulate cilomilast response in lung fibroblasts. Clin Immunol 2004;111:297-302.
27. Kohyama T, Liu X, Wen FQ, Kobayashi T, Abe S,
Rennard SI. IL-4 and IL-13 induce chemotaxis ofhuman foreskin fibroblasts, but not human fetallung fibroblasts. Inflammation 2004;28:33-7.
28. Wen FQ, Liu X, Kobayashi T, Abe S, Fang Q, Kohyama T, Ertl R, Terasaki Y, Manouilova L, Rennard SI. Interferon-gamma inhibits transforming
growth factor-beta production in human airway
epithelial cells by targeting Smads. Am J Respir
Cell Mol Biol 2004;30:816-22.
29. Takizawa H. Bronchial epithelial cells in allergic
reactions. Current Drug Targets-Inflammation &Allergy 2005;4:305-311.
30. Sunohara M, Takizawa H. Lung remodeling in interstitial pneumonia: A new molecular target of
pulmonary fibrosis. Curr Respir Med Rev 2005;1:
93-101.
31. Hiramatsu K, Saito Y, Sakakibara K, Azuma A,
Takizawa H, Sugawara I. The effects of inhalationof diesel exhaust on murine mycobacterial infection.
Exp Lung Res 2005;31:405-15.
32. Jang AS, Choi IS, Takizawa H, Rhim TY, Lee JH,
Park SW, Park CS. Additive effect of diesel exhaust
particulates and ozone on airway hyperresponsiveness and inflammation in a mouse model of asthma.
J Korean Med Sci 2005;20:759-63.
33. Miyajima K, Nakajima S, Taguchi M, Hayashi A,
Kajiwara N, Uchida O, Kono T, Takahashi M, Kawanishi K, Tanaka M, Takizawa H, Kato H. Cytokine responsiveness in cultured human small airway epithelial cells in relation to lung transplantation. Ann Thorac Cardiovasc Surg 2005;11:374-81.
34. Kurano M, Takizawa H. Diesel exhaust particles
and asthma. Korean J Asthma Allergy Clin Immu-

146

nol 2004;24:269-281.
35. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med 2004;117:5S-11S.
36. Saito A, Takizawa H, Sato M, Suzuki K, Miyata T,
Tazawa T, Nukiwa T, Morita Y. Alpha-1 antitrypsin
deficiency with severe pulmonary emphysema. Intern Med 2004;43:223-6.
37. Takizawa H. Diesel exhaust particles and their effect on induced cytokine expression in humanbronchial epithelial cells. Curr Opin Allergy Clin
Immunol 2004;4:355-359.
38. Takizawa H. Anti-inflammatory effects - Cytokines.
In: Rubin BK, Tamaoki J, editors. Antibiotics asanti-inflammatory and immunomodulatory agents.
Basel: Birkhaeuser Verlag; 2004. p. 77-86.
39. Terawaki K, Yokomizo T, Nagase T, Toda A, Taniguchi M, Hashizume K, Yagi T, Shimizu T. Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type
immune responses. J Immunol 2005;175:4217-25.
40. Nagase T, Aoki-Nagase T, Yamaguchi Y, Yamamoto H, Ouchi Y. Molecular mechanisms underlying inflammatory lung diseases in the elderly: development of a novel therapeutic strategy for acutelung injury and pulmonary fibrosis. Griatrics Gerontology International 2005;5:139-45.
41. Nagase T. Roles of lipid mediators in acute lunginjury and pulmonary fibrosis. In: Hamid Q, Shannon J, Martin J, editors. Physiologic basis of respiratory disease. Hamilton, Ontario: BC Decker;
2005. p. 489-94.
42. Ishii S, Nagase T, Shindou H, Takizawa H, Ouchi Y,
Shimizu T. Platelet-activating factor receptor develops airway hyperresponsiveness independentlyof airway inflammation in a murine asthma model.
J Immunol 2004;172:7095-102.

147

Department of Gastroenterology
Professor
Masao Omata, M.D., Ph.D.

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

Shuichiro Shiina, M.D., Ph.D.

Associate
Hiroshi Kanamori, M.D., Ph.D.
Hiroshi Mitsui, M.D., Ph.D.
Hirosato Mashima, M.D., Ph.D.
Keiji Ogura, M.D., Ph.D.
Mikio Yanase, M.D., Ph.D.
Hajime Fujie, M.D., Ph.D.
Hideo Yoshida, M.D., Ph.D.
Naoki Sasahira, M.D., Ph.D.

Tomoaki Tomiya, M.D., Ph.D.
Naoya Kato, M.D., Ph.D.
Makoto Okamoto, M.D., Ph.D.
Yutaka Yamaji, M.D., Ph.D.
Goichi Togo, M.D., Ph.D.
Hiroyuki Isayama, M.D., Ph.D.
Mitsuhiro Fujishiro, M.D., Ph.D.
Ryosuke Tateishi, M.D., Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/gastro/
Introduction and Organization
The Department of Gastroenterology was established through the reorganization of the Postgraduate
School of Medicine and that of the Division of Internal
Medicine of the University of Tokyo Hospital in 1998.
It is now constituted of a professor, three lecturers,
sixteen associates, six fellows, fifty graduates including five students from abroad, and several other visiting members. The north and south wings on the 11th
floor of Ward A provide core hospital rooms for the
department. The department is responsible for both
medical practice and education on gastroenterology.

Clinical Activities
The Department of Gastroenterology is in charge ofabout ninety inpatients on average. We receive about
40 new patients each week, with an average hospital
stay of 16 days. A resident, a junior and a senior staff
members bear the responsibility for the medical man-agement of each inpatient, in collaboration with concerned subspecialty groups. In addition, the staff
members examine about 4,700 outpatients with various
digestive diseases in a month. Professor’s ward roundis performed on Monday and Wednesday mornings andspecialty and subspecialty clinical conferences are heldon Monday evening.
The most frequent cause of admission is hepatocellular carcinoma (1,000 patients a year). Eighty % ofpatients with hepatocellular carcinoma receive medical
treatment; percutaneous radiofrequency ablation. We
also perform radiofrequency ablation for metastatic
liver tumors. ERCP is performed on 650 patients eachyear. Patients treated for choledocholithiasis with endoscopic papillary balloon dilation method exceeds
1,000, possibly the largest in the world. Internal endoscopic metallic stent is preferred to percutaneous external drainage in the palliative care of malignant obstructive jaundice (100 patients a year). ESD (endoscopic submucosal dissection) is performed as curativeendoscopic treatment for neoplasms in the stomach or

148

colon (210 patients a year) and endoscopic variceal
ligation for esophageal varices (50 patients a year) arealso frequently done. We recently introduced double-balloon endoscopy for thorough examination of thesmall intestines. All those interventions are performedby members of the department especially trained ineach technique.
On outpatient basis, ultrasonography is performedon 12,000 patients, gastroduodenal endoscopy on
5,000 patients and colonoscopy on 2,800 patients eachyear. About 200 cases of gastric cancer and 100 of colorectal cancer are detected annually and about 40 %of them are treated endoscopically.

Educational Activities
Systematic and clinical lectures on gastroenterology
are regularly given to undergraduate medical students
by staff members of the department. In addition, several courses of practical teaching are provided for the
students. In particular, the Department of Gastroenterology makes much of the importance of bed-side
teaching for the fifth grade students, where each student is allotted an inpatient and joins the group of physicians in charge of the patient in medical examinationand treatment. The results are to be reported to theprofessor at the end of the course. Students are also
requested to be present at the weekly round by theprofessor, various gastroenterological examinations
and treatments, and educational lectures on gastroenterology given by staff members. They also read andsummarize gastroenterological articles on top-notch
medical journals.
Residents of internal medicine join the Department
of Gastroenterology for 1-6 months in rotation in theirfirst year as a doctor, where they learn therapeutics anddiagnostics in gastroenterology together with general
medicine. Presentation at scientific meetings 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 educating residents. The majority of them also
start medical researches, basic or clinical, as a graduate
student. Currently, we have 50 students who were
graduated from more than 30 medical schools in Japan.

Research Activities
Since gastroenterology covers various organs, everything below the diaphragms except for the kidneys
and the reproductive system, and protean diseases,
such as neoplasm, infection, metabolic disorders andmechanical ones, themes of research are virtuallyunlimited, as shown in the list of publication described
below. Basic and clinical researches are equally encouraged, on condition that the results may eventually
benefit the cure of patients with gastroenterologicaldisorders. In basic researches, the department has been
eager to acquire cutting-edge methodologies, especially those in molecular biology and genetics. The
themes of our recent basic researches include mRNA
expression analysis using microarray, protein expression analysis using mass spectrometer, and gene mutation analysis using laser micro dissection of clinicallyobtained samples. Various clinical activities are recorded in database and analyzed. Studies oriented forevidence-based medicine are highly appreciated. Recent randomized-controlled trials include vitamin K orinterferon to prevent recurrence of hepatocellular carcinoma, evaluation of diagnostic usefulness of angiography during computed tomography, and radiofrequency ablation for liver metastasis of colorectal
cancer. We have also designed clinical trials for
TSU-68 for advanced hepatocellular carcinoma,
erythropoietin for anemia introduced by interferon plus
ribavirin therapy, TS-1 alone or plus gemcitabine forpancreatic and bile duct cancers.
The department of gastroenterology is dedicated topursuing better medicine, for which exclusively theseresearches, basic or clinical, are conducted.

References
1.

2.

Akamatsu M, Yoshida H, Obi S, Sato S, Koike Y,
Fujishima T, Tateishi R, Imamura M, Hamamura K,
Teratani T, Shiina S, Ishikawa T, Omata M.
Evaluation of transcatheter arterial embolization
prior to percutaneous tumor ablation in patientswith hepatocellular carcinoma: a randomized controlled trial. Liver Int 2004 ; 24 : 625-629.
Akamatsu M, Yoshida H, Shiina S, Teratani T,
Tateishi R, Obi S, Sato S, Koike Y, Fujishima T,
Ishikawa T, Shiratori Y, Omata M. Neither hepati-

149

3.

4.

5.

6.

7.

8.

9.

tis C virus genotype nor virus load affects survivalof patients with hepatocellular carcinoma. Eur J
Gastroenterol Hepatol 2004 ; 16 : 459-466.
Atarashi K, Ishiyama A, Minami M, Takagi M,
Omata M. Effects of acute hypercholesterolemia
on blood pressure and pressor response to norepinephrine in rats. Blood Press 2004 ; 13 : 56-61.
Fujishiro M, Yahagi N, Kashimura K, Mizushima
Y, Oka M, Enomoto S, Kakushima N, Kobayashi
K, Hashimoto T, Iguchi M, Shimizu Y, Ichinose M,
Omata M. Comparison of various submucosal injection solutions for maintaining mucosal elevation during endoscopic mucosal resection. Endoscopy 2004 ; 36 : 579-583.
Fujishiro M, Yahagi N, Kashimura K, Mizushima
Y, Oka M, Matsuura T, Enomoto S, Kakushima N,
Imagawa A, Kobayashi K, Hashimoto T, Iguchi M,
Shimizu Y, Ichinose M, Omata M. Different mixtures of sodium hyaluronate and their ability tocreate submucosal fluid cushions for endoscopic
mucosal resection. Endoscopy 2004 ; 36 : 584589.
Fukushima Y, Matsui T, Saitoh T, Ichinose M,
Tateishi K, Shindo T, Fujishiro M, Sakoda H, Shojima N, Kushiyama A, Fukuda S, Anai M, Ono H,
Oka M, Shimizu Y, Kurihara H, Nagai R, Ishikawa
T, Asano T, Omata M. Unique roles of G protein-coupled histamine H(2) and gastrin receptors
in growth and differentiation of gastric mucosa.
Eur J Pharmacol 2004 ; 502 : 243-252.
Hama K, Ohnishi H, Yasuda H, Ueda N, Mashima
H, Satoh Y, Hanatsuka K, Kita H, Ohashi A,
Tamada K, Sugano K. Angiotensin II stimulates
DNA synthesis of rat pancreatic stellate cells by
activating ERK through EGF receptor transactivation. Biochem Biophys Res Commun 2004; 315 :905-911.
Hippo Y, Watanabe K, Watanabe A, Midorikawa Y,
Yamamoto S, Ihara S, Tokita S, Iwanari H, Ito Y,
Nakano K, Nezu J, Tsunoda H, Yashino T, Ohizumi I, Tsuchiya M, Ohnishi S, Makuuchi M,
Hamakubo T, Kodama T, Aburatani H. Identification of soluble amino terminal fragment of glypican-3 as a serological marker for early stage hepatocellular carcinoma. Cancer Res 2004; 64 : 24182423.
Hirano K, Komatsu Y, Yamamoto N, Nakai Y, Sa-

10.

11.

12.

13.

14.

15.

16.

sahira N, Toda N, Isayama H, Tada M, Kawabe T,
Omata M. Pancreatic mass lesions associated withraised concentration of IgG4. Am J Gastroenterol
2004 ; 99 : 2038-2040.
Hirata Y, Yanai A, Shibata W, Mitsuno Y, Maeda S,
Ogura K, Yoshida H, Kawabe T, Omata M. Functional variability of cagA gene in Japanese isolatesof Helicobacter pylori. Gene 2004 ; 343 : 165-172.
Ijichi H, Otsuka M, Tateishi K, Ikenoue T, Kawakami T, Kanai F, Arakawa Y, Seki N, Shimizu K,
Miyazono K, Kawabe T, Omata M. Smad4-independent regulation of p21/WAF1 by transforming
growth factor-beta. Oncogene 2004 ; 23 :10431051.
Ikai I, Arii S, Kojiro M, Ichida T, Makuuchi M,
Matsuyama Y, Nakanuma Y, Okita K, Omata M,
Takayasu K, Yamaoka Y. Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanesenationwide survey. Cancer 2004 ; 101 : 796- 802.
Ikai I, Itai Y, Okita K, Omata M, Kojiro M, Kobayashi K, Nakanuma Y, Futagawa S, Makuuchi M,
Yamaoka Y. Report of the 15th follow-up surveyof primary liver cancer. Hepatol Res 2004 ; 28 :21-29.
Ikeda H, Nagashima K, Yanase M, Tomiya T, Arai
M, Inoue Y, Tejima K, Nishikawa T, Watanabe N,
Omata M, Fujiwara K. Sphingosine 1-phosphateenhances portal pressure in isolated perfused liver
via S1P(2) with Rho activation. Biochem Biophys
Res Commun 2004 ; 320 : 754-759.
Ikenoue T, Hikiba Y, Kanai F, Aragaki J, Tanaka Y,
Imamura J, Imamura T, Ohta M, Ijichi H, Tateishi
K, Kawakami T, Matsumura M, Kawabe T, Omata
M. Different effects of point mutations within the
B-raf glycine-rich loop in colorectal tumors on
mitogen-activated protein/extracellular signal-regulated
kinase kinase/extracellular eignal-regulated kinaseand nuclear factor kappa B pathway and cellulartransformation. Cancer Res 2004 ; 64 : 3428-3435.
Ikenoue T, Hikiba Y, Kanai F, Ijichi H, Togo G,
Ohta M, Watabe H, Yamaji Y, Okamoto M, Aragaki J, Matsumura M, Kawabe T, Omata M. Rapid
detection of mutations in the BRAF gene using
real-time polymerase chain reaction and melting
curve analysis. Cancer Genet Cytogenet 2004 ;149 : 68-71.

150

17. Imamura T, Kanai F, Kawakami T, Amarsanaa J,
Ijichi H, Hoshida Y, Tanaka Y, Ikenoue T, Tateishi
K, Kawabe T, Arakawa Y, Miyagishi M, Taira K,
Yokosuka O, Omata M. Proteomic analysis of the
TGF-beta signaling pathway in pancreatic carcinoma cells using stable RNA interference to silence Smad4 expression. Biochem Biophys Res
Commun 2004 ; 318 : 289-296.
18. Isayama H, Komatsu Y, Tsujino T, Sasahira N,
Hirano K, Toda N, Nakai Y, Yamamoto N, Tada M,
Yoshida H, Shiratori Y, Kawabe T, Omata M. A
prospective randomised study of "covered" versus"uncovered" diamond stents for the managementof distal malignant biliary obstruction. Gut 2004 ;53 : 729-734.
19. Jo T, Nagata T, Iida H, Imuta H, Iwasawa K, Ma J,
Hara K, Omata M, Nagai R, Takizawa H, Nagase
T, Nakajima T. Voltage-gated sodium channel expressed in cultured human smooth muscle cells:
involvement of SCN9A. FEBS Lett 2004 ; 567 :
339-343.
20. Kakushima N, Fujishiro M, Yahagi N, Oka M,
Kobayashi K, Hashimoto T, Miyoshi H, Moriyama
Y, Enomoto S, Iguchi M, Ichinose M, Omata M.
An unusual case of polypoid angiodysplasia. Endoscopy 2004 ; 36 : 379.
21. Kakushima N, Yahagi N, Fujishiro M, Iguchi M,
Oka M, Kobayashi K, Hashimoto T, Omata M.
The healing process of gastric artificial ulcers afterendoscopic submucosal dissection. Digestive Endoscopy 2004 ; 16 : 327-331.
22. Kamijo A, Kimura K, Sugaya T, Yamanouchi M,
Hikawa A, Hirano N, Hirata Y, Goto A, Omata M.
Urinary fatty acid-binding protein as a new clinicalmarker of the progression of chronic renal disease.
J Lab Clin Med 2004 ; 143 : 23-30.
23. Kamijo A, Sugaya T, Hikawa A, Okada M, Okumura F, Yamanouchi M, Honda A, Okabe M, Fujino T, Hirata Y, Omata M, Kaneko R, Fujii H,
Fukamizu A, Kimura K. Urinary excretion of Fatty
Acid-binding protein reflects stress overload on
the proximal tubules. Am J Pathol 2004 ; 165 :1243-1255.
24. Kato N, Ono-Nita SK, Omata M. New anti-virals
against wild-type and lamivudine-resistant hepatitis B virus. In: Omata M, Okita K, eds. Therapy
for Viral Hepattis and Prevention of Hepatocellular

25.

26.

27.

28.

29.

30.

31.

32.

Carcinoma. Tokyo: Springer, 2004: 25-31.
Koike Y, Shiratori Y, Yoshida H, Omata M. Vitamin K2 administration improves the prognoses ofpatients with hepatocellular carcinoma presenting
high levels of serum des-γ-carboxy prothrombin.
In: Omata M, Okita K, eds. Therapy for Viral
Hepattis and Prevention of Hepatocellular Carcinoma. Tokyo: Springer, 2004: 249-250.
Kondo H, Gotoda T, Fujishiro M. Percutaneous
traction-assisted EMR by using an insulation-tipped electrosurgical knife for early stage
gastric cancer. Gastrointest Endoscopy 2004; 59 :284-288.
Kusaka K, Imamura H, Tomiya T, Makuuchi M.
Factors affecting liver regeneration after right portal vein embolization. Hepato-gastroenterology
2004; 51 :532-535.
Ma J, Iida H, Jo T, Takano H, Oonuma H, Morita T,
Toyo-Oka T, Omata M, Nagai R, Okuda Y, Yamada N, Nakajima T. Ursodeoxycholic acid inhibits endothelin-1 production in human vascular endothelial cells. Eur J Pharmacol 2004 ; 505 :
67-74.
Miyata T, Ohnishi H, Suzuki J, Yoshikumi Y,
Ohno H, Mashima H, Yasuda H, Ishijima T,
Osawa H, Satoh K, Sunada K, Kita H, Yamamoto
H, Sugano K. Involvement of syntaxin 4 in thetransport of membrane-type 1 matrix metalloproteinase to the plasma membrane in human gastricepithelial cells. Biochem Biophys Res Commun
2004; 323 : 118-124.
Miyashita K, Tojo A, Kimura K, Goto A, Omata M,
Nishiyama K, Fujita T. Blood pressure response toerythropoietin injection in hemodialysis and predialysis patients. Hypertens Res 2004 ; 27 : 79-84.
Moriyama M, Hoshida Y, Kato N, Otsuka M, Yoshida H, Kawabe T, Omata M. Genes associatedwith human hepatocellular carcinoma cell chemosensitivity to 5-fluorouracil plus interferon-alphacombination chemotherapy. Int J Oncol 2004 ; 25 :1279-1287.
Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M,
Shojima N, Ono H, Fujishiro M, Kushiyama A,
Fukushima Y, Kikuchi M, Noguchi N, Aburatani H,
Gotoh Y, Komuro I, Fujita T. Oxidative stress induces insulin resistance by activating the nuclear
factor-kappaB pathway and disrupting normal

151

33.

34.

35.

36.
37.

38.

39.

40.

41.

42.

subcellular distribution of phosphatidylinositol
3-kinase. Diabetologia 2004 ; 47 : 794-805.
Ohnishi H, Miyata T, Yasuda H, Satoh Y, Hanatsuka K, Kita H, Ohashi A, Tamada K, Makita N,
Iiri T, Ueda N, Mashima H, Sugano K. Distinct
roles of Smad2-, Smad3-, and ERK-dependent
pathways in TGF-beta 1 regulation of pancreatic
stellate cellular functions. J Biol Chem 2004; 279 :
8873-8878.
Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneoustumor ablation methods: Ethanol injection therapy
and radiofrequency ablation. Gastroenterology
2004 ; 127 (5 Suppl 1):S159-166.
Omata M, Yoshida H. Prevention and treatment of
hepatocellular carcinoma. Liver Transpl 2004 ;10 : S111-114.
Omata M. Funding for research in hepatology.
Hepatology 2004 ; 40 : 520.
Omata M. Regression of liver fibrosis in patientstreated by interferon. Intern Med 2004 ; 43 :887-888.
Omata M. Opening lecture : what is accomplishedand what is needed. In: Omata M, Okita K, eds.
Therapy for Viral Hepattis and Prevention of
Hepatocellular Carcinoma. Tokyo: Springer, 2004:
3-21.
Otsuka M, Kato N, Shao R-X, Hoshida Y, Ijichi H,
Koike Y, Taniguchi H, Moriyama M, Shiratori Y,
Kawabe T, Omata M. Vitamin K2 inhibits thegrowth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation. Hepatology 2004 ; 40 : 243-251.
Qiu Y, Hoshida Y, Kato N, Moriyama M, Otsuka
M, Taniguchi H, Kawabe T, Omata M. A simple
combination of serum type IV collagen andprothrombin time to diagnose cirrhosis in patientswith chronic active hepatitis C. Hepatol Res 2004 ;30 : 214-220.
Sato S, Shiratori Y, Imamura M, Obi S, Shiina S,
Akahane M, Ohtomo K, Omata M. Re-appearanceof power Doppler signals in the tumor nodules ofhepatocellular carcinoma after transarterial embolization reflects residual viable tumor cells:histological confirmation. Hepatogastroenterology
2004 ; 51 : 56-61.
Sato S, Suzuki K, Takikawa Y, Endo R, Omata M;

43.

44.

45.

46.

47.

48.

49.

50.

Japanese National Study Group of Fluminant
Hepatitis. Clinical epidemiology of fluminant
hepatitis in Japan before the substantial introduction of liver transplantation: an analysis of 1309
cases in a 15-year national survey. Hepatol Res
2004 ;30 :155-161.
Satonaka H, Suzuki E, Nishimatsu H, Oba S, Takeda R, Goto A, Omata M, Fujita T, Nagai R, Hirata Y. Calcineurin promotes the expression of
monocyte chemoattractant protein-1 in vascular
myocytes and mediates vascular inflammation.
Circ Res 2004 ; 94 : 693-700.
Shimoyama S, Aoki F, Kawahara M, Yahagi N,
Motoi T, Kuramoto S, Kaminishi M. Early gaseric
cancer development in a familial adenomatous
polypoisis patiant; Dig Dis Sci 2004; 49 ; 2.
Suzuki E, Satonaka H, Nishimatsu H, Oba S, Takeda R, Omata M, Fujita T, Nagai R, Hirata Y.
Myocyte enhancer factor 2 mediates vascular inflammation via the p38-dependent pathway. Circ
Res 2004 ; 95 : 42-49.
Tanaka Y, Kanai F, Kawakami T, Tateishi K, Ijichi
H, Kawabe T, Arakawa Y, Kawakami T, Nishimura
T, Shirakata Y, Koike K, Omata M. Interaction of
the hepatitis B virus X protein (HBx) with heatshock protein 60 enhances HBx-mediated apoptosis. Biochem Biophys Res Commun 2004 ; 318 :
461-469.
Taniguchi H, Kato N, Otsuka M, Goto T, Yoshida
H, Shiratori Y, Omata M. Hepatitis C virus coreprotein upregulates transforming growth factor-beta 1 transcription. J Med Virol 2004 ; 72 :52-59.
Tejima K, Arai M, Ikeda H, Tomiya T, Yanase M,
Inoue Y, Nagashima K, Nishikawa T, Watanabe N,
Omata M, Fujiwara K. Ischemic preconditioning
protects hepatocytes via reactive oxygen species
derived from Kupffer cells in rats. Gastroenterology 2004 ; 127 : 1488-1496.
Teratani T, Yoshida H, Shiina S, Obi S, Sato S,
Koike Y, Hamamura K, Akamatsu M, Fujishima T,
Imai T, Kawabe T, Shiratori Y, Omata M. A novel
display of reconstruction computed tomography
for the detection of small hepatocellular carcinoma.
Liver Int 2004 ;24 : 619-624.
Toda N, Saito K, Wada R, Komatsu Y, Tada M,
Kawabe T, Mitsushima T, Shiratori Y, Omata M.

152

51.

52.

53.

54.

55.

56.

57.

58.

59.

Early removal of bile duct stones in patients withacute biliary pancreatitis by endoscopic papillaryballoon dilatation. Hepato-Gastroenterol 2004 ;51 : 1263-1266.
Tomiya T, Inoue Y, Yanase M, Arai M, Ikeda H,
Tejima K, Nagashima K, Nishikawa T, Watanabe
N, Omata M, Fujiwara K. Treatment with leucine
stimulates the production of hepatocyte growth
factor in vivo. Biochem Biophys Res Commun
2004 ; 322 : 772-777.
Tomiya T, Omata M, Fujiwara K. Branched-chainamino acids, hepatocyte growth factor and protein
production in the liver. Hepatol Res 2004 ; 30S :14-18.
Tomiya T, Omata M, Fujiwara K. Significance ofbranched chain amino acids as possible stimulatorsof hepatocyte growth factor. Biochem Biophys Res
Commun 2004 ; 313 : 411-416.
Wang Y, Kato N, Hoshida Y, Otsuka M, Taniguchi
H, Moriyama M, Shiina S, Kawabe T, Ito YM,
Omata M. UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associated with hepatocellular carcinoma in Japanese patients with hepatitis C virus infection. Clin Cancer Res 2004 ; 10 :2441-2446.
Yahagi N, Fujishiro M, Imagawa A, Kakushima N,
Iguchi M, Omata M. Endoscopic submucosal dissection for the reliable en bloc resection of colorectal mucosal tumors. Digesive Endoscopy 2004 ;16(Suppl) : S89-S92.
Yahagi N, Fujishiro M, Kakushima N, Kobayashi
K, Hashimoto T, Oka M, Iguchi M, Enomoto S,
Ichinose M, Niwa H, Omata M. Endoscopic submucosal dissection for early gastric cancer using
the tip of an electrosurgical snare (thin type). Digestive Endoscopy 2004 ; 16 : 34-38.
Yahagi N, Fujishiro M, Omata M: Endoscopic
submucosal dissection of colorectal lesion. Digestive Endoscopy 2004; 16(supple): S178-S181.
Yamaji Y, Mitsushima T, Ikuma H, Watabe H,
Okamoto M, Kawabe T, Wada R, Doi H, Omata M.
Incidence and recurrence rates of colorectal adenomas estimated by annually repeated colonoscopies on asymptomatic Japanese. Gut 2004 ; 53 :568-572.
Yoshida H, Tateishi R, Arakawa Y, Sata M, Fujiyama S, Nishiguchi S,Ishibashi H, Yamada G, Yo-

60.

61.

62.

63.

64.

65.

66.

67.

kosuka O, Shiratori Y, Omata M. Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C.
Gut 2004 ; 53 : 425-430.
Akamatsu M, Ishikawa T, Shiratori Y, Koike Y,
Shiina S, Teratani T, Hamamura K, Obi S, Sato S,
Tateishi R, Fujishima T, Imai Y, Yoshida H, Omata
M. Factors predisposing to poorly differentiatedhepatocellular carcinoma and its recurrence.
Hepatogastroenterology 2005 ; 52 : 391-397.
Fujishima T, Yoshida H, Obi S, Shiina S, Kanda M,
Tateishi R, Akamatsu M, Koike Y, Sato S, Teratani
T, Kawabe T, Shiratori Y, Omata M. Analysis offactors influencing hepatocellular carcinoma detection: efficient use of computed tomographyduring arterial portography and during hepatic arteriography. J Gastroenterol 2005; 40 : 266-273.
Fujishiro M, Yahagi N, Kashimura K, Matsuura T,
Nakamura M, Kakushima N, Kodashima S, Ono S,
Kobayashi K, Hashimoto T, Yamamichi N, Tateishi A, Shimizu Y, Oka M, Ichinose M, Omata M.
Tissue damage of different submucosal injection
solutions for endoscopic mucosal resection. Gastrointest Endosc 2005 ; 62 : 933-942.
Fujishiro M: Endoscopic resection for early gastriccancer. In: Kaminishi M, Takubo K, Mafune K(Eds). The diversity of gastric carcinoma; Pathogenesis, diagnosis, and therapy. Springer-Verlag
Tokyo, 2005 ; pp 243-252.
Fujishiro M, Yahagi N, Kakushima N, Kodashima
S, Nakamura M, Kobayashi K, Hashimoto T, Yamamichi N, Tateishi A, Miyoshi H, Moriyama Y,
Shimizu Y, Oka M, Ichinose M, Omata M, Miki K.
Early detection of asymptomatic gastric cancers
using serum pepsinogen levels to indicate endoscopic submucosal dissection for better quality oflife. Proceedings of 6th international gastric cancer
congress. 145-150, 2005.
Fujiwara K, Yokosuka O, Imazeki F, Saisho H,
Miki M, Omata M. Do high levels of viral replication contribute to fulminant hepatitis A? Liver Int
2005 ; 25 : 194-195.
Grasberger H, Ye H, Mashima H, Bell GI. Dualpromoter structure of ZFP106: regulation by myogenin and nuclear respiratory factor-1. Gene2005 ; 344 : 143-59.
Guleng B, Tateishi K, Kanai F, Jazag A, Ohta M,

153

68.

69.

70.

71.

72.

73.

74.

Asaoka Y, Ijichi H, Tanaka Y, Imamura J, Ikenoue
T, Fukushima Y, Morikane K, Miyagishi M, TairaK, Kawabe T, Omata M. Cancer-derived VEGF
plays no role in malignant ascites formation in themouse. World J Gastroenterol 2005 ; 11 : 54555459.
Guleng B, Tateishi K, Ohta M, Kanai F, Jazag A,
Ijichi H, Tanaka Y, Washida M, Morikane K, Fukushima Y, Yamori T, Tsuruo T, Kawabe T, Miyagishi M, Taira K, Sata M, Omata M. Blockadeof the stromal cell-derived factor-1/CXCR4 axis
attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res 2005 ; 65 :5864-5871.
Hanajiri K, Mitsui H, Maruyama T, Kondo Y, Shiina S, Omata M, Nakagawa K. (18)F-FDG PET
for hepatocellular carcinoma presenting with portal vein tumor thrombus. J Gastroenterol 2005 ;40 : 1005-1006.
Hoshida Y, Kato N, Yoshida H, Wang Y, Tanaka M,
Goto T, Otsuka M, Taniguchi H, Moriyama M,
Imazeki F, Yokosuka O, Kawabe T, Shiratori Y,
Omata M. Hepatitis C Virus Core Protein and
Hepatitis Activity Are Associated through Transactivation of Interleukin-8. J Infect Dis 2005 ;192 : 266-275.
Ikai I, Arii S, Ichida T, Okita K, Omata M, Kojiro
M, Takayasu K, Nakanuma Y, Makuuchi M, Matsuyama Y, Yamaoka Y. Report of the 16th follow-up survey of primary liver cancer. Hepatol
Res 2005 ; 32 : 163-172.
Ikeda H, Nagashima K, Yanase M, Tomiya T, Arai
M, Inoue Y, Tejima K, Nishikawa T, Watanabe N,
Kitamura K, Isono T, Yahagi N, Noiri E, Inao M,
Mochida S, Kume Y, Yatomi Y, Nakahara K,
Omata M, Fujiwara K. The herbal medicine
inchin-ko-to (TJ-135) induces apoptosis in cultured rat hepatic stellate cells. Life Sci 2005 (inpress)
Ikenoue T, Kanai F, Hikiba Y, Obata T, Tanaka Y,
Imamura J, Ohta M, Jazag A, Guleng B, Tateishi K,
Asaoka Y, Matsumura M, Kawabe T, Omata M.
Functional analysis of PIK3CA gene mutations inhuman colorectal cancer. Cancer Res 2005 ; 65 :4562-4567.
Ikenoue T, Kanai F, Hikiba Y, Tanaka Y, Imamura

75.

76.

77.

78.

79.

80.

81.

J, Ohta M, Jazag A, Guleng B, Asaoka Y, Tateishi
K, Kawakami T, Matsumura M, Kawabe T, Omata
M. Functional consequences of mutations in a putative Akt phosphorylation motif of B-raf in human cancers. Mol Carcinog 2005 ; 43 : 59-63.
Isayama H, Kawabe T, Komatsu Y, Sasahira N,
Toda N, Tada M, Nakai Y, Yamamoto N, Hirano K,
Tsujino T, Yoshida H, Omata M. Successful treatment for groove pancreatitis by endoscopic drainage via the minor papilla. Gastrointest Endosc
2005 ; 61 : 175-178.
Ishikawa T, Fukushima Y, Shiobara Y, Kishimoto T,
Tanno S, Shoji I, Suzuki T, Matsui T, Shimada Y,
Ohyama T, Nagai R, Miyamura T. Outbreak ofhepatitis C virus infection in an outpatient clinic. J
Gastroenterol Hepatol 2005; 20 : 1087-1093.
Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B,
Ohta M, Imamura J, Tanaka Y, Tateishi K, Ikenoue
T, Kawakami T, Arakawa Y, Miyagishi M, Taira K,
Kawabe T, Omata M. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference
and gene expression profiles induced by transforming growth factor-beta. Oncogene 2005 ; 24 :662-671.
Jazag A, Kanai F, Ijichi H, Tateishi K, Ikenoue T,
Tanaka Y, Ohta M, Imamura J, Guleng B, Asaoka
Y, Kawabe T, Miyagishi M, Taira K, Omata M.
Single small-interfering RNA expression vector
for silencing multiple transforming growth factor-beta pathway components. Nucleic Acids Res
2005 ; 33 : e131.
Kanda Y, Komatsu Y, Akahane M, Kojima S,
Asano-Mori Y, Tada M, Oshima K, Isayama H,
Ogawa S, Motokura T, Chiba S, Ohtomo K, Omata
M, Hirai H. Graft-versus-tumor effect against advanced pancreatic cancer after allogeneic reduced-intensity stem cell transplantation. Transplantation 2005 ; 79 : 821-827.
Kaneko Y, Maruyama T, Takegami K, Watanabe T,
Mitsui H, Hanajiri K, Nagawa H, Matsumoto Y.
Use of a microbuble agent to increase the effect ofhigh intensityfocused ultrasound on liver tissue.
Eur Radiol 2005 ; 92 : 55-62.
Kato N, Ji G, Wang Y, Baba M, Hoshida Y, Otsuka
M, Taniguchi H, Moriyama M, Dharel N, Goto T,
Shao RX, Matsuura T, Ishii K, Shiina S, Kawabe T,
Muramatsu M, Omata M. Large-scale search of

154

82.

83.

84.

85.

86.

87.

88.

single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with
hepatitis C. Hepatology 2005 ; 42 : 846-853.
Kawakami T, Hoshida Y, Kanai F, Tanaka Y,
Tateishi K, Ikenoue T, Obi S, Sato S, Teratani T,
Shiina S, Kawabe T, Suzuki T, Hatano N, Taniguchi H, Omata M. Proteomic analysis of sera fromhepatocellular carcinoma patients after radiofrequency ablation treatment. Proteomics 2005 ; 5 :4287-4295.
Keeffe EB, Omata M. Hepatitis C: clinic-basic
interface. Clin Gastroenterol Hepatol 2005 ; 3 :S77.
Kondo S, Isayama H, Akahane M, Toda N, Sasahira N, Nakai Y, Yamamoto N, Hirano K, Komatsu
Y, Tada M, Yoshida H, Kawabe T, Ohtomo K,
Omata M. Detection of common bile duct stones:
comparison between endoscopic ultrasonography,
magnetic resonance cholangiography, and helical-computed-tomographic cholangiography. Eur JRadiol 2005 ; 54 : 271-275.
Kushiyama A, Shojima N, Ogihara T, Inukai K,
Sakoda H, Fujishiro M, Fukushima Y, Anai M,
Ono H, Horike N, Viana AY, Uchijima Y, Nishiyama K, Shimosawa T, Fujita T, Katagiri H, Oka Y,
Kurihara H, Asano T. Resistin-like molecule beta
activates MAPKs, suppresses insulin signaling in
hepatocytes, and induces diabetes, hyperlipidemia,
and fatty liver in transgenic mice on a high fat diet.
J Biol Chem 2005; 280 : 42016-42025.
Liaw YF, Leung N, Guan R, Lau GK, Merican I,
McCaughan G, Gane E, Kao JH, Omata M; for the
Asian-Pacific consensus update working party on
chronic hepatitis B. Asian-Pacific consensus
statement on the management of chronic hepatitis
B: a 2005 update. Liver Int 2005 ; 25 : 472-489.
Matsumoto A, Tanaka E, Rokuhara A, Kiyosawa K,
Kumada H, Omata M, Okita K, Hayashi N, Okanoue T, Iino S, Tanikawa K; the Inuyama Hepatitis
Study Group. Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis
B: A multicenter retrospective study of 2795 patients. Hepatol Res 2005 ; 32 : 173-184.
Minami M, Ishiyama A, Takagi M, Omata M,
Atarashi K. Effects of allopurinol, a xanthine oxidase inhibitor, on renal injury in hypercholesterolemia-induced hypertensive rats. Blood Pres-

89.

90.

91.

92.

93.

94.

95.

96.

97.

sure 2005 ; 14 : 120-125.
Nagae G, Ido K, Isoda N, Sato S, Kita H, Sugano
K Laparoscopic ablation therapy for Hepatocellular carcinoma. Dig Endosc 2005; 17 : 1-8.
Nakai Y, Isayama H, Komatsu Y, Tsujino T, Toda
N, Sasahira N, Yamamoto N, Hirano K, Tada M,
Yoshida H, Kawabe T, Omata M. Efficacy andsafety of the covered Wallstent in patients with
distal malignant biliary obstruction. Gastrointest
Endosc 2005 ; 62 : 742-748.
Nakai Y, Otsuka M, Hoshida Y, Tada M, Komatsu
Y, Kawabe T, Omata M. Identifying genes withdifferential expression in gemcitabine-resistantpancreatic cancer cells using comprehensive transcriptome analysis. Oncol Rep 2005 ; 14 : 12631267.
Nakaya M, Fukushima Y, Takeuchi N, Kaga K.
Nasal allergic response mediated by histamine h3
receptors in murine allergic rhinitis. Laryngoscope
2005; 115 : 1778-1784.
Negoro H, Shin WS, Hakamada-Taguchi R, Eguchi N, Urade Y, Goto A, Toyo-Oka T, Fujita T,
Omata M, Uehara Y. Endogenous prostaglandin
D(2) synthesis decreases vascular cell adhesion
molecule-1 expression in human umbilical vein
endothelial cells. Life Sci 2005 ; 78 : 22-29.
Nishimatsu H, Suzuki E, Satonaka H, Takeda R,
Omata M, Fujita T, Nagai R, Kitamura T, Hirata Y.
Endothelial dysfunction and hypercontractility ofvascular myocytes are ameliorated by fluvastatin
in obese Zucker rats. Am J Physiol Heart Circ
Physiol 2005 ; 288 : H1770-1776.
Ohmae T, Hirata Y, Maeda S, Shibata W, Yanai A,
Ogura K, Yoshida H, Kawabe T, Omata M.
Helicobacter pylori Activates NF-{kappa}B via
the alternative pathway in B lymphocytes. J Immunol 2005 ; 175 : 7162-7169.
Ohta M, Tateishi K, Kanai F, Ueha S, Guleng B,
Washida M, Tanaka Y, Ijichi H, Ikenoue T, Sata M,
Sudo T, Shiina S, Kawabe T, Matsushima K,
Omata M. Reduced p38 mitogen-activated protein
kinase in donor grafts accelerates acute intestinal
graft-versus-host disease in mice. Eur J Immunol
2005 ; 35 : 2210-2221.
Ohta M, Tateishi K, Kanai F, Watabe H, Kondo S,
Guleng B, Tanaka Y, Asaoka Y, Jazag A, ImamuraJ, Ijichi H, Ikenoue T, Sata M, Miyagishi M, Taira155

K, Tada M, Kawabe T, Omata M. p53-Independent
negative regulation of p21/cyclin-dependent
kinase-interacting protein 1 by the sonic hedgehog-glioma-associated oncogene 1 pathway ingastric carcinoma cells. Cancer Res 2005 ; 65 :10822-10829.
98. Okamoto M, Kawabe T, Kato J, Yamaji Y, Md TI,
Omata M. Ultrathin Colonoscope With a Diameterof 9.8 mm for Total Colonoscopy. J Clin Gastroenterol 2005 ; 39 : 679-683.
99. Okamoto M, Kawabe T, Ohata K, Togo G, Hada T,
Katamoto T, Tanno M, Matsumura M, Yamaji Y,
Watabe H, Ikenoue T, Yoshida H, Omata M. Amebic colitis in a symptomatic subjects with positive
fecal occult blood test results: clinical featuresdifferent from symptomatic cases. Am J Trop Med
Hyg 2005 ; 73 : 934-935.
100. Okamoto M, Kawabe T, Yamaji Y, Kato J, Ikenoue
T, Togo G, Watabe H, Yoshida H, Shiratori Y,
Omata M. Flat-type early colorectal cancer preferentially develops in right-sided colon in older
patients. Dis Colon Rectum 2005 ; 48 : 101-107.
101. Okamoto M, Kawabe T, Yamaji Y, Kato J, Ikenoue
T, Togo G, Yoshida H, Shiratori Y, Omata M. Rectosigmoid findings are not associated with proximal colon cancer: analysisof 6 196 consecutive
cases undergoing total colonoscopy. World J Gastroenterol 2005 ; 11 : 2249-2254.
102. Omata M, Yoshida H, Shiratori Y. Prevention ofhepatocellular carcinoma and its recurrence inchronic hepatitis C patients by interferon therapy.
Clin Gastroenterol Hepatol 2005 ; 3 : S141-143.
103. Omata M. Modalities of prevention of recurrence
after tumor ablation/resection of HCC. J Gastroenterol Hepatol 2005 ; 19 : S270-S271.
104. Omata M. Can contrast-enhanced sonography be
used to characterize focal hepatic lesions in patients with liver disease? Nat Clin Pract Gastroenterol Hepatol 2005 ; 2 : 452-453.
105. Otsuka M, Kato N, Ichimura T, Abe S, Tanaka Y,
Taniguchi H, Hoshida Y, Moriyama M, Wang Y,
Shao RX, Narayan D, Muroyama R, Kanai F,
Kawabe T, Isobe T, Omata M. Vitamin K2 binds
17beta-hydroxysteroid dehydrogenase 4 andmodulates estrogen metabolism. Life Sci 2005 ;76 : 2473-2482.
106. Otsuka M, Kato N, Moriyama M, Taniguchi H,

Wang Y, Dharel N, Kawabe T, Omata M. Interaction between the HCV NS3 protein and the host
TBK1 protein leads to inhibition of cellular antiviral responses. Hepatology 2005;41:1004- 1012.
107. Sakoda H, Fujishiro M, Fujio J, Shojima N, Ogihara T, Kushiyama A, Fukushima Y, Anai M, Ono
H, Kikuchi M, Horike N, Viana AY, Uchijima Y,
Kurihara H, Asano T. Glycogen debranching enzyme association with beta-subunit regulates
AMP-activated protein kinase activity. Am J
Physiol Endocrinol Metab 2005; 289 : E474-481.
108. Sasahira N, Kawabe T, Nakamura A, Shimura K,
Shimura H, Itobayashi E, Asada M, Shiratori Y,
Omata M. Inflammatory pseudotumor of the liverand peripheral eosinophilia in autoimmune pancreatitis. World J Gastroenterol 2005 ; 11 : 922925.
109. Sasahira N, Tada M, Yoshida H, Tateishi R, Shiina
S, Hirano K, Isayama H, Toda N, Komatsu Y,
Kawabe T, Omata M. Extrahepatic biliary obstruction after percutaneous tumour ablation for hepatocellular carcinoma: aetiology and successfultreatment with endoscopic papillary balloon dilatation. Gut 2005 ; 54 : 698-702.
110. Sato S, Yoshida H, Teratani T, Obi S, Koike Y,
Shiina S, Omata M. Three-dimensional power
Doppler ultrasonography for hepatocellular carcinoma: a comparison with angiography? Hepatogastroenterology 2005 ; 52 : 72-75.
111. Shao R-X, Hoshida Y, Otsuka M, Kato N, Tateishi
R, Teratani T, Shiina S, Taniguchi H, Moriyama M,
Kawabe T, Omata M. Hepatic gene expression
profiles associated with fibrosis progression andhepatocarcinogenesis in hepatitis C patients. WorldJ Gastroenterol 2005 ; 11 : 1995-1999.
112. Shao RX, Otsuka M, Kato N, Chang JH,
Muroyama R, Taniguchi H, Moriyama M, Wang Y,
Kawabe T, Omata M. No mutations in the tyrosine
kinases of human hepatic, pancreatic, and gastriccancer cell lines. J Gastroenterol 2005 ; 40 : 918.
113. Shao R-X, Otsuka M, Kato N, Taniguchi H, Hoshida Y, Moriyama M, Kawabe T, Omata M.
Acyclic retinoid inhibits human hepatoma cell
growth by suppressing fibroblast growth factor-mediated signaling pathways. Gastroenterology
2005 ; 128 : 86-95.
114. Shibata W, Hirata Y, Yoshida H, Otsuka M, Ho-

156

shida Y, Ogura K, Maeda S, Ohmae T, Yanai A,
Mitsuno Y, Seki N, Kawabe T, Omata M.
NF-kappaB and ERK-signaling pathways contribute to the gene expression induced by cag
PAI-positive-Helicobacter pylori infection. WorldJ Gastroenterol 2005 ; 11 : 6134-6143.
115. Shiina S, Teratani T, Obi S, Sato S, Tateishi R,
Fujishima T, Ishikawa T, Koike Y, Yoshida H,
Kawabe T, Omata M. A randomized controlled
trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005 ; 129 : 122-130.
116. Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata
R, Tanaka N, Arakawa Y, Hashimoto E, Hirota K,
Yoshida H, Ohashi Y, Omata M; Tokyo-Chiba
Hepatitis Research Group. Antiviral therapy forcirrhotic hepatitis C: association with reduced
hepatocellular carcinoma development and improved survival. Ann Intern Med 2005 ; 142 :105-114.
117. Shojima N, Ogihara T, Inukai K, Fujishiro M, Sakoda H, Kushiyama A, Katagiri H, Anai M, Ono H,
Fukushima Y, Horike N, Viana AY, Uchijima Y,
Kurihara H, Asano T. Serum concentrations of resistin-like molecules beta and gamma are elevatedin high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bonemarrow. Diabetologia 2005; 48 : 984-992.
118. Takeda R, Suzuki E, Satonaka H, Oba S, Nishimatsu H, Omata M, Fujita T, Nagai R, Hirata Y.
Blockade of endogenous cytokines mitigates
neointimal formation in obese Zucker rats. Circulation 2005 ; 111 : 1398-1406.
119. Tamai H, Oka M, Maeda H, Shingaki N, Kanno T,
Enomoto S, Shiraki T, Iguchi M, Nakazawa K,
Arii K, Yanaoka K, Shimizu Y, Nakata H, Fujishiro M, Yahagi N, Shiina S, Ichinose M. Contrast harmonic sonographically guided radio frequency ablation for spontaneous ruptured hepatocellular carcinoma. J Ultrasound Med 2005; 24 :1021-1026.
120. Tateishi K, Ohta M, Guleng B, Kanai F, Tanaka Y,
Asaoka Y, Jazag A, Imamura J, Imamura T, Ijichi
H, Ikenoue T, Kawakami T, Fukushima Y, Washida
M, Sata M, Miyagishi M, Taira K, Yoshida H,
Kawabe T, Omata M. TRAIL-induced cell deathcooperates with IFN-gamma activation in thegraft-versus-tumor effect against colon tumors. Int
J Cancer 2005 ; 118(9) : 2237-2246.
121. Tateishi R, Shiina S, Teratani T, Obi S, Sato S,
Koike Y, Fujishima T, Yoshida H, Kawabe T,
Omata M. Percutaneous radiofrequency ablation
for hepatocellular carcinoma. Cancer 2005 ; 103 :
1201-1209 .
122. Tateishi R, Yoshida H, Shiina S, Imamura H, Hasegawa K, Teratani T, Obi S, Sato S, Koike Y, Fujishima T, Makuuchi M, Omata M. Proposal of anew prognostic model for hepatocellular carcinoma: an analysis of 403 patients. Gut 2005 ; 54 :419-425.
123. Toda N, Akahane M, Kiryu S, Matsubara Y, Yamaji Y, Okamoto M, Minagawa N, Ohgi K, Komatsu Y, Yahagi N, Yoshida H, Kawabe T, Ohtomo
K, Omata M. Pancreas duct abnormalities in patients with ulcerative colitis: a magnetic resonancepancreatography study. Inflamm Bowel Dis 2005 ;11 : 903-908.
124. Toda N, Saito K, Wada R, Kawabe T, Shiratori Y,
Mitsushima T, Omata M. Endoscopic sphincterotomy and papillary balloon dilation for bile ductstones. Hepatogastroenterology 2005 ; 52 :
700-704.
125. Tsujino T, Isayana H, Komatsu Y, Ito Y, Tada M,
Minagawa N, Nakata R, Kawabe T, Omata M.
Risk factors for pancreatitis in patients with common bile duct stones managed by endoscopic papillary balloon dilation. Am J Gastroenterol 2005 ;100 : 38-42.
126. Tsujino T, Komatsu Y, Isayama H, Hirano K, Sasahira N, Yamamoto N, Toda N, Itoh Y, Nakai Y,
Tada M, Matsumura M, Yoshida H, Kawabe T,
Shiratori Y, Omata M. Ulinastatin for pancreatitis
after endoscopic retrograde cholangiopancreatography: A randomized, controlled trial. Clin
Gastroenterol Hepatol 2005 ; 4 : 376-383.
127. Watabe H, Mitsushima T, Yamaji Y, Okamoto M,
Wada R, Kokubo T, Doi H, Yoshida H, Kawabe T,
Omata M. Predicting the development of gastriccancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective
endoscopic cohort study. Gut 2005 ; 54 : 764-768.
128. Yamamichi N, Yamamichi-Nishina M, Mizutani T,
Watanabe H, Minoguchi S, Kobayashi N, Kimura
S, Ito T, Yahagi N, Ichinose M, Omata M, Iba H.

157

The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducibleby transient HDAC inhibitor treatment, which exhibits antioncogenic potential. Oncogene 2005 ;24 : 5471-5481.
129. Yahagi N, Fujishiro M, Kakushima N, Kodashima
S, Nakamura M, Omata M. Clinical evaluation of
the multi-bending scope in various endoscopic
procedures of the upper GI tract. Dig Endosc
2005; 17: S94-96.
130. Yamamichi N, Yamamichi-Nishina M, Mizutani T,
Watanabe H, Minoguchi S, KobayashiN, Kimura S,
Ito T, Yahagi N, Ichinose M, Omata M, Iba H. The
Brm gene suppressed at the post-transcriptional
level in various human cell lines is inducible bytransient HDAC inhibitor treatment, which exhibits antioncogenic potential. Oncogene 2005; 24(35) : 5471-81.
131. Yamashiki N, Tateishi R, Yoshida H, Shiina S,
Teratani T, Sato S, Mine N, Kondo Y, Kawabe T,
Omata M. Ablation therapy in retaining extent of
hepatocellulcar carcinoma: A simulative analysis
of dropout from the waiting list for liver transplantation. Liver Transplant 2005;11: 508-514.
132. Yoshida H, Yoshida H, Shiina S, Omata M. Early
liver cancer: concepts, diagnosis, and management.
Int J Clin Oncol 2005 ; 10 : 384-390.
133. Yoshikumi Y, Mashima H, Ueda N, Ohno H, Suzuki J, Tanaka S, Hayashi M, Sekine N, Ohnishi H,
Yasuda H, Iiri T, Omata M, Fujita T, Kojima I.
Roles of CTPL/Sfxn3 and Sfxn family members inpancreatic islet. J Cell Biochem 2005 ; 95 : 11571168.

Internal Medicine
2. Medicine Ⅱ

⑰

160

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

Associate Professor
Tomoki Okazaki, M.D.,Ph.D.,
Keiichi Hishikawa, M.D.,Ph.D.,
Takanari Gotoda M.D.,Ph.D.,

Katsuyuki Ando, M.D., Ph.D.,
Shinya Kaname, M.D.,Ph.D.,
Yoshio Uehara, M.D.,Ph.D.

Lecturer
Shu Uwatoko, M.D., Ph.D.,
George Seki, M.D., Ph.D.,
Tatsuo Shimosawa, M.D., Ph.D.,
Taroh Iiri, M.D., Ph.D.,
Masaomi Nangaku, M.D., Ph.D.

Seiji Fukumoto, M.D., Ph.D.,
Eisei Noiri, M.D., Ph.D.,
Hideyuki Negoro, M.D., Ph.D.,
Koji Takano, M.D., Ph.D.,

Associate
Toshihiro Okuda, M.D., Ph.D.,
Etsu Suzuki, M.D., Ph.D.,
Masashi Isshiki, M.D., Ph.D.,
Takeshi Marumo, M.D., Ph.D.,
Yugo Shibagaki, M.D., Ph.D.,
Junichi Hirahashi, M.D., Ph.D.,
Hideomi Yamada, M.D., Ph.D.,

Akihiro Tojo, M.D., Ph.D.,
Katsutoshi Takahashi, M.D., Ph.D.,
Shigeyoshi Oba, M.D., Ph.D.,
Miki Nagase, M.D., Ph.D.,
Noriko Makita, M.D., Ph.D.,
Yuichi Hori, M.D., Ph.D.,
Yoshitaka Ishibashi, M.D., Ph.D.

Homepage http: http://plaza.umin.ac.jp/~kid-endo/top.html
Introduction and Organization
The Division of Nephrology and Endocrinology is
one of the major divisions in the Department of Internal
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. We
have 18 beds on the 12th floor of the Northern Ward of
the Tokyo University Hospital, and ten beds for hemodialysis. Usually we have up to 30 in-patients 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 the clinicalworks of our residents, and other 2 associates are involved mainly in the Hemodialysis Unit. We are intimately working together in all clinical activities under
the supervision of the Professor and the Associate Professors.

Clinical and Teaching activities
The residents are in charge of up to 30 patients of ourdivision and supervised by associates and faculty staffs.
Every Tuesday, we have a clinical conference to discuss

161

the diagnosis and treatment of our patients with all
members of the staff. Particular cases are further discussed with guest specialists from outside once amonth.
Nephritis should be morphologically diagnosed byrenal biopsy and the optimal treatment should be chosen for each patient. In our division, renal biopsy is actively performed to give the real benefits of treatment to
the patients. We also treat diabetic patients with proteinuria and end-stage renal failure. Each staff of ourdivision also works at the hemodialysis unit thus we
can manage patients in every stage of renal disease.
In the endocrine unit there is a variety of patients
having disorders in thyroid, parathyroid, pituitary gland,
adrenal glands and genital glands. It is also our specialty to diagnose and treat secondary hypertension
caused by primary aldosteronism, Cushing’s syndrome,pheochromocytoma, renal artery stenosis and so on. We
often have consultation from other divisions concerning
water and mineral metabolism disorders.

Research activities
In our department there are more than 30 students of
the Graduate School. We have research conferences
every Tuesday, to discuss the results of the researchwith the Professor and faculty members. As you see inthe references below, our research topics are various
and cover every field of Nephrology, Hypertension and
Endocrinology. We are also actively collaborating with
scientists outside the division and outside the University including foreign countries. Achievements of ourresearches are published in world top level journals ofNephrology, Hypertension and Endocrinology.

References
1. Isshiki M, Mutoh A, Fujita T. Subcortical Ca2+
waves sneaking under the plasma membrane in indothelial cells. Circ Res.2004;95:e11-21.
2. Kawai J, Ando K, Tojo A, Shimosawa T, Takahashi
K, Onozato ML. Endogenous adrenomedullin protects against vascular response to injury in mice.
Circulation. 2004;109: 1147-53.
3. Xing G, Shimosawa T, Ogihara T, Matsui H, Itakura K, Qingyou X. Angiotensin II-induced insulin
resistance is enhanced in adrenomedullin-deficientmice. Endocrinology. 2004;145:3647-51.
4. Shimosawa T, Takano K, Ando K, Fujita T. Magnesium inhibits norepinephrine release by blocking
N-type calcium channels at peripheral sympathetic
nerve endings. Hypertension. 2004;44:897-902.
5. Matsui H, Shimosawa T, Itakura K, Guanqun X,
Ando K, Fujita T. Adrenomedullin can protect
against pulmonary vascular remodeling induced byhypoxia. Circulation. 2004;109:2246-51.
6. Ando K, Fujita T. Role of lectin-like oxidized
low-density lipoprotein receptor-1 (LOX-1) in thedevelopment of hypertensive organ damage. Clin
Exp Nephrol. 2004;8:178-182.
7. Fujita T, Ando K. Salt, blood pressure, and kidney.
In Kidney and Blood Pressure Regulation. ed bySuzuki H, Saruta T, Contrib Nephrol, Karger, Basel.
2004;143:16-31.
8. Zou Y, Akazawa H, Qin Y, Takano H, Makita N,
Iwanaga K, et al. Mechanical stretch activates angiotensin II type 1 receptor without the involvement of angiotensin II.
9. Bastepe M, Weinstein LS, Ogata N, Kawaguchi H,
Jüppner H, Kronenberg HM. Chung U-I. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. PNAS.
2004;101:14794-9.
10. Asai M, Iwasaki Y, Yoshida M, Mutsuga-Nakayama N, Arima H, Ito M, et al. NFAT is involved in
the depolarization-induced activation of GrowthHormone-releasing Hormone gene transcription invitro. Mol Endocrinol. 2004;18:3011-9.
11. Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki
Y, Yamashita T, et al. Venous sampling for fibroblast growth factor (FGF)-23 confirms preoperative
diagnosis of tumor-induced osteomalacia. J Clin
Endocrinol Metab. 2004;89:3979-82.
12. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H,
Takeuchi Y, Fujita T, et al. Targeted ablation of
Fgf23 demonstrates an essential physiological roleof FGF-23 in phosphate and vitamin D metabolism.
J Clin Invest. 2004;113:561-8.
13. Suzuki E, Satonaka H, Nishimatsu H, Oba S,
Takeda R, Omata M, et al. Myocyte enhancer factor
2 mediates vascular inflammation via the
p38-dependent pathway. Circ Res. 2004;95:42-9.
14. Satonaka H, Suzuki E, Nishimatsu H, Oba S, Takeda R, Goto A, et al. Calcineurin promotes the162

expression of monocyte chemoattractant protein-1
in vascular myocytes and mediates vascular inflammation. Circ Res. 2004;94:693-700.
15. Onozato ML, Tojo A, Goto A, Fujita T. Radical
scavenging effect of gliclazide in diabetic rats fed
with a high cholesterol diet. Kidney Int. 2004;65:
951-60.
16. Nagata D, Takeda R, Sata M, Satonaka H, Suzuki E,
Nagano T, et al. AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smoothmuscle cell proliferation. Circulation. 2004;110:444-51.
17. Matsumoto M, Tanaka T, Yamamoto T, Noiri E,
Miyata T, Inagi R, et al. Hypoperfusion of peritubular capillaries induced chronic hypoxia prior toprogression of tubulointerstitial injury in a progressive model of rat glomerulonephritis. J Am Soc
Nephrol. 2004;15:1574-81.
18. Manotham K, Tanaka T, Matsumoto M, Ohse T,
Miyata T, Inagi R, et al. Evidence of tubular hypoxia in the early phase in the remnant kidneymodel. J Am Soc Nephrol. 2004;15:1277-88.
19. Ohse T, Ota T, Niamh K, Godson C, Yamada K,
Tanaka T, et al. Modulation of interferon-induced
genes by lipoxin analogue in anti-GBM nephritis. J
Am Soc Nephrol Nephrol. 2004;15:919-27.
20. Doi K, Suzuki Y, Nakao A, Fujita T, Noiri E. Radical scavenger edaravone developed for clinical use
ameliorates ischemia/reperfusion injury in rat kidney. Kidney Int. 2004;65:1714-23.
21. Doi K, Noiri E, Tokunaga K. The association ofNAD(P)H oxidase p22phox with diabetic nephropathy is still uncertain: response to Hodgkinson,
Millward, and Demaine. Diabetes Care. 2004;27:
1518-9.
22. Hino M, Nagase M, Kaname S, Shibata S, Nagase
T, Oba S, et al. Expression and regulation ofadrenomedullin in renal glomerular podocytes.
Biochem Biophys Res Commun. 2005;330:178185.
23. Takase O*, Marumo T*, Imai N, Hirahashi J, Takayanagi A, Hishikawa K, et al. * first co-author.
NF-κB dependent increase in intrarenal angiotensin
II induced by proteinuria. Kidney Int. 2005;68:46473.
24. Uchimura H, Marumo T, Takase O, Kawachi H,
Shimizu F, Hayashi M, et al. Intrarenal Injection ofBone Marrow-Derived Angiogenic Cells Reduces
Endothelial Injury and Mesangial Cell Activation inExperimental Glomerulonephritis. J Am Soc
Nephrol. 2005;16:997-1004.
25. Hishikawa K, Nakaki T, Fujita T. Oral flavonoid
supplementation attenuates atherosclerosis development in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005;25:442-6.
26. Kushiyama A, Shojima N, Ogihara T, Inukai K,
Sakoda H, Fujishiro M, et al. Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on ahigh fat diet. J Biol Chem. 2005;280:42016-25.
27. Fujita M, Kuwaki T, Ando K, Fujita T. Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in thebrain. Hypertension. 2005;45:1165-72.
28. Araya K, Fukumoto S, Backenroth R, Takeuchi Y,
Nakayama K, Ito N, et al. A novel mutation in fibroblast growth factor (FGF)23 gene as a cause oftumoral calcinosis. J Clin Endocrinol Metab.
2005;90:5523-7.
29. Yamashita H, Yamazaki Y, Hasegawa H, Yamashita
T, Fukumoto S, Shigematsu T, et al. Fibroblast
growth factor (FGF)-23 in patients with Graves'disease before and after antithyroid therapy: Its
important role in serum phosphate regulation. J
Clin Endocrinol Metab. 2005;90:4211-5.
30. Nishi H, Nii-Kono T, Nakanishi S, Yamazaki Y,
Yamashita T, Fukumoto S, et al. Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor-23 in dialysis patients withsecondary hyperparathyroidism. Nephron. 2005;
101:c94-9.
31. Nakanishi S, Kazama JJ, Nii-Kono T, Omori K,
Yamashita T, Fukumoto S, et al. Serum fibroblast
growth factor-23 levels predict the future refractory
hyperparathyroidism in dialysis patients. KidneyInt. 2005;67:1171-8.
32. Kazama JJ, Sato F, Omori K, Hama H, Yamamoto
S, Maruyama H, et al. Pretreatment serum FGF-23
levels predict the efficacy of calcitriol therapy indialysis patients. Kidney Int. 2005;67:1120-5.
33. Takeda R, Suzuki E, Satonaka H, Oba S, Nishimatsu H, Omata M, et al. Blockade of endogenous
cytokines mitigates neointimal formation in obese

163

Zucker rats. Circulation. 2005;111:1398-1406.
34. Kensuke Asaba, Akihiro Tojo, Maristela Lika
Onozato, Atsuo Goto, Mark T. Quinn, Toshiro Fujita, et al. Effects of NADPH oxidase inhibitor indiabetic nephropathy. Kidney Int. 2005;67:1890-8.
35. Tojo A, Onozato ML, Kobayashi N, Goto A, Matsuoka H, Fujita T. Antioxidative Effect of P38 Mitogen-Activated Protein Kinase Inhibitor in the
Kidney of Hypertensive Rat. J Hypertens. 2005;23:
165-74.
36. Kobayashi N, Hara K, Tojo A, Onozato ML, Honda
T, Yoshida K, et al. Eplerenone shows renoprotective effect by reducing LOX-1 mediated adhesion
molecule, PKC e-MAPK-p90RSK, and Rho-kinase
pathway. Hypertension. 2005;45:538-44.
37. Nishimatsu H, Suzuki E, Satonaka H, Takeda R,
Omata M, Fujita T, et al. Endothelial dysfunction
and hypercontractility of vascular myocytes areameliorated by fluvastatin in obese Zucker rats. Am
J Physiol Heart Circ Physiol. 2005;288:H1770-6.
38. Eto N, Kojima I, Inagi R, Miyata T, Fujita T, Uesugi N, et al. Protection of endothelial cells by dextran sulfate in rats of thrombotic microangiopathy. J
Am Soc Nephrol. 2005;16, 2997-3005.
39. Tanaka T, Kojima I, Ohse T, Ingelfinger JR, Adler
S, Fujita T, et al. Cobalt promotes angiogenesis via
hypoxia-inducible factors and protects ischemic
tubulointerstitium in the remnant kidney. Lab
Invest. 2005;85:1292-1307.
40. Katavetin P, Nangaku M, Fujita T. Wrong Primer
for Rat Angiotensinogen mRNA. Am J Physiol
Renal Physiol. 2005;288:F1078.
41. Zheng Y, Yamada H, Sakamoto K, Horita S,
Kunimi M, Endo Y, et al. Roles of insulin receptor
substrates in insulin-induced stimulation of renal
proximal bicarbonate absorption. J Am Soc
Nephrol. 2005;16:2288-95.
42. Horita S, Yamada H, Inatomi J, Moriyama N, Sekine T, Igarashi T, et al. Functional analysis of
NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities. J Am Soc
Nephrol. 2005;16:2270-8.
（Total 139 publications）

164

Department ofMetabolic Diseases
Professor
Takashi Kadowaki, M.D.,Ph.D.

Lecturer
Yoshiyasu Kaneko, M.D., Ph.D.,

Kazuyuki Tobe, M.D., Ph.D.

Associate
Kazuhisa Tsukamoto, M.D., Ph.D.,
Ken Ohashi, M.D., Ph.D.,
Masumi Hara, M.D. Ph.D.,
Midori Fujishiro, M.D., Ph.D.,

Jun-ichi Osuga, M.D., Ph.D.
Kazuo Hara, M.D., Ph.D.
Hideyuki Sakoda, M.D., PhD.
Mitsuru Ohsugi, M.D., PhD.

Homepage http://dm.umin.jp/
Introduction and Organization
In 1998 the Department of Internal Medicine at the
University of Tokyo was reorganized to the more functional units based on clinical specialties of diseasedorgans. The physicians specialized in the metabolic
diseases from 3 departments of Internal Medicine were
unified to the Department of Metabolic Diseases. The
Department of Metabolic Diseases is one of the major
divisions in the Department of Internal Medicine at the
University of Tokyo, and covers metabolic diseases
including diabetes mellitus, obesity and dyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003) and Dr.
Toshiro Fujita (2003) and the present Professor Dr. Takashi Kadowaki (2003-present), we have provided awide-ranged clinical, teaching and research activities.
Currently, we hold 35 beds mainly on the 12th floor of
the Inpatient Ward of the Tokyo University Hospital,
and take care of more than 30 patients constantly. Besides the staffs listed above, our division holds faculties
in branches, for example, 21st Century COE Program(associate professor, Dr. Kohjiro Ueki), Department ofIntegrated Molecular Science on Metabolic Diseases(associate professor, Dr. Toshimasa Yamauchi), andDepartment of Clinical Bioinformatics. With all thesestaffs, we intensively instruct and teach the residents
and under-graduate students; annual evaluation of theteaching skill by the students always rates our department within the three places of the top. In addition,
there are around 25 students of Graduate School in ourdivision. With all these members, we vigorously workon the research activities, which lead to the outstanding
contributions in the field of metabolism.

Clinical activities
Based on the update clinical evidences and with theexperienced skills, we provide superior and warmhearted medicine to each patient. We have outpatient
clinics from Monday through Friday, and take care ofmore than 4000 patients. In the inpatient care unit, we
not only take care of more than 30 patients in our division as mentioned above, but also provide a sophisticated management to all patients suffering from metabolic diseases, especially diabetes mellitus. Diabetes
mellitus, metabolic syndrome, hyperlipidemia and obesity are very popular in Japan, and cause complications

165

including nephropathy, retinopathy, neuropathy andcardiovascular diseases. Thus, in collaboration withother departments, we optimize the treatment of eachpatient.
We provide the educational lectures to the patients
every day in the inpatient ward, and also give lectures
once a week in the outpatient unit. In addition, in collaboration with co-medical staffs of our hospital, we
provide patients well-reasoned instructions regarding
diet therapy, excise therapy and medication therapy.
The weekly official activities of our department are thepre-round case conference and the Ward Round by theProfessor on Monday. We also hold a case conferenceby the consultation group staffs on Tuesday.

Teaching activities
As for under-graduate education, our department
takes a part in systemic lectures for the 4th year medical students, bed-side learning and clinical clerkship forthe 5th year medical students, and clinical lectures forthe 6th year medical students.
In systemic lectures, comprehensive presentation for
the understanding of basic knowledge about the concept,
pathogenesis, diagnosis and treatment of common
metabolic diseases is performed.
In clinical lectures, we present clinical cases of important diseases such as diabetes mellitus, and try to discuss with the students several points for planning thediagnosis and treatment in collaboration with the faculties of the Departments of Nephrology, Cardiology, andOphthalmology.
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 the Faculty members. Each student can learn how to make a
medical interview, check physical findings and makethe actual plans for the diagnosis and treatment. Several
lectures that lead to profound understandings of themetabolic diseases are provided by the staffs.
In clinical clerkship, we arrange the program so that thestudents can experience the clinical practice and learn
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 others or with other departments, we focus on the molecular mechanisms of themetabolic diseases and the establishment of the newtreatment.
1) Molecular mechanisms of type 2 diabetes
We have been studying molecular mechanisms oftype 2 diabetes and its susceptibility genes. By using gene targeting, we have been investigating therole of insulin signal transduction in the development of diabetes. We are also studying the molecular mechanisms by which obesity and hypertrophic
adipocytes cause insulin resistance. We are trying
to elucidate the mechanisms by which adipose-tissue-derived factors, adipokines, contributeto the development of the insulin resistance andmetabolic syndrome, and also to explore the signaltransduction pathways of major adipokines including adiponectin/AdipoR, MCP-1, resistin and
RELM.
2) Analysis of a glucose transport mechanism in insulin resistance
We analyze insulin-stimulated and contraction- induced glucose transport with technique of molecular biology. In addition, we have been trying to elucidate the pathogenesis of diabetes and establishment of a new treatment by analyzing a diabetes
model animal and mechanism of insulin resistancein a cultured cell.
3) Pathophysiological roles of lipid storage andatherosclerosis
We study to clarify the significance of metabolicrisk factors in the onset and development of
atherosclerosis. We are currently investigating thepathophysiological roles of lipid storage in obesity,
fatty liver, diabetes, hyperlipidemia and atherosclerosis using strategies of molecular biology andgenetic engineering techniques.
4) Lipid disorders and atherosclerosis

166

Utilizing the animal models of lipid disorders andmolecular biology technique, we are analyzing theroles of lipid transporters, enzymes, nuclear receptors and the anti-oxidative proteins on the lipid disorders and atherosclerosis. At present, we are interested in the cholesterol and lipid absorption fromthe intestine and lipid handling in the cells.

References
1. Abid MR, Guo S, Minami T, Spokes KC, Ueki K,
Skurk C, Walsh K, Aird WC. Vascular endothelial
growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler. Thromb. Vasc.
Biol. 24:294-300, 2004
2. Akune T, Ohba S, Kamekura S, Yamaguchi M,
Chung U, Kubota N, Terauchi Y, Harada Y, Azuma
Y, Nakamura K, Kadowaki T, Kawaguchi H.
PPAR-gamma insufficiency enhances osteogenesis
from bone marrow progenitors. J. Clin. Invest.113:
846-855, 2004
3. Asilmaz E, Cohen P, Miyazaki M, Dobrzyn P, Ueki
K, Fayzikhodjaeva G, Soukas AA, Kahn CR,
Ntambi JM, Socci ND, Friedman JM. Site andmechanism of leptin action in a rodent form ofcongenital lipodystrophy. J. Clin. Invest. 113:414424, 2004
4. Bernal-Mizrachi E, Fatrai S, Johnson JD, Ohsugi
M, Otani K, Han Z, Polonsky KS, Permutt MA.
Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet beta cells. J.
Clin. Invest. 114:928-36,2004
5. Chen D, Mauvais-Jarvis F, Bluher M, Fisher SJ,
Jozsi A, Goodyear LJ, Ueki K, Kahn CR:
p50alpha/p55alpha Phosphoinositide 3-Kinase
Knockout Mice Exhibit Enhanced Insulin Sensitivity. Mol. Cell. Biol. 24:320-329, 2004
6. Cras-Méneur C, Inoue H, Zhou Y, Ohsugi M,
Bernal-Mizrachi E, Pape D, Clifton S, Permutt MA.
An expression profile of human pancreatic islet
mRNAs by Serial Analysis of Gene Expression(SAGE). Diabetologia 47:284-99, 2004
7. Fukushima Y, Matsui T, Saitoh T, Ichinose M,
Tateishi K, Shindo T, Fujishiro M, Sakoda H,
Shojima N, Kushiyama A, Fukuda S, Anai M, Ono
H, Oka M, Shimizu Y, Kurihara H, Nagai R,

Ishikawa T, Asano T, Omata M. Unique roles of G
protein-coupled histamine H2 and gastrin receptors
in growth and differentiation of gastric mucosa. Eur.
J. Pharmacol. 502:243-52, 2004
8. Hoshi K, Ogata N, Shimoaka T, Terauchi Y,
Kadowaki T, Kenmotsu S, Chung U, Ozawa H,
Nakamura K,Kawaguchi H: Deficiency of insulin
receptor substrate-1 impairs skeletal growththrough early closure of epiphyseal cartilage. J.
Bone Miner. Res.19: 214-223, 2004
9. Inoue M, Sakuraba Y, Motegi H, Kubata N, Toki H,
Matsui J, Toyoda Y, Miwa I, Terauchi Y, Kadowaki
T, Shigeyama Y, Kasuga M, Adachi T, Fujimoto N,
Matsumoto R, Tsuchihashi K, Kagami T, Inoue A,
Kaneda H, Ishijima J, Masuya H, Suzuki T, Wakana S, Gondo Y, Minowa O, Shiroishi T, Noda T.
A series of maturity onset diabetes of the young,type 2 (MODY2) mouse models generated by alarge-scale ENU mutagenesis program, Hum.
Mol. Genet. 13: 1147-1157, 2004
10. Kaburagi Y, Yamashita R, Ito Y, Okochi H, Yamamoto-Honda R, Yasuda K, Sekihara H, Sasazuki T,
Kadowaki T, Yazaki Y. Insulin-induced cell cycle
progression is impaired in Chinese hamster ovary
cells overexpressing insulin receptor substrate-3.
Endocrinology 145: 5862-5874, 2004
11. Kadowaki T, Kubota N. Protective role of imatinibin atherosclerosis. Arterioscler.Thromb.Vasc.Biol.
24: 801-803, 2004
12. Kamon J., Yamauchi T., Muto S., Takekawa S., Ito
Y., Hada Y., Ogawa W., Itai A., Kasuga M., Tobe K.,
Kadowaki, T. A novel IKKbeta inhibitor stimulates
adiponectin levels and ameliorates obesity-linked
insulin resistance. Biochem. Biophys. Res. Commun. 323:242-248, 2004
13. Katayama K, Wada K, Miyoshi H, Ohashi K, Tachibana M, Furuki R, Mizuguchi H, Hayakawa T,
Nakajima A, Kadowaki T, Tsutsumi Y, Nakagawa S,
Kamisaki Y, Mayumi T. RNA interfering approachfor clarifying the PPARγ pathway using lentiviral
vector expressing short hairpin RNA. FEBS Letters
560:178-182, 2004
14. Kubota N., Terauchi Y., Tobe K., Yano W., Suzuki
R., Ueki K., Takamoto I., Satoh H., Maki T., Kubota T., Moroi M., Okada-Iwabu M., Ezaki O.,
Nagai R., Ueta Y., Kadowaki T., Noda T. Insulin
receptor substrate 2 plays a crucial role in β cells

167

and the hypothalamus. J. Clin. Invest. 114:917-927,
2004
15. Kubota T, Namiki A, Fukazawa M, Ishikawa M,
Moroi M, Ebine K, Yamaguchi T. Concentrationsof hepatocyte growth factor, basic fibroblast growth
factor, and vascular endothelial growth factor in
pericardial fluid and plasma. Jpn. Heart J. 45:98998, 2004
16. Masaki T., Chiba S., Noguchi H., Yasuda T., Tobe
K., Suzuki R., Kadowaki T., Yoshimatsu H. Obesity
in insulin receptor substrate-2-deficient mice: disrupted control of arcuate nucleus neuropeptides.
Obes. Res. 12:878-885, 2004
17. Matsui J, Terauchi Y, Kubota N, Takamoto I, Eto K,
Yamashita T, Komeda K, Yamauchi T, Kamon J,
Kita S, Noda M, Kadowaki T. Pioglitazone reduces
islet triglyceride content and restores impaired
glucose-stimulated insulin secretion receptorγ-deficent mice on a high-fat diet. Diabetes 53:
2844-2854, 2004
18. Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M,
Shojima N, Ono H, Fujishiro M, Kushiyama A,
Fukushima Y, Kikuchi M, Noguchi N, Aburatani H,
Gotoh Y, Komuro I, Fujita T. Oxidative stress induces insulin resistance by activating the nuclear
factor-kappa B pathway and disrupting normal sub
cellular distribution of phosphatidylinositol
3-kinase. Diabetologia. 47:794-805, 2004
19. Ohsugi M, Cras-Méneur C, Zhou Y, Warren W,
Bernal-Mizrachi E, Permutt MA . Signaling Pathways Activated by Glucose and Insulin in Mouse
Insulinoma Cells Induce Broadly Overlapping Setsof Genes. Diabetes 53: 1496-1508,2004
20. Otani K, Kulkarni RN, Baldwin AC, Krutzfeldt J,
Ueki K, Stoffel M, Kahn CR, Polonsky KS. Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in β IRKO mice. Am.
J. Physiol. Endocrinol. Metab. 286:E41-E49, 2004
21. Saito K. Ishizaka N. Aizawa T. Sata M. Iso-o N.
Noiri E. Ohno M. Nagai R. Role of Aberrant Iron
Homeostasis in the Upregulation of TGF-β1 in the
Kidney of Angiotensin II-Induced Hypertensive
Rat. Hypertension Research 27:599-607, 2004
22. Sasaoka T., Wada T., Fukui K., Murakami S., Ishihara H., Suzuki R., Tobe K., Kadowaki T., Kobayashi, M. SH2-containing inositol phosphatase 2
predominantly regulates akt2, and not akt1, phos-

phorylation at the plasma membrane in response toinsulin in 3T3-L1 adipocytes. J. Biol. Chem. 279:
14835-14843, 2004
23. Satoh H. Nguyen MT. Miles PD. Imamura T. Usui I.
Olefsky JM. Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistancein normal rats. J. Clin. Invest. 114:224-31, 2004
24. Schubert M, Gautam D, Surjo D, Ueki K, Baudler
S, Schubert D, Kondo T, Alber J, Galldiks N,
Kustermann E, Arndt S, Jacobs AH, Krone W,
Kahn CR, Bruning JC. Role for neuronal insulin
resistance in neurodegenerative diseases. Proc. Natl.
Acad. Sci. U S A. 101:3100-3105, 2004
25. Shimoaka T, Kamekura S, Chikuda H, Hoshi K,
Chung U, Akune T, Maruyama Z, Komori T, Matsumoto M, Ogawa W, Terauchi Y, Kadowaki T,
Nakamura K, Kawaguchi H. Impairment of bonehealing by insulin receptor substrate-1 deficiency. J.
Biol. Chem.279: 15314-15322, 2004
26. Shintani Y. Fujie H. Miyoshi H. Tsutsumi T. Tsukamoto K. Kimura S. Moriya K. Koike K. Hepatitis C Virus Infection and Diabetes : Direct Involvement of the Virus in the Development of Insulin Resistance. Gastroenterology 126:840-848,
2004
27. Suzuki R., Tobe K., Aoyama M., Yamauchi T.,
Kamon J., Kubota N., Terauchi Y., Yoshimatsu H.,
Matsuhisa M., Nagasaka S., Ogata H., TokuyamaK., Nagai R., Kadowaki T. Both insulin signaling
defects in the liver and obesity contribute to insulin
resistance and cause diabetes in Irs2-/- mice. J. Biol.
Chem. 279:25039-25049, 2004
28. Tsuchida A., Yamauchi T., Ito Y., Hada Y., Maki T.,
Takekawa S., Kamon J., Kobayashi M., Suzuki R.,
Hara K., Kubota N., Terauchi Y., Froguel P., Nakae
J., Kasuga M., Accili D., Tobe K., Ueki K., Nagai
R., Kadowaki T. Insulin/Foxo1 pathway regulates
expression levels of adiponectin receptors and adiponectin sensitivity. Biol. Chem. 279:30817-30822,
2004
29. Tamura Y, Osuga JI, Adachi H, Tozawa RI, Takanezawa Y, Ohashi K, Yahagi N, Sekiya M, Okazaki H, Tomita S, Iizuka Y, Koizumi H, Inaba T,
Yagyu H, Kamada N, Suzuki H, Shimano H,
Kadowaki T, Tsujimoto M, Arai H, Yamada N,
Ishibashi S. Scavenger receptor expressed by endothelial cells I (SREC-1) mediates the uptake of168

acetylated low density lipoproteins by macrophages
stimulated with lipopolysaccharide. J. Biol. Chem.
279: 30938- 30944, 2004
30. Terauchi Y, Matsui J, Kamon J, Yamauchi T, Kubota N, Komeda K, Aizawa S, Akanuma Y, Tomita
M, Kadowaki T. Increased serum leptin protectsfrom adiposity despite the increased glucose uptake
in white adipose tissue in mice lacking p85alphaphosphoinositide 3-kinase. Diabetes 53: 2261-2270,
2004
31. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by
discrete mechanisms. Mol. Cell. Biol. 24:54345446, 2004
32. Ueki K, Kondo T, Tseng YH, Kahn CR. Central
role of suppressors of cytokine signaling proteins inhepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc. Natl. Acad. Sci.
U S A. 101:10422-10427, 2004
33. Usui I. Imamura T. Huang J. Satoh H. Shenoy SK.
Lefkowitz RJ. Hupfeld CJ. Olefsky JM. beta-arrestin-1 competitively inhibits insulin-induced
ubiquitination and degradation of insulin receptor
substrate 1. Mol. Cell. Biol. 24:8929-37, 2004
34. Usui I. Imamura T. Satoh H. Huang J. Babendure
JL. Hupfeld CJ. Olefsky JM. GRK2 is an endogenous protein inhibitor of the insulin signaling
pathway for glucose transport stimulation. EMBO J.
23:2821-9, 2004
35. Wada K, Nakajima A, Takahashi H, Yoneda M,
Fujisawa N, Ohsawa E, Kadowaki T, Kubota N,
Terauchi Y, Matsuhashi N, Saubermann LJ, Nakajima N, Blumberg RS. Protective effect of endogenous PPARgamma against acute gastric mucosal
lesions associated with ischemia-reperfusion. Am. J.
Physiol. Gastrointest. Liver Physiol. 287: G452458, 2004
36. Waki H, Yamauchi T, Kamon J, Kita S, Ito Y, Hada
Y, Uchida S, Tsuchida A, Takekawa S, Kadowaki T.
Generation of globular fragment of adiponectin byleukocyte elastase secreted by monocytic cell line
THP-1. Endocrinology 146: 790-796, 2004
37. Yahagi N, Shimano H, Matsuzaka T, Sekiya M,
Najima Y, Okazaki S, Okazaki H, Tamura Y, Iizuka
Y, Inoue N, Nakagawa Y, Takeuchi Y, Ohashi K,

Harada K, Gotoda T, Nagai R, Kadowaki T, Ishibashi S, Osuga J, Yamada N. p53 involvement in
the pathogenesis of fatty liver disease. J. Biol.
Chem. 14: 20571-20575, 2004
38. Yamashita T, Eto K, Okazaki Y, Yamashita S, Yamauchi T, Sekine N, Nagai R, Noda M, Kadowaki
T. Role of uncoupling protein-2 up-regulation andtriglyceride accumulation in impaired glucosestimulated insulin secretion in a beta-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c. Endocrinology 145:35663577, 2004
39. Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, Kahn CR. Distinct pathwaysof insulin-regulated versus diabetes-regulated gene
expression: An in vivo analysis in MIRKO mice.
Proc. Natl. Acad. Sci. U S A 101:16525-16530,
2004
40. Yokote K, Hara K, Mori S, Kadowaki T, Saito Y,
Goto M. Dysadipocytokinemia in werner syndrome
and its recovery by treatment with pioglitazone.
Diabetes Care 27: 2562-2563, 2004
41. Amemiya-Kudo M, Oka J, Ide T, Matsuzaka T,
Sone H, Yoshikawa T, Yahagi N, Ishibashi S,
Osuga JI, Yamada N, Murase T, and Shimano H.
Sterol Regulatory Element-binding Proteins Activate Insulin Gene Promoter Directly and Indirectly
through Synergy with BETA2/E47. J Biol Chem.
280:34577-34589, 2005
42. Anai M, Shojima N, Katagiri H, Ogihara T,
Sakoda H, Onishi Y, Ono H, Fujishiro M,
Fukushima Y, Horike N, Viana A, Kikuchi M,
Noguchi N, Takahashi S, Takata K, Oka Y,
Uchijima Y, Kurihara H, Asano T. A novel protein
kinase B (PKB)/AKT-binding protein enhances
PKB kinase activity and regulates DNA synthesis. J.
Biol. Chem. 280:18525-35, 2005
43. Asano T, Ogihara T, Katagiri H, Sakoda H, Ono H,
Fujishiro M, Anai M, Kurihara H, Uchijima Y.
Glucose transporter and Na+/glucose cotransporteras molecular targets of anti-diabetic drugs. Curr.
Med. Chem. 11(20):2717-24, 2005
44. Brachmann SM, Ueki K, Engelman JA, Kahn RC,
Cantley LC. Phosphoinositide 3-kinase catalytic
subunit deletion and regulatory subunit deletion
have opposite effects on insulin sensitivity in mice.
Mol. Cell. Biol. 25:1596-1607, 2005

169

45. Fujimoto M, Shimizu N, Kunii K, Martyn JA, Ueki
K, Kaneki M. A Role for iNOS in Fasting Hyperglycemia and Impaired Insulin Signaling in theLiver of Obese Diabetic Mice. Diabetes 54:13401348, 2005
46. Furumoto T, Fujii S, Onozuka H, Zaman A.K.M.T,
Goto D, Sugawara T, Mikami T, Watanabe S, Abe
K, Terauchi Y, Kadowaki T, Kitabatake A, Sobel
BE. Loss if insulin receptor substrate-1 signaling
induces the cardiovascular and proteo(fibrino)lytic
system derangements typical of insulin resistance.
Coron. Artery Dis. 16: 117-123, 2005
47. Hara K, Horikoshi M, Kitazato H, Yamauchi T, Ito
C, NBoda M, Ohashi J, Froguel P, Tokunaga K
Nagai R, Kadowaki T. Absence of an association
between the polymorphisms in the genes encoding
adiponectin receptors and type 2 diabetes. Diabetologia 48: 1307-1314, 2005
48. Hara K, Yamauchi T, Kadowaki T. Adiponectin: an
adipokine linking adipocytes and type 2 diabetes inhumans. Curr. Diab. Rep. 5: 136-140, 2005
49. Ishigaki Y, Katagiri H, Yamada T, Ogihara T, Imai J,
Uno K, Hasegawa Y, Gao J, Ishihara H,
Shimosegawa T, Sakoda H, Asano T, Oka Y. Dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated withobesity. Diabetes 54:322-32, 2005
50. Iwasaki N, Horikawa Y, Tsuchiya T, Kitamura Y,
Nakamura T, Tanizawa Y, Oka Y, Hara K,
Kadowaki T, Awata T, Honda M, Yamashita K,
Oda N, Yu L, Yamada N, Ogata M, Kamatani N,
Iwamoto Y, Bosque-Plata L, Hayes M.G, Cox NJ.
Bell GI. Genetic variants in the calpain-10 geneand the development of type 2 diabetes in theJapanese population. J. Hum. Genet. 50: 92-98,
2005
51. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr. Rev. 26: 439-451, 2005
52. Kawaguchi H, Akune T, Yamaguchi M, Ohba S,
Ogata N, Chung UI, Kubota N, Terauchi Y,
Kadowaki T, Nakamura K. Distinct effects of
PPARγ insufficiency on bone marrow cells, osteoblasts, and osteoclastic cells. J. Bone Miner.
Matab 23: 275-279, 2005
53. Kushiyama A, Shojima N, Ogihara T, Inukai K,
Sakoda H, Fujishiro M, Fukushima Y, Anai M,
Ono H, Horike N, Viana AY, Uchijima Y, Nishi-

yama K, Shimosawa T, Fujita T, Katagiri H, Oka Y,
Kurihara H, Asano T. Resistin like molecule beta
activates MAPKs, suppresses insulin signaling inhe patocytes and induces diabetes, hyperlipidemia
and fatty liver in transgenic mice on a high-fat diet.
J Biol Chem. 280:42016-25, 2005
54. Liu R, Yamamoto M, Moroi M, Kubota T, Ono T,
Funatsu A, Komatsu H, Tsuji T, Hara H, Hara H,
Nakamura M, Hirai H, Yamaguchi T. Chlamydia
pneumoniae immunoreactivity in coronary artery
plaques of patients with acute coronary syndromes
and its relation with serology. Am. Heart J.
150:681- 8, 2005
55. Lu J, Imamura K, Nomura S, Mafune K, Nakajima
A, Kadowaki T, Kubota N, Terauchi Y, Ishii G,
Ochiai A, Esumi H, Kaminishi M. Chemopreventive effect of peroxisome proliferator activated receptor gamma on gastric carcinogenesis in mice.
Cancer Res. 65:4769-4774, 2005
56. Masuda T, Wada K, Nakajima A, Okura M, Kudo C,
Kadowaki T, Kogo M, Kamisaki Y. Critical role ofperoxisome proliferator-activated receptor gamma
on anoikis and invasion of squamous cell carcinoma. Clin. Cancer Res. 11: 4012-4021, 2005
57. Mori T, Sakaue H, Iguchi H, Gomi H, Okada Y,
Takashima Y, Nakamura K, Nakamura T,Yamauchi
T, Kubota N, Kadowaki T, Matsui Y, Ogawa W,
Hiramatsu R, Kasuga M. Role of Kruppel-like factor 15 (KLF15) in transcriptional regulation of
adipogenesis. J. Biol. Chem. 280: 12867-12875,
2005
58. Najima Y, Yahagi N, Takeuchi Y, Matsuzaka T, Sekiya M, Nakagawa Y, Amemiya-Kudo M, Okazaki
H, Okazaki S, Tamura Y, Iizuka Y, Ohashi K, Harada K, Gotoda T, Nagai R, Kadowaki T, Ishibashi
S, Yamada N, Osuga JI, Shimano H. High mobility
group protein-B1 (HMGB1) interacts with sterol
regulatory element-binding proteins (SREBPs) toenhance their DNA binding. J. Biol. Chem. 280:
27523-27532, 2005
59. Nakamura T. Shibata N. Nishimoto-Shibata T. Feng
D. Ikemoto M. Motojima K. Iso-o N. Tsukamoto K.
Tsujimoto M. Arai H. Regulation of SR-BI protein
levels by phosphorylation of its associated protein,
PDZK1. Proc. Natl. Acad. Sci. U S A. 102: 1340413409, 2005
60. Narasimhan LM, Coca MA, Jin J, Yamauchi T, Ito

170

Y, Kadowaki T, Kim KK, Pardo JM, Damsz B,
Hasegawa PM, Yun DJ, Bressan RA. Osmotin is ahomolog of mammalian adiponectin and controls
apoptosis in yeast through a homolog of mammalian adiponectin receptor. Mol. Cell 17: 171-180,
2005
61. Nguyen MT. Satoh H. Favelyukis S. Babendure JL.
Imamura T. Sbodio JI. Zalevsky J. Dahiyat BI. Chi
NW. Olefsky JM. JNK and Tumor Necrosis Factor-{alpha} Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes. J. Biol. Chem.
280:35361-71, 2005
62. Ohsugi M, Cras-Méneur C, Zhou Y, BernalMizrachi E, Jonson J, Luciani D, Polonsky KS,
Permutt MA . Reduced Expression of the Insulin
Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene
Expression, Proliferation, Insulin Content and Secretion. J. Biol. Chem. 280:4992-5003,2005
63. Ohsugi M, Srinivasan S, Liu Z, Fatrai S,
Bernal-Mizrachi E, and Permutt MA. Endoplasmic
Reticulum Stress Induced Apoptosis is mediated inpart by reduced insulin signaling through PI3K/Akt
and increased Glycogen Synthase Kinase 3 beta
(GSK3β) in Mouse Insulinoma Cells. Diabetes
54:968-975,2005.
64. Oike Y, Akao M, Yasunaga K, Yamauchi T, Morisada T, Ito Y, Urano T, Kimura Y, Kubota Y,
Maekawa H, Miyamoto T, Miyata K, Matsumoto
SI, Sakai J, Nakagata N, Takeya M, Koseki H,
Ogawa Y, Kadowaki T, Suda T. Angiopoietin-related growth factor antagonizes obesity andinsulin resistance. Nat. Med. 11: 400-408, 2005
65. Oishi Y., Manabe I., Tobe K., Tsushima K., ShindoT., Fujiu K., Nishimura G., Maemura, K., YamauchiT., Kubota N., Suzuki R., Kitamura T., Akira S.,
Kadowaki T., and Nagai, R. Krüppel-like transcription factor KLF5 is a key regulator of adipocyte
differentiation Cell Metabolism 1: 27-39, 2005
66. Riggs AC, Bernal-Mizrachi E, Ohsugi M, Wasson J,
Fatrai S, Welling C, Murray J, Schmidt RE, Herrera
PL, and Permutt MA. Mice Conditionally Lacking
the Wolfram Gene in Pacreatic Islet Beta Cells Exhibit Diabetes as a Result of Enhanced Endoplasmic Reticulum Strress and Apoptosis. Diabetologia
48:2313-21, 2005
67. Saito K. Ishizaka N. Aizawa T. Sata M. Iso-o N.

Noiri E. Mori I. Ohno M. Nagai R. Iron chelation
and a free radical scavenger suppress angiotensin
II-induced upregulation of TGF-β1 in the heart. Am.
J. Physiol. Heart. Circ. Physiol. 288:H1836- H1843,
2005
68. Saito K. Ishizaka N. Hara M. Matsuzaki G. Sata M.
Mori I. Ohno M. Nagai R. Lipid accumulation andtransforming growth factor β upregulation in thekidneys of rats administered angiotensin II. Hypertention 46:1180-5, 2005
69. Sakoda H, Fujishiro M, Fujio J, Shojima N,
Ogihara T, Kushiyama A, Fukushima Y, Anai M,
Ono H, Kikuchi M, Horike N, Viana AY, Uchijima
Y, Kurihara H, Asano T. Glycogen debranching
enzyme association with β-subunit regulates
AMP-activated protein kinase activity. Am. J.
Physiol. Endocrinol. Metab. 289(3):E474-81, 2005
70. Satoh H. Nguyen MT. Trujillo M. Imamura T. Usui
I. Scherer PE. Olefsky JM. Adenovirus-mediatedadiponectin expression augments skeletal muscle
insulin sensitivity in male Wistar rats. Diabetes
54:1304-13, 2005
71. Shojima N, Ogihara T, Inukai K, Fujishiro M,
Sakoda H, Kushiyama A, Katagiri H, Anai M, Ono
H, Fukushima Y, Horike N, Viana AY, Uchijima Y,
Kurihara H, Asano T. Serum concentrations of resistin-like molecules beta and gamma are elevatedin high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bonemarrow. Diabetologia 48:984-92, 2005
72. Suzuki M, Mamun M. R. I., Hara K, Ozeki T, Yamada Y, Kadowaki T, Honda H, Yanagihara Y, Minagawa Ito Y, Kameyama S, Ohta N, Hosoi T, Arai
T, Sawabe M, Takeuchi T, Takahashi S, Kitamura T.
The Val158Met polymorphism of the catechol-O-methyltransferase gene is associated with
the PSA-progression-free survival in prostate cancer patients treated with estramustine phosphate.
Eur. Urol. 48:752-9, 2005
73. Suzuki M, Muto S, Hara K, Ozeki T, Yamada Y,
Kadowaki T, Tomiya K, Kameyama S, Kitamura T.
Single-nucleotide polymorphisms in the 17β-hydroxysteroid dehydrogenase genes might predictthe risk of side-effects of estramustine phosphate
sodium in prostate cancer patients. Int. J. Urol. 12:
166-172, 2005
74. Suzuki R., Tobe K., Aoyama M., Sakamoto K.,

171

Ohsugi M., Kamei N., Nemoto S., Inoue A., Ito Y.,
Uchida S., Hara K., Yamauchi T., Kubota N., Terauchi Y., Kadowaki T. Expression of DGAT2 inwhite adipose tissue is regulated by central leptin
action. J. Biol. Chem. 280:3331-3337, 2005
75. Taniguchi CM, Ueki K, Kahn R. Complementaryroles of IRS-1 and IRS-2 in the hepatic regulationof metabolism. J. Clin. Invest. 115:718-727, 2005
76. Terauchi Y, Kadowaki T. Peroxisome proliferator-activated receptors and insulin secretion. Endocrinology 146: 3263-3265, 2005
77. Tsuchida A, Yamauchi T, Kadowaki T. Nuclear receptors as targets for drug development: Molecularmechanisms for regulation of obesity and insulin
resistance by peroxisome proliferator-activated receptor γ, CREB-binding protein, and adiponectin. J.
Pharmacol. Sci. 97: 164-170, 2005
78. Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito
Y, Maki T, Kadowaki T. Peroxisome proliferator-activated receptor (PPAR)[alpha] activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPAR[alpha], PPAR
[gamma], and their combination. Diabetes 54:
3358-3370, 2005
79. Usui I. Imamura T. Babendure JL. Satoh H. Lu JC.
Hupfeld CJ. Olefsky JM. G Protein-coupled Receptor Kinase 2 (GRK2) Mediates Endothelin-1-induced Insulin Resistance via the Inhibition of Both Gα q/11 and IRS-1 pathways in
3T3-L1 Adipocytes. Mol. Endocrinol. 19: 2760-8,
2005
80. Vasseur F, Helbecque N, Lobbens S, Vasseur-Delannoy V, Dina C, Clement K, Boutin P,
Kadowaki T, Scherer P.E., Froguel P. Hypoadiponectinemia and high risk for type 2 diabetes areassociated with adiponectin-encoding (ACDC)
gene promoter variants in morbid obesity: evidence
for a role for ACDC in diabesity. Diabetologia 48:
892-899, 2005
81. Waki K, Noda M, Sasaki S, Matsumura Y, Takahashi Y, Isogawa A, Ohashi Y, Kadowaki T, TsuganeS, for the JPHC Study Group. Alcohol consumption
and other risk factors for self-reported diabetes
among middle-aged Japanese: a population-based
prospective study in JPHC Study Cohort I. Diabet.
Med. 22: 323-331, 2005

82. Yahagi N, Shimano H, Hasegawa K, Ohashi K,
Matsuzaka T, Najima Y, Sekiya M, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Nagai R,
Ishibashi S, Kadowaki T, Makuuchi M, Ohnishi S,
Osuga J, and Yamada N. Co-ordinate activation of
lipogenic enzymes in hepatocellular carcinoma. Eur.
J. Cancer 41:1316-22, 2005
83. Yajima S, Ishikawa M, Kubota T, Moroi M, Sugi K,
Namiki A. Intramyocardial injection of fibroblast
growth factor-2 plus heparin suppresses cardiac
failure progression in rats with hypertensive heartdisease. Int. Heart J. 46:289-301, 2005
84. Yamaguchi M, Ogata N, Shinoda Y, Akune T,
Kamekura S, Terauchi Y, Kadowaki T, Hoshi K,
Chung UI, Nakamura K, Kawaguchi H. Insulin receptor substrate-1 is required for bone anabolic
function of parathyroid hormone in mice. Endocrinology 156: 2620-2628, 2005
85. Yoshikumi Y. Mashima H. Ueda N. Ohno H. Suzuki J. Tanaka S. Hayashi M. Sekine N. Ohnishi H.
Yasuda H. Iiri T. Omata M. Fujita T. Kojima I.
Roles of CTPL/Sfxn3 and Sfxn family members inpancreatic islet. J. Cell. Biochem. 95:1157-1168,
2005
86. Zheng Y., Yamada H., Sakamoto K., Horita S.,
Kunimi M., Endo Y., Li Y., Tobe K., Terauchi Y.,
Kadowaki T., Seki G., Fujita T. Roles of Insulin
Receptor Substrates in Insulin-Induced Stimulationof Renal Proximal Bicarbonate Absorption. J. Am.
Soc. Nephrol. 16: 2288-2295, 2005
87. Zhou H, Yamada Y, Tsukiyama K, Miyawaki K,
Hosokawa M, Nagashima K, Toyoda K, Naitoh R,
Mizunoya W, Fushiki T, Kadowaki T, Seino Y.
Gastric inhibitory polypeptide modulates adiposityand fat oxidation under diminished insulin action.
Biochem. Biophys. Res. Commun. 335: 937-942,
2005

172

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

Yoshinobu Kanda, M.D., Ph.D.

Special Lecturer (Hospital)
Akira Hagaishi, M.D., Ph.D.
Associate
Koji Izutsu, M.D., Ph.D.,

Takashi Asai, M.D., Ph.D.

Takuro Watanabe, M.D.,

Hiroyuki Sato, M.D., Ph.D.

Homepage
Introduction and Organization
Department of Hematology and Oncology is responsible for clinical activities in out-patient as well as
in-patient clinics of hematological disorders, conducting research activities for hematology and oncology,
and are also in charge of teaching activities for undergraduate medical students and graduate students. These
activities are performed by the united efforts of all
members who belong to the department. As of March in2006, the staff of Department of Hematology and Oncology consists of thirty-nine members including one
professor, 2 lecturers, one special lecturer (hospital),and 4 associates.

Clinical activities
On average, 60 patients with hematological diseases
are treated in the ward. Clinical facilities include patient
rooms with high-efficiency particulate air filtration andfiltrated water supply. Patients who are eligible for thetreatment with high-grade infection prophylaxis areadmitted to the facilities. Patient care is provided byteam management and three doctors composed of eachone of junior residents, senior residents, and associates
are assigned to one patient. A number of clinical problems involved in the patient management are discussed
in the morning clinical conference held every other day.
Diagnostic and therapeutic issues as well as pathological aspects are also discussed weekly in the clinicalconferences, each focusing on hematological diseases,
lymphomas, or hematopoietic stem cell transplantation.
All these conferences are also attended by the staff
member of Department of Cell Therapy and Transplantation because of clinical significance of hamatopoietic
stem cell transplantation in the treatment of hematological disorders.
Approximately 90 patients with acute leukemia, 100with malignant lymphoma, 25 with chronic leukemia,
15 with multiple myeloma, 20 with myelodysplastic
syndrome, and 60 with the other diseases are annuallyadmitted to our ward. Out-patient clinical services areprovided daily in the morning and afternoon using threebooths. One of our final goals in the clinical activities is
to cure all patients with hematological malignancies.
Here are some technical aspects on the treatment

173

strategy:
1. 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 ofstem cells. Similar procedures used in the allogeneic stem cell harvest are performed for leukapheresis and preservation.
2. 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 arepreserved in cooperation with Department ofTransfusion Medicine. Recently, transplantation
after pre-conditioning of reduced intensity (RIST
for reduced-intensity stem cell transplantation) is
commonly performed for the elderly patients andpatients with organ damages. The development of
this strategy is expanding the eligibility of transplant recipients. Several clinical studies with allogeneic stem cell transplantation have been also
conducted. These include RIST for pancreatic cancer, transplantation from a donor with mismatched
HLA at two loci or more. All these studies are approved by the 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 is provided
for the second grade medical students. The course contents include:
1. Mechanisms of hematopoiesis, transplantation
medicine and cell therapy
2. Acute leukemia and myeloproliferative disorders
3. Bone marrow failure syndrome (aplastic anemia
and myelodysplastic syndrome)
4. Lymphoma and myeloma
5. Hemostasis and thrombosis
6. Hemolytic anemia and anemia of various causes.
Courses for bedside learning on diagnostic and therapeutic issues and arts are given for the third grade

medical students on a man-to-man basis with a seniorfaculty member that are erudite both in general internal
medicine and in hematology and oncology. During theone-week case-oriented course, students learn the basic
techniques of medical interview and physical examination, interpretation of laboratory tests, and practical
medical procedures.

Research activities
The major research projects are focused on molecularmechanisms of hematopoietic tumors, hematopoietic
transcription factors, signal transduction mechanisms inhematopoietic cells, chromosomal and genomic approaches to leukemogenesis, generation of murine
models for leukemias, proliferation and differentiationof hematopoietic stem cells, and development of immunotherapy for hematopoietic tumors. Every effort
has been made to achieve the highest quality in bothclinical and basic medical research. The ultimate aimsof our research are the application of epoch-making
discoveries in research fields to the clinical hematology
and oncology. Representative publications from ourdepartments published in the past two years are listed in
the reference.

References
1. Crcareva A, Saito T, Kunisato A, Kumano K, Suzuki T, Sakata-Yanagimoto M, Kawazu M, Stojanovic A, Kurokawa M, Ogawa S, Hirai H, Chiba S.
Hematopoietic stem cells expanded by fibroblast
growth factor-1 are excellent targets for retrovirus-mediated gene delivery. Exp Hematol. 2005
Dec;33(12):1459-69.
2. Miyawaki S, Emi N, Mitani K, Oyashiki K, Kitamura K, Morishita T, Ogawa H, Komatsu N, Soma
T, Tamaki T, Kosugi H, Ohnishi K, Mizoguchi H,
Hiraoka A, Kodera Y, Ueda R, Morishima Y, Nakagawa M, Tobita T, Sugimoto K, Chiba S, Inoue
N, Hamaguchi M, Koga D, Tamaki H, Naoe T, Sugiyama H, Takaku F. Clinical course of the disease
and the level of WT1 mRNA in 191 patients withacute myeloid leukemia (AML): joint research by
23 institutions in Japan. Rinsho Ketsueki. 2005
Dec;46(12):1279-87.
3. Kanda Y, Sakamaki H, Sao H, Okamoto S, Kodera

174

Y, Tanosaki R, Kasai M, Hiraoka A, Takahashi S,
Miyawaki S, Kawase T, Morishima Y, Kato S; Japan Marrow Donor Program.for the Japan Marrow
Donor Program. Effect of conditioning regimen on
the outcome of bone marrow transplantation froman unrelated donor. Biol Blood Marrow Transplant.
2005 Nov;11(11):881-9.
4. Oshima K, Sakata-Yanagimoto M, Asano-Mori Y,
Izutsu K, Watanabe T, Shoda E, Ogawa S, Motokura T, Chiba S, Kurokawa M, Hirai H, Kanda Y.
Cardiac complications after haploidentical HLAmismatched hematopoietic stem cell transplantation using in vivo alemtuzumab. Bone Marrow
Transplant. 2005 Nov;36(9):821-4.
5. Asano-Mori Y, Oshima K, Sakata-Yanagimoto M,
Nakagawa M, Kandabashi K, Izutsu K, Hangaishi
A, Motokura T, Chiba S, Kurokawa M, Hirai H,
Kanda Y. High-grade cytomegalo-virus antigenemia after hematopoietic stem cell transplantation.
Bone Marrow Transplant. 2005 Nov;36(9):813-9.
6. Suzuki T, Chiba S. Notch signaling in hematopoietic stem cells. Int J Hematol. 2005 Nov;82(4):28594.
7. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita
J, Nakazaki K, Kurokawa M, Hayashi Y, Ogawa S,
Chiba S. Mutations of the Notch1 gene in T-cell
acute lymphoblastic leukemia: analysis in adults
and children. Leukemia. 2005 Oct;19(10):1841-3.
8. Kojima R, Kami M, Kanda Y, Kusumi E, Kishi Y,
Tanaka Y, Yoshioka S, Morishima S, Fujisawa S,
Mori SI, Kasai M, Hatanaka K, Tajima K, Kasai M,
Mitani K, Ichinohe T, Hirai H, Taniguchi S, Sakamaki H, Harada M, Takaue Y. Comparison between
reduced-intensity and conventional myeloablative
allogeneic stem-cell transplantation in patients withhematologic malignancies aged between 50 and 59.
Bone Marrow Transplant. 2005 Oct;36(8):667-74.
9. Nitta E, Izutsu K, Yamaguchi Y, Imai Y, Ogawa S,
Chiba S, Kurokawa M, Hirai H. Oligomerization ofEvi-1 regulated by the PR domain contributes torecruitment of corepressor CtBP. Oncogene. 2005
Sep 8;24(40):6165-73.
10. Seo S, Asai T, Saito T, Suzuki T, Morishita Y, Nakamoto T, Ichikawa M, Yamamoto G, Kawazu M,
Yamagata T, Sakai R, Mitani K, Ogawa S, Kurokawa M, Chiba S, Hirai H. Crk-associated substrate
lymphocyte type is required for lymphocyte traf-

ficking and marginal zone B cell maintenance. J
Immunol. 2005 Sep 15;175(6):3492-501.
11. Nannya Y, Sanada M, Nakazaki K, Hosoya N,
Wang L, Hangaishi A, Kurokawa M, Chiba S, Bailey DK, Kennedy GC, Ogawa S. A robust algorithm for copy number detection using high-density
oligonucleotide single nucleotide polymorphism
genotyping arrays. Cancer Res. 2005 Jul 15;65(14):6071-9.
12. Haraguchi K, Takahashi T, Matsumoto A, Asai T,
Kanda Y, Kurokawa M, Ogawa S, Oda H, Taniguchi M, Hirai H, Chiba S. Host-residual invariant
NK T cells attenuate graft-versus-host immunity. J
Immunol. 2005 Jul 15;175(2):1320-8.
13. Kojima R, Tateishi U, Kami, M Murashige N,
Nannya Y, Kusumi E, Sakai M, Tanaka Y, Kanda
Y, Mori S, Chiba S, Kusumoto M, Miyakoshi S,
Hirai H, Taniguchi S, Sakamaki H, Takaue Y.
Chest computed tomography of late invasive aspergillosis afterallogeneic hematopoietic stem celltransplantation. Biol Blood Marrow Transplant.
2005 Jul;11(7):506-11.
14. Sato H, Nakamura Y, Motokura T. Differential
14-3-3sigma DNA methylation and activatedH-ras-transformed cells under r- and K-selection.
Cancer Lett. 2005 Jun 24 [Epub ahead of print]
15. Komeno Y, Kurokawa M, Imai Y, Takeshita M,
Matsumura T, Kubo K, Yoshino T, Nishiyama U,
Kuwaki T, Kubo K, Osawa T, Ogawa S, Chiba S,
Miwa A, Hirai H. Identification of Ki23819, ahighly potent inhibitor of kinase activity of mutant
FLT3 receptor tyrosine kinase. Leukemia. 2005
Jun;19(6):930-5.
16. Masuda S, Kumano K, Shimizu K, Imai Y, Kurokawa M, Ogawa S, Miyagishi M, Taira K, Hirai H,
Chiba S. Notch1 oncoprotein antagonizes TGFbeta/Smad-mediated cell growth suppression via
sequestration of coactivator p300. Cancer Sci. 2005
May;96(5):274-82.
17. Kanda Y, Oshima K, Asano-Mori Y, Kandabashi K,
Nakagawa M, Sakata-Yanagimoto M, Izutsu K,
Hangaishi A, Tsujino S, Ogawa S, Motokura T,
Chiba S, Hirai H. In vivo alemtuzumab enables
haploidentical human leukocyte antigen- mismatched hematopoietic stem-cell transplantation
without ex vivo graft manipulation. Transplantation.
2005 May 27;79(10):1351-7.

175

18. Kanda Y, Komatsu Y, Akahane M, Kojima S,
Asano-Mori Y, Tada M, Oshima K, Isayama H,
Ogawa S, Motokura T, Chiba S, Ohtomo K, Omata
M, Hirai H. Graft-versus-tumor effect against advanced pancreatic cancer after allogeneic reduced-intensity stem cell transplantation. Transplantation. 2005 Apr 15;79(7):821-7.
19. Kawazu M, Asai T, Ichikawa M, Yamamoto G,
Saito T, Goyama S, Mitani K, Miyazono K, Chiba
S, Ogawa S, Kurokawa M, Hirai H. Functional
domains of Runx1 are differentially required forCD4 repression, TCRbeta expression, and CD4/8
double-negative to CD4/8 double-positive transition in thymocyte development. J Immunol. 2005
Mar 15;174(6):3526-33.
20. Hosoya N, Qiao Y, Hangaishi A, Wang L, Nannya
Y, Sanada M, Kurokawa M, Chiba S, Hirai H,
Ogawa S. Identification of a SRC-like tyrosine
kinase gene, FRK, fused with ETV6 in a patientwith acute myelogenous leukemia carrying at(6;12)(q21;p13) translocation. Genes Chromosomes Cancer. 2005 Mar;42(3):269-79.
21. Hori A, Kanda Y, Goyama S, Onishi Y, Komeno Y,
Mitani K, Kishi Y, Ogawa S, Imataki O, Chiba S,
Kojima R, Hamaki T, Sakiyama M, Kami M,
Makimoto A, Tanosaki R, Takaue Y, Hirai H; Japan
Hematology and Oncology Clinical Study GroupA
prospective trial to evaluate the safety and efficacy
of pravastatin for the treatment of refractorychronic graft-versus-host disease. Transplantation.
2005 Feb 15;79(3):372-4.
22. Goyama S, Yamaguchi Y, Imai Y, Kawazu M, Nakagawa M, Asai T, Kumano K, Mitani K, Ogawa S,
Chiba S, Kurokawa M, Hirai H. The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonicpara-aortic splanchnopleural (P-Sp) region. Blood.
2004 Dec 1;104(12):3558-64.
23. Goyama S, Kanda Y, Nannya Y, Ogawa S,
Asano-Moki Y, Ogawa N, Nakagawa M, Sakata-Yanagimoto M, Kawazu M, Komeno Y, Imai
Y, Hangaishi A, Kurokawa M, Tsujino S, Aoki K,
Chiba S, Motokura T, Hirai H. Clinical significanceof peripheral blood erythroblastosis after hematopoietic stem cell transplantation. Leuk Lymphoma.
2004 Dec;45(12):2439-43.
24. Niki M, Di Cristofano A, Zhao M, Honda H, Hirai

H, Van Aelst L, Cordon-Cardo C, Pandolfi PP. Roleof Dok-1 and Dok-2 in leukemia suppression. J
Exp Med. 2004 Dec 20;200(12):1689-95.
25. Yasuda T, Shirakata M, Iwama A, Ishii A, Ebihara
Y, Osawa M, Honda K, Shinohara H, Sudo K, Tsuji
K, Nakauchi H, Iwakura Y, Hirai H, Oda H, Yamamoto T, Yamanashi Y. Role of Dok-1 and Dok-2
in myeloid homeostasis and suppression of leukemia. J Exp Med. 2004 Dec 20;200(12):1681-7
26. Endo-Matsubara M, Ogawa S, Sasaki K, Takahashi
T, Chiba S, Hirai H. Immature granulocyte fractionin the peripheral blood is a practical indicator formobilization of CD34(+) cells. Am J Hematol.
2004 Nov;77(3):223-8.
27. Haraguchi K, Takahashi T, Hiruma K, Kanda Y,
Tanaka Y, Ogawa S, Chiba S, Miura O, Sakamaki
H, Hirai H. Recovery of Valpha24+ NKT cells after
hematopoietic stem cell transplantation. Bone
Marrow Transplant. 2004. Oct;34(7):595-602
28. Morishima Y, Ogura M, Nishimura M, Yazaki F,
Bessho M, Mizoguchi H, Chiba S, Hirai H, Tauchi
T, Urabe A, Takahashi M, Ohnishi K, Yokozawa T,
Emi N, Hirano M, Shimazaki C, Nakao S, Kawai Y,
Fujimoto M, Taguchi H, Jinnai I, Ohno R. Efficacy
and safety of imatinib mesylate for patients in thefirst chronic phase of chronic myeloid leukemia:
results of a Japanese phase II clinical study. Int J
Hematol. 2004 Oct;80(3):261-6.
29. Kojima R, Kami M, Nannya Y, Kusumi E, Sakai M,
Tanaka Y, Kanda Y, Mori S, Chiba S, Miyakoshi S,
Tajima K, Hirai H, Taniguchi S, Sakamaki H, Takaue Y. Incidence of invasive aspergillosis after allogeneic hematopoietic stem cell transplantation
with a reduced-intensity regimen compared withtransplantation with a conventional regimen. Biol
Blood Marrow Transplant. 2004 Sep;10(9):645-52.
30. Kuribara R, Honda H, Matsui H, Shinjyo T, InukaiT, Sugita K, Nakazawa S, Hirai H, Ozawa K, Inaba
T. Roles of Bim in apoptosis of normal and
Bcr-Abl-expressing hematopoietic progenitors. Mol
Cell Biol. 2004 Jul;24(14):6172-83.
31. Yanada M, Emi N, Naoe T, Sakamaki H, Iseki T,
Hirabayashi N, Karasuno T, Chiba S, Atsuta Y,
Hamajima N, Takahashi S, Kato S. Allogeneic
myeloablative transplantation for patients aged 50
years and over. Bone Marrow Transplant. 2004
Jul;34(1):29-35.

176

32. Kawazu M, Kanda Y, Nannya Y, Aoki K, Kurokawa M, Chiba S, Motokura T, Hirai H, Ogawa S.
Prospective comparison of the diagnostic potentialof real-time PCR, double-sandwich enzyme-linked
immunosorbent assay for galactomannan, and a(1-->3)-beta-D-glucan test in weekly screening forinvasive aspergillosis in patients with hematological disorders. J Clin Microbiol. 2004 Jun;42(6):2733-41.
33. Ichikawa M, Asai T, Chiba S, Kurokawa M, Ogawa
S. Runx1/AML-1 ranks as a master regulator of
adult hematopoiesis. Cell Cycle. 2004 Jun;3(6):722-4.
34. Nakamoto T, Shiratsuchi A, Oda H, Inoue K, Matsumura T, Ichikawa M, Saito T, Seo S, Maki K,
Asai T, Suzuki T, Hangaishi A, Yamagata T, Aizawa S, Noda M, Nakanishi Y, Hirai H. Impaired
spermatogenesis and male fertility defects in
CIZ/Nmp4-disrupted mice. Genes Cells. 2004
Jun;9(6):575-89.
35. Kunisato A, Chiba S, Saito T, Kumano K, Nakagami-Yamaguchi E, Yamaguchi T, Hirai H. Stemcell leukemia protein directs hematopoietic stem
cell fate. Blood. 2004 May 1;103(9):3336-41.
36. Kanda Y, Izutsu K, Hirai H, Sakamaki H, Iseki T,
Kodera Y, Okamoto S, Mitsui H, Iwato K, Hirabayashi N, Furukawa T, Maruta A, Kasai M, Atsuta Y,
Hamajima N, Hiraoka A, Kawa K. Effect ofgraft-versus-host disease on the outcome of bonemarrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate. Leukemia. 2004
May;18(5):1013-9.
37. Sakata-Yanagimoto M, Kanda Y, Nakagawa M,
Asano-Mori Y, Kandabashi K, Izutsu K, Imai Y,
Hangaishi A, Kurokawa M, Tsujino S, Ogawa S,
Chiba S, Motokura T, Hirai H. Predictors for severe
cardiac complications after hematopoietic stem celltransplantation. Bone Marrow Transplant. 2004
May;33(10):1043-7.
38. Sasaki K, Nakamura Y, Maki K, Waga K, Nakamura F, Arai H, Imai Y, Hirai H, Mitani K. Functional analysis of a dominant-negative DeltaETS
TEL/ETV6 isoform. Biochem Biophys Res Commun. 2004 May 14;317(4):1128-37.
39. Yamaguchi Y, Kurokawa M, Imai Y, Izutsu K, Asai
T, Ichikawa M, Yamamoto G, Nitta E, Yamagata T,

Sasaki K, Mitani K, Ogawa S, Chiba S, Hirai H.
AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues. J Biol
Chem. 2004 Apr 9;279(15):15630-8.
40. Maki K, Arai H, Waga K, Sasaki K, Nakamura F,
Imai Y, Kurokawa M, Hirai H, and Mitani K. Leukemia-related transcription factor TEL is negatively
regulated through ERK-induced phosphorylation.
Mol Cell Biol. 2004 Apr;24(8):3227-37.
41. Ichikawa M, Asai T, Saito T, Seo S, Yamazaki I,
Yamagata T, Mitani K, Chiba S, Ogawa S, Kurokawa M, Hirai H. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation,
but not for maintenance of hematopoietic stem cells
in adult hematopoiesis. Nat Med. 2004 Mar;10(3):299-304.
42. Izutsu K, Kanda Y, Ohno H, Sao H, Ogawa H, Miyazaki Y, Kawa K, Kodera Y, Kato S, Morishima Y,
Hirai H. Unrelated bone marrow transplantation for
non-Hodgkin lymphoma: a study from the Japan
Marrow Donor Program. Blood. 2004 Mar
1;103(5):1955-60.
43. Ogawa N, Kanda Y, Matsubara M, Asano Y, Nakagawa M, Sakata-Yanagimoto M, Kandabashi K,
Izutsu K, Imai Y, Hangaishi A, Kurokawa M, Tsujino S, Ogawa S, Aoki K, Chiba S, Motokura T,
Hirai H. Increased incidence of acute graft-versus-host disease with the continuous infusion of
cyclosporine A compared to twice-daily infusion.
Bone Marrow Transplant. 2004 Mar;33(5):549-52.
44. Imai Y, Kurokawa M, Yamaguchi Y, Izutsu K, Nitta
E, Mitani K, Satake M, Noda T, Ito Y, and Hirai H.
The corepressor mSin3A regulates phosphorylation-induced activation, intracellular localization,and stability of AML1. Mol Cell Biol. 2004
Feb;24(3):1033-43.
45. Mori T, Mori S, Kanda Y, Yakushiji K, Mineishi S,
Takaue Y, Gondo H, Harada M, Sakamaki H, Yajima T, Iwao Y, Hibi T, Okamoto S. Clinical significance of cytomegalovirus (CMV) antigenemia
in the prediction and diagnosis of CMV gastrointestinal disease after allogeneic hematopoietic stem
cell transplantation. Bone Marrow Transplant. 2004
Feb;33(4):431-4.

177

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

Lecturer
Hirokazu Okudaira, M.D. (Allergology)
Yoshikata Misaki, M.D. (Rheumatology)

Fujio Takeuchi, M.D. (Rheumatology)
Zen-ichiro Honda, M.D. (Rheumatology)

Assistant
Tetsuji Sawada, M.D. (Rheumatology)
Masao Yamaguchi, M.D. (Allergology)
Ryoichi Tanaka, M.D. (Allergology)
Takeshi Suzuki, M.D. (Rheumatology)
Yoshinori Komagata, M.D. (Rheumatology)
Hiroko Kanda, M.D. (Rheumatology)
Kimito Kawahata, M.D. (Rheumatology)

Homepage http://
Introduction and Organization
The Department of Allergy and Rheumatology presently consists of 12 staff mentioned above, who presideover 4 medical staff, 12 graduate students for "Doctorof Medical Science" and 3 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 Wardand the research rooms are located in the East HospitalWard, the Central Ward and the Internal Medicine Research Ward.

Education
In regard to undergraduate education, the Department
is in charge of internal medicine diagnosis and systemic
lectures for M2 students and clinical lectures and bedside education for M3 and M4 students in cooperation
with other departments of internal medicine. The systemic lectures and clinical lectures covers clinical immunology, connective tissue diseases and allergy. Bed-side education provides students with a good opportunity to learn about patients as well as practical knowledge through numerous seminars.
For postgraduate education, internal medicine trainees are accepted on rotation basis and trained as internist. Our department accepts students for "Doctor of
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 arerounded and on Tuesday afternoon the professor makes
his rounds. To achieve the highest quality of medicalcare, clinical conferences are held. Majority of patientsin the ward are suffered from connective tissue diseases
and usually exhibit multiple organ involvements.

178

Therefore, a careful, well-rounded approach to eachpatient as a whole is required rather than a limited special approach to a single organ system.

Research
The Department has 10 research laboratories inwhich clinical and basic studies are carried out concerning mainly rheumatology and allergology. Recently
the mainstream of research has employed various techniques of molecular biology and cellular immunology.
The principal research topics are listed below.
1) Analysis by means of autoantigen gene cloning andepitope mapping.
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 the pathogenesis of allergic conditions.
12) Analysis of interstitial pneumonitis associated withconnective tissue diseases,13) Mechanism of drug allergy

References(1) Chang X, Yamada R, Suzuki A, Sawada T, Yoshino
S, Tokuhiro S, Yamamoto K. Localization of peptidylarginine deiminase 4 (PADI4) and citrullinatedprotein in synovial tissue of rheumatoid arthritis.
Rheumatology. 44: 40-50, 2005.
(2) Nakayama-Hamada M, Suzuki A, Kubota K, Takazawa T, Ohsaka M, Kawaida R, Ono M, Kasuya
A, Furukawa H, Yamada R, Yamamoto K. Com-

parison of enzymatic properties between hPADI2
and hPADI4. Biochem Biophys Res Commun.
327: 192-200, 2005.
(3) Kochi Y, Yamada R, Suzuki A, Harley JB,
Shirasawa S, Sawada T, Bae SC, Tokuhiro S,
Chang X, Sekine A, Takahashi A, Tsunoda T, Ohnishi Y, Kaufman KM, Kang CP, Kang C, Otsubo
S, Yumura W, Mimori A, Koike T, Nakamura Y,
Sasazuki T, Yamamoto K. A functional variant in
FCRL3, encoding Fc receptor-like 3, is associatedwith rheumatoid arthritis and several autoimmunities. Nature Genet. 37:478-485, 2005.
(4) Kawaida R, Yamada R, Kobayashi K, Tokuhiro S,
Suzuki A, Kochi Y, Chang X, Sekine A, Tsunoda T,
Sawada T, Furukawa H, Nakamura Y, Yamamoto
K. CUL1, a component of E3 ubiquitin ligase, alters lymphocyte signal transduction with possible
effect on rheumatoid arthritis. Genes Immun. 6:
194-202, 2005.
(5) Yamada R, Yamamoto K. (Review) Recent findings on genes associated with inflammatory disease. Mutation Res. 573:136-151, 2005.
(6) Mori M, Yamada R, Kobayashi K, Kawaida R,
Yamamoto K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J
Hum Genet. 50:264-266, 2005.
(7) Suzuki A, Yamada R, Ohtake-Yamanaka M, Okazaki Y, Sawada T, Yamamoto K. Anti-citrullinatedcollagen type I antibody is a target of autoimmunity in rheumatoid arthritis. Biochem Biophys Res
Commun. 333:418-426, 2005.
(8) Takizawa Y, Sawada T, Suzuki A, Yamada R,
Inoue T, Yamamoto K. Peptidylarginine deiminase
4 (PADI4) identified as a conformation-dependent
autoantigen in rheumatoid arthritis. Scand J
Rheumatol. 34:212-215, 2005.
(9) Yamamoto K, Yamada R. Genome-wide single
nucleotide polymorphism analyses of rheumatoid
arthritis. J Autoimmun. 25:12-15, 2005.
(10) Tanaka G, Matsushita I, Ohashi J, Tsuchiya N,
Ikushima S, Oritsu M, Hijikata M, Nagata T, Yamamoto K, Tokunaga K, Keicho N. Evaluation of
microsatellite markers in association studies: asearch for an immune-related susceptibility gene insarcoidosis. Immunogenetics. 56:861-870, 2005.
(11) Kanda H, Kubo K, Tateishi S, Sato K, Yonezumi A,
Yamamoto K, Mimura T. Antiproteinuric effect of

179

ARB in lupus nephritis patients with persistent
proteinuria despite immunosuppressive therapy.
Lupus. 14:288- 292, 2005.
(12) Sato K, Tateishi S, Kubo K, Mimura T, Yamamoto
K, Kanda H. Downregulation of IL-12 and a novel
negative feedback system mediated by CD25+
CD4+ T cells. Biochem Biophys Res Commun.
330:226-232, 2005.
(13) Nagai T, Arinuma Y, Yanagida T, Yamamoto K,
Hirohata S. Anti-ribosomal P protein antibody inhuman systemic lupus erythematosus up-regulates
the expression of proinflammatory cytokines byhuman peripheral blood monocytes. Arthritis
Rheum. 52:847-855, 2005.
(14) Sagawa K, Nagatani K, Komagata Y, Yamamoto K.
Angiotensin receptor blockers suppress antigen-specific T cell responses and ameliorate collagen-induced arthritis in mice. Arthritis Rheum.
52:1920-1928, 2005.
(15) Yu R, Fujio K, Tahara H, Araki Y, Yamamoto K.
Clonal dynamics of tumor-infiltrating lymphocytes.
Eur J Immunol. 35:1754-63,2005(16) Okazaki Y, Sawada T, Nagatani K, Komagata Y,
Inoue T, Muto S, Itai A, Yamamoto K. Effect of
Nuclear Factor-kB Inhibition on Rheumatoid Fibroblast-like Synoviocytes and Collagen Induced
Arthritis. J Rheumatol. 32:1440-1447, 2005.
(17) Kawai S, Yamamoto K. Safety of tacrolimus, animmunosuppressive agent, in the treatment ofrheumatoid arthritis in elderly patients. Rheumatology. 45:441-4,2006.
(18) Shoda H, Kanda H, Tanaka R, Komagata Y,
Misaki Y, Yamamoto K. Wegener's granulomatosis with eosinophilia. Intern Med. 44:750-3, 2005.
(19) Takizawa K, Kitani S, Takeuchi F, Yamamoto K.
Enhanced expression of CD69 and CD25 antigen
on human peripheral blood mononuclear cells by
prolactin. Endocr J. 52:635-41,2005..
(20) Kono H, Kyogoku C, Suzuki T, Tsuchiya N,
Honda H, Yamamoto K, Tokunaga K, Honda Z.
FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus
erythematosus decreases affinity to lipid rafts andattenuates inhibitory effects on B cell receptor
signaling. Hum Mol Genet. 14:2881-92,2005.
(21) Suzukawa M, Hirai K, Iikura M, Nagase H, Komiya A, Yoshimura-Uchiyama C, Yamada H, Ra C,

Ohta K, Yamamoto K, Yamaguchi M. IgE- andFcεRI-mediated migration of human basophils. Int
Immunol. 17:1249-1255, 2005.
(22) Iikura M, Suzukawa M, Yamaguchi M, Sekiya T,
Komiya A, Yoshimura-Uchiyama C, Nagase H,
Matsushima K, Yamamoto K, Hirai K. 5-Lipoxygenase
products regulate basophil functions: 5-Oxo-ETE
elicits migration, and leukotriene B(4) induces degranulation. J Allergy Clin Immunol. 116:578-85,
2005.
(23) Shiratori I, Yamaguchi M, Suzukawa M, Yamamoto K, Lanier LL, Saito T, Arase H. Down-regulation of basophil function by human CD200 andhuman herpesvirus-8 CD200. J Immunol. 175:4441-4449, 2005.
(24) Nakagome K, Dohi M, Okunishi K, Komagata Y,
Nagatani K, Nagatani K, Tanaka R, Miyazaki J,
Yamamoto K. In vivo IL-10 gene delivery suppresses airway eosinophilia and hyperreactivity by
down-regulating APC functions and migration
without impairing the antigen-specific systemic
immune response in a mouse model of allergic
airway inflammation. J Immunol. 174:6955-6966,
2005.
(25) Nakagome K, Dohi M, Okunishi K, To Y, Sato A,
Komagata Y, Nagatani K, Tanaka R, Yamamoto K.
Antigen-sensitized CD4+CD 62Llow memory/effector T helper 2 cells can induce airway
hyperresponsiveness in an antigen free setting.
Respir Res. 28;6:46,2005.
(26) Okunishi K, Dohi M, Nakagome K, Tanaka R,
Mizuno S, Matsumoto K, Miyazaki J, Nakamura T,
Yamamoto K. A novel role of hepatocyte growth
factor as an immune regulator through suppressing
dendritic cell function. J Immunol. 175:4745-53,
2005.
(27) Nagatani K, Dohi M, To Y, Tanaka R, Okunishi K,
Nakagome K, Sagawa K, Tanno Y, Komagata Y,
Yamamoto K. Splenic dendritic cells induced byoral antigen administration are important for thetransfer of oral tolerance in an experimental modelof asthma. J Immunol. 176:1481-9,2006.
(28) Okazaki Y, Suzuki A, Sawada T, Ohtake-Yamanaka M, Inoue T, Hasebe T, Yamada R, Yamamoto K. Identification of citrullinated eukaryotic
translation initiation factor 4G1 as novel autoantigen in rheumatoid arthritis. Biochem Biophys Res

180

Commun. 341:94-100, 2006.

181

Department of Infectious
Diseases (Internal Medicine)
Professor
Kazuhiko Koike, M.D., Ph.D.

Associate Professor(To be appointed)

Associate
Yasuo Ota, 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 is located on
11th floor of the University of Tokyo Hospital Building,and has well-furnished research laboratories including
P-2 class laboratory, a departmental library and a computer room as own properties. In clinical and research
activities, we are collaborating with the Department of
Infection Control and Prevention. A professor, an associate professor, 6 guest lecturers, an associate, 9 graduate students and 15 full-time staff member are all performing their own duties in clinical, educational andresearch 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 the best careand best quality of life. Clinical associates, full-time
staff and residents take care of inpatients. The casepresentation by residents is held on a weekly basis.
Weekly clinical conference is held for discussing about
all cases, in particular, those with problems difficult tobe solved. Consultations are very frequent from otherdepartments on the management of infectious diseases.
The general diagnostic, therapeutic plans and decisions
for each patient are given at the Professor’s round.
Our department offers out-patient care everyday on infectious diseases and general medicine. We are also
engaged in infection control and prevention of emerging infectious diseases such SARS or avian influenza
virus, which appeared recently.

Teaching activities
Our department takes a part in clinical lectures andbed-side teaching of the internal medicine for undergraduate medical students according to the educational
programs of the University of Tokyo. For the fourthyear medical students, six lectures of infectious dis-

182

eases 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, the techniques of interrogation and physical examination, theway for interpretations of laboratory tests and othermedical examinations, and the basic medical procedures 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 the department.
(1) Establishment of effective therapy for HIV infection: we have made a great contribution in the establishment 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) Analysis of intracellular function and signaling of
the proto-oncogene Cbl.
(10) Establishment of new methods for practical diagnosis and treatment of respiratory infection.

Members
Kazuhiko Koike, Yasuo Ota, Hiroshi Yotsuyanagi,
Yoshizumi Shintani, Takeya Tsutsumi, Satoshi Itoyama,
Takatoshi Kitazawa, Kuniko Ueda, Shuji Hatakeyama,
Kunihisa Tsukada, Shu Okugawa, Miki Kawada, Shintaro Yanagimoto, Yohko Nukui, Katsutoshi Abe, Atsuhito Fukishima, Keita Tatsuno, Sohei Harada, Koji
Goto, Mahoko Kamimura.

References
1) Miyoshi H, Fujie H, Moriya K, Shintani Y, Tsutsumi
T, Makuuchi M, Kimura S, Koike K. Methylation
status of suppressor of cytokine signaling-1 gene inhepatocellular carcinoma. J Gastroenterol 2004;
39:563-569.
2) Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Kimura S, Moriya K, Koike K. Hepatitis C virus anddiabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology
2004;126:840-848.
3) Koike K, Fujie H, Shintani Y, Miyoshi H, Moriya
K. Hepatitis C and Diabetes Mellitus: what is themetabolic pathway? Gastroenterology 2004;127:
1280-1281.
4) Yano M, Hayashi H, Yoshioka K, Kohgo Y, Saito H,
Niitsu Y, Kato J, Iino S, Yotsuyanagi H, Kobayashi
Y, Kawamura K, Kakumu S, Kaito M, Ikoma J,
Wakusawa S, Okanoue T, Sumida Y, Kimura F, Kajiwara E, Sata M, Ogata K. A significant reduction
in serum alanine aminotransferase levels after
3-month iron reduction therapy for chronic hepati-

183

tis C: a multicenter, prospective, randomized, controlled trial in Japan. J Gastroenterol. 39: 570-574,
2004.
5) Yotsuyanagi H, Hashidume K, Suzuki M, Maeyama S, Takayama T, Uchikoshi T. Role of hepatitis B virus in hepatocarcinogenesis in alcoholics.
Alcohol Clin Exp Res. 28(Suppl):181S, 2004.
6) Fukuda Y, Yotsuyanagi H, Ooka S, Sekine T, Koike
J, Takano T, Suzuki M, Itoh F, Nishioka K, Kato T.
Identification of a new autoantibody in patientswith chronic hepatitis. Hum Immunol. 65:1530,
2004.
7) Nakayama K, Okugawa S, Yanagimoto S, Kitazawa T, Tsukada K, Kawada M, Kimura
8) S, Hirai K, Takagaki Y, Ota Y. Involvement of
IRAK-M in peptidoglycan-induced tolerance inmacrophages. J Biol Chem. 2004 Feb 20;279(8):6629-34.
9) Koike K, Moriya K. Metabolic aspects of hepatitis
C: steatohepatitis resembling but distinct from
NASH. J Gastroenterol 2005;40:329-336.
10) Hatakeyama S, Moriya K, Saijo M, Morisawa Y,
Kurane I, Koike K, Kimura S, Morikawa S. Persisting humoral anti-smallpox immunity among
current Japanese population after the discontinuation in 1976 of routine smallpox vaccinations. Clin
Diagn Lab Immun 2005;12:520-524.
11) Koike K. Steatosis in chronic hepatitis C: fuel for
overproduction of oxidative stress? J Gastroenterol 2005;40:664-665.
12) Miyoshi H, Fujie H, Shintani Y, Tsutsumi T, Shinzawa S, Makuuchi M, Kokudo N, Matsuura Y, Suzuki T, Miyamura T, Moriya K, Koike K. Hepatitis
C virus core protein exerts an inhibitory effect on
suppressor of cytokine signaling (SOCS)-1 gene
expression. J Hepatol 2005;43:757-763.
13) Koike K. Hepatitis C as a metabolic disease: implication for the pathogenesis of NASH. Hepatol
Res 2005;33:145-150.
14) Koike K. Molecular basis of hepatitis C virus-associated hepatocarcinogenesis: lessons fromanimal model studies. Clin Gastroenterol Hepatol
2005;3:S132-S135.
15) Saito R, Misawa Y, Moriya K, Koike K, Ubukata
K, Okamura N. Development and evaluation of aloop-mediated isothermal amplification assay for
rapid detection of Mycoplasma pneumoniae. J

Med Microbiol 2005;54:1037-1041.
16) Orita M, Masuko-Hongo K, Yotsuyanagi H, Matsui
T, Suzuki-Kurokawa M, Nishioka K, Kato T. Molecular transplantation: delivery of membranous
proteins onto live cells. Anal Biochem. 340:184186, 2005.
17) Katakura Y, Yotsuyanagi H, Hashizume K, Okuse
C, Okuse N, Nishikawa K, Suzuki M, Iino S, Itoh F.
Pancreatic involvement in chronic viral hepatitis.
World J Gastroenterol. 11: 3508, 2005.
18) Yotsuyanagi H, Okuse C, Yasuda K, Orito E, Nishiguchi S, Toyoda J, Tomita E, Hino K, Okita K,
Murashima S, Sata M, Hoshino H, Miyakawa Y,
Iino S; Japanese Acute Hepatitis B Group. Distinct
geographic distributions of hepatitis B virus genotypes in patients with acute infection in Japan. J
Med Virol. 77: 39-46, 2005.
19) Koike K. Hepatitis C virus infection presenting
with metabolic disease by inducing insulin resistance. Intervirology 2006;49:51-57.
20) Koike K, Miyoshi H. Oxidative stress and hepatitis
C viral infection. Hepatol Res 2006;34:65-76.
21) Nukui Y, Tajima S, Kotaki A, Ito M, Takasaki T,
Koike K, Kurane I. Novel dengue virus type 1 fromtravelers to Yap State, Micronesia. Emerg Infect
Dis 2006;12(2): 343-346.
22) Koike K. Oxidative stress and apoptosis in hepatitis
C: the core issue. J Gastroenterology 2006 inpress.
23) Matsuoka-Aizawa S, Gatanaga H, Sato H, Koike K,
Kimura K, Oka S. Gag substitutions responsible for
nelfinavir-dependent enhancement of precursor
cleavage and human immunodeficiency virus
type-1 replication. Virus Res 2006 Feb 3; [Epubahead of print]24) Koike K. Pathogenesis of HCV-associated HCC:
dual-pass carcinogenesis through the activation ofoxidative stress and intracellular signaling. Hepatol
Res 2006 in press.
25) Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol
Hepatol 2006 in press.
26) Okuse C, Yotsuyanagi H, Nagase Y, Kobayashi Y,
Yasuda Y, Koike K, Iino S, Suzuki M, Itoh F. Risk
Factors for Retinopathy Associated with Interferon
Alpha-2b and Ribavirin Combination Therapy in184

Patients with Chronic Hepatitis C. World J Gastroenterol 2006 in press.

185

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

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

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

Masami Nishikawa, M.D.

Homepage http://psmut.umin.ac.jp/
Introduction and Organization
The Department of Stress Science and Psychosomatic Medicine is one of 11 divisions of the Department of Internal Medicine, the University of Tokyo. It
covers eating disorder, panic disorder, and various psychosomatic diseases such as chronic headache, irritablebowel syndrome, non-ulcer dyspepsia, hypertension,
diabetes mellitus, or hyperthyroidism. We are responsible for 8 beds in the Tokyo University Hospital. Ourteaching staff consists of one professor, one associate
professor, two associates, and 5 adjunct professors, andother members are 2 senior residents, 9 graduate students, and 10 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 either an elder associate or an associate professor attend it every day andprovide close side-by-side instruction to junior residents. The weekly professor’s round is scheduled on
Thursday morning. During 2005 April to 2006 March,roughly 80 patients were admitted to the ward, many ofwhom were eating disorder patients. Outpatient clinic is

attended on every morning and afternoon in three consultation rooms by approximately fifteen physicians.
During 2005 April to 2005 March, the total number ofabout 600 patients newly visited our outpatient clinic.

Teaching activities
We are giving 6 methodical lectures on psychosomatic medicine for fourth grade medical students,‘problem-based learning’ lasting 12 weeks (net 24
hours) for 6 or 7 fourth grade students, ‘bed-side learning’ for fifth grade students lasting two weeks (net 4days), ‘clinical clerkship’ for 3 to 4 sixth grade students
lasting 4 weeks each, and a clinical lecture on panic
disorder for sixth grade students. We are trying hard toteach them not only basic knowledge of specific diseases, ways of physical examination, or interpretationof laboratory data but also relevant ways of clinicalinterview, doctor-patient relationship building, and behavior modification.
As for education for junior residents, our senior residents 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 roundfrom our teaching staff.

186

Research activities

References

Targeting stress-related diseases such as not only
those covered by our department but also other lifestyle-related diseases, cancers, and multiple chemicalsensitivities, we are investigating their pathophysiology
and psychopathology through assessing bio-psychobehavioral time-series data, various questionnaire data,
higher brain function, and autonomic nervous function.
We are also actively conducting basic as well as clinicalresearch on eating-related substances or on stress andsexual hormones.
Some representative research topics are as follows:
1) Investigation on neurobehavioral basis of stressrelated diseases such as tension-type headache,eating disorder, insomnia, panic disorder, and multiple chemical sensitivity by use of ecological momentary assessment (EMA) methods.
2) Interventional studies with cognitive behavioral
treatment or relaxation procedures on tension-type
headache, panic disorder, or insomnia.
3) Behavioral scientific studies of stress-related diseases such as irritable bowel syndrome, eating disorders, panic disorders, depression, cancer, andchronic renal failure by use of various questionnaires and physiological data.
4) Elucidation of brain processes closely related tomind/body correlation in stress-related diseases
such as eating disorders and panic disorders or in
meditative states in healthy people by use of brain
functional analysis methods such as positron emission tomography, electroencephalography, andevent-related potentials.
5) Investigation on neuroendocrine mechanisms related to the symptomatic improvement during
treatments on eating disorders or on male climacteric syndrome.
Nine graduate students and 10 researchers are actively conducting their researches along with our
teaching staff. We are also collaborating with many
scientists belonging to other departments either in Japanor abroad. Research conferences are held once a month,where one of graduate students takes charge and presents his or her research activities for open discussion
by all members of our department.

1. Yoshiuchi K, Quigley KS, Ohashi K, Yamamoto Y,
Natelson BH: Use of time-frequency analysis toinvestigate temporal patterns of cardiac autonomic
response during head-up tilt in chronic fatigue syndrome. Auton Neurosci. 113(1-2):55-62, 2004
2. Kumano H, Kaiya H, Yoshiuchi K, Yamanaka G,
Sasaki T, Kuboki T: Comorbidity of irritable bowel
syndrome, panic disorder and agoraphobia in a
Japanese representative sample. Am J Gastroenterol
99:370-376, 2004
3. Takimoto Y, Yoshiuchi K, Kumano H, Yamanaka G,
Sasaki T, Suematsu H, Nagakawa Y, Kuboki T: QTinterval and QT dispersion in eating disorders.
Psychother Psychosom 73:324-328, 2004
4. Kajimura N, Nishikawa M, Uchiyama M, Kato M,
Watanabe T, Nakajima T, Hori T, Nakabayashi T,
Sekimoto M, Ogawa K, Takano H, Imabayashi E,
Hiroki M, Onishi T, Uema T, Takayama Y, Matsuda
H, Okawa M, Takahashi K: Deactivation by benzodiazepine of the basal forebrain and amygdala innormal humans during sleep: a placebo-controlled[15O]H2O PET study. Am J Psychiatry. 161(4):748-51, 2004
5. Nakaya N, Kumano H, Minoda K, Koguchi T,
Tanouchi K, Kanazawa M, Fukudo S: Preliminary
study: psychological effects of the muscle relaxation on juvenile delinquents. Int J Behav Med
11(3):176-180, 2004
6. Nunes Amaral LA, Bezerra Soares DJ, da Silva LR,
Lucena LS, Saito M, Kumano H, Aoyagi N, Yamamoto Y: Power law temporal auto-correlations in
day-long records of human physical activity andtheir alteration with disease. Europhys Lett
66(3):448-454, 2004
7. Nakaya N, Kumano H, Minoda K, Kanazawa M,
Fukudo S: Laterality and imbalance of muscle
stiffness relates to personality. Behav Med
30(1):5-9, 2004
8. Yasuda A, Sato A, Miyawaki K, Kumano H, Kuboki T: Error-related negativity reflects detection ofnegative reward prediction error. NeuroReport15(16):2561-2565, 2004
9. Sato A, Yasuda A, Ohira H, Miyawaki K, Nishikawa M, Kumano H, Kuboki T: Effects of value
and reward magnitude on feedback negativity and187

P300. NeuroReport 16(4):407-412, 2005
10. Saito M, Kumano H, Yoshiuchi K, Kokubo N,
Ohashi K, Yamamoto Y, Shinohara N, Yanagisawa
Y, Sakabe K, Miyata M, Ishikawa S, Kuboki T:
Symptom profile of multiple chemical sensitivity inactual life. Psychosom Med 67:318-325, 2005
11. Miyawaki K, Sato A, Yasuda A, Kumano H, Kuboki T: Explicit knowledge and intention to learn insequence learning: an ERP study. NeuroReport16(7):705-708, 2005
12. Takaki J, Nishi T, Shimoyama H, Inada T, Matsuyama N, Kumano H, Kuboki T: Possible interactive effects of demographic factors and stress coping mechanisms on depression and anxiety inmaintenance hemodialysis patients. J Psychosom
Res 58(3):217-23, 2005
13. Sakai Y, Kumano H, Nishikawa M, Sakano Y,
Kaiya H, Imabayashi E, Ohnishi T, Matsuda H,
Yasuda A, Sato A, Diksic M, Kuboki T: Cerebral
glucose metabolism associated with a fear networkin panic disorder. NeuroReport 16(9):927-931,
2005
14. Leibowitz SF, Sepiashvili K, Akabayashi A,
Karatayev O, Davydova Z, Alexander JT, Wang J,
Chang GQ: Function of neuropeptide Y and agoutirelated protein at weaning: relation to corticosterone, dietary carbohydrate and body weight. Brain
Res. 1036(1-2):180-91, 2005
15. Kamijima K, Kuboki T, Kumano H, Burt T, Cohen
G, Arano I, Hamasaki T: A Placebo-controlled,
randomized withdrawal study of Sertraline forpanic disorder in Japan. Int Clin Psychopharm20(5):265-273, 2005
16. Sakamoto N, Martin RG, Kumano H, Kuboki T,
Al-Adawi S: Hikikomori, is it a culture-reactive or
culture-bound temperament?: Nidotherapy andclinical vignette from Oman. Int J Psychiatry Med
35(2):191-198, 2005
17. Kumano H, Haseme E, Fujimoto H, Matsuoka N,
Yoshiuchi K, Uchitomi Y, Akechi T, Nakano T,
Kobayashi M, Agari I, Kuboki T: Harmony-seeking
and the Risk of Prostate Cancer: a Prebioptic Study.
J Psychosom Res 59:167-174, 2005
18. Yoshida NM, Yoshiuchi K, Kumano H, Sasaki T,
Kuboki T: Analysis of energy expenditure, endocrine function, and autonomic nervous activity inanorexia nervosa patients during refeeding: A pilot

study. Nutr Res 25:959-970, 2005
19. Yoshida NM, Kumano H, Kuboki T: Does the Aging Males' Symptoms scale assess major depressive
disorder?: a pilot study. Maturitas 53:171-175,
2006
20. Takimoto Y, Yoshiuchi K, Kumano H, Kuboki T:
Bulimia Nervosa and Abnormal Cardiac Repolarization. J Psychosom Res 60(1):105-7, 2006
21. Yoshiuchi K, Farkas J, Natelson BH: Patients withchronic fatigue syndrome have reduced absolutecortical blood flow. Clin Physiol Funct Imaging.
26(2):83-6, 2006

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

⑱

190

Department ofTransfusion Medicine and
Immunohematology
Professor
Koki Takahashi, M.D.,Ph.D.

AssociateNobukazu Hori, M.D., Ph.D.,

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

Aki Kamijo, M.D., Ph.D.

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

Clinical activities

The department of Transfusion Medicine was established in 1949, initially as an internal provisional
measure, and officially in 1966. In 1997, when the
Graduate School of Medicine was established at the
University of Tokyo, the Department of Transfusion
Medicine, a chair of the Internal Medicine Division,
was created. In 1984, Professor Hiroshi Toyama assumed as the first Professor of the department. Professor Toyama had great achievements by publishing“Transfusion Medicine” (actually in its 3rd. edition),
which is the bible of transfusion medicine in Japan.
Other achievements from the department are as follows.
Dr. Kazuo Okochi, ex-lecturer of the department, introduced the Australia antigen (actually known as
HBsAg) testing of blood products, ex-Professor Takeo
Juji clarified the mechanisms of graft-versus-host disease (GVHD), a serious post-transfusional complication,and the previous professor, Professor Yoichi Shibata hascontributed enourmously in the field of platelet serology.
Actually, the department is composed of 6 medical
doctors (4 full-time, and 2 partial-time), 10 laboratory
technicians, 1 nurse and 1 office assistant.

The main function of the department is the control,
preservation, and provision of blood products and theirderivatives for transfusion. The control of all blood
products in the hospital is centralized to the department,
which, in addition, provides information and orientation
related to blood transfusion. Transfusion-related laboratory tests, tests for transfusion-transmitted infectious
diseases are routinely performed, and in case of
post-transfusion complication, the department takes
measures to help diagnosis and treatment. The department also actively takes part in autologous blood collection and preservation, and in January 2006, the outpatient clinic for autologous blood transfusion, the firstestablished in Japan, was started. In this outpatient
clinic, the transfusionist gives consultation to the patients, prepares the adequate blood collection schedule,
takes the informed consent, and performs the bloodcollection, according to the patient’s status and needs.
Preservation and provision of autologous blood are alsofunction of the department. Additionally, immunotherapy of cancer patients and patients with recurrent abortion, and collection and preservation of peripheral
blood stem cells are also important clinical activities ofthe department.

191

I.

Control and preservation of blood products and its
derivatives;
II. Laboratory tests
1) Blood typing and histocompatibility testing;2) Detection of anti-erythrocyte, anti-leukocyte andanti-platelet antibodies;3) Detection of HBV antigens and antibodies, HCV,
HAB, ATLA and HIV antibodies;
4) HLA typing for bone marrow and organ transplantation;
III. Clinical work
1) Pre-operative autologous blood collection and preservation;2) Lymphocyte vaccination therapy for patients with
habitual abortion;3) Collection and preservation of peripheral blood
stem cells for transplantation;4) Dendritic cell-based cancer immunotherapy.
5) Anti-angiogenic therapy of cancer.

Teaching activities
Sixth-year medical students are provided with practical courses focusing on clinical practice of bloodtransfusion and laboratory tests. Courses are given insmall groups of 6 students each, in a total of 18 groups
per year. The course lasts 3 days/week, including thefollowing subjects;
1) Visit to the laboratories of the department to understand the routine of a laboratory;
2) Introduction to the blood group types and their importance in transfusion medicine;3) Methodology of blood typing and compatibility
typing for transfusion;4) Methodology for screening of irregular antibodies,and their importance in transfusion practice;5) Introduction to the post-transfusional complications,
their etiology, prevention and treatment.
6) The indications and techniques of autologous bloodcollection and preservation;7) The techniques for peripheral blood stem cells(PBSCs) collection and preservation, as well as
their clinical application;8) The immunotherapy of cancer patients;
9) The recent advances in the field of blood transfusion, including the “New Blood Law”, and the recently revised “Indications of blood products” and“The principles of transfusion practice”.
10) One-day visit to the Japanese Red Cross Blood
Center, to learn the general process of blood donation and transfusion, including the types of blood
products, and their indications.

Research activities
Research on red cell, leukocyte, and platelet antigens,the post-tranfusional complications, transplantation
immunology, immunotherapy, and stem cell biology are
the main themes of the department. The HLA typing,which is an essential test for stem cell and organ transplantations, and platelet and granulocyte antigens, aswell as plasma antigens, which are involved in posttransfusional complications, are investigated by serological and DNA-based methods. Transplantation immunology, including stem cell biology, and development of immunotherapeutic strategies to treat cancer
patients and patients with recurrent abortion are also
being performed. Recently, development of new materials for medical use is being researched. Following are
the main themes.
1. Detection of platelet alloantigens and antibodies
and their role in the transfusion practice.
2. Diagnosis and prevention of post-transfusional
complications and thrombocytopenic purpura of thenewborn.
3. Clinical application of refrigerated and frozenstored blood for autologous transfusion in surgicalpatients.
4. Study on the mechanisms of transfusion-associated
GVHD and its prevention.
5. Development of a new methodology for plateletcross-match.
6. Detection and characterization of anti-endothelial
cell antibodies, and study on their role in the pathogenesis of inflammatory and autoimmune diseases,
as well as in organ transplantation.
7. HLA and HPA genotyping.
8. Study on the effect of irradiation and filtration onplatelet function.
9. Development of a new methodology for evaluationof platelet function.
10. Development of new strategies for the treatment ofcancer patients, by targeting the tumor vasculature.
11. Study on the mechanism of antigen presentation by192

dendritic cells.
12. Dendritic cell-based immunotherapy of cancer patients.
13. Ex-vivo expansion of hematopoietic stem cells andtheir clinical application.
14. Investigation of the self-renewal and differentiationof multipotent hematopoietic stem cells.

References
1. Tsuchiya T, Okaji Y, Tsuno NH, Sakurai D, Tsuchiya N, Kawai K, Yazawa K, Asakage M, Yamada
J, Yoneyama S, Kitayama J, Osada T, Watanabe T,
Tokunaga K, Takahashi K, Nagawa H. Targeting
Id1 and Id3 inhibits peritoneal metastasis of gastriccancer. Cancer Science. 96(11):784-90, 2005
2. Asakage M, Tsuno NH, Kitayama J, Yamada J,
Tsuchiya T, Yoneyama S, Takahashi K, Nagawa H.
The effect of cimetidine mainly increases CD4+
cells of peripheral blood T lymphocytes. Gan to
Kagaku Ryoho [Japanese Journal of Cancer &Chemotherapy]. 32(11):1576-7, 2005
3. Kawai K, Tsuno NH, Matsuhashi M, Kitayama J,
Osada T, Yamada J, Tsuchiya T, Yoneyama S, Watanabe T, Takahashi K, Nagawa H. CD11b-mediated migratory property of peripheral blood B cells.
Journal of Allergy & Clinical Immunology. 116(1):192-7, 2005
4. Asakage M, Kitayama J, Tsuno NH, Komuro Y,
Kaisaki S, Hori N, Nagawa H, Tsuno NH, Hori N,
Takahashi K. Primary malignant melanoma of theesophagus treated by esophagectomy and adjuvant
dendritic-cell therapy. Journal of Gastroenterology.
40(5):545-6, 2005
5. Kawai K, Tsuno NH, Kitayama J, Okaji Y, Yazawa
K, Asakage M, Yamashita H, Watanabe T, Takahashi K, Nagawa H. Anti-angiogenic properties ofplaunotol. Anti-Cancer Drugs. 16(4):401-7, 2005
6. Yazawa K, Tsuno NH, Kitayama J, Kawai K, Okaji
Y, Asakage M, Sunami E, Kaisaki S, Hori N, Watanabe T, Takahashi K, Nagawa H. Selective inhibition of cyclooxygenase-2 inhibits colon cancer
cell adhesion to extracellular matrix by decreased
expression of beta1 integrin. Cancer Science. 96(2):93-9, 2005
7. Kawai K, Tsuno NH, Kitayama J, Okaji Y, Yazawa
K, Asakage M, Sasaki S, Watanabe T, Takahashi

K, Nagawa H. Epigallocatechin gallate induces
apoptosis of monocytes. Journal of Allergy &Clinical Immunology. 115(1):186-91, 2005
8. Yazawa K, Tsuno NH, Kitayama J, Kawai K, Okaji
Y, Asakage M, Sunami E, Kaisaki S, Hori N, Watanabe T, Takahashi K, Nagawa H. Selective inhibition of cyclooxygenase (COX)-2 inhibits endothelial cell proliferation by induction of cell cycle
arrest. International Journal of Cancer. 113(4):5418, 2005
9. Okaji Y, Tsuno NH, Kitayama J, Saito S, Takahashi
T, Kawai K, Yazawa K, Asakage M, Tsuchiya T,
Sakurai D, Tsuchiya N, Tokunaga K, Takahashi K,
Nagawa H. A novel method for isolation of endothelial cells and macrophages from murine tumors
based on Ac-LDL uptake and CD16 expression.
Journal of Immunological Methods. 295(1-2):18393, 2004
10. Sakurai D, Tsuchiya N, Yamaguchi A, Okaji Y,
Tsuno NH, Kobata T, Takahashi K, Tokunaga K.
Crucial role of inhibitor of DNA binding/differentiation in the vascular endothelial
growth factor-induced activation and angiogenic
processes of human endothelial cells. Journal of
Immunology. 173(9):5801-9, 2004
11. Kawai K, Tsuno NH, Kitayama J, Okaji Y, Yazawa
K, Asakage M, Hori N, Watanabe T, Takahashi K,
Nagawa H. Epigallocatechin gallate attenuates adhesion and migration of CD8+ T cells by binding toCD11b. Journal of Allergy & Clinical Immunology.
113(6):1211-7, 2004
12. Asakage M, Tsuno NH, Kitayama J, Kawai K,
Okaji Y, Yazawa K, Kaisaki S, Takahashi K, Nagawa H. 3-Hydroxy-3-methylglutaryl-coenzyme A
reductase inhibitor (pravastatin) inhibits endothelial
cell proliferation dependent on G1 cell cycle arrest.Anti-Cancer Drugs. 15(6):625-32, 2004
13. Okaji Y, Tsuno NH, Kitayama J, Saito S, Takahashi
T, Kawai K, Yazawa K, Asakage M, Hori N, Watanabe T, Shibata Y, Takahashi K, Nagawa H.
Vaccination with autologous endothelium inhibits
angiogenesis and metastasis of colon cancer
through autoimmunity. Cancer Science. 95(1):8590, 2004

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

⑲

194

Department of
Reproductive Endocrinology
Professor
Yuji Taketani

Osamu Tsutsumi

Associate Professor
Tetsu Yano

Lecturer
Koji Kugu

Mikio Momoeda

Toru Takeuchi

Toshihiro Fujiwara

Yutaka Osuga

Homepage
Organization
The Department of Reproductive Endocrinology isorganized by two professors, one associate professor
and five lecturers. All the staff members are taking partin both clinical and research activities. For the clinicalaspect, we are engaged with in-patient and out-patientcare including the activities in the delivery units.

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases, genetic
counseling and assisted reproductive technologies(ART). We also perform minimal access surgery forendometriosis, uterine fibroid, benign tumor and so on.
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 higher level of treatment is necessary, ART isapplied to such cases. We have been engaged in in vitro
fertilization and embryo transfer (IVF-ET) as a main
axis of ART for eighteen years. Conventional IVF-ET
is mainly indicated to cases with tubal factor, mild male
factor, immunological factor or of unexplained infertil-ity factor. In case of severe male factor or other fertilization disorder intracytoplasmic sperm injection (ICSI)
is performed. Now we have about 250 OPU cycles of
IVF-ET every year, which conventional IVF-ET and
ICSI share almost equally. The clinical pregnancy rateof conventional IVF-ET is around 30% per embryotransfer cycle, which is comparable with that of ICSI.
Other ART techniques such as embryo cryopreservation and assisted hatching are also performed.
In the field of gynecological surgery, we have been
constantly trying to minimize surgical invasion to patients as much as possible. With both of well-equipped
instruments and well-trained expertise, more than 90%of surgery cases for benign gynecological disorders areoperated endoscopically. These endoscopic surgeries
include laparoscopic or laparoscopically assisted
cyctectomy (130 cases), laparoscopic hysterectomy orlaparoscopically assisted vaginal hysterectomy (16cases), laparoscopic or laparoscopically assisted myomectomy (50 cases), diagnostic laparoscopy for infertility (12 cases) laparoscopic surgery for ectopic pregnancy (10 cases), hysteroscopic surgery (55 cases) andso on, which make a total of 316 cases.
[Each number of cases indicates per year base.]
Primary care peri/post-menopausal women is becoming more important. We have already established195

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

References from April 2004 to March
2006(1) Koga K. Osuga Y. Hiroi H. Oishi H. Kugu K.
Yano T. Taketani Y. Images in reproductive medicine. A case of giant cystic adenomyosis. Fertility& Sterility. 85(3):748-9, 2006 Mar.
(2) Harada M. Osuga Y. Takemura Y. Yoshino O.
Koga K. Hirota Y. Hirata T. Morimoto C. Yano T.
Taketani Y. Mechanical stretch upregulates
IGFBP-1 secretion from decidualized endometrial
stromal cells. [Journal Article] American Journalof Physiology - Endocrinology & Metabolism.
290(2):E268-72, 2006 Feb.
(3) Hirota Y. Osuga Y. Hirata T. Harada M. Morimoto
C. Yoshino O. Koga K. Yano T. Tsutsumi O. Taketani Y. Activation of protease-activated receptor
2 stimulates proliferation and interleukin (IL)-6
and IL-8 secretion of endometriotic stromal cells.
Human Reproduction. 20(12):3547-53, 2005 Dec.
(4) Takemura Y. Osuga Y. Harada M. Hirata T. Koga
K. Morimoto C. Hirota Y. Yoshino O. Yano T. Taketani Y. Serum adiponectin concentrations are
decreased in women with endometriosis. Human
Reproduction. 20(12):3510-3, 2005 Dec.
(5) Morimoto C. Osuga Y. Yano T. Takemura Y. Harada M. Hirata T. Hirota Y. Yoshino O. Koga K.
Kugu K. Taketani Y. GnRH II as a possible cytostatic regulator in the development of endometriosis. Human Reproduction. 20(11):3212-8, 2005
Nov.
(6) Koga K. Osuga Y. Harada M. Hirota Y. Yamada H.
Akahane M. Kugu K. Taketani Y. Sciatic endometriosis diagnosed by computerized tomogra-

phy-guided biopsy and CD10 immunohistochemical staining. Fertility & Sterility. 84(5):1508,
2005 Nov.
(7) Takemura Y. Osuga Y. Harada M. Hirata T. Koga
K. Yoshino O. Hirota Y. Morimoto C. Yano T. Taketani Y. Concentration of adiponectin in peritoneal fluid is decreased in women with endometriosis. American Journal of Reproductive Immunology. 54(4):217-21, 2005 Oct.
(8) Hirata T. Osuga Y. Yoshino O. Hirota Y. Harada M.
Takemura Y. Morimoto C. Koga K. Yano T.
Tsutsumi O. Taketani Y. Development of an experimental model of endometriosis using mice thatubiquitously express green fluorescent protein.
Human Reproduction. 20(8):2092-6, 2005 Aug.
(9) Hirota Y. Osuga Y. Hirata T. Yoshino O. Koga K.
Harada M. Morimoto C. Nose E. Yano T. Tsutsumi
O. Taketani Y. Possible involvement of thrombin/protease-activated receptor 1 system in thepathogenesis of endometriosis. Journal of Clinical
Endocrinology & Metabolism. 90(6):3673-9, 2005
Jun.
(10) Koga K. Osuga Y. Yoshino O. Hirota Y. Yano T.
Tsutsumi O. Taketani Y. Elevated interleukin-16
levels in the peritoneal fluid of women with endometriosis may be a mechanism for inflammatory reactions associated with endometriosis. Fertility & Sterility. 83(4):878-82, 2005 Apr.
(11) Hirota Y. Osuga Y. Koga K. Yoshino O. Hirata T.
Harada M. Morimoto C. Yano T. Tsutsumi O. Sakuma S. Muramatsu T. Taketani Y. Possible implication of midkine in the development of endometriosis Human Reproduction. 20(4):1084-9,
2005 Apr.
(12) Hirota Y. Osuga Y. Hirata T. Koga K. Yoshino O.
Harada M. Morimoto C. Nose E. Yano T. Tsutsumi
O. Taketani Y. Evidence for the presence of protease-activated receptor 2 and its possible implication in remodeling of human endometrium. Journal of Clinical Endocrinology & Metabolism.
90(3):1662-9, 2005 Mar.
(13) Harada M. Osuga Y. Hirota Y. Koga K. Morimoto
C. Hirata T. Yoshino O. Tsutsumi O. Yano T. Taketani Y. Mechanical stretch stimulates interleukin-8 production in endometrial stromal cells:
possible implications in endometrium-related
events. Journal of Clinical Endocrinology & Me-

196

tabolism. 90(2):1144-8, 2005 Feb.
(14) Chen Q. Yano T. Matsumi H. Osuga Y. Yano N.
Xu J. Wada O. Koga K. Fujiwara T. Kugu K. Taketani Y. Cross-Talk between Fas/Fas ligand system and nitric oxide in the pathway subserving
granulosa cell apoptosis: a possible regulatory
mechanism for ovarian follicle atresia. Endocrinology. 146(2):808-15, 2005 Feb.
(15) Hirata T. Osuga Y. Hirota Y. Koga K. Yoshino O.
Harada M. Morimoto C. Yano T. Nishii O.
Tsutsumi O. Taketani Y. Evidence for the presenceof toll-like receptor 4 system in the human endometrium. Journal of Clinical Endocrinology &Metabolism. 90(1):548-56, 2005 Jan.
(16) Osuga Y. Hayashi K. Kobayashi Y. Toyokawa S.
Momoeda M. Koga K. Yoshino O. Tsutsumi O.
Hoshiai H. Terakawa N. Taketani Y. Dysmenorrhea in Japanese women. International Journal of
Gynaecology & Obstetrics. 88(1):82-3, 2005 Jan.
(17) Hiroi H. Tsutsumi O. Takeuchi T. Momoeda M.
Ikezuki Y. Okamura A. Yokota H. Taketani Y. Differences in serum bisphenol a concentrations inpremenopausal normal women and women withendometrial hyperplasia. Endocrine Journal. 51(6):595-600, 2004 Dec.
(18) Yoshino O. Osuga Y. Hirota Y. Koga K. Hirata T.
Harada M. Morimoto C. Yano T. Nishii O.
Tsutsumi O. Taketani Y. Possible pathophysiological roles of mitogen-activated protein kinases(MAPKs) in endometriosis. American Journal of
Reproductive Immunology. 52(5):306-11, 2004
Nov.
(19) Harada M. Osuga Y. Hirata T. Hirota Y. Koga K.
Yoshino O. Morimoto C. Fujiwara T. Momoeda M.
Yano T. Tsutsumi O. Taketani Y. Concentration of
osteoprotegerin (OPG) in peritoneal fluid is increased in women with endometriosis. Human
Reproduction. 19(10):2188-91, 2004 Oct.
(20) Kuramochi K. Osuga Y. Yano T. Momoeda M.
Fujiwara T. Tsutsumi O. Tamai H. Hanaoka K.
Koga K. Yoshino O. Taketani Y. Usefulness of
epidural anesthesia in gynecologic laparoscopic
surgery for infertility in comparison to general anesthesia. Surgical Endoscopy. 18(5):847-51, 2004(22) Koga K. Osuga Y. Yano T. Ikezuki Y. Yoshino O.
Hirota Y. Hirata T. Horie S. Ayabe T. Tsutsumi O.
Taketani Y. Evidence for the presence of angio-

genin in human testis. Journal of Andrology.
25(3):369-74, 2004 May-Jun.

197

Department of
Gynecologic Oncology
Associate

Professor

Tetsu Yano

Lecturer
Toshiharu Yasugi

Homepage
Organization
The Department of Gynecologic Oncology is organized by one associate professor and one lecturer, being
directed practically by Professor Yuji Taketani, theChairman of the Department of Obstetrics and Gynecology. The staff members are taking part in both clinical and research activities, as well as teaching activities,
with 18 associates of the University of Tokyo Hospital.
For the clinical aspect, they are engaged with in-patientand out-patient care.

Activities(1) Oncology research
In our division, the pathogenesis of uterine cervicalcancer has been investigated these two decades. To
identify the risk factors for cervical intraepithelial neoplasia (CIN), we reanalysed the data from our previous
case-control study by adjusting for human papillomavirus (HPV) antibodies. Unlike our previous study
based only on HPV DNA, smoking and Chlamydia
trachomatis infection were revealed as significant risk
factors for CIN after adjustment for HPV antibodies.
The enhanced oncogenicity of particular human papillomavirus type 16 (HPV16) E6 variants is population-dependent, implying the involvement of additional
genetic cofactors. This study was designed to investigate the association between E6 variants and humanleukocyte antigen (HLA) polymorphism within a Japa-

nese population. Fifty-seven women with HPV16positive cervical cancer were analyzed for E6 sequencevariation and its relationship to HLA class II alleles.
Compared with local controls (n = 138) and publishedcontrols (n = 916), DRB1*1501 and DQB1*0602 frequencies were significantly increased among patientswith HPV16 E6 prototype (n = 11). Additionally,
DRB1*1502 was positively associated with a particular
E6 variant designated D25E (n = 25), although we
could not find a significant association between HLAclass II alleles and L83V variants (n = 16). Our observations suggest that a specific match between E6 variant proteins and HLA types may contribute to HPV16related cervical carcinogenesis.
Studies of virus neutralization by antibody are prerequisite for development of a prophylactic vaccine
strategy against HPVs. To determine whether neutralizing antibodies (NAs) against HPV16 is responsible
for a higher regression rate of low-grade cervical intraepithelial neoplasia (CIN1), we investigated an association between the presence of the NAs and the fate of the
HPV16-related CIN1. The incidence of the presence of
the NAs in the women with a non-pathological cervix(85.7%) was significantly higher than in the CIN1 cases(21.5%), the CIN2/3 cases (15.7%), and the cervicalcancer cases (0%) (p<0.0001). The regression of the
CIN1 lesion was closely associated with the presence of
the N As (p=0.0002). The presence of the NAs was associated with low-level copy number of the viral DNA
relative to the NA-negative group (p=0.05). The pres-198

ence of the NAs against HPV16 was associated with ahigher regression rate of HPV-related CIN1 lesions.
The NAs seem to have a role in deterring HPV-related
cervical lesions from progressing to CIN2/3 by inhibiting the infection with de novo replicated HPV. Then we
designed a 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 andsystemic 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 showed neutralizing activities against HPV16 and 52. Serologicalresponses to the peptides were not found in the 0.1mggroup and the placebo group recipients. This study
suggests the L2-108/120 peptide is tolerable in humans
and has the potential as a broad-spectrum prophylactic
vaccine against genital HPV.
We also investigated interacting proteins with the
HPV E6 protein. Recently, a LAP protein, scribble, wasidentified 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 ubiquitin-mediated degradation by human papillomavirus
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 andhuman uterine cervical epithelial tissues by immunofluorescence. Human scribble colocalised rather
with the adherens junction protein E-cadherin, but notwith the tight junction protein ZO-1. Histochemical
analysis showed a dramatic decrease in the expressionof hScrib with the progression of disease from normal
uterine cervical tissues to invasive cervical cancers
through the precursor lesions. In contrast, the expression of hScrib was retained in the throughout epithelial
layer of the HPV-negative cervical high-grade
squamous intraepithelial lesions (H-SIL). Althoughquantitative RT-PCR revealed no significant 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 from low-grade squamous intraepithelial lesions to H-SIL, and a cooperative role of downregulation of hScrib mRNA expression and ubiquitin- mediated degradation of hScrib by E6 and E6AP led to thecomplete decrease of hScrib expression during theprocess of carcinogenesis from H-SIL to invasive cancer. These data underscore the importance of hScrib in
the construction of tissue architecture and prevention ofcancer development.
Another basic research is focused on analysis of tumor suppressor genes in gynecological malignancies asfollowing.
1 Human Scribble
Recently, a LAP protein, scribble, was identified in
Drosophila epithelia as a basolateral protein that controls the apical-basolateral polarity. Loss of scribble
causes disorganisation and overgrowth of the epithelia.
Scribble has a human homologue, human scribble(hScrib), which is a substrate of ubiquitin-mediateddegradation by human papillomavirus 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. Humanscribble 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 thethroughout epithelial layer of the HPV-negative cervical high-grade squamous intraepithelial lesions (H-SIL).
Although quantitative RT-PCR revealed no significant
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 forthe progressive decrease of hScrib expression during
the disease progression from low-grade squamous intraepithelial lesions to H-SIL, and a cooperative role of

199

downregulation of hScrib mRNA expression and ubiquitin-mediated degradation of hScrib by E6 and E6AP
led to the complete decrease of hScrib expression during the process of carcinogenesis from H-SIL to invasive cancer. These data underscore the importance of
hScrib in the construction of tissue architecture andprevention of cancer development.
Drosophila discs large (Dlg) is one of neoplastic tumor suppressors, which genetically links to scribble. E6
also targets human Dlg (hDlg) for ubiquitin-mediateddegradation. Ubiquitin-protein ligase involved in thisprocess has not been identified thus far. Here we investigated mechanism 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 in ubiquitin-mediated degradation of 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 theirability to interact with E6AP. Furthermore, hDlg wastargeted for in vitro ubiquitination in the presence ofboth E6 and E6AP. These data revealed that E6AP isextensively involved in the ubiquitin-mediated degradation 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 and C-terminal PDZ
domain-binding motif of E6 protein. Interaction between human Discs Large (hDlg), which is a substrateof E6 for the ubiquitin-mediated degradation, and adenomatous polyposis coli (APC) has been shown. Here,
we investigated whether hScrib and APC interact witheach 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 motifof APC. Human Scribble co-localized with APC at thesynaptic sites of hippocampal neuron and at the tip ofmembrane 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 andneural function by associating with APC.
2 PTEN
Although the mutation of PTEN, a tumor suppressor,
is known to be involved in tumorigenesis of endometrioid adenocarcinomas of the endometrium andovary, the role of PTEN alteration in endometrioid
adenocarcinoma of the cervix remains to be investigated. To elucidate the molecular pathogenesis of cervical adenocarcinoma and adenosquamous carcinoma,
and in particular to examine the potential role of PTEN
mutation in endometrioid-type cancer of the 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 were shown 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 HPV-negative
adenocarcinomas of the cervix and the most prevalentoccurrence of PTEN mutation in endometrioid subtype
is keeping with endometrial and ovarian carcinomas.
Next, we analyzed involvement of PTEN in treatment of endometrial cancer. Young patients with complex atypical hyperplasia (CAH) or stage Ia, G1 adenocarcinoma (IaG1) of the endometrium, who desire topreserve fertility, can select the conservative therapy byoral progestin, medroxyprogesterone acetate (MPA).
However, conservative treatments involve potential
risks of progression and recurrence. In an attempt tofind out molecular markers for sensitivity 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200(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 be significantly associatedwith receiving hysterectomy (p=0.04), while each factor showed a trend without statistical significance(p=0.07 and 0.2, respectively). Strong expression ofboth ER and PgR significantly correlated with successful pregnancy after infertility treatment following complete response to MPA (p=0.02). Our observations invivo suggest that anti-tumor action of MPA may be
mediated by dephosphorylation 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 is inactivatedby promoter methylation in human colon cancers. Here,
we analyzed promoter methylation of the SFRP1 genein human ovarian cancers, in which loss of heterozygosity in 8p is frequently observed and involvement of
the Wnt signaling pathway has been suggested. Methylation-specific PCR (MSP) analysis showed that four of
13 ovarian cancer cell lines and two of 17 primaryovarian cancers had methylated SFRP1, while an immortalized ovarian epithelial cell line, HOSE, andseven ovarian endometrial cyst samples did not. In thefour 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 as colon cancers.
4 hMSH2
The DNA mismatch repair gene is a key regulator in
the elimination of base-base mismatches and insertion/deletion loops (IDLs). Human MutS homologue 2(hMSH2), originally identified as a human homologueof the bacterial MutS, is a tumour suppressor gene frequently mutated in hereditary non-polyposis colorectal
cancer. Hereditary non-polyposis colorectal cancer ischaracterised by the early onset of colorectal cancer andthe development of extracolonic cancers such as endo-

metrial, ovarian, and urological cancers. Oestrogen receptor (ER) alpha and beta are members of a nuclear
receptor (NR) superfamily. Ligand-dependent transcription of ER is regulated by the p160 steroid receptor
coactivator family, the thyroid hormone receptor- associated proteins/the vitamin D receptor-interacting proteins (TRAP/DRIP) mediator complex, and the TATA
box-binding protein (TBP)-free TBP associated factor
complex (TFTC) type histone acetyltransferase complex. We identified the interaction between ER alpha/beta and hMSH2. Immunoprecipitation and glutathione-S-transferase pull-down assay revealed that ER
alpha and hMSH2 interacted in a ligand-dependent
manner, whereas ER beta and hMSH2 interacted in aligand-independent manner. Oestrogen receptor alpha/beta bound to hMSH2 through the hMSH3/hMSH6
interaction domain of hMSH2. In a transient expression
assay, hMSH2 potentiated the transactivation functionof liganded ER alpha, but not that 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 carcinoma of
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 or without
external RT from June 1991 to May 2004. The medianfollow-up time was 43.5 months (range, 1.0-130.0
months). The median age was 53 years (range, 25-81
years). There were 13 patients (9%) in stage 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 withpelvic 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 withstage I received ICBT-alone without external beam irradiation. RESULTS: The 5-year cause-specific survival (CSS) rates for surgery and RT were 79.9% and82.3%, respectively; the difference between these twotreatments was not statistically significant (P = 0.8524).
The differences in the survival rates between the two201

treatments for each of the stage I or stage II patientswere also not statistically significant (P = 0.8407 forstage I and P = 0.6418 for stage II). This retrospective
study suggests that RT results in compatible survivalwith conventional surgery for patients with stage I-II
cervical carcinoma.

References from April 2004 to
March 2006
1) Minaguchi T. Yoshikawa H. Nakagawa S. Yasugi T.
Yano T. Iwase H. Mizutani K. Shiromizu K. Ohmi
K. Watanabe Y. Noda K. Nishiu M. Nakamura Y.
Taketani Y. Association of PTEN mutation with
HPV-negative adenocarcinoma of the uterine cervix.
Cancer Letters. 210(1):57-62, 2004 Jul 8.
2) Kawana K. Nakayama M. Yasugi T. Ishiwata M.
Marumo G. Sakai M. Takeshima T. Kozuma S.
Tsutsumi O. Taketani Y. Differential clinical manifestations of congenital cytomegalovirus infection
between dizygotic twins: a case report. American
Journal of Perinatology. 21(7):383-6, 2004 Oct.
3) Onda T. Yoshikawa H. Yasugi T. Yamada M. Matsumoto K. Taketani Y. Secondary cytoreductive
surgery for recurrent epithelial ovarian carcinoma:
proposal for patients selection. British Journal ofCancer. 92(6):1026-32, 2005 Mar 28.
4) Wada-Hiraike O. Yano T. Nei T. Matsumoto Y.
Nagasaka K. Takizawa S. Oishi H. Arimoto T. Nakagawa S. Yasugi T. Kato S. Taketani Y. The DNA
mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor alpha. British Journal ofCancer. 92(12):2286-91, 2005 Jun 20.
5) Oda K. Stokoe D. Taketani Y. McCormick F. Highfrequency of coexistent mutations of PIK3CA andPTEN genes in endometrial carcinoma. Cancer
Research. 65(23):10669-73, 2005 Dec 1
6) Matsumoto K. Yasugi T. Oki A. Fujii T. Nagata C.
Sekiya S. Hoshiai H. Taketani Y. Kanda T. Kawana
T. Yoshikawa H. IgG antibodies to HPV16, 52, 58
and 6 L1-capsids and spontaneous regression of
cervical intraepithelial neoplasia. Cancer Letters.
231(2):309-13, 2006 Jan 18.

202

Department of Perinatal Medicine
Associate Professor
Shiro Kozuma

Tomoyuki Fujii

Lecturer
Yoshimasa Kamei

Homepage
Organization
The Department of Perinatal Medicine is organizedby two associate professors and one lecturer, being directed practically by Professor Yuji Taketani, thechairman of the Department of Obstetrics and Gynecology. All the staff members are taking part in both theclinical and research activities, as well as the teachingactivities, with 15 associates of the University of Tokyo
Hospital. For the clinical aspect, they are engaged within-patient and out-patient care including the activities inthe delivery units.

Activities
The clinical service for perinatology in the University of Tokyo Hospital consists of out-patient clinic andthe Delivery Unit. [See Delivery Unit of the Universityof Tokyo Hospital]
By the advance of the techniques for prenatal diagnosis of fetal growth and congenital malformations, thearea of fetal medicine is enlarging. Strict measurementof fetal growth during pregnancy has made the accurate
diagnosis of intrauterine growth retardation possible.
New techniques like fetal blood sampling and threedimensional ultrasonography have been introduced into
clinical service. The subjects of studies were focused on“fetus” and “ultrasound” in perinatology and medical
engineering research group. Fetal behavior, particularly
breathing movements and sleep-wakefulness cycle werestudied with ultrasound in human fetuses. Studies weredone 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 spontaneous abortions in the first trimester. Our “RSA clinic” opens oncea week. About 120 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 isadministered. Heparin injection is performed for thehigh risk group, for instance, patients with successive
intrauterine fetal death during the second or third trimester of pregnancy, or those with beta-2 glycoprotein I
dependent anticardiolipin antibody. Further to RSA patients with unknown etiology, the immunotherapy withher husband’s lymphocyte inoculation is indicated. The
inoculation is usually performed four to six times inevery two or three weeks. In our clinic, after the immunotherapy, their pregnancy outcomes have extremely
improved in these 10 years. Now the successful reproductive rate has achieved over 80%.

References from April 2004 to
March 2006
(1) Fujii T. Kozuma S. Kikuchi A. Hanada N. Sakamaki K. Yasugi T. Yamada M. Taketani Y.
Parovarian cystadenoma: sonographic features associated with magnetic resonance and histopa-

203

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

thologic findings. Journal of Clinical Ultrasound.
32(3):149-53, 2004
Kawana K. Nakayama M. Yasugi T. Ishiwata M.
Marumo G. Sakai M. Takeshima T. Kozuma S.
Tsutsumi O. Taketani Y. Differential clinical manifestations of congenital cytomegalovirus infection
between dizygotic twins: a case report. American
Journal of Perinatology. 21(7):383-6, 2004
Kikuchi A. Kozuma S. Yasugi T. Taketani Y. Fractal analysis of surface growth patterns in endometrioid endometrial adenocarcinoma. Gynecologic & Obstetric Investigation. 58(2):61-7, 2004.
Miki A. Fujii T. Yoshikawa H. Hyodo H. Kanai T.
Yamashita T. Yasugi T. Kozuma S. Taketani Y. A
novel method of preoperative autologous blood
donation with a large volume of plasma for surgery
in gynecologic malignancies. Transfusion &Apheresis Science. 31(1):21-8, 2004
Nagamatsu T. Fujii T. Yamashita T. Miki A. Kanai
T. Kusumi M. Osuga Y. Kozuma S. Taketani Y.
Hypoxia does not reduce HLA-G expression on
extravillous cytotrophoblasts. Journal of Reproductive Immunology. 63(2):85-95, 2004
Nagamatsu T. Fujii T. Kusumi M. Zou L. Yamashita T. Osuga Y. Momoeda M. Kozuma S. Taketani Y. Cytotrophoblasts up-regulate soluble
fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental
vascular development and the pathophysiology ofpreeclampsia. Endocrinology. 145(11):4838-45,
2004
Takada T. Nakagawa S. Hashimoto K. Sone K.
Kugu K. Kozuma S. Taketani Y. Preoperative diagnosis of colouterine fistula secondary to diverticulitis by sonohysterography with contrast medium. Ultrasound in Obstetrics & Gynecology.
24(6):682-3, 2004
Kanamori Y. Hashizume K. Sugiyama M. Tomonaga T. Goishi K. Yokoyama Y. Igarashi T. Kikuchi A. Kawana Y. Kozuma S. Taketani Y. A caseof intrapericardial diaphragmatic hernia with amassive pericardial effusion: fetal diagnosis andtherapy. Journal of Pediatric Surgery. 40(11):e43-5,
2005
Matsubara K. Nagamatsu T. Fujii T. Kozuma S.
Taketani Y. Lymphokine-activated killer cells induced from decidual lymphocytes reduce the an-giogenic activity of trophoblasts by enhancing therelease of soluble fms-like tyrosine kinase-1 fromtrophoblasts: an implication for the pathophysiology of preeclampsia. Journal of Reproductive Immunology. 68(1-2):27-37, 2005(10) Kikuchi A. Unno N. Horikoshi T. Shimizu T. Kozuma S. Taketani Y. Changes in fractal features offetal heart rate during pregnancy. Early Human
Development. 81(8):655-61, 2005(11)Hayashi A. Kikuchi A. Matsumoto Y. Tatematsu M.
Horikoshi T. Ogiso Y. Unno N. Massive cystic
lymphangiomas of a fetus. Congenital Anomalies.
45(4):154-6, 2005(12) Hayashi A. Kikuchi A. Joshita N. Matsumoto Y.
Tatematsu M. Horikoshi T. Ogiso Y. Unno N.
Monochorionic triplet pregnancy complicated bysevere fetofetal transfusion. Journal of Obstetrics& Gynaecology Research. 31(5):414-20, 2005(13) Horikoshi T. Kikuchi A. Matsumoto Y. Tatematsu
M. Takae K. Ogiso Y. Nakayama M. Unno N. Fetalhydrops associated with congenital pulmonary
myofibroblastic tumor. Journal of Obstetrics &Gynaecology Research. 31(6):552-5, 2005
(14) Horikoshi T. Kikuchi A. Tatematsu M. Matsumoto
Y. Hayashi A. Unno N. Two cases of a fetus withsirenomelia sequence. Congenital Anomalies.
45(3):93-5, 2005(15) Yoshida S. Furue M. Nagamine K. Abe T. Fukui Y.
Myoishi Y. Fujii T. Okamoto T. Taketani Y. Asashima M. Modulation of activin A-induced differentiation in vitro by vascular endothelial growth
factor in Xenopus presumptive ectodermal cells. In
Vitro Cellular & Developmental Biology. Animal.
41(3-4):104-10, 2005(16) Yoshida S. Kikuchi A. Naito S. Nakamura H. Hayashi A. Noguchi M. Kondo Y. Nakamura T. Gianthemangioma of the fetal neck, mimicking a teratoma. Journal of Obstetrics & Gynaecology Research. 32(1):47-54, 2006 Feb.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

⑳

206

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

Associate Professor
Masashi Mizuguchi, M.D., Ph.D.
Takashi Sekine, M.D., Ph.D.

Lecturer
Hiroshi Watanabe, M.D., Ph.D.
Hitoshi Kato, M.D., Ph.D.
Masaru Takamizawa, M.D., Ph.D.
Junko Takita, M.D., Ph.D. (Department of Cell Therapy and Transplantation Medicine)

Associate
Kazuhiko Shibuya, M.D., Ph.D.,
Hiroko Sugimura, M.D.,
Jun Inatomi, M.D., Ph.D.,
Hirotsugu Kano, M.D., Ph.D.,
Ken Satoh, M.D.,
Hiroki Yasudo, M.D., Ph.D.
(As of Dec. 1, 2005)

Komei Ida, M.D.,
Yoshitaka Yokoyama, M.D.,
Katsuyoshi Ko, M.D.,
Keiji Goishi, M.D.,
Hiroshi Ono, M.D.,
Fumie Kimura, M.D.,
Masakazu Mimaki, M.D., Ph.D.,
Shinya Tsuchida, M.D.,
Kan Takahashi, M.D.,

Homepage http://square.umin.ac.jp/ped/
Introduction and Organization
The former Department of Pediatrics developed into
Department of Pediatrics and Department of Developmental Pediatrics, which comprise subgroups of theGroup of Reproductive, Developmental and Aging
Medicines, Graduate School of Medicine, The University of Tokyo.
Our staff consist of 1 professor, 2 associate professors, 5 lecturers, 15 associates, 6 residents, 1 clinicalfellow, 1 research fellow, 12 graduate students and 1
foreign pediatrician as of Dec 1, 2005.
The outpatient clinic of our department is located on

the second floor of the outpatient clinic building. The
inpatient ward and conference rooms are located on thesecond 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 the second,
third and fourth floors of the Research Building of Internal Medicine and on the second and third floors of
the East Research Building.

Clinical activities
We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In the207pediatric and pediatric surgery ward, there are 96 beds
including 9 beds in the neonatal intensive care unit
(NICU), 6 beds in the growth care unit (GCU) and 26
beds in the high care unit (HCU). In NICU we are taking care of small premature babies weighing 400g to
3,000g with or without various complications. A varietyof patients with diseases such as hematological/oncological disorders (acute leukemia, neuroblastoma, Ewing sarcoma, osteosarcoma, brain tumors, etc.),
cardiac disorders (congenital heart diseases and Kawasaki disease), neuromuscular disorders, metabolic disorders, immunological/allergic disorders (common
variable immunodeficiency, chronic granulomatous
disease, bronchial asthma, etc.), renal and urinary tract
diseases (nephrotic syndrome, chronic glomeluronephritis, purpura nephritis and renal and urinary
tract anomalies), endocrinological disorders and psychosomatic diseases are admitted in the wards. So far
70 patients received hematopoietic stem cell transplantation. There are patients with severe combined immunodeficiency, aplastic anemia-myelodysplastic syndrome, acute lymphocytic leukemia with high-risk features, acute myelogenous leukemia, non-Hodgkin lymphomas, disseminated neuroblastoma and brain tumors.
We have a clinical conference and a grand round in
the Tuesday afternoon. Jeffrey C. Fahl, M.D., Professorof Pediatrics, Division of Pediatric Gastroenterology
and Nutrition attended this conference and gave several
lectures from January to April, 2006. He also opened
special education course for junior doctors in very Friday evening during that time. In the Thursday evening,
we have a special clinical conference. We also join in
conferences several times a month with cardiac surgeons, obstetricians, pediatric surgeons and pediatric
psychologists. In addition, each subspecialty group has
its own meeting and clinical round.
Many patients with significant disorders stay long in
the hospital. We provide an official in-hospital
school ”Kodama Gakkyu” where patients receive education and have chances to communicate with eachother and their parents in the hospital. “Niko-niko Volunteer” members, an official volunteer group in thehospital, visit the pediatric ward every weekday to playwith the patients and help their mothers. It is a great
pleasure for both the patients and their mothers. We
also provide various activities for the patients in thehospital such as the Tanabata festival, a Christmas party

and music concerts. All the residents, fellows andnurses participate in these activities. We had two childcare specialists in the pediatric ward in April, 2006.
(As of Dec 1, 2005)

Teaching activities
The staff members and the visiting lecturers give lectures of general pediatrics and pediatric diagnosis for
36 hours to the second year students, and clinical bedside learning in the inpatient ward for 2 weeks to thethird year students. During bedside learning for 2 weeks,
specialized teaching sessions, like seminars are held
every day. In the outpatient learning, medical students
take histories and perform physical examinations ofpatients under the supervision of the teaching staff. On
the second and third days of the outpatient clinic, each
student visits the local pediatricians or local hospitals inand around Tokyo. On the last day of clinical learning,
the Professor and an Associate Professor evaluate thestudents’ achievements. We have an elective clinicalclerkship course for the third year students.

Research activities
Our departments have the following research groups
as cardiology, hematology/oncology, neurology, endocrinology, immunology, nephrology, hepatology andinternational medical cooperation. We also have multidisciplinary research groups and laboratories such ascell biology, genetic molecular biology and epidemiology. The main subjects of research during the last few
years are listed as follows: molecular and epidemiological analysis of cancer disposition, molecular analysisof hereditary renal diseases, primary immunodeficiency,
neuromuscular diseases and certain syndromes with andwithout congenial cardiac defects, hemodynamics of
pulmonary circulation, and electrophysiological studies
of epidemic disorders. The Kanto district registration
center for children’s cancer is located in our Department.

References
1. Basnet NB, Kato H, Nakamura Y, Watanabe H,
Igarashi T: Newspaper reporting on child raising inJapan. J Pediatr Nursing 19: 113-120, 2004

208

2. Basnet NB, Noma S, Basnet SB, Igarashi T: Neonatal intensive care unit hospitalization of very low
birth weight Japanese infants with congenital heartdisease. J Nepal Med Asso 43: 28-30, 2004
3. Emura T, Kanamori Y, Ito M, Tanaka Y, Hashizume
K, Marumo G, Goishi K: Omphalocele associatedwith a large multilobular umbilical cord pseudocyst.
Pediatr Surg Int 20:636-9, 2004
4. Hirose H, Kubota M, Kimura I, Yumoto M, Sakakihara Y: N100m in adults possessing absolute
pitch. Neuroreport 15:1383-1386, 2004
5. Inatomi J, Horita S, Braverman N, Sekine T, Yamada H, Suzuki Y, Kawahara K, Moriyama N,
Kudo A, Kawakami H, Shimadzu M, Endou H, Fujita T, Seki G, Igarashi T: Mutational and functional
analysis of SLC4A4 in a patient with proximal renal
tubular acidosis. Pfluger Arch – Eur J Physiol 448:
438-444, 2004
6. Jouret F, Igarashi T, Gafflot F, Wilson PD, karet FE,
Thakker R, Devuyst O: Comparative ontogeny,
processing, and segmental distribution of the renal
chloride channel, ClC-5. Kidney Int 65: 198-208,
2004
7. Kanamori Y, Kitano Y, Hashizume K, Sugiyama M,
Tomonaga T, Takayasu H, Egami S, Goishi K,
Shibuya K, Kawana Y, Marumo G, Kikuchi A, Kozuma S, Taketani Y, Sekiyama Y: A case of laryngeal atresia (congenital high airway obstruction
syndrome) with chromosome 5p deletion syndrome
rescued by ex utero intrapartum treatment. J Pediatr
Surg 39:E25-8, 2004
8. Kimura I, Kubota M, Hirose H, Yumoto M, Sakakihara Y: Children are sensitive to averted eyes atthe earliest stage of gaze processing. Neuroreport
15:1345-1348, 2004
9. Kubota M, Sakakihara Y, Mori M, Yamagata T,
Momoi-Yoshida M: Beneficial effect of L-arginine
for stroke-like episode in MELAS. Brain Dev
26:484-486, 2004
10. Kubota M, Ozawa H, Kaneko K, Sakakihara Y: An
MEG study of astatic seizure in myoclonic astatic
epilepsy. Ped Neurol 31:207-210, 2004
11. Kubota M, Takeshita K, Saitoh M, Hirose H, Kimura I, SakakiharaY: Magnetoencephalographic
analysis of rolandic discharges in a patient with rolandic epilepsy associated with oromotor deficits. J
Child Neurol 19:456-459, 2004

12. Kubota M, Tran TD, Hirose H, Kimura I, Sakakihara Y. Patients with benign rolandic epilepsy havea longer duration of somatosensory evoked highfrequency oscillations. Pediatr Int 46:631-634,
2004
13. Kano H, Ito Y, Matsuoka K, Nakajima T, Iwata T,
Kohsaka T, Saito H, and Abe J: Critical role of T
cell migration in bacterial superantigen-mediatedshock in mice. Clinical Immunology 110:159-171,
2004
14. Kawaguchi H, Taketani T, Hongo T, Park MJ, Koh
K, Ida K, Kobayashi M, Takita J, Taki T, Yoshino H,
Bessho F, Hayashi Y. In vitro drug resistance toimatinib and mutation of ABL gene in childhood
Ph+ acute lymphoblastic leukemia. Leuk Lymphoma 46:273-276, 2004
15. Kitanaka S, Miki Y, Hayashi Y, Igarashi T: Promotor-specific repression of hepatocyte nuclear factor(HNF)-β and HNF-1α transcriptional activity
by an HNF-β missense mutant associated with
type 5 maturity-onset diabetes of the young with
hepatic and biliary manifestations. J Clin End Metab 89: 1369-1378, 2004
16. Komoda F, Sekine T, Inatomi J, Enomoto A, Endou
H, Ota T, Matsuyama T, Ogata T, Ikeda M, Awadzu
M, Muroya K, Kamimaki I, Igarashi T: The
W258X mutatio in SLC22A is the predominantcause of Japanese renal hypouricemia. Pediatr
Nephrol 19:728-733, 2004
17. Kosaka Y, Koh K, Kinukawa N, Wakazono Y,
Isoyama K, Oda T, Hayashi Y, Ohta S, Moritake H,
Oda M, Nagatoshi Y, Kigasawa H, Ishida Y, Ohara
A, Hanada R, Sako M, Sato T, Mizutani S, Horibe
K, Ishii E: Infant acute lymphoblastic leukemiawith MLL gene rearrangements: outcome following
intensive chemotherapy and hematopoietic stem
cell transplantation. Blood 104: 3527-3534, 2004
18. Matsuyama T, Awazu M, Oikawa T, Inatomi J, Sekine T, Igarashi T: Molecular and clinical studies ofDent’s disease in Japan: biochemical examination
and renal ultrasonography do not predict carrierstate. Clin Nephrol 61: 231-237, 2004
19. Mizuguchi M, Mori M, Nozaki Y, Momoi MY, Itoh
M, Takashima S, Hino O: Absence of allelic loss incytomegalic neurons of cortical tuber in the Eker
rat model of tuberous sclerosis. Acta Neuropathol(Berl) 107:47-52, 2004

209

20. Nagura M, Saito M, Iwamori M, Igarashi T: Alterations of fatty acid metabolism and membrane fluidity in peroxisome-defective mutant ZP102 cells.
Lipids 39:43-50, 2004
21. Ohta T, Sakano T, Igarashi T, Itami N, Ogawa T:
Exercise-induced acute renal failure associatedwith renal hypouricemia: results of a questionnaire-based survey in Japan. Nephrol Dial Transplant 19: 1447-1453, 2004
22. Saito Y, Yamamoto T, Ohtsuka-Tsurumi E, Oka A,
Mizuguchi M, Itoh M, Voit T, Kato Y, Kobayashi
M, Saito K, Osawa M: Fukutin expression in
non-muscle somatic organs: distribution pattern inmouse and its relationship to the hypoglycosylationof α-dystroglycan in Fukuyama-type congenital
muscular dystrophy. Brain Dev 26:469-479, 2004
23. Sato K, Sato U, Tateishi S, Kubo K, Horikawa R,
Mimura T, Yamamoto K, Kanda H: AIRE downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressivefunctions. Biochem Biophys Res Commun 318:
935-40, 2004
24. Sato U, Horikawa R, Katsumata N, Asakura Y, Kitanaka S, Tanaka T: Novel compound heterozygous
AIRE mutations in a Japanese patient with APECED.
J Pediatr Endocrinol Metab 17:917-21, 2004
25. Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E,
Hanada R, Tsuchida M, Sugita K, Ida K, Hayashi
Y: FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant
acute lymphoblastic leukemia (ALL) with MLL rearrangement and pediatric ALL with hyperdiploidy.
Blood 103: 1085-1088, 2004
26. Takita J, Ishii M, Tsutsumi S, Tanaka Y, Kato K,
Toyoda Y, Hanada R, Yamamoto K, Hayashi Y,
Aburatani H: Gene expression profiling and identification of novel prognostic marker genes in neuroblastoma. Genes Chromosomes Cancer 40:120-132,
2004
2005
1. Anzai N, Jutabha P, Enomoto A, Yokoyama H,
Nonoguchi H, Hirata T, Shiraya K, He X, Cha
SH, Takeda M, Miyazaki H, Sakata T, Tomita
K, Igarashi T, Kanai Y, Endou H: Functional
characterization of rat organic anion transporter
5 (SLC22A19) at the apical membrane of renal
proximal tubules. J Pharmacol Exp Ther 315: 534-

544, 2005
2. Araya K, Fukumoto S, Backenroth R, Takeuchi Y,
Kanayama K, Ito N, Yoshii N, Yamazaki Y, Yamashita T, Silver J, Igarashi T, Fujita T: A novel mutation in fibroblast growth factor (FGF) 23 gene as acause of tumor calcinosis. J Clin Endocrinol Metab
90: 5523- 5527, 2005
3. Bassermann F, von Klitzing C, Munch S, Bai RY,
Kawaguchi H, Morris SW, Peschel C, Duyster J:
NIPA defines an SCF-type mammalian E3 ligasethat regulates mitotic entry. Cell. 15: 45-57, 2005
4. Chen YY, Takita J, Tanaka K, Ida K, Koh K,
Igarashi T, Hanada R, Kikuchi A,Tanaka Y, Toyoda
Y, Hayashi Y: Aberrations of the CHK2 gene arerare in pediatric solid tumors. Int J Mol Med 16:
85-91, 2005
5. Chen YY, Takita J, Hiwatari M, Igarashi T, Hanada
R, Kikuchi A, Hongo T, Taki T, Ogasawara M,
Shimada A, Hayashi Y: Mutations of the PTPN11
and RAS Genes in Rhabdomyosarcoma and Pediatric Hematological Malignancies. Genes Chromosomes Cancer.（in press）
6. Cheong HI, Kang JH, Lee JH, Ha IS, Kim S, Komoda F, Sekine T, Igarashi T, Choi Y: Mutational
analysis of idiopathic renal hypouricemia in Korea.
Pediatr Nephrol 20:886-890, 2005
7. Emura T, Kanamori Y, Ito M, Tanaka Y, Hashizume K, Marumo G, Goishi K: Omphalocele associated with a large multilobular umbilical cord
pseudocyst. Pediatr Surg Int 20:636-9, 2004
8. Harita Y, Miyauchi N, Karasawa T, Suzuki K, Han
GD, Koike H, Igarashi T, Shimizu F, Kawachi H:
Altered expression of junctional adhesion molecule
4 (JAM4) in injured podocytes. Am J Physiol Renal
Physiol 290：F335-F344，2005
9. Horita S, Yamada H, Inatomi J, Moriyama N, Sekine T, Igarashi T, Endo Y, Dasouki M, Ekim M,
Al-Gazali L, Shimada M, Seki G, Fujita T: Functional analysis of NBC1 mutants associated withproximal tubular acidosis and ocular abnormalities.
J Am Soc Nephrol 16:2270-2278, 2005
10. Inatomi J, Miyazaki O, Fujimaru R, Iijima K:
Renovascular hypertension complicated with VATER
association. Pediatr Nephrol 20:1174-1176, 2005.
11. Kanamori Y, Kitano Y, Hashizume K, Sugiyama M,
Tomonaga T, Takayasu H, Egami S, Goishi K,
Shibuya K, Kawana Y, Marumo G, Kikuchi A, Ko-

210zuma S, Taketani Y, Sekiyama Y.: A case of laryngeal atresia (congenital high airway obstruction
syndrome) with chromosome 5p deletion syndrome
rescued by ex utero intrapartum treatment. J Pediatr
Surg 39:E25-8, 2004
12. Kanamori Y, Hashizume K, Sugiyama M, Motoi T,
Fukuyama M, Ida K, Igarashi T: Intrapulmonary
solitary fibrous tumor in an eight-year-old male.
Pediatr Pulmonol 40:261-264, 2005
13. Kanamori Y, Hashizume K, Sugiyama M, Tomonaga T, Goishi K, Yokoyama Y, Igarashi T, Kikuchi A, Kawana Y, Kozuma S, Taketani Y: A caseof intrapericardial diaphragmatic hernia with amassive pericardial effusion: fetal diagnosis andtherapy. J Pediatr Surg 40: e43-45, 2005
14. Kawaguchi H, Hitzler JK, Ma Z, Morris SW.
RBM15 and MKL1 mutational screening in megakaryoblastic leukemia cell lines and clinical samples. Leukemia. 19:1492-1494, 2005
15. Kawaguchi H, Taketani T, Hongo T, Park MJ, Koh
K, Ida K, Kobayashi M, Takita J, Taki T, Yoshino H,
Bessho F, Hayashi Y: In vitro drug resistance toimatinib and mutation of ABL gene in childhood
Ph+ acute lymphoblastic leukemia. Leukemia andLymphoma 46 :273-276, 2005
16. Kimura Y, Sugimura H, Toda M, Nakamura Y,
Shibuya K, Murakami A, Wakita S, Yanagawa Y,
Kato H: A case of a 2-year-old boy with tuberous
sclerosis complicated with descending aortic aneurysm. Pediatr Inter 47:224-226, 2005
17. Kornecki A, Tsuchida S, Ondiveeran HK, Engelberts D, Frndova H, Tanswell AK, Post M, Mckerlie C, Belik J, Fox-Robichaud A, and Kavanagh
BP: Lung development and susceptibility to ventilator-induced lung injury – American Journal of
Respiratory and Critical Care Medicine 171: 743752, 2005
18. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita
J, Nakazaki K, Kurokawa M,Hayashi Y, Ogawa S,
Chiba S: Mutations of the Notch1 gene in T-cell
acute lymphoblastic leukemia: analysis in adults
and children. Leukemia 19: 1841-1843, 2005
19. Nagao Y, Mazaki-Miyazaki E, Okamura N, Takagi
M, Igarashi T: A family of generalized epilepsy
with febrile seizures plus type 2-a new missense
mutation of SCN1A found in the pedigree of several patients with complex febrile seizures. Epi-

lepsy Res 63: 151-156, 2005
20. Nishimoto H, Lee SW, Hong H, Potter KG, MaedaYamamoto M, Kinoshita T, Kawakami Y, Mittler
RS, Kwon BS, Ware CF, Croft M, Kawakami T.
Costimulation of mast cells by 4-1BB, a member of
the tumor necrosis factor receptor superfamily, withthe high-affinity IgE receptor. Blood. 106:4241-8,
2005
21. Nunomura S, Gon Y, Yoshimaru T, Suzuki Y, Nishimoto H, Kawakami T, Ra C: Role of the FcepsilonRI beta-chain ITAM as a signal regulator formast cell activation with monomeric IgE. Int Immunol. 17:685-94,2005
22. Sato U, Kitanaka S, Sekine T, Takahashi S, AshidaA, Igarashi T. Functional Characterization of
LMX1B mutations associated with Nail-Patella
syndrome. Pediatr Res 57: 783-788, 2005
23. Sekine T, Namai Y, Yanagisawa A, Shirahama H,
Tashiro Y, Terahara M, Nagata M, Harita Y, Fukuoka U, Inatomi J, Igarashi T: A familial case of
muticystic dysplastic kidney. Pediatr Nephrol 20:
1245-1248, 2005
24. Sekine T, Miyazaki H, Endou H: Molecular physiology of renal organic anion transporters.
Am J Physiol (Invited Review Article) 290: F25161, 2006.
25. Shinjo Y, Kaga K, Igarashi T: Distal renal tubularacidosis associated with large ventricular aqueduct
and sensorineural hearing loss. Acta Oto-Laryngo
125: 667-670, 2005
26. Tsuchida S, Engelberts D, Roth M, Mckerlie C,
Post M and Kavanagh BP: Continuous positive
airway pressure causes lung injury in a model ofsepsis – American Journal of Physiology – Lung
Cellular and Molecular Physiology 289: 554-564,
2005
27. Wei J, Chiriboga L, Mizuguchi M, Yee H, Mittal K.
Expression profile of tuberin and some potential
tumorigenic factors in 60 patients with uterine
leiomyomata. Modern Pathology 18: 179-188,
2005
28. Xiao W, Nishimoto H, Hong H, Kitaura J, Nunomura S, Maeda-Yamamoto M, Kawakami Y,
Lowell CA, Ra C, Kawakami T: Positive and negative regulation of mast cell activation by Lyn via
the FcepsilonRI. J Immunol. 175:6885-92, 2005
29. Yamasoba T, Goto Y, Komaki H, Mimaki M, Sudo

211

A, Suzuki M: Cochlear damage due to germaniuminduced mitochondrial dysfunction in guinea pigs.
Neurosci Lett. Epub Nov 9, 2005

212

Department of Pediatric Surgery
Professor
Kohei Hashizume, M.D.,Ph.D.
Lecturer
Yutaka Kanamori, M.D.,Ph.D
Associate
Masahiko Sugiyama, M.D.,
Makoto Komura, M.D., Ph.D

Homepage

Tetsuya Tomonaga,M.D., Ph.D.,

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

Introduction and Organization
The Department of Pediatric Surgery was
founded in 1971 as a clinical department in thehospital, and then became a department in thefaculty of medicine in 1989. Pediatric surgery isa rather new speciality in the field of surgery. It
includes neonatal surgery, pediatric surgicaloncology, pediatric emergency medicine, transplantation surgery in childhood, and even fetal
surgery. Our department has the longest history
as an independent department of pediatric surgery in all the national university hospitals. Although the number of staff is small, we keep
very tight relationship with other departmentsof pediatric surgery in children's hospitals, andgeneral hospitals and also research centers inJapan and abroad. So the clinical and research
activity is very productive compared to thenumber of the staff. In February 1997 Hashizume became the professor of the department
and a new organization has started.

Clinical activities
We have 12 beds in the ward as proper, but wecan use 4 to 8 more beds if needed. There is apediatric intensive care unit (PICU), in which

surgical neonates, postoperative cases after major operations, and those cases which needs respiratory support are cared. An average of 300
operations are performed a year, in which included are 20 to 30 neonatal cases, ten caseswith malignant tumors, and several cases oftracheal resection or tracheoplasty which is avery new and challenging field in pediatric surgery. Also since April 1996 living-related livertransplantation (LRLT) program has implemented in our department in cooperation with
the Department of Transplantation and Artificial Organs. We moved to the new wards 3 years
ago, and because we use common wards with thedepartment of pediatrics, our cooperation has
become even tighter than before.

Teaching activities
For the M2, M3, and M4 students, general
pediatric surgery and neonatal surgery are lectured by the professor and the lecturer. Bedsideeducation program is also provided for the M3,
and M4 students. The bedside education of pediatric surgery consists of participation in clinical conferences, attendance at operations, andsmall group lectures concerning neonatal surgery, pediatric surgical oncology, pediatric hepato-

213

biliary surgery, and pediatric emergency medicine which includes practice of cardiac massage
and intra-tracheal intubation using dolls for thepractice. Although the duration of bedside education of pediatric surgery is only for 5 days, it
has a good reputation in students. Concerning
postgraduate education, there are 5 postgraduate students, one of them are from abroad. They
study very wide variety of topics, such as
anti-oncogene of neuroblastoma in chromosome
1p, abnormalities of beta-catenin in hepatoblastoma patients, mechanism and prevention ofreperfusion injury in liver transplantation andsmall intestinal transplantation, and a new
immunological therapy of neuroblastoma using
dendritic cells.

Research activities
In Department of Pediatric Surgery, we have 4
research groups, namely oncology group, hepatobiliary and transplantation group, prenatal developmental group, and gastro- intestinal group.
Professor Hashizume supervises the oncology
group. Studies going on in this group are
multi-drug resistance in pediatric solid tumors,
suppressor oncogenes in solid tumors such asneuroblastoma, Wilms' tumor, and Ewing's sarcoma. Professor Hashizume also supervises thehepato-biliary and transplantation group. Main
topics studied in this group are related to livertransplantation, small intestinal transplantation, new immunosuppressive drug, and pathology of biliary atresia. Lecturer Kanamori
supervises the gastro-intestinal group. The mainconcern in this group is growth and migration ofintestinal T-cells related to newly found intestinal lymph-apparatus, cryptopatch. Also change
of intestinal flora and bacterial translocation in
short bowel syndrome patients are studied. Recently we introduced probiotics and synbiotics
for the treatment of these patients and we foundthey started to grow very rapidly after the introduction of them. Professor Hashizume supervises the prenatal developmental group. The
main topic in this group is congenital diaphragmatic hernia (CDH), which is one of themost intractable congenital anomalies in thefield of pediatric surgery. Pathophysiology of
CDH and a possibility of fetal treatment of CDH
with severe hypoplasia of lungs are intensively
studied. Now we are doing a research with thedepartment of obstetrics using fetal lambs. We
are looking for the effects of tracheal occlusion
using specially designed balloon and the result
is very promising so far.

Publishing
1. Hiyama E, Yamaoka H, Matsunaga T, Hayashi Y,
Ando H, Suita S, Horie H, Kaneko M, Sasaki F,
Hashizume K, Nakagawara A, Yokoyama T Highexpression of telomerase is an independent prognostic indicator of poor outcome in hepatoblastoma
Brit J Cancer 91：972-979、2004
2. Ito M, Hashizume K, Kanamori Y New phenotype
of accessory scrotum with perineal lipoblastoma:
coexistence of midperineal and lateral accessory
scrotums Int J Urol 11：125-127、2004
3. Chang R, Andreoli S, Jennings R, Wilson J, Fauza
D Rapidly polymerizing hydrogel prevents balloon
dislodgement in a model of fetal tracheal occlusion
J Pediatr Surg 39(4)：557-60、2004
4. Chang R, Komura M, Andreoli S, Klingenberg M,
Jennings R, Wilson J, Fauza D Hyperoncotic enhancement of pulmonary growth after fetal tracheal
occlusion : a comparison between dextran and albumin J Pediatr Surg 39(3)：324-8、2004
5. Kodaka T, Kanamori Y, Sugiyama M, Hashizume
K A case of acrocephlosyndactyly with low imperforate anus. J Pediatr Surg 39：E10 (32-4)、2004
6. Kanamori Y, Hashizume K, Sugiyama M, Tomonaga T, Goishi K, Shibuya K, Kawana Y, Marumo G, Kikuchi A, Kozuma S, Sekiyama Y A caseof laryngeal atresia(congenital high airway obstruction syndrome: CHAOS) with chromosome 5p deletion syndrome rescued by ex utero intrapartum
treatment (EXIT) J Pediatr Surg 39：E25-28、2004
7. Kanamori Y, Sugiyama M, Hashizume K, Yuki N,
Morotomi M, Tanaka R Experience of long-term
synbiotic therapy in seven short bowel patientswith refractory enterocolitis
J Pediatr Surg 39：1686-1692、2004
8. Hashizume K, Sugiyama M, Tomonaga T, Naka-

214

nishi H Vascular-pedicled costal cartilage graft for
the treatment of subglottic and upper tracheal
stenosis J Pediatr Surg 39：1769-71、2004
9. Suzuki S, Yoshino H, et al Impact of worm
ischemic time on microsomal P450 isoforms in a
porcine model of therapeutic liver resection Life
Sciences 76 (1) ：39-46、2004
10. Yamada S, Ohira M, Horie H, Takayasu H, Suzuki
Y, Sugano S, Hirata T, Goto T, Matsunaga T, Hiyama E, Hayashi Y, Ando H, Suita S, Kaneko M,
Sasaki F, Hashizume K, Onuma N, Nakagawara A
Expression profiling and differential screening between hepatoblastomas and the corresponding
normal livers: identification of high expression of
the PLK1 oncogene as a poor-prognostic indicatorof hepatoblastomas Oncogene 23：5901-5911、2004
11. Emura T, Kanamori Y, Ito M, Hashizume K, Marumo G, Goishi K Omphalocele associated with alarge multilobular umbilical cord pseudocyst Pediatr Surg Int 20：636-639、2004
12. Tamai H, Sawamura S, Kanamori Y, Chinzei M,
Hanaoka K Thoracic epidural catheter insertion
using the caudal approach assisted with an electrical nerve stimulator in young children Regional
Anesthesia & Pain Medicine 29：92-95、2004
13. Shimizu H, Takahashi M, Takeda S, Inoue S, Fujishiro J, Hakamata Y, Kaneko T, Murakami T, Takeyoshi I, Morishita Y, Kobayashi E Conversion
from cyclosporine A to mycophenolate mofetil
protects recipient kidney and prevents intimal hyperplasia in rat aortic allografts Transpl Immunol
13：219-217、2004
14. Shimizu H, Takahashi M, Inoue S, Fujishiro J,
Hakamata Y, Kaneko T, Murakami T, Takeuchi K,
Takeyoshi I, Morishita Y, Kobayashi E Mycophenolate mofetil prevents transplant arteriosclerosis
by direct inhibition of vascular smooth muscle cellproliferation Transplantation 77：1661-1667、2004
15. Fujishiro J, Inoue S, Shimizu H, Yoshino H, Murakami T, Kobayashi E Effect of FTY 720 on rat
small bowel transplantation Transplantation 77：
1910-1911、2004
16. Ogata Y, Fujishiro J, Kawana H, Kobayashi E Adenovirus-mediated gene transfer to the rat heart graft
Transplantation 78：1408、2004
17. Tanaka H, Yoshino H, et al Molecular investigationof hepatitis E virus infection in domestic andminiature pigs used for medical experiments
Xenotransplantation 11 (6) ：503-510 2004
18. Okudaira R, Mukoyama T, Suzuki N, Hashizume K,
Iwata T, Juji F, Kohno Y, Shuto H, Okudaira H Epstein-Barr virus infection in childhood may precipitate atopic diseases. Allerg Int 54：345-349、2005
19. Tahara K, Murakami T, Fujishiro J, Takahashi M,
Inoue S, Hashizume K, Matsuno K, Kobayashi E
Regeneration of the rat neonatal intestine in transplantation Ann Surg 242：124-132、2005
20. Tanaka H, Verran D, Shun A, Dorney S, Stormon
M, Fisher J, McCaughan G Liver Transplantation
utilizing pediatric cadaver donor livers. Austr J :Pediatr Transplant 9：47-51、2005
21. Stitzel J, Liu J, Lee SJ, Komura M, Berry J, Soker
S, Lim G, Van Dyke M, Czerw R, Yoo JJ, Atala A
Controlled fabrication of a biological vascular substitute. Biomaterials 27：1088-1094、2005
22. Li D.h, Chan T.ch, Sato R, Komazaki S, Hashizume K, Asashima M The role of XTRAP-γin
Xenopus pronephros development. Int J Dev Biol
49：401-408、2005
23. Ishikawa H, Kanamori Y, Hamada H, Kiyono H
Development and function of organized gut-associated lymphoid tissues. In Mucosal Immunology
3rd ed., edited by Mestecky J, Bienenstock J,
Lamm ME, Mayer L, McGhee JR, Strober W. ( Elsevier Academic Press) P385-405、2005
24. Mushiroda T, Saito S, Tanaka Y, Takasaki J, Kamatani N, Beck Y, Tahara H, Nakamura Y, Ohnishi Y
A model of prediction system for adverse cardiovascular reactions by calcineurin inhibitors among
patients with renal transplants using gene-based
single-nucleotid polymorphisms. J Hum Genet 50：
442-447、2005
25. Kanamori Y, Hashizume K, Sugiyama M, Goishi K,
Igarashi T, Kawana Y, Kozuma S, Taketani Y Acase of intra-pericardial diaphragmatic hernia witha massive pericardial effusion : Fetal diagnosis andtherapy. J Pediatr Surg 40：e43-45、2005
26. Fujishiro J, Takeda S, Takeno Y, Ogata Y, Takahashi M, Hakamata Y, Kaneko T, Murakami T, Okada
T, Ozawa K, Hashizume K, Kobayashi E Genetransfer to the rat kidney in vivo and ex vivo using
an adenovirus vector: factors influencing transgene
expression. Nephrol Dial Transplant 20：1385-1391、

215

2005
27. Nishimata S, Kato K, Tanaka M, Ijiri R, Toyoda Y,
Kigasawa H, Ohama Y, Nakatani Y, Notohara K,
Kobayashi Y, Horie H, Hoshika A, Yanaka Y Expression pattern of keratin subclasses n pancreatoblastoma with special emphasis on squamoid corpuscles Pathol Int 6：297-302、2005
28. Kanamori Y, Hashizume K, Sugiyama M, Terawaki
K, Osawa K Type B intestinal neuronal dysplasia.
Pediatr Int 47：338-340、2005
29. Kanamori Y, Hashizume K, Sugiyama M, Motoi T,
Fukayama M, Ida K, Igarashi T Intrapulmonary
solitary fibrous tumor in an eight-year-old male.
Pediatr Pulmonol 40：261-264、2005
30. Fujishiro J, Iwanaka T, Arai M, Kawashima H, Hirukawa S, Inasaka O Disappearing cyst of the hepatic hilum in uncorrectable biliary atresia. Pediatr
Surg Int 21：116-118、2005
31. Sangkhathat S, Yoneda A, Kuroda S, Tanaka M,
Sakai N, Fukuzawa M Renal cell carcinoma in apediatric patient with an inherited mitochondrial
mutation. Pediatr Surg Int 21：745-748、2005
32. Fujishiro J, Kawana H, Inoue S, Yoshino H, Hakamata Y, Kaneko T, Murakami T, Hashizume K,
Kobayashi E Efficiency of adenovirus-mediatedgene transduction in heart grafts in rats. Transplant
Proc 37：67-69、2005
33. Komiya K, Wainai T, Murayama T, Yamada M,
Hiruta A, Seo N, Yoshino H, Tanaka H, Kobayashi
E Evaluation of intraoperative infusion solution
using a complete anhepatic model in baby pigs.
Transplant Proc 37：2341-2346、2005
34. Fujishiro J, Tahara K, Inoue S, Kaneko T, Kaneko
M, Hashizume K, Kobayashi E Immunologic benefits of longer graft in rat allogenic mal bowel transplantation. Transplantation 79：190-195、2005
35. Sato Y, Ajiki T, Inoue S, Fujishiro J, Yoshino H,
Igarashi Y, Hakamata Y, Kaneko T, Murakamid T,
Kobayashi E Gene silencing in rat-liver and limb
grafts by rapid injection of small interference RNA.
Transplantation 79：240-243、2005

216

Department of Pediatric Oncology
Professor
Kohei Hashizume, M.D.,Ph.D.

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

Associate
Masahiko Sugiyama, M.D.,
Makoto Komura, M.D., Ph.D

Tetsuya Tomonaga,M.D., Ph.D.,

Homepage http://square.umin.ac.jp/pedsurg/index.html
Introduction and Organization
When the graduate school of medicine started in the
University of Tokyo, the professor of pediatric surgery
at that time became the professor of pediatric oncology
concurrently. So the staff of the Department of PediatricOncology is common with the staff of the departmentof Pediatric Surgery. It consists of a professor, a lecturer,
and 4 assistants. Actually, however, the oncology groupin the Department of Pediatrics leaded by Dr. J. Takita
is a part of the department, and their contribution to thedepartment is tremendous.

Clinical activities
In clinical activities, oncology group in the department of Pediatric Surgery and the oncology group in
the department of Pediatrics always keep contact andtreat the patients with pediatric malignant diseases cooperatively. When a patient with malignant disease isadmitted to the ward, the treatment principles are determined at the conference attended by the doctors fromthe both groups. Sometimes patients with pediatric malignancies in the region of neurosurgery, orthopedics, or
ophthalmology, are also admitted to the pediatric ward,
and they at first receive chemotherapy by pediatric oncologists and an extirpation of the tumor is conductedby surgeons later. This is so-called multi-disciplinary
approach and it is well established in the pediatric on-

cology. This approach contributes greatly to the improvement of the prognosis of pediatric malignancies.

Education
Lectures of pediatric oncology are performed by pediatric oncologists and pediatric surgeons. At present
there are 3 lectures by pediatric oncologists and 1 lecture by pediatric surgeons. Children with malignant
diseases tend to be admitted long time, so in BSL(bedside learning) they have good chance of being charged
by students. And it is also a good experience for students to be in charge of patients with malignant diseases. They learn not only the therapies and examinations of pediatric malignant diseases, but also thelong-lasting fight against malignant diseases by patientsand their family.

Research
The themes of research in the department are various.
Just a few of them are presented here. They include 1)
significance of WT-1 gene mutations in Wilms tumor,
2) abnormalities of beta-catenin in liver tumors in children, 3) tumor-suppressor genes in neuroblastoma supposed to be resided in the short arm of no. 1 chromosome, 4) new tumor suppressor gene in pediatric malignant solid tumors and leukemias, 5) examination ofgenes at the breakpoints in leukemias. In 1), we re-217

cently have found a novel mutation of WT-1, and contributed to the understanding of the mechanism of tumorigenesis in Wilms tumor. In 2) we found for the firsttime, that not only in malignant tumors of the liver but
also in liver adenoma there are some abnormalities ofbeta-catenin. About 3), we study very intensively using
quite a various kinds of methods, but have not yet succeeded to determine the tumor suppressor gene in thisregion. This area is the area where most fierce competition is going between many laboratories in the world. In4) we clarify the function of translocated gene in thedevelopment of Rubinstein-Taybi syndrome. In thesemost advanced areas of research, it is almost impossible
to perform researches in a single laboratory, and we
co-study and change information constantly with manylaboratories in Japan and abroad.

References
1. Takita J, Ishii M, Tsutsumi S, Tanaka Y, Kato K,
Toyoda Y, Hanada R, Yamamoto K, Hayashi Y,
Aburatani H Gene expression profiling and identification of novel prognostic marker genes inneuroblastoma Genes Chromosomes Cancer 40(2):120-132, 2004
2. Hiyama E, Yamaoka H, Matsunaga T, Hayashi Y,
Ando H, Suita S, Horie H, Kaneko M, , Hashizume
K, Nakagawara A, Yokoyama T High expression of
telomerase is an independent prognostic indicatorof poor outcome in hepatoblastoma Brit J Cancer
91：972-979、2004
3. Yamada S, Ohira M, Horie H, Ando K, Takayasu H,
Suzuki Y, Sugano S, Hirata T, Goto T, Matsunaga
T, Hiyama E, Hayashi Y, Ando H, Suita S, Kaneko
M, Sasaki F, Hashizume K, Onuma N, Nakagawara
A Expression profiling and differential screening
between hepatoblastomas and the corresponding
normal livers: identification of high expression of
the PLK1 oncogene as a poor- prognostic indicatorof hepatoblastomas Oncogene 23：5901-5911、2004
4. Kawaguchi H, Taketani T, Hongo T, Park MJ, Koh
K, Ida K, Kobayashi M, Takita J, Taki T, Yoshino H,
Bessho F, Hayashi Y In vitro drug resistance toimatinib and mutation of ABL gene in childhood
Ph+ acute lymphoblastic leukemia. Leukemia andLymphom 46(2):273-276, 2005.
5. Chen YY, Takita J, Tanaka K, Ida K, Koh K, Igara-

shi T, Hanada R, Kikuchi A, Tanaka Y, Toyoda Y,
Hayashi Y Aberrations of the CHK2 gene are rarein pediatric solid tumors. Int J Mol Med. 16(1) :85-91, 2005
6. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita
J, Nakazaki K, Kurokawa M, Hayashi Y, Ogawa S,
Chiba S Mutations of the Notch1 gene in T-cell
acute lymphoblastic leukemia: analysis in adults
and children. Leukemia. 19(10): 1841-1843, 2005
7. Chen YY, Takita J, Hiwatari M, Igarashi T, Hanada
R, Kikuchi A, Hongo T, Taki T, Ogasawara M,
Shimada A, Hayashi Y Mutations of the PTPN11
and RAS Genes in Rhabdomyosarcom and Pediatric
Malignancies Genes Chromosomes Cancer. ( inpress)
8. Nagayama J, Tomizawa D, Koh K, Nagatoshi Y,
Hotta N, Kishimoto T, Takahashi Y, Kuno T, Sugita
K, Sato T, Kato K, Ogawa A, Nakahata T, Mizutani
S, Horibe K, Ishii E Infants with acute lymphoblastic leukemia and a germline MLL gene are highly
curable with use of chemotherapy alone: resultsfrom the Japan Infant Leukemia Study Group
Blood.(in press)
9. Nishimata S, Tanaka M, Toyoda Y, Kigasawa H,
Ohama Y, Nakatani Y, Notohara K, Kobayashi Y,
Horie H, Hoshika A, Yanaka Y Expression patternof keratin subclasses n pancreatoblastoma withspecial emphasis on squamoid corpuscles Pathol
Int 6：297-302、2005
10. Kanamori Y, Hashizume K, Sugiyama M, Motoi T,
Fukayama M, Ida K, Igarashi T Intrapulmonary
solitary fibrous tumor in an eight-year-old male
Pediatr Pulmonol 40：261-264、2005
11. Sangkhathat S, Kusafuka T, Yoneda A, Kuroda S,
Sakai N, Fukuzawa M Renal cell carcinoma in apediatric patient with an inherited mitochondrial
mutation Pediatr Surg Int 21：745-748、2005

Reproductive, Developmental andAging Sciences
3. Aging Sciences

21

220

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

Associate Professor
Masahiro Akishita, Ph.D.

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

Shinji Teramoto, M.D., Ph.D.

Associate
Katsuya Iijima, M.D., Ph.D.,
Tomohiko Urano, Ph.D.,

Sumito Ogawa, Ph.D.
Yumiko Ohike, Ph.D.,

Hiroshi Yamamoto, M.D.

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

Clinical activities

The Department of Geriatrics was established in
1962, as the first geriatric department in Japan.
Since elderly patients usually have multiple organ
disorders, we have to take care the patients as a wholefrom multiple points of view. In addition, in the elderly
patients, symptoms, signs and responses to the treatment are sometimes quite different from the young. We
have to have a broad knowledge on the physiologicaland metabolic changes with aging when we treat theelderly patients. Quality of life of the patients is anotherpoint of view which should be emphasized.
Our sub-specialty includes respirology, cardiology,
neurology, hematology, endocrinology, and bone metabolism, besides the general geriatric internal medicine.
We are trying to elucidate the pathophysiology of
aging process and understand elderly patients fromviewpoints of basic aging science using molecular biology technique and clinical aspects using the recent
advancement of technology and geriatric assessment.

In the clinical ward, there are around 20 patients who
are taken care of by junior, senior and chief residents ofour staff. Because senior and chief residents are very
experienced, they team up with a junior resident, give
instructions as to the assessment of the patient's problem, making of future plans, and help the resident withvarious procedures. Very important issues are discussed
and decisions are made in weekly professor's round.
Specialized services are provided to out-patients on adaily basis in all areas of internal medicine. Approximately 300 new and a total of 16,000 patients visit theout-patient clinic in a year.

Teaching activities
Clinical education is provided for fifth and sixth year
medical students on a man-to-man basis with a faculty
staff member. During the period, the student studies one
or two cases, through which the student learns the techniques interrogation and physical examination, interpretation of laboratory tests, and actual medical proce-

221

dures. Interpretation of the results of geriatric assessment is studied through lectures in a case-oriented
manner with an emphasis placed on the multidisciplinary basis of geriatric patients.

Research activities
Pulmonary unit
Lung mechanics, exercise physiology, management
and assessment of dyspnea, sleep study for nocturnal
disturbed breathing, latent virus infection in airways,
animal model of aging lung, prediction and preventionof aspiration pneumonia, pathophysiology of interstitiallung disease, role of adhesion molecule in airway disease, role of endothelin, leukotrienes, and neuropeptides in asthma, proliferation and differentiation of lungfibroblasts, proliferation and apoptosis of airway disease, defensin and infectious disease.
Shinji Teramoto, Yasuhiro Yamaguchi, Hiroshi Yamamoto, Yoko Hanaoka, Masaki Ishii, Mihoko Takizawa
Cardiovascular unit
Research on the mechanism and regulation of vascular calcification, sex hormone regulation of vascularfunction, clinical evaluation of vascular function using
vascular ultrasound and pulse wave velocity, metabolic
syndrome in the elderly.
Yasuyoshi Ouchi, Masahiro Akishita, Masato Eto,
Katsuya Iijima, Sumito Ogawa, Yumiko Ohike, Taro
Kojima, Hidetaka Ota, Hiroko Hashimoto, Kazushi
NomuraNeurology unit
Diagnosis and treatment of the demented patients,
neuro-protective function of Thioredoxin in Drosophila,
regulation of apoptosis by stress-responsive kinases, etc
Yumi Kameyama, Kiyoshi Yamaguchi, Aya Takemura
Osteoporosis and endocrinology unit
Bone metabolism, mechanism of action nuclear ofreceptors, genetic analysis of osteoporosis, vitamin K
action, hormone dependent cancer.
Satoshi Inoue, Tomohiko Urano, Atsushi Shionoiri,
Kotaro Azuma, Takahiko Usui, Hiroyuki Kinoshita,
Ken’ichi Takayama

References
1. Azuma K, Horie K, Inoue S, Ouchi Y, Sakai R.
Analysis of estrogen receptor alpha signaling complex at the plasma membrane. FEBS Lett 2004;
577:339-44.
2. Bachschmid M, van der Loo B, Schuler K, Labugger R, Thurau S, Eto M, Kilo J, Holz R, Luscher TF,
Ullrich V. Oxidative stress-associated vascular aging is independent of the protein kinase C/NAD(P)H oxidase pathway. Arch Gerontol Geriatr 2004;38:
181-90.
3. Eto M, Luscher TF. The cardioprotective effects ofstatins. Coron Artery Dis 2004;15:243-5.
4. Fujita M, Urano T, Shiraki M, Orimo H, Ouchi Y,
Inoue S. Association of a single nucleotide polymorphism in the secreted frizzled related protein 4(sFRP4) gene with bone mineral density. GeriatricGerontol Int 2004;4:175-80.
5. Horiuchi H, Matsuzawa Y, Mabuchi H, Itakura H,
Sasaki J, Yokoyama M, Ishikawa Y, Yokoyama S,
Mori S, Ohrui T, Akishita M, Hayashi T, Yamane K,
Egusa G, Kita T. Strategy for treating elderly Japanese with hypercholesterolemia. Geriatr Gerontol
Int 2004;4:151-56.
6. Ikeda K, Ogawa S, Tsukui T, Horie-Inoue K, Ouchi
Y, Kato S, Muramatsu M, Inoue S. Protein phosphatase 5 is a negative regulator of estrogen receptor-mediated transcription. Mol Endocrinol.
2004;18:1131-43.
7. Ishii S, Nagase T, Shindou H, Takizawa H, Ouchi Y,
Shimizu T. Platelet-activating factor receptor develops airway hyperresponsiveness independentlyof airway inflammation in a murine asthma model.
J Immunol 2004;172:7095-102.
8. Ito H, Kanno I, Kato C, Sasaki T, Ishii K, Ouchi Y,
Iida A, Okazawa H, Hayashida K, Tsuyuguchi N,
Ishii K, Kuwabara Y, Senda M. Database of normal
human cerebral blood flow, cerebral blood volume,
cerebral oxygen extraction fraction and cerebral
metabolic rate of oxygen measured by positronemission tomography with 15O-labelled carbon
dioxide or water, carbon monoxide and oxygen: amulticentre study in Japan. Eur J Nucl Med Mol
Imaging 2004;31:635-43.
9. Kobayashi K, Akishita M, Yu W, Hashimoto M,
Ohni M, Toba K. Interrelationship between non-222

invasive measurements of atherosclerosis; flowmediated dilation of brachial artery, carotid intima-media thickness and pulse wave velocity.
Atherosclerosis 2004;173:13-8.
10. Kouroedov A, Eto M, Joch H, Volpe M, Luscher TF,
Cosentino F. Selective inhibition of protein kinase
Cbeta2 prevents acute effects of high glucose on
vascular cell adhesion molecule-1 expression inhuman endothelial cells. Circulation 2004;110:916.
11. Mita Y, Akishita M, Tanaka K, Yamada S, Nakai R,
Tanaka E, Nakamura T, Toba K. Improvement of
inappropriate prescribing and adverse drug withdrawal events after admission to long-term care facilities. Geriatr Gerontol Int 2004;4:146-50.
12. Nagai K, Akishita M, Machida A, Sonohara K,
Ohni M, Toba K. Correlation between pulse wave
velocity and cognitive function in non-vasculardementia. J Am Geriatr Soc 2004;52:1037-8.
13. Teramoto S, Yamamoto H, Ouchi Y. Increased
plasma interleukin-6 is associated with the pathogenesis of obstructive sleep apnea syndrome. Chest
2004;125:1964-5.
14. Teramoto S, Yamamoto H, Yamaguchi Y, Ouchi Y,
Matsuse T. A novel diagnostic test for the risk ofaspiration pneumonia in the elderly. Chest 2004;
125:801-2.
15. Teramoto S, Yamamoto H, Yamaguchi Y, Tmoita T,
Ouchi Y. Diffuse aspiration bronchiolitis due toachalasia. Chest 2004;125:349-50.
16. Urano T, Shiraki M, Ezura Y, Fujita M, Sekine E,
Hoshino S, Hosoi T, Orimo H, Emi M, Ouchi Y,
Inoue S. Association of a single nucleotide
polymorphism in low-density lipoprotein receptorrelated protein 5 gene with bone mineral density. J
Bone Miner Metab 2004;22:341-5.
17. Urano T, Takahashi S, Suzuki T, Fujimura T, Fujita
M, Kumagai J, Horie-Inoue K, Sasano H, Kitamura
T, Ouchi Y, Inoue S. 14-3-3sigma is downregulated in human prostate cancer. Biochem
Biophys Res Commun 2004;319:795-800.
18. Watanabe T, Miyahara Y, Akishita M, Nakaoka T,
Yamashita N, Iijima K, Kim H, Kozaki K, Ouchi Y.
Inhibitory effect of low-dose estrogen on neointimal formation after balloon injury of rat carotid artery. Eur J Pharmacol 2004;502:265-70.
19. Watanabe T, Akishita M, Nakaoka T, He H, Miya-hara Y, Yamashita N, Wada Y, Aburatani H, Yoshizumi M, Kozaki K, Ouchi Y. Caveolin-1, Id3a andtwo LIM protein genes are upregulated by estrogenin vascular smooth muscle cells. Life Sci 2004;75:
1219-29.
20. Akishita M, Yamada S, Nishiya H, Sonohara K,
Nakai R, Toba K. Effects of physical exercise on
plasma concentrations of sex hormones in elderly
women with dementia. J Am Geriatr Soc 2005;53:
1076-7.
21. Arai H, Akishita M, Teramoto S, Arai H, Mizukami
K, Morimoto S, Toba K. Incidence of adverse drug
reactions in geriatric units of university hospitals.
Geriatr Gerontol Int 2005;5:293-7.
22. Arai H, Yamamoto A, Matsuzawa Y, Saito Y, Yamada N, Oikawa S, Mabuchi H, Teramoto T, Sasaki
J, Nakaya N, Itakura H, Ishikawa Y, Ouchi Y, Horibe H, Egashira T, Hattori H, Shirahashi N, Kita T.
Polymorphisms in four genes related to triglycerideand HDL-cholesterol levels in the general Japanese
population in 2000. J Atheroscler Thromb 2005;12:240-50.
23. Arai H, Yamamoto A, Matsuzawa Y, Saito Y, Yamada N, Oikawa S, Mabuchi H, Teramoto T, Sasaki
J, Nakaya N, Itakura H, Ishikawa Y, Ouchi Y, Horibe H, Kita T. Serum lipid survey and its recent
trend in the general Japanese population in 2000. J
Atheroscler Thromb 2005;12:98-106.
24. Azuma K, Tanaka M, Uekita T, Inoue S, Yokota J,
Ouchi Y, Sakai R. Tyrosine phosphorylation of
paxillin affects the metastatic potential of humanosteosarcoma. Oncogene 2005;24:4754-64.
25. Eto M, Kouroedov A, Cosentino F, Luscher TF.
Glycogen synthase kinase-3 mediates endothelial
cell activation by tumor necrosis factor-alpha. Circulation 2005;112:1316-22.
26. Eto M, Toba K, Akishita M, Kozaki K, Watanabe T,
Kim S, Hashimoto M, Ako J, Iijima K, Sudoh N,
Yoshizumi M, Ouchi Y. Impact of blood pressure
variability on cardiovascular events in elderly patients with hypertension. Hypertens Res 2005;
28:1-7.
27. Ishikawa T, Ito H, Ouchi Y, Ohashi Y, Saito Y, Nakamura H, Orimo H. Increased risk for cardiovascular outcomes and effect of cholesterol-loweringpravastatin therapy in patients with diabetes mellitus in the Pravastatin Anti- atherosclerosis Trial in

223

the Elderly. Current Therapeutic Research 2005;66:
48-65.
28. Kaneko A, Cho S, Hirai K, Okabe T, Iwasaki K,
Nanba Y, Ouchi Y, Cyong JC. Hange-koboku-to, a
Kampo medicine, modulates cerebral levels of
5-HT (5-hydroxytryptamine), NA (noradrenaline)
and DA (dopamine) in mice. Phytother Res
2005;19:491-5.
29. Kano MR, Morishita Y, Iwata C, Iwasaka S, Watabe T, Ouchi Y, Miyazono K, Miyazawa K.
VEGF-A and FGF-2 synergistically promoteneoangiogenesis through enhancement of endogenous PDGF-B/PDGFRβ signaling. J Cell Sci 2005;
118(Pt 16):3759-68.
30. Kojima T, Eto M, Yamaguchi Y, Yamaguchi K,
Kozaki K, Akishita M, Ouchi Y. Tako-tsubo left
ventricular dysfunction caused by a fall. J Am
Geriatr Soc 2005;53:2233-5.
31. Kozai T, Eto M, Yang Z, Shimokawa H, Luscher
TF. Statins prevent pulsatile stretch-induced proliferation of human saphenous vein smooth muscle
cells via inhibition of Rho/Rho-kinase pathway.
Cardiovasc Res 2005;68:475-82.
32. Ogawa S, Lozach J, Benner C, Pascual G, Tangirala
R, Westin S, Hoffmann A, Subramaniam S, David
M, Rosenfeld MG, Glass CK. Molecular determinants of crosstalk between nuclear receptors andToll-like receptors. Cell 2005;122:707-21.
33. Ogushi T, Takahashi S, Takeuchi T, Urano T,
Horie-Inoue K, Kumagai J, Kitamura T, Ouchi Y,
Muramatsu M, Inoue S. Estrogen receptor-binding
fragment-associated antigen 9 is a tumor-promoting
and prognostic factor for renal cell carcinoma.
Cancer Res 2005;65:3700-6.
34. Ohike Y, Kozaki K, Iijima K, Eto M, Kojima T,
Ohga E, Santa T, Imai K, Hashimoto M, Yoshizumi
M, Ouchi Y. Amelioration of vascular endothelial
dysfunction in obstructive sleep apnea syndromeby nasal continuous positive airway pressure-- possible involvement of nitric oxide and asymmetric
NG, NG-dimethylarginine. Circ J 2005;69:221-6.
35. Pascual G, Fong A, Ogawa S, Gamliel A, Li AC,
Perissi V, Rose DW, Willson TM, Rosenfeld MG,
Glass CK. A SUMOylation-dependent pathway
mediates transrepression of inflammatory response
genes by PPARgamma. Nature 2005;437:759-63.
36. Suzuki T, Urano T, Tsukui T, Horie-Inoue K, Mo-riya T, Ishida T, Muramatasu M, Ouchi Y, Sasano H,
Inoue S. Estrogen-responsive finger protein as a
new potential biomarker for breast cancer. Clin
Cancer Res 2005;11:6148-54.
37. Teramoto S, Ishii T, Yamamoto H, Yamaguchi Y,
Matsuse T. Xenobiotic enzymes and genetics of
COPD. Chest 2005;127:408-9.
38. Teramoto S, Yamamoto H, Yamaguchi Y, Namba R,
Ouchi Y. Obstructive sleep apnea causes systemic
inflammation and metabolic syndrome. Chest
2005;127:1074-5.
39. Teramoto S, Ishii T, Yamamoto H, Yamaguchi Y,
Ouchi Y. Apoptosis of circulating neutrophils andalveolar macrophages in COPD. Chest 2005;127:
1079-80.
40. Teramoto S, Ishii T, Yamamoto H, Yamaguchi Y,
Namba R, Hanaoka Y, Takizawa M, Okada T, Ishii
M, Ouchi Y. Significance of chronic cough as a defense mechanism or a symptom in elderly patientswith aspiration and aspiration pneumonia. Eur
Respir J 2005;25:210-1.
41. Urano T, Shiraki M, Fujita M, Hosoi T, Orimo H,
Ouchi Y, Inoue S. Association of a single nucleotide polymorphism in the lipoxygenase ALOX15
5'-flanking region (-5229G/A) with bone mineraldensity. J Bone Miner Metab 2005;23:226-30.
42. Yamazaki T, Akishita M, Kobayashi K, Machida A,
Toba K. Successful aging with constant physicaltraining. Geriatr Gerontol Int. 4:66-67, 2004.Akishita M, Nagai K, Xi H, Yu W, Sudoh N, Watanabe
T, Ohara-Imaizumi M, Nagamatsu S, Kozaki K,
Horiuchi M, Toba K. Renin-angiotensin systemmodulates oxidative stress-induced endothelial cell
apoptosis in rats. Hypertension 2005;45:1188-93.
43. Eto M, Rathgeb L, Cosentino F, Kozai T, Luscher
TF. Statins blunt thrombin-induced downregulationof endothelial nitric oxide synthase expression inhuman endothelial cells. J Cardiovasc Pharmacol(in press).
44. Glass CK, Ogawa S. Combinatorial roles of nuclear
receptors in inflammation and immunity. Nature
Reviews Immunology 2006;6:44-55.
45. Kume H, Teramoto S, Tomita K, Nishimatsu H,
Takahashi S, Takeuchi T, Ota N, Kitamura T.
Bladder recurrence of upper urinary tract cancer
after laparoscopic surgery. J Surg Oncol 2006;93:318-22.

224

46. Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K,
Eto M, Kozaki K, Akishita M, Ouchi Y, Kaneki M.
Sirt1 inhibitor, Sirtinol, induces senescence-likegrowth arrest with attenuated Ras-MAPK signalingin human cancer cells. Oncogene 2006;25:176-85.
47. Shukuwa K, Izumi SI, Hishikawa Y, Ejima K,
Inoue S, Muramatsu M, Ouchi Y, Kitaoka T, Koji T.
Diethylstilbestrol increases the density of prolactin
cells in male mouse pituitary by inducing proliferation of prolactin cells and transdifferentiation of
gonadotropic cells. Histochem Cell Biol (in press).
48. Teramoto S, Ishii T, Yamamoto H, Yamaguchi,
Ouchi Y. Nasogastric tube feeding is a significant
cause of aspiration pneumonia in mechanicallyventilated patients. Eur Respir J 2006;27:436-7.
49. Urano T, Shiraki M, Ouchi Y, Inoue S. Associationof a single nucleotide polymorphism in the steroid
and xenobitic receptor (SXR) gene (IVS1-579A/G)
with bone mineral density. Geriatric Gerontol Int(in press).
50. Urano T, Shiraki M, Narusawa K, Usui T, Sasaki N,
Hosoi T, Ouchi Y, Nakamura T, Inoue S. Q89R
polymorphism in the LDL receptor-related protein
5 gene is associated with spinal osteoarthritis in
postmenopausal Japanese women. Spine (in press).
51. Yu W, Akishita M, Xi H, Nagai K, Sudoh N, Hasegawa H, Kozaki K, Toba K. Angiotensin converting
enzyme inhibitor attenuates oxidative stress-induced endothelial cell apoptosis via p38 MAP
kinase inhibition. Clin Chim Acta 2006;364:32834.

Surgical Sciences
1. Surgery

22

226

Department of Thoracic Surgery
Professor
Takamoto, Shinichi

Associate Professor
Nakajima, Jun

StaffsMurakawa, Tomohiro and Fukami, Takeshi
Homepage URL: http://ctstokyo.umin.ne.jp/

History
Clinical and basic researches of the thoracic surgery
has been performed since the prewar era in this university, when Professor Masao Tsuduki adopted the modified Coryllos’s thoracoplasty for the treatment of thepulmonary tuberculosis in 1934. They initiated thoracoscopy for treatment of the tuberculosis in our country.
After successful application of the antituberculous drugs,
surgical treatment 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 with the cardiovascular surgery in the Japanese national universities.
Since then it has played an internationally leading roleand contributed to development of the field in ourcountry.
Professors and Chairs in the history of the department 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 ~).
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of Cardiovascular Surgery and Department of Thoracic Surgery
in 1998.

The mission of the Department of Thoracic Surgery
is to improve the patients with diseases of the thoracic
organs through clinical works, basic and clinical researches, and education of the medical students, postgraduates, and the surgical residents in our university.

Clinical activities
Three staffs (Nakajima J, Murakawa T, and FukamiT), certificated as members of the Japanese Board ofGeneral Thoracic Surgery, are in charge of the Department of Thoracic Surgery, University of Tokyo Hospital.
They specialize in surgical treatment of the diseases of
the respiratory and the mediastinal organs and the chest
wall, except for diseases of the esophagus and mammary glands. Approximately 200 surgeries are performed annually in the departmenｔ.
Primary lung cancer has been the leading cause ofdeath among the malignant neoplasms in our country.
As the number of the dead patients by the lung cancer
has been increasing, the basic and the clinical investigations for the treatment of the lung cancer are very
important. In our department, the staffs participate theclinical works, studies and educations of diagnostics
and therapeutics of the lung cancer as well as other
thoracic diseases.
We have performed the modern-style thoracoscopy
for the diagnosis and treatment of the thoracic diseases

227with less surgical invasiveness since 1992. Approximately a half of the surgical procedures in our department have been safely and successfully accomplishedthrough thoracoscopy. Researches on less-invasiveness,oncological advantage of the thoracoscopic surgery
have been studied actively.
Pulmonary metastasis represents far advanced malignant neoplasms of extrathoracic organs. Pulmonary
resection is an option for the treatment of pulmonary
metastasis. We actively perform pulmonary resection
through thoracoscopy on patients with pulmonary metastasis who are eligible for surgical therapy.
Thymic epithelial neoplasms, such as thymoma andthymic carcinoma, show broad spectrum in the degreeof malignancy. They also associated with paraneoplastic syndromes, such as the myasthenia gravis and thepure red cell aplasia. We have 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 inour department.

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

Current researches
Main subjects of current research at present
include basic and clinical studies on the malignant neoplasms in the thorax, transplantation of
the thoracic organs and the cryopreserved tissues. Recently we conducted clinical studies on
the immunotherapy with adopted gamma- deltaT-cell for the treatment of the advanced nonsmall cell lung cancer.
The following are the major themes under research:(1) New oncogenes or suppressor oncogenes ofthe lung cancer(2) New methods for quantitative analysis of the
DNA methylation of the lung cancer.
(3) Clinical studies on the less-invasive surgicaltreatment of the thoracic malignancies(4) Analysis of the factors influencing the prognosis of lung cancer or mediastinal neoplasms(5) Adoptive anticancer immunity of the autologous gamma-delta-T-cell(6) Mechanisms of acute or chronic rejection of
the allogeneic trachea graft.

Selected publications
1. Nakajima J. Takamoto S. Matsumoto J. Takeuchi E.
Ito YM. Effect of preoperative transbronchial biopsy on prognosis of non-small cell lung cancer.
Asian Cardiovascular & Thoracic Annals.12 (4):330-5, 2004
2. Shibahara J. Goto A. Niki T. Tanaka M. Nakajima J.
Fukayama M. Primary pulmonary paraganglioma:
report of a functioning case with immunohistochemical and ultrastructural study. American Journal of Surgical Pathology.28 (6): 825-9, 2004
3. Anraku M. Yokoi K. Nakagawa K. Fujisawa T.
Nakajima J. Akiyama H. Nishimura Y. Kobayashi
K. Metastatic Lung Tumor Study Group of Japan.
Pulmonary metastases from uterine malignancies:
results of surgical resection in 133 patients. Journalof Thoracic & Cardiovascular Surgery.127 (4):1107-12, 2004
4. Hara T. Ishii T. Fujishiro M. Masuda M. Ito T. Nakajima J. Inoue T. Matsuse T. Glutathione S-transferase P1 has protective effects on cell viability
against camptothecin. Cancer Letters.203 (2): 199207, 2004.
5. Goto A. Nakajima J. Hara K. Niki T. Fukayama M.
Lung adenocarcinoma associated with familial
adenomatous polyposis. Clear cell carcinoma withbeta-catenin accumulation accompanied by atypicaladenomatous hyperplasia. Virchows Archiv. 446(1):73-7, 2005
6. Goto A, Nakajima J, Hara K, Niki T, Fukayama M. Lung adenocarcinoma associatedwith familial adenomatous polyposis. Clear
cell carcinoma with beta-catenin accumulation accompanied by atypical adenomatous
hyperplasia. Virchows Arch. 2005 Jan; 446

228(1): 73-7.
7. Takeuchi E, Murakawa T, Tanaka M, Nakajima J, Takamoto S. Coccidioidomycosis of thelung contracted abroad. Jpn J Thorac Cardiovasc Surg. 2005 Mar; 53(3):173-5.
8. Nakajima J, Matsumoto J, Takeuchi E, Fukami T, Takamoto S. Rearrangement ofT-cell receptor beta and gamma genes inthymoma. Asian Cardiovasc Thorac Ann.
2005 Jun; 13(2): 149-52.
9. Nakajima J, Tanaka M, Matsumoto J, Takeuchi E, Fukami T, Takamoto S. Appraisalof surgical treatment for pulmonary metastasis from hepatocellular carcinoma. World J
Surg. 2005 Jun; 29(6): 715-8.
10. Akamatsu N, Sugawara Y, Nakajima J, Kishi Y, Niiya T, Kaneko J, Makuuchi M. Resection of a pulmonary lesion after livertransplantation: report of a case. Surg Today.
2005; 35(11): 976-8.
11. Nakajima J, Sato H, Takamoto S. Does preoperative transbronchial biopsy worsen thepostsurgical prognosis of lung cancer? A
propensity score-adjusted analysis. Chest.
2005 Nov; 128(5): 3512-8.
12. Murakawa T, Kerklo MM, Zamora MR, Wei Y,
Gill RG, Henson PM, Grover FL, Nicolls MR.
Simultaneous LFA-1 and CD40 ligand antagonism prevents airway remodeling in orthotopic airway transplantation: implications for the role of respiratory epithelium asa modulator of fibrosis. J Immunol. 2005 Apr
1; 174(7): 3869-79.

229

Department of
Cardiothoracic Surgery
Professor
Shinichi Takamoto, M.D.

Associate Professor
Arata Murakami, M.D.

Lecturer
Noboru Motomura, M.D.,
Minoru Ono, M.D.

Teturou Morota, M.D.,

Associate
Tetsuhiro Takaoka, M.D.,
Tetsuo Doi, M.D.

Tetsufumi Yamamoto, 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 was developed in the Department.
Establishment of Department of Thoracic Surgery in
the University of Tokyo Hospital was approved by thegovernment first in Japan December 15, 1964. Under
the leadership of Professor Kimoto excellent researchworks were created especially on pacemaker and artificial heart, and many opinion leaders were produced. Dr.
Masahiro Saigusa, the second Professor, endeavored tomake open heart surgery safer by introducing newgeneration heart-lung machines to the Department. Dr.
Kenichi Asano, the third Professor, started poste-rior-leaflet preserving mitral valve replacement first inJapan. He also dramatically improved surgical resultsof Tetralogy of Fallot. Dr. Akira Furuse, the fourth Professor, modernized management of extremely busy
clinical works. During this time, the Department was
divided into two Departments, Cardiovascular andGeneral 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 progressof cardiovascular surgery. Present staffs are one Chief
Professor, one Associate Professor and three Lecturer
and five Associates (two of them are in the US for research and clinical training).

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 and Thursday.
Adult patients are hospitalized in the South Wing of 5th

230

floor, and pediatric 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 2005 is about 300, which is one of
the highest in Japan. We are leading in Japan by showing excellent surgical results. There are eight Boardcertified surgeons, each of whom has his own subspecialty among adult cardiac, thoracic aortic or congenital
heart disease. We are famous for aortic valve sparing
root replacement, arch replacement using retrograde
cerebral perfusion, treatment of extended thoracic aortic
aneurysm, ventricular assist device implantation, offpump coronary artery bypass surgery, mitral valve
plasty and repair of complex congenital heart diseases,
such as Jatene, Fontan and Norwood operations.
The University of Tokyo Tissue Bank was founded in
1997, based on the Department of Cardiovascular Surgery. The Bank has been actively promoting procurement, preservation and shipping of human valve andblood vessel allograft in Japan. We take the lead in surgical treatment using allograft for severe active endocarditis or infection of aortic aneurysm or vascular
prosthesis. The University Hospital was approved by
the government as the fourth cardiac transplantation
center in Japan in 2002.

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We also take charge in clinical practiceon diagnosis of cardiovascular disease in the autumn
term at the 2nd grade. We expose the students to dailyclinical works as well as research works during thecourse of “Free Quarter” and “Research Lab Visit”,
which are scheduled in the summer and spring vacations at 1st and 2nd grade. Joint lectures with the Cardiology Department are scheduled 3rd through 4th grades.
Each student is assigned one or two cardiovascular surgical cases in the Bed Side Learning, in which he/she isrequired to learn preoperative patient evaluation andmanagement, surgical treatment and postoperative care,based on participatory 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 knowledgeof cardiovascular disease and surgery, and hemodynamic and respiratory evaluation as well as basic surgical techniques and patient management. Residents
who take the course of cardiovascular surgery are required four-year general surgical training. We havewell-developed specialty/ subspecialty training programs to allow the residents to pass Cardiovascular
Board Examination by 10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments, it isessential for cardiothoracic surgical department of the
University to have active research programs in clinicaland basic subjects. The cardiothoracic department of
the University of Tokyo has created highly active research programs in the every field of cardiothoracic
surgery, played an internationally leading role and contributed to its development. A research meeting is held
every Saturday on a research project for every memberof the department to understand and to make free thorough discussions of the subject.
Basic and/or clinical research activities are focusedon 1) new effective brain and spinal protection strategy,2) intracardiac repair technique on a beating heart
guided by three-dimensional echo, 3) basic and clinicalresearch on cryopreserved allograft, 4) treatment of
end-stage heart failure by ventricular assist device, 5) a
new technique of aortic valve sparing root replacement
and its hemodynamic evaluation, 6) regeneration ofischemic myocardium by growth factor, 7) postoperative adhesion-proof membrane, 8) treatment of acuteand chronic rejection after heart transplantation.

References
1. Higuchi K. Koseni K. Takamoto S.: Graft insertion
technique for distal anastomosis in cases of ascending aortic aneurysm. J Cardiovasc Surg 46:
537-8, 2005
2. Kubota H. Takamoto S. Furuse A. Sato M. Endo H.
Fujiki T. Sudo K.: Epicardial maze procedure on
the beating heart with an infrared coagulator. Ann
Thorac Surg 80:1081-6, 2005

231

3. Kawata M. Takamoto S. Morota T. Ono M.
Motomura N. Murakami A. Suematsu Y.: Is theguideline the cause of structural failure in current
polyester vascular prostheses? An experimental
study. Artif Organs. 29:820-5, 2005
4. Yamamoto T. Sata M. Fukuda D. Takamoto S.:
The angiotensin II type 1 receptor blocker valsartan
attenuates graft vasculopathy. Basic Res Cardiol
100:84-91, 2005
5. Miyaji K. Murakami A. Takasaki T. Ohara K.
Takamoto S. Yoshimura H.: Does a bidirec- tional
Glenn shunt improve the oxygenation of right ventricle-dependent coronary circulation in pulmonaryatresia with intact ventricular septum? J Thorac
Cardiovasc Surg 130:1050-3, 2005
6. Kawata M. Morota T. Takamoto S. Kubota H.
Kitahori K.: Non-anastomotic rupture in the guideline of a Dacron thoracic aortic graft. J Vasc Surg
42:573, 2005
7. Takamoto S.: Managing surgical quality based on
database. Jap J Thorac Cardiovasc Surge 53:337,
2005
8. Kitahori K. Takamoto S. Takayama H. Suematsu Y.
Ono M. Motomura N. Morota T. Takeuchi K.: A
novel protocol of retrograde cerebral perfusion withintermittent pressure augmentation for brain protection. J Thorac Cardiovasc Surg 130:363-70,
2005
9. Tanaka K. Sata M. Fukuda D. Suematsu Y.
Motomura N. Takamoto S. Hirata Y. Nagai R.:
Age-associated aortic stenosis in apolipoprotein
E-deficient mice. J Am Coll Cardiol 46:134-41,
2005
10. Miyairi T. Takamoto S. Kotsuka Y. Takeuchi A.
Yamanaka K. Sato H.: Comparison of neuroncognitive results after coronary artery bypass grafting
and thoracic aortic surgery using retrograde cerebral perfusion. Eur J Cardio- Thorac Surg 28:97101; 2005
11. Omoto R. Kyo S. Nishimura M. Matsuda H.
Matsumiya G. Kitamura S. Nakatani T. Takamoto
S. Ono M. Tabayashi K. Yozu R.: Japanese multicenter clinical evaluation of the HeartMate vented
electric left ventricular assist system. J Artif
Organs. 8:34-40, 2005
12. Kitamura T. Morota T. Motomura N. Ono M.
Shibata K. Ueno K. Kotsuka Y. Takamoto S.:

Management of infected grafts and aneurysms of
the aorta. Ann Vasc Surg 19:335-42, 2005
13. Kitamura T. Sata M. Motomura N. Takamoto S.:
Seeding of recipient bone marrow cells reduces
neointimal hyperplasia of deendo- thelialized rat
aortic allograft. Int Heart J 46:303-12, 2005
14. Taketani T. Imai Y. Morota T. Maemura K. Morita
H. Hayashi D. Yamazaki T. Nagai R. Takamoto S.:
Altered patterns of gene expression specific to thoracic aortic aneurysms: microarray analysis of surgically resected specimens. Int Heart J 46:265-77,
2005
15. Taketani T. Miyata T. Morota T. Takamoto S. Surgical treatment of atypical aortic coarctation complicating Takayasu's arteritis--experience with 33
cases over 44 years. J Vasc Surg 41:597-601, 2005
16. Hashimoto T. Sugawara Y. Kishi Y. Akamatsu N.
Matsui Y. Kokudo N. Motomura N. Takamoto S.
Makuuchi M.: Superior vena cava graft for right
liver and right lateral sector transplantation. Transplantation. 79:920-5, 2005
17. Hirata Y. Sata M. Motomura N. Takanashi M.
Suematsu Y. Ono M. Takamoto S.: Human umbilical cord blood cells improve cardiac function
after myocardial infarction. Biochem Bioph Res
Com 327:609-14, 2005
18. Taketani T. Motomura N. Toyokawa S. Kotsuka Y.
Takamoto S.: Beneficial effect of acute normovolemic hemodilution in cardio- vascular surgery.
Jap J Thorac Cardiovasc Surg 53:16-21, 2005
19. Miyaji K. Murakami A. Sato H. Takamoto S.: The
limiting factors for the transxiphoid approach incongenital cardiac surgery. Heart Surgery Forum.
7(3):E250-3, 2004.
20. Ueno K. Takamoto S. Miyairi T. Morota T. Shibata
K. Murakami A. Kotsuka Y.: Multichannel monitoring of cerebral circulatory and oxygenation
status using optical topography during deep hypothermic retrograde cerebral perfusion. Vascular.
12:325-30, 2004
21. Suematsu Y. Anttila V. Takamoto S. del Nido P.:
Cardioprotection afforded by ischemic pre- conditioning interferes with chronic beta- blocker treatment. Scan Cardiovasc J 38:293-9, 2004
22. Maeda K. Murakami A. Takaoka T. Takamoto S.
Sano K. Makuuchi M.: Usefulness of intra- operative color doppler ultrasonography in decision

232

making regarding conversion of an accessory hepatic vein after a Fontan-type operation. Pediatr
Cardiol 25:414-6, 2004
23. Maeda K. Yamaki S. Kado H. Asou T. Murakami
A. Takamoto S. Reevaluation of histomorphometric analysis of lung tissue in decision making for
better patient selection for fontan-type operations.
Ann Thorac Surg 78:1371-81, 2004
24. Maeda K. Yamaki S. Kado H. Asou T. Murakami
A. Takamoto S.: Hypoplasia of the small pulmonary arteries in hypoplastic left heart syndrome
with restrictive atrial septal defect. Circulation
110(11 Suppl 1):II139-46, 2004
25. Kubota H. Takamoto S. Ohtsuka T. Endo H. Sato
M. Fujiki T. Sudo K.: Epicardial pulmonary vein
isolation with a hook-shaped cryoprobe to treat
atrial fibrillation. Ann Thorac Surg 78:1056-9,
2004
26. Suematsu Y. Marx GR. Triedman JK. Mihaljevic T.
Mora BN. Takamoto S. del Nido PJ.: Three-dimensional echocardiography- guided atrial septectomy: an experimental study. J Thorac Cardiovasc
Surge 128:53-9, 2004
27. Miyairi T. Takamoto S. Kotsuka Y. Takeuchi A.
Yamanaka K. Sato H.: Neurocognitive outcome
after retrograde cerebral perfusion. Ann Thorac
Surg 77:1630-3, 2004
28. Murakami A. Takaoka T. Kobayashi J. Maeda K.
Yamamoto T. Motomura N. Takamoto S. Sugimura
H. Shibuya K. Kato H. Yamaki S.: In situ implantation of a valved femoral vein allograft in a neonate with pulmonary atresia with intact ventricular
septum and severe tricuspid regurgitation. J Thorac
Cardiovasc Surg 127:1198-9, 2004
29. Maeda K. Yamaki S. Yokota M. Murakami A.
Takamoto S.: Hypoplasia of the small pulmonary
arteries in total anomalous pulmonary venous connection with obstructed pulmonary venous drainage.
J Thorac Cardiovasc Surg 127:448-56, 2004
30. Takeuchi K. Otaki M. Kitamura N. Odagiri S.
Maeda K. Takaoka T. Murakami A. Takamoto S.:
Thoracic surgery residency program and healthcare system in the United States. Jap J of Thorac
Cardiovas Surg. 52:401-6, 2004
31. Takayama H. Otsuka T. Kubota H. Shibata K.
Kitamura T. Takamoto S.: Pseudoaneurysm developed after aortic root homograft implantation. Jap J

Thorac Cardiovasc Surg 52:158-60, 2004
32. Taketani T. Morota T. Shibata K. Kotsuka Y.
Takamoto S.: Thrombus originating from frayeddistal edge of an aortic stent-graft. Jap J Thorac
Cardiovasc Surg 52:95-7, 2004
33. Taketani T. Morota T. Shibata K. Motomura N.
Kotsuka Y. Takamoto S.: Successful repair of graft
failure and abdominal aortic aneurysm following
thoracoabdominal bypass for atypical aortic coarctation. Jap J Thorac Cardiovasc Surg 52:91-4, 2004

233

Department of
Gastrointestinal Surgery
Professor:
Michio Kaminishi, M.D.

Lecturer:
Sachiyo Nomura,M.D.

Associate:
Hirokazu Yamaguchi, M.D.
Kouji Nozaki, M.D.
Kazuhiko Yamada,MD.
Akemi Yoshikawa, M.D.
Ikuo Wada, M.D.

Nobuyuki Shimizu, M.D.
Tetsuya Ueda, M.D.
Atsushi Kaneda,MD.
Kazuhiko Mori, M.D.

Homepage
General Affairs:
Since 2001, the former Third Department of Surgery,which was located in a branch hospital of the University of Tokyo, has been divided into two departments,
the Department of Gastrointestinal Surgery and theDepartment of Metabolic Care and Endocrine Surgery,in line with the integration of the main and branch hospitals the elevation to a department in the graduate
school of medicine at our university. Our research activities in both departments have been well organized
and ultimately successful by maintaining a close connection. The Department of Gastrointestinal Surgery
presently comprises one Professor, one Lecturer，one
Hospital Lecturer and nine associates.
With the prolongation of life expectancy, there are
increasing numbers of multi-morbid patients requiring
multi-organ treatment, as well as a greater need for
multidisciplinary approaches to the patients. Our clinical and research activities have for the most part received the cooperation of members in the Departmentof Metabolic Care and Endocrine Surgery as well as
those in other surgical departments at the University ofTokyo.
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 lifespan provides a wealth of valuable information concerning theappropriateness of current treatment strategy, the establishment of new surgical designs, the development of
new basic research activities which can much contribute to clinical fields, and indications of desirable modesof 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:
We educate chief residents and junior residents inrotation ．Our educational systems for residents andstudents reflect our aforementioned principles. Medical
students are encouraged to be members of clinical staffs

234

rather than mere students during their bedside
Ｌearning. They learn generic patient care which encompasses not only perioperative management of diseases but also non-surgical management of postoperative disorders and terminal care. Our educational system provides medical students with a great deal ofpractical information from the medical point of view aswell as better opportunities to ponder the implicationsof life and death.
Junior residents rotate every three months. Aftercompletion of their initial training program, they go
into a further clinical training program for several consecutive years and become a chief resident. We havealso several postgraduate students who are mainly engaged in research work. Their research workｓ ａｒｅunder supervision of the Professor.

Research Activities:
The main research activities of the department of
Gastrointestinal Surgery are focused on diagnosis andtherapy for gastrointestinal diseases and clinical andbasic research for gastrointestinal carcinogenesis fromthe view point of “Surgery and Inflammation”. The department's research activities have focused on a wide
spectrum of research topics, ranging from basic research topics to clinical ones. Our research activities
have been well organized and ultimately achieved bymaintaining a close connection between hospital andlaboratory activities. Our medical staffs make every
effort to promote the research activities and obtain successful results. Current research topics are:1) Carcinogenesis of gastrointestinal cancer-Diversity of gastointestinal carcinogenesis-Gender differences in gastrointestinal cancers-Roles of sex hormones in gastrointetinal carcinogenesis-Monoclonality of intestinal metaplasia-Roles of Helicobactor pylori infection in gastriccarcinogenesis-Interaction between cancer and interstitial tissue-Experimental evaluation of promotive mechanisms of gastroduodenal reflux and denervation of
the gastric mucosa in gastric remnant carcinogenesis-Preventative roles of PPARr in gastric carcino-

genesis-Clinical and experimental studies on the Barrett
esophagus
2) Molecular mechanisms of gastrointestinal tract
cancer-Role of bone marrow derived progenitor cells ingastric carcinogenesis-Apoptosis-related molecules during multimodal
therapies for esophageal cancer-Angiogenic factors in gastrointestinal tract cancer-Genetic alterations in gastric cancer and colorectal
cancer-Methylation status of gastrointestinal cancers-Lymph node micrometastasis of gastric cancer
3) Minimally invasive surgery for the treatment of earlycancer of the stomach and large intestine-Endoscopic treatment-Laparoscopic surgery-Optimal scope of lymphadenectomy-Sentinel lymph node navigation surgery for earlygastric cancer-Evaluation of postoperative QOL after pylorus
preserving gastrectomy (PPG) and jejunal interposition for early gastric cancer4) Alternative surgical design for the improvement of
the patient's postoperative quality of life5) Radical treatment for advanced gastric cancer6) Multimodal treatment for gastrointestinal tract
cancer-Neoadjuvant or definitive chemoradiation therapy
for esophageal cancer-Neoadjuvant or adjuvant chemotherapy for gastricand colorectal cancer7) Gastrointestinal motility-Mechanism of pepermint oil solution of digestive
tract-Role of cytokine and COX-2 in gastrointestinal
motility-Manipulation of the intestine and postoperative
motility

235

Clinical Activities:
We have outpatient clinics from Monday throughFriday. We have specialized divisions for outpatientmanagement of esophageal, gastric, and colorectal diseases. The ward is divided into four subgroups, andeach of them has one medical staff for supervision, one
assistant supervisor, one chief resident, and one or two
junior residents in rotation. They are on duty for daily
patient care under the supervision of medical staffs.
Ordinary, each subgroup takes care of 10-12 patients.
We have our own multidisciplinary disease evaluation systems for inpatients and outpatients, such as endoscopy and endoscopic ultrasonography for upper andlower gastrointestinal tracts, ultrasound diagnosis, andbarium roentgenogram. These multidisciplinary services provide good opportunities to evaluate the diseases systematically from the surgeon's standpoint. We
also perform endoscopic treatment, especially mucosal
resection for strictly selected early cancers in the upperand lower gastrointestinal tract.
The weekly official activities of our department are
Ward Rounds by the Professor on Monday and by the
Associate Professor on Friday. We have post- and preoperative case conferences on Tuesday, Wednesday andThursday morning, respectively, and a journal club on
Monday. We also have a specialized upper gastrointestinal case conference on Tuesday evening. Nursing-staffs have meetings with medical doctors on every
Friday to ensure a high quality of patient care during
the patients' hospital stay.
Generally, elective surgery is scheduled on Tuesday，
Wednesday and Thursday. The statistics for 20５ show
more than 250 cases of elective surgery and emergency
surgery. All residents and medical personnel work many
extra hours with high motivation whenever it is necessary for the good of the patients.

References (2002 - March 2004)
1. A. Kaneda，M. Kaminishi，K. Yanagihara，T. Sugimura，T. Ushijima. Identification of silencing ofnine genes in human gastric cancers. Cancer Res
62：6645-6650, 2002
2. A. Kaneda，M. Kaminishi，Y. Nakanishi，T. Sugimura，T. Ushijima. Reduced expression of the insulin-induced protein 1 and p41 Arp2/3 complex

genes in human gastric cancers. Int J Cancer 100：
57-62,2002
3. A. Suzuki ， G. Kusakai ， A. Kishimoto ， J. Lu ，T.Ogura，MF. Lavin，H. Esumi. Identification of anovel protein kinase mediating Akt survival signaling to the ATM protein. J Biol Chem 278：48-53,
2002
4. H. Yamaguchi，J.R. Goldenring，M. Kaminishi，
J.R. Lee. Identification of Spasmolytic Polypeptide
Expressing Metaplasia（SPEM）in Remnant Gastric
Cancer and Surveillance Postgastrectomy Biopsies.
Dig Dis Science 47：573-578，2002
5. H. Yamaguchi，J.R. Goldenring，M. Kaminishi，
J.R. Lee. Association of Spasmolytic PolypeptideExpressing Metaplasia with Caricinogen Administration and Oxyntic Atrophy in Rats. Lab Invest
82：1045-1052, 2002
6. K. Kubota，S. Shimoyama，N. Shimizu，C. Noguchi，K. Mafune，M. Kaminishi，T. Tange. Studiesof 13C-urea breath test for diagnosis of Helicobacter pylori infection in patients after partial gastrectomy. Digestion 65：82-86, 2002
7. K. Nozaki，N. Shimizu，T. Tsukamoto，K. Inada，
X. Cao，Y. Ikehara，M. Kaminishi，A. Sugiyama，
M. Tatematsu. Reversibility of Heperotopic Proliferative Glands in Glandular Stomach of Helicobacter pylori-infected Mongolian Gerbils on
Eradication. Jpn J Cancer Res 93：374-381, 2002
8. K. Nozaki，N. Shimizu，K. Inada，T. Tsukamoto，
M. Inoue，T. Kumagai，A. Sugiyama，T. Mizoshita，
M. Kaminishi，M. Tatematsu. Synergistic Promoting Effects of Helicobacter pylori Infection andHigh-salt Diet on Gastric Carcinogenesis in Mongolian Gerbils. Jpn J Cancer Res 93：1083- 1089,
2002
9. M. Abe，E. Okochi，T. Kuramoto，A. Kaneda，T.
Takato，T. Sugimura，T. Ushijima. Cloning of the
57 Upstream Region of the Rat p16 Gene and Its
Role in Silencing. Jpn J Cancer Res 93：1100-1106,
2002
10. M. Kaminishi，H. Yamaguchi，S. Nomura，T. Oohara ， S. Sakai ， H. Fukutomi ， A. Nakahara ，H.
Kashimura ， M. Oda ， T. Kitahora. Endoscopic
Classificarion of Chronic Gastritis Based on a Pilot
Study by the Reserch Society for Gastriis. Dig Endoscopy 14：138-151, 2002
11. M. Kawahara, M. Kammori，H. Kanauchi，T. No-

236

guchi，S. Kuramoto，H. Endo，M. Kaminishi，K.
Takubo. Prognostic indicators of gastrointestinal
carcinoid tumors, with special refrence to the immunohistochemical detection of p21, p53, E-cadherin,
cyclin D1, Rb, bcl-2, and Ki-67. J Surg Oncol 28：
140-146, 2002
12. QL. Li，K. Ito，C. Sakakura，H. Fukamachi，K.
Inoue，XZ. Chi，KY. Lee，S. Nomura，CW. Lee，SB. Han，HM. Kim，WJ. Kim，H. Yamamoto，N.
Yamashita，T. Yano，T. Ikeda，S. Itohara，J. Inazawa，T. Abe，A. Hagiwara，H. Yamagishi，A. Ooe，A. Kaneda，T. Sugimura，T. Ushijima. Causal relationship between the loss of RUNX3 expression
and gastric cancer. Cell 109：113-124, 2002
13. S. Shimoyama ， Y. Mochizuki ， O. Kusada ， M.
Kaminishi. Supra-additive antitumor activity of
5FU with tumor necrosis factor-related apoptosis-inducing ligand on gastric and colon cancers
in vitro. Int J Oncol 21：643-648, 2002
14. T. Mimura，M. Kaminishi，MA. Kamm. Probiotics
for pouchitis and its endoscopic findings. Dig Endosc 14：47-52, 2002
15. T. Mimura，F. Rizzello，U. Hewlwig，G. Poggioli，
S. Schreiber ， IC. Talbot ， RJ. Nicholls ， P.
Gionchetti，M. Campieri，MA. Kamm. Four week
open label trial of metronidazole and ciprofloxacin
for the treatment of recurrent or refractomy pouchitis. Aliment Pharm Therapeut 16：909-917, 2002
16. T. Mimura，T. Nicholls，JB. Storrie，MA. Kamm.
Treatment of constipation in adults associated with
idiopathic megarectum by behavioural retraining（Biofeedback）. Col Dis 4：477-482, 2002
17. X. Cao，T. Tsukamoto，K. Nozaki，H. Tanaka，N.
Shimizu ， M. Kaminishi ， T. Kumagai ， M. Tatematsu. Earlier Helicobacte pylori Infection Increases the Risk for the N-Methyl-N-nitrosoureainduced Stomach Carcinogenesis in Mongolian
Gerbils. Jpn J Cancer Res 93：1293-1298, 2002
18. Y. Seto，M. Kaminishi，A. Yafune. An Experimental Study of Jejunal Pouch Replacements following
Total Gastrectomy. Hepatogastroenterol 49 ：853-856, 2002
19. K. Kato，Y. Hitomi，K. Imamura，H. Esumi. Hyperstable U1snRNA complementary to the K-ras
transcripts induces cell death. Br J Cancer 87：
898-904, 2002
20. K. Hashimoto，K. Kato，K. Imamura，A. Kishi-

moto ， H. Yoshikawa ， Y. Taketani ， H. Esumi.
5-amino-4-imidazolecarboxamide riboside confers
strong tolerance to glucose. Biochem Biophys Res
Commun 290：263-267, 2002
21. S. Shimoyama，N. Shimizu，E. Tsuji，K. Yamasaki，
M. Kawahara，M. Kaminishi. Distribution of angiogenin and its gene message in colorectal cancer
patients and their clinical relevance. Anticancer Res
22：1045-1052, 2002
22. S. Shimoyama ， H. Yasuda ， K. Mafune ， M.
Kaminishi. Indications of a minimized scope of
Lymphadenectomy for submucosal gastric cancer.
Ann Surg Oncol 9：625-631, 2002
23. K. Nozaki, N. Shimizu, Y. Ikehara, M. Inoue, T.
Tsukamoto, K. Inada, H. Tanaka, T. Kumagai,
M.Kaminishi. Effect of early eradication on
Helicobacter pylori-related gastric carcinogenesis
in Mongolian gerbils. Cancer Sci 94:235-239, 2003
24. H. Takikawa, K. Mafune, H. Hamada, DM.
Mettelbeck, R. Muller, M. Makuuchi, M.
Kaminishi. An advanced strategy of enhanced specific gene expression for hepatocellular carcinoma.
Int J Oncol 22:1051-1056,2003
25. A. Kaneda, D. Takai, M. Kaminishi, E. Okochi, T.
Ushijima. Methylation-Sensitive Representational
Difference Analysis and Its Application to Cancer
Research. Ann NY Acad Sci 983:131-141,2003
26. K. Kubota, H. Nakanishi, N. Hiki, N. Shimizu, E.
Tsuji, H.Yamaguchi, K. Mafune, T. Tange, M. Tatematsu. Quantitative detection of micrometastasesin the lymphnodes of gastric cancer patients withreal-time RT-PCR: A comparative study with immunohistochemistry. Int J Cancer 105:136-143,
2003
27. K. Kubota, S. Nomura, M. Kawahara, M.
Kaminishi. Familial urachal sinus associated with apossible congenital malformation:report of a case.
Surgery Today 33: 237-239,2003
28. K. Kubota, N. Hiki, N. Shimizu, S. Shimoyama, C.
Noguchi, T. Tange, K. Mafune, M. Kaminishi. Utility of [13C]urea breath test for Helicobacter pylori
detection in partial gastrectomy patients. Dig Dis
Sci 48: 2135-2138,2003
29. M. Tatematsu, K. Nozaki, T. Tsukamoto. Helicobacter pylori infection and gastric carcinogenesis in
animal models.Gastric Cancer 6:1-7,2003
30. T. Tsukamoto, M Yamamoto, N. Ogasawara, T.

237

Ushijima, T. Nomoto, H. Fujita, T. Matsushima, K.
Nozaki, X. Cao. beta-Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas. Cancer Sci 94: 1046- 1051,
2003
31. S. Shimoyama, F. Aoki, N. Shimizu, Y. Tatsutomi,
K. Mafune, M. Kaminishi. Activity and safety of alow dose, fractional administration of irinotecanhydrochloride (CPT-11) in combination with cisplatin for relapsed gastric cancer patients: a preliminary report. Int J Clin Oncol 8:49-52, 2003
32. T. Ushijima, N. Watanabe, E. Okochi, A. Kaneda, T.
Sugimoto, K. Miyamoto. Fifrlity of The Methylation Pattern and Its Variation in the Genome. Genome Res 13: 863-874,2003
33. N. Hiki, H. Kurosaka, Y. Tatsutomi, H. Yamaguchi,
N. Shimizu, K. Kubota, F. Aoki, S. Shimoyama, T.
Hirooka, K. Mafune, M. Kaminishi. Case of Gastric Outlet Stenosis With Features of Pyloric Stenosis Diagnosed by Using Peppermint Oil Solution asa New Antispasmodic. Dig Endosc 15: 224-227,
2003
34. N.Hiki, Y.Takeshita, E.Tsuji, H.Yamaguchi,
N.Shimizu, K. Imamura, S.Shimoyama, K.Mafune,
M.Kaminishi. A seasonal variation in the onset of
postoperative adhesive small bowel obstruction isrelated to changes in the climate. Dig Liver Dis 36：
125-129,2004
35. K. Mori, K. Aoyagi, T. Ueda, I. Danjoh,Y. Tsubosa,K. Yanagihara, Y. Matsuno, M.Sasako, K.Mafune,
M. Kaminishi. Highly specific marker genes for
detecting minimal gastric cancer cells in cytology
negative peritoneal washings. Biochem Biophy Res
Commun 313：931-937,2004
36. A.Kaneda,
T.Tsukamoto,
T.Takamura-Enya,
N.Watanabe, M. Kaminishi, T.Sugimura, M. Tatematsu,T.Ushijima. Frequent hypomethylation in
multipl epromoter CpG islands is associated with
global hypomethylation, but not with frequent
promoter hypermethylation. Cancer Sci 95：58-64,
2004
37. K.Kubota,T.Akasu, S.Fujita, K.Mafune, K.Sugihara,
Y.Moriya, S. Yamamoto. Clinical and Pathological
Prognostic Indicators with Colorectal Mucinous
Carcinomas. HepatoGastroenterol 51 ： 142-146,
2004
38. T.Mizoshita, K.Inada, T.Tsukamoto, K. Nozaki,

T.Joh, M. Itoh, Y. Yamamura, T.Ushijima, S. Nakamura. Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift toan intestinal phenotype in gastric cancer cells,J
Cancer Res Clin Oncol：in press, 2004
39. S. Nomura, M.Kaminishi, N.Takagi, H.Esumi.
Analysis of promotor redion of X-linked pgk1 genepolumorphisms: Evidence for polyclonality of adultmouse gastric glands. Dig Dis Sci 49：in press,2004
40. S.Nomura, T. Baxter, H. Yamaguchi, C.Leys, B.
Vartapetian, J.G.Fox, J.R. Lee, C. Wang, J.R.
Goldenring. Spasmolytic polpeptide expressing
127:582-594,2004

238

Department of Hepatobiliary
Pancreatic Surgery andDepartment of Artificial Organ
and Transplantation Surgery
Professor
Masatoshi Makuuchi, MD

Associate Professor
Norihiro Kokudo, MD,

Yasuhiko Sugawara, MD

Lecturer
Yoshifumi Beck, MD,

Hiroshi Imamura, MD,

Keiji Sano, MD

Katsutoshi Naruse, MD,
Kiyoshi Hasegawa, MD,
Junichi Kaneko, MD,

Hideki Abe, MD,
Sumihito Tamura, MD,
Yasuji Seyama, MD

Associates
Masami Minagawa, MD,
Wei Tang, MD,
Yasushi Midorikawa, MD,

Homepage
Organization
We specialize in hepato-pancreato-biliary surgery
and liver transplantation. The Hepatobiliary Pancreatic
Surgery Division and Artificial Organ and Transplantation Surgery Division precede the Second Departmentof Surgery, which was established in 1893. A professor
and chairman, two associate professors, three lecturers,
and nine associates take part in inpatient and outpatientcare as well as teaching and research activities. Department of plastic surgery, anesthesiology and staff ofintensive care unit assist us in performing liver transplantation. Research on artificial liver is actively performed by Dr. Katsutoshi Naruse.

Clinical Activities
We shared around 60 beds mainly on the A9 northfloor ward with hepatobiliary pancreatic surgery andtransplantation division, high care unit and intensive
care unit on the A4 floor. Each inpatient is taken care of
by senior and junior specialist surgeons and a resident
in the field of his or her disease throughout the pre- andpostoperative periods. Staff members are responsible
for the entire care of the patients on a 24-hour-a-day
basis. Elective operations are carried out on Monday,
Wednesday and Friday.
Form January 1996 to December 2005, the PediatricSurgery Division and our department performed around
350 living donor and one deceased donor liver transplantation. The operative mortality is around 5%.
Clinical conferences are held every day in which thelaboratory data and clinical status of the transplants are
discussed. Professor’s ward round for inpatients is performed on Tuesday, Thursday and holidays. Out patient
clinic is conducted in collaboration with other department of surgery. We have both general and special outpatient clinic. Specialist surgeons in liver transplanta-

239

tion surgery are in service on Monday, Tuesday andThursday.

Teaching Activities
We take part in clinical lectures and bed-side teaching for medical students in cooperation with the otherdepartments. Bed-side teaching is provided to the fifthand sixth grade students on a man-to-man basis withstaff members. During a three-week period each student
learns the basic way of thinking for correct diagnosis
and treatment, fundamental techniques of radiologicalexaminations and laboratory data, and pre- and postoperative patient care.
Doctor course students are doing research work under the supervision of the professor and the staff members. If they think it necessary, they can participate inclinical patient care as a junior specialist surgeon.
Residents learn basic patient care and operative procedures at the university hospital. Subsequently they
are sent to subsidiary hospitals for two years to learn
further surgical activities. After this postgraduate training course they decide whether they take a doctor
course.

References (2004-2005)
1. Hasegawa K, Kokudo N, Imamura H, Matsuyama
Y, Aoki T, Minagawa M, Sano K, Sugawara Y,Takayama T, Makuuchi M. Prognostic impact ofanatomic resection for hepatocellular carcinoma.
Ann Surg 2005 Aug;242(2):252-9.
2. Kokudo N, Imamura H, Sano K, Zhang K, Hasegawa K, Sugawara Y, Makuuchi M. Ultrasonicallyassisted retrohepatic dissection for a liver hanging
maneuver. Ann Surg 2005 Nov;242(5):651-4.
3. Kokudo N, Sugawara Y, Imamura H, Sano K, Makuuchi M. Tailoring the type of donor hepatectomy
for adult living donor liver transplantation. Am J
Transplant 2005 Jul;5(7):1694-703.
4. Sugawara Y, Makuuchi M. Should living donorliver transplantation be offered to patients with
hepatitis C virus cirrhosis? J Hepatol 2005 Apr;42(4):472-5.
5. Sugawara Y, Makuuchi M. Intraoperative direct
measurement of hepatic arterial buffer response inpatients with or without cirrhosis. Liver Transpl
2005 Jun;11(6):684-91.
6. Hashimoto T, Sugawara Y, Kishi Y, Akamatsu N,
Matsui Y, Kokudo N, Makuuchi M. Reconstructionof the middle hepatic vein tributary in a right lateral
sector graft. Liver Transpl 2005 Mar;11(3):309-13.
7. Kishi Y, Sugawara Y, Matsui Y, Akamatsu N,
Motomura N, Takamoto S, Makuuchi M. Alternatives to the double vena cava method in partial livertransplantation. Liver Transpl 2005 Jan;11(1):1013.
8. Okazaki M, Asato H, Takushima A, Nakatsuka T,
Sarukawa S, Inoue K, Harii K, Sugawara Y, Makuuchi M. Hepatic artery reconstruction with double-needle microsuture in living-donor liver transplantation. Liver Transpl 2006 Jan;12(1):46-50.
9. Satou S, Sugawara Y, Kokudo N, Makuuchi M.
Preoperative detection of hepatic venous collaterals
in right liver graft. Liver Transpl 2005 Jun;11(6):708-9.
10. Takemura N, Sugawara Y, Hashimoto T, Akamatsu
N, Kishi Y, Tamura S, Makuuchi M. New hepaticvein reconstruction in left liver graft. Liver Transpl
2005 Mar;11(3):356-60.
11. Yamazaki S, Takayama T, Inoue K, Higaki T,
Makuuchi M. Interposition of autologous portal
vein graft in left liver transplantation. Liver Transpl
2005 Dec;11(12):1615-6.
12. Arita J, Hasegawa K, Kokudo N, Sano K, Sugawara Y, Makuuchi M. Randomized clinical trial of
the effect of a saline-linked radiofrequency coagulator on blood loss during hepatic resection. Br J
Surg 2005 Aug;92(8):954-9.
13. Akamatsu N, Sugawara Y, Tamura S, Kaneko J,
Togashi J, Kishi Y, Imamura H, Kokudo N, Makuuchi M. Prevention of renal impairment by continuous infusion of human atrial natriuretic peptide
after liver transplantation. Transplantation 2005
Oct 27;80(8):1093-8.
14. Hashimoto T, Sugawara Y, Kishi Y, Akamatsu N,
Matsui Y, Kokudo N, Motomura N, Takamoto S,
Makuuchi M. Superior vena cava graft for right
liver and right lateral sector transplantation. Transplantation 2005 Apr 27;79(8):920-5.
15. Tamura S, Sugawara Y, Matsui Y, Kishi Y, Akamatsu N, Kaneko J, Makuuchi M. Thrombotic mi-240

croangiopathy in living-donor liver transplantation.
Transplantation 2005 Jul 27;80(2):169-75.
16. Otani T, Matsukura A, Takamoto T, Seyama Y,
Shimizu Y, Shinomiya M, Usui H, Gorelick FS,
Makuuchi M. ffects of Pancreatic Duct Ligation on
the Pancreatic Response to Bombesin. Am J
Physiol Gastrointest Liver Physiol 2005 Nov 17
17. Guo Q, Tang W, Kokudo N, Sugawara Y, Miki K,
Karako H, Qu X, Nakata M, Fujita-Yamaguchi Y,
Makuuchi M. Epidermal growth factor-mediatedgrowth control of confluent mammary epithelial
cells cultured on artificial basement membrane. Int
J Mol Med 2005 Sep;16(3):395-9.
18. Abe H, Kimura W, Mori M, Makuuchi M, Yanagisawam A. Mixed serous cystadenoma with mucinous cystadenoma of the pancreas.Pancreas 2005
Jul;31(1):98-100.
19. Natori T, Sata M, Nagai R, Makuuchi M. Cimetidine inhibits angiogenesis and suppresses tumor growth. Biomed Pharmacother 2005 Jan-Feb;
59(1-2):56-60.
20. Tang W, Kokudo N, Sugawara Y, Guo Q, Imamura
H, Sano K, Karako H, Qu X, Nakata M, Makuuchi
M. Des-gamma-carboxyprothrombin expression incancer and/or non-cancer liver tissues: association
with survival of patients with resectable hepatocellular carcinoma. Oncol Rep 2005 Jan;13(1):25-30.
21. Kaneko J, Sugawara Y, Tamura S, Togashi J, Matsui Y, Akamatsu N, Kishi Y, Makuuchi M. Coagulation and fibrinolytic profiles and appropriate
use of heparin after living-donor liver transplantation. Clin Transplant 2005 Dec;19(6):804-9.
22. Kishi Y, Sugawara Y, Akamatsu N, Kaneko J,
Tamura S, Kokudo N, Makuuchi M. Splenectomy
and preemptive interferon therapy for hepatitis C
patients after living-donor liver transplantation.
Clin Transplant 2005 Dec;19(6):769-72.
23. Tamura S, Sugawara Y, Kishi Y, Akamatsu N,
Kaneko J, Makuuchi M. Living-related liver transplantation for Wilson's disease. Clin Transplant2005 Aug;19(4):483-6.
24. Hasegawa K, Sugawara Y, Imamura H, Ikeda M,
Kokudo N, Makuuchi M. Living donor liver transplantation for primary biliary cirrhosis: retrospective analysis of 50 patients in a single center.
Transpl Int 2005 Jul;18(7):794-9.

25. Kishi Y, Sugawara Y, Tamura S, Kaneko J, Akamatsu N, Togashi J, Makuuchi M. I blood eosinophilia an effective predictor of acute rejection inliving donor liver transplantation? Transpl Int 2005
Oct;18(10):1147-51.
26. Kyoden Y, Sugawara Y, Matsui Y, Kishi Y, Akamatsu N, Makuuchi M. Hepatofugal portal flow
due to acute cellular rejection. Abdom Imaging
2005 May-Jun;30(3):303-5.
27. Akamatsu N, Sugawara Y, Kaneko J, Kishi Y,
Makuuchi M. Risk factors of cytomegalovirus infection after living donor liver transplantation.
Hepatogastroenterology 2005 Jan-Feb;52(61):1979.
28. Kaneko J, Sugawara Y, Akamatsu N, Kishi Y,
Kokudo N, Makuuchi M. Implantable Doppler
probe for continuous monitoring of blood flow after liver transplantation. Hepatogastroenterology
2005 Jan-Feb;52(61):194-6.
29. Kaneko J, Sugawara Y, Matsui Y, Akamatsu N,
Kishi Y, Makuuchi M. Correlation between drainage area volume of middle hepatic vein and liverfunction. Hepatogastroenterology 2005 May-Jun;
52(63):866-8.
30. Kobayashi T, Makuuchi M, Sano K, Koyama K,
Motoi T. Repeated obstructive jaundice and acutepancreatitis caused by metastatic liver tumor: an
unusual case. Hepatogastroenterology 2005 JanFeb;52(61):220-2.
31. Seyama Y, Makuuchi M, Takayama T, Cescon M,
Kokudo N. Can a small ultrasonic dissector
equipped for electrocautery improve the results ofhepatic resection? Hepatogastroenterology. 2005
Nov-Dec;52(66):1845-8.
32. Sugawara Y, Matsui Y, Noritomi T, Kaneko J,
Makuuchi M. Safe bile duct division in right lateral
sector graft. Hepatogastroenterology. 2005 JanFeb;52(61):170-2.
33. Tang W, Guo Q, Usuda M, Kokudo N, Seyama Y,
Minagawa M, Sugawara Y, Nakata M, Kojima N,
Makuuchi M. Histochemical expression of sialoglycoconjugates in carcinoma of the papilla of
Vater. Hepatogastroenterology 2005 Jan-Feb;52(61):67-71.
34. Yuan LW, Tang W, Kokudo N, Seyama Y, Shi YZ,
Karako H, Zhao B, Sugawara Y, Nagawa H, Makuuchi M. Disruption of pRb-p16INK4 pathway: a241common event in ampullary carcinogenesis. Hepatogastroenterology 2005 Jan-Feb;52(61):55-9.
35. Akamatsu N, Sugawara Y, Nakajima J, Kishi Y,
Niiya T, Kaneko J, Makuuchi M. Resection of apulmonary lesion after liver transplantation: reportof a case. Surg Today. 2005;35(11):976-8.
36. Naruse K, Nagashima H, Sakai Y, Kokudo N, Makuuchi M. Development and perspectives of perfusion treatment for liver failure. Surg Today 2005;
35(7):507-17.
37. Hashimoto T, Sugawara Y, Kishi Y, Akamatsu N,
Tamura S, Hasegawa K, Imamura H, Kokudo N,
Makuuchi M. Long-Term Survival and Causes of
Late Graft Loss After Adult-to-Adult Living Donor
Liver Transplantation. Transplant Proc. 2005 Dec;
37(10):4383-5.
38. Ishizawa T, Sugawara Y, Ikeda M, Hasegawa K,
Makuuchi M. Optimal initial dose of orally administered cyclosporine following intravenous cyclosporine therapy. Transplant Proc 2005 Dec;37(10):4370-2.
39. Kaneko J, Sugawara Y, Sato S, Kishi Y, Akamatsu
N, Togashi J, Makuuchi M. Relation between the
middle hepatic vein drainage area volume andalanine aminotransferease after left liver harvesting.
Transplant Proc 2005 Jun;37(5):2166-8.
40. Naruse K, Ishikawa H, Kawano HO, Ueda H, Kurome M, Miyazaki K, Endo M, Sawasaki T, Nagashima H, Makuuchi M. Production of a transgenic
pig expressing human albumin and enhanced green
fluorescent protein. J Reprod Dev 2005 Aug;51(4):539-46.
41. Akamatsu N, Sugawara Y, Nakajima J, Kishi Y,
Kaneko J, Makuuchi M. Cryptococcosis after living donor liver transplantation: report of three cases.
Transpl Infect Dis 2005 Mar;7(1):26-9.
42. Deli G, Jin CH, Mu R, Yang S, Liang Y, Chen D,
Makuuchi M. Immunohistochemical assessment ofangiogenesis in hepatocellular carcinoma and surrounding cirrhotic liver tissues. World J Gastroenterol 2005 Feb 21;11(7):960-3.
43. Imamura H, Sano K, Sugawara Y, Kokudo N, Makuuchi M. Assessment of hepatic reserve for indication of hepatic resection: decision tree incorporating indocyanine green test. J Hepatobiliary Pancreat Surg 2005;12(1):16-22.

44. Kogure K, Ishizaki M, Nemoto M, Kuwano H, Yorifuji H, Takata K, Ishikawa H, Makuuchi M.
Morphogenesis of an anomalous ligamentum
venosum terminating in the superior left hepaticvein in a human liver. J Hepatobiliary Pancreat
Surg 2005;12(4):310-3.
45. Sugawara Y, Makuuchi M. Living donor livertransplantation for patients with hepatitis C virus
Tokyo experience. Clin Gastroenterol Hepatol
2005 Oct;3(10 Suppl 2):S122-4.
46. Takayama T, Makuuchi M. Preoperative portal
vein embolization: is it useful? J Hepatobiliary
Pancreat Surg 2004;11(1):17-20.
47. Tang W, Inagaki Y, Kokudo N, Guo Q, Seyama Y,
Nakata M, Imamura H, Sano K, Sugawara Y, Makuuchi M. KL-6 mucin expression in carcinoma of
the ampulla of Vater: association with cancer progression.World J Gastroenterol 2005 Sep 21;11(35):5450-4.
48. Yamamoto J, Saiura A, Koga R, Seki M, Ueno M,
Oya M, Azekura K, Seto Y, Ohyama S, Fukunaga
S, Yamaguchi T, Kokudo N, Makuuchi M, Muto T.
Surgical treatment for metastatic malignancies.
Nonanatomical resection of liver metastasis: indications and outcomes. Int J Clin Oncol 2005
Apr;10(2):97-102.
49. Sugawara Y, Makuuchi M, Matsui Y, Kishi Y,
Akamatsu N, Kaneko J, Kokudo N. Preemptive
therapy for hepatitis C virus after living-donor livertransplantation. Transplantation. 2004 Nov
15;78(9):1308-11.
50. Hasegawa K, Kokudo N, Imamura H, Sano K,
Aoki T, Miki K, Hashimoto T, Sugawara Y, Makuuchi M. Bilioenteric reconstruction for small bileducts without mucosa-to-mucosa alignment:
long-term results. Arch Surg. 2004 Oct;139(10):1050-4.
51. Hashimoto T, Kokudo N, Aoki T, Natori T, Arita J,
Sano K, Imamura H, Sugawara Y, Makuuchi M.
Reconstruction of middle hepatic vein using a rotating left hepatic vein flap. J Am Coll Surg. 2004
Oct;199(4):656-60.
52. Dulundu E, Sugawara Y, Sano K, Kishi Y, Akamatsu N, Kaneko J, Imamura H, Kokudo N, Makuuchi M. Duct-to-duct biliary reconstruction in
adult living-donor liver transplantation. Transplantation. 2004 Aug 27;78(4):574-9.

242

53. Kishi Y, Sugawara Y, Akamatsu N, Kaneko J, Matsui Y, Kokudo N, Makuuchi M. Sharing the middle hepatic vein between donor and recipient: left
liver graft procurement preserving a large segment
VIII branch in donor. Liver Transpl. 2004 Sep;10(9):1208-12.
54. Kokudo N, Sugawara Y, Kaneko J, Imamura H,
Sano K, Makuuchi M. Reconstruction of isolatedcaudate portal vein in left liver graft. Liver Transpl.
2004 Sep;10(9):1163-5.
55. Sugawara Y, Makuuchi M. Right lateral sector
graft as a feasible option for partial liver transplantation. Liver Transpl. 2004 Sep;10(9):1156-7.
56. Yuan LW, Tang W, Kokudo N, Sugawara Y,
Karako H, Hasegawa K, Aoki T, Kyoden Y, Deli G,
Li YG, Makuuchi M. Measurement of desgamma-carboxy prothrombin levels in cancer andnon-cancer tissue in patients with hepatocellular
carcinoma. Oncol Rep. 2004 Aug;12(2):269-73.
57. Minematsu T, Sugiyama E, Kusama M, Hori S,
Yamada Y, Ohtani H, Sawada Y, Sato H, Takayama T, Sugawara Y, Makuuchi M, Iga T. Effectof hematocrit on pharmacokinetics of tacrolimus inadult living donor liver transplant recipients.
Transplant Proc. 2004 Jun;36(5):1506-11.
58. Sugawara Y, Kaneko J, Akamatsu N, Kishi Y, Hata
S, Kokudo N, Makuuchi M. Living donor livertransplantation for end-stage hepatitis C. Transplant Proc. 2004 Jun;36(5):1481-2.
59. Aoki T, Imamura H, Hasegawa K, Matsukura A,
Sano K, Sugawara Y, Kokudo N, Makuuchi M.
Sequential preoperative arterial and portal venous
embolizations in patients with hepatocellular carcinoma. Arch Surg. 2004 Jul;139(7):766-74.
60. Akamatsu N, Sugawara Y, Kaneko J, Kishi Y,
Niiya T, Kokudo N, Makuuchi M. Surgical repair
for late-onset hepatic venous outflow block after
living-donor liver transplantation. Transplantation.
2004 Jun 15;77(11):1768-70.
61. Imamura H, Kokudo N, Sugawara Y, Sano K, Kaneko J, Takayama T, Makuuchi M. Pringle's maneuver and selective inflow occlusion in living donor liver hepatectomy. Liver Transpl. 2004 Jun;10(6):771-8.
62. Guo L, Li XK, Enosawa S, Funeshima N, Suzuki S,
Kimura H, Sugawara Y, Tezuka K, Makuuchi M.
Significant enhancement by anti-ICOS antibody ofsuboptimal tacrolimus immunosuppression in rat
liver transplantation. Liver Transpl. 2004 Jun;10(6):743-7.
63. Sugawara Y, Makuuchi M. Advances in adult living donor liver transplantation: a review based onreports from the 10th anniversary of theadult-to-adult living donor liver transplantation
meeting in Tokyo. Liver Transpl. 2004 Jun;10(6):715-20. Review.
64. Kaneko J, Sugawara Y, Akamatsu N, Kishi Y,
Niiya T, Kokudo N, Makuuchi M, Mizuta K. Prediction of hepatic artery thrombosis by protocol
Doppler ultrasonography in pediatric living donorliver transplantation. Abdom Imaging. 2004
Sep-Oct;29(5):603-5. Epub 2004 May 27.
65. Guo L, Haga S, Enosawa S, Naruse K, Harihara Y,
Sugawara Y, Irani K, Makuuchi M, Ozaki M. Improved hepatic regeneration with reduced injury byredox factor-1 in a rat small-sized liver transplantmodel. Am J Transplant. 2004 Jun;4(6):879-87.
66. Kokudo N, Imamura H, Sugawara Y, Sakamoto Y,
Yamamoto J, Seki M, Makuuchi M. Surgery for
multiple hepatic colorectal metastases. J Hepatobiliary Pancreat Surg. 2004;11(2):84-91. Review.
67. Imamura H, Seyama Y, Kokudo N, Aoki T, Sano K,
Minagawa M, Sugawara Y, Makuuchi M. Single
and multiple resections of multiple hepatic metastases of colorectal origin. Surgery. 2004 May;135(5):508-17.
68. Sugawara Y, Makuuchi M, Akamatsu N, Kishi Y,
Niiya T, Kaneko J, Imamura H, Kokudo N. Refinement of venous reconstruction using cryopreserved veins in right liver grafts. Liver Transpl.
2004 Apr;10(4):541-7.
69. Kaneko J, Sugawara Y, Akamatsu N, Kokudo N,
Makuuchi M. Spleen volume and platelet number
changes after living donor liver transplantation in
adults. Hepatogastroenterology. 2004 Jan-Feb;51(55):262-3.
70. Noritomi T, Sugawara Y, Kaneko J, Matsui Y,
Makuuchi M. Central pontine myelinolysis after
living donor liver transplantation. Hepatogastroenterology. 2004 Jan-Feb;51(55):247-8.
71. Kaneko J, Sugawara Y, Akamatsu N, Kokudo N,
Makuuchi M. Cholestatic hepatitis due to hepatitis
C virus after a living donor liver transplantation.

243

Hepatogastroenterology. 2004 Jan-Feb;51(55):2434.
72. Ohkubo T, Sugawara Y, Imamura H, Kaneko J,
Matsui Y, Makuuchi M. Early recurrence of hepatocellular carcinoma after living donor liver transplantation. Hepatogastroenterology. 2004 Jan-Feb;
51(55):237-8.
73. Sugawara Y, Makuuchi M, Kaneko J, Ohkubo T,
Mizuta K, Kawarasaki H. Impact of previous multiple portoenterostomies on living donor livertransplantation for biliary atresia. Hepatogastroenterology. 2004 Jan-Feb;51(55):192-4
74. Aoki T, Sugawara Y, Imamura H, Seyama Y, Minagawa M, Hasegawa K, Kokudo N, Makuuchi M.
Hepatic resection with reconstruction of the inferior vena cava or hepatic venous confluence formetastatic liver tumor from colorectal cancer. J Am
Coll Surg. 2004 Mar;198(3):366-72.
75. Kishi Y, Sugawara Y, Kaneko J, Akamatsu N,
Imamura H, Asato H, Kokudo N, Makuuchi M.
Hepatic arterial anatomy for right liver procurement from living donors. Liver Transpl. 2004
Jan;10(1):129-33.
76. Hata S, Sugawara Y, Kishi Y, Niiya T, Kaneko J,
Sano K, Imamura H, Kokudo N, Makuuchi M.
Volume regeneration after right liver donation.
Liver Transpl. 2004 Jan;10(1):65-70.

244

Department of Urology
Professor
Tadaichi Kitamura, M.D.,Ph.D.

Associate Professor
Takumi Takeuchi, M.D.,Ph.D.

Kyoichi Tomita, M.D.,Ph.D.

Lecturer
Akira Ishikawa, M.D., Ph.D.
Hiroaki Nishimatsu, M.D., Ph.D.

Haruki Kume, M.D., Ph.D.
Hiroshi Fukuhara, M.D., Ph.D.

Associate
Shinya Matsumoto, M.D.,
Motofumi Suzuki, M.D., Ph.D.,
Shizue Nyomura, M.D.,
Etsuko Tanaka, Akiko Hirose

Tetsuya Fujimura, M.D.,
Aya Niimi, M.D.,
Ken’ichi Tajima, M.D.,

Chen Qin, M.D., Ph.D.,
Ryuji Tabata, M.D., Ph.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, theurinary tract and the male genital system by means of asurgical procedure as well as an approach of internal
medicine. In addition, urology encompasses pediatricurology, neurourology, female urology (especially,
stress incontinence), renal transplantation, renal vascular surgery, endocrine surgery and geriatric urology. For
this reason, urology requires the scientific backgroundof oncology, nephrology, endocrinology, andrology,
immunology, pediatrics, histology, microbiology, neurology and gerontology. Now we have commenced toutilize cellular and molecular biology to develop theresearch in urology. It is expected for our department todevote 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 by endoscopic management of the diseases in the upper urinary
tract, ESWL, or laser lithotripsy for urolithiasis, hyper-

thermic and laser therapies for BPH, and laparoscopic
adrenalectomy, nephrectomy, and prostatectomy substituting open procedures.
The professor, associate professors, instructors andassociates are involved in in-patient and out-patientcares and teaching of the students as well as research
activities. Clinical visiting professors are mainly engaged in the teaching.

Clinical activities
There are 44 beds in the ward (8th floor of the central-ward-building). The residents take care of all thepatients on 24-hour a day basis. Associate staff members team up with the residents on a man-to-man basis.
The total number of inpatients was 42.0 per day from
April 2004 to March 2005. More than half of in-patients suffer from urogenital cancers. Urolothiasis, benign prostatic hyperplasia, urinary incontinence andother many diseases are treated.
Elective operations are performed on Tuesday,245

Wednesday, and Thursday. A total of 991 operations
were performed in 2005. The main operations are total
cystectomy 16 (ileal neobladder 7), radical prostatectomy 95, radical nephrectomy 32, transurethral resection of the bladder tumor (TUR-Bt) 109, transurethralresection of the prostate (TUR-P) 31, transurethral lithotripsy (TUL) 32, laparoscopic surgery 33.
A weekly clinical conference is held for discussing
cases with difficult problems in detail and the besttreatment is chosen for each case. Furthermore at the
weekly professor’s round on Wednesday, data of all inpatients are presented and appropriate treatment strategies are recommended for them.
In out-patient clinic, services are provided from
Monday to Friday. Patients assigned to specialized services as andrology, neurourology, urolithiasis, kidneyand kidney transplantation receive sophisticated care on
the particular day of the week.
The number of newly registered patients was 1290
and the total number of out-patients was 27,193 patient-days from April 2004 to March 2005.

Teaching activities
Systematic urological lectures are provided for second year medical students. Both clinical lectures andbed side teaching are scheduled for third and fourthyear medical students. Thirteen times of systematic
lectures are performed by professor, associate professors and instructors 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 of operation, surgical anatomy and surgical techniques.

Research activities
There are 9 research groups with different clinicaland research activities shown as follows. Our basic
principles for research are in accord with the trends inmodern medicine; improvement of quality of life,
minimally invasive treatment, application of modern
technology and/or basic science and cost-effectiveness.
There are approximately 25 publications in English
each year.

Nephrology group
Urolithiasis group
Kidney Transplantation group
Oncology group
Endourology group
Neurourology and Geriatric urology group
Andrology and Endocrinology group
Immunology group
Virology group

References
1. Zheng H-Y, Kitamura T, Takasaka T, Chen Q, Yogo
Y. Unambiguous indentification of JC polyomavirus strains transmitted from parents to children.
Arch Virol. 2004; 149: 261-273.
2. Yogo Y, Sugimoto C, Zheng H-Y, Ikegaya H, Takasaka T, Kitamura T. JC virus genotyping offers a
new paradigm in the study of human populations.
Rev Med Virol. 2004; 14: 179-191.
3. Zheng H-Y, Yasuda Y, Kato S, Kitamura T, Yogo Y.
Stability of JC virus coding sequences in a case of
progressive multifocal leukoencephalopathy inwhich the viral control region was rearranged
markedly. Arch Pathol Lab Med. 2004; 128: 275278.
4. Takasaka T, Miranda JJ, Sugimoto C, Paraguison R,
Zheng H-Y, Kitamura T, Yogo Y. Genotypes of JC
virus in Southeast Asia and the Western Pacific:
implications for human migrations from Asia to the
Pacific. Anthropol Sci. 2004; 112: 53-59.
5. Enomoto Y, Enomoto K, Kitamura T, Kanda T.
Keratinocyte-specific POU transcription factor
hSkn-1a represses the growth of cervical cancer
cell lines. Oncogene. 2004; 23: 5014-5022.
6. Inoue Y, Kurimoto S, Kameyama S, Ohta N, Akahane M, Yoshikawa K, Yokoyama I, Minami M,
Ohtomo K, Kitamura T. Prolonged renal parenchymal retention of 99mTc mercaptoacetyltriglycine after nephron-sparing surgery. Nucl Med
Commun. 2004; 25: 509-513.
7. Zheng H-Y, Zhao P, Suganami H, Ohasi Y, Ikegaya
H, Kim J-C, Sugimoto C, Takasaka T, Kitamura T,
Yogo Y. Regional distribution of two related
Northeast Asian genotypes of JC virus, CY-a and-b: implications for the dispersal of Northeast
Asians. Microbes Infect. 2004; 6: 596-603.

246

8. Miranda JJ, Takasaka T, Zheng H-Y, Kitamura T,
Yogo Y. JC virus genotype profile in the Mamanwa,a Philippine Negrito tribe, and implications for its
population history. Anthropol Sci. 2004; 112: 173178.
9. Konno-Takahashi N, Takeuchi T, Nishimatsu H,
Kamijo T, Tomita K, Schalken JA, Tejima S, Kitamura T. Engineered FGF-2 expression induces
glandular epithelial hyperplasia in the murine
prostatic dorsal lobe. Eur Urol. 2004; 46: 126-132.
10. Takeuchi T, Konno-Takahasi N, Kasuya Y, Ogushi
T, Nishimatsu H, Kitamura T. Interleukin-2 blocks
the antitumour activity caused by depletion of
CD25＋ cells in a murine renal adenocarcinoma
model. BJU Int. 2004; 94: 171-176.
11. Nagata M, Kurimoto S, Takeuchi T, Ohta N, Minowada S, Kitamura T. Tiny nodule in the testicle:
Case report of a Sertoli cell tumor. Int J Urol. 2004;
11: 61-62.
12. Kato A, Kitamura T, Takasaka T, Tominaga T, Ishikawa A, Zheng H-Y, Yogo Y. Detection of the archetypal regulatory region of JC virus from thetonsil tissue of patients with tonsillitis and tonsilar
hypertrophy. J Neurovirol. 2004; 10: 244-249.
13. Takasaka T, Goya N, Tokumoto T, Tanabe K, Toma
H, Ogawa Y, Hokama S, Momose A, Funyu T, Fujioka T, Omori S, Akiyama H, Chen Q, Zheng H-Y,
Ohta N, Kitamura T, Yogo Y. Subtypes of BK virus
prevalent in Japan and variation in their transcriptional control region. J Gen Virol. 2004; 85: 2821282.
14. Akaza H, Usami M, Hinotsu S, Ogawa O, Kagawa
S, Kitamura T, Tsukamoto T, Naito S, Hirao Y,
Murai M, Yamanaka H. Characteristics of patientswith prostate cancer who have initially been treatedby hormone therapy in Japan: J-CaP surveillance.
Jpn J Clin Oncol. 2004; 34: 329-336.
15. Miyazaki H, Watabe T, Kitamura T, Miyazono K.
BMP signals inhibit proliferation and in vivo tumor
growth of androgen-insensitive prostate carcinoma
cells. Oncogene. 2004; 23: 9326-9335.
16. Nakagawa T, Kanai Y, Ushijima S, Kitamura T,
Kakizoe T, Hirohashi S. DNA hypomethylation on
pericentromeric satellite regions significantly correlates with loss of heterozygosity on chromosome
9 in urothelial carcinomas. J Urol. 2005; 173: 243246.

17. Takahashi S, Suzuki M, Kume H, Matsumoto S,
Okamoto N, Nishimatsu H, Tomita K, Kitamura T.
Combination chemotherapy of docetaxel, ifosfamide and cisplatin (DIP) in patients with metastatic urothelial cancer: a preliminary report. Jpn J
Clin Oncol. 2005; 35: 79-83.
18. Suzuki M, Muto S, Hara K, Ozeki T, Yamada Y,
Kadowaki T, Tomita K, Kameyama S, Kitamura T.
Single-nucleotide polymorphisms in the 17β-hydroxysteroid dehydrogenase genes might predictthe risk of side-effects of estramustine phosphate
sodium in prostate cancer patients. Int J Urol. 2005;
12: 166-172.
19. Nakagawa T, Kanai Y, Ushijima S, Kitamura T,
Kakizoe T, Hirohashi S. DNA hypomethylation
on multiple CpG islands associated with increased
DNA methyltransferase dnmt1 protein expression
during multistage urothelial carcinogenesis. J Urol.
2005; 173: 1767-1771.
20. Nishimatsu H, Suzuki E Satonaka H, Takeda R
Omata M, Fujita T, Nagai R, Kitamura T, Hirata Y.
Endothelial dysfunction and hypercontractility ofvascular myocytes are ameliorated by fluvastatin inobese Zucker rats. Am J Physiol Heart Circ Physiol.
2005; 288: H1770-H1776.
21. Zheng H-Y, Takasaka T, Noda K, Kanazawa A,
Mori H, Kabuki T, Joh K, Oh-ishi T, Ikegaya H,
Nagashima K, Hall WW, Kitamura T, Yogo Y. New
sequece polymorphisms in the outer loops of the JCpolyomavirus major capsid protein (VP1) possibly
associated with progressive multifocal leukoencephalopathy. J Gen Virol. 2005; 86: 2035-2045.
22. Fujimura T, Yamada Y, Nasu M, Hamasaki K, Minowada S, Kitamura T. Different transformation of
mature teratoma in a patient with mixed germ celltumor of the testis. Int J Urol. 2005; 12: 588-590.
23. Chen Q, Takahashi S, Zhong S, Hosoda C, Zheng
H-Y, Ogushi T, Fujimura T, Ohata N, Tanoue A,
Tsujimoto G, Kitamura T. Funciton of the lower
urinary tract in mice lacking α1ｄ-Adrenoceptor. J
Urol. 2005; 174: 370-374.
24. Kitamura T, Nishimatsu H, Suzuki M, Mohammed
R, Tomita K, Takahashi S, Takeuchi T, Ohota N,
Kameyama S. Dual interim report of low-dose estramustine phosphate (EMP) monotherapy and very
low-dose EMP therapy combined with LH-RH
agonist for previously untreated advanced prostate

247

cancer. J Appl Res. 2005; 5: 331-344.
25. Ogushi T, Takahashi S, Takeuchi T, Urano T,
Horie-Inoue K, Kumagai J, Kitamura T, Ouchi Y,
Muramatsu M, Inoue S. Estrogen receptor-binding
fragment-associated antigen 9 is a tumor-promoting
and prognostic factor for renal cell carcinoma.
Cancer Res. 2005; 65: 3700-3706.
26. Zheng H-Y, Ikegaya H, Takasaka T, MatsushimaOhno T, Sakurai M, Kanazawa I, Kishida S, Nagashima K, Kitamra T, Yogo Y. Characterization of
the VP1 loop mutations widespread among JC
polyomavirus isolates associated with progressive
multifocal leukoencephalopathy. Biochem Biophys
Res Comun. 2005; 333: 996-1002.
27. Zheng H-Y, Ikegaya H, Nakajima M, Sakurada K,
Takasaka T, Kitamura T, Yogo Ｙ. Two distinct
genotypes (MY-x and MX) of JC virus previously
identified in Hokkaido Ainu. Anthropol Sci. 2005;
113: 225-231.
28. Suzuki M, Mohammed R, Hara K, Ozeki T, Yamada Y, Kadowaki T, Honda H, Yanagihara Y, Ito
Minagawa Y, Kameyama S, Ohta N, Hosoi T, Arai
T, Sawabe M, Takeuchi T, Takahashi S, Kitamura T.
The val158met polymorphism of the catecholO-methyltransferase gene is associated with the
PSA-progression-free survival in prostate cancer
patients treated with estramustine phosphate. Eur
Urol. 2005; 48: 752-759.
29. Mohammed R, Suzuki M, Takahashi S, Hara K,
Ozeki T, Yamada Y, Kadowaki T, Yanagihara Y,
Kameyama S, Ito-Minagawa Y, Takeuchi T, Kitamura T. Incidence of gastrointestinal toxicity during estramustine phosphate therapy for prostatecancer is associated with the single-nucleotide
polymorphisms in the cytochrome P450 1A1(CYP1A1) gene. Cancer Therapy. 2005; 3: 525530.
30. Ikegaya H, Zheng H-Y, Saukko PJ, Varesmaa-Korhonen L, Hovi T, Vesikari T, Suganami H,
Takasaka T, Sugimoto C, Ohasi Y, Kitamura T,
Yogo Y. Genetic diversity of JC virus in the Saami
and the Finns: implications for their population
history. Am J Phys Anthropol. 2005; 128: 185-193.
31. Uchida T, Baba S, Irie A, Soh S, Masumori N,
Tsukamoto T, Nakatsu H, Fujimoto H, KakizoeT,
Ueda T, Ichikawa T, Ohta N, Kitamura T, Sumitomo M, Hayakawa M, Aoyagi T, Tachibana M,

Ikeda R, Suzuki K, Tsuru N, Suzuki K, Ozono S,
Fujimoto K, Hirao Y, Monden K, Nasu Y, Kumon
H, Nishi K, Ueda S, Koga H, Naitoh S. Transrectal
high-intensity focused ultrasound in the treatmentof localized prostate cancer: A multicenter study.
Acta Urol Jpn. 2005; 51: 651-658.
32. Fujimura T, Minowada S, Kishi H, Hamasaki K,
Saito K, Kitamura T. Hemiresective reconstructionof a redundant ileal conduit with severe bilateral
ileal conduit-ureteral reflux. Int J Urol. 2005; 12:917-919.
33. Matsumoto S, Takahashi S, Goto T, Tomita K, Takeuchi T, Kitamura T. Proteus syndrome with giant
myelolipoma in the pelvis. Int J Urol. 2005; 12:1005-1006.
34. Zheng H-Y, Kojima K, Ikegaya H, Takasaka T, Kitamura T, Yogo Y. JC virus genotyping suggests a
close contact or affinity between Greenland inuitand other circumarctic populations. 2005; Anthropol Sci. 113 291-293.
35. Kobayashi F, Kume H, Tomita K, Kitamura T.
Xanthoma of the urinary bladder. Scand J Urol
Nephrol. 2005; 39: 527-528.
36. Nyomura S, Tomita K, Kume H, Nishimatsu H,
Takahashi S, Takeuchi T, Kitamura T. A problematic complication of sex change operation. Surgery.
2005; 138:543-544.
37. Azuma M, Hirao A, Takubo K, Hamaguchi I, Kitamura T, Suda T. A quantitative matrigel assay forassessing repopulating capacity of prostate stem
cells. Biochem Biophys Res Commun. 2005; 16;338(2): 1164-1170.
38. Kitamura T, Nishimatsu H, Suzuki M, Mohammed
R, Tomita K, Takahashi S, Takeuchi T, Ohta N,
Kameyama S. Dual interim report of low-dose estramustine phosphate (EMP) monotherapy combined with LH-RH agonist for previously untreatedadvanced prostate cancer. J Appl Res. 2005; 5:
331-344.
39. Kume H, Teramoto S, Tomita K, Nishimatsu H,
Takahashi S, Takeuchi T, Ohta N, Kitamura T.
Bladder recurrence of the upper urinary tract cancer
after laparoscopic surgery. J Surg Oncol. 2006; 93:
318-322.
40. Takahashi S, Tajima A, Matsushima H, Kawamura
T, Tominaga T, Kitamura T. Clinical efficacy of analpha–1A/D adrenoceptor blocker (naftopidil) on248

overactive bladder symptoms in patients with benign prostatic hyperplasia. 2006; Int J Urol. 13:
15-20.
41. Takeuchi T, Suzuki M, Kumagai J, Sakai M, Kitamura T. Extracellular matrix dermatopontin modulates prostate cell growth in vivo. Eur Urol Suppl.
2006; 5(2): 125.
42. Tomita K, Tsurumaki Y, Kume H, Takahashi S, Takeuchi T, Kitamura T: Prognostic factors for patients with locally advanced prostatic cancer who
underwent radical prostatectomy. Eur Urol Suppl.
2006; 5(2): 213.
43. Tsurumaki Y, Tomita K, Kume H, Takahashi S, Takeuchi T, Kitamura T. Predictors of seminal vesicle
invasion before redical prostatectomy. Eur Urol
Suppl. 2006; 5(2): 241.
44. Takasaka T, Kitamura T, Sugimoto C, Guo J, Zheng
H-Y, Yogo Y. Phylogenetic analysis of major African genotype (Af2) of JC virus : implications fororigin and dispersals of modern Africans. Am J
Phys Anthropol. 2006; 129: 465-472.
45. Yamada D, Kikuchi S, Williams YN, SakuraiYageta M, Masuda M, Maruyama T, Tomita K,
Gutmann DH, Kakizoe T, Kitamura T, Kanai Y,
Murakami Y. Promoter hypermethylation of thepotential tumor suppressor DAL-1/4.1B gene inrenal clear cell carcinoma. Int J Cancer. 2006;
118(4): 916-923.
46. Fukuhara H, Matsumoto A, Kitamura T, Takeuchi T.
Neutralization of IL-2 retarded the growth ofmouse renal cancer. BJU Int. 2006; 97:1314-1321
47. Yamada Y, Fujimura T, Takahashi S, Takeuchi T,
Takazawa Y, Kitamura T. Tubulovillous adenoma
developing after urinary reconstruction using ileal
segments. Int J Urol.2006; 118(4): 916-923

249

Department of Surgical Oncology
Professor
Hirokazu Nagawa, M.D., Ph.D.
Lecturer
Joji Kitayama, M.D., Ph.D.
Clinical Lecturer
Shoichi Kaisaki, M.D.
Associate
Yoshiki Takei, M.D., Ph.D.,
Hironori Ishigami, M.D.,
Sinsuke Sito, M.D., Ph.D.,
Takamitsu Kanazawa, M.D.,

Giichiro Tsurita, M.D., Ph.D.,
Soichiro Ishihara, M.D., Ph.D.,
Sinsuke Kazama, M.D., Ph.D.,
Akio Hidemura, M.D., Ph.D.

Homepage http://all-1su.umin.jp/
Introduction and Organization
In 1997, 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 staffof the Department of Surgical Oncology consists of one
Professor, two Lecturers and eight Associates. The outpatient office is located on the third floor of the Outpatient Building. The ward is situated on the eighth floorof 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 and management for adult patients with both general and oncologic surgical problems, in the ambulatory as well as
inpatient setting. Additionally, surgical specialities inthe department include the treatment of benign and ma-

lignant disorders of the breast and management of malignancies of the gastrointestinal tract (esophageal, gastric, and colorectal). The department is also well known
for its innovative therapy for inflammatory bowel disease. Department specialists have expertise in biological cancer immunotherapy, chemotherapy for a variety
of malignancies, and radiotherapy for rectal cancer. The
outpatient clinic is open from Monday through Friday,
and twenty-four-hour consultation is available for urgent or emergency problems.
The outpatient clinic is specialized in the upper GI
tract, lower GI tract, and breast diseases. The Department was responsible for 360 and 360 surgically treatedinpatients in the 2004 and 2005 fiscal year, respectively.
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 and Thursday.
In addition to the clinical conferences, research conferences are held every Monday and Saturday morning.
Each research unit holds its own conference every
week.

250

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 surgical oncology. The Department of Surgical Oncology has a
Surgical Oncology Training Program and provides
broad reaching experience in technical aspects of diagnosis, treatment and management for adult patients withboth surgical and oncologic problems, development ofsurgical 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 scientificlines.
In the undergraduate education program, our department plays a role in the systemic and clinical lectures
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 2005, various fields were covered such as surgical oncology and immunology, injury, somatic reaction to surgery, infectious diseases, shock, pre- andpost-surgical management and nutrition. In the clinicallectures, we presented many diseases such as coloncancer, colonic polyp, colonic polyposis and ulcerative
colitis. In the postgraduate education program, newresidents are trained to become qualified surgeons. In
addition to pre- and post-surgery clinical conferences,
the residents are expected to attend research conferences and seminars, which are held periodically. They
are also asked to present cases at clinical meetings,
which are held locally such as the local meeting of theJapanese Society of Gastroenterology.

Research activities
At present, our department has three major research
units divided according to the members’ special fields.
The clinical and academic interests of our department
are the upper and lower gastrointestinal tract, and thebreast. We also apply the techniques used in molecularand cellular biology to our research. The following are
the major themes under research.
1) Preoperative radiotherapy in lower rectal cancer
2) Cancer surveillance in ulcerative colitis

3)
4)
5)
6)
7)
8)

Carcinogenesis in ulcerative colitis
Laparoscopically assisted colon surgery
Local immunity in colorectal cancer
Genetic analysis of colorectal cancer and adenoma
Prognostic factor of early colorectal cancer
Surveillance program following colectomy for colorectal cancer
9) The mechanism of liver metastasis of colorectal
cancer10) Carcinogenesis in superficial early colorectal cancer11) Genetic alterations in synchronous and metachronous multiple colorectal cancers12) Microsatellite instability and a risk of developing
multiple colorectal cancers13) Dendritic cell Immunotherapy for advanced cancer14) Cancer Immunotherapy targeting to the tumor vessels
15) Angiogenesis inhibition in peritoneal metastasis ofgastric cancer16) Role of LPA S1P and Edg receptors in tumor metastasis17) Lipid metabolism in carcinogenesis and tumor progression18) Sentinel lymph node identification using nanobeads
19) Genetic analysis on sensitivity to chemotherapeutic
agents20) Hemostasis and fibrinolysis in Oncology21) Leptin and adiponectin in Oncology22) Intraabdominal chemotherapy for peritoneal metastasis of gastric cancer23) Angiogenic progenitor cells and antigen presentation
24) Fibloblast Growth Factor (FGF) in inflammatory
bowel disease25) Genetic analysis of undifferentiated colorectal
cancer26) High Frequency Ultrasonography (HIFU) for solidcancer27) Endocannabinoid in acticancer therapy

References
1. Tsuchiya T, Okaji Y, Tsuno NH, Sakurai D, Tsuchiya N, Kawai K, Yazawa K, Asakage M, Yamada
J, Yoneyama S, Kitayama J, Osada T, Watanabe T,
Tokunaga K, Takahashi K, Nagawa H. Targeting

251

2.

3.

4.

5.

6.

7.

8.

9.

Id1 and Id3 inhibits peritoneal metastasis of gastriccancer. Cancer Sci 2005 Nov;96(11):784-90.
Ishikawa M, Kitayama J, Kaizaki S, Nakayama H,
Ishigami H, Fujii S, Suzuki H, Inoue T, Sako A,
Asakage M, Yamashita H, Hatono K, Nagawa H.
Prospective randomized trial comparing Billroth I
and Roux-en-Y procedures after distal gastrectomy
for gastric carcinoma. World J Surg 2005 Nov;29(11):1415-20.
Shida D, Kitayama J, Mori K, Watanabe T, Nagawa
H. Transactivation of epidermal growth factor receptor is involved in leptin-induced activation ofjanus-activated kinase 2 and extracellular signalregulated kinase 1/2 in human gastric cancer cells.
Cancer Res 2005 Oct 15;65(20):9159-63.
Ishikawa M, Kitayama J, Kaizaki S, Sako A, Nakao
K, Sugawara M, Nagawa H. Diagnosis of nasopharyngeal carcinoma metastatic to mediastinal
lymph nodes by endoscopic ultrasonographyguided fine-needle aspiration biopsy. Acta Otolaryngol 2005 Sep;125(9):1014-7.
Takegami K, Kaneko Y, Watanabe T, Watanabe S,
Maruyama T, Matsumoto Y, Nagawa H. Heating
and coagulation volume obtained with high-intensity focused ultrasound therapy: comparison of
perflutren protein-type A microspheres andMRX-133 in rabbits. Radiology 2005 Oct;237(1):132-6.
Konishi T, Sasaki S, Watanabe T, Kitayama J, Nagawa H. Exogenous expression of hRFI induces
multidrug resistance through escape from apoptosis
in colorectal cancer cells. Anticancer Res 2005
Jul-Aug;25(4):2737-41.
Kawai K, Tsuno NH, Matsuhashi M, Kitayama J,
Osada T, Yamada J, Tsuchiya T, Yoneyama S, Watanabe T, Takahashi K, Nagawa H. CD11b-mediated migratory property of peripheral blood B cells.
J Allergy Clin Immunol 2005 Jul;116(1):192-7.
Konishi T, Sasaki S, Watanabe T, Kitayama J, Nagawa H. Overexpression of hRFI (human ring finger homologous to inhibitor of apoptosis proteintype) inhibits death receptor-mediated apoptosis incolorectal cancer cells. Mol Cancer Ther 2005
May;4(5):743-50.
Ishikawa M, Kitayama J, Kohno K, Nagawa H. The
expression pattern of UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetyl-galactosaminyltransferase-3 in squamous cell carcinoma of theesophagus. Pathobiology 2005;72(3):139-45.
10. Kinoshita H, Yanagisawa A, Watanabe T, Nagawa
H, Oya M, Kato Y, Muto T. Increase in the frequency of K-ras codon 12 point mutation in colorectal carcinoma in elderly males in Japan: the1990s compared with the 1960s. Cancer Sci 2005
Apr;96(4):218-20.
11. Kazama Y, Watanabe T, Kanazawa T, Tada T, Tanaka J, Nagawa H. Mucinous carcinomas of thecolon and rectum show higher rates of microsatellite instability and lower rates of chromosomal instability: a study matched for T classification andtumor location. Cancer 2005 May 15;103(10):2023-9.
12. Takegami K, Kaneko Y, Watanabe T, Maruyama T,
Matsumoto Y, Nagawa H. Erythrocytes, as well as
microbubble contrast agents, are important factors
in improving thermal and therapeutic effects ofhigh-intensity focused ultrasound. Ultrasound Med
Biol 2005 Mar;31(3):385-90.
13. Kawai K, Tsuno NH, Kitayama J, Okaji Y, Yazawa
K, Asakage M, Yamashita H, Watanabe T, Takahashi K, Nagawa H. Anti-angiogenic properties ofplaunotol. Anticancer Drugs 2005 Apr;16(4):401-7.
14. Yazawa K, Tsuno NH, Kitayama J, Kawai K, Okaji
Y, Asakage M, Sunami E, Kaisaki S, Hori N, Watanabe T, Takahashi K, Nagawa H. Selective inhibition of cyclooxygenase-2 inhibits colon cancer
cell adhesion to extracellular matrix by decreased
expression of beta1 integrin. Cancer Sci 2005
Feb;96(2):93-9.
15. Ishikawa M, Kitayama J, Kazama S, Hiramatsu T,
Hatano K, Nagawa H. Plasma adiponectin and gastric cancer. Clin Cancer Res 2005 Jan 15;11(2 Pt
1):466-72.
16. Shida D, Kitayama J, Yamaguchi H, Yamashita H,
Mori K, Watanabe T, Nagawa H. Lysophospholipids transactivate HER2/neu (erbB-2) in human gastric cancer cells. Biochem Biophys Res Commun
2005 Feb 18;327(3):907-14.
17. Kawai K, Tsuno NH, Kitayama J, Okaji Y, Yazawa
K, Asakage M, Sasaki S, Watanabe T, Takahashi K,
Nagawa H. Epigallocatechin gallate induces apoptosis of monocytes. J Allergy Clin Immunol 2005
Jan;115(1):186-91.
18. Okaji Y, Tsuno NH, Kitayama J, Saito S, Takahashi

252

T, Kawai K, Yazawa K, Asakage M, Tsuchiya T,
Sakurai D, Tsuchiya N, Tokunaga K, Takahashi K,
Nagawa H. A novel method for isolation of endothelial cells and macrophages from murine tumors
based on Ac-LDL uptake and CD16 expression. J
Immunol Methods 2004 Dec;295(1-2):183-93.
19. Hata K, Yamaguchi H, Tsurita G, Watanabe S,
Wake K, Taki M, Ueno S, Nagawa H. Short term
exposure to 1439 MHz pulsed TDMA field does
not alter melatonin synthesis in rats. Bioelectromagnetics 2005 Jan;26(1):49-53.
20. Sasaki S, Watanabe T, Konishi T, Kitayama J, Nagawa H. Effects of expression of hRFI on adenoma
formation and tumor progression in colorectal
adenoma-carcinoma sequence. J Exp Clin Cancer
Res 2004 Sep;23(3):507-12.
21. Shida D, Kitayama J, Yamaguchi H, Yamashita H,
Mori K, Watanabe T, Yatomi Y, Nagawa H. Sphingosine 1-phosphate transactivates c-Met as well as
epidermal growth factor receptor (EGFR) in humangastric cancer cells. FEBS Lett 2004 Nov 19;577(3):333-8.
22. Tada T, Watanabe T, Kanazawa T, Kazama S,
Koketsu S, Nagawa H. Genetic characterization ofcolorectal cancers in young patients based on
chromosomal loss and microsatellite instability.
Scand J Gastroenterol 2004 Nov;39(11):1134-40.
23. Kitayama J, Shida D, Sako A, Ishikawa M, Hama
K, Aoki J, Arai H, Nagawa H. Over-expression oflysophosphatidic acid receptor-2 in human invasive
ductal carcinoma. Breast Cancer Res 2004;6(6):R640-6.
24. Shida D, Kitayama J, Yamaguchi H, Hama K, Aoki
J, Arai H, Yamashita H, Mori K, Sako A, Konishi T,
Watanabe T, Sakai T, Suzuki R, Ohta H, Takuwa Y,
Nagawa H. Dual mode regulation of migration bylysophosphatidic acid in human gastric cancer cells.
Exp Cell Res 2004 Dec 10;301(2):168-78.
25. Yazawa K, Tsuno NH, Kitayama J, Kawai K, Okaji
Y, Asakage M, Sunami E, Kaisaki S, Hori N, Watanabe T, Takahashi K, Nagawa H. Selective inhibition of cyclooxygenase (COX)-2 inhibits endothelial cell proliferation by induction of cell cycle
arrest. Int J Cancer 2005 Feb 10;113(4):541-8.
26. Ishikawa M, Kitayama J, Nagawa H. Enhanced
expression of leptin and leptin receptor (OB-R) in
human breast cancer. Clin Cancer Res 2004 Jul

1;10(13):4325-31.
27. Shida D, Watanabe T, Aoki J, Hama K, Kitayama J,
Sonoda H, Kishi Y, Yamaguchi H, Sasaki S, Sako A,
Konishi T, Arai H, Nagawa H. Aberrant expressionof lysophosphatidic acid (LPA) receptors in humancolorectal cancer. Lab Invest 2004 Oct;84(10):1352-62.
28. Kawai K, Tsuno NH, Kitayama J, Okaji Y, Yazawa
K, Asakage M, Hori N, Watanabe T, Takahashi K,
Nagawa H. Epigallocatechin gallate attenuates adhesion and migration of CD8+ T cells by binding toCD11b. J Allergy Clin Immunol 2004 Jun;113(6):1211-7.
29. Sako A, Kitayama J, Koyama H, Ueno H, Uchida
H, Hamada H, Nagawa H. Transduction of soluble
Flt-1 gene to peritoneal mesothelial cells can effectively suppress peritoneal metastasis of gastriccancer. Cancer Res 2004 May 15;64(10):3624-8.
30. Koketsu S, Watanabe T, Hori N, Umetani N, Takazawa Y, Nagawa H. Hemophagocytic syndromecaused by fulminant ulcerative colitis and cytomegalovirus infection: report of a case. Dis Colon Rectum 2004 Jul;47(7):1250-3.
31. Sako A, Kitayama J, Kaisaki S, Nagawa H. Hyperlipidemia is a risk factor for lymphatic metastasis
in superficial esophageal carcinoma. Cancer Lett
2004 May 10;208(1):43-9.
32. Ishikawa M, Kitayama J, Nariko H, Kohno
K, Nagawa H. The expression pattern of
UDP-N-acetyl-alpha-d-galactosamine: polypeptide
N-acetylgalactosaminyl transferase-3 in early gastric carcinoma. J Surg Oncol 2004 Apr 1;86(1):28-33.
33. Kitayama J, Hatano K, Kaisaki S, Suzuki H, Fujii S,
Nagawa H. Hyperlipidaemia is positively correlated with lymph node metastasis in men with earlygastric cancer. Br J Surg 2004 Feb;91(2):191-8.
34. Okaji Y, Tsuno NH, Kitayama J, Saito S, Takahashi
T, Kawai K, Yazawa K, Asakage M, Hori N, Watanabe T, Shibata Y, Takahashi K, Nagawa H. Vaccination with autologous endothelium inhibits angiogenesis and metastasis of colon cancer throughautoimmunity. Cancer Sci 2004 Jan;95(1):85-90.

253

Department of Vascular Surgery
Professor
Hirokazu Nagawa, M.D., Ph.D.
Associate Professor
Tetsuro Miyata, M.D., Ph.D.
Associate
Kunihiro Shigematsu, M.D., Ph.D.,
Hideo Kimura, M.D., Ph.D.,

Juno Deguchi, M.D., Ph.D.,
Seiji Nishikage, M.D.

Homepage http://all-1su.umin.jp/
Introduction and Organization
In 1997, 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 is situated on the eighth floor of the Ward Building. The administrative office and research laboratories are locatedin the Administration and Research Building. Current
activities of the Department of Surgical Oncology inclinical practice, education, and research are summarized as follows.

Clinical activities
The Department of Vascular Surgery has an extensive
clinical program in both primary and tertiary care for
vascular problems, and manages patients with peripheral arterial occlusion, abdominal and thoraco- abdominal 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.
The outpatient clinic is open from Monday throughFriday, and twenty-four-hour consultation is available
for urgent or emergency problems.
The department was responsible for 242 and 279
surgically treated inpatients in the 2004 and 2005 fiscal
year, respectively. Included in the department is the
non-invasive Clinical Vascular Laboratory, which sees
over 500 patients per year, with broad reaching expertise in peripheral vascular diagnostic modalities. Also
the department has an active angiography program,which encompasses all aspects of diagnostic and therapeutic intervention in over 500 patients per year and afull range 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 vascular angiographic 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 vascular surgery. The Department of Vascular Surgery has a Vascular Surgery Training Program and provides broadreaching experience in technical aspects of vascularsurgery, development of surgical judgment, and in-254creasing knowledge about routine and complex conditions. In addition, the dedicated staff offers multiple
opportunities for academic development both along
clinical and basic scientific lines.
In the undergraduate education program, the Department of Vascular Surgery plays a role in the systemic and clinical lectures and the bedside learning
program for 3rd year medical students, in cooperation
with other departments of surgery. In the postgraduate
education program, new residents are trained to become
qualified surgeons in our department. In addition to 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 specific problems
being addressed. The basic vascular laboratories areactively performing research on endothelial biology, themechanism of intimal hyperplasia, microcirculation,
application of gene therapy to vascular surgery andvascular prosthesis development. The following are themajor themes under research.
1) Three-dimensional visualization abdominal aorta
2) Pathophysiology of the development of the aneurysm
3) Prevention of the anastomotic intimal hyperplasia
4) Pathophysiology of stent restenosis
5) Analyzing the intercellular transmission of thegrowth signal in the vascular smooth muscle cells6) Tissue oxygen dynamics assessed by near infrared
spectroscopy7) Application of near infrared spectroscopy to bloodflow monitoring during carotid endarterectomy8) Lower limb arterial circulation in a patient with
end-stage renal disease assessed by near infrared
spectroscopy9) Microvascular permeability changes induced by
PAF10) Pharmacological analysis of microcirculation in
in-vivo model11) Mechanism of ischemic preconditioning of thelimb12) Development of a new drug delivery system fortherapeutic angiogenesis13) Introduction of gene into vascular wall cells byelectroporation
14) Application of nano technology for in-vivo genetransfer to vascular wall cells
15) Basic research for arterialization of artificial organ
16) Development of a new method for evaluation oflimb ischemia
17) Develolpment of a new machine forauto-evaluation of in-vivo endothelial function

References
1. Miyahara T, Miyata T, Shigematsu K, Shigematsu
H, Koyama H, Okamoto H, Nakazawa T, Nagawa
H. Persistent sciatic artery in a patient with extracranial internal carotid artery aneurysm and infrarenal abdominal aortic aneurysm. A case report. Int
Angiol 2005 Dec;24(4):391-4.
2. Miyahara T, Miyata T, Shigematsu H, Shigematsu
K, Okamoto H, Nakazawa T, Nagawa H. Longterm results of combined iliac endovascular intervention and infrainguinal surgical revascularization
for treatment of multilevel arterial occlusive disease. Int Angiol 2005 Dec;24(4):340-8.
3. Saito T, Hosoi Y, Onozuka A, Komiyama T, Miyata
T, Shigematsu H, Nagawa H. Impaired ambulatory
venous function in lymphedema assessed by nearinfrared spectroscopy. Int Angiol 2005 Dec;24(4):336-9.
4. Yu P, Hatakeyama T, Aramoto H, Miyata T, Shigematsu H, Nagawa H, Hobson RW, Duran WN. Mitogen-activated protein kinases regulate platelet-activating factor-induced hyperpermeability.
Microcirculation 2005 Dec;12(8):637-43.
5. Hosaka A, Miyata T, Momose T, Nakazawa T, Shigematsu H, Nagawa H. Evaluation of cerebral hypoperfusion by nuclear medicine imaging in a patient with Takayasu's arteritis. Ann Vasc Surg 2005
Nov;19(6):917-20.
6. Hosaka A, Miyata T, Aramoto H, Shigematsu H,
Nakazawa T, Okamoto H, Shigematsu K, Nagawa
H. Clinical implication of plasma level of soluble
fibrin monomer-fibrinogen complex in patients255

with abdominal aortic aneurysm. J Vasc Surg 2005
Aug;42(2):200-5.
7. Hosaka A, Miyata T, Shigematsu H, Shigematsu K,
Okamoto H, Ishii S, Miyahara T, Yamamoto K,
Akagi D, Nagayoshi M, Nagawa H. Long-term
outcome after surgical treatment of arterial lesionsin Behçet disease. J Vasc Surg 2005 Jul;42(1): 11621.
8. Yamamoto K, Komiyama T, Miyata T, Kitagawa T,
Momose T, Shigematsu H, Nagawa H. Contralateral stenosis as a risk factor for carotid endarterectomy measured by near infrared spectroscopy. Int
Angiol 2004 Dec;23(4):388-93.
9. Hoshina K, Miyata T, Hatakeyama T, Shigematsu
H, Nagawa H. Hemodynamic influence of peripheral vascular occlusive disease on abdominal aortic
aneurysms. Int Angiol 2004 Dec;23(4):373-8.
10. Hosaka A, Koyama H, Kushibiki T, Tabata Y, Nishiyama N, Miyata T, Shigematsu H, Takato T,
Nagawa H. Gelatin hydrogel microspheres enablepinpoint delivery of basic fibroblast growth factor
for the development of functional collateral vessels.
Circulation 2004 Nov 23;110(21):3322-8.
11. Miyahara T, Koyama H, Miyata T, Shigematsu H,
Inoue J, Takato T, Nagawa H. Inflammatory signaling pathway containing TRAF6 contributes toneointimal formation via diverse mechanisms. Cardiovasc Res 2004 Oct 1;64(1):154-64.
12. Hoshina K, Koyama H, Miyata T, Shigematsu H,
Takato T, Dalman RL, Nagawa H. Aortic wall cellproliferation via basic fibroblast growth factor genetransfer limits progression of experimental abdominal aortic aneurysm. J Vasc Surg 2004 Sep;40(3):512-8.
13. Saito T, Komiyama T, Aramoto H, Miyata T, Shigematsu H. Ischemic preconditioning improves
oxygenation of exercising muscle in vivo. J SurgRes 2004 Jul;120(1):111-8.
14. Nishikage S, Koyama H, Miyata T, Ishii S, Hamada
H, Shigematsu H. In vivo electroporation enhances
plasmid-based gene transfer of basic fibroblast
growth factor for the treatment of ischemic limb. J
Surg Res 2004 Jul;120(1):37-46.
15. Kanetaka T, Komiyama T, Onozuka A, Miyata T,
Shigematsu H. Laser Doppler skin perfusion pressure in the assessment of Raynaud's phenomenon.
Eur J Vasc Endovasc Surg 2004 Apr;27(4):414-6.

16. Ishii S, Koyama H, Miyata T, Nishikage S, Hamada
H, Miyatake S, Shigematsu H. Appropriate control
of ex vivo gene therapy delivering basic fibroblast
growth factor promotes successful and safe development of collateral vessels in rabbit model of hindlimb ischemia. J Vasc Surg 2004 Mar;39(3):629-38.
17. Kondoh K, Koyama H, Miyata T, Takato T,
Hamada H, Shigematsu H. Conduction performance of collateral vessels induced by vascular endothelial growth factor or basic fibroblast growth
factor. Cardiovasc Res 2004 Jan 1;61(1):132-42.

256

Department of Metabolic Care andEndocrine Surgery
Professor;
Michio Kaminishi, M.D.,
Associate Professor;
Toshihisa Ogawa, M.D., Yoshikazu Mimura, M.D.,(Surgical Center)
Lecturer;
Hajime Kanauchi, M.D.,
Associate;
Makoto Kammoro, M.D.,

Ei-ichi Tsuji, M.D.,

Homepage
Organization
Our section is staffed by one professor, one associate
professor, ｏｎｅ ｌｅｃｔｕｒｅｒ and ｔｗｏ assistants andtwo or three residents. Official activities of our sections 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 reconstruction of
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, andadrenal gland. In additional to treatment for malignant
cases of these diseases, we perform surgical proceduresfor hyperfunctional diseases. We co-work with the department of endocrinological internal medicine andhave about 60 surgical procedures annually in total.
In breast surgery, more than a half of the mammary
cancer patients undergo the breast-preserving surgery.
In addition, sentinel node navigation surgery has been
adopted, resulting in better quality of postoperative life.
Reconstruction surgery for the breast cancer is likely toprovide much better QOL. In this field, we have started
collaboration with the Department of Plastic Surgery.
Chemotherapy, hormone therapy and molecular- targeting therapy play important roles in treatment of thebreast cancer. We have accumulated a lot of experienceand achievement in this field.
Our clinical themes are 1) establishment of safe procedures for endocrinｅ diseases without complications;2) diagnosis and treatment of micro-breast lesions under ultrasonographic guides; 3) preoperative diagnosis
for thyroid neoplasmas and breast tumors based on telomere length and telomerase activity using Q-Fish.
Research Acitivities
Our section has been studying about the most fundamental issues to surgery, i.e., “surgical stress” whichmeans postoperative physiological and endocrinologi-

257

cal internal reaction and “nutritional support” for the
postoperative patients. These are subjects to reduce theintra- and post-operative stresses that would be risky
for the patients. Our section is like a pioneer for thisarea in Japan and we established Japanese Society for
Surgical Metabolism and Nutrition in 1965. Graduate
students organize main study group and we have presentations at some international conferences each year.
The focus of our research is “surgical metabolism
and nutrition” and “the body’s adaptive responses during postoperative recovery”. In addition, we have been
engaged in the project of chemo-sensitivity of breast
cancer and of treatment for breast tumors by high-energy ultrasound. Research details follow.
1) Mechanisms of cross tolerance among different
stresses (endotoxin - hypoxia/ hypoxia - hypoxia)
after surgery
2) Role of catecholamines in adaptation to surgicalstresses such as endotoxemia3) Bacterial translocation after anti-cancer chemotherapy4) Gender difference is a modulating factor for postoperative morbidity
5) Measurement of endotoxin activity through Tolllike receptor 46) Role of oxygen on local and systemic protein metabolism after major surgery7) Ischemic preconditioning preserves renal dysfunction after ischemia-reperfusion
8) Telomere-length and telomere activity in the thyroid and the breast tumors9) Application of Q-Fish in diagnosis of the thyroid
and the breast tumors10) Chemo-sensitivity in breast cancer

Publications (2002 - March 2004)
1. K. Matsuo，T. Fukutomi，T. Hasegawa，S. Akashi-Tanaka，T. Nanasawa，H. Tsuda. Histologicaland immunohistochemical analysis of apocrine
breast carcinoma. Breast Cancer 9：43-49, 2002
2. K. Matsuo，T. Fukutomi，T. Watanabe，T. Hasegawa，H. Tsuda，S. Akashi-Tanaka. Concordancein pathological response to neoadjuvant chemotherapy between invasive and noninvasive compo-

nents of primary breast carcinomas. Brast Cancer
9：75-81, 2002
3. K. Shimozuma，T. Okamoto，N. Katsumata，M.
Koike，K. Tanaka，S. Osumi，M. Saito，N. Shikama ， T. Watanabe ， M. Mitsumori. Systematic
Overview of Quality of Life Studies for Breast
Cancer. Breast Cancer 9：196-202, 2002
4. K. Takubo，N. Honma，M. Sawabe，T. Arai，N.
Izumiyama-Shimomura ， M. Kammori ， K. Sasajima，Y. Esaki. Oncocytic Adenocarcinoma of the
Stomach: Parietal Cell Carcinoma. Am J Surg
Pathol 26：458-465, 2002
5. M. Kammori ， KI. Nakamura ， H. Kanauchi ， T.
Obara，M. Kawahara，Y. Mimura，M. Kaminishi，
K. Takubo. Consistent Decrease in Telomere
Lenght in Parathyroid Tumors but Alteration in Telomerase Activity limited to Malignancies: Preliminary Report. World J Surg 26：1083-1087, 2002
6. M. Kammori，KI. Nakamura，M. Kawahara，Y.
Mimura ， M. Kaminishi ， K. Takubo. Telomere
shortening with aging in human thyroid and parathyroid tissue. Exp Gerontol 37：513-521, 2002
7. M. Kammori，H. Kanauchi，KI. Nakamura ，M.
Kawahara，K. Thomas，K. Weber，K. Mafune，M.
Kaminishi，K. Takubo. Demonstration of Human
Telomerase Reverse Transcriptase（hTERT）in Human Colorectal Carcinomas by In Situ Hybridization. Int J Oncol 20：15-21, 2002
8. T. Ogawa，AK. Nussler，E. Tuzuner，Y. Mimura，M, Kaminishi，HG. Beger. Inhibition of nitric oxide
synthase does not influence urinary nitrite plus nitrate excretion after renal ischemic injury. Langenbecks Arch Surg 386：518-524, 2002
9. T. Ogawa，Y. Mimura，M. Kaminishi. Renal denervation abolishes the protective effects of ischaemic preconditioning on function and haemodynamics in ischaemia-reperfused rat kidneys. Acta
Physiol Scand 174：291-297, 2002
10. H. Kanauchi ， N. Wada ， OH. Clark ， QY. Duh.
Apoptosis regulating genes，bcl-2 and bax，and
human telomerase reverse transcriptase（hTERT）
mRNA expression in adrenal tumors: Possible diagnostic and prognostic importance. Surgery 132：
1021-1027, 2002
11. R. Zarnegar，L. Brunaud，H. Kanauchi，W. Wong，
W. Fung，D. Ginginger，QY. Duh，OH. Clark. Increasing the effectiveness of radioactive iodine

258

therapy in the treatment of thyroid cancer using
trichostatin A （ TSA ） ， a histone deacetylase（HDAC）inhibitor. Surgery 132：984-990, 2002
12. N. Hiki, H. Kurosaka, Y. Tatsutomi, S. Shimoyama,
E. Tsuji, J. Kojima, N. Shimizu, H. Ono, T. Hirooka,
C.Noguchi, K. Mafune, M. Kaminishi. Peppermint
oil reduces gastric spasm during upper endoscopy:arandomized, double-blind, double-dummy controlled trial. Gastrointest Endosc 57:475-482,2003
13. N. Hiki, Y. Mimura, F. Hatao, J. Kojima, T. Ogawa,E. Tsuji, M. Kaminishi. Sublethal Endotoxin Administration Evokes Super-Resistance to Systemic
Hypoxia in Rats. J Trauma 54:584-589,2003
14. T.Kojima, M.Kammori, M. Hashimoto, T. Ogawa,
H. Yasuda, Y. Takazawa, K.Takubo, M.Kaminishi.
Diabetic Mastopathy in an Advanced Elderly
Woman with Insulin-Dependent Type 2 Diabetes
Mellitus. Breast Cancer 10: 374-377,2003
15. M. Kammori, K. Nakamura, M. Hashimoto, T.
Ogawa, M. Kaminishi, K. Takubo. Clinical application of human telomerase reverse transcriptase
gene expression in thyroid follicular tumors byfine-needle aspirations using in situ hybridization.
Int. J Oncol 22:985-991,2003
16. M. Kammori, K. Nakamura, T. Ogawa, K. Mafune,
Y. Tatutomi, T. Obara, N. Onoda, M. Fujiwara, N.
Izumiyama-Shimomura, M. Mori, M. Kaminishi, K.
Takubo. Demonstration of human telomerase reverse transcriptase(hTERT) in human parathyroid
tumours by in situ hybridization with a new oligonucleotide probe. Clin Endocrinol 58:43-48,
2003
17. E. Tsuji, N. Hiki, S. Nomura, R.Fukushima, J. Kojima, T. Ogawa, K. Mafune, Y. Mimura, M.
Kaminishi. Multaneous onset of acute inflammatory response, sepsis-like and intestinal mucosal
injury after cancer chemotherapy. Int J Cancer
107:303-308,2003

Surgical Sciences
2. Sensory and Motor System Medicine

23Surgical Sciences
3.Vital Care Medicine

24

Health Sciences and Nursing
1. Health Sciences25

Health Sciences and Nursing
2. Nursing Sciences

26

International Health
1. International Social Medicine

27

International Health
2. International Biomedical Sciences

28

University Hospital
Clinical Divisions

29

University Hospital
Central Clinical Facilities

30

University Hospital
Pharmaceutical Service

31Center for Disease Biology andIntegrative Medicine

32Surgical Sciences
2. Sensory and Motor System Medicine

23

260

Department of Dermatology
Professor
Kunihiko Tamaki, M.D., Ph.D.

Associate Professor
Kanako Kikuchi, M.D., Ph.D.

Hironobu Ihn, M.D., Ph.D.

LecturerMayumi Komine, M.D., Ph.D.
Hidehisa Saeki, M.D., Ph.D.
Norihito Yazawa, M.D.,Ph.D

Takafumi Kadono,M.D., Ph.D.
Takahiro Watanabe, M.D., Ph.D.

Associate
Makoto Sugaya, M.D. Ph.D.
Yayoi Tada, M.D., Ph.D
Masatoshi Jinnin, M.D., Ph.D.
Shinji Kagami, M.D. Ph.D. .
Yuki Ohno, M.D.

Takashi Kakinuma, M.D. Ph.D.
Toshihiko Hoashi,M.D.,Ph.D.
Yuichiro Tsunemi, M.D., Ph.D.
Shoichiro Yano, M.D.,Ph.D.

Home page http://www.h.u-tokyo.ac.jp/der/Introduction and Organaization

Clinical Activities

The Department of dermatology celebrated its 100th
anniversary in 1990. Originally it was founded as the
Department of dermatology and Urology, which also
encompassed veneology. In 1946 the Department ofdermatology was separated from that of Urology. Regarding venereology, sexually transmitted diseases only
related to skin manifestations are now dealt in our department.
The professor, two associate professors, four lecturers and nine associates take part in inpatient and outpatient cares as well as research and teaching activities.
Twenty doctors who basically belong to our department
are currently out in affiliated hospitals mainly engaged
in clinical works there Additionally, six staff members
are abroad at present, mainly involved in advanced research activities in cell biology and molecular biology.

In the out-patient clinic we see around 200 patients aday. Incisional and excisional biopsies are frequently
performed under local anesthesia at the outpatient operation facilities belonging to our department. Daily
discussions are made for initially consulted cases when
they are rather difficult to diagnose, by all staff members including Professor and Associate Professors. Furthermore, retrospective clinical and histological discussions are held regularly, which always gives us invaluable lessons.
Concerning the in-patient clinic, there are about ten
staff members under the supervision of the ward-chief.
Surgical operations such as removal of malignancies
and skin grafting that require general anesthesia arealso performed weekly in the central surgical facilities.

Education
We have ten dermatologist and are studying in the261

postgraduate course under the guidance of staff members of our department.
In addition to series of lectures , clinical education isprovided for fifthand six grade medical students, which aims at givinga general introduction for how make dermatologicalapproaches for diagnosis and treatment, with a stress onlearning how to observe and describe a variety of skineruptions. Actually the students are supposed to see
patients in outpatient clinic every day for an entire
week, as well as to participate in the inpatient clinic.

References Activities
Each specialized outpatient service reflects its
own research field in a disease-oriented manner.
However, those specialized groups performing
their own clinical and research activities arenever 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.
1. Komine M, Kakinuma T, Kagami S, Hanakawa Y, Hashimoto K, Tamaki K.
Mechanism of thymus- and activationregulated chemokine (TARC)/CCL17 production and its modulation by roxithromycin.
J Invest Dermatol. 2005 Sep;125(3):491-8.
2. Kagami S, Saeki H, Komine M, Kakinuma T,
Tsunemi Y, Nakamura K, Sasaki K,Asahina
A, Tamaki K. Interleukin-4 and interleukin13
enhance CCL26 production in a humn
keratinocyte cell line, HaCaTcells. Interleukin-4 and interleukin-13 enhance CCL26
production
in a human keratinocyte cell line, HaCaT
cells.
3. Fujita H, Asahina A, Tada Y, Fujiwara H,
Tamaki K. Type I interferons inhibit maturation and activation of mouse
Langerhans cells.J Invest Dermatol. 2005

Jul;125(1):126-33.
4. Kagami S, Kakinuma T, Saeki H, Tsunemi Y,
Fujita H, Sasaki K, Nakamura K,Takekoshi
T, Kishimoto M, Mitsui H, Komine M,
Asahina A, Tamaki K. Increased serum
CCL28 levels in patients with atopic dermatitis, psoriasis vulgaris and bullous pemphigoid.
J Invest Dermatol. 2005 May;124(5):1088-90.
No abstract available.
5. Fujita H, Asahina A, Sugaya M, Nakamura
K, Gao P, Fujiwara H, TamakiK. Type I interferons inhibit maturation and activationof mouseLangerhans cells. J Invest Dermatol.
2005 Jul;125(1):126-33.
6. Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K.Increased expression of
integrin alpha(v)beta3 contributes to theestablishment of autocrine TGF-beta signaling in scleroderma fibroblasts.
J Immunol. 2005 Dec 1;175(11):7708-18.
7. Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K.Involvement of alphavbeta5 integrin-mediated activation oflatent transforming growth factor beta1 in
autocrine transforming growth factor beta
signaling in systemic sclerosis fibroblasts.
Arthritis Rheum. 2005 Sep;52(9):2897-905.
8. Ihn H, Yamane K, Tamaki K. Increased
phosphorylation and activation of mitogen-activated protein kinase p38 inscleroderma fibroblasts.J Invest Dermatol.
2005 Aug;125(2):247-55.
9. Mimura Y, Uhn H, Jinnin M, Asano Y, Yamane K, Tamaki K.Constitutive thrombospondin-1 overexpression contributes to
autocrine transforming growth factor-beta
signaling in cultured scleroderma fibroblasts.
Am J Pathol. 2005 May;166(5):1451-63.
10. Mimura Y, Ihn H, Jinnin M, M. Yamane K,
Tamaki K.Constitutive phosphorylation of
focal adhesion kinase is involved in the myofibroblast differentiation of scleroderma fibroblasts. J Invest Dermatol. 2005 May;124(5):886-92.
11. Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K.Differential effects of the262

immunosuppressant FK-506 on human alpha2(I) collagen gene expression and transforming growth factor beta signaling innormal and scleroderma fibroblasts. Arthritis Rheum. 2005 Apr;52(4):1237-47.
12. Jinnin M, Ihn H, Yamane K, Mimura Y,
Asano Y, Tamaki K.Alpha2(I) collagen gene
regulation by protein kinase C signaling inhuman dermal fibroblasts. Nucleic Acids Res.
2005Mar ;33(4):1337-51. Print 2005.
13. Furuta J, Umebayashi Y, Miyamoto K, Kikuchi K, Otsuka F, Sugiura T, Ushijima T:
Promoter methylation profiling of 30 genes
in human malignant melanoma. Cancer Sci
95:962-968,2004
14. Ihn H: Pathogenesis of scleroderma: The roleof autocrine TGF-β signaling. Connective
Tissue 36: 209-216, 2004.
15. Furukawa H, Nakamura K, Zheng X, Tojo M,
Oyama N, Akiba H, Nishibu A, Kaneko F,
Tsunemi Y, Saeki H, Tamaki K: Enhanced
TARC production by dust-mite allergens andits modulation by immunosuppressive drugs
in
PBMCs from patients with atopic dermatitis.
J Dermatol Sci 35: 35-42, 2004.
16. Chen H-C, Kadono T, Mimura Y, Saeki H,
Tamaki K: High-frequency ultrasound as a
useful device in the preliminary differentiation of lichen sclerosus et atrophicus frommorphea. J Dermatol 31: 556-9, 2004.
17. Mizutani K, Tamada Y, Matsumoto Y, Hara
K, Tsuzuki T, Saeki H, Tamaki K: Imatinib
Masylate inhibits the growth of matastatic
lung lesions in a patient with dermatofibrosarcoma protuberans. Br J Dermatol 151:
235-7, 2004.
18. Watanabe T, Murakami T, Okochi H, Kikuchi
K, Furue M: Eccrine poroma
associated with Bowen's disease. Int J Dermatol 43: 472-473, 2004.
19. Sugaya M, Lore K, Koup RA, Douek DC,
Blauvelt A. HIV-infected Langerhans cells
preferentially transmit virus to proliferating
autologous CD4+ memory T cells locatedwithin Langerhans cell- T cell clusters. J
Immunol. 172:2219-24, 2004.

20. Tada Y, Asahina A, Fujita H, Mitsui H, Torii
H, Watanabe T, Tamaki K: Differential effects of LPS and TGF-beta on the productionof IL-6 and IL-12 by Langerhans cells,
splenic dendritic cells, and macrophages.
Cytokine 25: 155-161, 2004.
21. Riedl E, Tada Y, Udey MC: Identification andcharacterization of an alternatively spliced
isoform of mouse Langerin/CD207. J Invest
Dermatol 123:78-86, 2004.
22. Yano S, Komine M, Fujimoto M, Okochi H,
Tamaki K. Mechanical stretching in vitro
regulates signal transduction pathways andcellular proliferation in human epidermal
keratinocytes. J Invest Dermatol 122: 783790, 2004.
23. Mitsui H, Watanabe T, Jinnin M, Kadono T,
Idezuki T, Tamaki K.Mucinous carcinoma of
the skin could have either an eccrine or an
apocrine origin. Br J Dermatol. 151:1285-6,
2004.
24. Mitsui H, Watanabe T, Saeki H, Mori K, Fujita H, Tada Y, Asahina A, Nakamura K,
Tamaki K. Differential expression and function of Toll-like. Receptors in Langerhans
cells: comparison with splenic dendritic cells.
J Invest Dermatol 122:95-102,2004
Differential expression and function of Tolllike receptors in Langerhans cells: comparison with splenic dendritic cells. J Invest
Dermatol. 122:95-102, 2004.
25. Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Phosphatidylinositol 3kinase is involved in a2(1) collagen geneecpression In noemal and scleroderma fibroblasts. J Immunol 172:7123-7135,2004
Phosphatidylinositol 3-kinase is 172:7123-35,
2004.
26. Asano Y, Ihn H, Yamane K, Kubo M, Tamaki
K. Increased expression levels of integrin
avb5 on scleroderma fibroblasts. Am J
Pathol. 164:1275-1292, 2004.
27. Asano Y, Ihn H, Yamane K, Kubo M, Tamaki
K. Impaired Smad7-Smurf-mediated negative regulation of TGF-β signaling inscleroderma fibroblasts. J Clin Invest. 113:
253-264, 2004.

263

28. Asano Y, Ihn H, Shikada J, Kadono T, Kikuchi K, Tamaki K. A case of
peplomycin-induced scleroderma. Br J Dermatol. 150:1213-1214, 2004.
29. Fujita H, Asahina A, Gao P, Fujiwara H,
Tamaki K: Expression and regulation of
RANTES/CCL5, MIP-1a/CCL3, and MIP-1b/
CCL4 in mouse Langerhans cells. J Invest
Dermatol 122; 1331-1333, 2004
30. Fujita H, Asahina A, Mitsui H, Tamaki K:
Langerhans cells exhibit low responsivenessto double-stranded RNA. Biochem Biophys
Res Com 319; 832-839, 2004
31. Tsunemi Y, Ihn H, Saeki H, Tamaki K: Thelesional skin of linear IgA bullous dermatosis
expresses growth-regulated peptide (GRO)alpha. J Dermatol; 31: 546-51, 2004.
32. Tsunemi Y, Komine M, Sekiya T, Saeki H,
Nakamura K, Hirai K, Kakinuma T, Kagami
S, Fujita H, Asano N, Tanida Y, Wakugawa
M, Torii H, Tamaki K: The -431C>T polymorphism of thymus and activation- regulated
chemokine increases the promoter activity
but is not associated with susceptibility toatopic dermatitis in Japanese patients. Exp
Dermatol 13: 715-9, 2004.
33. Tsunemi Y, Tada Y, Saeki H, Ihn H, Tamaki
K: Multiple dermatofibromas in a patientwith systemic lupus erythematosus and
Sjogren's syndrome. Clin Exp Dermatol 29:
483-5, 2004.
34. Tsunemi Y, Sekiya T, Saeki H, Hirai K, Ohta
K, Nakamura K, Kakinuma T, Fujita H,
Kagami S, Asano N, Tanida Y, Wakugawa M,
Torii H, Tamaki K: Lack of association of
CCR4 single nucleotide polymorphism withatopicdermatitis in Japanese patients. Acta Derm
Venereol 84: 187-90, 2004.
35. Furukawa H, Nakamura K, Zheng X, Tojo M,
Oyama N, Akiba H, Nishibu A, Kaneko F,
Tsunemi Y, Saeki H, Tamaki K: Enhanced
TARC production by dust-mite allergens andits modulation by immunosuppressive drugs
in
PBMCs from patients with atopic dermatitis.

J Dermatol Sci 35: 35-42,2004.
36. Tsunemi Y, Saeki H, Ihn H, Tamaki K: Eosinophilic pustular folliculitis witha butterfly rash-like distribution. Dermatology 208: 229-30, 2004.
37. Tsunemi Y, Tada Y, Saeki H, Ihn H, Tamaki
K: Multiple dermatofibromas in a patientswith systemic lupus erythematosus and
Sjogren’s syndrome. Clin Exp Dermatol 29:
483-485, 2004.
38. Jinnin M, Ihn H, Asano Y, Yamane K, Trojanowska M, Tamaki K: Tenascin-C upregulation by transforming growth factor-b in human dermal fibroblasts involves Smad3, Sp1
and Ets-1. Oncogene 23: 1656-1667, 2004.
39. Jinnin M, Ihn H, Yazawa N, Asano Y, Yamane K, Tamaki K: Serum levels of manganese superoxidase dismutase in patients
withl localized scleroderma. Exp Dermatol
13: 357-360, 2004.
40. Jinnin M, Ihn H, Asano Y, Yamane K, Yazawa N, Tamaki K: Serum matrix
metaloproteinase-3 in systemic sclerosis.
Arch Dermatol Res 296: 25-29, 2004.
41. Jinnin M, Ihn H, Yamane K, Asano Y, Yazawa N, Tamaki K: Serum levelsof tissue inhibitor of metalloproteinase-1 and
2 in patients with eosinophilic faciitis. Br J
Dermatol 151: 407-412, 2004.
42. Jinnin M, Ihn H, Yamane K, Tamaki K: Interleukin-13 stimulates the transcription of
the human a2(I) collagen gene in humandermalfibroblasts. J Biol Chem 279: 41783-41791,
2004.
43. Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Yazawa N, Tamaki K: Rheumatoid
factor isotypes and anti-agalactosyl IgGantibodies in systemic sclerosis. Br J Dermatol
151:803-808, 2004
44. Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K: Epidermal growth factor
induces fibronectin expression in humandermal fibroblasts via protein kinase C deltasignaling pathway. J Invest Dermatol 122:
1390-1398, 2004
45. Sasaki K. Sugaya M. Fujita H. Takeuchi K.

264

Torii H. Asahina A. Tamaki K. A case of
primary cutaneous anaplastic large cell
lymphoma with variant anaplastic lymphoma kinase translocation. Br J Dermatol.
150: 1202-7, 2004

265

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

Hirotaka Asato, M.D.

Lecturer
Kotaro Yoshimura, M.D.

Associate
Koichi Gonda, M.D.,
Masayuki Okochi, M.D.,

Mutsumi Okazaki, M.D.,
Katsujiro Sato, M.D.

Homepage
Organization
The present faculty of the Department of Plastic andReconstructive Surgery consists of 1 professor, 1 associate professor, 1 lecturer, 5 associates and 6 physicians.
There are about 90 doctors in the department, including
16 medical trainees, 8 graduate school students, but
most are serving in rotation at affiliated hospitals.
The outpatient clinic is located on the 3rd floor of theoutpatients building, while there are wards with about
25 available beds on the 10th floor in the New Ward.
Our faculty room is located in the Medical Laboratory
Building and laboratory rooms in the East Laboratory
Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized clinics
for trauma, scars and keloids, facial paralysis, hand,replantation, microsurgery, breasts, head and neck reconstruction, cleft lip and palate, craniofacial malformation, congenital anomalies, vascular malformations,
lymphedema, and cosmetic surgery including cosmetic

dermatology. There are about 2,700 new patients andthe total number of revisiting patients are about 25,000
in a year. In the operating theater over 300 operations
are achieved under general anesthesia, while in theoutpatient clinic about 300 operations are achieved under local anesthesia in a year. Each week, the professor
goes the round of inpatients on Wednesday morning.
Preoperative and postoperative conferences and seminar that all members of the department should attend
are held on Wednesday evening. Research conferences
are held on every Thursday evening.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd, 3rd and 4th year medical students, and also of instructing 4th medical students in bed side practice. The subjects taken up in thelectures include general concepts of plastic surgery,wound healing, congenital malformations, skin grafts
and flaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine. In
the bed side practice the students have the opportunityof seeing various diseases and disorders in the field ofplastic surgery and attending outpatient clinics, surgical266

operations and clinical lectures by faculty members.
For graduate school students, microsurgical training
program is undertaken in the laboratory room. In the
postgraduate course, after completing the 6-year training program, a trainee can sit for the board examinationof the Japan Society of Plastic and Reconstructive Surgery.

Research Activities
Basic and clinical researches are performed in groups.
The major research subjects are as follows:
1) Studies on cell isolation from human tissue such as
adipose, amnion, and placenta.
2) Studies on mechanism of hypermelanogenesis of
the skin.
3) Studies on differentiation induction of human adultstem cells from adipose, amnion, and placenta
4) 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 stromal progenitor cells.
7) Studies on biological function of extracellular matrix 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 the celladhesive function.
14) Studies on clinical application and growth factor
extraction of a fluid from continuous suction
drainage.
15) Studies on mechanism of biological effects of retinoids on epidermis and dermis.
16) Studies on regeneration of peripheral nerves.

References (2004-2005)
1. Yamada Y, Nagase T, Nagase M, Koshima I. Gene
expression changes of sonic hedgehog signalingcascade in a mouse embryonic model of fetal alcohol syndrome.
J Craniofac Surg. 2005 Nov;16(6):1055-61.
2. Koshima I, Ozaki T, Gonda K, Okazaki M, Asato H.
Posterior tibial adiposal flap for repair of wide,
full-thickness defect of the Achilles tendon. J Reconstr Microsurg. 2005 Nov;21(8):551-4.
3: Nagase T, Gonda K, Inoue K, Higashino T, Fukuda
N, Gorai K, Mihara M, Nakanishi M, Koshima I.
Treatment of lymphedema with lymphaticovenular
anastomoses. Int J Clin Oncol. 2005 Oct;10(5):30410.
4: Koshima I. Short pedicle superficial inferior epigastric artery adiposal flap: new anatomical findings and the use of this flap for reconstruction of
facial contour.
Plast Reconstr Surg. 2005 Sep 15;116(4):1091-7.
5: Nagase T, Nagase M, Yoshimura K, Fujita T, Koshima I. Angiogenesis within the developing mouseneural tube is dependent on sonic hedgehog signaling: possible roles of motor neurons. Genes Cells.
2005 Jun;10(6):595-604.
6: Kaji N, Nagase T, Nagase M, Koshima I. Changes
in angiogenic gene expression in a case of expanded capillary malformation: does an expanded
capillary malformation grow? Ann Plast Surg. 2005
Jun;54(6):645-50.
7: Koshima I, Fujitsu M, Ushio S, Sugiyama N, Yamashita S. Related Articles, Links
Flow-through anterior thigh flaps with a shortpedicle for reconstruction of lower leg and foot defects. Plast Reconstr Surg. 2005 Jan;115(1):155-62.
8: Koshima I, Yamashita S, Sugiyama N, Ushio S,
Tsutsui T, Nanba Y. Successful delayed venous
drainage in 16 consecutive distal phalangeal replantations. Plast Reconstr Surg. 2005 Jan;115(1):149-54.
9: Koshima I, Nanba Y, Tsutsui T, Takahashi Y, Itoh S,
Fujitsu M. Minimal invasive lymphaticovenular
anastomosis under local anesthesia for leg lymphedema: is it effective for stage III and IV? Ann
Plast Surg. 2004 Sep;53(3):261-6.
10: Koshima I, Nanba Y, Tsutsui T, Takahashi Y, Itoh S.

267

New one-stage nerve pedicle grafting techniqueusing the great auricular nerve for reconstruction of
facial nerve defects. J Reconstr Microsurg. 2004
Jul;20(5):357-61.
11: Koshima I, Nanba Y, Tsutsui T, Takahashi Y,
Urushibara K, Inagawa K, Hamasaki T, Moriguchi
T. Superficial circumflex iliac artery perforator flap
for reconstruction of limb defects. Plast Reconstr
Surg. 2004 Jan;113(1):233-40.
12: Koshima I, Nanba Y, Tsutsui T, Itoh S. Sequential
vascularized iliac bone graft and a superficial circumflex iliac artery perforator flap with a single
source vessel for established mandibular defects.
Plast Reconstr Surg. 2004 Jan;113(1):101-6.
13: Yoshimura K, Wakita S, Sato K, Kaji N, Aiba E,
Matsumoto D, Yamaoka H, Nagase T. A Clinical
trial of Simultaneous Reconstruction of Breast andWell-Projected Nipple Following Expansion ofBreast Skin. Scand J Plast Reconstr Surg Hand
Surg, 2005 39: 77-84.
14:. Nagase T, Yoshimura K, Aiba E, Matsumoto D,
Sato K, Machino C. Angle-splitting Ostectomy
Followed by Facelift for Elderly Patients with
Prominent Mandibular Angles. Plast Reconstr Surg,2005 115: 633-40.
15. Okazaki M, Yoshimura K, Uchida G, Suzuki Y, Kitano Y, Harii K. Epidermal hyperpigmentation in
non-syndromic solitary cafe-au-lait macules may
be associated with increased secretion of endothein-1 by lesional keratinocytes. Scand J Plast
Reconstr Surg Hand Surg, 2005 39: 213-217.
16: Nagase T, Nagase M, Osumi N, Fukuda S, Nakamura S, Ohsaki K, Harii K, Asato H, Yoshimura K.
Craniofacial Anomalies of the Cultured Mouse
Embryo Induced by Inhibition of Sonic Hedgehog
Signaling: An Animal Model of Holoprosencephaly.
Journal of Craniofacial Surgery 2005 16: 80-88.
17: Nagase T, Nagase M, Yoshimura K, Fujita T, Koshima I. Angiogenesis within the developing mouseneural tube is dependent on sonic hedgehog signaling: possible roles of motor neurons. Genes Cells
2005 10: 595-604.
18: Mochizuki Y, Ojima K, Uezumi A, Masuda S, Yoshimura K, Takeda S. Participation of bone marrow-derived cells in fibrotic changes in denervatedskeletal muscle. Am J Pathol 2005 166: 1721-1732.
19: Okazaki M, Suzuki Y, Yoshimura K, Harii K. Con-

struction of pigmented skin equivalent and its application to the study of congenital disorders ofpigmentation. Scand J Plast Reconstr Surg Hand
Surg, 2005 39: 339-43.
20. Okazaki M, Asato H, Sarukawa S, Okochi M. A
revised method for pharyngoesophageal reconstruction using free jejunal transfer. Ann Plast Surg.
2005 Dec;55(6):643-7.

268

Department ofOral-Maxillofacial Surgery
Professor
Tsuyoshi Takato, M.D.,Ph.D.

Associate Professor
Takafumi Susami, D.D.S., Ph.D.

Yoshiyuki Yonehara, M.D., Ph.D.

Lecturer
Yoshiyuki Mori, D.D.S., Ph.D.
Ken Tomizuka, D.D.S., Ph.D.

Hisako Hikiji, D.D.S., Ph.D.,
Meiko Ohki, D.D.S., Ph.D.

Associate
Jun-ichi Kuroe, D.D.S.
Nobuhiko Kumazawa, D.D.S.
Katsumi Ohhashi, D.D.S.
Masako Matsuzaki, D.D.S., Ph.D.
Hideto Saijo, D.D.S., Ph.D.
Mamiko Wada, M.S.

Yukiko Suzuki, D.D.S.
Gen-ichiro Takagi, D.D.S.
Daichi Chikazu, D.D.S., Ph.D.
Yuji Ogihara, D.D.S., Ph.D.
Toru Ogasawara, D.D.S., Ph.D.

Homepage http://plaza.umin.ac.jp/%7Eoralsurg/
Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is one ofthe oldest departments in Graduate School of Medicine,the University of Tokyo. This department consists of awide variety of specialists, including oral surgeons, orthodontists and prosthodontists. We handle all diseases
in the oral-maxillofacial region, such as congenital
anomalies, jaw deformities, benign and malignant tumors, bone fractures and inflammation. Dental care forthe patients who have systemic disorders and are under
medical control is another field of our department.
Multidisciplinary treatment teamed by these specialists
is characteristic and has performed excellent results inclinical works. In research fields, all staffs participate in
the clinical and basic research to support the treatment
scientifically and to develop new treatment protocols,
and we have mainly performed the experimental studies

on the regenerative capacity of tissues, especially bone,
periosteum, cartilage, perichondrium, vessels, nerve,skin, etc. At present, we are focusing on tissue engineering in research works especially in bone, cartilage,
vessels. Professor Takato has established Tissue Engineering Division in Tokyo University Hospital and ourdepartment has two endowment departments: Department of Cartilage and Bone Regeneration (FUJI SOFT
Inc.) and Department of Clinical Vascular Regeneration(Daiichi Pharmaceutical Co., Ltd.) in Tissue Engineering Division. These departments have 1 associate professor, 1associate, and some graduate students in each.
These staffs are focusing on translational researchworks in maxillofacial regions.

Clinical activities
In the outpatient clinic, we have 12 dental treatment
booths, one operation room and one speech therapy

269

room, and treat about 90 patients per day. Dental treatments for systemic diseases are mainly performed inthis clinic. Dental surgeries such as extraction of impacted teeth, amputation of infected dental root andgingivoplasty are performed in the operation room.
Dental implants are also set in an outpatient basis andoften utilized in maxillofacial prosthodontic treatments
in reconstructed jaws after surgical resection of malignant tumors. Facial growth control and tooth movements in patients with congenital facial anomalies suchas cleft lip and palate are the most popular orthodontic
treatment. Pre- and post-surgical orthodontic treatments
combined with surgical correction of dentofacial deformities are another important role. Speech therapy tothe patients with cleft lip and palate are being done byspeech-langage-hearing therapists in the same outpatient clinic.
In the ward, we have about 350 new inpatients and330 cases are operated per year. The main surgical operations are primary closure of cleft lip and palate, secondary bone grafting in alveolar cleft, surgical correction of dentofacial deformities using maxillo- mandibular osteotomies, resection of malignant tumors followed by micro-surgical reconstruction by plastic surgeons, and correction of facial bone fractures. Both forin- and out-patients, we treat by multidisciplinary teamapproach consisted of oral and maxillofacial surgeons,orthodontists and prosthodontists. Recently, we carryout facial bone lengthening by distraction osteogenesis,
and grafting the original artificial bone which is madeby the 3D data of CT and tissue engineering techniquefor patients with dento-facial deformity.

Education
Teaching activities are divided into two parts; forundergraduate medical students and for postgraduate
dental students. For undergraduate students, we make 5
systematic lectures in their second year of specialized
course, and one lecture and one week bedside learningin final year. Through these curriculums, we demonstrate the characteristics and treatments of the diseases
in oral-maxillofacial region. Teaching is focused onfollowing points; congenital anomalies such as cleft lip
and palate and branchial arch syndromes, dentofacial
deformities caused by developmental and acquired
problems, surgical resection and functional reconstruc-tion of benign and malignant tumors, temporomandibular joint disorders, inflammation and maxillofacial
trauma. Minimum dental knowledge concerning jaw
movement, tooth pain, periodontal disease, malocclusion and dental restorations are instructed.
As for postgraduate dental students, we have a twoyears training course. This course aims to train for awide range of dental treatments and to learn about
medical cares. Various specialists instructed dental
treatments for them in outpatient clinic. Carious treatments, periodontal cares and applications of dentures
are taught by prosthodontists. Tooth extractions andorthodontic treatment are instructed by oral surgeons
and orthodontists. Medical cares in the ward are taught
by medical doctors and oral surgeons.

ResearchResearch projects are made both clinically and basically on themes closely related to clinical problems.
The main projects are as follows.
Clinical research:
1） Multidisciplinary treatment of facial deformities inpatients with cleft lip and palate or other congenital
maxillofacial anomalies
2） Multidisciplinary treatment of dentomaxillofacial
deformities, fractures and temporomandibular diseases3） Multidisciplinary treatment of malignant tumors inhead and neck region4） Combined surgical-chemical-radiological treatment
for malignant tumors5） Development of dental implant
6） Effects of arthrocentesis or therapeutic exercisesfor temporomandibular disorders
7） Non-surgical treatment system for facial bone
fractures
8） Bone repair in dentomaxillofacial region using
tissue engineering technique
Basic and experimental research:
1) Osteogenic capacity of periosteum2) Capacity of perichondrial regeneration
3) Osteogenic capacity of growth plate4) Development of various types of new skin flaps
5) Metabolism of poly ADP-ribose in DNA repair and270cell differentiation
6) Gene analysis of congenital anomalies of oral andmaxillofacial region7) Effect of free radicals on bone metabolism
8) Intracellular calcium handling on osteoblasts9) Differentiation mechanism of osteoblasts in termsof cell cycle molecule10) Osteochondrogenic differentiation of bone marrowderived mesenchymal stem cells by spheroid culture11) Mandibular lengthening by floating bone method
12) Periodontal tissue regeneration on dental implants
13) Characterization of skin derived multipotent stem
cells, especially differentiation mechanism into
neuronal cell
14) Bone and cartilage repair in dentomaxillofacial
region using tissue engineering technique

Publications
1) Kawase Y, Yanagi Y, Takato T, Fujimoto M, Okochi
H. Characterization of multipotent adult stem cells
from the skin: transforming growth factor-β(TGF-β) facilitates cell growth. Experimental Cell
Research 2004; 295: 194-203.
2) Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S,
Takato T, et al. The combination of SOX5, SOX6,
and SOX9(the SOX trio)provides signals sufficientfor induction of permanent cartilage. Arthritis
Rheum 2004; 50(11): 3561-73.
3) Hikiji H, Ishii S, Shindou H, Takato T, Shimizu T.
Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy. J. Clin. Invest 2004; 114:85-93.
4) Ogasawara T, Kawaguchi H, Jinno S, Hoshi K,
Itaka K, Takato T, et al. Bone morphogenetic protein 2-induced osteoblast differentiation requires
Smad-mediated down-regulation of Cdk6. Mol Cell
Biol 242004; 6560-6568.
5) Ogasawara T, Katagiri M, Yamamoto A., Hoshi K,
Takato T, Nakamura K, et al. Osteoclast differentiation by RANKL requires NF-kappaB-mediateddownregulation of cyclin-dependent kinase 6(Cdk6). J Bone Miner Res 2004; 19(7):1128-1136.
6) Chikuda H, Kugimiya F, Hoshi K, Ikeda T, Ogasawara T, Shimoaka T, et al. Cyclic GMP- dependent protein kinase II is a molecular switchfrom proliferation to hypertrophic differentiation ofchondrocytes. Genes Dev 2004; 18: 2418-2429, .
7) Suenaga H, Furukawa KS, Ushida T, Takato T,
Tateishi T. Aggregate formation of bone marrowstromal cells by rotation culture. Materials Scienceand Engineering: C.-Bio.S2004; 24(3): 421-424.
8) Long F, Chung UI, Ohba S, McMahon J, Kronenberg HM, McMahon AP. Ihh signaling is directly
required for the osteoblast lineage in the endochondral skeleton. Development 2004; 131(6),1309-1318.
9) Akune T, Ohba S, Kamekura S, Yamaguchi M,
Chung UI, Kubota N, et al.: PPARyinsufficiency
enhances osteogenesis through osteoblast formationfrom bone marrow progenitors. J Clin Invest 2004;
113(6), 846-855.
10) Abe M, Ohira M, Kaneda A, Yagi Y, Yamamoto S,
Kitano Y, et al. CpG island methylator phenotype isa strong determinant of poor prognosis in neuroblastomas. Cancer Res 2005; 65(3): 828-34.
11) Chikazu D, Xiaodong Li, Kawaguchi H, Sakuma Y,
Olga S Voznesensky, Douglas J Adams, et al. Bonemorphogenetic protein 2 induces cyclo-oxygenase
2 in osteoblasts via a Cbfa1 binding site: role in effects of bone morphogenetic protein 2 in vitro andin vivo. J Bone Miner Res 2005; 20:1888-1898.
12) Chikazu D, Ohba S, Ogasawara T, Saijyo H, MoriY, Tomizuka K, et al. Combination of platelet-richplasma and cyclooxygenase-2 inhibitor potently
stimulates bone marrow stromal cell proliferationin vitro. Asian J Oral Maxillofac Surg 2005; 17:8187.
13) Eguchi T, Nakatsuka T, Mori Y, Takato T. Total
reconstruction of the upper lip after resection of amalignant melanoma. Scand J Plast Reconstr Surg
Hand Surg 2005; 39:45-47.
14) Fujihara Y, Koyama H, Nshiyama N, Eguchi T,
Takato T. Gene Transfer of bFGF to recipient bed
improves survival of ischemic skin flap. Brit J Plast
Surg 2005; 58:511-517.
15) Hikiji ., Koshikiya N, Fujihara H, Hatano N, Matsuzaki M, Matsuzaki A, et al. Changes in theawareness of oral health among new students
newly enrolled at the University of Tokyo over the
past 15 years. Int J of Dent Hyg 2005; 137-144.
16) Kugimiya F, Chikuda H; Kamekura S, Ikeda T,
Hoshi K, Ogasawara T, et al. Involvement of cyclic

271

guanosine monophosphate-dependent protein kinase
II in chondrocyte hypertrophy during endochondral
ossification. Mod Rheumatol 2005; 15: 391–396.
17) Kugimiya F, Yano F, Ohba S, Igawa K, Nakamura
K, Kawaguchi H, et al. Mechanism of osteogenic
induction by FK506 via BMP/Smad pathways.
Biochem Biophys Res Commun 2005; 338(2): 8729.
18) Kugimiya F, Kawaguchi H, Kamekura S, Chikuda
H, Ohba S, Yano F, et al. Involvement of endogenous bone morphogenetic protein (BMP) 2 and
BMP6 in bone formation. J Biol Chem 2005;
280(42): 35704-12.
19) Moro T, Ogasawara T, Chikuda H, Ikeda T, Ogata
N, Maruyama Z, et al. Inhibition of Cdk6 expression through p38 MAP kinase is involved in differentiation of mouse prechondrocyte ATDC5. J
Cell Physiol 2005; 204: 927-933.
20) Takahashi ., Ogasawara T, Kishimoto J, Liu G,
Asato H, Nakatsuka T, et al. Synergistic effects of
FGF-2 with insulin or IGF-I on the proliferation ofhuman auricular chondrocytes. Cell Transplant
2005; 14:683-693.
21) Taji M, Takato T, Susami T, Eguchi T. Reconstruction necessitated by severe hypoplasia or a columella defect. J Craniofac Surg 2005; 16(4): 672-5.
22) Yano F, Kugimiya F, Ohba S, Ikeda T, Chikuda H,
Ogasawara T, et al. The canonical Wnt signaling
pathway promotes chondrocyte differentiation in a
Sox9-dependent manner. Biochem Biophys Res
Commun 2005; 333(4):1300-1308.
23) Yonehara Y, Hirabayashi S, Tachi M, Ishii H.
Treatment of zygomatic fractures without inferior
orbital rim fixation. J Cranio Surg 2005; 16: 481185.
24) Takato T, Yonehara Y, Susami T, editors. Team Approach for Oral-Maxillofacial trauma. Tokyo:
Kanehara&Co., Ltd.; 2005.
25) Takato T, Susami T, Yonehara Y, editors. Team Approach for Cleft Lip and Palate. Tokyo: Kanehara&
Co., Ltd.; 2005.

272

Department ofOrthopaedic Surgery
Professor
Kozo Nakamura, M.D., Ph.D.

Associate Professors
Yoshio Takatori, M.D., Ph.D.,

Hiroshi Kawaguchi, M.D., Ph.D.

Lecturers
Isao Ohnishi, M.D., Ph.D.,
Sakae Tanaka, M.D., Ph.D.,

Atsushi Seichi, M.D., Ph.D.,
Katsushi Takeshita, M.D., Ph.D.

Associates
Motoi Yamamoto, M.D., Ph.D.,
Hirotaka Kawano, M.D., Ph.D.
Toshiki Miura, M.D., Ph.D.
Hirotaka Chikuda, M.D., Ph.D.,
Toru Ogata, M.D., Ph.D.,
Atsushi Fukai M.D.

Tatsuro Karita, M.D., Ph.D.,
Ko Matsudaira, M.D., Ph.D.,
Hideya Itoh, M.D.,
Yuho Kadono, M.D., Ph.D.
Toru Akiyama, M.D., Ph.D.,
Nobuhiro Hara, M.D.,
Koji Osuka, M.D.,

Homepage http://www.h.u-tokyo.ac.jp/ortho/
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 had learned
orthopedic surgery in German and Austria. Hence, wecelebrate the centennial of the department this year.
Initially, the department treated patients with infectious disorders and congenital malformations, such aspoliomyelitis, tuberculosis of the spine, congenital
clubfoot and hip dislocation. The number of outpatients
visiting our department in 1910 was estimated to be no
more than 3.3% that of the two surgical 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 the acuteneeds of society from the beginning. Prof. Tashiro believed that trauma should be treated by orthopedists, so

he provided his pupils with this training. Since 1950’s,
the department has increasingly been involved in thetreatment of traffic and industrial accident victims. Prof.
Tashiro and his successor Professor Kenji Takagi devoted themselves to the establishment of an institute forchildren with disabilities. The arthroscope was developed by Prof. Takagi, and is now considered to represent a breakthrough in the development of minimallyinvasive surgery. We have recently been conducting
many studies related to the ossification of spinal ligaments (OPLL), rheumatoid arthritis, biomechanics, andthe degenerative skeletal disorders such as osteoporosis
and osteoarthritis in response to the progressive agingof our society.
Our department is now adept in the entire field of
medical science and medical practice related to the human motor system, the importance of which is now
clearly recognized not only in Japan, but also all over
the world. To meet the expanding needs of society, we273

have been conducting the teaching, clinical, and research activities described below.
Faculty members of the department are the top professor, two associate professors, four lecturers, 13 associates, 12 medical staff members, and 11 part-timeteachers.

Teaching activities
In undergraduate education, our department takes
part in systemic lectures, diagnostic lectures, and problem based learning (PBL) for 4th year medical students,
bedside learning and Clinical Clerkship for 5th year
medical students, and clinical lectures for 6th year
medical students.
Systemic lectures offer comprehensive presentation
for covering basic knowledge of the concept, pathogenesis, pathology, diagnosis and treatment of various
motor system disorders is performed. The 12 consecutive lectures cover bone and soft tissue tumors, spinal
diseases, joint diseases (hand, shoulder, elbow, hip,knee, and ankle), sports injuries, traumatology, andrheumatoid diseases. In the diagnostic lectures, weteach diagnostic maneuvers and radiological diagnosis
of a variety of skeletal diseases. PBL is offered to asmall group work to learn medical humanity and systematic methods to develop medical research.
During the 10-day period of bed-side learning, students have opportunities to experience daily clinicalcare with residents as well as practicing with faculty
members. We have developed an original text for the
students to learn orthopedics effectively. They participate in clinical conferences and surgery, and make reports on diagnostic and therapeutic procedures. They
learn how to conduct a medical interview, check physical findings and draw up actual plans for a diagnosis
and treatment including surgery.
Clinical Clerkship provides 4 weeks of early exposure to the clinical practice. The students are attached toa clinical team and are involved in most of the clinicalactivities performed by the team.
In clinical lectures, we present the clinical aspects ofimportant skeletal diseases, and discuss with the students several points for reaching a diagnosis and planning a treatment. Compression myelopathy and osteoarthritis were focused on in 2004 and 2005, respectively.

For postgraduate education, junior residents join our
department for 5-8 months. Since the training period isshort, the residents are expected to experience emergency cases as often as possible. A postgraduate seminar and a basic research conference are held weekly.
Twelve basic orthopaedic seminars by invited guest
speakers were held in 2004 and 2005.
Including the postgraduate training, a ten-year course
has been adopted with clinical and research training
taking place either in the University of Tokyo Hospitalor 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, bone lengthening,knee, hand, elbow, shoulder, sports, peripheral nerves,and bone systemic disorders. A total of 42,504 patients
visited the outpatient clinic from April 2004 throughMarch 2005.
The ward has approximately 60 to 75 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 are ward rounds by the professor on
Tuesday. We have post- and preoperative case conferences on Monday, Tuesday and Thursday evenings.
Six hundred and eleven and 533 operations were performed in 2004 and 2005, respectively. These included
cervical and thoracic spine (84 and 60), lumbar spine(19 and 8), scoliosis (8 and 8), rheumatoid arthritis (61and 51), hip (99 and 95), knee (19 and 47), shoulder (8and 2), hand (35 and 26), limb lengthening and reconstruction using external fixators (8 and 7), and tumor(59 and 61).
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 these cases. This
procedure was invented and developed in our department and is now used nationwide. The present professor Kozo Nakamura has also been the chief investigatorof a national project to investigate OPLL. Difficult operations such as subluxation of the cervical spine due torheumatoid arthritis, Down’s syndrome or cerebral
palsy were treated using a navigation system that has

274

been officially approved as a high-level advanced
medical treatment.
The lumbar spine group developed a new posterior
decompression technique which preserves the spinous
processes and interspinous ligaments, and successfully
uses it for lumbar spinal canal stenosis. Randomized
clinical trials are now ongoing by this group.
Operations performed by the rheumatoid arthritis
clinic group were primarily total joint arthroplasty, andthey reported the usefulness of absorbable screws forwrist arthroplasty.
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 acetabular osteotomy(RAO). The RAO was originated and established in our
department. They are now developing a long-life artificial joint using the MPC polymer in collaboration with
the Department of Materials Engineering in Tokyo
University.
The knee clinic group developed a new endoscopic
anterior cruciate ligament reconstruction technique using the navigation system based on fluoroscopic images
to realize ideal graft placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
Limb reconstruction operations using external fixators included non-union, leg lengthening and deformity
correction. One of the main interests of this group is thedevelopment of a system to analyze the mechanicalproperties of a skeletal system. During this period ofanalysis, the mechanical properties of the fracture site
in vivo are to be evaluated by monitoring the motion ofa dynamic pin clamp during simulated walking.

Research activities
Our research activities cover the full range of the
motor system medicine, using the in-depth sciences of
biology and technology. Especially in the field of molecular biology of bone and cartilage metabolism, weare regarded as being on the leading edge in the world.
Basic research is performed under the supervision of
the faculty staff members. The main research topics wehave focused on are as follows.
1) Molecular backgrounds of bone and joint diseases

using forward and reverse genetics approaches
2) Signaling of differentiation and apoptosis of osteoclasts
3) Etiology of OPLL
4) Molecular background underlying the joint destruction by rheumatoid arthritis
5) Molecular background of osteoarthritis using amouse genomics approach6) Non-invasive evaluation of bone strength using afinite elementary measurement
7) In vivo bone formation by cytokines and its clinicalapplication
8) Molecular mechanism of age-related bone and cartilage disorders
In addition to the activities inside the department,
we have established two endowment departments in the22th Century Medical Center that deal with clinical research, which houses the largest clinical database of
osteoarthritis patients in the world for the pursue ofgenomic and etiological research. Another endowment
department is in the Division of Tissue Engineering,which seeks to aims develop epochal bone and cartilage
regenerative medicine. Furthermore, we collaborate
with the Center for Disease Biology and Integrative
Medicine (CDBIM), and are developing nonviral genedelivery vectors (polyion complex micelles) andlong-life artificial joints for clinical application in thenear future.

References
1. Mabuchi A, Momohara S, Ohashi H, Takatori Y,
Haga N, Nishimura G, Ikegawa S. Circulating
COMP is decreased in pseudoachondroplasia andmultiple epiphyseal dysplasia patients carrying
COMP mutations. Am J Med Genet 2004; 129A:
35-38.
2. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S,
Nakamura K, Kawaguchi H, Ikegawa S, Chung UI.
Combination of SOX5, SOX6 and SOX9 (the SOXtrio) provides signals sufficient for chondrogenesis.
Arthritis Rheum 2004; 50: 3561-3573.
3. Setoguchi K, Misaki Y, Kawahata K, Shimada K,
Juji T, Tanaka S, Oda H, Shukunami C, Nishizaki
Y, Hiraki Y, Yamamoto K. Chondromodulin-I, acartilage-derived angiogenesis inhibitory factor,
suppresses T cell response; an implication of a

275

therapeutic potential for the treatment of arthritis.
Arthritis Rheum 2004; 50: 828-839.
4. Matsubara T, Tsutsumi S, Pan H, Hiraoka H, Oda
R, Nishimura M, Kawaguchi H, Nakamura K, Kato
Y. A new technique to expand human mesenchymal stem cells using basement membrane extracellular matrix. Biochem Biophys Res Commun
2004; 313: 503-508.
5. Sakuma Y, Li X, Pilbeam CC, Alander CB, Chikazu D, Kawaguchi H, Raisz LG. Stimulation ofcAMP production and cyclooxygenase-2 by prostaglandin E2 and selective prostaglandin receptor
agonists in murine osteoblastic cells. Bone 2004;
34: 827-834.
6. Itaka K, Miyata K, Harada A, Kawaguchi H, Nakamura K, Kataoka K. Clinically available endosomolytic agent for gene delivery. in "Carrier-Based Drug Delivery - ACS Symposium Series(879)" edited by Sonke Svenson: 154-160, 2004
(American Chemical Society, Washington, D.C.).
7. Chikuda H, Kugimiya F, Hoshi K, Ikeda T, Ogasawara T, Shimoaka T, Kawano H, Kamekura S,
Tsuchida A, Yokoi N, Nakamura K, Komeda K,
Chung UI, Kawaguchi H. Cyclic GMP-dependent
protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes. Genes Dev 2004; 18: 2418-2429.
8. Itaka K, Kanayama N, Nishiyama N, Jang WD,
Yamasaki Y, Nakamura K, Kawaguchi H, andKataoka K: Supramolecular nanocarrier of siRNAfrom PEG-based block catiomer carrying diamineside-chain distinctive pKa directed to enhance intracellular gene silencing. J Am Chem Soc 2004;
126: 13612-13613.
9. Kamei D, Yamakawa K, Takegoshi Y, MikamiNakanishi M, Nakatani Y, Oh-ishi S, Yasui H,
Azuma Y, Hirasawa N, Ohuchi K, Ohuchi K, Kawaguchi H, Ishikawa Y, Ishii T, Uematsu S, Akira
S, Murakami M, Kudo I. Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E syntase-1. J Biol Chem
2004; 279: 33684-33695.
10. Hoshi K, Ogata N, Shimoaka T, Terauchi Y,
Kadowaki T, Kenmotsu S, Chung U, Ozawa H,
Nakamura K, Kawaguchi H. Deficiency of insulin
receptor substrate-1 impairs skeletal growththrough early closure of epiphyseal cartilage. J

Bone Miner Res 2004; 19: 214-223.
11. Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne
WC, Baron R. Src kinase activity is essential for
osteoclast function. J Biol Chem 2004; 279:
17660-17666.
12. Ogasawara T, Katagiri M, Yamamoto A, Hoshi K,
Takato T, Nakamura K, Tanaka S, Okayama H, andKawaguchi H: Osteoclast differentiation by
RANKL requires NF-kB-mediated down-regulationof cyclin-dependent kinase 6 (Cdk6). J Bone
Miner Res 2004; 19: 1128-1136.
13. Shimoaka T, Kamekura S, Chikuda H, Hoshi K,
Chung UI, Akune T, Maruyama Z, Komori T, Matsumoto M, Ogawa W, Terauchi Y, Kadowaki T,
Nakamura K, Kawaguchi H. Impairment of bonehealing by insulin receptor substrate-1 deficiency. J
Biol Chem 2004; 279: 15314-15322.
14. Yamada T, Kawano H, Sekine K, Matsumoto T,
Fukuda T, Azuma Y, Itaka K, Chung UI, Chambon
P, Nakamura K, Kato S, Kawaguchi H: SRC-1 isnecessary for skeletal responses to sex hormones inboth males and females. J Bone Miner Res 2004;
19: 1452-1461.
15. Akune T, Ohba S, Kamekura S, Yamaguchi M,
Chung U, Kubota N, Terauchi Y, Harada Y,
Azuma Y, Nakamura K, Kadowaki T, Kawaguchi
H: PPAR insufficiency enhances osteogenesis
through osteoblast formation from bone marrowprogenitors. J Clin Invest 2004; 113: 846-855.
16. Ikeda F, Nishimura R, Matsubara T, Tanaka S,
Inoue J, Reddy SV, Hata K, Yamashita K, Hiraga T,
Watanabe T, Kukita T, Yoshioka K, Rao A, Yoneda
T. Critical roles of c-Jun signaling in regulation of
NFAT family and RANKL-regulated osteoclastdifferentiation. J Clin Invest 2004; 114: 475-484.
17. Seto H, Fujii T, Kamekura S, Miura T, Yamamoto
A, Chikuda H, Ogata T, Imamura T, Miyazono K,
Oda H, Nakamura K, Kurosawa H, Chung U, Kawaguchi H, Tanaka S. Regulation of chondrogenic
differentiation of synovial fibroblasts: segregationof the roles of Smad pathways and p38 MAP
kinase pathways. J Clin Invest 2004; 113: 718-726.
18. Itaka K, Harada A, Yamasaki Y, Nakamura K,
Kawaguchi H, Kataoka K: In situ single cell observation by fluorescence resonance energy transfer
reveals fast intra-cytoplasmic delivery and easy release of plasmid DNA complexed with linear poly-276

ethylenimine. J Gene Med 2004; 6: 76-84.
19. Matsudaira K, Seichi A, Yamazaki T, Kishimoto J,
Takeshita K, Nakamura K. Efficacy of tricyclic antidepressant for somatoform pain disorders withchronic lower back and leg pain. J Lumbar Spine
Disord 2004; 10: 155-162.
20. Ogata T, Iijima S, Hoshikawa S, Miura T, Yamamoto S, Oda H, Nakamura K, Tanaka S. Opposing
Erk and Akt pathways control Schwann cell myelination. J Neuroscience 2004; 24: 6724-32.
21. Bessho M, Ohnishi I, Okazaki H, Sato H, Kominami H, Matsunaga S, Nakamura K. Prediction of
the Strength and Fracture Location of the Femoral
Neck by CT Based Finite Element Method: A Preliminary Study on Patients with Hip Fracture. J
Orthop Sci 2004; 9: 545-550.
22. Chung UI, Kawaguchi H, Takato T, Nakamura K:Distinct osteogenic mechanisms of bone of distinct
origins. J Orthop Sci 2004; 9: 410-414.
23. Oohori Y, Seichi A, Kawaguchi H, Tajiri Y, Oda H,
Nakamura K: Retroodontoid pseudotumor resectedby a high cervical lateral approach in a rheumatoid
arthritis patient: a case report. J Orthop Sci 2004;
9: 90-93.
24. Saito T, Anamizu Y, Nakamura K, Seichi A: Caseof idiopathic thoracic spinal cord herniation with achronic history. J Orthop Sci 2004; 9: 94-98.
25. Saito T, Shimode M, Azuma S, Seichi A: Giantschwannoma of the cauda equina with dural ectasia: a case report. J Orthop Sci 2004; 9: 635-637.
26. Arany I, Megyesil JK, Kaneto H, Tanaka S,
Safirstein RL: Activation of ERK or inhibition of
JNK ameliorates hydrogen peroxide-cytotoxicity inmouse kidney proximal tubular cells. Kidney Int
2004; 65: 1230-1231.
27. Kawanishi M, Ushida T, Kaneko T, Niwa H, Fukubayashi T, Nakamura K, Oda H, Tanaka S,
Tateishi T. New type of biodegradable porous
scaffolds for tissue-engineered articular cartilage.
Mater Sci Engineer 2004; C 24: 431-435.
28. Ogasawara T, Kawaguchi H, Jinno S, Hoshi K,
Itaka K, Takato T, Nakamura K, Okayama H. Bonemorphogenetic protein 2-induced osteoblast differentiation requires smad-mediated down-regulationof cdk6. Mol Cell Biol 2004; 24: 6560-6568.
29. Moro T, Takatori Y, Ishihara K, Konno T, Takigawa
Y, Matsushita T, Chung UI, Nakamura K, Kawa-

guchi H. Surface grafting of artificial joints with abiocompatible polymer for preventing periprosthetic osteolysis. Nat Mater 2004; 3: 829-836.
30. Sato T, Matsumoto T, Kawano H, Watanabe T,
Uematsu Y, Sekine K, Fukuda T, Aihara K, KrustA, Yamada T, Nakamichi Y, Yamamoto Y, Nakamura T, Yoshimura K, Yoshizawa T, Metzger D,
Chambon P, Kato S. Brain masculinization requires
androgen receptor function. Proc Natl Acad Sci
USA 2004; 101: 1673-1678.
31. Maruyama T, Kitagawa T, Takeshita K, Mochizuki
K, Nakamura K. Effectiveness of conservative
treatment for idiopathic scoliosis - a combination ofbrace treatment and physical treatment. PediatricRehabilitation 2004; 7: 56.
32. Bastepe M, Weinstein LS, Ogata N, Kawaguchi H,
Juppner H, Kronenberg HM, Chung UI. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc
Natl Acad Sci USA 2004; 101: 14794-14799.
33. Maruyama T, Takeshita K, Nakamura K, Kitagawa
T: Spatial relations between the vertebral body andthe thoracic aorta in idiopathic scoliosis. Spine
2004; 29: 2067-2069.
34. Miyoshi K, Nakamura K, Haga N, Mikami Y. Surgical Treatment for Atlantoaxial Subluxation with
Myelopathy in Spondyloepiphyseal Dysplasia
Congenita. Spine 2004; 29: E488-491.
35. Seichi A, Takeshita K, Kawaguchi H, Nakajima S,
Akune T, Nakamura K. Postoperative expansion of
intramedullary high-intensity areas on T2-weighted
magnetic resonance imaging after cervical laminoplasty. Spine 2004; 29: 1478-1482.
36. Shoda N, Takeshita K, Seichi A, Akune T, Nakajima S, Anamizu Y, Nakamura K. Measurement ofoccipitocervical angle. Spine 2004; 29: E204-E208.
37. Takeshita K, Bylski-Austrow D, Peterson E, Nakamura K, Crawford AH. The nuchal ligament restrains cervical spine flexion. Spine 2004; 29:
E388-E393.
38. Takeshita K, Lowe TG, Pinteric R: A radiographic
comparison of combined anterior-posterior fusions
with hybrid instrumentation vs posterior fusion
alone with pedicle screw instrumentation in patients with Scheuermann's kyphosis. Spine J 2004;
4: 64S.
39. Itaka K, Miyata K, Harada A, Kawaguchi H, Na-277

kamura K, Kataoka K. Clinically available endosomolytic agent for gene delivery. Edited by
Sonke Svenson. Carrier-Based Drug Delivery ACS Symposium Series (879) . Washington, D.C.:
American Chemical Society; 2004. P154-160.
40. Tanaka S: Molecular mechanism of life and deathof the osteoclast. Int J Oral Biol 2004; 29: 121126.
41. Chung UI, Kawaguchi H, Takato T, Nakamura K.
Distinct osteogenic mechanisms of bone of distinct
origins. J Orthop Sci 2004; 9: 410-414.
42. Kawaguchi H, Katagiri M, Chikazu D. Osteoclastic
bone resorption through receptor tyrosine kinase
and extracellular signal-regulated kinase signaling
in mature osteoclasts. Mod Rheumatol 2004, 14:
1-5.
43. Anamizu Y, Kawaguchi H, Seichi A, Yamaguchi S,
Kawakami E, Kanda N, Matsubara S, Kuro-o M,
Nabeshima Y, Nakamura K, Oyanagi K. Klotho
insufficiency causes decrease of ribosomal RNA
gene transcription activity, cytoplasmic RNA andrough ER in the spinal anterior horn cells. Acta
Neuropathol 2005; 109: 457-466.
44. Nakashima E, Kitoh H, Maeda K, Haga N, Kosaki
R, Mabuchi A, Nishimura G, Ohashi H, Ikegawa S.
Novel COL9A3 mutation in a family with multiple
epiphyseal dysplasia. Am J Med Genet 2005;
132A: 181-184.
45. Kugimiya F, Yano F, Ohba S, Igawa K, Nakamura
K, Kawaguchi H, Chung UI. Mechanism of osteogenic induction by FK506 via BMP/Smad pathways. Biochem Biophys Res Commun 2005; 338:
872-879.
46. Yano F, Kugimiya F, Ohba S, Ikeda T, Chikuda H,
Ogasawara T, Ogata N, Takato T, Nakamura K,
Kawaguchi H, Chung UI. The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner. Biochem Biophys Res Commun 2005; 333: 1300-1308.
47. Kwak HB, Lee SW, Jin HM, Ha H, Lee SH, Takeshita S, Tanaka S, Kim HM, Kim HH, Lee ZH:
Monokine induced by interferon-gamma is induced
by receptor activator of nuclear factor B ligand andinvolved in osteoclast adhesion and migration.
Blood 2005; 105: 2963-2969.
48. Takahashi T, Ogasawara T, Kishimoto J, Liu G,
Asato H, Nakatsuka T, Uchinuma E, Nakamura K,

Kawaguchi H, Takato T, and Hoshi K. Synergistic
effects of FGF-2 with insulin or IGF-I on the proliferation of human auricular chondrocytes. Cell
Transplant 2005; 14: 683-693.
49. Ohnishi I, Kurokawa T, Sato W, Nakamura K:
Measurement of the tensile forces during bonelengthening. Clin Biomech 2005; 20: 421-427.
50. Matsuyama J, Ohnishi I, Kageyama T, Oshida H,
Suwabe T, Nakamura K. Osteogenesis and Angiogenesis in the Regenerating Bone during Transverse Distraction-Quantitative Evaluation Using a
Canine Model. Clin Orthop Rel Res 2005; 433:
243-50.
51. Ohashi S, Ohnishi I, Kageyama T, Fukuda S, Tsuchiya S, Imai K, Matsuyama J, Nakamura K. The
Effect of Vascularity on the Canine Distracted
Tibial Callus Consolidation. Clin Orthop Rel Res
2005; 438: 253-259.
52. Fan W, Yanase T, Nomura M, Okabe T, Goto K,
Sato T, Kawano H, Kato S, Nawata H. Androgen
receptor null male mice develop late-onset obesity
caused by decreased energy expenditure andlipolytic activity but show normal insulin sensitivity with high adiponectin secretion. Diabetes 2005;
54: 1000-1008.
53. Gohda J, Akiyama T, Koga T, Takayanagi H, Tanaka S, Inoue JI: RANK-mediated amplification of
TRAF6 signaling leads to NFATc1 induction duringosteoclastogenesis. EMBO J 2005; 24: 790-799.
54. Kadono Y, Okada F, Perchonock C, Jang HY, Lee
SH, Kim N, Choi Y: Strength of TRAF6 signallingdetermines osteoclastogenesis. EMBO report 2005;
6: 171-176.
55. Yamaguchi M, Ogata N, Shinoda Y, Akune T,
Kamekura S, Terauchi Y, Kadowaki T, Hoshi K,
Chung UI, Nakamura K, Kawaguchi H. Insulin receptor substrate-1 is required for bone anabolic
function of parathyroid hormone in mice. Endocrinology 2005; 146: 2620-2628.
56. Ikeda Y, Aihara KI, Sato T, Akaike M, Yoshizumi
M, Suzaki Y, Izawa Y, Fujimura M, Hashizume S,
Kato M, Yagi S, Tamaki T, Kawano H, Matsumoto
T, Azuma H, Kato S, Matsumoto T: Androgen receptor gene knockout male mice exhibit impaired
cardiac growth and exacerbation of angiotensin
II-induced cardiac fibrosis. J Biol Chem 2005;
280: 29661-29666.

278

57. Kugimiya F, Kawaguchi H, Kamekura S, Chikuda
H, Ohba S, Yano F, Ogata N, Katagiri T, Harada Y,
Azuma Y, Nakamura K, Chung UI. Involvement ofendogenous bone morphogenetic protein (BMP)2and BMP6 in bone formation. J Biol Chem 2005;
280: 35704-35712.
58. Yagishita N, Ohneda K, Amano T, Yamasaki S,
Sugiura A, Tsuchimochi K, Shin H, Kawahara K,
Ohneda O, Ohta T, Tanaka S, Yamamoto M, Maruyama I, Nishioka K, Fukamizu A, Nakajima T. Essential role of synoviolin in embryogenesis. J Biol
Chem 2005; 280: 7909-7916.
59. Kawaguchi H, Akune T, Yamaguchi M, Ohba S,
Ogata N, Chung UI, Kubota N, Terauchi Y,
Kadowaki T, Nakamura K. Distinct effects of
PPAR-gamma insufficiency on bone marrow cells,
osteoblasts, and osteoclastic cells. J Bone Miner
Metab 2005; 23: 275-279.
60. Chikuda H, Kugimiya F, Hoshi K, Ikeda T, Ogasawara T, Kamekura S, Ogata N, Nakamura K,
Chung UI, Kawaguchi H. Mutation in
cGMP-dependent protein kinase II causes dwarfism
in a rat mutant KMI through uncoupling of proliferation and differentiation of chondrocytes. J Bone
Miner Metab 2005; 23: 200-204.
61. Ikeda T, Kawaguchi H, Kamekura S, Ogata N,
Mori Y, Nakamura K, Ikegawa S, Chung UI. Distinct roles of SOX5, SOX6 and SOX9 in different
stages of chondrogenic differentiation. J Bone
Miner Matab 2005, 23: 337-340.
62. Moro T, Ogasawara T, Chikuda H, Ikeda T, Ogata
N, Maruyama Z, Komori T, Hoshi K, Chung UI,Nakamura K, Okayama H, and Kawaguchi H: Inhibition of Cdk6 expression through p38 MAP
kinase is involved in differentiation of mouse prechondrocyte ATDC5. J Cell Physiol 2004: 927-933,
2005.
63. Seichi A, Takeshita K, Kawaguchi H, Kawamura N,
Higashikawa A, Nakamura K. Image-guided surgery for thoracic ossification of the posterior longitudinal ligament. J Neurosurg Spine 2005; 3:
165-168.
64. Hotta, Morita, Seichi A, Kirino T: Aberrant courseof the vertebral artery in a case with Chiari malformation and occipital-atlas assimilation. J Neurosurgery Spine 2005; 3: 246-248.
65. Matsudaira K, Yamazaki T, Seichi A, Takeshita K,

Hoshi K, Kishimoto J, Nakamura K. Spinal stenosis in grade 1 degenerative lumbar spondylolisthesis: a comparative study of outcomes following
laminoplasty and laminectomy with instrumented
spinal fusion. J Orthop Sci 2005; 10: 270-276.
66. Seichi A, Takeshita K, Nakajima S, Akune T, Kawaguchi H, Nakamura K: Revision cervical spine
surgery using transarticular or pedicular screws
under a computer-assisted image-guidance system.
J Orthop Sci 2005; 10: 385-390.
67. Kobayashi D, Satsuma S, Kamegaya M, Haga N,
Shimomura S, Fujii T, Yoshiya S: Musculoskeletal
conditions of acute leukemia and malignant lymphoma in children. J Pediatr Orthop B 2005; 14:
156-161.
68. Ohnishi I, Sato W, Matsuyama J, Yajima H, Haga
N, Kamegaya M, Minami A, Sato M, Yoshino S,
Oki T, Nakamura K. Treatment of congenital pseudarthrosis of the tibia: A multicenter study in Japan.
J Pediatr Orthop 2005; 25: 219-224.
69. Masuda H, Chikuda H, Suga T, Kawaguchi H, andKuro-o M. Regulation of multiple ageing-likephenotypes by inducible klotho gene expression in
klotho mutant mice. Mech Ageing Dev 2005; 126:
1274-1283.
70. Fujiwara S, Nakamura I, Higo R, Tajiri Y, Nakamura K, Oda H. A case report of repeated postoperative laryngeal obstruction due to bilateral cricoarytenoid joint involvement in rheumatoid arthritis. Mod Rheumatol 2005; 15: 123-125.
71. Kugimiya F, Chikuda H, Kamekura S, Ikeda T,
Hoshi K, Ogasawara T, Nakamura K, Chung UI,Kawaguchi H. Involvement of cyclic quanosine
monophosphate-dependent protein kinase II inchondrocyte hypertrophy during endochondral ossification. Mod Rheumatol 2005; 15: 391-396.
72. Matsumoto T, Kuga Y, Seichi A, Oda H, Nakamura
K. Bone resorption of the facet joint in rheumatoid
arthritis as a predictor of lower cervical myelopathy.
Mod Rheumatol 2005; 15: 352-357.
73. Kamekura S, Hoshi K, Shimoaka T, Chung U,
Chikuda H, Yamada T, Uchida M, Ogata N, Seichi
A, Nakamura K, Kawaguchi H. Osteoarthritis development in novel experimental mouse model induced by knee joint instability. Osteoarthr Cartilage 2005; 13: 632-641.
74. Kurosu H, Yamamoto M, Clark JD, Pastor JV,

279

Nandi A, Gurnani P, McGuinness OP, Chikuda H,
Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, andKuro-o M: Suppression of aging in mice by thehormone Klotho. Science 2005; 309: 1829-1833.
75. Takeshita K, Seichi A, Akune T, Kawamura N,
Kawaguchi H, Nakamura K. Can laminoplasty
maintain the cervical alignment even when the C2
lamina is contained? Spine 2005; 30: 1294-1298.
76. Tanaka S. Intracellular signal transduction pathways: good therapeutic targets for joint destruction
in rheumatoid arthritis. Mod Rheumatol 2005; 15:
19-27.
77. Hsia, DA, Lim S-T, Bernard-Trifilo JA, Mitra, SK,
Tanaka S, den Hertog, J, Streblow, DN, IlicZ D,
Ginsberg, MH, Schlaepfer DD. Integrin α4β1 promotes FAK-independent cell motility via α4 cytoplasmic domain –specific activation of Src. Mol
Cell Biol 2005, 25:9700-9712.
78. Fukuda A, Hikita A, Wakeyama H, Akiyama T, Oda
H, Nakamura K, Tanaka S. Regulation of osteoclast
apoptosis and motility by small GTPase binding
protein Rac1. J Bone Miner Res 2005, 20:22452253.
79. Hikita A, Kadono Y, Chikuda H, Fukuda A, Wakeyama H, Yasuda H, Nakamura K, Oda H, Miyazaki
T, Tanaka S. Identification of an alternatively
spliced variant of CAPRI as a possible regulator of
RANKL shedding. J Biol Chem 2005, 280: 4170041706.
80. Hu K, Yang J, Tanaka S, Gonias SL, Mars WM,
Liu Y. Tissue-type plasminogen activator acts as acytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene
expression. J Biol Chem 2005, 281: 2120-2127.
81. Akiyama T, Miyazaki T, Bouillet P, Nakamura K,
Strasser A, Tanaka S. In vitro and in vivo assays forosteoclast apoptosis. Biol Proced Online 2005, 7:
48-59.
82. Tanaka S, Takahashi N, Nakamura K, Suda,. T.
Role of RANKL in physiological and pathologicalbone resorption and therapeutics targeting
RANKL-RANK signaling system. Immunol Rev
2005, 108:30-49.
83. Kugimiya F, Ohba S, Nakamura K, Kawaguchi H,
Chung UI. Physiological role of bone morphogenetic proteins in osteogenesis. J Bone Miner Me-

tab 2006; 24: 95-99.
84. Katagiri M, Ogasawara T, Hoshi K, Chikazu D,
Kimoto A, Noguchi M, Sasamata M, Harada S,
Akama H, Tazaki H, Chung UI, Takato T, Nakamura K, Kawaguchi H. Suppression of adjuvantinduced arthritic bone destruction by cyclooxygenase-2 selective agents with and without inhibitory potency against carbonic anhydrase II. J Bone
Miner Res 2006; 21: 219-227.
85. Ogata T, Yamamoto S, Nakamura K and Tanaka S.
Signaling Axis in Proliferation and Differentiationof Schwann Cell. Mol Neurobiol 2006, 33:51-62.
86. Yoshimura N, Kinoshita H, Hori N, Nishioka T,
Ryujin M, Mantani Y, Miyake M, Takeshita T,
Ichinose M, Yoshida M, Oka H, Kawaguchi H,
Nakamura K, Cooper C: Risk factors for knee osteoarthritis in Japanese men: a case-control study.
Mod Rheumatol 2006; 16: 24-29.
87. Koshizuka Y, Ogata N, Shiraki M, Hosoi T, Seichi
A, Takeshita K, Nakamura K, and Kawaguchi H:
Distinct association of gene polymorphisms of estrogen receptor and vitamin D receptor with lumbar
spondylosis in postmenopausal women. Eur Spine
J 2006, 15: 1521-1528.
88. Shinoda Y, Yamaguchi M, Ogata N, Akune T, Kubota N, Yamauchi T, Terauchi Y, Kadowaki T, Takeuchi Y, Fukumoto S, Ikeda T, Hoshi K, Chung UI,Nakamura K, and Kawaguchi H: Regulation ofbone formation by adiponectin through autocrine/
paracrine and endocrine pathways. J Cell Biochem
2006, 99: 196-208.
89. Yamaoka H, Asato H, Ogasawara T, Nishizawa S,
Takahashi T, Nakatsuka T, Koshima I, Nakamura K,
Kawaguchi H, Chung UI, Takato T, and Kazuto
Hoshi: Cartilage tissue engineering using humanauricular chondrocytes embedded in different hydrogel materials. J Biomed Mater Res 2006,78:
1-11.
90. Seichi A, Takeshita K, Kawaguchi H, Matsudaira K,
Higashikawa A, Ogata N, and Nakamura K: Neurological level diagnosis of cervical stenotic myelopathy. Spine 2006:31:1338-1343.
91. Yamada T, Kawano H, Koshizuka Y, Fukuda T,
Yoshimura K, Kamekura S, Saito T, Ikeda T, Kawasaki Y, Azuma Y, Ikegawa S, Hoshi K, Chung UI,Nakamura K, Kato S, and Kawaguchi H: Carminerin contributes to chondrocyte calcification during

280

endochondral ossification under physiological andpathological conditions. Nat Med 2006, 12: 665670.
92. Ogata N, Roth SI, Kawaguchi H, and Segre
GV: Continuous activation of PKC by Gαq in
osteoblasts results in osteopenia by blocking
osteoblast differentiation. J Bone Miner Res(in press).
93. Moro T, Takatori Y, Ishihara K, Nakamura K, andKawaguchi H: Grafting of biocompatible MPC
polymer on cross-linked polyethylene liner surface
for extending longevity of artificial hip joints. Clin
Orthop Rel Res (in press).

281

Department of Ophthalmology
Professor
Makoto Araie, M.D., Ph.D.

Associate Professor
Goji Tomita, M.D., Ph.D.,

Yasuhiko Tamaki, M.D., Ph.D.

Lecturer
Satoru Kato, M.D., Ph.D.,
Atsushi Tomidokoro, M.D., Ph.D.,

Makoto Aihara, M.D., Ph.D.,
Miyuki Nagahara, M.D., Ph.D.

Associate
Toshikatsu Kaburaki, M.D., Ph.D.,
Tomohiko Usui, M.D., Ph.D.,
Yasuo Noda, M.D., Ph.D.,
Koichi Mishima, M.D., Ph.D.,
Takashi Shigeeda, M.D.,
Akira Hirose, M.D.,

Ryuichi Ideta, M.D.,
Yasuo Yanagi, M.D., Ph.D.,
Yuji Inoue, M.D., Ph.D.,
Keiko Hayashi, M.D.,
Tae Arakawa, M.D.,
Kenji Sugisaki, M.D.,

Homepage http://plaza.umin.ac.jp/ophl
Introduction and Organization
The Department of Ophthalmology, University ofTokyo School of Medicine, was founded in 1989. Since
then, the department has contributed to Japanese ophthalmology not only by educating a large number ofeminent ophthalmologists in Japan, but also by producing 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 5000 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 inunits 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 theambulatory 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 2000 cases underwent
operations in our department. Surgeries can be monitored by TV system which is mounted on operating microscopes. Since multiple observers can watch the sameimages and share findings, this system has a great potential in training and promoting discussion.

Teaching activities
As an undergraduate course, we give lectures on corneal physiology, corneal diseases, and corneal transplantation. In addition, we are engaged in practical

282

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 and molecular biology.
Special laboratories for physiology, pharmacology andgenetic engineering have been established. Specificfields of research in our department are as follows.
1. Analysis with laser-speckle method of vascularflow in retina and iris
2. Clinical investigation of normal tension glaucoma
3. Analysis of dynamics of aqueous flow
4. Drug effect on glaucoma
5. Screening method of glaucoma
6. Tissue engineering of the cornea
7. Clinical investigation of corneal shape
8. Gene therapy in corneal transplantation
9. Role of advanced glycation endproducts in oculardiseases
10. Clinical and basic research of excimer laser refractive surgery
11. Molecular analysis of retinal degenerative diseases
12. Color blindness and visual function
13. Electrophysiological analysis of the effect of drugs
on the retina
14. Biocompatibility of intraocular lenses
15. Immuno-hereditary analysis of Harada’s disease
and Bechet’s disease
16. Immunosuppressive reagents on Bechet’s disease
17. Pathophysiology and molecular mechanisms of
diabetic retinopahty

References
1. Adhikary AK, Inada, Suzuki E, Ushijima H, Banik
U, Mukouyama A, Matsuno S, Numaga J, Okabe
N: Characterization of hexon and fiber gene of anovel strain of adenovirus involved in epidemic
keratoconjunctivitis. J Clin Pathol 57:95-97, 2004
2. Adhikary AK, Inada T, Banik U, Numaga J, Okabe
N: Identification of subgenus C adenoviruses byfiber-based multiplex polymerase chain reaction. J
Clin Microbiol 42:670-673, 2004
3. Adhikary AK, Inada T, Numaga J, Suzuki E, Banik
U, Okabe N: Heterogeneity of fiber sequence insubgenus C adenoviruses. J Clin Pathol 57:612-617,
2004
4. Adhikary AK, Inada T, Banik U, Mukouyama A,
Ikeda Y, Noda M, Ogino T, Suzuki E, Kaburaki T,
Numaga J, Okabe N: Serological and genetic characterisation of a unique strain of adenovirus involved in an outbreak of epidemic keratoconjunctivitis. J Clin Pathol 57:411-416, 2004
5. Akiyama K, Numaga J, Kagaya F, Takazawa Y,
Suzuki S, Koseki N, Kato S, Kaburaki T, Kawashima H.: Case of optic nerve involvement in metastasis of a gastrointestinal stromal tumor. Jpn J
Ophthalmol 48:166-168, 2004
6. Amano S, Amano Y, Yamagami S, Miyai T, Miyata K, Samejima T, Oshika T: Age-relatedchanges in corneal and ocular higher order wavefront aberrations. Am J Ophthalmol 137:988-992,
2004
7. Atarashi T, Tamaki Y, Inoue Y, Obata R, Muranaka
K, Yanagi Y: Transpupillary thermotherapy fortreatment of exudative age-related macular degeneration in Japanese patients. Eye 18:615-618, 2004
8. Bernd AS, Aihara M, Lindsey JD, Weinreb RN:
Influence of molecular weight on intracameral dextran movement to the posterior segment of themouse eye. Invest Ophthalmol Vis Sci 45:480-484,
2004
9. Crowston JG, Aihara M, Lindsey JD, Weinreb RN:
Effect of latanoprost on outflow facility in themouse. Invest Ophthalmol Vis Sci 45:2240-2245,
2004
10. Crowston JG, Lindsey JD, Aihara M, Weinreb RN:
Effect of Latanoprost on intraocular pressure inmice lacking the prostaglandin FP receptor. Invest
Ophthalmol Vis Sci 45: 3555-3559, 2004
11. Dale S, Gregerson, Kawashima H: APC derived
from donor splenoctes support retinal autoimmune
disease in allogeneic recipients. J Leukocyte Biology 76:383-387, 2004
12. Funatsu H, Yamashita H, Noma H, Mimura T, Sakata K, Hori S: Risk evaluation of outcome of vitreous surgery for proliferative diabetic retinopathy
based on vitreous level of vascular endothelial

283

growth factor and angiotensin II. Br J Ophthalmol
88:1064-1068, 2004
13. Funatsu H, Yamashita H, Shimizu E, Mimura T,
Nakamura S, Hori S: Quantitative measurement of
retinal thickness in patients with diabetic macularedema is useful for evaluation of therapeutic agents.
Diabetes Res Clin Pract 66:219-227, 2004
14. Gekka M, Miyata K, Nagai Y, Nemoto S, Sameshima T, Tanabe T, Maruoka S, Nakahara M,
Kato S, Amano S: Corneal epithelial barrier function in diabetic patients. Cornea 23:35-37, 2004
15. Goto W, Ichikawa M, Tanaka E, Hara H, Araie M.
Bunazosin hydrochloride reduces glutamate- induced neurotoxicity in rat primary retinal cultures.
Brain Res 1003:130-137, 2004
16. Hayashi Y, Kato S, Fukushima H, Numaga J, T
Kaiya, MD, Tamaki Y, Oshika T: Relationship between anterior capsule contraction and posterior
capsule opacification after cataract surgery in patients with diabetes mellitus. J Cataract Refract
Surg 30:1517-1520, 2004
17. Honda N, Hamada N, Amano S, Kaji Y, Hiraoka T,
Oshika T: Five-year follow-up study of photorefractive keratectomy for myopia. J Refract Surg
20:116-120, 2004
18. Ichikawa M, Okada Y, Asai Y, Hara H, Ishii K,
Araie M: Effects of topically instilled bunazosin, analpha1-adrenoceptor antagonist, on constrictions
induced by phenylephrine and ET-1 in rabbit retinal arteries. Invest Ophthalmol Vis Sci 45:40414048, 2004
19. Ideta R, Yanagi Y, Tamaki Y, Tasaka F, Harada A,
Kataoka K: Effective accumulation of polyion
complex micelle to experimental choroidal neovascularization in rats. FEBS Lett 557:21-25,
2004
20. Inoki T, Endo H, Inoki Y, Hamamoto T, Tsuru T,
Mori T, Miyata K, Amano S, Yamagami S: Damaged DNA-binding protein 2 accelerates UVdamaged DNA repair in human corneal endothelium. Exp Eye Res 79:367-376, 2004
21. Inoue K, Hashida S, Tajima Y, Wakakura M, Inoue
J, Tomita G: Progression of visual field defect in anormal-tension glaucoma patient after laser in situ
keratomileusis. Eye 18: 850-853, 2004
22. Inoue T, Yanagi Y, Tamaki Y, Kami J, Kato Y: Massive subretinal hemorrhage secondary to age-re-lated macular degeneration in a patient with idiopathic thrombocytopenic purpura. Eye 18:656- 657,
2004
23. Iriyama A, Uchida S, Yanagi Y, Tamaki Y, Inoue Y,
Matsuura K, Kadonosono K, Araie M: Effects of
indocyanine green on retinal ganglion cells. Invest
Ophthalmol Vis Sci 45:943-947, 2004
24. Iriyama A, Yanagi Y, Uchida S, Tamaki Y, Aihara
M, Obata R, Inoue Y: Retinal nerve fiber layer
damage after indocyanine green assisted vitrectomy.
Br J Ophthalmol 88:1606-1607, 2004
25. Ishii K，Fukaya Y, Araie M, Tomita G: Topical administration of iganidipine, a new water-solubleca(2+) antagonist, increases ipsilateral optic nerve
head circulation in rabbits and cynomolgus monkeys. Curr Eye Res 29:67-73, 2004
26. Iwase A, Suzuki Y, Araie M，Yamamoto T, Abe H,
Shirato S, Kuwayama Y, Mishima HK, Shimizu H,
Tomita G, Inoue Y, Kitazawa Y, Tajimi Study Group,Japan Glaucoma Society: The prevalence of primary open-angle glaucoma in Japanese: the Tajimi
Study. Ophthalmology 111:1641-1648, 2004
27. Kamiya K, Miyata K, Tokunaga T, Kiuchi T, Hiraoka T, Oshika T: Structural analysis of the cornea
using scanning-slit corneal topography in eyes undergoing excimer laser refractive surgery. Cornea
23:59-64, 2004
28. Kashiwagi K, Iizuka Y, Tanaka Y, Araie M, Suzuki
Y, Tsukahara S. Molecular and cellular reactions ofretinal ganglion cells and retinal glial cells undercentrifugal force loading. Invest Ophthalmol Vis
Sci 2004 45:3778-3786, 2004
29. Kawana K, Tokunaga T, Miyata K, Okamoto F,
Kiuchi T, Oshika T：Comparison of corneal thickness measurements using Orbscan Ⅱ, noncontact
specular microscopy, and ultrasonic pachymetry ineyes after laser in situ keratomileusis. Br J Ophthalmol 88:466-468, 2004
30. Kawase Y, Yanagi Y, Fujimoto M, Takato T, Okochi
H: Characterization of multipotent stem cells fromthe skin: Transforming growth factor (TGF)-β facilitates the cell growth. Exp Cell Res 295:194-203,
2004
31. Mabuchi F, Lindsey JD, Aihara M, Mackey MR,
Weinreb RN: Optic nerve damage in mice with atargeted type I collagen mutation. Invest Ophthalmol Vis Sci 45:1841-1845, 2004

284

32. Mabuchi F, Aihara M, Mackey MR, Lindsey JD,
Weinreb RN: Regional optic nerve damage in experimental mouse glaucoma. Invest Ophthalmol
Vis Sci 45:4352-4358, 2004
33. Mayama C, Tomidokoro A, Araie M, Mizuno K:
Influence of peripheral iridectomy on intravitreous
penetration of topical nipradilol. Curr Eye Res
28:129-133, 2004
34. Mayama C, Araie M, Suzuki Y, Ishida K, Yamamoto T, Kitazawa Y, Shirakashi M, Abe H, Tsukamoto H, Mishima HK, Yoshimura K, Ohashi Y:
Statistical evaluation of the diagnostic accuracy of
methods used to determine the progression of visual field defects in glaucoma. Ophthalmology 111:
2117-2125, 2004
35. Mimura T, Amano S, Funatsu H, Yamagami S,
Araie M, Kaji Y, Arimoto A, Ishida Y, Usui T,
Okamoto S: Correlations between each allergen-specific IgE serum levels in patients with allergic conjunctivitis in Spring. Ocul Immunol Inflamm 12:45-51, 2004
36. Mimura T, Amano S, Usui T, Araie M, Ono K,
Hashizume A, Yokoo S, Yamagami S: Transplantation of corneas reconstructed with cultured adulthuman corneal endothelial cells in nude rats. Exp
Eye Res 79:231-237, 2004
37. Mimura T, Yamagami S, Yokoo S, Usui T, Tanaka
K, Hattori S, Irie S, Miyata K, Araie M, Amano S:
Cultured human corneal endothelial cell transplantation with a collagen sheet in a rabbit model. Invest Ophthalmol Vis Sci 45:2992-2997, 2004
38. Mimura T, Amano S, Sugiura T, Funatsu H, Yamagami S, Araie M, Eguchi S: Refractive change after
transscleral fixation of posterior chamber intraocular lenses in the absence of capsular support. Acta
Ophthalmologica Scandinavica, 82:544-546, 2004
39. Mimura T, Funatsu H, Kitano S, Noma H, Shimizu
E, Amano S, Kato S, Araie M, Yoshino O, Hori S:
HLA typing is not preditive of proliferative diabetic
retinopathy in patients with younger-onset type 2
diabetes mellitus. Br J Ophthalmol 88:303-305,
2004
40. Mimura T, Funatsu H, Uchigata Y, Kitano S, Shimizu E, Noma H, Amano S, Araie M, Iwamoto Y,
Hori S: Development and progression of diabetic
retinopathy in patients with type 1 diabetes who arepositive for GAD autoantibody. Diabetic Med

21:559-562, 2004
41. Mimura T, Yamagami S, Amano S, Funatsu H,
Arimoto A, Usui T, Ono K, Araie M, Okamoto S:
Allergens in Japanese patients with allergic conjunctivitis in autumn. Eye 24:Epub ahead of print,
2004
42. Miyata K, Tokunaga T, Nakahara M, Ohtani S,
Nejima R, Kiuchi T, Kaji Y, Oshika T: Residual bed
thickness and corneal forward shift after laser insitu keratomileusis. J Cataract Refract Surg 30:
1067-1072, 2004
43. Nejima R, Miyata K, Honbou M, Tokunaga T, Tanabe T, Sato M, Oshika T: A prospective, randomised cpmparison of single and three piece acrylic
foldable intraocular lenses. Br J Ophthalmol 88:
746-749, 2004
44. Ohno S, Nakamura S, Hori S, Shimakawa M, Kawashima H, Mochizuki M, Sugita S, Ueno S, Yoshizaki K, Inaba G: Efficacy, safety, and pharmacokinetics of multiple administration of infliximab
in Behcet’s disease with refractory uveoretinitis. J
Rheumatol 31:1362-1368, 2004
45. Okada Y, Ichikawa M, Ishii K, Hara H: Effects of
topically instilled bunazosin hydrochloride andother ocular hypotensive drugs on endothelin-1induced constriction in rabbit retinal arteries. Jpn J
Ophthalmol 48:465-469, 2004
46. Obstbaum SA, Cioffi GA, Krieglstein GK,
Fennerty MB, Alm A, Araie M, Carassa RG, Greve
EL, Hitchings RA, Kaufman PL, Kitazawa Y,
Pongpun PR, Susanna R Jr, Wax MB, Zimmerman
TJ. Gold standard medical therapy for glaucoma:
defining the criteria identifying measures for anevidence-based analysis. Clin Ther 26:2102-2120,
2004
47. Oshika T, Eguchi S, Oki K, Yaguchi S, Bissen-Miyajima H, Ota I, Sugita G, Miyata K: Clinical comparison of Healon 5 and Healon inphacoemulsification and intraocular lens implantation randomized multicenter study. J Cataract Refract Surg 30:357-362, 2004
48. Sakamoto T, Enaida H, Kubota T, Nakahara M,
Yamakiri K, Takehiro Yamashita, Yokoyama M ,Hata Y, Murata T, Miyata k, Uemura A, Kimura W,
Ishibashi T: Incidence of acute endophthalmitis after triamcinolone-assisted pars plana vitrectomy.
Am J Ophthalmol 137:137-138, 2004

285

49. Sugita M, Kato S, Sugita G, Oshika T: Migration oflens epithelial cells through haptic root of single-piece acrylic-foldable intraocular lens. Am J
Ophthalmol 137:377-379, 2004
50. Suzuki J, Tomidokoro A, Araie M, Tomita G, Yamagami J, Okubo T, Masumoto T: Visual fielddamage in normal-tension glaucoma patients withor without ischemic changes in cerebral magnetic
resonance imaging. Jpn J Ophthalmol 48:340-344,
2004
51. Suzuki Y，Kiyosawa M, Mochizuki M, Wakakura
M, Ishii K, Senda M：Oscillopsia associated with
dysfunction of visual cortex. Jpn J Ophthalmol
48:128-132, 2004
52. Takahashi H, Yanagi Y, Tamaki Y, Muranaka K,
Usui T, Sata M: Contribution of bone marrow-derived cells to choroidal neovascularization.
Biochem Biophys Res Commun 320, 372-375,
2004
53. Takahashi H, Yanagi Y, Tamaki Y, Uchida S, Muranaka K: COX-2-selective inhibitor, etodolac, suppresses chroidal neovascularization in a micemodel. Biochem Biophys Res Commun 325:
461-466, 2004
54. Takayama J, Mishima A, Ishii K: Effects of topicalphenylephrine on blood flow in the posterior segments of monkey and aged human eyes. Jpn J Ophthalmol 48:243-8, 2004
55. Tanabe T, Miyata K, Samejima T, Hirohara Y,
Mihashi T, Oshika T: Influence of wavefront aberration and corneal subepithelial haze on low-contrast visual acuity after photorefractive keratectomy.
Am J Ophthalmol 138:620-624, 2004
56. Tanabe T, Tomidokoro A, Samejima T, Miyata K,
Sato M, Kaji Y, Oshika T: Corneal regular and irregular astigmatism assessed by Fourier analysis ofvideokeratography data in normal and pathologic
eyes. Ophthalmology 111:752-757, 2004
57. Tanaka Y, Kato S, Miyata K, Honbou M, Nejima R,
Kitano S, Amano S, Oshika T: Limitation of
Scheimpflug videophotography system in quantifying posterior capsule opacification after intraocular lens implantation. Am J Ophthalmol,
137:732-735,2004
58. Tomidokoro A, Takayama J, Araie M: Optic nerve
blood flow after acute intraocular pressure increasein rabbit. 5th International Symposium on Ocular

Pharmacology and Therapeutics ISOPT. 2004:179182.
59. Tomita G, Araie M, Kitazawa Y, Tsukahara S: A
three-year prospective, randomized and open comparison between latanoprost and timolol in Japanese normal-tension glaucoma patients. Eye 18:984-989, 2004.
60. Usui T, Yamagami S, Yokoo S, Mimura T, Ono K,
Amano S: Gene expression profile in corneal neovascularization identified by immunology-related
macroarray. Mol Vis 10, 832-836, 2004
61. Usui T, Ishida S, Yamashiro K, Kaji Y, Moore J,
Moore T, Poulaki V, Amano S, Horikawa Y, Dartt
D, Goldberg M, Shima D, Adamis AP: VEGF164/
165 as the pathological isofom; differential leukocyte and endothelial responses via VEGFR1 and
VEGFR2. Invest Ophthalmol Vis Sci 45, 368-374,
2004
62. Wakakura M, Tsubouchi T, Inouye J: Etizolam andbenzodiazepine induced blepharospasm. J Neurol,
Neurosurg Psych 75：506-507, 2004
63. Yamagami S, Yokoo S, Mimura T, Amano S: Effects of TGF-beta2 on immune response-related
gene expression profiles in the human corneal endothelium. Invest Ophthalmol Vis Sci 45:515-521,
2004
64. Yamane N, Miyata K, Samejima T, Hiraoka T,
Okamoto F, Hiro Y, Mihashi T, Oshika T: Ocularhigher-order aberrations and contact sensitivity after conventional laser in situ keratomileusis. Invest
Ophthalmol Vis Sci. 45:3986-3990, 2004
65. Yanagi Y, Tamaki Y, Takahashi H, Sekine H, Mori
M, Hirato T, Okajima O: Clinical and functional
findings in crystalline retinopathy. Retina 24:267274, 2004
66. Yanagi Y, TamakiY, Sekine H: Fluorescein angiography-guided indocyanine green angiography
for the detection of feeder vessels in subfoveal
choroidal neovascularization. Eye 18:474-477,
2004
67. Yoshida A, Kawashima H, Motoyama Y, Shibui H,
Kaburaki T, Shimizu K, Ando K, Hijikata K, Izawa
Y, Hayashi K, Numaga J, Fujino Y, Masuda K,
Araie M: Comparison of patients with Behcet's
disease in the 1980s and 1990s. Ophthalmology
111:810-815, 2004
68. Yoshimoto M, Matsumoto S: Orbital varix rupture

286

during cataract surgery. J Cataract Refract Surg
30:722-725, 2004
69. Yamamoto T, Iwase A, Araie M, Suzuki Y, Abe H,
Shirato S, Kuwayama Y, Mishima HK, Shimizu H,
Tomita G, Inoue Y, Kitazawa Y; Tajimi Study
Group, Japan Glaucoma Society.The Tajimi Study
report 2: prevalence of primary angle closure andsecondary glaucoma in a Japanese population.
Ophthalmology. 112:1661-1669, 2005
70. Ota T, Murata H, Sugimoto E, Aihara M, Araie M.
Prostaglandin analogues and mouse intraocularpressure: effects of tafluprost, latanoprost, travoprost, and unoprostone, considering 24-hour variation. Invest Ophthalmol Vis Sci. 46:2006-2011,
2005
71. Suzuki S, Suzuki Y, Iwase A, Araie M.Corneal
thickness in an ophthalmologically normal Japanese population. Ophthalmology. 112:1327-1336,
2005
72. Ota T, Aihara M, Narumiya S, Araie M. The effects of prostaglandin analogues on IOP inprostanoid FP-receptor-deficient mice. Invest
Ophthalmol Vis Sci. 46:4159-4163, 2005
73. Kunimatsu S, Tomidokoro A, Mishima K, Takamoto H, Tomita G, Iwase A, Araie M: Prevalence ofappositional angle closure determined by ultrasonicbiomicroscopy in eyes with shallow anteriorchambers. Ophthalmology 112:407-412, 2005
74. Takayama J, Tomidokoro A, Tamaki Y, Araie M:
Time-course of changes in optic nerve head circulation after acute reduction in intraocular pressure.
Invest Ophthalmol Vis Sci 46:1409-1419, 2005

287

Department ofOtorhinolaryngology andHead & Neck Surgery
Professor
Kimitaka Kaga, M.D.,Ph.D.

Associate Professor
Tatsuya Yamasoba, Ph.D.

Lecturer
Kenichiro Ishio, M.D., Ph.D,
Takahiro Asakage, M.D.,Ph.D,

Ken Ito, M.D.,Ph.D,
Kazunari Nakao, M.D., Ph.D

Associate
Shinichi Iwasaki, M.D., Ph.D,
Shotaro Karino, M.D,
Yasuhiro Ebihara, M.D,
Yoshinori Fujishiro, M.D,
Miwako Kimura, M.D,
Muneo Nakaya, M.D.

Kenji Kondo, M.D.,Ph.D,
Takaharu Nito, M.D,
Chikako Yamada, M.D,
Hiroko Watanabe, M.D,
Kenta Watanabe, 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 of otorhinolaryngology of the national university in Japan. It has
passed 105 years. Our department covers all otorhinolaryngological diseases and associated systemic diseases, and has specialized clinics in middle ear and inner ear diseases, hearing impaired infant and children,
adult and elderly patients, facial paresis, vertigo andbalance disorders, olfactory disorders and paranasal
diseases, voice and speech disorders, taste and swallowing respiratory disorders, aphasia, central auditory
disorders and head & neck cancers.
A professor, two associate professors, four lecturers
and 15 associates participate in surgery, out-patient andin-patient care as well as research and educational activities. Two associates are abroad at present for basic
research in the U.S.A. and Australia Moreover five
Japanese graduate students two Chinese foreign graduate students and one Bulgarian doctor participate inbasic 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 clubis held to introduce current research papers and a
weekly temporal bone histology conference is held
every Monday evening.

Clinical activities
In the out-patient clinic, general and special services

288

are provided to approximately 150 out-patients on adaily basis in all areas of otorhinolaryngology and related specialties, and approximately 400 new patients
visit monthly.
In the new inpatient hospital, 45 beds are preparedfor patients under the supervision of lecturers and senior residents from each subspecialty group including
head & neck surgery, middle ear surgery and cochlear
implant surgery; voice and bronchoesophagologicalsurgery, and paranasal surgery and other minor surgery.
Peroperative and postoperative problems are checkedand discussed by each group, the professor’s and associate professor’s rounds. Approximately 650 operations
are performed annually.
Cochlear implant surgery over 100 cases has been
actively performed for infants, children and adult patients with profound hearing loss and is very successful
to provide new hearing. Head and neck surgery is performed to extirpate malignant tumor with neighboring
tissues and reconstruct upper respiratory and swallowing functions at one stage operation cooperating withplastic surgeons. Reconstructive surgery of microtia andatresia to reconstruct external ear is routinely performed
with plastic 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 in consultation with neurosurgons.

Teaching activities
For the third year medical students’ serial lecturesand for the fifth and sixth year medical students special
lectures on current topics are provided by the professor
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 a clinical case or a clinical problem. The students participate
to see surgery, special clinics and clinical examinations
such as otoscope, fiberscope, auditory brainstem response, and caloric test. Interview with patient is encouraged. They are questioned many aspects of clinicalproblems in seminars by professor and associate professor. Medical interviewing for cancer patients is prac-

ticed. During half and a week period, the students participate in surgery special clinics and practice of clinic
examination such otoscope, fiberscope auditory brainstem, caloric test and so on.

Research activities
Clinical and basic research activities are highly encouraged. Clinical research, which is supervised bysenior doctors, is very actively pursued even by young
residents. Case reports presentation and writing skills
are regarded as important experience in order to develop young doctors’ research activity and investigate
important findings in patients. The clinical research isrelated to ear surgery, neurotology, audiology, head &neck surgery, bronchoesophagology and rhinology andis related to case resersch, clinical statistics and clinicalelectrophysiology. Basic research is also encouraged tosolve essence of clinical problems and to elucidate basic phenomena or anatomical and cellular structures.
Our research topics cover:1) Morphology and neurophysiology of the inner ear
focusing on sensory neural deafness: human temporal bone pathology, electron microscopic study inanimal models, gene therapy.
2) Clinical application of otoacoustic emissions andauditory brainstem responses.
3) Histochemistry of olfactory epithelium in development and aging.
4) Clinical neurophysiology of the facial nerves focusing on degeneration and regeneration in patients.
5) Histochemistry of head and neck cancer pathology.
6) The central auditory corex research using MEG.
7) Auditory brainstem response and speech and hearing after the new born hearing screening.
8) Pathology and electrophysiology of the larynx.
9) Basic and clinical research on auditory brainstem
implant.
10) Vestibular research on the oculomotor and balancesystems in the brain.
11) Vestibular myogenic evoked potentials in cochlear
implant and inner ear anomaly.
12) Hair cell physiology in the vestibular end organ.
13) Newborn hearing screening and language development in deaf childen.
14) Myelination of central auditory and vestibular

289

pathway using MRI.
15) Physiology bone conduction innovation of bone
conduction hearing and bilateral hearing.
16) Acoustic research on development of babbling in
neonates.
17) Embryology of middle, inner ear and central auditory system.
Various clinical and basic research are conducted bystaffs, residents, postgraduate doctors and senior doctors at affiliated hospitals.

References
1. Higo R, Tayama N, Nito T: Longitudinal analysis
of progression of dysphagia in amyotrophic lateralsclerosis. Auris Nasus Larynx 31:247-254,2004
2. Imauchi Y, Laine P, Sterkers O, Ferrary E, Bozorg
Grayeli A: Effect of 17 beta-estradiol on diastrophic dysplasia sulfate transporter activity in otosclerotic bone cell cultures and SaOS-2 cells. Acta
Otolaryngol 124:890-895,2004
3. Inoue M, Nishimura S, Hori G, Nakahara H, Saito
M, Yoshihara Y, Amari S: Improved parameter estimation for variance-stabilizing transformaiton ofgene-expression microarray data. J Bioinform
Comput Biol 2:669-679,2004
4. Ishibashi Y, Murofushi T: A case of Cronkhite
Canada syndrome with vestibular disturbances. Eur
Arch Otorhinolaryngol 261:558-559,2004
5. Ishii K, Adachi H, Tsubaki K, Ohta Y, Yamamoto
M, Ino T: Evaluation of recurrent nerve paralysis
due to thoracic aortic aneurysm and aneurysm repair. Laryngoscope 114:2176-2181,2004
6. Ishimoto S, Ito K, Kondo K, Yamasoba T, Kaga K:
The role of the external auditory canal in the development of the malleal manubrium in humans.
Arch Otolaryngol Head Neck Surg 130:913-916,
2004
7. Ito K, Takai Y, Morita A, Murofushi T: Chondroid
chordoma at the jugular foramen causing retrolabyrinthine lesions in both the cochlear and vesatibular
branches of the eighth cranial nerve. Ann Otol
Rhinol Laryngol 113:82-86, 2004
8. Ito K, Momose T, Oku S, Ishimoto S Yamasoba T,
Sugasawa M, Kaga K: Cortical activation shortly
after cochlear implantation.

Audiol Neurotol 9:282-293,2004
9. Ito K, Iwasaki S, Kondo K, Dulon D, Kaga K: Action of subtype-specific purinergic ligands on rat
spiral ganglion neurons. Acta Otolaryngol Suppl
553:23-27,2004
10. Iwasaki S, Ito K, Abbey K, Murofushi T: Predictionof canal paresis using head-shakings nystagmus test.
Acta Otolaryngol 124:803-806,2004
11. Kaga K, Kobayashi K: Deafness in infants andchildren – early detection, auditory training andeducation. Pp148-152 in Hearing Impairment. An
Invisible Disability. (ed by J-I Suzuki, T Kobayashi,
K Koga) Springer Tokyo 2005
12. Kaga K, Nakamura M, Takayama Y, Momose H:
Case Report.
A case of cortical deafness and anarthria. Acta
Otolaryngol 124:202-205,2004
13. Kaga K, Kurauchi T, Yumoto M, Uno A: Middle-latency auditory-evoked magnetic fields in patients with auditory cortex lesions. Acta Otolaryngol 124:376-380,2004
14. Karino S, Hayashi N, Aoki S, Ohtomo K, Yamasoba T: New method of using reconstructed images for assessment of patency of intracochlear
spaces for cochlear implant candidates.
Laryngoscope 114:1253-1258,2004
15. Karino S, Yumoto M, Itoh K, Uno A, Matsuda M,
Yamakawa K, Sekimoto S, Kaneko Y, Kaga K:
Magnetoencephalographic study of hman auditor
steady-state responses to binaural beat. International Congress Series 1270:169-172,2004
16. Kikkawa Y, Tsunoda K, Niimi S: Prediction andsurgical management of difficult laryngoscopy.
Laryngoscope 114:776-779,2004
17. Maeda Y, Okita W, Ichimura K: Increased nasal
patency caused by smoking and contraction of isolated human nasal mucosa.
Rhinology 42:63-67,2004
18. Maeda Y, Ichimura K: Rosai-Dorfman disease revealed in the upper airway: a case reports and review of the literature. Auris Nasus Larynx 31:279282,2004
19. Monobe H, Murofushi T: Vestibular testing byelectrical stimulation in patients with unilateral
vestibular differentiation: galvanic evoked myogenic responses testing versus galvanic body swaytesting. Clinical Neurophysiology 115:807-811,

290

2004
20. Monobe H, Murofushi T: Vestibular neuritis in achild with otitis media with effusion; clinical application of vestibular evoked myogenic potential
by bone-conducted sound. Int J Pediatric Otorhinolaryngol 68:1455-1458,2004
21. Murofushi T, Ochiai A, Ozeki H, Iwasaki S: Laterality of vestibular evoked myogenic potentials. Int J
Audiol 43:66-68,2004
22. Murofushi T, Matsuzaki M, Iwasaki S, Takai Y:
Vestibular evoked myogenic potentials in vestibular
neuritis. Med J Malaysia 59: Suppl A:136,2004
23. Nakahara H, Zhang Li, Merzenich MM: Specialization of primary auditory cortex processing bysound exposure in the “Critical Period”. Proc Nat
Aca Sci USA 101:7170-7174,2004
24. Nakaya M, Takeuchi N, Kondo K: Immunohistochemical localization of histamine receptor subtypes in human inferior turbinates.
Ann Otol Rhinol Laryngol 113:552-557,2004
25. Ando M, Matsuzaki M, Murofushi T: Mucosa- associated lymphoid tissue lymphoma presented as
diffuse swelling of the parotid gland. Am J Otolaryng Head Neck Surg 26:285-288,2005
26. Fujimoto C, Iwasaki S, Matsuzaki M, Murofushi T:
Lesion site in idiopathic bilateral vestibulopathy: agalvanic vstibular-evoked myogenic potential study.
Acta Otolaryngol 125:430-432,2005
27. Higo R, Nito T, Tayama N: Swallowing function inpatients with multiple-system atrophy with a clinical predominance of cerebellar symptoms (MSAC) Eur Arch Otorhinolaryngol 262:646- 950, 2005
28. Higo R, Nito T, Tayama N: Videofluoroscopic assessment of swallowing function in patients withmyasthenia gravis. J Neurol Sci 231:45-48,2005
29. Fujiwara S, Nakamura I, Higo R, Tajiri Y, Nakamura K, Oda H: Repeated postoperative laryngeal
obstruction due to bilatearal cricoarytenoid joint
involvement in rheumatoid arthritis. Mod Rheumatol 15:123-125,2005
30. Imauchi Y, Krino S, Yamasoba T: Acquired
atrophy of the long process of the incus.
Otolaryngol Head Neck Surg
132:156-158,2005
31. Ito K, Suzuki S, Murofushi T, Ishimoto S, Iwasaki
S, Kariono S: Neuro-otologic findings in unilateralisolated narrow internal auditory meatus. Otology

Neurotology 26:767-772,200531.
32. Iwasaki S Takai Y, Ozeki H, Ito K, Karino S,
Murofushi T: Extent of lesions in idiopathic sudden
hearing loss with vertigo. Arch Otolaryngol Head
Neck Surg 131:857-862,2005
33. Iwasaki S, Takai Y, Ito K, Murofushi T: Abnormal
vestibular evoked myogenic potential in the presence of normal caloric responses. Otology Neurotology 26:1196-1199,2005.
34. Kaga K, Tamai F, Kodama M, Kodama K: Case
Report. Three young adult patients with Pelizeus-Merzbacher disease who showed only wave
I and II in auditory brainstem responses but had
good auditory perception. Acta Otolaryngol 125:
1018-1023,2005
35. Kaga K, Kurauchi T, Nakamura M,
Shindo M, Ishii K:
Magnetoencephalography and positron emission
tomography studies of a patient with auditory agnosia caused by bilateral lesions confined to theauditory radiations.
Acta Otolaryngol 125:1351-1355,2005
36. Takahashi H, Nakao M, Kikuchi Y, Kaga
K: Alaryngeal speech aid using an intra-oral electrolarynx and a miniature fingertip switch. Auris
Nasus Larynx 32:157-162,2005
37. Takahashi H, Nakao M, Kaga K: Accessing ampli-tonotopic organization of rat auditory cortex bymicrostimulation of cochlea nucleus. Transact
Biomed Engineering 52:1333-1344,2005
38. Takahashi H, Suzurikawa J, Nakao M, Mase F,
Kaga K: Easy-to-prepare assembly array of tungsten microelectrodes. Transact Biomed Engineering
52:952-956,2005
39. Takahashi H, Nakao M, Kaga K: Spatial and temporal strategy to analyze steady-state sound intensity in cortex. Neuro Report 16:137-140,2005
40. Karino S, Yamasoba T, Ito K, Kaga K: Alteration of
frequency range for binaural beats in acutelow-tone hearing loss. Audiol Neurotol 10:201-208,
2005
41. Karino S, Yumoto M, Itoh K, Yamakawa K, Mizuochi T, Kaga K: A modified parallel paradigm forclinical evaluation of auditory echoic memory.
Neuro Report 16:683-687,2005
42. Karino S, Ito K, Ochiai A, Muorufshi T: Independent effects of simultaneous inputs form the saccule291

and lateral semicircular canal. Evaluation using
VEMPs.ClinNeurophys 116:1707-1715,2005
43. Karino S, Yamasoba T, Kashio A, Kaga K: Fibrouos
dysplasia of the temporal bone: Assessment by
three-dimensional helical CT imaging. Otolaryngol
Head Neck Surg 133:1-3,2005
44. Koyama S, Kaga K, Sakata H, Iino Y, Kodera K:
Pathological findings in the temporal bone of newborn infants with neonatal asphyxia.
Acta Otolaryngol 125:1028-1032,2005
45. Maeda Y, Tsuchida M, Fukaya T: Extensive endoscopic sinus surgery from the viewpoint ofout-patients in a metropolitan area. J Laryngol Otol
119:23-26,2005
46. Mizuochi T, Yumoto M, Karino S, Itoh K, Yamakawa K, Kaga K: Perceptual categorization ofsound spectral envelopes reflected in auditoryevoked NIm. Neuro Report 16:555-558,2005
47. Murofushi T, Takai Y, Iwasaki S, Matsuzaki M:
VEMP recording by binaural simultaneous stimulation in subjects with vestibule-cochlear disorders.
Eur Arch Otorhinolaryngol 262:864-867,2005
48. Murofushi T, Iwasaki S, Takai Y, Takegoshi H:
Sound-evoked neurogenic responses with short latency of vestibular origin. Clin Neurophysiol 116:
401-405,2005
49. Murofushi T, Iwasaki S, Takai Y, Takegoshi H:
Sound-evoked neurogenic responses with short latency: are they of vestibular origin? Int Cong Series
1278:433-436,2005
50. Nakaya M, Fukushima Y, Takeuchi N, Kaga K:
Nasal allergic response mediated by histamine H₃
receptors in murine allergnic rhinitis. Laryngoscope
115:1778-1784,2005
51. Ozeki H, Iwasaki S, Murofushi T: Effect of stimulation repetition rate on galvanic-evoked vestibulo-collic reflexes. Acta Otolaryngol 125:1591162,2005
52. Sakamoto T, Uozaki H, Kondo K, Imauchi Y, Yamasoba T, Sugasawa M, Kaga K: Cyclooxygenase-2 regulates the degree of apoptosis bymodulating bcl-2 protein in plemorphic adenoma
and mucoepidermoid carcinoma of the parotid
gland. Acta Otolaryngol 125:191-195,2005
53. Sano M, Kaga K, Kitazumi E, Kodama K: Sensorineural hearing loss in patients with cerebra
palsy after asphyxia and hyperb8lirubinemia. Int J

Pediatri Otorhinolaryngol 69:1211-1217,2005
54. Sano M, Kitahara N, Toma M: Hypopharyngeal
small cell carcinoma: A case report. Auris Nasus
Larynx 32:319-322,2005
55. Sano M Kaga K, Takeuchi N, Kitazumi E, Kodama
K: A case of mobius syndrome – radiological andelectrophysiological findings. Int J Pediatri Otorhinolaryngol 69:1583-1586,2005
56. Tanaka K, Nibu K: Laryngeal squamous cell carcinoma with ectopic production of granulocyte colony-stimulating factor and parathyroid hormone-related protein. Int J Clin Oncol 10:195-197,
2005
57. Tsunoda K Amagai N, Kondou K, Baer T, Kaga K,
Niimi S: Autologous replacement of the vocal fold:a new surgical approach for adduction-type spasmodic dysphonia. Laryngol Otol 119:222-225,2005
58. Yabe T, Kaga K: Sound lateralization test in adolescent blind individuals. Neuro Report 16:939-942,
2005
59. Yamasoba T Pourbakht A, Sakamoto T, Suzuki M:
Ebselen prevents noise-induced excitotoxicity andtemporary threshold shift. Neuroscience Letters
380:234-238,2005

292

Department of
Rehabilitation Medicine
Professor
Fumio ETO, M.D.,Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/patient/depts.html
Introduction and Organization
The Department of Rehabilitation Medicine was established by Ministry of Education, Culture, Sports,
Science and Technology in April 2001. It is one of thenewest fields in the University of Tokyo Graduate
School of Medicine. It belongs to the Sensory and Motor System Medicine Course of the Surgical Sciences
Study Major. Current authorized staff is only one professor.
This department derives from the establishment of
the physical therapy room in the central diagnostic andtherapeutic sections in order to develop the clinicalpractice of rehabilitation medicine in 1963. The chair ofprofessor 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 established clinical section which was born in development of the modern principle of the medical health service by which itcame to value the enhancement of not only adding
years of patient's life but also adding life to the years.
Regardless of rapid expansion of needs, acknowledgment of rehabilitation medicine was delayed in theframe of old-fashioned clinical departments. In ourcountry, it was 1996 when the rehabilitation specialty
was authorized as formal clinical practice by the former
Ministry of Health and Welfare.
On the other hand, it was positioned as an assistanceinstructor 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 installedin 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, the arrangement of additional teaching staff is not still materialized. Therefore, thestaff of the graduate school is only one professor,
and seven graduate school students are on theregister in 2005.

Clinical activities
There is not enough doctors arranged for the department of rehabilitation medicine, and we cannot run own
beds for rehabilitation patients at present. The professor
serves as a director of central rehabilitation service department of the University of Tokyo Hospital. Both departments are united and engage in clinical practice. We
have at present no charged ward, and treat about 1,000
new referrals annually from almost all the departmentsof the university hospital. We always take charge of 200
patients or more corresponding about 20% of the whole
number of inpatients. We also see 10-12 people/day at
the ambulatory rehabilitation setting. The numericalratio of ambulatory patient is reduced to around half incomparison with that of 10 years ago in order to givepriority to the clinical service corresponding to needs
expansion of service to an inpatient.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year medical students since 1973. The systematic lecture series

293

for 4th year medical students (M2) include the subjects
on rehabilitation for disorders such as cerebrovascular
disturbances, spinal cord injuries, neuromuscular diseases, bone and joint diseases, and cerebral palsy as
well as on multidisciplinary team approach. We haveprovided a clinical practice in small group, so-called
bedside learning for 5th year students from Wednesday
to Friday every other week. They experience a few patients and learn how to take a patients’ history, physicalfindings, functional evaluation, and how to plan rehabilitation programs. We have introduced a few of elective students for clinical clerkship to our collaborating
hospitals with specialized rehabilitation ward.
In addition, we have provided the training of comedical students including physical therapy and occupational therapy. Twenty students or more come andstay at the university hospital annually as a long-term
clerkship from several PT/OT training schools.
Nine graduate school students entered by 2005 andtwo of them acquired a degree of Ph.D. and graduated.
One of the graduate school students is a foreign student
from Mongolia. She is a rehabilitation specialist physician in Mongolia, and is supported for her staying by
the MEXT scholarship of Japanese government. Another graduate school foreign student is a Chinese doctor, who visited Japan by the own expense. In addition,a rehabilitation specialist doctor from Italy was registered as a study student for two years since 2003 to
2005, as the MEXT scholarship student of Japanese
government. Other two specialist doctors from China
by a scholarship of the Japan-China Medical Association or by the Chinese government scholarship stayed
and were registered as a study student from 2004 to2005.

Research activities
Our mission is to provide exceptional rehabilitationfor our patients through clinical excellence and compassionate care, all dedicated to helping patientsachieve their maximum functional capacity and highest
quality of life. Another significant focal point of thedepartment is research. The research objectives of thedepartment are to make clear configuration of disabilities and to develop measures to reduce the obstacles forpatients’ independent living as well as to promote reintegration in their society. However, rehabilitation medi-cine has not been recognized as an established course in
the University of Tokyo, and there is no space of an
exclusive research laboratory and medical office.
Two or more equipment (force platform, video operation analysis system, surface electromyography, andataxiameter, etc.) are combined for the evaluation ofwalking and motion disturbances. Synchronous measurements such as the torque machines for the muscularpower measurement and the surface electromyography
are available. Using these has carried out the research,which clarifies the effect of shoe insole in healthy
population and subjects with various gait disorders.
We also engage in research on development of appropriate training method for recovery from physicaldeconditioning state, or disuse syndromes. Usual activity performances may need the functional integration of
respiratory, cardiovascular, and metabolic system,
which adequately supplies energy to the locomotion
system including not only musculoskeletal organs but
also central and peripheral nervous system organs.
The development of evaluation method of the intellectual impairment and the physical fitness measurement are also important subjects of our research for an
appropriate rehabilitation program. Unilateral neglect,or hemispacial neglect, is one of the serious obstruction
factors of stroke rehabilitation.
The detailed pathophysiology of unilateral neglect is
unknown. There may be several subgroups of clinicalfeature, and we engage in development of those differential assessment methods in unilateral neglect. In addition, we have used the event related potential and magnetoencephalogram (MEG) in order to reveal the liability lesion of unilateral neglect.
Acupuncture is now popular as a complimentary andalternative medicine in Europe and America. However,mechanism of the effect is still vague. We have examined the effects of acupuncture by using the measurement system of autonomic nervous function.
Under current poor condition of our research environment, however, the research projects may be recommended to be accomplished in cooperation with thelaboratory and the organization outside the hospital. In
collaboration with some outside laboratories we havestudied a pathological mechanism of muscle atrophy,
joint contracture and bone atrophy, which are main
components of disuse syndromes.

294

References
1. Eto F, Wada N, Maeno T, Miyake N, Saotome I:
The effect of heel elevation in Parkinsonian gait.
Geriatrics Gerontology International 2004; 4 Suppl:
S202-S204.
2. Casanova E, Eto F, Yamashita H, Tsukayama H,
Takeuchi Y: Current state of acupuncture in Europe.
Jpn J Rehabil Med 2004; 41(12): 846-848.
3. Takano H, Morita T, Iida H, Kato M, Uno K, Hirose K, Matsumoto A, Takenaka K, Hirata Y, Furuichi T, Eto F, Nagai R, Sato Y, Nakajima T: Effectsof low-intensity “Kaatsu” resistance exercise on
hemodynamic and growth hormone responses. Int J
KAATSU Training Res 2005; 1(1): 15-20.
4. Eto F: Preface. Training systems for specialist rehabilitation physicians: current status and future
development. Jpn J Rehabil Med 2005; 42(3):187-188.
5. Takano H, Morita T, Iida H, Asada KI, Kato M,
Uno K, Hirose K, Matsumoto A, Takenaka K, Hirata Y, Eto F, Nagai R, Sato Y, Nakajima T:
Hemodynamic and hormonal responses to ashort-term low-intensity resistance exercise withthe reduction of muscle blood flow. Eur J Appl
Physiol. 2005; 95(1): 65-73.
6. Chiba Y, Yamaguchi A, Eto F: A simple method todissociate sensory attentional and motor intentionalbiases in unilateral neglect. Brain and Cognition
2005; 58(3): 269-273.
7. Chiba Y, Nishio S, Yamaguchi A, Eto F: Laryngeal
Phonation after tracheoesophageal diversion. Dysphagia 2005; 20(3):235-237.
8. Saotome T, Sekino M, Eto F, Ueno S: Quantitative
measurement of creatine content in skeletal muscle
using H-1-MRS. IEEE TRANSACTIONS ON
MAGNETICS 2005; 41 (10): 4164-4166.
9. Iida H, Takano H, Meguro K, Asada K, Oonuma H,
Morita T; Kurano M, Sakagami, F Uno K, Hirose
K, Nagata T, Takenaka K, Suzuki J, Hirata Y, Furuichi T, Eto F, Nagai R, Sato Y, Nakajima T:
Hemodynamic and autonomic nervous responses tothe restriction of femoral blood flow by KAATSU.
Int. J. KAATSU Training Res. 2005; 1(2): 57-64.
10. Saotome T, Sekino M, Eto F, Ueno S: Evaluationof diffusional anisotropy and microscopic structure
in skeletal muscles using magnetic resonance.

Magn Reson Imaging 2006; 24(1): 19-25.
11. Kasuya D, Eto F: Acupuncture and Moxibustion
Treatment for Rheumatoid Arthritis. Jpn J Rehabil
Med 2004; 41(12): 836-841. (Japanese)
12. Furukawa S, Eto F: Psychiatric Day-hospital in theCentral Rehabilitation Service of University of Tokyo Hospital. Jpn J Rehabil Med 2005; 42(6):383-387. (Japanese)
13. Kazuta T, Dekura Y, Okiyama R, Miyake N,
Yokoti F, Eto F: The working situation of juvenile parkinsonism. Sogo Rehabilitation
2005; 33(8): 775-778. (Japanese)
14. Kazuta T, Saotome I, Miyake N, Eto F: Rehabilitation of critical illness polyneuropathy
after living donor liver transplantation: casereport. Journal of Clinical Rehabilitation
2005; 14(12): 1160-1163. (Japanese)
15. Eto F: Problem and Prospect of Aged Society. Jpn J
Rehabil Med 2004; 41(5): 282-285. (Japanese)
16. Eto F: President’s Lecture: Activities as an Indicator of Medical Intervention, and Rehabilitation
Medicine. Jpn J Rehabil Med 2004; 41(9): 581586. (Japanese)
17. Eto F: Rehabilitation of the elderly. Jpn J Geriat:
41 (5), 507-509, 2004 (Japanese)
18. Eto F: Treatment of vascular dementia.
Nippon Rinsho 2004; 62 Suppl 1: 34-40.
(Japanese)
19. Eto F: Disuse syndromes and mental disorders. J
Jpn Med Ass 2004; 132(11): 1431-1435. (Japanese)
20. Fujita K, Kawagoe M, Eto F: A longitudinal
study of cognitive function and the relationshipbetween cognition and activities of daily livingin the elderly. Jpn J Geriat: 42 (6), 669-676, 2005.
(Japanese)

Surgical Sciences
3.Vital Care Medicine

24

296

Department of Anesthesiology
Professor
Kazuo Hanaoka, M.D., Ph.D.

Associate Professor
Hideko Arita, M.D., Ph.D.,

Tomoki Nishiyama, M.D., Ph.D.

Lecturer
Choku Yajima, M.D., Ph.D.,

Ryo Orii, M.D., Ph.D.

Associate
Hiroshi Sekiyama, M.D.,
Yuichiro Saito, M.D.,
Masahiro Suzuki, M.D.,
Makoto Ogawa, M.D.,
Masahiko Bogaki, M.D.,
Satoshi Kasahara, M.D.,
Ju Mizuno, M.D., Ph.D.

Makoto Ogawa, M.D., Nobuko Ito, M.D., Ph.D.,
Nobuhide Kin, M.D.,
Takayuki Kitamura, M.D.,
Toshiya Tomioka, M.D., Ph.D.,
Erika Sano, M.D.,
Masako Seyama, M.D.,
Yoshie Suzuki, M.D.,
Nagara Ono, M.D.,
Kaori Fujita, M.D.,
Kyung-Ho Chang, M.D., Ph.D.,

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/aprc_md.html/
http://www.anes.umin.ne.jp/
Introduction and Organization
The Department of Anesthesiology was establishedin 1952. Our department has residents, chief residents
and three researchers from China besides the members
above. We introduce the activities about Teaching, Research and Clinical work of our department.

Clinical activities
Pain clinic services are provided for out-patients (including patients in the ward of the other department) ona daily basis in all areas of painful diseases. From April
2004 to March 2006, we had 803 new patients and total
number was 27000.
There are three beds in the ward and about 100 patients admitted. From the other department, about 1500
patients visited our clinic to control pain, and 1500 patients visited to have a preoperative consultation.

Anesthesia service including pre and post-operative
care is given every day for elective and emergency surgery. Recently, the number of high risk or geriatric patents are increasing. In addition, more than 20% of thesurgery (about 8000 cases in total per year) spends
more than eight hours.

Teaching activities
We give lectures for fourth year medical students andprovide clinical education for fifth and sixth year
medical students on a man-to-man basis with our faculty staff members. The lectures of the last year were
the history of anesthesia and the preliminary consideration, the mechanisms of anesthesia, inhalational anesthesia, intravenous anesthesia and circulation, the balance of body fluid, acid-base balance, muscle relaxants,
the management of the patient during anesthesia,
monitoring, resuscitation, pain clinic and the physiol-

297

ogy and the management of pain.

Research activities
There are six laboratories in our department andmaking clinical and basic research about respiration,
circulation, neuro-physiology, shock, etc.
These themes of the research groups of our department
are listed below.
(1) Physiology of pain and the mechanisms of analgesia using spinal rat(2) Relationship between noxious stimuli and catecholamines in the anesthetized rat(3) Response to immunologic system against the endotoxin in the blood(4) Measurement of pulmonary vascular resistance of
normal and pulmonary edema using rabbit(5) Mechanisms and the pharmacological analysis of
non-depolarizing muscle relaxants in human(6) The effect of anesthetics upon pulmonary function(7) Mechanisms of H-typed epidural-spinal anesthesia(8) Inhalational anesthetics and rate potential(9) The effects of midazolam upon the spinal analgesic
mechanisms(10) Analgesic mechanisms of hyperventilation(11) The interaction of central analgesic and spinal analgesic mechanisms(12) Development of skin surface anesthetics by lidocaine tape(13) Clinical assessment of the induction by midazolam
combined with barbiturates(14) The effects of epidural buprenorphine and morphine on post-operative pain control(15) Clinical usefulness of patient-controlled analgesia(PCA)(16) Clinical assessment of stellate ganglion block(17) Assessment of anesthetic machines(18) The effects of peripheral sensory nervous activities
by acupuncture(19) Clinical assessment of malignant hyperthermia(20) Basic research of the changes in transmission anddistribution of gas with pulmonary lesion(21) Simulation of general anesthesia(22) Clinical assessment of anti-hypertensive agents(23) Basic and clinical assessment of benzodiazepine
antagonist(24) Basic and clinical assessment of non-depolarizing
muscle relaxants(25) Basic and clinical assessment of enkepharonase
inhibitor(26) Prostaglandins and tissue blood flow of the liverand kidney(27) Relationship between sympathetic nervous systemand cardiac function(28) Clinical assessment of pulse-oximeter(29) The effects of poly-enzyme inhibitor upon tissue
microcirculation(30) Analgesic mechanisms of nociceptin in spinal rat(31) Assessment of Bispectral Index monitor(32) Clinical evaluation of drug challenge test(33) Analgesic mechanisms of laser treatment(34) Analgesic mechanisms of oriental herbal medicine(35) Clinical assessment of acupuncture(36) Development of device for Intubation(37) Analgesic efficacy of α2 agonist in a postoperative pain model

References
1. Hayashida M, Sato K, Fukunaga A, Fukuda K, Sekiyama H, Sawamura S,Arita H, Hanaoka K. Intravenous infusion of adenosine 5-triphesphate alleviated a disabling postherpetic neuralgia. Journalof Anesthesia. 2004;18(1):36-38.
2. Chang KH, Ogawa M, Hanaoka K. “Takotsubo“-shaped cardiomyopathy manifesting as
perioperative T-wave inversion. Journal of Anesthesia. 2004;18(1):65.
3. Nishiyama T, Kawasaki-Yatsugi S, Yamaguchi T,
Hanaoka K. Spinal neurotoxicity and tolerance after repeated intrathecal administration of YM872,
an AMPA receptor antagonists, in rats. Journal of
Anesthesia. 2004;18:113-117.
4. Arita H, Hayashida M and Hanaoka K. Pain control
for elderly patients in Japan. Geriatrics and Gerontology International. 2004;4:S239-241.
5. Hanaoka K, Arita H, Hayashida M, Yajima C, and
Lee SC. Pain control in Asia. Geniatrics and Gerontology International. 2004;4:S237-238.
6. Nishiyama T, Hanaoka K. The A-line ARX index
may be a more sensitive detector of arousal thanthe bispectral index during propofol-fentanyl- mitrous oxide anesthesia: a preliminary investigation.

298

Canadian Journal of Anesthesia. 2004;51(6):539544.
7. Chinzei M, Sawamura S, Hayashida M, Kitamura T,
Tamai H, Hanaoka K. Change in bispectral index
during epileptiform electrical activity under sevoflurane anesthesia in a patient with epilepsy.
Aneshtesia & Analgesia. 2004;98(6):1734-1736.
8. Kuramochi K, Osuga Y, Momoeda M, Fujiwara T,
Tsutsumi O, Tamai H, Hanaoka K, Koga K, Yoshino O, Taketani Y. Laparoscopic surgery for intertility in comparison to general anesthesia. Surgical Endoscopy. 2004;18(5):847-851.
9. Tamai H, Sawamura S, Kanamori Y, Takeda K,
Chinzei M, Hanaoka K. Thoracic epidural cathoter
insertion using the cardal approach assisted with anelectrical neune stimulator in young children. Regional Anesthesia & Pain Medicine. 2004;29(2):9295.
10. Tomioka T, Hayashida M, Hanaoka K. Pressurealopecia in living donors for liver transplantation.
Canadian Journal of Anesthesia. 2004;51(2):186187.
11. Kin N, Konstadt SN, Sato K, Hanaoka K. Reduction of bispectral index value associated with clirically significant cerebral air embolism. Journal of
Cardiothoracic & Vascular Anesthesia. 2004;18(1):82-84.
12. Hayashida M, Kin N, Tomoki T, Orii R, Sekiyama
H, Usui H, Chinzei M, Hanaoka K. Cerebral
Ischemia during cardiac surgery in children detected by combined monitoring of BIS andmear-infrared spectroscopy. British Journal of Anesthesia. 2004;92(5):662-669.
13. Takeda K, Sawamura S, Sekiyama H, Tamai H,
Hanaoka K. Effect of methylpredomisolone on
neuropathic pain and spinal glial activation in rats.
Anesthesiology. 2004;100(5):1249-1257.
14. Nishiyama T, Matsukawa T, Hanaoka K. A comparison of the clinical usefulness of three different
electroen cephalogram monitors: Bispectral Index,
processed electroencephalogram and Alaris auditory evoked potentials. Anesthesia & Analgesia.
2004;98(5):1341-1345.
15. Nishiyama T, Hanaoka K. Intrathecal clonidine andbupivacaine have synergistic analgesia for acutethermally or inflammatory-induced pain in rats.
Anesthesia & Analgesia. 2004;98(4):1056-1061.

16. Nishiyama T, Fujimoto T, Hanaoka K. A comparison of liver function after hepatectory in cirrhotic
patients between sevoflurane and isoflurane in anesthesia with mitrous oxide and epidural block.
Anesthesia & Analgesia. 2004;98(4):990-993.
17. Uchida K, Nakata K, Trapnell B.C, Terakawa T,
Hamano E, Mikami A, Matsushita I, Seymour J.F,
Oh-Eda M, Ishige I, Eishi Y, Kitamura T, Yamada Y,
Hanaoka K, Keicho N. High-affinity autoantibodies
specifically eliminate qranulocute-macrophagecolony- stemurating factor activity in the lungs ofpatients with idiopathic pulmonary alveolar protenosis. Blood. 2004;103(3):1089-1098.
18. Bougaki M, Sawamura S, Matsushita F, Hanaoka K.
Different intubation due to ossification of the anterior longitudinal ligament. Anesthesia. 2004;59(3):303-304.
19. Kin N, Tarui K, Hanaoka K. Successful lung isolation with one bronchial blocker in a patient withtracheal bronchus. Anesthesia & Analgesia.
2004;98(1):270.
20. Mizuno J, Mohri S, Shimizu J, Suzuki S, Mikane T,
Araki J, Nishiyama T, Hanaoka K, Kajya F and
Suga H. Load Independence of Temperature-dependent Ca2⁺ Recirculation Fraction in Canine Heart (87 letters). Japanese Journal of Physiology. 2004;54:118-128.
21. Hanaoka K, Toyooka H, Kugimiya T, Obashi Y.
The efficacy of proplylactic intravenous granisetronon postoperative emesis in adults; The Gramisetron
Study Group of Japan. Journal of Anesthesia.
2004;18(3):158-165.
22. Nishiyama T, Matsukawa T, Hanaoka K. Is the
ARX index a more sevsitive indicator of anesthetic
depth than the bispectral index during sevoflurane/nitrous oxide anesthesia. Acta Anaesthesiologica Scandinavica. 2004;48(8):1028-32.
23. Sato-Takeda M, Ihn H, Ohashi J, Tsuchiya N, Satake M, Arita H. Tmaki K, Hanaoka K, Tokunaga K,
Yabe T. The human his to compatibility leukocyte
onset of postherpetic neuralgia after herpes zoster.
Pain. 2004;110:329-336.
24. Nishiyama T, Yokoyama T, Hanaoka K. Sedation
guidelines for midazolam infusion during combined spinal and epidural Anesthesia. Journal of
Clinical Anesthesia. 2004;16(8):568-572.
25. Nishiyama T, Matsukawa T, Hanaoka K. Intrathe-299

cal propofol has analgesic effects on inflammation-induced pain. Canadian Journal of Anaesthesia.
2004;51(9):899-904.
26. Hayashida M, Fukunaga A, Fukuda K, Yamazaki
SY, Arita H, Hanaoka K. A rabbit model for evaluation of surgical anesthesia and analgesia:characterization and validation with isoflurane
anesthesia and fentanyl analgesia. Journal of Anesthesia. 2004;18(4):282-291.
27. Sawamura S, Obara-Nawata M, Takeda K, Hanaoka K. General anesthetics inhibit the nitrousoside-induced activation of corticotropin releasing
factor containing neurons in rats. European Journalof Pharmacology. 2004;503 (1-3):49-53.
28. Nishiyama T. Dose-finding. Study of intravenous
midazolam for sedation and amnesia during spinal
anesthesia in patients premedicated with intramuscular Midazolam. Journal of Anesthesia. 2004;18(4):257-61.
29. Hayashida M, Fukuda K, Fukunaga A, Meno A,
Sato K, Tarui K, Arita H, Kaneko Y, Hanaoka K.
Analgesic effect of intravenous ATP on postherpetic neuralgia in comparison with responses to intravenous ketamine and lidocaine. Journal of Anesthesia. 2005;19(1):31-35.
30. Iwamori M, Suzuki H, Ito N, Iwamori Y and Hanaoka K. Lipid Compositions of Human Gastric
Fluid and Epithelium. J.Clin.Gastroenterol. 2005;
39(2):1-5.
31. Tamai H. Sawamura S. Takeda K. Orii R. Hanaoka
K. Anti-aalodynic and anti-hyperalgic effects of
nociceptin receptor antagonist,JTC-801, in rats after spinal nerve injury and inflammation. European
Jounrnal of Pharmacology. 2005;510(3):223-228.
32. Tamai H. Sawamura S. Atarashi H. Takeda K. Ohe
K. Hanaoka K. The electrical properties of epidural
catheters: what are the requirements for nerve
stimulation guidance?. Anesthesia & Analgesia.
2005;100(6):1704-7.
33. Fujimoto T. Nishiyama T. Hanaoka K. Inhibitory
effects of intravenous anesthetics on mast cellfunction. Anesthesia & Analgesia. 2005;101(4):1054-9.
34. Takeda K. Sawamura S. Tamai H. Sekiyama H.
Hanaoka K. Role for cycloxygenase 2 in the development and maintenance of neuropathic pain
and spinal glial activation. Anesthesiology. 2005;

103(4):837-44.
35. Nishiyama T. Ogawa M. Intrathecal edaravone, afree radical scavenger, is effective on inflammatory-induced pain in rats. Acta Anaesthesiologica
Scandinavica. 2005;49(2):147-51.
36. Yamashita K. Yokoyama T. Kitaoka N. Nishiyama
T. Manabe M. Blood flow velocity of the femoral
vein with foot exercise compared to pneumatic footcompression. Journal of Clinical Anesthesia. 2005;
17(2):102-5.
37. Yamashita K. Nishiyama T. Yokoyama T. Abe H.
Manabe M. Cardiac output by PulseCO is not interchangeable with thermodilution in patients undergoing OPCAB. Canadian Journal of Anaesthesia.
2005;52(5):530-4.
38. Nishiyama T. Effects of a 5-HT2A receptor antagonist, sarpogrelate on thermal or inflammatory pain.
European Journal of Pharmacology. 2005;516(1):18-22.
39. Nishiyama T. Spinal cord blood flow change byintravenous midazolam during isoflurane anesthesia. Anesthesia & Analgesia. 2005;101(1):242-5.
40. Nishiyama T. Hemodynamic and catecholamine
response to a rapid increase in isoflurane or sevoflurane concentration during a maintenancephase of anesthesia in humans. Journal of Anesthesia. 2005;19(3):213-7.
41. Nishiyama T. Comparison of the intracuff pressuresof three different tracheostomy tubes. Journal of
Anesthesia. 2005;19(3):260-2.
42. Yamashita K. Nishiyama T. Yokoyama T. Abe H.
Manabe M. A comparison of the rate of bacterial
contamination for prefilled disposable and reusable
oxygen humidifiers. Journal of Critical Care.
2005;20(2):172-5.
43. Nishiyama T. Changes in the auditory evoked potentials index by induction doses of four different
intravenous anesthetics. Acta Anaesthesiologica
Scandinavica. 2005;49(9):1326-9.
44. Bougaki M, Hayashida M, Kin N, Tomioka T,
Chinzei M, Hanaoka K. Bispectral Index Monitoring during pediatric cardiac surgery: effects of anesthetic doses, hypothermic cardiopulmonary bypass, and age. Cardiovascular Anesthesia. 2005;9(1): 3-9.
45. Hayashida M, Fukuda K, Fukunaga A.
Clinical application of adenosine and ATP for300

pain control. Journal of Anesthesia. 2005;19(3): 225-235.
46. Ikeda K, Ide S, Han W, Hayashida M, Uhl
GR, Sora I. How individual sensitivity to
opioids can be predicted by gene analyses.
Trends in Pharmacological Science. 2005;23(6): 311-317.
47. Li C, Sekiyama H, Hayashida M, Sumida T, Arita
H and Hanaoka K. Effects of repeated topical application of clonidine cream in a rats model of
postoperative pain. Pain Research. 2006;21（1）17－32.
48. Xu H, Arita H, Hayashida M, Zhang L, Sekiyama H, Hanaoka K. Pain-relieving effects
of processed Aconiti tuber in CCI-neuropathic rats. Journal of Ethnopharmacology.
2006;103: 392-397.
49. Shu H, Arita H, Hayashida M, Sekiyama H, Hanaoka K. Effects of processed Aconiti tuber and its
ingredient alkaloids on the development of antinociceptive tolerance to morphine. Journal of Ethnopharmacology. 2006;103: 398-405.
50. Shu H., Arita H., Hayashida M., Chiba S., Sekiyama H., Hanaoka K. Inhibition of morphine tolerance by processed Aconiti tuber is mediatedthrough activation of kappa opioid receptors. Journal of Ethnopharmacology. 2006;104:in press.
(2006 Jan 27; [Epub ahead of print])
51. Hayashida M, Sekiyama H, Orii R, Chinzei M,
Ogawa M, Arita H, Hanaoka K, Takamoto S. Effects of deep hypothermic circulatory arrest withretrograde cerebral perfusion on EEG bispectral
index and suppression ratio. Journal of Cardiothoracic and Vascular Anesthesia 21. 2006;in press.

301

Department ofEmergency andCritical Care Medicine
Professor
Naoki Yahagi, M.D.

Lecturer
Yukio Tanaka, M.D., Ph.D.
Susumu Nakajima, M.D., Ph.D.

Associate
Shoichi Katada, M.D.,
Yoichi Kitsuta, M.D.,
Daisuke Yamaguchi, M.D.,

Takeshi Ishii, M.D.,
Tetsuya Inoue, M.D.,
Toshihiro Morita, M.D.,

Kyoko Komatsu, M.D.,
Tsuneo Suzuki, M.D.,
Yasushi Imai, M.D.

Makoto Furukawa, M.D.,

Hiroshi Shinbori, M.D.

Staff
Shinji Matsuse, M.D.,

Homepage://www.h.u-tokyo.ac.jp
Introduction and Organization
Department of Emergency and Critical Care medicine was established in 1965, as the emergency service
within the Central Clinical Service Facilities of the
University of Tokyo Hospital and at the same time as
the intensive care service for in-hospital patients, it became a tertiary emergency care and critical care centerin 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 ofone of the newest Life Flight aeromedical services in
the country.
The Emergency Center sees approximately 16,800
patients per year. It contains major trauma and cardiac
resuscitation rooms complete with STAT X-ray and fullmonitoring and resuscitation equipment. There are 9
treatment spaces including space for orthpedics, gynecology, and optho-ENT evaluations. X-ray, rapid spiralCT, ultrasound, angiography and STAT Lab are locatedadjacent to the Emergency Center.
In September, 2001, the University of Tokyo Hospital opened the In-patient Ward A and our department
has necessarily extended services for management of
ICU/CCU, MHCU and HCU.
The new Critical Care Center contains adult intensive
care unit (ICU) of 8 beds, coronary care unit (CCU) of
6 beds, surgical high care unit (SHCU) of 36 beds,
medical high care unit (MHCU) of 15 beds, pediatricintensive care unit (PICU) of 6 beds and neonatal intensive care unit (NICU) of 6 beds.
The Emergency Care Center and the Critical Care
Center see an excellent mix of multiple trauma,
high-acuity medical, surgical, pediatric, and gynecologic patients. The Life Flight service provides anotheropportunity for exposure to critically ill patients. Consult services are available from all of the clinical departments of the Medical School.

302

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 2004, we
had 6,452 ambulance patients out of total 17,370
ER outpatients.
The new ER, four times the size of the present ER
is scheduled to be built in 2006. The facility will
have 5 consultation rooms, 4 specialized consultation rooms for dentistry, ophthalmology, otorhinolaryngology and gynecology, 2 resuscitation bays,
1 operating room and 11 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 forthe entire care of the critically ill patients (i.e. patients with respiratory insufficiency such as ARDS,
with sepsis, with MOF, with shock), post-operative
patients, and tertiary emergency patients, placing
an emphasis on evidence-based medical therapy.
We had 1,000 ICU patients in the 2004. In 2006,
the number of beds in ICU will increase to 16 andthe facility will include the 24 beds for the surgical
ICU patients by 2007.
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 are allocated to three types of wards, that is, general ward,
HCU and ICU/CCU in accordance with their critical condition. The surgical HCU undertakes theleading 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 man-agement, our hospital has been authorized by the
Tokyo Metropolitan Government as a disaster basehospital, and also the Government has requested
the formation of Disaster Medical Assistant Team(DMAT) from us. We are now proceeding with adrastic revision of in-hospital manual for disaster
control, holding seminars on disaster medicine, andenforcing the disaster training. We are planning to
set oxygen and medical suction equipment on thepassageways in the new ER within 2006 fiscal year
in order to treat the large number of disaster patients.

Teaching activities
1) Six hours of lecture for the 2nd year medical student, the topics include the prehospital emergency
care, the initial evaluation of emergency patients,
disaster medicine, serious infections disease, andmedical equipment. Four hours of simulation 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 practice of
emergency medicine as fellow passengers in theambulance and as 2.5-day trainees in affiliated 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 of
view.

303

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
and Support) program, triage training, and risk
communication techniques using wireless network.
In addition, we produce the seminar for nurses suchas medical support in the big earthquake.

Research activities
The on-going researches include “the Vital Care
Network System” which manages the great number ofhigh-risk people continually, electrolyzed water, elucidation of peripheral neural regulation of heart, andbrain resuscitation. In collaboration with Department ofPharmacy, Department of Clinical Laboratory Medicine,
Department of Infectious Diseases, we focus on several
clinical research on issues including intra-nuclear transcription of β-D-glucan in blood products .

References
1. Kobayashi K, Ikeda H, Higuchi R, Nozaki M, Yamamoto Y, Urabe M, Shimazaki S, Sugamata N,
Aikawa N, Ninomiya N, Sakurai H, Hamabe Y,
Yahagi N, Nakazawa H. Epidemiological and outcome characteristics of major burns in Tokyo.
Burns 2005; 31S: S3-11.
2. Hale SI, Kloner RA, Katada S, Obayashi T, Ishii T,
Nakajima S, Yahagi N. Myocardical ischemia andinfarction. In Tisherman SA and Sterz F, editors.
Therapeutic Hypothermia. New York: Springer;
2005. pp191-209.

Health Sciences and Nursing
1. Health Sciences

25

306

Department of Health Sociology
Associate Professor
Yoshihiko Yamazaki, Ph.D.(Dr.Hlth.Sc.)

Homepage

http://www.hlthsoc.m.u-tokyo.ac.jp/indexj.htm/

Introduction and Organization
The Department of Health Sociology is one of thetwo departments which ex-Depautment of Health Sociology was devided into in 1997, when most departments in the University of Tokyo were reorganized
into the Graduate School of the University of Tokyo.
The department of Health Sociology is one of sixteen
departments in the Graduate School of Health Sciences and Nursing. The department consists of one
Associate Professor (Head of Health Sociology), 33
graduate students (20 master course students and 13
doctor course students) including 2 international students and 18 students qualified with nurse, and 3 research students. More than forty visiting researchers
are affiliated with the department.

Teaching activities
In Graduate Courses, School of Health Sciences andNursing, Dr. Yamazaki, A. prof. and Head of HealthSociology, runs runs two seminars every year: HealthSociology(I) in summer semester, and Health Sociology(II) in winter semester, with a lecturer, prof. Nakayama from St. Luca Nursing College.
The purpose of Health Sociology(I) is for students
to obtain a basic understanding of the health sociological approach through a quick overview of major
concepts, principles, and research in sociology ofhealth and medicine.
Health Sociology(II) introduces students to basic
methods and techniques in designing and conducting
social research- in general, both quantitative andqualitative- in the health field. For these years, thisseminar has been provided as Introduction to Multi-

variate Statistical Methods, and designed to learn thebasic statistical methods such as factor analysis,
analysis of variance/covariance, multiple regression
analysis, multiple logistic regression analysis, andstructural equation modeling. In the fiscal 2004-05,
the membership in each seminar above-mentioned was
25 – 30 and over.
For the graduate students and the other members in
Dept. of Health Sociology, a workshop and a journal
club are held every week. In the former, a student’s
research proposal or paper is to be reported and discussed. In the latter, a student is supposed to introduce
an English article in the recent issue of an international refereed journal.
In our department in the fiscal 2004-05, 13 MC students submitted Master Thesis and gained Master’s
Degree. Four DC students submitted Doctoral Dissertation and got Doctor’s Degree. Eight graduate students have got a job as a university teacher, professor,
or researcher.
In Undergraduate Courses, School of Health Sciences and Nursing, our department is in charge of thefollowing subjects as: Health Sociology (with a lecturer, Dr. Tamura), Social Welfare and Social Security(with two lecturers, Dr. Sakano from Okayama Prefectural University and Prof. Takagi from Keio University), Social Research Method Practice, Social and
Human Relations, Graduation Thesis (many graduate
students the last three subjects are shared with many
graduate students in Dept.of Health Sociology), andthe other two.

Research activities
Our department studies social and psychological307

factors related to health problems and health care systems, through developing and applying theories, concepts and methods, which have been developed in sociology, psychology, and social and behavioral sciences.
We have been conducting the following 7 research
projects these two years.
1. Studies on Antonovsky’s Salutogenesis and Sense
of Coherence (SOC) Concept
We have introduced Antonovsky’s Salutogenesis
and its core concept ‘Sense of Coherence (SOC)’
to Japanese fields of health and stress. The objective of this project is to develop and apply Japanese version Antonovsky’s SOC scale to examine
SOC and correlates among different population,
people with chronic illness/disability, and so on.
2. Study on People with Medically Induced HIV
Nearly 1,500 hemophilia patients were infectedwith HIV through blood products in the mid
1980’s in Japan, and so far more than five hundred
patients have died of AIDS and others. They are
suffering not only from health damage but also
various types of stigma and discrimination. In thisproject, several research studies are being conduced in order to explore the problems of theirlives, and to suggest the needed social supports
3. Studies on Social Differences and Inequalities in
HealthThis project is designed to explore evidence aboutsocio-economic differences in health, especiallyamong the middle-aged, in Japan. Another purpose of this project is to cinsider possible explanations for these differences and the implications
for policy.
4. Studies on Changing Professional-Patient Relationship and Patient Autonomy
The aim of this project is to examine the current
situation of professional-patient relationship andpatient autonomy in Japan, and to derive newtheories. Both empirical and theoretical studies
have been conducted from various perspectives.
5. Studies on “Way of Working and Living” and Fatigue/Stress of Working People
Recently Japanese industrial society has been subjected to the never-experienced structural changes.
The aims of this project are to explore the effectsof these changes on “ways of working and living”,
work-family balance and fatigue/stress of working
people, and to clarify the mechanism of the effects.
6. Studies on Characteristics of the Physical andPsychological Distresses in Human Service Work
Human service work is spread over the many
fields including medicine, nursing and caring. The
aims of this project is to examine the characteristics of the psychological and physical distress ofhuman service workers and their related factors.
7. Studies on the Onset of Pneumoconiosis among
Tunnel Construction Workers
In Japan, many tunnel construction workers suffered from the onset of severe pneumoconiosis in
1970’s. It is still continuing in 1990’s. The purpose of this research project is to reveal the process and the related factors on the onset of pneumoconiosis in recent years.

References
1. Mizota Y, Ozawa O, Yamazaki Y, Inoue Y.
Psychosocial problems of bereaved familiesof HIV-infected hemophiliacs in Japan Social Science & Medicine. 2006; 62: 23972410.
2. Hirano YM, Yamazaki Y, Shimizu J, Togari
T, Bryce JT, Ventilator dependence and expressions of need: A study of patients withamyotrophic lateral sclerosis in Japan. Social Science & Medicine. 2006; 62: 14031413.
3. Ishikawa H, Yamazaki Y. How applicable
are western models of patient-physician
relationship in Asia?: Changing patientphysician relationship in contemporary
Japan. International J. of Japanese Sociology. 2005; 14: 84-93.
4. Ishikawa H, Roter DL, Yamazaki Y., Takayama T. Physician - elderly patient - companion communication and roles of companions in Japanese geriatric encounters.
Social Science & Medicine 2005; 60(10):2307-2320.
5. Ishikawa H, Hashimoto H, Roter DL, Yamazaki Y, Takayama T, Yano E. Patient308

contribution to the medical dialogue andperceived patient-centeredness: An observational study in Japanese geriatric consultations. Journal of General Internal
Medicine. 2005; 20: 906-910.
6. Kondo K, Yamazaki Y. Living with facialdisfigurement: Stigmatizing situations,
coping strategies and their influence on
psychological well-being. Jpn. J. HealthHum. Ecol. 2005; 71(4): 142-156.
7. Kusunaga WT, Yamazaki Y, Takayama T,
Ryu J, Seki Y, Inoue Y, Kumagai T. Psychosocial factors related to climacteric symptoms of women in Tokyo. Jpn. J. HealthHum. Ecol. 2004; 70(6): 235-244.
8. Togari T, Ikezaki S, Yamazaki Y, Ito M,
Zenko A, Taguchi R. The development ofPerceived Health Competence Scale (PHCS)
Japanese version. Jpn. J. Health Hum. Ecol.
2004; 70(5):184-195.
9. Inoue Y, Yamazaki Y, Seki Y, Wakabayashi
C, Kihara M. Sexual activities and social
relationships of people with HIV in Japan.
AIDS CARE. 2004; 16(3): 349-362.
10. Takayama T, Yamazaki Y. How breast cancer outpatients perceive mutual participation in patient-physician interactions. Patient Education and Counseling. 2004; 52(3): 279-289.
11. Yamaki CK, Yamazaki Y. ‘Instrument’, ‘employees’ , ‘companions’, ‘social assets’: Understanding relationship between persons
with disabilities and their assistants inJapan. Disability & Society. 2004; 19(1):31-46.
12. Togari Y, Yamazaki Y. Examination of thereliability and factor validity of 13-item
five-point version Sense of Coherence Scale.
Jpn. J. Health Hum. Ecol. 2005; 7(4): 168182. (in Japanese)
13. Yamazaki Y. Health and human ecology, life,and Salutogenesis. Jpn. J. Health Hum.
Ecol. 2005; 7(3): 105-106. (in Japanese)
14. Mandai Y, Yamazaki Y, Yamaki C, Ishikawa
H, Ozawa M, Shimizu J, Fujimura K, Kato
M. Daily hassles and their relationship withlifestyle factors, personality traits, and so-cial support among first and second year
Japanese university students. Japanese J.
of Health Education and Promotion. 2005;
13(1): 34-45. (in Japanese)
15. Seki Y, Yamazaki Y. Prevention of adverse
drug events: Error-producing conditions
detrimental effect defenses. 2005; The
Japanese Journal of Health and Medical
Sociology. 16(1): 37-49. (in Japanese)
16. Suzuki Y, Yamazaki Y. A study of a publichealth nurse’s viewpoints of health support
activity and intervention for “the homeless”
with tuberculosis. Bulletin of Social Medicine. 2005; 23: 75-82. (in Japanese)
17. Tei M, Yamazaki Y. The effect of work andorganizational characteristics on workers incall centers: Longitudinal study in an information service company. San Ei Shi.
2005; 47: 210-223. (in Japanese)

309

Department of Mental HealthProfessor
Norito Kawakami, M.D., D.M.Sc.

Assosicate Professor
Iwao Oshima, Ph.D.

Assistant Professor
Toshio Mori, Ph.D.

Homepage http://plaza.umin.ac.jp/heart/
Introduction and Organizationof psychiatric nursing.

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 Schoolof 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 result of the shift to the chairsystem of the Graduate School of Medicine in 1996,
two departments were established, Department of
Mental Health and Department of Psychiatric Nursing.
Faculty, staff, and students of two departments havebeen working cooperatively ever since.
The department currently has faculty members introduced above, part-time lecturers, a technical specialist, visiting research fellows, 10 doctoral course students, 7 master course students, research associates, andsecretaries.
The department has two major objectives: one is toteach mental health to undergraduate and graduate students in order to produce leading practitioners andclinical researchers in the field. The other is to conductclinical research in the fields of mental health.
All of the activities of the department are conductedin collaboration with staff members in the department

Teaching activities
The department is responsible for giving lectures onmental health; mental disorders; clinical psychology;
and psychometry and behavior evaluation to undergraduate students. Other than lectures, the department
provides students opportunities to practice mental
health activities in several relevant mental health facilities.
The department is also obliged to educate graduate
students in master and doctor programs in mental health.
To accomplish this objective, the department has specialized lecture courses on mental health, which areheld for 1.5 hours every Wednesday morning for 10
weeks in each semester; seminars; and field works onmental health for graduate students. These activities are
conducted and supervised by the professor and assistantprofessor. We also have the department seminar every
Wednesday evening, where relevant English articles are
introduced by graduate students and a prominent guest
speaker gives a lecture every other month.

Research activities
Due to broad interests of the staff members, the department has many research projects across diverse
fields as follows: psychiatric epidemiology, social psy-

310

chiatry, mental health services research, community
mental health, occupational mental health; psychiatricrehabilitation, clinical psychology, psychotherapy, childand adolescent psychiatry; and developmental disorders.
The department staff members employ many researchmethodologies adopted from various fields, such as
medicine, psychiatry, psychology, sociology, social
work, nursing and education. We are conducting studies
in collaboration with researchers in institutions anduniversities in and outside Japan.

References
1. Koyama, T., Tachimori, H., Osada, H. and Kurita,
H.: Cognitive and symptom profiles in high-functioning pervasive developmental disorder not otherwise specified and attention-deficit/hyperactivity
disorder. Journal of Autism and Developmental
Disorders (in press).
2. Mino, Y., Oshima, I.: Seasonality of birth in patients with schizophrenia in Japan. Psychiatry andClinical Neuroscience (in press).
3. Naganuma, Y., Tachimori, H., Kawakami, N.,
Takeshima, T., Ono, Y., Uda, H., Hata, Y., Nakane,Y., Nakane, H., Iwata, N., Furukawa, TA., Kikkawa,T.: Twelve-month Use of Mental Health Services inFour Areas in Japan: Finding from the World Mental Health Japan Survey 2002-2003. Psychiatry andClinical Neurosciences (in press).
4. Wada, K., Satoh, T., Tsunoda, M., Aizawa, Y., The
Japan Work Stress and Health Cohort Study Group.
Associations of health behaviors on depressive
symptoms among employed men in Japan. Industrial Health (in press).
5. Honjo, K., Tsutsumi, A., Kawakami, N.: What accounts for the relationship between social class andsmoking cessation? Results of a path analysis. Social Science and Medicine, 62: 317-328, 2006.
6. Kawakami, N., Takao, S., Kobayashi, Y., Tsutsumi,
A.: Effects of web-based supervisor training on job
stressors and psychological distress among workers: A workplace-based randomized controlled trial.
Journal of Occupational Health, 48: 28-34, 2006.
7. Kawakami, N., Tsutsumi, A., Haratani, T., Kobayashi, F., Ishizaki, M., Hayashi, T., Fujita, O., Aizawa, Y., Miyazaki, S., Hiro, H., Masumoto, T.,
Hashimoto, S., Araki, S.: Job Strain, Worksite

Support, and Nutrient Intake among Employed
Japanese Men and Women. Journal of Epidemiology, 16: 79-89, 2006.
8. Kondo, K., Kobayashi, Y., Hirokawa, K., Tsutsumi,A., Kobayashi, F., Haratani, T., Araki, S., Kawakami, N.: Job strain and sick leave among Japaneseemployees: A longitudinal study. International Archives of Occupational and Environmental Health,79: 213-9, 2006.
9. Oshima, I., Kuno, E.: Living Arrangements of Individuals with Schizophrenia in Japan: Impact ofCommunity-Based Mental Health Services. International Journal of Social Psychiatry, 52(1): 55-64,
2006
10. Oshima, I., Mino, Y., Inomata, Y.: The effects ofenvironmental deprivation on negative symptomsof schizophrenia: A nationwide survey in Japan’s
psychiatric hospitals. Psychiatry Research, 136:
163-171, 2005.
11. Shimazu, A., Kawakami, N., Irimajiri, H., Sakamoto, M., Amano, S.: Effects of web-based psychoeducation on self-efficacy, problem solving behavior, stress responses and job satisfaction among
workers: A controlled clinical trial. Journal of Occupational Health, 47: 405-413, 2005.
12. Izutsu, T., Tsutsumi, A., Asukai, N., Kurita, H. and
Kawamura, N.: Relationship between traumatic life
event and an alteration in stress response. Stress &Health, 20: 65-73, 2004
13. Kanai, C., Koyama, T., Kato, S., Miyamoto, Y.,
Osada, H., Kurita, H.: Comparison of high-functioning atypical autism and childhood autism byChildhood Autism Rating Scale-Tokyo version.
Psychiatry & Clinical Neurosciences, 58: 217-21,
2004.
14. Kayama, M., Sagami, A., Watanabe, Y., Senoo, E.,
Ohara, M.: Child abuse prevention in Japan: an approach to screening and intervention with mothers.
Public Health Nursing, 21: 513-8, 2004.
15. Koyama, A., Akiyama, T., Miyake, Y. and Kurita,
H.: Family functioning perceived by patients andtheir family members in three DSM-IV diagnostic
groups. Psychiatry and Clinical Neurosciences, 58:
495-500, 2004.
16. Kurita, H., Koyama, T., Setoya, Y., Shimizu, K. andOsada, H.: Validity of childhood disintegrative disorder apart from autistic disorder with speech loss.

311

European Child & Adolescent Psychiatry, 13: 221226, 2004.
17. Kurita, H., Osada, H. and Miyake, Y.: External validity of childhood disintegrative disorder in comparison with autistic disorder. Journal of Autism
and Developmental Disorders, 34: 355-362, 2004.
18. Kurita, H., Osada, H., Shimizu, K. and Tachimori,H.: Bipolar disorders in mentally retarded persons
with pervasive developmental disorders. Journal of
Developmental and Physical Disabilities, 16: 377389, 2004.
19. Oshima, I., Cho, N., Takahashi, K.: Effective components of a nationwide case management programin Japan for individuals with severe mental illness.
Community Mental Health Journal, 40(6): 525-537,
2004.
20. Sagami, A., Kayama, M., Senoo, E.: The relationship between postpartum depression and abusive
parenting behavior of Japanese mothers: a surveyof mothers with a child less than one year old. Bulletin of the Menninger Clinic, 68(2):174-87, 2004.

312

Department of
Biostatistics / Epidemiology andPreventive Health Sciences
Professor
Yasuo Ohashi, Ph.D.

Associate Professor
Yutaka Matsuyama, Ph.D.

Lecturer

AssociateTakuhiro Yamaguchi, Ph D.
Yoichi Ito

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 of biostatistics and methodological aspects of epidemiology ispoor in Japanese universities and graduate schools, although the necessity for collaboration with biostatisticians in clinical research (especially clinical trials) isrecently being to be claimed by clinical researchers andpharmaceutical industry. One mission of our educational courses is to provide detailed knowledge and experiences in biostatistics/ epidemiology to students whoare expected to take part in clinical/epidemiologicalresearch as experts and the other mission is to provide
basic principles of biostatistics/epidemiology to students who will work in many health-related fields in-cluding nursing. Our main research project is the development of methodology for clinical/epidemiologicalresearch and it requires keeping touch with real clinical/epidemiological problems. For these purposes andresearch 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 research support in design, data
management and statistical analysis in many projects
inside/outside the university.
The faculty of the department is providing lectures ina series of educational courses organized by ‘The
Clinical Bioinformatics Research Unit’ established in2002.

Teaching activities
1. Undergraduate courses
1) Epidemiology and Biostatistics (2 credits)
2) Applied Mathematics (2 credits)

313

3) Statistical Methods and Information Processing(2 credits, practice)4) Design and Analysis of Epidemiological Research (2+1 credits, 1 practice)5) Medical Data analysis (2 credits)
6) Biostatistics (2 credits; for the School of Medicine)
2. Garduate courses
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences (4credits)
3) Introduction to Medical Statistics (2 credits; for
the School of Medicine)
3. ‘The Clinical Bioinformatics Research Unit’ courses
1) Introduction of Biostatistics required for biomedical research2) Methodology of Clinical Trials (2 credits)

Research activities
1) Biostatistics and Theoretical Epidemiology
Analysis of longitudinal missing /incomplete data
Analysis of multiple events data
Analysis of QOL data
Causal analysis
Analysis of micro/macro array data
Meta analysis of epidemiological studies
2) Methodology and Information Systems for Clinical
TrialsDesign of clinical trials
Data management of large-scale clinical trials3) Pharmacoepidemiology4) Coordination of collaborative epidemiological/
clinical research
Japan Longitudinal Arteriosclerosis StudyJapan Diabetes Collaborative Study
5) Consultation Works

3.

4.

5.

6.

7.

References

8.

1. Sone H, Yoshimura Y, Ito H, Ohashi Y, Yamada N;
Japan Diabetes Complications Study Group. Energy intake and obesity in Japanese patients with
type 2 diabetes. Lancet 2004 Jan 17; 363(9404):
248-9.
2. Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, et al.; Japanese Taxotere Lung

9.

Cancer Study Group. Phase III randomized trial of
docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lungcancer: the Japanese Taxotere Lung Cancer Study
Group. J Clin Oncol 2004 Jan 15;22(2):254-61.
Sakamoto J, Ohashi Y, Hamada C, Buyse M,
Burzykowski T, Piedbois P; Meta-Analysis Groupof the Japanese Society for Cancer of the Colonand Rectum; Meta-Analysis Group in Cancer. Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol 2004 Feb 1;22(3):484-92.
Homma Y, Akaza H, Okada K, Yokoyama M,
Usami M, Hirao Y, et al.; Prostate Cancer Study
Group. Endocrine therapy with or without radical
prostatectomy for T1b-T3N0M0 prostate cancer.
Int J Urol 2004 Apr;11(4):218-24.
Ito K, Nakazato H, Koike A, Takagi H, Saji S, Baba
S, et al.; Study Group of Immuno- chemotherapy
with PSK for Colon Cancer. Long-term effect of
5-fluorouracil enhanced by intermittent administration of polysaccharide K after curative resection ofcolon cancer. A randomized controlled trial for
7-year follow-up. Int J Colorectal Dis 2004 Mar;19(2):157-64.
Ogura M, Morishima Y, Kobayashi Y, Uike N,
Sugai S, Chou T, et al.; Cladribine Study Group.
Durable response but prolonged cytopenia after
cladribine treatment in relapsed patients with indolent non-Hodgkin's lymphomas: results of a Japanese phase II study. Int J Hematol 2004 Oct;80(3):267-77.
Tobinai K, Igarashi T, Itoh K, Kobayashi Y, Taniwaki M, Ogura M, et al.; IDEC-C2B8 Japan Study
Group. Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma.
Ann Oncol 2004 May;15(5): 825-834.
Zheng HY, Zhao P, Suganami H, Ohasi Y, Ikegaya
H, Kim JC, et al. Regional distribution of two related Northeast Asian genotypes of JC virus, CY-aand -b: implications for the dispersal of Northeast
Asians. Microbes Infect 2004 May;6(6):596-603.
Watanabe M, Nishida O, Kunii Y, Kodaira S, Takahashi T, Tominaga T, et al. Randomized controlled trial of the efficacy of adjuvant immunochemotherapy and adjuvant chemo- therapy for314

colorectal cancer, using different combinations of
the intracutaneous strepto- coccal preparation
OK-432 and the oral pyrimidines 1-hexylcarbamoyl5-fluorouracil and uracil/tegafur. Int J Clin Oncol
2004 Apr; 9(2):98-106.
10. Morita S, Ohashi Y, Hirakawa K, Nakata B, Saji S,
Sakamoto J. Phase I/II study of combination therapy of oral fluorinated pyrimidine compound S-1
with low-dose cisplatin in patients with unresectable and/or recurrent advanced gastric cancer: anovel study design to evaluate safety and efficacy.
Jpn J Clin Oncol 2004 Mar;34(3):159-61.
11. Homma Y, Akaza H, Okada K, Yokoyama M, Moriyama N, Usami M, et al.; Prostate Cancer Study
Group. Radical prostatectomy and adjuvant endocrine therapy for prostate cancer with or without
preoperative androgen deprivation: Five-year results. Int J Urol 2004 May;11(5):295-303.
12. Akaza H, Yamaguchi A, Matsuda T, Igawa M,
Kumon H, Soeda A, et al. Free Full Text Superioranti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist
monotherapy as first-line treatment for advanced
prostate cancer: interim results of a randomized
study in Japanese patients. Jpn J Clin Oncol 2004
Jan;34(1):20-8.
13. Hanaoka K, Toyooka H, Kugimiya T, Ohashi Y;
Granisetron Study Group of Japan. Efficacy ofprophylactic intravenous granisetron in postoperative emesis in adults. J Anesth 2004; 18(3):158-65.
14. Mayama C, Araie M, Suzuki Y, Ishida K,
Yamamoto T, Kitazawa Y, et al. Statisticalevaluation of the diagnostic accuracy of
methods used to determine the progressionof visual field defects in glaucoma. Ophthalmology 2004 Nov; 111(11):2117-25.
15. Sone H, Yamada N, Mizuno S, Ohashi Y, Ishibashi
S, Yamazaki Y. Requirement for hypertension andhyperlipidemia medication in U.S. and Japanesepatients with diabetes. Am J Med 2004 Nov
1;117(9):711-2.
16. Sone H, Yamada N, Mizuno S, Aida R, Ohashi Y.
Alcohol use and diabetes mellitus. Ann Intern Med
2004 Sep 7;141(5):408-9.
17. Sone H, Mizuno S, Ohashi Y, Yamada N. Type 2
diabetes prevalence in Asian subjects. Diabetes

Care 2004 May;27(5):1251-2.
18. Hagino A, Hamada C, Yoshimura I, Ohashi Y, Sakamoto J, Nakazato H. Statistical comparison of
random allocation methods in cancer clinical trials.
Control Clin Trials 2004 Dec;25(6): 572-84.
19. Ogura M, Morishima Y, Kobayashi Y, Uike N,
Sugai S, Chou T, et al.; Cladribine Study Group.
Durable response but prolonged cytopenia after
cladribine treatment in relapsed patients with indolent non-Hodgkin's lymphomas: results of a Japanese phase II study. Int J Hematol 2004 Oct;80(3):267-77.
20. Akizawa T, Ohashi Y, Akiba T, Suzuki M, Nishizawa Y, Ogata E, et al. Dose-response study of
22-oxacalcitriol in patients with secondary hyperparathyroidism. Ther Apher Dial 2004 Dec;8(6):480-91.
21. Ishizaki T, Kai I, Kobayashi Y, Matsuyama Y, Imanaka Y. The effect of aging on functional decline
among older Japanese living in a community: a
5-year longitudinal data analysis. Aging Clin Exp
Res 2004 Jun;16(3):233-9.
22. Teramukai S, Matsuyama Y, Mizuno S, Sakamoto J.
Individual patient-level and study-level metaanalysis for investigating modifiers of treatment
effect. Jpn J Clin Oncol 2004 Dec;34(12):717-21.
23. Ikai I, Arii S, Kojiro M, Ichida T, Makuuchi M,
Matsuyama Y, et al. Reevaluation of prognostic
factors for survival after liver resection in patientswith hepatocellular carcinoma in a Japanese nationwide survey. Cancer 2004 Aug 15;101(4):796802.
24. Matsuyama Y, Yamaguchi T, Hashimoto S, Kawado
M, Ichikawa S, Umeda T, et al. Epidemiologicalcharacteristics of HIV and AIDS in Japan based on
HIV/AIDS surveillance data: An international
comparison. J AIDS Res 2004;6(3):184-93.
25. Tanimoto TE, Yamaguchi T, Tanaka Y, Saito A,
Tajima K, Karasuno T, et al. Comparative analysisof clinical outcomes after allogeneic bone marrowtransplantation versus peripheral blood stem celltransplantation from a related donor in Japanesepatients. Br J Haematol 2004 May;125(4):480-93.
26. Yamaguchi T, Ohashi Y. Adjusting for differential
proportions of second-line treatment in cancer
clinical trials. Part I: structural nested models andmarginal structural models to test and estimate

315

treatment arm effects. Stat Med 2004 Jul 15;23(13):1991-2003.
27. Yamaguchi T, Ohashi Y. Adjusting for differential
proportions of second-line treatment in cancer
clinical trials. Part II: an application in a clinical
trial of unresectable non-small-cell lung cancer.
Stat Med 2004 Jul 15;23(13):2005- 22.
28. Takahashi S, Iseki T, Ooi J, Tomonari A, Takasugi
K, Shimohakamada Y, et al. Single- institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adultpatients with hematologic malignancies. Blood
2004 Dec 1;104(12):3813-20.

29. Wang Y, Kato N, Hoshida Y, Otsuka M, Taniguchi
H, Moriyama M, et al. UDP-glucuronosyltransferase 1A7 genetic polymorphisms are associatedwith hepatocellular carcinoma in japanese patientswith hepatitis C virus infection. Clin Cancer Res
2004 Apr 1;10(7):2441-6.
30. Tsuda H, Birrer MJ, Ito YM, Ohashi Y, Lin M, Lee
C, et al. Identification of DNA copy number
changes in microdissected serous ovarian cancer
tissue using a cDNA microarray platform. Cancer
Genet Cytogenet 2004 Dec; 155(2):97-107.
31. Nakajima J, Takamoto S, Matsumoto J, Takeuchi E,
Ito YM. Effect of preoperative transbronchial biopsy on prognosis of non-small cell lung cancer.Asian Cardiovasc Thorac Ann 2004 Dec;12(4):330-5.
32. Kihira T, Sato J, Shibata T. Pharmacokineticpharmacodynamic analysis of fluoroquinolones
against Bacillus anthracis. J Infect Chemother 2004
Apr;10(2):97-100.
33. Machii T, Chou T, Suzuki M, Ohe Y, Katagiri S,
Kitano EK, et al.; Cladribine Study Group. Phase II
clinical study of cladribine in the treatment of hairycell leukemia. Int J Hematol 2005 Oct;82(3):230-5.
34. Sone H, Mizuno S, Fujii H, Yoshimura Y, Yamasaki
Y, Ishibashi S, et al.; Japan Diabetes Complications
Study. Is the diagnosis of metabolic syndrome useful for predicting cardiovascular disease in asiandiabetic patients? Analysis from the Japan Diabetes
Complications Study. Diabetes Care. 2005 Jun;28(6):1463-71.
35. Makuuchi H, Furuse A, Endo M, Nakamura H,
Daida H, Watanabe M, et al. Effect of pravastatin
on progression of coronary atherosclerosis in pa-

tients after coronary artery bypass surgery. Circ J
2005 Jun;69(6):636-43.
36. Ishikawa T, Ito H, Ouchi Y, Ohashi Y, Saito Y, Nakamura H, et al.; PATE Investigators. Increased risk
for cardiovascular outcomes and effect of cholesterol-lowering pravastatin therapy in patients withdiabetes mellitus in the pravastatin anti-atherosclerosis trial in the elderly (PATE). Curr Ther Res
2005;66(1):48- 65.
37. Matsuda T, Takayama T, Tashiro M, Nakamura Y,
Ohashi Y, Shimozuma K. Mild cognitive impairment after adjuvant chemotherapy in breast cancer
patients--evaluation of appropriate research design
and methodology to measure symptoms. Breast
Cancer 2005;12(4):279-87.
38. Kotake K, Ohashi Y, Kodaira S, Koyama Y;
East-Japan Colorectal Cancer Chemotherapy Study
Group. A multicenter randomized study comparing
5-fluorouracil continuous infusion (ci) plus
1-hexylcarbamoyl-5-fluorouracil and 5-FU ci alone
in colorectal cancer. Oncol Rep 2005 Jul;14(1):129-34.
39. Saida T, Tashiro K, Itoyama Y, Sato T, Ohashi Y,
Zhao Z; Interferon Beta-1b Multiple Sclerosis
Study Group of Japan. Interferon beta-1b is effective in Japanese RRMS patients: a randomized,
multicenter study. Neurology 2005 Feb 22;64(4):621-30.
40. Ogihara T, Matsuzaki M, Matsuoka H, Shimamoto
K, Shimada K, Rakugi H, et al.; COPE Trial Group.
The combination therapy of hypertension to prevent cardiovascular events (COPE) trial: rationale
and design. Hypertens Res 2005 Apr;28(4):331-8.
41. Yamanaka H, Ito K, Naito S, Tsukamoto T, Usami
M, Fujimoto H, et al. Effectiveness of adjuvant intermittent endocrine therapy following neoadjuvant
endocrine therapy and external beam radiation
therapy in men with locally advanced prostate cancer. Prostate 2005 Apr 1;63(1):56-64.
42. Maeno T, Ohta A, Hayashi K, Kobayashi Y, Mizunuma H, Nakai S, et al. Impact of reproductive
experience on women's smoking behaviour inJapanese nurses. Public Health 2005 Sep;119(9):816-24.
43. Kohno N, Aogi K, Minami H, Nakamura S, Asaga
T, Iino Y, et al. Zoledronic acid significantly reduces skeletal complications compared with pla-

316

cebo in Japanese women with bone metastases
from breast cancer: a randomized, placebo-controlled
trial. J Clin Oncol 2005 May 20;23 (15):3314-21.
44. Chiba Y, Matsuyama Y, Sato T, Yoshimura I. A
simulation study for a linear measurement error
model when error variances vary between measurements. J Agric Biol Environ Stat 2005; 10: 118130.
45. Mizuno S, Yamaguchi T, Fukushima A, Matsuyama
Y, Ohashi Y. Overlap coefficient for assessing thesimilarity of pharmacokinetic data between ethnically different populations. Clin Trials. 2005;2(2):174-81.
46. Aoki T, Imamura H, Kaneko J, Sakamoto Y, Matsuyama Y, Kokudo N, et al. Intraoperative direct
measurement of hepatic arterial buffer response inpatients with or without cirrhosis. Liver Transpl
2005 Jun;11(6):684-91.
47. Hasegawa K, Kokudo N, Imamura H, Matsuyama
Y, Aoki T, Minagawa M, et al. Prognostic impact ofanatomical resection for hepatocellular carcinoma.
Ann Surg 2005 Aug;242(2):252-9.
48. Ikai I, Arii S, Ichida T, Okita K, Omata M, Kojiro
M, et al. Report of the 16th follow-up survey ofprimary liver cancer. Hepatol Res 2005;32(3):16372.
49. Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata
R, Tanaka N, et al.; Tokyo-Chiba Hepatitis Research Group. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann
Intern Med 2005 Jan 18;142(2):105-14.
50. Kobayashi K, Green J, Shimonagayoshi M, Kanemoto N, Kasai R, Itoh Y, et al. Validation of thecare notebook for measuring physical, mental andlife well-being of patients with cancer. Qual LifeRes 2005 May;14(4):1035-43.
51. Tsuda H, Ito YM, Ohashi Y, Wong KK, Hashiguchi
Y, Welch WR, et al. Identification of overexpression and amplification of ABCF2 in clear cellovarian adenocarcinomas by cDNA microarray
analyses. Clin Cancer Res 2005 Oct 1;11(19 Pt
1):6880-8.

317

Department ofSocial Gerontology
Professor
Ichiro Kai, M.D., M.P.H.

Associate
Miyako Takahashi, M.D., Dr.Hlth.Sc.

Tami Saito, M.Hlth.Sc.

Homepage http://www.sg.m.u-tokyo.ac.jp
Introduction and Organization
It is often voiced from the general public that recent
advancement of medicinal technology would not necessarily lead to the happiness of people: Life prolongation technology enables even the terminally ill to live
for a considerable period. How to use the technology isa serious problem in clinical practice. Also, there isevidence that the prolongation of life expectancy for theelderly does not mean the prolongation of health andproductivity, but that of morbidity. Taking another example, we are experiencing ethical dilemmas with theapplication of medical technology such as genetic
screenings and organ transplantation. When we turn to
the worldwide situation regarding health, we will findpoverty and unequal distribution in terms of health resources and outcomes.
The department is studying these health-related
problems from social perspective, many of which areoften difficult to decide upon. Major topics include elderly health, terminal care, medical ethics and international health among others. We are currently conducting
several research projects as described below.
Our educational activities include lectures, practicaltraining and supervision of writing theses for students
in graduate level as well as undergraduate level. The
department consists of one professor, five visiting lecturers, two associates and 17 graduate students (including six international students from Korea, China, Philippines and Nepal).

Teaching activities
1. Graduate Courses, School of Health Sciences andNursing
1) Social Gerontology: The course is to provide thestudents with the basic understanding of social
sciences in the field of gerontology. The topics
include (1) the concept and measurements ofquality of life, (2) the influences of psychosocial
factors on health status, health behavior andhealth belief, and (3) policy considerations for
medical care and prevention.
2. Undergraduate Courses, School of Health Sciences
and Nursing
1) Health Education: This course provides fundamental understanding in health education andhealth promotion in various settings such ascommunity, workplace, school and clinics. Emphasis is put upon preparing students to conduct
heath education in their future career as a healthprofessional.
2) Practice in Social Surveys: This is for practicing
to conduct social surveys using questionnaire/interview method. The students are divided
into several groups, and each group is given asurvey area. They will go through all the processes of a health sociological survey, from planning the survey to writing a report based on thesurvey. They have the opportunity to report and318

discuss their surveys with each other.
3) Health Behavior: This seminar aims to help thestudents to practice the basic research methods
related to health behaviors. Final product will bea research proposal and the review of relevant
literature.
4) Decision-making in Health: This course introduces students to recent developments in medical
and health decision-making. Topics include thedefinition and measurement of quality of life
(QOL), cost-effectiveness and cost-benefit
analysis, technology assessment and optimal allocation of scarce medical resources. Readings
are selected from extensive range of literature inbehavioral sciences, economics and philosophy
as well as medical decision-making.

Research activities
1) Reciprocity of Social Support on Subjective
Well-being of the Elderly: Traditional support study
emphasizes the importance of receiving support.
We examine the pattern of support exchange (i.e.,
receiving and providing) and its effects on the subjective well-being of the elderly in rural Japan aswell as a number of Asian countries such as Korea,
Nepal, Malaysia, and Indonesia. Intervention studies regarding intergeneration exchanges and targeting the relocated elderly are now in progress.
2) Disability-free Life Expectancy in Japan: We calculate disability-free expectancy using a large-scalecohort of the residents in Nagano Prefecture andexamine variables influencing the life expectancy.
3) Multi-disciplinary Collaboration in the Psychosocial Care for the People with Cancer in ClinicalSetting: The survey we performed indicated thatJapanese surgeons considered themselves mainly
responsible for medical aspects of patient care andpaid less attention to psychosocial issues. We examine the possibilities of integrating other support
resources such as clinical psychologists, psychiatrists and medical social workers in the clinicalpractices of cancer in Japan.
4) Activities of Cancer Self-help Groups in Japan:
Although cancer self-help groups are growing
presence in Japan, they do not attract as many patients as they do in other countries such as US.

Through semi-structured interviews and a questionnaire survey, we revealed how Japanese cancer
survivors and surgeons view peer support activities
implemented by cancer survivors.
5) Socio-cultural Analysis of Sexuality after Cancer:
Researchers have long neglected sexuality aftercancer. Through intensive semi-structured interviews with Japanese women with breast cancer, we
examine how the cancer diagnosis and the following treatments have affected their sexuality and thewhole relationship with their partners. Based on thefindings of the qualitative approach, we intend to
perform a large-scale survey on sexual complications among Japanese cancer survivors.
6) Role and Function of Ethics Committees in Japan:
In this project, we surveyed and analyzed the roleand function of ethics committees at various levels,from hospital level to national level.

References
1. Kono A, Kai I, Sakato C, et al. Frequency of goingoutdoors: A predictor of functional and psychosocial change among ambulatory frail elders living at
home. J Gerontol (Medical Science). 2004;59A(3):275-280.
2. Akabayashi A, Slingsby BT, Kai I, et al. The development of a brief and objective method forevaluating moral sensitivity and reasoning inmedical students. BMC Medical Ethics. 2004;5:1(7 pages).
3. Ishizaki T, Kai I, Kobayashi Y, et al. The effect ofaging on functional decline among older Japaneseliving in a community: A 5-year longitudinal data
analysis. Aging Clin Exp Res. 2004;16(3):233-239.
4. Kono A, Kai I, Sakato C, et al. Effect of preventive
home visits for ambulatory housebound elders inJapan: A pilot study. Aging Clin Exp Res. 2004;16(4):293-299.
5. Miyata H, Tachimori H, Takahashi M, et al. Disclosure of cancer diagnosis and prognosis: A surveyof the general public’s attitudes toward doctors andfamily holding discretionary powers. BMC Medical
Ethics. 2004; 5:7 (6 pages).
6. Yokokawa Y, Kai I. Influence of self efficacy for
health for health promotion on functional decline ofelderly living in a rural community in Japan. J J P

319

H. 2004;51(11):945-950.
7. Ohta M, Kai I. Factors affecting attitudes towardcare of elderly mothers. J J P H. 2004;51(11):951957.
8. Maly RC, Umezawa Y, Leake B, et al. Determinants of participation in treatment decision-making
by older breast cancer patients. Breast Cancer Res
Treatment. 2004;85:201-209.
9. Watanabe Y, Okumura J, Chiu TY, et al. Social
support and depressive symptoms among displaced
older adults following 1999 Taiwan earthquake. J
Traumatic Stress. 2004;17(1):63-67.
10. Sato H, Akabayashi A, Kai I. Public appraisal ofgovernment efforts and participation intent in medico-ethical policymaking in Japan: A large scale national survey concerning brain death and organtransplant. BMC Medical Ethics. 2005;6:1 (12pages).
11. Takahashi M, Kai I. Sexuality after breast
cancer treatment: Changes and coping
strategies among Japanese survivors. Soc Sci& Med. 2005;61(6):1278-1290.
12. Miyata H, Takahashi M, Saito T, et al. Disclosure
preferences regarding cancer diagnosis: To tell or
not to tell? J Med Ethics. 2005;31(8):447-451.
13. Okubo S, Takahashi M, Saito T, et al. Evaluation ofuniversal newborn hearing screening in Japan: An
analysis of the literature. J J P H. 2005;52(11):928-933.
14. Maly RC, Umezawa Y, Leake B, et al. Mental
health outcomes in older women with breast cancer: Impact of perceived family support and adjustment. Psycho-oncology. 2005;14(7):535-545.
15. Chalise HM, Shrestha S. Situation of the elderly in
the Himalayan Kingdom of Nepal. Indian J Soc
Work. 2005;66(2):136-143.

320

Department of Biomedical
Ethics & Department of
Health Promotion Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Lecturer
Jung Su Lee, Ph.D.

Associate
Satoshi Kodama, Ph.D.,

Kenji Matsui, M.D., Ph.D.

Homepage http:// www.ethps.m.u-tokyo.ac.jp/
Introduction and Organization
The former Department of Health Administration
was established in 1967 and Dr. Tsuneo Tanaka became
its first professor in 1974. He devoted himself to 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 care systems, especially health careeconomics and the quality of hospital care.
In 1996, the Department of Health Administration
developed into two departments: the Department of
Health Economics and the Department of Health Promotion Sciences. Both were established as departmentsof the Graduate School of Medicine. In 1998, Dr. Ya-

suki Kobayashi became the professor of the Department
of Health Economics. He conducted research into
health care delivery systems in Japan. In 2001, hemoved to the Department of Public Health. From 1996
to 2002, Dr. Kiyoshi Kawakubo took charge of the Department of Health Promotion Sciences as the associate
professor.
In June 2002, Dr. 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.
Staff members of the two departments include a professor, a lecturer, two associates, and a technical assistant. All five members, a total of eight lecturers fromother organizations and nine visiting researchers contribute to department teaching and research activities.
Department graduate students included three masterprogram students and five doctoral program students(including two international students from the USA andChina) in 2004, and two master program students andfive doctoral program students (including one international student from the USA) in 2005.
In this annual report, the organization and teaching

321

activities are reviewed followed by an explanation ofresearch activities.

Teaching activities
Our departments highly prioritize the teaching andguidance of graduate students and their research activities. Two bachelor theses, three master theses, and four
doctoral dissertations were completed between April
2004 and March 2006. Our departments’ staff members
are also responsible for the following undergraduate
and graduate courses.
Undergraduate Courses
Required courses
1) Health Administration (2 credits, lecture)2) Biomedical Ethics (2 credits, lecture)3) Occupational Health and Law (1 credit, lecture)
Elective courses
4) Health Care & WelfareⅠ&Ⅱ (2 credits, lecture)5) Field Work for Health Administration (2 credits,
practicum)6) Health Promotion Sciences (1 credit, lecture)7) Health Policy & Administration (2 credits, lecture)8) Introduction to Health Economics (2 credits, lecture)
Graduate Courses
1) Biomedical Ethics Ⅰ
2) Biomedical Ethics Ⅱ
3) Health Promotion Sciences Ⅰ
4) Health Promotion Sciences Ⅱ
Graduate level courses in Biomedical Ethics focus on
the analytical study of ethical theories and on the review of several empirical studies within the field and its
related areas. The main foci in the graduate courses of
Health Promotion Sciences are the assessment and design of the health promotion projects in the community
and at the work place, the development of preventive
health strategies and health promotion related tolife-style related disease.

Research activities
Department of Biomedical Ethics

The Department of Biomedical Ethics is interested in
the current topics of health care ethics. We are currently
conducting studies in the fields of biomedical ethics,
research ethics and clinical ethics. Methodology is
two-folded – theoretical and empirical. While conducting theoretical research on ethics and philosophy ofhealth care, we also have adopted a descriptive approach.
We have recently established the Center for Biomedical Ethics and Law (CBEL) adjunct to the Department of Biomedical Ethics (http://square.umin.
ac.jp/CBEL/index.html). The Center is funded by aministry grant and is aimed to provide educational opportunities both to students and healthcare professionals
outside the university. The Center holds 10 faculty positions and has started several public activities as of
October 2003. In July 2003, an international collaboration resulted in a joint symposium with Case Western
Reserve University (Clinical Bioethics: A Starting Pointfor Dialogue: A proposal for an Intercultural Exchange
Between Japan and the United States).
Specific research topics include;
1) Study of methods for promoting social consensus
on topics related to advanced medical technology
2) Study of the function and responsibilities of ethics
committees in Japan
3) Acceptability of advance directives in Japanesesociety4) Development of evaluative methods for biomedical
ethics education
5) Ethical and psychosocial aspects of living relatedorgan transplantation
6) Publication of a medical ethics case book for Japan
7) Comparative study of clinical ethics in the Asian
region8) Historical analyses for the term “bioethics” in theJapanese context
Department of Health Promotion Sciences
The main research activity of the Department of
Health Promotion Sciences is making health policy
proposals concerning health promotion in the community and work place through experimental and survey
research. The main research fields are health behavior
and life-style related disease. The main focus of healthbehaviors are physical activity including exercise, diet

322

and nutrition, and obesity. Our department is providing
lectures and practical training with the aim of helping
students to understand the method of planning, implementation and evaluation of the health promotion programs in the community and work place.
Specific research topics include;1) Development of effective health promotion programs2) Assessment of and supporting methods for healthbehavior, and the impact on health status
3) Short and long term effects of behavior change
4) Influence of behavior change on medical costs, andcost effectiveness analysis
5) Determinants in the social and physical environment on the adherence to behavior change
6) Survey of health promotion resources in the community and at the work place
7) The development of a physical activity questionnaire for the Japanese8) Multiple risk factors and health behavior
9) Glycemic index as a tool for nutritional education
10) Dietary patterns among overweight men andwomen

References
1. Lee JS, Kawakubo K, Inoue S, Akabayashi A. Effect of β3-Adrenergic receptor gene polymorphism
on body weight change in middle-aged, overweight
women. Environ Health Prev Med 2006; 11(3):69-74.
2. Akabayashi A, Slingsby BT, Takimoto Y. Conflictof interests: A Japanese perspective. Cambridge
Quarterly of Healthcare Ethics. 2005; 14:277-280.
3. Sato H, Akabayashi A, Kai I. Public Appraisal of
Government Efforts and Participation Intent in
Medico-ethical Policymaking in Japan: A large
scale national survey concerning brain death andorgan transplant. BMC Medical Ethics. 2005;
6(1):1.
4. Matsui K, Kita Y, Ueshima H. Informed consent,
participation in, and withdrawal from a population-based cohort study involving genetic analysis.
Journal of Medical Ethics 2005; 31:385-92.
5. Slingsby BT, Akabayashi A. Live organ-donation
for islet transplantation. Lancet 2005; 366:26-27.

6. Sato H, Akabayashi A. Bioethical policy making
for advanced medical technologies: Institutional
characteristics and citizen participation in eight
OECD countries. Review of Policy Research 2005;
22(4):571-587.
7. Kawakubo K, Lee JS. Nine self-help groups after
12 week walking program at a community based
health promotion center. Walking Research 2005;
9: 11-13 (in Japanese).
8. Kawakubo K, Lee JS. Lifestyle related disease andexercise: hypertension, dyslipidemia, diabetes mellitus and obesity. Journal of Clinical Rehabilitation
2005; 14(9): 836-841 (in Japanese).
9. Kawakubo K, Lee JS. Incidence of sudden death.
Nippon Rinsho 2005; 63(7): 1127-1134 (in Japanese).
10. Kawakubo K, Lee JS. From fast sports to slow
sports. Japanese Journal of Physical Fitness andSports Medicine. 2005; 54(1): 42-43 (in Japanese).
11. Kawakubo K, Lee JS. Supporting health promotion
for patients with lifestyle related disease. Japanese
Journal of Health Promotion 2005; 7(1): 63 (inJapanese).
12. Akabayashi A, Slingsby BT, Kai I, Nishimura T,
Yamagishi A. The development of a brief and objective method for evaluating moral sensitivity andreasoning in medical students. BMC Medical Ethics 5(1), 2004. (http://www.biomedcentral.com/
1472-6939/5/1)
13. Akabayashi A, Slingsby BT, Fujita M. The first
donor death after living-related liver transplantationin Japan. Transplantation 77:634, 2004.
14. Slingsby BT, Nagao N, Akabayashi A. Administrative legislation in Japan: guidelines on scientificand ethical standards. Cambridge Quarterly of
Healthcare Ethics 13:245-253, 2004.
15. Fujita M, Slingsby BT, Akabayashi A. Three patterns of voluntary consent in the case of adult toadult living related liver transplantation in Japan.
Transplantation Proceedings 36:1425-1428, 2004.
16. Lee JS, Kawakubo K, Kashihara H, Mori K. Effectof long-term body weight change on the incidenceof hypertension in Japanese men and women. Int J
Obes Relat metab Disord 2004; 28(3): 391-395.
17. Amano Y, Kawakubo K, Lee JS, Tang AC, Sugiyama M and Mori K. Correlation between dietary
glycemic index and cardiovascular disease risk

323

factors among Japanese women. Eur J Clin Nutr
2004; 53: 473-478.
18. Tamura M, Lee JS, Haga H, Kashihara H. How tomodify life-style after automated multiphasic
health testing and services. Health Evaluation andPromotion 2004; 31(6): 67-69 (in Japanese).

Health Sciences and Nursing
2. Nursing Sciences

26

326

Department of Nursing
Administration / Advanced
Clinical Nursing
Professor
Katsuya Kanda, R.N., P.H.N., Ph.D.

Associate
Minako Sasaki, R.N., P.H.N., M.S.N.
Yukie Takemura, R.N., P.H.N., M.S.N.
Hideyuki Kobayashi, R.N., P.H.N., B.S.N.
Ayako Nagata, R.N., P.H.N., M.S.N.

Homepage http://nurs-adm.m.u-tokyo.ac.jp/2004activities.htm
Introduction and Organization
Nursing Administration department provides broad
opportunities to learn about societal issues related tonursing education, nursing ethics, nursing administration, and safety and quality issues in nursing.
Advanced Clinical Nursing department provides 1)
critical analysis and synthesis of conceptual frameworks, nursing theories and models for advanced practice, and 2) generation and utilization of evidence related to practice, understanding of clients, and fundamental skills.
As we expect much of the graduates to develop theirprofessional carriers in various settings, we are constantly exploring new issues to make students be able totake wide and long viewpoints.

Teaching activities
A. Graduate courses
1. Nursing Administration 1 (2 credits, Lecturers)
Prof. Kanda and Affiliates
Exploration of political and administrative functional role in nursing. The course offers criticalanalysis of theories in nursing administration re-lated to quality assurance/ improvement and costeffective/efficient care delivery systems. Discussions include concepts and structures in organization, decision/policy making process, and application of management theory and nursing process tonursing administration. Theory and practice innursing education is also explored.
2. Nursing Administration 2 (2 credits, Lecturers)
Prof. Kanda and Affiliates
Studies on application of management theory tonursing administration. Focuses are on 1) issues innursing management such as budgetary management, nursing informatics, patient classification
systems, staffing, and quality improvement, and 2)
issues in staff management such as staff development and continuing education. Students will learn
concepts and skills essential to solving economic
issues in health care and nursing to meet professional demands in the complexity of health caresystems.
3. Advanced Clinical Nursing 1 (2 credits , Lecturers)
Prof. Kanda and Affiliates
An overview on models and theories in nursing,conceptual frameworks in nursing research, andclients' potential and actual physiological and psy-

327

chosocial responses to health problems. Focuses
are on 1) conceptual frameworks of clients' potential and actual physiological and psychosocial responses to health problems, 2) health assessment
skills in nursing practice, 3) measurement of clients' health and nursing intervention outcome. Students will establish their own theoretical knowledge and practical skills essential to advanced
clinical nursing.
4. Advanced Clinical Nursing 2 (2 credits, Lecturers
and practice)Prof. Kanda and Affiliates
This course explores issues related to advanced
clinical practice, research, and education with anemphasis on specific theoretical perspectives,
methodologies, practice and economic implications.

4.

5.

6.
B. Undergraduate Courses
1. First Aid & CPR (1 credit Lecturers & practice)Prof. Kanda and Affiliates
Students will understand the EMS (Emergency
Medical Services) system and learn how to act inemergency situations. The practicum includes following subjects; 1) observation and measurementof vital signs, 2) first aid to the victim with bleeding, intoxication, or burn, 3) how to carry an injured person, and 4) CPR (cardiopulmonary resuscitation).
2. Fundamental Nursing 1 (2 credits, Lecturers)
Prof. Kanda and Affiliates
This course offers fundamental knowledge of nursing, such as history and theory in nursing, conceptsof professional nursing practice, nursing service
and care delivery systems, nursing administration,and nursing education. Discussions include contemporary challenging issues and future strategies
in nursing.
3. Fundamental Nursing 2 (2 credits, Lecturers)
Prof. Kanda and Affiliates
This course offers fundamentals in understanding
interpersonal relationships and assessing clients'
health. Students will learn 1) theory and practice incommunication, 2) knowledge necessary for identifying health problems and care priorities, 3) skills
essential to health assessment, 4) nursing process
and nursing diagnosis, and 5) current ethical issues

7.

8.

in nursing and health.
Fundamental Nursing 3 (4 credits, Lecturers andlaboratory practicum)
Prof. Kanda and Affiliates
This course provides theory and practice of fundamental nursing skills, which are essential to providing clients with: 1) safe and effective care environment, 2) physiological and psychosocial integrity, and 3) health promotion and maintenance.
Clinical Practicum in Fundamental Nursing (2credits, practice)Prof. Kanda, Staffs and Affiliates
Under instructors' supervision, students have opportunity to apply their fundamental knowledge
and skills of nursing in a variety of settings. Students will assess clients' health and needs throughapplication of nursing process.
Nursing Administration (1 credit, Lecturers)
Prof. Kanda and Affiliates
This course prepares students for nurse administrators/managers of all types of health care settings
such as institutions, organizations, community andpolitics. Students will learn fundamental theory andpractice in nursing administration/management
through analyzing current issues in health care andnursing.
Nursing Administration Practicum (1 credit, practice)Prof. Kanda and Staffs
Students have administrative/management practicum in units or divisions in hospitals. Students willlearn care delivery systems such as staffing and patient classification systems, nursing informatics,
and budgetary issues including cost effectivenessand quality improvement.
Nursing Research (2 credits, Lecturers)
Prof. Kanda and Affiliates
This course offers examples of nursing research invarious settings. Students will learn fundamentals
of identifying problems for nursing research,measures taken, methods of quantitative/qualitative
data collection and analysis, and reviewing research articles in nursing and health.

Research activities
Nursing research starts with an approach to address a328

variety of complex problems related to health experience of human beings' daily life. Philosophical orientations and research methodologies may include naturalscientific (or biomedical, quantitative, statistical) approaches, or social and human scientific (or narrative,
qualitative) approaches, or combination of both approaches.
1. Issues of Nursing Administration
Critical analysis and international comparative
study of administrative, socioeconomic and political issues in contemporary nursing. Focuses are on1) patient classification systems and nursing caredelivery systems, 2) cost-effectiveness of nursing
services, 3) nursing case management, and 4) nursing policy and strategies to meet the professional
demands.
2. Quality Improvement, Safety Issues, and Risk
Management in Nursing
This work examines 1) quality of nursing care, 2)
outcome management for nursing practice, 3) risk
management in acute care settings, 4) occupationalsafety and health of health care workers, and 5) infection control.
3. Physiological and Psychological Human Responses
to Stimulus
This area of study aims at exploring the nature, or
determining various effects of physiological andpsychological stimulus to participants' physiological bio-information and psychological measurements. Research scenarios include; 1) patient' daily
activities, 2) caregivers' workload and sleep deprivations, or 3) nurses focus of attention, eye movement, and electroencephalography activities. Data
collections take place through field studies or laboratory/experimental settings.
4. Nursing Assessment and Intervention
Exploration of structure of existing discipline anddevelopment of new nursing theories in clinicalpractice. Emphases are on 1) explorations of structure of nursing theories and models in nursing, 2)
development of clinical and scholarly knowledge
for the identification of health problems and assessment of care priorities, and 3) testing hypotheses effective for nursing interventions
5. Studies of Nursing Education
Exploration of nursing education systems and func-

tional roles of professional nurses in various settings in advanced countries and developing countries as well. Higher education for the advanced
practice nurses in Japan is also explored.

References
1. Kawana N, Ishimatsu S, Matsui Y, Tamaki, S,
Kanda K. Chronic Posttraumatic Stress Symptoms
in Victims of Tokyo Subway Sarin Gas Attack.
Traumatology 2005;11(2):87-102.
2. Kondo A, Kanda K, Isokawa Y, Nishibayasi K,
Nanpo S, Kadowaki R, Anai K, Mibu Y. The relationship between hip fracture patients' post-operative days to initiate rehabilitation activities andtheir ambulatory ability on post-operative day 20.
Journal of Orthopaedic Nursing. 2005;9(3):146155.
3. Zhao H, Kanda K. Testing psychometric propertiesof the standard Chinese version of the European
organization for research and treatment of cancer
quality of life core questionnaire 30 (EORTCQLQ-C30). Journal of Epidemiology 2004; 14(6):193-203.
4. Takemura Y：Cultural traits and nursing care particular to Japan. In: de Chesnay M. (ed.) Caring for
the Vulnerable: Perspectives in Nursing Theory,
Practice, and Research. Boston: Jones and Bartlett
Publishers, Inc.; 2004. Chapter 24, p. 235-43.

329

Department of
Adult Nursing / Terminal andLong-term Care Nursing
Professor
Keiko Kazuma, R.N., Dr.Hlth.Sci.
Lecturer
Masako Kawa, R.N., Dr.Hlth.Sci.
Associate
Mitsunori Miyashita, R.N., M.Hlth.Sci.
Naomi Ito, R.N., Dr.Hlth.Sci.

Homepage http://www.adng.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Adult Nursing / Terminal andLong-term Care Nursing originated as the “Departmentof Adult Health” in the School of Health Sciences(1965-1992), later becoming the “Department of Adult
Health and Nursing” in the School of Health Sciences& Nursing (1992-).
From 1995 to 1997, the Graduate School of Medicine
shifted to a Graduate School chair system, and our two
newest departments were established. The members ofthese two departments cooperate in educational andresearch projects.

Teaching activities
In undergraduate courses, our departments have thechair of Lecturer and school- and hospital-based practicums in adult nursing. In addition, our departments
have the educational responsibility of teaching students
about “disease in adult populations I and II”, which is abasic discipline for adult nursing.
In graduate courses, the two departments cooperatein education and research. In particular, during the firstterm of the doctoral course (master’s course), in which
students learn basic research skills, the focus is on theeffective and efficient management of both fields.
Graduate students prepare their dissertations
by developing research question from their own
scientific interests or by participating in departmental projects. Since we consider that theprocess itself is a part of the educational trainingof researchers, we focus our energy on seminars
for developing master’s and doctoral theses.

Research activities
Our department conducts research on adult nursing
from various points of view. One such perspective focuses on the course of a disease, in which not only theperiods of recovery and terminal treatment but also the
upstream preventive steps, before disease onset, areassessed with the chronic phase in the center; therefore,such nursing comprises an extremely wide range of
periods of practice. We have been conducting studies
which are expected to allow us to understand the stateof individuals who require nursing in those periods, andinvestigations on effective and efficient nursing care for330such individuals.
Another theme regarding nursing systems is how
care should be provided for individuals in the most appropriate ways. We have been investigating how nursing should be provided, and the continuity of nursing
care in various settings, such as outpatient clinics, athome, and in palliative care facilities, by focusing on
individuals before disease onset, in the chronic phase,in the recovery period, and in the terminal period. We
consider that it is essential to eliminate and/or improvethe difficulties nurses in these settings must confront,
since they are associated with the improvement of care;
therefore, such issues have also been investigated.
Furthermore, one of our research themes is the development of evaluation measures and scales, which arerequired in such studies.
Herein, we describe our current research areas. You
may refer to our homepage for more information, suchas the details of our research achievements, and the acquisition of research funds. The resources that havebeen developed in our research, such as evaluation
scales, are freely available to the public via our homepage. It is our intention that these “research resources”
will be widely utilized.
1) Nursing for Patients with Chronic Illnesses
It is necessary for individuals with chronic illnesses
to conduct self-management for symptom control intheir daily lives. Nursing has the important role of supporting patients to maintain their lifestyle by continuingself-management in their daily life.
We have developed various instruments for measuring the difficulties that patients with chronic illnesses
experience in their daily lives, and have described actual situations of difficulties using these instruments.
Furthermore, we have conducted a study regarding
support for controlling symptoms in order to reducesuch difficulties.
The summaries of these studies, including some theses in preparation for publication, are briefly described
below.
Diabetes Focusing on the effects of drinking behavior on blood sugar control, we examined patients’ actual
drinking behaviors and the related factors. We havedeveloped a scale for eating behaviors associated with
QOL, and investigated the QOL-associated factors. We
have conducted a randomized clinical trial (RCT) for an

efficacy verification and economic evaluation of nursing support (individual nursing consultation) for the
improvement of blood sugar control in collaboration
with the Department of Diabetes and Metabolic Diseases at the University of Tokyo Hospital.
Inflammatory intestinal diseases: As ulcerative colitis(UC) and Crohn’s disease (CD) occur in young patients,
and tend to relapse, long-term support for symptom
control is required. We have developed a scale for assessing perceptions of daily life difficulties among UC
patients, investigated the factors associated with thedifficulties, and obtained suggestions for reducing suchdifficulties. Regarding CD, a one-year follow-up investigation was conducted with a focus on eating habits asa factor associated with relapse.
Bone and joint diseases: Regarding chronic rheumatoid arthritis, we investigated patients’ actual practice of
exercising at home for symptom control and related
factors. Regarding coxarthrosis (hip osteoarthritis), we
described the QOL and difficulties experienced by patients who did not have operations, and investigatedassociated factors. Currently, we are conducting a survey on a wider range of subjects, including patients
who had operations.
Physical activities of the elderly: We have developed
and verified the validity and reliability of a Japaneseversion of a physical activity measurement scale thatwas developed in the United States. This study was
conducted as a part of a Japan and Korea collaboration
with contributions from members of the Seoul National
University. Using this scale, the actual condition ofphysical activities of Japanese elderly was described,
and related factors were identified.
2) Promotion of Patients’ Adaptation following Gastrointestinal Surgeries
Resection and reconstruction of gastrointestinal tracts
are the main procedures used in cancer treatment, andare also used for other diseases, such as UC. A postoperative problem is the occurrence of physical impediments due to resection and reconstruction. The role ofnurses includes supporting patients’ adaptive behaviors
following a surgical procedure, and attempting to reduce the physical impediments the patients experience
as much as possible.
We have developed a scale for assessing the life-stability perceptions of life stability in patients, who re-331quired a permanent stoma due to cancer. We suggested
that the factors improving the perceptions of stability
included “frequency of visits to stoma care outpatient
clinics,” and “receiving support from nurses.” We are
currently conducting a longitudinal study regarding thelife-stability perceptions of individuals with stoma using this scale.
For patients with UC, during internal medical treatment, intake of lipids is limited. Since the limitation
becomes unnecessary after total extirpation of the large
intestine, the possibility of excess intake of lipids due toextreme changes in diet, and development of symptoms
due to the surgery emerge; however, no investigation
had been conducted on these issues. Therefore, we
conducted a detailed patient survey regarding diet,postoperative symptoms, and coping behaviors (eating
behaviors to reduce symptoms) following total extirpation of the large intestine.
3) Nursing for Recipients and Donors in Advanced
Medicine (organ transplantation)
In a transplantation therapy in advanced medicine,both recipients and donors experience various difficulties, which have not been observed in conventional
medicine. Reduction of such difficulties is also important in nursing. The University of Tokyo Hospital is a
medical facility that provides one of the highest levelsof treatment in living donor liver transplantation andbone marrow transplantation in the world. Therefore,
we are currently conducting the following studies on
cases at the hospital:
We have described the QOL of patients who underwent adult living donor liver transplantation, and theexperiences of donors before and after transplantation.
In addition, we initiated a study regarding difficulties in
the chronic stage following bone marrow transplantation and support for reducing such difficulties.
4) Nursing Care System for Outpatients
Recently, the role of nursing in hospital outpatientcare and home care has changed dramatically due to thedecrease in the duration of hospitalization, the increaseof chronic diseases, and the increase of the elderly
population. In the field of adult nursing, we focus on
consultation and guidance in outpatient care in order tosupport self-management of chronic diseases. We have
performed a nation-wide survey, and have been con-ducting educational activities regarding the promotionof nursing activity in outpatient care.
Regarding diabetes, which is predicted to rapidly increase in prevalence in the near future, we have clarified the current prevalence and problems regarding
nursing support in outpatient clinics across Japan. We
have also established protocols for consultation andguidance in outpatient care, and are promoting them foruse in medical facilities across Japan.
Regarding HIV/AIDS, we have been promoting collaboration on nursing support for reinforcing patients’
drug adherence with other facilities, and are attempting
to spread these consultation and guidance activities
across Japan.
5) Spiritual Pain of End-Stage Cancer Patients, andSpiritual Care
Although it has been said that end-stage cancer patients experience not only physical and psychological
pain but also spiritual pain, this field has been ignoredin modern medicine. We revealed the spiritual pain ofJapanese end-stage cancer patients based on qualitative
research. As the next step, we are attempting to develop
nursing care for spiritual pain.
6) Evaluation of Specialized Palliative Care and Quality Assurance
Palliative care services in Japan are primarily provided by palliative care teams in general wards, in palliative care units, and at home. We have conducted research on methods for evaluating palliative care services by focusing on various categories, such as symptom control and communication. We have developed aJapanese version of the STAS-J, which is an evaluation
scale developed in the U.K., and are attempting topromote its utilization. We have participated in the development of a care evaluation scale for bereaved families. Furthermore, we are conducting a survey on thecurrent status of palliative care teams, and research regarding the evaluation. We are also strongly motivated
to evaluate palliative care for patients with hematological cancers, which remain uncommon in Japan.
7) Continuity of the Palliative Care System
End-stage cancer patients receive care in generalwards, palliative care units, and at home. We have conducted a study on the preparation of a system for transi-

332

tion in the care setting. Actual research goals include
the identification of preference in care settings and related factors, and the factors that facilitate a smoothtransition from general wards or palliative units to thepatient’s home.
8) Good Death in Japan
Recently, the conceptualization of good death, which
is one of the goals of palliative care, and investigationsof the current status are being conducted in Westerncountries. We have conceptualized good death in Japanby conducting qualitative research, followed by quantitative research, on groups comprised of the generalpublic and bereaved families. Our next step is to establish intervention measures by investigating the attainment of good death and possible barriers. We also consider that it is important to provide education for thegeneral public.
9) Palliative Care at HomeA large number of patients wish to receive end-stage
care at home; however, many difficulties are involvedin the realization of such requests. Thus, it is one of themost important problems in palliative care in Japan.
We have conducted a study regarding the actual careprovided at home based on a survey of patients andtheir families, and a study that described and evaluatedthe experiences of bereaved families who attended thehome death.
10) The Field of Basic Preparation for Nursing Research
We have been continuously conducting investigations on the tasks associated with nursing researchmethodology, and the nursing terms that are the foundation for the establishment of the field of nursing.

References
1. Kazuma, K. Development and perspective of nursing in outpatient department of hospital. Japanese
Journal of Nursing 2004; 68(10): 954-8. (in Japanese)
2. Kawa, M. Studying on spirituality, spiritual pain,
and taking a step toward spiritual care. Japanese
Journal of Hospice and Palliative Care 2005; 15:368-74. (in Japanese)

3. Kawa, M. The spiritual pain of patients sufferingfrom terminal cancer and being cared for at Japanese palliative care units. Death and Life Studies
2005; Spring: 48-82. (in Japanese)
4. Miyashita M, Matoba K, Sasahara T, Kizawa Y,
Maruguchi M, Abe M, Kawa M, Shima Y. Reliability and validity of Japanese version STAS (STASJ). Palliat Support Care 2004; 2(4): 379-84.
5. Ito N, Kazuma K. Factors associated with the feeling of stability in the daily life among colostomy
patients. Jpn J Nurs Sci 2005; 2: 25-31.
6. Ito N, Tanaka M, Kazuma K. Health-related qualityof life among persons living in Japan with a permanent colostomy. J wound ostomy continence
nurs 2005; 32: 178-83.
7. Hagiwara A, Kanagawa K. Cardiovascular responses during bed-to-wheelchair transfers in frail
elderly who live at home. Geriatrics and Gerontology International 2004; 4(4): 215-22.
8. Tanaka M, Kazuma K. Ulcerative colitis: factors
affecting difficulties of life and psychological wellbeing of patients in remission. Journal of ClinicalNursing 2005; 14: 65-73.
9. Sasahara T, Miyashita M, Kawa M, Kazuma K.
Factors associated with difficulties encountered bynurses in the care of terminally ill cancer patients in
hospitals in Japan. Palliat Support Care 2005; 3(1):15-22.
10. Sasahara T, Umenai M, Shirai Y, Iwase S, Murakami T, Saito Y, Kawa M, Nakagawa K. Needs assessment prior to establishment of palliative careteam at Tokyo University Hospital: Attitude towards death and palliative care among physician
and nurses. The Japanese Journal of Hospice andPalliative Care 2005; 15(6): 669-74. (in Japanese)
11. Shibayama T, Kazuma K, Sato H. Assessment offactors affecting home exercise by rheumatoid arthritis outpatients. Jpn.J.Prim.Care 2005; 28(3):155-60. (in Japanese)
12. Shibayama T, Kobayashi K, Kazuma K. Factors
Related to Nurses' perception of outcomes ofcounseling services performed by nursing professionals in Japan for diabetic outpatients not on Insulin. Journal of Japan Academy of Diabetes Education and Nursing 2004; 8(2): 98-107. (in Japanese)
13. Kobayashi K, Kazuma K. Changes in alcohol con-

333

sumption and related factors in diabetic Japanesemen. Japan Journal of Nursing Science 2005; 2(2):95-105.
14. Kobayashi K, Kazuma K. Drinking behavior andrelated factors to excess drinking in diabetic men.
Journal of the Japan Diabetes Society 2004; 47:
141-6. (in Japanese)
15. Sato E, Suzukamo Y, Miyashita M, Kazuma K.
Development of a Diabetes Diet-Related Quality-of-Life Scale. Diabetes Care 2004; 27(6): 12715.
16. Sato E, Miyashita M, Kazuma K. Factors that influence diet-related quality of life in middle-aged
patients with type 2 diabetes. J Jpn Acad Nurs Sci
2004; 24(4): 65-73.
17. Shirai Y, Kawa M, Miyashita M, Kazuma K.
Nurses' perception of adequacy of care for leukemia patients with distress during the incurable
phase and related factors. Leukemia Research
2005; 29(5): 293-300.
18. Shirai Y, Miyashita M, Maeyama E, Kawa M, Kazuma K. The perception of nurses regarding theterminal phase of leukemia patients and factors related to it. Japanese Journal of Cancer Care 2005;
10(6): 541-5. (in Japanese)
19. Murakami Y, Okamura H, Sugano K, Yoshida T,
Kazuma K, Akechi T, Uchitomi Y. Psychologic
Distress after disclosure of genetic test results regarding hereditary nonpolyposis colorectal carcinoma. Cancer 2004; 101(2): 395-403.
20. Kato N, Shibayama T, Watanabe M, Fukuyama Y,
Ikeda K, Ogane M. et al. Study on the consultation
activities of HIV/AIDS coordinator nurses at theoutpatient department Part 1. Time of activities andrelated factors. The Journal of the Japan Academyof Nursing Administration and Policies 2004; 8(1):23-33. (in Japanese)
21. Kato N, Shibayama T, Watanabe M, Fukuyama Y,
Ikeda K, Ogane M. et al. Study on the consultation
activities of HIV/AIDS coordinator nurses at theoutpatient department Part 2. Types of activities
and actions. The Journal of the Japan Academy of
Nursing Administration and Policies 2004; 8(1):34-42. (in Japanese)
22. Misawa T, Imamura Y, Shirai Y, Hasada T, Ozawa
T, Ashiya T, Koyama C, Maeyama E, Kawa M.
Spiritual care provided by health care professionals

in palliative care settings. Japanese Journal for
Clinical Thanatology 2005; 10(1): 8-17. (in Japanese)
23. Morita T, Kawa M, Honke Y, Kohara H, Maeyama
E, Kizawa Y, Akechi T, Uchitomi Y. Existential
concerns of terminally ill cancer patients receiving
specialized palliative care in Japan. Support Care
Cancer 2004; 12: 137-40.
24. Morita T, Hyodo I, Yoshimi T, Ikenaga M, Tamura
Y, Yoshizawa A, Shimada A, Akechi T, Miyashita
M, Adachi I. Association between hydration volume and symptoms in terminally ill cancer patientswith abdominal malignancies. Annals of Oncology
2005; 16(4): 640-64.
25. Morita T, Shima Y, Miyashita M, Kimura R, Adachi I. Physician- and nurse-reported effects of intravenous hydration therapy on symptoms of terminally ill patients with cancer. J Palliat Med 2004;
7(5): 683-93.
26. Morita T, Miyashita M, Kimura R, Adachi I, ShimaY. Emotional burden of nurses in palliative sedation
therapy. J Palliat Med 2004; 18: 550-7.
27. Shoda N, Takeshita K, Seichi A, Akune T, Nakajima S, Anamizu Y, Miyashita M, Nakamura K.
Measurement of occipitocervical angle. Spine
2004; 29(10): E204-8.
28. Morita T, Hirai K, Sakaguchi Y, Maeyama E, Tsuneto S, Shima Y, Quality Assurance Committee,
Japanese Association of Hospice and Palliative
Care Units. Measuring the quality of structure andprocess in end-of-life care from the bereaved family perspective. J Pain Symtom Manage; 2004;
27(6): 492-501.

334

Department of Family Nursing
Professor
Associate Professor
Kiyoko Kamibeppu, R.N., P.H.N., Ph.D.

Lecturer
Akemi Yamazaki, R.N., R.M., P.H.N., Ph.D.

Associate
Noriko Matsui, P.H.N., M.H.S.,

Shiho Ozeki, R.N., R.M., P.H.N., M.S.

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

Research activities

This Department was established in 1992. The Japanese Association for Research in Family Nursing was
founded by this department in 1994. Currently, it has
three faculty members; an associate professor, a lecturer
and an associates.

Topics of our current research projects are as follows:
1. Psychological upset and psychological preparationof children undergoing minor surgery
2. Psychosocial factors related symptom managementof children with cancer
3. Studies of Post Traumatic Stress Disorder (PTSD)
and other late effects among survivors of childhood
cancer
4. The development of an instrument measuring thequality of life of the caregivers for children withchronic illness
5. The development of an instrument measuring thequality of life for children
6. Qualitative research to explore childbearing family
formation process
7. Postnatal depression and difficulties in childrearing
8. A study of mourning work in the family bereaved
children

Teaching activities
1. Graduate Courses, School of Health Sciences andNursing
Advanced Family Nursing I
Advanced Family Nursing II
Laboratory and/or Field Work on Family
Nursing
2. Undergraduate Courses, School of Health Sciences
and Nursing
Family Nursing
Pathophysiologic Immunology
3. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
Pediatric Nursing
4. Undergraduate Courses of Midwifery, School of
Health Sciences and Nursing
Midwifery III.

References
1. Kamibeppu K. Reconsideration of "Motherhood" incontemporary Japan. Am J Psychoanal. 2005; 65(1): 13-29.
2. Kamibeppu K, Sugiura H. The impact of mobile335

phone on the junior high-school students' friendship in Tokyo metropolitan area. Cyberpsychol
Behav. 2005; 8(2): 121-30.
3. Yamazaki A, Lee K, Kennedy H, Weiss J.
Sleep-wake cycles, social rhythms, and sleeping
arrangement during Japanese childbearing familytransition. J Obstet Gynecol Neonatal Nurs. 2005;
34(3):342-8.
4. Yamazaki A, Lee K, Kennedy H, Weiss S. Parent
chronotypes and sleeping and crying/fussing in 4-5
week infants. Sleep and Biological Rhythms. 2005;
3: 158-61.
5. Kondo K. Yamazaki Y. Living with facial disfigurement: Stigmatizing situations, coping strategies
and their influence on psychological well-being.
Japanese Journal of Health and Human Ecology.
2005; 71(4): 142-56.
6. Kamibeppu K. Clinical psychologist in General
Hospitals – Focusing on consultation-liason psychology- Japanese Journal of Clinical Psychology.
2006; 6(1): 14-9. (in Japanese)
7. Matsui N, Sugai Y. Systematic Review of Accidental Falls in Institutional Settings in Japan. Japanese
Journal of Geriatric Psychiatry. 2006; 17（1）: 65-74.
(in Japanese)
8. Hososaka Y, Hanaki H, Hayashi I, Kamibeppu K,
Sunakawa K. Epidemiological investigation ofbeta-lactam antibiotic induced vancomycin- resistant MRSA from clinical isolated MRSA-- comparison of detection rate of BIVR with or without
CZX，Kansenshogaku Zasshi. 2004; 78(8): 717-21.
(in Japanese)
9. Fukahori H, Sugai Y, Mizuno Y, Matsui N Sugishita C. Mental health and related factors of caregivers for elderly in special-care nursing home forthe aged. Japanese Journal of Public Health. 2005;
52(5）: 399-410. (in Japanese)
10. Wakimizu R, Ozeki S, Kamibeppu K. Psychological upset and its related factors of children after
leaving hospital from undergoing minor surgery,
Journal of Japan Academy of Nursing Science.
2005; 25(3): 75-82. (in Japanese)
11. Sato I, Kamibeppu K, Hoshi Y. Adolescent mourning after losing a sibling to pediatric cancer. Japanese Journal of Child and Adolescent Psychiatry.
2005; 46(1): 56-64. (in Japanese)
12. Watanabe K, Kamibeppu K. The whole experienceof mothers who have breastfed their firstborn infants for six months –Interviews at a babyfriendly-Hospital in metropolitan area-. The journalof Child Health. 2005; 64(1): 65-72. (in Japanese)
13. Kumai A， Saeki K, Shimoda K, Takahashi M,
Hyogo C, Kita S, et al. The effect of Kangaroo-Care to promote breastfeeding for mother withfull-term infants. Japanese Journal of Maternal
Health. 2006; 46（4）： 649-54．(in Japanese)
14. Asaka T, Kuroki N, Unoki K, Adachi M, Noda R,
Matsui N. Sexual activity and perceptions of sex inwomen with spinal cord injury. Japanese Journal of
Maternal Health. 2005; 45(4)： 481-8. (in Japanese).
15. Otagaki M, Yamashita M, Someya H, Mizoguchi N,
Takahashi M, Moriya M, et al. Counseling of thesex activities of the patients with colostomy, in relation to the qualification of the nurses and years ofclinical experience of the nurses. Journal of Japanese wound Ostomy and Continence Nursing Society. 2004; 8(2): 36-42. (in Japanese)
16. Osada H, Ueno R. Internet Addiction - The Japanese version of Internet Addiction Test. Japanese
Journal of Addiction and Family. 2005; 22(2):141-7. (in Japanese)
17. Osada H, Ueno R. Usability of the Japanese versionof the Internet Addiction Test (JIAT). Japanese
Journal of Addiction and Family. 2005; 22(3):269-75. (in Japanese)

336

Department ofCommunity Health Nursing
Professor
Sachiyo Murashima, D.H.S., R.N., P.H.N.

Lecturer
Satoko Nagata, D.H.S., R.N., P.H.N.

Associate
Atsuko Taguchi, M.H.S., R.N., P.H.N.

Homepage http://park.itc.u-tokyo.ac.jp/chn/
Introduction and Organization
Department of Community Health Nursing was established in June 1992. At present, there are three faculty members introduced above and 12 graduate course
students (5 in master course, 7 in doctoral course) in thedepartment. Also, we accept many visiting researchers
from other colleges and institutions.

Teaching activities
1. Undergraduate program, in the School of Health
Sciences and Nursing
1) Community Health Nursing (4 credits, lectures)
Community health nursing is a study to develop
the caring techniques and the method to evaluate
the effectiveness of care not only for a person but
also for a whole community. This class is to
study , the concepts and functions of community
health nursing, developing process of community
health nursing, community assessment and activities of community health nurses.
2) Community Health Nursing Practice (3 credits,
practice)This program is intended to understand the system of health promotion and prevention by attending the actual community health nursing ac-

tivities. Students are expected to realize the principle and the common technique of community
health nursing activities by observing the activities of public health nurses.
3) Geriatric Community Health Nursing (2 credits,
lectures)
The aim of this class is to have a deep understanding of the social context around the elderly
and the medical, health and welfare system. Also,
students attend the nursing practice at a visiting
nurse station to understand the home care.
4) Health Guidance (2 credits, lectures)This class is to study the methodology and practice of health guidance, which is the supporting
technique to promote health of the people livingin the community
2. Graduate program, in the Graduate School of
Health Sciences and Nursing
1) Advanced Community Health Nursing I (2 credits, lectures)This program is to study the health at the community-level and theory and application of thecommunity organization.
2) Advanced Community Health Nursing II (2 credits, lectures)This program is to study the research on homecare and methodology of qualitative research for337

community health nursing.
3) Advanced Community Health Nursing Seminar I,
II (4 credits)
Student participate one of the projects which encourage their study and promote their ability.
4) Field Work on Advanced Community HealthNursing I, II (4 credits)
In addition to these programs, we have department meeting (journal reading and research introduction) on every Tuesday, and monthly
seminar on every 3rd Friday.

Research activities
Our research focuses on the development and evaluation of health care programs, establishment of community health care systems, and standardization of skills of
public health nurses, in response to the health careneeds of individuals, families, aggregates and thecommunities. Research projects which are undergoingin our department are listed below.
1. Developing activity model of public health nurse
and terminology of community health nursing
We intend to standardize the terms used in community health nursing and develop the activity model
for community health nursing (primarily for publichealth nurses). Through review and brainstorming,
we will systematize the terms which explain the activity of public health nurses, develop the activity
model, and verify the validity of the model.
2. Skills of public health nurses
For the purpose of health maintenance and improvement of the community residents, publichealth nurses provide services (i.e. “personal support”) to each resident and family with healthproblems. On the other hand, they play a role todevelop new services to provide more effective andefficient support to more residents with same kindsof problems and influence the administrative decision. These activities are called “development ofprogram,” which lately had been recognized as animportant function of public health nurses. We areconducting researches to clarify the techniques
used by the public health nurse’s in program development.
3. Establishment and evaluation of community healthcare systems

The project has been designed to reform service
systems and currently being evaluated. The aroundthe-clock in-home care system and discharge planning system are examples of these researches
which are now being conducted.
Especially about the around-the-clock in-homecare system, through the model project at visiting
nurse services stations, we clarify the effects of theservices and the methods to establish the system.
Also we are developing and validating the checksheet to detect the patients who have the potential
need of visiting nurse services.
4. Expansion and enforcement of visiting nursing activities
We are conducting researches to develop and expand the field of visiting nurse services, throughthe model projects to deliver the visiting nurse services to group-homes for elderly, and to find andencourage the role of visiting nurse service stations
in rural and remote areas.
5. Support for families with babies and children
We are conducting researches covering two fields,
community health and occupational health. For
example, we compare the work-family conflicts ofworking mothers and fathers with small children inorder to reduce their stress and burden. Also, thenetwork for childrearing was investigated to avoid
child abuse.

References
1. Satoko Nagata，Marie Tabata，Hiroko Ooshima，Naomi Sumi，Sachiyo Murashima，Megumi Haruna．
Current status of discharge planning activities andsystems: National survey of discharge planning inJapan．Japan Journal of Nursing Science 2004;1(2);87-97．
2. Hiroko Ohshima, Sachiyo Murashima, Ryutaro
Takahashi. Assessments of Nursing Care for Right
Brain-damaged Stroke Patients: Focusing on Neglect and related symptoms. Nursing and Health
Sciences 2004;6;115-121.
3. Masae Ueno, Mami Kayama, Sachiyo Murashima.
How public health nurses understand mothers ofabused and neblected children: The perception of‘Shindosa’ in mothers. Japan Journal of Nursing
Science 2004;1(1);117-124.

338

4. Emiko Saito, Junko Takai, Katsuko Kanagawa,Akiko Honda, Kazuko Saeki. Changes in functional capacity in older adults living alone: A threeyear longitudinal study in a rural area of Japan.
Japanese Journal of Public Health 2004; 51(11);958-968.
5. Marshelle Thobaben, Deborah A. Roberts, Aysel
Badir, Wan Hongwei, Hiroshi Murayama，Sachiyo
Murashima，Atsuko Taguchi. Exploring Nursing
Education in The People’s Republic of China, Japan and Turkey. Contemporary Nurse 2005;19(1-2);5-16.
6. Hiroko Ohshima, Sachiyo murashima, Ryutaro Takahashi, Ayako Soyano. Neglect and Related Disorders among Right Brain –Damaged Stroke Patients: Toward Development for Japanese Versionof the Catherine Bergego Scale. Journal of Japan
Academy of Nursing Science 2005; 25(4); 90-95.
(Japanese)
7. Naomi Sumi, Sachiyo Murashima. Development ofa screening tool to predict needs of discharge planning for elderly patients upon hospital admission(Part 1). Journal of the Japanese Society on Hospital Administration 2005; 42(3);277-288. (Japanese)
8. Naomi Sumi, Sachiyo Murashima. Development ofa screening tool to predict needs of discharge planning for elderly patients upon hospital admission(Part 2) Validation of screening tool in a university
hospital. Journal of the Japanese Society on Hospital Administration 2005;42(4);479-491. (Japanese)
9. Noriko Nishikido, Atsuko Taguchi, Kiyomi Asahara, Yukiko Anzai, Masako Kageyama, Chikage
Tsuzuki, Satoko Nagata, Azusa Arimoto, Yukari
Matsuzaka, Naoko Takeuchi, Sachiyo Murashima.
Features and Directions of Group Support Practices
by Public Health Nurses –A Synthesis of Qualitative Studies for Providing a Conceptual Framework–. Journal of Japan Academy of Community
Health Nursing 2005;8(1);46-52.(Japanese)
10. Momoe Sashida, Satoko Nagata, Sachiyo Murashima. Social rehabilitation experiences of people
with a history of Hansen’s disease: Interviews ofreadmitted residents in a sanatorium. Japanese
Journal of Public Health 2005;52(2);146-157.
(Japanese)
11. Satoko Nagata, Hiroko Ooshima. Marie Tabata,
Naomi Sumi, Sachiyo Murashima, Megumi Haruna.

National survey of discharge planning in Japan: An
examination of the discharge planning system at
hospital. Journal of the Japanese Society on Hospital Administration 2004;41(4);301-310. (Japanese)
12. Kyoko Yoshioka, Kiyomi Asahara, Sachiyo Murashima. Processes and strategies for developing
public health nurse directed community health projects in municipalities of Japan -Focusing on setting agendas and making project alternatives-.
Japanese Journal of Public Health 2004;51 (4);257-271. (Japanese)
13. Hiroshi Murayama, Megumi Haruna, Sachiyo Murashima, Kyoko Yoshioka, Satoko Nagata. Factors
on Development of Community-based Activities
for Maternal and Child Health. Japan Academy ofCommunity Health Nursing 2004;6(2); 55-61.
(Japanese)
14. Atsushi Matsunaga, Satoko Nagata, Sachiyo Murashima. Implementation and perception of discharge planning by ward nurses at two special
functioning hospitals –Comparison between hospitals with and without a discharge planning department-. Journal of the Japanese Society on Hospital
Administration 2004;41(3);185-194. (Japanese)
15. Yukiko Anzai, Sumie Yoshida, Kiyomi Asahara,
Sachiyo Murashima, Noriko Sato, Taichi Sakai.
Characteristics of New Planning and Administrative Project Processes on the Practice of Public
Health Nurses in Municipalities. Japan Academy ofCommunity Health Nursing 2004;7(1);55-61.
(Japanese)
16. Atsuko Taguchi, Reiko Okamoto. Characteristics ofSupport Process by Public Health Nurses to Community Organization for the Purpose of Progressing
Health Promotion. Japan Academy of Community
Health Nursing 2004;6(2);19-27.(Japanese)

339

Department of
Psychiatric Nursing
Professor
Norito Kawakami, M.D., Ph.D.

Lecturer
Yuki Miyamoto, R.N., P.H.N., P.S.W., Ph.D.

Homepage http://plaza.umin.ac.jp/heart/
Introduction and Organization
Our department was firstly established as Department of Fourth Clinical Medical Nursing in School of
Health Care and Nursing in 1957. When the School of
Health Care and Nursing was reorganized as the Schoolof 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 result of the shift to the chairsystem of the Graduate School of Medicine in 1996,
two departments were established, Department of
Mental Health and Department of Psychiatric Nursing.
Faculty, staff, and students of two departments havebeen working cooperatively ever since.
Our department currently has two faculty members
introduced above, part-time lecturers, visiting research
fellows, 5 doctoral course students, 3 master course
students, and research associates.
Our department’s mission comprises two elements.
One is to provide education and research training inmental health and psychiatric nursing to undergraduate
and graduate students in order to prepare students toassume leadership roles in nursing clinical practice,administration, teaching, and research in this field. The
other is to conduct clinical research in the fields of
psychiatric nursing and advance knowledge and theory
through research.

All of the activities of our department are conductedin collaboration with staff members in the Departmentof Mental Health.

Teaching activities
Our department is responsible for giving lectures on
psychiatric nursing to undergraduate students. Other
than lectures, our department provides students opportunities to practice psychiatric nursing activities in several relevant facilities.
Our department is also obliged to educate graduate
students in master and doctor programs in psychiatricnursing. To accomplish this objective, our department
has a specialized lecture course on psychiatric nursing,and seminars on mental health and psychiatric nursing
for graduate students. These activities are conducted
and supervised by the faculty. In collaboration with thedepartment of mental health, we also have the department seminar every Wednesday evening, where relevant English articles are introduced by graduate students. Also, prominent guest speakers give lecturesfrom time to time in this seminar.

Research activities
Our department has many research projects acrossdiverse fields as follows: study of community support
system for the people with mental health needs; issuesof caregiver burden in family caregivers; psychiatric

340

clinical pathways; behavioral and psychological symptoms of dementia; and patient satisfaction with psychiatric services. We are conducting studies in collaboration with researchers in other institutions and universities.

References
1. Koyama T, Tachimori H, Osada H, Kurita H. Cognitive and symptom profiles in high-functioning
pervasive developmental disorder not otherwise
specified and attention-deficit/hyperactivity disorder. Journal of Autism and Developmental Disorders. In press 2006.
2. Naganuma Y, Tachimori H, Kawakami N, Takeshima T, Ono Y, Uda H, Hata Y, Nakane Y, Nakane
H, Iwata N, Furukawa TA, Kikkawa T. Twelvemonth Use of Mental Health Services in Four Areas in Japan: Finding from the World Mental
Health Japan Survey 2002-2003. Psychiatry andClinical Neurosciences. In press 2006.
3. Wada K, Satoh T, Tsunoda M, Aizawa Y, The JapanWork Stress and Health Cohort Study Group. Associations of health behaviors on depressive symptoms among employed men in Japan. Industrial
Health. In press 2006.
4. Akiyama MO, Kayama M, Takamura S, Kawano Y,
Ohbu S, Fukuhara S. A study of the burden of caring for patients with amyotrophic lateral sclerosis(MND) in Japan. British Journal of Neuroscience
Nursing. 2006; 2(1): 38-43.
5. Honjo K, Tsutsumi A, Kawakami N. What accounts
for the relationship between social class and smoking cessation? Results of a path analysis. Social
Science and Medicine. 2006; 62: 317-28.
6. Kawakami N, Takao S, Kobayashi Y, Tsutsumi A.
Effects of web-based supervisor training on job
stressors and psychological distress among workers: A workplace-based randomized controlled trial.
Journal of Occupational Health. 2006; 48: 28-34.
7. Kawakami N, Tsutsumi A, Haratani T, Kobayashi F,Ishizaki M, Hayashi T, Fujita O, Aizawa Y, Miyazaki S, Hiro H, Masumoto T, Hashimoto S, Araki S.
Job Strain, Worksite Support, and Nutrient Intake
among Employed Japanese Men and Women.
Journal of Epidemiology. 2006; 16: 79-89.
8. Kondo K , Kobayashi Y , Hirokawa K, Tsutsumi A ,Kobayashi F, Haratani T, Araki S, Kawakami N.
Job strain and sick leave among Japanese employees: A longitudinal study. International Archives ofOccupational and Environmental Health. 2006; 79:
213-9.
9. Shimazu A, Kawakami N, Irimajiri H, Sakamoto M,
Amano S. Effects of web-based psychoeducation
on self-efficacy, problem solving behavior, stressresponses and job satisfaction among workers: A
controlled clinical trial. Journal of Occupational
Health. 2005; 47: 405-13.
10. Izutsu T, Tsutsumi A, Asukai N, Kurita H, Kawamura N. Relationship between traumatic life event
and an alteration in stress response. Stress & Health.
2004; 20: 65-73.
11. Kanai C, Koyama T, Kato S, Miyamoto Y, Osada H,
Kurita H. A comparison of high-functioning atypical autism and childhood autism by Childhood Autism Rating Scale-Tokyo Version. Psychiatry andClinical Neurosciences. 2004; 58: 217-21.
12. Kayama M, Sagami A, Watanabe Y, Senoo E,
Ohara M. Child abuse prevention in Japan: an approach to screening and intervention with mothers.
Public Health Nursing. 2004; 21(6): 513-8.
13. Koyama A, Akiyama T, Miyake Y, Kurita H. Family functioning perceived by patients and their family members in three DSM-IV diagnostic groups.
Psychiatry and Clinical Neurosciences. 2004; 58:495-500.
14. Kurita H, Koyama T, Setoya Y, Shimizu K, Osada
H. Validity of childhood disintegrative disorderapart from autistic disorder with speech loss.
European Child & Adolescent Psychiatry. 2004; 13:
221-6.
15. Kurita H, Osada H, Miyake Y. External validity ofchildhood disintegrative disorder in comparison
with autistic disorder. Journal of Autism and Developmental Disorders. 2004; 34: 355-62.
16. Kurita H, Osada H, Shimizu K, Tachimori H. Bipolar disorders in mentally retarded persons with
pervasive developmental disorders. Journal of Developmental and Physical Disabilities. 2004; 16:377-89.
17. Sagami A, Kayama M, Senoo E. The relationshipbetween postpartum depression and abusive parenting behavior of Japanese mothers: a survey ofmothers with a child less than one year old. Bulle-

341

tin of the Menninger Clinic. 2004; 68(2): 174-87.
18. Ueno M, Kayama M, Murashima S. How publichealth nurses understand mothers of abused andneglected children: the perception of 'Shindosa' inmothers. Japan Journal of Nursing Science. 2004;
1(2): 117-24.

342

Department of Midwifery and
Women's HealthProfessor
Satiyo Murashima, Ph.D., R.N., P.H.N.
(Concurrent office: Community Health Nursing)

Lecturer
Megmi Haruna, Ph.D., R.N., R.M., P.H.N.
Ryoko Murayama, MS., R.N., R.M.

Associate
Etsuko Watanabe, MS., R.N., R.M., P.H.N.

Homepage http://park.itc.u-tokyo.ac.jp/midwifery/index.html
Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
Currently, it has 4 faculty members introduced aboveand 6 part-time lecturers, 3 graduate students (2 inmaster course, 1 in doctoral course), and one research
student.

Teaching activities
We teach graduate and undergraduate courses for
midwifery and maternal care, and women's health.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health 1 (2credits, lectures)
2) Advanced Midwifery and Women’s Health 2 (2credits, lectures)
2. Undergraduate Courses of Nursing, School of Health
Sciences and Nursing
1) Maternity Care and Nursing(2 credits, lectures)
2) Maternity Care and Nursing Practice(2 credits, practice)

3. Undergraduate Advanced Courses for Midwifery,
School of Health Sciences and Nursing1) Midwifery 1 (1 credit, lectures)
2) Midwifery 2 (1 credit, lectures)
3) Midwifery 4 (3 credits, lectures)
4) Administration for Midwifery(1 credit, lectures)
5) Clinical Practice of Midwifery 1(1 credit, practice)6) Clinical Practice of Midwifery 2(7 credits, practice)

Research activities
Our research activities focus on maternal-child healthcare as well as health promotion and quality of life of
women in each life cycle.
Current research projects are as follows.
1) Life style and oxidative stress during pregnancy
2) Maternal body composition during pregnancy
3) Nutrition and weight management during pregnancy and postpartum4) Quality of sleep and sleeping posture of women5) Promotion of women’s health care during postpartum.

3436) Application of the ICF (International Classificationof Functioning Disability and Health) to an assessment of quality of life among pregnant women

References
1. Murayama R, Kubota T. Study on the relationshipbetween sleeping posture and subjective sleep
quality during the menstrual cycle of healthy
women. Japanese Journal of Maternal Health 2005;
46: 53-61.
2. Murayama R, Suzuki S, Imai M, ItoY, Kaneko Y,
Watanabe Y. Tendency in social support to teenage
pregnancy and childbirth, and its problems in Japan: A literature review. Adolescentology 2005; 23:
179-89.
3. Sashida M, Nagata S, Murashima S, Haruna M.
Social rehabilitation experiences of people with ahistory of Hansen’s disease: Interviews of readmitted residents in a sanatorium. Japanese Journal of
Public Health 2005; 52:146-57.
4. Koyasu M, Haruna M, Matsuzaki M, Murashima S,
Fukuoka H, Tsukamoto H, Yoshihara H. Gestational weight gain and the 1-month postpartum
weight retention stratified by prepregnancy bodymass index. Japanese Journal of Maternal Health
2005; 46: 325-32.
5. Ueda Y, Maruo M, Ashitaka Y, Honda Y, Miyama T.
The validity of the present criteria for optimal maternal weight gain during pregnancy: changes ofmaternal and neonatal weight reevalution of the period of 15 years beginning from 1988. Adv Obstet
Gynecol. 2005;57(2):121-30.
6. Ueda Y, Maruo M, Ashitaka Y, Miyama T, Honda Y,
Nakabayashi M. Fat Mass and Total Body Water
Composition in Normal Pregnancy and Preeclampsia using Bioelectrical Impedance Analysis with
Fetal Component Weight. Adv Obstet Gynecol.
2004; 56(3):275-86.

344

Department ofGerontological Nursing
Professor
Hiromi Sanada, R.N., P.H.N., WOCN., Ph.D.

Lecturer
Etsuko Tadaka, R.N., P.H.N., Ph.D.

Associate
Atsuko Kitagawa, R.N., M.S.N.

Homepage http://www.rounenkango.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Gerontological Nursing is thenewest department of the Health Sciences and Nursing
Division of the Graduate School of Medicine, The
University of Tokyo, which was established in June
2003, and currently it has the members; a professor, alecturer, an associate, five adjunctive lecturers, three
graduate students and three research students. Our main
activity policy involves the "Practice and Developmentof Gerontological Nursing Based on Evidence" We
wish to create a society that respects the beauty of aging and recognizes it to be a joyful process in life.

Teaching activities
1.Undergraduate course
1) Gerontological Nursing (4 credits, Theory)
As for undergraduate education, our department
takes a part in systemic lectures of GerontologicalNursing for the 3rd to 4th year students. In the 3rd year,
the goal is set to comprehend the physical, psychological and social characteristics of the elderly population,and the main contents in 2004-2005 were as follows; a)Introduction to Gerontological Nursing, b) Physical,
psychological and social characteristics of the elderly,c) Legal and policy for the elderly, d)Health assess-ment and care approach of the healthy elderly, e)
Features of health and illness in the elderly, and f)
Feeding and swallowing difficulty in the elderly. In the
4th year, the goal is set to understand basic knowledge
about concept, pathology, diagnosis, treatment and careof major geriatric syndrome, and the main contents in
2004-2005 were as follows; a)Pharmacologic management in the elderly, b)Rehabilitative approach in theelderly, c)Age-related changes in the physiologic system, d)Respiratory disorders of the elderly, e)Urinary
disorders of the elderly, f) cognitive disorders of theelderly, g)cardiovascular disorders of the elderly,h)Osteoporosis of the elderly, i)Physical assessment of
the elderly, and j)Comprehensive geriatrics assessment
and care of the elderly with dementia The above lectures were developed under the cooperation by the Department of Geriatric Medicine and The University ofTokyo Hospital.
2) Clinical Practice in Gerontological Nursing (3credits, Theory )The program goal is set to develop knowledge andskills of the professional nursing care for the elderly,
especially for the elderly with dementia, in a clinicalsetting. The program was supported by The Tokyo
Musashino Hospital Affiliated with a Juridical Foundation,
The Institute of Clinical Psychiatry in 2004-2005.

3) Bachelor’s thesis

345(1) Research themes in 2004 were as follows;‘The prevention of heel pressure ulcers: Effect of vibration on blood flow’, ‘The preventable pressure ulcers and The unpreventable pressure ulcers -Wound
Ostomy and Continence Nurse’s opinion-’(2) Research themes in 2005 were as follows;’Developing the air mattress with a pressure monitoring sensor: Validity test of the sensing property anddetermination of the sensing area’, ‘Vibration increases
the skin blood flow in the auricle: Investigation using
mouse model for visualizing the microcirculation’,‘Depressive state of the elderly living alone in an urban
area’
2. Graduate course
1) Gerontological Nursing Ⅰ(2credits, Theory )2) Gerontological Nursing Ⅱ(2credits, Theory )The course program focuses on understanding anddevelopment of the practice, research, education, andperspectives in advanced gerontological nursing.
Gerontological Nursing Ⅰ offers review and criticalanalysis of recent world-wide researches around gerontological nursing. The main research in 2004 was ‘Assessing care of vulnerable elders: ACOVE project’
which was organized by RAND, USA (Wenger NS., etal., 2001) and the main research in 2005 was ‘The Nun
Study’ which was organized by NIH, USA (SnowdonD., et al.,2003). Gerontological NursingⅡprovide lectures and discussion about the recent topics aroundgerontological nursing, and main themes in 2004-2005
were as follows; a)Introduction to Geriatrics syndrome，b)Accidental fall in the elderly，c)Homebound in theelderly，d)Dementia from the inside，e)Needs at natural
disaster in the elderly，f)Social support in the elderly，g)Feeding and swallowing difficulty in the elderly，h)Pressure ulcer in the elderly.
3) Master’s thesis
A research theme in 2005 was as follows;’Bilateral Comparison Study to Evaluate a New Pressure Ulcer Preventive Dressing Containing Ceramide 2
with a Low Friction Outer Layer’Research activities
1. Activity policy
In Our main activity policy involves the "Practiceand Development of Gerontological Nursing Based on
Evidence" where we are striving to develop new nursing techniques and instruments to improve the prediction, prevention, diagnosis and treatment of the elderlywith issues of geriatric syndrome, specificallypressure ulcers, incontinence, malnutrition, pain,
depression, and dementia. Almost researches are
conducted under industry-academia cooperation. We
hope to increase physical activity and enhanceself-esteem of the elderly in order to maintain their independent lifestyles through the researches.
2. Research fields and themes
1) Development of new techniques and instruments
for wound care management for the elderly
・Risk assessment
・Preventive care・Malnutrition
・Skin care・Wound management
2) Development of care program and system for theelderly・Health promotion program for the healthy elderly/ theelderly living alone
・Preventive approach in long term care for the frail
elderly・Therapeutic care program for the elderly with dementia
・Reminiscence group care program for the elderly

References
1. Omote, S., Sugama, J., Sanada, H., Konya, C.,
Okuwa, M., Kitagawa, A.: Healing process ofpressure ulcers after a change in the nutrition regimen of bedridden elderly: A case series, Japan J of
Nursing Science, 2(2): 85-93, 2005.
2. Sanada, H., H., Nakagami G., Romanelli M.:
Clinical identification of wound infection: a Delphi
approach. In: Identifying criteria for pressure ulcer
infection. London:MEPLtd, 2005.
3. Sugama, J., Sanada, H., Nakatani, T., Nagakawa,T.,
Inagaki,M.:Pressure-induced ischemic woundhealing with bacterial inoculation in the rat,
WOUNDS, 17(7): 157-168, 2005.
4. Konya, C., Sanada, H., Sugama, J., Okuwa, M.,
Kitagawa, A.: Does the use of a cleanser on skin

346

surrounding pressure ulcers in older people promote healing?, J of Wound Care, 14(4): 169-171,
2005.
5. Sugama, J., Inagaki, M., Sanada, H. : Structuralmodel of the prognostic factors affecting healing ofpressure ulcers in elderly patients, Japanese J ofPressure Ulcers, 7(1): 115-123, 2005.
6. Okuwa, M., Sugama, J., Sanada, H., Konya, C.,
Kitagawa, A.: Measuring the pressure applied tothe skin surrounding pressure ulcers while patientsare nursed in the 30°position, J of Tissue Viability,
15(1): 3-8, 2005.
7. Konya,C., Sanada,H., Sugama,J., Kitayama,
Y.,Ishikawa,S., Togashi, H., et al.:Skin Debris andMicro-organisms on the Periwound Skin of Pressure Ulcers and the Influence of Periwound Cleansing on Microbial Flora, Ostomy Wound Management, 51(1): 50-59, 2005.
8. Tadaka,E. ： Nursing Intervention for the elderlywith dementia, International conference of Strokeand Dementia Care, 6:23-39, 2005.
9. Nagakawa,T., Sanada,H., Inagaki,M., Sugama, J.,
Ueno, K., Konishi, I., et al. :Long-term survivors
after resection of carcinoma of the head of the pancreas: significance of histologically curative resection. J Hepatobiliary Pancreat Surg, 11: 402-408,
2004.
10. Sugama, J., Sanada, H., Okuwa, M., Konya, C.,
Kitagawa, A., Tamai, N., et al.: Effectiveness of
double-layer air-cell oberlay on tangential force inhealthy young women with their head in an elevated position. Japan J of Nursing Science, 1(2):125-131, 2004.
11. Tanaka, A., Nakatani, T., Sanada, H., Kitagawa, A.,
Tanaka, S.: Histological examination of the distribution change of myofibroblasts in wound contraction. EWMA J, 4(1): 13-20, 2004.
12. Tadaka, E., Kanagawa, K.: A randomized controlled trial of a group care program for community-dwelling elderly people with dementia, JapanJ of Nursing Science, 1: 19-25, 2004.
13. Kitagawa, A., Sanada, H., Nakatani, T., Sugama, J.,
Konya, C., Okuwa, M., et al.: Histological examination of pressure ulcer tissue in terminally ill cancer patients, Japan J of Nursing Science, 1: 35-46,
2004.
14. Ohura, T., Sanada, H., Mino, Y.: Clinical activ-

ity-based cost effectiveness of traditional versus
modern wound management in patients with pressure ulcers. WOUNDS, 16(5): 157-163, 2004.
15. Queen,D., Orsted,H., Sanada,H., Sussman,G.:Adressing history. Intl Wound J, 1(1): 59-77, 2004.
16. Sanada,H., Moriguchi, T. Miyachi, Y., Ohura, T.,
Nakajo, T., Tokunaga, K., et al.: Reliability and validity of DESIGN, a tool that classifies pressure
ulcer severity and monitors healing. J of Wound
Care, 13(1): 13-18, 2004

International Health
1. International Social Medicine

27

348

Department of
Health Policy and Planning
Associate Professor
Chushi Kuroiwa, M.D., Ph.D.

Associate
Ali Moazzam

Homepage http://www.sih.m.u-tokyo.ac.jp/index-E.html
Introduction and Organization
Our planet has faced enormous challenges such asfamine, scarcity of clean water, growing number of
population, and environment degradation, which haveserious impacts on our health. International society had
hoped that the end of the cold war would prove to be aturning point; however, globalization has been gaining
huge power, showing some negative aspects as well as
benefits. The poor have been pushed farther away from
reaping its benefits. Global warming might cause
frequent storms, floods, receding glaciers, and arising
sea level; such climate change pose worrying healthrisks.
Industrialized countries have developed sophisticatedhealth policies on behalf of developing countries, yetmany issues remain when considering the sustainabilityof such projects. As one of the leading universities in
Asia, our aim is to reveal the hidden realities of healthpolicy, and provide clues to improving health situationin the developing countries through understanding theexisting health system and respecting the indigenous
culture of the country.

Teaching activities
There are the following academic courses:
1) Master Degree (Health Science) : 2 years
2) Doctoral Degree (Health Science) : 3 years
We accept any students who have bachelor degrees,

but preferably those who have some experience ofworking in developing countries and good English
ability. We have network with IMCJ (International
Medical Center of Japan), which operate various
international projects overseas.
The following are the main topics covered in theacademic year 2005;
1. Introduction, health situation in the country with
IMR 150, and community based health care forchildren: PHC, IMCI
2. The history of ODA and international health:driving force of development and anotherapproach
3. Role of NPO/NGO in International Health
4. Policy Advocacy and Roles of Civil Society
Actors – Applicability of Lessons Learnt fromODA Reform for Health Policies
5. Japanese ODA, International Health, ODA
Evaluation and monitoring
6. Public health response to bio-terrorism / Role ofinternational health by PKO
7. Green revolution
8. EPI (expanded programme on immunization) &global eradication of infectious disease
9. Health Policy, an introduction to process andpower
11. Introduction to health systems / Health planning
cycle / Health sector reforms in recent times
12. PHC and community participation

349

13. Malaria control and health policy
14. TB control and PHC, ARI
15. Infectious disease surveillance in Japan
16. Nutrition programme and health policy

Department meeting
Department meeting is held every Monday(10:00am-12:00pm), which is divided into two
sessions; 1) Journal reading and 2) Presentation ofresearch progress. Presentations of field experience are
given on ad hoc basis by guest speakers (e.g. IMCJ,
JICA experts, NPO/NGO, WHO staff etc.), visiting
researchers, students or department staff.
Below are the presentations given by guest speakers
in 2004;- Access to safe water in developing countries- Japan disaster relief- Aid coordination & harmonization: Case study in
Vietnam- A brief overview of international health education
programs- Participatory Evaluation- Human resource development for maternal health inpost-conflict countries- Maternal health in Republic of Armenia- Development study in health sector (JICA)- Geographical Information Science Approach for
health policy and planning- Reaching the poorest and making the world
equitable
etc…

Research activities
1. Evaluation of ODA (official development
assistance) and international health policy
2. Health system improvement in developing
countries
3. EPI and vaccine preventable diseases in developing
countries
4. IMCI (Integrated Management of Childhood
Illness) in developing countries
5. Community PHC: malaria prevention; hygiene
behavior in developing countries
6. HIV/AIDS, STIs control and prevention

7. Injury epidemiology in developing countries
8. Asthma epidemiology and risk factors in developing
countries
9. Reproductive health in developing countries
10. Medical wastes in developing countries

Reference (April 2004 – March 2005)
1. Kuroiwa C. Japan’s activities for an immunization
service in developing countries (in Japanese).In
Special issue on vaccine ,The Journal of Pediatric
Practice. 2004; 67 (11): 319-326.
2. Kuroiwa C, Suzuki A, Yamaji Y, Miyoshi M.
Hidden reality on the introduction of auto-disable
syringes in developing countries. South Asian J
Trop Med Public Health. 2004; 35 (4): 1019-1023.
3. Mariko Kaneko, Moazzam Ali and Hiroshi
Ushijima. Relationship between decreasing fertility
during the post-war period and maternal age in a
Japanese population. The Tohoku Journal of
Experimental Medicine. 2004; 202(3) : 221-226.
4. Moazzam Ali, Saqib Shahab, Hiroshi Ushijima,
Aime de Muynck. Street children in Pakistan: A
situational analysis of social conditions andnutritional status. Social Science and Medicine.
2004; 59(8): 1707-17
5. Moazzam Ali. Hiroshi Ushijima. Emerging role ofthe private sector in HIV/AIDS disease prevention
in Pakistan. Tropical Doctor. 2004; 34(3): 189-90
6. Moazzam Ali, Mohammad Ayaz Bhatti, Hiroshi
Ushijima. Reproductive health needs of adolescentmales in rural Pakistan- an exploratory study.
Tohoku Journal of Experimental Medicine. 2004;
204(1): 17-25
7. Moazzam Ali, Humayun Rizwan, Hiroshi Ushijima.
Men and reproductive health in rural Pakistan: thecase for increased male participation. European
Journal of Contraceptive and Reproductive Health.
2004; 9: 260-266
8. Ako Yoshinaga, Noriko Nagasaka, Moazzam Ali,
Li Luibai, Hiroshi Ushijima. Maternal and childhealth in Japan 2004. Mother’s and Children’s
Health Organization. Tokyo, Japan (Book). 2004
9. Hansman G, Kuramitsu M, (PhD), Yoshida H,
Katayama K, Takeda N, Ushijima H, Surenkhand G,
Gantulga D, and Kuroiwa C. Viral Gastroenteritis

350

in Mongolian Infants. Emerging Infectious Disease.
2005; 11(1):180-183.
10. Moazzam Ali, Hiroshi Ushijima.Perceptions ofmen on role of religious leaders in reproductive
health issues in rural districts in Pakistan. Journalof Biosocial Science. 2005; 37(1): 115-122
11. Moazzam Ali, Chiaki Miyoshi, Hiroshi Ushijima.
Emergency medical services in Pakistan: A publicprivate partnership. Public Health. 2005 (in press)
12. Moazzam Ali, Aime de Muynck. Illness incident
and health seeking behaviour among street children
in Rawalpindi and Islamabad, Pakistan - a qualitative
study. Child: care, health and development. 2005. (inpress)
13. Moazzam Ali, Masanaka Hotta, Hiroshi Ushijima.
Emergency obstetric care in Pakistan: Potential for
reduced maternal mortality through basic EmOC
facilities, services and access. The International
Journal of Gynecology and Obstetrics. 2005. (inpress)
14. Kuramitsu M, Kuroiwa C, Yoshida H, Miyoshi M,
Okurmura J, Shimizu H, Narantuya L, and
Bat-Ochir D. Non-polio enterovirus isolation
among families in Ulaanbaatar and Tov province,
Mongolia: prevalence, intrafamilial spread, and risk
factors for infection. Epidemiology and Infection
2005;133:1131-1142.
15. Aiga H, Kuroiwa C. Quantity and distribution ofcontinuing professional education opportunities
among health workers in Ghana. Journal ofContinuing Education in Nursing 2005 (in press)
16. Miyoshi M, B Phommasack, Nakamura S, Kuroiwa
C. Nutritional status of children in rural Lao PDR:
who are the most vulnerable? European Journal of
Clinical Nutrition 2005.;59:887-890.
17. Kuroiwa C. Japan’s International Cooperation in
Health in Laos. Shonika Rinsho. 2005;58:14591461.
18. Kuroiwa C. Health system towards sustainability:
vertical approach of polio eradication versus
comprehensive approach in Laos (in Japanese).
Shoni Kansensho Meneki. 2005;17 (2):125－133.
19. Ali M, Hotta M, Kuroiwa C, Ushijima H.
Emergency obstetric care in Pakistan: Potential for
reduced maternal mortality through improved basic
EmOC facilities, services, and access. Gynecology& Obstetrics 2005 (in press)

20. Phengxay P, Okumura J, Miyoshi M, Sakisaka K,
Phengxay M, Kuroiwa C. Health care waste
management in Lao PDR: A case study. Waste
Management & Research 2005; 23: 571-581.
21. Sakisaka K, Wakai S, Kuroiwa C, Cuadra Flores L,
Hanada K. Nutritional status and associated factors
in children aged 0-23 months in Granada,
Nicaragua. Public Health 2005 (in press)
22. Gai R, Huang Y, Han J, Yao Q, Kuroiwa C, Tang W.
To avoid potential threat of emerging virus diseases
for public health: An etiological review ofhuman-transmissible avian influenza. Journal ofpathogen biology 2006 (in press,).
23. Tanimura S, Kuroiwa C, Mizota T. Proposal
Symbol Mapping in R. Journal of Statistics
Software 2006;15(5):1-7.
24. Gai R, Huang Y, Han J, Yao Q, Cui S, Lou H, Qu X,
Nakata M, Kokudo N, Sugawara Y, Makuuchi M,
Kuroiwa C, Tang W: Avoid the Potential Threat ofEmerging Virus Diseases for Public Health: An
Etiological Review of Human-Transmissible Avian
Influenza. Journal of Pathogen Biology. 2006 (inpress)
25. Gai R, Han J, Huang Y, Yao Q, Qu X, Nakata M,
Kokudo N, Sugawara Y, Makuuchi M, Kuroiwa C,
Tang W: Avoiding A Human Avian Influenza
Pandemic: Improvements and Concerns in China’s
Public Health System. Journal of Health Care andSociety. 2006. (in press)

351

Department of International
Community HealthProfessor
Susumu Wakai, MD, PhD

Lecturer
Masamine Jimba, MD,PhD, MPH

Associate
Shinji Nakahara, MD
Masao Ichikawa, PhD, MPH

Homepage: http://www.ich.m.u-tokyo.ac.jp
Introduction and Organization
The department of international community healthhas been headed by three professors since 1993; Professors Gen Oi (1993-1996), Som-Arch Wongkhomthon(1996-1999), and Susumu Wakai (1999-2005).
The mission of the department is to seek equity andsocial justice in health within and across the nations.
Our aim is to bring together the clinical, public healthand social science research to address the broad issuesof pubic health in the world. The goals are to:
1. Investigate how to improve health status of the mostvulnerable people, in particular, in developing
countries,
2. Undertake research on the influences of ‘globalization’ and ‘free market’ system on health and social
development,
3. Investigate the mechanisms to reduce inequalities
between and within nations on health and development.
The organization of the department is as follows:
Professor (1), Lecturer (1), Associate (2), Visiting Lecturer (6), PhD course student (9), Master course student(11), Visiting fellow (2), Visiting scientist (16).

International Cooperation Activities
Our department has conducted a variety of international cooperation activities through JICA and nongovernmental organizations. The target countries havebeen Nicaragua, Lao PDR, Cambodia, Thailand, Vietnam, and Myanmar. In particular in Lao PDR, we haveworked together with the Ministries of Health and
Education as well as WHO, UNESCO and completed acomprehensive school health policy and its guideline ata national level.

Teaching Activities
The objectives of our teaching activities are summarized as follows.
1. Train those who are willing to work for international cooperation in future,
2. Train those who are willing to contribute to carryout research in international health,
3. Teach general students who are interested in international health.
The major topics for teaching is as follows: 1) What isinternational health? 2) Health promotion in developing

352

countries, 3) Health economics, 4) Research ethics, 5)
Project management, 6) Reproductive health.
Our department has accepted students of various
disciplines: medical doctors, nurses, co-medical workers, social scientists and others. The academic year ofMaster Course (MA, 2 years) and Doctor Course (PhD,
3 years) starts in April and ends in March every year. All
the lectures and seminars are conducted in English.

Research activities
We have carried our research by working together
with different international organizations, NGOs, universities in developing countries. The major focus ofresearch has been primary health care, health promotion,school health, health and human rights (including migrants’ health), conflict and health, injury prevention,
HIV/AIDS, tuberculosis, leprosy, etc. The target countries have been those in South Asia, South East Asia andNicaragua. The outcomes of our research are listed in
the next section.

References
1. Watanabe C, Okumura J, Chiu TY, Wakai S. Social
support and depressive symptoms among displaced
older adults following the 1999 Taiwan earthquake.
J Trauma Stress. 2004; 17:63-7.
2. Tanaka Y, Kunii O, Okumura J, Wakai S. Refugee
participation in health relief services during thepost-emergency phase in Tanzania. Public Health.
2004; 118:50-61.
3. Yanagisawa S, Mey V, Wakai S. Comparison ofhealth-seeking behaviour between poor and better-off people after health sector reform in Cambodia. Public Health. 2004; 118:21-30.
4. Miura S, Jimba M, Wakai S. Thought for food in thePhilippines. Lancet. 2004; 363: 246.
5. Poudel KC, Jimba M, Okumura J, Sharma M,
Poudel K, Wakai S. Migration in far western Nepal:
A time bomb for a future HIV/AIDS epidemic?
Trop Doct. 2004; 34: 30-1.
6. Jimba M, Nabae K, Wakai S. Avian influenza: achance to strengthen agriculture-health links. Lancet. 2004; 363:1078.

7. Fujiya R, Jimba M, Sieber NL, Wakai S. Conflictand home birth increase in the West Bank. TropDoct. 2004; 34: 116-7.
8. Sase E, Jimba M, Wakai S. Scar of Japan's leprosy
isolation policy in Korea. Lancet. 2004; 363:1396.
9. Poudyal AK, Jimba M, Murakami I, Sherchand JB,
Silwal RC, Wakai S. Community perception andreadiness for anti-helminth programmes in rural
Nepal. Trop Doct. 2004 ;34 :87-9.
10. Poudel KC, Jimba M, Okumura J, Joshi AB, Wakai
S. Migrants’ risky sexual behaviours in India and athome in far western Nepal. Trop Med Int Health.
2004; 9: 897-903.
11. Jimba M, Wakai S. Learning from low income
countries: what are the lessons?: Communities improve health systems. BMJ. 2004; 329:1183.
12. Poudel KC, Nakahara S, Okumura J, and Wakai S,
Day-care centre supplementary feeding effects onchild nutrition in urban slum areas of Nepal. J Trop
Pediatr. 2004; 50:116-9.
13. Nakahara S, Ichikawa M, Wakai S. Depiction of
tobacco use in popular children's picture books.
Arch Pediatr Adolesc Med. 2004; 158:498.
14. Nakahara S, Ichikawa M, Wakai S. Drowning
deaths among Japanese children aged 1-4 years:
different trends due to different risk reductions. Inj
Prev. 2004; 10:125-6.
15. Tsutsumi A, Izutsu T, Islam MD, Amed JU, Nakahara S, Takagi F, Wakai S. Depressive status of
leprosy patients in Bangladesh: association with
self-perception of stigma. Lepr Rev. 2004; 75:5766.
16. Poudel-Tandukar K, Nakahara S, Poudel KC, Ichikawa M, Wakai S. Traffic Fatalities in Nepal.
JAMA. 2004; 291:2542.
17. Ichikawa M, Nakahara S, Wakai S, Okubo T. Seat
belt use during pregnancy. J Trauma. 2004;
57:682-3.
18. Nakahara S, Nakamura Y, Ichikawa M, Wakai S.
Relation between increased numbers of safe playing
areas and decreased vehicle related child mortality
rates in Japan from 1970 to 1985: a trend analysis. J
Epidemiol Community Health. 2004; 58:976-981.
19. Ichikawa M, Natpratan C. Quality of life amongpeople living with HIV/AIDS in northern Thailand:
MOS-HIV Health Survey. Qual Life Res. 2004;
13:601-610.

353

20. Jimba M. Another lesson from the Japan Medical
Association. BMJ. 2005; 330: 310-1.
21. Jimba M, Waikugul J, Kojima S, Takeuchi T,
Singhasivanon P. Beyond deworming. Lancet.
2005; 365: 751.
22. Sugimoto N, Ichikawa M, Siriliang B, Nakahara S,
Jimba M, Wakai S. Herbal medicine use and qualityof life among people living with HIV/AIDS innortheastern Thailand. AIDS Care. 2005; 17:252-262.
23. Jimba M, Wakai S. South-Asian Tsunami. Lancet.
2005; 365: 933-4.
24. Poudel KC, Jimba M, Poudel-Tandukar K, Wakai S.
Lack of occupational health research in Nepal. Am J
Public Health. 2005; 95: 550.
25. Jimba M, Wakai S. School health in rural Nepal:
Why and How? Southeast Asian J Trop Med Public
Health. 2005; 36: 237-9.
26. Jimba M, Aitken IW, Silwal RC, Poudyal AK,
Wakai S. First aid kit: a challenging new tool for
traditional healers in Nepal. Trop Doct. 2005;
35:113-4.
27. Poudyal AK, Jimba M, Wakai S. Difficulties ofdoing peace-building efforts in Nepal. CMAJ. 2005;
172:1663.
28. Jimba M, Poudel KC, Wakai S. One-journal-forMedline initiative in Nepal. Bull of World HealthOrg. 2005; 83: 400.
29. Poudel KC, Jimba M, Joshi AB, Poudel-Tandukar K,
Sharma M, Wakai S. Retention and effectiveness of
HIV/AIDS training of traditional healers in far
western Nepal. Trop Med Int Health. 2005; 10:
640-6.
30. Jimba M, Poudel KC, Poudel-Tandukar K, Wakai S.
School health research in low-income countries in
East Asia and the Pacific. Japan Med Assoc J. 2005;
48:168-174.
31. Feder G, Rohde JE, Sebastian MS, Janlert U, Jimba
M et al. Reed Elsevier and the international arms
trade. Lancet. 2005; 366:889.
32. Poudyal AK, Jimba M, Poudyal B Wakai S. Traditional healers’ roles on eye care services in Nepal.
Br J Ophthalmol. 2005; 89: 1250-3.
33. Jimba M, Nomura Y, Poudel KC, Fujiya R, Wakai S.
Increase of ‘health and human rights’ research articles in Japan. Japan Med Assoc J. 2005; 48; 545-9.

34. Zheng G, Jimba M, Wakai S. Exploratory study on
psychosocial impact of the Severe Acute Respiratory Syndrome (SARS) outbreak on Chinese students already staying in Japan Asia Pac J Public
Health. 2005; 124-9.
35. Nakahara S, Ichikawa M, Wakai S. Smoking scenes
in Japanese comics: a preliminary study. Tob Control. 2005; 14:71.
36. Ichikawa M, Nakahara S, Wakai S. Lowered tuberculosis notifications and deterred health careseeking during the sars epidemic in Hong Kong.
Am J Public Health. 2005; 95:933-4.
37. Nakahara S, Chadbunchachai W, Ichikawa M, Tipsuntornsak N, Wakai S. Temporal distribution of
motorcyclist injuries and risk of fatalities in relation
to age, helmet use, and riding while intoxicated inKhon Kaen, Thailand. Accid Anal Prev. 2005;
37:833-42.
38. Nakahara S. Smoking brings another danger tochildren in Japan. Inj Prev. 2005; 11:318.
39. Ichikawa M, Nakahara S, Wakai S. Factors related
to participation in the Japan Trauma Data Bank.
JJAAM. 2005; 16:552-6.
40. Izutsu T, Tsutsumi A, Islam A, Firoz AH, Wakai S,
Kurita H. Reliability and validity of the YouthSelf-Report, Bangladesh version. Int J Methods
Psychiatr Res. 2005; 14:213-20.
41. Izutsu T, Tsutsumi A, Sato T, Naqibullah Z, Wakai
S, Kurita H. Nutritional and mental health status of
Afghan refugee children in Peshawar, Pakistan: adescriptive study. Asia Pac J Public Health. 2005;
17:93-8.
42. Tsutsumi A, Izutsu T, Sakami S, Miyazaki T, Wakai S, Kawamura N. Long-term influence ofworking abroad on returnees' mental health. J R Soc
Health. 2005; 125:281-6.
43. Izutsu T, Tsutsumi A, Islam A, Matsuo Y, Yamada
HS, Kurita H, Wakai S. Validity and reliability of
the Bangla version of WHOQOL-BREF on anadolescent population in Bangladesh. Qual Life Res.
2005; 14:1783-9.
44. Okumura J, Wakai S. Concern over localized
HIV/sexually transmitted infection epidemic duringconflict in Nepal. Trop Doct. 2005; 35:125-6.
45. Nakagawa J, Juarez J, Nakatsuji K, Akiyama T,
Hernandez G, Macal R, Flores C, Ortiz M, Marroquin L, Bamba T, Wakai S. Geographical charac-

354

terization of the triatomine infestations in northcentral Guatemala. Ann Trop Med Parasitol. 2005;
99:307-15.
46. Uetani M, Jimba M, Kaku T, Ota K, Wakai S. Oral
health status of vulnerable groups in a village of theCentral Highlands, southern Vietnam. International
J Dent Hyg. 2005 (in press).
47. Poudel KC, Jimba M, Poudel-Tandukar K, Wakai S.
Reaching hard-to-reach migrants by letters: an
HIV/AIDS awareness programme in Nepal. HealthPlace, 2005 (in press).
48. Achariya S, Yoshino E, Jimba M, Wakai S. Empowering women through a community development approach in Nepal. Community Dev J. 2005
(in press).
49. Poudel KC, Jimba M, Wakai S. AIDS and humanrights research: who is caring? Trop Doct. 2005 (inpress).
50. Poudel KC, Jimba M, Okumura J, Wakai S.
Emerging co-infection of HIV and HBV in far
western Nepal. Trop Doct. 2005 (in press).
51. Fujiya R, Jimba M, Giacaman R, Nakahara S, Ichikawa M,Wakai S. The influence of economic factors on the location of birth among Palestinian
women in Bethlehem during the second Palestinian
uprising. Trop Doct. 2005 (in press).
52. Jongsuksuntigul P, Thongthien P, Okabayashi H,
Jimba M. School health for parasite control in
Thailand: a review and current model activities.
Southeast Asian J Trop Med Public Health. 2005
( in press).
53. Jimba M, Aitken IW, Joshi AB, Ohashi T, Poudyal
AK, Wakai S. A challenge for monitoring iodine
deficiency disorders in rural Nepal. Trop Doct. 2005
(in press).
54. Uetani M, Jimba M, Niimi T, Natsume N, Katsuki T,
Xuan LTT, Wakai S. Effects of a long-term volunteer surgical program in a developing country: thecase in Vietnam from 1993 to 2003. Cleft Palate
Craniofac J. 2005 (in press).
55. Okabayashi H, Thongthien P, Singhasvanon P,
Waikagul J, Looareesuwan S, Jimba M, Kano S,
Kojima S, Takeuchi T, Kobayashi J, Tateno S. Keys
to success for a school-based malaria control program in primary schools in Thailand. Parasitol Int.
2005 (in press).

International Health
2. International Biomedical Sciences

28

356

Department of Human Genetics
Professor
Katsushi Tokunaga, D.Sc.

Associate Professor
Naoyuki Tsuchiya, M.D., D.M.Sc.

Research Associate
Jun Ohashi, D.H.Sc.
Hiroko Miyadera, D.M.Sc.

Homepage

http://www.sih.m.u-tokyo.ac.jp/departments-E.html

Introduction and Organization
The Department of Human Genetics was establishedin 1992. Currently, the department has one professor,
one associate professor, two research associates, 19
graduate students, 6 research fellows, and 7 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 are provided.
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 broadly interested in the human genome diversity, especially in the
Asian populations. Specifically, we are using genomic
research tools including SNP and microsatellite analy-

ses, as well as gene expression profiling, to better understand the genetic background of a variety of complex diseases, especially autoimmune diseases, infectious diseases and sleep disorders.
Major research projects:
1) Theoretical and experimental analyses on the genetics of complex diseases, including the development of statistical approaches for susceptibility
gene mapping in complex diseases, genomic studies for the understanding of genetic backgroundand pathogenesis of autoimmune diseases, sleep
disorders, hypertension, diabetes, as well as forhost 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) Development of methodologies for the analysis ofprotein interactions.

References
1. Chu ZT, Tsuchiya N, Kyogoku C, Ohashi J, Qian
YP, Xu SB, Mao CZ, Chu JY, and Tokunaga K:
Association of Fcγ receptor llb polymorphism withsusceptibility to systemic lupus erythematosus in
Chinese: a common susceptibility gene in the Asian
populations. Tissue Antigens 63(1): 21-27, 2004.

357

2. Miyashita R, Tsuchiya N, Hikami K, Kuroki K,
Fukazawa T, Biji M, Kallenberg C, Hashimoto H,
Yabe T, and Tokunaga K: Molecular genetic analyses on human NKG2C (KLRC2) gene deletion. Int.
Immunol. 16(1): 163-168, 2004.
3. Kyogoku C, Tsuchiya N, Wui H, Tsao BP, and Tokunaga K: Association of Fcγ receptor llA, but notof llB and lllA, polymorphisms with systemic lupus
erythematosus; A family-based association study in
Caucasians. Arthritis Rheum. 50(2): 671-673, 2004.
4. Omi K, Tokunaga K, and Hohjoh H: Long-lasting
RNAi activity in mammalian neurons. FEBS Lett.
558(1-3): 89-95, 2004.
5. Ohashi J, Naka I, Ohtsuka R, Inaoka T, Ataka Y,
Nakazawa M, Tokunaga K, and Matsumura Y: Molecular polymorphism of ABO blood group gene inAustronesian and Non-Austronesian populations in
Oceania. Tissue Antigens 63(4): 355-361, 2004.
6. Bannai M, Higuchi K, Akesaka T, Furukawa M,
Yamaoka M, Sato K, and Tokunaga K: Single- nucleotide-polymorphism genotyping for whole- genome-amplified samples using automated fluorescence correlation spectroscopy. Anal. Biochem.
327(2): 215-221, 2004.
7. Doi K, Doi H, Noiri E, Nakao A, Fujita T, and TokunagaK: High-throughput single nucleotide
polymorphism tying by fluorescent single-strand
conformation polymorphism analysis with capillaryelectrophoresis. Electrophoresis 25(6): 833-838,
2004.
8. Hase H, Kanno Y, Kojima M, Hasegawa K, Sakurai
D, Kojima H, Tsuchiya N, Tokunaga K, Masawa N,
Azuma M, Okuma K, and Kobata T: BAFF/BlyS
can potentinate B-cell selection with the B-cell
co-receptor complex. Blood 103: 2257-2265, 2004.
9. Nakajima T, Wooding S, Sakagami T, Emi M, Tokunaga K, Tamiya G, Ishigami T, Umemura S,
Munkhbat B, Jin F, Guan-jun J, Hayasaka I, Ishida
T, Saito N, Pavelka K, Lalouel JM, Jorde L, andInoue I: Natural selection and population history inthe human angiotensinogen gene (AGT): 736 complete AGT sequences in worldwide chromosomes.
Am. J. Hum. Genet. 74(5): 898-916, 2004.
10. Tajima A, Hayami M, Tokunaga K, Juji T, Matsuo
M, Marzuki S, Omoto K, and Horai S: Genetic origins of the Ainu inferred from combined DNA
analyses of maternal and paternal lineages. J. Hum.

Genet. 49(4): 187-193, 2004.
11. Ohashi J, Naka I, Patarapotikul J, Hananantachai H,
Brittenham G, Looaresseuwan S, Clark AG, andTokunaga K: Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial
selection. Am. J. Hum. Genet. 74(6): 1198-1208,
2004.
12. Sago N, Omi K, Tamura Y, Kunugi H, Toyo-Oka T,
Tokunaga K, and Hohjoh H: RNAi induction andactivation in mammalian muscle cells where Dicerand eIF2C translation. Biochem. Biophys. Res.
Commun. 319(1): 50-57, 2004.
13. Doi K, Noiri E, and Tokunaga K: The associationof NAD(P)H oxidase p22phox with diabetic nephropathy is still uncertain: Response to Hodgkinson,
Millward, and Demaine. Diabetes Care 27(6):1518-1519, 2004.
14. Tochigi M, Zhang X, Umekage T, Ohashi J, Kato C,
Marui T, Otowa T, Hibino H, Otani T, Kohda K,
Liu S, Kato N, Tokunaga K, and Sasaki T: Association of six polymorphisms of the NOTCH4 genewith schizophrenia in the Japanese population. Am.
J. Med. 128(B): 37-40, 2004.
15. Sato-Takeda M, Ihn H, Ohashi J, Tsuchiya N, Ishikawa Y, Satake M, Arita H, Tamaki K, Hanaoka K,
Tokunaga K, and Yabe T: The human histocompatibility leukocyte antigen (HLA) haplotype isassociated with the onset of postherpetic neuralgia
after herpes zoster. Pain 110: 329-336, 2004.
16. Kamio K, Matsushita I, Ohashi J, Hijikata M, Nakata K, Tokunaga K, Kudoh S, and Keicho N: Direct determination of MUC5B promoter haplotypes
based on the method of single-strand conformation
polymorphism and their statistical estimation. Genomics 84(3): 613-622, 2004.
17. Furuya T, Hakoda M, Tsuchiya N, Ichikawa N,
Nanke Y, Nakajima A, Takeuchi M, Nishinarita M,
Kondo H, Kawasaki A, Kobayashi S, Mimori T,
Tokunaga K, and Kamatani N: Immunogenetic
features in 120 Japanese patients with idiopathic
inflammatory myopathy. J. Rheumatol. 9: 17681774, 2004.
18. Sakurai D, Tsuchiya N, Yamaguchi A, Okaji Y,
Tsuno NH, Kobata T, Takahashi K, and Tokunaga
K: Crucial role of inhibitor of DNA binding/differentiation in the vascular endothelial
growth factor-induced activation and angiogenic

358

processes of human endothelial cells. J. Immunol.
173(9): 5801-5809, 2004.
19. Tachibana-Iimori R, Tabara Y, Kusuhara H, Kohara
K, Kawamoto R, Nakura J, Tokunaga K, Kondo I,
Sugiyama Y, Miki T: Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering
response to HMG-CoA reductase inhibitors. Drug
Metab. Pharmacokinet. 19(5): 375-380, 2004.
20. Akesaka T, Lee S-G, Ohashi J, Bannai M, Tsuchiya
N, Yoon Y, Tokunaga K, and Song K: Comparative
study of the haplotype structure and linkage disequilibrium of chromosome 1p36.2 region in the
Korean and Japanese populations. J. Hum. Genet.
49(11): 603-609, 2004.
21. Hitomi Y, Tsuchiya N, Kawasaki A, Kyogoku C,
Ohashi J, Suzuki T, Fukazawa T, Bejrachadra S,
Siriboonrit U, Chandanayingyong D, Suthipinittharm P, Tsao BP, Hashimoto H, Honda Z, and Tokunaga K: CD72 polymorphisms associated withalternative splicing modify susceptibility to humansystemic lupus erytematosus through epistatic interaction with FCGR2B. Hum. Mol. Genet. 13(23):2907-2917, 2004.
22. Ehara Y, Sakurai D, Tsuchiya N, Nakano K, Tanaka
Y, Yamaguchi A, and Tokunaga K: Follistatin-related
protein gene (FRP) is expressed in the synovial
tissues of rheumatoid arthritis, but its polymorphisms are not associated with genetic susceptibility. Clin. Exp. Rheumatol. 22(6): 707- 712, 2004.
23. Tsuchiya N, Kuroki K, Fujimoto M, Murakami Y,
Tedder TF, Tokunaga K, and Sato S: Association ofa functional CD19 polymorphism with susceptibility to systemic sclerosis. Arthritis Rheum. 50(12):4002-4007, 2004.
24. Okaji Y, Tsuno NH, Kitayama J, Saito S, Takahashi
T, Kawai K, Yazawa K, Asakage M, Tsuchiya T,
Sakurai D, Tsuchiya N, Tokunaga K, Takahashi K,
and Nagawa H: A novel method for isolation ofendothelial cells and macrophages from murine
tumors based on Ac-LDL uptake and CD16 expression. J Immunol. Methods 295(1-2): 183-193,
2004.
25. Ohashi J, Naka I, Patarapotikul J, Hananantachai H,
Brittenham G, Looareesuwan S, Clark AG, and Tokunaga K: Strong linkage disequilibrium of a HbEvariant with the (AT)9(T)5 repeat in the BP1 binding site upstream of the β-globin gene in Thai

population. J. Hum. Genet. 50(1): 7-11, 2005.
26. Vu HA, Xinh PT, Kikushima M, Zhu Y, Tokuhara
M, Tani M, Shimizu T, Saito K, Tokunaga K, andSato Y: A recurrent duodenal gastrointestinal stromal tumor with a frameshift mutation resulting in astop codon in KIT exon 13. Genes Chromosomes
Cancer 42(2): 179-183, 2005.
27. Hananantachai H, Patarapotikul J, Ohashi J, Naka I,
Looareesuwan S, and Tokunaga K: Polymorphismsof HLA-B and HLA-DRB1 genes in Thai malaria
patients. Jpn. J. Infect. Dis. 58(1): 25-28, 2005.
28. Katoh T, Munkhbat B, Tounai K, Mano S, Ando H,
Oyungerel G, Chae GT, Han H, Jia GJ, Tokunaga K,
Munkhtuvshin N, Tamiya G, and Inoko H: Genetic
features of Mongolian ethnic groups revealed by
Y-chromosomal analysis. Gene 346: 63-70, 2005.
29. Ohnishi Y, Tokunaga K, and Hohjoh H: Influenceof assembly of siRNA elements into RNA-induced
silencing complex by fork-siRNA duplex carrying
nucleotide mismatches at the 3'- or 5'-end of thesense-stranded siRNA element. Biochem. Biophys.
Res. Commun. 329(2): 516-521, 2005.
30. Tanaka G, Matsushita I, Ohashi J, Tsuchiya N, Ikushima S, Oritus M, Hijikata M, Nagata T, Yamamoto K, Tokunaga K, and Keicho N: Evaluation of
microsatellite makers in association studies: asearch for an immune-related susceptibility gene insarcoidosis. Immunogenet. 56(12): 861-870, 2005.
31. Kamio K, Matsushita I, Hijikata M, Tanaka G, Nakata K, Tokunaga K, Kobashi Y, Taguchi Y,
Homma S, Nakata K, Azuma A, Kudoh S, andKeicho N: Promoter analysis and aberrant expression of MUC5B gene in diffuse panbronchiolitis.
Am. J. Respir. Crit. Care Med. 171(9): 949-957,
2005.
32. Tamura Y, Sakasegawa Y, Omi K, Kishida H,
Asada T, Kimura H, Tokunaga K, Hachiya NS,
Kaneko K, and Hohjoh H: Association study of thechemokine, CXC motif, ligand 1 (CXCL1) genewith sporadic Alzheimer's disease in a Japanese
population. Neurosci. Lett. 379(3): 149-151, 2005.
33. Nakajima T, Wooding S, Satta Y, Jinnai N, Goto S,
Hayasaka I, Saitou N, Guan-Jun J, Tokunaga K,
Jorde LB, Emi M, and Inoue I: Evidence for natural
selection in the HAVCR1 gene: High degree ofamino-acid variability in the mucin domain of human HAVCR1 protein. Genes Immun. 6(5):359

398-406, 2005.
34. Satoh M, Takamiya Y, Oka S, Tokunaga K, andTakiguchi M: Identification and characterization of
HIV-1-specific CD8+ T cell epitopes presented by
HLA-A*2601. Vaccine 23(29): 3783-3790, 2005.
35. Noguchi E, Yokouchi Y, Zhang J, Shibuya K, Shibuya A, Bannai M, Tokunaga K, Doi H, Tamari M,
Shimizu M, Shirakawa T, Shibasaki M, Ichikawa K,
and Arinami T: Positional identification of anasthma susceptibility gene on human chromosome
5q33. Am. J. Respir. Crit. Care Med. 172(2): 183188, 2005.
36. Nam MH, Hijikata M, Tuan LA, Lien LT, Shojima
J, Horie T, Nakata K, Matsushita I, Ohashi J, Tokunaga K, and Keicho N: Variations of the CFTR
gene in the Hanoi-Vietnamese. Am. J. Med Genet
A. 136(3): 249-253, 2005.
37. Kuroki K, Tsuchiya N, Shiroishi M, Rasubala L,
Yamashita Y, Matsuta K, Fukazawa T, Kusaoi M,
Murakami Y, Takiguchi M, Juji T, Hashimoto H,
Kohda D, Maenaka K, and Tokunaga K: Extensive
polymorphisms of LILRB1 (ILT2, LIR1) and theirassociation with HLA-DRB1 shared epitope negative rheumatoid arthritis. Hum. Mol. Genet. 14(16):2469-2480, 2005.
38. Hara K, Horikoshi M, Kitazato H, Yamauchi T, Ito
C, Noda M, Ohashi J, Froguel P, Tokunaga K, Nagai R, and Kadowaki T: Absence of an association
between the polymorphisms in the genes encoding
adiponectin receptors and type 2 diabetes. Diabetologia 48(7): 1307-1314, 2005.
39. Van PNT, Xinh PT, Kano Y, Tokunaga K, and Sato
Y: Establishment and characterization of a novel
Philadelphia-chromosome positive chronic myeloid
leukemia cell line, TCC-S, expressing P210 and
P190 BCR/ABL transcripts but missing normal ABL
gene. Hum. Cell 18(1): 25-33, 2005.
40. Ohashi J, Naka I, Patarapotikul J, Hananantachai H,
Tangpukdee N, Looareesuwan S, and Tokunaga K:
A functional polymorphism in the IL1B gene promoter, IL1B -31C>T, is not associated with cerebral malaria in Thailand. Malaria J. 4(1): 38, 2005.
41. Kono H, Kyogoku C, Suzuki T, Tsuchiya N, Honda
H, Yamamoto K, Tokunaga K, and Honda Z:
FcγRIIB lle232Thr transmembrane polymorphism
associated with human systemic lupus erythematosus decreased affinity to lipid rafts and attenuates

inhibitory effects on B cell receptor signaling. Hum.
Mol. Genet. 14(19): 2881-2892, 2005.
42. Katoh T, Mano S, Munkhbat B, Tounai K,
Oyungerel G, Chae GT, Han H, Jia GJ, Tokunaga K,
Munkhtuvshin N, Tamiya G, and Inoko H: Genetic
features of Khoton Mongolians revealed by SNP
analysis of the X chromosome. Gene. 357(2):95-102, 2005.
43. Watanabe M, Kobayashi K, Jin F, Park KS, Yamada
T, Tokunaga K, and Toda T: Founder SVA retrotransposal insertion in Fukuyama-type congenital
muscular dystrophy and its origin in Japanese andNortheast Asian populations. Am J Med Genet A.
138(4): 344-348, 2005.
44. Tsuchiya T, Okaji Y, Tsuno NH, Sakurai D, Tsuchiya N, Kawai K, Yazawa K, Asakage M, Yamada
J, Yoneyama S, Kitayama J, Osada T, Watanabe T,
Tokunaga K, Takahashi K, Nagawa H: Targeting
Id1 and Id3 inhibits peritoneal metastasis of gastriccancer. Cancer Sci. 965(11): 789-790, 2005.
45. Omi K, Hachiya NS, Tokunaga K, Kaneko K:
siRNA-mediated inhibition of endogenous Huntington disease gene expression induces an aberrant
configuration of the ER network in vitro. Biochem
Biophys Res Commun. 338(2): 1229-1235, 2005.
46. Nishida N, Tanabe T, Hashido K, Hirayasu K, Takasu M, Suyama A and Tokunaga K: DigiTag assay
for multiplex SNP typing with high success rate.
Anal. Biochem. 346(2): 281-288, 2005.
47. Zhang X, Tochigi M, Ohashi J, Maeda K, Kato T,
Okazaki Y, Kato N, Tokunaga K, Sawa A, and Sasaki T: Association study of the DISC1/TRAX locus with schizophrenia in a Japanese population.
Schizophr. Res. 79(2-3): 175-180, 2005.
48. Doi K, Noiri E, Nakao A, Fujita T, Kobayashi S,
and Tokunaga K.: Haplotype analysis of NAD(P)H
oxidase p22 phox polymorphisms in end-stage renal disease. J Hum Genet. 50(12): 641-647, 2005.
49. Tsuchiya N, Kobayashi S, Hashimoto H, Ozaki S,
and Tokunaga K: Association of HLA-DRB1*
0901-DQB1*0303 haplotype with microscopic
polyangitis in Japanese. Genes Immun. 7: 81-84,
2005.
50. Tsuchiya N, Kyogoku C: Role of Fcγ receptor IIb
polymorphism in the genetic background of systemic lupus erythematosus: Insights from Asia.
Autoimmunity 38: 347-352,2005.

360

51. Ohashi J, Clark AG: Application of the stepwise
focusing method to optimization of the cost-effectiveness of genome-wide association study withlimited research budget for genotyping and phenotyping. Annals of Human Genetics 69: 323-328,
2005.

361

Department of Developmental
Medical Sciences
Professor
Hiroshi Ushijima, M.D., Ph.D.

Associate Professor
Hideoki Fukuoka, M.D., Ph.D.

Associate
Masaaki Oda, Ph.D.,

Shoko Okitsu, Ph.D.

Homepage
Introduction and Organization
From the scholarly point of view, the history of maternal and child health, which is the previous name ofour department, has started recently. As far as Japan isconcerned, our department, which was established a
few decades ago, is the very first one. Maternal andchild health involves all activities conducting to maintain and promote psychological and physiologicalhealth of mothers and children. The field of maternaland child health covers (1) countermeasure for infectious diseases, (2) maternal and child nutrition, (3) prevention of diseases, and (4) protection of mothers andchildren from environmental unhealthy factors.
Under the study of maternal and child health, medical care and welfare are also considered to compensate
diseases and abnormalities that cannot be prevented.
Maternal and child health services in communities are
the responsibilities of administration, however, optimal
policy making and technological development for ideal
services must fall within the scope of researches in the
study of maternal and child health.
Since 1998, the department changed to a new name,
Developmental Medical Sciences for the purpose of
expansion of research and teaching activities. Aging,
human and environment, and their related items are
newly added to our theme.

Teaching activities
1. Undergraduate course, Faculty of Medicine, Schoolof Health Science and Nursing (Lectures: all staff,
150 hr; Laboratory course: 50 hr)
1) Maternal and child health2) Growth and development
3) Aging
4) School health5) Molecular medicine for maternal and child health6) Virology7) Immunology
8) Diseases in maternity cases and in children9) Human embryology
10) Special topics in maternity cases and children11) Practicing how to care diseases in maternity
cases and in children
12) Sexual medicine and sexual education
2. Graduate course, Faculty of Medicine, School ofInternational Health Science (Lecture; 90 hr)
1) Child health2) Maternal health3) Growth and development

362

In addition to lectures and laboratory courses by ourown staff, special lectures are given by the experts both
inside and outside the University.

Research activities(1) Community health services for mothers and children(2) Studies on molecular epidemiology of infection(3) Studies on prenatal and perinatal behavior in relation to child health(4) Effects of high-rise living on physical and mental
development of children.
(5) Biochemical study of post-translational modification of glycoprotein hormones(6) Calcium and bone metabolism in puberty, during
pregnancy and puerperium and in the post-menopausal state(7) Research on statistical evaluation, sex educationand health promotion in maternal and child health(8) Immunological and molecular immunogenetical
approach to bacteria(9) Brain and development(10) Biochemical analysis of immobilization on calcium
and bone metabolism(11) Gene expression of biologically active peptide in
the human placenta(12) Antiviral agents and their mechanisms(13) Development of new diagnosis(14) HIV(15) Research on Children’s Environments(16) Mother to Child Transmission of Infection(17) Fetal origins of adult disease

References
1. Gu Y-H, Lee S, Ushijima H. A study on the needsof medical, maternal and child health care in Chinese women students at the University of Tokyo.
Tohoku J Exp Med 2004 204: 71-8.
2. Ali M, Ushijima H. Emerging role of private sector
in HIV/AIDS disease prevention in Pakistan.
Tropical Doc 2004 34(3):189-190.
3. Phan TG, Nguyen AT, Okame M, Maneekarn N,
Nishio O, Okitsu S, et al. Human astrovirus, Norovirus (GI, GII), and Sapovirus infections among

diarrheal children in Pakistan. J Med Virol 2004 73(2):256-261.
4. Hansman GS, Katayama K, Maneekarn N, Peerakome S, Khamrin P, Tonusin S, et al. Genetic diversity of Norovirus and Sapovirus in hospitalized
infants with sporadic cases of acute gastroenteritis
in Chiang Mai, Thailand. J Clin Microbiol 2004 42:
1305-7.
5. Adhikary AK, Inada T, Numaga J, Suzuki E, Ushijima H, Banik U, et al. Characterization of hexon
and fiber genes of a novel strain of adenovirus involved in epidemic keratoconjunctivitis. J Clin
Pathol 2004 57: 95-7.
6. Mueller WEG, Thakur NL, Ushijima H, Thakur AN,
Krasko A, Pennec GL, et al. Matrix-mediated canalformation in primmorphs from the sponge
Suberites domuncula involves the expression of a
CD36 recepto-ligqand system. J Cell Sciences 2004
117: 2579-90.
7. Ali M, Shahab S, Ushijima H, diMuynck A. Street
children in Pakistan. A situational analysis of social
conditions and nutritional stauts. Social Scienceand Medicine 2004 59 (8): 1707-17.
8. Huy TT, Ushijima H, Quang VX, Win KM, Luengrojanakul P, Kikuchi K, et al. Genotype C ofhepatitis B virus can be classified into at least two
subgroups. J Gen Virol 2004 85: 283-92.
9. Ushijima H, Eshita Y. Foreward: Molecular epidemiology of viral infection in Asia. Pediatr Int. 2004
46(2):202-6.
10. Okitsu-Negishi S, Nguyen TA, Phan TG, Ushijima
H. Molecular epidemiology of viral gastroenteritis
in Asia. Pediatr Int. 2004 46(2):245-52.
11. Yan H, Nguyen TA, Phan TG, Okitsu S, Li Y, Ushijima H. Development of RT-multiplex PCR assay
for detection of adenovirus, group A and C rotaviruses in diarrheal fecal specimens from children in
China. Kansensho-Zasshi 2004 78(8): 699-709.
12. Kaneko M, Ali M, Ushijima H. Relationship between decreasing fertility during the post-war period and maternal age in a Japanese population.
Tohoku J Exp Med 2004 202: 221-266.
13. Ali M, Ushijima H. Emerging role of the private
sector in HIV/AIDS disease prevention in Pakistan.
Trop Doct 2004 34(3): 189-90.
14. Ali M, Rizman H, Ushijima H. Men and reproductive health in rural Pakistan:the case for increased

363

male participation. Eur J Contracept Reprod Health
Ccare. 2004 9(4):260- 6.
15. Phan TG, Nishimura S, Okame M, Nguyen TA,
Khamrin P, Okitsu S, et al. Virus diversity and an
outbreak of group C rotavirus among infants andchildren with diarrhea in Maizuru city, Japan during 2002-2003. J Med Virol 2004 74(1):173-9.
16. Li L, Shimizu H, Doan L, Phan TG, Okitsu S, Nishio O, et al. Characterization of adenovirus type
41 isolated from children with acute gastroenteritis
in Japan. J Clin Microbiol 2004 42 (9): 4032-9.
17. Hansman GS, Doan LT, Nguyen TA, Okitsu S,
Katayama K, Ogawa S, et al. Detection of norovirus and sapovirus infection among children withgastroenteritis in Ho Chi Minh City, Vietnam Arch
Virol 2004 149(9): 1673-88.
18. Huy TTT, Ushijima H, Quang X, Ngoc TT, Hayashi S, Sata T, et al. Characteristics of core promoter
and precore stop codon mutants of hepatitis B virus
in Vietnam. J Med Virol 2004 74: 228-36.
19. Ali M, Bhatti MA, Ushijima H. Reproductive
health needs of adolescent males in rural Pakistan:an exploratory study. Tohoku J Exp Med 2004 204(1): 17-25.
20. Katayama K, Sato K, Akima H, Ishida K, Kanehisa
H, Fukuoka H. Ventilatory and cardiovascular responses to hypercapnia after 20 days of head down bed rest. Avitation, Space, and Environmental
Medicine 2004 75:312-6.
21. Akamatsu M, Tsukamoto H, Inoue K, Hayashi K,
Fukunaga T, Fukuoka H. Metabolic turnover ofbone induced by microgravity in head-down tilting
bed rest. Space Utilization Research 2004 20:1-2.
22. Ishizaki Y, Fukuoka H, Ishizaki T, Kino M, Higashino H, Ueda N, et al. Measurement of inferior
vena cava diameter for evaluation of venous returnin subjects on the 10th day of bed rest experiment. J
Appl Physiol 2004 96 (6):2179-86.
23. Kubo K, Akima H, Ushiyama J, Tabata I, Fukuoka
H. Effects of 20 days of bed rest on the viscoelastic
properties of tendon structures in lower limb muscles. Brit J Sport Ｍed 2004 38(8):324－30．
24. Kubo K, Akima H, Ushiyama J, Tabata I, Fukuoka
H. Effects of resistance training during bed rest on
the viscoelastic properties of tendon structures in
the lower limb ． Sci J Med Sci Sports 2004
14:296-302．

25. Ishizaki Y, Fukuoka H, Ishizaki T, Tanaka H, Ishitobi H. The implementation of game in a 20-day
head down tilting bed rest experiment upon moodstatus and neurotic levels of rest subjects. Acta Astronaut 2004 55:945-52.
26. Oda,M. Does high-rise living induce a psychological distortion? Architect 2004 May15; 7-10.
27. Oda,M. Children in informationoriented society.
Health Care 2004; 46(5):363-8.
28. Oda,M.. Establishing healthy environments forchildren. Health Care 2004; 46(9): 636-41.
29. Oda,M., Hanai,M. and Higurashi,M.. Health effects
of urbanization on maternal and child health.
Health Care 2004; 46(9):656-63.
30. Hotta M, Li Y, Anme T, Ushijima H. Risk factors
for low Kaup index among children in rural ethnic
minority areas of Yunnan, China. Pediatrics Int
2005 47(2): 147-153.
31. Ali M, Ushijima H. Perseption of men on role ofreligious leaders in reproductive health issues inrural Pakistan. J Biosoc. Sci 2005 37: 115-122.
32. Hien N, Ushijima H. Frequency of prenatal carevisits by ethnic minority mothers and association
with infant birth weight in Bac Kan province,
Vietnam. Tropical Doct 2005 35: 103-4.
33. Ali M, Ushijima H. Perceptions of the roles of religious leaders in reproductive health issues in rural
districts in Pakistan. J Biosocial Sciences 2005
37(1): 115-22,
34. Yagyu F, Okitsu S, Tanamoto K, Ushijima H. Determination of HIV-1 subtypes (A-D, G,
CRF01_AE) by PCR in the transmembrane region(gp41) with novel designed primers. 2005 J Med
Virol 76(1): 16-23,.
35. Oka T, Katayama K, Ogawa S, Hansman G,
Kageyama T, Ushijima H, et al. Proteolytic processing of sapovirus ORF1 polyprotein J Virol 2005
79: 7283-90.
36. Ali M, Hotta M, Kuroiwa C, Ushijima H. Emergency obstetric care in Pakistan: potential for reduced maternal mortality through improved basic
EmOC facilities, services, and access. Int J Gynecol Obstet 2005 91 (1): 105-21.
37. Phan TG, Nguyen TA, Yan H, Okitsu S, Ushijima H.
A novel RT-multiplex PCR for enterovirus, hepatitis A and E viruses and influenza A virus among
infants and children with diarrhea in Vietnam Arch

364

Virol 2005 150: 1175-85.
38. Phan TG, Okame M, Nguyen TA, Nishio O, Okitsu
S, Ushijima H. Genetic diversity of sapovirus infecal specimens from infants and children withacute gastroenteritis in Pakistan. Arch Virol 2005
150(2): 371-7.
39. Hansman GS, Natori K, Oka T, Ogawa S, Tanaka K,
Nagata N, et al. Cross-reactivity among sapovirus
recombinant capsid proteins. Arch Virol 2005
150(1): 21-36.
40. Li L, Phan TG, Nguyen TA, Kim KS, Seo JK, Shimizu H, et al. Molecular epidemiology of adenovirus infection among pediatric population with diarrhea in Asia. Microbiol Immunol 2005 49(2):1218.
41. Hansman G, Yoshida H, Kuramitsu M, Katayama H,
Takeda N, Ushijima H, et al. Viral gastroenteritis in
Mongolian infants. Emerg Infect Dis. 2005 11:
180-182.
42. Yan H, Abe T, Phan TG, Nguyen TA, Iso T, et al.
Outbreak of acute gastroenteritis associated withgroup A rotavirus and genogroup I astrovirus
among adults in a mental health care facility in Japan. J Med Virol 2005 75(3): 475-81.
43. Hansman GS, Natori K, Ushijima H, Katayama K,
Takeda N. Characterization of polyclonal antibodies raised against sapovirus genogroup five virus-like particle. Arch Virol 2005 150(7): 1433-7.
44. Phan TG, Nguyen TA, Nishimura S, Nishimura T,
Yamamoto A, Okitsu S, et al. Etiologic agents ofacute gastroenteritis among Japanese infants andchildren: virus diversity and genetic analysis ofsapovirus. Arch Virol 2005 150(7): 1415-24.
45. Wiens M, Korzhev M, Krasko A, Thakur NL,
Perovic-Ottstadt S, Breter HJ, et al. Innate immune
defense of the sponge Suberites domuncula against
bacteria involves a MyD88-dependent signaling
pathway: Induction of a perforin-like molecule. J
Bioll Chem 2005 .280(30): 27949-59.
46. Kano N, Lee S, Iwai K, Nagase T, Komatsu M,
Muraki T, et al. A trial study on gender-based violence with ecological framework in one city in Ibaraki prefecture. Ibaraki Pref. Medical Univ 2005
10: 75-84.
47. Muller WEG, Borejko A, Brandt D, Osinga R,
Ushijima H, Hamer B, et al. Selenium affects
biosilica formation in the demosponge Suberites

domuncula: Effect on gene expression and spicule
formation. FEBS J 272(15) 2005 3838-52.
48. Akihara S, Phan TG, Nguyen TA, Hansman G,
Okitsu S, Ushijima H. Existence of multiple outbreaks of viral gastroenteritis among infants in a
day care center in Japan. Arch Virol. 2005
50(10):2061-75.
49. Akihara S, Phan TG, Nguyen TA, Yagyu F, Okitsu
S, Mueller WEG, et al. Identification of sapovirus
infection among Japanese infants in a day carecenter. J Med Virol 2005 77(4): 595-601.
50. Phan TG, Nyuyen T, Shimizu H, Yagyu F, Okitsu S,
Muller WEG, et al. Identification of enteroviral infection among infants and children admitted tohospital with acute gastroenteritis in Ho Chi Minh
City, Vietnam. J Med Virol 2005 77(2): 257-264.
51. Phan TG, Nguyen TA, Kuroiwa T, Ueda Y, Nakaya
S, Nishimura S, et al. Viral diarrheal in Japanesechildren: results from a one-year epidemiologic
study. Clin Lab 2005 51: 183-91.
52. Phan TG, Nguyen TA, Yan H, Yagyu F, Kozlow V,
Kozlov A, et al. Development of a novel protocol
for RT-multiplex PCR to detect diarrheal viruses
among infants and children with acute gastroenteritis in Eastern Russia. Clin Lab. 2005 51:429-35.
53. Hien NT, Ushijima H. Frequency of prenatal carevisits by ethnic minority mothers and association
with infant birthweitht in Bac Kan Province, Vietnam. Trop Doct 2005 35(2): 103-4.
54. Takimoto H, Yokoyama T, Yoshiike N, Fukuoka H.
Increase in low-birth-weight infants in Japan andassociated risk factors,1980-2000．J Obstet Gynaecol Res 2005 31(4):314-322．
55. Kim CS, Park DH, Lee DS, Kin HS, Fukuoka H,
Igawa S. Evaluation of osteopenia induced by
2-week tail suspension in rats. J Human- Environmental System 2005 8(1):25-31.
56. Ryan L, Krishnaswamy S, Oda Mi. Culture andperception of child abuse. Child,Youth and Environmental Studies 2005; 1(1): 70-1.
57. Oda,M. Divorce in terms of maternal and childhealth proc. BK21 Intn’l Conf 2005 33-41.
58. Oda,M. Environmental problems of children andperspective in urbanized society in terms of maternal and child health. Child,Youth and Environmental Studies 2005; 1(1): 92-5.
59. Oda,M. Children’s environment in terms of growth365

and developmental medical sciences. Health Care
2005; 47(12):844-9.
60. Ali M, Miyoshi C, Ushijima H. Emergency medical
services in Islamabad, Pakistan: a public-private
partnership. Public Health 2006 120(1):50-7.
61. Huy TT, Ushijima H, Sata T, Abe K. Genome
characterization of HBV genotype E in Bolivia:
genotype F subgenotypes correlate with geographic
distribution and T(1858) variant. Arch Virol 2006
151(3):589-97.
62. Huy TT, Ishikawa K, Ampofo W, Izumi T, Nakajima A, Ansah J, et al. Characteristics of hepatitis B
virus in Ghana: full length genome sequences indicate the endemicity of genotype E in West Affica. J
Med Virol 2006 78(2):178-84.
63. Yoshinaga M, Phan TG, Nguyen TA, Yan H, Yagyu
F, Okitsu S, et al. Changing distribution of group A
rotavirus G-types and genetic analysis of G9 circulating in Japan. Arch Virol 2006 151(1):183-92.
64. Khamrin P, Peeracome S, Wongsawasdi L, Tonusin
S, Sornchai P, Maneerat Y, et al. Emergence of human G9 rotavirus with an exceptionally high frequency in children admitted to hospital with diarrhea in Chiang Mai, Thailand. J Med Virol 2006
78(2): 273-80.
65. Takimoto T, Sugiyama H, Fukuoka H, Kato N and
Yoshiike N. Maternal weight gain ranges for optimal fetal growth in Japanese women. Int J Gynecol
Obstet 2006 92(3):272-8.
66. Muller WE, Ushijima H, Batel R, Krasko A, Borejko A, Meller IM, et al. Novel mechanism for theradiation-indeuced bystander effect: Nitric oxideand ethylene determine the response in sponge cells.
Mutat Res 2006 [Epub ahead of print}
67. Phan TG, Kuroiwa T, Kaneshi K, Ueda Y, Nakaya S,
Nishimura S, et al. Changing distribution of norovirus genotypes and genetic characterization of recombinant GIIb among infants and children withdiarrhea in Japan. J Med Virol 2006 in press.
68. Phan TG, Yagyu F, Kozlov V, Kozlov A, Okitsu S,
Müller WEG, et al. Viral gastroenteritis and genetic
characterization of recombinant norovirus among
infants and children with diarrhea in Eastern Russia.
Clin Lab 2006 in press.
69. Phan TG, Yan H, Li Y, Okitsu S, Müller WEG,
Ushijima H. Novel recombinant norovirus in China.
Emerg Infect Dis 2006 in press.

70. Phan TG, Okitsu S, Müller WEG, Kohno H, Ushijima H. Identification of novel recombinantsapovirus in Japan. Emerg Infect Dis 2006 in press.

366

Department of Human Ecology
Professor
Chiho WATANABE, D. Hlth Sc.

Associate Professor
Masahiro UMEZAKI, Ph.D.

Associate
Taro YAMAUCHI, Ph.D.
Hana SHIMIZU, Ph.D.

Homepage http://www.humeco.m.u-tokyo.ac.jp
Introduction and Organization
Ex-Professor Ryutaro Ohtsuka retired in March, 2005,
who was succeeded by current Professor Watanabe in
April, 2005. Dr. Shimizu (associate) and Dr. Umezaki(associate professor) joined in May and August, 2005,
respectively. Together with Dr. Yamauchi (associate),
we have four research/teaching faculties since then.
Apart from the faculty staffs, a secretary (Ms. Tamami
AOYAGI), five doctoral candidates (including two foreign students), five master course students (including
two foreign students), and two research fellows areworking in the department. There are nine extra-university lecturers delivering lectures in either
graduate or undergraduate courses.

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, and environment. In “Human Ecology Special Lecture II”, emphases were on recent topics and ongoing researches in thefield of Human Ecology and related areas. With theseclasses for the Graduate Students, we tried to describe
Human Ecology as a basic component of International
Health, and gave examples of the recent issues thathave been dealt with and approaches used in this field.
The lectures for the Graduate Course were given in
English.
In the undergraduate course, the department is incharge of a part of the School of Health Sciences andNursing, providing the lectures on “Human Ecology”,“Environmental Health”, “Demography”, “International
Health”. We were also responsible for organizing“Pharmacology and Toxicology”, “Physiology”,“Anatomy”, as well as “Environmental Engineering/
Human Engineering”．At the undergraduate level, ouremphases were in introducing pressing global-scaleissues such as population explosion, food security, andenvironmental issues in relation to the problems that
Asia-Pacific region (including Japan) has been facing.
Another emphasis was on the relation between humanactivities and chemical contamination of the environment.

Research activities
Most of our researches fell into the field of “Environmental Health” and/or “Population biology [of human]”, and we utilized both fieldwork and experimental
approach. Most of our study fields were Asian-Oceanian rural communities, focusing on population, nutrition/growth, and environment. Experimental studies
focusing on the effects of perinatal exposures to heavy

367

metals have been conducted, emphasizing the factorsthat modify the effects. What follows is a list of major
projects conducted in the past two years.
1. Neurodevelopmental effects of perinatal exposure
to environmental chemicals:
Modern human societies, regardless developed ordeveloping, consume and are exposed to a variety ofchemical substances, which would be regarded as a
substantial part of the environment. Since often the fetus/newborn is relatively sensitive to these chemical
substances, we focused the exposure to chemicals during perinatal period. Collaborating with several institutes/universities, we have conducted studies on theeffects of heavy metals (mercury and cadmium), toxicity of which were still being debated in Japan and othercountries, as well as of so called endocrine disrupting
chemicals. Toxicity was evaluated at cellular as well asorganism levels, and major findings included susceptibility of metallothionein knock-out mice to the neurodevelopmental toxicity of metals, and demonstration ofdevelopmental neurotoxicity of low-dose of cadmium.
Another experimental study regarding the interaction
between selenium and arsenic was conducted, hinted by
our field study finding; effects of thyroid hormones aswell as mutual modification of the kinetics were found.
2. Water and air quality and health in developing
countries:
In many Asian and Latin American countries, pollution of groundwater has been a serious problem for
health. We have conducted surveys in Bangladesh,
where a large-scale groundwater contamination by arsenic pauses serious threat. We have extended this survey to Nepal, confirming our previous findings ofmales’ susceptibility to arsenic, and demonstrated themutual relationship between malnutrition and arsenic
toxicity.
In Indonesia, we have started a study on water pollution by pesticides, metals, and others, the final goal ofwhich is to evaluate the effects of contamination on
children’s health. A survey of water quality has been
conducted as the first step.
Air pollution in the developing countries is anothervexing environmental issue, especially in Asian urban
areas. Body burden of lead (Pb) in bus terminal workers
in an Indonesian city has been examined; possible

modification of body burden by nutritional status wasshown.
3. Studies on nutrition, growth, and physical activities(energetics) in developing countries:
Nutrition is one of the fundamental requirement for
health and is especially important in developing countries.
In rural Bangladesh, food consumption, nutritional
status, and activity of the villagers were examined; distinct gender-related difference was found.
In rural Western Java, Indonesia, the relationshipbetween the nutritional status during the preadolescentperiod and biological parameters at birth were analyzed.
In Tonga, where the prevalence of obesity is high, anthropometry was conducted for adolescent girls, andfactors associated with obesity were identified.
In the schoolchildren of rural China, prevalence of
the infection with schistosomiasis was examined andthe relative importance of the parasite infection andnutritional status for the physical growth of the children
was evaluated.
Physical activity and energetics are important not
only from the viewpoint of Human Ecology but also
from the prevention of lifestyle-related diseases. Our
focus has been on the energetics of the people living intheir daily life. In Papua New Guinea, it was examined
how the domestic migration from rural villages to urban
area changed the physical activity of the people. Also,
the energetics of Sumo-wrestlers were characterized.
４. Development and subsistence activity, subsistencetransition and adaptation:
In many Asian and Oceanean countries, various typesof developmental projects have been undertaken aiming
at economic development, procurement of natural resources, or accelerating tourism. Such developmental
projects brought about drastic changes in the subsistence activity of people, availability of natural resources, or ecosystem, and in turn, caused changes inlifestyle and health status, disease patterns of the people.
Attempts to describe such changes were made in China
as well as Solomon Islands. Adaptive strategy athousehold level was analyzed in China, where subsistence transition has been taking place, and possible determinant of the difference in the strategy was identified.
In some studies, Geographical Information System

368(GIS)/GPS was used for analyzing the relationship between the subsistence transition and land-use.

References
1. Andoh, S.Y., Umezaki, M., Nakamura, K., Kizuki,M., and Takano, T. (in press) Association ofhousehold demographic variables with child mortality in Cote d'Ivoire. Journal of biosocial Science.
2. Ahmad, S., Mahrajan, M., Watanabe, C. and
Ohtsuka, R. (2004) Arsenicosis in two villages in
Terai, lowland Nepal. Environmental Sciences, 11(3): 179-188.
3. Dewanti, L., Watanabe, C., Sulistiawati and
Ohtsuka, R. (2006) Unexpected chages in bloodpressure and hematological parameters among
fasting and nonfasting workers during Ramadan inIndonesia. European Journal of Clinical Nutrition
online publication, February 8.
4. Fukuda, Y. Umezaki, M., Nakamura, K. and Takano, T. (2005) Variations in societal characteristics
of spatial disease clusters: examples of colon, lungand breast cancer in Japan. International Journal of
Health Geographics, 4: 16. (Online Journal:
http://www.ij-healthgeographics.com/content/4/1/1
6)
5. Fukuyama, S., Inaoka, T., Matsumura, Y., Yamauchi, T., Natsuhara, K., Kimura, R. and Ohtsuka, R.
(2005) Anthropometry of 5-19-year-old Tongan
children with special interest in the high prevalenceof obesity among adolescent girls. Annals of Human Biology, 32(6): 714-723.
6. Fukuyama, S., Nakazawa, M. and Ohtsuka, R.
(2005) Simulating the spread of Chlamydia trachomatis infection with an individual-based stochastic model: Evaluation of the effects of approvalof low-dose oral contraceptive pill in Japan. Minzoku Eisei, Japan Journal of Health and Human
Ecology, 71(4): 157-167.
7. Furusawa, T., Pahari, K., Umezaki, M. and Ohtsuka,
R. (2004) Impacts of selective logging on New
Georgia Island, Solomon Islands, evaluated using
very-high-resolution-satellite (IKONOS) data. Environmental Conservation, 31(4): 1-7.
8. Ishitobi, H. and Watanabe, C. (2005) Effects of
low-dose perinatal cadmium exposure on tissue
zinc and copper concentrations in neonatal miceand on the reproductive development of female
offspring. Toxicology Letters, 159(1): 38-46.
9. 蒋宏（2005）作物和克服困的．广
西民族学院学，27(1).
10. Jiang, H., Umezaki, M. and Ohtsuka, R. (2006)
Inter-household variation in adoption of cash cropping and its effects on labor and dietary patterns: astudy in a Li hamlet in Hainan island, China. Anthropological Science, Published on line DOI: 10.
1537.
11. Maharjan, M., Watanabe, C., Ahmad, S. and
Ohtsuka, R. (2005) Arsenic contamination in
drinking water and skin manifestations in lowland
Nepal: The first community-based survey. American Journal of Tropical Medicine and Hygiene,
73:477-479.
12. Mori K., Yoshida K., Tani JI., Hoshikawa S., Ito S.
and Watanabe C. (2006) Methylmercury inhibits
type II 5'-deiodinase activity in NB41A3 neuroblastoma cells. Toxicol Lett. 161: 96-101.
13. Miyazaki, K., Watanabe, C., Mori, K., Yoshida, K.
and Ohtsuka, R. (2005) The effects of gestationalarsenic exposure and dietary selenium deficiency
on selenium and selenoenzymes in maternal andfetal tissues in mice. Toxicology,208:357-365.
14. Ohashi, J., Naka, I., Ohtsuka, R., Inaoka, T., Ataka,Y., Nakazawa, M., Tokunaga, K. and Matsumura, Y.
(2004) Molecular polymorophism of ABO bloodgroup gene in Austronesian and non-Austronesian
populations in Oceania. Tissue Antigens, 63: 355361.
15. Ohtsuka, R., Sudo, N., Sekiyama, M., Watanabe, C.,
Inaoka, T. and Kadono, T. (2004) Gender difference
in daily time and space use among Bangladeshi
villagers under arsenic hazard: Application of thecompact spot-check method. Journal of Biosocial
Science, 36: 317-332.
16. Perikesit, Salim, H., Triharyanto, E., Gunawan, B.,
Sunardi, Abdoellah, O.S. and Ohtsuka, R. (2005)
Multi-source water pollution in the Upper Citarum
watershed, with special reference to its spatiotemporal variation. Environmental Sciences, 12(3):121-131.
17. Sekiyama, M. and Ohtsuka, R. (2005) Significant
effects of birth-related biological factors on
pre-adolescent nutritional status among Sundanesein West Java, Indonesia. Journal of Biosocial Sci-

369

ence.37:413-426.
18. Shimizu H, Tamam M, Soemantri A, Ishida T.
(2005) Glucose-6-phosphate dehydrogenase deficiency and Southeast Asian ovalocytosis in asymptomatic Plasmodium carriers in Sumba island, Indonesia. J Hum Genet. 2005; 50(8): 420-4.
19. Sudo, N., Sekiyama, M, Watanabe, C., Bokul,
A.T.M.M.H. and Ohtsuka, R. (2004) Gender differences in food and energy intake among adult villagers in northwestern Bangladesh: A food frequency survey. International Journal of Food Sciences and Nutrition, 55: 499-509.
20. Sueyoshi, S. and Ohtsuka, R. (2004) Ineffective
contraceptive use and its causes in a natural fertility
population in southern Jordan. Human Biology, 76:
711-722.
21. Tanaka, M., Ohtani-Kaneko, R., Yokosuka, M. and
Watanabe, C. (2004) Low-dose perinatal diethylstilbestrol exposure affected behaviors and hypothalamic estrogen receptor-α-positive cells in themouse. Neurotoxicology and Teratology, 26:261-269.
22. Tanaka, M., Umezaki, M., Natsuhara, K., Yamauchi,T., Inaoka, T., Hongo, T., Nagano, M., Watanabe, C.
and Ohtsuka, R. (2005) No difference in serum
leptin concentrations between urban-dwelling Austronesians and Non-Austronesians in Papua New
Guinea. American Journal of Human Biology, 17:
696-703.
23. Umezaki, M., Jiang, H.W. and Liang, J.Y. (2005)
Transformation of human-environment relationships in Wuzhishan region, Hainan, China: 1930s
to present. PLEC News and Views, 7: 6-11.
24. Umezaki, M., Sengebau-Kinzio, J.M., Ridep, E.,
Sikyang, B., Ngiruchelbad, D., Tadao, R., Watanabe, M., Nakamura, K. and Takano, T. (in press)
Microbiological safety of ready-to-eat foods in
Republic of Palau. Pacific Health Dialog, 12.
25. Watanabe, C., Kawata A., Sudo, N., Sekiyama, M.,
Inaoka, T., Bae, M. and Ohtsuka, R. (2004) Water
intake in an Asian population living in arsenic-contaminated area. Toxicology and Applied
Pharmacology, 198: 272-282.
26. Yamauchi, T., Abe, T., Midorikawa, T. and Kondo,
M. (2004) Body composition and resting metabolic
rate of Japanese college Sumo wrestlers andnon-athlete students: Are Sumo wrestlers obese?

Anthropological Science, 112, 179-185.
27. Yamauchi, T. and Umezaki, M. (2005) Rural-urban
migration and changing physical activity among
Papua New Guinea Highlanders from the perspective of energy expenditure and time use. Environmental Sciences, 12:155-166.
28. Yoshida, M., Watanabe, C., Horie, K., Satoh, M.,
Sawada, M. and Shimada, A. (2005) Neurobehavioral changes in metallothionein-null mice prenatally exposed to mercury vapor. Toxicology Letters,
155:361-368.
29. Yoshida, M., Watanabe, C., Satoh, M., Yasutake, A.,
Sawada, M., Ohtsuka, Y., Akama, Y. and Tohyama,
C. (2004) Susceptibility of metallothionein-nullmice to the behavioral alterations caused by exposure to mercury vapor at human-relevant concentration. Toxicological Science, 80: 69-73.
30. Yoshinaga, M. (2005) Gender difference in the perception of environmental health risk among university students: A preliminary research. Transactionsof the Kokushikan University Faculty of Engineering, 38. (in press)
31. Zhou, H., Yamauchi, T., Natsuhara, K., Yan, Z.,
Lin, H., Ichimaru, N., Kim, S. W., Ishii, M. and
Ohtsuka, R. (2006) Overweight in Urban Schoolchildren Assessed by Body Mass Index and Body
Fat Mass in Dalian, China. Journal of Physiological Anthropology, 25: 41-48.
32. Zhou, H., Ohtsuka, R., He, Y., Yuan, L., Yamauchi,
T. and Sleigh, A.C. (2005) Impacts of parasite infections and dietary intake on child growth in theschistosomiasis-endemic Dongting lake region,
China. American Journal of Tropical Medicine andHygiene,72:534-539.
33. Zhou, H., He, Y. and Ohtsuka, R. (2005) Sex difference in malnourished status of Chinese children
due to schistosomiasis infection and inadequate
dietary intake. Environmental Sciences, 12:145153.

370

Department of
Biomedical Chemistry
Professor
Kiyoshi Kita, Ph.D.

Lecturer
Yoh-ichi Watanabe, Ph.D.

Associate
Kimitoshi Sakamoto, Ph.D.,

Shigeo Yoshinari, Ph.D.

Homepagehttp://www.sih.m.u-tokyo.ac.jp/departments-J.html#Anchor-33869
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 or experimental point of view
Graduate Course: Biochemistry and Nutrition I, IIThis course is comprised of lectures and seminars toprovide basic concepts and newer vistas for understanding nutrition with special reference to biochemistry and molecular biology. These include the structureand 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, Practiceon 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 and bacterial respiratory chain. In addition, we are interested in
the basic biological reactions such as protein 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)

3713) C. elegans as a model system of parasitic nematode (expression of foreign genes or cDNAs,
gene knockout)
III. Parasitic protozoa (Plasmodium falciparum , Trypanosoma brucei, Trypanosoma cruzi, Cryptosporidium)1) characterization of mitochondria as a target forthe chemotherapy2) molecular biology of mitochondrial DNA3) structure based drug design (SBDD)
IV. Protein synthesis
1) Mitochondrial protein synthesis
2) Biogenesis of cytoplasmic ribosomes

References
1. Rhodoquinone reaction site of mitochondrial complex I, in parasitic helminth, Ascaris suum. Yamashita, T., Ino, T., Miyoshi, H., Sakamoto K., Osanai,A., Nakamaru-Ogiso, E., and Kita, K. (2004) Biochim Biophys. Acta (Bioenergetics), 1608, 97-103
2. Direct evidence for cyanide insensitive quinol oxidase (alternative oxidase) in apicomplexan parasite
Cryptosporidium parvum: Phylogenetic andTherapeutic Implication. Suzuki, T., Hashimoto, T.,
Yabu, Y., Kido, Y., Sakamoto, K., Nihei, C., Hato,
M., Suzuki, S., Amano, Y., Nagai, K., Hosokawa, T.,
Minagawa, N., Ohta, N., and Kita, K. (2004) Biochem. Biophys. Res. Commun. 313, 1044-1052
3. Developmental stage-specific triacylglycerol biosynthesis, degradation and trafficking as lipid bodies in Plasmodium falciparum-infected erythrocyte.
Palacpac, N. M.., Hiramine, Y., Mi-ichi, F., Kita, K.,
Hiramatsu, R., Horii, T., and Mitamura, T. (2004) J.
Cell Sci., 117, 1469-1480
4. Molecular cloning and characterization of Trypanosoma vivax alternative oxidase (AOX) gene, atarget of the trypanocide ascofuranone Suzuki, T.,
Nihei, C., Yabu, Y., Hashimoto, T., Suzuki, M.,
Yoshida, A., Nagai, K., Hosokawa, T., Minagawa,N., Suzuki, S., Kita, K., and Ohta, N. (2004) Parasitol. Int. 53, 235-245
5. Field trials of a new, simple and rapid test for detection of G6PD deficiency in Southeast Asia, Jalloh, A., Tantular, I. S., Pusarawati, S., Kawilarang,

A. P., Kerong, H. Lin, K., Ferreira, M. U., Matsuoka, H. , Arai, M., Kita, K. and Kawamoto, M.
(2004) Trop. Med. Int. Health, 9, 615-623
6. Expression of mRNAs and proteins for peroxiredoxins of the human malaria parasite Plasmodium
falciparum in the blood stage. Yano, K., Komaki-Yasuda, K., Kobayashi, T., Takemae, H., Kita,
K., Kano, S. and Kawazu, S. (2005) Parasitol. Int.,54, 35-41
7. Proteomic analysis of phagocytosis in the enteric
protozoan parasite Entamoeba histolytica. Okada,M., Huston, C. D., Mann, B. J., Petri, W. A., Kita,
K. and Nozaki, T. (2005) Eukaryotic Cell, 4,827-831
8. A γ-Lactone Form Nafuredin, Nafuredin-γ, also
Inhibits Helminth Complex I Shiomi, K., Ui, H.,
Suzuki, H., Hatano , H., Nagamitsu, T., Takano, D.,
Miyadera, H., Yamashita , T., Kita, K., Miyoshi, H.,
Harder, A., Tomoda, H. and Omura, S. (2005) J.
Antibiot. 58, 50-55
9. Mutational analysis of the Trypanosoma vivax alternative oxidase: the E(X)6Y motif is conserved inboth mitochondrial alternative oxidase and plastid
terminal oxidase and is indispensable for enzyme
activity. Nakamura, K., Sakamoto, K. Kido, Y., Fujimoto, Y., Suzuki, T., Suzuki, M., Yabu, Y., Ohta,
N., Tsuda, A., Onuma, M. and Kita, K. (2005) Biochem. Biophys. Res. Commun. 334, 593-600
10. Functional Reconstitution of a Crenarchaeal Splicing Endonuclease in vitro. Yoshinari, S., Fijita, S.,
Masui, R., Kuramitsu, S., Yokobori, S., Kita, K.
and Watanabe, Y. (2005) Biochem. Biophys. Res.
Commun. 334, 1254-1259
11. Expression, purification, and crystallization of Trypanosoma cruzi dihydroorotate dehydrogenase
complexed with orotate. Inaok, D. K., Takashima,E., Osanai, A., Shimizu, H., Nara, T., Aoki, T., Harada, S. and Kita, K. (2005) Acta Crystallographica
F61, 875-878
12. PfPDE1, a novel cGMP-specific phosphodiesterase,from the human malaria parasite Plasmodium falciparum. Yuasa, K., Mi-ichi, F., Kobayashi, T.,
Yamanouchi, M., Kotera, J., Kita, K. and Omori, K.
(2005) Biochem. J. 392, 221-229
13. Parasite mitochondria as a target of chemotherapy:
The inhibitory effect of licochalcone A on the
Plasmodium falciparum respiratory chain. Mi-ichi,

372

F., Miyadera, H., Kobayashi, T., Takamiya, S.,
Waki, S., Iwata, S. Shibata, S. and Kita, K. (2005)
Ann.New York Acad. Sci. 1056, 46-54
14. Fibrillarin cDNA and Gene Structure in Euglena
gracilis and Conservation of Box C/D snoRNP Proteins in the Domain Eucarya. Russell, A.G., Watanabe, Y., Charette, J.M., Gray, M.W. (2005) Nucleic Acids Res. 33, 2781-2791.

University Hospital
Clinical Divisions

29

374

General Medicine
Professor
Yasuyoshi Ouchi, M.D., Ph.D.

Homepage
Organization
The Department of General Medicine started as an
outpatient primary care at the reorganization of Department of Internal Medicine in 1994. Our department
functions as a primary care unit, and new patients withmedical problems first seen and undergo screening
examinations by the staffs in this department. Once diagnosis is made, the patients are referred to appropriate
specialists. Our department consists of one professor(Chairman of Internal Medicine), one lecturer andmany other staffs nominated by subspecialty departments of Internal Medicine. Most of them rotate between General Medicne and subspecialty with the dutyof General Medicine for 1-2 months a year. A few staffs
practice oriental medicine.

Activities
Three booths in outpatient clinic are allocated to ourdepartment every day. New patients without appointment or referral letters first visit our department. Mostof the acute illnesses and common diseases are tentatively treated or referred to the specialists if needed. In
the case of chronic diseases, they will be referred to thespecialists after appropriate screening and evaluation of
the morbidity. We see 70-80 such patients every day,and the total number of outpatients in 2005 was about
20,000. At present, our department is not provided withward. Therefore, the patients who needed hospitalization are referred to relevant subspecialty. In addition to
the management of outpatients, we provide an opportunity for medical students and junior residents to learn
the skill of medical interview, physical examination,
medical planning, diagnosis, treatment and so on under

the setting of primary care with guidance by our staff.

375

General Surgery
Professor
Masatoshi Makuuchi, MD

Homepage
Organization
The Department of General Surgery started as an
outpatient primary care unit in 1994. The Department
serves as a screening centers for the patients with surgical problems first seen. Once diagnosis is made, thepatients are referred to appropriate specialists. Our department consists of one professor and many otherstaffs nominated by sub-speciality departments of Surgery. Most of them rotate between General Surgery andsub-speciality with the duty of General Surgery for 2-3
months a year.

Activities
Three booths in outpatient clinic are allocated to our
Department every week day. New patients without appointments or referral letters first visit our Department.
Acute surgical diseases are initially treated at our Department or referred to specialist if needed. Most of thepatients with diseases that needs operation will be referred to specialists after appropriated screening. We
see 20-30 such patients every day and the total numberof outpatients per year is appropriately 5000. At present,
our department is not provided with ward. The patients
who need hospitalization are referred to relevant subspeciality.

University Hospital
Central Clinical Facilities

30

378

Clinical Laboratory Center
Professor
Yutaka Yatomi, M.D.

Associate Professor
Hitoshi Ikeda, M.D.

Lecturer
Katsu Takenaka, M.D.,
Daiya Takai, M.D.,

Tatsuo Shimosawa, M.D.
Makoto Yumoto, M.D.

Associate
Katsumi Higashi, Ph.D.,

Aya Ebihara, M.D.,

Makoto Kaneko, M.D.

Chief Technologist
Minoru Toduka, Ph.D.
(As of March, 2006)

Homepage http://www.cc.h.u-tokyo.ac.jp/mulins/kensa/index.htm
Introduction and Organization
Clinical Laboratory Center consists of 11 doctors, achief technologist, 63 technicians, and 2 nurses, and isdivided 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
of analysis, and data reporting are all controlled by the
Laboratory Automation computer system. This system
has greatly improved the quality, safety, and efficiencyof the laboratory and contributed to both patients anddoctors by providing rapid and high-quality laboratory
testing.
The Administration Section
This Section has been newly established and deals
with management issues in Clinical Laboratory Center.
The 1st Section
This section deals mainly with the maintenance oflaboratory system, blood and urine sampling, and urinalysis. In 2004, 185,000 outpatient blood sampling
were performed while 73,000 urine samples were analyzed, in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2004, over 250,000 serum
enzyme tests (such as AST and ALT), and 200,000 CRP
tests were performed. On the other hand, 37,000 STS
and 28,000 CEA tests were performed, which is just a
few examples of the tests performed in the last year.
The 3rd Section
This section deals with hematology and DM-related
tests, and gene analysis tests. In 2004, 280,000 samples
were examined for complete blood cell counts, while
1,600 cell surface marker analysis and 100,000
prothrombin time, 65,000 fibrinogen, 90,000 glucose,and 61,000 HbAIC tests were performed. As for genetic
tests, 450 leukemia-related gene tests and 4,000

379

HCV-RNA tests were performed.

constantly performed in all laboratory sections.

The 4th Section
This section deals with physiological tests, including
circulatory, pulmonary, and neuromuscular function
ones. In 2004, 26,000 ECG, 7,200 pulmonary function
tests, 7,900 echocardiography tests, 9,600 abdominal
echography tests, and 1,700 EEG were performed.

References

The Hospital Ward Section
This section has been recently founded and is incharge of laboratory tests, mainly ECG, for seriously-ill,
hospitalized patients. Blood glucose measurements andabdominal echography tests are also performed in theward by technologists belonging to this section. In the
future, this section is going to be further expanded since
there is so much demand from clinical doctors.

Teaching activities
Lectures are given to the fourth and fifth grade
medical students on clinical tests including hematology,
chemistry, endocrinology, immunology, bacteriology,
cardiology, and pulmonary function. The reversed CPC
program is presented to the fifth and sixth grade students. Laboratory practice teaching is provided for thefifth year medical students, in small groups of 6-7 students for one-week duration. In this course, students
learn clinical and practical knowledge and techniques
on various laboratory tests. Students from professional
schools also study laboratory medicine under the guidance of members in Clinical Laboratory Center.

Research activities
The main goal of our research projects is the development of new and useful laboratory tests, and elucidation of pathophysiology of diseases through laboratory
tests. The areas included are: i) hematological analysis,ii) cell surface analysis using flow cytometry, iii) analysis of life-style involvement in clinical laboratory data,iv) bioactive lipids, iv) hormones, including FGF-23
and adrenomedullin, v) analysis of cardiac functions
using ultrasound, vi) the influence of diesel exhaust
particles on respiratory functions, and vii) analysis ofbrain functions using magnetoencephalography. The
improvement of the current laboratory test methods is

1. Amemiya N, Yatomi Y, Yanagi M, Endo T, Ozaki Y.
Mixed blast crisis of chronic myelogenous leukemia involving minimally differentiated myeloblastand megakaryoblast lineages. Lab Hematol. 2004;
10:254-255.
2. Hirose H, Kubota M, Kimura I, Yumoto M, andSakakihara Y. N100m in adults possessing absolute
pitch. Neuroreport. 2004;15(9): 1383-1386.
3. Ikeda H, Nagashima K, Yanase M, Tomiya T, Arai
M, Inoue Y, Tejima K, Nishikawa T, Watanabe N,
Omata M, and Fujiwara K. Sphingosine
1-phosphate enhances portal pressure in isolated
perfused liver via S1P2 with Rho activation. Biochem Biophys Res Commun. 2004;320: 754-759.
4. Kaga K, Kurauchi T, Yumoto M, and Uno A.
Middle-latency auditory-evoked magnetic fields inpatients with auditory cortex lesions. Acta Otolaryngol. 2004;124(4):376-380.
5. Kato M, Matsumoto A, Nakajima T, Hirose K,
Iwasawa K, Takenaka K, Yamashita H, Sugiura S,
Hirata Y, and Nagai R. Amlodipine increases nitricoxide production in exhaled air during exercise inpatients with essential hypertension. Am J Hypertens. 2004;17(9):729-733.
6. Kawai J, Ando K, Tojo A, Shimosawa T, Takahashi
K, Onozato ML, Yamasaki M, OgitaT, Nakaoka T,
and Fujita T. Endogenous adrenomedullin protects
against vascular response to injury in mice. Circulation 2004;109:1147-53.
7. Kimura I, Kubota M, Hirose H, Yumoto M, andSakakihara Y. Children are sensitive to averted eyes
at the earliest stage of gaze processing. Neuroreport.
2004;15(8):1345-1348.
8. Maruyama N, Ishigami A, Kuramoto M, Handa S,
Kubo S, Imasawa T, Seyama K, Shimosawa T, andKasahara Y. Senescence marker protein-30 knockout mouse as an aging model. Ann NY Acad Sci.
2004;1019:383-387.
9. Matsui H, Shimosawa T, Itakura K, Guanqun X,
Ando K, and Fujita T. Adrenomedullin can protect
against pulmonary vascular remodeling induced byhypoxia. Circulation 2004;109:2246-2251.
10. Miura Y, Yatomi Y, Ohmori T, Osada M, and Ozaki

380

Y. Independence of tumor necrosis factor-alpha-induced adhesion molecule expression
from sphingosine 1-phosphate signaling in vascularendothelial cells. J Thromb Haemost. 2004;2:10191021.
11. Naganuma Y, Satoh K, Yi Q, Asazuma N, Yatomi Y,
and Ozaki Y. Cleavage of platelet endothelial celladhesion molecule-1 (PECAM-1) in platelets exposed to high shear stress. J Thromb Haemost.
2004;2: 1998-2008.
12. Ohmori T, Yatomi Y, Osada M, and Ozaki Y. Platelet-derived sphingosine 1-phosphate induces contraction of coronary artery smooth muscle cells via
S1P2. J Thromb Haemost. 2004;2:203-205.
13. Sakurai S, Takenaka K, Shiojima I, Sonoda M, Uno
K, Nakahara K, and Nagai R. Close physical contact of the heart with diaphragm causes
pseudo-asynergy of left ventricular inferior wall innormal subjects. Echocardiography. 2004;21(7):573-579.
14. Satoh K, Yatomi Y, Osada T, Takeda S, Tsuyuguchi
N, Kubota F, and Ozaki Y. Clear visual detection of
circulating platelet aggregates in acute myocardial
infarction using a flow cytometer equipped with animaging device. Platelets 2004;15:61-62.
15. Shida D, Kitayama J, Yamaguchi H, Yamashita H,
Mori K, Watanabe T, Yatomi Y, and Nagawa H.
Sphingosine 1-phosphate transactivates c-Met aswell as epidermal growth factor receptor (EGFR) in
human gastric cancer cells. FEBS Lett. 2004;577:
333-338.
16. Shimada T, Hasegawa H, Yamazaki Y, Muto T,
Hino R, Takeuchi Y, Fujita T, Nakahara K., Fukumoto S, and Yamashita T. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19(3):429-435.
17. Shimosawa T, Takano K, Ando K, and Fujita T.
Magnesium inhibits norepinephrine release byblocking N-type calcium channels at peripheral
sympathetic nerve endings. Hypertension 2004;44:897-902.
18. Sonoda M, Yonekura K, Yokoyama I, Takenaka, K,
Nagai R, and Aoyagi T. Common carotid intima-media thickness is correlated with myocardial
flow reserve in patients with coronary artery disease: a useful non-invasive indicator of coronary
atherosclerosis. Int J Cardiol. 2004;93(2-3):131-

136.
19. Takano K, Asazuma N, Satoh K, Yatomi Y, andOzaki Y. Collagen-induced generation of platelet-derived microparticles in whole blood is dependent on ADP released from red blood cells andcalcium ions. Platelets 2004;15:223-229.
20. Tejima K, Arai M, Ikeda H, Tomiya T, Yanase M,
Inoue Y, Nagashima K, Nishikawa T, Watanabe N,
Omata M, and Fujiwara K. Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats. Gastroenterology 2004;127(5):1488-1496.
21. Tomiya T, Inoue Y, Yanase M, Arai M, Ikeda H,
Tejima K, Nagashima K, Nishikawa T, Watanabe N,
Omata M, and Fujiwara K. Treatment with leucine
stimulates the production of hepatocyte growth
factor in vivo. Biochem Biophys Res Commun.
2004;322(3):772-777.
22. Xing G, Shimosawa T, Ogihara T, Matsui H, Itakura K, Qingyou X, Asano T, Ando K, and Fujita T.
Angiotensin II-induced insulin resistance is enhanced in adrenomedullin -deficient mice. Endocrinology 2004;145(8):3647-3651.
23. Yamasue H, Yamada H, Yumoto M, Kamio S,
Kudo N, Uetsuki M, Abe O, Fukuda R., Aoki S,
Ohtomo K, Iwanami A, Kato N, and Kasai K. Abnormal association between reduced magnetic
mismatch field to speech sounds and smaller left
planum temporale volume in schizophrenia.
Neuroimage. 2004;22(2):720-727.
24. Yatomi Y, Yamamura S, Hisano N, Nakahara K,
Igarashi Y, and Ozaki Y. Sphingosine 1-phosphate
breakdown in platelets. J Biochem. 2004;136(4):495-502.
25. Yatomi Y, Yoneyama A, and Nakahara K. Usefulness of CD9 detection in the diagnosis of acutemegakaryoblastic leukemia. Eur J Haematol. 2004;
72:229-230.
26. Yokoo E, Yatomi Y, Takafuta T, Osada M, OkamotoY, and Ozaki Y. Sphingosine 1-phosphate inhibits
migration of RBL-2H3 cells via S1P2: cross-talkbetween platelets and mast cells. J Biochem.
2004;135:673-681.
27. Yokota H, Yatomi Y, Mashige F, and Nakahara K.
Expression of ceramide kinase in hematopoietic
cells. Eur J Haematol. 2004;73(4):307-308.
28. Takai D, Jones PA. Origins of bidirectional pro-381

moters: computational analyses of intergenic distance in the human genome. Mol. Biol. Evol.
2004;21(3):463-7.
29. Takai D, Nagase T, Shimizu T. New therapeutic key
for cystic fibrosis: a role for lipoxins (Editorial).
Nature Immunol. 2004;5(4):357-8.
30. Takai D, Jones PA. Origins of bidirectional promoters: computational analyses of intergenic distance in the human genome. Mol. Biol. Evol.
2004;21(3):463-7.
31. Hirose H, Kubota M, Kimura I, Yumoto M, Sakakihara Y. Increased right auditory cortex activity
in absolute pitch possessors. Neuroreport
2005;16:1775-1779.
32. Karino S, Yumoto M, Itoh K, Yamakawa K, Mizuochi T, Kaga K. A modified parallel paradigm forclinical evaluation of auditory echoic memory.
Neuroreport 2005;16:683-687.
33. Kasai K, Hashimoto O, Kawakubo Y, Yumoto M,
Kamio S, Itoh K, Koshida I, Iwanami A, Nakagome K, Fukuda M, Yamasue H, Yamada H, Abe O,
Aoki S, Kato N. Delayed automatic detection ofchange in speech sounds in adults with autism: amagnetoencephalographic study. Clin Neurophysiol
2005;116:1655-1664.
34. Mizuochi T, Yumoto M, Karino S, Itoh K, Yamakawa K, Kaga K. Perceptual categorization ofsound spectral envelopes reflected in auditory-evoked N1m. Neuroreport 2005;16:555-558.
35. Terao Y, Furubayashi T, Okabe S, Arai N, Mochizuki H, Kobayashi S, Yumoto M, Nishikawa M,
Iwata NK, Ugawa Y. Interhemispheric transmissionof visuomotor information for motor implementation. Cereb Cortex 2005;15:1025-1036.
36. Yumoto M, Matsuda M, Itoh K, Uno A, Karino S,
Saitoh O, Kaneko Y, Yatomi Y, Kaga K. Auditory
imagery mismatch negativity elicited in musicians.
Neuroreport 2005;16:1175-1178.
37. Yumoto M, Uno A, Itoh K, Karino S, Saitoh O,
Kaneko Y, Yatomi Y, Kaga K. Audiovisual phonological mismatch produces early negativity inauditory cortex. Neuroreport 2005;16:803-806.
38. Kushiyama A, Shojima N, Ogihara T, Inukai K,
Sakoda H, Fujishiro M, Fukushima Y, Anai M, Ono
H, Horike N, Viana AY, Uchijima Y, Nishiyama K,
Shimosawa T, Fujita T, Katagiri H, Oka Y, Kurihara H, Asano T. Resistin like molecule beta acti-

vates MAPKs, suppresses insulin signaling in
hepatocytes and induces diabetes, hyperlipidemia
and fatty liver in transgenic mice on a high-fat diet.
J Biol Chem. 2005;280:42016-42025.
39. Shimosawa T, Fujita T. Adrenomedullin and its
related Peptide. Endocr J. 2005;52:1-10.
40. Shimosawa T, Fujita T. Adrenomedullin as a potent
antioxidative and antiatherosclerotic substance.
Drug News Perspect. 2005;18:185-189.
41. Standridge JB, Sealey JE, Laragh JH, Houston MC,
Gavras H, Johnson RJ, Blumenfeld JD, Brown M,
Egan BM, Meltzer JI, Shimosawa T, Fujita T. A
free-ranging roundtable discussion on hypertension.
J Hum Hypertens. 2005;17:259-66.
42. Yumoto M, Uno A, Itoh K, Karino S, Saitoh O,
Kaneko Y, Yatomi Y, Kaga K. Audiovisual phonological mismatch produces early negativity inauditory cortex. Neuroreport. 2005; 16: 803-806.
43. Yumoto M, Matsuda M, Itoh K, Uno A, Karino S,
Saitoh O, Kaneko Y, Yatomi Y, Kaga K. Auditory
imagery mismatch negativity elicited in musicians.
Neuroreport. 2005; 16: 1175-1178.
44. Ohmori T, Yatomi Y, Osada M, Ozaki Y. The intracellular action of sphingosine 1-phosphate in
GPVI-mediated Ca2+ mobilization in platelets.
Thromb Res. 2005; 115: 409-415.
45. Ohkawa R, Hirowatari Y, Nakamura K, Ohkubo S,
Ikeda H, Okada M, Tozuka M, Nakahara K, Yatomi
Y. Platelet release of beta-thromboglobulin andplatelet factor 4 and serotonin in plasma samples.
Clin Biochem. 2005; 38: 1023-1026.
46. Kaneko M, Takafuta T, Cuyun-Lira O, Satoh K,
Arai M, Yatomi Y, Ozaki Y. Evaluation of platelet
function under high shear condition in thesmall-sized collagen bead column. J Lab Clin Med.
2005; 146: 64-75.
47. Aoki S, Yatomi Y, Ohta M, Osada M, Kazama F,
Satoh K, Nakahara K, Ozaki Y. Sphingosine
1-phosphate-related metabolism in the blood vessel.
J Biochem (Tokyo). 2005; 138: 47-55.
48. Ikeda H, Nagashima K, Yanase M, Tomiya T, Arai
M, Inoue Y, Tejima K, Nishikawa T, Watanabe N,
Kitamura K, Isono T, Yahagi N, Noiri E, Inao M,
Mochida S, Kume Y, Yatomi Y, Nakahara K, Omata
M, Fujiwara K. The herbal medicine inchin-ko-to(TJ-135) induces apoptosis in cultured rat hepatic
stellate cells. Life Sci. 2005

382

49. Sugimoto K, Makihara T, Saito A, Ohishi N, Nagase T, Takai D. Betaine improved restriction digestion. Biochem Biophys Res Commun. 2005;337(4):1027-9.

383

Surgical Center
Director (Professor)
Masatoshi Makuuchi M.D., Ph.D.
Associate Professor
Yoshikazu Mimura, M.D., Ph.D.
Yushi Uetera, M.D., Ph.D.
Lecturer
Nobusuke Ohara, M.D., Ph.D.
Ryoji Fukushima, M.D., Ph.D.
Mieko Chinzei, M.D., Ph.D.
Associate
Toshihiko Obayashi, M.D., Ph.D.
Saito Yuhei, Ph.D.
Chizuru Komori, M.D., Ph.D.

Homepage
Introduction and Organization
Operating rooms were centralized as a surgical centerfor the first time in Japan, in the University of Tokyo on
July 1955. Surgical center was located in the surgicalward building till December 1987. The center moved to
the new central building on January 1988. The newsurgical center has 14 operating rooms, one of which isa bio-clean room, The administration staffs consist of 5
doctors, 54 nurses, 6 technical officials, 6 temporary
employees. Our surgical center affords services to 18
clinical departments of our hospital, In 2004, 7546 operations were performed in our surgical center including 1096 emergency operations.
In July 2001, the branch hospital of our university
located in Mejiro was closed and joined to our University Hospital located in Hongo. Furthermore, a newward building was opened in October 2001. Then, thenumber of operations bas been remarkably increased
and reached to more than 7500. Another new central
building including new operating rooms is now constructing. Our hospital is in the state of chronic shortageof available operating rooms.
Two new operating rooms are tentatively prepared toovercome the increase in operations. One operating
room is prepared in the ICU, CCU, HCU floor of the
new ward building and the other is prepared in the outpatient clinic of the orthopedic surgery. The operating
room in the outpatient. clinic is also used for the
short-stay and day surgery procedures in orthopedics.
Another effort was made to increase the availabilityof the operating rooms in light of the efficient management of the surgical center, Until September 2001,
nine operating rooms were used daily for the elective
operations on the average, However, 12 operatingrooms have been used daily for the elective operations
since October 2001 , As a result, the number of operations has been increasing remarkably since October
2001, We had 8013 operations in 2005 which is 1.4
times of those in 2001.

Activities of our surgical center
Activities of our surgical center encompass teaching384

activities, research activities and management of thesurgical center.

Management of the surgical centerAll operations of in-patients are performed in 14 operating rooms of the surgical center. In addition, one
operating room is also used for the short-stay and day
surgery procedures in orthopedics. The number of operations is increasing annually. As mentioned before,
there were 7546 operations in 2004, including 1096
emergency cases.
However, the total number of operations has not increased between 1999 and 2000 apparent]y, partly because of the shortage in the number of operating rooms
and nursing staffs. There is also 5 to 18% annual increase over these 4 years in the number of operated patients with either unknown results or positive results inthe microbiological tests regarding such as lens, tuberculosis, MRSA, pseudomonas aeruginosa, HBV, HCV
and HIV.
Computer system has been introduced in the management of information in the surgical center. In May
1999, on-]ine computer system was introduced to ordering system for the planned and emergency operations. Namely, all operations have been ordered throughthe computer terminal installed at each clinical department since May l 999, Furthermore, the computer system has also been introduced to manage the postoperative information in the surgical center since March
2000.
To encourage the efficient management of operatingrooms, the information has been disclosed on the hospital computer network since May 1997, regarding if
there are any operating rooms without any planned operations on the following day. Furthermore, since November 2000, it is disclosed on the hospital computer
network how each clinical department plans to use theoperating rooms on the following week in order to use
the available operating rooms efficiently.
Digitalized visual information such as photographsof operative fields and resected organs has been distributed to each clinical department through hospital computer network system since February 1997. Moreover,real-time monitoring visual information of the operative
fields has been distributed to each clinical department
on the hospital computer network since June 1999.

Since the new ward building began to be used in October 2001 , SPD and progressive patient care systemhave been introduced in the management of our hospital. SPD system was introduced in the management of
the surgical center in September 2002.
Recent trend is a remarkable increase of complex
procedures such as in transplantation surgery, microvascular surgery, cardiovascular surgery, minimallyinvasive surgery and orthopedic surgery. In addition,none-human implants such as vascular prosthesis, joint
prosthesis and intraocular lenses have come to be usedfrequently.
Furthermore, advanced techniques have been employed in the operating theatres. They are navigatjon
surgery in neurosurgical, orthopedic and ENT (ear, noseand throat) operations, treatment of thoracic aortic aneurysms using stent devices under fluroscopic monitoring. In addition, application of minimally invasive surgery such as MIDCAB operations are performed in theaortocoronary bypass procedures as well as a heart-port
surgery in the correction of heart anomalies such as
ASD and VSD. In addition, transplantation operations
and intraoperative three-dimensional echosonography
are performed in the surgical center.
Another recent trend is the presence of emergenceand re-emergence infectious diseases such as HIV andtuberculosis among the operated patients. Therefore, it
is mandatory to educare how to prevent nosocomial andoccupational infections in the surgical center. For instance, the principles of standard precautions andtransmission-based precautions should be lectured to all
health care workers in the surgical center.
It is considered that the number of immunocompromised hosts and complex surgical procedures will increase remarkably in the perioperative services of thesurgical center. Therefore, it is mandatory to improve
the quality and management of the surgical center in thetwenty-first century, As a result, it is considered that therole of surgical center is extremely important in healthcare services of hospital.

Teaching activities
Lectures to the undergraduates and postgraduates are
as follows: aseptic techniques, sterilization methods,
disinfection methods, prevention of perioperative infections, humoral and cellular responses to trauma and385

shock, training of handwashing and gown techniques,
Curriculum is updated every year. For example, introductory course for disinfection, sterilization and preservation of surgical instruments and medical devices
was added in the training courses in 1998, which gainedinterest and popularity among students.
It is one of the recent trends in the surgical center
that innovative surgical instruments and medical devices are introduced to perform highly advanced operations such as in the navigation surgery. transplantation
surgery, cardiovascular surgery and so forth. Consequently, education has become one of the most important activities in the surgical center. Advanced technologies are lectured to the surgeons, nursing staffs andmedical electronics engineers so that they understandhow to use them correctly.
Lectures to the nursing staffs consist of a freshmancourse and an advanced course. The freshman course isa basic training course as a scrub nurse and a circulating nurse. It consists of lectures an aseptic techniques,de-contamination methods, disinfecion methods, sterilization methods, prevention of perioperative infections, and training of hand-washing and gown techniques as wall as aseptic preparation of surgical instruments in the operating room. An advanced course isalso prepared to the experienced nurses. The purpose ofthis course is to upgrade their perioperative nursing
abilities so that they can afford satisfactory nursing services in the complex surgical procedures such as transplantation surgery, open-heart surgery and neurosurgery.
There is also a training course to medical electronics
engineers and students of medical electronics, This
training course consists of introduction on the medical
electronic instruments and devices, precautions of accidental troubles in handling surgical instruments andmedical devices, development of new surgical instruments and 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 staffs and contribute to decrease the number of accidents in handling surgical instruments and medical devices.
Lectures the non-nursing staffs such as technical officials and temporary employees and performed when
they start their careers in the surgical center. They arelectured on aseptic techniques, sterilization methods,
disinfection methods, prevention of perioperative infections and how to check the faults in the reusable surgical instruments such as forceps, scissors and clamps.
These contents are summarized in the manual. Lectures
are also performed to senior technical officials andtemporary employees to upgrade their technicalknowledge and skills.

Research activitiesl)Introduction of aseptic environment in the operating theaters
2) Development of new sterilization methods
3) International standardization of sterilization methods
4) Perioperative infection control of patients undergoing operations and prevention of occupational
infection of medical staffs working in the surgicalcenter5) Improvement of cost-effectiveness in the management of surgical center
6) Precautions of accidental troubles in the handlingsurgical instruments and medical devises7) Improvement of cost-effectiveness in sterilizationand preservation of medical instruments
8) Cost-effectiveness analysis of disposable and reusable surgical instruments
9) Development of new surgical instruments andmedical devisesl0) Computer aided surgery11) Intra-operative radiation therapy12) Surgical treatment on the basis of molecular biology13) Inter-hospital visual communications via satellite
system14) International comparison of effectiveness in the
management of surgical center15) Computer aided anesthesia
16) Three dimensional processing of visual information17) Improvement of minimally invasive surgery andmicrosurgery

References（2004-2005）
1. Komiyama T, Kihara H, Hirose K, Yoshimoto R,
Shigematsu H;AT-1015, anovel serotonin 2 A re-386

ceptor antagonist,improves resaturation of exercised ischemio muscle in hyperchalesterolemic
rabbits. J Vasc Surg 39:661-667,2004
2. Nishikage S, Koyama H, Miyata T, Ishii S, Hamada
H, Shigematsu H; In vivo electroporation enhances
plasmid-based gene transfer of basic fibroblast
growth factor for the reatment of ischemic limb. J
Surg Res 120:37-46,2004
3. Hosaka A, Koyama H,Kushibiki T,Tabata Y, Nishiyama N,Miyata T, Shigematsu H,Takato
T,Nagawa H: Gelatin hydrogel microspheres enablepinpoint delivery of basic fibroblast growth factor
for the development of functional collateral vessels.
Circulation 110:3322-3328,2004
4. Hoshina K, Koyama H, Miyata T, Shigematsu H,
Takato T, Dalman RL,Nagawa H:Aortic wall cellproliferation via basic fibroblast growth factor genetransfer limits progression of experimental abdominal aortic aneurysm. J Vasc Surg 40:512-518,
2004
5. Ishii S, Koyama H, Miyata T,Nishikage S, Hamada
H, Miyatake S, Shigematsu H:Appropriate control
of ex vivo gene therapy delivering basic fibroblast
growth factor promotes successful and safe development of collateral vessels in rabbit model of hindlimb ischemia. J Vasc Surg 39:629-638,2004
6. Kanetaka T, Komiyama T, Onozuka A, Miyata T,
Shigematsu H, Laser Doppler skin perfusion pressure in the assessment of Raynaud’s phenomenon.Eur J Vasc Endvasc Surg 27:414-416,2004
7. Kondo K, Koyama H, Miyata T, Takato T, Hamada
H,Shigematsu H:Conduction performance of collareral vessels induccd by vascular endothelial
growth factor or basic fibroblast growth factor,
Cardiovasc Res 61:132-142,2004
8. Miyahara Y, Koyama H, Miyata T, Shigematsu H,
Inoue J, Takato T, Nagawa H:Inflammatory signaling pathway containing TRAF6 contributes toneointimal hyperplasia.Cardiovasc Res 64:154-164,
2004
9. Saito A, Komiyama T, Aramoto H, Miyata T, Shigematsu H:Ischemio precondirioning improves
oxygenation of exercising muscle in vivo. J Surg
Res 120;111-118,2004
10. Sugiura M, Komiyama T, Akagi D, Miyata T, Shigematsu H:Compression of the iliac vein by asynovial cyst. Ann Vasc Surg 18:369-371,2004

11. Uetera Y, Shigematsu H, Baba Z, Kumada N,
Kawamura K:Air removal effect of vacuum pulses
evaluated using the wireless logger in the prevacuum autoclave without sensor ports. PDA Journalof GMP and Validation in Japan 6;46-50,2004
12. Hatao F, Muroi M, Hiki N, Ogawa T, Mimura Y,
Kaminishi M, Tanamoto K: Prolonged toll-like receptor stimulation leads to down-regulation of
IRAK-4 protein. J Leukocyte Biol 76:904-908,
2004.
13. Tamai H, Sawamura S, Kanamori Y, Takeda K,
Chinzei M, Hanaoka K: Thoracic epidural catheter
insertion using the caudal approach assisted with anelectrical nerve stimulator in young children. Reg
Anesth Pain Med 29: 92-5, 2004.
14. Hayashida M, Kin N, Tomioka T, Orii R, Sekiyama
H, Usui H, Chinzei M, Hanaoka K: Cerebral ischaemia during cardiac surgery in children detectedby combined monitoring of BIS and near-infrared
spectroscopy. Br J Anaesth 92: 662-9, 2O
15. Hatao F, Hiki N, Mimura Y, Ogawa T, Kojima J,
Mafune K, Hawkins LD, Muroi M, Tanamoto K,
Kaminishi M: The induction of super-resistanceusing synthetic lipopolysaccharide receptor agonist
rescues fatal endotoxemia in rats without excessive
immunosuppression. Shock 23: 365-370, 2005

387

Department of Clinical Radiology
Professor (department manager)
Kuni Ohtomo, M.D.,Ph.D.

Lecturer (vice manager)
Tomohiko Masumoto, M.D.,Ph.D.

Associate
Shinichi Inoh, M.D.

Homepage http://www.ut-radiology.umin.jp/
Introduction and Organization
In the Department of Clinical Radiology, clinicalservices on Diagnostic Radiology (imaging and intervention), Radiation Oncology (radiotherapy), Nuclear
Medicine and the Radiation Safety Control System areprovided in cooperation with radiology technologists
and nurses. Present constituent members are as follows:
three medical doctors, 52 radiological technicians, 2assistants, 18 nurses, and 1 technical official of the radiation control. The staff members and the of the Department of Radiology teachers, the graduate school
students, medical staffs, and the clinical trainees join
this. In addition, the doctors and the nurses of otherclinical departments cooperate and are also engaged in
the clinical radiology activities. The educational training and registration of the radiation engaging persons
are controlled according to the University of Tokyo
Hospital Ionizing Radiation Injury Prevention Rules.
Department of Clinical Radiology covers four major
fields: (1) Diagnostic Radiology, (2) Radiation Oncology, (3) Nuclear Medicine and (4) the Radiation Safety
Control System. The Diagnostic Radiology Section ismainly operated at the first floor in the Central Clinic
Building. Parts of the diagnostic activities are done at
the MR building, the operation rooms, the emergency
department, and some other clinical departments. The
services provided are X-ray imaging, fluoroscopic imaging, computed tomography (CT), magnetic resonanceimaging (MRI) and angiography. Radiation Oncology
Section is operated at basement of the inpatient building B. The outpatient clinic is also located here and notin the Outpatient Clinic building. The methods of therapy provided are linear accelerator (LINAC),
gamma-knife, Remote After Loading System (RALS)
and Brachytherapy (Radioactive Seed Implantation
Therapy). Nuclear Medicine Section is operated at thebasement floor of the Central Clinic Building. The
methods of examination provided are conventional
scintigram, SPECT and PET. The office of Radiation
Safety Control System is located at the third floor of the
old Central Clinic Building.
Department of Clinical Radiology is actively participating in the following projects. 1) PACS: We have recently developed a radiology information system (RIS)
networking with hospital information system (HIS) and
PACS (picture archiving and communicating system).
The PACS of the whole hospital (the film-less imaging
system) was established in 2003. The new reporting
system was installed in 2002. 2) Radiation Safety Control: Stimulated by the need for evaluating the individual accumulated exposure dose by medical radiation,
we have started a working group to solve this problem.
We aim to provide the accumulated exposure dose dataon RIS. 3) Image Computing & Analysis Laboratory:
The clinical section of this project is located at thereading room in the Diagnostic Radiology Section. The
main services are processing of volume image data into

388

clinical 3D-images and analysis of imaging data. 4)
Researches on new radiology techniques: Ongoing collaborative researches are as follows: 3D-conformation
therapy, clinical PET, multi-detector row CT, interventional MRI, flat panel detector.

Clinical activities
1) Diagnostic Radiology:
The section of diagnostic radiology is responsible forall the clinical examinations of CT, MRI, and angiography and vascular interventional procedures except for cardiac and peripheral arterial studies. All ofthese examinations are performed under the requests ofclinicians. One hundred and fifty CT examinations are
performed using four MDCT scanners each day. Interventional procedure such as percutaneous biopsy andabscess drainage are also done by CT guidance. About
forty MR examinations are done using two 1.5-Teslaand one 0.3-Tesla machines every day. About six angiographies, most of which are interventional procedures including arterial embolization, arterial infusion
therapy, arterial infusion port placement, angioplasty,
and TIPS, are done by the radiologists using two angiographic units.
In clinical research works, efficacy of MDCT has been
investigated in all parts from the head to extremities.
New three-dimensional approaches have been also developed. Clinical research and basic animal experiments are in progress in the field of functional MR imaging and diffusion and perfusion MR techniques.
2) Radiation Oncology:
The radiation therapy is performed with two linear
accelerators, an intracavitary irradiation device (RALS),
and a gamma knife for radiosurgery. The network system connecting these radiotherapy equipments, CT/MR
devices, and treatment planning systems was alreadyconstructed. 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 is utilized mainly for non-coplanar radiation
therapy in many patients especially with brain tumor orhead and neck tumor. The rate of the non-coplanar radiation therapy is over 25% and surpasses those ofother institutions.
3) Nuclear medicine:
Positron Emission Tomography (PET) and Single
Photon Emission Computed Tomography (SPECT) are
the main activities in the clinical and research work.
These nuclear imaging procedures are chiefly performed and reported by radiologists and cardiologists.
Cerebral blood flow, glucose metabolism and neuralsynaptic functions are measured for the understandingof normal and pathophysiological states of CNS disorders, using a variety of positron-emitter radiotracer,such as [O-15] H2O, CO2, O2, CO, [F-18] FDG, [C-11]
methionine, [F-18] Dopa, [C-11] NMSP, NMPB and[C-11] raclopride. The study of dementia using SPECTand the standard brain atlas has made it possible tocategorize the type of dementia. Evaluation of dopaminergic function by PET is very important in the differential diagnosis of Parkinsonism. Cardiac PET and
SPECT are also active fields. Myocardial viability,
vascular reserve and sympathetic nerve denervation in
the ischemic heart disease are evaluated with [F-18]
FDG, [N-13] NH3, Tl-201 and [I-123] MIBG. Higher
brain functions such as reading, speech and thinking
have been studied with PET by comparing blood flow
and receptor binding potential (BP) under various tasks
and at rest. For the precise localization of activatedbrain function, computer processing and reconstructionof composite images of function and anatomy is an essential subject for investigation. Whole body FDG-PET
is one of the most promising studies 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 an important role in the clinical management of the patients.
In conclusion, the department of clinical radiology isa service section to all clinical departments. Main supporter as the doctor is a radiologist. However, the cooperation with the radiation diagnosis and treatment engaging persons of other clinical departments, technicians and nurses must be reinforced. We want to makestill more effort to achieve the cooperation and improve
clinical activities in the department of clinical radiology.

389

References
See the corresponding part of the department of Radiology.

390

Delivery Unit
Professor
Yuji Taketani

Homepage
Organization
The Delivery Unit of the University of Tokyo Hospital is organized by one professor, one associate, and5-10 fellows. All the staff members are taking part inresearch activities of reproductive endocrinology, gynecologic oncology, or perinatal medicine, as well as
being engaged with in-patient and out-patient care forpregnant women including the activities in the delivery units.

Activities
Total number of delivery cases from April 2005 to
March 2006 is 557, whereas that from April 2004 to
March 2005 is 514.
Recently cases of obstetrical emergencies like
abruptio placentae, eclampsia and uterine rupturestransported from neighboring hospitals have been increasing. These patients are treated by two or three
doctors and three midwives in charge under roundthe-clock system. Our service is an important part ofTokyo Metropolitan Service System for Maternal
Welfare and Perinatal Medicine.

References from April 2004 to
March 2006
[See Department of Perinatal Medicine.]

391

Central Rehabilitation Service
Professor
Fumio ETO, M.D., Ph.D.

Associate
Naoyuki MIYAKE, M.D.,
Ikuko SAOTOME, M.D., Ph.D.

Tosikazu Furukawa, M.D.

Homepage http://www.h.u-tokyo.ac.jp/patient/depts.html
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 the Central
Diagnostic and Therapeutic Service Department. The
Central Rehabilitation Service became an independent
unit in 1970. After the reorganization of University ofTokyo Hospital according to major organic classification in 1998, outpatient clinic as rehabilitation medicine
was installed. 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 the orthopedic surgery
department and the physical medicine department.
At the present time (April, 2005) our department
consists of 4 sections. Rehabilitation physicians’ section
includes three full-time doctors and two other part-time
doctors. They work chiefly for clinical practice in
medical rehabilitation service, but also have to engage
in teaching activities for medical students. Fourteen
physical therapists and five acupuncture therapists areworking in the physical therapy section. In the occupational therapy section, three occupational therapists
work for the general rehabilitation service and two occupational therapists work for the psychiatric rehabilitation. A part-time clerk is also working for administration section concerning medical rehabilitation service.

Clinical, teaching and research
activities
A professor of the department of rehabilitation medicine holds an additional post of the director of the central rehabilitation service department. Both departments
are united and engage in clinical, teaching and research
activities. We have no own ward for the patients inmedical rehabilitation but accept about 1,000 new inpatient referrals every year from other departments of theuniversity hospital. Approximately 200 inpatients areunder care of our rehabilitation service everyday. At
outpatient clinic ten to twelve patients visit us everyday
mainly as follow-up cases.
As for the characteristic of our patients, the numberof severely deconditioned patients with high-risk factor
for physical training has recently increased. They sufferfrom remarked disabilities with underlying disorders
such as cancer, cardiac and pulmonary failure, renal andhepatic insufficiency, and various degenerative diseases.
The establishment of a new therapeutic regime for thesepatients with difficult complications and comorbidity
may be urgent. Most of them cannot come to the rehabilitation room because of their severe medical condition. Therefore, the therapists have to visit the ward andto conduct the rehabilitation trainings for them.
Concerning the rehabilitation of the mental disorders,
two occupational therapists specifically engage intreatment activities. The occupational therapy in thepsychiatry ward and large-scale day-hospital has been

392

allotted in cooperation with the psychiatry department
staffs. About 40 people, mostly with schizophrenia, areregistered in day hospital service. They are called
members and come to the hospital since Monday to
Friday and participate in various activities.
Acupuncture therapy is a traditional medical activityof long history and a unique section in Japanese university hospital. This is nowadays the most popular complimentary and alternative medicine and may be expected its usefulness in rehabilitation treatment. We
have provided an acupuncture and moxibustion treatment for many patients with pain syndrome and myofascitis at the University of Tokyo hospital for dozens
of years, but have been not able to contribute to a hospital income because of the limitation on insurance
medical care. Then, as a result of having reviewed
measures in this country, we get possible to charge
therapeutic fee as free medical care since April, 2005.
As for teaching activities, we have provided athree-day clinical presentation for small group(so-called bedside learning) of 5th year students on
every other Wednesday to Friday. All the medical students see a few patients and also experience orthoses,
prostheses, mobility aids, wheel chairs and others. We
also have accepted co-medical students for clerkshipand internship as second, third and fourth year curriculum from several PT and OT training schools.
Research Activities are almost same as those in thedepartment of rehabilitation medicine. Our co-medical
staffs are also interested in research activity. The research fields done by the present staffs are as follows:(1) gait analysis for evaluation of prosthesis and orthosis for various limb amputees, rheumatoid, poststroke hemiplegic patients.
(2) biomechanical study on shoes or physical aids.
(3) biophysical control of growth, repair and remodeling of musculoskeletal systems using mechanicalstress and electromagnetic fields.
(4) prevention of disuse change of bone and joints, andrespiratory function.
(5) development of rehabilitation program for severely
deconditioned (cancer and other progressive diseases).
(6) Study on disability stages for various neuromuscular diseases.

References(See Department of Rehabilitation Medicine)

393

Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D.,Ph.D.*

Lecturer
Hisako Endo, M.D., Ph.D. (Deputy Director)
Noriyoshi Fukushima, M.D., Ph.D. *,Hiroshi Uozaki, M.D., Ph.D. *Lecturer (Hospital)
Kenji Kashima, M.D., Ph.D.,
Yutaka Takazawa, M.D., Ph.D.
Toru Motoi, M.D., Ph.D. (visiting researcher, USA)

AssociateJunji Shibahara, M.D., Ph.D.,
Satoshi Ota, M.D. *, Ph.D.,
Akiteru Goto, M.D., Ph.D. *Tetsuo Ushiku, M.D., Ph.D.
Tateru Ishida, M.D., Ph.D. *Clinical Fellow
Moon-Sung Chang, M.D.

Homepage http://pathol.umin.ac.jp/
Introduction and Organization

Clinical activities

Department of Human Pathology and Diagnostic Pathology (*) and Division of Diagnostic Pathology of
University Hospital have been merged to function as aunit, like other departments of clinical medicine. This
union declares the responsibility of our department forthe pathological practice (autopsy and surgical pathology) of the University Hospital, and education and research of human pathology. It is also expected to facilitate the translational research in the hospital.
The proper staffs in 2005 were 1 lecturer, two lecturers (hospital), two associates, and a clinical staff. Lecturer Dr. H Endo was the Deputy Director of the Division in 2004-5.
We cerebrated the 30th memorial year of the Divisionof Diagnostic Pathology, and published a commemorative issue in 2005.

Annual statistics of the pathology practice in 2004
are 12,534 cases of biopsy, 603 frozen histology, 17,845
cytology and 109 autopsy (21% as autopsy rate). In
2005, these are 12,672 biopsy, 693 frozen, 18,515 cytology and 114 autopsy cases (21% as autopsy rate).
Clinico-pathological conferences (CPCs) for the autopsy cases are held every month in the hospital, andtwo autopsy cases are discussed in each conference.
105th – 114th CPC were held in 2004 and 115th –125th in2005. CPCs of surgical pathology are regularly held fortumors of thorax, upper gastrointestinal tract, neurosurgery, liver, pancreato-biliary tract, urology, gynecology, mammary gland, and orthopedics, and for biopsy of liver, kidney and skin.
Our aim for surgical pathology is to provide the correct diagnosis as soon as possible. We are addressing
two challenging issues. The one is the ‘one-day pathology’ using the specific histoprocessing machinery. We394

have adopted a continuous rapid tissue processing system (CRTP), which have been developed by Prof.
Morales at Department of Pathology, Minami University. In order to shorten the turn aroud time (TAT) in the
University Hospital, the diagnostic system of staff pathologists and residents is being altered. Chief technician, Mr. Kaneko is taking a central role in further improvement of CRTP. The other issue is to apply molecular medicine to the diagnostic practice. We havedeveloped the diagnostic system for the gene rearrangement analysis of lymphomas and for the chimera
gene analysis of soft tissue sarcomas.

Teaching activities
The lectures and exercise course of systemic pathology are for the 2nd grade–students. Clinical clerkshipand bed-side learning (BSL) course of autopsy and surgical pathology are for 3rd and 4th grade students, respectively.
The new system of internship has started since 2004,
and all interns are required to submit at least one reportof CPC case. The Division of Diagnostic Pathology
received five interns in 2005 for the second year program of their internship.

Research activities
We are now developing the tumor specific antibodies
in collaboration with Genome Science Division, Research Center for Advanced Science and Technology,
the University of Tokyo. Based on the DNA array dataof various human neoplasms, monoclonal antibodies
against the candidate gene products are generated. In
addition, to facilitate the screening process of immunohistochemistry, we are now in the process of constructing the tissue array of neoplastic and non-neoplastic
tissues.

References
See the corresponding section of Department of Human Pathology and Diagnostic Pathology

395

Department of Corneal
Transplantation
Associate Professor
Shiro Amano, M.D., Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/kakumaku.html
Introduction and Organization
The department of corneal transplantation was established in 1976 as one of clinical sections in the University of Tokyo Hospital. The purpose of the establishment of this section is to carry out and promote corneal
transplantation and to perform clinical and basic research in the corneal diseases and corneal transplantation. The section is composed of a director (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 ophthalmological practice as a senior staff member of Department of Ophthalmology,
University of Tokyo. The corneal service is held every
Wednesday. At the corneal service, we determine indication for corneal transplantation and follow up patients
after the surgery. We also diagnose and treat various
corneal diseases. The corneal service is conducted by
the director and doctors from related hospitals. The patients who enrolled in the corneal service have exceeded 5000. The total number of corneal transplantation has reached 1500 cases since we started keratoplasties in 1971. Approximately 50 corneal transplantations have been performed annually.
The other important activities of the section include
mediation of donor eyes to other university hospitals
and medical institutes that need donor eyes for corneal

transplantation.
Followings are our main clinical themes to be pursued
to improve the safety and prognosis of corneal transplantation.
1) Thorough examination of donor eyes not only byslit-lamp biomicroscope but also by specular microscope.
2) Positive proof that donors were free of such infectious diseases as viral hepatitis, syphilis, AIDS andacute T-cell leukemia to prevent transmission to recipient patients through grafting.
3) Introduction of sclero-corneal preservation of donor eyes, because sclero-corneal preservation ismore suitable for longer preservation than conventional whole eye preservation.
4) The long-term natural course of keratoconus has
been investigated with corneal topography.

Teaching activities
As an undergraduate course, we give lectures on corneal physiology, corneal diseases, and corneal transplantation. In addition, we are engaged in practicaltraining 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
1. Regenerative medicine for corneal diseases
We have pursued to apply regenerative medicine to396

corneal diseases. In patients with chemical burn ofocular surface and Stevens-Johnson syndrome, we
try to reconstruct the ocular surface with autologous cultivated limbal, conjunctival or oral epithelial cells. We also use cultured human corneal endothelial cells, collagen sheet and amniotic membrane to construct sheets with corneal endothelial
cells. These sheets have the same degree of pumpfunction as corneal endothelium. We have investigated the potentiality of collagen extracted fromanimal dermis for reconstruction of corneal stroma.
We also examined the potential clinical usefulnessof acellularized porcine corneal stroma.
2. Tissue stem cells in the cornea
Using neurosphere method, we successfully isolated tissue stem cells in the corneal epithelium,
stroma and endothelium. Each tissue stem cells
show multipotency and self-renewality. We try toutilize these tissue stem cells in corneal regenerative medicine.

References
1. GekkaM, Miyata
K, NagaiY, Nemoto
S, Sameshima T, Tanabe T, Maruoka S, Nakahara
M, Kato S, Amano S. Corneal epithelial barrier
function in diabetic patients. Cornea 23:35-37,
2004
2. Yamagami S, Yokoo S, Mimura T, Amano S. Effects of TGF-beta2 on immune response-related
gene expression profiles in the human corneal endothelium. Invest Ophthalmol Vis Sci 45:515-521,
2004
3. Mimura T, Funatsu H, Kitano S, Noma H, Shimizu
E, Amano S, Kato S, Araie M, Yoshino O, Hori S.
HLA typing is not preditive of proliferative diabetic
retinopathy in patients with younger-onset type 2
diabetes mellitus. Br J Ophthalmol 88:303-305.
2004
4. Usui T, Ishida S, Yamashiro K, Kaji Y, Poulaki V,
Moore J, Moore T, Amano S, Horikawa Y, Dartt D,
Golding M, Shima DT, Adamis AP. VEGF164(165)
as the pathological isoform: differential leukocyte
and endothelial responses through VEGFR1 and
VEGFR2. Invest Ophthalmol Vis Sci 45:368-374,
2004

5.

Mimura T, Amano S, Funatsu H, Yamagami S,
Araie M, Kaji Y, Arimoto A, Ishida Y, Usui T,
Okamoto S. Correlations between each allergenspecific IgE serum levels in patients with allergic
conjunctivitis in Spring. Ocul Immunol Inflamm
12:45-51, 2004
6. Honda N, Hamada N, Amano S, Kaji Y, Hiraoka T,
Oshika T. Five-year follow-up study of photorefractive keratectomy for myopia. J Refract Surg
20:116-120, 2004
7. Mimura T, Funatsu H, Uchigata Y, Kitano S, Shimizu E, Noma H, Amano S, Araie M, Iwamoto Y,
Hori S. Development and progression of diabetic
retinopathy in patients with type 1 diabetes and
GAD autoantibody positivity. Diabet Med
21:559-562, 2004
8. Tanaka Y, Kato S, Miyata K, Honbou M, Nejima R,
Amano S, Kitano S, Oshika T. Limitation of
Scheimpflug videophotography system in quantifying posterior capsule opacification after intraocular lens implantation. Am J Ophthalmol
137:732-735, 2004
9. Amano S, Amano Y, Yamagami S, Miyai T, Miyata K, Samejima T, Oshika T. Age-relatedchanges in corneal and ocular higher order wavefront aberrations. Am J Ophthalmol 137:988-992,
2004
10. Mimura T, Amano S, Usui T, Araie M, Ono K,
Hashizume A, Yokoo S, Yamagami S. Transplantation of corneas reconstructed with cultured adulthuman corneal endothelial cells in nude rats. Exp
Eye Res 79:231-237, 2004
11. Mimura T, Yamagami S, Yokoo S, Usui T, Tanaka
K, Hattori S, Irie S, Miyata K, Araie M, Amano S.
Cultured human corneal endothelial cell transplantation with a collagen sheet in a rabbit model. Invest Ophthalmol Vis Sci 45:2992-2997, 2004
12. Mimura T, Amano S, Sugiura T, Funatsu H, Yamagami S, Araie M, Eguchi S. Refractive change after
transscleral fixation of posterior chamber intraocular lenses in the absence of capsular support. Acta
Ophthalmologica Scandinavica, 82:544-546, 2004
13. Inoki T, Endo H, Inoki Y, Hamamoto T, Tsuru T,
Mori T, Miyata K, Amano S, Yamagami S. Damaged DNA-binding protein 2 accelerates UVdamaged DNA repair in human corneal endothelium. Exp Eye Res 79:367-376, 2004

397

14. Usui T, Yamagami S, Yokoo S, Mimura T, Ono K,
Amano S. Gene expression profile in corneal neovascularization identified by immunology related
macroarray. Mol Vis 10:832-836, 2004
15. Mimura T, Yamagami S, Amano S, Funatsu H,
Arimoto A, Usui T, Ono K, Araie M, Okamoto S.
Allergens in Japanese patients with allergic conjunctivitis in autumn. Eye, Sep 24; [Epub ahead ofprint], 2004
16. Hamada
N, Amano
S, Yamagami
S, Araie
M, Oshika T, Wada T, Miyai H, Notsu Y. Change incorneal permeability to timolol after laser in situ
keratomileusis and photorefractive keratectomy inrabbit. Jpn J Ophthalmol 49:12-14, 2005
17. Mimura T, Funatsu H, Yamagami S, Usui T, Ono K,
Araie M, Amano S. Vasovagal syncope evoked byneedle phobia when inserting a contact lens. Ophthalmic Physiol Opt 25:171-173, 2005
18. Mimura T, Yamagami S, Usui T, Ishii Y, Ono K,
Yokoo S, Funatsu H, Araie A, Amano S. Long-term
outcome of iron-endocytosing cultured corneal endothelial cell transplantation with magnetic attraction. Exp Eye Res 80:149-157, 2005
19. Nanba A, Amano S, Oshika T, Uno T, Toshino A,
Ohashi Y, Yamaguchi T, Mihashi T. Corneal higher
order wavefront aberrations after hyperopic laser insitu keratomileusis. J Refract Surg 21:46-51, 2005
20. Yamagami S, Ebihara N, Yokoo S, Amano S.
Chemokine receptor gene expression in giant papillae of atopic keratoconjunctivitis. Mol Vis
11:192-200, 2005
21. Miyai T, Miyata K, Nejima R, Amano S. Late-onset
repetitive traumatic flap folds and partial dehiscence of flap edge after laser in situ keratomileusis.
J Cataract Refract Surg 31:633-635, 2005
22. Nakahara M, Miyata K, Otani S, Miyai T, Nejima
R, Amano S. A randomized, placebo-controlled
clinical trial of the aldose reductase inhibitor
CT-112 as management of corneal epithelial disorders in diabetic patients. Br J Ophthalmol 89:266268, 2005
23. Inoue K, Okugawa K, Amano S, Oshika T, Takamura E, Egami F, Umizu G, Aikawa K, Kato S.
Blinking and superficial punctate keratopathy inpatients with diabetes mellitus. Eye 19:418-421,
2005
24. Kamiya K, Wang M, Uchida S, Amano S, Oshika T,

Sakuragawa N, Hori J. Topical application of culture supernatant from human amniotic epithelial cells suppresses inflammatory reactions in cornea. Exp Eye Res 80:671-679, 2005
25. Uchida S, Yokoo S, Yanagi Y, Usui T, Yokota C,
Mimura T, Araie M, Yamagami S, Amano S.
Sphere formation and expression of neural proteins
by human corneal stromal cells in vitro. Invest
Ophthalmol Vis Sci 46:1620-1625, 2005
26. Yokoo S, Yamagami S, Yanagi S, Uchida S, Mimura T, Usui T, Amano S. Human corneal endothelium precursors isolated by sphere-forming assay.
Invest Ophthalmol Vis Sci 46:1626-1631, 2005
27. Kaji Y, Oshika T, Amano S, Okamoto F, Koito W,
Horiuchi S. Immunohistochemical localization ofadvanced glycation end products in pinguecula.
Graefes Arch Clin Exp Ophthalmol 21:1-5, 2005
28. Mimura T, Yokoo S, Kaji Y, Usui T, Yamagami S,
Ono K, Araie M, Amano S. Ultraviolet transmittance of human limbal epithelial cells cultured onhuman amniotic membranes. Curr Eye Res 30:555561, 2005
29. Miyai T, Hara R, Nejima R, Miyata K, Yonemura T,
Amano S. Limbal allograft, amniotic membranetransplantation, and intraoperative mitomycin C forrecurrent pterygium. Ophthalmology 112:12631267, 2005
30. Mimura T, Yamagami S, Yokoo S, Yanagi Y, Usui T,
Ono K, Araie M, Amano S. Spheretherapy for corneal endothelium deficiency in a rabbit model. Invest Ophthalmol Vis Sci 46:3128-3135, 2005
31. Mimura T, Yokoo S, Araie M, Amano S, Yamagami
S. Treatment of rabbit bullous keratopathy withprecursors derived from cultured human corneal
endothelium. Invest Ophthalmol Vis Sci 46:36373644, 2005
32. Mimura T, Yamagami S, Yokoo S, Araie M, Amano
S. Comparison of rabbit corneal endothelial cell
precursors in the central and peripheral regions. Invest Ophthalmol Vis Sci 46:3645-3648,
2005
33. Amano S, Nanba A, Hamada N, Oshika T, Uno T,
Toshino A, Ohashi Y. Corneal irregular astigmatism
after hyperopic laser in situ keratomileusis. Cornea
24:789-792, 2005
34. Miyata K, Yamagami S, Nejima R, Miyai T, Shimizu K, Amano S. Corneal endothelial cell protec-

398tion with viscoat and healon or healon alone duringpenetrating keratoplasty. Cornea 24:962-966, 2005
35. Hashizume A, Usui T, Yokoo S, Mimura T, Araie M,
Yamagami S, Amano S. Intraocular pressure measurement over amniotic membrane patch in humansubjects. Cornea 24:925-927, 2005
36. Yamagami S, Usui T, Amano S, Ebihara N. Bonemarrow-derived cells in mouse and human cornea.
Cornea 24 (8 Suppl 1):S71-S74, 2005
37. Usui T, Sugisaki K, Amano S, Jang WD,
Nishiyama N, Kataoka K. New drug delivery forcorneal neovascularization using polyion complex
micelles. Cornea 24 (8 Suppl 1):S39-S42, 2005
38. Mimura T, Funatsu H, Uchigata Y, Kitano S, Shimizu E, Amano S, Yamagami S, Noma H, Araie M,
Hori S. Glutamic acid decarboxylase autoantibody
prevalence and association with HLA genotype inpatients with younger-onset type 1 diabetes andproliferative diabetic retinopathy. Ophthalmology
112:1904-1909, 2005
39. Amano S, Mimura T, Yamagami S, Osakabe Y,
Miyata K. Properties of cornea reconstructed with
cultured human corneal endothelial cells and human corneal stroma. Jpn J Ophthalmol 49:448-452,
2005
40. Yamagami S, Yokoo S, Usui T, Yamagami H,
Amano S, Ebihara N. Distinct populations of dendritic cells in the normal human donor corneal epithelium. Invest Ophthalmol Vis Sci 46:4489-4494,
2005

399

University hospital
Medical Information Network(UMIN) Center
Professor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Noriaki Aoki, M.D., Ph.D, M.S.

Homepage http://www.umin.ac.jp/umin/
Introduction and Organization

6. upport medical education and clinical training

The University hospital Medical Information Network (an original name was the University Medical
Information Network: UMIN), was established in 1989.
While general-use computer systems had been implemented at all national university hospitals around theend of the Showa era (late 1980s), Dr. Kaihara, a chairand professor of Hospital Computer Center, the University of Tokyo Hospital, led a project to connect thesecomputer systems in a network in order to share information for better communication. Finally, the Ministryof Education, Culture, Sports, Science and Technology
accepted a budget to initiate the UMIN Center. The
UMIN Center was founded within the Hospital Computer Center, the University of Tokyo Hospital, andofficially started in March, 1989. Followings were purposes of the UMIN center, which were initially described in 1989 (No.6 was added later)

The original UMIN system utilized N1 protocol,
which was developed in Japan and was the only solution at the time to connect together general-use computers of the five major computer vendors in Japan,
although it was poor in function, supporting only
line-mode, character-based terminals. Dr. Tsunetaro
Sakurai became an associate professor as the first
UMIN exclusive staff.
In 1994, we started service through the Internet
whose spread began as in those days. A number of
UMIN users had been gradually increased mainly on an
E-mail service.
In 1996, Dr. Takahiro Kiuchi took up his new post
while Dr. Sakurai promoted to a professor at the Hokkaido University, and updated the system to web-based.
With a rapid spread of the Internet in Japan, UMIN users had been drastically increased afterwards.
The UMIN Center, then started to provide three major information services, (1) ELBIS (Electronic Libraryfor Biomedical Sciences) since 1997, (2) INDICE(Internet Data and Information Center of Clinical Research) since 2000, and (3) EPOC (Evaluation system
of Postgraduate Clinical training) since 2004.
In April, 2002, the UMIN Center became independent entity as the University hospital Medical Information Network Center (UMIN) by an internal arrange-

1. rovide up-to-date information for health care professionals
2. romote digitalized communication among healthcare professionals
3. upport collaborative project among university hospitals
4. upport collaborative medical research
5. tandardize data format and support data collection

400

ment at the University of Tokyo Hospital. In 2003, a
budget for new professor position was officially approved by the Ministry of Education, Culture, Sports,
Science and Technology. Then, Dr. Kiuchi was promoted to the first professor of the UMIN Center on
April 1, 2004. On October 1, 2004, Ms. Hisako Matsuba arrived at the post of the associate whom thelower part diverted the associate professor post. She
resigned from her job in the end of March, 2006, and,Dr. Noriaki Aoki, an assistant professor of the School of
Health Information Sciences, University of Texas
Health Science Center at Houston, became an associate
professor of the Center.
In addition to the professor and associate professor,
the center employs one part-time staff assistant, six
contract computer operators, and four to five systemengineers, who are responsible for computer administration, operation maintenance support, and softwaredevelopment.

Teaching activities
We provide one lecture for medical school students,
Medical Literature Informatics by Dr. Kiuchi, and two
lectures for MPH students: Science Communication by
Dr. Kiuchi and Health Communication by Dr. Aoki.
In addition, we provide briefing sessions and symposiums to disseminate 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. These sessions and symposiums were broadcasted through the MINCS system,
and can be downloaded as VOD from the UMIN server.

Research activities
The two main distinguished characteristics of researches at the UMIN Center, which are different fromstudies at other medical informatics programs, are followings.
(1) Researches for health informatics and communication
The UMIN Center is the only one research institutethat study health informatics and communica-tion-related researches, such as the Internet, satellite communications.
(2) Research targeting on health information science,
not healthcare information practiceCurrently, main topics of researches at most medical informatics programs in Japan focus on study
for information for healthcare practice, such as
hospital information system, electronic medical
record system, telemedicine, and electronic billingsystem. In contrast, the UMIN Center has focusedon the information systems for medical science,such as medical literature database, data registry
for clinical studies, information system for medical
education.
The followings are current research topics at the
UMIN center.
(1) UMIN activities related Research
Most systems developed at the UMIN Center havebeen subjects for the research. We especially reported and published systems utilizing advanced
technologies and having scientifically meaningfulconcepts at the academic conferences.
(2) Information system for clinical epidemiologic
studies
We have developed and applied information systems for clinical epidemiological studies. Recently,
we have focused on research for electronic format
and standardization that are related to clinical research, such as CDISC. We utilized the achievements for medical research data center at the
UMIN.
(3) Study about security of an information network
Virtual Private Network (VPN)、secure transaction
with electronic mail (encryption), which have been
also utilized for system management for UMIN
center.
(4) Study plan development / a statistical analysis ofclinical studies
In cooperation with clinicians, the UMIN Center
performs development of clinical research plans
and support statistical analysis. In addition, we
have done data mining research for information
extraction, knowledge discovery and prognostic
modeling. Furthermore, we have conducted research and development for decision support sys-

401

(5)

(6)

(7)

(8)

(9)

tems to utilize the results in clinical practice.
Technology assessment of health information andcommunication technologies
Although information technology is expected toplay aｎ important role in health care, its comprehensive usefulness, including cost-effectiveness,has been rarely evaluated. We conducted literature
review in 2003 and concluded that there were few
cost-effectiveness analyses for telemedicine program even though many telemedicine programs
have been installed throughout many developed
countries, such as the USA and Japan. Based on
the review, we have done cost-effectiveness analysis for information technologies.
Research for health communication
Recently, “health communication” is becoming
important concept in order to distribute the clinicalresults for population-based clinical outcomes improvement. We have conducted health communication research, which is focused on knowledge
and skills in “informatics” and “communication”.
Research for edutainment
To disseminate clinical knowledge and information
to lay persons, it is important to consider about“easy-to-understand” and “acceptable by unknowledgeable persons”. We focus on studies related to media, entertainment, and interface design.
For example, we have conducted development andevaluation of edutainment tools for health education to type-1 diabetes patients as concrete application.
The patient registry system for quality improvement
Many data have been accumulated in the existing
hospital information system such as electronic record systems, however these data have been hardly
utilized for quality improvement, patient safety or
medical management. We have deployed an interactive web-based patient registry system withreal-time feedback system of quality indicators(QIs).
Research regarding medical management
It is important to make proper judge and decision
to achieve the optimal outcomes, which is called as
management. However, scientific researches andevaluations related to patient safety, quality improvement and medical management have notbeen?are not well established in Japan. We focus
on the Theory of Constraint (TOC) as a tool for
medical management from a perspective of information utilization, and conducted research for
medical error prevention and quality improvement.

References
1. Aoki N, Ohta S, Okada T, Oishi M, Fukui T.
INSULOT - An edutainment learning tool for
type-1 diabetes children. Diabetes Care. 2005; 28:760.
2. Kiuchi T, Igarashi T. UMIN - Current status andfuture perspectives. MEDINFO 2004, IOS press,
1068-1072, 2004.
3. Aoki N, Ohta S, Masuda H, Naito T, Sawai T, Nishida K, Okada T, Oishi M, Iwasawa Y, Toyomasu
K, Hira K, Fukui T. Edutainment Tools for Initial
Education of Type-1 Diabetes Mellitus - Initial
Diabetes Education with Fun -. MEDFINO 2004,
IOS press, 855-859, 2004.
4. Liang H, Aoki N, Chen JZ. Assessment of the Esophageal Pressure in Gastroesophageal Reflux Disease by the Local Regression. Proceedings in Intelligence Data Analysis in Medicine and Pharmacology (IDAMAP) Proceeding 2004; 15-20, 2004.
5. Aoki N, Dunn K, Beck JR, Fukui T, Schull WJ, Li
HK. Cost-effectiveness analysis of teleophthalmology for screening and follow-up of diabetic
retinopathy in a prison inmate in Texas prison system. Diabetes Care. 2004; 27: 1195-1101.
6. Aoki N, Nishimura A, Pretto EA. Sugimoto K,
Beck JR, Fukui T. Survival and Cost Analysis of
fatalities of Kobe Earthquake. Prehosp Emerg Care.
2004; 8:217-222.
7. Hira K, Aoki N, Fukui T. Pseudohyperkalaemia at
Commercial Laboratories in Japan: A Questionnaire Survey. Ann Clin Biochem. 2004; 41:155156.
8. Hira K, Aoki N, Fukui T. Pseudonormokalaemia
caused by recentrifugation of blood samples after
storage in gel-separator tubes. Ann Clin Biochem.
2004; 41:82-83.

402

Organ Transplantation Service
Director Professor
Masatoshi Makuuchi

Homepage
Organ Transplant Service started to function since2003. In the Western countries the solid organ transplantation is widely performed and in contrast deceased
donor organs are extremely rare due to religious andcultural traditions. in Japan the number of the recipientsfrom the deceased donors has been limited around 40
under the act of law. The University of Tokyo Hospital
has aggressively performed organ transplantation. In
1966, kidney transplantation for chronic renal failure
was firstly performed in Japan. In 1996 the living donorliver transplantation was performed and totally 352 patients underwent liver transplantation. The 5-year survival rate is around 85% which is much superior to thenational average (~70%). The University of Tokyo
Hospital has been one of the authorized institutions forheart transplantation.

403

Department of Cell Therapy andTransplantation Medicine
Associate Professor
Shigeru Chiba, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Junko Takita, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Associate
Noriko Hosoya, M.D., Ph.D. (Hematology-Oncology)

Homepage http://www.h.u-tokyo.ac.jp/mukin/index.htm
Introduction and Organization
Department of Cell Therapy and Transplantation
Medicine was institutionally established in 1995, andformally organized in 1996. At present, the staff consists of three medical doctors listed above. Clinical facilities include 8 single-patient rooms with high-efficiency particulate air filtration and other high standards.
Patients who are eligible for the treatment withhigh-grade infectious prophylaxis are admitted to thefacilities.

Clinical activities
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 theuse of an automated continuous flow blood cell separator, and harvested cells are preserved at -196°C in cooperation with Department of Transfusion Medicine.
Recently, transplantation after pre-conditioning of reduced intensity (RIST for reduced-intensity stem celltransplantation or NST for non-myeloabrative stem celltransplantation) is commonly performed for the elderly
patients and patients with organ damages, etc. The development of this strategy is expanding the eligibility oftransplant recipients.
Several clinical studies with allogeneic stem celltransplantation have been also conducted. These include RIST for pancreatic cancer, transplantation froma donor with mismatched HLA at two loci or more. All
these studies are approved by the ethical committee ofthe Faculty of Medicine.
High-dose chemotherapy with or without autologous
stem cell support: High-dose chemotherapy is administered according to the malignant disease. For the
autologous stem cell support, peripheral blood stem cellis usually selected as a source of stem cells. Similar
procedures used in the allogeneic stem cell harvest are
performed for leukapheresis and preservation.
Clinical conference for hematopoietic stem celltransplantation : The conference is held monthly, inwhich the members of Department of Hematology/Oncology and Hematology/Oncology group in the
Department of Pediatrics, and some members of Department of Transfusion Medicine routinely participate
and discuss on the patients receiving hematopoietic
stem cell transplantation.

404

Teaching activities
Together with the members of Department of Hematology/Oncology and Hematology/Oncology group in
the Department of Pediatrics, lecture courses on etiology, pathogenesis, clinical and laboratory features, differential diagnosis, therapy and prognosis for all hematological diseases are provided for the second grade
medical students. Courses for bedside learning on diagnostic and therapeutic issues and arts are given for
the third grade medical students on a man-to-man basiswith a senior faculty member. Clinical clerkshipcourses are given to the fourth grade medical students,
who join the patient care teams consisting of junior andsenior medical doctors and learn medical practices andpatient management, through playing a role as a juniormember of the team, as well as through discussions andpresentations.

4.

5.

Research activities
The major research projects are focused on clinicalstudies such as development of improved/new methods
for hematopoietic stem cell transplantation, immunotherapy for hematopoietic tumors, and basic studies onhematopoietic stem cells and leukemogenesis. In thearea of pediatric oncology, we continue the studies onmolecular mechanisms of pediatric malignancies, suchas neuroblastoma, rhabdomyosarcoma, and infant leukemia. Representative publications from our department published in the past two years are listed in thereferences.

6.

7.

References
1. Endo-Matsubara M, Ogawa S, Sasaki K, Takahashi
T, Chiba S, Hirai H. Immature granulocyte fractionin the peripheral blood is a practical indicator formobilization of CD34(+) cells. Am J Hematol
77:223-228, 2004
2. Yanada M, Emi N, Naoe T, Sakamaki H, Iseki T,
Hirabayashi N, Karasuno T, Chiba S, Atsuta Y,
Hamajima N, Takahashi S, Kato S. Allogeneic
myeloablative transplantation for patients aged 50
years and over. Bone Marrow Transplant 34:29-35,
2004
3. Morishima Y, Ogura M, Nishimura M, Yazaki F,

8.

9.

Bessho M, Mizoguchi H, Chiba S, Hirai H, Tauchi
T, Urabe A, Takahashi M, Ohnishi K, Yokozawa T,
Emi N, Hirano M, Shimazaki C, Nakao S, Kawai Y,
Fujimoto M, Taguchi H, Jinnai I, Ohno R. Efficacy
and safety of imatinib mesylate for patients in thefirst chronic phase of chronic myeloid leukemia:
results of a Japanese phase II clinical study. Intl J
Hematol 80:261-266, 2004
Sakata-Yanagimoto M, Kanda Y, Nakagawa M,
Asano Y, Nakagawa M, Sakata-Yanagimoto M,
Kandabashi K, Izutsu K, Imai Y, Hangaishi A, Kurokawa M, Tsujino S, Ogawa S, Aoki K, Chiba S,
Motokura T, Hirai H. Predictors for severe cardiac
complications after hemato- poietic stem cell transplantation. Bone Marrow Transplant 33:10431047, 2004
Kojima R, Kami M, Nannya Y, Kusumi E, Sakai M,
Tanaka Y, Kanda Y, Mori S, Chiba S, Miyakoshi S,
Tajima K, Hirai H, Taniguchi S, Sakamaki H, Takaue Y. Incidence of invasive aspergillosis after allogeneic hematopoietic stem cell transplantation
with a reduced- intensity regimen compared withtrans- plantation with a conventional regimen. Biol
Blood Marrow Transplant 10:645-652, 2004
Kawazu M, Kanda Y, Nannya Y, Aoki K, Kurokawa M, Chiba S, Motokura T, Hirai H, Ogawa S.
Prospective comparison of the diagnostic potentialof real-time PCR, double-sandwich enzyme-linked
immuno- sorbent assay for galactomannan, and a(1-->3)-beta-D-glucan test in weekly screening forinvasive aspergillosis in patients with hematological disorders. J Clin Microbiol 42:2733-2741, 2004
Haraguchi K, Takahashi T, Hiruma K, Kanda Y,
Tanaka Y, Ogawa S, Chiba S, Miura O, Sakamaki
H, Hirai H. Recovery of Valpha24(+) NKT cells
after hematopoietic stem cell trans- plantation.
Bone Marrow Transplant 34:595- 602, 2004
Goyama S, Yamaguchi Y, Imai Y, Kawazu M, Nakagawa M, Asai T, Kumano K, Mitani K, Ogawa S,
Chiba S, Kurokawa M, Hirai H. The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonicpara-aortic splanchnopleural (P-Sp) region. Blood
104:3558-3564, 2004
Goyama S, Kanda Y, Nannya Y, Ogawa S,
Asano-Moki Y, Ogawa N, Nakagawa M, SakataYanagimoto M, Kawazu M, Komeno Y, Imai Y,

405

Hangaishi A, Kurokawa M, Tsujino S, Aoki K,
Chiba S, Motokura T, Hirai H. Clinical significanceof peripheral blood erythro- blastosis after hematopoietic stem cell trans- plantation. Leukemia
Lymphoma 45:2439- 2443, 2004
10. Takita J, Ishii M, Tsutsumi S, Tanaka Y, Kato K,
Toyoda Y, Hanada R, Yamamoto K, Hayashi Y,
Aburatani H. Gene expression profiling and identification of novel prognostic marker genes in neuroblastoma. Genes Chromosomes Cancer. 40:120132, 2004
11. Hosoya N, Qiao Y, Hangaishi A, Wang L, Nannya
Y, Sanada M, Kurokawa M, Chiba S, Hirai H,
Ogawa S. Identification of a SRC-like tyrosine
kinase gene, FRK, fused with ETV6 in a patientwith acute myelogenous leukemia carrying at(6;12)(q21;p13) translocation. Genes Chromosomes Cancer 42:269-279, 2005
12. Kawazu M, Asai T, Ichikawa M, Yamamoto G,
Saito T, Goyama S, Mitani K, Miyazono K, Chiba
S, Ogawa S, Kurokawa M, Hirai H. Functional
domains of Runx1 are differentially required forCD4 repression, TCRβ expression, and CD4/8
double-negative to CD4/8 double-positive transition in thymocyte development. J Immunol 174:3526-3533, 2005
13. Hori A, Kanda Y, Goyama S, Onishi Y, Komeno Y,
Mitani K, Kishi Y, Ogawa S, Imataki O, Chiba S,
Kojima R, Hamaki T, Sakiyama M, Kami M,
Makimoto A, Tanosaki R, Takaue Y, Hirai H. A
prospective trial to evaluate the safety and efficacy
of pravastatin for the treatment of refractorychronic graft-versus-host disease. Transplantation
79:372-374, 2005
14. Komeno Y, Kurokawa M, Imai Y, Takeshita M,
Matsumura T, Kubo K, Yoshino T, Nishiyama U,
Kuwaki T, Kubo K, Osawa T, Ogawa S, Chiba S,
Miwa A, Hirai H. Ki23819 inhibits kinase activityof wild type and mutant FLT3 receptor tyrosine
kinase in vitro. Leukemia 19:930-935, 2005
15. Kanda Y, Oshima K, Asano-Mori Y, Kanda- bashi
K, Nakagawa M, Sakata-Yanagimoto M, Izutsu K,
Hangaishi A, Tsujino S, Ogawa S, Motokura T,
Chiba S, Hirai H. In vivo alemtuzumab enables
haploidentical HLA- mismatched hematopoietic
stem cell trans- plantation without ex vivo graft
manipulation. Transplantation 79:1351-1357, 2005

16. Kanda Y, Komatsu Y, Akahane M, Kojima S,
Asano-Mori Y, Tada M, Oshima K, Isayama H,
Ogawa S, Motokura T, Chiba S, Ohtomo K, Omata
M, Hirai H. Graft-versus-tumor effect against advanced pancreatic cancer after allogeneic reduced-intensity stem cell trans- plantation. Transplantation 79:821-827, 2005
17. Nitta E, Izutsu K, Yamaguchi Y, Imai Y, Ogawa S,
Chiba S, Kurokawa M, Hirai H. Oligomerization ofEvi-1 regulated by the PR domain contributes torecruitment of corepressor CtBP. Oncogene 24:
6165-6173.
18. Seo S, Asai T, Saito T, Suzuki T, Morishita Y, Nakamoto T, Ichikawa M, Yamamoto G, Kawazu M,
Yamagata T, Sakai R, Mitani K, Ogawa S, Kurokawa M, Chiba S, Hirai H. Crk-associated substrate
lymphocyte type is required for lymphocyte trafficking and marginal zone B cell maintenance. J
Immunol 175:3492-3501, 2005
19. Masuda S, Kumano K, Shimizu K, Imai Y, Kurokawa M, Ogawa S, Miyagishi M, Taira K, Hirai H,
Chiba S. The Notch1 oncoprotein antagonizes
TGF-β/Smad-mediated cell growth suppression via
sequestration of co-activator p300. Cancer Science
96:274-282, 2005
20. Oshima K, Sakata-Yanagimoto M, Asano-Mori Y,
Izutsu K, Watanabe T, Shoda E, Ogawa S, Motokura T, Chiba S, Kurokawa M, Hirai H, Kanda Y.
Cardiac complications after haploidentical HLAmismatched hematopoietic stem cell transplantation
using in vivo alemtuzumab. Bone Marrow Transplant 36: 821-824, 2005
21. Crcareva A, Saito T, Kunisato A, Kumano K, Suzuki T, Sakata-Yanagimoto M, Kawazu M, Stojanovic A, Kurokawa M, Ogawa S. Chiba S. Hematopoietic stem cells expanded by fibroblast growth
factor-1 are excellent targets for retrovirus-mediated gene delivery. Exp Hematol 33:14591469, 2005
22. Haraguchi K, Takahashi T, Matsumoto A, Asai T,
Kanda Y, Kurokawa M, Ogawa S, Oda H, Taniguchi M, Hirai H, Chiba S. Host-residual invariant
NK T cells attenuate graft-versus-host immunity. J
Immunol 175:1320-1328, 2005
23. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita
J, Nakazaki K, Kurokawa M, Hayashi Y, Ogawa S,
Chiba S. Mutations of the Notch1 gene in T-cell406

acute lymphoblastic leukemia: analysis in adults
and children. Leukemia 19:1841-1843, 2005
24. Nannya Y, Sanada M, Nakazaki K, Hosoya N,
Wang L, Hangaishi A, Kurokawa M, Chiba S, Bailey DK, Kennedy GC, Ogawa S. A robust algorithm for copy number detection using high-density
oligonucleotide single nucleotide polymorphism
genotyping arrays. Cancer Res 65:6071-6079, 2005
25. Chen YY, Takita J, Tanaka K, Ida K, Koh K, Igarashi T, Hanada R, Kikuchi A,Tanaka Y, Toyoda Y,
Hayashi Y. Aberrations of the CHK2 gene are rarein pediatric solid tumors. Int J Mol Med 16:85-91,
2005
26. Kawaguchi H, Taketani T, Hongo T, Park MJ, Koh
K, Ida K, Kobayashi M, Takita J, Taki T, Yoshino H,
Bessho F, Hayashi Y. In vitro drug resistance toimatinib and mutation of ABL gene in childhood
Ph+ acute lymphoblastic leukemia. Leukemia andLymphoma 46:273- 276, 2005

407

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Takao Kawabe, Ph.D.

Homepage
Introduction and Organization
Department of Endoscopy and Endoscopic Surgery
was established in April 1997. Although the present
staff of our department is only an associate professor,
about 80 doctors of other departments, including thedepartment of internal medicine, surgery, gynecology
and otorhinolaryngology, participate the examinations.

Clinical activities

stone removal, and endoscopic stenting for biliary malignant diseases, are recently increasing. Our recent
clinical activities are summarized in Table 1.
Another important activity of our department is thedisinfection and maintenance of endoscopic apparatuses
used in other units including outpatient clinic, radiolographic procedure rooms, surgery rooms or intensive
care units. All endoscopes are collected in our department after use and disinfected.

Teaching activities

Endoscopic examinations, including upper gastrointestinal endoscopy, colonoscopy, bronchoscopy,
otorhinolaryngological examinations and gynecologycal examinations, are performed from Monday to Friday.
Therapeutic endoscopies, including endoscopic variceal
ligation, endoscopic resection including submucosal
dissection for esophageal, gastric and colorectal tumors,polypectomy for colonic polyps, endoscopic biliary

We participate in under-graduate education as a partof systemic lectures and bed-side learning for medical
students by the department of gastroenterology, surgery
and other departments. As for post-graduate education,
training opportunities for endoscopy and endoscopic
surgery are given to resident or young doctors in a program of each department.

Table 1. Enoscopic examinations in Depatment of Endoscopy and Endoscooic Surgery
1997

1998 1999

2000

2001

2002

2003

2004

2005

UGI endoscopy
Colonoscopy
Bronchoscopy
EUS**

4384
1398
190

5555 5667
2415 2472
239 282

5923
2799
233

6346
3212
194

7324
3529
220

7920
3873
207

7597
3728
194

8265
4084
212

347

562

569

470

479

583

586

476

461

Laparoscopy
Otophino-laryngological examination
Gynecological examination

19
131
272

7
96
213

2
99
153

0
115
149

154
181

93
103

68
124

61
139

89
88

Total

6741

9087 9244

9689

*

*

UGI; upper gastrointestinal, **Endoscopic ultarasonography

10566 11852

12778 12195 13199

408

Research activities
Our researches cover a variety of fields including theupper and lower gastrointestinal tract and the pancreatobilialy system. They are mainly performed in cooperation with the department of Gastroenterology.

References
1. Yamaji Y, Mitsushima T, Ikuma H, Watabe H,
Okamoto M, Kawabe T, Wada R, Doi H, Omata M.
Incidence and recurrence rates of colorectal adenomas estimated by annually repeated colonoscopies on asymptomatic Japanese. Gut 2004; 53:
568-72.
2. Isayama H, Komatsu Y, Tsujino T, Sasahira N, Hirano K, Toda N, Nakai Y, Yamamoto N, Tada M,
Yoshida H, Shiratori Y, Kawabe T, Omata M. A
prospective randomised study of "covered" versus"uncovered" diamond stents for the management of
distal malignant biliary obstruction. Gut 2004; 53:
729-34.
3. Ikenoue T, Hikiba Y, Kanai F, Aragaki J, Tanaka Y,
Imamura J, Imamura T, Ohta M, Ijichi H, Tateishi
K, Kawakami T, Matsumura M, Kawabe T, Omata
M. Different effects of point mutations within the
B-Raf glycine-rich loop in colorectal tumors on
mitogen-activated protein/extracellular signal-regulated
kinase kinase/extracellular signal-regulated kinaseand nuclear factor kappaB pathway and cellulartransformation. Cancer Res 2004; 64: 3428-35.
4. Imamura T, Kanai F, Kawakami T, Amarsanaa J,
Ijichi H, Hoshida Y, Tanaka Y, Ikenoue T, Tateishi
K, Kawabe T, Arakawa Y, Miyagishi M, Taira K,
Yokosuka O, Omata M. Proteomic analysis of the
TGF-beta signaling pathway in pancreatic carcinoma cells using stable RNA interference to silence
Smad4 expression. Biochem Biophys Res Commun
2004; 318: 289-96.
5. oda N, Saito K, Wada R, Komatsu Y, Tada M,
Kawabe T, Mitsushima T, Shiratori Y, Omata M.
Early removal of bile duct stones in patients withacute biliary pancreatitis by endoscopic papillaryballoon dilatation. Hepatogastroenterology 2004;
51: 1263-6.
6. Hirano K, Komatsu Y, Yamamoto N, Nakai Y, Sasahira N, Toda N, Isayama H, Tada M, Kawabe T,

Omata M. Pancreatic mass lesions associated withraised concentration of IgG4. Am J Gastroenterol
2004; 99: 2038-40.
7. Hirata Y, Yanai A, Shibata W, Mitsuno Y, Maeda S,
Ogura K, Yoshida H, Kawabe T, Omata M. Functional variability of cagA gene in Japanese isolatesof Helicobacter pylori. Gene 2004; 343: 165-72.
8. Okamoto M, Kawabe T, Yamaji Y, Kato J, Ikenoue
T, Togo G, Watabe H, Yoshida H, Shiratori Y,
Omata M. Flat-type early colorectal cancer preferentially develops in right-sided colon in older patients. Dis Colon Rectum 2005; 48: 101-7.
9. Isayama H, Kawabe T, Komatsu Y, Sasahira N,
Toda N, Tada M, Nakai Y, Yamamoto N, Hirano K,
Tsujino T, Yoshida H, Omata M. Successful treatment for groove pancreatitis by endoscopic drainage via the minor papilla. Gastrointest Endosc
2005; 61: 175-8.
10. Tsujino T, Isayama H, Komatsu Y, Ito Y, Tada M,
Minagawa N, Nakata R, Kawabe T, Omata M. Risk
factors for pancreatitis in patients with common
bile duct stones managed by endoscopic papillaryballoon dilation. Am J Gastroenterol 2005; 100:
38-42.
11. Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B,
Ohta M, Imamura J, Tanaka Y, Tateishi K, Ikenoue
T, Kawakami T, Arakawa Y, Miyagishi M, Taira K,
Kawabe T, Omata M. Smad4 silencing in pancreatic cancer cell lines using stable RNA interference
and gene expression profiles induced by transforming growth factor-beta. Oncogene 2005; 24:
662-71.
12. Sasahira N, Kawabe T, Nakamura A, Shimura K,
Shimura H, Itobayashi E, Asada M, Shiratori Y,
Omata M. Inflammatory pseudotumor of the liverand peripheral eosinophilia in autoimmune pancreatitis. World J Gastroenterol 2005; 11: 922-5.
13. Tsujino T, Komatsu Y, Isayama H, Hirano K, Sasahira N, Yamamoto N, Toda N, Ito Y, Nakai Y, Tada
M, Matsumura M, Yoshida H, Kawabe T, Shiratori
Y, Omata M. Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography: arandomized, controlled trial. Clin Gastroenterol
Hepatol 2005; 3: 376-83.
14. Okamoto M, Kawabe T, Yamaji Y, Kato J, Ikenoue
T, Togo G, Yoshida H, Shiratori Y, Omata M. Rectosigmoid findings are not associated with proximal

409

colon cancer: analysis of 6 196 consecutive cases
undergoing total colonoscopy. World J Gastroenterol 2005; 11: 2249-54.
15. Kondo S, Isayama H, Akahane M, Toda N, Sasahira N, Nakai Y, Yamamoto N, Hirano K, Komatsu
Y, Tada M, Yoshida H, Kawabe T, Ohtomo K,
Omata M. Detection of common bile duct stones:
comparison between endoscopic ultrasonography,
magnetic resonance cholangiography, and helical-computed-tomographic cholangiography. Eur JRadiol 2005; 54: 271-5.
16. Sasahira N, Tada M, Yoshida H, Tateishi R, Shiina
S, Hirano K, Isayama H, Toda N, Komatsu Y,
Kawabe T, Omata M. Extrahepatic biliary obstruction after percutaneous tumour ablation for hepatocellular carcinoma: aetiology and successful treatment with endoscopic papillary balloon dilatation.
Gut 2005; 54: 698-702.
17. Toda N, Saito K, Wada R, Kawabe T, Shiratori Y,
Mitsushima T, Omata M. Endoscopic sphincterotomy and papillary balloon dilation for bile ductstones. Hepatogastroenterology 2005; 52: 700-4.
18. Watabe H, Mitsushima T, Yamaji Y, Okamoto M,
Wada R, Kokubo T, Doi H, Yoshida H, Kawabe T,
Omata M. Predicting the development of gastriccancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective
endoscopic cohort study. Gut 2005; 54: 764-8.
19. Ikenoue T, Kanai F, Hikiba Y, Obata T, Tanaka Y,
Imamura J, Ohta M, Jazag A, Guleng B, Tateishi K,
Asaoka Y, Matsumura M, Kawabe T, Omata M.
Functional analysis of PIK3CA gene mutations inhuman colorectal cancer. Cancer Res 2005; 65:4562-7.
20. Ohta M, Tateishi K, Kanai F, Ueha S, Guleng B,
Washida M, Tanaka Y, Ijichi H, Ikenoue T, Sata M,
Sudo T, Shiina S, Kawabe T, Matsushima K, Omata
M. Reduced p38 mitogen-activated protein kinase
in donor grafts accelerates acute intestinal graftversus-host disease in mice. Eur J Immunol 2005;
35: 2210-21.
21. Shao RX, Otsuka M, Kato N, Chang JH,
Muroyama R, Taniguchi H, Moriyama M, Wang Y,
Kawabe T, Omata M. No mutations in the tyrosine
kinases of human hepatic, pancreatic, and gastriccancer cell lines. J Gastroenterol 2005; 40: 918.
22. Okamoto M, Kawabe T, Kato J, Yamaji Y, Ikenoue

T, Omata M. Ultrathin colonoscope with a diameterof 9.8 mm for total colonoscopy. J Clin Gastroenterol 2005; 39: 679-83.
23. Toda N, Akahane M, Kiryu S, Matsubara Y, Yamaji
Y, Okamoto M, Minagawa N, Ohgi K, Komatsu Y,
Yahagi N, Yoshida H, Kawabe T, Ohtomo K,
Omata M. Pancreas duct abnormalities in patientswith ulcerative colitis: a magnetic resonance pancreatography study. Inflamm Bowel Dis 2005; 11:903-8.
24. Shibata W, Hirata Y, Yoshida H, Otsuka M, Hoshida Y, Ogura K, Maeda S, Ohmae T, Yanai A,
Mitsuno Y, Seki N, Kawabe T, Omata M.
NF-kappaB and ERK-signaling pathways contribute to the gene expression induced by cag
PAI-positive-Helicobacter pylori infection. World J
Gastroenterol 2005; 11: 6134-43.
25. Okamoto M, Kawabe T, Ohata K, Togo G, Hada T,
Katamoto T, Tanno M, Matsumura M, Yamaji Y,
Watabe H, Ikenoue T, Yoshida H, Omata M. Amebic colitis in asymptomatic subjects with positive
fecal occult blood test results: clinical features different from symptomatic cases. Am J Trop Med
Hyg 2005; 73: 934-5.
26. Nakai Y, Isayama H, Komatsu Y, Tsujino T, Toda N,
Sasahira N, Yamamoto N, Hirano K, Tada M, Yoshida H, Kawabe T, Omata M. Efficacy and safetyof the covered Wallstent in patients with distal malignant biliary obstruction. Gastrointest Endosc
2005; 62: 742-8.
27. Ohmae T, Hirata Y, Maeda S, Shibata W, Yanai A,
Ogura K, Yoshida H, Kawabe T, Omata M.
Helicobacter pylori activates NF-kappaB via thealternative pathway in B lymphocytes. J Immunol
2005; 175: 7162-9.

410

Clinical Research Center
Professor
Masao Omata, M.D., Ph.D.

Associate Professor
Yoshihiro Arakawa, Ph.D.

Associate
Fumihiko Kanai, M.D., Ph.D. (Transferred to Clinical Drug Evaluation Endowed Department
on Nov. 2005)
Hirotsugu Watabe, M.D., Ph.D. (Appointed on Dec. 2005)

Homepage http://www.h.u-tokyo.ac.jp/gcp/home/index.htm
Introduction and Organization
The Clinical Research Center was established in
April 2001 as one of the regular departments in thecentral division in our hospital. The Center not only
took over the duties of the former provisional Clinical
Trial Research Center, which dealt industry-initiatedclinical trials, but also newly-incorporated the commission to support investigator-initiated clinical trials. The
staff of the center as of March, 2006, is comprised of
one professor, one associate professor, one associate,five pharmacists, seven nurses, one clinical psychologist and three officials, of which one pharmacist andfive nurses were full-time workers with three years'
tenure and two officials and one clinical psychologist
were part-time workers. The center consists of four
subdivisions: a division of consultation on protocol development (one associate professor and one associate),
a division of pharmaceutical administration (threepharmacists), a division of clinical research coordination (seven nurses, two pharmacists and one clinicalpsychologist) and a division of clerkship (three officials).

Clinical activities
The duties of the center are wide-ranging from serving as a secretariat for the institutional review board(IRB) to supporting the conduct of clinical trials. Clinical trials that we dealt with covered all regulatory
clinical trials for approval and investigator-initiatedclinical trials concerned with medicinal treatments.
As an IRB secretariat, to which all the staffs are responsible, we dealt 43 new protocols and 55 ongoingprotocols for industry-initiated clinical trials in fiscal
2004. We also dealt with 3 new protocols for investigator-initiated regulatory clinical trials and 34 investigator-initiated non-regulatory clinical trials, which include
the ethical use of non-approved drugs. A peer-review
meeting was held every month for applications of new
industry-initiated protocols to facilitate a review withmeaningful discussion in the IRB and to give practicaladvice in carrying out the protocols properly. The
meeting was held with the attendance of applicant
company representatives, pre-registered review members from our hospital (pharmacists, doctors, nurses)
and the staffs of the center. We also dealt applications
for changes in the initial application documents (347applications), safety information (396 reports), andother reports in fiscal 2004.
As for pharmaceutical administration, we tookcharge of 102 clinical trial drugs and filled 812 prescriptions in fiscal 2004. Pharmacists in the division are
also in charge of the primary review of safety information about clinical trial drugs and the database management in the Center. Our databases concerning pro-

411

tocols and subjects were transferred to a new system as
a part of the hospital clinical information system inMarch 2006, allowing the direct access to the clinical
trial information from the hospital system.
Clinical research coordinators (CRC) supported theimplementation of all the ongoing regulatory clinical
trials in fiscal 2004. The coordination covered all aspects in pursuing clinical trials: preparation for the trials, screening for patients, assistance to obtain patients’
informed consent, coordinating outpatients’ visit, assistance with inspections, assistance in the preparation ofcase report forms (CRF), arrangements for monitoring
and audits, and arrangements for medical accounting.
There were a total of 2959 times of coordination of
outpatients' visits and medical treatments of inpatientsin fiscal 2004. CRC also supported the implementationof four investigator-initiated non-regulatory clinical
trials partly. In 2005, we introduced a principle that
beneficiaries should pay for part of a personnel cost of
CRCs and adopted two investigator-initiated protocols
for the CRC support on this principle.
Publicity activity has been continued including theprovision of the information about the protocols undersubject recruitment both in our internet home page andin our takeaway leaflets.
The consultation division started at May 2002 to
support the investigator-initiated clinical trial. The mission of the division is to help investigators to conductclinical research under the ethically and scientificallyreviewed protocols. Namely, the division supports protocol development, application to IRB and monitoringof the progress and amendment of clinical trials. As foreducational programs of clinical research for investigators, the division also gives a training course 3 to 4
times a year and a symposium every year. The division
dealt with 34 investigator-initiated clinical trials which
include the ethical use of non-approved drugs in fiscal
2004.

Teaching activities
The Center is taking charge of a part of bedsidelearning (BSL) of medical students in collaboration
with the Pharmaceutical Department. The Center also
accepted 90 third grade students of the Faculty of
Pharmaceutical Sciences for visit and 36 fourth gradestudents in five groups for training. Arakawa is taking

charge of one half-year lecture on clinical pharmacology for the graduate course students in the Faculty of
Pharmaceutical Sciences every year. One fourth gradestudent and two graduate students belonged to our research labs in fiscal 2004.
The Center is involved as an on-the-job training institution in CRC training programs. In fiscal 2004, we
accepted 8 three-week trainees from the program operated by Pharmacist Training Center.

Research activities
We performed the publication of 22 original
papers written in English, 2 original papers inJapanese and 7 review papers in Japanese andthe 45 presentations in academic conferences in
2004-2005.

References
1. Takayanagi R, Watanabe K, Nakahara A, Nakamura H, Yamada Y, Suzuki H, Arakawa Y, Omata
M, and Iga T. Items of concern associated withsource document verification of clinical trials for
new drugs. Yakugaku Zasshi 2004;124:89-92.
2. Takayanagi R, Nakamura Y, Nakajima Y, Shimizu
A, Nakamura H, Yamada Y, Suzuki H, Arakawa Y,
Omata M, Iga T. Analysis of information submitted
by clinical trial sponsors regarding the safety ofinvestigational drugs. Yakugaku Zasshi
2004;124:225-229.
3. Akazawa C, Tsuzuki H, Nakamura Y, Sasaki Y,
Ohsaki K, Nakamura S, Arakawa Y, Kohsaka S.
The upregulated expression of Sonic hedgehog inmotor neurons after rat facial nerve axotomy. J
Neurosci 2004;24:7923-7930.
4. Ijichi H, Otsuka M, Tateishi K, Ikenoue T, Kawakami T, Kanai F, et al. Smad4-independent regulation of p21/WAF1 by transforming growth factor-beta. Oncogene 2004;23(5):1043-51.
5. Ikenoue T, Hikiba Y, Kanai F, Aragaki J, Tanaka Y,
Imamura J, et al. Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinasekinase/extracellular signal-regulated kinase and nuclear factor kappaB pathway and cellular transfor-412

mation. Cancer Research 2004;64(10):3428-35.
6. Ikenoue T, Hikiba Y, Kanai F, Ijichi H, Togo G,
Ohta M, et al. Rapid detection of mutations in the
BRAF gene using real-time polymerase chain reaction and melting curve analysis. Cancer Genetics &Cytogenetics 2004;149(1):68-71.
7. Imamura T, Kanai F, Kawakami T, Amarsanaa J,
Ijichi H, Hoshida Y, et al. Proteomic analysis of the
TGF-beta signaling pathway in pancreatic carcinoma cells using stable RNA interference to silence
Smad4 expression. Biochemical & Biophysical Research Communications 2004;318(1):289-96.
8. Tanaka Y, Kanai F, Kawakami T, Tateishi K, Ijichi
H, Kawabe T, Arakawa Y et al. Interaction of thehepatitis B virus X protein (HBx) with heat shockprotein 60 enhances HBx-mediated apoptosis. Biochemical & Biophysical Research Communications
2004;318(2):461-9.
9. Yamaji Y, Mitsushima T, Ikuma H, Watabe H,
Okamoto M, Kawabe T, et al. Incidence and recurrence rates of colorectal adenomas estimated byannually repeated colonoscopies on asymptomaticJapanese. Gut 2004;53(4):568-72.
10. Guleng B, Tateishi K, Kanai F, Jazag A, Ohta M,
Asaoka Y, et al. Cancer-derived VEGF plays norole in malignant ascites formation in the mouse.
World Journal of Gastroenterology
2005;11(35):5455-9.
11. Guleng B, Tateishi K, Ohta M, Kanai F, Jazag A,
Ijichi H, et al. Blockade of the stromal cell-derived
factor-1/CXCR4 axis attenuates in vivo tumor
growth by inhibiting angiogenesis in a vascularendothelial growth factor-independent manner.
Cancer Research 2005;65(13):5864-71.
12. Ikenoue T, Kanai F, Hikiba Y, Obata T, Tanaka Y,
Imamura J, et al. Functional analysis of PIK3CA
gene mutations in human colorectal cancer. Cancer
Research 2005;65(11):4562-7.
13. Ikenoue T, Kanai F, Hikiba Y, Tanaka Y, Imamura
J, Ohta M, et al. Functional consequences of mutations in a putative Akt phosphorylation motif of
B-raf in human cancers. Molecular Carcinogenesis
2005;43(1):59-63.
14. Jazag A, Ijichi H, Kanai F, Imamura T, Guleng B,
Ohta M, et al. Smad4 silencing in pancreatic cancer
cell lines using stable RNA interference and gene
expression profiles induced by transforming growth

factor-beta. Oncogene 2005;24(4):662-71.
15. Jazag A, Kanai F, Ijichi H, Tateishi K, Ikenoue T,
Tanaka Y, et al. Single small-interfering RNA expression vector for silencing multiple transforming
growth factor-beta pathway components. Nucleic
Acids Research 2005;33(15):e131.
16. Kanai F, Omata M. [Glucose intolerance caused byinterferon therapy]. Nippon Rinsho - Japanese
Journal of Clinical Medicine 2005;63 Suppl
2:315-9.
17. Kawakami T, Hoshida Y, Kanai F, Tanaka Y,
Tateishi K, Ikenoue T, et al. Proteomic analysis ofsera from hepatocellular carcinoma patients afterradiofrequency ablation treatment. Proteomics
2005;5(16):4287-95.
18. Ohta M, Tateishi K, Kanai F, Ueha S, Guleng B,
Washida M, et al. Reduced p38 mitogen-activatedprotein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice. European
Journal of Immunology 2005;35(7):2210-21.
19. Ohta M, Tateishi K, Kanai F, Watabe H, Kondo S,
Guleng B, et al. p53-Independent negative regulation of p21/cyclin-dependent kinase-interacting
protein 1 by the sonic hedgehog-glioma-associatedoncogene 1 pathway in gastric carcinoma cells.
Cancer Research 2005;65(23):10822-9.
20. Okamoto M, Kawabe T, Yamaji Y, Kato J, Ikenoue
T, Togo G, Watabe H, et al. Flat-type early colorectal cancer preferentially develops in right-sided
colon in older patients. Diseases of the Colon &Rectum 2005;48(1):101-7.
21. Otsuka M, Kato N, Ichimura T, Abe S, Tanaka Y,
Taniguchi H, Hoshida Y, Moriyama M, Wang Y,
Shao RX, Narayan D, Muroyama R, Kanai F,
Kawabe T, Isobe T, Omata M. Vitamin K2 binds
17beta-hydroxysteroid dehydrogenase 4 andmodulates estrogen metabolism. Life Sciences
2005;76(21):2473-82.
22. Watabe H, Mitsushima T, Yamaji Y, Okamoto M,
Wada R, Kokubo T, et al. Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogenstatus: a prospective endoscopic cohort study. Gut
2005;54(6):764-8.

413

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D.,Ph.D.

Visiting Associate Professors
Ung-il Chung, Ph.D. (Vice Director),
Kazuto Hoshi, Ph.D.,

Keiichi Hishikawa, Ph.D.,

Hiroyuki Koyama, Ph.D.,

Seishi Ogawa, Ph.D.,

Takeshi Marumo, Ph.D.,
Makoto Ohba, Ph.D.,

Toru Ogasawara, Ph.D.,
Takahiro Suzuki, Ph.D.,

Satoru Yamagami, Ph.D.

Visiting Research Associates
Toshiyuki Ikeda, Ph.D.,
Naoshi Ogata, M.D.,
Seiichi Yokoo, Ph.D.,

Homepage: http://square.umin.ac.jp/t-e/
Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo Hospital, in October 2001 and has a fully equipped 800 m2
laboratory on the 8th floor of the Inpatient Word B. Division of Tissue Engineering consists of Department ofBone ＆ Cartilage Regenerative Medicine (Takeda
Chemical Industries, Ltd.), Department of Vascular
Regeneration (Daiichi Pharmaceutical Co), Departmentof Regeneration Medicine for Hematopoiesis (Kirin
Brewery Co., Ltd.), Department of Corneal Tissue Regeneration (ArBlast Co., Ltd.), Department of ClinicalRenal Regeneration (Mochida Pharmaceutical Co.,
LTD.), Department of “ Fujisoft ABC” Cartilage &Bone Regeneration (FIJISOFT ABC INCORPORATED.). We have invited talented personnel of various
fields from home and abroad. One visiting associate
professor and one or two visiting 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 for treatment at a GMP level, safety evaluation studies and organization for clinical trials are necessary in order torealize regenerative medicine, which is now recognized
as a national project. As foundation and operation ofventure companies as well as industry-university– government cooperation is essential to the success, it seems
that state-level efforts are necessary. It is expected thatbroad progress in tissue engineering technologies andregenerative medicine contributes to treatment anddrug discovery of all medical fields regardless of specialties.
October, 2001 Division of Tissue Engineeringfounded as 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 Co.,
Ltd.

414

July, 2002 Department of Bone & Cartilage Regenerativen Medicine founded by a donation from
TAKEDA Chemical Industries., Ltd.
September, 2002 Department of Regeneration medicine for Hematopoiesis founded by a donation fromKIRIN 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 donation fromMENICON Co., Ltd.
March, 2003 The Cell Processing Center set up on
the 8th floor of the Inpatients Ward B.
June, 2005 Department of Corneal Tissue Regeneration was renewed by a donation from AMNIO TEC Co.,Ltd (now ArBlast Co., Ltd.)
July, 2005 Department of Bone & Cartilage Regenerative Medicine was renewed by a donation from
TAKEDA Chemical Industries, Ltd.
September, 2005 Department of Regeneration Medicine for Hematopoiesis was renewed by a donationfrom KIRIN Brewery Co., Ltd.
November, 2005 Department of Clinical Renal Regeneration was renewed by a donation from MOCHIDA Pharmaceutical Co., Ltd.
November,2005 By a donation from FUJISOFT ABC
Co., Ltd. Department of MENICON Cartilage & BoneRegeneration was renewed to Department of Fuji Software ABC Cartilage & Bone Regeneration.

Research activities
As for corneal regeneration, we aim at constructionof regenerated cornea, clinical application of corneal
epithelial sheet transplantation for ocular surface reconstruction and establishment and clinical application of
corneal endothelium transplantation. To achieve thesegoals, we are conducting functional analysis on cultured corneal cells, reconstruction of cornea with cultured epithelium and endothelium, and artificial stroma,
research on adult stem cell biology in corneal tissues
and immunological analysis on amniotic membrane forocular surface reconstruction
As for vascular regeneration, we aim at establishment of effective and safe “therapeutic angiogenesis”
and its clinical application, development of non-invasive

soft-tissue reconstruction technique assisted by induction of angiogenic reactions and development of thetechniques to induce microcirculation to regeneratedorgans. To achieve these goals, we are conducting research on angiogenic gene therapy using adenovirus
vector, research on angiogenic gene therapy using
non-viral vector, development of drug delivery method
for therapeutic angiogenesis and research on inductionof 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, to determine a finite set of signaling factors sufficient for induction of osteoblasts and chondrocytes, to develop acell-sheet culture system for bone and cartilage, to devise a method to induce osteogenesis and angiogenesis
simultaneously, to screen for compounds that inducebone and cartilage regeneration, to develop non-viralgene transfer methods by nano-micelle technology andto generate and transplant regenerated bone and cartilage. To achieve these goals, we are conducting research on bone and cartilage biology, developmental
biology, stem cell biology and regenerative medicine.
As for renal regeneration, we aim at clinical application of kidney-derived adult stem cell, clinical application of new scaffold material and matrix for renal regeneration and clinical renal regeneration by using cord
blood. To achieve these goals, we are conducting research on adult stem cell biology in regeneration, comprehensive research on stem cell dysfunction in renal
failure and development of 3-D culture system for induction of metanephros in vitro.
As for regenerative medicine for hematopoiesis, we
aim to develop effective systems for in vitro expansionof cord blood hematopoietic stem cells (CB-HSCs) andits clinical application to human hematopoietic stem
cell transplantation, and for inducing various hematopoietic components from HSCs and embryonic stem
cells. To achieve these goals, we are conducting research on the regulatory mechanisms of proliferation,
self-renewal, and differentiation of human hematopoietic stem cells (HSCs), plasticity of HSCs and clinicalapplication of the in vitro expansion and differentiation
system of HSCs.
In the department donated by Fuji Software, we aim
to produce regenerated cartilage and bone with highsafety and usefulness, to realize production system and415

establish practical quality control and to promote theapplication of regenerated cartilage and bone. 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 of novel scaffolds incartilage and bone regeneration, development of 3-D
reconstruction system for regenerated tissues, evaluation on biochemical and biophysical properties of regenerated tissues in vivo and clinical trials and application of regenerated cartilage and bones.

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 to equip
with, such as a confocal laser scanning microscope, acell analyzer and a cell sorter to the Hospital staff, letting them use with cost sharing. (Actually,) Department
of Plastic Surgery is conducting research using this facility.

Basic Research on human ES cells
Besides, to promote basic research on human embryonic stem cells with our eyes set on applications in
the future, Department of Clinical Renal Regeneration
and Department of Bone and Cartilage Regenerative
Medicine are carrying forward the application procedures to obtain human ES cells from Institute for Frontier Medical Sciences, Kyoto University, which will beapproved shortly.

1. Yamagami S, Yokoo S, Mimura T, Amano S. Effects of TGF-beta2 on immune response-related
gene expression profiles in the human corneal endothelium. Invest Ophthalmol Vis Sci 2004;45:515-521.
2. Mimura T, Amano S, Funatsu H, Yamagami S,
Araie M, Kaji Y, et al. Correlations between eachallergen-specific IgE serum levels in patients withallergic conjunctivitis in Spring. Ocul Immunol Inflamm 2004;12: 45-51.
3. Usui T, Yamagami S, Yokoo S, Mimura T, Ono K,
Amano S. Gene expression profile in corneal neovascularization with immunology-related macroarray.
Mol Vis. 2004;10:832-6.
4. Endo-Matsubara M, Ogawa S, Sasaki K, Takahashi
T, Chiba S, Hirai H. Immature granulocyte fractionin the peripheral blood is a practical indicator formobilization of CD34(+) cells. Am J Hematol
2004;77:223-228.
5. Goyama S, Kanda Y, Nannya Y, Ogawa S,
Asano-Moki Y, Ogawa N, et al. Clinical significance of peripheral blood erythroblastosis after
hematopoietic stem cell transplantation. Leuk
Lymphoma 2004;45:2439-2443.
6. Haraguchi K, Takahashi T, Hiruma K, Kanda Y,
Tanaka Y, Ogawa S, et al. Recovery of Valpha24+
NKT cells after hematopoietic stem cell transplantation. Bone Marrow Transplant 2004;34:595-602.
7. Yamaguchi Y, Kurokawa M, Imai Y, Izutsu K, Asai
T, Ogawa S, et al . AML1 is functionally regulated
through p300-mediated acetylation on specific lysine residues. J Biol Chem 2004;279:15630-15638.
8. Shimoaka T, Kamekura S, Chikuda H, Hoshi K,
Chung UI, Akune T, et al . Impairment of bonehealing by insulin receptor substrate-1 deficiency. J

Clinical Studies
Of particular note is clinical studies started in thefour departments as a result of basic research. In Department of Regenerative Medicine for Hematopoiesis,
clinical study on expansion of human cord blood hematopoietic cells (Institutional Review Board approval
number #351) has been started. In Department of Vascular Regeneration, clinical studies on claudication
limbs and severe ischemic limbs caused by peripheral
vascular diseases (IRB approval number #825 and#826) have been started and continued without causingmajor side effects. In Department of Corneal Tissue
Regeneration, clinical studies on transplantation of cultured autologous oral mucous epithelial sheet on amniotic membrane for ocular surface reconstruction, andcorneal endothelial stem cell transplantation for decrease in number of corneal endotheliums (IRB approval number #363 and #898) have been started. In
Department of Bone & Cartilage Regenerative Medicine, clinical study on bone implants into non-loading
parts (IRB approval number #1310) will be started by
the end of March. As stated above, we are proceedingtranslational research aiming at clinical application oftissue engineering and regenerative medicine.

References

416

Biol Chem. 2004;279:15314-15322
9. Ogasawara T, Kawaguchi H, Jinno S, Hoshi K,
Itaka K, Takato T, et al . Bone morphogenetic protein 2-induced osteoblast differentiation requires
Smad-mediated down-regulation of Cdk6. Mol Cell
Biol. 2004;24:6560-6568
10. Ogasawara T, Katagiri M, Yamamoto A, Hoshi K,
Takato T, Nakamura K, et al. Osteoclast Differentiation by RANKL Requires NF-kappaB-MediatedDownregulation of Cyclin-Dependent Kinase 6(Cdk6). J Bone Miner Res. 2004;19:1128-1136
11. Hoshi K, Ogata N, Shimoaka T, Terauchi Y,
Kadowaki T, Kenmotsu S, et al. Deficiency of insulin receptor substrate-1 impairs skeletal growththrough early closure of epiphyseal cartilage. J
Bone Miner Res. 2004;19:214-223
12. Watabe M, Hishikawa K, Takayanagi A, Shimizu N,
Nakaki T. Caffeic acid phenethyl ester induces
apoptosis by inhibition of NFkappaB and activationof Fas in human breast cancer MCF-7 cells. J. Biol
Chem. 2004;279(7):6017-6026
13. Hishikawa K, Miura S, Marumo T, Yoshioka H,
Mori Y, Takato T, et al. Gene expression profile ofhuman mesenchymal stem cells during osteogenesis in three-dimensional thermoreversible gelation
polymer. Biochem. Biophys. Res. Commun. 2004;
317(4): 1103-1107
14. Uchimura, H, Marumo, T, Takase, O, Kawachi, H,
Shimizu, F, Hayashi, M, Saruta, T, et al, Intrarenal
injection of bone marrow-derived angiogenic cells
reduces endothelial injury and mesangial cell activation in experimental glomerulonephritis. J Am
Soc Nephrol 2004;16:997.
15. Long F, Chung U (Co-first), Ohba S, McMahon J,
Kronenberg HM, McMahon AP. Genetic Evidence
That Ihh Signaling Is Directly Required For The
Osteoblast Lineage In The Endochondral Skeleton.
Development 2004;131:1309-1318.
16. Akune T, Ohba S, Kamekura S, Yamaguchi M,
Chung U, Kubota N, et al. PPARg insufficiency
enhances osteogenesis from bone marrow progenitors. J Clin Invest 2004;113:846-855.
17. Yamada T, Kawano H, Sekine K, Matsumoto T,
Fukuda T, Chung U, et al.SRC-1 is necessary forskeletal responses to sex hormones in both males
and females. J Bone Miner Res 2004;19:14521461.

18. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S,
Takato T, et al. The combination of SOX5, SOX6
and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Arthritis
Rheum 2004;50:3561-3573.
19. Moro T, Takatori Y, Ishihara K, Konno T, Takigawa
Y, Chung U, et al. Surface grafting of artificial
joints with a biocompatible polymer for preventing
periprosthetic osteolysis. Nat Mat 2004;83:829836.
20. Bastepe M, Weinstein LS, Ogata N, Kawaguchi H,
Jüppner H, Chung U, et al. Stimulatory G protein(Gs) directly regulates hypertrophic differentiationof growth plate cartilage in vivo. Proc Nat Acad Sci
USA 2004;101:14794-14799.
21. Hosaka A, Koyama H et al (2/9). Gelatin hydrogel
microspheres enable pinpoint delivery of basic fibroblast growth factor for development of functional collateral vessels. Circulation 2004;110:3322-3328.
22. Miyahara T, Koyama H et al (2/7). Inflammatory
signaling pathway containing TRAF6 contributes
to neointimal formation via diverse mechanisms.
Cardiovascular Research 2004;64:154-164.
23. Kondoh K, Koyama H et al (2/6). Conduction performance of collateral vessels induced by vascularendothelial growth factor or basic fibroblast growth
factor. Cardiovascular Research 2004;61:132-142.
24. Sako A, Koyama H et al (3/7). Transduction ofsoluble Flt-1 gene to peritoneal mesothelial cells
can effectively suppress peritoneal metastasis ofgastric cancer. Cancer Research 2004;64:36243628.
25. Miyata K, Koyama H et al (6/7). Block catiomer
polyplexes with regulated densities of charge anddisulfide cross-linking directed to enhance gene
expression. Journal of American Chemical Society
2004;126:2355-2361.
26. Itaka K, Kanayama N, Nishiyama N, Jang W, Yamasaki Y, Nakamura K, et al, Supramolecular
nanocarrier of siRNA from PEG-based block catiomer carrying diamine side chain with distinctive
pKa directed to enhance intracellular gene silencing.
J. Am. Chem. Soc. 2004;126:13612-13613.
27. Wakebayashi D, Nishiyama N, Yamasaki Y, Itaka K,
Kanayama N, Harada A, et al, Lactose-conjugatedpolyion complex micelles incorporating plasmid

417

DNA as a targetable gene vector system: their
preparation and gene transfecting efficiency against
cultured HepG2 cells. J. Controlled Release
2004;95:653- 664.
28. Miyata K, Kakizawa Y, Nishiyama N, Harada A,
Yamasaki Y, Koyama H, et al, Block catiomer polyplexes with regulated densities of charge and disulfide cross-linking directed to enhance gene expression. J. Am. Chem. Soc. 2004;126: 2355-2361.
29. Yamagami S, Hamrah P, Miyamoto K, Miyazaki D,
Dekaris I, Dawson T,et al. The CCR5 chemokine
receptor mediates recruitment of MHC-class
II-positive Langerhans cells in the mouse corneal
epithelium. Invest Ophthalmol Vis Sci 2005;46:1201-1207.
30. Yokoo S, Yamagami S, Yanagi Y, Uchida S,
Mimura T, Usui T,et al. Human corneal endothelial
cell precursors isolated by sphere-forming assay.
Invest Ophthalmol Vis Sci 2005;46:1626-1631.
31. Yamagami S, Hamrah P, Zhang Q, Liu Y, Huq S,
Dana MR. Early ocular chemokine gene expression
and leukocyte infiltration after high-risk corneal
transplantation. Mol Vis 2005;11:632-640.
32. Miyata K, Yamagami S, Nejima R, Miyai T, Shimizu K, Amano S. Corneal endothelial cell protection with Viscoat and Healon or Healon alone during penetrating keratoplasty. Cornea 2005;24:962966.
33. Yamagami S, Yokoo S, Yamagami H, Amano S,
Ebihara N. Distinct population of dendritic cells innormal human donor corneal epithelium. Invest
Ophthalmol Vis Sci 2005;46:4489-4494.
34. Hori A, Kanda Y, Goyama S, Onishi Y, Komeno Y,
Ogawa S, et al . A Prospective Trial to Evaluate theSafety and Efficacy of Pravastatin for the Treatment of Refractory Chronic Graft-Versus-Host
Disease. Transplantation 2005;79:372-374.
35. Hosoya N, Qiao Y, Hangaishi A, Wang L, Nannya
Y, Ogawa S, et al. Identification of a SRC-like tyrosine kinase gene, FRK, fused with ETV6 in a patient with acute myelogenous leukemia carrying at(6;12)(q21;p13) translocation. Genes Chromosomes Cancer 2005;42:269-279.
36. Fujihara Y, Koyama H, Nishiyama N, Eguchi T,
Takato T, Gene transfer of bFGF to recipient bed
improves survival of ischemic skin flap. Br J Plast
Surg. 2005;58: 511-517.

37. Nishiyama N, Iriyama A, Jang W, Miyata K, Itaka
K, Inoue Y, et al. Light-induced gene transfer frompackaged DNA enveloped in a dendrimeric photosensitizer. Nat. Mater. 2005;4 (12) 934-941.
38. Jang W, Nishiyama N, Zhang G, Harada A, Jiang
D, Kawauchi S, et al. Supramolecular nanocarrierof anionic dendrimer porphyrins with cationicblock copolymers modified with poly(ethylene
glycol) to enhance intracellular photodynamic efficacy. Angew. Chem. Int. Ed. Engl. 2005;44(3) :419-423.
39. Cabral H, Nishiyama N, Okazaki S, Koyama H,
Kataoka K. Preparation and biological properties ofdichloro(1,2-diaminocyclohexane)platinum(II)(DACHPt)-loaded polymeric micelles. J. Control.
Release 2005;101 (1-3) :223-232.
40. Cabral H, Nishiyama N, Okazaki S, Koyama H,
Kataoka K. Preparation and biological properties ofdichloro(1,2-diaminocyclohexane) platinum (II)loaded polymeric micelles. J. Controlled Release
2005;101(1-3):223-232.
41. Suzuki T, Chiba S.Notch signaling in hematopoietic stem cells. Int J Hematol. 2005 ;82(4):285- 94.
42. Hishikawa, K., Marumo, T., Miura, S., Nakanishi,A., Matsuzaki, Y., Shibata, K., et al. Leukemia inhibitory factor induces multi-lineage differentiationof adult stem-like cells in kidney via kidney-specific cadherin 16. Biochem Biophys Res
Commun 2005;328:288-291.
43. Hishikawa K, Nakaki T, Fujita T. Oral Flavonoid
Supplementation Attenuates Atherosclerosis Development in Apolipoprotein E-Deficient Mice.
Arterioscler Thromb Vasc Biol. 2005;25(2): 442446.
44. Hishikawa K, Marumo T, Miura S, Nakanishi A,
Matsuzaki Y, Shibata K, et al . Leukemia inhibitory
factor induces multi-lineage differentiation of adultstem-like cells in kidney via kidney-specific cadherin 16. Biochem. Biophys. Res. Commun. 2005;
328:288-291.
45. Hishikawa, K, Marumo, T, Miura, S, Nakanishi, A,
Matsuzaki, Y, Shibata, K, et al. Musculin/MyoR is
expressed in kidney side population cells and canregulate their function. J Cell Biol 2005;169:921928.
46. Moro T, Ogasawara T, Chikuda H, Ikeda T, Ogata
N, Maruyama Z,et al. Inhibition of Cdk6 expres-418

sion through p38 MAP kinase is involved in differentiation of mouse prechondrocyte ATDC5. J
Cell Physiol 2005;204(3):927-933.
47. Chikuda H, Kugimiya F, Hoshi K, Ikeda T, Ogasawara T, Kamekura S, et al.Mutation in cGMP-dependent protein kinase II causes dwarfism in a rat
mutant KMI through uncoupling of proliferationand differentiation of chondrocytes. J Bone Miner
Metab 2005;23(3):200-4.
48. Kamekura S, Hoshi K, Shimoaka T, Chung U,
Chikuda H, Yamada T, et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 2005;13(7):632-41.
49. Yano F, Kugimiya F, Ohba S, Ikeda T, Chikuda H,
Ogasawara T, et al. The canonical Wnt signaling
pathway promotes chondrocyte differentiation in a
Sox9-dependent manner. Biochem Biophys Res
Commun 2005;333(4):1300-8.
50. Kugimiya F, Kawaguchi H, Kamekura S, Chikuda
H, Ohba S, Yano F, Ogata N, Katagiri T, Harada Y,
Azuma Y, Nakamura K, Chung U. Involvement ofendogenous bone morphogenetic protein (BMP)2and BMP6 in bone formation. J Biol Chem
2005;280:35704-35712.
51. Kugimiya F, Yano F, Ohba S, Igawa K, Nakamura
K, Kawaguchi H,et al. Mechanism of osteogenic
induction by FK506 via BMP/Smad pathways.
Biochem Biophys Res Commun 2005;338:872-9.
52. Kamekura S, Hoshi K, Shimoaka T, Chung U,
Chikuda H, Yamada T, et al.2005 Osteoarthritis
development in novel experimental mouse models
induced by knee joint instability. Osteoarthritis
Cartilage 2005;13(7):632-641.

419

Hospital Planning andManagement
Associate Professor
Tomoaki Imamura, M.D.
Associate
Hideo Yasunaga, M.D., Hiroo Ide, M.A.

Homepage http://www.cc.h.u-tokyo.ac.jp/mulins/kikakushitsu/index.htm
Introduction and Organization

staff member, and ten administrative staff.

In recent years, the medical system in Japan has been
experiencing times of major change. University hospitals, as well, have been under pressure for sweeping
reforms. There are demands, greater than ever before,
for the development and practical application ofhigh-quality advanced medical treatment, and for theefficient promotion of graduate and postgraduate education, and of clinical research. And there are demands
for those results to be expressed clearly to Japanesecitizens in specific terms. In April 2004, as the University of Tokyo was incorporated 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 clinicalmanagement (Inpatient Service Administration; Outpatient Service Administration; and Central Hospital Service Administration).
Hospital Planning and Management is a key working
organization in the management of the hospital. It has
three full-time instructors from the Department ofPlanning, Information and Management, and boasts ateam of two pharmacists, two nurses, one engineering

Clinical activities
Hospital Planning and Management is responsible
for all of the organizational and strategic business affairs 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 hospital management analyses by utilizing management information and standardized hospital information.
(2) Planning and strategy
Based on the hospital management analyses, thedivision designs short-term management planningand strategy proposals, and provides effective
support for the Hospital Executives to make swift
management decisions. The division is also responsible for formulating medium- and long-termplans. Following is a list of hospital management
achievements in which Hospital Planning andManagement was deeply involved.
・ Launched the “22nd Century Medical Center”
・ Launched the new central hospital wing
・ Enhanced functions in the inpatient ward (expansion of ICU/CCU, increase in number ofbeds in the Psychiatry Department)
・ Reduced the average length of hospital stays,
and improved the bed occupancy rate

420

・ Achieved reductions in medication costs andcosts for medical materials
In addition to these achievements, the division
has also strived to improve innovative patient
services, such as introducing a credit card forpatients, attracting commercial stores to set up
in the hospital, 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 in Japanand at deregulating medical care.
The division submitted an application for “The
University of Tokyo Hospital Special Zone” to thegovernment’s “Special Zones for Structural Reform” under the theme of deregulating the Pharmaceutical Affairs Law. In Japan, there are certain
medicines which cannot be used due to delays intheir approval, despite their having been approved
overseas. There are also certain highly-advanced
technologies which have had their approval for insurance coverage delayed despite their medical effectiveness having been demonstrated. The conceptbehind the university hospital’s application is toallow these medicines and technologies to be usedat the University of Tokyo Hospital. The University of Tokyo Hospital posed to society at large thatthe inconsistencies in the Japanese medical systemshould be eliminated. Our concept had a significant impact on the ensuing reforms to that medical
system.
Furthermore, we point out issues related to Japan’s
medical insurance system based on evidence, andwe constantly issue messages for their improvement.

Teaching activities
Turning to postgraduate education, the division accepts one doctoral student from the Department ofMedical Informatics and Economics at the Graduate

School of Medicine, and one master’s student and one
research student from the Department of Clinical Bioinformatics Research Unit 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 hospital management, 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 the collection ofdata. The students present regular research progress
reports, they are given thorough instruction on writing
academic papers, and they also follow a rigid scheduleof academic presentations.

Research activities
The research activities of the division are not limited
to merely healthcare management and hospital management, but cover a broader area, including healthcare
policy and healthcare economics.
（1） Research in healthcare management
The division analyzed the impact that a 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 lengthof hospital stays.
The division also conducted research related to theefficient use of medical facilities, by studying therelationship between the running of operatingrooms and the number of hospital beds.
In an attempt to systemize healthcare management,
the division edited a standard textbook. The division is also conducting research into the development of an education program for healthcare management.
(2) Research in healthcare policy
The division carried out assessments related to Japan’s medical insurance system, and in particular,
conducted research into improvements to the prospective payment system based on DPC, and theeffectiveness of such improvements.
The division is also undertaking comparative studies between medical systems in Japan and otherdeveloped countries, as well as empirical studies

421

related to the disparity of domestic and imported
prices of medical equipment, and studies into thecareer paths of medical doctors.
(3) Research in healthcare economics
Using the contingent valuation method, the division is carrying out research related to the benefit
evaluation of healthcare services. The division is
also running empirical studies on the distributive
efficiency of healthcare services, using cost analyses and cost-benefit analyses.
In addition, the division is also conducting economic analyses related to the effects that the promotion of preventative medicine has had on controlling national medical expenses.
Furthermore, the division is also conducting economic analyses on medical safety (research on cost
analysis of medical accidents, and analysis on thecost effectiveness of medical safety measures).
(4) Health-related risk analysis and research
Risk analysis is comprised of risk assessment, risk
management, and risk communication, and is a
new approach for minimizing all kinds of damage.
Based on this technique, the division is investigating and analyzing what exactly is necessary tominimize damage caused by incidents involving
health risks. In recent years, there has been a risingnecessity for the protection of citizens from thethreat of terrorism. We have been conducting research to develop effective measures, especiallyagainst foodborne bioterrorism and chemical terrorism. Furthermore, in light of the globalization ofrecent years, a key issue has been food safety standards—the bringing into synch of the standards ofindividual countries, and the development of unified international standards. International standards
are deliberated and determined at the Codex Alimentarius Commission (CAC). We use the risk
analysis approach to study the various issues related to food safety which are discussed at the
CAC.
In terms of risk communication, we conduct research on the disparities between the public information released by government agencies and theinformation circulated by the media. We also conduct research on risk communication for managing
crises during times of health hazards. Furthermore,
for the purpose of empirically clarifying whether

risk communication can actually reduce damage,
we are investigating and studying the effect that
displaying allergy-causing substances on foodpackaging has on reducing incidences of food allergies.
(5) Research into health statistics
The division conducts a great deal of healthcare-related statistical research and analysis. Oneof these is a cohort study on Kanemi rice oil poisoning. Recently, thanks to improvements in verification technology, it has become possible tomeasure the concentration of dioxins in the blood.
We are conducting investigations and research on
the relationship between the concentration of dioxins in the blood of patients with Kanemi rice oil
poisoning and their clinical symptoms.
We are also conducting resident surveys to ascertain the actual facts on allergy diseases and symptoms, as well as follow-up surveys to investigate
the allergy-causing substances.

References
1. Yasunaga H, Ide H, Imamura T, Ohe K. Willingness to pay for health care services in common cold,
retinal detachment, and myocardiac infarction: an
Internet survey in Japan. BMC Health Services Research 2006; 6: 12.
2. Yasunaga H, Ide H, Imamura T, Ohe K. Analysis of
the factors affecting willingness to pay for the
medical services of cardiovascular diseases. International Heart Journal 2006; 47(2) in press.
3. Yasunaga H, Ide H, Imamura T, Ohe K. Impact of
the Japanese Diagnosis Procedure Combinationbased payment system on cardiovascular medicine
related costs. International Heart Journal 2005;
46(5): 855-866.
4. Yasunaga H, Ide H, Imamura T, Ohe K. Medical
research using Internet questionnaire in Japan. (inJapanese) Japanese Journal of Public Health 2006;
53(1): 40-50.
5. Yasunaga H, Ide H, Imamura T, Ohe K. A proposalof reforms in the prospective payment system
based on DPC. (in Japanese) Journal of the Japanese Society on Hospital Administration 2005;
42(2): 147-159.
6. Yasunaga H, Ide H, Imamura T, Ohe K. Does DPC

422

system really offer incentives for shortening lengthof stay? : Examination of the simulation model using general solutions. (in Japanese) Journal of theJapanese Society on Hospital Administration 2004;
41(2): 115-127.
7. Akiyama H, Izugawa K, Harikai N, Watanabe H,
Iijima K, Yamakawa H, Mizuguchi Y, Yoshikawa R,
Yamamoto M, Sato H, Watai M, Arakawa F, Ogasawara T, Nishihara R, Kato H, Yamaguch A, Takahata Y, Morimatsu F, Mamegoshi S, Muraoka S,
Honjo T, Watanabe T, Wakui C, Imamura T, Toyoda
M, Maitani T. Inter-laboratory Evaluation Studies
of Notified ELISA Methods for Allergic Substances(Egg). Journal of Food Hygienics Society of Japan
2003; 44: 213-219.
8. Akiyama H, Izugawa K, Harikai N, Watanabe H,
Iijima K, Yamakawa H, Mizuguchi Y, Yoshikawa R,
Yamamoto M, Sato H, Watai M, Arakawa F, Ogasawara T, Nishihara R, Kato H, Yamaguch A, Takahata Y, Morimatsu F, Mamegoshi S, Muraoka S,
Honjo T, Watanabe T, Wakui C, Imamura T, Toyoda
M, Maitani T. Inter-laboratory Evaluation Studies
of Notified ELISA Methods for Allergic Substances(Wheat). Journal of Food Hygienics Sosciety ofJapan 2004; 45(3): 128-134.
9. Akiyama H, Izugawa K, Harikai N, Watanabe H,
Iijima K, Yamakawa H, Mizuguchi Y, Yoshikawa R,
Yamamoto M, Sato H, Watai M, Arakawa F, Ogasawara T, Nishihara R, Kato H, Yamaguch A, Takahata Y, Morimatsu F, Mamegoshi S, Muraoka S,
Honjo T, Watanabe T, Wakui C, Imamura T, Toyoda
M, Maitani T. Inter-laboratory Evaluation Studies
of Notified ELISA Methods for Allergic Substances(Milk). Journal of Food Hygienics Society of Japan
2004; 45(3): 120-127.
10. Akiyama H, Nakamura K, Harikai N, Waranabe H,
Iijima K, Yamakawa H, Mizuguchi Y, Yoshikawa R,
Yamamoto M, Sato H, Watai M, Arakawa F, Ogasawara T, Nishihara R, Kato H, Yamauchi A, Takahata Y, Morimatsu F, Mamegoshi S, Muraoka S,
Honjoh T, Watanabe T, Sakata K, Imamura T, Toyoda M, Matsuda R, Maitani T. Inter-laboratory
Evaluation Studies of Notified ELISA Methods forAllergic Substances (Buckwheat). Journal of Food
Hygienics Sosciety of Japan 2004; 45(6): 313-318.
11. Akiyama H, Nakamura K, Harikai N, Waranabe H,
Iijima K, Yamakawa H, Mizuguchi Y, Yoshikawa R,

Yamamoto M, Sato H, Watai M, Arakawa F, Ogasawara T, Nishihara R, Kato H, Yamauchi A, Takahata Y, Morimatsu F, Mamegoshi S, Muraoka S,
Honjoh T, Watanabe T, Sakata K, Imamura T, Toyoda M, Matsuda R, Maitani T. Inter-laboratory
Evaluation Studies of Notified ELISA Methods forAllergic Substances (Peanuts). Journal of Food
Hygienics Society of Japan 2004; 45(6): 325-331.
12. Nihio N, Imamura T. Smoking Prevalence among
Dentists in Hyogo, Japan. Japanese Journal of
Dental Practice Administration 2005; 40(3):170-174.
13. Uenotsuchi T, Nakayama J, Asahi M, Kohro O,
Akimoto T, Muto M, Shimizu K, Katayama I,
Kanzaki T, Kanagawa Y, Imamura T, Furue M.
Dermatological manifestations in Yusho: correlation
between skin symptoms and blood levels of dioxins,
such as polychlorinated dibenzofurans (PCDFs) andpolychlorinated biphenyls (PCBs). Journal of Dermatological Science 2005; Supplement 1: S73S80.
14. Uenotsuchi T, Lio Y, Tadakuma S, Harazuka R,
Kanagawa Y, Imamura T, Furue M. Sex ratio in thechildren of Yusho patients. Journal of Dermatological Science 2005; Supplement 1: S81-S83.
15. Kanagawa Y, Imamura T. Relationship of clinicalsymptoms and laboratory findings with blood levels of PCDFs in patients with Yusho. Journal of
Dermatological Science 2005; Supplement 1:
S85-S92.
16. Imamura T, Yasunaga H, Ide H. Iryo-Keiei-Gaku.
(in Japanese) Tokyo: Igaku-Shoin; 2006.

423

Department of Child Psychiatry
Professor
Nobumasa Kato, M.D.,Ph.D.

Specially Appointed Associate Professor
Yukiko Kano, M.D.,Ph.D.

Specially Appointed Lecturer
Keiichiro Watanabe, M.D., Ph.D.

Specially Appointed Associate
Soo-Yung Kim, M.D., Ph.D.

Homepage http://kokoro.umin.jp/
Introduction and Organization

Clinical activities

The Department of Child Psychiatry was established in April 2005 as the clinical counterpart to theClinical 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 invarious fields with a fundamental grounding in childpsychiatry and neurosciences. Much of the services
provided are based on the 37 years of experience inintervention and treatment for developmentally disabled children established in the former child psychiatry division of Department of Neuropsychiatry.
The department uses a multidisciplinary approach byworking in collaboration not only with the Departmentof Neuropsychiatry, Department of Pediatrics andGraduate School of Education in the University ofTokyo but also several other educational and/or clinical facilities on mental development or developmental
disorders. The Department of Child Psychiatry complements the Clinical Education Center by providing
fieldwork for clinical training. It also offers clinicalservices to patients with various development problems and places an emphasis on research to provide
evidence-based clinical and educational activities.

Staff and faculty in the Department of Child Psychiatry consist of 7 psychiatrists including 3 full-timechild psychiatrists and 10 psychologists (full-time andpart-time). Although patients with various disorders
are seen, the focus of the department is mainly on patients with developmental disorders. We offer services
to patients with a broad range of developmental disorders including Pervasive Developmental Disorders(PDD), Attention-Deficit/Hyperactivity Disorder(AD/HD), Learning Disabilities (LD), Mental Retardation (MR), tic disorders and child Obsessive-Compulsive Disorders (OCD). In the year of
2005, services were offered to more than 300 new
patients. Among these new patients, PDD was themost prevalent diagnosis (nearly 40%), followed bytic disorders and AD/HD. The age group of these patients was distributed widely from early infancy toadulthood, and the largest number of patients being
those in the late infancy to early childhood group.
Among follow-up patients, PDD was also the mostprevalent diagnosis (approximately 50%), followed bytic disorders, stress-related disorders, MR and AD/HD.
Approximately 40% of the patients at follow-up clinic
were adult patients, highlighting the need for longterm follow-up in patients with developmental dis-424

abilities.
Clinical activities are largely divided into two areasof general child psychiatry outpatient services andinterventions for developmentally disabled children.
Services for the general child psychiatry outpatientsare provided by psychiatrists in the areas of pharmacotherapy, psychotherapy, psychoeducation and theyalso work closely with the schools and community.
Interventions for developmentally disabled children
consist of “developmental psychology outpatient services” and “short-term group therapy”. Patients involved in interventions are children with developmental disabilities, and individualized cognitive developmental therapy is planned for each child. “Developmental psychology outpatient clinic” provides
services in the following areas: (1) evaluation of cognitive and behavioral development, (2) individual
treatment of the child (3) counseling of parents andproviding information to the child’s support network(relatives, schools). “Short-term group therapy” is a
10 session group therapy for a small group of children
with similar developmental levels. These services areprovided mainly by psychologists under the supervision of child psychiatrists.

Teaching activities
As part of the Clinical Education Center of Mental
Development, two training courses (Course A and B)
are offered for graduate level students and various
mental health professionals including psychiatrists
and pediatricians. Course A is a lecture course which
incorporates an interactive component with role-playexercises and case conferences. Course B is an intensive training course, which includes more clinical experience through participation in intervention andpsychological assessment. Course A is composed of
11 lectures and is offered twice a year, with a total of
approximately 100 trainees per year. Course B is offered for a duration of 6 months with ten or moretrainees per year including graduate students of the
Department of Education. Also, one seminar and one
symposium is held each year in order to facilitate understanding of mental development and developmental disorders among the general public.
Undergraduates and psychiatry residents from the
University of Tokyo have opportunities to observe

evaluations and outpatients services as part of theircourse. They are also required to actively participate
in “short-term group therapy”.

Research activities
We participate in investigation of etiology and development of effective treatment on PDD and AD/HD,
which are organized with the Department of Neuropsychiatry and other research, educational and clinicalfacilities. In addition, research related specifically tothe clinical activities in the Department of Child Psychiatry are currently being investigated.
Clinical evaluation and treatment
The reexamination of reliability and validity of
Ohta Staging (an evaluation system using symbol development for cognitive developmental therapy developed in the former child division of the Departmentof Neuropsychiatry) and investigation of effectivenessof the present interventions for children with PDD are
conducted.
A comparison study of the effectiveness of individual treatment and “short-term group therapy” in a randomized control study is being undertaken.
The possible relations among clinical characteristics such as tics and obsessive-compulsive symptoms
in Tourette syndrome (chronic tic disorder with multiple motor tics and one or more vocal tics) and child
OCD are being evaluated.
Neuropsychological research
Neuropsychological data on PDD, AD/HD andTourette syndrome are being collected. Analysis of therelations among neuropsychological findings and theclinical evaluation as well as comparisons between
patients and their healthy siblings are being conducted.
Genetic research
Research exploring susceptibility genes of PDD inchromosome 2, long arm of chromosome 7 and longarm of chromosome 15 are conducted. As we are interested in gene-environment interaction, we are examining influence of endocrinologic change including
thyroid hormone in PDD. In addition to the molecular
genetic study, investigation of specific family and en-425

vironment of Tourette syndrome is being undertaken.
Neuroimaging
Studies include structural MRI, MEG and
Near-Infrared Spectroscopy (NIRS) and exploration of
the pathogenesis of developmental disorders such as
PDD. The main focus is the examination of prefrontal
blood flow in PDD and Tourette syndrome by NIRS
which is non invasive and easily applicable to children
and developmentally disabled individuals.

References
1. Ishizaki Y, Kobayashi Y, Yamagata Z, Eto T, Hoshika A, Kano Y, Koeda T, Miike T, Oki J, Tanaka
H, Watanabe H. Research on promotion of management of children with psychosomatic andpsychosocial disorders in Japan. Pediatr Int 2005;
47: 352-7.
2. Ohta M, Kano Y, Nagai Y. Catatonia in individuals with autism spectrum disorders in adolescenceand early adulthood: A long-term prospective
study. Int Rev Neurobiol 2006; 72: 41-54.
3. Koishi S, Yamamoto K, Matsumoto H, Koishi S,
Enseki Y, Oya A, Aaskura A, Aoki Y, Atsumi M,
Iga T, Inomata J, Inoko H, Sasaki T, Nanba E,
Kato N, Ishii T, Yamazaki K. Serotonin transporter gene promotor polymorphism and autism: afamily-based genetic association study in Japanese population. Brain Dev 2006; 28: 257-60.
4. Marui T, Koishi S, Funatogawa I, Yamamoto K,
Matsumoto H, Hashimoto O, Nanba E, Kato C,
Ishijima M, Watanabe K, Kasai K, Kato N, Sasaki
T. No association of FOXP2 and PTPRZ1 on 7q31
with autism from the Japanese population. Neurosci Res 2005; 53: 91-4.
5. Paraguison RC, Higaki K, Sakamoto Y, Hashimoto O, Miyake N, Matsumoto H, Yamamoto K,
Sasaki T, Kato N, Nanba E. Polyhistidine tract
expansions in HOXA1 result in intranuclear aggregation and increased cell death. Biochem
Biophys Res Commun 2005; 336:1033-9.
6. Sadamatsu M, Nanai H, Xu X, Liu Y, Kato N. A
review of animal models for autism: implicationof thyroid hormone. Congenit Anom (Kyoto)
2006; 46: 1-9.
7. Kasai K, Hashimoto O, Kawakubo Y, Yumoto M,

Kamio S, Itoh K, Koshida I, Iwanami A, Nakagome K, Fukuda M, Yamasue H, Yamada H, Abe
O, Aoki S, Kato N. Delayed automatic detectionof change in speech sounds in adults with autism:a magnetoencephalographic study. Clin Neurophysiol 2005; 116: 1655-64.
8. Yamasue H, Ishijima M, Abe O, Sasaki T, Yamada
H, Suga M, Rogers M, Minowa I, Someya R, Kurita H, Aoki S, Kato N, Kasai K. Neuroanatomy inmonozygotic twins with Asperger disorder discordant for comorbid depression. Neurology
2005; 65: 491-2.

426

Clinical Genomics
Professor
Shoji Tsuji, M.D., Ph.D.

Homepage
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 andefficient application of results of recently advanced
human genetics and genomics to clinical practice in thehospital and as the unit of training and educating 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, an endoclinologist, and neurologists), an urologist, a dermatologist, a staff of the department of clinical laboratory
medicine and faculty members of the Departments of
Human Genetics and Nursing Science.

Activities
The exclusive consultation room (Room 200) is allocated in the outpatient clinic. Consultation and counseling is performed by a team of medical doctor andnon-M.D. staffs. All cases are reviewed and discussed
at the conference which is held on the 4th Friday every
month.
Counseling of participants in researches including
genome or gene analysis is a duty with which the hospital and the faculty charge the department.
To build suitable clinical systems including modern
genomic medicine we are cooperating with other departments. We are participating in Marfan’s Syndrome
Clinic which is managed collaboratively by the Departments of Cardiovascular Surgery, Cardiovascular
Medicine, Pediatrics, Spinal Surgery and Ophthalmol-ogy. We are also collaborating with Clinical Laboratory
Center, Pharmaceutical Services, Departments of Planning Information and Management, Gastroenterology,
Cardiovascular Medicine and Neurology have started
clinical pharmacogenetics service since Augast 2006.

427

Cooperative Unit of Medicine andEngineering Research
Professor
Shinichi Takamoto, M.D.,Ph.D.

Homepage http://plaza.umin.ac.jp/~ikourenk/
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 andmaxillofacial Surgery, Radiology, Tissue Engineering
Unit, Department of Clinical Bioinformatics, Clinical
Vascular Regeneration, Bone & Cartilage Regenerative
Medicine, Cartilage of Bone Regeneration, Department
of Immunotherapeutics (Medinet)
Engineering and Pharmaceutical Research
Chemical System Engineering, Mechanical 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
Biomedical Materials and Systems, Center for Disease
Biology and Integrative Medicine Clinical Biotechnology, Research Center for Advanced Science and Technology, Institute of Industrial Science

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 established Cooperative Unit of Medicine and Engineering Research at The University of Tokyo Hospitalto create a new research and education center, whichcross-sectionally unites medicine with engineering research for the development of a next generation medical technology.
2002 June. The establishment of Cooperative Unit ofMedicine and Engineering Research was approved by ahospital administration committee as a special practiceunit 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 clinicaldepartments. The committee made a decision of thefollowing basic principles; recruitment for the participation 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 expenseof 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 theunit, a review and approve of the steering committee is
indispensable.
2002 October. An open call for participants to thisunit started. There were 18 applications and the steeringcommittee approved all projects after review. A liaison
conference of Cooperative Unit of Medicine and Engineering Research was organized by a representative
member of each project. Configuration of each projectin a space of 554.4m2 that is consisted of a portion of
the first floor and the basement of an administrationbuilding came to a decision by the conference.
2003 May. The construction of Cooperative Unit of428

Medicine and Engineering Research was completed.
The cost of the construction was shared by the participation 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.

Research activities
Development of Advanced Sterotactic Rediation
Cancer Rherapy System
Department of Radiation Oncology
Nuclear Engineering Research Laboratory
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Theraoy System. Development of Advanced Compact Electron
Linear Accelerator for Cancer Inspection and Therapy
Laboratory of Nano-crystals in Oncology
Department of Chemical System Engineering
Department of Surgical Oncology
To develop an exact diagnosis and treatment system forthe micro-metastasis of neoplasm by using nano-crystal
particles, and to introduce it to clinical use. To visualize
peritoneum metastases (peritonitis) and micro-metastasisof neoplasm which cannot be checked 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 by using 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 in deep situ.
To make a precise assessment on tumor invasion in _m
order by injecting microbubbles into tumor arteries. To

develop a non-invasive treatment system using HIFU
devise and microbubble contrast agents.
Medico-engineering Laboratory for Microsurgical
Robotics and Virtual Simulation Laboratory (MRVLabo)
Laboratories of A Morita, Neurosurgery
Dept. Engineering Synthesis, M Mitsuishi
To develop Microsurgical robotic system and 3D visualsystem for telesurgery
Laboratory of Cavitation & Lithotripsy
Department of Urology, Faculty of Medicine
Department of Mechanical Engineering, School of Engineering
Development of a new method of lithotripsy using highintensity focused ultrasound induced cavitation.
Department of Clinical Bioinformatics
Department of Clinical Bioinformatics
Chemical System Engineering
Our specific targets include clinical support information
systems (e.g.: electronic medical records and nursing
support information systems) to support clinical practice with knowledge gained from genomic information;clinical testing information systems to support genome-based drug development and translational research; database systems to integrate disease and genomic information; and information management systems of genome and clinical information.
Surgical Robot System Lab.
Robotics, Dynamics, and Control Laboratory
Department of Mechano-Informatics
University of Tokyo
To develop: robot systems for endoscopic cardiac surgery, small-occupancy endoscopic robots, virtual stillness technology for cardiac surgery, and highly reliable
surgical robot systems
Vascular Biomebical Engineering Laboratory
Department of Vascular Surgery
Department of Tissue Engineering, The University ofTokyo Hospital
Medical Precision Engineering Laboratory, Institute ofEnvironmental Studies, The University of Tokyo
Development of minimally invasive diagnostic and429

therapeutic technologies for vascular surgery throughcollaboration research.
Orthopedic clinical biomechanics laboratory
The Department of Orthopaedic Surgery, The University of Tokyo.
Graduate School of Information Science and Technology, The University of Tokyo.
To develop a non-invasive method for predicting bonestrength. To develop osteosynthetic devices.
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 and Technology, University of Tokyo
To develop: real-time three-dimensional echocardiography, suture device with liner probe, integral videography, and minimal invasive cardiac surgery monitored by real-time three-dimensional echocardiography
without cardiopulmonary bypass
Division of Neutron Capture Therapy & Immunotherapy for Cancer
Department of Cardiothoratic Surgery, Graduate /School of Medicine
Department of Radiology, University of Tokyo Hospital
Department of Quantum Engineering and System Science, School of Engineering
Department of Nuclear Engineering and Management,
School of Engineering
Research Center for Advanced Science & Technology
Endowment Department, Department of Immunotherapeutics (Medinet)
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (BNCT) using
small neutron accerelator equipped to hospital and also
develp more effective immumotherapeutic approaches.
Molecular Imaging Laboratory, Cooperative Unit ofMedicine, Engineering and Pharmaceutical Reserch
Tetsuo Nagano, Laboratory of Chemistry and Biology,
Graduate School of Pharmaceutical Sciences
Yasunobu Hirata, Department of Cardiovascular Medi-cine
To develop chemical probes for imaging of biomolecules To elucidate mechanisms and to establish
cures of arteriosclerosis
Laboratory of Artificial Organs
Division of Artificial Organs & Transplantation: Katsutoshi Naruse and Lei Guo
Institute of Industrial Science and Center for Disease
Biology and Integrative Medicine, Graduate School of
Medicine: Yasuyuki Sakai
Laboratory of Artificial Organs consists of researchers
belonging to Division of Artificial Organs & Transplantation, and Sakai Laboratory. We have been collaborating in the research of bioartificial liver support
systems in the past 10 years. Our current specializationis, development of artificial liver support, clinical useof new apheresis therapy, development of transgenic
pig producing human serum albumin, and developmentof implantable liver tissue equivalents.
Laboratory of Applied Metabolic Biotechnology
Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Metabolic Diseases, Graduate School of
Medicine
Department of Chemistry and Biotechnology, School ofEngineering
To establish the system and methods for engineering thenovel model mice of life style-related diseases using
RNAi technology and biotechnology. To elucidate themechanisms by which adipose tissue derived factors,
adipokines, contribute to the development of the metabolic syndrome. To explore the signal transduction
pathways of major adipokines including adiponectin
Laboratory of Biomaterial Science
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials Science,
Graduate School of Engineering, The University of Tokyo
Division of Biomedical Materials and Systems, Center
for Disease Biology and Integrative Medicine, Facultyof Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery, Facultyof Medicine, The University of Tokyo

430

Inhibition of aseptic loosening of artificial joints bynano-grafting of a novel biocompatible polymer MPC.
Creation of biocompatible biomaterials optimized forbone, cartilage and vascular regeneration. Regenerationof bone and cartilage tissue in vitro promoted byphysical stimulation
Molecular and cellular physiology, Computational
mechanics
Department of Cardiothoracic Surgery, The Universityof Tokyo Hospital
Biomechanics Laboratory, Graduate School of Frontier
Sciences, The University of Tokyo
Inhibition of aseptic loosening of artificial joints bynano-grafting of a Objectives and Research Fields. Development of multi-scale, multi-physics heart simulator
and its clinical application. Molecular and cellularphysiology, Computational mechanics.
Laboratory of Hard-Tissue Nanomedicine
Kataoka & Yamasaki Lab, Department of Materials
Science, Graduate School of Engineering, The University of Tokyo
Department of ″Menicon″ Cartilage & Bone Regeneration, Graduate School of Medicine, The Universityof Tokyo
Department of Bone & Cartilage Regenerative Medicine, Graduate School of Medicine, The University ofTokyo
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo Department of Oral andMaxillofacial Surgery, Faculty of Medicine, The University of Tokyo
Division of Clinical Biotechnology, Center for Disease
Biology and Integrative
Medicine, Graduate School of Medicine, The Universityof Tokyo
Division of Tissue Engineering, The University of Tokyo
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 application of regenerated cartilage and bone. Development of easy, precise,

non-invasive systems to detect osteoblastic and chondroocytic differentiation. Determination of a finite setof signaling factors sufficient for induction of osteoblasts and chondrocytes. Development of a method
to induce osteogenesis and angiogenesis simultaneously . Development of a cell-sheet culture system forbone and cartilage. Screening for compounds that induce bone and cartilage regeneration
Cooperative Unit of Kataoka Laboratory and Department of Vascular Regeneration
Department of Vascular Regeneration, Division of Tissue Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering, The
University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we are developing
non-viral gene vectors based on nano-scaled polymer
assemblies (polymeric micelles). Polymeric micelles,
which are spontaneously formed from block copolymers, have a core containing packaged genes surrounded by biocompatible poly(ethylene glycol) (PEG)
palisades, and a variety of pilot molecules can be installed on the surface of polymeric micelles. This "virusmimicking" nanoparticles might achieve efficientgene transfer to the targeted tissues or cells because ofprotection of the loaded DNA from nuclease attack,their lowered non-specific interaction with proteins andcells and facilitated internalization by the targeted cells
through specific 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.

References
1. Akiyama T, Bouillet P, Miyazaki T, Kadono Y,
Chikuda H, Chung U, Fukuda A, Hikita A, Seto H,
Okada T, Inaba T, Sanjay A, Baron R, Kawaguchi
H, Oda H, Nakamura K, Strasser A, and Tanaka S
EMBO J : Regulation of osteoclast apoptosis byubiquitylation of proapoptotic BH3-only Bcl-2
family member Bim. 22: 6653-6664, 2003.
2. Kawano H, Sato T, Yamada T, Matsumoto T, Sekine K, Watanabe T, Nakamura T, Fukuda T, Yoshimura K, Yoshizawa T, Aihara K, Yamamoto Y,

431

Nakamichi Y, Metzger D, Chambon P, Nakamura
K, Kawaguchi H, and Kato S Suppressive functionof androgen receptor in bone resorption.: Proc Natl
Acad Sci USA 100: 9416-9421, 2003.
3. Yoshihiro Suematsu, Marx GR, Triedman JK,
Mihaljevic T, Mora BN, Takamoto S, del Nido PJ:
Three-dimensional echocardiography-guided atrial
septectomy: an experimental study. Journal ofThoracic & Cardiovascular Surgery 128:53-59,
2004.
4. Yoshihiro Suematsu, Marx GR. Stoll JA, DuPont
PE, Cleveland RO, Howe RD, Triedman JK,
Mihaljevic T, Mora BN, Savord BJ, Salgo IS, delNido PJ: Three-dimensional echocardiography-guided beating-heart surgery without cardiopulmonary bypass: a feasibility study, Journal ofThoracic & Cardiovascular Surgery 128:579-584,
2004.
5. Yoshihiro Suematsu, del Nido PJ: Robotic pediatriccardiac surgery: present and future perspectives,
American Journal of Surgery 188:98S-103S, 2004.
6. Saeki Y, Kobayashi T, Yasuda S, Nishimura S,
Sugiura S, Yamashita H, Sugi H Role of Ca2+ indetermining the rate of tension development andrelaxation in rat skinned myocardium (2004) J Mol
Cell Cardiol 36:371-380
7. Nishimura S, Yasuda S, Katoh M, Yamada KP,
Yamashita H, Saeki Y, Sunagawa K, Nagai R, Hisada T, Sugiura S Single cell mechanics of rat cardiomyocytes under isometric, unloaded andphysiologically loaded conditions. Am J Physiol(2004) 287:H196-202
8. Kato M, Matsumoto A, Nakajima T, Hirose K,
Iwasawa K, Takenaka K,Yamashita H, Sugiura S,
Hirata Y, Nagai R Amlodipine Increases Nitric
Oxide Production in Exhaled Air during Exercise
in atients with Essential Hypertension Am J Hyperten (2004) 17:729-33, 2004
9. Watanabe H, Sugiura S, Hisada T Multi-physics
simulation of left ventricular filling dynamics using fluid-structure interaction finite element
method Biophys J 87:2074-2085 (2004)
10. Okada J, Sugiura S, Nishimura S, Hisada T 3D
simulation of calcium waves and contraction in
cardiomyocytes using the finite element method
Am J Physiol 288:C510-C522 (2004)
11. Watanabe H, Sugano T, Sugiura S, Hisada T Finite

element analysis of ventricular wall motion andintra-ventricular blood flow in heart with myocardial infarction JSME International Journal SeriesC, 47:1019-1026 (2004)
12. Sugiura S, Yasuda S, Yamashita H, Kato K, Saeki
Y, Kaneko H, Suda Y, Nagai R, Sugi H Measurement of force developed by a single cardiac myocyte using novel carbon fibers In Sugi H ed. Molecular and cellular aspects of muscle contraction.
Plenum Press, New York (2004) 381-387
13. Yamashita H, Sugiura S, Fujita H, Yasuda S, Nagai
R, Saeki Y, Sugi H Myosin heavy chain isofroms
modulate motor function of cardiac myosin bychanging crossbridge kinetics. Pathophysiology ofcardiovascular disease Eds. Dahlla NS, Rupp H,
Angel A, Pierce GN Kluwer Academic Publishers
Boston 2004:35-49
14. Asai, D., Katopo, S., Arata, J., Warisawa, S., Mitsuishi, M., Morita, A., Sora, S., Kirino, T. andMochizuki, R.: Micro-Neurosurgical System in the
Deep Surgical Field, Proceedings of the 7th International Conference on Medical Image Computing
and Computer-Assisted Intervention (MICCAI2004), Part II, pp.33-40, 2004.
15. Y. Sakai, M. Otsuka, S. Hanada, Y. Nishiyama, Y.
Konishi, A. Yamashita. A novel poly-L-lactic acidscaffold that possesses a macroporous structure
and a branching/joining three-dimensional flow
channel network: Its fabrication and application to
perfusion culture of human hepatoma Hep G2 cells.
Mat. Sci. Eng. C, 24(3), 379-386, 2004.
16. Y. Sakai, M. Otsuka, J. Kozasa, F. Miyata, K. S.
Furukawa, A. Yamashita. Ultra-violet-light irradiation-based photofabrication that simultaneously
produces a macroporous structure and flow channels using a photo-reactive biodegradable polymer
and a gas-forming azoamide compound. Biochem.
Eng. J., 20, 163-171 2004.
17. Y. Sakai, O. Fukuda, S-H. Choi and A. Sakoda: Useof a perfusion coculture system consisting of
Caco-2 and Hep G2 cell compartments for the kinetic analysis of benzo[a]pyrene toxicity. ATLA(Special Issue), Supplement 1A, 99-104, 2004.
18. Sakai, Y., Leclerc, E., Fujii, T.: Microfluidic
Cell-culture Devices, Lab-on-Chips for Cellomics,
Kluwer Academic Publishers, pp.299-318, 2004.
19. Guo L, Haga S, Enosawa S, Naruse K, Harihara Y,

432

Sugawara Y, Makuuchi M, Ozaki M. Improved
hepatic regeneration with reduced injury by redox
factor-1 in a rat small-sized liver transplant model.
American Journal of Transplantation. 4, 879-887,
2004
20. H. Shindoh, K. Naruse, Y. Sakai, M. Makuuchi.
Efficacy of immunoadsorbent devices for maintaining hepatic function in ex vivo xenogenic direct hemoperfusion. Int. J. Artif. Organs, 27(4),294-302, 2004.
21. Jinlan J, Kojima N, Guo L, Naruse K, Makuuchi M,
Miyajima A, Yan W, Sakai Y. Efficacy of engineered liver tissue based on poly-L-lactic acidscaffolds and fetal mouse liver cells cultured with
Oncostatin M, nicotinamide and dimethyl sulfoxide. Tissue Engineering. 10, 1577-1586, 2004
22. J. Jinlan, N. Kojima, A. Miyajima, W. Yan, Y. Sakai. Cultivation and induction of fetal liver cells inpoly-L-lactic acid scaffolds. Mat. Sci. Eng. C,
24(3), 361-363 2004.
23. S-H. Choi, A. Sakoda, Y. Sakai: Enhanced cytochrome P450 capacities of Caco-2 and Hep G2
cells in new coculture systems under static andperfused conditions: Evidence for possible organ-to-organ interactions against exgeneous stimuli: Mat. Sci. Eng. C, 24(3), 333-339, 2004.
24. E. Leclerc, F. Miyata, K. S. Furukawa, Y. Sakai, T.
Fujii: Effect on liver cells of stepwise microstructures fabricated in a photosensitive biodegradable
polymer by soft lithography：Mat. Sci. Eng. C,
24(3), 349-354, 2004.
25. Sue Hyung Choi, Masaki Nishikawa, Akiyoshi
Sakoda, and Yasuyuki Sakai. Feasibility of a simple double-layered coculture system incorporating
metabolic processes of the intestine and liver tissue: Application to the analysis of benzo[a]pyrene
toxicity. Toxicology in Vitro, 18(3), 393-402,
2004.
26. E. Leclerc, Y. Sakai, T. Fujii. Perfusion Culture of
Fetal Human Hepatocytes in Microfluidic- Environments. Biochem. Eng. J., 20, 143-148, 2004.
27. E.Leclerc, K.S.Furukawa, F. Miyata, Y.Sakai, T.
Ushida, T. Fujii. Fabrication of microstructures inphotosensitive biodegradable polymers for tissue
engineering applications. Biomat., 25, 4683-4690,
2004.
28. E. Leclerc, Y. Sakai and T. Fujii. A microfluidic

PDMS (polydimethylsiloxane) bioreactor forlarge-scale culture of hepatocytes. Biotechnol.
Prog., 20(3), 750-755, 2004.
29. J. Jiang, N. Kojima, L. Guo, K. Naruse, M. Makuuchi, A. Miyajima, W.-Q. Yan, Y. Sakai. Efficacy of engineered liver tissue based onpoly-L-lactic acid scaffolds and fetal mouse liver
cells cultured with oncostatin M, nicotinamide anddimethyl sulfoxide. Tissue Eng., 10, 1577-1586,
2004.
30. K. Shimizu, O. Endo, S. Goto, Y. Ono, A. Sakoda,
Y. Sakai. Bioassay-based evaluation of toxicity ofsuspended particulate matter in humans: Integrated
uses of alveolar cells (A549) in air-liquid interface
culture and hepatocarcinoma cells (Hep G2): Biochem. Eng. J., 22, 2-9, 2004.
31. S. Ostrovidov, J. Jiang, Y. Sakai, T. Fujii. Membrane-based PDMS microbioreactors for perfused
3D primary rat hepatocyte cultures. Biomed. Microdevices, 6(4), 279-287, 2004.
32. Itaka K et al. Supramolecular nanocarrier of siRNAfrom PEG-based block catiomer carrying diamineside chain with distinctive pKa directed to enhance
intracellular gene silencing. J Am Chem Soc
126:13612, 2004
33. Miyata K et al. Block Catiomer Polyplexes with
Regulated Densities of Charge and Disulfide
Cross-Linking Directed To Enhance Gene Expression. J Am Chem Soc 126:2355, 2004
34. Itaka K et al. In situ single cell observation byfluorescence resonance energy transfer reveals fast
intra-cytoplasmic delivery and easy release ofplasmid DNA complexed with linear polyethylenimine. J Gene Med 6: 7, 2004
35. Kanayama N. et al. PEG-Based Biocompatible
Block Catiomer with High-Buffering Capacity for
the Construction of Polyplex Micelles Showing
Efficient Gene Transfer Toward Primary Cells.
ChemMedChem (in press)
36. Kenji Takegami, Yukio Kaneko, Toshiaki Watanabe,Toshiyuki Maruyama, Yoichiro Matsumoto, Hirokazu Nagawa : Polyacrylamide gel containing egg
white as new model for irradiation experiments
using focused ultrasound. Ultrasound in Medicine
And Biology 30(10):1419-22,2004
37. Bessho M, Ohnishi I, Okazaki H, Sato H, Kominami H, Matsunaga S, Nakamura K: Prediction of

433

the Strength and Fracture Location of the Femoral
Neck by CT Based Finite Element Method: A Preliminary Study on Patients with Hip Fracture.
Journal of Orthopaedic Science. 9(6), 545-550,
2004
38. Moro T, Takatori Y, Ishihara K, Konno T, Takigawa
Y, Matsushita T, Chung UI, Nakamura K, andKawaguchi H : Surface grafting of artificial joints
with a biocompatible polymer for preventing periprosthetic osteolysis. Nature Mater 3: 829-836,
2004.
39. Seto H, Fujii T, Kamekura S, Miura T, Yamamoto
A, Chikuda H, Ogata T, Imamura T, Miyazono K,
Oda H, Nakamura K, Kurosawa H, Chung U, Kawaguchi H, and Tanaka S : Regulation of chondrogenic differentiation of synovial fibroblasts:
segregation of the roles of Smad pathways and p38
MAP kinase pathways. J Clin Invest 113: 718-726,
2004.
40. Ogasawara T, Katagiri M, Yamamoto A, Hoshi K,
Takato T, Nakamura K, Tanaka S, Okayama H,
and Kawaguchi H : Osteoclast differentiation by
RANKL requires NF-kB-mediated down-regulationof cyclin-dependent kinase 6 (Cdk6). J Bone
Miner Res 19: 1128-1136, 2004.
41. Ogasawara T, Kawaguchi H, Jinno S, Hoshi K,
Itaka K, Takato T, Nakamura K, and Okayama H :Bone morphogenetic protein 2-induced osteoblast
differentiation requires smad-mediated downregulation of cdk6. Mol Cell Biol 24: 6560-6568,
2004.
42. Chikuda H, Kugimiya F, Hoshi K, Ikeda T, Ogasawara T, Shimoaka T, Kawano H, Kamekura S,
Tsuchida A, Yokoi N, Nakamura K, Komeda K,
Chung UI, and Kawaguchi H : Cyclic GMP- dependent protein kinase II is a molecular switchfrom proliferation to hypertrophic differentiationof chondrocytes. Genes Dev 18: 2418-2429, 2004.
43. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S,
Nakamura K, Kawaguchi H, Ikegawa S, andChung UI : Combination of SOX5, SOX6 and
SOX9 (the SOX trio) provides signals sufficientfor chondrogenesis. Arthritis Rheum 50:
3561-3573, 2004.
44. Akune T, Ohba S, Kamekura S, Yamaguchi M,
Chung U, Kubota N, Terauchi Y, Harada Y, Azuma
Y, Nakamura K, Kadowaki T, and Kawaguchi H :PPAR gamma insufficiency enhances osteogenesis
through osteoblast formation from bone marrowprogenitors. J Clin Invest 113: 846-855, 2004.
45. H. Otsuka, Y. Nagasaki, K. Kataoka, Characterization of aldehyde-PEG tethered surfaces: influenceof PEG chain length on the specific biorecognition.
Langmuir 20 (26) 11285-11287 (2004)
46. T. Taguchi, Y. Sawabe, H. Kobayashi, Y. Moriyoshi,
K. Kataoka, J. Tanaka, Preparation and characterization of osteochondral scaffold. Mat. Sci. Eng.,
C.- Bio. S. C24 (6-8) 881-885 (2004)
47. T. Kajiyama, H. Kobayashi, T. Taguchi, Y. Komatsu, K. Kataoka, J. Tanaka, Study on the hydrolytic
degradation of poly(α,β-malic acid) by direct
polycondensation. Mat. Sci. Eng., C.- Bio. S. C24(6-8) 821-825 (2004)
48. T. Kajiyama, H. Kobayashi, T. Taguchi, H. Saito, Y.
Komatsu, K. Kataoka, J. Tanaka, Synthesis of activated poly(α,β-malic acid) using N-hydroxysuccinimide and its gelation with collagen as biomaterials. Mat. Sci. Eng., C.- Bio. S. C24 (6-8) 815819 (2004)
49. H. Aoki, T. Taguchi, H. Saito, H. Kobayashi, K.
Kataoka, J. Tanaka, Rheological evaluation ofgelatin gels prepared with a citric acid derivative
as a novel cross-linker. Mat. Sci. Eng., C.- Bio. S.
C24 (6-8) 787-790 (2004)
50. H. Saito, T. Taguchi, H. Kobayashi, K. Kataoka, J.
Tanaka, S. Murabayashi, Y. Mitamura, Physicochemical properties of gelatin gels prepared using
citric acid derivative. Mat. Sci. Eng., C.- Bio. S.
C24 (6-8) 781-785 (2004)
51. T. Taguchi, H. Saito, Y. Uchida, M. Sakane, H.
Kobayashi, K. Kataoka, J. Tanaka, Bonding of soft
tissues using a novel tissue adhesive consisting of
a citric acid derivative and collagen. Mat. Sci.
Eng., C.- Bio. S. C24 (6-8) 775-780 (2004)
52. A. Hirano, M. Iijima, K. Emoto, Y. Nagasaki, K.
Kataoka, Multi-layered nanoball as high performance permselective membrane. Mat. Sci. Eng., C.Bio. S. C24 (6-8) 761-767 (2004)
53. D. Wakebayashi, N. Nishiyama, K. Itaka, K. Miyata, Y. Yamasaki, A. Harada, H. Koyama, Y. Nagasaki, K. Kataoka, Polyion complex micelles of
pDNA with acetal-poly(ethylene glycol)-poly(2-(dimethylamino)ethyl methacrylate) block copolymer as the gene carrier system. Physico-434

chemical properties of micelles relevant to genetransfection efficacy. Biomacromolecules 5 (6)2128-2136 (2004)
54. K. Itaka, N. Kanayama, N. Nishiyama, W. -D. Jang,
Y. Yamasaki, K. Nakamura, H. Kawaguchi, K.
Kataoka, Supramolecular nanocarrier of siRNAfrom PEG-based block catiomer carrying diamineside chain with distinctive pKa directed to enhance
intracellular gene silencing. J. Am. Chem. Soc.
126 (42) 13612-13613 (2004)
55. J. -S. Park, Y. Akiyama, F. M. Winnik, K. Kataoka,
Versatile synthesis of end-functionalized thermosensitive poly(2-isopropyl-2-oxazolines). Macromolecules 37 (18) 6786-6792 (2004)
56. Y. Nagasaki, T. Ishii, Y. Sunaga, Y. Watanabe, H.
Otsuka, K. Kataoka, Novel molecular recognition
via fluorescent resonance energy transfer using a
biotin-PEG/polyamine stabilized CdS quantum dot.
Langmuir 20 (15) 6396-6400 (2004)
57. H. Hayashi, M. Iijima, K. Kataoka, Y. Nagasaki,
pH-sensitive nanogel possessing reactive PEG
tethered chains on the surface. Macromolecules 37(14) 5389-5396 (2004)
58. E. Jule, Y. Yamamoto, M. Thouvenin, Y. Nagasaki,
K. Kataoka, Thermal characterization ofpoly(ethylene glycol)-poly(D,L-lactide) block copolymer micelles based on pyrene excimer formation. J. Control. Release 97 (3) 407-419 (2004)
59. E.-C. Kang, A. Ogura, K. Kataoka, Y. Nagasaki,
Preparation of water-soluble PEGylated semiconductor nanocrystals. Chem. Lett. (Jpn.) 33 (7)840-841 (2004)
60. Y. Kakizawa, S. Furukawa, K. Kataoka, Block copolymer-coated calcium phosphate nanoparticles
sensing intracellular environment for oligodeoxynucleotide and siRNA delivery. J. Control. Release 97 (2) 345-356 (2004)
61. H. Otsuka, A. Hirano, Y. Nagasaki, T. Okano, Y.
Horiike, K. Kataoka, Two-dimensional multiarray
formation of hepatocyte spheroids on a microfabricated PEG-brush surface. ChemBioChem 5 (6)850-855 (2004)
62. T. Ishii, Y. Sunaga, H. Otsuka, Y. Nagasaki, K.
Kataoka, Preparation of water soluble CdS quantum dots stabilized by functional poly(ethylene
glycol) and its application for bioassay. J. Photopolym. Sci. Technol. 17 (1) 95-98 (2004)

63. A. Matsumoto, R. Yoshida, K. Kataoka, Glucose-responsive polymer gel bearing phenylborate
derivative as a glucose-sensing moiety operating at
the physiological pH. Biomacromolecules 5 (3)1038-1045 (2004)
64. Y. Kakizawa, K. Miyata, S. Furukawa, K. Kataoka,
Size-controlled formation of a calcium phosphate-based organic-inorganic hybrid vector forgene delivery using poly(ethylene glycol)-block-poly(aspartic acid). Adv. Mater. Weinheim 16 (8) 699-702 (2004)
65. C. Diab, Y. Akiyama, K. Kataoka, F. M. Winnik,
Microcalorimetric study of the temperature- induced phase separation in aqueous solutions ofpoly(2-isopropyl-2-oxazolines). Macromolecules
37 (7) 2556-2562 (2004)
66. T. Kajiyama, H. Kobayashi, K. Morisaku, T. Taguchi, K. Kataoka, J. Tanaka, Determination ofend-group structures and by-products ofpoly(α,β-malic acid) synthesized by direct polycondensation. Polym. Degrad. Stab. 84 (1) 151157 (2004)
67. H. Katakura, A. Harada, K. Kataoka, M. Furusho, F.
Tanaka, H. Wada, K. Ikenaka, Improvement of retroviral vectors by coating with poly(ethylene glycol)-poly(L-lysine) block copolymer (PEG-PLL). J.
Gene Med. 6 (4) 471-477 (2004)
68. D. Wakebayashi, N. Nishiyama, Y. Yamasaki, K.
Itaka, N. Kanayama, A. Harada, Y. Nagasaki, K.
Kataoka, Lactose-conjugated polyion complex
micelles incorporating plasmid DNA as a targetable gene vector system: their preparation andgene transfecting efficiency against cultured
HepG2 cells. J. Control. Release 95 (3) 653-664(2004)
69. Y. Akiyama, Y. Nagasaki, K. Kataoka, Synthesis ofheterotelechelic poly(ethylene glycol) derivatives
having α-benzaldehyde and ω-pyridyl disulfide
groups by ring opening polymerization of ethyleneoxide using 4-(diethoxymethyl)benzyl alkoxide asa novel initiator. Bioconjug. Chem. 15 (2) 424-427(2004)
70. M. Jaturanpinyo, A. Harada, X. Yuan, K. Kataoka,
Preparation of bionanoreactor based on core-shellstructured polyion complex micelles entrapping
trypsin in the core cross-linked with glutaraldehyde. Bioconjug. Chem. 15 (2) 344-348 (2004)

435

71. K. Miyata, Y. Kakizawa, N. Nishiyama, A. Harada,
Y. Yamasaki, H. Koyama, K. Kataoka, Block catiomer polyplexes with regulated densities of charge
and disulfide cross-linking directed to enhancegene expression. J. Am. Chem. Soc. 126 (8)2355-2361 (2004)
72. M. Tabuchi, M. Ueda, N. Kaji, Y. Yamasaki, Y.
Nagasaki, K. Yoshikawa, K. Kataoka, Y. Baba,
Nanospheres for DNA separation chips. Nat. Biotechnol. 22 (3) 337-340 (2004)
73. A. Matsumoto, T. Kurata, D. Shiino, K. Kataoka,
Swelling and shrinking kinetics of totally synthetic,
glucose-responsive polymer gel bearing phenylborate derivative as a glucose-sensing moiety.
Macromolecules 37 (4) 1502-1510 (2004)
74. T. Ishii, H. Otsuka, K. Kataoka, Y. Nagasaki,
Preparation of functionally PEGylated gold
nanoparticles with narrow distribution throughautoreduction of auric cation by α-biotinyl-PEGblock-[poly(2-(N,N-dimethylamino)ethyl
methacrylate)]. Langmuir 20 (3) 561-564 (2004)
75. R. Ideta, Y. Yanagi, Y. Tamaki, F. Tasaka, A. Harada,
K. Kataoka, Effective accumulation of polyion
complex micelle to experimental choroidal neovascularization in rats. FEBS Letters 557 (1-3)
21-25 (2004)
76. K. Itaka, A. Harada, Y. Yamasaki, K. Nakamura, H.
Kawaguchi, K. Kataoka, In situ single cell observation by fluorescence resonance energy transfer
reveals fast intra-cytoplasmic delivery and easy
release of plasmid DNA complexed with linear
polyethylenimine. J. Gene Med. 6 (1) 76-84(2004)
77. H. Kobayashi, M. Kato, A. Matsuda, T. Taguchi, K.
Kataoka, J. Tanaka, Collagen immobilized PVA
hydrogel - hydroxyapatite composites for keratoprosthesis. Trans. Mater. Res. Soc. Jpn. 29 (6)2897-2900 (2004)
78. T. Kajiyama, H. Kobayashi, T. Taguchi, K. Kataoka,
J. Tanaka, Improved synthesis with high yield andincreased molecular weight of poly(α,β-malicacid) by direct polycondensation. Biomacromolecules 5 (1) 169-174 (2004)
79. N. Nishiyama, Arnida, W. -D. Jang, K. Date, K.
Miyata, K. Kataoka, Photochemical enhancementof transgene expression by polymeric micelles incorporating plasmid DNA and dendrimer-based

photosensitizer. J. Drug Target. in press
80. M. M. Ali, M. Oishi, F. Nagatugi, N. Uchida, K.
Mori, Y. Nagasaki, K. Kataoka, S. Sasaki, Intracellular ability of an inducible alkylation system toexhibit antisense effects with greater potency andselectivity. Angew. Chem. Int. Ed. Engl. in press
81. N. Kanayama, S. Fukushima, N. Nishiyama, K.
Itaka, W. -D. Jang, K. Miyata, Y. Yamasaki, U.
Chung, K. Kataoka, PEG-based biocompatible
block catiomer with high-buffering capacity forthe construction of polyplex micelles showing efficient gene transfer toward primary cells.
ChemMedChem in press
82. H. Otsuka, Y. Nagasaki, K. Kataoka, Functionalized poly(ethylene glycol) (PEG) layer on polylactide (PLA) surface using heterogifunctional
PEG/PLA block copolymers. Trans. Mater. Res.
Sco. Jpn. in press
83. Zhidkov A, Koga J, Hosokai T, Kinoshita K, Uesaka M: Effect of plasma density on relativistic
self-injection for electron laser wake-field acceleration. PHYSICS OF PLASMAS Vol.11
No.12:5379,2004
84. Hosokai T, Kinoshita K, Zhidokov A, Nakamura K,
Kotaki H, Kando M: Refraction effects on the cavity formation and interaction of an intense ultra-short laser pulse with a gas jet. PHYSICS OF
PLASMAS Vlo.11 No.10:L57,2004
85. Uesaka M: Femtosecond Beam Sources and Applications. American Institute of Physics Conference Proceedings Vol.737:171-177,2004
86. Dobashi K, Uesaka M, Fukasawa A, Sakamoto F,
Ebina F, Ogino H, Urakawa J, Higo T, Akemoto M,
Hayano H, Nakagawa K:X-band RF gun and Linac For Medical Compton Scattering X-ray source.
American Institute of Physics Conference Proceeding Vol.737:684-690,2004
87. Iijima H, Uesaka M, Ueda T, Sakumi A, Muroya Y:
Performance of Synchronization and Emittance ofthe Mg cathode Photojector.American Institute ofPhysics Conference Proceeding Vol.737:997-1003,
2004
88. Kinoshita K, Zhidkov A, Hosokai T, ohkubo T,
Uesaka M: Propagation of an intense femtosecond
laser pulse through a thin foil filter. APPLIED
PHIYSICS LETTERS Vol.84, No.23:4623,2004
89. Zhidokov A, Koga J, Kinoshita K, Uesaka M: Ef-436

fect of self-injection on ultraintense laser
wake-filed acceleration. PHYSICAL REVIEW E
69,: 035401(R), 2004
90. Zhidokov A, Koga J, Esirkepoy T, Hosokai T, Uesaka M, Tajima T: Optical-field-ionization effects
on the propagation od an ultraintese laser pulse inhigh-Z gas jets. PHYSICAL REVIEW E 69:
066408,2004
91. Ohkubo T, Kinoshita K, Zhidokov A, Hosokai T,
Kanegae Y, Uesaka M: Efficiency of Laser Plasma
KEmission for Time-Resolved X-ray Imaging.
Japanese Journal of Applied Physics, Vol.43,
No.4A:1608-1611,2004
92. K. Takegami, Y. Kaneko, T. Watanabe, T.
Maruyama, Y. Matsumoto, H. Nagawa ：Polyacrylamide gel containing egg white as
new model for irradiation experiments using
focused ultrasound. Ultrasound in Medicine
and Biology 30:1419-1422, 2004.
93. Y. Matsumoto, J. S. Allen, S. Yoshizawa, T.
Ikeda, Y. Kaneko：Medical ultrasound withmicrobubbles. Experimental Thermal andFluid Science 29:255-265, 2005.
94. Y. Kaneko, T. Maruyama, K. Takegami, T.
Watanabe, H. Mitsui, K. Hanajiri, H. Nagawa, Y. Matsumoto：Use of a microbubble
agent to increase the effects of high intensity focused ultrasound on liver tissue.
European Radiology 15:1415-1420, 2005.
95. K. Takegami, Y. Kaneko, T. Watanabe, T.
Maruyama, Y. Matsumoto, H. Nagawa ：Erythrocytes, as well as microbubble contrast agents, are important factors in improving thermal and therapeutic effects ofhigh-intensity focused ultrasound. Ultrasound in Medicine and Biology 31:385-390,
2005.
96. K. Takegami, Y. Kaneko, T. Watanabe, S.
Watanabe, T. Maruyama, Y. Matsumoto, H.
Nagawa：Heating and Coagulation Volume
Obtained with High-Intensity Focused Ultrasound therapy: Comparison of Perflutren
Protein-Type A Microspheres and MRX-133
Rabbits. Radiology 237:132-136, 2005.
97. Y. Matsumoto and S. Yoshizawa：Behaviourof a bubble cluster in an ultrasound field.
International Journal for Numerical Meth-ods in Fluids 47:591-601, 2005.
98. Yoshihiro Suematsu, Martinez JF, Wolf BK, Marx
GR. Stoll JA, DuPont PE, Howe RD, Triedman JK,
del Nido PJ: Three-dimensional echo-guided beating heart surgery without cardiopulmonary bypass:atrial septal defect closure in a swine model, Journal of Thoracic & Cardiovascular Surgery
130:1348-57, 2005.
99. Nicholas Herlambang, Hongen Liao, Kiyoshi Matsumiya, Hiroyuki Tsukihara, Shinichi Takamoto,Takeyoshi Dohi: Realtime Integral Videographyusing Intra-operative Three-dimensional Ultrasound for Minimally Invasive Heart Surgery. In
Proc. The 1st Asian Symposium of Computer
Aided Surgery 2005, 2005.
100. Uozaki H, Fukayama, Nakagawa K, Ishikawa T,
Misawa S, Doi M, Maekawa K: The Pathology ofMulti-Organ Involvement: Two Autopsy Cases ofTokaimura Criticality Accident. The British Journal of Radiology, Suppl. 27:13-16, 2005
101. Nakagawa K, Fukuhara N, Kawakami H: A
PackedBuilding-Block
Compensator(TETRIS-RT) for IMRT Delivery. Medical Physics 32 (7):2231- 2235, 2005
102. Yamashita H, Nakagawa K, Tago M, Nakamura N,
Shiraishi K, Ohtomo K. Salvage radiotherapy for
postoperative loco-regional recurrence of esophageal cancer. Dis Esophagus. 2005;18(4):21520.
103. Yamashita H, Nakagawa K, Tago M, Shiraishi K,
Nakamura N, Ohtomo K. Treatment results andprognostic analysis of radical radiotherapy for locally advanced cancer of the uterine cervix. Br J
Radiol. 2005 Sep;78(933):821-6.
104. Yamashita H, Nakagawa K, Tago M, Shiraishi K,
Nakamura N, Ohtomo K, Oda K, Nakagawa S,
Yasugi T, Taketani Y. Comparison between conventional surgery and radiotherapy for FIGO stage
I-II cervical carcinoma: a retrospective Japanesestudy. Gynecol Oncol. 2005 Jun;97(3):834-9.
105. Komuro Y, Watanabe T, Hosoi Y, Matsumoto Y,
Nakagawa K, Suzuki N, Nagawa H: Prognostic
significance of Ku70 protein expression in patientswith advanced colorectal cancer. Hepatogastroenterology. 2005 Jul-Aug;52(64):995-8
106. Keiichi Nakagawa, Hiroki Koyanagi, Takashi
Shiraki, Shigeki Saegusa, Katsutake Sasaki, Ta-437

kashi Oritate, Kazuo, Mima, Masanori Miyazawa,
Tatsuyo Ishidoya, Kuni Ohtomo, Kiyoshi Yoda: A
radiophotoluminescent glass plate system for medium-sized field dosimetry. review of scientificinstruments, 76, 106104 (2005) (4 pages)
107. Minoru Tanaka, Yasushi Ino, Keiichi Nakagawa,
Masao Tago,and Tomoki Todo: High-Dose Conformal Radiotherapy for Supratentorial Malignant
Glioma. Lancet Oncology 2005 Dec;6(12):953-60.
108. Hideomi Yamashita, Keiichi Nakagawa, Masao
Tago, Naoki Nakamura, Kenshiro Shiraishi,
Naoko Yamauchi and Kuni Ohtomo: Pathologicalchanges after radiotherapy for primary pituitarycarcinoma: a case report. Journal of Neuro- Ongology. 2005 Nov;75(2):209-14.
109. Yamashita H, Nakagawa K, Tago M, Igaki H,
Nakamura N, Shiraishi K, Sasano N, Ohtomo K:
The experience of concurrent chemoradiation forJapanese patients with superficial esophageal
squamous cell carcinoma: a retrospective study.
Am J Clin Oncol. 2005 Dec;28(6):555-9.
110. Hanajiri K, Mitsui H, Maruyama T, Kondo Y,
Shiina S, Omata M, Nakagawa K: 18F-FDG PET
for hepatocellular carcinoma presenting withportal vein tumor thrombus. J Gastroenterol. 2005
Oct;40(10):1005-6.
111. Igaki H, Karasawa K, Sakamaki H, Saito H,
Nakagawa K, Ohtomo K, Tanaka Y: Renal
Dysfunction
after
Total-Body
Irradiation
Significance of Selective Renal Shielding Blocks.
Strahlenther Onkol. 2005 Nov;181(11):704-708.
112. Nishimura S, Yamashita H, Katoh M, Yamada
K.P., Sunagawa K, Saeki Y, Ohnuki Y, Nagai R,
Sugiura S Contractile dysfunction of cardiomyopathic hamster myocytes is pronounced underhigh load conditions J Mol Cell Cardiol 39:
231-239 (2005)
113. Nishimura S, Nagai S, Katoh M, Yamashita H,
Saeki Y, Okada J-I, Hisada T, Nagai R, Sugiura S
Microtubules modulate the stiffness of cardiomyocytes against shear stress Circ Res (2006)
98:81-87
114. Nishimura S, Nagai S, Sata M, Katoh M, Yamashita H, Saeki Y, Nagai R, Sugiura S Expressionof green fluorescent protein impairs theforce-generating ability of isolated rat ventricularcardiomyocytes Mol Cell Biochem (2006) in press

115. Morita,A., Sora,S., Mitsuishi,M., Warisawa,S.,
Surman,K., Asai,D., Arata,J., Baba,S., Takahashi,H., Mochizuki,R., and Kirino,T. : Microsurgical robotic system for the deep surgicalfield: development of a prototype and feasibility studies inanimal andcadaveric modes, Journal of Neurosurgery, Vol.103, pp.320-327, 2005.
116. Mitsuishi,M., Baba,S., Takahashi,H., Asai,D.,
Warisawa,S., Sora,S., Kirino,T., Mochizuki,R.,
Shiraishi,T., Morita,A.: Development of a Computer-Integrated Micro-Neurosurgical System inthe Deep Surgical Field, 36th International Symposium on Robotics (ISR2005), 2005.
117. Baba,S., Asai,D., Warisawa,S., Mitsuishi,M., Morita,A., Sora,S., Mochizuki,R., Shiraish, T.: Development of an Advanced Micro-neurosurgical
Robotic System for the Deep Surgical Field, The
first IEEE / RAS-EMBS International Conference
on Biomedical Robotics and Biomechatronics,
Pisa, Italy, 2006.
118. Naruse K, Ishikawa H, Ueda H, Kurome M, Miyazaki K, Sawasaki T, Nagashima H, Makuuchi M
Production of a transgenic pig expressing humanalbumin and enhanced green fluorescent protein.
Journal of Repruduction and Development, 51,
539-546, 2005
119. Naruse K Artificial Liver Support; Future Aspect
Journal of Artificial Organs, 8, 71-76, 2005
120. Naruse K, Nagashima H, Sakai Y, Kokudo N, Makuuchi M Development and perspectives of perfusion treatment for liver failure. Surgery Today 35,
507-517, 2005
121. Y. Sakai, K. Tomita, M. Suzuki, Y. Ono, A. Sakoda: Development of a toxicity evaluation system for gaseous compounds using air-liquid interface culture of a human bronchial epithelial cellline, Calu-3: AATEX, 11(1), 59-67, 2005.
122. N. Kojima, N. Shiojiri, Y. Sakai and A. Miyajima:
Expression of neuritin during liver maturation andregeneration. FEBS Lett., 579(21), 4562-4566,2005.
123. S. Okajima, Y. Sakai, T. Yamaguchi. Development of regenerable cell cutlure material systemsensing and releasing dead cells, Langmuir, 21(9),4043-4049, 2005.
124. Oishi M. et al. Lactosylated poly(ethylene glycol)-siRNA
conjugate
throughacid-labile438

beta-thiopropionate
linkagetoconstruct
pH-sensitive polyion complex micelles achieving
enhanced gene silencing in hepatoma cells. J Am
Chem Soc 127: 1624, 2005
125. Kenji Takegami, Yukio Kaneko, Toshiaki Watanabe, Toshiyuki Maruyama, Yoichiro Matsumoto,
Hirokazu Nagawa : Erythrocytes, as well as Microbubble Contrast Agents, are Important Factors
in Improving Thermal and Therapeutic Effects ofHigh Intensity Focused Ultrasound. Ultrasound in
Medicine And Biology. 31(3):385-390,2005
126. Yukio Kaneko, Toshiyuki Maruyama, Kenji Takegami, Shunsuke Watanabe, Toshiaki Watanabe,
Hirokazu Nagawa, Hiroshi Mitsui,Kazuyuki
Hanajiri, Shu Takagi, Yoichiro Matsumoto : Use ofa microbubble agent to increase the effects of highintensity focused ultrasound on liver tissue. European Radiology 15(7):1415-20,2005
127. Kenji Takegami, Yukio Kaneko, Toshiaki Watanabe, Shunsuke Watanabe, Toshiyuki Maruyama,
Yoichiro Matsumoto, Hirokazu Nagawa : Comparison of Optison and MRX-133 microbubble
contrast agent: Heating and coagulation volume
with high intensity focused ultrasound in rabbits.
Radiology 237(1):132-136,2005
128. Ohnishi I, Sato W, Matsuyama J, Yajima H, Haga
N, Kamegaya M, Minami A, Sato M, Yoshino S,
Oki T, Nakamura K: Treatment of Congenital
Pseudoarthrosis of the Tibia-A Multi-Center Studyin Japan- Journal of Pediatric Orthopaedics. 25(2): 219-24, 2005 Mar-Apr.
129. Matsuyama J, Ohnishi I, Kageyama T, Oshida H,
Suwabe T, Nakamura K: Osteogenesis and Angiogenesis in the Regenerating Bone during Transverse Distraction-Quantitative Evaluation Using a
Canine Model. Clinical Orthopaedics and Related
Research, 433, 243-50, 2005
130. Ohnishi I, Kurokawa T, Sato W, Okazaki H, Nakamura K, Measurement of the tensile forces during bone lengthening. Clinical Biomechanics, 20(4), 421-427, 2005.
131. S. Ohashi, I. Ohnishi, T. Kageyama, S. Fukuda, A.
Tsuchiya, K. Imai, J. Matsuyama, K. Nakamura:
The Effect of Vascularity on the Canine Distracted
Tibial Callus Consolidation. Clinical Orthopaedics
and Related Research. 438, 253-259, 2005
132. Moro T, Ogasawara T, Chikuda H, Ikeda T, Ogata

N, Maruyama Z, Komori T, Hoshi K, Chung UI,Nakamura K, Okayama H, and Kawaguchi H : Inhibition of Cdk6 expression through p38 MAP
kinase is involved in differentiation of mouse prechondrocyte ATDC5. J Cell Physiol 204 (3):927-33, 2005.
133. R. Ideta, F. Tasaka, W. -D. Jang, N. Nishiyama, G.
-D. Zhang, A. Harada, Y. Yanagi, Y. Tamaki, T.
Aida, K. Kataoka, Nanotechnology-based photodynamic therapy for neovascular disease using a
supramolecular nanocarrier loaded with a dendritic
photosensitizer. Nano Lett. 5 (12) 2426-2431(2005)
134. K. Miyata, Y. Kakizawa, N. Nishiyama, Y. Yamasaki, T. Watanabe, M. Kohara, K. Kataoka,
Freeze-dried formulations for in vivo gene delivery of PEGylated polyplex micelles with disulfide
crosslinked cores to the liver. J. Control. Release
109 (1-3) 15-23 (2005)
135. N. Nishiyama, A. Iriyama, W. -D. Jang, K. Miyata,
K. Itaka, Y. Inoue, H. Takahashi, Y. Yanagi, Y.
Tamaki, H. Koyama, K. Kataoka, Light-induced
gene transfer from packaged DNA enveloped in adendrimeric photosensitizer. Nat. Mater. 4 (12)934-941 (2005)
136. T. Takahashi, Y. Yamada, K. Kataoka, Y. Nagasaki,
Preparation of a novel PEG-clay hybrid as a DDS
material: dispersion stability and sustained releaseprofiles. J. Control. Release 107 (3) 408-416(2005)
137. T. Sakura, T. Takahashi, K. Kataoka, Y. Nagasaki,
One-pot preparation of mono-dispersed andphysiologically stabilized gold colloid. Colloid.
Polym. Sci. 284 (1) 97-101 (2005)
138. H. Uchino, Y. Matsumura, T. Negishi, F. Koizumi,
T. Hayashi, T. Honda, N. Nishiyama, K. Kataoka,
S. Naito, T. Kakizoe, Cisplatin-incorporating
polymeric micelles (NC-6004) can reduce
nephrotoxicity and neurotoxicity of cisplatin in
rats. Br. J. Cancer 93 (6) 678-687 (2005)
139. M. Oishi, T. Hayama, Y. Akiyama, S.Takae, A.
Harada, Y. Yamasaki, F. Nagatsugi, S. Sasaki, Y.
Nagasaki, K. Kataoka, Supramolecular assemblies
for the cytoplasmic delivery of antisense oligodeoxynucleotide: polyion complex (PIC) micelles
based on poly(ethylene glycol)-SS- oligodeoxynucleotide conjugate. Biomacromolecules 6 (5)439

2449-2454 (2005)
140. Y. Nagasaki, M. Nakamae, T. Takahashi, K.
Kataoka, Design of stable bionanoparticles by
PEG based surface modifications. J. Photopolym.
Sci. Technol. 18 (4) 513-514 (2005)
141. X. Yuan, Y. Yamasaki, A. Harada, K. Kataoka,
Characterization of stable lysozyme-entrappedpolyion complex (PIC) micelles with crosslinked
core by glutaraldehyde. Polymer 46 (18) 77497758 (2005)
142. Y. Bae, W. -D. Jang, N. Nishiyama, S. Fukushima,
K. Kataoka, Multifunctional polymeric micelles
with folate-mediated cancer cell targeting andpH-triggered drug releasing properties for active
intracellular drug delivery. Molecular BioSystems
1 (3) 242-250 (2005)
143. K. Osada, Y. Yamasaki, S. Katayose, K. Kataoka,
A synthetic block copolymer regulates S1 nucleasefragmentation of supercoiled plasmid DNA.
Angew. Chem. Int. Ed. Engl 44 (23) 3544-3548(2005)
144. S. Fukushima, K. Miyata, N. Nishiyama, N.
Kanayama, Y. Yamasaki, K. Kataoka, PEGylated
polyplex micelles from triblock catiomers withspatially ordered layering of condensed pDNA andbuffering units for enhanced intracellular gene delivery. J. Am. Chem. Soc. 127 (9) 2810-2811(2005)
145. A. Matsuda, H. Kobayashi, S. Itoh, K. Kataoka, J.
Tanaka, Immobilization of laminin peptide inmolecularly aligned chitosan by covalent bonding.
Biomaterials 26 (15) 2273-2279 (2005)
146. T. Hamaguchi, Y. Matsumura, M. Suzuki, K. Shimizu, R. Goda, I. Nakamura, I. Nakatomi, M. Yokoyama, K. Kataoka, T. Kakizoe, NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity andreduce the neurotoxicity of paclitaxel. Br. J. Cancer 92 (7) 1240-1246 (2005)
147. M. Oishi, F. Nagatsugi, S. Sasaki, Y. Nagasaki, K.
Kataoka, Smart polyion complex micelles for targeted intracellular delivery of PEGylated antisense
oligonucleotides containing acid-labile linkages.
ChemBioChem 6 (4) 718-725 (2005)
148. T. Taguchi, L. Xu, H. Kobayashi, A. Taniguchi, K.
Kataoka, J. Tanaka, Encapsulation of chondrocytes
in injectable alkali-treated collagen gels preparedusing poly(ethylene glycol)-based 4-armed starpolymer. Biomaterials 26 (11) 1247-1252 (2005)
149. X. Yuan, A. Harada, Y. Yamasaki, K. Kataoka,
Stabilization of lysozyme-incorporated polyion
complex micelles by the ω-end derivatization ofpoly(ethylene glycol)-poly(α,β-aspartic acid) block
copolymers with hydrophobic groups. Langmuir
21 (7) 2668-2674 (2005)
150. Y. Yang, K. Kataoka, F. M. Winnik, Synthesis of
diblock copolymers consisting of hyaluronan andpoly(2-ethyl-2-oxazoline). Macromolecules 38 (6)2043-2046 (2005)
151. S. Takae, Y. Akiyama, H. Otsuka, T. Nakamura, Y.
Nagasaki, K. Kataoka, Ligand density effect onbiorecognition by PEGylated gold nanoparticles:
regulated interaction of RCA120 lectin with lactose installed to the distal end of tethered PEG
strands on gold surface. Biomacromolecules 6 (2)818-824 (2005)
152. T. Ishii, Y. Suzuki, Y. Akiyama, H. Otsuka, K.
Kataoka, Y. Nagasaki, Construction of PEGylated
gold colloid-assembled surface for high performance biosensor. Kobunshi Ronbunshu 62 (2) 81-86(2005)
153. M. Oishi, Y. Nagasaki, K. Itaka, N. Nishiyama, K.
Kataoka,
Lactosylatedpoly(ethylene
glycol)-siRNA conjugate
throughacid-labile
β-thiopropionate linkage to construct pH-sensitive
polyion complex micelles achieving enhanced
gene silencing in hepatoma cells. J. Am. Chem.
Soc. 127 (6) 1624-1625 (2005)
154. K. Uchida, H. Otsuka, M. Kaneko, K. Kataoka, Y.
Nagasaki, A reactive poly(ethylene glycol) layer toachieve specific surface plasmon resonance sensing with a high S/N ratio: the substantial role of ashort underbrushed PEG layer in minimizing nonspecific adsorption. Anal. Chem. 77 (4) 1075-1080(2005)
155. M. Tabuchi, Y. Katsuyama, K. Nogami, H. Nagata,
K. Wakuda, M. Fujimoto, Y. Nagasaki, K. Yoshikawa, K. Kataoka, Y. Baba, A design of nanosized
PEGylated-latex mixed polymer solution for microchip electrophoresis. Lab Chip 5 (2) 199-204(2005)
156. Y. Bae, N. Nishiyama, S. Fukushima, H. Koyama,
Y. Matsumura, K. Kataoka, Preparation and biological characterization of polymeric micelle drug

440

carriers with intracellular pH-triggered drug release property: Tumor permeability, controlled
subcellular drug distribution, and enhanced in vivo
antitumor efficacy. Bioconjug. Chem. 16 (1)122-130 (2005)
157. W. -D. Jang, N. Nishiyama, G. -D. Zhang, A. Harada, D. -L. Jiang, S. Kawauchi, Y. Morimoto, M.
Kikuchi, H. Koyama, T. Aida, K. Kataoka, Supramolecular nanocarrier of anionic dendrimer
porphyrins with cationic block copolymers modified with poly(ethylene glycol) to enhance intracellular photodynamic efficacy. Angew. Chem. Int.
Ed. Engl. 44 (3) 419-423 (2005)
158. H. Cabral, N. Nishiyama, S. Okazaki, H. Koyama,
K. Kataoka, Preparation and biological propertiesof dichloro(1,2-diaminocyclohexane)platinum(II)(DACHPt)-loaded polymeric micelles. J. Control.
Release 101 (1-3) 223-232 (2005)
159. H. Otsuka, T. Satomi, A. Hirano, Y. Nagasaki, K.
Kataoka, Two-dimensional array formation ofmulti-cellular spheroids on micro-patterned brushsurface. Key Eng. Mater. 288-289(Advanced
Biomaterials VI) 449-452 (2005)
160. Dobashi K, Ebina F, Fukasawa A, Kaneyasu T,
Ogino H, Sakamoto F, Uesaka M, Yamamoto T,
Akemoto M, Hayano H, Higo T: X-Band Linac
Beam-Line for Medical Coompton Scattering
X-Ray Source. American Institute of Physics
Conference Proceedings:994-996,2005
161. Ohkubo T, Zhidkov A, Uesaka M: Numerical
study of injection Mechanisms for Generation of
mono-energetic fomtsecond Electron bunvh fromthe plasma cathode. American Institute of Physics
Conference Proceedings:859-861,2005
162. Uesaka M, Kaneyasu T, Dobashi K, Torikoshi M:
Dual Energy X-Ray CT by Compton Scattering
Hard X-Ray Source. American Institute of Physics
Conference Proceedings:1291-1293,2005
163. Fukasawa A, Sakamoto F, Ebina F, Ogino H, Uesaka M, Dobashi K: X-band thermionic cathodeRF gun at UTNL. American Institute of Physics
Conference Proceedings:1646-1648,2005
164. Yamaoka N, Ohkubo T, Hosokai T, Kinoshita K,
Nakamura K, Uesaka M: Development of Spatial
Filter for Laser-Plasuma-Cathode. Beam Interactions with Materials and Atoms Vol.241 Issues1-4:901-904,2005

165. Ebina F, Fukasawa A, Sakamoto F, Ogino H, Uesaka M, Dobashi K:Laser Pulse Circulation System for Compact Monochromatic Hard X-ray
Source. Beam Interactions with Materials andAtoms Vol.241 Issues1-4:905-908
166. Fukasawa A, Uesaka M, Sakamoto F, Ebina F,
Dobashi K, Urakawa J, Akemoto M, Higo T, Hayano H: A Tunable Monochromatic Hard X-ray
CT Device Composed of An X-band Linear Accelerator And AQ-Switched Laser.Beam Interactions with Materials and Atoms Vol.241 Issues1-4:921-925,2005
167. Uesaka M, Hosokai T, Kinoshita K, Yamaoka N,
Zhidkov A, Ohkubo T, Sakumi A, Uesa T, Muroya
Y, Katsumura Y, Iijima H, Tomizawa H, Kumagai
N: New accelerators for femtosecond beam
pump-and-probe analysis.Beam Interactions with
Materials and Atoms Vol.241 Issues1-4:880-884,
2005
168. Dobashi K, Fukasawa A, Uesaka M, Iijima H,
Imai T, Sakamoto F, Ebina F, Urakawa J, Akemoto
M, Higo T, Hayano H: Design of Compact Monochromatic Tunable Hard X-Ray Source Based on
X-band linac. Japanese Journal of Applied Physics,
Vol.44, No.4A:1999-2005,2005
169. Sakamoto F, Iijima H, Dobashi K, Imai T, Ueda T,
Watanabe T, Uesaka M: Emittance and Energy
Measurements of Low-Energy Electron Beam Using Optical
170. Transition Radiation Techniques. Japanese Journalof Applied Physics, Vol.44, No.3:1485-1491

University Hospital
Pharmaceutical Service

31

442

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Associate Professor
Kousei Ito, Ph.D.

Assistant Professor
Akihiro Hisaka, Ph.D.

Associate
Yoshitsugu Yanagihara, Ph.D.,
Kazuo Takayama,
Masashi Honma,

Tomonobu Uchino, Ph.D.,
Erika Sugiyama,
Nobuhiro Yasuno Ph.D.

Tappei Takada, Ph.D.,
Takehito Yamamoto,Homepage http://square.umin.ac.jp/todaiyak/index.htm
Introduction and Organization
We have eleven faculty members, 47 pharmacy staffs,
32 pharmacy residents, and 5 graduate students and 4
undergraduate students from the faculty of pharmaceutical sciences (fiscal year 2005).

Clinical activities
Department of Pharmacy consists of the following
six sections:1) Drug information and research section
This section offers drug information for questions
from the medical person, executes and supports the
medicine management to inpatients. In addition,
the section prepares materials for pharmaceuticalaffair committee, where each medicine is discussed
whether it should be adopted or deleted. Preparation of several periodicals regarding drug information for clinicians is also included.
2) The dispensing section
After inspecting all prescriptions for contraindications or improper use, medications are dispensed.
Drug information is given to outpatients from thissection, using a private room if necessary. The
computerized order system is linked with automatic
packaging machines for oral medicines, bar codelabel printer, and automatic dispensing system 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 dispense anti- malignant tumor medicine (database is constructedbased on the submitted protocols and the patient
information). They also do mixing of injections at
each staff station of ICU, CCU, HCU (both thesurgical department and internal department), internal medicines for hematology and oncology. 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.

4434) 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, andalso manages the accountings of all the medicinesand other materials used in our department. Thissection also takes statistics of every information of
drug affairs. Drug management section takes careof supplying and safekeeping of all the in-hospital
medicines (approx. 2,150 items), out-patient medicines, anesthetics, muscle relaxation drugs, psychotropic drugs, poison medicines.
5) Nacrotic section
Under the supervision of authorized manager fornarcotics (the director of the pharmacy department),
narcotics are properly managed, recorded, reported,
inspected and directed. Nacrotics are properly arranged and managed at the dispensing section andeach medical care section.
6) Ward section
They contribute to the team medical care by providing specialized drug information and sharing
them with all the staffs involved in the treatment.
① Investigation of carrying medicines and the side
effect histories, allergy histories etc. at the timeof hospitalization② Procurement and appraisal of patient’s basic information about the disease, compilation of the
medicine history③ Participation for conferences④ Arrangement and mixing of injections for eachpatient⑤ Monitoring of medication guidance and the side
effect for the patient, and compilation of guidance record⑥ Offering the doctor with drug information, prescription design support and detailed contents ofmedication guidance to each patient⑦ Investigation and management of ward stock
medicine. We extended these activities to 12
floors and 17 diagnosis and treatment courses
Statistical Data (fiscal year 2005)
Number of items on in-hospital formulary:
approx. 2,150
Number of prescriptions filled (annual)out-patients:
483,818(outside:418,549)(inside:30,910)(chemotherapy:
4,359)
in-patients:
407,878(oral and external: 181,739)(injection drugs: 201,851)(IVH:
19,360)(chemotherapy:
4,928)
TDM consultations (annual):
17,941
Numbers of hospital pharmaceutical cares (annual):
5,786

Educational Activities
We have lectures for the students in the health science and nursing of the medical department (ClinicalPharmacokinetics part in the Pharmacology and Toxicology (compulsory subject)) and for the students in the
medical course of the medical department (Pathogenetic and Pathology (an optional course)). In those lectures, we give outlines of drug absorption, distribution,
metabolism and excretion. We also introduce the theoryof pharmacokinetics and pharmacodynamics to understand clinical drug-drug interactions. We take care of 2
to 3 medical students (M1 and M2) for 2 weeks as freequarter students and teach them basic molecular andbiochemical techniques, as well as the pharmacokinetic
theory. We also take care of all medical students (M3and M4) for 3 days each and teach them clinical pharmaceutics, which is conducted as a part of clinical practice of the course (compulsory subject). During thiscourse, students are expected to acquire knowledge forproper prescription design and medication. Moreover, italso helps understanding of the role of pharmacists in aclinical team and importance of the cooperation.
We also hold two series of lectures for the undergraduate students in the faculty of pharmaceutical sciences: Clinical Pharmacy I (compulsory subject) andClinical Pharmacy II (an optional course). They are
educated for the clinical pharmacology and pharmacokinetics. At the graduate school of pharmaceuticalsciences, we are in charge of “Advanced Theory for
Medical Pharmacy” as a cooperator of clinical pharmacokinetic lectures (every other year), where recent
developments of the working field as well as the direction and future vision of pharmacists are reviewed. We
are training 150 students (a year) from the faculty of444

pharmaceutical sciences from our university and outside. Moreover, we have one-year training course forpost-graduates (32 pharmacists in 2005). In addition,technical workshops are hold every month to promote
life-long education of pharmacists who are engaged inregional medical care.

Research activities
A proper medication requires scientific evidences.
However, it is not fully understood that what is the target for main and side-effect of the drug, as well as the
enzymes and transporters involved in the disposition ofdrugs. Moreover, a number of patients are waiting fordevelopment of new pharmacotherapy. We are trying toclarify basic mechanisms of the genetic or acquired
diseases to develop useful pharmacotherapy for an individual patient. Our research fields include the regulation of the expression and function of transporters related to the pharmacotherapy, polymorphism of drug
metabolizing enzymes and transporters governing the
drug disposition, and drug information research.
Followings are the topics of our recent research:
1) Regulation of transcription and function of transporters in the liver and intestine involved in cholesterol homeostasis.
2) Intracellular trafficking and dynamic rearrangementof transporter complexes.
3) Polymorphism of drug metabolizing enzymes andtransporters. Quantitative prediction of clinical effects.
4) Clinical data analysis and utilization of drug package
insert, information on drug-drug interaction, and patient data for the development of safer and bettermedications for patients.

References
1. Ishiguro A., Kubota T., Sasaki H. and Iga T., A
long PCR assay to distinguish CYP2D6*5 andnovel CYP2D6 mutant allele associated with an
11-kb EcoRI haplotype. Clin. Chim. Acta. 347:
217-21 (2004).
2. Futatsugawa Y., Kubota T., Ishiguro A., Suzuki H.,
Ishikawa H. and Iga T., PCR- based haplotype determination to distinguish CYP2B6*1/*7 and *5/*6.
Clin. Chem. 50: 1472-3 (2004).

3. Minematsu T., Sugiyama E., Kusama M., Hori S.,
Yamada Y., Ohtani H., Sawada Y., Sato H., Takayama T., Sugawara Y., Makuuchi M. and Iga T.,
Effect of hematocrit on pharmacokinetics of tacrolimus in adult living donor liver transplant recipients. Transplant. Proc. 36: 1506-11 (2004).
4. Matsuno K., Kubota T., Matsukura Y., Ishikawa H.
and Iga T., Genetic analysis of glutathione
S-transferase A1 and T1 polymorphisms in a Japanese population. Clin. Chem. Lab. Med. 42: 560-2(2004).
5. Yamada Y., Sugiura M., Higo K., Ozeki T., Takayanagi R., Okuyama K., Yamamoto K., Satoh H.,
Sawada Y. and Iga T., Receptor occupancy theory-based analysis of antiemetic effects and standard doses of 5-HT3 receptor antagonists in cancer
patients, Cancer Chemother. Pharmacol. 54:
185-90 (2004).
6. Kubota T., Nishida A., Takeuchi K., Iida T., Yokota H., Higashi K., Nakahara K., Hanai H. and Iga
T., Frequency distribution of thiopurine
S-methyltransferase activity in red blood cells of ahealthy Japanese population. Ther. Drug Monit..
26: 319-21 (2004).
7. Ishiguro A., Kubota T., Ishikawa H. and Iga T.,
Metabolicactivityofdextromethorphan
O-demethylation in healthy Japanese volunteers
carrying duplicated CYP2D6 genes: duplicated allele of CYP2D6*10 dose not increase CYP2D6
metabolic activity. Clin. Chim. Acta. 344: 201-4(2004).
8. Adachi Y, Suzuki H, Schinkel AH, Sugiyama Y.,
Role of breast cancer resistance protein(Bcrp1/Abcg2) in the extrusion of glucuronide andsulfate conjugates from enterocytes to intestinal
lumen. Mol. Pharmacol. 67: 923-8 (2004).
9. Iwai M, Suzuki H, Ieiri I, Otsubo K, Sugiyama Y.,
Functional analysis of single nucleotide polymorphisms of hepatic organic anion transporter
OATP1B1 (OATP-C). Pharmacogenetics. 14:
749-57 (2004).
10. Kondo C, Suzuki H, Itoda M, Ozawa S, Sawada J,
Kobayashi D, Ieiri I, Mine K, Ohtsubo K, Sugiyama Y., Functional analysis of SNPs variants of
BCRP/ABCG2. Pharm. Res. 21: 1895-903 (2004).
11. Ieiri I, Suzuki H, Kimura M, Takane H, Nishizato Y,
Irie S, Urae A, Kawabata K, Higuchi S, Otsubo K,445

Sugiyama Y., Influence of common variants in thepharmacokinetic genes (OATP-C, UGT1A1, and
MRP2) on serum bilirubin levels in healthy subjects. Hepatol. Res. 30: 91-95 (2004).
12. Sasaki M, Suzuki H, Aoki J, Ito K, Meier PJ, Sugiyama Y., Prediction of in vivo biliary clearance
from the in vitro transcellular transport of organic
anions across a double-transfected Madin-Darby
canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2. Mol. Pharmacol. 66: 450-9 (2004).
13. Mizuno N, Suzuki M, Kusuhara H, Suzuki H, Takeuchi K, Niwa T, Jonker JW, Sugiyama Y., Impaired
renalexcretionof6-hydroxy5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole (E3040) sulfate in breast cancer resistance protein (BCRP1/ABCG2) knockout mice.
Drug Metab. Dispos. 32: 898-901 (2004).
14. Shoda J, Inada Y, Tsuji A, Kusama H, Ueda T, Ikegami T, Suzuki H, Sugiyama Y, Cohen DE, Tanaka
N., Bezafibrate stimulates canalicular localizationof NBD-labeled PC in HepG2 cells by PPARalpha-mediated redistribution of ABCB4. J. Lipid
Res. 45: 1813-25 (2004).
15. Shoji T, Suzuki H, Kusuhara H, Watanabe Y, Sakamoto S, Sugiyama Y., ATP-dependent transportof organic anions into isolated basolateral membrane vesicles from rat intestine. Am. J. Physiol.
287: G749-56 (2004).
16. Hirouchi M, Suzuki H, Itoda M, Ozawa S, Sawada
J, Ieiri I, Ohtsubo K, Sugiyama Y., Characterizationof the cellular localization, expression level, andfunction of SNP variants of MRP2/ABCC2. Pharm.
Res. 21: 742-8 (2004).
17. Shoda J, Miura T, Utsunomiya H, Oda K, Yamamoto M, Kano M, Ikegami T, Tanaka N, Akita H,
Ito K, Suzuki H, Sugiyama Y. Genipin enhances
Mrp2 (Abcc2)-mediated bile formation and organic
anion transport in rat liver. Hepatology. 39: 167-78(2004).
18. Takada T., Weiss HM., Kretz O., Gross G., and Sugiyama Y., Hepatic transport of PKI166, an epidermal growth factor receptor kinase inhibitor of
the pyrrolo-pyrimidine class, and its main metabolite, ACU154. Drug Metab. Dispos. 32: 1272-8(2004).

19. Sugiura M., Ohno Y., Yamada Y., Suzuki H. andIga T., Pharmacokinetic / pharmacodynamic analysis of neutrophil prolongation induced by rhG-CSF
in patients receving antineoplasmic. Yakugaku
Zasshi. 124: 599-604 (2004).
20. Miyazaki N., Sekine Y., Aoyama T., Yasuno N,
Nakamura H., Yamada Y. and Iga T., Development
and evaluation of pharmaceutical services in the
ICU/CCU by medical staffs. Yakugaku Zasshi. 124:279-86 (2004).
21. Takayanagi R., Nakamura Y., Nakajima Y., Shimizu A., Nakamura H., Yamada Y., Suzuki H.,
Arakawa Y., Omata M. and Iga T., Analysis of information submitted by clinical trial sponsors regarding the safety of investigational drugs. Yakugaku Zasshi. 124: 225-9 (2004).
22. Nakamura H., Yanagihara Y., Sekiguchi H., OhtaniM., Kariya S., Uchino K., Suzuki H. and Iga T.,
Effect of particle size on mixing degree in dispensation. Yakugaku Zasshi. 124: 135-9 (2004).
23. Nakamura H., Yanagihara Y., Sekiguchi H., Komada F., Kawabata H., Ohtani M., Saitoh M.,
Kariya S., Suzuki H., Uchino K. and Iga T., Effectof mixing method on the mixing degree during the
preparation of triturations. Yakugaku Zasshi. 124:
127-34 (2004).
24. Takayanagi R., Watanabe K., Nakahara A., Nakamura H., Yamada Y., Suzuki H., Arakawa Y.,
Omata M. and Iga,T., Items of concern associatedwith source document verification of clinical trials
for new drugs. Yakugaku Zasshi. 124: 89-92(2004).
25. Ohno Y., Yamada Y., Takayanagi R., Nagahara M.,
Araie M. and Iga T., Pharmacokinetic and Pharmacodynamic Analysis of Systemic Effect ofTopically Applied Timolol Maleate Ophthalmic
Gelling Vehicle (Rysmon TG). Curr. Eye Res. 30:
319-28 (2005).
26. Kusama M., Kubota T., Matsukura Y., Matsuno K.,
Ogawa S., Kanda Y. and Iga T., Influence of glutathione S-transferase A1 polymorphism on thepharmacokinetics of busulfan. Clin. Chim. Acta. inpress
27. Takada T., Suzuki H., Gotoh Y. and Sugiyama Y.,
Regulation of the cell surface expression of human
BCRP/ABCG2 by the phosphorylation state of Akt
in polarized cells. Drug Metab. Dispos. 33:905-909

446(2005).
28. Hayashi H., Takada T., Suzuki H., Akita H. andSugiyama Y., Two common PFIC2 mutations areassociated with the impaired membrane traffickingof BSEP/ABCB11. Hepatology. 41: 916-24 (2005).
29. Takada T., Suzuki H. and Sugiyama Y., Characterization of polarized expression of point- or deletion-mutated human BCRP/ ABCG2 in LLC-PK1
cells. Pharm. Res. 22: 458-64 (2005).
30. Hayashi H., Takada T., Suzuki H., Onuki R., Hofmann AF. and Sugiyama Y., Transport by vesiclesof glycine- and taurine-conjugated bile salts andtaurolithocholate 3-sulfate: A comparison of human
BSEP with rat Bsep. Biochim. Biophys. Acta. 1738:
54-62 (2005).
31. Suzuki M., Mamun MR., Hara K., Ozeki T., Yamada Y., Kadowaki T., Honda H., Yanagihara Y.,
Ito YM., Kameyama S., Ohta N., Hosoi T., Arai T.,
Sawabe M., Takeuchi T., Takahashi S. and Kitamura T., The Val158 Met polymorphism of thecatechol-O-methyltransferase gene is associatedwith the PSA-progression-free survival in prostatecancer patients treated with estramustine phosphate.
Eur. Urol. 48: 752-59 (2005).
32. Yamamoto T., Kubota T., Ozeki T., Sawada M.,
Yokota S., Yamada Y., Kumagai Y. and Iga T.,
Effects of the CYP3A5 genetic polymorphism on
the pharmacokinetics of diltiazem. Clin. Chim.
Acta. 362: 147-54 (2005).
33. Yamada T., Arai T., Nagino M., Oda K., Shoda J.,
Suzuki H., Sugiyama Y. and Nimura Y., Impaired
expression of hepatic multidrug resistance protein 2
is associated with posthepatectomy hyperbilirubinemia in patients with biliary cancer. Langenbecks Arch. Surg. 390: 421-9 (2005).
34. Matsushima S., Maeda K., Kondo C., Hirano M.,
Sasaki M., Suzuki H. and Sugiyama Y., Identification of the hepatic efflux transporters of organic
anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1
B1)/multidrug resistance-associated protein 2,
OATP1B1/multidrug resistance 1, and OATP1B1/
breast cancer resistance protein. J. Pharmacol. Exp.
Ther. 314: 1059-67 (2005).
35. Hirouchi M., Suzuki H. Sugiyama Y., Treatment ofhyperbilirubinemia in Eisai hyperbilirubinemic rat

by transfecting human MRP2/ABCC2 gene. Pharm.
Res. 22: 661-66 (2005).
36. Kondo C., Onuki R., Kusuhara H., Suzuki H., Suzuki M., Okudaira N., Kojima M., Ishiwata K.,
Jonker JW. and Sugiyama Y., Lack of improvement of oral absorption of ME3277 by prodrug
formation is ascribed to the intestinal efflux mediated by breast cancer resistant protein (BCRP/
ABCG2). Pharm. Res. 22: 613-18 (2005).
37. Adachi Y., Suzuki H., Schinkel AH. and Sugiyama
Y., Role of breast cancer resistance protein(Bcrp1/Abcg2) in the extrusion of glucuronide andsulfate conjugates from enterocytes to intestinal
lumen. Mol. Pharmacol. 67: 923-28 (2005).
38. Kobayashi D., Ieiri I., Hirota T., Takane H.,
Maegawa S., Kigawa J., Suzuki H., Nanba E.,
Oshimura M., Terakawa N., Otsubo K., Mine K.
and Sugiyama Y., Functional assessment of
ABCG2 (BCRP) gene polymorphisms to protein
expression in human placenta. Drug Metab. Dispos.
33: 94-101 (2005).
39. Mita S., Suzuki H., Akita H., Stieger B., Meier PJ.,
Hofmann AF. and Sugiyama Y., Vectorial transportof bile salts across MDCK cells expressing both rat
Na+- taurocholate cotransporting polypeptide andrat bile salt export pump. Am. J. Physiol. 288:
G159-67 (2005).
40. Ito K, Wakabayashi T and Horie T. Mrp2/ Abcc2
transport activity is stimulated by protein kinase
Calpha in a baculo virus co-expression system. Life
Sci. 77:539-50 (2005).
41. Hakata T, Ito K and Horie T. Enhanced absorptionof 3-O-methyl glucose following gastrointestinal
injury induced by repeated oral administration of
5-FU in mice. J. Pharm. Sci. 94:1713-22 (2005).
42. Ninomiya M, Ito K and Horie T. Functional analysis of dog multidrug resistance- associated protein
2 (Mrp2) in comparison with rat Mrp2. Drug Metab. Dispos. 33:225-32 (2005).
43. Ito K., Suzuki H., Horie T. and Sugiyama Y., Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport.
Pharm. Res. 22: 1559-77 (2005).

Center for Disease Biology andIntegrative Medicine

32

448

Division of
Basic Medical Sciences (2)Professor
Haruo Kasai, M.D.,Ph.D.
Lecturer
Noriko Takahashi, M.D., Ph.D.
Assistant Professors
Masanori Matsuzaki, Ph.D.,

un Nogichi, Ph.D.,

akuya Kishimoto, Ph.D.

Homepage http://www.bm2.m.u-tokyo.ac.jp/
Introduction and Organization
The Center for Disease Biology and Integrative
Medicine (CDBIM) has been established in 2003, andelected Dr. Kasai as the professor of the Division of
Basic Medical Sciences (2) of CDBIM in July of 2004.
Dr. Kasai was in the National Institute for Physiological
Sciences at that time, and officially took office in the
University of Tokyo in Novermber, 2005. The Kasailaboratory has moved to the first building in January,
2006. Our division belongs to the Section of Functional
Biology field in the Graduate School of Medicine, andour division is named the Division of Biophysics in thegraduate school.

Teaching activities
In 2005, we were involved education in the graduate
school. We have two graduate students in our own
graduate school, and two from the Graduate School of
Advanced Studies and one from the Graduate School of
Science in the University of Tokyo.

Research activities
Functional imaging is a central theme inmodern biology and medicine. All biological

functions involve a multitude of interactions at
the molecular, cellular, and system levels, and it
is ultimately desirable to perform molecuslar
and cellular imaging in intact preparations inwhich 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 the ability to penetrate deep into tissues andis the only imaging instrument that allows investigations of intact tissues at the cellular andmolecular levels. Two-photon microscopy canalso be readily combined with molecular 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 andsecretory cells. We welcome multidisciplinary
collaborations to promote our research goals andto help to adapt the new microscopic techniquesand lasers to a wide range of biomedical applications.
1) Dynamics of synapses in the cerebral cortex.

449

We have developed a method to stimulate
and control single synapses in the cerebral
cortex with the use of two-photon excitationof photoactive glutamate analogs. Our investigations have revealed that the major
functions of synapses depend on theirstructure. We have thus shown that small
synapses are ready to learn, enlarging rapidly (within 10s) after stimulation, whereas
large synapses are structurally stable andact as long-term memory traces. These observations suggest that learning, memory,and other activities of the brain are mediatedby changes in synaptic structure, and thatthey can be directly visualized. Moreover, weare now in a position to manipulate synaptic
plasticity with a laser beam at the level ofthe individual synapse. Such notions andmethodology will be further exploited to understand brain functions and disorders.
2) Exocytosis. Exocytosis is the most essentialfunction of synaptic terminals and secretory
cells. Knowledge of the mechanisms of andthe ability to control exocytosis artificiallyhave been limited, however. With the use of
two-photon excitation-based simultaneous
multicolor imaging of various tracers, wehave, for the first time, visualized exocytosis
in intact islets of Langerhans, pancreaticacini, the adrenal medulla, and synaptic
preparations. By further extending our approaches, we aim to develop new methods forimaging and control of secretory functions
and their molecular processes in the cerebral
cortex and secretory tissues.

References
1. Takahashi N, Hatakeyama H, Okado H, Miwa A,
Kojima T, Abe T, Kasai H. Sequential exocytosis ofinsulin granules is associated with redistribution of
SNAP25. J Cell Biol 2004;165:255-262.
2. Matsuzaki M, Honkura N, Ellis-Davies GCR, Kasai H. Structural basis of long-term potentiation insingle dendritic spines. Nature 204;429:761-766.

3. Nemoto T, Kojima T, Oshima A, Bito H, Kasai H.
Stabilization of exocytosis by dynamic F-actin
coating of zymogen granules in pancreatic acini. J
Biol Chem 2004;279:37544-37550.
4. Sakai N, Tsubokawa H, Matsuzaki M, Kajimoto T,
Takahashi E, Ren Y, Ohmori S, Shirai Y, Matsubayashi H, Chen J, Duman RS, Kasai H, Saito N.
Propagation of gammaPKC translocation along thedendrites of Purkinje cell in gammaPKC-GFP
transgenic mice. Genes Cells 2004;9:945-957.
5. Kasai H, Matsuzaki M, & Ellis-Davies GCR
Two-photon uncaging microscopy. In: Yuste R,
Konnerth A, editors. Imaging in neuroscience anddevelopment. New York, CSH Lab. Press; 2004.
p.102-106.
6. Tanaka J, Matsuzaki M, Tarusawa E, Momiyama A,
Molnar E, Kasai H, Shigemoto R. Number and density of AMPA receptors in single synapses in immature cerebellum. J Neurosci 2005; 25:799-807.
7. Oshima A, Kojima T, Dejima K, Hisa I, Kasai H,
Nemoto T. Two-photon microscopic analysis ofacetylcholine-induced mucus secretion in guinea
pig nasal glands. Cell Calcium 2005;37: 349-357.
8. Hayakawa Y, Nemoto T, Iino M, Kasai H. Rapid
Ca2+-dependent increase in oxygen consumption by
mitochondria in single mammalian central neurons.
Cell Calcium 2005;37: 359-370.
9. Kasai K, Ohara-Imaizumi M, Takahashi N, Mizutani S, Zhao S, Kikuta T, Kasai H, Nagamatsu S,
Gomi H, Izumi T. Rab27a mediates the tight docking of insulin granules onto the plasma membrane
during glucose stimulation. J Clin Invest
2005;115:388-396.
10. Noguchi J, Matsuzaki M, Ellis-Davies GCR, Kasai
H. Spine-neck geometry determines NMDA receptor–dependent Ca2+ signaling in dendrites. Neuron
2005;46:609-622.
11. Kasai H, Hatakeyama H, Kishimoto T, Liu T-T,
Nemoto T, Takahashi N. A new quantitative (twophoton extracellular polar-tracer imaging-based
quantification (TEPIQ)) analysis for diameters of
exocytic vesicles and its application to pancreatic
islets. J Physiol 2005;568:891-903.
12. Kishimoto T, Liu T-T, Hatakeyama H, Nemoto T,
Takahashi N, Kasai H. Sequential compound exocytosis of large dense-core vesicles in PC12 cells
studied with TEPIQ (two-photon extracellular po-

450

lar-tracer imaging-based quantification) analysis. J
Physiol 2005;568:905-915.
13. Liu T-T, Kishimoto T, Hatakeyama H, Nemoto T,
Takahashi N, Kasai H. Exocytosis and endocytosisof small vesicle in PC12 cells studied with TEPIQ(two-photon extracellular polar-tracer imagingbased quantification) analysis. J Physiol 2005;
568:917-929.
14. Ohkura M, Matsuzaki M, Kasai H, Imoto K, Nakai
J. Genetically encoded bright Ca-2+ probe applicable for dynamic Ca-2+ imaging of dendritic spines.
Analytical Chem 2005;77:5861-5869.
15. Fukui K, Yang Q, Cao Y, Takahashi N, Hatakeyama
H, Wang H, Wada J, Zhang Y, Marselli L, Nammo T,
Yoneda K, Onishi M, Higashiyama S, Matsuzawa Y,
Gonzalez FJ, Weir GC, Kasai H, Shimomura I, Miyagawa J, Wollheim CB, Yamagata K. The HNF-1
target Collectrin controls insulin exocytosis by
SNARE complex formation. Cell Metab. 2005;2:
373-384.

451

Division of Biomedical Materials
and Systems
Professor
Takashi Ushida, Ph.D.

Associate Professor
Yasuyuki Sakai, Ph.D.

Associate
Kouhei Tsuchiya, M.D., Ph.D.

Homepage http://www.cdbim.m.u-tokyo.ac.jp/
Introduction and Organization
The Division is composed of two laboratories,
Ushida laboratory and Sakai Laboratory. The Divisiontightly collaborates with Faculty of Engineering. Prof.
Ushida is also charged at Department of MechanicalEngineering, where the laboratory members include
Assistant Professor, two Associates and 15 graduate
students (as of April 1, 2004). Prof. Sakai also holds a
position in Institute of Industrial Science (IIS), University of Tokyo. The current laboratory members at IIS(as of April 1, 2004) include one research associate, one
JSPS postdoctoral fellow, one technical assistant, andsix graduate students from Department of Chemical
System Engineering, Graduate School of Engineering.
In addition, four graduate students who belong to otheruniversities do research in our laboratory.

Teaching activities
Prof. Ushida and Prof. Sakai are sharing duties forundergraduate and graduate students of both Graduate
School of Medicine and Graduate School of Engineering. They give lectures on biomedical engineering at
Graduate School of Medicine. Prof. Ushida has also
lectures on tissue engineering, advanced biomaterials
and biomechanics at Graduate School of Engineering.

Prof. sakai gives an introductory lecture concerning
medical application of chemical engineering at the
Komaba Campus, a special lecture concerning organs
and biosystem engineering at the Chemical System Engineering course at Graduate School of Engineering
School.

Research activities
Prof. Ushida’s laboratory aims to establish key technologies for regenerative medicine. One of the projectsof 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 or inorganic materials combined with stem cell biotechnology. Secondly, we try to
elucidate mechanisms of cellular responses to physicalstimulations such as hydrostatic pressure, shear stress,
stretch, through observing intracellular signaling, and to
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,

452

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 by biomaterials that spur new blood vessel growth.
2) Cellular signal transduction induced by physicalstimulations- Hydrostatic pressure loading to chondrocytes orarticular cartilage- Shear stress loading to endothelial cells- Stretch loading to endothelial cells, smooth muscle cells
The general objective of Prof. Sakai’s laboratory is toorganize experimentally human systems or its subsystems such as organ or tissue using cultured human cells
for fundamental understanding of systemic responses ofa human body or organs and biomedical or environmental applications. At present, we need several different technologies to achieve the goal in addition to usualcell culture technologies. These include in vitro controlof the growth and differentiation of organ stem or progenitor cell populations, cultivation technologies ranging from micro- to clinically significant-sizes, threedimensional microfabrication of biodegradable organ
templates, etc. About such topics, we are actively doingcollaborative research with other institutes outside Univ.
of Tokyo. The most important thing is to organize thesetechnologies originally derived from different academic
background from engineering point of view.
3) Engineering of human large internal organs- Design of inner microstructure of reconstituted
human organs- Three-dimensional microfabrication of biodegradable organ templates- In vitro control of growth and differentiation oforgan progenitor cells......
4) Development of in vitro models for human organs
and their applications- Development of biohybrid simulator for absorption and biotransformation- In vitro models for lung alveolar tissue and its application to toxicity evaluation of gaseous chemicals or environmental samples- Micro-organ model devices

References
1. Shuichi Mizuno, Tetsuya Tateishi., Takashi Ushida,
Julie Glowacki, J Hydrostatic Fluid Pressure Enhances Matrix Synthesis and Accumulation by Bovine Chondrocytes in Three-dimensional Culture. ,Cell Physiol, 193:319-327, 2002
2. Yoshimasa Ishii, Takashi Ushida, Tetsuya Tateishi,
Hitoshi Shimojo, Yutaka Miyanaga Effects of different exposures of hyperbaric oxygen on ligamenthealing in rats., J Orthp Res, 20: 353-356, 2002
3. Katsuko S Furukawa, Takashi Ushida, Kenshi Toita,
Yasuyuki Sakai, Tetsuya Tateishi, Hybrid of
gel-cultured smooth muscle cells with PLLA
sponge as a scaffold towards blood vessel regeneration, Cell Transplantation, 11(5): 475-480, 2002
4. Kensuke Ochi, Guoping Chen, Takashi Ushida,
Satoshi Gojo, Kaoru Segawa, Hitoshi Tai, Kenju
Ueno, Hiroyuki Ohkawa, Taisuke Mori, Akira Yamaguchi, Yoshiaki Toyama, Junichi Hata and Akihiro Umezawa, Use of Isolated Mature Osteoblasts
in Abundance Acts as Desired-Shaped Bone Regeneration in Combination with a Modified
Poly-DL-Lactic-Co-Glycolic Acid (PLGA)- Collagen Sponge, J Cell Physiol 194: 45-53, 2002
5. Takashi Ushida, Katsuko Furukawa., Kenshi Toita,
Tetsuya Tateishi, Three dimensional seeding ofchondrocytes encapsulated in collegen gel into
PLLA scaffolds, Cell Transplantation, 11(5): 489494, 2002
6. Guoping Chen, Takashi Ushida, Tetsuya Tateishi,
Scaffold Design for Tissue Engineering., Macromole. Biosci,. 2, 67-77, 2002
7. Kamiya A, Kojima N, Kinoshita T, Sakai Y, Miyajima A. Maturation of fetal liver cells by extracellular matrices and oncostatin M: Induction of tryptophan oxygenase. Hepatol., 35: 1351-1359, 2002.
8. Sakai Y, Jiang J, Kojima N, Kinoshita T, Miyajima
A. Enhanced in vitro maturation of fetal liver cellswith oncostatin M, nicotinamide and dimethylsulfoxide. Cell Transplant., 11: 435-441, 2002.
9. Jiang J, Kojima N, Kinoshita T, Miyajima A, Yan
W, Sakai Y. Cultivation of fetal mouse liver cells ina three-dimensional poly-L-lactic acid scaffold in
the presence of oncostatin M. Cell Transplant., 11:403-406, 2002.

453

10. Kim BS, Fujita H, Sakai Y, Sakoda A, Suzuki M.
Catalitic ozonation of an organophophorous pesticide using microporous silicate and its effect on total toxicity reduction. Water Sci. Technol., 46:
35-41, 2002.
11. Naruse K, Sakai Y, Guo L, Shindoh J, Son JC,
Makuuchi M. Development of a xenogeneic direct
hemoperfusion method in a bioartificial liver system. J. Artif. Organs, 5: 257-264, 2002.
12. Guoping Chen, T. S., Takashi Ushida, Rei Hirochika, Tetsuya Tateishi "Redifferentiation of dedifferentiated bovine chondrocytes when cultured invitro in a PLGA-collagen hybrid mesh." FEBS
Letters 542: 95-99, 2003
13. Guoping Chen, T. S., Takashi Ushida, Rei Hirochika, Yoshio Shirasaki, Naoyuki Ochiai and Tetsuya Tateishi. The use of a novel PLGA fiber / collagen composite web as a scaffold for engineeringof articular cartilage tissue with adjustable thickness. J. Biomed. Mater. Res. 67A: 1170-1180, 2003
14. Katsuko S Furukawa, Hideyuki Suenaga, Kenshi
Toita, Akiko Numata, Junzo Tanaka, Takashi
Ushida, Yasuyuki Sakai, Tetsuya Tateishi. Rapidand Large-Scale Formation of Chondrocytes Aggregates by Rotational Culture.", Cell Transplantation 12: 475-479, 2003
15. Katsuko S Furukawa, Takashi Ushida, Takuya Noguchi, Tamotsu Tamaki, Tetsuya Tateishi. Development of cone and plate-type rheometer for quantitative analysis of endothelial cell detachment by
shear stress. Int J Artif Organs 26(5): 436-41, 2003
16. Yoshimasa Ishii, Takashi Ushida , Tetsuya Tateishi,
Yutaka Miyanaga . Efects of transcutaneous topicalinjection of oxygen on vascular endothelial growth
factor gene into the healing ligaments in rats. J
Orthp Res 21: 1113-1117, 2003
17. Yuka Nakanishi, G. C., Hiroaki Komuro, Takashi
Ushida, Setsuko Kaneko, Tetsuya Tateishi, Michio
Kaneko. Tissue-Engineered Urinary Bladder Wall
Using PLGA Mesh-Collagen Hybrid Scaffolds: A
Comparison Study of Collagen Sponge and Gel asa Scaffold. J Pediatr Surg 38: 1781-1784, 2003
18. Leclerc E, Sakai Y, Fujii T. Cell culture in athree-dimensional network of PDMS microchannel.
Biomed. Microdevices, 5: 109-114, 2003.
19. Naruse K, Sakai Y, Natori T, Guo L, Shindoh J, Iida
Y, Michishita K, Karasawa Y, Kojima K, Makuuchi

M. Xenogeneic direct hemoperfusion using wholeswine liver for liver failure in dogs J. Surg. Res.,
111: 229-235, 2003.
20. Naruse K, Sakai Y, Guo L, Natori T, Shindoh J,
Karasawa Y, Iida Y, Kojima K, Michishita K, Makuuchi M. Development of a new extracorporeal
whole-liver perfusion system. J. Artif. Organs, 6:
211-217, 2003.
21. Kohei Tsuchiya, Taisuke Mori, Guoping Chen, Takashi Ushida, Tetsuya Tateishi, Takeo Matsuno,Michiie Sakamoto, Akihiro Umezawa, Custom-shaping system for bone regeneration byseeding marrow stromal cells onto a web-like biodegradable hybrid sheet, Cell Tissue Res 316:
141-153, 2004
22. Katsuko S. Furukawa , Shunsuke Miyauchi, Daisuke Suzuki , Yoshikazu Umezu , Tsuneo Shinjo ,Takashi Ushida , Miki Eguchi and Tetsuya Tateishi ,"Bone tissue engineering based on bead-cell sheetscomposed of calcium phosphate beads and bonemarrow cells." Material Science & Engineering C
24(3): 437-440, 2004
23. Guoping Chen , Takashi Sato, Takashi Ushida , Rei
Hirochika , Naoyuki Ochiai and Tetsuya Tateishi ,"Regeneration of cartilage tissue by combination of canine chondrocyte and a hybrid meshscaffold." Material Science & Engineering C 24(3):373-378, 2004
24. Hideyuki Suenaga , Katsuko S. Furukawa, Takashi
Ushida , Tsuyoshi Takato and Tetsuya Tateishi,"Aggregate formation of bone marrow stromal cellsby rotation culture." Material Science & Engineering C 24(3): 421-424, 2004
25. Hiroshi Akaogi , Takayuki Akimoto, Shigeru Miyaki , Takashi Ushida , Naoyuki Ochiai , Tetsuya
Tateishi and Junzo Tanaka, "Basic fibroblast
growth factor supports in vitro chondrogenesis ofbone marrow-derived mesenchymal stem cells
from patients with osteoarthritis." Material Science& Engineering C 24(3): 403-406, 2004
26. Kohei Tsuchiya , Guoping Chen, Takashi Ushida ,Takeo Matsuno and Tetsuya Tateishi , "The effectof coculture of chondrocytes with mesenchymal
stem cells on their cartilaginous phenotype in vitro." Material Science & Engineering C 24(3):391-396, 2004
27. Makoto Kawanishi , Takashi Ushida, Tadashi Ka-

454

neko , Hideo Niwa , Toru Fukubayashi , Kozo Nakamura , Hiromi Oda , Sakae Tanaka and Tetsuya
Tateishi , "New type of biodegradable porous scaffolds for tissue-engineered articular cartilage." Material Science & Engineering C 24(3): 431-435,
2004
28. Shigeru Miyaki , Ken-ich Tezuka, Takashi Ushida ,Takayuki Akimoto , Hiroshi Akaogi , Toshio Kitamura , Yutaka Miyanaga , Junzo Tanaka , Naoyuki
Ochiai and Tetsuya Tateishi, "Identification of
membrane and secreted proteins in anterior cruciate
ligament derived cells using "signal-sequence-trap",a retrovirus-mediated expression screening
method." Material Science & Engineering C 24(3):397-401, 2004
29. Shogo Miyata , Katsuko S. Furukawa, Takashi
Ushida , Yasuo Nitta and Tetsuya Tateishi, "Staticand dynamic mechanical properties of extracellularmatrix synthesized by cultured chondrocytes." Material Science & Engineering C 24(3): 425-429,
2004
30. Takahiro Ohno , Keizo Tanisaka, Yosuke Hiraoka ,Takashi Ushida , Tamotsu Tamaki and Tetsuya
Tateishi, "Effect of type I and type II collagensponges as 3D scaffolds for hyaline cartilage-liketissue regeneration on phenotypic control of seededchondrocytes in vitro." Material Science & Engineering C 24(3): 407-411, 2004
31. Takashi Sato , Guoping Chen, Takashi Ushida ,Tomoo Ishii , Naoyuki Ochiai , Tetsuya Tateishi
and Junzo Tanaka, "Evaluation of PLLA-collagenhybrid sponge as a scaffold for cartilage tissue engineering." Material Science & Engineering C
24(3): 365-372, 2004
32. Takayuki Akimoto , Takashi Ushida, Shigeru Miyaki , Hiroshi Akaogi , Tetsuya Tateishi and Toru
Fukubayashi , "Effect of mechanical stretch on
TGF-1 expression of C2C12 myogenic cells." Material Science & Engineering C 24(3): 387-389,
2004
33. Yoshimasa Ishii , Takashi Ushida, Tetsuya Tateishi ,Hideo Nishimagi and Yutaka Miyanaga, "Efficacy
of topical hyperbaric oxygen for refractory foot ulcer." Material Science & Engineering C 24(3):329-332, 2004
34. Choi SH, Sakoda A, Sakai Y. Enhanced cytochrome P450 capacities of Caco-2 and Hep G2

cells in new coculture systems under static andperfused conditions: Evidence for possible organ-to-organ interactions against exgeneous stimuli.
Mat. Sci. Eng. C, 24: 333-339, 2004.
35. Leclerc E, Miyata F, Furukawa KS, Sakai Y, Fujii T.
Effect on liver cells of stepwise microstructuresfabricated in a photosensitive biodegradable polymer by soft lithography. Mat. Sci. Eng. C, 24:
349-354, 2004.
36. Jiang J, Kojima N, Miyajima A, Yan W, Sakai Y.
Cultivation and induction of fetal liver cells inpoly-L-lactic acid scaffolds. Mat. Sci. Eng. C, 24:
361-363, 2004.
37. Sakai Y, Otsuka M, Hanada S, Nishiyama Y, Konishi Y, Yamashita A. A novel poly-L-lactic acidscaffold that possesses a macroporous structure anda branching/joining three-dimensional flow channel
network: Its fabrication and application to perfusion culture of human hepatoma Hep G2 cells. Mat.
Sci. Eng. C, 24: 379-386, 2004.
38. Choi SH, Nishikawa M, Sakoda A, Sakai Y. Feasibility of a simple double-layered coculture system
incorporating metabolic processes of the intestineand liver tissue: Application to the analysis ofbenzo[a]pyrene toxicity. Toxicol. in Vitro, 18:393-402, 2004.
39. Y. Sakai, M. Otsuka, J. Kozasa, F. Miyata, K. S.
Furukawa, A. Yamashita. Ultra-violet-light irradiation-based photofabrication that simultaneously
produces a macroporous structure and flow channels using a photo-reactive biodegradable polymer
and a gas-forming azoamide compound. Biochem.
Eng. J., 20, 163-171 2004.
40. E. Leclerc, Y. Sakai, T. Fujii. Perfusion Culture of
Fetal Human Hepatocytes in Microfluidic- Environments. Biochem. Eng. J., 20, 143-148, 2004.
41. E.Leclerc, K.S.Furukawa, F. Miyata, Y.Sakai, T.
Ushida, T. Fujii. Fabrication of microstructures inphotosensitive biodegradable polymers for tissue
engineering applications. Biomat., 25, 4683-4690,
2004.
42. E. Leclerc, Y. Sakai and T. Fujii. A microfluidic
PDMS (polydimethylsiloxane) bioreactor forlarge-scale culture of hepatocytes. Biotechnol.
Prog., 20(3), 750-755, 2004.
43. J. Jiang, N. Kojima, L. Guo, K. Naruse, M. Makuuchi, A. Miyajima, W.-Q. Yan, Y. Sakai. Efficacy

455

of engineered liver tissue based on poly-L-lactic
acid scaffolds and fetal mouse liver cells cultured
with oncostatin M, nicotinamide and dimethyl sulfoxide. Tissue Eng., 10, 1577-1586, 2004.
44. H. Shindoh, K. Naruse, Y. Sakai, M. Makuuchi.
Efficacy of immunoadsorbent devices for maintaining hepatic function in ex vivo xenogenic direct
hemoperfusion. Int. J. Artif. Organs, 27(4), 294-302,
2004.
45. K. Shimizu, O. Endo, S. Goto, Y. Ono, A. Sakoda,
Y. Sakai. Bioassay-based evaluation of toxicity ofsuspended particulate matter in humans: Integrated
uses of alveolar cells (A549) in air-liquid interface
culture and hepatocarcinoma cells (Hep G2): Biochem. Eng. J., 22, 2-9, 2004.
46. S. Ostrovidov, J. Jiang, Y. Sakai, T. Fujii. Membrane-based PDMS microbioreactors for perfused
3D primary rat hepatocyte cultures. Biomed. Microdevices, 6(4), 279-287, 2004.
47. Y. Sakai, O. Fukuda, S-H. Choi and A. Sakoda: Useof a perfusion coculture system consisting of
Caco-2 and Hep G2 cell compartments for the kinetic analysis of benzo[a]pyrene toxicity. ATLA(Special Issue), Supplement 1A, 99-104, 2004.
48. Sakai, Y., Leclerc, E., Fujii, T.: Microfluidic
Cell-culture Devices, Lab-on-Chips for Cellomics,
Kluwer Academic Publishers, pp.299-318, 2004.
49. Chen G, Sato T, Ohgushi H, Ushida T, Tateishi T,
Tanaka J , Culturing of skin fibroblasts in a thin
PLGA-collagen hybrid mesh,., Biomaterials 26(15), 2559-2566 , 2005
50. Takayuki Akimoto, Takashi Ushida, Shigeru Miyaki, Hiroshi Akaogi, Kohei Tsuchiya, Zhen Yan, R.
Sanders Williams, Tetsuya Tateishi, Mechanicalstretch inhibits myoblast-to-adipocyte differentiation through Wnt signaling, Biochem Biophys Res
Commun 392, 382-386, 2005
51. Shogo MIYATA, Tetsuya TATEISHI, Katsuko S
FURUKAWA, Takashi USHIDA , Influence ofStructure and Composition on Dynamic ViscoElastic Property of Cartilaginous Tissue: Criteria
for Classification Between Hyaline Cartilage andFibrocartilage Based on Mechanical Function, ,JSME International Journal:C, Vol.48, No.4,
547-554 , 2005
52. Ayako Oyane, Takashi Ishizone, Masaki Uchida,
Katsuko Furukawa, Hideaki Yokoyama, Spontane-

ous Fromation of Blood-Compatible Surfaces on
Hydrophilic Polymers: Surface Enrichment of a
Block Copolymer with a Water-Soluble Block, Adv.
Mater. Vol.17, 2329-2332 , 2005
53. Masaki Uchida, Atsuo Ito, Katsuko S Furukawa,
Keigo Nakamura, Yuji Onimura, Ayako Oyane,
Takashi Ushida, Takashi Yamane, Tamotsu Tamaki,
Tetsuya Tateishi, Reduced platelet adhesion to titanium metal coated with apatite, albumin-apatitecomposite or laminin-apatite composite, Biomaterials, 26, 6924-6931, 2005
54. Wei-Heong Tan, Yuji Suzuki, Nobuhide Kasagi,
Naoki Shikazono, Katsuko Furukawa, Takashi
Ushida, A Lamination Micro Mixer for microImmunomagnetic Cell Sorter, JSME International
Journal:C, 48 (4), 425-435, 2005
55. N. Kojima, N. Shiojiri, Y. Sakai and A. Miyajima:
Expression of neuritin during liver maturation andregeneration. FEBS Lett., 579(21), 4562-4566,
2005.
56. Y. Sakai, K. Tomita, M. Suzuki, Y. Ono, A. Sakoda:
Development of a toxicity evaluation system forgaseous compounds using air-liquid interface culture of a human bronchial epithelial cell line,
Calu-3: AATEX, 11(1), 59-67, 2005.
57. S. Okajima, Y. Sakai, T. Yamaguchi. Developmentof regenerable cell cutlure material system sensing
and releasing dead cells, Langmuir, 21(9),4043-4049, 2005.

456

Division of Clinical Biotechnology
Professor
Kazunori Kataoka, Ph.D.

Associate Professor
Yuichi Tei / Ung-il Chung, M.D., Ph.D.

Lecturer
Keiji Itaka, M.D., Ph.D.

AssociateNobuhiro Nishiyama, Ph.D.,

Younsoo Bae, Ph.D.

Homepage: http://www.cdbim.m.u-tokyo.ac.jp/research/01_04.html
http://www.bmw.t.u-tokyo.ac.jp/

Introduction and Organization
Division of Clinical Biotechnology in The Center for
Disease Biology and Integrative Medicine (CDBIM)
was established in April 2003. This Division wishes tocontribute to the realization of nanomedicine, which isone of major goals for Research Cluster for Frontier
Medicine Development at The University of Tokyo
Hospital and The Center for NanoBio Integration(CNBI) at The University of Tokyo. We actively collaborate and have an interchange of graduate students
with Graduate Schools of Engineering & Medicine at
The University of Tokyo and Division of Tissue Engineering at The University of Tokyo Hospital. Our division also plays a major role in the Nano- Bioengineering Education Program (NBEP), which started in 2004
as a novel medicine-engineering interdisciplinary program, and tries to contribute to the production of medical ventures by promoting liaison with the industrial
sector and to the production of professionals who understand both advanced medicine and nanotechnology.
The division consists of one professor, one associate
professor, one associate and several project staff members belonging to the CNBI and NBEP.
Our division focuses on the realization of nanomedi-cine. Nanotechnology, which has recently been attracting tremendous attention as a leading scientific field in
the 21st century, attempts to process and assemble materials with precision at the atomic/ molecular level toproduce units with sophisticated functions. Nanodevices produced by nanotechnology integrate materials
and systems on a nanometer scale, and hold the key torealizing the futuristic medical system that can serve
the needed function at the right time and the right placewith minimal invasiveness. Furthermore, nanodevices
are expected to become an important interface between
basic biomedical science and clinical medicine by facilitating the translation of basic achievements into
clinical applications. Our division wishes to produce
revolutionary medical nanodevices based on nanotechnology and thereby to spread the idea of "Nanomedicine" intranationally and internationally.

Teaching activities
Traditional medicine-engineering interdisciplinary
programs have focused on the exchange of researchers
and the promotion of collaborative researches between
these two different academic areas. However, the next
generation medicine such as "minimum-invasive diag-457

nosis-treatment" and "targeting medical treatment" andnanotechnologies are developing so quickly with increasing complexity that scholars in both areas find it
hard to understand each other. For this reason, it is becoming increasingly difficult for medical doctors tolocate technological seeds meeting their medical needs
and for engineers to find ways of applying their technological seeds to corresponding medical needs. Thissituation prevents the effective development of revolutionary medical diagnostical and therapeutic inventions.
Division of Clinical Biotechnology intends to create an
optimal milieu where undergraduate and graduate students from the medical and engineering fields can respect each other's background, ignores the boundaryand study the fusion area in order to achieve the common goal of developing intelligent nanodevices for the
futuristic medical system.

Research activities
Drug delivery to the targeted site is strongly desired
to enhance the drug function and minimize the side effects. In this regard, drug delivery systems based on
self-assemblies of block copolymers (i.e., polymeric
micelles) recently draw much attention as one of the
medical applications of the nanotechnology. Block copolymers spontaneously form polymeric micelles,
which are characterized by the core-shell structure andthe size of ~100 nm, in aqueous media. The core of themicelles behaves as a nanoreservoir for drugs, while thecoronal shell providing the biocompatible surface.
Polymeric micelles can incorporate a variety of drugs
including hydrophobic drugs, metal complex drugs, andmacromolecular drugs such as proteins and DNA, andrelease them in a sustained manner or in response toenvironmental changes such as pH. The site-specificdrug delivery can be achieved by conjugation of thepilot molecules on the surface of polymeric micelles.
Thus, polymeric micelles behave as intelligent chemical
nanomachines for the drug targeting.
The long-circulation of drug carriers is a requisite forthe successful drug targeting. The main obstacles tolong-circulatio are considered to be glomerular excretion in the kidney and recognition by the reticuloendothelial system (RES) located at the liver, spleen andlung. Polymeric micelles can escape from those barriersin the body, resulting in stable blood circulation. An-other advantage of using polymeric micelles is theirpreferential accumulation in solid tumors, which might
be due to microvascular hyperpermeability and immature lymphatic system in tumor tissues. We have succeeded in the tumor-selective delivery of several antitumor drugs including adriamycin (ADR) and cisplatin(CDDP) by polymeric micelles, and observed enhanced
antitumor activity with reduced side effects. These micellar formulations are currently being tested in clinical
trials.
Recently, plasmid DNA (pDNA) and siRNA are receiving much attention as promising tools for thetreatment of genetic and intractable diseases. One of the
major requirements for therapeutic use of pDNA andsiRNA is the development of gene vectors, which cansafely and effectively deliver them into specific cells
and regulate their expressions. Recently, we have prepared polymeric micelles incorporating pDNA throughthe electrostatic interaction between DNA and positively charged block copolymers. The polymeric micelles protected the loaded DNA from degradation by
nuclease attack and showed efficient gene transfer to avariety of cells. Also, various smart functions such as
the targeting ability and environmental sensitivity canbe integrated with polymeric micelles, offering the opportunities to develop effective synthetic vectors resembling viral functions. Recently, we have developed
the light-responsive gene carriers, and have achieved invivo gene transfer in a light-specific manner. Further,polymeric micelles can be used for the tissue engineering without cell transplantation. Recently, polymeric
micelles carrying pDNA encoding osteogenic factors
were implanted to mouse calvaria bone defects in theform of calcium phosphate paste, resulting in rapid induction of bone regeneration. Thus, polymeric micelles
are expected as useful nanocarriers of pDNA andsiRNA for in vivo use.

References
1. Nishiyama N, Arnida, Jang WD, Date K, Miyata K,
Kataoka K. Photochemical enhancement of transgene expression by polymeric micelles incorporating plasmid DNA and dendrimer-based photosensitizer. J Drug Target. in press.
2. Kanayama N, Fukushima S, Nishiyama N, Itaka K,
Chung U, Kataoka K, et al. PEG-based biocom-

458

patible block catiomer with high-buffering capacity
for the construction of polyplex micelles showing
efficient gene transfer toward primary cells.
ChemMedChem, in press.
3. Ideta R, Tasaka F, Nishiyama N, Tamaki Y, Aida T,
Kataoka K. Nanotechnology-based photodynamic
therapy for neovascular disease using a supramolecular nanocarrier loaded with a dendritic
photosensitizer. Nano Lett. 2005; 5 (12): 2426-31.
4. Miyata K, Kakizawa Y, Nishiyama N, Yamasaki Y,
Kohara M, Kataoka K, et al. Freeze-dried formulations for in vivo gene delivery of PEGylated polyplex micelles with disulfide crosslinked cores to theliver. J Control Release. 2005; 109(1-3): 15-23.
5. Nishiyama N, Iriyama A, Jang WD, Itaka K,
Tamaki Y, Kataoka K, et al. Light-induced genetransfer from packaged DNA enveloped in a dendrimeric photosensitizer. Nat Mater. 2005; 4(12):934-41.
6. Kugimiya F, Yano F, Ohba S, Igawa K, Nakamura
K, Chung U, et al. Mechanism of osteogenic induction by FK506 via BMP/Smad pathways. Biochem
Biophys Res Commun. 2005; 338: 872-9.
7. Kugimiya F, Kawaguchi H, Kamekura S, Chikuda
H, Ohba S, Chung U, et al. Involvement of endogenous bone morphogenetic protein (BMP)2 and
BMP6 in bone formation. J Biol Chem. 2005; 280:
35704-12.
8. Uchino H, Matsumura Y, Nishiyama N, Kataoka K,
Naito S, Kakizoe T, Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats. Br J Cancer. 2005; 93(6): 678-87.
9. Bae Y, Jang WD, Nishiyama N, Fukushima S,
Kataoka K. Multifunctional polymeric micelles
with folate-mediated cancer cell targeting andpH-triggered drug releasing properties for active
intracellular drug delivery. Mol BioSyst. 2005;
1(3): 242-50.
10. Osada K, Yamasaki Y, Katayose S, Kataoka K. A
synthetic block copolymer regulates S1 nucleasefragmentation of supercoiled plasmid DNA. Angew
Chem Int Ed. 2005; 44(23): 3544-48.
11. Fukushima S, Miyata K, Nishiyama N, Kanayama
N, Yamasaki Y, Kataoka K. PEGylated polyplex
micelles from triblock catiomers with spatially ordered layering of condensed pDNA and buffering

units for enhanced intracellular gene delivery. J Am
Chem Soc. 2005; 127(9): 2810-11.
12. Hamaguchi T, Matsumura Y, Suzuki M, Shimizu K,
Kataoka K, Kakizoe T, et al. NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel. Br J Cancer.
2005; 92(7): 1240-46.
13. Oishi M, Nagasaki Y, Itaka K, Nishiyama N,
Kataoka K. Lactosylated poly(ethylene glycol)siRNA conjugate through acid-labile β-thiopropionate linkage to construct pH-sensitive
polyion complex micelles achieving enhanced genesilencing in hepatoma cells. J Am Chem Soc. 2005;
127(6): 1624-25.
14. Bae Y, Nishiyama N, Fukushima S, Koyama H,
Matsumura Y, Kataoka K, Preparation and biological characterization of polymeric micelle drug
carriers with intracellular pH-triggered drug releaseproperty: Tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjug Chem. 2005; 16(1):122-30.
15. Jang WD, Nishiyama N, Zhang GD, Harada A,
Aida T, Kataoka K, et al. Supramolecular nanocarrier of anionic dendrimer porphyrins with cationicblock copolymers modified with poly (ethylene
glycol) to enhance intracellular photodynamic efficacy. Angew Chem Int Ed. 2005; 44(3): 419-23.
16. Cabral H, Nishiyama N, Okazaki S, Koyama H,
Kataoka K. Preparation and biological properties ofdichloro(1,2-diaminocyclohexane)platinum(II)(DACHPt)-loaded polymeric micelles. J. Control.
Release. 2005; 101(1-3) 223-32.
17. Wakebayashi D, Nishiyama N, Itaka K, Miyata K,
Yamasaki Y, Kataoka K, et al. Polyion complex
micelles of pDNA with acetal-poly(ethylene glycol)-poly(2-(dimethylamino)ethyl
methacrylate)block copolymer as the gene carrier system. Physicochemical properties of micelles relevant to genetransfection efficacy. Biomacromolecules. 2004;
5(6): 2128-36.
18. Itaka K, Kanayama N, Nishiyama N, Jang WD,
Yamasaki Y, Kataoka K, et al. Supramolecular
nanocarrier of siRNA from PEG-based block
catiomer carrying diamine side chain with distinc-459

tive pKa directed to enhance intracellular gene silencing. J Am Chem Soc. 2004; 126(42): 13612-13.
19. Kakizawa Y, Furukawa S, Kataoka K. Block copolymer-coated calcium phosphate nanoparticles
sensing intracellular environment for oligodeoxynucleotide and siRNA delivery. J Control Release 2004; 97(2): 345-56.
20. Otsuka H, Hirano A, Nagasaki Y, Okano T, Horiike Y, Kataoka K. Two-dimensional multiarray
formation of hepatocyte spheroids on a microfabricated PEG-brush surface. ChemBioChem. 2004;
5(6): 850-55.
21. Kakizawa Y, Miyata K, Furukawa S, Kataoka K.
Size-controlled formation of a calcium phosphate-based organic-inorganic hybrid vector forgene delivery using poly(ethylene glycol)- blockpoly(aspartic acid). Adv Mater. 2004; 16(8):699-702
22. Wakebayashi D, Nishiyama N, Yamasaki Y, Itaka
K, Kanayama N, Kataoka K, et al. Lactose- conjugated polyion complex micelles incorporatingplasmid DNA as a targetable gene vector system:
their preparation and gene transfecting efficiency
against cultured HepG2 cells. J Control Release.
2004; 95(3): 653-64.
23. Miyata K, Kakizawa Y, Nishiyama N, Harada A,
Yamasaki Y, Kataoka K, et al. Block catiomer
polyplexes with regulated densities of charge anddisulfide cross-linking directed to enhance gene
expression. J Am Chem Soc. 2004; 126(8): 235561.
24. Tabuchi M, Yamasaki Y, Nagasaki Y, Yoshikawa
K, Kataoka K, Baba Y, et al. Nanospheres for DNA
separation chips. Nat Biotechnol. 2004; 22(3): 33740.
25. Itaka K, Harada A, Yamasaki Y, Nakamura K,
Kawaguchi H, Kataoka K. In situ single cell observation by fluorescence resonance energy transfer
reveals fast intra-cytoplasmic delivery and easy release of plasmid DNA complexed with linear polyethylenimine. J Gene Med. 2004; 6(1): 76-84.
26. Bastepe M, Weinstein LS, Ogata N, Kawaguchi H,
Jüppner H, Chung U, et al. Stimulatory G protein(Gs) directly regulates hypertrophic differentiationof growth plate cartilage in vivo. Proc Nat Acad Sci
USA 2004; 101: 14794-9.
27. Moro T, Takatori Y, Ishihara K, Konno T, Takigawa

Y, Chung U, et al. Surface grafting of artificial
joints with a biocompatible polymer for preventing
periprosthetic osteolysis. Nat Mat. 2004; 83:829-36.
28. Chikuda H, Kugimiya F, Ikeda T, Ogasawara T,
Shimoaka T, Chung U, et al. Cyclic GMP- dependent kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes. Genes Dev. 2004; 18: 2418-29.
29. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki
Chung U, et al. The combination of SOX5, SOX6
and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Arthritis
Rheum. 2004; 50: 3561-73.
30. Long F, Chung U (Co-first), Ohba S, McMahon J,
Kronenberg HM, McMahon AP. Genetic Evidence
That Ihh Signaling Is Directly Required For The
Osteoblast Lineage In The Endochondral Skeleton.
Development 2004; 131: 1309-18.

460

Division ofEnvironmental Health Sciences
Professor
Chiharu Tohyama, Ph.D., Dr.Med.Sci.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Assistant Professor
Masaki Kakeyama, Ph.D.

Homepage http://env-health.m.u-tokyo.ac.jp
Introduction and Organization
Division of Environmental Health Sciences is alaboratory established as a part of the Center for Disease Biology and Integrative medicine, and comprisesof Professor, Associate Professor, and Assistant Professor and other staff members as well as postdoctoral fellows, graduate and undergraduate students. The laboratory settings have been renovated, which makes it possible to start research and educational activities in full
capacity as of January, 2006. Staff members have been
engaged in environmental toxicology for many years at
the National Institute for Environmental Studies, Tsukuba, and the mission of this division for research andeducation is described below.

Research activities
Humans are exposed in our environment to various
hazardous chemicals via food, air, and water. Whenthese chemicals are absorbed, distributed and metabolized in the body, perturbation of homeostasis andadverse signs and symptoms of toxicity may occur. At
the Division of Environmental Health Sciences, theadverse effects caused by exposure to an individual
chemical or to mixtures of chemicals are identified, thedose response relationship for causing the adverse ef-

fects is determined, and the precise mechanism bywhich the toxicity is produced at the molecular andcellular level is elucidated by using two approaches.
The first approach is based on ‘forward toxicology’.
Here we start from a specific disease or health problem
humans are facing in the real world that might becaused by exposure to certain chemicals in our environment and we determine if the adverse effects causedby exposure to the particular chemical or mixture ofchemicals are similar to the adverse effects associatedwith the human disease or human health problem. Thisis done by exposing laboratory animals and cultured
cells to increasing doses of the chemical or chemical
mixture and identifying adverse effects, called ‘endpoints of toxicity’, at each dose.
The other approach is ‘reverse toxicology’. In thisapproach we utilize a particular laboratory animalmodel in which a specific adverse effect can be reproducibly observed, and we attempt to clarify the physiological significance of altered expression of genes andproteins in causing the adverse effect. In this ‘reverse
toxicology’ approach we use modern, molecular biology based technologies such as global gene analysis
and genetic engineering to identify the mechanism of
toxicity at the molecular and cellular levels.
The primary goal of the Division’s research programis to elucidate toxicity mechanisms for various envi-

461

ronmentally hazardous chemicals. To achieve this goal,‘forward and reverse toxicology’ approaches are used
to determine how adverse responses of laboratory animals, which are used as an experimental substitute forhumans, to a particular chemical are similar to or different from the adverse responses of humans.
The outcomes of our research provide not only fundamental information for human health risk assessmentthat can lead to the establishment of adequate margins
of safety for human exposure to environmental chemicals. They give the general public a greater sense of
security in their surroundings and they provide clinicalmedicine and the basic life sciences new knowledge
that is human health relevant.
Division’s Research Themes
1. Elucidation of mechanisms of toxicity at the molecular and cellular level for adverse effects of environmentally hazardous chemicals (dioxin, PCBs,
and heavy metals).
2. Identification of differences in susceptibility to thetoxicity caused by a particular environmentallyhazardous chemical between different animal species and between different genetic strains of thesame species.
3. Determination of the cause of such species andstrain differences in sensitivity to an environmental
toxicant at the molecular and cellular level.

Teaching activities
Unfortunately, ‘Environmental Toxicology’ is not
fairly placed in the curriculum of medicine, pharmacy,
nursing, and other allied health sciences at most universities. In addition to its research mission, the Division
of Environmental Health Sciences has an equally important education mission. The Division is actively involved in educating graduate students and training
postdoctoral fellows to become promising scientist
leaders in the field of environmental health sciences in
the future.
For the upcoming year, the Division will be responsible for a full credit course on ‘Principles and Applications of Environmental Health Sciences’. In addition,
several lectures are to be given to graduate students for
Master’s degree as well as to undergraduate students at
School of Medicine and School of Health Sciences andNursing.

Publications
1. Ishimura R., Kawakami T., Ohsako S., Nohara K.
and Tohyama C. Suppressive effect of 2,3,7,8- tetrachlorodibenzo-p-dioxin on vascular remodelingthat takes place in the normal labyrinth zone of rat
placenta during late gestation. Toxicol. Sci.,
91:265-274,2006
2. Kawakami T., Ishimura R., Nohara K., Takeda K.,
Tohyama, C. and Ohsako, S. Differential susceptibilities of Holtzman and Sprague-Dawley rats tofetal death and placental dysfunction induced by
2,3,7,8-teterachlorodibenzo-p-dioxin (TCDD) despite the identical primary structure of the aryl hydrocarbon receptor. Tox. Appl. Pharmacol.
212:224-206,2006
3. Shiizaki K., Ohsako, S., Koyama, T., Nagata R.,
Yonemoto, J. and Tohyama, C. Lack of CYP1A1
expression is involved in unresponsiveness of thehuman hepatoma cell line SKHEP-1 to dioxin.
Toxicol. Lett. 160: 22-33, 2005
4. Inouye K, Pan X, Imai N, Ito T, Takei T, Tohyama
C, Nohara K.:cell-derived IL-5 production is a sensitive target of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) Chemosphere 60: 907-913, 2005
5. Nishimura N, Yonemoto J, Miyabara Y, Fujii-Kuriyama Y, Tohyama C.: Altered thyroxin andretinoid metabolic response to 2,3,7,8- tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice. Arch Toxicol 79: 260-267, 2005
6. Ikeda M, Mitsui T, Setani K, Tamura M, Kakeyama
M, Sone H, Tohyama C, Tomita T.: In utero andlactational exposure to 2,3,7,8- tetrachlorodibenzop-dioxin in rats disrupts brain sexual differentiation.Toxicol Appl Pharmacol. 205: 98-105, 2005.
7. Nohara K, Pan X, Tsukumo S, Hida A, Ito T, Nagai
H, Inouye K, Motohashi H, Yamamoto M, Fujii-Kuriyama Y, Tohyama C.: Constitutively active
aryl hydrocarbon receptor expressed specifically in
T-lineage cells causes thymus involution and suppresses the immunization-induced increase insplenocytes. J Immunol. 174: 2770-2777, 2005.
8. Nishimura N, Yonemoto J, Nishimura H, Ikushiro S,
Tohyama C.: Disruption of thyroid hormone homeostasis at weaning of Holtzman rats by lactational but not in utero exposure to 2,3,7,8- tetra-

462

chlorodibenzo-p-dioxin. Toxicol Sci. 85: 607-614.
2005.
9. Nagai H, Takei T, Tohyama C, Kubo M, Abe R,
Nohara K.: Search for the target genes involved in
the suppression of antibody production by TCDD
in C57BL/6 mice. Int Immunopharmacol. 5: 331343, 2005.
10. Watanabe H, Suzuki A, Goto M, Ohsako S, Tohyama C, Handa H, Iguchi T.: Comparative uterine
gene expression analysis after dioxin and estradiol
administration. J Mol Endocrinol. 33: 763-771,
2004
11. Ito T., Tsukumo S., Suzuki N., Motohashi H., Yamamoto M., Fujii-Kuriyama Y., Mimura J., Lin
T-M., Peterson R.E., Tohyama C., and Nohara K. A
constitutively active arylhydrocarbon receptor inhibits growth of Jurkat T cells through changes inthe expression of genes related to apoptosis andcell cycle arrest. J. Biol. Chem. 279: 25204-25210,
2004.
12. Wu Q., Ohsako S., Ishimura R., Suzuki J. S., andTohyama C. Exposure of Mouse Preimplantation
Embryos to 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) Alters the Methylation Status of Imprinted
Genes H19 and Igf2. Biol. Reproduction 70:
1790-1797. 2004.
13. Fukuzawa N. H., Ohsako S. , Wu Q., Sakaue M.,
Fujii-Kuriyama Y., Baba T., and Tohyama C. Testicular cytochrome P450scc and LHR as possible
targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) in the mouse. Mol. Cell. Endocrinol.
221(1-2): 87-96, 2004.
14. Kusumegi T., Tanaka J., Kawano M., Yonemoto J.,
Tohyama C., and Sone H. MP7/ActRIIB regulates
estrogen-dependent apoptosis: New biomarkers forenvironmental estrogens. J. Biochem. Mol. Toxicol.
18: 1-11 ,2004.

463

Section of Animal Research,
Division of Research Resources
and Support
Professor
Akio Nomoto, Ph.D.

Associate Professor
Lecturer
Associate
Ken-Ichi Hanaki, D.V.M., Ph.D.,

Haruyuki Hirata, D.V.M., Ph.D.

Homepage http:// www.cdbim.m.u-tokyo.ac.jp/research/01_06.html
Introduction and Organization
Section of Animal Research (formerly Animal Center
for Biomedical Research) was established in April 1971
to provide laboratory animal husbandry and veterinary
consultation services for the investigators in the Facultyof Medicine. A full-time teaching staff, a veterinarian,
was arrived in April 1972. The building was completed
in March 1973, and the center began to provide services
for animal experimentation in April 1973. The buildinghas 7 floors and the basement.
Basement; operating room for plants, central heating
plant room, electric-transformation room, animal quarantine rooms, etc.
1st Floor; office rooms, conference room, dressing room,etc.
2nd Floor; staff rooms, laboratories for this section staff,
cage washing rooms, rabbit and rat rooms.
3rd Floor; SPF rodent rooms.
4th Floor; SPF rodent rooms and radioisotope laboratories.
5th Floor; procedure rooms (autopsy, surgery, x-ray) andno-human primate rooms.
6th Floor; no-human primate, dog, pig rooms.
7th Floor; air-conditioning plant room.
Animal Center for Biomedical Research was at first afacility attached to the faculty. Today the animal centeris one of sections, Division of Research Resources andSupport, the Center for Disease Biology and Integrative
Medicine (CDBIM).
The members of this section are 3 teaching staffs, 2technical support staffs, head official of CDBIM, ateaching assistant, 3 assistant laboratory animal technicians, and 4 assistance clerks. In addition, about 10
contracted employees work together with us in thebuilding to maintain the facilities; animal care, airconditioning, cage-washing, etc. One of our missions isto provide quality care for all animals used in ourbuilding. The other is to assist the registered users intheir mission of quality research with respect to the useof laboratory animals. In particular, research associates(attending veterinarians) have overall responsibility forthe health and welfare of animals used in research. The
office of this section is also the secretariat of the Ani-

464

mal Care and the Use Committee of Graduate School of
Medicine, the University of Tokyo (IACUC). We checksubmitted animal experiment plans to the committee
whether the plans would be carried out in considerationof animal welfare, and then give comment and/or advice to the principal investigator. The committee (Chair,Prof. Akio Nomoto) will review the latest plans andwill approve, withhold approval, or require modifications to secure approval in accordance with law, regulations and University policies governing the use of animals.
All investigators in the University of Tokyo are able
to use facilities in our building after the registration.
However the most of registered patrons are the investigators in the Graduate School of Medicine. The numberof registered patrons was 729 in 2005.

Teaching activities
Our teaching responsibility is to give lectures on
Laboratory Animal Science to the 2nd-year students of
the Science Course III of the College of Arts and Sciences. The teaching staff of this section teaches the following subjects.
(i) Animal Welfare, Law, Rules and Regulations(ii) Refinement of Animal Experiments (Anesthesia
and Euthanasia)(iii) Animal Breeding and Animals Used in Medical
Science(iv) Infectious dieseases of Laboratory Animals andZoonoses
There is no regular teaching curriculum for graduate
students. However Laboratory Animal Science is taught
as a part of Microbiology.

Research activities
Each research associate has own research theme, andthey are responsible for the research in this section.
Followings are the research profiles.
(i) Detection of a trace amount of antigen in tissue.
The purpose of this research is the development ofa signal amplification technique suitable for thedetection of antigen in tissue. We have developed a
new signal amplification technique using nucleic
acid that would be suitable for the detection of
immobilized antigen on protein chip or tissue.

Now we try to adapt the technique for the detection of PrPBSE in brain. This study is collaboration
with National Institute of Infectious Diseases(NIID).
(ii) Elucidation of the mechanisms to escape host immunity by pathogen in parasitic infections.
We expect this investigation will be helpful for thedevelopment of new therapeutic approaches anddrugs.

References
1. Bork S, Okamura M, Boonchit S, Hirata H, Yokoyama N, Igarashi I. Identification of Babesia bovis
L-lactate dehydrogenase as a potential chemotherapeutical target against bovine babesiosis. Mol
Biochem Parasitol. 2004;136:165-172.
2. Fujiyuki T, Takeuchi H, Ono M, et al. A novel insect picorna-like virus identified in the brain of aggressive worker honeybees. J Virol. 2004;78:10931100.
3. Hanaki K, Ohka S, Yamamoto K, Nomoto A, Yoshikura H. Oligo(dA-dT)-dependent signal amplification for the detection of proteins in cells. Biotechniques. 2004;36:856-860,862-863.
4. Hoshino A, Hanaki K, Suzuki K, Yamamoto K.
Applications of T-lymphoma labeled with fluorescent quantum dots to cell tracing markers in mouse
body. Biochem Biophys Res Commun. 2004;314:46-53.
5. Huang X, Xuan X, Hirata H, et al. Rapid immunochromatographic test using recombinant SAG2 fordetection of antibodies against Toxoplasma gondii
in cats. J Clin Microbiol. 2004;42:351-353.
6. Nagata N, Iwasaki T, Ami Y, et al. A poliomyelitis
model through mucosal infection in transgenic
mice bearing human poliovirus receptor, TgPVR21.
Virology. 2004;321:87-100.
7. Oda T, Ohka S, Nomoto A. Ligand stimulation of
CD155a inhibits cell adhesion and enhances cell
migration in fibroblasts. Biochem Biophys Res
Commun. 2004;319:1253-1264.
8. Ogino T, Fukuda H, Imajoh-Ohmi S, et al. Membrane binding properties and terminal residues ofthe mature hepatitis C Virus capsid protein in insect
cells. J Virol. 2004;78:11766-11777.
9. Ohka S, Matsuda N, Tohyama K, et al. Receptor

465(CD155)-dependent endocytosis of poliovirus andretrograde axonal transport of the endosome. J Virol. 2004;78:7186-7198.
10. Otsuka Y, Hanaki K, Zhao J, et al. Detection of
Mycobacterium bovis Bacillus Calmette-Guerin
using quantum dot immuno-conjugates. Jpn J InfectDis. 2004;57:183-184.
11. Shiohara A, Hoshino A, Hanaki K, et al. On thecyto-toxicity caused by quantum dots. Microbiol
Immunol. 2004;48:669-675.
12. Tamaki Y, Hirata H, Takabatake N, et al. Molecularcloning of a Babesia caballi gene encoding the
134-kilodalton protein and evaluation of its diagnostic potential in an enzyme-linked immunosorbent assay. Clin Diagn Lab Immunol. 2004;11:211215.
13. Taniguchi T, Taniguchi R, Takahashi A, et al. Sequence comparison of the ORF 7 region of transmissible gastroenteritis viruses isolated in Japan. J
Vet Med Sci. 2004;66:717-719.
14. Alhassan A, Pumidonming W, Okamura M, et al.
Development of a single-round and multiplex PCR
method for the simultaneous detection of Babesia
caballi and Babesia equi in horse blood. Vet Parasitol. 2005;129:43-49.
15. Fujiyuki T, Takeuchi H, Ono M, et al. Kakugo virus
from brains of aggressive worker honeybees. Adv
Vir Res. 2005;65:1-27.
16. Hirata H, Yokoyama N, Xuan X, Fujisaki K, Suzuki N, Igarashi I. Cloning of a novel Babesia equigene encoding a 158-kilodalton protein useful for
serological diagnosis. Clin Diagn Lab Immunol.
2005;12:334-338.
17. Tomasec P, Wang ECY, Davidson AJ, et al. WilkinsonDown-regulation of NK cell activating
ligand CD155 by human cytomegalovirus UL141.
Nature Immunol. 2005;6:181-188.
18. Yanagiya A, Jia Q, Ohka S, Horie H, Nomoto A.
Blockade of poliovirus-induced cytopathic effect inneural cells by monoclonal antibody against poliovirus or human poliovirus receptor. J Virol. 2005;
79:1523-1532.

466

Section of Radiation Biology
Professor
Kiyoshi Miyagawa, M.D.,Ph.D.

Associate Professor
Yoshio Hosoi, M.D.,Ph.D.

Lecturer
Takahiko Suzuki, Ph.D.

Associate
Yoshihisa Matsumoto, Ph.D.,

Atsushi Enomoto, Ph.D.

Homepage http://www.cdbim.m.u-tokyo.ac.jp/
Introduction and Organization
The Section of Radiation Biology belongs to the Division of Research Resources and Support in Center for
Disease Biology and Integrative Medicine. The main
duty of the section is to support the use of radioisotope
at Graduate School of Medicine. Historically, in 2003,
the Department of Radiation Oncology and the Radiation Research Institute were joined to form a new department.
To maintain the facility of radiation research, responsible staffs at two facilities are elected from our department. Although the law that regulates the use ofradioisotope in Japan was largely revised this year, themaintenance system and frequency of the use of radioisotope have not been changed.
Present staffs came from the previous departments.
However, the position of the professor had been vacantsince 2003. The present professor took the position on
16 June 2005. Since then, the new research projects
have been carried out.
Although the supportive work is very important,education and research on effects of radiation on humanbodies are the most important duties in this section. We
cannot deny the fact that individual works have notbeen integrated thus far, the present staffs are constructing a new group that plays a leading role in radiation biology.

Teaching activities
We are responsible for the education of basic radiation medicine for the 2nd year medical students. The
students are expected to start with understanding of thephysics and the chemistry for radiation and then understand the basic biology of radiation. After that, theylearn how to handle radioactive materials by the 2-daypractical course.
In addition to these courses, a new course for the 4thyear medical students was opened this year. The students are expected to learn how to use clinical radiation
technology safely in hospitals. The background for thisaddition is that clinical problems arising from the lackof knowledge of radiation effects have been increasing.
Furthermore, the education of radiation casualty medicine is included in this new course. Even though radiation casualty is rare, all clinicians should know how totreat patients exposed to radiation.
We also take part in the education of radiation healthscience for the 3rd year students specialized in health467

science. Radiation protection is emphasized in thiscourse.
At Graduate School of Medicine, molecular biology
of DNA damage response to radiation is more emphasized.
In addition, education courses for users of radioactive 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, non homologous end joining(NHEJ) for DNA double-strand breaks, apoptosis that
responds to DNA damage, and radio-sensitization had
been topics in this department. Since 2005, homologous
recombinational repair has been the main subject.
RecA in E. coli and its homolog Rad51 in budding
yeast play a central role in homologous recombinational
repair. Historically, mechanism of homologous recombination was extensively studied in these organisms,
whereas homologous recombination had been recognized as a minor pathway of DNA double-strand breakrepair in higher organisms. However, subsequent studies revealed that homologous recombination as well as
NHEJ plays an important role in DNA double-strand
break repair in higher organisms. There are two majordifferences 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 an error-free
repair pathway.
We have been studying on the functions of Rad51
paralogs, which share structural similarity with Rad51.
There are five genes that belong to this paralog family
in mitotic cells. Although they share structural similarity with each other, there is no functional redundancy.
To clarify their roles, we have generated their mutant
human cells by gene targeting and RNA interference.
Rad51B dysfunction due to chromosomal translocations has been found in some benign tumors. In
Rad51B mutant cells, the Rad51-dependent recombinational repair pathway is impaired. In addition, centrosome fragmentation and aneuploidy were found to be
increased in these cells. Haploinsufficiency of the genecauses these aberrations. Thus, Rad51B plays a role incentrosome and chromosome integrity.
In contrast to early stages of homologous recombination, little is known about the mechanisms of homologous recombination at late stages. The Mus81-Eme1
complex has been shown to resolve recombination intermediates. Subsequent studies revealed that this enzyme plays a role in the resolution of stalled replication
forks. We have studied on the function of this complex
in human cells. Unexpectedly, the mutant cells are hypersensitive to DNA cross-linking agents rather than toreplication inhibitors. The growth of the mutant cells
was reduced by the Chk1 and Chk2-dependnet checkpoint activation at the S and G2 phases, leading to the
reduction in Cdk1 and Cdk2 functions. Chromosome
analysis revealed that the frequency of chromosome
doubling was significantly increased in the mutant cells.
Restoration of Cdk1 activity by ectopic expression reduced the frequency of chromosome doubling, suggesting that the checkpoint activation may cause chromosome doubling.
Thus, the impaired recombinational repair pathway is
associated with numerous chromosomal aberrations. It
is established that some breast cancers arise from defective recombination. It is also possible that othercancers are caused by the similar processes. Furthermore, we hypothesize that non-cancerous diseases canbe associated with DNA damage responses. The study
on homologous recombination also contributes to thedevelopment of radiation therapy. Radiation and DNAdamaging 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 therapeutic targets.
From the clinical point of view, we will establish thebasic science of homologous recombinational repair.

References
1. Hiyama T, Katsura M, Yoshihara T, Ishida M, Kinomura A, Tonda T, Asahara T, Miyagawa K. Haploinsufficiency of the Mus81-Eme1 endonucleaseactivates the intra-S-phase and G2/M checkpoints
and promotes rereplication in human cells. Nucleic
Acids Res. 2006;34:880-892.
2. Adachi N, So S, Iiizumi S, Nomura Y, Murai K,

468

Yamakawa C, Miyagawa K, Koyama H. The human pre-B cell line Nalm-6 is highly proficient ingene targeting by homologous recombination. DNA
Cell Biol. 2006;25:19-24.
3. Nakagawa K, Kanda Y, Yamashita H, Hosoi Y,
Oshima K, Ohtomo K, Ban N, Yamakawa, S, Nakagawa S, Chiba S. Preservation of ovarian function by ovarian shielding when undergoing total
body irradiation for hematopoietic stem cell transplantation: a report of two successful cases. Bone
Marrow Transplant. 2006;37:583-587.
4. Li Z, Hosoi Y, Cai K, Tanno Y, Matsumoto Y,
Enomoto A, Morita A, Nakagawa K, Miyagawa K.
Src tyrosine kinase inhibitor PP2 suppresses
ERK1/2 activation and epidermal growth factor receptor transactivation by X-irradiation. Biochem
Biophys Res Commun. 2006;341:363-368.
5. Someya M, Sakata K, Matsumoto Y, Yamamoto H,
Monobe M, Ikeda H, Aono K, Hosoi Y, Suzuki N,
Hareyama M. The association of DNA-dependent
protein kinase activity with chromosomal instability and risk of cancer. Carcinogenesis. 2006;27:
117-122.
6. Morita A, Zhu J, Suzuki N, Enomoto A, Matsumoto Y, Tomita M, Suzuki T, Ohtomo K, Hosoi Y.
Sodium orthovanadate suppresses DNA damage-induced caspase activation and apoptosis byinactivating p53. Cell Death Differ. 2006;13:499511.
7. Nakagawa K, Yamashita H, Shiraishi K, Nakamura
N, Tago M, Igaki H, Hosoi Y, Shiina S, Omata M,
Makuuchi M, Ohtomo K: Radiation therapy for
portal venous invasion by hepatocellular carcinoma.
World J Gastroenterol. 2005;11: 7237-7241.
8. Tokuzumi S, Hori M, Monobe M, Hosoi Y, Kojima
S. Effect of nitric oxide on gamma-ray-induced
micronucleus frequency in RAW264.7 cells. Radiat
Res. 2005;164: 723-732.
9. Komuro Y, Watanabe T, Hosoi Y, Matsumoto Y,
Nakagawa K, Suzuki N, Nagawa H. Prognostic
significance of Ku70 protein expression in patientswith advanced colorectal cancer. Hepatogastroenterology. 2005; 52:995-998.
10. Komiyama S, Taniguchi S, Matsumoto Y, Tsunoda
E, Ohto T, Suzuki Y, Yin H-L, Tomita M, Enomoto A, Morita A, Suzuki T, Ohtomo K, Hosoi Y,
Suzuki N. Potentiality of DNA-dependent protein

kinase to phosphorylate Ser46 of human p53. Biochem Biophys Res Commun. 2004;323: 816-822.
11. Yin HL, Suzuki Y, Matsumoto Y, Tomita M, Furusawa Y, Enomoto A, Morita A, Aoki M, YatagaiF, Suzuki T, Hosoi Y, Ohtomo K, Suzuki N. Radiosensitization by hyperthermia in the chicken
B-lymphocyte cell line DT40 and its derivatives
lacking nonhomologous end joining and/or homologous recombination pathways of DNA double-strand break repair. Radiat Res. 2004;162:
433-431
12. Ono T, Ikehata H, Pithani VP, Uehara Y, Chen Y,
Kinouchi Y, Shimosegawa Y, Hosoi Y. Spontaneous mutations in digestive tract of old mice show
tissue-specific patterns of genomic instability.
Cancer Res. 2004;64:6919-6923.
13. Hosoi Y, Watanabe T, Nakagawa K, Matsumoto Y,
Enomoto A, Morita A, Nagawa H, Suzuki N.
Up-regulation of DNA-dependent protein kinase
activity and Sp1 in colorectal cancer. Int J Oncol.
2004;25:461-468.
14. Hosoi Y, Matsumoto Y, Enomoto A, Morita A,
Green J, Nakagawa K, Naruse K, Suzuki N. Suramin sensitizes cells to ionizing radiation by inactivating DNA-dependent protein kinase. Radiat Res.
2004;162:308-314.

469

Section of Bioinformatics
AssociateKenji Hatano, M.D.

Homepage http://www.cdbim.m.u-tokyo.ac.jp/
Organization
Section of Bioinformatics started in 2003 as a division of Research and Support of the Center for Disease
Biology and Integrative Medicine. Targeting biomedical research support using information technologies,
this division performs management and maintenance ofthe research network and information servers working
with the Information Promoting Office of the Graduate
School of Medicine.

Research activities
Medical terminology and ontology:
Standardization and systematization of medical vocabularies are major issue for appropriate utilization of
medical information implied in various medical terms.
We are committed the working group for the Japanesestandard disease code master (standard vocabulary ofJapanese disease names) and studying about the strategies for perform the standardization of Japanese medical vocabularies for electronic medical records. Using
current techniques of systematization of terms andconcepts, such as terminology or ontology, we are testing systematization of Japanese medical terms andconcepts and automatic classification system for free
medical words.
Distributed processing system for medical terms:
As an efficient method for the distribution of medical
term information and promotion of the standard vocabularies, we focused distributed processing systemusing the network and are developing distributed
methods service system in the internet for evaluation ofutilities and effectiveness of the system.

Main targets of our research are:z Standardization of medical vocabularies and coding
system
z Biomedical terminology and ontology
z Distributed processing system for medical information using the internetz Security of biomedical research networkz Privacy and anonymization of personal data inclinical researchz Digitalization and indexing of old Japanese medical
libraries.

References
1. Hatano K., Ohe K. Information Retrieval System
for Japanese Standard Disease-Code Master Using
XML Web Service. J. American Medical Informatics Association. Symposium Suppl. 597, 2003.
2. J. Kitayama, K.Hatano, S. Kaisaki, H.Suzuki, S.
Fujii, H. Nagawa. Hyperlipidemia is positively
correlated with lymph node metastasis in men withearly gastric cancer. British Journal of Surgery
91:191-198, 2004.

470

Office ofInternational Academic Affairs
Head
Kazuhiko Yamamoto
Assistant Professor
Joseph Green
Assistant Professor
Toshiyuki Maruyama
Foreign Member of the Teaching Staff
Christopher Holmes

Homepage
Status and functions
The Office of International Academic Affairs is under 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.

Personnel
The office is headed by Professor Kazuhiko
Yamamoto. Christopher Holmes joined as foreign
member of the teaching staff in 1999.
Drs. Green and Maruyama share the duties of the Office of International Academic Affairs.

Activities
This document reports on the office's activities inthese areas over the academic years 2004 and 2005
(April to March).
1. International Educational Exchange

1.1 Student counseling about education and research
In 2004, there were 165 foreign students (28 countries) officially registered in the Graduate School of
Medicine; in 2005, there were 162 from 29 countries.
Many inquiries were received during this period fromprospective applicants for foreign student and trainee
status: responses were sent to 88 such inquiries.
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.
Admission of foreign students to research positions
or graduate study in Japan is extremely difficult, for avariety of reasons, but positions were found for 1 applicants of the 9 whose applications were channeledthrough the Office of International Academic Affairs in2004 or 2005.
Every year, 20 or more University of Tokyo students

471

go overseas to study, and the office makes its best efforts to accommodate their needs.
It has become a tradition to hold a Spring get-together of foreign students and University of Tokyo students who will study or have studied abroad at the
Sanjo Kaikan, a reception hall on the Hongo campus. It
is attended by the Dean of the Faculty of Medicine, theteaching staff, and students: both in 2004 and 2005,
about 80 people attended this event.
Another tradition since the mid-1970s is the Autumn
foreign students' trip; In 2004, a group of 30 from 10
countries traveled to Tokyo DisneySea. In 2005, agroup of 45 from 12 countries traveled to Lake Kawaguchi and Fuji-kyuko Highland.
Ryugakusei Ronbun Contest which began in 1999
was held in both 2004 and 2005. The authors presented
their papers to interested fellow students and faculty
and the better five 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, four
University of Tokyo students have taken research electives at the University of Pennsylvania every year, andone student from the University of Pennsylvania havetaken clinical electives at the University of Tokyo.
A new agreement on academic cooperation was
signed between the Graduate School of Medicine of the
University of Tokyo and the Ohio State University in
May 2001. Since the start of the program in 2001,
eleven University of Tokyo students visited to attend
clinical electives at the Ohio State University.
Another new agreement on academic cooperation
was signed between the Graduate School of Medicineof the University of Tokyo and Johns Hopkins University in December 2002. Since the start of the program in
2002, eight University of Tokyo students visited to attend clinical electives at Johns Hopkins University.
Another new agreement on academic cooperation
was signed between the Graduate School of Medicineof the University of Tokyo and Michigan Medical
School in January 2005. Since the start of the programin 2005, two University of Tokyo students visited toattend clinical electives at Michigan Medical School.
Another new agreement on academic cooperation
was signed between the Graduate School of Medicineof the University of Tokyo and the Munich University
in February 2005. Since the start of the program in

2005, one University of Tokyo students visited to attend research electives at the Munich University, andone student from the Munich University have taken
clinical electives at the University of Tokyo.
1.2 Counseling University of Tokyo medical students
and researchers about short-term and longer overseas
study programs
Every year, about 30 requests from students forcounseling regarding pre-graduation or post-graduation
studies abroad are received by the Office of International Academic Affairs. The office responds to theserequests by providing information, advice, and letters ofrecommendation.

2. International contacts in research and scientific fields
2.1 Promotion of academic exchange between Japanand Thailand
Through the good offices of the Japan Society for the
Promotion of Science, a 10-year program of scientificexchange with Mahidol University in Thailand began in
1999. Quite unlike previous forms of academic exchange, this one is designed from the start to achieve
results by focusing clearly on one area of research andon specific outcomes. The focus is on infectious diseases and related fields, within which two major research projects are underway, in nosocomial infections
and in new and re-emerging infections. A total of 11
researchers were invited to Japan (571 researcher-days)
and 18 Japanese researchers were sent abroad (84 researcher-days) in 2004, and a total of 11 researchers
were invited to Japan (511 researcher-days) and 27
Japanese researchers were sent abroad (189 researcher-days) in 2005.
3. Education and research
3.1 Education
In 2004 and 2005, Dr. Joseph Green and Dr. Toshiyuki Maruyama taught a course open to all students in
the Graduate School of Medicine: Introduction to
Clinical Epidemiology Research.
In 2005, Dr. Green taught a course open to all students in the Graduate School of Medicine: Introduction
to Scale Development.
Dr. Green also taught two other graduate-levelclasses: International Epidemiology 1 and 2.

472

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 2004 and 2005, 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. Kaneko Y, Maruyama T, Takegami K, Watanabe T,
Mitsui M, Hanajiri K, Nagawa H, Matsumoto Y.
Use of a microbubble agent to increase the effects
of high intensity focused ultrasound on liver tissue.
European Radiology 15: 1415-1420, 2005
2. Hanajiri K, Mitsui H, Maruyama T, Kondo Y, Shiina S, Omata M, Nakagawa K.
18F-FDG PET for hepatocellular carcinoma presenting with portal vein thrombus.
Journal of Gastroenterology. 2005. 40. 1005-1006.
3. Takegami K, Kaneko K, Watanabe T, Maruyama T,
Matsumoto Y, Nagawa H.
Erythrocytes, as well as microbubble contrast
agents, are important factors in improving thermal
and therapeutic effects of high-intensity focusedultrasound.
Ultrasound in Medicine and Biology 31: 385-390,
2005.
4. Takegami K, Kaneko K, Watanabe T, Maruyama T,
Matsumoto Y, Nagawa H.
Comparison of Optison and MRX-133 microbubble
contrast agent in improving heating and coagulation volume efficiency of high intensity focused ultrasound.
Radiology 237: 132-136, 2005
5. Takegami K, Kaneko K, Watanabe T, Maruyama T,
Matsumoto Y, Nagawa H.
Polyacrylamide gel containing egg white as newmodel for irradiation experiments using focused ultrasound.
Ultrasound in Medicine and Biology 30:
1419-1422, 2004.
6. Yoko Tsuji-Hayashi, Bessie A Young, Joseph
Green, Akiko Tsuji, Tatsuo Hosoya, Shunichi Fukuhara, Christopher R Blagg. Health-related Quality of Life among Community-dwelling Elderly

People in the General Populations of the US andJapan. Japan Medical Association Journal
2005;48(10),489-496.
7. Suzukamo Y, Oshika T, Yuzawa M, Tokuda Y,
Tomidokoro A, Oki K, Mangione CM, Green J,
Fukuhara S. Psychometric properties of the 25-item
National Eye Institute Visual Function Questionnaire (NEI VFQ-25), Japanese version. Health Qual
Life Outcomes. 2005,3:65.
8. Yamazaki S, Fukuhara S, and Green, J. Usefulnessof five-item and three-item Mental Health Inventories to screen for depressive symptoms in the general population of Japan. Health Qual Life Outcomes. 2005,3:48.
9. Kobayashi K, Green J, Shimonagayoshi M, Kanemoto N, Kasai R, Itoh Y, Fujiki Y, Ohashi Y,
Gotay C, Kudoh S. Validation of the Care Notebook for Measuring Physical, Mental and Life
Well-Being of Patients with Cancer. Qual Life Res.
2005;14:1035-43.
10. Ohbu S, Igarashi H, Okayasu H, Sakai F, Green J,
Heller RF, Fukuhara S, Patrick DL. Development
and testing of the Japanese version of the migraine-specific quality of life instrument. Qual Life
Res. 2004 Oct;13(8):1489-93.

473

International Research Center for
Medical Education (IRCME)
Director & Professor
Kimitaka Kaga, M.D.,Ph.D

Professor
Kiyoshi Kitamura, M.D.,Ph.D.

Associate Professor
Yuko Takeda, M.D.,Ph.D.

Lecturer
Hirotaka Onishi, M.D., Ph.D.

Guest Researcher
Takuya Adachi,M.D

Invited foreign professor
Ellen Cosgrove, M.D., FRCPNew Mexico University, School of Medicine

Homepage http://www.ircme.u-tokyo.ac.jp
History and organization
Three years after it was first proposed, the University of Tokyo’s International Research Center for
Medical Education (IRCME) was established on April
1, 2000. The Ministry of Education, the University ofTokyo, and the Graduate School of Medicine established IRCME as a base for promoting international
cooperative studies of medical education. We would
like to express our thanks to all who have supported
this center.
IRCME comprises a department of International
Cooperative Study for Medical Education, Department
of Planning and Coordination for International Cooperative Projects and Information on Medical Education, and a position for a visiting professor fromabroad. We hope that the research in medical education carried out of IRCME will improve medical edu-

cation and health care in many countries.
One of IRCME’s most important is to study andpromote a broad view of medical education, and to
make the results of our efforts available both within
Japan and worldwide. We aim to promote international cooperation and to construct a database of educators, researchers, and clinicians interested and active
in medical education. On behalf of the entire IRCME
staff, we reaffirm our commitment to these goals.

Educational activity for medical
education
In recent years, medical education has moved away
form systems in which students merely observe theirteachers interacting with patients; now students are
increasingly expected to participate actively in theirlearning and in solving clinical problems. Moreover,474

the knowledge required for modern medicine increased both in range and in depth. As educators andresearchers, not only must we help today’s students
become familiar with problem solving
Contemporary biomedical sciences, advanced medical equipment, and computer-based sources of information, we must also ensure that appropriate attention
is given to the ethical and socioeconomic aspects ofmedicine. With the goal of improving medical education, we do research on a broad range of topics including action research both at the University of Tokyo an at other universities. In doing so, it incorporate
insights form medical anthropology and form experiences with international cooperation in many otherfields into research aimed at maximizing the benefitsof international cooperation in medical education. As
contributions to the progress of medical education, theresults of this research are made available both in andoutside Japan via research papers, to her publications,presentations at academic meetings, and thorough newincluding the internet and a network of university
hospitals liked by a communications satellite. Some
activities of this department are listed below.
1. Research on theory and method in adult learning:This includes analysis of published literature andother relevant materials, visits to and surveys of
institutions with outstanding educational programs, and discussion with leaders in the field.
2. Action research to improve medical education:
a. Development of curriculab. Improvement of educational methods (examples include faulty development, small grouptutorials and problem-based learning, use ofsimulated patients to teach basic clinicalskills, and a super-rotation system centeredon primary care)c. Development of educational resources (collaborative research among multiple institutions to development course work plans, materials for tutorials, audio-visual materials,
simulated patients, models and simulators forteaching physical examination, and Objective
Structured Clinical Examinations); evaluation of educational outcomes.
3. Research on the needs regarding international
cooperation in medical education:

This includes analysis of published literature andother materials, collection of information fromrelevant organizations, sites visits and surveys,
and discussions with leaders in the field.
4. Action research on international cooperation in
medical education:
This includes support for the development of curricula and other educational resources, and for thedevelopment of teacher-physicians.

Educational research activity
Emphasizing international educational cooperation
in medicine, dentistry, pharmacy, nursing, nutrition,
public health, and related areas, this department seeks
to enhance the university’s role in humanizing Japan’scontribution to international development, by building
a database of researchers and practitioners and byforming networks among individuals and institutions.
Some activities of this department are listed below.
1. Coordinating the planning, establishment, andimplementation of education and training for international cooperation in medical education projects initiated in Japan.
2. Forming and contributing to a world wide consortium of specialists working for international cooperation in medical education.
3. Holding a Forum on International Cooperation
and Research on Medical education, and publicizing its proceedings.
4. Developing a database of information on Japanese
researchers and practitioners interested and active
in international educational cooperation in medicine.
5. Development of international cooperation projects
in health professions education area budgeted by
official development assistance (ODA), research
grants, etc, especially in developing countries.
Currently, several projects for Afghanistan are
under implementaiton.
6. Support for international cooperation projects inhealth professions education area through the efforts on information gathering and interpersonal
exchange in both domestics and international
level. Currently, we have constructed strong relationship with the Committee for International Affair (Japan Society for Medical Education), Na-475

tional Institute for Public Health and International
Medical Center of Japan in medical area, and St
Luke’s College of Nursing in nursing area.

International medical education
activity
Medical education has recently shifted from methods focused on Inculcating biological knowledge toapproaches that incorporate problem-based learningand integrated, fully humanistic viewpoints. As medical educators, we are responsible both for scientificand technical training and for rehumanizing our students. Furthermore, while we must teach medicine s it
is now, the exponential increase in medical information requires us also to help our students develop theskills and approaches they need to become lifelong
learners.
In these changing times, we realizes the acute andpressing need to do interdisciplinary research on new
methods in medical education and to make the resultsof our work widely available. International activities
in medical education have important roles also within
Japan: acquiring new information about approaches to
medical education found in other countries and making that information available domestically canbroaden the horizons of educators and improve thequality of medical education in Japan.
Since its founding on April 12, 2000, the International Research Center for Medical Education has
worked both within in University of Tokyo and in a
wider context, using the ideas outlined above as thebasis for research intended to inform international
cooperation in medical education and to develop tomorrow’s medical practitioners. The Center is devoted
to enhancing medical education and to a high standardof international cooperation.

Invited foreign guest activity
Visiting ProfessorshipTo facilitate international cooperative study and information exchange,
IRCME invites researchers from abroad who specialize in medical education.
Invited professors are chosen in part for theirknowledge and experience in international coopera-tion and medical education. They advice and instruction to IRCME on practical aspects of planning andpromoting cooperative projects. They also collaborate
on research projects with researchers in other parts of
the University of Tokyo and in other academic organizations.

Activities
1. Giving practical advice and instruction on international cooperation in medical education.
2. Doing international cooperative research on international collaboration for medical education.
3. Doing research on interdisciplinary planning andcoordination and on generalizing methods among
various areas of specialization.

Visiting Professors
Thomas S Inui, ScM, MD: American Associationof Medical College, Harvurd Medical school(June-September 2000)
Gordon L Noel, MD, FACP: Oregon Health Sciences
University(October 2001-March 2002)
Jerome R Hoffman, MA, MD:
University ofCalifornia, Los Angeles(July-September 2002)
Daniel R. Wolpaw, MD, Case Westem Reserve University(Nov 2003-Jcn2004)
Georges Bordage, MD,PhD
University of lllinois Chicago (Feb-Jul, 2004)
Bounsai Thovisouk.MD
National University of Laos (Dec. 2004-Mar. 2005)
Edward Peskin, MD. FACOG
University of Massachusetts Medical School(Mar-Jun. 2005)
Helen Cosgrove, MD FACP: New Mexico University(November 2005-April 2006)

References
1. Kaga K, Nakamura M, Takayama Y, Momose H:
Case Report.
A case of cortical deafness and anarthria. Acta
Otolaryngol 124:202-205,2004

476

2. Kaga K, Kurauchi T, Yumoto M, Uno A: Middle-latency auditory-evoked magnetic fields inpatients with auditory cortex lesions.
Acta Otolaryngol 124:376-380,2004
3. Kaga K, Tamai F, Kodama M, Kodama K: Three
young adults patients with Pelizaeus- Merzabacher disease who showed only wave I and II in
auditory brainstem responses but had good auditory perception.
Acta Otolaryngologica 125:1018-1023,2005
4. Kaga K, Kurauchi T, Nakamura M, Shindo M:
Magnetoencephalography
and position emission tomography studies of a patient with auditory agnosia caused by bilateral lesions confined to the auditory radiations. Case
report. Acta Otolaryngol 125:1351-1355,2005
5. Mori M, Kitamura K, Masuda M, et al: Long-term
results of a multicenter randomized, comparative
trial of modified CHOP versus THP-COP versus
THP-COPE regimens in elderly patients with
non-Hodgkin’s lymphoma. International Journalof HEMATOLOGY 81:246-254,2005
6. Mizushima S, Ohshige K, Watanabe J, Kimura M,
Kadowaki T, Nakamura Y, Tochikobo O, Ueshima
H: Randomized controlled trial of sour mild on
blood pressure in border line hypertensive men.
Ame J Hipertension 17:701-706,2004
7. Takeda Y, Nakamoto M, Wakunami M, Yasutania
T, Asato T: Faculty development for physicians
who participate in teaching communitybased medicine in Okinawa. Primary Care Japan
2:60-68,2004
8. Ainoda N, Onishi H, Yasuda Y: Definition andgoals of “self-directed learning” in contemporary
medical education literature. Ann Acad Med Singapore 34:515-519,2005
9. Koide D, Peskin E: New uses for computer inmedical education, clinical practice, and patient
safety in the US and Japan. Progress in Informatics 2:3-15,2005

477

The Tokyo Journal of Medical Sciences. Vol. 113, October 2006

編集

東京大学医学部年報は平成 4 年度から刊行されており、平成 7 年度からは日本語版（偶数年版）と英語
版（奇数年版）が隔年で刊行されていました。平成
16 年度までは医学部年報編集委員会が編集を行っていましたが、17 年度から年報編集委員会が医学部広報委員会に統合されたのを契機に、今回お届けする
17 年度版からは日本語版と英語版をともに毎年刊行することによって、東京大学医学系研究科・医学部の教育・研究・診療等の活動をこれまで以上に広く公表する一助とすることになりました。
今回お届けするのは平成 17 年度版で、業績については暦年で 2004 と 2005 の 2 年分を掲載していただ
いてもよいという方針で編集しました。編集にあたっては、木内貴弘委員（年報編集担当）、山田喜朗医学部専門員をはじめ広報委員会の委員の方々、各教室の方々に大変ご努力いただきましたことをお礼申し上げます。
また、本年報は従来から東京医学の刊行物として東京医学会から刊行していただいていますが、今回も引き続き東京医学会から支援していただいたおかげで、

（ご注意）

後

記

医学部広報予算とあわせて日本語版と英語版とを同時に発行することができました。また今回から印刷データはＷｅｂデータとしても作成して医学系研究科・医学部のホームページにも掲載されます。関係の方々のご尽力に感謝いたします。
なお編集には誤りのないよう関係者で努力したつもりですが、もし不備がありましたらご指摘の上、お許しいただきますようお願いします。
広報委員会委員長 大江 和彦
本年度は、収集した原稿をそのまま印刷できるように MS-WORD のテンプレートと執筆要綱を作成しました。ある程度の直しはやはり必要でしたが、まずまずのできだったと思います。次年度は、オンライン収集が実現できればと考えています。
広報委員会委員

木内

本誌の一部または全部を当編集委員会の許可なく転載または複製することは著作権法によって禁じられています.

Copyright © 2004

The Tokyo Society of Medical Sciences, The University of Tokyo Medical Society& The University of Tokyo Faculty Of Medicine (Printed in Japan)（季 刊）

東 京 医 学第113巻

編集・発行者

東京都文京区本郷7-3-1

平成18年10月31日発行
東京大学医学部内（〒113-0033）
財団法人

印

刷

者

ナカバヤシ株式会社

東

京

医

学

東京都板橋区東坂下2-5-1

会貴弘