2009-2013（PDF形式:3.46MB

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RESEARCH ACTIVITIES OF SAPPORO MEDICAL UNIVERSITY 2009 -2013
RESEARCH ACTIVITIES OF SAPPORO MEDICAL UNIVERSITY 2009 -2013
SAPPORO MEDICAL UNIVERSITY
Committee for International
Affairs and Medical Exchanges
RESEARCH ACTIVITIES OF
SAPPORO
MEDICAL
UNIVERSITY
2009-2013
Hokkaido, JAPAN
RESEARCH ACTIVITIES OF
2009 – 2013
Edited by
Committee for International Affairs and Medical Exchanges
Sapporo Medical University
Tetsuo Himi
Tetsuji Miura
Tsuyoshi Saito
Kiyoji Matsuyama
Hiromu Suzuki
Toshihiko Torigoe
Kazuhiko Yamaguchi
Otolaryngology, School of Medicine
Cardiovascular, Renal and Metabolic Medicine, School of Medicine
Obstetrics and Gynecology, School of Medicine
Second Division of Occupational Therapy, School of Health Sciences
Molecular Biology, School of Medicine
Pathology ( I ), School of Medicine
Liberal Arts and Sciences (English), Center for Medical Education
Contents
Ⅰ　OUTLINE OF SAPPORO MEDICAL UNIVERSITY 1
Respiratory Medicine and Allergology 58
１　OUTLINE 2
Medical Oncology and Hematology 60
Neurology 62
２　ORGANIZATION 5
Surgery, Surgical Oncology and Science 64
Organization 5
Cardiovascular Surgery 66
Number of Teaching Staffs & Fellows 8
Orthopaedic Surgery 68
Number of Students 9
Neurosurgery 70
Obstetrics and Gynecology 72
Ⅱ　RESEARCH ACTIVITIES 11
Pediatrics 74
Ａ　SCHOOL OF MEDICINE 12
Ophthalmology 76
１　Basic Medical Science (Subjects) 12
Dermatology 78
Intellectual Property Management 12
Urology 80
Medical Genetics 13
Otolaryngology 82
Neuropsychiatry 84
２　Clinical Medical Sciences (Subjects) 15
Radiology 86
Pharmaceutical Health Care and Sciences 15
Anesthesiology 88
Surgical Pathology 16
Community and General Medicine 90
Obstetrics and Perinatal Medicine 18
Clinical Laboratory Medicine 92
Plastic and Reconstructive Surgery 20
Emergency Medicine 94
Diagnostic Radiology 22
Oral Surgery 96
Rehabilitation Medicine 98
Health Care Administration
and Medical Management 24
Intensive Care Medicine 25
５　Research Institute for Frontier Medicine 100
Thoracic Surgery 27
Cell Science 100
Medical Genome Sciences 102
３　Basic Medical Sciences (Courses) 28
Tissue Development and Regeneration 104
Anatomy ( I ) 28
Molecular Medicine 106
Anatomy ( II ) 30
Biomedical Engineering 108
Cellular Physiology and Signal Transduction 32
Neural Regenerative Medicine 110
Systems Neuroscience 34
Human Immunology 112
Medical Biochemistry 36
Molecular Biology 38
６　Animal Research Center 114
Pathology ( I ) 40
Pathology ( II ) 42
Ｂ　SCHOOL OF HEALTH SCIENCES 116
Microbiology 44
１　Nursing 116
Pharmacology 46
Medical and Behavioral Subjects 116
Hygiene 48
Fundamental and Adult Nursing 118
Public Health 50
Maternal-Child Nursing 120
Legal Medicine 52
Community Health, Gerontological
４　Clinical Medical Sciences (Courses) 54
Cardiovascular, Renal
and Metabolic Medicine 122
２　Physical Therapy 124
First Division of Physical Therapy 124
Second Division of Physical Therapy 126
54
Gastroenterology, Rheumatology
and Clinical Immunology and Psychiatric Nursing 56
３　Occupational Therapy 128
First Division of Occupational Therapy 128
Second Division of Occupational Therapy 130
Ｃ　GRADUATE COURSE IN MIDWIFERY 132
Ｄ　CENTER FOR MEDICAL EDUCATION 134
１　Admissions Research 134
２　Liberal Arts and Sciences 136
Philosophy and Ethics 136
Psychology 137
Jurisprudence and Sociology 139
Sociology 140
English 141
Exercise Science 143
Physics 144
Biophysics 146
Chemistry 147
Biology 148
Information Science 150
Mathematics 151
Information Science 152
３　Educational Development 153
Ｅ　SCHOLARLY COMMUNICATION CENTER 155
Ｆ　SPECIAL COURSES 156
Okhotsk Medical Treatment
Environment Research 156
Regional Health Care and Medicine 158
Ⅲ　INTERNATIONAL EXCHANGES 159
１　Medical Exchanges with
The Northern Region Countries 160
２　Visiting Research Fellows 160
３　International Contributions 160
４　Researchers in Overseas 160
５　System of International Medical Exchanges 160
６　International Medical Exchange Center 160
７　List of Exchanges Scientists 162
Ⅳ　INDEX (Key Words) 175
I OUTLINE OF SAPPORO MEDICAL UNIVERSITY
2
PREFACE
AIM OF THE UNIVERSITY
Research Activities of Sapporo
Medical
University
has
been
improvement of the healthcare of the local community as well as
published at intervals of four years
the cultural development of mankind by teaching theories and
since March, 2010. Written in
applications regarding medicine and health sciences, researching
English, and accessible on the
in depth, and fostering students’ intellectual and moral abilities and
university website, it outlines the
their capacity for application.
scientific research activities of
research groups
Kazuaki Shimamoto, M.D,
Ph.D. President,
Sapporo Medical University aims to contribute to the
and
individual
(departments)
researchers
of
Sapporo Medical University from
September 2009- August 2013.
Founded in 1950, our school is a medical university with a history
of more than 60 years.
Presently, the university consists of the School of Medicine and
School of Health Sciences, which are made up of four faculties
(Medicine, Nursing, Physical Therapy and Occupational Therapy),
and the Center for Medical Education.
All strive to enhance education, research, and medical care and
contribute to medical services in Hokkaido, while adhering to the
following three principles: train medical professionals with a
well-rounded character, improve medical services for the residents
of Hokkaido, and promote advanced international research.
In addition, Sapporo Medical University promotes international
exchange program mainly with northern countries and Asian
nations that have similar climates and living environments in order
to promote the health and welfare of people in Hokkaido and the
rest of the world.
The university has concluded exchange agreements with Canada,
China, Finland, and the United States, and has dispatched and
hosted researchers since 1977.
Mutual exchanges for clinical training programs with students from
China Medical University and The Catholic University of Korea
have also been conducted since 2009 and 2011, respectively.
Furthermore, to improve standards of health and welfare for
people worldwide, the university actively dispatches researchers to
developing countries and welcome trainees from overseas.
Through this brochure, we hope to introduce our research
activities to scientists around the world and we hope that it provide
you with an opportunity to collaborate with us.
3
HISTORY
As part of Hokkaido’s comprehensive development, Sapporo
Medical University was founded in 1950 using Hokkaido Women’s
Medical College as a model. The most recent development was
the establishment of the School of Health Sciences in April, 1993 in
accordance with the reorganization of the Health Sciences Junior
College – which opened in April 1983 – attached to Sapporo
th
Medical College. In June 2001, the University celebrated its 50
anniversary.
Chronology of Hokkaido Women’s Medical College
April 1945
Hokkaido Women’s Medical College was
founded.
Chronology of Sapporo Medical College
April 1950
Sapporo Medical College opened.
June 1950
Opening ceremony held - June 25
Administration Building and Basic Medical Research Building
designated as the college’s foundation day.
September 1955
Cancer Research Institute established as
an affiliated research institution.
March 1955
Establishment of the Graduate School of
Medicine approved. Enrollment capacity is
25 students.
January 1958
Premedical course provided.
September 1968
Marine Biomedical Institute established.
April 1979
Divided courses - premedical and special
courses abolished.
April 1983
Health Sciences Junior College, attached
to Sapporo Medical College, opened.
Chronology of Sapporo Medical University
April 1993
School of Health Sciences - Departments
of
Nursing,
Physical
Therapy
and
Occupational Therapy - established to
Clinical Research Building and University Hospital
accept 90 students.
April 1998
Graduate School of Health Sciences Nursing,
Physical
Occupational
Therapy
Therapy
–
and
established.
Enrollment capacity is 24 students.
April 1999
Information
Center
of
Computer
Communication established.
April 2000
Doctoral course for Physical Therapy and
Occupational Therapy established in the
Graduate School of Health Sciences.
April 2001
Ph.D. course of Medicine for three
programs reorganized in the Graduate
School of Medicine. Total enrollment
capacity is 50.
School of Health Sciences Building
4
April 2001
Community Health Care Support Center
established.
April 2002
Critical Care Center established in the
University Hospital.
October 2002
Advanced Critical Care Center established
In the University Hospital.
December 2002
April 2004
Memorial Hall established.
New doctor dispatch system start
Resident system start
April 2006
Scholarly Communication Center established.
(The unification organization of the library and
the information center.)
Collaboration Center for Community and
Industry established.
Doctoral course for Nursing established in the
Graduate School of Health Sciences .
April 2007
Transition to Hokkaido Public University
Corporation Sapporo Medical University.
April 2008
School of Medicine enrollment capacity is
105 students.
October 2008
Center of Medical Education established.
April 2011
Cancer Research Institute and other facilities
reorganized into the Research Institute for
Frontier Medicine in the School of Medicine.
April 2012
Graduate Course in Midwifery established
Basic Medical Research Building
5
ORGANIZATION
SCHOOL OF MEDICINE
CENTER OF MEDICAL EDUCATION
The School of Medicine offers 36 courses and 10 subjects. Its
The Center for Medical Education was established in 2008. The
affiliated institutions include the Research Institute for Frontier
purpose of this center to help the development of the medical
Medicine, which consists of seven departments, and the
experts who will play a leadership role in promoting the education of
Biomedical Research, Education and Instrumentation Center . It
medical science and medical health care, and contribute to the
also
community health care in Hokkaido.
hosts
the
Biomedical
Research,
Education
and
Instrumentation Center, which consists of eight departments, and
It consists of three departments: Admissions Research, Liberal Arts
the Animal Research Center.
and Science, Educational Development.
BIOMEDICAL
RESEARCH,
EDUCATION
AND
GRADUATE SCHOOL OF MEDICINE
INSTRUMENTATION CENTER
The graduate school of medicine research course was set up in
Due to the rapid progress of the technology in molecular biology,
1956 to foster research capabilities necessary for the students to
the techniques used for medical treatment and biological research
conduct independent research activities as researchers or engage
have rapidly improved. For this reason, the Biomedical Research,
in other highly professional tasks, and to acquire knowledge that
Education and Instrumentation Center is supplied with the latest
forms the basis of such capabilities. Since its establishment, the
research equipment so that the most advanced research in the
degree has been given to approximately 2,700 students who are
world can be conducted. This equipment can be shared by
now playing active roles in their respective fields.
researchers. The collaboration between basic researchers and
In April 2001, the fields of specialization were broadened in order to
clinical researchers is expected to result in significant contributions
keep pace with advances in medical science and practice. The
to the world’s scientific community.
initial setup included five specialties (physiology, pathology, social
medicine, internal medicine and surgical science) and 39 subjects
RESEARCH INSTITUTE FOR FRONTIER MEDICINE
with an enrollment capacity of 31 students. This has evolved to
The Cancer Research Institute, the Marine Biomedical Institute and
three specialties consisting of comprehensive research areas in
the Biomedical Research, Education and Instrumentation, Center in
which basic and advanced research results are used in clinical
the School of Medicine were reorganized and consolidated into the
disciplines (community health and comprehensive medicine,
Research Institute for Frontier Medicine in April 2011.
molecular and organ regulation, and signal transduction medicine).
The Institute consists of seven departments. In order to provide
These three specialties are futher subdivided into 11 sub-specialties
medical care and promote the health of the Hokkaido populace, the
(58 subjects) with an enrollment capacity of 50 students.
Institute is
involved in translational research based on
In April 2008, the Medical Science Course (Master’s Program) was
state-of-the-art medical research to facilitate the clinical application
opened. The new Doctoral Programs established includes five
and practical use of research results.
clinical oncology courses along with the Clinical Research Course
and Medical Science Course.
ANIMAL RESEARCH CENTER
Animal experiments have greatly contributed to basic and
GRADUATE SCHOOL OF HEALTH SCIENCES
advanced research on highly advanced medical treatment. The
The Master’s Program of the Graduate School of Health Sciences
Animal Research Center offers the facilities to conduct and support
was established in April 1998 for the purpose of providing students
advanced research.
with profound knowledge from a broad perspective and cultivating
research capability for their specialties or skills necessary for
SCHOOL OF HEALTH SCIENCES
occupations that require high expertise. In 2006, the Certified
In compliance with the increasing demand for health care, the
Nursing Specialist Course was established.
School of Health Sciences was established in April 1993 aiming to
The purpose of the Doctoral Program of the Graduate School is to
train humane, highly skilled practitioners who have learned practical
foster research capabilities necessary for the students to conduct
theory and procedures in the fields of nursing, physical therapy and
independent research activities in their major fields or engage in
occupational therapy, as well as to build a foundation for
other highly professional tasks, and to acquire knowledge that
contributing to their development in each field as educators and
forms the basis of such capabilities. The Graduate Program for
researchers.
Physical Therapy and Occupational Therapy and Graduate
Program for Nursing were established in April 2000 and April 2006,
respectively.
6
UNIVERSITY HOSPITAL
The hospital attached to Sapporo Medical University has facilities in
26 clinical divisions and 938 inpatient beds. It provides advanced,
state-of-the-art medical care, such as emergency medical care,
cancer treatment and regenerative medicine, and also plays a
significant role as a medical institution that assists the development
of local medical services and accepts patients from remote areas in
Hokkaido in cases of disasters.
In 1996, the hospital was certified as an advanced treatment facility
capable of providing advanced medical treatment, developing
medical technologies, and offering training. In 2002, Hokkaido’s first
advanced emergency medical care center was established within
the hospital to accept critical emergency patients and provide
advanced specialized medical treatment. The hospital also
functions as an AIDS treatment core hospital (HIV Hokkaido
Regional Hospital), a disaster base hospital, the Hokkaido
Rehabilitation Support Center, and a Hokkaido regional cancer
center.
The hospital provides advanced medical treatment for various
intractable diseases. A cancer vaccine therapy as a new approach
to treatment and nerve regenerative medical techniques to repair
cerebral infractions and spinal cord injuries are among the medical
practice based on original fundamental research that have attracted
the attention of medical experts in Japan and abroad.
The University Hospital as a medical institution attached to a
university plays a central role in clinical education and research and
produces excellent human resources through the education and
training of medical staff and professionals with high levels of
expertise.
7
STRUCTURE AND ORGANIZATION OF SAPPORO MEDICAL UNIVERSITY
University
School of
Medicine
Medical Sciences
Subjects
Basic Medical
Sciences
Clinical Medical
Sciences
Cources
Basic Medical
Sciences
(Department of)
Intellectual Property Management
Medical Genetics
(Department of)
Pharmaceutical Health Care and Sciences
Surgical Pathology
Obstetrics Perinatal Medicine
Plastic and Reconstructive Surgery
Diagnostic Radiology
Health Care Administration and Management
Intensive Care Medicine
Thoracic Surgery
(Department of)
Anatomy ( I )
Anatomy ( II )
Physiology
Neuroscience
Biochemistry
Molecular Biology
Pathology ( I )
Pathology ( II )
Microbiology
Pharmacology
Hygiene
Public Health
Legal Medicine
Clinical Medical
Sciences
Research Institute for
Frontier Medicine
Biomedical Research, Education
and Instrumentation Center
Animal Research Center
School of Health
Sciences
(Division of)
System Management
Morphological Research
Electron Microscopy
Proteomics
Gene Analysis
Cell Bank
Radioisotope Research
Digital Imaging
(Divisoin of)
Medical and Behavioral Subjects
Fundamental and Adult Nursing
Maternal and Child Nursing
Community Health, Gerontological and Psychiatric Nursing
Dept. of Nursing
Dept. of Physical
Therapy
First Division of Physical Therapy
Second Division of Physical Therapy
Dept. of Occupational
Therapy
Center for Medical
Education
(Department of)
Cell Science
Medical Genome Sciences
Tissue Development and
Regeneration
Genetic Engineering
Biomedical Engineering
Neural Regenerative Medicine
Medical Biology
First Division of Occupational Therapy
Second Division of Occupational Therapy
(Division of)
Philosophy and Ethics
Phychology
Jurisprudence and Sociology
English
Exercise Science
Physics
Biophysics
Chemistry
Biology
Mathematics and Information Science
Department of Admissions Research
Department of Liberal Arts and Sciences
Department of Educational Development
Graduate School of Medicine
Graduate School
(Department of)
Gastroenterology, Rheumatology and Clinical
Immunology
Cardiovascular, Renal and Metabolic Medicine
Respiratory Medicine and Allergology
Medical Oncology and Hematology
Neurology
Surgery, Surgical Oncology and Science
Cardiovascular Surgery
Orthopaedic Surgery
Neurosurgery
Obstetrics and Gynecology
Pediatrics
Ophthalmology
Dermatology
Urology
Otolaryngology
Neuropsychiatry
Radiology
Anesthesiology
Community and General Medicine
Clinical Laboratory Medicine
Emergency Medicine
Oral Surgery
Rehabilitation Medicine
Master's Course
Medical Science
Docter's Course
Program of Community
Health &
Comprehensive
Program of Molecular
and Organ Regulation
Graduate School of
Health Sciences
Program of Signal
Transduction Medicine
Program of
Physical Therapy and Occupational
Graduate Course In Midwifery
University Hospital
Program of Nursing
Clinical Divisions
Central Clinical
Divisions
Department of Student Affairs
Department of International Affair
and Medical Exchanges
Scholarly Communication Center
Collaboration Center for Community and Industry
Div. of Health Care Administration and
Management
Div. of Hospital Pharmacy
Div. of Laboratory Diagnosis
Div. of Clinical Pathology
Div. of Radiology and Nuclear Medicine
Div. of Operating Facilities
Div. of Linen and Appliance Supply
Div. of Rehabilitation Medicine
Advanced Critical Care and Emergency Center
Div. of Intensive Care Medicine
Div. of Safety Promotion
Div. of Infection Control
Clinical Engineering Office
Div. of Nursing
Medical Liaison and General Consultation Center
Clinical Training Center
Funded Projects
Special Courses
Administration
Department of Planning and Management
Department of University Administration
Department of Hospital Administration
Biomedical Museum
(Division of)
Internal Medicine(Ⅰ)
Internal Medicine(Ⅱ)
Internal Medicine(Ⅲ)
Internal Medicine(Ⅳ)
Neurology
Surgery(Ⅰ)
Thoracic Surgery
Orthopaedic Surgery
Neurosurgery
Gynecology
Perinatal Medicine
Pediatrics
Ophthalmology
Dermatology
Urology
Otolaryngology
Neuropsychiatry
Radiology Oncology
Anesthesiology
General Medicine
Oral Surgery
8
NUMBER OF TEACHING STAFFS & FELLOWS
(as of February 1, 2014)
SCHOOL OF MEDICINE
BASIC MEDICAL SCIENCES (Courses)
Prof.
Anatomy (I)
Anatomy (II)
Cellular Physiology
Signal Transduction
1
1
＆
System neuroscience
Medical biochemistry
Molecular Biology
Pathology (I)
Pathology (II)
Microbiology
Pharmacology
Hygiene
Public Health
Legal Medicine
Total
Assoc.
Prof.
1
1
Assist.
Prof.
BASIC MEDICAL SCIENCES (Subjects)
Instructor
Assistant
1
1
1
2
1
0
Research
Fellow
Total
3
7
5
5
1
0
1
2
0
0
4
1
1
1
1
1
1
1
1
1
1
13
1
1
0
1
0
0
0
1
2
1
10
1
1
1
0
2
0
1
1
1
1
11
2
2
3
3
1
4
2
0
1
1
26
0
0
0
0
0
0
0
0
0
0
1
0
1
0
4
1
0
0
0
1
0
17
5
5
5
5
4
5
4
3
5
4
61
CLINICAL MEDICAL SCIENCES (Courses)
Gastroenterology
Rheumatology and Clinical
Immunology
Cardiovascular, Renal and
Metabolic Medicine
Respiratory Medicine and
Allergology
Medical Oncology and
Hematology
Neurology
Surgery, Surgical Oncology
and Science
Orthopaedic Surgery
Neurosurgery
Obstetrics ＆
Gynecology
Pediatrics
Ophthalmology
Dermatology
Urology
Otolaryngology
Neuropsychiatry
Radiology
Anesthesiology
Community &
General Medicine
Clinical Laboratory
Medicine
Emergency Medicine
Oral Surgery
Total
Prof.
1
Intellectual
Property
Management
Medical Genetics
Assoc.
Prof.
Assist.
Prof.
Instructor
Assistant
0
0
0
0
0
0
0
1
1
0
0
0
1
2
Total
Research
Fellow
Total
0
1
0
0
2
3
CLINICAL MEDICAL SCIENCES (Subjects)
Assoc
Prof.
Assist.
Prof.
Instructor
Assistant
0
0
0
1
0
0
1
0
0
3
3
1
0
1
2
Prof.
1
Pharmaceutical
Health Care＆ Sciences
Surgical Pathology
Obstetrics and
Perinatal Medicine
Plastic＆
Reconstruction Surgery
0
Research
Fellow
Total
0
1
0
0
0
0
4
4
0
1
4
1
0
2
1
0
4
4
Assoc.
Prof.
Assist.
Prof.
Instructor
Assistant
Clinical
Fellow
Prof.
Total
Health Care Administration
and Management
1
0
0
0
0
0
1
1
2
3
6
0
6
12
Thoracic Surgery
0
1
2
0
1
0
2
1
0
0
1
0
5
2
Total
6
2
5
12
0
6
25
1
2
2
6
0
25
11
1
1
1
7
0
11
10
1
2
4
4
0
1
11
1
0
2
3
0
7
6
1
2
3
5
0
3
11
1
1
1
0
2
1
1
4
2
5
4
4
0
0
0
1
3
0
7
11
8
1
0
4
5
0
0
10
1
1
1
1
1
1
1
1
0
1
1
0
1
1
0
0
5
4
2
2
3
2
3
3
4
3
4
5
3
4
3
6
0
0
0
0
0
0
0
0
19
1
2
0
4
2
0
1
10
9
8
8
8
8
7
10
1
0
0
2
0
0
3
1
0
3
2
0
0
6
1
1
1
23
0
2
0
17
2
0
1
57
6
5
3
101
0
0
0
0
9
3
1
99
9
8
5
198
RESEARCH INSTITUTE FOR FRONTIER MEDICINE
Prof.
1
1
Cell Science
Medical Genome
Sciences
Assoc.
Prof.
Assist
Prof.
Instructor
Assistant
1
0
0
1
0
0
1
1
Research
Fellow
Total
0
0
3
3
Tissue Development
and Regeneration
Molecular Medicine
Biomedical
Engineering
1
0
1
1
0
1
3
0
1
0
0
0
1
1
1
1
0
0
1
2
3
1
0
2
0
0
0
3
Human Immunology
1
6
0
2
0
5
0
4
1
1
0
2
2
18
Neural Regenerative
Medicine
Total
ANIMAL RESEARCH CENTER
Prof.
Total
0
Assoc.
Prof.
1
Assist..
Prof.
0
Instructor
Assistant
0
0
Research
Fellow
Total
0
1
Research
Fellow
Total
SCHOLARLY COMMUNICATION CENTER
Prof.
Total
0
Assoc.
Prof.
0
Assist.
Prof.
0
Instructor
Assistant
1
0
1
1
9
SCHOOL OF HEALTH SCIENCES
NURSING
Prof.
Medical &
Behavioral
Subjects
Fundamental &
Adult Nursing
Maternal &
Child Nursing
Community
Health,
Gerontological
&Psychiatric
Nursing
Total
1
Assoc.
Prof.
0
Assist.
Prof.
1
Instructor
Assistant
0
0
Research
Fellow
Total
2
2
3
3
1
1
10
1
1
2
1
0
5
2
2
3
1
1
9
6
6
9
2
3
26
PHYSICAL THERAPY
Prof.
First Division of
Physical Therapy
Second Division
of
Physical
Therapy
Total
3
Assoc.
Prof.
0
Assist.
Prof.
Instructor
Assistant
1
1
1
Research
Fellow
1
Total
6
2
1
1
3
0
7
5
1
2
4
1
13
CENTER FOR MEDICAL EDUCATION
ADMISSIONS
Prof.
Total
1
Prof.
Philosophy & Ethics
Psychology
Jurisprudence
& Sociology
English
Exercise Science
Physics
Chemistry
Biology
Mathematics&
Information Sciences
Total
First Division of
Occupational
Therapy
Second Division
of Occupational
Therapy
Total
Assist.
Prof.
Instructor
Assistant
0
2
0
3
1
2
1
0
7
6
3
2
3
0
14
3
2
Research
Fellow
Total
1
0
Assist.
Prof.
2
Instructor
Assistant
Total
0
0
2
Prof.
Assoc.
Prof.
Assist.
Prof.
Instructor
Assistant
Total
0
0
0
0
2
2
1
0
0
0
1
0
0
0
0
1
3
2
1
0
2
1
1
0
1
1
0
0
2
2
1
0
1
1
0
1
0
0
0
0
0
0
0
0
0
0
0
0
3
1
3
2
3
3
5
10
5
1
0
21
Instructor
Assistant
Total
1
2
0
7
Assoc.
Prof.
1
Assist.
Prof.
3
7
NUMBER OF STUDENTS
Undergraduate
Graduate
Total
GRADUATE COURSE IN MIDWIFERY
Assoc.
Prof.
1
Total
Graduate Course
Prof.
Assist.
Prof.
EDUCATIONAL DEVELOPMENT
Total
Assoc.
Prof.
0
LIBERAL ARTS AND SCIENCES
Prof.
OCCUPATIONAL THERAPY
Assoc.
Prof.
Instructor
Assistant
Total
3
0
6
(as of February 1, 2014)
School of Medicine
658
School of Health Sciences
361
School of Medicine
213
School of Health Sciences
78
Midwifery
20
1,330
II RESEARCH ACTIVITIES
12
A SCHOOL OF MEDICINE
1 Basic Medical Science(Subjects)
Intellectual Property Management
The development of new medical technology is supported by vast
investment, which is impossible without the backing of intellectual
property rights. However, patent protection strategy of advanced
technology in biomedical fields is difficult due to description
requirements, the difficulty in specifying cells and tissues, and limited
patentability of medical methods. Technology transfer in these fields
is also challenging because it often requires costly and timeconsuming clinical studies to prove that a novel research theory
indeed works in practice. In this department, we perform studies,
based on our practical experience, aiming to improve the environment
for the development and practical realization of state-of-the-art
medical technology.
Professor
Masaho Ishino, Ph.D.
1. Effective protection of medical technology through
3) Ishino M. Revision in 2009 of patent examination
the patent system
standards and regenerative medical techniques --- may
・IP-protection of tissue derived materials and therapeutic
patent examination strategy relying on simple typing be
methods in regenerative medicine
・Establishment of increased logic in the examination of drug
patents
・Safeguarding scientific logicalness in technical lawsuits
・Patent protection of induced pluripotent stem cells
・Ideal system for patent term extension
2. Promotion of technology transfers in the medical
reaching untenable state? Journal of the Japanese
Group of the International Association for the Protection
of Intellectual Property 55(4), 36-253, 2010
4) Ishino M, Okina M. Present state analysis of iPS cell
technology: research progress and patent warfare.
PATENT 63, 59-71, 2010
5) Ishino M. Problems in extension of patent term for
research field
pharmaceuticals: current status following the decision of
・Establishment and development of Medical University
the Supreme Court of Japan, case no. 2009 (gyo-hi) nos.
Network for Technology Transfer
・Support of translational research
324-326. PATENT 64,59-71, 2011
6) Ishino M, Iida K. Copyright Protection of Tangible
3. Practice and theory of patent strategy for medical
Research Materials. Journal of the Japanese Group of
innovation promotion
the International Association for the Protection of
・IP-strategy in the regenerative medicine technology
development
・Copyright protection of research materials
・Strategy for the development of novel and practical
inspection tools for regenerative medicine
Intellectual Property 57(9), 584-597, 2012
7) Ishino M. Management of Intellectual Property in
Academic Medical Research. IGAKU TOSHOKAN 60(1),
23-26, 2013
8) Ishino M. A case in which unobviousness was reversed
by a misinterpretation as “exaggerated”. Journal of the
List of Main Publications from 2009 to 2013
Japanese Group of the International Association for the
1) Ishino M. Analysis of trends in iPS cell technology and
Protection of Intellectual Property 59, 2014 (in press)
related patent applications, PATENT, 62, 23-32, 2009
2) Ishino M, Mae N, Umeda S. Intellectual property strategy
of Japan Tissue Engineering Co., Ltd. PATENT, 62, 4246, 2009
13
Medical Genetics
Our department was established in April 2013, and our main interests
in research are cancer genetics and pediatric genetics. We also work
closely with the Department of Clinical Genetics in Sapporo Medical
University Hospital where we provide genetic counseling for clients.
Professor
Instructor:
Akihiro Sakurai, M.D., Ph.D.
Aki Ishikawa, M.D., Ph.D.
Interests:
Interests.
Cancer Genetics, Molecular
Pediatric Genetics, Cytogenetics
Endocrinology
1. Hereditary Endocrine Tumors
Multiple endocrine neoplasia (MEN) is an autosomal
dominant inherited endocrine tumor syndrome characterized
by tumor development in various endocrine organs.
Prevalence of MEN1 and MEN2 has been estimated to be
about 2-3/100,000, respectively. To ascertain the clinical
features of MEN and current management conditions, in 2008
we established a MEN study group designated the “MEN
Consortium of Japan” and constructed a database of
Japanese patients with MEN (1). Analysis of the database,
which consists of more than 1,000 cases, has revealed many
important features of MEN in Japan and these findings have
been reflected in recently published international clinical
guidelines (2).
a) Delay in the diagnosis of MEN1 (3)
Main tumors were identified up to 7.0 years after symptoms
appeared. In patients with typical symptoms (peptic ulcers,
urolithiasis, fasting hypoglycemia, bone fracture/loss and
amenorrhea), the mean interval between symptom
manifestation and tumor detection was extended up to 9.6
years. In particular, 21.7% of patients with amenorrhea of less
than one year’s duration were diagnosed with pituitary tumors.
In patients with peptic ulcers and urolithiasis (from parathyroid
tumors or GEPNETs), the interval was positively correlated
with age at tumor detection. The interval between tumor
detection and MEN1 diagnosis was also prolonged to
approximately four years in patients with fasting hypoglycemia
and amenorrhea. A substantial delay in the diagnosis of
symptom-related tumors and subsequent MEN1 and
inadequate screening of GEPNETs in family members were
indicated.
b) Young onset of insulinoma in MEN1 (4,5)
Insulinoma is the second most common functioning tumor in
MEN1. Among 560 registered patients to our database,
insulinoma was seen in 69 patients. Age at diagnosis of
insulinoma, 34.8 ± 16.7 yrs, was significantly younger than
that of gastrinoma (50.6 ± 14.3 yrs) and nonfunctioning tumor
(44.7 ± 13.3 yrs) in patients with MEN1. Patients diagnosed
as having insulinoma in their middle age (30-49 yrs) tended to
have a long period between the appearance of hypoglycemic
symptoms and diagnosis of the tumor. Of note, 13 patients
(24%) were diagnosed before 20 yrs of age. Such young
onset was not seen in other GEPNETs.
c) Thymic tumor in MEN1 (6)
Thymic neuroendocrine tumors have a high malignant
potency accompanying recurrence and distant metastasis.
Among 560 registered Japanese cases, Th-NET was seen in
28 (5.0%) patients. Of note, 36% of these patients (10/28)
were female; of whom only one was a smoker and the otherr
6 patients were apparent non-smokers. Age at diagnosis of
Th-NET and MEN1, tumor size and prevalence of other
MEN1-related tumors did not differ between male and female
patients. The 10-year survival probability was 0.271 ± 0.106.
Given that Th-NET is a major determinant of life expectancy
of patients, our results should alert clinicians who treat
patients with MEN1 that surveillance of Th-NET is essential
even for female patients who do not smoke.
d) Pheochromocytoma in MEN2 (7)
MEN2 is characterized by tumor development in various
endocrine organs such as the thyroid, adrenal medulla and
parathyroid. Approximately 50% of patients with MEN2
developed pheochromocytoma (PHEO) during their lifetime.
Codon 634 mutations of RET oncogene account for 76% of
patients. Earliest manifestation of PHEO was observed in
15-year-old patients with codon 634 and 918 mutations, and
in 16-year-old patients with codon 620 mutations. The average
age at diagnosis was 30.3 years for those with mutations at
codon 918, 39.8 years at codon 634, and 44.1 years at other
codons. Those who had codon 634 and 918 mutations had a
higher risk of occurrence of PHEO (more than 60%), whereas
those who had the other mutations were less likely to develop
PHEO (up to 17%). Codon specific, age dependent penetrance
for PHEO was 25% by age 30, 52% by age 50, and 88% by
age 77 in patients with mutations at codon 634. Other codon
specific, age dependent penetrance for PHEO was 25% by
age 50 at codon 611, 24% by age 52 at codon 620, 12.5% by
age 54 at codon 768, and 12% by age 45 at codon 618. Most
of the patients with codon 918 mutations were proband, and
all patients developed PHEO by age 56.
14
2. Pediatric genetics (8-10)
Genetic disorders and birth defects account for a high
percentage of the admissions in children’s hospitals.
Congenital malformations and chromosomal abnormalities
are the most common causes of infant mortality. As such, their
effects pose serious problems for perinatal health care in
Japan, which has a very low infant mortality rate. We
retrospectively reviewed charts of 900 patients who were
admitted to the high-care unit (HCU) of a major tertiary
children’s referral centers in Japan. Genetic disorders and
malformations accounted for a significant proportion of the
cases requiring admission to the HCU. Further, the rate of
recurrent admission was higher for patients with genetic
disorders and malformations than for those with acquired,
non-genetic conditions. Over the past 30 years, admissions
attributed to genetic disorders and malformations have
consistently impacted the children’s hospital. These results
reflect improvements in medical care for patients with genetic
disorders and malformations and further highlight the large
proportion of cases with genetic disorders, for which highly
specialized management is required. Moreover, this study
emphasizes the need for involvement of clinical geneticists in
HCUs at children’s hospitals.
3. Genetic variation and training effect
We assessed whether single nucleotide polymorphism
rs1042615 of the vasopressin V1a receptor altered the indices
of lifestyle-related diseases in middle-aged and older people
(mean+/-SD: 64+/-7 years), and, if so, whether it also altered
the effects of interval walking training (IWT). CC, CT and TT
carriers of rs1042615 (42, 118 and 64 men, respectively; 113,
263 and 154 women, respectively) performed IWT. We
included 5 sets of 3-minute fast walking at ≧ 70% peak
aerobic capacity for walking and 3-minute slow walking at
40% peak aerobic capacity per day for > or =4 days per week
for 5 months. Before IWT, the body mass index and diastolic
2
blood pressure (DBP) for men were 25.1+/-0.3 kg/m (mean+/2
SE) and 84+/-1 mm Hg in TT, higher than the 23.6+/-0.4 kg/m
and 78+/-1 mm Hg in CC, respectively (P<0.01), but these
differences disappeared after IWT despite similar training
achievement between groups (P>0.6). After IWT, body mass
2
index and DBP decreased in TT (-0.9+/-0.1 kg/m and -5+/-1
2
mm Hg, respectively), more than in CC (-0.5+/-0.1 kg/m and
1+/-1 mm Hg, respectively; P<0.05), with a greater decrease
in low-density lipoprotein cholesterol in TT than CC carriers
(P<0.01). The decreases in DBP and low-density lipoprotein
cholesterol were still greater in TT carriers even after
adjustment for their pretraining values. However, in the
women, these parameters before IWT and their changes after
IWT were similar among CC, CT, and TT carriers. Thus,
polymorphism rs1042615 of the V1a receptor altered both the
body mass index and DBP in middle-aged and older men and
the training-induced responses of DBP and low-density
lipoprotein cholesterol, whereas in women they did not elicit
any of these responses.
1) Sakurai A, Suzuki S, Kosugi S, Okamoto T, Uchino S,
Miya A, Imai T, Kaji H, Komoto I, Miura D, Yamada M,
Uruno T, Horiuchi K, Miyauchi A, Imamura M: Multiple
endocrine neoplasia type 1 in Japan: establishment and
analysis of a multicentre database. Clin Endocrinol (Oxf)
(2012) 76: 533-539.
2) Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H,
Ebeling P, Melmed S, Sakurai A, Tonelli F, Brandi ML:
Clinical practice guidelines for multiple endocrine
neoplasia type 1 (MEN1). J Clin Endocrinol Metab
(2012) 97: 2990-3011.
3) Yamazaki M, Suzuki S, Kosugi S, Okamoto T, Uchino S,
Miya A, Imai T, Kaji H, Komoto I, Miura D, Yamada M,
Uruno T, Horiuchi K, Sato A, Miyauchi A, Imamura M,
Sakurai A: Delay in the diagnosis of multiple endocrine
neoplasia type 1: typical symptoms are frequently
overlooked. Endocr J (2012) 59: 797-807.
4) Sakurai A, Yamazaki M, Suzuki S, Fukushima T, Imai T,
Kikumori T, Okamoto T, Horiuchi K, Uchino S, Kosugi S,
Yamada M, Komoto I, Hanazaki K, Itoh M, Kondo T,
Mihara M, Imamura M: Clinical features of insulinoma in
patients with multiple endocrine neoplasia type 1:
analysis of a database of MEN Consortium of Japan.
Endocr J (2012) 59: 859-866.
5) Hanazaki K, Sakurai A, Munekage M, Okabayashi T,
Imamura M: Effective perioperative management of
MEN1-associated insulinomas. Arch Surg (2012) 147:
991-992.
6) Sakurai A, Imai T, Kikumori T, Horiuchi K, Okamoto T,
Uchino S, Kosugi S, Suzuki S, Suyama K, Yamazaki M,
Sato A: Thymic neuroendocrine tumor in multiple
endocrine neoplasia type 1: female patients are not rare
exceptions. Clin Endocrinol (Oxf) (2013) 78: 248-254.
7) Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S,
Kikumori T, Sakurai A, MEN Consortium of Japan: High
penetrance of pheochromocytoma in multiple endocrine
enneoplasia type 2 caused by germline RET 634
mutation in Japanese patients. Eur J Endocrinol (2013)
168: 683-687.
8) Ishikawa A, Enomoto K, Tominaga M, Saito T, Nagai J,
Furuya N, Ueno K, Ueda H, Masuno M,Kurosawa K.
Pure duplication of 19p13.3. Am J Med Genet A. (2013)
161: 2300-2304.
9) Enomoto K, Kishitani Y, Tominaga M, Ishikawa A, Furuya
N, Aida N, Masuno M, Yamada K, Kurosawa K.
Expression analysis of a 17p terminal deletion, including
YWHAE, but not PAFAH1B1, associated with normal
brain structure on MRI in a young girl. Am J Med Genet
A (2012) 158A: 2347-2352.
10) Soneda A, Teruya H, Furuya N, Yoshihashi H, Enomoto
K, Ishikawa A, Matsui K, Kurosawa K. Proportion of
malformations and genetic disorders among cases
encountered at a high-care unit in a children’s hospital.
Eur J Pediatr (2012) 171: 301-305.
11) Masuki S, Mori M, Tabara Y, Miki T, Sakurai A, Morikawa M,
Miyagawa K, Higuchi K, Nose H, Shinshu University Genetic
Research Consortium: Vasopressin V1a receptor
polymorphism and interval walking training effects in middleaged and older people. Hypertension (2010) 55: 747-754.
15
2 Clinical Medical Sciences(Subjects)
Pharmaceutical Health Care and Sciences
（Div. of Hospital Pharmacy）
Patient safety and improving medication safety, drug information
service,
therapeutic
drug
monitoring
service,
and
bedside
pharmaceutical care service comprise our main activities. Additionally,
we are conducting research in chemotherapy-induced renal
dysfunction and drug-induced torsade de points in response to some
inpatients who have voiced dissatisfaction about their medication.
Professor
Atsushi Miyamoto, M.P., Ph.D.
Interests:
Pharmaceutical Health Care and Sciences,
Patient safety and improving medication safety
The decreased atazanavir plasma concentration
suggested that interactions between atazanavir and tenofovir
were exacerbated by an increase in TDF plasma concentration
caused by renal dysfunction (10). Controlling vancomycin
concentrations to <20ug/mL protects patients against renal
dysfunction. Linezolid is an appropriate initial therapy for
severe infections in patients with acute renal dysfunction, but
monitoring of platelet counts is essential after initiation of
therapy (11).
1)Katakura M, Toda N, Kunimoto Y, Takahashi K, Nakamura
K, Masuko H, Sasaki N, Yamazaki K, Araya N, Fujimori
M, Okahara K, Funayama M, Nakata H, Noda N,
Miyamoto A. Error prevention through written check of
medicine identification codes and total numbers. Jpn J
Pharm Health Care Sci (2008) 34(11): 997-1003 (in
Japanese).
2) Onogi H, Ishigaki S, Nakagawasai O, Arai-Kato Y, Arai Y,
Watanabe H, Miyamoto A, Tan-no K, Tadano T. Influence
of memantine on brain monoaminergic neurotransmission
parameters in mice: Neurochemical and Behavioral
study. Biol Pharm Bull (2009) 32: 850-855.
3) Shiozaki Y, Hashimoto A, Sasaki N, Shimamoto K,
Miyamoto A. The follow-up survey of medicinal drugs
associated with QT prolongation, and a new software for
avoidance and early recognition of drug-induced QT
prolongation. Sapporo Med J (2010) 79(1-6): 13-19 (in
Japanese).
4) Makino S, Fujii S, Kunimoto Y, Nakamura K, Miyamoto A.
Changing circumstances in the field felt and asked for
correspondence. Rx Info (2011) 17(10): 90-94 (in
Japanese).
5) Miyamoto A. The manner of medicinal treatment and
crisis management of medical supply systems for largescale disasters. Sapporo Med J (2011) 80(1-6): 7-13 (in
Japanese).
6) Miyamoto A. High-risk drugs. Nippon Rinsho (2012)
70(Suppl 6): 766-770 (in Japanese).
7) Miyamoto A. Promotion of the team medical treatment by
Ward placement of pharmacists. Hospital pharmacist
business promotion case studies. Medicine seminar
information education center, (2013) Tokyo 22-27 (in
Japanese).
8) Kitagawa M, Miyamoto A. High-risk drugs. Doctors and
Pharmacists for Drug Side Effects Handbook.
Nipponrinshosha, (2013) Tokyo 11-15 (in Japanese).
9) Nakamura K, Okita K, Matsuda Y, Takahashi K, Noda N,
Nakata H, Ishida A, Miyamoto A. Evaluation and
investigation of usage granulocyte-colony stimulating
factor (G-CSF) in outpatient cancer chemotherapy. J Jpn
Soc Hos Pharm (2013) 49(3): 251-255 (in Japanese).
10) Kunimoto Y, Yasui H, Touda N, Okazaki M, Nakata H,
Noda N, Ikeda H, Hayashi T, Takahashi S, Shinomura Y,
Ishida T, Miyamoto A. Coadministration of tenofovir
decreased atazanavir plasma concentration after
unilateral nephrectomy. J Infect Chemother (2013) 19:
750-753.
11) Fujii S, Takahashi S, Makino S, Kunimoto Y, Nakata H,
Noda N, Sakurai K, Miyamoto A. Impact of vancomycin or
linezolid therapy on development of renal dysfunction
and thrombocytopenia in Japanese patients. Chemotherapy
(2013) 59: 319-324.
16
Surgical Pathology
Our research activities are primarily based on routine surgical
pathology practices consisting of histopathology, cytopathology and
autopsy. We strive to contribute to greater accuracy in diagnoses and
improved patient treatment by analyzing pathological features in a
variety
of
soft
tissue
tumors
and
carcinomas
using
immunohistochemical and molecular techniques.
Professor
Instructor
Tadashi Hasegawa, M.D., Ph.D.
Katsuya Nakanishi, M.D., Ph.D.
Interests:
Shintaro Sugita, M.D., Ph.D.
Soft tissue tumor,
Jiro Ogino, M.D., Ph.D.
Gastrointestinal stromal tumor,
Molecular diagnosis
1. Molecular diagnosis of soft tissue tumor
mesenchymal tumors of the GI tract, including GISTs, with the
We have searched fusion gene mutations using
use of an immunohistochemical panel is high, despite the use
fluorescence in situ hybridization (FISH) analysis on the
of a tissue microarray (TMA). PDGFRA immunophenotyping,
histological sections for the application to daily pathological
although not highly reproducible or specific, may predict the
diagnosis of soft tissue tumors. Interphase FISH using
presence of PDGFRA mutations in KIT-negative or weakly
commercially available or in-house, dual-color split-signal and
positive GISTs. In consideration of the therapeutic benefit of
fusion-signal probes is sensitive and specific for detecting the
imatinib mesylate in the treatment of GISTs, mutation analysis
chimeric gene rearrangement and is useful in the routine
will be required (5).
clinical diagnosis of extraskeletal myxoid chondrosarcoma,
In order to standardize Ki-67 immunohistochemistry, we
angiomatoid
assessed interobserver and interlaboratory variability of the
fibrous
histiocytoma
and
mesenchymal
chondrosarcoma (1-3).
Ki-67 labeling index and Ki-67 score for GISTs and
We conducted FISH analysis on 280 cases of soft tissue
leiomyosarcomas among 8 general pathologists from different
and other tumors. The detection rate of the FISH split-signal
institutes. We used digital image analysis of TMAs that were
was 84% for the translocation-associated soft tissue tumors,
immunostained with antibodies for Ki-67 according to the
such as Ewing sarcoma, synovial sarcoma, alveolar
technique
rhabdomyosarcoma, myxoid liposarcoma, clear cell sarcoma
reproducibility of a 10% cut-off value for the Ki-67 labeling
and so forth. Positive split signals from EWSR1, SS18 and
index for predicting the prognosis of GISTs is relatively high;
FOXO1A probes were detected in 3% of various histological
however, there is an urgent need to standardize the staining
types of carcinoma, lymphoma, melanoma, meningioma and
technique used among regional hospitals, which will result in
soft tissue tumors. As these results demonstrate the high
optimal clinical management (6).
sensitivity and specificity of FISH, we concluded FISH to be a
We showed that the expression of potassium channel
useful pathological diagnostic adjunct for definite and
tetrmerization domain-containing 12 (KCTD12), which was
differential diagnosis of soft tissue tumors (4).
discovered by a proteomics approach, is associated with
2. Gastrointestinal stromal tumor
high-risk behavior of GISTs (7,8). We then examined the
We assessed interobserver variability of 7 general pathologists
distribution and expression of this protein by immunostaining
with respect to the histological diagnosis of gastrointestinal
with a commercially available polyclonal KCTD12 antibody in
stromal tumors (GISTs) and other spindle-cell tumors. The
GISTs and other types of malignancies to clarify its diagnostic
overall
and clinical significance. Overall, KCTD12 expression was
concordance
with
the
original
diagnosis
in
used
at
each
participating
institute.
The
17
specific for GISTs from neoplastic and non-neoplastic adult
immunohistochemistry to standardize the diagnosis of
tissues other than the brain and served as a predictor of GIST
gastrointestinal stromal tumors. Pathol Int (2010) 60:
recurrence. These findings suggest that KCTD12 is a useful
707-713.
and reliable biomarker for both the diagnosis and prognosis of
6) Ogino J, Asanuma H, Hatanaka Y, Matsuno Y, Gotoda H,
GIST (9).
Muraoka S, Tsuji T, Fukazawa Y, Yamashiro K, Kondo N,
3. Molecular targeted therapy for soft tissue tumors
Iwaki H, Miyokawa N, Hasegawa T. Validity and
To explore promising molecular targeting agents with
reproducibility of Ki-67 assessment in gastrointestinal
antiangiogenic effects, we examined the correlations between
stromal tumors and leiomyosarcomas. Pathol Int (2013)
6 immunohistochemical biomarkers—KIT, PDGFRA, PDGFRB,
63: 102-107.
VEGFR-1, VEGFR-2 and VEFR-3—and overall survival (OS)
7) Kikuta K, Gotoh M, Kanda T, Tochigi N, Shimoda T,
in 34 patients with angiosarcoma. A significant positive
Hasegawa T, Katai H, Shimada Y, Suehara Y, Kawai A,
correlation was observed between short OS and the
Hirohashi S, Kondo T. Pfetin as a prognostic biomarker in
immunohistochemical score for PDGFRB and between long
gastrointestinal
OS and the immunohistochemical score for VEGFR-2. We
antibody and external validation study in multiple clinical
therefore expect that antiangiogenic agents, particularly
facilities. Jpn J Clin Oncol (2010) 40: 60-72.
stromal
tumor:
novel
monoclonal
molecularly targeted drugs for PDGFRB and VEGFR kinases,
8) Kubota D, Orita H, Yoshida A, Gotoh M, Kanda T, Tsuda
may be promising candidates for drug development either for
H, Hasegawa T, Katai H, Shimada Y, Kaneko K, Kawai A,
use as single agents or in combination with paclitaxel for
Kondo T. Pfetin as a prognostic biomarker for
treatment of patients with angiosarcoma (10).
gastrointestinal stromal tumor: validation study in multiple
clinical facilities. Jpn J Clin Oncol (2011) 41: 1194-1202.
9) Hasegawa T, Asanuma H, Ogino J, Hirohashi Y,
1) Noguchi H, Mitsuhashi T, Seki K, Tochigi N, Tsuji M,
Shinomura Y, Iwaki H, Kikuchi H, Kondo T. Use of
Shimoda T, Hasegawa T. Fluorescence in-situ hybridization
potassium channel tetramerization domain-containing 12
analysis using EWSR1 and NR4A3 probes in extraskeletal
as a biomarker for diagnosis and prognosis of
myxoid chondrosarcomas. Hum Pathol (2010) 41: 336-
gastrointestinal stromal tumor. Hum Pathol (2013) 44:
342.
1271-1277.
2) Matsumura T, Yamaguchi T, Tochigi N, Wada T, Yamashita
10) Yonemori K, Tsuta K, Ando M, Hirakawa A, Hatanaka Y,
T, Hasegawa T. Angiomatoid fibrous histiocytoma
Matsuno Y, Chuman H, Yamazaki N, Fujiwara Y,
including cases with pleomorphic features analysed by
Hasegawa T. Contrasting prognostic implications of
fluorescence in situ hybridization. J Clin Pathol (2010)
platelet-derived growth factor receptor-β and vascular
63: 124-128.
endothelial growth factor receptor-2 in patients with
3) Nakayama R, Miura Y, Ogino J, Susa M, Watanabe I,
angiosarcoma. Ann Surg Oncol (2011) 18: 2841-2850.
Horiuchi K, Anazawa U, Toyama Y, Morioka H, Mukai M,
Hasegawa T. Detection of HEY1-NCOA2 fusion by
formalin-fixed
Key words: Surgical pathology, Molecular diagnosis,
paraffin-embedded tissues as a possible diagnostic tool
Soft tissue tumor, Gastrointestinal stromal tumor,
for mesenchymal chondrosarcoma. Pathol Int (2012) 62:
Molecular targeted therapy
fluorescence
in-situ
hybridization
in
823-826.
4) Miura Y, Keira Y, Ogino J, Nakanishi K, Noguchi H, Inoue
T, Hasegawa T. Detection of specific genetic abnormalities
by fluorescence in situ hybridization in soft tissue tumors.
Pathol Int (2012) 62: 16-27.
5) Ogino J, Asanuma H, Sakurai S, Matsuno Y, Miyokawa
N, Yamashiro K, Fukazawa Y, Muraoka S, Iwaki Y, Kondo
N, Hasegawa T. Use of tissue microarrays and
18
Obstetrics and Perinatal Medicine
Our departmental goal is to provide the best healthcare for women
with an advanced commitment to education and research. Our
subspecialities include reproductive endocrinology and infertility and
maternal-fetal medicine. Current research interests are infertility, the
molecular biological study of obstetrical problems for diagnosis and
treatment, the clinical study of endoscopic surgery, and the molecular
endocrinological study of ovaries.
Professor
Assistant Professor
Instructor
Tsuyoshi Saito, M.D., Ph.D.
Shin-ichi Ishioka, M.D., Ph.D.
Masaki Kobayashi, M.D.
Interests:
Risa Igarashi, M.D.
Associate Professor
Obstetrics and Oncology
Toshiaki Endo, M.D., Ph.D.
Interests:
Reproductive endocrinology and
Obstetrics
1. Clinical research
a) Gynecologic surgery, in particular endoscopic surgery,
which includes laparoscopic surgery, resectoscopy and
falloposcopic tuboplasty, is performed at our clinic, and each
modified technique is quite sophisticated. Clinical studies on
new operative procedures for these endoscopic operations
have been performed.
b) Assisted reproductive technologies such as IVF-ET, embryo
cryopreservation and intracytoplasmic sperm injection have
been performed, especially for high-risk patients.
c) Polycystic ovary syndrome and ovarian hyperstimulation
syndrome have been studied to make clear their etiologies
and to find new treatments for them.
d) Management of gynecologic cancer in pregnancy is a
challenge not only for patients, but also for obstetricians
because we have to take both the mother’s and fetus’s lives
into consideration. Furthermore, both are at high risk for
various pregnancy-related complications such as preterm
labor and chorioamnionitis. We are working hard for such
patients to improve their pregnancy outcomes and their
prognosis.
e) Placenta accrete is one of the most serious obstetrical
diseases, and preoperative diagnosis of this disease is
extremely difficult. We are trying to diagnose this disease
preoperatively by using MRI and ultrasonography. Contrast
MRI and ultrasonography during the operation might have an
impact on the diagnosis of this disease. Operative
improvement to reduce the amount of bleeding for this
condition is also being studied.
f) Operative improvement for better wound healing after
cesarean sections is being studied.
g) High-risk pregnancies involving conditions such as
pregnancy induced hypertension, placenta previa and
placenta accrete have been extensively treated throughout
Hokkaido.
h) The NICU (neonate intensive care unit) section is well
established for high-risk neonates.
2. Reproductive endocrinology
We have studied ovarian physiology and pathology
related to reproductive endocrinology. Recently, we have
found some mechanisms of structural involution of the corpus
luteum. Using a treated rat model, we found that MMP
activation and apoptosis are two major phenomena occurring
during structural luteolysis. MMP-2 activated with MT1-MMP
and MT-1MMP itself caused remodeling of the extracellular
matrix in corpus luteum. We have also investigated the
mechanisms of ovarian hyperstimulation syndrome (OHSS).
VEGF is known to be a pivotal factor in OHSS. We found that
continuation of GnRHa for some days after hCG injection
significantly reduced VEGF in the ovaries of the rat OHSS
model. The mechanism of anovulation in PCOS patients is
still unknown. Our experiments showed that anovulation of
PCO could be caused by apoptosis and elevation of MT1MMP expression in the ovaries. We are also studying the
relationship between insulin resistance and anovulation, and
genetic polymorphism in PCOS patients.
3. Mechanisms of intrauterine growth restriction
Intrauterine growth restriction (IUGR) has a multifactorial
pathogenesis and is an important cause of peritoneal mortality.
Placental findings are thought to indicate the presence of
extensive placental ischemia resulting from occlusion of the
spiral artery. These findings suggest that ischemia-reperfusion
(I/R) injury is possibly a pivotal mechanism for IUGR. We
have investigated the effects of I/R on placental functions of
IUGR rats.
4. Serum markers for the preoperative diagnosis of
placenta accrete.
Placenta accrete is one of the most serious diseases
among pregnant woman. However, it is impossible to diagnose
this disease preoperatively. Invasion of trophoblastic cells to
the myometrium is thought to activate various invasion-related
genes, and it produces various invasion-related proteins.
Using genomic and proteomic techniques, we are looking for
such proteins as serum markers for the detection of this
disease.
5. Early detection of preeclampsia
Hypoxic changes in the placenta are thought to be the
main cause of preeclampsia. We investigated the changes of
19
apoptosis related proteins induced by hypoxia in trophoblastic
cells accompanied by increased expression of Bcl-x,
caspase-3 and 9, Hsp70, PTEN and Bag-1. Those proteins or
related proteins may be key molecules for the early detection
of preeclampsia.
6. Norovirus infection in gastroenteritis
Norovirus is a major cause of acute nonbacterial
gastroenteritis worldwide. Recently, several sporadic cases
due to naturally occurring recombinant norovirus have been
reported.
In January 2000, there was an outbreak of gastroenteritis
in an infant home in Sapporo, Japan. The recombination of
NV/GII was analyzed using a phylogenetic tree and nucleotide
identity.
1) Baba T, Endo T, Kitajima Y, Kamiya H, Moriwaka O, Saito
T. Spontaneous ovarian hyperstimulation syndrome and
pituitary adenoma: incidental pregnancy triggers a
catastrophic event. Fertil Steril. (2009) Jul 92(1):390.e13.
2) Ishioka S, Ezaka Y, Endo T, Nagasawa K, Shimizu A,
Sato A, Inoue M, Saito T. Outcomes of planned delivery
delay in pregnant patients with invasive gynecologic
cancer. Int J Clin Oncol. (2009) Aug 14(4): 321-5.
3) Baba T, Endo T, Sata F, Nagasawa K, Honnma H, Kitajima
Y, Hayashi T, Manase K, Kanaya M, Moriwaka O, Kamiya
H, Yamada H, Minakami H, Kishi R, Saito T. The
contributions of resistin and adiponectin gene single
nucleotide polymorphisms to the genetic risk for polycystic
ovary syndrome in a Japanese population. Gynecol
Endocrinol. (2009) Aug 25(8): 498-503.
4) Endo T, Hayashi T, Simizu A, Matsuura M, Mizuuchi M,
Nagasawa K, Ezaka Y, Baba T, Ishioka S, Saito T.
Successful Uterus-Preserving Surgery for Treatment of
Chemotherapy-Resistant Placenta Increta Gynecol
Obstet Invest. (2009) Nov 28;69(2):112-115.
5) Kishi R, Sasaki S, Yoshioka E, Yuasa M, Sata F, Saijo Y,
Kurahashi N, Tamaki J, Endo T, Sengoku K, Nonomura
K, Minakami H; for the Hokkaido Study on Environment
and Children’s Health. Cohort Profile: The Hokkaido
Study on Environment and Children's Health in Japan. Int
J Epidemiol. (2010)
6) Honnma H, Endo T, Kiya T, Shimizu A, Nagasawa K,
Baba T, Fujimoto T, Henmi H, Kitajima Y, Manase K,
Ishioka S, Ito E, Saito T. Remarkable features of ovarian
morphology and reproductive hormones in insulinresistant Zucker fatty (fa/fa) rats. Reprod Biol Endocrinol.
8-73. (2010)
7) Iwami N, Ishioka S, Endo T, Baba T, Nagasawa K,
Takahashi M, Mizunuma M, Saito T. CASE REPORT:
First case of vaginal radical trachelectomy in a pregnant
Japanese woman Int. J. Clin. Oncol. (2011) 16(6): 737-40.
8) Honnma H, Hashiba Y, Asada Y, Endo T. Failure of
triggering oocyte maturation with a GnRH agonist in
polycystic ovary syndrome: two case reports. Eur J
Obstet Gynecol Reprod Biol. (2011)157(2):239-40.
9) Baba T, Endo T, Ikeda K, Shimizu A, Honnma H, Ikeda H,
Masumori N, Ohmura T, Kiya T, Fujimoto T, Koizumi M,
Saito T. Distinctive Features of Female-to-Male
Transsexualism and Prevalence of Gender Identity
Disorder in Japan. J. Sex. Med. (2011) 8(6):1686-93.
10) Endo T, Nagasawa K, Umemura K, Baba T, Henmi H,
Saito T. A remarkably easy knot tying technique for single
TM
incision laparoscopic surgery using the SILS Port for
gynecological diseases. J Minim Invasive Gynecol.
(2011)18(4):500-2.
11)Honnma H, Hashiba Y, Asada Y, Endo T. Failure of
triggering oocyte maturation with a GnRH agonist in
polycystic ovary syndrome:two case reports. Eur J Obstet
Gynecol Reprod Biol. (2011)157:239-40.
12)Honnma H, Baba T, Sasaki M, Hashiba Y, Oguri H,
Fukunaga T, Endo T, Asada Y. Different ovarian response
by age in an anti-Müllerian hormone-matched group
undergoing in vitro fertilization. J Assist Reprod Genet.
(2012) 29(2):117-25.
13)Baba T, Endo T, Ikeda K, Takenami N, Shimizu A,
Morishita M, Honnma, H, Ikeda H, Saito T. Simultaneous
presentation of tubal and primary abdominal pregnancies
following clomiphene citrate treatment. Arch Gynecol
Obstet. (2012) 286(2):395-8.
14) Kanaya M, Nagasawa K, Baba T, Ishioka S, Yamada H,
Endo T, Saito T. A successful birth of severe secondary
recurrent miscarriage case after a decline of
phosphatidylserine-dependent anti-prothrombin antibody
by intravenous immunoglobulin administration. Open
Journal of Obstetrics and Gynecoloty (in press))
15)Kanaya M, Baba T, Kitajima Y, Ikeda K, Shimizu A,
Morishita M, Honnma H, Endo T, Saito T. Continuous
follicle-stimulating hormone exposure from pituitary
adenoma causes periodic follicle recruitment and atresia,
which mimics ovarian hyperstimulation syndrome. Int J
Womens Health. (2012) 4:427-31.
16)Honnma H, Baba T, Sasaki M, Hashiba Y, Ohno H,
Fukunaga T, Endo T, Saito T, Asada Y. Trophectoderm
morphology significantly affects the rates of ongoing
pregnancy and miscarriage in frozen-thawed singleblastocyst transfer cycle in vitro fertilization. Fertil Steril.
(2012)98:361-7.
17)Endo T, Baba T, Sugio A, Morishita M, Takahashi M,
Akashi Y, Ishioka S, Tachi N, Imai T, Tamakawa M, Saito
T. A myotonic dystrophy 1 patient complicated with
placental adherence after miscarriage of one dichorionic
diamniotic twin following her tenth in vitro fertilization and
embryo transfer. Arch Gynecol Obstet. (2012) 6:1605-8.
18)Honnma H, Baba T, Sasaki M, Hashiba Y, Oguri H,
Fukunaga T, Endo T, Asada Y. Serum anti-mullerian
hormone levels affect the rate of ongoing pregnancy after
in vitro fertilization. Reprod Sci. (2012) 20(1):51-9.
19) Takada S, Ishioka SI, Endo T, Baba T, Morishita M, Akashi
Y, Mizuuchi M, Adachi H, Kim M, Saito T. Difficulty in the
management of pregnancy after vaginal radical
trachelectomy. Int J Clin Oncol. 2012 Oct 3. [Epub ahead
of print])
20) Ikeda K, Baba T, Noguchi H, Nagasawa K, Endo T, Kiya
T, Saito T. Excessive androgen exposure in female-tomale transsexual persons of reproductive age induces
hyperplasia of the ovarian cortex and stroma but not
polycystic ovary morphology. Hum Reprod.(2013)28(2):
453-61.
21) Yamada T, Morikawa M, Yamada T, Kishi R, Sengoku K,
Endo T, Cho K, Minakami H. First-trimester serum folate
levels and subsequent risk of abortion and preterm birth
among Japanese women with singleton pregnancies.
Arch gynecol Obstet. 287:9-14(2013)
22) Asada Y, Itoi F, Honnma H1, Takiguchi S, Fukunaga N,
Hashiba Y, Baba T, Endo T. Failure of GnRH agonisttriggered oocyte maturation: its cause and management.
J Assisu Reprod Genet. (2013) 30:581-585
23) Baba T, Endo T, Ikeda K, Shimizu A, Morishita M, Kuno Y,
Honnma H, Kiya T, Ishioka S, Saito T. Assisted
reproductive technique increases the risk of placental
polyp.(Gynecol Endocrinol.(2013)29(6):611-4.
24) Kim M, Ishioka S, Endo T, Baba T, Akashi Y, Morishita M,
Adachi H, Saito T. Importance of uterine cervical cerclage
to maintain a successful pregnancy for patients who
undergo vaginal radical trachelectomy. International
journal of clinical oncology, DOI 10.1007/s10147-0130631- 9 Oct.2013 Epub)
20
Plastic surgery is the restoration of form and function. The
development of many kinds of treatments is required in this field,
because each person has individual symptoms. Our research aims
to: 1) develop and investigate various ways of surgical treatment for
facial and body defects; 2) explore clinical research of congenital
auricular deformities for both disease and treatment; 3) conduct
basic medical research regarding keloid cell cultures.
Professor
Assistant Professor
Takatoshi Yotsuyanagi, M.D., Ph.D.
Tamotsu Saito, M.D., Ph.D.
Interests: Microtia, Congenital deformities,
Interests:
Microvascular surgery
Chronic ulcers
Facial
1. Congenital auricular deformities
We have been conducting research on ideal treatments
for congenital auricular deformities, especially microtia. At
present, there is debate about whether microtia has a
multifactorial inheritance. In order to study possible hereditary
factors, we conducted and reported the result of a
questionnaire survey (1). We found that microtia is more
common in men than in women as male:female of 3:2, and in
right side than in others as left:right:bilateral of 3:6:1. Microtia
is often accompanied by congenital heart disease, cleft lip
and/or palate, vertebral defects, and anomalies of extremities.
We found a tendency toward its development in infants born
at a low birth weight with mothers of a high maternal age, but
it is not possible to identify these as clear causes of microtia.
We consider it unlikely that the hereditary pattern of microtia
is multifactorial, as there was only one finding in this survey.
We also reported on treatments for rare auricular
deformities. One example of such a deformity is Mozart ear,
the study of which is currently insufficient. Mozart ear is mainly
characterized by the bulging appearance of the anterosuperior
margin of auricle, a convexly protruded cavum conchae, and
a slit-like narrowing of the orifice of the external auditory
meatus. The auricle was treated with a technique in which the
deformed cartilage of the cavum conchae was dissected out,
turned over, and replaced in as a free graft of cartilage.
Results from this treatment were positive (2).
2. Reconstruction of facial defects by using various flaps
For the reconstruction of facial defects caused by various
reasons such as trauma or tumor excisions, we are working
hard to improve surgical results not only functionally, but also
aesthetically by the use of various flaps (3-8).
Various methods of treating lower lip defects have been
reported, whereas the choice of reconstruction method for
large defects of the lower lip is often difficult. We attempted to
resolve this problem by using a novel V-Y advancement flap,
or the modified Estlander flap (3,4). A V-Y advancement flap
from the submandibular region is a useful technique to
reconstruct a wide horizontal defect of the lower lip. However,
the flap is insufficiently mobile and the vermilion is thin,
resulting in a sagging lip. We developed a new way to raise
the flap (3). The skin side of the flap is undermined, and the
orbicularis oris muscles are preserved on both sides as
pedicles. The flap is then raised as a bipedicled
musculocutaneous flap, which has adequate movement. After
the flap has been sutured, the superior margin of the flap is
de-epithelized and used to create the volume of the vermilion
border. The mucosal flap is also used to reconstruct the
vermilion border. The appearance was almost cosmetically
Instructor
injuries,
Ken Yamashita, M.D.
Burns,
Makoto Yamauchi, M.D., Ph.D.
satisfactory. Alternatively, if a large defect of the lower lip with
oral commissure is presented, we choose a reconstruction
method in which the entire upper lip is incised and extended,
a portion of which is reflected as a traditional Estlander flap
(4). Four cases were treated using this method, and the
wound healed well without complication. When reconstructing
a red lip that has a defect in one half, we choose a technique
that uses the remaining area of the red lip (5). A horizontal
incision is made in the dry lip of the remaining red lip, from the
outermost part at the corner of the mouth to the defect,
separating the upper part from the lower part. The flap is
elevated from the outer side with some of the orbicularis oris
muscle and rotates toward the defect. The donor site is
primarily closed. Sphincter function and sensitivity of the red
lip recovered completely and the symmetrical balance of the
red lip was well maintained.
For treating the other defects of the face, when
considering reconstruction of small-sized defects, we reported
on the effects of elevating the reverse superficial temporal
artery (STA) flap from the preauricular region (6). The flap,
including the STA under the skin island in the preauricular
region and the temporoparietal fascia around the superficial
temporal vessels in the temporal region, is retrogradely
elevated. We treated six cases with this flap and the results
were cosmetically good without complications. As compared
to the retroauricular flap, our method is easier to perform and
the flap has a reliable blood circulation. When the defect
exists in the lower two-thirds of the face, reverse facial artery
flap, elevated from the submandibular region has good results
(7). This method creates a flap that includes only the platysma
under the skin island, without either the submental or facial
artery. However, above the superior border of the skin island,
the flap includes the facial artery along with subcutaneous
soft tissue. The blood circulation of the skin island is in a
random pattern and that of the subcutaneous pedicle is in an
axial pattern. Four cases were treated using this method
without complications. We reconstructed the various defect
using these techniques, such as severe defect after purpura
fulminans, and obtained good results (8).
3. Surgical treatment for various defects of the body
Surgical indication of flaps is applicable to the various
defects of the body (9,10). For example, we developed the
technique for reconstruction along the large defect with the
entire umbilicus and surrounding skin after tumor removal (9).
The two subcutaneous pedicle flaps with a rectangular shaped
skin incision on cranial and caudal skin areas around the
defect were made to form the reconstructed umbilical wall.
This technique made it possible to create an umbilicus with a
21
deep-seated umbilical crater with sufficient blood supply on
any size.
We also reconstruct the severe defect using free flaps,
such as the foot ulcer with Buerger disease (10). Buerger
disease is a limb-threatening condition occurring in young
smokers, and its treatment has been a challenging problem.
Combined surgery for revascularization and free-tissue
transfer for Buerger disease is an aggressive and attractive
option. This complex surgery enables successful treatment of
tissue loss caused by ischemia. We performed this operation,
and attempted to salvage a limb from amputation.
4. Treatment for burn patients
To investigate the treatment of burn patients is important
(11-13). Deformity or loss of the ear may be caused by
superficial dermal burns or deep burns. The depth of ear
burns is progressive because the ear protrudes from the head
and is easily affected by external pressure. Therefore, burn
wounds of the ear should be debrided as early as possible
and covered with healthy tissues before irreversible changes
of the cartilage occur. We describe a surgical procedure for
treatment of the extensively burned ear. We have consistently
obtained satisfactory outcomes with this technique (11).
Burns to the dorsum of the fingers and hands also require
debridement and immediate coverage by skin flaps at the
earliest opportunity. In such situations, the conventional
abdominal wall flap is still commonly used because it is a
convenient and safe technique, but it also has several
problems due to its thickness or bulkiness. We have developed
a modified thin abdominal flap (glove flap), which attains good
results (12). This modified flap makes it possible to acquire
functionally and aesthetically better results within a short time.
For the burn scar contracture, we describe a novel
technique to release contracture effectively for any wide scars
using a new design called double combined Z-plasty (13).
The main limb of Z is set to incise the wide scar, and this main
limb is shared as a peripheral limb by two other Z-plasty
designs. Two triangular intact skin flaps can be inserted into
the wide scar from both sides, making it possible to release
contracture. We performed this technique on eight patients,
and all wounds healed well and scar contracture was
satisfactorily released. Compared to conventional Z-plasty,
this procedure is very useful for wide-scar contracture.
5. Basic research
A collagen sponge is one of the medical materials
frequently used in clinical medicine. However, the problem of
prion disease harmfully affects the usage of mammals-derived
medical materials. Since there have been no reports about
prion disease occurring in marine products, we produced a
collagen and elastin sponge (CES) made from salmon, and
investigated whether the CES could be a substitute for
mammalian collagen sponges. Fibroblasts were seeded in
the CES to examine whether the CES could be used as a
scaffold for tissue engineering. The results of the WST-1
assay showed that the fibroblasts were viable and were well
proliferated in the CES. To examine whether the CES could
be used as an artificial dermis, the CES and TERUDERMIS
were grafted onto the skin defects on the dorsum of rats. The
histological findings of these ulcers showed non-significant
differences between the CES and TERUDERMIS. Due to
their safety and abundance, and also because they exhibited
the same abilities as TERUDERMIS, it may be possible to
consider biomedical materials derived from marine products
as a substitute for those derived from mammals (14).
Keloids are benign dermal fibrotic tumors arising during
the sound healing process. The mechanisms of keloid
formation and development still remain unknown. Resveratrol,
a dietary compound, has anticancer properties and, from
recent studies, it has been suggested that resveratrol may
have an antifibrogenic effect on organs such as the liver and
kidney. Based on this idea, we investigated its effect on the
regulation of extracellular matrix expression, proliferation, and
apoptosis of keloid fibroblasts. Type I collagen, α-smooth
muscle actin, and heat shock protein 47 expression decreased
in resveratrol-treated keloid fibroblasts in a dose-dependent
manner. We also demonstrated that it suppressed their
proliferation and induced apoptosis of the fibroblasts.
Conversely, resveratrol did not decrease type I collagen
α-smooth muscle actin or heat shock protein 47 mRNA
expression in normal skin fibroblasts and barely suppressed
cell proliferation. Our data indicate that resveratrol may have
an antifibrogenic effect on keloid fibroblasts without any
adverse effects on normal skin fibroblasts, suggesting the
potential application of resveratrol for the treatment of keloids
(15).
List of Main Publications from 2009-2013
1) Yamauchi M, Yotsuyanagi T, Ikeda K, Yoshikawa M,
Urushidate S, Mikami M, Kamo K. Clinical and genetic
analysis of microtia in Japan. J Plast Surg Hand Surg.
(2012)46:330-334
2) Yamashita K, Yotsuyanagi T, Saito T, Isogai N, Mori H,
Itani Y. Mozart ear: diagnosis, treatment, and literature
review. Ann Plast Surg. (2011)67:547-550
3) Urushidate S, Yokoi K, Higuma Y, Mikami M, Watanabe Y,
Saito M, Saito Y, Yamauchi M, Yotsuyanagi T. New way to
raise the V-Y advancement flap for reconstruction of the
lower lip: bipedicled orbicularis oris musculocutaneous
flap technique. J Plast Surg Hand Surg. (2011)45:66-71
4) Yamauchi M, Yotsuyanagi T, Ezoe K, Saito T, Yokoi K,
Urushidate S. Estlander flap combined with an extended
upper lip flap technique for large defects of lower lip with
oral commissure. J Plast Reconstr Aesthet Surg. 62:9971003(2009)
5) Suda T, Yotsuyanagi T Ezoe K, Saito T, Ikeda K, Yamauchi
M, Arai K. Reconstruction of a red lip that has a defect in
one half, using the remaining red lip. J Plast Reconstr
Aesthet Surg. 62:e570-573(2009)
6) Yamauchi M, Yotsuyanagi T, Yamashita K, Ikeda K,
Urushidate S, Mikami M. The reverse superficial temporal
artery flap from the preauricular region, for the small
facial defects. J Plast Reconstr Aesthet Surg.
(2012)65:149-155
7) Yamauchi M, Yotsuyanagi T, Ezoe K, Saito T, Ikeda K,
Arai K. Reverse facial artery flap from the submental
region. J Plast Reconstr Aesthet Surg. (2010)63:583-588
8) Urushidate S, Yokoi K, Higuma Y, Mikami M, Watanabe Y,
Saito M, Saito Y, Yamauchi M, Yotsuyanagi T. Nose and
upper lip reconstruction for purpura fulminans. J Plast
Reconstr Aesthet Surg. 6(2012)5:252-255
9) Arai K, Yamashita K, Suda T, Ikeda K, Yamauchi M,
Yotsuyanagi T. Primary reconstruction of the umbilicus,
using two rectangular subcutaneous pedicle flaps. J Plast
Reconstr Aesthet Surg. (2012)65:132-134
10) Ikeda K, Yotsuyanagi T, Arai K, Suda T, Saito T, Ezoe K.
Combined revascularization and free-tissue transfer for
limb salvage in a buerger disease patient. Ann Vasc
Surg. 2(2012)6:e5-8
11) Saito T, Yotsuyanagi T, Ezoe K, Ikeda K, Yamauchi M,
Arai K, Urushidate S, Mikami M. The acute surgical
management of injury to the helix and antihelix in patients
with large body surface area burns. J Plast Reconstr
Aesthet Surg. 62:1020-1024(2009)
12)Urushidate S, Yotsuyanagi T, Yamauchi M, Mikami M,
Ezoe K, Saito T, Yokoi K, Ikeda K, Higuma Y, Shimoyama
M. Modified thin abdominal wall flap (glove flap) f o r
the treatment of acute burns to the hands and fingers. J
Plast Reconstr Aesthet Surg. (2010)63:693-600
13) Yotsuyanagi T, Yamashita K, Gonda A, Kato S, Sugai A,
Yamada T, Kayama M, Ikeda K, Yamauchi M, Saito T.
Double combined Z-plasty for wide scar contracture
release. J Plast Reconstr Aesthet Surg. 6(2013)6:629-633
14) Matsumoto Y, Ikeda K, Yamaya Y, Yamashita K, Saito T,
Hoshino Y, Koga T, Enari H, Suto S, Yotsuyanagi T. The
usefulness of the collagen and elastin sponge derived
from salmon as an artificial dermis and scaffold for tissue
engineering. Biochem Res. (2011)32:29-36
15)Ikeda K, Torigoe T, Matsumoto Y, Fujita T, Sato N,
Yotsuyanagi T. Resveratrol inhibits fibrogenesis and
induces apoptosis in keloid fibroblasts. Wound Repair
Regen. (2013)21:616-623
22
Medical imaging has developed so rapidly that it has changed clinical
medicine altogether. CT, MRI, and PET-CT are necessary not only for
detecting lesions or diagnosing clinical stage but for evaluating
treatment effects and prognosis. The aim of our department is to
apply novel imaging techniques into clinical medicine, making what
had been considered impossible possible and creating future of
clinical medicine through medical imaging.
Professor
Assistant Professor
Masamitsu Hatakenaka, M.D., Ph.D.
Naoya Yama, M.D., Ph.D.
Interests:
Interests:
General radiology, MRI
Genelal radiology, Nuclear medicine
Assistant Professor
Instructor:
Mitsuharu Tamakawa, M.D., Ph.D
Takaharu Shonai, M.D., Ph.D.
Interests:
Musculoskeletal radiology, Breast
imaging
1. Predicting prognosis through diffusion-weighted
magnetic resonance imaging (DWI)
The development of DWI has enabled us to obtain
microscopic tissue information, such as cellularity,
noninvasively. We analyzed the correlation between apparent
diffusion coefficient (ADC) and prognosis (local control,
regional control, disease-free survival and overall survival) in
head and neck cancers treated with chemoradiotherapy using
the Cox proportional hazard test. It was observed that ADC
calculated with relatively high b-factors associated significantly
with local control, regional control, disease-free survival and
overall survival. Lower ADC showed a favorable prognosis.
Tumors with high cellularity are known to be susceptible to
radiation probably due to bystander effects. Moreover, tumors
with low ADC show high cellularity. Therefore, results from our
study suggest that tumors with low ADC show high cellularity
and high radiation sensitivity. With an appropriate threshold
ADC value, accuracy of correctly predicting prognosis before
treatment initiation is over 80%. Our aim is to develop and
apply the present methods to other types of cancers.
2. Evaluation of complication after total hip arthroplasty
(THA) using metal artifact reduction technique on CT
The presence of high atomic number materials (e.g.
metal) in CT images may cause severe artifacts. These
artifacts exhibit themselves as steaks, dark areas in the image
that obscure the overall data. SEMAR (single energy metal
artifact reduction) is a metal artifact reduction technique.
Object displacement in a CT scan is generally reflected in CT
projection data or sinogram. The metal sinogram data is now
utilized as a mask to remove all of the non-metal data points
from the error sinogram. This error sinogram data is
backprojected to generate the correction image. The metal
data points in sinogram are identified and removed. These
points are replaced with interpolated values that will simulate
tissue in place of the metal. An innovative aspect of this
sinogram is in the first iteration. This sinogram is backprojected
and the resultant image is used to segment tissue and create
the tissue classified image. For subsequent iterations, this
step is not performed. Though SEMAR does not totally
eliminate metal artifacts, it is capable of reducing their effect
on CT images to significantly enhance the diagnostic quality
of the images. An orthopedic hip prosthesis can cause severe
metal artifacts in the CT images. The diagnostic improvement
with SEMAR is self-evidence. Both the streak and darkening
artifacts have been mitigated. We plan to examine deep vein
thrombosis (DVT), infection, fracture, and loosening as postoperative changes of total hip arthroplasty using SEMAR on
CT.
3. Vascular image in CNS and lung
We are interested in time resolved angiography and
perfusion imaging of the central nervous system using 320row area detector CT and MRI. In CT angiography, high tube
voltage is needed to reduce image noise and represent small
branches. In contrast, to reduce radiation exposure and
increase the sensitivity to low concentrations of iodine, low
tube voltage has been used for CT perfusion. Because 320row area detector CT can simultaneously obtain both CT
angiography and CT perfusion information, we need a novel
method to procure high quality images from both under low
radiation exposure. Time MIP, which combines different phase
images with MIP calculations, improves the image quality of
CT angiography without an increase of radiation exposure.
We are striving to achieve CT perfusion through the use of
dual energy data acquisition to maintain the image quality of
CT angiography and radiation exposure. MRI is advantageous
to CT angiography and CT perfusion in that it consists of no
radiation exposure and has the capability for non-contrast
enhancement. This makes it possible to obtain multiple data
acquisitions, thereby providing an advantage for clinical follow
up studies. At present, ASL method has problems in that
23
parameters of perfusion images are limited compared with
contrast enhanced methods. Additionally, evaluation of the
venous phase is difficult.
We plan to apply the non-contrast enhanced MR
angiography and perfusion using the ASL method described
above to pulmonary disease. Comparisons of results of
perfusion analysis obtained with contrast enhanced and noncontrast enhanced acquisitions are needed. Non-contrast
enhanced MR angiography and perfusion should have
advantages for evaluation of the therapeutic effect of
pulmonary embolization and follow up for pulmonary
hypertension.
We are also interested in vessel wall imaging of intra- and
extra-cranial regions. Combining the information of vessel
walls and hemodynamics should help shape clinical decisions
for cerebral vascular disease patients. Detection of lower
contrast enhancement of Gadolinium is also a longstanding
interest.
4. Magnetic resonance imaging for interstitial lung disease
For lung imaging, chest radiography and computed
tomography (CT) have been considered the standard
radiological tools. CT yields excellent anatomic details of the
lung. However, despite low-radiation-dose volume CT
protocols, radiation exposure is still a great concern especially
in young patients and pregnant women. Furthermore, patients
with chronic lung disorders need to undergo repeated CT
scans, resulting in a high cumulative dose of radiation. As
such, radiation free imaging method for follow-up and therapy
monitoring is desirable. Until recently, magnetic resonance
imaging (MRI) of the lung has been a challenge. Difficulties
are related to three main factors: (a) signal loss due to
physiological motion (cardiac pulsation and respiratory motion
of the diaphragm and chest wall); (b) T2* dephasing from
magnetic susceptibility gradients at the air-soft-tissue
interfaces; (c) low proton density and a low signal-to-noise
ratio because of the small amount of lung tissue. However,
due to technical progressions, imaging quality of MRI of the
lung has been improving. Additionally, though spatial
resolution is still lower than in CT, MRI has the advantages of
making it possible to evaluate different aspects of tissue,
improve lesion characterization and assess function. We
therefore plan to investigate whether evaluation of an
interstitial lung disease can be performed by MRI.
5. Research about nuclear medicine
As I-131 therapy for differentiated thyroid cancer has
come into wide use in Japan, the number of patients treated
with I-131 has increased. The consequent shortage of facilities
interferes with the provision of suitable I-131 therapy. Only
one patient is commonly treated per week in an isolation room
of a hospital in Japan. Nevertheless, there have not been
enough discussions about the transition of the radiation dose
rate and accurate restriction periods in accordance with the
Japanese guidelines. We evaluated the transition of the
radiation dose rate and iodine distributions in patients with
well-differentiated thyroid cancer who were treated with I-131,
and we concluded that planning of bed control with a quicker
turnover could be achieved in accordance with the guidelines
issued by the Japanese Ministry of Welfare in June 1998 and
November 2010. Especially in cases of bone metastases with
high levels of external radiation, we must consider short
effective half-lives over a period of a few days, separately
from long effective half-lives after more than a few days, due
to functional cellular uptake.
At present we are performing research projects
concerning diagnosis with nuclear imaging collaborated with
magnetic resonance imaging to predict therapeutic effects
and to standardize the protocol of radioisotope therapy.
1) Tamakawa M, Kawaai Y, Shirase R, Satoh T, Akiba H,
Hyodoh H, Hareyama M. Gadolinium-enhanced dynamic
magnetic resonance imaging with endorectal coil for
recral cancer. Jpn J Radiol. (2010) 28:290-8.
2) Hyodoh K, Hyodod H, Kasahara M, Washio Y, Asai M,
Hareyama M. Dynamic MR imaging of kidneys psefused
with EOB-Gd-DTPA. Acta Chir Iugosal. (2011) 58:29-32.
3) Hatakenaka M, Nakamura K, Yabuuchi H, Shioyama Y,
Matsuo Y, Ohnishi K, Sunami S, Kamitani T, Setoguchi T,
Yoshiura T, Nakashima T, Nishikawa K, Honda H.
Pretreatment apparent diffusion coefficient of the primary
lesion correlates with local failure in head-and-neck
cancer treated with chemoradiotherapy or radiotherapy.
Int J Radiat Oncol Biol Phys. (2011) 81:339-45.
4) Yabuuchi H, Hatakenaka M, Takayama K, Matsuo Y,
Sunami S, Kamitani T, Jinnouchi M, Sakai S, Nakanishi Y,
Honda H. Non-small cell lung cancer: detection of early
response to chemotherapy by using contrast-enhanced
dynamic and diffusion-weighted MR imaging. Radiology.
(2011) 261: 598-604.
5) Hatakenaka M, Shioyama Y, Nakamura K, Yabuuchi H,
Matsuo Y, Sunami S, Kamitani T, Yoshiura T, Nakashima
T, Nishikawa K, Honda H. Apparent diffusion coefficient
calculated with relatively high b-values correlates with
local failure of head and neck squamous cell carcinoma
treated with radiotherapy. AJNR Am J Neuroradiol. (2011)
32:1904-10.
6) Nagao M, Hatakenaka M, Matsuo Y, Kamitani T, Higuchi
K, Shikata F, Nagashima M, Mochizuki T, Honda H.
Subendocardial contractile impairment in chronic
ischemic myocardium: assessment by strain analysis of
3T tagged CMR. J Cardiovasc Magn Reson. (2012)
14:14.
7) Hatakenaka M, Yonezawa M, Nonoshita T, Nakamura K,
Yabuuchi H, Shioyama Y, Nagao M, Matsuo Y, Kamitani
T, Higo T, Nishikawa K, Setoguchi T, Honda H. Acute
cardiac impairment associated with concurrent
chemoradiotherapy for esophageal cancer: magnetic
resonance evaluation. Int J Radiat Oncol Biol Phys.
(2012) 83:e67-73.
8) Yama N, Sakata KI, Hyodoh H, Tamakawa M, Hareyama
M. A retrospective study on the transition of radiation
dose rate and iodine distribution in patients with I-131treated well-differentiated thyroid cancer to improve bed
control shorten isolation periods. Ann Nucl Med. (2012)
26:390-6.
9) Hyodoh H, Sato T, Onodera M, Washio H, Hasegawa T,
Hatakenaka M. Vascular measurement changes
observed using postmortem computed tomography. Jpn
J Radiol. (2012) 30:840-5.
10) Kamitani T, Hatakenaka M, Yabuuchi H, Matsuo Y, Fujita
N, Jinnouchi M, Nagao M, Shirahane K, Tokunaga E,
Honda H. Detection of axillary node metastasis using
diffusion-weighted MRI in breast cancer. Clin Imaging.
(2013) 37: 56-61.
24
Health Care Administration and Medical Management
This intent of this newly founded division (2013) is to provide many
indices on the economic and medical management of future heath
care administration (hospital cooperation). Therefore, we analyze the
regional medical and insurance records to establish appropriate
goals of heath care administration. Furthermore, we study IT controls,
tools of medical teachings and the practical guide of intra-hospital
cooperation.
Professor
Kazufumi Tsuchihashi, M.D., Ph.D.
Interests:
Heath care administration, Multicenter trials and the methods
on various medical issues mainly in cardiovascular medicine,
Appropriate economical and occupational indices on medical
service, IT controls on medical data and records
1. Multi-center trial on cardiovascular medicine
In cooperation with the Cardiovascular, Renal and
Endocrine/Metabolic Medicine department and its affiliates,
we conducted several multicenter trials and observational
studies on (1) pathophysiology on takotsubo cardiomyopathy
and its long-term prognosis, (2) the use of anticoagulation on
end-staged renal disease and the risks of cerebrovascular
accident and (3) clinical indices determining the prognosis in
patients with heart failure.
List of main publication from 2009 to 2013
1) Kosuga M, Kimura K, Mirita S, Kojima S, Sakamoto T,
Ishihara M, Asada Y, Tei C, Miyazaki S, Sonoda M,
Tsuchihashi K, Yamagishi M, Shirai M, Hiraoksa H,
Honda T, Ogata Y, Ogawa H, the JACCS investigators.
Combined Prognosis utility of WBC count, plasma
glucose and GFR on patients undergoing primary stent
replavcement for acute myocardial infarction. Am J
Cardiol 2009, 103: 322-327.
2) Kamakura S, Ohe T, Nakazawa K, AizawaY, Shimizu A,
Horie M, Ogawa S, Okumura K, Tsuchihashi K, Sugi K,
Makita N, Hagiwara N et al. Long-term prognosis of
probands with Brugada-pattern ST elevation in V1-V3.
Circ Arrhythm Electrophysiol 2009, Oct 2 (5):495-503.
3) Ishihara M, Kojima S, Sakamoto T, Kimura K, Kosuge M,
Asada Y, Tei C, Miyazaki S, Sonoda M, Tsuchihashi K,
Yamagichi M, Shirai M, Hiraoka H, Honda T, Ogata Y,
Ogawa H; Japanease Acute Coronary Syndrome Study
(JACSS) Investigators . Am J Cardiol 2009, 105:769-774.
4) Guidelines for diagnosis and treatment of patients with
vasospastic angina (Coronary Spastic Angina)(JCS
2008)-Digest Version- JCS Joint Working Group. Ogawa
H, Akasaka T, Hattori R, Kawashima S, Kawasuji M,
Kimura K, Miwa K, Mizuno K, Mohri M, Murohara T, Node
K, Okumura K, Saito S, Shimokawa H, Sueda S,
Takeyama Y, Tanabe Y, Tsuchihashi K, Yamagishi M,
Yoshimura M, Ibuki C, Inoue T, Kaikita K, Kawano H,
Kojima S, Kosuge M, Nakayama M, Oshita A, Soejima H,
Takarada S, Yasuda S, Haze K, Kishida H, Tomoike H,
Yokoyama M. Circ J 2010, 74: 1745-1762,.
5) Nishizato K, Hashimoto A, Nakata T, Doi T, Ymanoto H,
Nagahara D, Shimoshige S, Yuda S, Tsuchihashi K,
Shimamoto K. Impaired cardiac sympathetic innervation
and myocardial perfusion are related to lethal arrhythmia:
Quantification of cardiac tracers inn patients with ICDs. J
Nucl Med 2010, 51:1241-1249.
6) Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL;
J-LANCELOT (Japanese-Lesson from Antagonizing the
Cellular Effect of Thrombin) Investigators. (Tanaka K,
Uesugi M, Fujii K, Ueda Y, Itoh A, Kajiya T, Furukawa Y,
Kawagoe T, Hiasa Y, Iwabuchi M, Saito T, Kobayashi Y,
Hirayama A, Tobaru T, Ozaki Y, Kawasaki T, Takazawa K,
Noda T, Nanto S, Ueno T, Shimomura H, Tsuchihashi K,
Noda M, Iwahashi N, Miyamoto T, Nakashima H, Oshiro
K, Ohnishi S, Tanaka T, Fukushima S, Haruta S,
Yamamoto H, Yamada T, Betsuyaku T, Suzuki M, Iwade
K, Hashizume T, Yanagihara K, Shigematsu S, Oku K,
Ohyanagi M, Shindo N, Segawa T, Uesugi M, Ueda Y,
Ohyanagi M, Kajiya T, Nakao K, Kaikita K, Urasawa K,
Hirata Y, Takano H, Nakamura M, Kimura A, Awata N,
Fujimoto K, Osawa H, Oiwa H, Ozaki T, Momomura S,
Obayashi T, Houda N, Kakuta T, Kanaya H, Ikeda M, Doi
O, Murakami H, Tsuzuki M, Hirasawa K, Yamazaki J,
Sato Y, Sasaoka T, Fukui K, Yokoya M.). Double-blind,
placebo-controlled Phase II studies of the proteaseactivated receptor 1 antagonist E5555 (atopaxar) in
Japanese patients with acute coronary syndrome or
high-risk coronary artery disease. Eur Heart J. 2010,
1(21):2601-2613.
7) Uemura N, Sugano K, Hiraishi H et al. The MAGIC Study
Group. Risk factor profiles, drun usage, and prevalence
of aspirin-associated gastroduodenal injuries aong
highrisk cardiovascular Japanese patients: the result
from the MAGIC study. J Gastroenterology 2013
published onlined 12 June 2013.
25
The department of Intensive Critical Medicine became a separate
unit from the Department of Traumatology and Critical Care Medicine
in 2012.
Patients who enter the Intensive Care Unit (ICU) can be
classified by two primary pathogeneses The first includes postoperative patients with serious complications or those who require
cardiovascular, cerebral or pancreatico-duadenal surgery, and the
second includes patients with septic shock or acute respiratory failure
in the ward. In addition to elucidating the pathophysiology of severe
illnesses, intensive care management, including drug therapy and
mechanical support, is performed in critically ill patients with acute
dysfunction including respiratory failure, shock and metabolic failure.
Professor
Asssistant Professor
Michiaki Yamakage, M.D., Ph.D.
Hiroomi Tatsumi, M.D., Ph.D.
Interests:
Associate Professor
Intensive care medicine, Management of sepsis, Blood
Hitoshi Imaizumi, M.D., Ph.D.
purification,
Interests:
Research for enteral nutrition in critically ill patients
Emergency medicine, Intensive care medicine, Blood
purification, Artificial ventilation,
Instructor
Research for pathophysiology of sepsis and ARDS
Satoshi Kazuma, M.D.
Interests:
Yoshiki Masuda, M.D., Ph.D.
Intensive care medicine, Management of sepsis,
Interests:
Research for cognitive function of inhalation anesthetics
Emergency medicine, Intensive care medicine, Management
of sepsis,
Kazuhito Nomura, M.D.
Research for sepsis-induced coagulopathy and fibrinolytic
Interests:
abnormalities
Emergency medicine, Intensive care medicine, Management
of infection
1. Pathophysiological study for severe sepsis
It has been demonstrated that sepsis is triggered by
alarmines such as DAMPs (damage-associated molecular
patterns) and PAMPs (pathogen-associated molecular
patterns) that are released from cells into blood stream and
these proteins subsequently activate macrophages, resulting
in the formation of pathogenesis of severe sepsis.
We have found that nucleophosmin acts as an alarmine
in severe sepsis (1). HMGB-1 is known to act as an alarmine
and we have reported on the inhibition of HMGB-1 and a
receptor for HMGB-1 (RAGE) by using an antibody that
attenuated sepsis-induced diaphragm dysfunction in rats (2).
Results obtained in our report may lead to possible treatment
in patients with severe sepsis. We have demonstrated that
removal of HMGB-1 and/or endocannabinoid that induces
hemodynamic derangement by direct hemoperfusion therapy
results in favorable outcomes in patients with septic shock
(3,4).
2. The latest treatment of acute respiratory failure
Sepsis is often accompanied by acute respiratory failure
such as acute respiratory distress syndrome (ARDS). Treatment of ARDS is considered to be refractory and
mortality is still high despite advances in modern medicine.
In our ICU, we treat ARDS using images from lung
computed tomography (CT). Serological determination of
surfactant protein (SP)-D and KL-6 have also been conducted.
These lung CT images and serological protein concentrations
have indicated the pathogenesis of ARDS. Therefore, we
are performing management of respiratory care according to
these examinations. Practical procedures for treatment of
severe ARDS include prone position respiratory care,
extracorporeal membrane oxygenation (5) and drugs such as
high-dose steroids, neutrophil elastase inhibitors,and artificial
surfactant.
3. Latest treatment of shock and severe sepsis
It is important that the diagnostic confirmation of shock
does not necessarily require hypotension but reflects an
26
imbalance between oxygen delivery and consumption in
tissues. This imbalance can result in increases in serum
lactate. Shock can be classified by four different
pathophysiologies: cardiogenic, obstructive, hypovolemic and
distributional. Early diagnosis and optimal treatment play a
pivotal role in the management of shock.
According to the guidelines for the management of septic
shock and severe sepsis, optimal volume replacement,
commonly referred to as “early goal directed-therapy (EGDT)”,
early administration of broad-spectrum antibiotic after blood
culture and determination of lactate level are performed in
patients with sepsis.
We have reported on rare cases of those who have survived
cardiac arrest due to iatrogenic hypermagnesemia (7).
4. Systemic management in patients with intestinal
ischemia and with hematological malignancies
Intestinal necrosis in intra-abdominal infections is a
cause of sepsis. Superior mesenteric artery obstruction
(SMAO) can be diagnosed by abdominal computed
tomography (CT) ; however, its confirmative diagnosis is
difficult in the case of non-obstructive mesenteric ischemia
(NOMI). We have reported that dextro-rotatory lactate
(d-lactate) increases in the progress of intestinal ischemia in
an intestinal ischemic model of rats. We also have investigated
on how d-lactate is a useful adjunctive determinant in the
diagnosis of SMAO or NOMI in humans (8).
It is well known that patients with hematological
malignancies who require management in ICU have a poor
prognosis (9). However, we have demonstrated that potential
survival rates for these patients increase in cases of fewer
than two organ failures. Therefore, we are exploring
therapeutic strategies of aggressive treatment for the
regulation of mediators that cause organ failures. We are
particularly interested in techniques for blood purification such
as high volume CHDF (Alias, Tapering CHDF), plasma
exchange and direct hemoporfusion with polymixin B
immobilezed column.
5. Enteral nutrition therapy for severe sepsis
According to recent studies, enteral nutrition has resulted
in improvement of critically ill patients. Since 1980 we have
provided enteral nutrition to critically ill patients in our ICU. We have conducted a clinical study of the benefits of enteral
nutrition including its initiation, administration route and
quality. Based on the results of our investigation, we have
advocated early initiation of enteral nutrition and recommended
its administration via tube feeding. We also believe the
decision to use enteral nutrition is dependent on the
pathogenesis of disease (10).
6. Effects of temperature on metabolism and function of
platelets and red blood cells of autologous blood during
storage
In the ICU, target hemoglobin levels are 10~12g/dl for
those in hemorrhagic shock and 7g/dl in cases of advanced
anemia. We have studied how temperature in autologous
blood storage during the surgery affects the metabolism and
function of platelets and red blood cells. We found that even
in situations in which the platelet function is kept under the
room temperature, metabolism of the red blood cells enhances
over time, which results in hyperlactatemia and hyperkalemia.
We concluded that autologous blood should be transfused
within 8 hours (11).
1) Nawa Y, Kawahara K, Tancharoen S, Meng X, Sameshima
H, Ito T, Masuda Y, Imaizumi H, Hashiguchi T, Maruyama
I.:Nucleophosmin may act as an alarmin: implications for
severe sepsis. J Leukoc Biol (2009) ; 86(3): 645-53
2) Susa Y, Masuda Y, Imaizumi H, Namiki A: Neutralization
of receptor for advanced glycation end-products and high
mobility group box-1 attenuates septic diaphragm
dysfunction in rats with peritonitis. Crit Care Med (2009);
37(9): 2619-24.
3) Wang Y, Liu Y, Ito Y, Hashiguchi T, Kitajima I, Yamakuchi
M, Shimizu H, Matsuo S, Imaizumi H, Maruyama I:
Simultaneous measurement of anandamide and
2-arachidonoylglycerol
by
polymyxin
b-selective
adsorption and subsequent high-performance liquid
chromatography analysis: increase in endogenous
cannabinoids in the sera of patients with endotoxic shock.
Anal Biochem (2001); 294 (1): 73-82
4) Yoshida SI, Chihara S, Tatsumi H, Imaizumi H, Masuda Y,
Goto K, Takahashi K, Shichinohe Y,
Hazama K,
Yamakage M: Evaluation of the effect of polymyxin B
direct hemoperfusion on improvement hemodynamic
instability in patients with septic shock. LIVES 2013,
ESICM’s 26th Annual Congress. (2013.10.5-9), Paris
5) Kuroda H, Masuda Y, Imaizumi H, Kozuka Y, Asai Y,
Namiki A: Successful extracorporeal membranous
oxygenation for a patient with life-threatening transfusionrelated acute lung injury. J Anesth. (2009);23(3):424-6.
6) Masuda Y, Yoshida SI, Imaizumi H, Yamakage M: Regional
Anesthesia for a Pregnant Patient with Symptomatic
Hypothyroidism. Anesthesia and Resuscitation (2013)
49(3) 81-3.
7) Tatsumi H, Masuda Y, Imaizumi H, Kuroda H, Yoshida SI,
Kyan R, Goto K, Asai Y: A case of cardiopulmonary arrest
caused by laxatives-induced hypermagnesemia in a
patient with anorexia nervosa and chronic renal failure. J
Anesth (2011) 25:935-8
8) Yoshida SI, Tatsumi H, Masuda Y, Imaizumi H, Goto K,
Kyan R, Asai Y, Yamakage M. Elevated serum D-lactate
is associated with intestinal ischemia in rats. American
Society of Anesthesiologist Annual Meeting, (2011)
10.14-19, Chicago
9) Yoshida SI, Masuda Y, Imaizumi H, Takahashi K, Kimijima
T, Tatsumi H, Yamakage M: Evaluation of prognostic
factors in patients with hematological malignancies
treated in the ICU. The annual meeting of the American
Society of Anesthesiologists. (2012) 10.13-17,
Washington DC, USA
10) Tatsumi H, Masuda Y, Imaizumi H, Yoshida SI, Sakawaki
E, Goto K, Kazuma S, Takahashi K, Yamakage M:
Evaluation about the efficacy of management of fecal
evacuation in critically ill patients receiving early enteral
nutrition. LIVES 2013, ESICM’s 26th Annual Congress.
(2013) 10.5-9, Paris
11) Yoshida SI, Masuda Y, Imaizumi H, Kimijima T, Goto K,
Kyan R, Tatsumi H, Yamakage M: Effects of storage
temperature of the blood on erythrocyte metabolism and
platelet function. Anesthesia and Resuscitation (2013) 49
(2), 53-5
27
Thoracic Surgery
Thoracic surgery treats all disorders that occur in the organs inside
the chest as well as in the bony structures and tissues that form the
chest cavity except for the heart and esophagus disorders. As such,
our clinical research fields cover various diseases such as lung
cancer, benign lung disease, mediastinal tumors and chest wall
disorders. In particular, minimally invasive thoracoscopic surgery is
extensively and effectively applied for diagnosis and surgical
treatment of lung cancer and mediastinal tumors. Additionally, our
basic research focuses on cancer biology, proteomics oncologic
gene analysis of lung cancer, pulmonary regeneration, transplantation
immunology and pulmonary preservation of lung transplantation.
Professor
Assistant Professor
Atsushi Watanabe, M.D., Ph.D.
Masahiro Miyajima, M.D., Ph.D.
Interests:
Interests:
Minimally invasive thoracic surgery,
Minimally invasive thoracic surgery
Lung cancer
1. cancer biology
2. proteomics oncologic gene analysis of lung cancer
3. pulmonary regeneration
mediastinal lymph node dissection for lung cancer..
Semin Thorac Cardiovasc Surg. 2012 Spring;24(1):68-73.
6) Watanabe A, Kawaharada N, Higami T.Postoperative
4. transplantation immunology
Acute Exacerbation of IPF after Lung Resection for
5. pulmonary preservation of lung transplantation
Primary Lung Cancer. Pulm Med. 2011;2011:960316.
7) Nakashima S, Watanabe A, Mishina T, Obama T,
Mawatari T, Higami T. Feasibility and safety of
1) Nakazawa J, Watanabe A, Nakajima T, Mishina T,
postoperative management without chest tube placement
Miyajima M, Higami T. Henoch-schönlein purpura with
after thoracoscopic wedge resection of the lung. Surg
lung abscess. Article in Japanese. Kyobu Geka. (2013)
Today. 2011 Jun;41(6):774-9.
10:886-9.
8) Miyajima M, Watanabe A, Uehara M, Obama T, Nakazawa
2) Watanabe A, Miyajima M, Mishina T, Nakazawa J, Harada
J, Nakajima T, Ogura K, Higami T. Total thoracoscopic
R, Kawaharada N, Higami T. Surgical treatment for
lung segmentectomy of anterior basal segment of the
primary lung cancer combined with idiopathic pulmonary
right lower lobe (RS8) for NSCLC stage IA (case report).
fibrosis. Gen Thorac Cardiovasc Surg. (2013) 61(5):254-61.
J Cardiothorac Surg. (2011) Sep 24;6:115.
3) Hayashi N, Chiba H, Kuronuma K, Go S, Hasegawa Y,
9) Nakashima S, Watanabe A, Obama T, Yamada G,
Takahashi M, Gasa S, Watanabe A, Hasegawa T, Kuroki
Takahashi H, Higami T. Need for Preoperative Computed
Y, Inokuchi J, Takahashi H. Detection of N-glycolyated
Tomography-Guided
gangliosides in non-small-cell lung cancer using GMR8
Thoracoscopic
monoclonal antibody. Cancer Sci.(2013);104(1):43-7.
Metastatic Pulmonary Nodules, Ann Thorac Surg, 2010:
4) Sato T, Teramukai S, Kondo H, Watanabe A, Ebina M,
Localization
Surgery
in
Pulmonary
Video-Assisted
Resections
of
89:212-219
Kishi K, Fujii Y, Mitsudomi T, Yoshimura M, Maniwa T,
10) Watanabe A, Ohori S, Nakashima S, Mawatari T, Inoue
Suzuki K, Kataoka K, Sugiyama Y, Kondo T, Date H.
N, Kurimoto Y, Higami T. Feasibility of video-assisted
Impact and predictors of acute exacerbation of interstitial
thoracoscopic surgery segmentectomy for selected
lung diseases after pulmonary resection for lung cancer.
peripheral lung carcinomas. Eur J Cardiothorac Surg.
J Thorac Cardiovasc Surg. (2013)
2009 35:775-80
5) Watanabe A, Nakazawa J, Miyajima M, Harada R,
Nakashima S, Mawatari T, Higami T.Thoracoscopic
28
3 Basic Medical Sciences (Courses)
Anatomy (I) [Biological Informatics & Anatomy]
We are investigating the mystery of life from molecular to social
levels. Utilizing IT (Information Technology) as well as AT (Anatomical
Technology) in the bio-medical field, we research the eternal truth of
living organisms including our society. Based on cell biology
knowledge, we have developed SDMCI (Strategic Defensive MedicalCare Initiative) and Info-Medicine (Joho-Yaku:
Professor
Assistant Professor
Haruyuki Tatsumi, M.D., Ph.D.
Ryoichi Ichikawa, M.D., Ph.D.
Interests: Cell biology, Computerized anatomy & histology,
Interests: Neurobiology, Neuroanatomy
).
Applied Sciences with IT and AT for full-powered medicine,
Community medicine networks
Instructor
Shin Kikuchi, Ph.D.
Associate Professor
Interests: Cell biology, Neurobiology
Takafumi Ninomiya, Ph.D.
Interests: Cell biology, Neurobiology
Takahiko Shimmi, B.S.
Interests: Cell biology, Community medicine networks
Morphological analysis on big data
1. SDMCI
From our research on life sciences, utilizing Information
Technology (IT) we have made a proposal for the development
of a “Strategic Defensive Medical-Care Initiative (SDMCI)”
named after President Reagan's SDI (Strategic Defense
Initiative).
a) Ver. 1.0 for patients
“Reserved-nurse-call with zero-click” is one part of the
core technology of SDMCI. Image a bedroom in a hospital in
which patients press the nurse-call-button when they need
nurses to help. This indicates a request path from patients to
the medical staff. We would like to revise this situation in an
“inside-out” manner. Based on a patient’s data and records
collected and stored via networks (LAN and the Internet), an
efficient and timely call (Info-Med) could be provided to the
patient even if he or she is unaware of the bad health status.
These kinds of systems not only improve the quality of
patients’ lives, but also save their lives proactively. This
requires continuous and ubiquitous collection of a variety of
information related to the patients without any workloads
(Zero-Click) like nervous system and we are going to take
immediate actions when necessary, triggered by big data
analysis. The proactive system is known as “Reversed-nursecall.”
To realize SDMCI, we have to improve the Internet
infrastructure, medical-care devices and various systems (1)
via an anatomical point of view. We are striving to develop
new systems, including IPv6 Topological Addressing Policy,
End-to-End multi-homing and ubiquitous zero-click homehealthcare devices.
b) Ver. 2.0 for doctors
We proposed the guidelines for human body dissection
for clinical anatomy education and research as a SDMCI,
Version 2.0 (2). This version first describes the required basic
guidelines for human cadaver usage to allow medical and
dental doctors to conduct clinical education and research in
accordance with existing regulations. The guidelines are also
expected to give physicians a regulatory framework to carry
out cadaver training in accordance with the current legal
framework. Specialized “Info-Med” is also useful here (3).
c) Ver. 3.0 (Info-Med: Joho-Yaku)
We define "information" as multimedia stimuli, which
move our mind. The mind is the brain function composed of
brain cells. Generally speaking, external as well as internal
stimuli change the cell status. Some patterns of stimuli
become a signal, and then information. Therefore, appropriate
and timely information exerts therapeutic effects on the cells
of our body in addition to our mind. Taking advantage of this
nature of the multimedia stimuli, we could develop good
medicine in order to improve human health. We have coined
the concept of "Info-Medicine (Info-Med)." According to our
definition, conventional drugs, gene therapies, psychotherapies,
and Tsubo (acupuncture points) stimulations all come under
the scope of "Info-Med." Based around the current
understandings in cell biology, socio-psychology, and "The
Theory of Moral Sentiments" written by Adam Smith, we
29
developed "Info-Med" into a much broader sense and
proposed "Full-Powered Medicine (4)" utilizing everything
good for the health such as traditional medicine (Tsubo,
Qigon, Naikan and so on), in contrast to the Western medicine,
which is totally partial, one-sided and imcomplete.
2. Tight junction proteins in epithelial tissue and nervous
tissue
Tight junctions in endothelial and epithelial cells consist
of the integral membrane proteins claudins (Cldns), occludin,
and junctional adhesion molecules (JAMs). More recently,
tricellulin (TRIC) has been identified as the first marker of the
tricellular tight junction in epithelial cells. The loss of TRIC
affects the organization of the tricellular tight junction and the
barrier function of epithelial cells (5-10)
Autotypic tight junctions of myelinating Schwann cells are
also composed of various transmembrane and peripheral
cytoplasmic tight junction proteins, including Cldn-19 and
JAM-C. However, in the autotypic tight junctions of myelinating
Schwann cells, little is known about the expression and
localization of TRIC, which may play a crucial role in bicellular
and tricellular tight junctions of epithelial cells. We found the
identity and subcellular distribution of TRIC proteins in
autotypic tight junctions of mouse myelinating Schwann cells,
and compared them with the autotypic adherens junction
protein E-cadherin and the autotypic tight junction protein
JAM-C, which are expressed in the paranodal loops, Schmidt–
Lanterman incisures, and mesaxons (11).
3. Analysis of acid-sensing ion channels (ASICs)
Acid-sensing ion channel 2 (ASIC2) plays a role in
mechanopereception. ASIC2 is expressed in several organs
in addition to the nervous system. We found that ASIC2 was
expressed in both ciliated cells and stereociliated cells, but
the localization differed between these cell types. Observation
by electron microscope suggested that ASIC2 expression
was present at the apical side of the cilial membrane in ciliated
cells and at the apical side of the cell body in stereociliated
cells (12).
4. Generation of synaptic wiring onto the neuron
Neurons, which receive excitatory and inhibitory inputs,
compute the receiving information and generate proper
outputs. The computation is attributable to the wiring pattern
onto the neuron. To examine the genesis of synaptic wiring,
we chose a cerebellar Purkinje cell due to its relatively simple
structure. Sets of serial ultra thin sections for an electron
microscopic observation, which include at least entire single
Purkinje cell, are were prepared. Combined with post- or preembedding immuno-electron microscopic observation, we are
seeking the mechanisms of synaptic wiring formation from a
molecular level. We recently disclosed a notable mechanism,
which is the developmental switching of perisomatic
innervation from excitatory to inhibitory input (13-14). We are
finding other mechanisms in synaptic wiring formation. and so
on.
1) Tamura T, Mizukura I, Kimura Y, Tatsumi H. Designing
pervasive healthcare applications in the home. In
Pervasive and Smart Technologies for Healthcare,
Coronato A, Pietro GD.(2010) 282-294. Medical
Information Science Reference.
2) Shichinohe T, et al. Draft of guidelines for human body
dissection for clinical anatomy education and research
and commentary. Acta Anat Nippon (2011) 86:33-37
3) Tatsumi H, et al. A latent need for strategic defensive
medical-care initiatives (Ver.2). J Physiol Sci (2011) 61:
s247
4) Tatsumi H. Mizoguchi S, et al. The development and
application of "Info-Med": aiming at "Full-Powered
Medicine". Jpn J Med Inf 33 suppl (2013) :754-757
5) Ohkuni T, Kojima T, Ninomiya T, et al. Expression and
localization of tricellulin in human nasal epithelial cells in
vivo and in vitro. Med Mol Morphol (2009) 42 : 204-211
6) Kojima T, Ninomiya T, Kikuchi S, et al. c-Jun N-terminal
kinase is largely involved in the regulation of tricellular
tight junctions via tricellulin in human pancreatic duct
epithelial cells. J Cell Physiol (2010) 225 : 720-733
7) Masaki T, Kojima T, Ninomiya T, et al. A nuclear factor-κB
signaling pathway via PKCδ regulates replication of
respiratory syncytial virus in polarized normal human
nasal epithelial cells. Mol Biol Cell (2011) 22 : 2144-2156
8) Takasawa A, Kojima T, Ninomiya T, et al. Behavior of
tricellulin during destruction and formation of tight
junctions under various extracellular calcium conditions.
Cell Tissue Res. (2013) 351 : 73-84.
9) Someya M, Kojima T, Ninomiya T, et al. Regulation of
tight junctions by sex hormones in normal human
endometrial epithelial cells and uterus cancer cell line
Sawano. Cell Tissue Res (2013) 354 : 481-494
10) Kojima T, Ninomiya T, et al. Expression of tricellulin in
epithelial cells and non-epithelial cells. Histol Histopathol
(2013) 28 : 1383-1392
11) Kikuchi S, Ninomiya T, Tatsumi H, et al. Tricellulin is
expressed in autotypic tight junctions of peripheral
myelinating Schwann cells. J Histochem Cytochem (2010)
73 : 81-89
12) Kikuchi S, Ninomiya T, Tatsumi H, et al. The acid-sensing
ion channel 2 (ASIC2) of ciliated cells in the developing
rat nasal septum. Arch Histol Cytol (2010) 73 : 83-89
13) Ichikawa R, Yamasaki M, Miyazaki T, Konno K, Hashimoto
K, Tatsumi H, Inoue Y, Kano M, Watanabe M.
Developmental switching of perisomatic innervation from
climbing fibers to basket cell fibers in cerebellar Purkinje
cells. J. Neurosci. (2011) 31: 16916 -16927
14) Ichikawa R, Miyazaki T, Yamasaki M, Tatsumi H,
Watanabe M, Developmental Switching of Perisomatic
Innervation from Climbing Fibers to Basket cell Fibers in
Developing Cerebellar Purkinje Cells. In 7th Forum of
European Neuroscience :Amsterdam. the Netherlands,
(programme: S201) (2010)
30
Anatomy (II)
In our department we focus on the therapeutic strategies for diabetic
complications and Alzheimer’s dementia by autologous bone marrow
mesenchymal stem cell (MSC) transplantation. In our translational
research, target organs include bone marrow, kidney, liver, brain and
blood vessels. We have already succeeded in reversing hepatocyte
damage and renal dysfunction as well as cognitive impairments
caused by diabetes by bone marrow MSC treatment in animal
experiments. Our goal is for successful treatment on patients in the
near future.
Professor
Assistant Professor
Instructor
Mineko Fujimiya, M.D., Ph.D.
Kanna Nagaishi (Kobayashi),
Koji Ataka, Ph.D.
Interests:
M.D., Ph.D.
Interests:
Bone marrow mesenchymal stem
Interests:
Brain-gut axis, Brain-bone marrow
cells, Electron microscopy, Translational
Mesenchymal stem cell therapy
axis,
study
Masako Nakano, M.D.
Interests:
Associate Professor
Cognitive impairment, Diabetes,
Hirofumi Matsumura, Ph.D.
Mesenchymal stem cell
Interests:
Biological Anthropology
1. Functional significance of bone marrow mesenchymal
stem cells (MSCs) on tissue damage (directed by M.F.)
To know the detail of mechanism for MSCs to reverse
degenerative changes in diabetes and Alzheimer’s disease,
we performed ultrastructural observations of bone marrow
and the kidney, liver and brain from experimental animals with
and without MSC treatment and human materials. This
approach has provided us with an important concept regarding
how bone marrow MSCs primarily exert functions to maintain
the homeostasis of our whole body (1,2).
2. Biological Anthropology (directed by H.M.)
Eastern Eurasia, occupied by anatomically modern
humans (AMH) at least 50,000 years ago, was a corridor
through which AMH expanded to Oceania and America. Our
research project challenges the potential issues for
understanding the population history of the Asia-Pacific
region, through mapping a population genetic landscape
based on the skeletal and dental morphological data. Our
recent works (3-5) have revealed a demographic transition
and demic migration throughout prehistoric to modern times
in various regions, with a clearly supporting “Two layer” model,
which hypothesizes that the AMH initially occupied Southeast
Asia (the first layer, akin to Australo-Melanesians) and later
exchanged genetic material by demic expansion (the second
layer) from Northeast Asia, leading to the formation of present
day East Asians.
3. Mesenchymal stem cell therapy for IBD and diabetic
complications (directed by K.N.)
We have focused on the role of the neonatal receptor for
IgG (fcRn) in the development of inflammatory bowel disease
(IBD) (6). As IBD is refractory chronic inflammatory colitis, it is
absolutely necessary to develop novel therapeutic tools that
could achieve a radical cure for epithelial mucosa.
Mesenchymal stem cells exert immunoregulatory effects and
participate in regeneration of damaged tissues through both
cell complement effects via cell differentiation or various
paracrine effects via trophic factors secreted by MSCs. We
have investigated how systemic administrations of MSCs
enhance the intestinal tissue repair via trophic effects in
experimental colitis (7,8). Furthermore, we have ascertained
that MSC therapy reverses fatty degeneration and apoptotic
damage of hepatocytes as well as insulin resistance caused
by diabetes in the liver (9). The most prevalent cause of death
in diabetes is severe complications, such as systemic
angiopathy, nephropathy and liver cirrhosis. Investigating the
therapeutic effect of MSCs and their mechanism for diabetic
complications might open the door for a new approach to
systemic organ disorders.
4. Brain-Bone marrow axis (directed by K.A.)
We reported that chronic psychological stress induced by
the communication box technique (10) caused the infiltration
of bone marrow-derived microglia into the hypothalamus
31
through the MCP-1/CCR2 axis in the brain and the SDF-1/
CXCR4 axis in bone marrow. The peripheral injection of a
CCR2 antagonist inhibited the infiltration of bone marrowderived microglia and anxiety-like behavior (11). These results
suggest that bone marrow-derived microglia participate in the
regulation of neurotransmissions in the brain.
5. Niche in bone marrow (directed by K.A.)
We reported that the interaction of hematopoietic stem
cells and osteoblastic niche cells was abnormal in diabetes,
and the abnormalities of hematopoietic stem cells were
normalized when they contacted normal osteoblastic niche
cells (12). These results suggest that the replacement of
niche cells might cure the diabetes-associating dysfunctions.
6. Mesenchymal stem cell treatment for diabetes-induced
cognitive impairment (directed by M.N.)
Diabetes mellitus is associated with cognitive impairments
and patients present a high risk of dementia and Alzheimer
disease. Using the Morris water maze test we have shown
how learning and memory deficits occur in streptozotocin
(STZ) induced diabetic mice. STZ mice show significant
down-regulation of GFAP (astrocyte) in hippocampus CA1.
Astrocytes are known to be critical for maintaining cognitive
function. Ultrastructure study also revealed that astrocytes in
the CA1 region are abnormally swollen and that organelle in
astrocytes and neurons are damaged.
Our aim is examine whether diabetic cognitive dysfunction
diabetes-induced cognitive impairment is ameliorated by
bone marrow derived mesenchymal stem cell (MSC)
administration intravenously. MSCs are multipotent stromal
cells that can differentiate into various cells and have an antiinflammatory and neuroprotective effect. We also investigate
whether MSCs differentiate into astrocytes and/or neurons
and whether MSCs ameliorate degeneration in astrocytes
and neurons through an anti-inflammatory and neuroprotective
effect (13,14).
1) Fujimiya M, Nagaishi K, Yamashita T, Ataka K. Bone
marrow stem cell abnormality and diabetic complications.
Anat Rec (Hoboken). (2012) Jun;295(6):917-21
2) Yamashita T, Fujimiya M, Nagaishi K, Ataka K, Tanaka M,
Yoshida H, Tsuchihashi K, Shimamoto K, Miura T. Fusion
of bone marrow-derived cells with renal tubules
contributes to renal dysfunction in diabetic nephropathy.
FASEB J. (2012) Apr;26(4):1559-68.
3) Matsumura H, Oxenham MF, Thuy NK, Cuong NL, Dung
NK. The population history of mainland Southeast Asia:
Two layer model in the context of northern Vietnam. In:
Enfield N, White J, eds. Dynamics of Human Diversity:
the Case of Mainland Southeast Asia. (2011) 153-178,
Pacific Linguistics, Canberra.
4) Matsumura H, Oxenham MF. Eastern Asia and Japan:
human biology. In: Ness I, Bellwood P, eds. The
Encyclopedia of Global Human Migration. Essay of
Human Migration, Prehistory. (2013) DOI:10.1002/
9781444351071, Wiley-Liss, New York.
5) Matsumura H, Oxenham MF. Population dispersal from
East Asia into Southeast Asia: Perspectives from
prehistoric human remains. In: Pechenkina K, Oxenham
MF, eds. Bioarchaeological Perspectives on Migration
and Health in Ancient East Asia. (2013) 179-212,
University of Florida, Florida.
6) Kobayashi K, Qiao SW, Yoshida M, Baker K, Lencer WI,
Blumberg RS. An FcRn-Dependent Role for Anti-flagellin
in Pathogenesis of Immunoglobulin G-Mediated Colitis in
Mice. Gastroenterology (2009)137: 1746-56.
7) Arimura Y, Nagaishi K, Naishiro Y, Yamashita K,
Shinomura Y, Imai K. Regenerative medicine for
inflammatory bowel disease. Inflammation and
Regeneration (2012)32:61-66.
8) Watanabe S, Arimura Y, Nagaishi K, Isshiki H, Onodera
K, Nasuno M, Yamashita K, Idogawa M, Naishiro Y,
Murata M, Adachi Y, Fujimiya M, Imai K, Shinomura Y.
Conditioned Mesenchymal Stem Cells Produce
Pleiotropic Gut Trophic Factors. J Gastroenterol.(2013)
in press.
9) Nagaishi K, Ataka K, Echizen E, Arimura Y, Fujimiya M.
Mesenchymal
stem
cell
therapy
ameliorates
diabetichepatocyte damage in mice by inhibiting
infiltration of bone marrow derived cells. Hepatology
(2013) in press.
10)Ataka K, Nagaishi K, Asakawa A, Inui A, Fujimiya M.
Alteration of antral and proximal colonic motility induced
by chronic psychological stress involves central urocortin
3 and vasopressin in rats. Am J Physiol Gastrointest
Liver Physiol. (2012) 303:G519-28.
11) Ataka K, Asakawa A, Nagaishi K, Kaimoto K, Sawada A,
Hayakawa Y, Tatezawa R, Inui A, Fujimiya M. Bone
marrow-derived microglia infiltrate into the paraventricular
nucleus of chronic psychological stress-loaded mice.
PLOS ONE. (2013) in press.
12)Chiba H, Ataka K, Iba K, Nagaishi K, Yamashita T,
Fujimiya M. Diabetes impairs the interactions between
long-term hematopoietic stem cells and osteopontinpositive cells in the endosteal niche of mouse bone
marrow. Am J Physiol Cell Physiol. (2013) 305:C693-C703.
13) Nakano M, Asakawa A, Inui A. Long-term correction of
type1 and 2 diabetes by central leptin gene therapy
independent of effects on appetite and energy
expenditure. Indian J Endocrinol Metab. (2012)16:S55661.
14) Nakano M, Inui A. Metformin and incretin-based therapies
up-regulate
central
and
peripheral
adenosine
monophosphate-activated protein affecting appetite and
metabolism. Indian J Endocrinol Metab. (2012)16:S52931.
32
Cellular Physiology and Signal Transduction
Our department is pursuing the mechanism of physiological functions
at the cellular and subcellular levels. Particular attention is paid to ion
channels and their regulatory systems in order to understand their
physiological functions. Electrophysiology, including the patch clamp
method, and confocal fluorescence imaging of calcium are
fundamental tools for us. Because the function of ion channels is
closely related to their structure, we analyze the gene structure of ion
channels using techniques of molecular biology.
Professor
Assistant Professor
Instructor
Noritsugu Tohse, M.D., Ph.D.
Takeshi Kobayashi, M.D., Ph.D.
Sachiko Maeda, Ph.D.
Interests:
Interests:
Signal transduction for regulation of
Excitation-contraction
ion channels,
embryonic heart,
Development of cardiac ion channels
Molecular mechanisms of ion channel
and excitation-contraction coupling
regulation
Nobutoshi Ichise, Ph.D.
coupling
of
1. Development of cardiac ion channels and excitation-
a constant rate. Interestingly, a spontaneous calcium transient
contraction coupling
was observed before the initiation of contraction. The
Cellular
change
frequency of the calcium transients was regular and they
dramatically during development. Ion channels are responsible
exhibited a small amplitude at first, which subsequently
for cellular signaling and maintenance of the intracellular
increased over several seconds. In contrast to the situation at
environment. The ion channels change in their types, number,
the initiation of contraction, which appeared in a small area,
and kinetic properties during the embryonic/fetal period and
the calcium transient first appeared throughout the heart
the neonatal period.
Particularly in excitable cells (i.e.,
primordium. After the beginning of contraction, the frequency
cardiomyocytes, skeletal muscle fibers, neurons), their resting
of calcium transients was the same as the heart rate calculated
potential (RP) and action potentials (APs) are progressively
from the contractions (1,2).
functions
and
tissue
structures
altered during the developmental stages. Our laboratory
2. Influence of sympathetic nerves on lumbar radiculopathy
focuses primarily on the ion channels of cardiomyocytes.
Lumbar radicular pain caused by lumbar disc herniation
Changes in the excitation-contraction coupling process
or lumbar spinal canal stenosis is one of the most common
also occur during development of the heart. The cardiovascular
symptoms of neuropathic pain treated by orthopaedic
system is necessary for animals to transport oxygen, carbon
surgeons or pain clinicians. Nonoperative treatment and
dioxide, nutrients and waste products to/from cells. Therefore,
surgery can alleviate lumbar radiculopathy, but some patients
the heart must begin to contract during early development.
continue to experience pain resistant to conventional
Observation of Wistar rat embryos transferred to a small
treatment. Intractable pain frequently is believed to be of
incubator mounted on a microscope revealed that the heart
neuropathic origin, a complex pain state typically accompanied
primordium, the so-called cardiac crescent, began to contract
by tissue and nerve injury. Neuropathic pain is defined as pain
at embryonic day 9.99-10.13. The observed first contractions
arising as a direct consequence of a lesion or disease affecting
were so weak that it was difficult to count the beating rate.
the somatosensory system, commonly observed in lumbar
Several minutes later, contractions became gradually stronger
radicular
and counting became feasible. When counting was feasible,
neuralgia. Postganglionic neurons in the sympathetic nervous
the heart primordia contracted regularly at a rate of 43.5 ± 5.0
system are considered to be involved in lumbar radicular pain
beats/min. The contractions subsequently became stronger at
and release norepinephrine (NE), a neurotransmitter. In order
pain,
diabetic
neuropathy,
and
postherpetic
33
to better understand the mechanism of lumbar radicular pain,
Therefore, the increase in lung resistance by desflurane might
we created a root constriction model rat that L5 root that was
be due to antidromic tachykinin release from afferent C-fibres
sutured proximal to the DRG. Increased numbers of
but not acetylcholine release from parasympathetic efferent
sympathetic nerve fibers were found in DRG neurons in the
nerves (5).
root constriction model. Electrophysiologic studies showed
that NE enhanced the excitability of DRG neurons in the root
constriction model. The effects of NE were inhibited by
1) Kobayashi T, Tohse N, Yokoshiki H, Sperelakis N,
pretreatment with the α-antagonist phentolamine or the α2-
Developmental Changes in Ion Channels., in Cell
antagonist yohimbine. However, the α1-antagonist prazosin
Physiology Source Book ~Fourth Edition~, Editor:
failed to abolish the responses to NE. These results suggested
Sperelakis N, 2012. p. 453-473, Academic Press.
that NE plays an important role in generating lumbar radicular
2) Kobayashi T, Maeda S, Ichise N, Sato T, Iwase T, Seki S,
pain mainly via α2-adrenoceptors.
Yamada Y, Tohse N. The beginning of the calcium
If the sympathetic nervous system generates pain after
transient in rat embryonic heart. J Physiol Sci 2011;
nerve damage, sympathectomy may attenuate pain behavior.
61(2): 141-149.
Next, we checked the effect of sympathectomy on a lumbar
3) Tanimoto K, Takebayashi T, Kobayashi T, Tohse N,
radiculophathy model. In behavioral analysis, sympathectomy
Yamashita T. Does norepinephrine influence pain
attenuated the mechanical allodynia and thermal hyperalgesia
behavior mediated by dorsal root ganglia?: a pilot study.
caused by lumbar root constriction. In electrophysiological
Clin Orthop Relat Res 2011; 469(9): 2568-2576.
analysis, single isolated DRG neurons with root constriction
4) Iwase T, Takebayashi T, Tanimoto K, Terashima Y,
exhibited a lower threshold current, more depolarized resting
Miyakawa T, Kobayashi T, Tohse N, Yamashita T.
membrane potential, prolonged action potential duration, and
Sympathectomy attenuates excitability of dorsal root
more
hyperexcitable
ganglion neurons and pain behaviour in a lumbar
alterations caused by root constriction were significantly
radiculopathy model. Bone Joint Res 2012; 1(9): 198-
attenuated in rats treated with surgical sympathectomy. These
204.
depolarization
frequency.
These
results suggest that sympathectomy attenuates lumbar
5) Satoh JI, Yamakage M, Kobayashi T, Tohse N, Watanabe
radicular pain resulting from root constriction by altering the
H, Namiki A. Desflurane but not sevoflurane can increase
electrical property of the DRG neuron itself. Therefore, the
lung resistance via tachykinin pathways. Br J Anaesth
sympathetic nervous system was closely associated with
2009; 102(5): 704-713
lumbar radicular pain, and suppressing the activity of the
sympathetic nervous system may lead to pain relief (3,4).
3. Desflurane but not sevoflurane can increase lung
resistance via tachykinin pathways
Sevoflurane is one of the volatile anaesthetics known as
a potent bronchodilator that has a direct relaxation effect on
airway smooth muscle cells. Although desflurane is also one
of the volatile anaesthetics that can directly relax preconstricted
airway smooth muscles in vitro, this anaesthetic increases the
lung resistance in vivo. Evaluating the effects of desflurane
and sevoflurane on total lung resistance (RL) and dynamic
lung compliance (CDyn) revealed that desflurane but not
sevoflurane increased RL concomitant with a decrease in CDyn
in guinea pigs. Antagonization of tachykinin receptors of
airway smooth muscles completely diminished the increase in
RL induced by desflurane. Desflurane also had little effect on
respiratory parameters after the capsaicin pretreatment, in
which tachykinin containing afferent C-fibres was desensitized.
34
Systems Neuroscience
In year 2008, we changed the name of our department from the
Second Department of Physiology to Systems Neuroscience, and
expanded our activities to include system level studies related to
human subjects in addition to animal level of experiments. Scopes
obtained from healthy subject as well as diseased conditions are
essential to conduct research not only for clinicians but also for basic
medical scientists. Human brain functions such as motor control,
memory, cognition and attention will be new targets for our study in
addition to basic studies on neural plasticity and cerebral circulation.
Professor
Interests:
Takashi Nagamine, M.D., Ph.D.
Cognitive function, Motor control, Electroencephalography,
Interests:
Epilepsy, Movement disorders
lnvestigation of human higher brain function using non-invasive
methods, Motor control, Cognitve function, Movement
Instructor
disorders
Masanori lshiguro, M.D., Ph.D.
lnterests:
Associate Professor
Cerebral vasospasm, Cerebral vascular disease, Patch clamp,
Yutaka Fujito, M.S., Ph.D.
Oxyhemoglobin, Hippocampus, GABAA receptor, Propofol
Interests:
Synaptic plasticity, Neural mechanisms of learning
Jun Shinozaki, Ph.D.
Neural mechanisms of respiration
lnterests:
Functional magnetic resonance imaging (fMRI), Cognitive
Neuroscience,Social cognition, Decision making
Assistant Professor
Shogo Yazawa, M.D., Ph.D.
1. Non-invasive exploration of human brain function
using 3 tesla scanner are ongoing (1), and the simultaneous
Human daily behavior is mostly driven by electric activities
EEG/EMG recording system during fMRI acquisition is also
in the brain and thus can be investigated from outside of the
helpful.
brain
the
b) MEG: We are currently exploring for cerebral responses
electromagnetic signal itself and secondary events. A
produced by somatosensory perception, loaded motor
combination
execution, and reactive movements by using MEG in Hokkaido
by
recording
of
physical
various
activities
methods
such
employing
as
different
paradigms could complement each other and provide direct
University collaborating with various departments.
insight into the relationship between the behavior and brain
2. Higher brain function of healthy human and patient
activities.
by
Exploration of higher brain function is an important issue.
electroencephalography (EEG), magnetoencephalography
Motor control mechanism (movement inhibition/ imagination,
(MEG), transcranial magnetic stimulation (TMS), and change
the effect under the low concentration of alcohol), meditation
of regional blood flow or metabolism shown by functional
(special attention process), and face cognition are being
magnetic resonance imaging (fMRI) are the main tools for this
studied by using various tools. A combination of several
study. The scope of this investigation can be further expanded
methods has facilitated the comprehension of higher brain
with the addition of trials performed on patients and animals,
function.
along with the efforts to verify the accuracy of methodological
Non-invasive brain mapping has been conducted for
issues.
presurgical evaluation of patients undergoing neurosurgery.
a) fMRI:
Electromagnetic
events
revealed
To examine human neural mechanisms non-
Surveys by MEG for patients with orofacial sensory
invasively, functional MRI is particularly useful. Functional
disturbance have made it possible to evaluate their complaints
MRI studies with radiologists and radialogical technologists
quantitatively (2). TMS studies have clarified the age-
35
dependent reduction of cortical plasticity in MI (3) and wide
those at small arteries and for the response to any chemicals
suppression of MI excitability accompanying voluntary
and animal models.
movement has ceased (4).
6. Automatic EEG interpretation
Collaborating with departments of neurology and
Reading EEG requires special skill and experience. We
neurosurgery, we have started scalp/subdural video-EEG
have been collaborating with Kyoto University and Saga
monitoring in epilepsy patients. Subdural recordings should
University to develop an automatic EEG interpretation for
produce substantial benefits for our exploration in the near
adult recordings which is composed of various steps (9). This
future.
project is to assist EEGers’ visual inspections, and has been
3. Neural mechanisms of learning and memory
validated for its integrated prototype form.
Synaptic plasticity in the red nucleus after partial
denervation or crossinnervation of forelimb muscles has been
investigated using electrophysiological and histological
1) Shinozaki J, Harada K, Nagahama H, Sakurai Y, Akatsuka
methods in cats. The pond snail, Lymnaea, can maintain a
Y, Nagamine T. In the range of 20 to 35 ms, an echo-time
conditioned taste aversion (CTA) as a long-term memory. In
of 20 ms is preferred for 3-tesla functional magnetic
the course of our research, we showed the long-term
resonance imaging. Adv Biomed Eng. 2: 47-54 (2013)
enhancement of both inhibitory and excitatory synaptic
2) Maezawa H, Matsuhashi M, Yoshida K, Mima T,
connections in the feeding central pattern generator in CTA
Nagamine T, Fukuyama H. Evaluation of lip sensory
trained snails (5). Findings suggested that cyclic AMP-
disturbance using somatosensory evoked magnetic
responsive element binding protein and insulin like peptide
have important roles in the acquisition and consolidation of
fields. Clin Neurophysiol 125(2): 363-9 (2014).
3) Fathi D, Ueki Y, Mima T, Koganemaru S, Nagamine T,
CTA in the Lymnaea central nervous system (6).
Tawfik A, Fukuyama H. Effects of aging on the human
4. Investigation of central nervous system in vivo and in
motor cortical plasticity studied by paired associative
vitro
stimulation. Clin Neurophysiol 121(1):90-3 (2011)
Studies have been conducted on the central nervous
4) Badry R, Mima T, Aso T, Nakatsuka M, Abe M, Fathi D,
system for respiratory rhythm generation in cats and mice.
Foly N, Nagiub H, Nagamine T, Fukuyama H. Suppression
Findings suggested that the 5-HT released from the raphe
of human cortico-motoneuronal excitability during the
nuclei (predominantly the raphe pallidus) plays a critical role
Stop-signal task.
in sustaining rhythmic respiratory bursts in brain stem slices
(2009)
Clin Neurophysiol 120(9):1717-23
prepared from newborn mice (7). We have shown that the
5) Ito E, Otsuka E, Hama N, Aonuma H, Okada R,
spinal neuronal circuit for generating respiratory rhythm is
Hatakeyama D, Fujito Y, Kobayashi S. Memory trace in
localized in the upper cervical segments that contain upper
feeding neural circuitry underlying conditioned taste
cervical inspiratory neurons in the C1/C2 slices.
aversion in Lymnaea. PLoS One 7:e43151 (2012).
The γ-aminobutyric acid type A (GABAA) receptors are
6) Murakami J, Okada R, Sadamoto H, Kobayashi S, Mita
the major inhibitory neurotransmitter receptors in the
K, Sakamoto Y, Yamagishi M, Hatakeyama D, Otsuka E,
mammalian brain. We are looking at the inhibitory postsynaptic
Okuta A, Sunada H, Takigami S, Sakakibara M, Fujito Y,
currents of the rat hippocampus CA1 pyramidal cells and
Awaji M, Moriyama S, Lukowiak K, Ito E. Involvement of
dentate gyrus granular cells using the whole cell patch clamp
insulin-like peptide in long-term synaptic plasticity and
technique. The effect of anesthetic agents such as midazolam
long-term memory of the pond snail Lymnaea stagnalis. J
and propofol on inhibitory postsynapitc currents is also being
Neurosci 33:371-383 (2013).
explored.
7) Kobayashi S, Fujito Y, Matsuyama K, Aoki M. Raphe
5. Pressure induced vasoconstriction (Bayliss effect) of
modulation of the pre-Botzinger complex respiratory
cerebral artery
bursts in in vitro medullary half-slice preparations of
Small diameter arteries play a critical role in the control of
neonatal mice. J Comp Physiol A 196: 519-528 (2010).
cerebral blood flow. Under physiological conditions, small
8) Kawamura M, Ishiguro M, Nagamine T, Houkin K.
diameter cerebral arteries exist in a partially constricted state
Sarpogrelate dilates cerebral arteries in the absence of
that allows various metabolic, humoral and/or neurogenic
exogenous
factors to increase or decrease arterial diameter to match
cerebral blood flow with tissue demand.
serotonin.
Neurol
Med
Chir
(Tokyo).
53(5):291-8 (2013).
9) Ji Z, Sugi T, Goto S, Wang X, Ikeda A, Nagamine T,
We are examining how the small diameter cerebral
Shibasaki H, Nakamura M. An automatic spike detection
arteries react under physiological or pathological condition
system based on elimination of false positives using the
(8). The methodological setup designed for this study can be
large-area context in the scalp EEG. IEEE Trans Biomed
useful not only for studies aimed at cerebral artery but also for
Eng. 58(9):2478-88 (2011).
36
Medical Biochemistry
Our department has been investigating the molecular mechanisms of
the regulation of protein functions and studying through biochemical
approaches the pathophysiology of diseases. We are now focusing
on the mechanisms of innate immunity and on the regulation of signal
transduction by N-glycan.
Professor
Associate Professor
Assistant Professor
Yoshio Kuroki, M.D., Ph.D.
Motoko Takahashi, M.D., Ph.D.
Shigeru Ariki, Ph.D.
Interests:
Interests:
Instructor:
Innate immunity and disease
Regulation of signal transduction by
Yoshihiro Hasegawa, M.D.
pathophysiology
N-glycans
Rina Takamiya, Ph.D.
1. Collectins and innate immunity
biological events. Since most of the molecules involved in
Pulmonary surfactant proteins A and D (SP-A and SP-D)
cell-cell communication are glycosylated, it is important in
belong to the collectin family that is characterized by the
signal transduction study to clarify the mechanisms by which
collagen-like domain and the C-type lectin domain. The
glycosylation regulates protein functions. We determined the
collectins play pivotal roles in host defense and regulation of
role of modification of the N-glycan core, such as core
inflammation (8, 18, 19). We have found that SP-A and SP-D
fucosylation, in signaling molecules (1, 20-21). We also found
play important roles in host defense against intracellular
that specific glycosylation is involved in EGFR-family dimer
pathogens such as Legionella pneumophila and Mycobacterium
formation, and developed a novel heregulin-signaling inhibitor
avium (13-14). Collectins directly bind to these pathogens and
by manipulating N-glycan of sErbB3 (2).
attenuate growth of the bacteria in a culture medium.
4. In vivo role of aldehyde reductase
Furthermore, collectins suppress intracellular growth of L.
Aldehyde reductase (AKR1A; EC 1.1.1.2) catalyzes the
pneumophila by promoting the lysosomal fusion with
reduction of aldehydes in an NADPH-dependent manner, and
Legionella-containing phagosomes.
has been implicated in detoxification of various carbonyl
We have also been studying the function of collectins
compounds. We analyzed AKR1A knockout mice to determine
expressed in urinary tracts. SP-D decreases uropathogenic
its physiological role, and found that it is involved in ascorbic
E. coli (UPEC) adherence to bladder cells and UPEC-induced
acid biosynthesis (7).
cytotoxicity both by direct interaction with UPEC and by
competing with FimH, a lectin on UPEC, for uroplakin Ia
binding (6). These data indicate that SP-D protects the
1) Hasegawa Y, Takahashi M, Ariki S, Asakawa D, Tajiri M,
urothelium against UPEC infection.
Wada Y, Yamaguchi Y, Nishitani C, Takamiya R, Saito A,
2. SP-A decreases cytotoxicity of human β-defensin 3
Uehara Y, Hashimoto J, Kurimura Y, Takahashi H, Kuroki
(hBD3)
Y. Surfactant protein D suppresses lung cancer
Although antimicrobial peptides (AMP) play important
progression by downregulation of epidermal growth
roles in innate immune responses and wound healing, higher
factor signaling. Oncogene in press.
concentration of AMP causes excess inflammation and tissue
2) Takahashi M, Hasegawa Y, Ikeda Y, Wada Y, Tajiri M,
injury. We found that SP-A protects lung epithelium from
Ariki S, Takamiya R, Nishitani C, Araki M, Yamaguchi Y,
tissue injury caused by hBD3 both in vitro and in vivo (11).
Taniguchi N, Kuroki Y. Suppression of heregulin β
Furthermore, we found that the functional region of SP-A lies
signaling by single N-glycan deletion mutant of soluble
within Tyr
161
-Lys
201
. The synthetic peptide of the functional
region of SP-A is a candidate as a therapeutic reagent that
ErbB3 protein. J Biol Chem. (2013) 288: 32910-32921.
3) Kondo Y, Ikeda K, Tokuda N, Nishitani C, Ohto U, Akashi-
prevents tissue injury during inflammation.
Takamura S, Ito Y, Uchikawa M, Kuroki Y, Taguchi R,
3. The regulation of signal transduction by N-glycans
Miyake K, Zhang Q, Furukawa K, Furukawa K. TLR4-
Glycosylation is one of the most common post-
MD-2 complex is negatively regulated by an endogenous
translational modifications, and is involved in a variety of
ligand, globotetraosylceramide. Proc Natl Acad Sci
37
USA (2013) 110: 4714-4719.
14)Sawada K, Ariki S, Kojima T, Saito A, Yamazoe M,
Nishitani C, Shimizu T, Takahashi M, Mitsuzawa H,
Yokota S, Sawada N, Fujii N, Takahashi H, Kuroki Y.
Pulmonary collectins protect macrophages against pore-
gangliosides in non-small cell lung cancer using GMR8
forming activity of Legionella pneumophila and suppress
monoclonal antibody. Cancer Sci. (2013) 104: 43-47.
its intracellular growth. J Biol Chem. (2010) 285: 8434-
5) Miyashita H, Kuroki Y, Kretsinger RH, Matsushima N.
8443.
Horizontal gene transfer of plant-specific leucine-rich
15) Murata M, Otsuka M, Mizuno H, Shiratori M, Miyazaki S,
repeats between plants and bacteria. Natural Sci. (2013)
Nagae H, Kanazawa S, Hamaoki M, Kuroki Y, Takahashi
5: 580-598.
H. Development of an enzyme-linked immunosorbent
6) Kurimura Y, Nishitani C, Ariki S, Saito A, Hasegawa Y,
assay for measurement of rat pulmonary surfactant
Takahashi M, Hashimoto J, Takahashi S, Tsukamoto T,
protein D using monoclonal antibodies. Exp Lung Res.
Kuroki Y. Surfactant protein D inhibits adherence of
(2010) 36: 463-468.
uropathogenic Escherichia coli to the bladder epitherial
16) Matsushima N, Miyashita H, Mikami T, Kuroki Y. A nested
cells and the bacteria-induced cytotoxicity: A POSSIBLE
leucine rich repeat (LRR) domain: the precursor of LRRs
FUNCTION IN URINARY TRACT. J Biol Chem. (2012)
is a ten or eleven residue motif. BMC Microbiol. (2010)
287: 39578-39588.
10: 235.
7) Takahashi M, Miyata S, Fujii J, Inai Y, Ueyama S, Araki M,
17) Hoshino S, Konishi M, Mori M, Shimura M, Nishitani C,
Soga T, Fujinawa R, Nishitani C, Ariki S, Shimizu T, Abe
Kuroki Y, Koyanagi Y, Kano S, Itabe H, Ishizaka Y. HIV-1
T, Ihara Y, Nishikimi M, Kozutsumi Y, Taniguchi N, Kuroki
Vpr induces TLR4/MyD88-mediated IL-6 production and
Y. In vivo role of aldehyde reductase. Biochim Biophys
reactivates viral production from latency. J Leukoc Biol.
Acta (2012) 1820: 1787-1796.
(2010) 87: 1133-1143.
8) Ariki S, Nishitani C, Kuroki Y. Diverse functions of
18) Shimizu T, Nishitani C, Mitsuzawa H, Ariki S, Takahashi
pulmonary collectins in host defense of the lung. J
M, Ohtani K, Wakamiya N, Kuroki Y. Mannose binding
Biomed Biotechnol. (2012) 2012: article ID 532071.
lectin and lung collectins interact with Toll-like receptor 4
[Review]
and MD-2 by different mechanisms. Biochim Biophys
9) Yokota SI, Amano KI, Nishitani C, Ariki S, Kuroki Y, Fujii
N. Implication of antigenic conversion of Helicobacter
Acta. (2009) 1790: 1705-1710.
19) Nishitani C, Takahashi M, Mitsuzawa H, Shimizu T, Ariki
88
pylori lipopolysaccharides involving interaction with
S, Matsushima N, Kuroki Y. Mutational analysis of Cys
surfactant protein D. Infect Immun. (2012) 80: 2956-
of Toll-like receptor 4 highlights the critical role of MD-2 in
2962.
cell surface receptor expression. Int Immunol. (2009)
10) Mikami T, Miyashita H, Takatsuka S, Kuroki Y, Matsushima
21: 925-934.
N. Molecular evolution of vertebrate Toll-like receptors:
20)Takahashi M, Kuroki Y, Ohtsubo K, Taniguchi N. Core
Evolutionary rate difference between their leucine-rich
fucose and bisecting GlcNAc, the direct modifiers of the
repeats and their TIR domains. Gene (2012) 503: 235-
N-glycan core: their functions and target proteins.
Carbohydr Res. (2009) 344: 1387-1390. [Review]
243.
11) Saito A, Ariki S, Sohma H, Nishitani C, Inoue K, Ebata N,
21)Osumi D, Takahashi M, Miyoshi E, Yokoe S, Lee SH,
Takahashi M, Hasegawa Y, Kuronuma K, Takahashi H,
Noda K, Nakamori S, Gu J, Ikeda Y, Kuroki Y, Sengoku K,
Kuroki Y. Pulmonary surfactant protein A protects lung
Ishikawa M, Taniguchi N. Core fucosylation of E-cadherin
epithelium from cytotoxicity of human β-defensin 3. J Biol
enhances cell-cell adhesion in human colon carcinoma
Chem. (2012) 287: 15034-15043.
WiDr cells. Cancer Sci. (2009) 100: 885-895.
12)Tu Z, Hamalainen-Laanaya HK, Nishitani C, Kuroki Y,
22) Kuronuma K, Mitsuzawa H, Takeda K, Nishitani C, Chan
Crispe IN, Orloff MS. HCV core and NS3 proteins
ED, Kuroki Y, Nakamura M, Voelker DR. Anionic
manipulate
cell
pulmonary surfactant phospholipids inhibit inflammatory
development and promote Th 17 differentiation. Int
responses from alveolar macrophages and U937 cells by
Immunol. (2012) 24: 97-106.
binding the lipopolysaccharide interacting proteins CD14
human
blood-derived
dendritic
13) Ariki S, Kojima T, Gasa S, Saito A, Nishitani C, Takahashi
and MD2. J Biol Chem. (2009) 284: 25488-25500.
M, Shimizu T, Kurimura Y, Sawada N, Fujii N, Kuroki Y.
23) Matsushima N, Mikami T, Tanaka T, Miyashita H, Yamada
Pulmonary collectins play distinct roles in host defense
K, Kuroki Y. Analyses of non-leucine rich repeat (Non-LRR)
against Mycobacterium avium. J Immunol. (2011) 187:
regions intervening between LRRs in proteins. Biochim
2586-2594.
Biophys Acta. (2009) 1790: 1217-1237.
38
Molecular Biology
Epigenetic alterations including aberrant DNA methylation and
histone modifications are hallmarks of human malignancies. Our
department is working on cancer epigenetics to understand the
molecular mechanism of tumorigenesis and to apply our findings to
develop new diagnoses and treatment strategies. We have
discovered a number of tumor-related genes and noncoding RNA
genes that are epigenetically dysregulated in cancer. We also provide
evidence that they could be useful biomarkers as well as potential
therapeutic targets.
Professor
Assistant Professor
Instructor:
Hiromu Suzuki, M.D., Ph.D.
Masahiro Kai, Ph.D.
Reo Maruyama, M.D., Ph.D.
Interests:
Interests:
Akiko Sato, M.D., Ph.D.
Cancer genetics and epigenetics
Signal transduction in cancer cells
Takeshi Niinuma, M.D., Ph.D.
1. Screen for epigenetically silenced genes in cancer
DNA methylation plays a key role in the silencing of
cancer-related genes, thereby affecting numerous cellular
processes, including the cell cycle checkpoint, apoptosis,
signal transduction, cell adhesion and angiogenesis. By
combining the demethylating treatment and gene expression
microarray analysis, we identified a number of tumor-related
genes that are epigenetically silenced in multiple myeloma
(MM) and breast cancer cells (1,2). We also found that
inactivation of RASD1 plays a key role in the dexamethasone
resistance in MM (2).
2. The role of genetic and epigenetic events during the
colorectal tumorigenesis
It is generally accepted that colorectal cancers (CRCs)
can exhibit either of two genetic instabilities: chromosomal
instability (CIN) or microsatellite instability (MSI) (3). In
addition, epigenetic alterations are thought to be the main
driving force in a subset of CRCs exhibiting concurrent
hypermethylation of multiple loci, which is termed the CpG
island methylator phenotype (CIMP) (4). We carried out
integrative genomic and epigenetic analysis and revealed
early onset of CIMP during CRC development (5). We also
identified a novel surface microstructure that is highly specific
to the premalignant lesions of CIMP-positive CRCs, and this
could be a useful hallmark to identify precursors of CIMP/MSIpositive CRCs (6).
3. Epigenetic alterations of noncoding RNA genes in
cancer
MicroRNAs (miRNAs) are a class of small noncoding
RNAs that regulate gene expression by inducing translational
inhibition or direct degradation of target mRNAs. Altered
expression of miRNAs occurs commonly in human cancer,
but the mechanisms are generally poorly understood. We
screened for epigenetically silenced miRNA genes in gastric,
colorectal and bladder cancer and malignant melanoma cells,
and identified a number of miRNA genes silenced in
association with aberrant DNA methylation (7-9). We carried
out high-resolution ChIP-seq to analyze genome-wide histone
modifications in CRC cells, and revealed epigenetic
dysregulation of miRNA genes (8). Moreover, we identified
frequent upregulation of miR-196a and a large intergenic
noncoding RNA (lincRNA) HOTAIR in gastrointestinal stromal
tumors (GISTs), suggesting that these noncoding RNAs could
be useful biomarkers and potential therapeutic targets (10).
4. Epigenetic alterations as cancer biomarkers
DNA methylation could be a useful biomarker for
detecting cancer and predicting its outcome. We collected
DNA present in mucosal wash fluid from patients undergoing
colonoscopy and found that DNA methylation in the wash fluid
may be a good molecular marker for predicting the
invasiveness of colorectal tumors (11). Aberrant DNA
methylation is implicated in the epigenetic field defect seen in
gastric cancer (GC). We analyzed DNA methylation in the
background gastric mucosa from patients with GC and found
that methylation of RASGRF1 and miR-34b/c is significantly
involved in an epigenetic field defect in the stomach, and that
it could be a predictive marker of GC risk (7,12,13). We also
showed that aberrant DNA methylation of miRNA genes
detected in the urine specimens of bladder cancer patients
could be a biomarker for cancer detection (7). Genome wide
hypomethylation is also implicated in various malignancies,
and we found that hypomethylation of a repetitive element
LINE-1 could be a biomarker for predicting the risk and
prognosis of GIST and multiple myeloma (14,15).
39
1) Nojima M, Maruyama R, Yasui H, Suzuki H, Maruyama Y,
Tarasawa I, Sasaki Y, Asaoku H, Sakai H, Hayashi T, Mori
M, Imai K, Tokino T, Ishida T, Toyota M, Shinomura Y.
Genomic screening for genes silenced by DNA
methylation revealed an association between RASD1
inactivation and dexamethasone resistance in multiple
myeloma. Clin Cancer Res (2009) 15: 4356-4364.
2) Fujikane T, Nishikawa N, Toyota M, Suzuki H, Nojima M,
Maruyama R, Ashida M, Ohe-Toyota M, Kai M, Nishidate
T, Sasaki Y, Ohmura T, Hirata K, Tokino T. Genomic
screening for genes upregulated by demethylation
revealed novel targets of epigenetic silencing in breast
cancer. Breast Cancer Res Treat (2010) 122: 699-710.
3) Sawada T, Yamamoto E, Suzuki H, Nojima M, Maruyama
R, Shioi Y, Akasaka R, Kamimae S, Harada T, Ashida M,
Kai M, Adachi Y, Yamamoto H, Imai K, Toyota M, Itoh F,
Sugai T. Association between genomic alterations and
metastatic behavior of colorectal cancer identified by
array-based comparative genomic hybridization. Genes
Chromosomes Cancer (2013) 52:140-149.
4) Suzuki H, Igarashi S, Nojima M, Maruyama R, Yamamoto
E, Kai M, Akashi H, Watanabe Y, Yamamoto H, Sasaki Y,
Itoh F, Imai K, Sugai T, Shen L, Issa JP, Shinomura Y,
Tokino T, Toyota M. IGFBP7 is a p53-responsive gene
specifically silenced in colorectal cancer with CpG island
methylator phenotype. Carcinogenesis (2010) 31: 342349.
5) Yamamoto E, Suzuki H, Yamano HO, Maruyama R,
Nojima M, Kamimae S, Sawada T, Ashida M, Yoshikawa
K, Kimura T, Takagi R, Harada T, Suzuki R, Sato A, Kai M,
Sasaki Y, Tokino T, Sugai T, Imai K, Shinomura Y, Toyota
M. Molecular dissection of premalignant colorectal
lesions reveals early onset of the CpG island methylator
phenotype. Am J Pathol (2012) 181: 1847-1861.
6) Kimura T, Yamamoto E, Yamano HO, Suzuki H, Kamimae
S, Nojima M, Sawada T, Ashida M, Yoshikawa K, Takagi
R, Kato R, Harada T, Suzuki R, Maruyama R, Kai M, Imai
K, Shinomura Y, Sugai T, Toyota M. A novel pit pattern
identifies the precursor of colorectal cancer derived from
sessile serrated adenoma. Am J Gastroenterol (2012)
107: 460-469.
7) Suzuki H, Yamamoto E, Nojima M, Kai M, Yamano HO,
Yoshikawa K, Kimura T, Kudo T, Harada E, Sugai T,
Takamaru H, Niinuma T, Maruyama R, Yamamoto H,
Tokino T, Imai K, Toyota M, Shinomura Y. Methylationassociated silencing of microRNA-34b/c in gastric cancer
and its involvement in an epigenetic field defect.
Carcinogenesis (2010) 31: 2066-2073.
8) Suzuki H, Takatsuka S, Akashi H, Yamamoto E, Nojima
M, Maruyama R, Kai M, Yamano HO, Sasaki Y, Tokino T,
Shinomura Y, Imai K, Toyota M. Genome-wide profiling of
chromatin signatures reveals epigenetic regulation of
microRNA genes in colorectal cancer. Cancer Res (2011)
71: 5646-5658.
9) Shimizu T, Suzuki H, Nojima M, Kitamura H, Yamamoto
E, Maruyama R, Ashida M, Hatahira T, Kai M, Masumori
N, Tokino T, Imai K, Tsukamoto T, Toyota M. Methylation
of a panel of microRNA genes is a novel biomarker for
detection of bladder cancer. Eur Urol (2013) 63:10911100.
10) Niinuma T, Suzuki H, Nojima M, Nosho K, Yamamoto H,
Takamaru H, Yamamoto E, Maruyama R, Nobuoka T,
Miyazaki Y, Nishida T, Bamba T, Kanda T, Ajioka Y,
Taguchi T, Okahara S, Takahashi H, Nishida Y, Hosokawa
M, Hasegawa T, Tokino T, Hirata K, Imai K, Toyota M,
Shinomura Y. Upregulation of miR-196a and HOTAIR
drive malignant character in gastrointestinal stromal
tumors. Cancer Res (2012) 72: 1126-1136.
11)Kamimae S, Yamamoto E, Yamano HO, Nojima M,
Suzuki H, Ashida M, Hatahira T, Sato A, Kimura T,
Yoshikawa K, Harada T, Hayashi S, Takamaru H,
Maruyama R, Kai M, Nishiwaki M, Sugai T, Sasaki Y,
Tokino T, Shinomura Y, Imai K, Toyota M. Epigenetic
alteration of DNA in mucosal wash fluid predicts
invasiveness of colorectal tumors. Cancer Prev Res
(2011) 4: 674-683.
12)Takamaru H, Yamamoto E, Suzuki H, Nojima M,
Maruyama R, Yamano HO, Yoshikawa K, Kimura T,
Harada T, Ashida M, Suzuki R, Yamamoto H, Kai M,
Tokino T, Sugai T, Imai K, Toyota M, Shinomura Y.
Aberrant methylation of RASGRF1 is associated with an
epigenetic field defect and increased risk of gastric
cancer. Cancer Prev Res (2012) 5: 1203-1212.
13) Suzuki R, Yamamoto E, Nojima M, Maruyama R, Yamano
HO, Yoshikawa K, Kimura T, Harada T, Ashida M, Niinuma
T, Sato A, Nosho K, Yamamoto H, Kai M, Sugai T, Imai K,
Suzuki H, Shinomura Y. Aberrant methylation of
microRNA-34b/c is a predictive marker of metachronous
gastric cancer risk. J Gastroenterol (2013) [Epub ahead
of print]
14) Igarashi S, Suzuki H, Niinuma T, Shimizu H, Nojima M,
Iwaki H, Nobuoka T, Nishida T, Miyazaki Y, Takamaru H,
Yamamoto E, Yamamoto H, Tokino T, Hasegawa T, Hirata
K, Imai K, Toyota M, Shinomura Y. A novel correlation
between LINE-1 hypomethylation and the malignancy of
gastrointestinal stromal tumors. Clin Cancer Res (2010)
16: 5114-5123.
15)Aoki Y, Nojima M, Suzuki H, Yasui H, Maruyama R,
Yamamoto E, Ashida M, Itagaki M, Asaoku H, Ikeda H,
Hayashi T, Imai K, Mori M, Tokino T, Ishida T, Toyota M,
Shinomura Y. Genomic vulnerability to LINE-1
hypomethylation is a potential determinant of the
clinicogenetic features of multiple myeloma. Genome
Med. (2012) [Epub ahead of print]
40
Pathology (I)
Pathology covers enormously diverse fields of medicine across the
organs. Surgical digagnosis helps a clinician’s decision concerning
therapeutic treatment, and moreover molecular-based basic and
translational researches contribute largely to the develepment of
future medicine. Since 1945, our department has been studying the
pathogenesis of various human diseases, particularly tumors; one of
our current interests is immunologic approaches to curing malignant
tumors. Education also has a significant role in our missions.
Professor and Chairman
Instructor
Instructor
Noriyuki Sato, M.D., Ph.D
Yoshihiko Hirohashi,M.D., Ph.D
Takayuki Kanaseki, M.D., Ph.D.
Interests:
Interests:
Tumor biology, cancer stem cells
Immunology, antigen processing
Associate Professor
Toshihiko Torigoe, MD, PhD
Interests:
Instructor
Cell and stress biology
Tomohide Tsukahara, M.D., Ph.D.
Interests:
Bone and soft tissue tumors
Four independent research groups are currently working on
composed of cancer stem cells (CSCs) and other cells. CSCs
the subjects described below. Our research is guided by a
have the ability to renew themselves (self-renewal) and give
wide range of experience and expertise in numerous fields in
rise to non-CSCs (differentiation), and surprisingly, even a
addition to pathology, including immunology, tumor biology
small CSC population rapidly forms a mass of tumors in vivo,
and cell biology.
or are even resistant to chemotherapies. Thus, CSCs are
arguably the best target for cancer therapy.
1. Tumor Immunoregulation
We have so far investigated and identified several genes
Circulating cytotoxic T lymphocytes (CTL) discriminate
responsible for their unique characteristics that initiate tumor
the cells presenting a particular peptide-MHC class I complex
formation, which potentially allows us to distinguish CSCs
(pMHCI), and are consequently able to eliminate ‘non-self’
from non-CSCs or non-tumor cells (1-5).
such as virally-infected or transformed tumor cells. However,
3. Tumor Antigen Processing
in contrast to many viral infections, malignant tumors on their
A key toward eliciting CTL responses is pMHCI, which is
own hardly regress, suggesting their nature is to escape from
produced inside the cells by extremeley complicated
the immune surveillance in vivo.
mechanisms consisting of multiple steps. This pathway,
Our ultimate goal is to develop a cure for many patients
antigen processing, is often defected in tumor cells, and an
by applying tumor antigens for effective CTL inductions
altered pMHCI repertoire on tumor surfaces consequently
specific to malignant tumor cells (vaccination). In order to
allows them to escape from CTL surveillance (6). In order to
maximize the effects, we carefully select the target populations
ensure a target specificity of induced CTL, we developed a
(CSCs, see below), or take advantage of natural antigenic
comprehensive system to screen an array of NAPs, which are
peptides (NAPs). We deal with a broad range of malignant
naturally processed and displayed by HLA-A24 molecules of
tumors including those of digestive, respiratory, gynecological,
tumor cells.
urological, bone and soft tissue origins.
4. Cellular Stress Biology
2. Cancer Stem Cells
Cellular stresses alter the gene expression patterns of
Tumors are considered as a heterogenious population
cells, which in turn affects their immune responses. Heat
41
Shock Protein (HSP) is a group of chaperone molecules
Edit the Amino and Carboxyl Termini of MHC Class I
whose expressions are induced by a heat shock. Interestingly,
Peptides. J Immunol, 15;191(4):1547-55, 2013.
we found HSP plays a significant role in enhancing antigen
7) Takahashi A, Torigoe T, Tamura Y, Kanaseki T, Tsukahara
processing, or CTL responses. In addition, we are also
T, Sasaki Y, Kameshima H, Tsuruma T, Hirata K, Tokino T,
interested in the relationship between stress gene expressions
Hirohashi Y, Sato N. Heat shock enhances the expression
and gain of ‘stemness’ (7-10).
of cytotoxic granule proteins and augments the activities
5. Clinical Applications
of
One of the identified peptides derived from a tumor
lymphocytes. Cell Stress Chaperones. 2012 Nov;17(6):
antigen, survivin, is being used as an anti-cancer vaccine, in
clinilal trials targeting advanced colorectal cancer patients
tumor-associated
antigen-specific
cytotoxic
T
757-63.
8) Tamura Y, Hirohashi Y, Kutomi G, Nakanishi K, Kamiguchi
K, Torigoe T, Sato N. Tumor-produced secreted form of
and pancreatic cancer patients (12-13).
binding of immunoglobulin protein elicits antigen-specific
tumor immunity. J Immunol. 2011 Apr 1;186(7):4325-30.
1) Nishizawa S, Hirohashi Y, Torigoe T, Takahashi A, Tamura
9) Okuya K, Tamura Y, Saito K, Kutomi G, Torigoe T, Hirata
Y, Mori T, Kanaseki T, Kamiguchi K, Asanuma H, Morita
K, Sato N. Spatiotemporal regulation of heat shock
R, Sokolovskaya A, Matsuzaki J, Yamada R, Fujii R,
protein
Kampinga HH, Kondo T, Hasegawa T, Hara I, Sato N.
oligodeoxynucleotide for type I IFN induction via targeting
HSP DNAJB8 controls tumor-initiating ability in renal
to static early endosome. J Immunol. 2010 Jun
cancer
15;184(12):7092-9.
stem-like
cells.
Cancer
Res.
2012
Jun
1;72(11):2844-54.
90-chaperoned
self-DNA
and
CpG-
10) Torigoe T, Hirohashi Y, Yasuda K, Sato N. Constitutive
2) Inoda S, Hirohashi Y, Torigoe T, Morita R, Takahashi A,
expression and activation of stress response genes in
Asanuma H, Nakatsugawa M, Nishizawa S, Tamura Y,
cancer stem-like cells/tumour initiating cells: potent
Tsuruma T, Terui T, Kondo T, Ishitani K, Hasegawa T,
targets for cancer stem cell therapy. Int J Hyperthermia.
Hirata K, Sato N. Cytotoxic T lymphocytes efficiently
2013 Aug;29(5):436-41.
recognize human colon cancer stem-like cells. Am J
Pathol. 2011 Apr;178(4):1805-13.
11) Kameshima H, Tsuruma T, Kutomi G, Shima H, Iwayama
Y, Kimura Y, Imamura M, Torigoe T, Takahashi A,
3) Morita R, Hirohashi Y, Suzuki H, Takahashi A, Tamura Y,
Hirohashi Y, Tamura Y, Tsukahara T, Kanaseki T, Sato N,
Kanaseki T, Asanuma H, Inoda S, Kondo T, Hashino S,
Hirata K. Immunotherapeutic benefit of α-interferon
Hasegawa T, Tokino T, Toyota M, Asaka M, Torigoe T,
(IFNα) in survivin2B-derived peptide vaccination for
Sato N. DNA methyltransferase 1 is essential for initiation
advanced pancreatic cancer patients. Cancer Sci. 2013
of the colon cancers. Exp Mol Pathol. 2013 Apr;94(2):322-
Jan;104(1):124-9.
9.
12)Kameshima H, Tsuruma T, Torigoe T, Takahashi A,
4) Yamada R, Takahashi A, Torigoe T, Morita R, Tamura Y,
Hirohashi Y, Tamura Y, Tsukahara T, Ichimiya S, Kanaseki
Tsukahara T, Kanaseki T, Kubo T, Watarai K, Kondo T,
T, Iwayama Y, Sato N, Hirata K. Immunogenic
Hirohashi Y, Sato N. Preferential expression of cancer/
enhancement and clinical effect by type-I interferon of
testis genes in cancer stem-like cells: proposal of a novel
anti-apoptotic protein, survivin-derived peptide vaccine,
sub-category, cancer/testis/stem gene. Tissue Antigens.
in advanced colorectal cancer patients. Cancer Sci. 2011
2013 Jun;81(6):428-34.
Jun;102(6):1181-7.
5) Kano M, Tsukahara T, Emori M, Murase M, Torigoe T,
Kawaguchi S, Wada T, Yamashita T, Sato N. Autologous
CTL response against cancer stem-like cells/cancerinitiating cells of bone malignant fibrous histiocytoma.
Cancer Sci. 2011 Aug;102(8):1443-7.
6) Kanaseki T, Lind KC, Escobar H, Nagarajan N, ReyesVargas E, Rudd B, Rockwood AL, Van Kaer L, Sato N,
Delgado JC, Shastri N. ERAAP and Tapasin Independently
42
Pathology (ll)
The human body includes various compartments that maintain
considerable independence from blood by means of a continuous
cell sheet. For the functions of these compartments, passage through
the intercellular spaces of the sheet must be strictly regulated by tight
junctions. Once tight junctions are disturbed, illnesses such as
edema, jaundice or diarrhea will develop. Our department has been
trying to expand our understanding of the molecular regulation of
tight junctions in regard to treatment of human diseases.
Professor
Assistant Professor
Instructor
Norimasa Sawada, M.D., Ph.D.
Satoshi Tanaka, M.D., Ph.D.
Akira Takasawa, M.D.
Interests:
Interests:
Tight junctions and human diseases,
Cell differentiation, Tetraspanin
Biology of hepatocytes
Tight junctions, Redox
Assistant Professor
Masaki Murata, M.D., Ph.D.
Interests:
Tight junction and cell polarity,
Cell differentiation
1. What are tight junctions? (1)
dendritic cells are shown to express tight junction proteins (5).
Tight junctions are intercellular junctions adjacent to the
Nasal epithelium is first infected by Respiratory syncytial virus
apical end of the lateral membrane surface. They have two
(RSV). RSV infection causes the induction of tight junction
functions, the barrier function and the fence function. The
function of the cells with an increase of tight junction proteins
barrier function of tight junctions regulates the passage of
(6) and MMP-10 (7). RSV replication depends on the
ions, water, and various macromolecules through paracellular
PKCdelta/HIF-1alpha/NFkappa-B pathway(6). RSV replication
spaces. The fence function maintains cell polarity. In other
was inhibited by antagonists of the pathway (8). Tight junctions
words, tight junctions work as a fence to prevent intermixing
of hepatocytes seal the bile canaliculi, preventing leakage of
of molecules in the apical membrane with those in the lateral
the bile(9). We suggested that claudin2 is essential to form
membrane. Recently, two novel aspects of tight junctions
bile canaliculi (10). Tri-cellular tight junctions show a distinct
have been reported. One aspect concerns their involvement
anatomical structure, where tricellulin is concentrated at
in signal transduction. The other is that fact that tight junctions
tricellular contact areas. Tricellulin is regulated via c-Jun
are considered to be a crucial component of innate immunity.
N-terminal kinase even in pancreatic duct carcinoma cells as
Our study focuses on regulation of functions of tight junctions
well as the normal duct cells (11). Tricellulin is considered to
under patho-physiological conditions. Recent advances of our
contribute considerably to the barrier and fence functions(12).
works will be overviewed in the following paragraphs.
3. Tight junctions of cancer cells in various tissues
2. Patho-physiological changes of tight junctions in
In general, cancer cells lose their polarity with a decrease
nasal mucosa
in the functions of tight junctions. However, certain components
The airway epithelium, in particular the nasal epithelium,
of tight junction proteins are up-regulated in cancer cells.
is the first line of defense against allergens and infectious
Tight junction protein claudin4 is shown to increase in several
agents. Using cultures of human nasal epithelial cells, we
kinds of malignant tissues (1). Claudin4 is a receptor for the
revealed that tight junctions of the epithelium were regulated
enterotoxin of Clostridium perfringens (CPE). Its binding
by TSLP and TLRs (2,3). PPAR-gamma agonists enhance the
exerts cytotoxicity. We revealed that
tight junction barrier of the culture cells (4). In addition,
malignant cells derived from the pancreas(13,14), and
claudin4-expressing
43
prostate(15) are more sensitive than normal cells. PKCalpha
Gap and tight junctions in liver: composition, regulation,
enhances its toxic effects on pancreas cancer cells (16).
and function. The Liver: Biology and Pathobiology, 5th
During the epithelial-mesenchymal transition critical for
Edition,
invasion and metastasis, tight junction proteins are down-
Williams&Wilkins, Philadelphia (2009) pp201-220.
regulated (17). Some of these tight junction proteins may be
target molecules of cancer therapy.
edited
by
Arias
IM,
et
al.
Lippincott
10)Son S, Kojima T, Decaens C, Yamaguchi H, Ito T,
Imamura M, Murata M, Tanaka S, Chiba H, Hirata K,
Sawada N. Knockdown of tight junction protein claudin-2
List of Main Publications 2009 to 2013
1) Sawada N. Tight junction-related human diseases. Pathol
Int (2013) 63(1): 1-12.
prevents bile canalicular formation in WIF-B9 cells.
Histochem Cell Biol (2009) 131: 411-424.
11) Kojima T, Fuchimoto J, Yamaguchi H, Ito T, Takasawa A,
2) Kamekura R, Kojima T, Koizumi J, Ogasawara N, Kurose
Ninomiya T, Kikuchi S, Ogasawara N, Ohkuni T, Masaki
M, Go M, Harimaya A, Murata M, Tanaka S, Chiba H,
T, Hirata K, Himi T, Sawada N. c-Jun N-terminal kinase is
Himi T, Sawada N. Thymic stromal lymphopoietin
largely involved in the regulation of tricellular tight
enhances tight junction barrier function of human nasal
junctions via tricellulin in human pancreatic duct epithelial
epithelial cells. Cell Tissue Res (2009) 338: 283-293.
cells. J Cell Physiol (2010) 225:720-733.
3) Ohkuni T, Kojima T , Ogasawara N, Masaki T, Fuchimoto
12) Takasawa A, Kojima T, Ninomiya T, Tsujiwaki M, Murata
J, Kamekura R, Koizumi J, Ichimiya S, Murata M, Tanaka
M, Tanaka S, Sawada N. Behavior of tricellulin during
S, Himi T, Sawada N. Poly(I:C) reduces expression of
destruction and formation of tight junctions under various
JAM-A and induces secretion of IL-8 and TNF-a via
extracellular calcium conditions. Cell Tissue Res (2013)
distinct NF-kB pathways in human nasal epithelial cells.
351(1): 73-84.
Toxicology and Applied Pharmacology (2011) 250: 29-38.
13) Yamaguchi H, Kojima T, Ito T, Kimura Y, Imamura M, Son
4) Ogasawara N, Kojima T, Go M, Ohkuni T, Koizumi J,
S, Koizumi J, Murata M, Nagayama M, Nobuoka T,
Kamekura R, Masaki T, Murata M, Tanaka S, Fuchimoto
Tanaka S, Hirata K, Sawada N. Transcriptional control of
J, Himi T, Sawada N. PPARγ agonists upregulate the
tight junction proteins via a protein kinase C signal
barrier function of tight junctions via a PKC pathway in
pathway in human telomerase reverse transcriptase-
human nasal epithelial cells. Pharmacol Res (2010) 61:
transfected human pancreatic duct epithelial cells. Am J
489-498.
Pathol (2010) 177: 698-712.
5) Ogasawara N, Kojima T, Go M, Fuchimoto J, Kamekura
14)Yamaguchi H, Kojima T, Ito T, Kyuno D, Kimura Y,
R, Koizumi J, Ohkuni T, Masaki T, Murata M, Tanaka S,
Imamura M, Hirata K, Sawada N. Effects of Clostridium
Ichimiya S, Himi T, Sawada N. Induction of JAM-A during
perfringens enterotoxin via claudin-4 on normal human
differentiation of human THP-1 dendritic cells. Biochem
pancreatic duct epithelial cells and cancer cells. Cell Mol
Biophys Res Commun (2009) 389: 543-549.
Biol Lett (2011) 16(3): 385-397.
6) Masaki T, Kojima T, Okabayashi T, Ogasawara N, Ohkuni
15) Maeda T, Murata M, Chiba H, Takasawa A, Tanaka S,
T, Obata K, Takasawa A, Murata M, Tanaka S, Hirakawa
Kojima T, Masumori N, Tsukamoto T, Sawada N. Claudin-
S, Fuchimoto J, Ninomiya T, Fujii N, Tsutsumi H, Himi T,
4-targeted
Sawada N. An NF-kB signaling pathway via PKCd
enterotoxin for prostate cancer. Prostate (2012) 72(4):
regulates replication of respiratory syncytial virus in
351-360.
polarized normal human nasal epithelial cells. Mol Biol
Cell (2011) 22(13): 2144-2156.
7) Hirakawa S, Kojima T, Obata K, Okabayashi T, Yokota SI,
therapy
using
Clostridium
16) Kyuno D, Kojima T, Yamaguchi H, Ito T, Kimura Y,
Imamura M, Takasawa A, Murata M, Tanaka S, Hirata K,
Sawada N. Protein kinase Cα inhibitor protects against
Nomura K, Obonai T, Fuchimoto J, Himi T, Tsutsumi H, Sawada
downregulation
N. Marked induction of matrix metalloproteinase-10 by
mesenchymal
respiratory syncytial virus infection in human nasal
Carcinogenesis (2013) 34(6): 183-187.
epithelial cells. J Med Virol (2013) 85(12): 2141-2150.
perfringens
of
claudin-1
transition
of
during
pancreatic
epithelialcancer.
17) Kojima T, Takasawa A, Kyuno D, Ito T, Yamaguchi H,
8) Obata K, Kojima T, Masaki T, Okabayashi T, Yokota S,
Hirata K, Tsujiwaki M, Murata M, Tanaka S, Sawada N.
Hirakawa S, Nomura K, Takasawa A, Murata M, Tanaka
Downregulation of tight junction-associated MARVEL
S, Fuchimoto J, Fujii N, Tsutsumi H, Himi T, Sawada N.
protein marvelD3 during epithelial-mesenchymal transition
Curcumin prevents replication of respiratory syncytial
in human pancreatic cancer cells. Exp Cell Res (2011)
virus and the epithelial responses to it in human nasal
317(16): 2288-2298.
epithelial cells. PLoS One (2013) 8(9): e70225.
9) Kojima T, Sawada N, Yamaguchi H, Fort AG, Spray DC.
44
Microbiology
Our laboratory focuses on the interactions between hosts and
microorganisms. We are particularly interested in how infected or
colonized bacteria and viruses affect a host’s innate immune system.
In addition, we investigate molecular epidemiology and resistant
mechanisms of antibiotic resistant bacteria.
Professor
Instructor:
Shin-ichi Yokota, M.S., Ph.D.
Soh Yamamoto, M.S., Ph.D.
Interests:
Noriko Ogasawara, M.D., Ph.D.
Structure, biological activity and antigenicity of pathogen-
Tsukasa Shiraishi, M.S., Ph.D.
associated molecular patterns (PAMPs) and damage-
Musashi Kayama, M.D.
associated
molecular
patterns
(DAMPs),
Molecular
mechanisms of battle between microorganisms and host
innate immunity, Molecular epidemiology of antibiotic resistant
bacteria
1. Structure, biological activity, and antigenicity of
epithelial cancer cell line A549. The IFN-l production occurred
pathogen-associated molecular patterns (PAMPs)
via the RIG-I pathway, but not the mda5 pathway (4).
We are investigating novel biological activities of
We have investigated immunomodulation, especially its
Helicobacter pylori lipopolysaccharides (LPS) with low
effect on the IFN system, during viral infection. The measles
endotoxic activity. Previously, we found that LPS derived from
virus C protein interacted with Tyr-phosphorylated STAT1 and
Japanese H. pylori strains were classified into two antigenic
inhibited its dimer formation. This led to cancellation of host
types, namely highly-antigenic and weakly-antigenic.
The
cell growth suppression respond to infection via suppression
weakly-antigenic LPS, which were frequently found in strains
of interferon regulatory factor-1 (IRF-1) induction, and it
derived from gastric cancer, upregulated TLR4 expression on
caused efficient virus replication.
gastric epithelial cells via the MEK1/2-ERK1/2 mitogen-
observed more strongly in wild strains of the measles virus
activated protein kinase pathway and NF-Y transcription
than in laboratory strains, and correlated with the expression
factor. As such, weakly-antigenic type H. pylori LPS sensitized
levels of C protein (5).
the cells against other bacterial, such as E. coli, LPS (1). In
3. Role of heat shock proteins and their autoantibodies
another study, we found that a b-linked N-acetyl-D-
on infectious diseases and autoimmune diseases
glucosamine residue and b-linked D-galactose residue are
We found anti-heat shock protein (HSP) autoantibodies
involved in the highly-antigenic and weakly-antigenic epitopes,
in patients with various immunological disorders, and
respectively. Surfactant protein D interacted with a structure
investigated their pathophysiological roles.
involved in the weakly-antigenic epitope, and enhanced the
autoantibodies were found in cerebrospinal fluids (CSF)
activities of the weakly-antigenic type H. pylori LPS (2).
derived from multiple sclerosis patients. The autoantibodies
We have also investigated the immunomodulating activity
specifically reacted with various HSP70 family proteins, such
of lactic acid bacteria, especially focusing on lipoteichoic acid
as HSP70, HSC70 and bacterial DnaK. The CSF containing
(LTA), a cell surface component. We found a novel structure
anti-HSP70
in LTA, tetrahexosyl glycerophosphate lipid anchor, that
proinflammatory cytokine production in monocytes (6, 7).
autoantibodies
This phenomenon was
enhanced
Anti-HSP70
HSP70-induced
originated from Lactobacillus gasseri (3).
4. Molecular epidemiology and resistant mechanisms of
2. Modulation of innate immune signal transduction by
antibiotic resistant bacteria
viral infection
We have investigated the molecular epidemiology of
We investigated RS virus-induced interferon (IFN)
antibiotic resistant bacteria found in community-acquired
production in epithelial cells. IFN-ls, but not IFN-b, were
infection. We screened fluoroquinolone-resistant Escherichia
induced by the RS virus in normal nasal epithelial cells. In
coli isolated in Hokkaido prefecture, Japan. O25b:H4-ST131
contrast, both IFN-ls and IFN-b were induced in pulmonary
strains constituted about 80% of the fluoroquinolone-resistant
45
strains (about 25% of the total isolates). Fluoroquinolone-
Tsutsumi H, Himi T, Fujii N, Sawada N. Type-III interferon,
resistant O25b:H4-ST131, which has spread throughout the
not type-I, is the predominant interferon induced by
world, frequently shares the CTX-M-15 (a member of group 1)
respiratory viruses in nasal epithelial cells. Virus Res
extended spectrum b-lactamase gene. In contrast, Japanese
(2011) 160: 360-366.
strains analyzed in our study frequently shared group 9 and 2
5) Yokota S, Okabayashi T, Fujii N. Measles virus C protein
suppresses gamma-activated factor formation and virus-
CTX-M genes, but not CTX-M15 (8).
We found a novel fluoroquinolone-resistant E. coli clinical
induced cell growth arrest. Virology (2011) 414: 74-82.
isolate that did not have any resistant mutations in
6) Yokota S, Chiba S, Furuyama H, Fujii N. Cerebrospinal
topoisomerase IV or DNA gyrase. This strain shared qnrS1
fluids containing anti-HSP70 autoantibodies from multiple
and oqxAB genes and overexpressed efflux pumps, including
sclerosis patients augment HSP70-induced proinflammatory
AcrAB-TolC (9).
cytokine production in monocytic cells. J Neuroimmunol
5. Novel actions of antimicrobial agents
(2010) 218:129-133.
We have investigated immunomodulating activities of
7) Yokota S, Fujii N. Immunomodulatory activities of
fosfomycin and clarithromycin. Both antibiotics suppressed
extracellular heat shock proteins and their autoantibodies.
RS virus-induced chemokine production via the NF-kB
Microbiol. Immunol. (2010) 54: 299-307.
pathway in airway epithelial cells.
Additionally, these
8) Yokota S, Sato T, Okubo T, Ohkoshi Y, Okabayashi T,
of
Kuwahara O, Tamura Y, Fujii N. Prevalence of
Streptococcus pneumoniae and Haemophilus influenzae
fluoroquinolone-resistant Escherichia coli O25:H4-ST131
through suppressing the induction of the PAF receptor, which
(CTX-M-15 non-producing) strains isolated in Japan.
antibiotics
suppressed
RS
virus-induced
adhesion
Chemotherapy (2012) 58: 52-59
is a receptor for these bacteria (10-12).
We found that various aminoglycosides bound to HSP70
9) Sato T, Yokota S, Uchida I, Okubo T, Usui M, Kusumoto
family proteins, and inhibited their substrate binding and
M, Akiba M, Fujii N, Tamura Y. Fluoroquinolone resistance
protein folding activities. This activity correlated well with
mechanisms in an Escherichia coli isolate, HUE1, without
nephrotoxicity.
quinolone
6. Clinical bacteriology of Helicobacter pylori
region
mutations.
Front Microbiol (2013) 4: 125.
We examined the relationship between iron-deficiency
anemia (IDA) and H. pylori infection. We found that strains
isolated from IDA patients showed stronger Fe
resistance-determining
2+
and Fe3+
uptake activity and more rapid cell growth dependent to Fe
10) Okabayashi T, Yokota S, Yoto Y, Tsutsumi H, Fujii N.
Fosfomycin suppresses chemokine induction in airway
epithelial cells infected with the respiratory syncytial
virus. Clin Vaccine Immunol (2009) 16: 859-865.
ions than strains isolated from patients without anemia. A
11) Yokota S, Okabayashi T, Yoto Y, Hori T, Tsutsumi H, Fujii N.
polymorphism (Ser70Thr) was significantly frequently found
Fosfomycin suppresses RS-virus-induced Streptococcus
in the napA gene, which encodes neutrophil activating protein
pneumoniae and Haemophilus influenzae adhesion to
A, a bacterioferritin of H. pylori, in strains of IDA patients (13).
respiratory epithelial cells via the platelet-activating factor
receptor. FEMS Microbiol Lett (2010) 310: 84-90.
12) Yokota S, Okabayashi T, Hirakawa S, Tsutsumi H, Himi T,
1) Yokota S, Okabayashi T, Rehli M, Fujii N, Amano K.
Fujii N. Clarithromycin suppresses human respiratory
Helicobacter pylori lipopolysaccharides upregulate Toll-
syncytial virus infection-induced Streptococcus pneumoniae
like receptor 4 expression and proliferation of gastric
adhesion and cytokine production in a pulmonary
epithelial cells via the MEK1/2-ERK1/2 mitogen-activated
epithelial cell line. Mediators Inflamm (2012) 2012: Article
protein kinase pathway. Infect Immun (2010) 78: 468-
ID 528568.
13) Yokota S, Toita N, Yamamoto S, Fujii N, Konno M.
476.
2) Yokota S, Amano K , Nishitani C, Ariki S, Kuroki Y, Fujii N.
Positive
relationship
between
a
polymorphism
in
Implication of antigenic conversion of Helicobacter pylori
Helicobacter pylori neutrophil-activating protein A gene
lipopolysaccharides
and iron-deficiency anemia. Helicobacter (2013) 18: 112-
that
involve
interaction
with
surfactant protein D. Infect Immun (2012) 80: 2956-2962.
3)Shiraishi T, Yokota S, Morita N, Fukiya S, Tomita S,
Tanaka N, Okada S, Yokota A. Characterization of a
T
Lactobacillus gasseri JCM1131 lipoteichoic acid with a
novel glycolipid anchor structure. Appl Environ Microbiol
(2013) 79: 3315-3318.
4) Okabayashi T, Kojima T, Masaki T, Yokota S, Imaizumi T,
116.
46
Pharmacology
Elucidation of aging is one of the most important goals of science in
the post-genomic era. NAD-dependent protein deacetylase was first
identified as yeast silent information regulator 2 (Sir2), which has the
ability to extend the life span in yeast. There are seven mammalian
homologues of Sir2, i.e., SIRT1-7 (1). Among them, we are studying
SIRT1 and investigating roles of SIRT1 in health and diseases.
Professor
Assistant Professor
Instructor
Yoshiyuki Horio, M.D., Ph.D.
Atsushi Kuno, M.D., Ph.D.
Takashi Hayashi, M.D.
Risa Kunimoto, M.D., Ph.D.
1. SIRT1 and cardiomyopathy
of α-smooth muscle actin (α-SMA) myofibroblast cells and
We found that SIRT1 was a nucleo-cytoplasmic shuttling
endomysial fibrosis in the biceps femoris, although the
protein (Tanno M. et al. J Biol Chem (2007) 282: 6823-6832).
infiltration of CD45 inflammatory cells and increase in
Nuclear SIRT1 bound and deacetylated FOXO4 transcription
transforming growth factor-b1 (TGF-b1) were still observed
factor and enhanced its activity, resulting in an increase of
(3). Cardiomyopathy is the main cause of death in Duchenne
oxidative stress resistance in cells (Kobayashi Y. et al. Int J
muscular
Mol Med. (2005)16: 237-243). Cardiac myocytes usually
hypertrophy and fibrosis and restores cardiac diastolic
expressed SIRT1 in the cytoplasm, but some myocytes
function in mdx mice (4). The pro-hypertrophic co-activator
expressed it in the nucleus in situations of congenital heart
p300 protein but not p300 mRNA was up-regulated in the mdx
failure. Nuclear expression of SIRT1 increased cellular
heart, and resveratrol administration down-regulated the p300
resistance against oxidative stress, which was at least partly
protein level. In cultured cardiomyocytes, cardiomyocyte
mediated by induction of SOD2, a mitochondrial superoxide
hypertrophy induced by the α-agonist phenylephrine was
dismutase. In C2C12 myoblast cells, administration of
inhibited by the overexpression of SIRT1 as well as resveratrol,
resveratrol, a potent activator of SIRT1, further enhanced
both of which down-regulated p300 protein levels but not
induction of SOD2 by nuclear SIRT1 and decreased cell
p300 mRNA levels. In addition, activation of the atrial
death by oxidative stress. Administration of resveratrol, an
natriuretic peptide promoter by p300 was inhibited by SIRT1.
activator of SIRT1, on TO-2 hamsters that had spontaneously
We found that SIRT1 induced p300 down-regulation via the
developed
the
ubiquitin-proteasome pathway by deacetylation of lysine
development of symptoms and extended the life span of the
residues for ubiquitination. These findings indicate the
hamsters (2).
pathological significance of p300 up-regulation in the
congenital
heart
failure,
attenuated
dystrophy.
Resveratrol
suppresses
cardiac
dystrophic heart and indicate that SIRT1 activation has
2. SIRT1 and muscular dystrophies
therapeutic potential for dystrophic cardiomyopathy (4).
Muscular dystrophies are inherited myogenic disorders
accompanied by progressive skeletal muscle weakness and
3. SIRT1 and inhibition of apoptosis
degeneration that are caused by mutation of genes in the
SIRT1 modulates the transcription factor p53, a tumor
dystroglycan complex. Because TO-2 hamsters have a defect
suppressor and inducer of apoptosis, and the Forkhead O
of δ-sarcoglycan, a component of the dystroglycan complex,
(FOXO) family, both of which play roles in cell survival and cell
we hypothesized that resveratrol might be a new therapeutic
death (1). We aimed to understand the functional role of p53
tool for muscular dystrophies. We found that resveratrol
and FOXOs on SIRT1’s cell-protection against oxidative
decreased muscular oxidative damage and inhibited muscle
stress (5). The antimycin A-induced increase in ROS levels
mass loss in mdx mice, an animal model of Duchenne
and apoptosis was enhanced by SIRT1 inhibitors nicotinamide
muscular dystrophy (3). Resveratrol also reduced the number
and splitomicin, whereas it was suppressed by SIRT1 activator
47
resveratrol and SIRT1 cofactor NAD+. SIRT1-siRNA abolished
5. SIRT1 and neurite extension
the effects of splitomicin and resveratrol. p53-knockdown
SIRT1 is expressed in the cytoplasm of some neural cells
experiments in C2C12 cells and experiments using p53-
including PC12 (pheochromocytoma) cells. Nerve growth
deficient HCT116 cells showed that splitomicin and resveratrol
factor (NGF)-induced neurite outgrowth of these cells was
modulated apoptosis by p53-dependent and p53-independent
promoted by activators of SIRT1, while inhibitors of SIRT1 or
pathways. In the p53-independent cell protective pathway, we
SIRT1-siRNA significantly inhibited it (7). The overexpression
found that FOXO1, FOXO3a and FOXO4 were involved in
of a mutant SIRT1 that localised to the cytoplasm but not the
SOD2’s up-regulation by resveratrol. The knockdown of these
nucleus enhanced the NGF-dependent neurite outgrowth,
three FOXOs by siRNAs completely abolished the SOD2
and a cytoplasmic dominant-negative SIRT1 suppressed it.
induction, ROS reduction and anti-apoptotic function of
Thus, cytoplasmic SIRT1 increases the NGF-induced neurite
resveratrol. Our results indicate that FOXO1, FOXO3a and
outgrowth of PC12 cells (7).
FOXO4 are indispensable for SIRT1-dependent cell survival
against oxidative stress, although deacetylation of p53 also
List of main Publications from 2009 to 2013
has a role in the cell protective function of SIRT1 (5).
1) Horio Y, Hayashi T, Kuno A, Kunimoto R. Cellular and
molecular effects of sirtuins in health and disease. Clin
4. Resveratrol as a SIRT1 activator
Sci (2011) 121: 191-203.
Resveratrol (trans-3,5,4’-trihydroxystilbene, RSV), a
2) Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa
natural polyphenol, activates SIRT1; in turn, SIRT1 induces
S, Shimamoto K, Horio Y. Induction of manganese
an intracellular antioxidative mechanism by inducing SOD2.
superoxide dismutase by nuclear translocation and
Most RSV found in plants is glycosylated, and the effect of
activation of SIRT1 promotes cell survival in chronic heart
these glycosylated forms on SIRT1 has not been studied.
failure. J Biol Chem (2010) 285: 8375-8382.
Here, we compared the effects of RSV and two glycosyl
3) Hori YS, Kuno A, Hosoda R, Tanno M, Miura T, Shimamoto
RSVs, resveratrol-3-O-β-D-glucoside (3G-RSV, polydatin/
K, Horio Y. Resveratrol ameliorates muscular pathology
piceid) and resveratrol-4’-O-β-D-glucoside (4’G-RSV), at the
in the dystrophic mdx mouse, a model for Duchenne
cellular level. In oxygen radical absorbance capacity (ORAC)
muscular dystrophy. J Pharmacol Exp Ther (2011) 338:
and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging
784-794.
assays, 3G-RSV's antioxidant activity was comparable to that
4) Kuno A, Hori YS, Hosoda R, Tanno M, Miura T, Shimamoto
of RSV, while 4’G-RSV's radical-scavenging efficiency was
K, Horio Y. Resveratrol improves cardiomyopathy in
less than 50% of that of RSV. However, 4’G-RSV, but not
dystrophin-deficient
3G-RSV, induced SIRT1-dependent histone H3 deacetylation
mediated modulation of p300 Protein. J Biol Chem (2013)
and SOD2 expression in mouse C2C12 skeletal myoblasts;
mice
through
SIRT1
Protein-
288: 5963-5972.
as with RSV, SIRT1 knockdown blunted these effects. RSV
5) Hori YS, Kuno A, Hosoda R, Horio Y. Regulation of
and 4’G-RSV, but not 3G-RSV, mitigated oxidative stress-
FOXOs and p53 by SIRT1 modulators under oxidative
induced cell death in C2C12 cells and primary neonatal rat
stress. PLoS One (2013) 8: e73875.
cardiomyocytes (6). RSV and 4’G-RSV inhibited C2C12 cell
6) Hosoda R, Kuno A, Hori YS, Ohtani K, Wakamiya N,
proliferation, but 3G-RSV did not. RSV was found in both the
Oohori A, Hamada H, Horio Y.Differential cell-protective
intracellular and extracellular fractions of C2C12 cells that
function of two resveratrol (trans-3,5,4’- trihydroxystilbene)
had been incubated with 4’G-RSV, indicating that 4'G-RSV
glucosides against oxidative stress. J Pharmacol Exp
was extracellularly deglycosylated to RSV, which was then
Ther (2013) 344: 124-132.
taken up by the cells. C2C12 cells did not deglycosylate
7) Sugino T, Maruyama M, Tanno M, Kuno A, Houkin K,
3G-RSV. Our results point to 4'G-RSV as a useful RSV
Horio Y. Protein deacetylase SIRT1 in the cytoplasm
prodrug with high water solubility. These data also show that
promotes nerve growth factor-induced neurite outgrowth
the in vitro antioxidative activity of these molecules did not
in PC12 cells. FEBS Lett. (2010) 584: 2821-2826.
correlate with their ability to protect cells from oxidative stressinduced apoptosis (6).
48
Hygiene
The department of hygiene has been engaged in the epidemiological
study of infectious diseases, focusing on molecular epidemiology
and time-series analysis. Current research topics include whole
genomic analysis of rotavirus, molecular epidemiology of norovirus,
methicillin-resistant Staphylococcus aureus (MRSA), enterococcus,
and Streptococcus pneumoniae and time-series analysis of measles,
influenza, viral hepatitis and tuberculosis. Some parts of these
studies are performed as collaborative work with researchers in
China, India, Bangladesh, Myanmar and Cuba. Our department is
also interested in international health, and we are making efforts to
support the research activities of collaborators in developing
countries.
Professor
Associate Professor
Assistant Professor
Nobumichi Kobayashi, M.D., Ph.D.
Ayako Sumi, Ph.D.
Noriko Urushibara, Ph.D.
Interests:
Mathematical biology, Nonlinear science,
Interests:
Molecular epidemiology of infectious
Time series analysis
Molecular epidemiology and genetics of
diseases, Rotavirus, Staphylococcus,
staphylococcus
Drug-resistant bacteria
1. Molecular epidemiology of rotavirus and other enteric
combined with phylogenetic analysis for all of the 11 RNA
viruses causing diarrhea / gastroenteritis
segments. Through this analysis, it was revealed that
Diarrheal diseases caused by enteric viruses are highly
reassortment of gene segments between human and animal
prevalent worldwide and have posed public health problems.
rotaviruses, or between human rotaviruses belonging to
One of the major subjects of our department is the study of
different genogroups, occurred in nature. To date, we have
enteric viruses represented by rotavirus and norovirus for
analyzed various human rotavirus strains with common and
their epidemiologic characteristics and molecular evolution.
uncommon genotypes, and also some animal rotaviruses.
Group A rotavirus is the most important cause of diarrheal
Other enteric virus, norovirus and picobirnavirus have
diseases in children under 5 years of age worldwide, causing
also been genetically analyzed in our laboratory. Norovirus
more than 450,000 deaths per year in developing countries.
has spread globally as an important pathogen of gastroenteritis.
Although two oral live vaccines to prevent severe rotavirus
Picobirnavirus is a novel emerging pathogen recognized to be
disease are available in most countries, epidemiological study
important for its zoonotic potential.
on rotavirus antigenic specificity and genomic diversity is
2. Molecular epidemiology of drug-resistant bacteria
important to estimate potential efficacy of rotavirus vaccines
Methicillin-resistant Staphylococcus aureus (MRSA) is
and to improve or develop rotavirus vaccines in the near
the most well-known drug-resistant bacteria worldwide, and
future.
still recognized as the major nosocomial pathogen. Recently,
Rotavirus has double-stranded RNA as a genome that is
in addition to hospital-acquired MRSA (HA-MRSA), which has
separated into 11 gene segments. Conventionally, G and P
been known conventionally, community-acquired MRSA (CA-
genotypes, defined by outer capsid proteins VP7 and VP4,
MRSA) has emerged and spread globally. CA-MRSA is
respectively, have been studied in epidemiological studies of
genetically distinct from HA-MRSA, and often produces PVL,
rotavirus because these genotypes correspond to antigenic
a leukocyte toxin, which is associated with severe symptoms
specificity recognized by neutralizing antibodies. Recently,
of CA-MRSA infection. Recently we have been investigating
our molecular epidemiological study on rotavirus has focused
the prevalence of CA-MRSA in Hokkaido, and have found
on whole genomic sequencing and phylogenetic analysis. In
increasing trends of strains with CA-MRSA-like genetic traits
2008, a whole genome-based genotyping scheme was
as well as PVL genes. In our study, remarkably we identified
proposed. Subsequently, we employed this typing system,
strains identical to CA-MRSA clone “USA300,” which has
49
been prevalent in the US in the last decade and is spreading
3) Luo T, Sumi A, Zhou D, Kamo K, Yu B, Zhao D, Mise K,
globally. The USA300 clone possesses a genomic island
Kobayashi N. Study on the effect of measles control
named ACME (arginine catabolic mobile element), which
programmes on periodic structures of disease eidemics
contributes to the persistence and successful spread of this
in a large Chinese city. Epidemiol Infect, 2011, 139:257-
clone. In our department, prevalence, genetic diversity and
264.
structure of ACME as well as PVL genes have been analyzed
4) Sumi A, Kamo K, Ohtomo N, Mise K, Kobayashi N. Time
extensively in order to estimate mechanisms of genetic
series analysis of incidence data of influenza in Japan. J
evolution and the spread of these genetic elements.
Epidemiol, 2011, 21:21-29.
Enterococcus is also an important nosocomial pathogen,
5) Ghosh S, Gatheru Z, Nyangao J, Adachi N, Urushibara
and is acquiring resistance to various antimicrobial agents.
N, Kobayashi N. Full Genomic analysis of a simian SA11-
We analyzed clinical isolates of enterococci for resistance to
like G3P[2] Rotavirus strain isolated from an asymptomatic
glycopeptides, aminoglycosides, tetracyclines, macrolides
infant : identification of novel VP1, VP6, and NSP4
and quinolones, as well as their genetic mechanisms. Through
genotype. Infect Genet Evol, 2011, 11:57-63.
these studies, a novel high-level aminoglycoside resistance
6) Yamamoto D, Ghosh S, Kuzuya M, Wang Y-H, Zhou X,
gene was identified.
Chawla-Sarkar M, Paul SK, Ishino M, Kobayashi N.
Streptococcus pneumoniae is commonly distributed
Whole genomic characterization of human group C
among the general population, and causes community-
rotaviruses: identification of two lineages in VP3 gene. J
acquired infections including invasive infections such as
Gen Virol, 2011, 92:361-369.
meningitis. Resistance to penicillin and macrolides has been
7) Kawaguchiya M, UrushibaraN, Kuwahara O, Ito M, Mise
recognized as a threat to public health. Globally introduced
K, Kobayashi N. Molecular characteristics of community-
pneumococcal conjugate vaccine (PCV) seems to change
acquired methicillin-resistant Staphylococcus aureus
serotypes as well as the resistance pattern of wild strains. We
(CA-MRSA) in Hokkaido, northern main island of Japan :
have been investigating the prevalence of serotypes and drug
identification of ST6 and ST59 PVL-positive CA-MRSA.
resistance in clinical isolates in Hokkaido, using newly
Microbial Drug Resistance, 2011, 17:241-250.
developed genetic methods in our laboratory.
8) Urushibara N, Paul SK, Hossain MA, Kawaguchiya M,
3. Time series analysis of infectious diseases
Kobayashi N. Analysis of staphylococcal cassette
Recurrent epidemics of infectious diseases such as
chromosome
measles, chickenpox and influenza are of great interest in the
haemolyticus and Staphylococcus sciuri: identification of
field of preventive medicine. To understand the biological
a novel ccr gene complex with a newly identified ccrA
mechanisms that cause or affect occurrence of epidemics,
allotype (ccrA7). Microbial Drug Resistance, 2011,
time-series analysis is employed to investigate temporal
mec
(SCCmec)
in
Staphylococcus
17:291-297.
variation structures of infectious diseases. In our department,
9) Urushibara N, Kawaguchiya N, Kobayashi N. Two novel
this approach was used for analyzing epidemics of measles,
arginine catabolic mobile elements and staphylococcal
cholera, norovirus and rotavirus infections. Recently we also
chromosome
analyzed epidemic structures of influenza, viral hepatitis and
community-acquired methicillin-resistant Staphylococcus
cassette
mec
composite
islands
in
tuberculosis. These analyses can contribute to the control of
aureus genotypes ST5-MRSA-V and ST5-MRSA-II. J
infectious diseases by suggesting how environmental factors
Antimicrob Chemother, 2012, 67:1828-1834.
are associated with the epidemics, and predicting potential
future epidemics,
10) Ghosh S, Shintani T, Urushibara N, Taniguchi K,
Kobayashi N. Whole genomic analysis of a human
G1P[9]
1) Yamamoto D, Ghosh S, Ganesh B, Krishnan T, Chawla-
rotavirus
strain
reveals
intergenogroup
reassortment events. J Gen Virol, 2012, 93:1700-1705.
11) Kawaguchiya M, Urushibara N, Yamamoto D, Yamashita
Sarkar M, Alam MM, Aung TS, Kobayashi N. Analysis on
T,
genetic diversity and molecular evolution of human group
Characterization
B rotaviruses based on whole genome segments. J Gen
resistant Staphylococcus aureus (genotypes ST8-MRSA-
Virol, 2010, 91:1772-1781.
IV and ST5-MRSA-II) isolated from a university hospital
2) Ghosh S, Alam MM, Ahmed MU, Talukdar RI, Paul SK,
Shinagawa
M,
of
Watanabe
N,
Kobayashi
PVL/ACME-positive
N.
methicillin-
in Japan. Microb Drug Resist, 2013, 19:48-56.
Kobayashi N. The complete genome constellation of a
12) Sumi A, Luo T, Zhou D, Yu B, Kong D, Kobayashi N. Time
caprine group A rotavirus strain reveals common evolution
series analysis of hepatitis A, B, C and E infections in a
with ruminant and human rotavirus strains. J Gen Virol.,
large Chinese city: Application to prediction analysis.
2010, 91:2367-2373.
Epidemiol Infect, 2013, 141:905-915.
50
Public Health
Incidences of sex hormone-associated cancers have risen in
Hokkaido, Japan. Accordingly, we have conducted epidemiological
studies to identify risk factors for these cancers, aiming at preventing
their occurrence. We have also carried out epidemiological studies
on cardiovascular disease and osteoporosis. Additionally, we conduct
research regarding such topics as caregivers of disabled children,
the frail elderly, health promotion of the elderly and efficacy of
influenza vaccination.
Professor
Associate Professor
Assistant Professor
Mitsuru Mori, M.D., Ph.D.
Fumio Sakauchi, M.D., Ph.D.
Tomoko Sonoda, D.D.S., Ph.D.
Interests:
Interests:
Interests:
Epidemiology on cancer and other
Epidemiology on female cancer and
Epidemiology of prostate cancer and
chronic diseases.
intractable liver disease
osteoporosis.
Hirofumi Ohnishi, M.D., Ph.D.
Interests:
Instructor
Epidemiological studies on obesity,
Nobuaki Himuro, P.T., Ph.D.
life-style related disease
and cardiovascular disease
1. Epidemiology of sex hormone-associated cancers
In a case-control study comprised of 63 histologically
confirmed breast cancer patients and 76 controls, serum
isoflavone, insulin and high molecular weight (HMW)
adiponectin levels and breast cancer risks were examined for
their association with breast cancer risks after adjustment for
various risk factors. Women in the high tertile of serum
adiponectin levels were associated with a statistically
significant decreased risk for breast cancer compared with
women in the low tertile. This association was observed in
postmenopausal women but not in premenopausal women.
The observed associations were independent of the possible
effects of insulin, body mass index (BMI) and known risk
factors for breast cancer. Serum isoflavones and insulin levels
were not associated with breast cancer risk (1).
In a separate study, 117 (82.3%) of the 142 prostate
cancer patients invited to participate in a survey filled out selfadministrated questionnaires that included items about their
lifestyle habits over a period of one or two years before their
diagnosis. Four controls per case, a total of 468, were
randomly selected from resident registries with age and
address matched with each case, and 318 (69.5%) filled out
the same questionnaire as the cancer patients. The conditional
logistic regression model was utilized for analyzing the
individual age and address-matched data. Higher body mass
index at 20 years of age had a marginally significant
association with decreased risk, and larger weight gain in
adult age was significantly associated with increased risk. A
history of prostate cancer in fathers or brothers was
significantly associated with an increased risk and a history of
breast cancer in mothers or sisters was also significantly
associated with increased risk (2).
2. Epidemiology of cardiovascular diseases
Cross-sectional and longitudinal analyses were
conducted using normotensive subjects who were selected
among 1,399 subjects in the Tanno-Sobetsu cohort. In the
cross-sectional analysis (n=740), blood pressure (BP) level
was correlated with HOMA-IR and with ISI-M, but correlation
coefficients indicate a tighter correlation with ISI-M. Multiple
linear regression analysis adjusted by age, sex, body mass
index (BMI) and serum triglyceride levels (TG) showed
contribution of ISI-M and fasting plasma glucose, but not of
HOMA-IR. In the longitudinal analysis (n=607), 241 subjects
(39.7%) developed hypertension during a 10-year follow-up
period, and multiple logistic regression indicated that age, TG,
systolic BP and ISI-M, but not HOMA-IR, were associated
with development of hypertension (3).
3. Epidemiology of osteoporosis
We hypothesized that environmental factors might affect
the relationship between genetic predisposition and the risk of
bone mineral density (BMD) loss. Subjects consisted of 114
Japanese women with a confirmed diagnosis of
postmenopausal osteoporosis and the controls were 171
general Japanese women. The interaction between gene and
environmental factors for osteoporosis were assessed by a
case-only design. Significant increases in osteoporosis risk
were observed with minor alleles of rs2077647 located in the
first exon and rs2234693 located in the first intron of estrogen
receptor α (ESRα). Haplotype CC at these risk SNPs was
strongly associated with osteoporosis risk. There was a
statistically significant interaction between haplotype CC and
alcohol consumption (4).
4. Epidemiology of caregivers for the disabled persons
The Measure of Processes of Care (MPOC) that was
developed in Canada is a widely used quantitative measure of
51
parents' perceptions of the extent to which family-centered
care is conducted. The Canadian validation procedures were
followed, consisting of concurrent validity, construct validity
and test-retest reliability. The Japanese version of the MPOC
was completed by 261 families with children receiving
rehabilitation services. The Japanese version of the MPOC
showed adequate internal consistency with Cronbach's alpha,
varying between 0.76 and 0.94. Correlations between the
MPOC scale scores and satisfaction questions scores were
positive, and that to a question about parents' stress was
negative. For test-retest reliability, the intraclass correlation
coefficients were between 0.76 and 0.89 (5).
In January, 2010, 51 out of the 238 group homes (GHs)
in Sapporo responded to our request for participation in a
survey. During February and March of 2010, 438 out of 700
care workers (62.6%) in those GHs returned a completed
questionnaire. Of these, 395 subjects (90.1%) responded to a
follow-up survey that was conducted until March 2012. During
these two years, 91 subjects were found to commit turnover.
Less provision of social support by supervisors, colleagues,
family or friends was significantly associated with increased
risk of turnover. Financial aid for off-the-job training was
marginally significantly associated with reduced risk of
turnover (6).
5. Epidemiology of health promotion in the elderly
The aim of this study was to clarify risk factors of urinary
incontinence (UI) in elderly Japanese women. We randomly
selected 1,600 women, aged between 65 and 74 years, from
the resident registration of Sapporo. In total we analyzed 746
women, who responded twice (2010 and 2011) to survey
requests. Multivariate logistic regression analysis revealed
that the past maximum body weight, smoking index, past
history of bladder disease or hemorrhoids, and a participant’s
mother’s history of UI were significantly associated with an
increased risk of UI. Lifestyle habits such as weight gain and
smoking habits were associated with an increased risk of UI in
Japanese women (7).
In another study, in August 2007 we randomly selected
3,583 individuals aged 65 to 84 years from the residential
registries of 7 study areas in Hokkaido, Japan.1,955 (54.6%)
returned completed questionnaires with written informed
consent by mail. We later conducted a follow-up survey of the
participants to ascertain all-cause mortality and incident frailty.
After adjusting for potential confounding variables, we found
that the risk of incident frailty among respondents participating
in solitary physical activities was significantly lower than in
those who did not participate in such activities. Furthermore,
the risk of incident frailty among respondents taking part in
group cultural activities was significantly lower than in those
who did not participate in such activities (8).
In a study involving Parkinson's disease (PD), 127
patients gave their informed consent and were enrolled. We
used the Beck Depression Inventory (BDI) questionnaire to
determine the participants' depressive states, and also used a
questionnaire to assess participants' state of dysphagia. For
the categories regarding depression, we compared the PD
patients with Swallowing Disturbances Questionnaire (SDQ)
scores of more than or equal to 11 with the SDQ scores of less
than 11. A logistic regression analysis was conducted adjusting
for age, sex, disease duration, wearing-off phenomenon and
severity of movement disorder. Odds ratios of depressive
categories, in which the trivial class was set as a reference
group, were 3.28, 13.44 and 30.35 in the mild class, moderate
class and severe class, respectively. (9).
6. Epidemiology on effectiveness of vaccination
We conducted a retrospective cohort study for evaluating
the effectiveness of the trivalent inactivated influenza vaccine
(TIV) among children aged 0 to 6 years in the 2011-2012
season in Sapporo. 629 parents of children attending 10
Sapporo day-care centers participated in the study. After
adjusting for potential confounding variables such as the daycare center characteristics, presence of comorbidity, size of
household, number of siblings, and number of smokers in the
home in addition to the age and sex of the child, it was found
that HR was significantly reduced in the subjects aged 1 year
as well as in the total subjects. Consequently, the effectiveness
of TIV was calculated as 78% for the subjects aged 1 year
and 28% for the total subjects (10).
1) Minatoya M, Kutomi G, Asakura S, Otokozawa S,
Sugiyama Y, Ohnishi H, Akasaka H, Miura T, Mori M,
Hirata K. Relationship of serum isoflavone, insulin and
adiponectin levels with breast cancer risk. Breast Can
(2013) in press.
2) Mori M, Masumori N, Fukuta F, Nagata Y, Sonoda T,
Miyanaga N, Akaza H, Tsukamoto T. Weight gain and
family history of prostate or breast cancers as risk factors
for prostate cancer: results of a case-control study in
Japan. Asian Pacific J Can Prev (2011) 12: 743-747.
3) Furugen M, Saitoh S, Ohnishi H, Akasaka H, Mitsumata
K, Chiba M, Furukawa T, Miyazaki Y, Shimamoto K, Miura
T. Matsuda-DeFronzo insulin sensitivity index is a better
predictor than HOMA-IR of hypertension in Japanese:
the Tanno-Sobetsu study. J Hum Hypertens (2012) 26:
325-333.
4) Sonoda T, Takada J, Iba K, Asakura S, Yamashita T, Mori
M. Interaction between ESRα polymorphisms and
environmental factors in osteoporosis. J Orthop Res
(2012) 30: 1529-1534..
5) Himuro N, Kozuka N, Mori M. Measurement of familycentred care: translation, adaptation and validation of the
Measure of Processes of Care (MPOC-56 and -20) for
use in Japan. Child Care Health Develop 2013; 358-365.
6) Suzumura M1, Fushiki Y1, Kobayashi K, Oura A,
Suzumura S, Yamashita M, Mori M. A prospective study
of factors associated with risk of turnover among care
workers in group homes for the elderly with dementia. J
Occup Health (2013) in press.
7) Harai M, Oura A, Mori M. Risk factors for urinary
incontinence in Japanese elderly women. Lower Urinary
Sympt (2013) in press.
8) Fushiki Y, Ohnishi H, Sakauchi F, Oura A, Mori M.
Relationship of hobby activities with mortality and frailty
among community-dwelling elderly adults: results of a
follow-up study in Japan. J Epidemiol (2012) 22: 340347.
9) Han M, Ohnishi H, Nonaka M, Yamauchi R, Hozuki T,
Hayashi T, Saitoh M, Hisahara S, Imai T, Shimohama S,
Mori M. Relationship between dysphagia and depressive
states in patients with Parkinson’s disease. Parkinsonism
Related Disord (2011) 17: 437-439.
10) Mori M, Hasegawa J, Showa S, Matsushima A, Ohnishi
H, Yoto Y, Tsutsumi H. Effectiveness of influenza vaccine
in children in day-care centers of Sapporo. Pediatr Int
(2013) in press.
52
Legal Medicine
Our department routinely performs more than 100 forensic autopsies
in Hokkaido prefecture per year. Since the aim of forensic autopsy is
not only diagnosing cause of death of an individual but also disclosing
the process of the individual’s death or injuries, we are investigating
the mechanism of diseases and death to improve the precision of
autopsy forensic diagnoses. In particular, we perform exclusive
computed tomography (CT) for cadavers, which is possible in
nondestructive postmortem examinations.
Professor
Associate professor
Associate professor
Hiromasa Inoue, M.D., Ph.D.
Satoshi Watanabe, M.D., Ph.D.
Shun-ichiro Okazaki, M.D., Ph.D.
Interest:
Interests:
Interest:
Interaction between hypoxia and
Application of clinical instruments in
Pathogenesis of non-traumatic
sexual arousal in autoerotic asphyxia
forensic autopsies
osteonecrosis
Instructor
Keisuke Mizuo, Ph.D.
1. Forensic diagnosis of heat stroke
are many cases where findings in the airway during the
Heat stroke is defined as a direct injury of the main
autopsy provide convincing evidence of cause of death. We
organs induced by excessive hyperthermia (>42ºC) and a
have introduced a rhino-laryngo fiberscope as a supporting
severe systemic inflammatory state due to sepsis and
diagnostic device of the postmortem examination for the
hypercytokinemia, which is a severe condition with a high
purpose of raising the precision of the diagnosis. For example,
mortality rate. Heat stroke clinically is diagnosed by
attached soot on the trachea and small bubbles in the trachea
hyperthermia, central nerve system (CNS) disorder, injuries of
can be seen in burn death cases and drowning cases,
liver and kidneys and disseminated intravascular coagulation
respectively.
(DIC). To date the forensic diagnosis of heat stroke has been
b) The role of postmortem CT imaging for forensic diagnosis
based only on the situation of the individual’s death.
Recently, because of its non-destructive evaluation
In an autopsy case in which an individual died under high
testing technique, postmortem computed tomography (CT)
ambient temperature, we were able to detect pulmonary fat
imaging has been recognized as a supporting diagnostic tool
embolization in the alveolar capillaries. Moreover, the
in forensic practice, which can alleviate the complications of
pulmonary fat embolization significantly developed during
autopsies conducted during a destructive investigation.
antemortem exposure due to high ambient temperature
However, it is unclear how CT imaging can precisely picture
although this may not be related to other cases in which the
the macroscopic findings in an autopsy. We examined the
postmortem core body temperature was extremely elevated
postmortem CT imaging comparatively to autopsy findings in
for reasons such as severe infection, intracranial hemorrhage
order to provide solutions to the problem of postmortem CT in
and methamphetamine intoxication. It is possible that
forensic diagnosis (4,5).
pulmonary fat embolization is suggestive of antemortem
3. Clarifying the pathogenesis of non-traumatic
exposure of high ambient temperature, and could be one of
osteonecrosis of the femoral head
the diagnostic findings of heat stroke in forensic autopsy
a) Corticosteroid-induced ONFH
cases.
We established a corticosteroid-induced ONFH rat model
2. Application of clinical instruments to forensic autopsy
with
for complete autopsy
lipopolysaccharides, a ligand for TLR4, induced ONFH with
a) Application of rhino-laryngo fiberscope to forensic
fatty liver in rats, suggesting that TLR4 signaling contributes
diagnoses
to the pathogenesis of corticosteroid-induced ONFH in rats
When the cause of a corpse’s death is diagnosed, there
(6).
corticosteroid
treatment
after
an
injection
of
53
The hip joint is a major structure in the human body, and
administration of oleic acid. Legal Med (2012) 14: 304-8.
supports the weight of the upper body and decreases
2) Inoue H, Nakagawa Y, Ikemura M, Shinone K, Okada K,
impulsion loading from the lower body to the upper body.
Nata M. A subacute epidural haematoma extending over
Therefore, it is often believed that weight bearing, as a cause
the occipital region and posterior cranial fossa due to a
of ischemia, may contribute to the development of non-
laceration in the transverse sinus. Int J Legal Med (2012)
traumatic ONFH. However, we revealed that weight bearing
126: 467-71.
does not contribute to the development of non-traumatic
3) Hyodoh H, Watanabe S, Katada R, Hyodoh K, Matsumoto
H. Postmortem computed tomography lung findings in
ONFH in rats (7).
fatal of hypothermia. Forensic Sci Int (2013) 231:190-4.
b) Alcohol-induced ONFH
Alcohol-induced ONFH is observed in alcohol abusers
4) Watanabe S, Katada R, Mizuo K, Nishitani Y, Matsumoto
and patients with alcoholic fatty liver disease. It has been
H. Postmortem computed tomography images and
reported that TLR4 signaling plays a crucial role in the
autopsy findings of the five cases with pulmonary edema.
pathogenesis of alcoholic fatty liver disease. The pathogenesis
Res Pract Forens Med (2009) 52: 25-33 (in Japanese).
of alcoholic fatty liver disease has been studied using
5) Okazaki S, Nishitani Y, Nagoya S, Kaya M, Sasaki M,
experimental rat and mouse models being fed an alcohol-
Yamashita T, Matsumoto H. Femoral head osteonecrosis
containing liquid diet, and especially the Lieber-DeCarli liquid
can be caused by disruption of the systemic immune
diet. It has also been reported that the TLR4 signaling pathway
Response via the toll-like receptor 4 signalling pathway.
plays a crucial role in the pathogenesis of alcoholic fatty liver
Rheumatology (2009) 48: 227-32.
disease. Therefore, we established a new rat model of
6) Okazaki S, Nagoya S, Tateda K, Katada R, Mizuo K,
alcohol-induced ONFH based on the feeding to rat and mouse
Watanabe S, Yamashita T, Matsumoto H. Weight-bearing
models of an ethanol liquid diet. Initial findings indicate that it
does not contribute to the development of osteonecrosis
remains unclear whether the proinflammatory response via
of the femoral head. Int J Exp Path (2012) 93: 458-62.
TLR4 signaling contributes to the development of alcohol-
7) Okazaki S, Nagoya S, Tateda K, Katada R, Mizuo K,
induced ONFH in rats fed with an ethanol liquid diet (8).
Watanabe S, Yamashita T, Matsumoto H. Experimental
4. Epigenetics of alcoholism
rat model for alcohol-induced osteonecrosis of the
Alcohol dependence is a complex disorder characterized
femoral head. Int J Exp Path (2013) 94: 312-9.
by strong cravings for alcohol, increases in tolerance and
8) Mizuo K, Nishitani Y, Katada R, Tateda K, Okazaki S,
obsessive drinking to avoid withdrawal symptoms. The
Watanabe S and Matsumoto H, Expression of miR-132 in
withdrawal from chronic alcohol treatment causes the
murine brain after acute ethanol administration. Alcohol
persistent neuroadaptations, such as changes in the gene
Biomed Res (2010) 29: 52-4 (in Japanese).
expression and the release of neurotransmitters.
The
9) Mizuo K, Katada R, Tateda K, Okazaki S, Watanabe S
alterations are thought to increase in the risk of relapse.
and Matsumoto H. Effect of acute ethanol administration
A neuroadaptation can be caused by the regulation of
on histone deacetylases in mouse brain. Alcohol Biomed
gene expression. A growing body of evidence suggests that
Res (2011) 30: 61-3 (in Japanese).
the gene expression is regulated by an epigenetic mechanism
10) Mizuo K, Katada R, Okazaki S, Tateda K, Watanabe S,
such as DNA methylation of histone modification. Recently,
Matsumoto H Epigenetic regulation of MIR-124 under
several investigations have demonstrated that histone
ethanol dependence and withdrawal. Jpn J Drug Alcohol
acetylation modulates the dopaminergic neuronal activities
Dependedce (2012) 47:155-63.
and affects the reinforcement of abuse of drugs such as
cocaine and morphine. However, the epigenetics in alcohol
dependence, withdrawal and relapse have never been
established.
To clarify the mechanisms of the development of
dependence and relapse, through the use of animal models
we are investigating the epigenetics in alcohol dependence,
withdrawal and relapse.
1) Inoue H, Nakagawa Y, Ikemura M, Usugi E, Nata M.
Molecular-biological analysis of acute lung injury (ALI)
induced
by
heat
exposure
and/or
intravenous
54
4
Clinical Medical Sciences (Courses)
Gastroenterology, Rheumatology and Clinical
Immunology
Our research field covers gastroenterology, hepatology, rheumatology,
immunology, hematology and novel therapeutic strategies for cancer.
In particular, molecular biological and immunological approaches are
extensively and effectively applied to understand the etiology of a
disease and develop novel diagnostic and therapeutic strategies.
Professor
Assistant Professor
Instructor
Yasuhisa Shinomura, M.D., Ph.D.
Yoshiaki Arimura, M.D., Ph.D.
Toshiaki Hayashi, M.D., Ph.D.
Interests:
Interests:
Kentaro Yamashita, M.D., Ph.D.
Gastroenterology
Gastroenterology
Hideyasu Takagi, M.D.
Shigeru Sasaki, M.D., Ph.D.
Motohisa Yamamoto, M.D., Ph.D.
Interests:
Eiichiro Yamamoto, M.D., Ph.D.
Hiroki Takahashi, M.D., Ph.D.
Hepatogastroenterology,
Masayo Motoya, M.D., Ph.D
Interests:
Katsuhiko Nosho, M.D., Ph.D.
Rheumatology, Clinical Immunology
Interests:
Tadao Ishida, M.D., Ph.D.
Gastroenterology, Oncology
Interests:
Cancer genetics and epigenetics
Associate Professor
Hematology, Oncology
1. Molecular diagnosis and targeted therapy for cancer
a) Biomarker for predicting the risk of gastric cancer (GC)
DNA methylation plays a key role in gastric carcinogenesis.
We have shown that the level of miR-34b/c gene methylation
is significantly higher in noncancerous gastric mucosa of
patients with multiple GCs than in that of patients with a single
gastric cancer or in Helicobacter pylori-positive healthy
individuals. We performed a prospective study in patients with
GC who underwent endoscopic resection and found that the
level of miR-34b/c methylation in noncancerous gastric body
mucosa is a useful biomarker for predicting the risk of
metachronous GC (1). Our findings may be useful to
significantly improve surveillance strategies used after
endoscopic resection of GC.
b) HERs–PI3K signaling pathway in GC
We systematically characterized PIK3CA mutations and
expressions of pAkt and HER2, all of which are involved in the
HERs–PI3K pathway, in patients with GC. PIK3CA mutations
were detected in 8.7% of those with GCs, and pAkt expressions
significantly correlated with HER2 overexpressions but not
with PIK3CA mutations. In addition, pAkt expressions are
significantly associated with poor prognosis (2). These results
have potentially important clinical implications because
molecular alterations can be used to stratify patients with
cancer for genotype-based molecular therapies of the HERs–
PI3K pathway.
c) Biomarker for predicting the prognosis of gastrointestinal
stromal tumors (GISTs)
Predicting the malignant potential of GISTs is difficult. We
have shown that long interspersed nuclear element-1 (LINE1) hypomethylation significantly correlates with the
aggressiveness of GISTs, suggesting that LINE-1 methylation
could be a useful marker for predicting prognoses. We have
also shown that overexpression of miR-196a was associated
with high-risk grade, metastasis, and poor survival among
GIST specimens (3. Microarray expression analysis revealed
that the HOXC and noncoding RNA HOTAIR gene were also
coordinately upregulated in GISTs. RNA interferencemediated knockdown of HOTAIR altered the expression of the
reported HOTAIR target genes and suppressed GIST cell
invasiveness. These findings reveal that miR-196a and
HOTAIR are potentially useful biomarkers and therapeutic
targets in malignant GISTs.
d) Biomarker for predicting the prognosis of multiple myeloma
(MM)
We assessed global methylation levels in MM samples to
determine the role of global hypomethylation of repetitive
elements to determine the genetic and clinical features of MM
(4). Global levels of repetitive-element methylation decline
with the degree of malignancy of plasma cells (normal plasma
cells > monoclonal gammopathy of undetermined significance
> MM), and there was a significant inverse correlation between
the degree of genomic loss and LINE-1 methylation levels.
We also showed that there was a significant association
between LINE-1 hypomethylation and poorer overall survival.
Global hypomethylation of LINE-1 is associated with the
progression of and poorer prognosis for MM, possibly because
of frequent copy-number loss.
e) Molecular targeting therapy for hepatocellular carcinoma
(HCC)
Fibroblast growth factor receptor 1 (FGFR1) has been
shown to be expressed in HCC and is known to promote the
55
development of HCC in response to a carcinogenic stimulation.
We found that IFN-α/β induces the expression of FGFR1, and
treatment with a combination of IFN-α/β and an anti-FGFR1
monoclonal antibody (mAb) suppresses HCC cell growth in
vitro and in vivo. We also confirmed that IFN-α/β enhances
the accumulation of the anti-FGFR1 mAb within tumors (5).
This treatment protocol selectively inhibits the growth of HCC
cells without affecting the normal cells, suggesting it could be
used in the treatment of patients with HCC without reducing
the hepatic preliminary performance. Therefore, we propose
that our results may provide the basis for a novel approach to
the treatment of HCC.
2. Stem cell biology and regenerative medicine
Inflammatory bowel disease (IBD) could be curable by
“immune rest” and correction of the genetic predisposition
inherent in allogeneic hematopoietic stem cell transplantation.
However, balancing the risks against benefits remains
challenging. The application of mesenchymal stem cells
(MSCs) serving as a site-regulated “drugstore” is a recent
concept and suggests the possibility of a definitive treatment
for IBD.
Stem cell biology holds great promise for a new era of
cell-based therapy and has sparked considerable interest
among scientists, clinicians and patients. Early results from
several clinical studies using MSCs suggest several inherent
problems among which optimization of MSC therapy appears
to be the most urgent. These problems can be resolved only
by scientifically unveiling the mechanisms of therapeutic
action. In light of this background, we have been investigating
how such information could facilitate critical steps in the
paradigm shift from basic research on stem cell biology to
clinical practice of regenerative medicine for effectively
treating IBD in the near future (6,7).
3. IgG4-related disease (IgG4-RD)
IgG4-RD is a recently recognized systemic disease entity
characterized by tumefactive and hyperplastic lesions in
various organs, including the lacrimal and salivary glands,
pancreas and kidneys. Patients with IgG4-RD have elevated
serum IgG4 levels and characteristic histopathological
features, including dense infiltration of IgG4-positive plasma
cells, storiform fibrosis, and obliterative phlebitis. Although we
have contributed to the establishment of IgG4-RD as a distinct
clinical entity, the precise mechanism causing IgG4-RD
remained unknown. Therefore, we reported several features
regarding clinical characteristics and prognosis of IgG4-RD to
elucidate its etiology and pathogenesis (8). Although elevated
serum IgG4 levels are highly suggestive of IgG4-RD, we
reported that several pathological conditions showed elevated
serum IgG4 levels, which were not specific for the diagnosis
of IgG4-RD (9). There are few reports regarding the prognosis
of IgG4-RD. We analyzed the relationship between the
duration of the disease and efficacy of treatment with
glucocorticoids to determine the long-term outcomes in IgG4RD (10). Salivary secretions significantly decreased in
patients ill for >2 years, and the area of fibrosis negatively
correlated with an increase in the secretion of saliva. These
results indicate that the salivary gland function gradually
decreases because of glandular destruction and fibrosis in
the long term, and that early therapeutic intervention is
recommended for the preservation of salivary function.
1) Suzuki R, Yamamoto E, Nojima M, Maruyama R, Yamano
H, Yoshikawa K, Kimura T, Harada T, Ashida M, Niinuma
T, Sato A, Nosho K, Yamamoto H, Kai M, Sugai T, Imai K,
Suzuki H, Shinomura Y. Aberrant methylation of
microRNA-34b/c is a predictive marker of metachronous
gastric cancer risk. J Gastroenterol. (2013) [Epub ahead
of print]
2) Sukawa Y, Yamamoto H, Nosho K, Kunimoto H, Suzuki
H, Adachi Y, Nakazawa M, Nobuoka T, Kawayama M,
Mikami M, Matsuno T, Hasegawa T, Hirata K, Imai K,
Shinomura Y. Alterations in the HER2-PI3K-Akt pathway
in gastric cancer. World J Gastroenterol. (2012) 18:65776586.
3) Niinuma T, Suzuki H, Nojima M, Nosho K, Yamamoto H,
Takamaru H, Yamamoto E, Maruyama R, Nobuoka T,
Miyazaki Y, Nishida T, Bamba T, Kanda T, Ajioka Y,
Taguchi T, Okahara S, Takahashi H, Nishida Y, Hosokawa
M, Hasegawa T, Tokino T, Hirata K, Imai K, Toyota M,
Shinomura Y. Upregulation of miR-196a and HOTAIR
drive malignant character in gastrointestinal stromal
tumors. Cancer Res (2012) 72: 1126-36
4) Aoki Y, Nojima M, Suzuki H, Yasui H, Maruyama R,
Yamamoto E, Ashida M, Itagaki M, Asaoku H, Ikeda H,
Hayashi T, Imai K, Mori M, Tokino T, Ishida T, Toyota M,
Shinomura Y. Genomic vulnerability to LINE-1
hypomethylation is a potential determinant of the
clinicogenetic features of multiple myeloma. Genome
Med. (2012) 4:101. [Epub ahead of print]
5) Sasaki S, Ishida T, Toyota M, Ota A, Suzuki H, Takaoka A,
Yasui H, Yamamoto H, Takagi H, Maeda M, Seito T,
Tsujisaki M, Shinomura Y, Imai K. Interferon-α/β and antifibroblast growth factor receptor 1 monoclonal antibody
suppress hepatic cancer cells in vitro and in vivo. PLoS
One. (2011) 6:e19618.
6) Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M,
Nagaishi K, Yamashita K, Yamamoto H, Adachi Y, Sasaki
Y, Isobe M, Fujimiya M, Imai K, Shinomura Y. Enhancing
epithelial engraftment of rat mesenchymal stem cells
restores epithelial barrier integrity. J Pathol. (2009)
218:350-9.
7) Tanaka H, Arimura Y, Yabana T, Goto A, Hosokawa M,
Nagaishi K, Yamashita K, Yamamoto H, Sasaki Y,
Fujimiya M, Imai K, Shinomura Y. Myogenic lineage
differentiated mesenchymal stem cells enhance recovery
from dextran sulfate sodium-induced colitis in the rat. J
Gastroenterol. (2011) 46:143-52.
8) Takahashi H, Yamamoto M, Tabeya T, Suzuki C, Naishiro
Y, Shinomura Y, Imai K. The immunobiology and clinical
characteristics of IgG4 related diseases. J Autoimmun
(2012) 39: 93-96.
9) Yamamoto M, Tabeya T, Naishiro Y, Yajima H, Ishigami K,
Shimizu Y, Obara M, Suzuki C, Yamashita K, Yamamoto
H, Hayashi T, Sasaki S, Sugaya T, Ishida T, Takano K,
Himi T, Suzuki Y, Nishimoto N, Honda S, Takahashi H,
Imai K, Shinomura Y. Value of serum IgG4 in the diagnosis
of IgG4-related disease and in differentiation from
rheumatic diseases and other diseases. Mod Rheumatol
(2012) 22: 419-425.
10) Shimizu Y, Yamamoto M, Naishiro Y, Sudoh G, Ishigami
K, Yajima H, Tabeya T, Matsui M, Suzuki C, Takahashi H,
Seki N, Himi T, Yamashita K, Noguchi H, Hasegawa T,
Suzuki Y, Honda S, Abe T, Imai K, Shinomura Y. Necessity
of early intervention for IgG4-related disease—delayed
treatment induces fibrosis progression. Rheumatology
(2013) 52: 679-83.
56
Cardiovascular, Renal and Metabolic Medicine
We have used multidisciplinary approaches to the pathogenesis of
cardiovascular, renal and metabolic diseases and the development
of novel methodologies for diagnosis and treatment of the diseases.
In the last three years, we have mainly focused on metabolic
modifications of the cardiovascular system, which underlie increases
in cardiovascular events due to diabetes mellitus and chronic kidney
disease.
Professor
Akiyoshi Hashimoto, M.D., Ph.D.
Instructor:
Tetsuji Miura, M.D., Ph.D.
Interests:
Masato Furuhashi, M.D., Ph.D.
Interests:
Pulmonary hypertension, Cardiac
Shinya Shimoshige, M.D.
Myocardial infarction, Heart failure
imaging
Nobuaki Kokubu, M.D., Ph.D.
Cardiomyocyte biology
Atsuko Muranaka, M.D., Ph.D.
Assistant Professor
Hidemichi Kouzu, M.D., Ph.D.
Associate Professor
Hideaki Yoshida, M.D., Ph.D.
Shutaro Ishimura, M.D.
Takayuki Miki, M.D., Ph.D.
Interests:
Interests:
Hypertension, Chronic renal disease
Ischemic heart disease, Diabetes
Masaya Tanno, M.D., Ph.D.
mellitus
Interests:
Heart failure, Ischemic heart disease
1. Molecular mechanisms of cardioprotection afforded
by ischemic preconditioning and its related cell signaling
Our series of studies showed that the gap junction and
the mitochondrial permeability transition pore (mPTP) are two
main targets of cytoprotective signaling activated by ischemic
preconditioning (2,4,8). We identified protein kinases
responsible for modulation of the gap junction and the mPTP
by preconditioning and characterized roles of glycogen
synthase kinase-3b (GSK-3b) in mPTP regulation (1,5,12).
Dysregulation of the mPTP was found to be a mechanism of
hypertension-induced infarct size enlargement (6). In addition,
we are currently examining the role of sirtuins in mPTP
regulation in the heart (13).
2. Mechanisms of diabetic cardiomyopathy and nephropathy
By using animal models of diabetes, we found that
increased ER stress and upregulated calcineurin activity
contribute to enlargement of infarct size and loss of myocardial
response to protective agents in diabetic hearts (1,3,17).
Involvement of ER stress was shown also in diabetes-induced
ventricular dysfunction (15,19). As for diabetic nephropathy,
we demonstrated fusion of pathological bone marrow cells
with renal tubular epithelial cells as a mechanism of renal
dysfunction (10).
3. Noninvasive imaging and assessment of cardiovascular
functions
A series of studies have been conducted to characterize
utilities of 2D- and 3D-speckle tracking methods of
echocardiography. The studies have disclosed non-uniform
modification of ventricular dysfunction through hypertension
and early functional changes that precede morphological
remodeling in the left atrium by paroxysmal atrial fibrillation
(7,18). Longitudinal study using 123I- MIBG imaging showed
that cardiac sympathetic nerve activity is a determinant of
prognosis in heart failure patients and prognosis of heart
failure is much better predicted by a combination of MIBG
imaging with assessment of anemia and renal function (11).
4. Roles of fatty acid binding proteins in metabolic
syndrome and cardiovascular events
Although fatty acid-binding proteins (FABPs) have been
thought to function as intracellular acceptors of free fatty
acids, accumulating evidence indicates that FABPs have
roles as humoral factors mediating various pathological
processes. Our studies have shown that increased plasma
FABP4 is predisposed by family history of hypertension and
contributes to blood pressure elevation (14). In addition, we
found that the plasma FABP4 level predicts cardiovascular
events in patients with end-stage renal diseases (9).
5. Etiology of human hypertension
Using data from the Tanno-Sobetsu cohorts, which have
been followed up from 1976, we found that parental
hypertension has an age-independent impact on elevation of
blood pressure, plasma glucose and triglyceride levels (16).
57
Recently, we found that reduced secretory function of GLP-1
is observed in a number of apparently healthy non-diabetic
subjects and that the GLP-1 insufficiency is associated with
blood pressure elevation (20).
1) Miki T, Miura T, Hotta H, Tanno M, Yano T, Sato T,
Terashima Y, Takada A, Ishikawa S, Shimamoto K.
Endoplasmic reticulum stress in diabetic hearts abolishes
erythropoietin-induced
myocardial
protection
by
impairment of phospho-glycogen synthase kinase-3betamediated suppression of mitochondrial permeability
transition. Diabetes (2009) 58:2863-72.
2) Miura T, Miki T, Yano T. Role of the gap junction in
ischemic preconditioning. Am J Physiol Heart Circ
Physiol (2010) 298:H1115-H1125.
3) Hotta H, Miura T, Miki T, Togashi N, Maeda T, Kim SJ,
Tanno M, Yano T, Kuno A, Itoh T, Satoh T, Terashima Y,
Ishikawa S, Shimamoto K. Angiotensin II type 1 receptormediated upregulation of calcineurin activity underlies
impairment of cardioprotective signaling in diabetic
hearts. Circ Res (2010) 106:129-132.
4) Miura T, Miki T, Yano T. Role of the gap junction in
ischemic preconditioning in the heart. Am J Physiol Heart
Circ Physiol (2010) 298:1115-25.
5) Terashima Y, Sato T, Yano T, Maas O, Itoh T, Miki T,
Tanno M, Kuno A, Shimamoto K, Miura T. Roles of
phospho-GSK-3β in myocardial protection afforded by
activation of the mitochondrial K ATP channel. J Mol Cell
Cardiol (2010) 49:762-70.
6) Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato
T, Kouzu H, Shimamoto K, Miura T. Hypertensive
hypertrophied myocardium is vulnerable to infarction and
refractory to erythropoietin-induced protection. Hypertension
(2011) 57110-5.
7) Kouzu H, Yuda S, Muranaka A, Doi T, Yamamoto H,
Shimoshige S, Hase M, Hashimoto A, Saitoh S,
Tsuchihashi K, Miura T, Watanabe N, Shimamoto K. Left
ventricular hypertrophy causes different changes in
longitudinal, radial, and circumferential mechanics in
patients with hypertension: a two-dimensional speckle
tracking study. J Am Soc Echocardiogr (2011) 24:192-9.
8) Miura T, Tanno M. The mPTP and its regulatory proteins:
final common targets of signalling pathways for protection
against necrosis. Cardiovasc Res (2012) 94:181-9.
9) Furuhashi M, Ishimura S, Ota H, Hayashi M, Nishitani T,
Tanaka M, Yoshida H, Shimamoto K, Hotamisligil GS,
Miura T. Serum fatty acid-binding protein 4 is a predictor
of cardiovascular events in end-stage renal disease.
PLoS One (2011) 6:e27356
10) Yamashita T, Fujimiya M, Nagaishi K, Ataka K, Tanaka M,
Yoshida H, Tsuchihashi K, Shimamoto K, Miura T. Fusion
of bone marrow-derived cells with renal tubules
contributes to renal dysfunction in diabetic nephropathy.
FASEB J (2012) 26:1559-68.
11) Doi T, Nakata T, Hashimoto A, Yuda S, Wakabayashi T,
Kouzu H, Kaneko N, Hase M, Tsuchihashi K, Miura T.
Cardiac mortality assessment improved by evaluation of
cardiac sympathetic nerve activity in combination with
hemoglobin and kidney function in chronic heart failure
patients. J Nucl Med (2012) 53:731-40.
12) Ishikawa S, Kuno A, Tanno M, Miki T, Kouzu H, Itoh T,
Sato T, Sunaga D, Murase H, Miura T. Role of connexin-43
in protective PI3K-Akt-GSK-3β signaling in cardiomyocytes.
Am J Physiol Heart Circ Physiol (2012) 302:2536-44.
13) Tanno M, Kuno A, Horio Y, Miura T. Emerging beneficial
roles of sirtuins in heart failure. Basic Res Cardiol (2012)
107:273.
14) Ota H, Furuhashi M, Ishimura S, Koyama M, Okazaki Y,
Mita T, Fuseya T, Yamashita T, Tanaka M, Yoshida H,
Shimamoto K, Miura T. Elevation of fatty acid-binding
protein 4 is predisposed by family history of hypertension
and contributes to blood pressure elevation. Am J
Hypertens (2012) 25:1124-30.
15) Takada A, Miki T, Kuno A, Kouzu H, Sunaga D, Itoh T,
Tanno M, Yano T, Sato T, Ishikawa S, Miura T. Role of ER
stress in ventricular contractile dysfunction in type 2
diabetes. PLoS One (2012) 7:39893.
16) Mitsumata K, Saitoh S, Ohnishi H, Akasaka H, Miura T.
Effects of parental hypertension on longitudinal trends in
blood pressure and plasma metabolic profile: mixedeffects model analysis. Hypertension (2012) 60:1124-30.
17) Itoh T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga
D, Murase H, Miura T. Cytoprotective regulation of the
mitochondrial permeability transition pore is impaired in
type 2 diabetic Goto-Kakizaki rat hearts. J Mol Cell
Cardiol (2012) 53:870-9.
18)Mochizuki A, Yuda S, Oi Y, Kawamukai M, Nishida J,
Kouzu H, Muranaka A, Kokubu N, Shimoshige S,
Hashimoto A, Tsuchihashi K, Watanabe N, Miura T.
Assessment of left atrial deformation and synchrony by
three-dimensional speckle-tracking echocardiography:
comparative studies in healthy subjects and patients with
atrial fibrillation. J Am Soc Echocardiogr (2013) 26:16574.
19) Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy:
pathophysiology and clinical features. Heart Fail Rev
(2013) 18:149-66.
20) Yoshihara M, Akasaka H, Ohnishi H, Miki T, Furukawa T,
Yuda S, Saitoh S, Miura T. Glucagon-like peptide-1
secretory function as an independent determinant of
blood pressure: analysis in the Tanno-Sobetsu study.
PLoS One (2013) 8:675-78.
58
Respiratory Medicine and Allergology
Our department strives to cure patients with refractory respiratory
and allergic diseases. We have studied clinical aspects and the
pathophysiology of interstitial lung diseases (ILDs), pulmonary
infectious diseases, chronic obstructive pulmonary disease (COPD),
bronchial
asthma
and
lung
tumors
through
radiological,
immunological, biochemical and bacteriological approaches.
Professor
Associate Professor
Instructor
Hiroki Takahashi, M.D., Ph.D.
Gen Yamada, M.D., Ph.D.
Kazumi Kudo, M.D., Ph.D.
Interests:
Interests:
Mitsuo Otsuka, M.D., Ph.D.
Interstitial lung diseases
Pulmonary oncology
Koji Kuronuma, M.D., Ph.D.
Pulmonary oncology
Bronchoendoscopic intervention
Mamoru Takahashi, M.D., Ph.D.
Pulmonary surfactant
Pulmonary Infection and Immunology
Junya Kitada, M.D., Ph.D.
Host defense
Pneumonia
Satsuki Miyajima, M.D., Ph.D
Assistant Professor
Hirotaka Nishikiori, M.D.
Hirofumi Chiba, M.D., Ph.D.
Interests:
Interstitial lung diseases,
Pulmonary surfactant
Pulmonary oncology
1. Interstitial Lung Diseases
For many years we have studied interstitial lung diseases
(ILDs), such as hypersensitivity pneumonia, collagen vascular
diseases, asbestosis, drug induced interstitial lung disorders,
radiation pneumonia and idiopathic interstitial pneumonias
(IIPs). We have a particular interest in IIPs, lung diseases of
unknown origin that include idiopathic pulmonary fibrosis
(IPF), which has a very poor prognosis. We have emphasized
the study of ILD on a research board organized by the Ministry
of Health, Labor and Welfare of Japan.
Recently, through a prospective cohort study in Hokkaido,
we have clarified the Japanese epidemiologic feature of IPF
for the first time through our report. Our results showed a
lower prevalence and incidence rate in Japan compared with
Western countries. In men, the incidence of death due to
acute exacerbation was higher in Japan than in Western
studies. These results may suggest racial and regional
differences in IPF.
IPF is often associated with a syndrome, called combined
pulmonary fibrosis and emphysema (CPFE). We found out
SP-D is a practical predictor for prognosis in IPF patients
associated with CPFE.
We are currently attempting to develop new therapeutic
strategies. Toward that end, we first took a role of core
members in multi-centered prospective phase II and III trials
of pirfenidone (1,2), which is a new anti-fibrotic agent for IPF
and acts though the inhibition of several molecules involved in
fibrogenesis. We suggested that the inhibitory effect of
pirfenidone on delta vital capacity / year was observed
prominently in patients showing not only higher vital capacity
(%VC>70%) at base line but also lower SP-D. Thus, SP-D
and VC at baseline may be independent parameters to predict
the effectiveness of PFD in patients with IPF.
We also clarified the protective effect of angiotensin type
1 receptor blockers and siRNA of heat shock protein 47
against pulmonary fibrosis.
2. Pulmonary Oncology
We performed bronchovideoscopy in combination with a
newly developed endocytoscopy system (3). Observed
cancer cells were similar to the cell images of the
endocytoscopy system. This technology may have the
potential to provide pathologic diagnosis during bronchoscopy.
Ganglioside (GM3) synthase gene (SAT-1) mRNA
expression level is a good biomarker for sensitivity of anticancer drugs such as anti-epidermal growth factor receptor
tyrosine kinase in non-small cell lung cancer (4). In
collaboration with the Department of Pathology, we are
engaged in research of antigen-specific lung cancer
immunotherapy as a novel treatment for the disease.
Our recent study showed that Lengsin splicing variant 4
might be an immunogenic lung cancer-specific antigen that is
suitable as a diagnostic marker and for molecular targeting
therapy. We also demonstrated that SOX2 has a role in
maintenance of stemness and tumorigenicity of human lung
59
adenocarcinoma and is a potential target for treatment (5).
3. Respiratory allergy and COPD
Studies of respiratory allergies and environmental
medicine are mainly in the field of bronchial asthma,
hypersensitivity pneumonitis and chronic obstructive
pulmonary disease (COPD) of which morphologic findings
observed on computed tomography indicate a low attenuation
area (LAA). We advocated a new classification of
morphological features of LAA in centrilobular emphysema
(6). By using this classification, we showed that the
morphological differences of LAA may be related to an airflow
limitation and alveolar diffusing capacity and that assessing
the morphological features of LAA may be helpful regarding
expectations of respiratory function (7).
The main research concentrates on both basic and
clinical issues of small airways disease in asthma, the
functions of cysteinyl leukotiene receptor 1&2 and
prostaglandin receptors, pathological studies of small airways
remodeling, pathological-radiological correlation in small
airways in asthma and COPD, and an insufficient effect of
current asthma therapy. We divide airway resistance into two
components: small airways disease and large airways disease
separately: using biomarkers of exhaled nitric oxide and
impulse oscillometry (IOS).
4. Biochemistry of Respiratory Diseases
We have studied biochemical and pathophysiologic
aspects of many diffuse lung disorders. Using assay kits
originally developed in collaboration with the Department of
Biochemistry, we found that surfactant proteins (SP-A and
SP-D), major glycoproteinous components of the surfactant,
increase in sera from patients with a specific pathophysiologic
state of ILDs,. These kits are novel tools for the diagnosis and
prognosis of ILDs. This clinical application of the assay for
SP-A and SP-D was authorized by the Ministry of Health,
Labor and Welfare. We developed an enzyme-linked
immunosorbent assay for measurement of rat pulmonary
surfactant protein D using monoclonal antibodies in
collaboration with Yamasa Corporation (8). This assay system
will contribute to the evaluation of adverse effects of novel
drugs in animal experiments prior to phase I study. We have
investigated the significance of the surfactant proteins as
factors in host defense situating on the opposite site of several
proinflammatory cytokines in infections caused by
Mycobacterium avium, Streptococcus pneumoniae, Mycoplasma
pneumoniae and Legionella pneumophila (9). We have also
clarified that SP-A protects lung epithelium from cytotoxicity of
human β-defensin 3 (10). We have continued the study of
SP-A in association with lung transplant outcomes in
collaboration with a US research group (11).
1) Azuma A, Taguchi Y, Ogura T, Ebina M, Taniguchi H,
Kondoh Y, Suga M, Takahashi H, Nakata K, Sato A,
Kudoh S, Nukiwa T; Pirfenidone Clinical Study Group in
Japan. Exploratory analysis of a phase III trial of
pirfenidone identifies a subpopulation of patients with
idiopathic pulmonary fibrosis as benefiting from treatment.
Respir Res. 2011;12:143.
2) Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A,
Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A,
Takeuchi M, Raghu G, Kudoh S, Nukiwa T; Pirfenidone
Clinical Study Group in Japan. Pirfenidone in idiopathic
pulmonary fibrosis. Eur Respir J. 2010;35(4):821-9.
3) Kitamura Y, Yamada G, Narita Y, Kameda M, Yamada Y,
Kitada J, Ikeda K, Takahashi H. Bronchoscopic
observation of endobronchial tumor cells. J Bronchology
Interv Pulmonol. 2012;19(4):311-2.
gangliosides in non-small-cell lung cancer using GMR8
monoclonal antibody. Cancer Sci. 2013;104(1):43-7.
5) Nakatsugawa M, Takahashi A, Hirohashi Y, Torigoe T,
Inoda S, Murase M, Asanuma H, Tamura Y, Morita R,
Michifuri Y, Kondo T, Hasegawa T, Takahashi H, Sato N.
SOX2 is overexpressed in stem-like cells of human lung
adenocarcinoma and augments the tumorigenicity. Lab
Invest. 2011;91(12):1796-804.
6) Takahashi M, Yamada G, Koba H, Takahashi H.
Classification of Centrilobular Emphysema Based on CTPathologic Correlations. Open Respir Med J. 2012;6:1559.
7) Takahashi M, Yamada G, Koba H, Takahashi H.
Computed tomography-based centrilobular emphysema
subtypes relate with pulmonary function. Open Respir
Med J. 2013;7:54-9.
protein D using monoclonal antibodies. Exp Lung Res.
2010;36(8):463-8.
9) Sawada K, Ariki S, Kojima T, Saito A, Yamazoe M,
Nishitani C, Shimizu T, Takahashi M, Mitsuzawa H,
Yokota S, Sawada N, Fujii N, Takahashi H, Kuroki Y.
Pulmonary Collectins Protect Macrophages against
Pore-forming Activity of Legionella pneumophila and
Suppress Its Intracellular Growth. J Biol Chem.
2010;285(11):8434-43.
10) Saito A, Ariki S, Sohma H, Nishitani C, Inoue K, Ebata N,
Takahashi M, Hasegawa Y, Kuronuma K, Takahashi H,
Kuroki Y. Pulmonary surfactant protein A protects lung
epithelium from cytotoxicity of human β-defensin 3. J Biol
Chem. 2012;287(18):15034-43.
11) D'Ovidio F, Kaneda H, Chaparro C, Mura M, Lederer D,
Di Angelo S, Takahashi H, Gutierrez C, Hutcheon M,
Singer LG, Waddell TK, Floros J, Liu M, Keshavjee S.
Pilot study exploring lung allograft surfactant protein A
(SP-A) expression in association with lung transplant
outcome. Am J Transplant. 2013;13(10):2722-9.
60
Medical Oncology and Hematology
Since the establishment of the clinical division of our cancer laboratory
in 1953, our research, broadly speaking, has focused on oncology. At
present, Medical Oncology (gastrointestinal, hepatobiliary and
pancreatic cancers/hematological malignancies and bone and softtissue sarcomas) and Hematology are the main branches of clinical
and basic research carried out in our department. Our objective is to
create benefits for patients by achieving advances in the clinical field
and resolving unanswered questions. Given the global nature of
clinical research, the achievements of our department are evaluated
and have clinical applications worldwide.
Professor
Assistant Professor
Instructor
Junji Kato, M.D., Ph.D.
Yasushi Sato, M.D., Ph.D.
Satoshi Iyama, M.D., Ph.D.
Interests:
Interests:
Kohichi Takada, M.D., Ph.D.
Oncology, Hematology
Oncology, Gastroenterology
Yutaka Kawano, M.D., Ph.D.
Koji Miyanishi, M.D., Ph.D.
Hirotoshi Ishiwatari, M.D., Ph.D.
Associate Professor
Interests:
Hiroyuki Onuma, M.D., Ph.D.
Masayoshi Kobune, M.D., Ph.D.
Interests:
Tsutomu Sato, M.D., Ph.D.
Interests:
Rishu Takimoto, M.D., Ph.D.
Interests:
Tsuyoshi Hayashi, M.D., Ph.D.
Interests:
1. Medical Oncology
a) Clinical research
Concerning cancer chemotherapy, we have developed a
triplet combination with S-1, docetaxel and CDDP (DCS) for
the treatment of unresectable metastatic gastric cancer (1).
Recently, we demonstrated that DCS therapy is effective as
neoadjuvant chemotherapy for locally advanced resectable
gastric cancer. In addition, we identified the DDB2/ERCC1high phenotype as a possible useful predictor of resistance to
DCS chemotherapy (2). We have also conducted a phase I
study of arterial infusion chemotherapy with gemcitabine and
5-fluorouracil for unresectable biliary tract cancer (3).
Regarding chemoprevention of pancreatic cancer, we showed
the suppressive effect of sulindac on branch duct-intraductal
papillary mucinous neoplasms (4). Although increased
oxidative stress is presumed to play a role in carcinogenesis
in patients with nonalcoholic steatohepatitis, this relationship
remains to be directly proven. We revealed that the 8-OHdG
content in liver tissue may serve as a marker of oxidative
stress and could be a particularly useful predictor of
hepatocarcinogenesis (5). For hemorrhagic radiation
proctopathy, we reported argon plasma coagulation treatment
yields a high success rate and long-lasting clinical remission
with no significant complications (6). We showed the
usefulness of double-balloon enteroscopy and capsule
endoscopy for the diagnosis of Enteropathy-type T-cell
lymphoma (7).
b) Basic research
One of our goals is to translate the ideas gleaned from
our studies to clinical applications. We developed fucosebound nanoparticles as vehicles for delivery of anticancer
drugs specifically to pancreatic cancer (8). This modality
represents a new strategy for pancreatic cancer cell-targeting
therapy. Furthermore, we demonstrated Fucosylated TGF-ß
receptors transduce a signal for epithelial-mesenchymal
transition in colorectal cancer cells (9).
Based on previous results that indicated we could protect
fibrosis by inhibiting the expression of HSP47, which is a
procollagen-specific molecular chaperone by using HSP47
ribozyme, we have recently succeeded in showing resolution
of pancreatic fibrosis utilizing VA-liposome HSP47/siRNA
targeting pancreatic stellate cells (10). We identified iron
chelator deferasirox rescued mice from Fas-induced fulminant
hepatitis (11).
2. Hematology
The manner of involvement of the hedgehog-signaling
system in the bone marrow microenvironment during the
development of myeloid neoplasms is unknown. We
demonstrated that stromal cells expressing the hedgehoginteracting protein regulate the proliferation of myeloid
neoplasms (12). Elevated serum ferritin (SF) due to ineffective
erythropoiesis and increased iron absorption from the gut is
often observed in non-transfused MDS patients, suggesting
involvement of iron overload in its pathogenesis. However,
61
the prognostic value of the baseline SF is unclear. We
identified leukemia-free survival (LFS) as being significantly
longer in the low SF group than the high SF group. Baseline
SF level may therefore be a prognostic factor for overall
survival and LFS in MDS patients (13). Moreover, we revealed
that excess iron could contribute to the pathophysiology of
MDS and iron chelation therapy could improve the oxidative
DNA damage in MDS patients (14).
In terms of iron metabolisms, we identified a Japanese
female with iron-refractory iron deficiency anemia, who carried
a novel mutation (K253E) in the CUB (complement factor C1r/
C1s, urchin embryonic growth factor and bone morphogenetic
protein 1) domain of the TMPRSS6 gene (15). Furthermore,
we developed an oral iron absorption test to evaluate
gastrointestinal iron absorption (16).
In clinical fields, we found the compound heterozygosity
for UGT1A1*28 and *6 could be a cause of unconjugated
hyperbilirubinemia during nilotinib treatment (17). We reported
on successful treatment by fibrin glue sealant for pneumothorax
with chronic GVHD resistant to autologous blood patch
pleurodesis (18).
1) Sato Y, Takayama T, Sagawa T, Takahashi Y, Ohnuma H,
Okubo S, Shintani N, Tanaka S, Kida M, Sato Y, Ohta H,
Miyanishi K, Sato T, Takimoto R, Kobune M, Yamaguchi
K, Hirata K, Niitsu Y, Kato J. Phase II study of S-1,
docetaxel and cisplatin combination chemotherapy in
patients with unresectable metastatic gastric cancer.
Cancer Chemother Pharmacol(2010) 66(4):721-8.
2) Hirakawa M, Sato Y, Ohnuma H, Takayama T, Sagawa T,
Nobuoka T, Harada K, Miyamoto H, Sato Y, Takahashi Y,
Katsuki S, Hirayama M, Takahashi M, Ono M, Maeda M,
Takada K, Hayashi T, Sato T, Miyanishi K, Takimoto R,
Kobune M, Hirata K, Kato J. A phase II study of
neoadjuvant combination chemotherapy with docetaxel,
cisplatin, and S-1 for locally advanced resectable gastric
cancer: nucleotide excision repair (NER) as potential
chemoresistance marker. Cancer Chemother Pharmacol
(2013) 71(3):789-97.
3) Hayashi T, Ishiwatari H, Yoshida M, Sato T, Miyanishi K,
Sato T, Kobune M, Takimoto R, Sonoda T, Kato J. A
phase I trial of arterial infusion chemotherapy with
gemcitabine and 5-fluorouracil for unresectable biliary
tract cancer. Int J Clin Oncol (2012)17(5):491-7.
4) Hayashi T, Ishiwatari H, Ihara H, Kawano Y, Takada K,
Miyanishi K, Kobune M, Takimoto R, Sonoda T, Takayama
T, Kato J, Niitsu Y. Suppressive effect of sulindac on
branch duct-intraductal papillary mucinous neoplasms. J
Gastroenterol (2009)44(9):964-75.
5) Tanaka S, Miyanishi K, Kobune M, Kawano Y, Hoki T,
Kubo T, Hayashi T, Sato T, Sato Y, Takimoto R, Kato J.
Increased hepatic oxidative DNA damage in patients with
nonalcoholic steatohepatitis who develop hepatocellular
carcinoma. J Gastroenterol. Epub ahead of print (2013).
6) Sato Y, Takayama T, Sagawa T, Hirakawa M, Ohnuma H,
Miyanishi K, Sato T, Takimoto R, Kobune M, Okamoto K,
Takeuchi H, Kato J. Argon plasma coagulation treatment
of hemorrhagic radiation proctopathy: the optional setting
for application and long-term outcome. Gastrointest
Endosc(2011) 73(3):543-9 .
7) Sato Y, Ono M, Sagawa T, Takimoto R, Hirakawa M,
Ohnuma H, Sato T, Iyama S, Murase K, Miyanishi K,
Kobune M, Kato J. Endoscopic findings of enteropathytype-T-cell lymphoma by double-balloon enteroscopy
and capsule endoscopy. Dig Endosc (2010)22(3):243-5.
8) Yoshida M, Takimoto R, Murase K, Sato Y, Hirakawa M,
Tamura F, Sato T, Iyama S, Osuga T, Miyanishi K, Takada
K, Hayashi T, Kobune M, Kato J. Targeting anticancer
drug delivery to pancreatic cancer cells using a fucosebound nanoparticle approach. PLoS One(2012) 7(7):
e39545 .
9) Masahiro Hirakawa, Rishu Takimoto, Fumito Tamura,
Makoto Yoshida, Michihiro Ono, Kazuyuki Murase,
Yasushi Sato, Takahiro Osuga, Tsutomu Sato, Satoshi
Iyama, Koji Miyanishi, Kohichi Takada, Tsuyoshi Hayashi,
Masayoshi Kobune, and Junji Kato. Fucosylated TGF-ß
receptors transduces a signal for epithelial-mesenchymal
transition in colorectal cancer cells. British J Cancer. in
press 2013
10) Ishiwatari H, Sato Y, Murase K, Yoneda A, Fujita R,
Nishita H, Birukawa NK, Hayashi T, Sato T, Miyanishi K,
Takimoto R, Kobune M, Ota S, Kimura Y, Hirata K, Kato
J, Niitsu Y. Treatment of pancreatic fibrosis with siRNA
against a collagen-specific chaperon in vitamin A-copled
liposomes. Gut (2013)62(9):1328-39 .
11) Sato T, Kobune M, Murase K, Kado Y, Okamoto T, Tanaka
S, Kikuchi S, Nagashima H, Kawano Y, Takada K, Iyama
S, Miyanishi K, Sato Y, Takimoto R, Kato J. Iron chelator
deferasirox rescued mice from Fas-induced fulminant
hepatitis. Hepatol Res (2011)41(7):660-7.
12) Kobune M, Iyama S, Kikuchi S, Horiguchi H, Sato T,
Murase K, Kawano Y, Takada K, Ono K, Kamihara Y,
Hayashi T, Miyanishi K, Sato Y, Takimoto R, Kato J.
Stromal cells expressing hedgehog-interacting protein
regulate the proliferation of myeloid neoplasms. Blood
Cancer J 7;2:e87 (2012)
13) Kikuchi S, Kobune M, Iyama S, Sato T, Murase K,
Kawano Y, Takada K, Ono K, Hayashi T, Miyanishi K,
Sato Y, Takimoto R, Kato J. Prognostic significance of
serum ferritin level at diagnosis in myelodysplastic
syndrome. Int J Hematol(2012)95(5):527-34.
14) Kikuchi S, Kobune M, Iyama S, Sato T, Murase K,
Kawano Y, Takada K, Ono K, Kaneko Y, Miyanishi K, Sato
Y, Hayashi T, Takimoto R, Kato J. Improvement of ironmediated oxidative DNA damage in patients with
transfusion-dependent myelodysplastic syndrome by
treatment with deferasirox. Free Radic Biol Med
(2012)23(6):548-50.
15) Sato T, Iyama S, Murase K, Kamihara Y, Ono K, Kikuchi
S, Takada K, Miyanishi K, Sato Y, Takimoto R, Kobune M,
Kato J. Novel missense mutation in the TMPRSS6 gene
in Japanese female with iron-refractory deficiency
anemia. Int J Hematol (2011)41(7):660-7.
16) Kobune M, Miyanishi K, Takada K, Kawano Y, Nagashima
H, Kikuchi S, Murase K, Iyama S, Sato T, Sato Y, Takimoto
R, Kato J. Establishment of a simple test for iron
absorption from the gastrointestinal tract. Int J
Hematol(2011) 93(6):715-9.
17) Takada K, Sato T, Iyama S, Ono K, Kamihara Y, Murase
K, Kawano Y, Hayashi T, Miyanishi K, Sato Y, Kobune M,
Takimoto R, Kato J. UGT1A1*28 and *6 polymorphisms
and nilotinib-induced unconjugated hyperbilirubinemia in
a Japanese patient with chronic myelogenous leukemia.
Int Canc Conf J1;220-3 (2012)
18) Iyama S, Sato T, Murase K, Kikuchi S, Kamihara Y, Ono
K, Takada K, Miyanishi K, Sato Y, Takimoto R, Kobune M,
Obama T, Miyajima M, Watanabe A, Higami T, Hirayama
Y, Kato J. Successful treatment bu fibrin glue sealant for
pneumothorax with chronic GVHD resistant to autologous
blood patch pleurodesis. Intern Med (2012)51(15):20114.
62
Neurology
To offer the best quality of life for patients suffering from various kinds
of neurological disorders, we have been conducting numerous
matters of clinical and basic research. Our main interests include
neurobiology and treatment of neurodegenerative diseases such as
Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral
sclerosis. We also conduct research on strokes, epilepsy,
demyelinating diseases and autoimmune diseases.
Professor
Assistant Professor
Instructor:
Shun Shimohama, M.D., Ph.D.
Jun Kawamata, M.D., Ph.D.
Masaki Saitoh, M.D., Ph.D.
Interests:
Interests:
Emiko Tsuda, M.D., Ph.D.
Dementia, Neurodegenerative disease,
Genetics of Neurodegenerative
Shuichiro Suzuki, M.D., Ph.D.
Alzheimer disease, Parkinson disease
diseases, Epilepsy
Shin Hisahara, M.D., Ph.D.
Interests:
Demyelinating diseases
1. Mechanism of neuronal degeneration in neurodegenerative
diseases such as Alzheimer’s disease and Parkinson’s
disease
We study the molecular mechanism of neuronal death in
neurodegenerative disorders including Alzheimer’s disease
(AD) and Parkinson’s disease (PD), and are trying to develop
novel therapy for these diseases. AD and PD, the two most
common neurodegenerative disorders, have multiple lines of
evidence, from molecular and cellular to epidemiological, that
implicate nicotinic transmission in their pathogenesis. Our
research presents evidence of nicotinic acetylcholine receptor
(nAChR)-mediated protection against neurotoxicity induced
by amyloid-β (Aβ), glutamate, rotenone and 6-hydroxydopamine
(6-OHDA) and indicates how the signal transduction is
involved in this mechanism. Our studies clarify that survival
signal transduction, the α7 nAChR-Src family-PI3 K-AKT
pathway and subsequent upregulation of Bcl-2 and Bcl-x lead
to neuroprotection. We also clarify the 4th independent
neuroprotective pathway, which is mediated by enhancement
of microglial α7 nAChR resulting in upregulation of Aβ
phagocytosis. Galantamine sensitizes microglial α7 nAChRs
to choline and induce Ca2+ influx into microglia. The Ca2+induced intracellular signaling cascades may then stimulate
Aβ phagocytosis through actin reorganization. The discovery
of the 4th pathway will facilitate further investigation of
possible drugs that target nAChRs, not only those that are
neuronal but also microglial nAChRs.
2. Epilepsy
Autosomal dominant lateral temporal lobe epilepsy
(ADLTE) caused by LGI1 (leucine-rich gene, glioma
inactivated 1) mutations is a rare familial epileptic syndrome
characterized by an auditory ictal manifestation and rare
nocturnal generalized seizures. We have examined the
sequence of the LGI1 gene in Japanese families with lateral
temporal lobe epilepsies displaying characteristic auditory
features, and identified one novel (1421G>A), and one
reported (1418C>T) point mutation each in two families.
3. Molecular involvement of deacetylase SIRTs in
neurological disorders
SIRTs (Sirtuins) are a conserved family of deacetylases
whose activities are dependent on nicotinamide adenine
dinucleotide (NAD+). In mammals, seven SIRTs (SIRT1 to
SIRT7) have been identified to date. They were first found to
participate in histone deacetylation and heterochromatic
silencing. The roles of SIRTs are now widely identified in
aging, metabolism, and tumorigenesis. As such, they also
have been studied in neurogenesis and neurodegenerative
disorders. Previously, we found that SIRT1 expresses in the
subventricular zone of the adult brain. This finding indicates
that SIRT1 constantly expresses in undifferentiated neural
progenitor cells including neural stem cells. We have also
shown that SIRT1 promotes neuronal differentiation via
regulating the Notch-Hes1 signaling pathway. Recently, we
have focused on investigating molecular mechanisms of
SIRTs in oligodendrocyte differentiation. Oligodendrocytes
are one of the glial cells that produce myelin proteins in the
central nervous system. Multiple sclerosis is characterized by
inflammatory demyelination. Preliminary, we have found that
regulation of SIRTs results in alteration of oligodendrocyte
differentiation. We are just exploring detailed analyses for
involvement of SIRTs in oligodendrocyte biology. Our aim is to
clarify the mechanism of promoting remyelination and
contribute to the development of therapeutic strategies in the
treatment of multiple sclerosis.
4. Education and Cooperation of stroke and dementia
prevention
Stroke and dementia are critical issue in Japanese public
health because they are major causes for people becoming
63
bedridden. In cooperation with the Hokkaido Critical-pass
Council and Hokkaido government we have promoted
strategies for stroke and dementia prevention and social
education. We have additionally participated in the
development of the Hokkaido stroke regional pass system
(Nōsotsū Anshin Renkei Note) and developed and run a
portal website for stroke and arteriosclerotic disease
prevention.
5. Clinical Neurophysiology on myasthenia gravis
Excitation-contraction (E-C) coupling of skeletal muscle
has been a somewhat under-explored field in clinical
neurophysiology. It includes several processes from the
generation of a muscle action potential to muscle contraction.
Physiologically, E-C coupling has rarely been evaluated in
neuromuscular disorders because of the lack of appropriate
methods to assess E-C coupling in vivo.
In 2010, we reported a novel physiologic assessment
method of E-C coupling. In that study, the electrical and
mechanical muscle responses were simultaneously recorded.
The compound muscle action potentials (CMAPs) from the
masseter muscle and jaw movement-related potentials were
recorded by using an accelerometer after trigeminal nerve
stimulation with a needle electrode. The E-C coupling time
(ECCT) was calculated as the onset latency difference
between CMAP and movement-related potential. We also
measured bite force using a specialized pressure-sensitive
sheet, and this enabled us to analyze the correlation of ECCT
and bite force. ECCT was prolonged in MG patients compared
to normal subjects, and correlated with bite force. The data
supported the view that E-C coupling may be impaired in MG.
We extended our earlier findings, focusing on the
relationship among the ECCT, ryanodine receptor (RyR) and
anti-RyR antibody in MG patients because RyR plays an
essential role in E-C coupling. Our results indicated that E-C
coupling was impaired by anti-RyR antibodies, and contributed
to muscle weakness in MG patients with this antibody. We
also demonstrated that tacrolimus could result in early clinical
improvement in MG patients, suggesting the existence of
positive short-term pharmacologic effects of tacrolimus
2+
mediated by RyR-related Ca release on MG symptoms.
1) Tsuda E, Imai T, Hozuki T, Yamamoto D, Harada K,
Shimohama S. Transient oculomotor palsy correlated
with nerve enhancement on MRI in chronic inflammatory
demyelinating polyneuropathy. Intern Med. (2009)
48(22)1985-87.
2) Shimohama S. Nicotinic receptor-mediated neuroprotection
in neurodegenerative disease models. Biol Pharm Bull.
32(3):332-6, 2009
3) Hisahara S and Shimohama S.Toxin-Induced and
Genetic Animal Models of Parkinson’s Disease.
Parkinson’s Disease. Volume 2011, Article ID 951709,
2010
4) Tsuda E, Imai T, Hozuki T, Yamauchi R, Saitoh M,
Hisahara S, Yoshikawa H, Motomura M, Shimohama S.
Correlation of bite force with excitation-contraction
coupling time of the masseter in myasthenia gravis. Clin
Neurophysiol. (2010)121(7):1051-8.
5) Hozuki T, Imai T, Tsuda E, Matsumura A, Yamamoto D,
Toyoshima T, Suzuki S, Yamauchi R, Hayashi T, Hisahara
S, Shimohama S. Response of serum carboxylated and
undercarboxylated osteocalcin to risedronate monotherapy
and combined therapy with vitamin K(2) in corticosteroidtreated patients: a pilot study. Intern Med. (2010)49(5):3716.
6) Kawamata J, Ikeda A, Fujita Y, Usui K, Shimohama S,
Takahashi R. Mutations in LGl1 gene in Japanese
families with autosomal dominant lateral temporal lobe
epilepsy: the first report from Asian families. Epilepsia
(2010)51(4):690-693.
7) Hisahara S and Shimohama S. Dopamine Receptors and
Parkinson’s Disease. International Journal of Medicinal
Chemistry. Volume 2011, Article ID 403039, 16 pages,
2011
8) Han M, Ohnishi H, Nonaka M, Yamauchi R, Hozuki T,
Hayashi T, Saitoh S, Hisahara S, Imai T, Shimohama S,
Mori M. Relationship between dysphagia and depressive
states in patients with Parkinson’s disease. Parkinsons
Disease & Related Disorders. (2011)17, 437-439.
9) Matsushita T, Kibayashi T, Katayama T, Yamashita Y,
Suzuki S, Kawamata J,Honmou O, Minami M, Shimohama
S. Mesenchymal stem cells transmigrate across brain
microvascular endothelial cell monolayers through
transiently formed inter-endothelial gaps. . Neurosci Lett.
(2011)502(1):41-5.
10) Imai T, Tsuda E, Toyoshima T, Yoshikawa H, Motomura
M, Shimohama S. Anti-ryanodine receptor-positive
acetylcholine receptor-negative myasthenia gravis:
evidence of impaired excitation-contraction coupling.
Muscle Nerve. (2011)43(2):294-5.
11) Kawamata J, Shimohama S. Stimulating nicotinic
receptors trigger multiple pathways attenuating
cytotoxicity in models of Alzheimer’s and Parkinson’s
diseases. J Alzheimers Dis. 24 Suppl 2: 95-109,2011
12) Kawamata J, Suzuki S, Shimohama S. Enhancement of
nicotinic receptors alleviates cytotoxicity in neurological
disease models. Ther Adv Chronic Dis.;(2011)2(3):197208.
13) Hisahara S and Shimohama S. Animal models of
Parkinson’s disease induced by toxins and genetic
manipulation; Mechanisms in Parkinson’s Disease Models and Treatments chapter 17 323-350, InTech. Inc,
2012
14) Imai T, Tsuda E, Hozuki T, Yamauchi R, Saitoh M,
Hisahara S, Yoshikawa H, Motomura M, Kawamata J,
Shimohama S. Early effect of tacrolimus in improving
excitation-contraction coupling in myasthenia gravis. Clin
Neurophysiol. (2012)23(9):1886-90.
15) Imai T, Tsuda E, Hozuki T, Yoshikawa H, Yamauchi R,
Saitoh M, Hisahara S, Motomura M, Kawamata J,
Shimohama S. Contribution of anti-ryanodine receptor
antibody to impairment of excitation-contraction coupling
in myasthenia gravis. Clin Neurophysiol. (2012)123(6):
1242-7.
16) Kawamata J, Suzuki S, Shimohama S. α7 nicotinic
acetylcholine receptor mediated neuroprotection in
Parkinson's disease. Curr Drug Targets. (2012)13(5):62330.
17) Suzuki S, Kawamata J, Matsushita T, Matsumura A, Hisahara
S, Takata K, Kitamura Y, Kem W, Shimohama S.
3-[(2,4-Dimethoxy) benzylidene]-anabaseine dihydrochloride
protects against 6-hydroxydopamine-induced parkinsonian
neurodegeneration through α7 nicotinic acetylcholine
receptor stimulation in rats. J Neurosci Res. (2013)
91(3):462-71.
64
Surgery, Surgical Oncology and Science
The department of Surgery, Surgical oncology and Science covers
wide academic topics ranging from basic research to clinical
treatment. The focus of basic research is regenerative medicine,
oncological regulation and physiological cellular function. Clinical
research is focused on identifying a predictive factor for short-term
and long-term prognosis of various GI tract diseases. In addition, we
are one of the national leaders in charge of establishing clinical
guidelines. Our hope is to improve surgery and to see patients smile.
Professor
Assistant Professor
Instructor:
Koichi Hirata, M.D., Ph.D.
Yasutoshi Kimura, M.D., Ph.D.
Masafumi Imamura, M.D., Ph.D.
Interests:
Interests:
Masaki Kawamoto, M.D., Ph.D.
Regenerative medicine, Gene therapy,
Pancreatobiliary Surgery, Oncology
Kenji Okita, M.D., Ph.D.
Peptide vaccine therapy for pancreatic
Takayuki Nobuoka, M.D., Ph.D.
Toshihiko Nishidate, M.D., Ph.D.
cancers, Clinical cancer guidelines
Interests:
Tatsuya Ito, M.D., Ph.D.
Laparoscopic upper GI surgery,
Associate Professor
Nutrition science
Tomohisa Furuhata, M.D., Ph.D.
Goro Kutomi, M.D., Ph.D.
Interests:
Interests:
Laparoscopic colorectal surgery,
Breast endocrine surgery, Oncology
Oncology
Toru Mizuguchi, M.D., Ph.D.
Interests:
Laparoscopic liver surgery, Cell
transplantation, Regenerative medicine
1. Oncology
Oncological research is conducted through both basic
and clinical approaches. Our target organs were the colon,
rectum (1-3), liver (4), pancreas (5) and breast (6). A low fat
meal increased oral bioavailability of UFT and leucovorin in
colorectal cancer patients (1). Prognostic factors of stage II
colorectal cancer had been controversial. We found that
metalloproteinase (MMP)-2 expression (2) and vascular
endothelial growth factor 165b expression (3) in the stromal
cells surrounding cancer cells could be key regulators in
determining the prognosis. In the liver, we reviewed current
approaches to molecular pathogenesis including molecular
targets and therapies (4). In the pancreas, we also reviewed
surgical management of intraductal papillary mucinous
neoplasms (IPMN) (5). In the breast, we found human
endoplasmic reticulum oxidoreductin 1-α (hERO1-α) could
be a novel prognostic molecular marker for breast cancer (6).
2. Liver regeneration
Liver regeneration (LR) occurs when the liver has lost its
volume due to any cause (7-9). Basic research revealed a
mechanism by which the liver regenerates including how and
when the process starts. We found that urinary trypsin inhibitor
(UTI) is one of the key regulators for LR (7). Pre-coagulation
for liver resection might disturb LR and it could be reversed by
low-dose steroid administration (8). Liver cirrhosis is a risk for
liver failure after a hepatectomy. However, liver stem cell
transplantation rescued cirrhotic animals from liver failure (9).
3. Clinical study
Our clinical study focused on liver surgery including short
and long-term prognoses (10-17). To improve the short-term
prognosis, we evaluated various serum protein alterations.
We found that nutritional assessment is also important to
avoid unnecessary complications (10-12). We also developed
a radiological evaluation for liver function (13) and proposed
eligible criteria for liver resection (14,16,17). Intraoperative
monitoring helps us estimate the possibilities of postoperative
liver failure (15).
4. Laparoscopic surgery
Laparoscopic surgery is widely applied for elective
surgery including stomach, esophagus, duodenum, pancreas,
liver, gallbladder, intestine, colon, and rectal disease. We
actually performed a laparoscopy assisted whipple operation
a decade ago. We have reviewed the current status of
laparoscopic liver resection (18). Furthermore, we have
65
demonstrated a novel technique for vascular clump using our
patent product (19).
5. Peptide vaccine therapy for advanced pancreatic
cancer
We have collaborated with the department of Pathology
to establish a novel cancer therapy. A peptide vaccine has
been developed and the official clinical phase I trial was
completed at the midway point of 2013. The preliminary result
of this phase I clinical trial has been encouraging to patients
suffering from advanced pancreatic cancer. The phase II
clinical trial will commence at the end of 2013 in multi-centers.
1) Furuhata T, Meguro M, Nishidate T, Okita K, Ishiyama G,
Iwayama Y, Hosokawa Y, Tsuruma T, Kimura Y, Mizuguchi
T, Sasaki K. Effects of a low-fat meal on the oral
bioavailability of UFT and leucovorin in patients with
colorectal cancer. Int J ClinOncol. 2009;14: 529-533.
2) Inafuku Y, Furuhata T, Tayama M, Okita K, Nishidate T,
Mizuguchi T, Kimura Y, Hirata K. Matrix metalloproteinase-2
expression in stromal tissues is a consistent prognostic
factor in stage II colon cancer. Cancer Sci. 2009; 100:
852-858.
3) Tayama M, Furuhata T, Inafuku Y, Okita K, Nishidate T,
Mizuguchi T, Kimura Y, Hirata K. Vascular endothelial
growth factor 165b expression in stromal cells and
colorectal cancer. World J Gastroenterol. 2011;17:486774.
4) Meguro M, Mizuguchi T, Kawamoto M, Hirata K: The
molecular pathogenesis and clinical implications of
hepatocellular carcinoma. Int J Hepatol. 2011;2011:
818672.
5) Hirata K, Kimura Y, Mizuguchi T, Mimamura M, Meguro
M, Nakamura Y, Ito T, Yamaguchi H, Kyuno D. Surgical
management of intraductal papillary mucinous
neoplasms. Rozhl Chir. 2012; 91:340-5.
6) Kutomi G, Tamura Y, Tanaka T, Kajiwara T, Kukita K,
Ohmura T, Shima H, Takamaru T, Satomi F, Suzuki Y,
Torigoe T, Sato N, Hirata K. Human Endoplasmic
Reticulum Oxidoreductin 1-α (hERO1-α) is a Novel
Predictor for Poor Prognosis of Breast Cancer. Cancer
Sci. 2013 Apr 11. [Epub ahead of print]
7) Nobuoka T, Mizuguchi T, Oshima H, Shibata T, Kaji S,
Nagayama M, Meguro M, Mitaka T, Hirata K: Impaired
liver regeneration with humoral and genetic disturbances
in urinary trypsin inhibitor-deficient mice. Liver Int. 2009;
29: 986-94.
8) Shibata T, Mizuguchi T, Nakamura Y, Kawamoto M,
Meguro M, Ota S, Hirata K, Ooe H, Mitaka T. Low dose
steroid pretreatment ameliorates transient impairment of
the liver regeneration due to radiofrequency ablation.
World J Gastroenterol. 2012; 18: 905-14.
9) Nakamura Y, Mizuguchi T, Tanimizu N, Ichinohe N, Ooe
H, Kawamoto M, Meguro M, Hirata K, Mitaka T.
Preoperative hepatocyte transplantation improves the
survival of rats with non -alcoholic steatohepatitis-related
cirrhosis after partial hepatectomy. Cell Transplant. 2013
Jun 13. [Epub ahead of print]
10) Mizuguchi T, Kawamoto M, Meguro M, Nakamura Y,
Harada K, Kukita K, Hirata K. Prognostic impact of
preoperative branched-chain amino acids to the tyrosine
ratio level in hepatocellular carcinoma patients after initial
hepatectomy. J Gastroint Surg. 2011; 15: 1433-9.
11) Nakamura Y, Mizuguchi T, Kawamoto M, Meguro M,
Harada K, Ota S, Hirata K. Cluster analysis of liver
functional indicators and preoperative low BTR indicate
high risk of early recurrence in analysis of 165 HCC
patients after initial hepatectomy. Surgery 2011; 150:
250-62.
12) Mizuguchi T, Kawamoto M, Son S, Meguro M, Shibata T,
Nakamura Y, Harada K, Furuhata T, and Hirata K. Serum
antithrombin III level is well correlated with multiple
indicators for assessment of liver function and diagnostic
accuracy for predicting postoperative liver failure in
hepatocellular carcinoma patients. Hepatogastroenterology
2012;59: 551-7.
13) Harada K, Mizuguchi T, Katagiri Y, Kawamoto M,
Nakamura Y, Meguro M, Ota S, Sasaki S, Miyanishi K,
Sonoda T, Shinomura Y, Hirata K. Area among the hepatic
and heart curves of 99mTc-galactocyl-human serum
albumin scintigraphy represents liver function and
disease progression for preoperative evaluation in
hepatocellular carcinoma patients. J Hepatobiliary
Pancreat Sci. 2012; 19:667-73.
14) Mizuguchi T, Kawamoto M, Meguro M, Nakamura Y, Ota
S, Hui TT, Hirata K. Prognosis and Predictors of Surgical
Complications in Hepatocellular Carcinoma Patients
With or Without Cirrhosis after Hepatectomy. World J
Surg. 2013; 37:1379-87.
15) Meguro M, Mizuguchi T, Kawamoto M, Nakamura Y, Ota
S, Kukita K, Ishii M, Tatsumi H, Hirata K. Continuous
monitoring of central venous oxygen saturation predicts
postoperative liver dysfunction after liver resection.
Surgery. 2013;154:351-62.
16) Mizuguchi T, Kawamoto M, Meguro M, Hui TT, Hirata K.
Preoperative liver function assessments to estimate the
prognosis and safety of liver resections. Surg Today.
2013 Mar 9. [Epub ahead of print]
17) Harada K, Mizuguchi T, Kawamoto M, Meguro M, Ota S,
Sasaki S, Miyanishi K, Hatakenaka M, Shinomura Y,
Kato J, and Hirata K. Prediction of postoperative liver
failure and evaluation of modified criteria for liver
resection
with
computed
volume
analysis.
Hepatogastroenterology 2013 (in press).
18) Mizuguchi T, Kawamoto M, Meguro M, Shibata T,
Nakamura Y, Kimura Y, Furuhata T, Sonoda T, and Hirata
K. Laparoscopic hepatectomy: a systematic review,
meta-analysis and power analysis.Surg Today
2011;41:39-47.
19)Mizuguchi T, Kawamoto M, Nakamura Y, Meguro M,
Harada K, OtaS , Hui TT, and Hirata K. New technique of
extracorponeal hepatic inflow control for pure
laparoscopic liver resection. Surg Laparosc Endosc
Percutan Tech. 2013 (in press).
66
Our department started offering courses in 1958 as the first thoracic
surgery department established in Japan. Thereafter, the department
was referred to as the Second Department of Surgery and in
September 2012, it was renamed the Department of Cardiovascular
Surgery after the university was restructured. This year marks 54
years since the establishment of this department. In 2006, professor
Tetsuya Higami was appointed as a fourth generation professor and
a new neonatal cardiovascular surgery team with superb skilled in
surgical techniques established. All of our department’s staff believe
that “medical care is for the sake of the patient” and therefore provide
high quality care and practice team medicine with a warm personal
touch.
Professor
Instructor
Tetsuya Higami, M.D., Ph.D.
Nobuyuki Takagi, M.D., Ph.D.
Tetsuya Koyanagi, M.D.
Assistant Professor
Yasuko Miyaki, M.D., Ph.D.
Toshiro Ito, M.D., Ph.D.
Kazutoshi Tachibana, M.D., Ph.D.
Seiichi Funamoto, C.E., Ph.D.
1. Medical care
Thoracic and cardiovascular surgery, which has been
conducted over 50 years since our establishment, has
included over 6,800 cases of cardiac surgery, 1,000 cases of
large vessel surgery, and 19,000 cases of thoracic surgery.
Currently, in this department, officially qualified specialists
perform extremely high quality specialized medical care that
can only be conducted at university hospitals in specialized
areas of acquired heart disease such as valvular heart disease
and coronary artery disease, large vessel, peripheral vessel
and venous disease, and congenital heart disease.
Our university hospital has a tertiary emergency care
center and provides emergency support for cardiac and large
vessel diseases 24 hours a day. In October 2011, the
cardiovascular center was established in which cardiovascular
surgery and internal medicine teams work closely together to
provide the highest quality medical care. The total number of
surgeries performed is over 600 per year, including over 300
cases per year of cardiovascular surgery. Further, the number
of patients wishing to undergo surgery in our department has
increased annually. A specialist team of approximately 11
individuals scrupulously examines the pathology of each
patient and provides treatment while maintaining an advanced
level of care.
a) Cardiac surgery
Angina pectoris and myocardial infarction are the most
common ischemic heart diseases. These diseases are
surgically treated with coronary artery bypass grafting
(CABG). We perform our own unique technique of on-pump
CABG that prioritizes the use of arterial grafts.
Mitral insufficiency (mitral regurgitation) and aortic
stenosis are the most common valvular diseases (heart valve
diseases). Surgery for mitral insufficiency involves actively
performing valve-sparing mitral valvuloplasty, and we have
achieved a success rate of close to 100% through our own
intraoperative assessment method (cardioprotective beating
heart regurgitation assessment method).
For aortic stenosis, normal aortic valve replacement is
performed as the first-choice procedure. However, due to the
influence of improved surgical outcomes and Japan’s
development into a super-aging society, we believe that the
time has come to consider catheter surgery for high-risk cases
involving very elderly patients who until now have not been
indicated for surgery. Transcatheter Aortic Valve Implantation
(TAVI), which has been conducted as a treatment in Europe
for more than 10 years, is advancing in Japan now that trials
have just been completed. Approval for TAVI is also being
bestowed on our department and we are scheduled to start
this treatment as of next spring in cooperation with the
Department of Cardiology.
b) Vessel disease
Sapporo Medical University Second Department of
Surgery is the hospital department with the highest number of
surgical cases and successful treatments involving both
artificial blood vessel replacement and stent grafting for aortic
aneurysms in Hokkaido, providing high-grade treatment 24
hours a day. In 2010, surgery was performed for 119 cases of
thoracic aortic aneurysms. Referrals from facilities specializing
in cardiovascular surgery are also increasing in Hokkaido,
especially in Sapporo.
67
c) Other considerations
We also offer repeat surgery for past recipients of cardiac
surgery who unfortunately suffer disease progression or the
development of a new heart disease. Our department
established its own technique for safe and reliable repeat
surgery in cases of a second, third, and up to a maximum of
fifth repeat cardiac surgery. Most patients are able to return to
a healthy everyday life. We actively pursue the latest medical
technology including highly-advanced medical technology in
the surgical treatment of all heart diseases, and strive to
provide this to patients.
2. Research
Clinically-grounded research is mainly conducted in our
department by graduate students. Research currently being
conducted related to mitral valvuloplasty includes “research
on the retrograde cardioplegic beating test (RC-beating test)
in mitral valvuloplasty’’ (lead researcher: Dr. Tachibana)
focusing on intraoperative regurgitation assessment, “valvular
function assessment after mitral valvuloplasty (rough-zone
trimming) in our department (lead researcher: Dr. Yanase)”
focusing on the durability of surgical procedures, and “the
systemization of mitral valvuloplasty using rough-zone
trimming (lead researcher: Dr. Miyaki)” focusing on the
universalization of surgical procedures.
Research is also underway on methods of assessing
new coronary artery bypass grafts after coronary artery
bypass surgery using transit time flow measurement and
MemCalc software. Other research is aimed at the
development of new surgical devices, including “the
development of new bioadhesive devices (lead researcher:
Dr. Funamoto),” and “research into regenerative medicine
materials that promote self-healing (lead researcher: Dr.
Tabuchi).”
3. Training
Based on the idea that “in order to become a leading
cardiovascular surgeon, doctors require 50% effort, 40%
good training environments, and 10% skill,” our course
provides an individually tailored educational program that
follows doctors’ developmental stages.
During wet laboratory research conducted at the
university 5-6 times a year, young doctors perform their own
coronary artery bypass surgery and valve replacement, which
is usually performed by an assistant, and brush up their skills
by practicing with their own hands. The doctors are also able
to experience cardiac surgery on a live pig 2-3 times. This wet
laboratory experience is a step in improving their skills by
actually getting involved in off-pump CABG and internal
thoracic artery harvesting.
Further, these doctors aim to participate in academic
conferences (including national academic conferences) from
an early age and endeavor to become globally recognized,
academic surgeons.
Even without having published any abstracts in Europe
for cardiovascular surgery society publications, our doctors
are permitted to travel abroad with a senior doctor while they
are young. We encourage our doctors to acquire skills from all
over the world from a young age.
4. Conclusions
Cardiovascular surgery involves situations directly
connected to the life and death of individuals. We always keep
in mind the patient’s life while we are providing critical
treatment. The idea of “medical care is for the sake of the
patient” is not about life and death but about remembering to
make full use of our skills to improve patients’ lives. We
passionately manage patients’ lives 24 hours a day and
provide the best treatment possible.
1) Kawaharada N, Kurimoto Y, Ito T, Koyanagi T, Yamauchi
A, Nakamura M, Takagi N, Higami T. Hybrid treatment for
aortic arch and proximal decending thoracic aneurysm:
experience with stent grafting for second-stage elephant
trunk repair. European Journal of Cardio-Thoracic
Surgery 2009.12;36(6):956-961
2) Ito T, Kurimoto Y, Kawaharada N, Higami T. Perforation of
the duodenum by a vascular prosthesis following hybrid
repair of a thoracoabdominal aortic aneurysm. European
Journal of Cardio-Thoracic surgery 2009. 1; 35(1): 177
3) Nakamura M, Yamauchi A, Miyaki M, Higami T. Left
ventricular pseudo-aneurysm after mitral valve
replacement : accurate diagnosis enables treatment.
European Journal of Cardio-Thoracic surgery. 2010
38(2): 235-236
4) Ito T, Kawaharada N, Kurimoto Y, Watanabe A, Tachibana
K, Harada R, Maeda T, Hashiguchi H, Hashimoto M,
Higami T. Renal Cysts as Strongest Association with
Abdominal Aortic Aneurysm in Elderly. Annuls of Vascular
Disease 2010. 9; 3(2): 111-116
5) Takagi N, Tachibana K, Myaki Y, Yamauchi A, Muraki S,
Higami T. Influence of pressure load on durability of
pulmonic xenobioprostheses in young adults. J Artif
Organs. 2011. 14(4) : 289-293
6) Yanase Y, Kawaharada N, Hagiwara T, Nakazawa J,
Maeda T, Koyanagi T, Ito T, Kurimoto Y, Higami T. Surgical
Treatment for Aortic Coarctation with Chronic Type B
Dissection: Report of a Case. Ann Vasc Dis. 2011. 4: 774779
7) Toshiro Ito, Tetsuya Koyanagi, Nobuyoshi Kawaharada,
Yoshihiko Kurimoto, Takeshi Uzuka, Mayuko Uehara,
Takayuki Hagiwara, Yohsuke Yanase, Toshiyuki Maeda,
and Tetsuya Higami. Coversion to open repair from
emergency EVAR in a patient with ruptured AAA: Report
of a case. Ann Vasc. Dis. 5(4):454-457, 2012
8) Toshiro Ito, MD, PhD, Yoshihiko Kurimoto, MD, PhD,
Nobuyoshi Kawaharada, MD, PhD, Tetsuya Koyanagi,
MD, Toshiyuki Maeda, MD, Yohsuke Yanase, MD, Junji
Nakazawa, MD, Naoki Hirokawa, MD, PhD, and Tetsuya
Higami, MD, PhD. Ischemic colitis following transarterial
embolization for type 2 endoleak of EVAR: Report of a
Case. Ann Vasc Dis Vol.5, No.1: 92-95, 2012
9) Kawaharada N, Kurimoto Y, Ito T, Uehara M, Maeda T,
Koyanagi T, Muraki S, Watanabe A, Higami T.
Endovascular Stent-Graft Repair of Aortobronchial
Fistulas. Ann Thorac Surg.94(2): 524-9, 2012
10)Takagi T, Yamashita A, Uzuka T, Muraki S, Higami T.
Repeat conduit replacement in the pulmonary position
without sternal resplitting for the patient with repaired
Tetralogy of Fallot and the absent inferior caval vein. Gen
Thorac Cardiovasc Surg 2012; 60: 840-842
68
Orthopaedic Surgery
Regarding the research of orthopaedic surgery, there are fields of
musculoskeletal studies. Our focus is on elucidating the causal
mechanisms of various musculoskeletal disorders including
spondylosis, osteoarthritis, tumors, bone metabolic disorders and
sports injuries, and to develop effective treatments for these
disorders. Our main research interests are (1) the mechanism of
musculoskeletal pain, (2) immunotherapy for malignant bone and
soft tissue tumors, (3) bone metabolic disorders, (4) the anatomical
and biomechanical study of the spine and joints, (5) minimum
invasive surgery of the spine and joints and (6) nerve regeneration
after spinal cord injuries.
Professor
Toshihiko Yamashita, M.D., Ph.D.
Interests:
Spine surgery, Sports medicine, Pain
mechanism
Specially Appointed Professor
(Department of Regional Health Care
and Medicine)
Takuro Wada, M.D., Ph.D.
Interests:
Hand surgery, Bone and soft tissue tumor
Associate Professor
Kousuke Iba, M.D., Ph.D.
Interests:
Hand surgery, Bone metabolic
disorders
Tsuneo Takebayashi, M.D., Ph.D.
Interests:
Spine surgery, Pain mechanism
Interests:
Knee surgery, Ankle and foot surgery,
Sports medicine
Mitsunori Yoshimoto, M.D., Ph.D.
Interests:
Spine surgery
Assistant Professor
Kohei Kanaya, M.D., Ph.D.
Interests:
Hand surgery, Microsurgery
Mitsunori Kaya, M.D., Ph.D.
Interests:
Hip surgery, Bone and soft tissue tumor
Kota Watanabe, M.D., Ph.D.
Instructor
Kazunori Ida, M.D., Ph.D.
Mikito Sasaki, M.D., Ph.D.
Atsushi Teramoto, M.D., Ph.D.
Katsumasa Tanimoto, M.D., Ph.D
1. Spine and spinal cord
Using new methods of Magnetic Resonance (MR) imaging,
we analyzed the anatomical pathology of intervertebral discs or
nerve roots in several spinal disorders. Our study demonstrated
that a decrease of MR T2 mapping values in intervertebral discs
reflected a decrease in proteoglycan and water content, and
suggests that MR T2 mapping could be a useful method for
assessment on degenerative disc diseases (1). Minimum
invasive spinal surgeries such as spinal selective laminoplasty
for spondylotic myelopathy and microendoscopic posterior
decompression for lumbar spinal canal stenosis can reduce
post-operative pain and the hospitalization period for patients.
We reported on a minimally invasive microendoscopic technique
for lumbar foraminal stenosis to decompress the entire length of
the nerve root from the spinal canal to the extraforaminal zone
while preserving the posterior elements (2) and a selective
laminoplasty with segmental decompression for cervical
spondylotic amyotrophy as an advantageous technique for
minimizing postoperative neck pain (3).
Through electrophysiologic analysis of DRG and spinal cord
neurons using a lumbar root constriction model, we investigated
the physiologic properties of DRG and spinal cord neurons with
in vitro or in vivo patch clamp recordings (4,5). We showed the
changes in synaptic transmission of substantia gelatinosa
neurons after an injury to the L5 nerve root in a rat model using
in vivo patch-clamp recording, which suggested one of the
pathophysiological mechanisms of radicular pain (5).
From 2013, we started a new research project to regenerate
nerves after spinal cord injuries by means of a mesenchymal
stem cell implantation through peripheral venous injection.
2. Upper extremities
Upper extremity research has focused on understanding
the anatomy, biomechanics and biology of the hand and elbow,
the anatomical and biomechanical study of the wrist and elbow
using fresh frozen cadavers and the proteomics of peripheral
nerve regeneration and neurogenic pain. We evaluated instability
of the distal radioulnar joint by wrist motion analysis and three
clinical tests using fresh frozen cadaver specimens (6). According
to proteomics analysis, we showed that metallothioneins, zincbinding proteins, were involved in protection against injury and
subsequent regeneration after nerve damage (7). Clinical study
has focused on understanding the pathology of lateral humeral
epicondylitis and elbow osteoarthritis. We investigated cartilage
lesions of the radiocapitellar joint accompanying lateral
epicondylosis and identified their correlation with the extensor
carpi radialis brevis status (8).
3. Lower extremities
a) Hip joint
We explored the effectiveness of muscle sparing surgical
approaches in total hip replacement. We performed a surgical
simulation of the modified Watson-Jones anterolateral approach
using fresh frozen cadavers and found that it was important not
to dissect the anteroproximal portion of the greater trochanter to
prevent rupture of the piriformis tendon (9). In the basic study, we
focused on elucidating the pathogenesis of osteonecrosis of the
femoral head (ONFH) using the rat model that we had previously
established. We showed the role of tripartite motif-containing 21
(TRIM21) in the pathogenesis of ONFH and that the suppression
of TRIM21 resulting from altered nuclear factor-κB and interferon
regulatory factor homeostasis accelerates the ONFH in rats
treated with corticosteroids following lipopolysaccharide
69
administration (10).
b) Knee joints
Two bundle reconstruction methods for anterior cruciate
ligament (ACL) ruptures, which we have employed for the
treatment of patients, were evaluated for their effectiveness
regarding the ACL reconstruction. Using fresh frozen cadaver
specimens, we studied the arrangement of ACL fiber bundles
and their attachment sites to provide information on the tunnel
placement in anatomical ACL reconstruction (11).
c) Ankle joints
In biomechanical analysis, we evaluated the several
treatment methods for ankle ligament injuries using fresh frozen
cadaver models. We examined the roles of the calcaneofibular
ligament, cervical ligament and interosseous talocalcaneal
ligament in stabilizing the subtalar joint, and showed that the
ankle brace limited inversion of the subtalar joint (12). We also
demonstrated that ankle syndesmosis fixation by a suture-button
construct provides adequate stabilization of the ankle and could
benefit athletes with syndesmosis injuries (13).
4. Bone metabolism
We demonstrated that bisphosphonate, which is an antiosteoporotic agent, improved skeletal pain associated with bone
metabolic disorders in osteoporosis, Paget’s disease and
Complex regional pain syndrome (14). We are now focusing on
the pathogenesis through which bone metabolic disorders cause
the skeletal pain, and elucidating the molecular mechanisms.
We are also interested in the relationship between osteoporosis
and lifestyle related diseases. In particular, our focus is on
secondary osteoporosis related with diabetes, and we have
demonstrated that diabetes impairs the interactions between
hematopoietic stem cells and osteoblastic cells in bone marrow
(15).
5. Bone and soft tissue tumors
We have established new therapeutic strategies for the
treatment of bone and soft tissue tumors using synthesized
peptides derived from the SYT-SSX or papillomavirus binding
factor gene and reported on a clinical trial data for patients with
synovial sarcoma and osteosarcoma (16,17). In one study, we
evaluated the safety and effectiveness of SYT-SSX-derived
peptide vaccines in patients with advanced synovial sarcoma.
Nine patients showed a greater than twofold increase in the
frequency of CTLs in tetramer analysis and six patients had
stable disease during the vaccination period (17).
We have also focused on cancer stem cells to explore more
effective peptide vaccine therapies for bone and soft tissue
tumors. Currently, we have reported that side population cells
have the characteristics of cancer stem-like cells/cancer-initiating
cells in bone sarcomas. We showed that side population cells
exist in the bone malignant fibrous histiocytoma (MFH) cell line
which had cancer-initiating ability in vitro and in vivo, and those
cells could serve as candidate markers for cancer stem cells in
bone sarcomas (18).
1) Takashima H, Takebayashi T, Yoshimoto M, Terashima Y,
Tsuda H, Ida K, Yamashita T. Correlation between T2
relaxation time and intervertebral disk degeneration.
Skeletal Radiology (2012) 41: 163–167.
2) Yoshimoto M, Takebayashi T, Kawaguchi S, Tsuda H, Ida K,
Wada T, Suzuki D, Yamashita T.
Minimally invasive technique for decompression of lumbar
foraminal stenosis using a spinal microendoscope: technical
note. Minim Invasive Neurosurg (2011) 54:142–146.
3) Takebayashi T, Yoshimoto M, Ida K, Tsuda H, Terashima Y,
Yamashita T. Minimum invasive posterior decompression
for cervical spondylotic amyotrophy. J Orthop Sci (2012)
18:205-207.
4) Tanimoto K, Takebayashi T, Kobayashi T, Tohse N,
Yamashita T. Does norepinephrine influence pain behavior
mediated by dorsal root ganglia? A pilot study. Clin Orthop
Relat Res (2011) 469: 2568–2576.
5) Terashima Y, Kawamata M, Takebayashi T, Tanaka S,
Tanimoto K, Yamashita T. Changes in synaptic transmission
of substantia gelatinosa neurons in a rat model of lumbar
radicular pain revealed by in vivo patch–clamp recording.
Pain (2011) 152: 1024–1032.
6) Moriya T, Aoki M, Iba K, Ozasa Y, Wada T, Yamashita T.
Effect of triangular ligament tears on distal radioulnar joint
instability and evaluation of three clinical tests: A
biomechanical study. J Hand Surg (2009) 34-E: 219-223.
7) Oki G, Wada T, Iba K, Aiki H, Sasaki K, Imai S, Sohma H,
Matsumoto K, Yamaguchi M, Fujimiya M, Yamashita T,
Kokai Y. Metallothionein deficiency in the injured peripheral
nerves of complex regional pain syndrome as revealed by
proteomics. Pain (2012) 153: 532–539.
8) Sasaki K, Onda K, Ohki G, Sonoda T, Yamashita T, Wada T.
Radiocapitellar cartilage injuries associated with tennis
elbow syndrome. J Hand Surg (2012) 37-A: 748–754.
9) Sasaki M, Nagoya S, Kaya M, Okazaki S, Tateda K,
Kosukegawa I, Yamashita T. Relationship between the hip
joint capsule and piriformis tendon in a simulation of the
modified Watson–Jones anterolateral approach in THA
cadaver study. Clin Anat (2012) 26: 610-613.
10) Tateda K, Okazaki S, Nagoya S, Katada R, Mizuo K,
Watanabe S, Yamashita T, Matsumoto H. The suppression
of TRIM21 and the accumulation of IFN–α play crucial roles
in the pathogenesis of osteonecrosis of the femoral head.
Laboratory Investigation (2012) 92: 1318–1329.
11) Otsubo H, Shino K, Kamiya T, Suzuki D, Suzuki T, Watanabe
K, Yamashita T. The arrangement and the attachment areas
of three ACL bundles. Knee Surg Sports Traumatol Arthrosc
(2012) 20: 127–134.
12) Kamiya T, Kura H, Suzuki D, Uchiyama E, Fujimiya M,
Yamashita T. Mechanical stability of the subtalar joint after
lateral ligament sectioning and ankle brace application: A
biomechanical experimental study. Am J Sports Med (2009)
37: 2451-2458.
13) Teramoto A, Suzuki D, Kamiya T, Chikenji T, Watanabe K,
Yamashita T. Comparison of different fixation methods of
the suture–button implant for tibiofibular syndesmosis
injuries. Am J Sports Med (2011) 39: 2226–32.
14) Abe Y, Iba K, Takada J, Wada T, Yamashita T. Improvement
of pain and regional osteoporotic changes in the foot and
ankle by low–dose bisphosphonate therapy for complex
regional pain syndrome. type1: a case series. J Med Case
Reports (2011) 5: 349.
15) Chiba H, Ataka K, Iba K, Nagaishi K, Yamashita T, Fujimiya
M. Diabetes impairs the interactions between long-term
hematopoietic stem cells and osteopontin-positive cells in
the endosteal niche of mouse bone marrow. Am J Physiol
Cell Physiol (2013) 305: 693-703.
16) Tsukahara T, Kawaguchi S, Torigoe T,Murase M,Wada T,
Kaya M, Nagoya S, Yamashita T, Sato N. HLA-A*0201restricted CTL epitope of a novel osteosarcoma antigen,
papillomavirus binding factor. J Transl Med (2009) 7: 44.
17) Kawaguchi S, Tsukahara T, Ida K, Kimura S, Murase M,
Kano M, Emori M, Nagoya S, Kaya M, Torigoe T, Ueda E,
Takahashi A, Ishii T, Tatezaki S, Toguchida J, Tsuchiya H,
Osanai T, Sugita T, Sugiura H, Ieguchi M, Ihara K, Hamada
K, Kakizaki H, Morii T, Yasuda T, Tanizawa T, Ogose A, Yabe
H, Yamashita T, Sato N, Wada T. SYT–SSX breakpoint
peptide vaccines in patients with synovial sarcoma: A study
from the Japanese Musculoskeletal Oncology Group.
Cancer Sci (2012) 103: 1625–1630.
18) Murase M, Kano M, Tsukahara T, Takahashi A, Torigoe T,
Kawaguchi S, Kimura S,Wada T, Uchihashi Y, Kondo T,
Yamashita T, Sato N. Side population cells have the
characteristics of cancer stem-like cells/cancer-initiating
cells in bone sarcomas. Br J Cancer (2009) 101: 14251432.
70
Neurosurgery
A concept of our department is a precise neurosurgical treatment as
a part of neuroscience. Neurosurgeons at Sapporo Medical University
have remained focused on providing the best patient care possible.
We know that each individual patient has a unique problem that
requires carefully developed and individualized treatment. Our
facilities include modern surgical microscopes, neuroendoscopes,
interventional neuroradiological systems, advanced image-guided
brain navigational tools, neurophysiological monitoring techniques,
and sophisticated MR imaging. We have also made strong
commitments to laboratory research to establish a method of
functional preservation by detecting an intraoperative brain shift.
Professor
Assistant Professor
Instructor
Nobuhiro Mikuni, M.D., Ph.D.
Takeshi Mikami, M.D., Ph.D.
Satoko Ochi, M.D., Ph.D.
Interests:
Interests:
Satoshi Iihoshi, M.D., Ph.D.
Brain tumor
Cerebrovascular surgery
Yoshifumi Horita, M.D., Ph.D.
Epilepsy surgery
Katsuya Komatsu, M.D., Ph.D.
Yukinori Akiyama, M.D., Ph.D.
Associate Professor
Interests:
Masahiko Wanibuchi, M.D., Ph.D.
Brain tumor
Interests:
Brain tumor
Skull base surgery
1. Clinical neurosurgery
outcomes for deep seated pathologies in the cranium which
A main venture in the clinical neurosurgery for the past 5
are very difficult to treat with conventional techniques. A well-
years from 2009 is the introduction of sophisticated brain
organized vascular surgery to treat difficult vascular diseases
tumor surgery in combination with awake surgery, which are
such as moyamoya disease and large cerebral aneurysms
the key to accomplish the maximum tumor removal and the
has become one of major interests of our department. The
functional preservation of the eloquent area. Furthermore,
interventional neurosurgical approach is known as a less
application of hybrid operating room facilitates the reliability
invasive technique to treat vascular diseases. We have
and safety of surgical removal. Patients with epilepsy and
introduced intravascular surgery for ischemic diseases,
Parkinson disease are treated by an expert team of functional
cerebral aneurysms, AVM, dual AVF, and vascular tumors to
neurosurgery. A conference about brain function with
radically treat or to assist the microsurgical cure of patients.
neurosurgeons,
who
Another venture has been introduce the Stroke Care Unit at
specialized for neuro-rehabilitation is periodically held to
the Department of Emergency Medicine to save acute stroke
obtain the adequate surgical treatment protecting the cortical
patients
and white matter function. Eletrophysiological monitoring
intravascular surgery.
such as MEP, SEP, and VEP contributes to improve patient
2. Clinical neuroradiology
outcomes. The modern neuronavigational tools and functional
Clinical
brain mapping have allowed us to perform operations more
advancement in diagnosis by utilizing recent MRI technology
safely and a laser Doppler, intraoperative tumor staining with
such as diffusion-weighed imaging, perfusion weighted-
ALA, endoscopic exploration contributes to improve patient
image, three-dimensional surface anatomical scanning, fast
outcomes.
imaging employing steady-state acquisition, flow-sensitive
Induction of skull base techniques under the precise
alternating
anatomical research can lead to improvement of surgical
imaging, periodically rotated overlapping parallel lines with
neurologists,
pediatrics,
doctors
from
major
neurological
neuroradiology
inversion
has
recovery,
deficit
made
by
a
susceptibility
modern
remarkable
weighted
71
enhanced reconstruction, 3D-MR angiography, cine MRI for
Brain Tumor Pathol. 2013, 30(1):61-5.
CSF dynamics study, MR spectroscopy, functional mapping,
7) Suzuki K, Momota H, Tonooka A, Noguchi H, Yamamoto
in addition to the refinement of conventional T1- and T2-
K, Wanibuchi M, Minamida Y, Hasegawa T, Houkin K:
weighted images to improve anatomical resolution. This new
Glioblastoma simultaneously present with adjacent
diagnostic
meningioma: case report and review of the literature. J
modality
has
provided
very
important
pathophysiological information to help decide the most
Neurooncol. 2010, 99：147-153.
and
8) Wanibuchi M, Ohtaki M, Fukushima T, Friedman AH,
degenerative patients, to evaluate malignancy of tumors, or to
Houkin K：Skull base training and education using an
locate an epilepotogenic focus. In addition, the fusion images
artificial skull model created by selective laser sintering.
appropriate
treatment
for
the
vascular
patients
of CT and MRI as a virtual reality facilitate promote the
Acta Neurochir (Wien). 2010, 152: 1055-1059.
9) Wanibuchi M, Murakami G, Yamashita T, Minamida Y,
presurgical planning and contribute the surgical safety.
3. Research
Fukushima T, Friedman AH, Fujimiya M, Houkin
Innovation
of
functional
neurosurgery
leads
to
K：Midsubtemporal Ridge as a Predictor of the Lateral
preservation of neurons and neuronal fibers under the
Loop formed by the Maxillary Nerve and Mandibular
electrophysiological monitoring. To reflect the preoperative
Nerve: A Cadaveric Morphological Study. Neurosurgery.
functional analysis into actual operation, an intraoperative
2011, 69: 95-98.
brain deformation (brain shift) should significantly compromise
10)Wanibuchi M, Fukushima T, Zomordi AR, Nonaka Y,
the spatial accuracy of a neuronavigation system guided by
Friedman AH：Trigeminal Schwannomas - Skull Base
preoperative image data. Focusing on image alignment and
Approaches and Operative Results in 105 Patients -.
brain displacement, we developed a convenient method for a
Neurosurgery. 2012, 70:132-43.
fast intraoperative correction for brain shift in computed
11) Iihoshi S, Miyata K, Murakami T, Kaneko T, Koyanagi
tomography (CT) images registered for neuronavigation.
I：Dissection Aneurysm of the Radiculomedullary Branch
Based on nonlinear geometric algorithms that involve
of Artery of Adamkiewicz With Subarachnoid Hemorrhage.
intraoperative measurements of the anatomical landmark
Case Report. Neurol Med Chir. 2011, 51: 649-652.
positions, our model is sufficient for use in pterional craniotomy,
12)Sugino T, Maruyama M, Tanno M, Kuno A, Houkin K,
which is the most common approach in neurosurgery. Future
Horio Y：Protein deacetylase SIRT1 in the cytoplasm
improvements and accumulation of patient data will enable
promotes nerve growth factor-induced neurite outgrowth
our model to be applied to another surgical approaches.
in PC12 cells. FEBS Lett . 2010, 584: 2821-2826.
13) Suzuki K, Mikami T, Sugino T, Masahiko W, Miyamoto S,
Hashimoto N, Mikuni N: Discrepancy Between Voluntary
1) Mikuni N: Guidelines Committee of The Japan Awake
Surgery
Conference.
The
Guidelines
for
Awake
Craniotomy. Neurol Med-Chir. 2012, 52(3):119-41.
2) Wanibuchi, M, Fukushima T, Zomordi AR, Nonaka Y,
Friedman AH: Trigeminal schwannomas: skull base
approaches and operative results in 105 patients.
Neurosurgery. 2012, 70 (1 Suppl Operative)：132-143.
3) Mikami T, Hirano T, Sugino T, Miyata K, Iihoshi S,
Wanibuchi M, Mikuni N: Presurgical planning for
arteriovenous malformations using multidetector row CT.
Neurosurg. 2012, Rev 35：393-400.
4) Mikami T, Minamida Y, Akiyama Y, Wanibuchi M, Sugino
T, Houkin K, Mikuni N: Microvascular decompression for
hemifacial spasm associated with the vertebral artery.
Neurosurg Rev. 2013, 36(2):303-8.
5) Mikami T, Wanibuchi M, Mikuni N: Bumping phenomenon
during continuous coagulation with bipolar forceps.
Neurol Med-Chir 2012, 52：731-735.
6) Sugino T, Mikami T, Akiyama Y, Wanibuchi M, Hasegawa
T, Mikuni N: Primary central nervous system anaplastic
large-cell lymphoma mimicking lymphomatosis cerebri.
Movement and Motor-Evoked Potentials in Evaluation of
Motor Function During Clipping of Anterior Circulation
Aneurysms. World Neurosurg. 2013. [Epub ahead of
print]
72
Obstetrics and Gynecology
Our departmental goal is to provide the best healthcare for women
with an advanced commitment to education and research.
subspecialties
include
gynecologic
oncology,
Our
reproductive
endocrinology and infertility, and maternal-fetal medicine. Current
research interests are cytopathological, molecular biological study of
gynecological cancer for diagnosis and treatment, clinical study of
vaginal surgery, and the molecular endocrinological study to ovary
Professor
Tsuyoshi Baba, M.D., Ph.D
Instructor
Tsuyoshi Saito, M.D., Ph. D
Interests:
Madoka Takahashi, M.D., Ph.D
Interests:
Reproductive endocrinology and
Yushi Akashi, M.D., Ph.D
Oncology and Pathology
Obstetrics
Mizue Teramoto, M.D., Ph.D
Seiro Satohisa, M.D., Ph.D
Assistant Professor
Ryoichi Tanaka, M.D., Ph.D
Miyuki Morishita, M.D.
Masahiro Iwasaki, M.D., Ph.D
Interests:
Hideo Matsumoto, M.D.
Interests:
Oncology and Molecular biology
Oncology and Molecular biology
1. Clinical research
a) Surgery
Gynecologic Surgery, especially through the vagina is
also actively analyzed in our department, including total
vaginal hysterectomy and radical vaginal hysterectomy.
Clinical studies on new operative procedures for extended
and radical hysterectomy with preservation of bladder
function.
b) Combination chemotherapy for primary, advanced, or
recurrent cervical adenocarcinoma.
In the present study, patients with locally advanced
cervical adenocarcinoma were treated with neoadjuvant
chemotherapy using cisplatin, aclacinomycin-A and
mitomycin-C, followed by radical surgery or irradiation
concluding that the overexpression of p53 was found to be a
factor to predict the chemoresistance and positive expression
of Bcl-2 indicated as a better prognostic value.
2. Playing the role of epoidermal growth factor (EGF)
receptor (EGFR)
Epidermal growth factor (EGF) receptor (EGFR) is
involved in various basic biochemical pathways and is thus
thought to play an important role in cell migration. We
examined the effect of EGF on motility, migration, and
morphology of a human adenocarcinoma cell line CAC-1.The
results suggest that EGF promotes cell motility and migration
and increases the expression of alpha2beta1-integrin,
possibly by decreasing FAK phosphorylation.
3. Genetic diagnosis and clinicopathological analysis for
gynecologic malignant tumor
Genetic analysis of gynecologic cancers is also performed
including Matrix metalloproteinase-1 (MMP-1) promoter
polymorphism, Epigenetic inactivation of TMS1/ASC in
ovarian cancer. Also some of clinicopathological studies were
done in cervical, endometrial, and ovarian cancer and uterine
sarcoma.
4. Drug resistance and apoptosis in chemotherapy of
ovarian cancer
Mechanisms of paclitaxel-induced apoptosis in an
ovarian cancer cell line and its paclitaxel-resistant clone were
verified using DNA microarray and RT-PCR techniques.
5. Molecular analysis of cell adhesion molecules during
endometrial carcinogenesis
The correlation between sex steroids and gap junctional
intercellular communication (GJIC), which is considered to
play an important role in the control of cell growth and
differentiation, is not well known in endometrial carcinoma.
Thus, we focused on the influence of estrogen and its receptor
in connexin (Cx) expression and GJIC in endometrial
carcinoma cells, established stable clone IK-ER1
overexpressing ER-alpha to transfect the expression vector
and analysed them in various hormonal conditions. These
results suggest that activation of ER-alpha by estrogen results
in tumor progression by stimulating cell growth and
suppressing GJIC via suppression of the expression of Cxs in
endometrial carcinogenesis.
6. Progression of endometrial carcinoma and sex steroid
It is well known that the functions of reproductive organs
are regulated by sex steroids and their receptors and it is
hypothesized that the progression of neoplasms that originate
from the reproductive organs is influenced by them. However,
the correlation between sex steroids and tumor progression,
especially tumor invasion, is not well known in endometrial
73
carcinoma. We focused on the influence of estrogen and its
receptor in invasion and matrix metalloproteinases (MMPs),
which are known to be important in tumor invasion, as well as
on endometrial carcinoma cells. These results suggest that
activation of ER-alpha by estrogen results in tumor progression
by stimulating cell growth and invasiveness via acceleration
of the expression of MMPs.
7. Reproductive endocrinology
We have studied ovarian physiology and pathology as
regards reproductive endocrinology. Recently, we found some
mechanisms of structural involution of corpus luteum. Using a
treated rat model, we found that MMP activation and apoptosis
are two major phenomena during structural luteolysis. MMP-2
activated with MT1-MMP and MT-1MMP itself caused
remodeling of extracellular matrix in corpus luteum. We have
also investigated the mechanisms of ovarian hyperstimulation
syndrome (OHSS). VEGF is known to be a pivotal factor of
OHSS. We found that continuation of GnRHa for some days
after hCG injection significantly reduced VEGF in ovaries of
the rat OHSS model. The mechanism of anovulation in PCOS
patients is still unknown. This experiment showed that
anovulation of PCO could be caused by reduction of MMP
expression and increases in lysyl oxidase, which initiates
cross-link formation of the collagen and elastin.
8. Placental change in preeclampsia
Preeclampsia is one of the life threatened disease in
pregnancy. Hypoxic changes in placenta is thought to be main
causation of preeclampsia. We research the pathophisiological
changes in preeclampsia with examinating the hypoxic related
gene and protein under the hypoxic culture of trophoblastic cells.
List of Main Publication from 2009 to 2013
1) Baba T, Endo T, Kitajima Y, Kamiya H, Moriwaka O, Saito
T. Spontaneous ovarian hyperstimulation syndrome and
pituitary adenoma: incidental pregnancy triggers a
catastrophic event. Fertil Steril. (2009) Jul 92(1):390.e13.
2) Ishioka S, Ezaka Y, Endo T, Nagasawa K, Shimizu A,
Sato A, Inoue M, Saito T. Outcomes of planned delivery
delay in pregnant patients with invasive gynecologic
cancer. Int J Clin Oncol. (2009)Aug 14(4): 321-5.
3) Umemura K, Ishioka S, Endo T, Baba T, Ezaka Y,
Nagasawa K, Takahashi M, Mizuuchi M, Iwami N, Adachi
H, Takeda N, Tamagawa M, Saito T. Changes of uterine
blood flow after vaginal radical trachelectomy(VRT) in
patients with early-atage uterine invasive cervical cancer.
International Journal of Medical Sciences(2010)7(5):
260-266.
4) Suzuki M, Suzuki T, Matsuura M, Iwasaki M, Tanaka R,
Ito E, Fujii M, Saito T. Prediction of Histologic Type and
Lymph Node Metastasis for Advanced Ovarian Cancer
on Uterine Cervical and Endometrial Cytology. Acta
Cytologica. (2010) 54(4): 575-581.
5) Iwasaki M, Tanaka R, Hishiya A, Homma S, Reed JC,
Takayama S. BAG3 directly associates with guanine
nucleotide exchange factor of Rap1, PDZGEF2, and
regulates cell adhesion. Biochem Biophys Res Commun.
(2010)400(3): 413-418.
6) Matsuura M, Suzuki T, Suzuki M, Tanaka R, Ito E, Saito T.
Statin-mediated reduction of osteopontin expression
induces apoptosis and cell growth arrest in ovarian clear
cell carcinoma. Oncology Reports(2011) 25(1):41-47.
7) Suzuki M, Iwasaki M, Sugio A, Hishiya A, Tanaka R, Endo
T, Takayama S, Saito T. BAG3 (BCL2-associated
athanogene 3) interacts with MMP-2 to positively regulate
invasion by ovarian carcinoma cells. Cancer Lett. (2011)
303(1): 65-71.
8) Baba T, Endo T, Ikeda K, Shimizu A, Honnma H, Ikeda H,
Masumori N, Ohmura T, Kiya T, Fujimoto T, Koizumi M,
Saito T. Distinctive Features of Female-to-Male
Transsexualism and Prevalence of Gender Identity
Disorder in Japan. J. Sex. Med. (2011) 8(6):1686-93.
9) Mizuuchi M, Hirohashi Y, Torigoe T, Kuroda T, Yasuda K,
Shimizu Y, Saito T, Sato N. Novel oligomannose liposomeDNA complex DNA vaccination efficiently evoke anti-HPV
E6 and E7 CTL responses. Exp Mol Pathol.
(2012)92(1):185-90.
10)Endo T, Baba T, Sugio A, Morishita M, Takahashi M,
Akashi Y, Ishioka S, Tachi N, Imai T, Tamakawa M, Saito
T. A myotonic dystrophy 1 patient complicated with
placental adherence after miscarriage of one dichorionic
diamniotic twin following her tenth in vitro fertilization and
embryo transfer. Arch Gynecol Obstet. (2012) 6:1605-8.
11) Wang W, Feng L, Zhang H, Hachy S, Satohisa S, Laurent
LC, Parast M, Zheng J, Chen DB. Preeclampsia upregulates angiogenesis-associated microRNA (i.e., miR17, -20a, and -20b) that target ephrin-B2 and EPHB4 in
human placenta. J Clin Endocrinol Metab. (2012)
Jun;97(6):E1051-9
12) Ikeda K, Baba T, Noguchi H, Nagasawa K, Endo T, Kiya
T, Saito T. Excessive androgen exposure in female-tomale transsexual persons of reproductive age induces
hyperplasia of the ovarian cortex and stroma but not
polycystic ovary morphology. Hum Reprod. (2013)
28(2):453-61.
13) Baba T, Endo T, Ikeda K, Shimizu A, Morishita M, Kuno Y,
Honnma H, Kiya T, Ishioka S, Saito T. Assisted
reproductive technique increases the risk of placental
polyp.(Gynecol Endocrinol. (2013)29(6):611-4.
14) Mariya T, Suzuki T, Habata S, Matsuura M, Suzuki M,
Tanaka R, Saito T. Development of vesicovaginal fistula
caused by vaginal adenosis: A case report. OJOG, (2013)
3:435-437.
15) Kim M, Ishioka S, Endo T, Baba T, Akashi Y, Morishita M,
Adachi H, Saito T. Importance of uterine cervical cerclage
to maintain a successful pregnancy for patients who
undergo vaginal radical trachelectomy. International
journal of clinical oncology, 2013 DOI 10.1007/s10147013-0631-9 Oct. Epub)
74
Pediatrics
Our main interests of research are pediatric infectious and
hematological, neoplastic, neurological and cardiovascular diseases.
We have investigated the etiology, pathogenesis and development of
new diagnostic assays and treatment for these pediatric diseases.
Professor
Hotaka Kamasaki, M.D. , Ph.D.
Instructor
Hiroyuki Tsutsumi, M.D. , Ph.D.
Interests:
Kinya Hatakayama, M.D. , Ph.D.
Interests:
Endocrinology and metabolism
Norihisa Horita, M.D. , Ph.D.
Infectious diseases
Tsukasa Hori, M.D. , Ph.D.
Koki Nikaido, M.D. , Ph.D.
Interests:
Yoshino Sumi, M.D. , Ph.D.
Assistant professor
Hematology and oncology
Yuko Yoto, M.D. , Ph.D.
Masaki Yamamoto, M.D. , Ph.D.
Interests:
Interests:
Infectious Diseases
Naoki Hatakeyama, M.D. , Ph.D.
Interests:
1. Respiratory syncytial virus (RSV) infection
in Sapporo, Japan were detected (6). Phylogenetic and
We established an in vitro RSV infection system in
computational structural analysis of the VP7 gene (7) or NSP4
hTERT-transfected human nasal epithelial cells. RSV infection
gene (8) of a group of human rotavirus G1P[8] strains obtained
itself gradually develops several tight junctions of nasal
in Sapporo, Japan from 1987 to 2000 was performed.
epithelial cells (1). RSV infection may induce the system by
4. Endocrinology and metabolic diseases
which propagated RSV can be secreted from the apical side
We investigated iodine deficient states in patients with
of the infected cells to spread infection efficiently to adjacent
severe motor and intellectual disabilities and implemented a
cells. We also confirmed the marked induction of matrix
regime involving long-term total enteral nutrition and iodine
metalloproteinase-10 by respiratory syncytial virus infection in
supplementation with daily powdered kelp (9, 10).
human nasal epithelial cells (2).
5. Neuromuscular diseases
2. Human parvovirus B19 infection
We analyzed IMZ-SPECT using 3D-SSP in mesial
The human parvovirus B19 infection shows a variety of
temporal lobe epilepsy resulting from hippocampal sclerosis.
clinical manifestations. We have reported on rare cases of the
Results showed a significantly decreased uptake of IMZ in the
neurological disorders. One involves rhabdomyolysis in a
amygdale-hippocampus, insula and lateral temporal cortices
patient with Fukuyama-Type congenital muscular dystrophy
of the involved side compared to those of the non-involved
during the B19 infection (3). Another case focuses on
side. Recently, we have identified a new mutation of the
transverse myelitis associated with the B19 infection (4). The
CACNA1A gene in a pedigree. They had a novel homozygous
epidemiological aspects on human parvovirus B19 have been
missense mutation G1165A leading to E389K (11).
studied following molecular biological methods. Viral genomes
6. Hematology / Oncology / Transplantation
collected over a period of 30 years were analyzed in samples
Using proteomics techniques, we have previously shown
taken from patients with various symptoms caused by B19
that CC-chemokine ligand motif 8 (CCL8) is a potential
infections (5).
biomarker for the diagnosis of acute graft-vs-host disease
3. Human rotavirus infection
(GVHD) in a mouse model. Our further study showed that
In one study, enteric viruses in rectal swabs from children
early and preclinical expression of CCL8 in plasma predicts
with acute gastroenteritis attending pediatric outpatient clinics
overall survival of GVHD mice (12). Long-term venous access
75
is essential when treating malignant diseases. All peripherally
6) Nakanishi K, Tsugawa T,, Nakata S, Tatsumi M, Yoto Y,
inserted central venous catheters (PICCs) have been inserted
Tsutsumi H. Detection of enteric viruses in rectal swabs
in most of the patients with malignant diseases in our
from children with acute gastroenteritis attending the
institution. Our study demonstrated that PICCs provided a
pediatric outpatient clinics in Sapporo, Japan. J Clin Virol
reliable access for prolonged intravenous administration and
2009;46:94-7
blood sampling in children with malignant diseases (13).
7) Nagaoka Y, Tatsumi M, Tsugawa T, Yoto Y, Tsutsumi H.
7. Cardiovascular diseases
Phylogenetic and computational structural analysis of
Through the use of 2D and 3D echo methods, we have
VP7 gene of group a human rotavirus G1P[8] strains
been investigating the cardiac function of post-operative adult
obtained in Sapporo, Japan from 1987 to 2000. J Med
congenital heart disease such as tetralogy of Fallot and
Virol. 2012;84:832-8
Fontan procedures. Cardiopulmonary Exercise Test (CPX) is
8) Tatsumi M, Nagaoka Y, Tsugawa T, Yoto Y, Hori T,
strongly correlated with exercise intolerance in the case of
Tsutsumi H. Characterization of the NSP4 gene of group
cardiac patients. We have utilized CPX in cases involving
A human rotavirus G1P[8] strains circulating in Sapporo,
adult post-operative patients to evaluate daily life exercise
Japan from 1987 to 2000. J Med Virol 2014;86:354-9
intolerance. Additionally, our institution has received approval
9) Takeuchi T, Kamasaki H, Hotsubo T, Tsutsumi H.
from the Japanese Society of Fetal Cardiology to perform
Treatment of Hypothyroidism due to Iodine Deficiency
fetal echocardiographies. We plan to evaluate fetal and
Using Daily Powdered Kelp in Patients Receiving Long-
neonatal cardiac functions using echo modality.
term Total Enteral Nutrition. Clin Pediatr Endocrinol.
2011;20:51-5
List of main publications from 2009-2013
10) Takeuchi T, Kamasaki H, Yoto Y, Honjo T, Tsugawa S,
Hotsubo T, Tsutsumi H. Investigation of iodine deficient
state and iodine supplementation in patients with severe
motor and intellectual disabilities on long-term total
Sawada N. A nuclear factor-κB signaling pathway via
enteral nutrition. Endocr J 2012;59:697-703
protein kinase C δ regulates replication of respiratory
11) Nikaido K, Tachi N, Ohya K, Wada T, Tsutsumi H. New
syncytial virus in polarized normal human nasal epithelial
mutation of CACNA1A gene in episodic ataxia type 2.
cells. Mol Biol Cell 2011;.22:2144-56
Pediatr Int 2011;53:415-6
2) Hirakawa S, Kojima T, Obata K, Okabayashi T, Yokota S,
12) Yamamoto M, Ota A, Hori T, Imai SI, Sohma H, Suzuki N,
Nomura K, Obonai T, Fuchimoto J, Himi T, Tsutsumi H,
Hatakeyama N, Inazawa N, Ito YM, Kimura H, Tsutsumi
Sawada N. Marked induction of matrix metalloproteinase-10
H, Kokai Y. Early expression of plasma CCL8 closely
by respiratory syncytial virus infection in human nasal
correlates with survival rate of acute graft-versus-host
epithelial cells. J Med Virol. 2013;85:2141-50
disease in mice. Exp Hematol 2011;39:1101-12
3) Ishikawa A, Yoto Y, Ohya K, Tsugawa T, Tsutsumi H.
13) Hatakeyama N, Hori T, Yamamoto M, Mizue N, Inazawa
Rhabdomyolysis Associated With Human Parvovirus
N, Igarashi K, Tsutsumi H, Suzuki N. An evaluation of
B19 Infection in a Patient With Fukuyama-Type
peripherally inserted central venous catheters for children
Congenital Muscular Dystrophy. J Child Neurol (in press)
with cancer requiring long-term venous access. Int J
(2013)
Hematol 2011;94:372-7
4) Suzuki M, Yoto Y, Ishikawa A, Asakura H, Tsutsumi H.
Acute Transverse Myelitis Associated With Human
Parvovirus B19 Infection. J Child Neurol (in press) (2013)
5) Suzuki M, Yoto Y, Ishikawa A, Tsutsumi H.Analysis of
nucleotide sequences of human parvovirus B19 genome
reveals two different modes of evolution, a gradual
alteration and a sudden replacement: a retrospective
study in Sapporo, Japan, from 1980 to 2008. J Virol
2009;83:10975-80
76
Ophthalmology
Our department is composed of 4 major units: vitreo-retina, glaucoma,
neuro-ophthalmology and strabismus & amblyopia. These units
collaborate in clinical practice and basic research for all patients who
suffer from visual disturbances.
Professor
Assistant Professor
Instructor
Hiroshi Ohguro, M.D., Ph.D.
Futoshi Ishikawa, M.D., Ph.D.
Shuichiro Inatomi, M.D., Ph.D.
Hirokatsu Kawata, M.D., Ph.D.
Atsushi Sugawara, M.D., Ph.D.
Associate Professor
Miki Hiraoka, M.D., Ph.D.
Kaori Yoshida, M.D., Ph.D.
Masato Hashimoto, M.D., Ph.D.
Akira Abe, Ph.D.
1. Retinal and vitreous diseases
Hiroshi Ohguro, M.D., Ph.D., professor of ophthalmology,
and the other two surgeons have performed more than 400
vitreoretinal surgical procedures annually. Our hospital is one
of the leading centers for vitreoretinal diseases in the northern
Japan area. We have treated various cases such as
proliferative diabetic retinopathy, retinal detachment,
idiopathic macular holes, epi-retinal membranes, branch
retinal vein occlusion, age-related macular degeneration and
vitreous opacities caused by uveitis, trauma and
endophthalmitis. We have often performed advanced
operations to treat complicated intraocular proliferative
retinopathies. In addition to the surgical management of
vitreoretinal diseases, we are also trying to develop laser
speckle flowgraphy to visualize and evaluate the ocular
microcirculatory changes. The retinal microcirculatory is
analyzed with the latest equipment before and after treatment.
2. Glaucoma
The functional loss of vision in glaucoma is caused by
cell death of retinal nerve cells and their axons. This is at least
partially due to apoptosis. The exact mechanisms that induce
apoptosis in glaucoma are not known. We have been focusing
on the potential role of decreased ocular blood flow. Toward
this end, we are studying prospective clinical trials that focus
on the effects of added Dorzolamide on ocular blood flow
levels in glaucoma patients as well as trials that examine the
effects of oral anthocyanoside on the optic nerve and visual
field In normal-tension glaucoma.　Additional fields or research include: 1) Features of
morphology in narrow angle eyes by ultrasound biomicroscopy;
2) Correlation between Glaucomatous visual field loss and
retinal nerve fiber layer thickness by optical coherence
tomography (OCT); 3) Outcomes of glaucoma surgeries; 4)
Comparisons of dorzolamide and nipradiol in addition to
latanoprost with glaucoma.
3. Neuro-ophthalmology
We have been studying new neuro-imaging techniques
for evaluating the functional and metabolic change in optic
nerve disorders such as optic neuritis, ischemic optic
neuropathy and compressive optic neuropathy. Recently, we
measured the concentration of N-acetylaspartate (NAA),
which is a neuron specific marker, in the chiasm in normal
subjects and chiasmal optic neuritis using proton magnetic
resonance spectroscopy (1H-MRS). Our results indicated that
the levels of NAA in patients with chiasmal optic neuritis were
significantly lower than those seen in the normal controls.
Moreover, improvement of their visual functions after
corticosteroid pulse therapy occurred, followed by a significant
increase in their NAA levels. These results suggest that
1
H-MRS may be a new clinical parameter to monitor the
axonal damage following optic neuritis.
We are also investigating precise MRI techniques in
order to detect the focal lesion within the clinical neuroophthalmologic findings. We reported the usefulness of newly
designed MRI sequences, such as spoiled gradient recalled
acquisition in the steady state (SPGR) and fast imaging
employed steady state (FIESTA) in a patient with vascular
compressive superior oblique myokymia. We are also
developing new methods to evaluate the functional change of
the cranial nerve in eye movement disorders such as
oculomotor nerve palsy or abducens nerve palsy using
magnetic resonance axonography that utilizes the threedimensional anisotropy contrast imaging.
4. Strabismus and amblyopia
1) In progressive esotropia associated with high myopia and
axial elongation, eso-hypodeviation of the eyeball occurs due
to ocular dislocation and often progresses to complete fixed
esotropia in the terminal stage. We reported a rare case of
this condition in which manual pushing of the eyeball
temporarily moved the ocular dislocation back into the muscle
cone. A normal eye position and ocular movement were
obtained during subsequent strabismus surgery.
It is uncertain if medial rectus muscle recession should
be performed simultaneously with a combination of the
muscle bellies of the superior and lateral rectus muscles in
surgery for progressive esotropia caused by high myopia. We
77
encountered a case of progressive esotropia caused by high
myopia in which ocular dislocation could be temporarily
reversed. In this disease, pushing of the eyeball (push test)
can be used to determine whether dislocation can be
temporarily reversed. If this is possible, determination of the
degree of abduction may be useful for selection of an
appropriate surgical procedure.
2) We reported the outcome of surgery for 12 cases of
strabismus in thyroid-associated ophthalmopathy. All the
cases showed good final eye positions. There was a tendency
for cases with a larger amount of expected correction to result
in overcorrection. Strabismus in thyroid-associated
ophthalmopathy has a tendency to overcorrect compared with
general cases of strabismus. This phenomenon may be due
to adhesion of the affected extraocular muscles to the
surrounding tissue.
1) Matsuo S, Ohguro H, Ohguro I, Nakazawa M:
Clinicopathological roles of aberrantly expressed
recoverin in malignant tumor cells. Ophthalmic Res 2010;
43:139-144.
2) Ohguro H, Ohguro I, Tsuruta M, Katai M, Tanaka S:Clinical
distinction between nasal optic disc hypoplasia (NOH)
and glaucoma with NOH-like temporal visual field defects.
Clin Ophthalmol 2010; 4:547-555.
3) Ohguro H, Mashima Y, Nakazawa M:Low levels of
plasma endothelin-1 in patients with retinitis pigmentosa.
Clin Ophthalmol 2010; 4:569-573.
4) Abe A, Kelly R, Shayman JA: The measurement of
lysosomal phospholipase A2 activity in plasma. J Lipid
Res 2010; 51: 2464-2470.
5) Hiraoka M, Takahashi H, Orimo H, Hiraoka M, Ogata T,
Azuma N: Genetic screening of Wnt signaling factors in
advanced retinopathy of prematurity. Mol Vision 2010; 6:
2572-2577.
6) Takeda K, Sato J, Goto K, Fujita T, Watanabe T, Abo M,
Yoshimura E, Nakagawa J, Abe A, Kawasaki S, Nimura
+
Y: Escherichia coli ferredoxin-NADP reductase and
oxygen-insensitive nitroreductase are capable of
functioning as ferric reductase and of driving Fenton
reaction. Biometals 2010; 23: 727-737.
7) Sato J, Takeda K, Nishiyama R, Fusayama K, Arai T,
Sato T, Watanabe T, Abe A, Nakagawa J, Kawasaki S,
Nimura Y: Chlorella vulgaris aldehyde reductase is
capable of functioning as ferric reductase and of driving
the Fenton reaction in the presence of free flavin Biosci
Biotecnol Biochem 2010; 74: 854-857.
8) Machida S, Ohguro H, Tateda M, Sato H, Kurosaka D:
Melanoma-associated retinopathy associated with
intranasal melanoma. Doc Ophthalmol 2011; 122: 191197.
9) Osanai H, Abe S, Rodrígues-Vázquez J, Verdugo-López
S, Murakami G, Ohguro H: Human orbital muscle; a new
point of view from the fetal development of extraocular
connective tissues. Invest Ophthalmol Vis Sci 2011; 52:
1501-1506.
10) Nakazawa M, Ohguro H, Takeuchi K, Miyagawa Y, Ito T,
Metoki T: Effect of nilvadipine on central visual field in
retinitis pigmentosa : A 30-month clinical trial.
Ophthalmologica 2011; 225: 120-126.
11) Kondo M, Sanuki R, Ueno S, Nishizawa Y, Hashimoto N,
Ohguro H, Yamamoto S, Machida S, Terasaki H, Adamus
G, Furukawa T: Identification of autoantibodies against
TRPM1 in patients with paraneoplastic retinopathy
associated with ON bipolar cell dysfunction. PLOS ONE
2011; 6: 1-7.
12) Osanai H, Rodrígues-Vázquez J, Abe H, Murakami G,
Ohguro H, Fujimiya M: Fetal check ligament connected
between the conjunctiva and the medial and lateral recti.
Invest Ophthalmol Vis Sci 2011; 52: 7175-7179.
13) Katai M, Ohguro H: Study of effects of aging, refraction
and intraocular pressure levels on retinal nerve fiber
layer thickness of normal healthy eyes. “Selected topics
in optical coherence tomography” 2012, p171-184,
INTECH, Croatia
14) Inatomi S, Ohguro H, Nishikiori N, Sawada N: Glial cellderived cytokines and vascular integrity in diabetic
retinopathy. “Visual dysfunction in diabetes” 2012, p325338, HUMANA PRESS, New York
15) Abe A, Hiraoka M, Inatomi S, Ohguro I, Ohguro H:
Lysosomal phospholipase A2 activity in pig aqueous
humor. Invest Ophthalmol Vis Sci 2012; 53: 152-156.
16)Ohguro H, Ohguro I, Katai M, Tanaka S: Two-year
randomized, placebo-controlled study of black currant
anthocyanins on visual field in glaucoma. Ophthalmologica
2012; 228: 26-35.
17) Ohguro I, Ohguro H: The effects of a fixed combination of
0.5% timolol and 1% dorzolamide on optic nerve head
blood circulation. J Ocul Pharmacol Ther 2012; 28: 392396.
18)Larsen SD, Wilson MW, Abe A, Shu L, George CH,
Kirchhoff P, Showalter HDH, Xiang J, Keep RF, Shayman
JA: Property-based design of a glucosylceramide
synthase inhibitor that reduces glucosylceramide in the
brain. J. Lipid Res. 2012; 53: 282-291.
19)Ohguro H, Ohguro I, Yagi S: Effects of black currant
anthocyanins on intraocular pressure in healthy
volunteers and patients with glaucoma. J Ocul Pharmacol
Ther 2013; 29: 61-67.
20) Hosaka F, Rodríguez-Vázquez JF, Abe H, Murakami G,
Fujimiya M, Ohguro H: Qualitative changes in fetal
trabecular meshwork fibers at the human iridocorneal
angle. Anat Cell Biol 2013; 46: 49-56.
21)Saito W, Kase S, Ohguro H, Ishida S: Autoimmune
retinopathy associated with colonic adenoma. Grafes
Arch Clin Exp Ophthalmol 2013; 251: 1447-1449.
22)Yoshida K, Ohguro I, Ohguro H: Black currant
anthocyanins normalized abnormal levels of serum
concentrations of endothelin-1 in patients with glaucoma.
J Ocul Pharmacol Ther 2013; 29: 480-487.
78
Dermatology
Our department has been engaged in basic and clinical research and
treatment of a variety of cutaneous disorders. We are particularly
interested in the biology, biochemistry and molecular biology of
melanocytes and melanoma cells. We are also engaged in other
fields including genetic analysis of congenital disorders, clinical
research of melanoma and non-melanoma skin cancers, atopic
dermatitis, viral diseases and laser therapy.
Professor
Interests:
Interests:
Toshiharu Yamashita, M.D., Ph.D.
Wound healing, Laser therapy
Allergology, Atopic dermatitis
Cutaneous biology, Molecular oncology,
Assistant Professor
Instructors
Melanoma research
Akihiro Yoneta, M.D., Ph.D.
Tokimasa Hida, M.D., Ph.D.
Interests:
Interests:
Junji Kato, M.D.
Associate Professor
Melanoma and skin cancer
Yasue Osai, M.D., Ph.D.
Ichiro Ono, M.D., Ph.D.
Yasuyuki Sumikawa, M.D., Ph.D.
Yuji Kan, M.D., Ph.D.
1. Basic research of melanocytes and melanoma cells
To elucidate the molecular bases of various pigmentary
disorders, we have been studying melanocyte biology
focusing on vesicular transport of melanogenic proteins,
tyrosinase and tyrosinase-related protein 1, and their
biological and biochemical functions (1). Hair and eye color
are genetically determined through the relative amounts of
eumelanin and pheomelanin. The ability to regulate the switch
between eumelanin and pheomelanin synthesis in cultured
melanocytes would greatly aid studies of mutagenesis and
photocarcinogenesis. Our work sheds some light on how
cAMP levels and the agouti signaling protein can control
pigment-type switching (2).
To analyze the molecular mechanism of cytotoxicity of
interferons (IFNs) against melanoma cells, we examined
apoptotic activities of IFNs by using cultured human melanoma
cells. We found that IFN-β possessed potent apoptotic activity
in melanoma cells and IFN-β-mediated apoptosis is
accompanied by caspase-2 activation (3). We have been
studying the molecular bases of selective cytotoxicity of
N-propionyl-4-S-cysteaminylphenol (NPrCAP) against melanoma
cells (4). We showed that NPrCAP generated reactive oxygen
species associated with apoptosis of melanoma cells (5). We
also showed that NPrCAP induced CD8+ T-cell immune
responses, resulting in the suppression of growth of the
secondary melanoma (4,6). We have established melanomatargeted chemo-thermo-immunotherapy by using heatproducible magnetite-conjugated NPrCAP in a mouse model
(4,6,7). It was shown that the thermotherapy at 43℃ against
the transplanted B16F1 tumor suppressed secondary tumors
and induced immune responses more significantly than the
thermotherapy at 45℃ (7). These results suggest that
NPrCAP-magnetite can be applicable to the systemic therapy
for melanoma.
2. Basic research and clinical application of imiquimod
Imiquimod is an agonist for TLR-7 in immunocompetent
cells. We found that imiquimod had an IFN-independent
antiviral effect in non-immune FL cells, since replication of
herpes simplex type-1 (HSV-1) was significantly suppressed
in its presence (8). We analyzed gene expression in FL cells
after treatment with imiquimod using microarray analysis to
find that cystatin A was upregulated and played a major role in
the anti-HSV-1 activity (8). In clinical research, we have
treated inoperable non-melanoma skin cancers through the
use of the topical imiquimod, resulting in remarkable efficacies
against actinic keratosis, Bowen’s disease and extramammary
Paget’s disease.
3. Clinical research of melanoma and non-melanoma
skin cancers
We routinely use a dermoscope for the differential
diagnosis of pigmented lesions and tumors (9,10). We have
established a precise and reliable system for the detection of
sentinel lymph nodes in melanoma patients, by using RI, blue
dye (patent blue) (11) and indocyanine green (ICG). We have
analyzed sentinel nodes in more than130 cases of melanoma
patients and obtained high detection rates of over 95%. By
using an ICG fluorescence technique that detects the
lymphatic stream, we have been considering potential regions
for the adjuvant radiation therapy for the prevention of intransit recurrence of skin cancers.
79
4. Analysis of genetic skin disorders
We have a special outpatient clinic that offers a genetic
analysis/diagnosis and genetic counseling for patients with
genetic skin diseases of Mendelian inheritance. Our main
research interests are xeroderma pigmentosum (XP),
oculocutaneous albinisms and ectodermal dysplasia. To
establish easy and rapid diagnostic procedures for XP groups,
we have constructed recombinant adenoviruses that express
one of the XP genes. When fibroblasts derived from each of
the XP-A, -B, -C, -D, -F and -G patients were infected with
XP-adenoviruses and irradiated by UV-C, cells of XP-A, -B,
-C, -D, -F and -G were rescued only by the corresponding
recombinant adenoviruses (Haiying J et al: East-Asian
Dermatological Congress 2012, Beijing). Differentiation of
XP-E and XP-V from other complementation groups requires
BrdU assay in addition to UVB irradiation and survival assay.
5. Investigation of atopic dermatitis based on epidemiology
Atopic dermatitis (AD) is well known to be one of the
refractory allergic skin diseases. Worldwide research about
AD reports that its prevalence is high in developed nations
and industrial countries, suggesting that AD is partially caused
by environmental factors. We have also previously (2007)
reported on the relation between the prevalence of AD and
the environmental factors in China. Our recent cohort study
from 2006 in Hokkaido examining the prevalence of AD in
school children shows that about half the students afflicted
with AD in the seventh grade did not have it in the first grade.
This result indicates the importance of preventing the
development of AD in school children. We are also interested
in the relation between AD development and ABCC11, one of
the ABC transporters known as an earwax type-determining
gene. We have shown that a dry earwax type was more
prevalent in patients with AD than in those without it. This
suggests that ABCC11 has a role in the pathogenesis of AD.
1) Hida T, Sohma H, Kokai Y, Kawakami A, Hirosaki K,
Okura M, Tosa N, Yamashita T, Jimbow K. Rab7 is a
critical mediator in vesicular transport of tyrosinaserelated protein 1 in melanocytes. J Dermatol (2011) 38:
432-441.
2) Hida T, Wakamatsu K, Sviderskaya EV, Donkin AJ,
Montoliu L, M. Lamoreux L, Yu B, Millhauser GL, Ito S,
Barsh GS, Jimbow K, Bennett DC: Agouti protein,
mahogunin, and attractin in pheomelanogenesis and
melanoblast-like alteration of melanocytes: a cAMPindependent pathway. Pigment Cell Melanoma Res
(2009) 22: 623–634.
3) Kamiya T, Okabayashi T, Yokota S, Kan Y, Ogino J,
Yamashita T, Fujii N, Jimbow K: Increased caspase-2
activity is associated with induction of apoptosis in IFNbeta sensitive melanoma cell lines. J Interferon Cytokine
Res (2010) 30: 349-357.
4) Sato M, Yamashita T, Ohkura M, Osai Y, Sato A, Takada
T, Matsusaka H, Ono I, Tamura Y, Sato N, Sasaki Y, Ito A,
Honda H, Wakamatsu K, Ito S, Jimbow K: N-PropionylCysteaminylphenol- Magnetite Conjugate (NPrCAP/M) Is
a Nanoparticle for the Targeted Growth Suppression of
Melanoma Cells. J Invest Dermatol (2009) 129: 22332241.
5) Ishii-Osai Y, Yamashita T, Tamura Y, Sato N, Ito A, Honda
H, Wakamatsu K, Ito S, Nakayama E, Okura M, Jimbow
K: N-propionyl-4-S-cysteaminylphenol induces apoptosis
in B16F1 cells and mediates tumor-specific T-cell immune
responses in a mouse melanoma model. J Dermatol Sci
(2012) 67: 51-60.
6) Sato A, Tamura Y, Sato N, Yamashita T, Takada T, Sato
M, Osai Y, Okura M, Ono I, Ito A, Honda H, Wakamatsu
K, Ito S, Jimbow K: Melanoma-targeted chemo-thermoimmuno (CTI) -therapy using N-propionyl-4-Scysteaminylphenol-magnetite nanoparticles elicits CTL
response via heat shock protein-peptide complex
release. Cancer Sci (2010) 101: 1939-1946.
7) Takada T, Yamashita T, Sato M, Sato A, Ono I, Tamura Y,
Sato N, Miyamoto A, Ito A, Honda H, Wakamatsu K, Ito S,
Jimbow K: Growth inhibition of re-challenge B16
melanoma transplant by conjugates of melanogenesis
substrate and magnetite nanoparticles as the basis
for developing melanoma-targeted chemo-thermoimmunotherapy. J Biomed Biotechnol (2009) doi:10.
1155/2009/457936.
8) Kan Y, Okabayashi T, Yokota S, Yamamoto S, Fujii N,
Yamashita T: Imiquimod suppresses propagation of
herpes simplex virus 1 by upregulation of cystatin A via
the adenosine receptor A1 pathway. J Virol (2012) 86:
10338-10346.
9) Hida T, Yamashita T: Pigmented mammary Paget’s
disease presenting with dermoscopic features of multiple
dots. Australas J Dermatol (2013) doi: 10.1111/ajd.12086.
10) Yoneta A, Horimoto K, Nakahashi K, Mori S, Maeda K,
Yamashita T: A case of cystic basal cell carcinoma which
shows a homogenous blue/black area under
dermatoscopy. J Skin Cancer (2011) 450472. Epub2010
Sep23.
11) Uhara H, Yamazaki N, Takata M, Inoue Y, Sakakibara A,
Nakamura Y, Suehiro K, Yamamoto A, Kamo R, Mochida
K, Yamashita T, Takenouchi T, Takenaka H, Yoshikawa S,
Takahashi A, Uehara J, Kawai M, Iwata H, Kadono T, Kai
Y, Watanabe S, Murata S, Ikeda T, Fukamizu H, Tanaka
T, Hatta N, Saida T: Applicability of radiocolloids, blue dye
and fluorescent indocyanine green to sentinel node
biopsy in melanoma. J Dermatol (2012) 39: 336-338.
80
Urology
We have dedicated ourselves to better care for patients with urological
diseases. We provide various strategies for treatment of the diseases,
with a view toward patient satisfaction. These include functionpreserved radical surgeries for cancer and minimally invasive
treatments such as robot-assisted laparoscopic surgery. We are also
enthusiastic about studying the basic science of urology that will lead
to future innovative treatments. Integration of humanity, art and
science is our goal.
Professor
Associate Professor
Instructor
Naoya Masumori, M.D., D.Med.Sci.
Satoshi Takahashi, M.D., Ph.D.
Toshiaki Tanaka, M.D., Ph.D.
Interests:
Interests:
Ko Kobayashi, M.D., Ph.D.
Urologic oncology, BPH, Lower urinary
Urinary tract infection, Sexually
Naotaka Nishiyama, M.D., Ph.D.
tract dysfunction, Laparoscopic
transmitted infection, Surgical site
Toshihiro Maeda, M.D., Ph.D.
surgery, Gender identity disorder
infection, Interstitial cystitis, Chronic
Shintaro Miyamoto, M.D.
prostatitis/chronic pelvic pain
syndrome
Assistant Professor
Hiroshi Kitamura, M.D., Ph.D.
Interests:
Urologic oncology, Robotic surgery
1. Urologic oncology
carcinoma (5) and biomarker study of urologic cancers (6).
We have been working to establish a novel immunotherapy
2. Benign prostatic hyperplasia (BPH) and voiding
for urologic cancers. We have developed a survivin-derived
function
peptide vaccine therapy with positive and immunological and
We demonstrated the natural history of BPH in the
oncological effects in patients with advanced urothelial
general population by a longitudinal community-based study
carcinoma. Several clinical trials are ongoing.
over a time span of 15 years (7,8). Results from this study
We conducted SUOC (Sapporo Medical University
indicated that internal prostatic architecture by transrectal
Urologic Oncology Consortium), a large multi-institutional
ultrasonography could predict the future change of prostatic
collaboration group. We have carried out not only retrospective
volume. In addition, we also showed that lower urinary tract
but also prospective studies of various kinds of urologic
symptoms progressed according to age. In clinical practice,
malignancies (1).
we are researching the long-term efficacy of surgical treatment
Our hospital is one of the highest volume centers in
and alpha 1-blockers (9,10).
Japan concerning urothelial cancer (including among others,
3. Infection and inflammation
bladder cancer, renal pelvic cancer and ureteral cancer). We
We intensively conduct both clinical and basic research
have analyzed data from our prospectively collected database
to contribute to results obtained previously from studies on
to answer various clinical questions (2). Additionally, new
urological real clinical practices. The field of our research
findings from clinical researches including surgical treatment
covers UTI, STI and SSI (11-13). In addition, we are conducting
(3) about kidney, prostate and testicular cancers have been
research on how to develop better treatment regimens for
published regularly (4).
patients with interstitial cystitis and CP/CPPS.
The main themes of our basic research have been the
4. Andrology, endocrinological surgery and male infertility
exploration of the biology of prostatic neuroendocrine
We investigate both clinical studies and actual clinical
81
practice thoroughly in these fields (14). Here, andrology and
history of lower urinary tract symptoms in Japanese men
aging male health are the principal fields of our research.
from 15-year longitudinal community-based study. Brit J
5. Gender identity disorder
Urol Int(2012) 110; 1023-1029.
Patients with gender identity disorder have been treated
9) Masumori N, Furuya R, Tanaka Y, Furuya S, Ogura H,
in our department. Both male to female and female to male
Tsukamoto T. The 12-year symptomatic outcome of
sex reassignment surgery is performed in routine clinical
transurethral resection of the prostate for patients with
practice (15).
lower urinary tract symptoms suggestive of benign
prostatic obstruction compared to the urodynamic
findings before surgery. BJU Int. (2010)105:1429-1433
List of Publications from 2009 to 2013
1) Kitamura H, Taguchi K, Kunishima Y, Yanase M,
10) Masumori N, Tsukamoto T, Horita H, Sunaoshi K, Tanaka
Takahashi A, Shigyo M, Tanaka T, Mutoh M, Fukuta F,
Y, Takeyama K, Sato E, Miyao N. Alpha1-blocker
Masumori N, Tsukamoto T. Paclitaxel, ifosfamide, and
tamsulosin as initial treatment for patients with benign
nedaplatin as second-line treatment for patients with
prostatic hyperplasia: 5-year outcome analysis of a
metastatic urothelial carcinoma: A phase II study of the
prospective multicenter study. Int J Urol. (2013)20:421-
SUOC group. Cancer Sci. (2011)102:1171-1175.
428
2) Kitamura H, Igarashi M, Tanaka T, Shindo T, Masumori N,
11)Kyoda Y, Takahashi S, Takeyama K, Masumori N,
Tamakawa M, Kawaai Y, Tsukamoto T. A role for
Tsukamoto T. Decrease in incidence of surgical site
preoperative systemic chemotherapy in node-positive
infections I contemporary series of patients with radical
upper tract urothelial carcinoma treated with radical
cystectomy. J Infect Chemother (2010)15; 118-122.
nephroureterectomy. Jpn J Clin Oncol. 2012;42:1192-6.
12) Takahashi S, et al. A randomized clinical trial to evaluate
3) Masumori N, Itoh N, Takahashi S, Kitamura H, Nishida S,
the preventive effect of cranberry juice (UR65) for patients
Tsukamoto T. New technique with combination of felt,
with recurrent urinary tract infection. J Infect Chemother
Hem-o-lok
and
Lapra-Ty
for
suturing
the
renal
parenchyma in laparoscopic partial nephrectomy. Int J
Urol.(2012) 19:273-276
(2013) 19; 112-117 .
13) Takahashi S, Kurimura Y, Hashimoto J, Uehara T, Hiyama
Y, Iwasawa A, Nishimura M, Sunaoshi K, Takeda K,
4) Shindo T, Masumori N, Kobayashi K, Fukuta F, Hirobe M,
Suzuki N and Tsukamoto T. Antimicrobial susceptibility
Tonooka A, Hasegawa T, Kitamura H, Tsukamoto T.
and penicillin-binding protein 1 and 2 mutations in
Long-term outcome of small, organ-confined renal cell
Neisseria gonorrhoeae isolated from male urethritis in
carcinoma is not always favorable. BJU Int.(2013)
Sapporo, Japan. J Infect Chemother (2013)19; 50-56.
111:941-5 .
14) Maehana T, Tanaka T, Itoh N, Masumori N, Tsukamoto T.
5) Hashimoto K, Masumori N, Tanaka T, Maeda T, Kobayashi
Clinical outcomes of surgical treatment and longitudinal
K, Kitamura H, Hirata K, Tsukamoto T. Zoledronic acid
non-saurgical observatgion of patients with subclinical
but not somatostatin analogs exerts anti-tumor effects in
Cushing’s syndrome and nonfunctioning adrenocortical
a model of murine prostatic neuroendocrine carcinoma of
adenoma. Ind J Urol (2012)28; 179-183.
the development of castration-resistant prostate cancer.
Prostate (2013)73:500-11.
6) Kitamura H, Torigoe T, Hirohashi Y, Asanuma H, Inoue R,
Nishida S, Tanaka T, Fukuta F, Masumori N, Sato N,
Tsukamoto T. Prognostic impact of the expression of
ALDH1 and SOX2 in urothelial cancer of the upper
urinary tract. Mod Pathol. (2013)26:117-24.
7) Fukuta F, Masumori N, Mori M and Tsukamoto T. Internal
prostatic architecture on transrectal ultrasonography
predicts future prostatic growth: Nature history of prostatic
hyperplasia in a 15-year longitudinal community-based
study. The prostate (2011)71; 597-603.
8) Fukuta F, Masumori N, Mori M and Tsukamoto T. Natural
15)Masumori N. Status of sex reassignment surgery for
gender identity disorder in Japan. Int J Urol. (2012)19:
402-414
82
Otolaryngology
Otolaryngology – Head and Neck Surgery treats all disorders in the
head and neck except the brain and eyeball. Therefore, our research
field covers a wide variety of diseases such as sensorineural hearing
loss, acute and chronic otitis media, head and neck cancers, tonsillar
focal infection, salivary gland diseases and nasal allergies. In
particular, molecular biological and immunological approaches for
the epithelial barrier of the upper respiratory tract are extensively and
effectively applied for understanding the etiology of a disease and for
developing novel diagnostic therapeutic strategies.
Professor
Assistant Professor
Ken-ichi Takano, M.D., Ph.D.
Tetsuo Himi, M.D., Ph.D.
Atsushi Kondo, M.D., Ph.D.
Interests:
Interests:
Interests:
Otology, Mucosal immunity of upper
Otology, Defense immunological
Head and neck cancer
airway eputelium
mechanism of upper respiratory tract
Makoto Kurose, M.D., Ph.D.
Instructor
Associate Professor
Interests:
Estuko Kanaizumi-Saikawa, M.D.,
Hideaki Shirasaki, M.D., Ph.D.
Head and neck cancer, Chemotherapy
Ph.D.
Interests:
for head and neck cancer
Tsuyoshi Okuni, M.D., Ph.D.
Nasal allergy
Nobuhiko Seki, M.D., Ph.D.
1. Mucosal Immunity of upper respiratory tract
2. Nasal Allergy
The upper respiratory tract including the nasal cavity,
Our department has been establishing unique data in this
which is the first site of invading antigen exposure, plays a
field. Several projects are in progress. One major project
crucial role in host defense via the mucosal immune response.
concerns the role of chemical mediators, such as Th2
The epithelium of nasal mucosa forms a continuous barrier
cytokines in the regulation of Leukotriene receptors on
against a wide variety of exogenous antigens. The epithelial
leukocyte, capsaicin receptors or thromboxane A2 receptors
barrier function is regulated in large part by the apical-most
on inferior turbinate mucosa. Related to this project, we are
intercellular junction, referred to as the tight junction. Antigen-
investigating localization and up-regulation of the CysLT2
presenting cells, particularly dendritic cells (DCs), are known
receptor in perennial allergic rhinitis. This is the first report on
to play an important role in human nasal mucosa (1-4).
how the CysLT2 receptor plays a primary role in the vascular
Our department discovered a new mechanism for
responses in the upper respiratory tract (5).
pathogen uptake in the nasal mucosa, by which DCs open the
3. IgG4-Related Disease
tight junctions between epithelial cells and send dendrites
Ever since Morgan reported on it in 1953, Mikulicz’s
outside the epithelium to directly sample the pathogen. In
disease (MD) has been considered a part of primary Sjögren’s
order to preserve the integrity of the epithelial barrier and
syndrome (SS). However, MD has a unique presentation,
penetrate beyond well-developed epithelial tight junctions,
including persistent swelling of the lacrimal and salivary
DCs express tight junction proteins. We also found that these
glands, and is characterized by good responsiveness to
DCs are activated by nasal epithelial-derived TSLP induced
glucocorticoids, leading to recovery of gland function.
by stimuli such as cytokines and Toll-like receptor ligands.
Recently, it has been revealed that MD patients show elevated
One aspect of our research focuses on the novel mechanisms
serum immunoglobulin G4 (IgG4) levels and prominent
in host defense in terms of innate immunity of the nasal
infiltration of IgG4-positive plasmacytes. The complications of
mucosa from the point of view of the mucosal barrier function
MD include autoimmune pancreatitis, retroperitoneal fibrosis,
(1-4).
tubulointerstitial nephritis, autoimmune hypophysitis, and
83
Riedel’s thyroiditis, all of which show IgG4 involvement in their
cells. Mol Biol Cell. 2011 Jul 1;22(13):2144-56.
pathogenesis. Thus, MD is a systemic “IgG4-related disease.”
MD differs from SS and is thought to be singular systemic
IgG4-related plasmacytic disease. Our department has
especially investigated the igG4-related salivary glands and
enhances tight-junction barrier function of human nasal
nasal diseases (6-8).
epithelial cells. Cell Tissue Res. 2009 Nov;338(2):283-
4. Head and neck cancer
93.
We are also performing diagnosis and treatment of head
5) Shirasaki H, Kanaizumi E, Seki N, Fujita M, Kikuchi M,
and neck cancers to aim at effective and functionally preserved
Himi T. Localization and up-regulation of cysteinyl
treatment. Additionally, pretreatment biopsies of oropharyngeal/
leukotriene-2 receptor in human allergic nasal mucosa.
hypopharyngeal cancer are being examined for their
Allergol Int. 2013 Jun;62(2):223-8.
expressions of various molecular biomarkers (EGFR, HPV-
6) Takano K, Yamamoto M, Kondo A, Takahashi H, Himi T. A
infection) and analyzed for effects on response to therapy and
clinical study of olfactory dysfunction in patients with
survival (9).
Mikulicz’s
Several projects are on going in this field. One is the
Jun;38(3):347-51.
disease.
Auris
Nasus
Larynx.
2011
study of JAM-A as a new biomarker for head and neck
7) Seki N, Yamazaki N, Kondo A, Nomura K, Himi T.
cancers. Another concerns the new diagnostic marker of
Spontaneous regression of lung lesions after excision of
papillary thyroid carcinoma (10). The goal here is to be able to
the submandibular gland in a patient with chronic
more quickly diagnosis head and neck cancers and predict
sclerosing sialadenitis. Auris Nasus Larynx. 2012
cancer metastasis.
Apr;39(2):212-5.
5. Otology
8) Himi T, Takano K, Yamamoto M, Naishiro Y, Takahashi H.
Basic and clinical research of cochlear implants is a very
A novel concept of Mikulicz’s disease as IgG4-related
important theme for our department. Supported by the large
disease. Auris Nasus Larynx. 2012 Feb;39(1):9-17.
number of operation cases, we are studying indications,
9) Kondoh A, Takano K, Kojima T, Ohkuni T, Kamekura R,
outcomes and long post-operative courses of cochlear
Ogasawara N, Go M, Sawada N, Himi T. Altered
implants. Responding to the increased demand of pediatric
expression
cases of cochlear implants and hearing loss, we are studying
regardless of human papilloma virus infection in human
the development of speech and hearing ability in both children
tonsillar squamous cell carcinoma. Acta Otolaryngol.
with cochlear implants and those with hearing aids (11).
2011 Aug;131(8):861-8.
of
claudin-1,
claudin-7,
and
tricellulin
10) Ara S, Kikuchi T, Matsumiya H, Kojima T, Kubo T, Ye RC,
List of main Publications from 2009 to 2013
Sato A, Kon S, Honma T, Asakura K, Hasegawa T, Himi T,
1) Himi T, Takano K, Ogasawara N, Go M, Kurose M,
Sato N, Ichimiya S. Sorting nexin 5 of a new diagnostic
Koizumi J, Kamekura R, Kondo A, Ohkuni T, Masaki T,
marker
Kojima T, Sawada N, Tsutsumi H. Mucosal immune
Caspase-2. Cancer Sci. 2012 Jul;103(7):1356-62.
barrier and antigen-presenting system in human nasal
of
papillary
thyroid
carcinoma
regulates
11) Kitagawa K, Mitsuzawa H, Shintani T, Go M, Himi T.
epithelial cells. Adv Otorhinolaryngol. 2011;72:28-30.
Audiological chronological findings in children with
2) Nomura K, Kojima T, Fuchimoto J, Obata K, Keira T, Himi
congenital anomalies of the central nervous system. Int J
T, Sawada N. Regulation of interleukin-33 and thymic
stromal lymphopoietin in human nasal fibroblasts by
proinflammatory
cytokines.
Laryngoscope.
2012
Jun;122(6):1185-92.
Sawada N. A nuclear factor-κB signaling pathway via
protein kinase C δ regulates replication of respiratory
syncytial virus in polarized normal human nasal epithelial
Pediatr Otorhinolaryngol. 73(8):1105-1110, 2009
84
Neuropsychiatry
Department of Neuropsychiatry treats various brain disorders related
to dysfunctions of emotion, memory&learning and cognition.
Disorders that we examine include such as depression, schizophrenia,
alcohol-induced brain damage, Alzheimer’s disease and dementia
with Lewy bodies. Our research is mainly focusing primarily on
regenerative strategy of damaged neural circuits in these disorders,
through a series of anticipated studies of neurogenesis activation
and epigenetic regulation in collaboration with prominent institutes
worldwide.
Professor
Assistant Professor
Instructor
Toshikazu Saito, M.D., Ph.D.
Wataru Ukai, Ph.D.
Takao Ishii, M.D., Ph.D.
Interests:
Interests:
Ryuji Sasaki, M.D., Ph.D.
Alcohol related problems and
Stem cell therapy, Schizophrenia
Shigeki Hatakeyama, M.D.
depression
Seiju Kobayashi, M.D., Ph.D.
Toru Yoshikawa, M.D.
Interests:
Associate Professor
Dementia with Lewy bodies,
Eri Hashimoto, M.D., Ph.D.
Neuroimaging
Interests:
Biological markers, Stem cell theories
in regarding depression
Neural stem cells (NSCs) have been identified in every
mammal investigated to date including human. NSCs attract
interests of a large number of researchers in various scientific
fields by their possibility of becoming innovative therapeutic
strategy for neurodegenerative disorders previously
considered untreatable. As the candidate approach of
regenerative medicine for psychiatric disorders, we have
been establishing a new strategy of stem cell treatment,
especially against refractory case of depression, schizophrenia
and alcohol-induced brain damage. In a grant program of
JSPS, Scientific Research on Innovative Area (Research in a
proposed research area), “Unraveling the Microendophenotype
of Psychiatric Disorders at the Molecular, Cellular and Circuit
levels”, we are focusing on the possibility of neural circuit
repair and behavioral recovery of schizophrenia and bipolar
disorder model animals by human iPS cell treatment. In this
project, we are also trying to establish a modeling of new
psychiatric disease model animals by iPS cell treatment
derived from schizophrenia and bipolar disorder patients, in
collaborations with RIKEN Brain Institute and Keio University.
For progressing our candidate data to a clinical stage, we are
emphasizing collaborative studies with Department of Neural
Regenerative Medicine and Department of Anatomy (II), in a
point of clinically useful stem cell source of adult bone marrowderived mesenchymal stem cells (MSCs).
1. Mood Disorders
In the adult hippocampal formation, neurogenesis occurs
in the dentate gyrus subgranular zone (SGZ). In the studies of
biological mechanisms of depression, we have been focusing
on the abnormality of neurogenesis. In the collaborative study
with National Center of Neurology and Psychiatry (NCNP),
Japan, we have analyzed the gene expression profiles of cells
from hippocampal SGZ laser capture microdissection and an
antidepressant-related genes microarray to analyze gene
expression profiles of cells, where neurogenesis actively
occurs in the adult brain. Among the differentially expressed
genes, we have found that neuroserpin plays important role in
early stage of neurogenesis in adult hippocampus (5). We
have also demonstrated that rhotekin is required for
maintenance/survival of neurons and positively regulates
differentiation but regulate proliferation negatively of NSCs
(7). In the same collaborative study, we have first investigated
the role of Plasticity-related gene 1 (Prg1), a membraneassociated lipid phosphate phosphatase in the survival of
neurons derived from rat neural stem cells (NSCs) using small
interfering RNA (siRNA) and demonstrated that Prg1 was
important for survival of neurons through its dephosphorylation
activity (12). In another project, we are focusing on the role of
brain-derived neurotrophic factor (BDNF) change in
depression. BDNF is reported to promote neurogenesis and
protect against cell loss in hippocampus. Recent reports
indicate that serum BDNF levels in depressive patients are
lower than in control subjects but the mechanisms of changes
in BDNF blood levels are still unclear. In this project, we have
indicated that BDNF was released from platelets by direct
treatment with various kinds of antidepressants and suggested
the platelet BDNF function as a candidate predictor of
antidepressant treatment response (4).
2. Schizophrenia
Recent studies suggest that antipsychotic drugs regulate
the activities of NSCs. However, the molecular mechanisms
underlying antipsychotic-induced changes of the activity of
NSCs, particularly protein expression, are still unknown. We
studied the growth and protein expression in haloperidol (HD)
and risperidone (RS) treated rat NSCs using 2-DE based
proteomics in the collaborative study with Sydney University.
85
We have identified differentially regulated proteins which
could be classified into several functional groups, such as
cytoskeletal, calcium regulating protein, metabolism, signal
transduction and proteins related to oxidative stress. The
result might explain the molecular mechanisms underlying the
different effects of both drugs on NSCs activities relate to their
clinical efficacies for schizophrenia (1). In addition to druginduced NSC activation, transplantation of exogenous NSCs
has been proposed as a possible approach to repair the
damaged brain in psychiatric disease. NSC transplantation
embraces not only neuron replacement but also enhanced
neuroprotection of existing neurons with the goal of restoring
the impaired brain. However, little is known about the cell-cell
interactions of exogenous NSCs with existing neurons, or
about their neuroprotective actions especially in psychiatric
diseases. In the in vitro experiment using cortical neuron
cultures, we demonstrated that exogenous NSCs have antiapoptotic activities and can rescue cortical neurons by
directing cellular survival signaling of neurons into the proper
direction, without cell contact (2).
3. Alcohol related disorders
Stem cell therapy is well proposed as a potential method
for the improvement of neurodegenerative damage in the
brain. Among several different procedures to reach the cells
into the injured lesion, the intravenous (IV) injection has
benefit as a minimally invasive approach. However, for the
brain disease, prompt development of the effective treatment
way of cellular biodistribution of stem cells into the brain after
IV injection is needed. We have found that IV treated NSCs
complexed with atelocollagen could effectively migrate into
the brain rather than NSC treated alone using chronic alcohol
binge model rat, suggesting atelocollagen induces beneficial
effect on regenerative approach of IV administration of NSCs
for CNS disease (10). In another project, we exposed pregnant
rats to ethanol followed by intravenous administration of
NSCs complexed with atelocollagen to the new born rats, and
demonstrated the important role for synaptic remodeling and
GABAergic interneuron genesis in the pathophysiology and
treatment of FASD and highlight the therapeutic potential for
intravenous NSC administration in FASD utilizing atelocollagen
(8). As a taskforce of World Federation of Societies of
Biological Psychiatry (WFSBP), we represents an overview of
the current literature on biological markers for alcoholism,
including markers associated with the pharmacological effects
of alcohol and markers related to the clinical course and
treatment of alcohol-related problems (13).
4. Dementia/Cognitive disorders
Background: Alzheimer’s disease (AD) differs from other
forms of dementia in its relation to amyloid beta peptide
(Aβ42). Using a cell culture model we identified annexin A5, a
Ca2+, and phospholipid binding protein, as an AD biomarker
(3). In the collaborative study with Center for Medical
Education to examine whether or not plasma annexin A5 is a
specific marker for AD, when being compared with the levels
of DLB patients, we suggested that both annexin A5 and
ApoE4 are common markers for AD and DLB (11).
5. Epigenetics in psychiatric disorders
Epigenome information in mammalian brain cells reflects
their developmental history, neuronal activity, and
environmental exposures. In the collaborative study with
RIKEN Brain Institute, We performed comprehensive DNA
methylation analysis in neuronal and non-neuronal nuclei
obtained from the human prefrontal cortex, and suggesting
that neuronal cells have more potential ability to change their
epigenetic status in response to developmental and
environmental conditions compared with non-neuronal cells
(6). Gene expression of the alpha-1 subunit of the L-type
voltage-gated calcium channel, CACNA1C, is known to be
complexly regulated. In another project with RIKEN, we
examined DNA methylation status of CpG islands and a CpG
island shore on mouse Cacna1c in neuronal and non-neuronal
nuclei, which were separated with a fluorescent activated cell
sorting technique. We found that neurons and non-neurons
showed differential DNA methylation profile on a CpG island
shore (9).
1) Kashem MA, Ummehany R, Ukai W, Hashimoto E, Saito
T, Mcgregor IS, Matsumoto I. Neurochem Int. Effects of
typical (haloperidol) and atypical (risperidone)
antipsychotic agents on protein expression in rat neural
stem cells. Neurochem Int (2009)55: 558-565
2) Ono T, Hashimoto E, Ukai W, Ishii T, Saito T. The role of
neural stem cells for in vitro models of schizophrenia:
neuroprotection via Akt/ERK signal regulation. Schizophr
Res(2010) 122: 239-247
3) Yamaguchi M, Kokai Y, Imai S, Utsumi K, Matsumoto K,
Honda H, Mizue Y, Momma M, Maeda T, Toyomasu S, Ito
YM, Kobayashi S, Hashimoto E, Saito T, Sohma H.
Investigation of annexin A5 as a biomarker for Alzheimer’s
disease using neuronal cell culture and mouse model. J
Neurosci Res (2010)88: 2682-2692
4) Watanabe K, Hashimoto E, Ukai W, Ishii T, Yoshinaga T,
Ono T, Tateno M, Watanabe I, Shirasaka T, Saito S, Saito
T. Effect of antidepressants on brain-derived neurotrophic
factor (BDNF) release from platelets in the rats. Prog
Neuropsychopharmacol Biol Psychiatry (2010)34: 14501454
5) Yamada M, Takahashi K, Ukai W, Hashimoto E, Saito T,
Yamada M. Neuroserpin is expressed in early stage of
neurogenesis in adult rat hippocampus. Neuroreport(2010)
21: 138-142
6) Iwamoto K, Bundo M, Ueda J, Oldham MC, Ukai W,
Hashimoto E, Saito T, Geschwind DH, Kato T. Neurons
show distinctive DNA methylation profile and higher
interindividual variations compared with non-neurons.
Genome Res(2011) 21: 688-696
7) Iwai T, Saitoh A, Yamada M, Takahashi K, Hashimoto E,
Ukai W, Saito T, Yamada M. Rhotekin modulates
differentiation of cultured neural stem cells to neurons. J
Neurosci Res (2012)90: 1359-1366
8) Shirasaka T, Hashimoto E, Ukai W, Yoshinaga T, Ishii T,
Tateno M, Saito T. Stem cell therapy: social recognition
recovery in a FASD model. Transl Psychiatry 2: e188
(2012)
9) Nishioka M, Shimada T, Bundo M, Ukai W, Hashimoto E,
Saito T, Kano Y, Sasaki T, Kasai K, Kato T, Iwamoto K.
Neuronal cell-type specific DNA methylation patterns of
the Cacna1c gene. Int J Dev Neurosci(2013) 31: 89-95
10) Yoshinaga T, Hashimoto E, Ukai W, Ishii T, Shirasaka T,
Kigawa Y, Tateno M, Kaneta H, Watanabe K, Igarashi T,
Kobayashi S, Sohma H, Kato T, Saito T. Effects of
atelocollagen on neural stem cell function and its
migrating capacity into brain in psychiatric disease model.
J Neural Transm(2013) 120: 1491-198
11)Sohma H, Imai S, Takei N, Honda H, Matsumoto K,
Utsumi K, Matsuki K, Hashimoto E, Saito T, Kokai Y.
Evaluation of annexin A5 as a biomarker for Alzheimer’s
disease and dementia with lewy bodies. Front Aging
Neurosci 5: 15 (2013)
12) Hashimoto T, Yamada M, Iwai T, Saitoh A, Hashimoto E,
Ukai W, Saito T, Yamada M. Plasticity-related gene 1 is
important for survival of neurons derived from rat neural
stem cells. J Neurosci Res(2013) 91: 1402-1407
13) Hashimoto E, Riederer PF, Hesselbrock VM, Hesselbrock
MN, Mann K, Ukai W, Sohma H, Thibaut F, Schuckit MA,
Saito T. Consensus paper of the WFSBP task force on
biological markers: Biological markers for alcoholism.
World J Biol Psychiatry(2013) 14: 549-564
86
Radiology
Our department consists of 2 major divisions, Radiation Oncology
and Interventional Radiology (IR). There are 7 senior staff members.
Principles of our department are as follows: 1) Development of
radiotherapy to help patients achieve a high quality of life, 2) Evolution
of IR for more clinical adaptations, and 3) Advancement of education
about radiation therapy and IR for the general public.
Professor
Masanori Someya, M.D., Ph.D.
Instructor
Koh-ichi Sakata, M.D., Ph.D.
Interests:
Kensei Nakata, M.D.
Interests:
Radiation oncology
Radiation oncology
Masakazu Hori, M.D., Ph.D.
Kunihiko Tateoka, Ph.D.
Assistant Professor
Interests:
Naoki Hirokawa, M.D., Ph.D.
Radiation physics
Masato Saito, M.D., Ph.D.
Interests:
Interventional radiology
1. Radiation oncology
addition of camptothecin leads to effective chemoradiosensitization
a) Clinical radiation oncology
in vitro (8).
We have reported on the safety and efficacy of breast-
We reported the treatment results of chemoradiotherapy
conserving radiotherapy performed on more than 1,000
for hypopharyngeal cancer and analyzed the relationship
breast cancer patients (1). Additionally, we elucidated the
between expression of DNA damage repair proteins, Ku70/86
efficacy of oral chemotherapeutic drugs S-1 for the treatment
and XRCC4 and prognostic importance (9).
of head neck cancer. We determined safe doses of S-1 and
2. Interventional Radiology (IR)
performed phase-1 trials of concurrent S-1 and radiotherapy
Interventional radiology is a pioneer in minimally invasive
for head neck cancer, subsequently confirming its safety and
treatment and has been recently developed. Interventional
efficacy (2).
Radiologists treat several vascular diseases and cancers with
b) Basic research
the catheter and puncture needle, making full use ultrasound,
DNA-dependent protein kinase (DNA-PK) has an
X-rays, CT and MRI. Our department performs approximately
important role in DNA double-strand break repair. DNA-
400 cases of IR in a year. IR types include:
dependent protein kinase activity of peripheral blood
a) Vascular IR
lymphocytes was associated with prognosis of cancer (3).
A new procedure of embolization with 3D and PGLA coils
We found that Gimeracil had radiosensitizing effects by
has been used to treat large and amorphous aneurysms in
inhibiting the homologous recombination DNA damage repair
peripheral lesions. We obtained good results in the
pathway (4).
organization and neointima formation of peripheral aneurysms
Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase,
through biological tests. This research is being continued,
inhibits the early step in homologous recombination (5). This
with the ultimate goal being no recurrences and decreases in
phenomenon was confirmed by depletion of dihydropyrimidine
coils in aneurysmal embolization.
dehydrogenase on focus formation and RPA phosphorylation.
b) Non-vascular IR and ultrasound
Using Gimeracil or siRNA for dihydropyrimidine dehydrogenase,
Our IR group examined for cancer around the liver, bile
the binding of DNA damage repair proteins NBS1 and RPA
duct and pancreas by external, endoscopic, intraductal and
was partly inhibited (6).
intravascular ultrasound. External ultrasound easily and
The combination of hyperthermia or chemotherapy with
rapidly revealed the disease in high spatial and temporal
Gimeracil proved to have a higher rate of radiosensitization
resolution (10). In addition, ultrasound enabled us to treat the
(7). We clarified the mechanism of radiosensitization by PARP
lesion with non-vascular IR.
inhibitor, oraparib for cell lines without BRCA1/2 mutation. An
Recently, ablation therapy with high-intensity focused
87
ultrasound (HIFU) has been developed in oncology area.
expressions of hypopharyngeal cancer tissues and
However, HIFU therapy has not yet become popular as an
results treated with chemoradiotherapy. Oncol Letters
extracorporeal ablation therapy for liver tumors. We
investigated the causes of cell death other than thermal
ablation when ultrasound energy is reduced (11).
(2012) 4:151-155.
10)Nishida M, Koito K, Hirokawa N, Hori M, Satoh T,
Hareyama M. Does contrast-enhanced ultrasound reveal
tumor angiogenesis in pancreatic ductal carcinoma? A
prospective study. Ultrasound in Med.& Biol. (2009)
1) Oouchi A, Sakata K, Masuoka H, Tamakawa M, Nagakura
135:175-185.
H, Someya M, Nakata K, Asaishi K, Okazaki M, Okazaki
11) Hirokawa N, Koito K, Okada F, Kudo N, Yamamoto K,
Y, Ohmura T, Hareyama M, Hori M, Shimokawara I,
Fujimoto K, Nishida M, Ichimura T, Hori M, Satoh T,
Okazaki A, Watanabe Y, Yamada T, Satoh T, Hirata K.
Hareyama M. High-intensity focused ultrasound induced
The treatment outcome of patients undergoing breast-
apoptosis with caspase 3, 8, and 9/6 activation in rat
conserving therapy: the clinical role of postoperative
hepatoma. J Med Ultrasonics (2009) 36:177-185.
radiotherapy. Breast Cancer (2009) 16: 49-57.
12)Tsuchimoto T, Sakata K, Someya M, Yamamoto H,
2) Nakata K, Sakata KI, Someya M, Miura K, Hayashi J,
Hirayama R, Matsumoto Y, Furusawa Y, Hareyama M.
Hori M, Takagi M, Himi T, Kondo A, Hareyama M. Phase
Gene expression associated with DNA-dependent
I study of oral S-1 and concurrent radiotherapy in patients
protein kinase activity under normoxia, hypoxia and
with head and neck cancer. J Radiat Res (2013) 54:679-
reoxygenation. J Radiat Res (2011) 52:464-471.
13) Yaegashi Y, Tateoka K, Nakazawa T, Fujimoto K, Shima
683.
3) Someya M, Sakata K, Matsumoto Y, Kamdar P. R, Kai M,
K, Suzuk J, Nakata A, Saitoh Y, Sakata K, Hareyama M.
Toyota M, Hareyama M. The association of DNA-
Analysis of the optimum internal margin for respiratory-
dependent protein kinase activity of peripheral blood
gated
lymphocytes with prognosis of cancer. Br J Cancer
assessments using a motion phantom. J Appl Clin Med
(2011)104:1724-1729.
Phys (2012) 13:3715.
radiotherapy
using
end-expiratory
phase
4) Takagi M, Sakata K, Someya M, Tauchi H, Iijima K,
14)Shima K, Tateoka K, Saitoh Y, Suzuki J, Yaegashi Y,
Matsumoto Y, Torigoe T, Takahashi A, Hareyama M,
Fujimoto K, Nakazawa T, Nakata A, Abe T, Imai S, Sakata
Fukushima M. Gimeracil sensitizes cell to radiation via
K, Hareyama M. Analysis of post-exposure density
inhibition of homologous recombination. Radiother Oncol
growth in radiochromic film with respect to the radiation
(2010) 96:259-266.
dose. J Radiat Res (2012) 53:301-305.
5) Sakata K, Someya M, Matsumoto Y, Tauchi H, Kai M,
15) Suzuki J, Tateoka K, Shima K, Yaegashi Y, Fujimoto K,
Toyota M, Takagi M, Hareyama M, Fukushima M.
Saitoh Y, Nakata A, Abe T, Nakazawa T, Sakata K,
Gimeracil,
dihydropyrimidine
Hereyama M. Uncertainty in patient set-up margin
dehydrogenase, inhibits the early step in homologous
analysis in radiation therapy. J Radiat Res (2012) 53:615-
recombination. Cancer Sci (2011) 102:1712-1716.
619.
an
inhibitor
of
6) Someya M, Sakata K, Matsumoto Y, Tauchi H, Kai M,
Hareyama M, Fukushima M. Effects of depletion of
dihydropyrimidine dehydrogenase on focus formation
and RPA phosphorylation. J Radiat Res (2012) 53:250256.
7) Takagi M, Sakata K, Someya M, Matsumoto Y, Tauchi H,
Hareyama M, Fukushima M. The combination of
hyperthermia or chemotherapy with Gimeracil for
effective radiosensitization. Strahlenther Onkol (2012)
188:255-261.
8) Miura K, Sakata K, Someya M, Matsumoto Y, Matsumoto
H, Takahasi A, Hereyama M. The combination of olaparib
and camptothecin for effective radiosensitization. Radiat
Oncol (2012) 7:62.
9) Hayashi J, Sakata K, Someya M, Matsumoto Y, Satoh M,
Nakata K, Hori M, Takagi M, Kondoh A, Himi T, Hareyama
M, Kondoh A. Himi T. Analysis of Ku and XRCC4
88
Anesthesiology
Our department has continued investigating the basic mechanisms
of anesthetics, pain, sepsis, respiration, circulatory, vascular, cardioprotection and neuromuscular transmission to be aimed at improving
the safety of clinical anesthesia, pain management, palliative medicine
and intensive care. We also engaged in improving perioperative
systems of monitoring the safety and QOL of surgical patients. We
have presented these findings at the most authoritative international
conferences (American Society of Anesthesiologists) every year and
now are leading department of this 2 years in the world.
Professor
Mitsutaka Edanaga, M.D., Ph.D.
Instructor
Michiaki Yamakage, M.D., Ph.D.
Interests:
Tomohisa Niiya, M.D., Ph.D.
Interests:
Echocardiography, Clinical research,
Shigekazu Sugino, M.D., Ph.D.
Pain, Respiration, Education
Education
Soshi Iwasaki, M.D., Ph.D.
Yukitoshi Niiyama, M.D., Ph.D.
Naoyuki Hirata, M.D., Ph.D.
Assistant Professor
Interests:
Yasuyuki Tokinaga, M.D., Ph.D.
Akihiko Watanabe, M.D., Ph.D.
Pain, Medical safety
Yoshinobu Kimura, Ph.D.
Interests:
Palliative medicine, Cancer pain,
Education
1. Elucidation of the interaction of lipophilic drugs and
2. New bronchodilative effect of PDE3 in perioperative
lipid emulsion
period
Intravenous lipid infusion is currently recommended for
There has been a worldwide increase in the recognition
the treatment of toxicity caused by lipophilic local anesthetic
of patients with airway hyperreactivity (such as chronic
(bupivacaine), but the recommendation has been based
obstructive pulmonary disease (COPD) and asthma). The
mainly on published human case reports. Therefore, we
elevated perioperative respiratory morbidity rates in these
investigated the interaction of intravenously administered
patients pose challenges to anesthetists. Using an asthmatic
lipophilic drugs and lipid emulsion in anesthetized pigs. First,
model, our department has investigated the interaction
we
lipophilic
between anesthetics and perioperative drugs. The latest
antiarrhythmic drugs, was sequestered to a great extent by
investigation in our department has revealed that combined
the intravenously administered lipids in plasma. This
administration of roflumilast, a PDE4 inhibitor and sevoflurane,
completely prevented the decrease in arterial blood pressure
a volatile anaesthetic, exerts an additive relaxation effect on
that IV amiodarone can cause (1). We speculate that lipid
airway hyperresponsiveness in an animal model (3). These
infusion may prevent the antiarrhythmic effects of amiodarone
findings suggest that those patients under the PDE4 inhibitors
when amiodarone and lipid are administered concomitantly
treatment could be anesthetized safely with a sevoflurane
for the treatment of local anesthetic intoxication. Second, we
based general anesthesia, and a combination of these two
reported that lipid emulsion neither had any measurable effect
agents might provide better protection against airway disease.
on the disposition of the studied bupivacaine in plasma, nor
3. Strategies for cardioprotection from ischemia and
did it improve the rate of recovery from intoxication by
reperfusion injury in anesthesia and critical care
bupivacaine as measured by hemodynamic variables (2). We
Volatile anesthetics have cardioprotective effects against
found no support for the use of lipid emulsion as a treatment
ischemia-reperfusion injury when administrated before a
for local anesthetic intoxication in our model of local anesthetic
period of myocardial ischemia, and this phenomenon is
intoxication.
referred to as anesthetic preconditioning. We have previously
reported
that
amiodarone,
one
of
the
demonstrated that reactive oxygen species from cardiac
mitochondria during preconditioning could be involved in the
89
cardioprotective effects (4,5). Myocardial ischemia occasionally
PH. Intravenous lipid emulsion sequesters amiodarone in
induces lethal ventricular arrhythmias in a clinical setting. We
plasma and eliminates its hypotensive action in pigs. Ann
also focused on the effects of anesthetics on ischemia-
Emerg Med(2010) 56: 402-408.
induced ventricular arrhythmias using rat models. We have
2) Litonius E, Niiya T, Neuvonen PJ, Rosenberg PH.
demonstrated that compared to sevoflurane, propofol could
Intravenous lipid emulsion only minimally influences
more effectively reduce the incidence of lethal arrhythmias
bupivacaine and mepivacaine distribution in plasma and
caused by acute myocardial ischemia via preservation of
does not enhance recovery from intoxication in pigs.
connexin-43 phosphorylation (6). Recently, we have also
Anesth Analg(2012) 114: 901-906.
focused on other strategies for cardioprotection against
3) Zhou J, Iwasaki S, Watanabe A, Yamakage M: Synergic
ischemia and reperfusion injury in anesthesia and the critical
bronchodilator effects of a phosphodiesterase 3 olprinone
care field. As mentioned above, volatile and intravenous
with a volatile anaesthetic sevoflurane in ovalbumin-
anesthetics have several cardioprotective effects. However,
sensitized guinea pigs. Eur J Anaesthesiol(2011) 28:519-
they also have negative inotropic and chronotropic effects.
524.
Therefore, critical conditions may limit the administration of
4) Hirata N,Shim YH, Pravdic D, Lohr NL, Pratt PF Jr,
cardioprotective anesthetics. We have therefore highlighted
Weihrauch D, Kersten JR, Warltier DC, Bosnjak ZJ,
several agents with less potency for negative inotropic effects
Bienengraeber M. Isoflurane differentially modulates
that can be used as cardioprotective medications against
mitochondrial reactive oxygen species production via
ischemia and reperfusion injury for patients under critical
forward
conditions.
implications for preconditioning. Anesthesiology(2011)
4. Pain research
Using
versus
reverse
electron
transport
flow:
115: 531-540.
biological
5) Pravdic D, Hirata N, Barber L, Sedlic F, Bosnjak ZJ,
techniques, we investigated the involvement of BMDM in
Bienengraeber M. Complex I and ATP synthase mediate
negative emotions in a model mouse of neuropathic pain
membrane depolarization and matrix acidification by
following partial sciatic nerve ligation (PSNL).
isoflurane
neurochemical
and
molecular
Neuropathic pain often induces negative emotions such
in
mitochondria.
Eur
J
Pharmacol.
(2012)690:149-157.
as anxiety and depression. The neuropathology of negative
6) Hirata N, Kanaya N, Kamada N, Kimura S, Namiki A.
emotions has recently been reported to be closely associated
Differential effects of propofol and sevoflurane on
with microglia in the brain parenchyma. In addition, several
ischemia-induced
studies have shown that the expression of inflammatory
phosphorylated
cytokines in the brain is a possible mechanism in the
Anesthesiology(2009)110: 50-57.
ventricular
connexin
43
arrhythmias
and
proteins
rats.
in
development of negative emotions. Microglia are resident
7) Yamakage M, Bepperling F, Wargenau M, Miyao H.
immune-related glial cells of the central nervous system, and
Pharmacokinetics and safety of 6 % hydroxyethyl starch
the existence of a new population of BMDM has been shown
130/0.4 in healthy male volunteers of Japanese ethnicity
in various clinical situations. Neuropathic pain induced
after single infusion of 500 ml solution. J Anesth
anxiety-like behavior in model mice at 4 weeks after PSNL.
(2012)26:851-857.
BMDM in model mice at 4 weeks after PSNL had significantly
8) Edanaga M, Azumaguchi R, Yamakage M. Ultrasound-
accumulated in the central nucleus of the amygdala (CeA). At
guided and radiographic monitoring-assisted peripherally
the same time, the mRNA expression level of IL-1βin BMDM
inserted central catheterization. J Anesth. (2012)26:623.
had migrated into the CeA in model mice but not in sham or
9) Edanaga M, Mimura M, Azumaguchi T, Kimura M,
control mice. These results indicate that migration of BMDM
Yamakage M. Comparison of ultrasound-guided and
into the CeA might cause negative emotions induced by
blindly placed radial artery catheterization. Masui.
neuropathic pain.
5. New drug and clinical safety
We have conducted considerable clinical research and
continue our research on clinical anesthesia. We have found
(2012)61:221-224.
10) Sawada A, Kii N, Yoshikawa Y, Yamakage M. Epidrum®:a
new device to identify the epidural space with an epidural
Tuohy needle. J Anesth(2012) 26:292-295.
that a new 6% hydroxyethyl starch can be considered safe (7)
11) Watanabe A, Yamakage M: Intrathecal neurolytic block in
and continue to explore anesthesia techniques (8-11) and
a patient with refractory cancer pain. J Anesth(2011) 25:
new anesthetic education (12).
603-605.
12)
Maruyama
D,
Edanaga
M,
Yamakage
M.
The
bronchoscopy model LM-092 has educational benefits. J
1) Niiya T, Litonius E, Petaja L, Neuvonen PJ, Rosenberg
Anesth. Aug 9(2013).
90
Community and General Medicine
The scope of our research activities covers community oriented
primary care (COPC), medical education, narrative based medicine
(NBM), medical professionalism and medical anthropology. Through
these activities, we have been encouraging the researchers and
general physicians who contribute to community medicine in
Hokkaido.
Professor
Instructor
Wari Yamamoto, M.D., Ph.D.
Takeshi Matsuura, M.D.
Interests:
Shinnchi Takeda, M.D.
Clinical epidemiology, Community
medicine
1. Community oriented primary care (COPC)
One of our department’s aims is to contribute to the
health promotion of communities in Hokkaido. To attain this
aim we have been conducting action research in several
communities. One example of this is a health promotion
program at a community in east Hokkaido. We used a Delphi
method to understand important health issues in the
community, and discovered that there was an undesirable lifestyle problem among the children. Another example concerns
a management trial by general physicians of patients with
cognitive impairment in one community in south Hokkaido.
We learned that general physicians could manage the patients
properly and may have a favorable impact on their quality of
life
2. Medical education
a) Community medicine clerkship
Community medicine clerkship is said to be an important
element of current undergraduate medical education.
However, there is little study on what medical students have
actually learned from it. Therefore we conducted a study on
what medical students had learned from their two-week
community medicine clerkship experience using significant
event analysis (SEA). Students in the year 2006 experienced
a two-week community medicine clerkship and upon its
conclusion they participated in reflection sessions of their
experiences. The sessions were recorded, and the contents
of their experiences were extracted and categorized. The
depth of their reflection was categorized into four levels
(describing, commenting, generalizing, and planning).
Students reflected on the general medical system, the role of
physicians, patient centeredness, role models and clinical
ethics. Most of the students demonstrated the level of
commenting and generalizing. Medical students learned
system based practice and medical professionalism during
their community medicine clerkships, and SEA was a valuable
tool for deepening their experiences.
b) Primary care career choice
The selection of a primary care career by Japanese
medical students is said to be increasing, yet there are no
studies to support this belief. In order to fully understand the
alleged increase in the number of medical students choosing
primary care we believed that an examination of the factors
influencing medical students’ decision-making would be
helpful. We distributed questionnaires to 298 medical students
in 2004 who would graduate in four months from three
Japanese medical universities. Questionnaires covered topics
such as demographic factors, career choice, important career
choice factors, interest in community medicine, willingness to
engage in community medicine, opinions on the usefulness of
community medicine, and satisfaction with curricula. In their
replies, there were significant associations between primary
care choice and social experience, lifestyle preference,
interest in community medicine, willingness to engage in
community medicine, and contact with primary care faculty.
Use of a logistic regression model, lifestyle preference, male
gender, and social experience before entrance to a medical
university and contact with primary care faculty were four
significant factors in the questionnaire. It may be important to
consider those factors, in addition to curriculum reform, to
increase the number of Japanese medical students who
choose a career in primary care.
3. Narrative based medicine (NBM)
Recently the importance of narrative based medicine
(NBM) has been emphasized in many fields of medicine. One
reason seems to be the drastic change in patient illness
patterns. Chronic diseases and psychosocial problems are
the main reasons for most patients to come to our office.
When we see these patients, we cannot deal with their
problems by using a bioscience model of medicine. Their
health problems are usually related to their sense of value,
the context in which they live, persons with whom they live
and other social factors. Their problems are therefore beyond
the domain of biomedicine. We need to understand the patient
as a whole person and his/her background in order to establish
a common ground for understanding patient issues. This
approach is referred to as bio-psycho-social medicine or
91
patient-centered medicine. However, even if we use these
models, we cannot solve patient problems completely
because they are usually very complicated. Furthermore, in
many cases, their problems are lifelong. We need to have
other models in order to better serve these patients. We think
that a valuable paradigm is NBM. Although there have been
many articles that support the usefulness of NBM in primary
care medicine, they seldom explain the specific methods that
are effective with patients. In a case analysis study, we
presented one example of effectively practicing NBM and
introduced the 6 Cs (Curiosity, Conversation, Circularity,
Context, Co-creation and Caution) of NBM.
4. Medical professionalism
The relationship between physicians and drug companies
has been discussed repeatedly. Maintaining trust by managing
conflicts of interest is one of the major commitments of
medical professionalism. Keeping an adequate relationship is
said to be important in our medical education society. We
conducted this survey to comprehend physicians’ attitudes
towards interests offered by drug companies. 1) Questionnaires
were distributed to 1,200 physicians who registered to an
internet survey company. 2) Results indicated that almost all
physicians received ball pens and memo pads, and many
physicians received booklets of clinical guidelines, food and
drink, as well as after medical conferences offered by drug
companies. 3) Compared to young physicians, experienced
physicians tended to receive gifts from drug companies.
Physicians who work at clinics received gifts more frequently
than hospital physicians. Physicians who work at public
hospitals and university hospitals were offered travel and
lodging expenses for attending clinical conferences. 4) Most
physicians received gifts offered by drug companies. The
frequencies of these differed, depending on the number of
years that had passed since a physician’s graduation from
medical school, and the characteristics of work places. 5) The
results of this survey show valuable fundamental data that
can be used when discussing and teaching about the
relationship between physicians and drug companies
5. Medical anthropology
At a university hospital, patients play an important role in
medical students’ education during their clinical clerkships.
We conducted a study that clarified patients’ feelings and
thoughts about medical students’ participation in their care at
the hospital. We conducted semi-structured interviews with
five patients in whose care medical students were involved.
The interview data were analyzed with qualitative research
methodology. We extracted six themes from the data, which
were “students were rather poor in communication,” “students
were not very interested in associating with patients,” “patients
have certain expectations for and demands on students,”
“students were not someone with whom patients were keen
on establishing a rapport,” “patients have some doubt if
students were receiving appropriate instructions and
supervision,” and “attending physicians have considerable
influence on clerkships.” It became clear through the
interviews that although patients had expectations for, and
demands on the students to some extent, they were not very
interested in student education and that their acceptance of
students was heavily influenced by the attending physicians’
approach during the clerkship. This suggests that the
attending physicians’ attitudes and approach toward the
patients are important in improving patients’ acceptance of
medical students.
1) Kazuo Yagita, Yasushi Miyata, Portfolio-based students
learning about family and community in their community
medicine clerkship : qualitative change in student learning
resulting from use of a reflection sheet. Jpn J Prim Care.
2011. 34, 14-23.
2) Shizuko Nagata-Kobayashi, Hiroshi Koyama, Atsushi
Asai, Yoshinori Noguchi, Tetsuhiro Maeno, Osamu
Fukushima, Wari Yamamoto, Shunzo Koizumi, Takuro
Shimbo. Experiences of alcohol-related harassment
among medical students. Medical Education. 2010. 44:
1213–1223.
3) Takao Wakabayashi, Yasushi Miyata, Minori Yamagami,
Wari Yamamoto. Examination of opinions of patients
regarding physicians and medical care after withdrawal
of community hospital internists. Jpn J Prim Care . 2010.
33, 360-367.
4) Masaki Saitoh, Masuyuki Yonemasu, Wari Yamamoto, et
al. Motivation change of medical students after stroke
seminar by stroke team. Stroke (Japan) .2010. 32, 689693.
5) Masaki Saitoh, Masuyuki Yonemasu, Wari Yamamoto, et
al. Stroke team leadership over education for medical
students and stroke care workers in the community.
Stroke(Japan) . 2010. 32(6), 684-688.
6) Yasushi Miyata , Wari Yamamoto. Curriculum development
of medical professionalism in undergraduate medical
education at Sapporo Medical University. Medical
education (Japan). 2010. 41:189-193.
7) Yasushi Miyata , Yutaka Terada. Curriculum development
of narrative-based medicine in undergraduate medical
education:The narrative-based medicine course at
Sapporo Medical University. Medical education(Japan).
2010. 41:35-40.
8) Kazuo Yagita, Yasushi Miyata. What kind of a doctor do
people in community want to have?: a qualitative study of
competency of a Japanese general practitioner. Family
Medicine (Japan). 2010. 15:16-23.
9) Yasushi Miyata , Tatsuro Morisaki, Kazuo Yagita, Norio
Fukumori, Toshihiko Natsume, Wari Yamamoto.
Undergraduate Medical Education to foster primary care
physicians for the field of community medicine. Jpn J
Prim Care. 2009. 32：295-301.
10) Takao Wakabayashi, Yasushi Miyata, Masahiko Abe,
et.al. A case of lithium intoxication managed by general
physician. Family Medicine (Japan) . 2009. 15:26-30.
11) Minori Yamagami, Yasushi Miyata. A qualitative study on
general physicians’ negative emotions towards their
patients in a clinical setting. Family Medicine (Japan)
2009. 15:4-19.
12) Yasushi Miyata. An internet survey of physicians’ attitude
towards gifts from drug companies. Medical education
(Japan). 2009. 40:95-104.
92
Clinical Laboratory Medicine
Our department has been attempting to produce a high quality of
laboratory data in order to produce molecular and genetic diagnoses.
The mainstay to achieve our purposes is the development of new
methods and markers for biochemical, immunological, molecular and
genetic diagnoses for various cancers, infectious diseases and
hereditary diseases.
Professor
Assistant Professor
Instructor
Naoki Watanabe, M.D., Ph.D.
Satoshi Yuda, M.D., Ph.D.
Hiroyuki Onuma, M.D., Ph.D.
Interests:
Interests:
Interests:
Laboratory medicine, Oncology,
Laboratory medicine, Cardiology,
Gastroenterology, Ultrasonography
Hematology, Gastroenterology,
Ultrasonography
Maki Tanaka, D.D.S., Ph.D.
Molecular biology
Kageaki Kuribayashi, M.D., Ph.D.
Interests:
Interests:
Laboratory medicine
Infection control
Daisuke Kobayashi, M.D., Ph.D.
Interests:
Hematology, Gastroenterology,
Molecular biology
1. Cancer cell biology and molecular diagnosis for cancer
a) Analysis of survivin expression and its molecular function in
cancer cells.
Expression of the inhibitor-of-apoptosis protein (IAP)
family leading to suppression of apoptosis is thought to
contribute to carcinogenesis by several mechanisms,
including aberrant prolongation of the cellular lifespan, which
facilitates the accumulation of gene mutations and permits
growth factor-independent cell survival. Several proteins
involved in inhibition of apoptotic signaling have been
identified, including the bcl-2 family and IAP family. We have
focused on survivin, a member of the IAP family, and examined
its role in cancer cells. We found the following evidence: 1)
Expression of survivin mRNA was greater in tumors, including
those of the colon, breast and lung, than in paired nontumorous tissues. 2) Survivin blocked CDDP-, tamoxifen- or
radiation-induced apoptosis; 3) Survivin expression was
down-regulated by wild-type p53; 4) Survivin enhances Fas
ligand expression and human telomerase reverse
transcriptase by augmenting Sp1-mediated gene transcription.
These findings depict survivin as a multi- functional protein
that is important for cancer cell proliferation and indicate that
survivin is a good target molecule for cancer diagnosis and
treatment. Survivin was also found to be a target molecule in
dietary supplement-induced apoptosis of cancer cells.
b) Detection of autoantibodies against IAP family in patients
with cancer
We established the ELISA system for detection of the
anti-survivin and -livin antibody. By using this system we
made the following observations: 1) Positivity rates of sera
from patients with lung cancer for the anti-survivin antibody
and anti-livin antibody were 58% and 51%, respectively; 2)
Combining both antibodies increased the positivity ratio to
71.2%; 3) Positivity rates of sera from patients with gastrointestinal cancer for the anti-survivin antibody and anti-livin
antibody were 40% and 47%, respectively. In order to elevate
the positivity as a tumor marker, we are using the ELISA
system to detect the anti-IAP family antibodies, including antisurvivin, -livin, -XIAP, -cIAP-1 and -cIAP-2.
c) Development of a new approach for cancer treatment by
survivin targeting
It has been reported that down-regulation of survivin
induces apoptosis in various cancer cells. We also
demonstrated that introduction of the small inhibitory RNA
(siRNA) targeting survivin gene induced apoptosis in various
cancer cells, including those of the colon, breast and pancreas.
However, this approach may not be feasible in routine clinical
therapy for cancer unless a technique for efficiently introducing
survivin siRNA into cancer cells is established. Therefore,
development of a pharmacological approach targeting survivin
is warranted. We found that HMG-CoA reductase inhibitor
(HRI) down-regulated survivin expression by prevention of
93
phosphatidylinositol 3-kinase (PI 3-kinase) activation through
blocking of Ras isoprenylation, and induced apoptosis in
colon cancer cells. Since HRI are widely used to reduce
serum cholesterol and are tolerated well by patients with
hypercholesterolemia, HRI could be a new agent for cancer
treatment.
d) Finding new molecular targets for cancer diagnosis and
treatment
In addition to the IAP family, we are trying to find new
molecular targets for cancer diagnosis and treatment. We
demonstrated that mRNA expression of novel oncogene with
kinase-domain (NOK), a receptor protein tyrosine kinase, was
elevated in lung and breast cancer tissues (positivity, lung:
80%, breast: 67%). We also found that expression of
antiapoptotic molecule Olfactomedin 4 (OLFM4/GW112/
hGC−1) mRNA was up-regulated in colon, breast and lung
cancer tissues (positivity, colon: 68%, breast: 50%, lung:
62%). We also showed that expression of Beclin 1, an
important regulator of autophagy, was elevated in gastric
cancer tissues and down-regulation of Beclin 1 enhanced
CDDP-induced apoptosis via enhancing caspase-9 activity.
In addition, we found that key molecules for stem cell
renewal are up-regulated in various cancers.
2. Genetic analysis of infectious disease
a) Characterization of methicillin-resistant staphylococcus
aureus (MRSA)
MRSA is an important pathogen in healthcare associated
infection. It is important to analyze types of pathogens to
identify sources of infection and trace their routes. For
genotyping pulse-field gel electrophoresis (PFGE) has been
used. However, it is laborious, time consuming, expensive,
and requires special equipment. We analyzed the genotypes
of MRSA using multiple-locus variable-number tandem
repeats fingerprinting (MLVF) and made the following
observations: 1) MLVF classified 78 isolates into 28 subtypes;
2) 78 isolates were classified into 48 subtypes by a combination
of MLVF and PFGE. We are now analyzing the genotype of
multiple-drug-resistant pseudomonas aeruginosa (MDRP)
using MLVF.
b) Control of nosocomial norovirus infections
Norovirus is one of the major causes of acute
gastroenteritis worldwide. In particular, norovirus infections in
hospitals can be detrimental for young children and
immunocompromised hosts. Therefore, rapid diagnosis and
efforts to localize the disease are important tasks for a hospital
infection control team.
We are monitoring the excretion of norovirus of infected
individuals by real-time RT-PCR. The patients or infected
medical staff members are isolated or suspended until the
tests become negative. This protocol is effective in controlling
nosocomial norovirus infections.
1) Moriai R, Tsuji N, Moriai M, Kobayashi D, Watanabe N.
Survivin plays as a resistant factor against tamoxifen-
induced apoptosis in human breast cancer cells. Breast
Cancer Res Treat (2009)117:261-271.
2) Saeki M, Kobayashi D, Tsuji N, Kuribayashi K, Watanabe
N. Diagnostic importance of overexpression of Bmi-1
mRNA in early breast cancers. Int J Oncol (2009)35: 511515.
3) Nirasawa S, Kobayashi D, Tsuji N, Kuribayashi K,
Watanabe N. Diagnostic relevance of overexpressed
Nanog gene in early lung cancers. Oncol Rep (2009)22:
587-591.
4) Koshida S, Asanuma K, Kuribayashi K, Goto M, (Tsuji N),
Kobayashi D, Tanaka M, Watanabe N. Prevalence of
human anti-mouse antibodies (HAMAs) in routine
examinationns. Clin Chim Acta (2010)411: 391-394.
5) Yamada K, Tsuji N, Fujita T, Tanaka M, Kuribayashi K,
Kobayashi D, Watanabe N. Comparison of four direct
homogeneous methods for the measurement of lowdensity lipoprotein cholesterol. Clin Lab (2010)56: 327333.
6) Kobayashi D, Kuribayashi K, Watanabe N. SALL4 is
essential for cancer cell proliferation and is overexpressed
at early clinical stages in breast cancer. Int J Oncol
(2011)38: 933-939.
7) Furuya D, Kuribayashi K, Hosono Y, Tsuji N, Furuya M,
Miyazaki K, Watanabe N. Age, viral copy number, and
immunosuppressive therapy affect the duration of
norovirus RNA excretion in inpatients diagnosed with
norovirus infection. Jpn J Infect Dis (2011)64: 104-108.
8) Onoda C, Kuribayashi K, Nirasawa S, Tsuji N, Tanaka M,
Kobayashi D , Watanabe N. -)-Epigallocatechin-3-gallate
induces apoptosis in gastric cancer cell lines by downregulating survivin expression. Int J Oncol (2011) 38:
1403-1408.
9) Tanabe H, Kuribayashi K, Tsuji N, Tanaka M, Kobayashi
D, Watanabe N. Sesamin induces autophagy in colon
cancer cells by reducing tyrosine phosphorylation of
EphA1 and EphB2. Int J Oncol (2011)39: 33-40.
10) Goto M, Kuribayashi K, Takahashi Y, Kondoh T, Tanaka
M, Kobayashi D, Watanabe N. Identification of
autoantibodies expressed in acquired aplastic anaemia.
Br J Haematol (2013)160: 359-362.
11) Murai R, Yamada K, Tanaka M, Kuribayashi K, Kobayashi
D, Tsuji N, Watanabe N. Reconstructing a 3-dimensional
image of the results of antinuclear antibody testing by
indirect immunofluorescence. J Immunol Methods
(2013)387: 312-316.
12)Tanaka M, Kuribayashi K, Kogawa K, Nakamura K,
Watanabe N. Intracellular superoxide dismutase activity
defines invasiveness of the murine T – lymphoma cell
line L5187-ML25 in vitro and in vivo. Leukemia Res
(2013)37: 89-92.
94
Emergency Medicine
As the leading facility of the emergency medical center, our
department covers various aspects of severe, emergency and critical
care for patients from all hospitals in our prefecture as well as
emergency medical technicians. Our main specializations are
resuscitation using cardiopulmonary bypass, treatment of mild
hypothermia for post cardiac arrest syndrome, treatment of multiple
trauma, critical burn treatment and disaster medicine. We also
provide high-skilled treatment for stroke care and cardiovascular
intervention.
Professor
Cardiopulmonary resuscitation,
Instructor
Eichi Narimatsu, M.D., Ph.D.
Cardiovascular medicine,
Keisuke Harada, M.D., Ph.D.
Interests:
Coronary intervention
Kei Miyata, M.D.
Intensive care medicine,
Katsutoshi Tanno, M.D., Ph.D.
Shuji Uemura, M.D., Ph.D.
Anesthesiology, Neurophysiology
Interests:
Suguru Hirayama, M.D.
Emergency medicine,
Naofumi Bunya, M.D.
Emergency medicine,
Hideto Irifune, M.D., Ph.D.
Assistant Professor
Prehospital and disaster medicine
Mamoru Hase, M.D., Ph.D.
Interests:
Emergency medicine,
of human studies, to investigate some unrevealed neurological
1. Cardiopulmonary Cerebral Resuscitation
We
of
problems impairing severe critical care patients. Toxic
cardiopulmonary bypass (CPB) for out-of-hospital cardiac
mechanisms in intoxications of organophosphorus (OP)-
arrest patients for more than 20 years. Patients with cardiac
cholinesterase inhibitors and actions of their therapeutic
arrest who are refractory to conventional advanced cardiac
drugs in central and peripheral synaptic transmissions have
life support benefit from extracorporeal cardiopulmonary
not fully been investigated. We have revealed the intricate
resuscitation
have
been
investigating
the
usefulness
performed
influences of an OP-cholinesterase inhibitor (paraoxon) and
immediately after CPB induction. In cases of cardiopulmonary
detailed action of the therapeutic drugs (atropine and
arrest caused by acute myocardial infarction, CPB plays a
pralidoxime) on (central) hippocampal CA1-synaptic transmissions
major role during percutaneous coronary intervention. In our
(9) and (peripheral) neuromuscular transmissions (10) in rats
experience
(ECPR).
Mild
hypothermia
is
favorable
in vitro. Pathophysiological mechanisms in secondary brain
neurological recovery rates are 30% and 12%, respectively.
damage that deteriorate kinds of primary brain damages,
Immediate ECPR is considered a feasible and effective
especially in central synaptic transmission, have not
method of treating patients with OHCA (1-6). Our department
satisfactorily been investigated. We have clarified that
also provides high-skilled treatment for patients with severe
excessive glutamate, one of the main mechanisms eliciting
cardiovascular diseases in our coronary care unit (CCU) and
secondary brain damage, irreversibly impairs hippocampal
stroke care unit (SCU), which has enabled definitive
CA1-synaptic transmissions in rats in vitro (11).
with
ECPR,
total
survival
and
treatments following ECPR without delay (7,8).
3. Trauma Care
2. Experimental Neuroscience for Critical Care Medicine
Our department consists of a great variety of board
Advanced research is necessary for progress of critical
certified surgeons and emergency physicians. Immediate
care medicine; however, conducting detailed human studies
surgery is always available, including for multiple trauma,
investigating patho-physiology in severe critical care patients
digital or limb amputation. Emergency thoracotomies and
is often difficult because of their severe homeostatic
laparotomies are also feasible in our emergency room. We
conditions. We have been performing animal studies, instead
have equipped the emergency room with a mobile digital
95
subtraction angiography device, which enable us to make
arrest: A review of the Japanese literature. Resuscitation.
prompt diagnoses and perform emergency endovascular
2011 Jan; 82:10-4.
therapy, including stent-grafting for blunt aortic injury (12-14).
7) Miyata K, Mikami T, Asai Y, Iihoshi S, Mikuni N, Narimatsu
4. Burn Care
E. Subarachnoid Hemorrhage after Resuscitation from
We provide advanced treatment for burn patients. We are
Out-of-hospital Cardiac Arrest. J Stroke Cerebrovasc
able to use banked allograft and cultured autografts. We are
Dis. 2013; 13: 106-7.
actively using the Negative Pressure Wound Therapy for the
8) Miyata K, Mikami T, Mikuni N, Aisaka W, Irifune H,
purpose of enhance healing of burn wounds in patients with
Narimatsu E. Malignant Hemispheric Cerebral Infarction
extensive burns. We have conducted research on antibiotic-
Associated with Idiopathic Systemic Capillary Leak
resistance of bacteria infected with burn wounds (15).
5. Prehospital and Disaster Medicine
Syndrome. Case Rep Neurol 2013; 5: 175-82
9) Narimatsu E, Niiya T, Kawamata T, Kawamata M,
We routinely make the best use of air travel, especially
Yamakage M. Effects of atropine and pralidoxime on
utilizing helicopters, for severe patients from remote rural
neuronal actions of paraoxon in rat hippocampal slices.
hospitals. When a disaster arises, we dispatch the disaster
Neurosci Res 2010; 68: 276-84.
medical assistance team (DMAT) not only for triage or
10) Narimatsu E, Niiya T, Takahashi K, Yamauchi M,
treatment of victims, but also to manage other DMATs as a
Yamakage M. Pralidoxime inhibits paraoxon-induced
management support team. In addition, as the only key
depression of rocuronium-neuromuscular block in a time-
disaster hospital in Hokkaido we work closely with the Ministry
of Welfare and Labor to further our education and research.
dependent fashion. Am J Emerg Med. 2012; 30: 901-7.
11) Narimatsu E, Niiya T, Takada Y, Takahashi K, Yamauchi
M, Yamakage M. Blockers of adenosine A1, but not
muscarinic acetylcholine, receptors improve excessive
1) Sawamoto K, Tanno K, Takeyama Y, Asai Y. Successful
extracellular glutamate-induced synaptic depression.
treatment of severe accidental hypothermia with cardiac
arrest for a long time using cardiopulmonary bypass report of a case. Int J Emerg Med. 2012; 5: 9
2) Kouzu H, Hase M, Kokubu N, Nishida J, Kawamukai M,
Usami Y, Hirokawa N, Meguro M, Tsuchihashi K, Miura T,
Asai Y, Shimamoto K. Delayed visceral bleeding from
Neurosci Res. 2013; 75: 103-11.
12) Kurimoto Y, Asai Y, Nara S, Mori K, Hase M, Ohori S, Ito
T, Baba T, Kawaharada N, Higami T. Fenestrated stentgraft facilitates emergency endovascular therapy for
blunt aortic injury.J Trauma. 2009; 66: 974-8
13) Kurimoto Y, Watanabe A, Koyanagi T, Ito T, Higami T,
liver injury after cardiopulmonary resuscitation. J Emerg
Maekawa K, Tanno K, Asai Y. Video-Assisted Thoracic
Med 2012; 43: e245-e248
Surgery as a Less-Invasive Management for Acute
3) Maekawa K, Tanno K, Hase M, Mori K, Asai Y.
Extracorporeal cardiopulmonary resuscitation for patients
Hemothorax in Blunt Trauma. Surgical Science. 2012; 3:
136-40
with out-of-hospital cardiac arrest of cardiac origin: a
14) Kurimoto Y, Maekawa K, Tanno K, Mori K, Koyanagi T, Ito
propensity-matched study and predictor analysis.. Crit
T, Kawaharada N, Watanabe A, Higami T, Asai Y. Blind
Care Med. 2013; 41:1186-96
subxiphoid pericardiotomy to relieve critical acute
4) Soga T, Nagao K, Sawano H, Yokoyama H, Tahara Y,
Hase M, Otani T, Shirai S, Hazui H, Arimoto H, Kashiwase
hemopericardium a final report. Eur J Trauma Emerg
Surg. 2012; 38: 563 – 8
K, Kasaoka S, Motomura T, Kuroda Y, Yasuga Y,
15) Uemura S, Yokota S, Mizuno H, Sakawaki E, Sawamoto
Yonemoto N, Nonogi H. Neurological benefit of
K, Maekawa K, Tanno K, Mori K, Asai Y, Fujii N. Acquisition
therapeutic hypothermia following return of spontaneous
of a Transposon Encoding Extended-Spectrum β-Lactamase
circulation for out-of-hospital non-shockable cardiac
SHV-12 by Pseudomonas aeruginosa Isolates during the
arrest. Circ J 2012; 76: 2579-85
Clinical Course of a Burn Patient. Antimicrob Agents
5) Yokoyama H, Nagao K, Hase M, Tahara Y, Hazui H,
Arimoto H, Kashiwase K, Sawano H, Yasuga Y, Kuroda Y,
Kasaoka S, Shirai S, Yonemoto N, Nonogi H. Impact of
therapeutic hypothermia in the treatment of patients with
out-of-hospital cardiac arrest from the J-PULSE-HYPO
study registry. Circ J 2011; 75: 1063-70
6) Morimura N, Sakamoto T, Nagao K, Asai Y, Yokota H,
Tahara Y, Atsumi T, Nara S, Hase M. Extracorporeal
cardiopulmonary resuscitation for out-of-hospital cardiac
Chemother.2010; 54: 3956–9
96
Oral Surgery
Our department specializes in various diseases of the oral cavity and
our ultimate goal is to contribute to the improvement of patients’ oral
health. Our research consists mainly of oral oncology using molecular
biological and immunological approaches. We conduct clinical
research as well, focusing on jaw deformities, TMJ disorder,
maxillofacial trauma and dentoalveolar surgery. We are currently
discussing the need for scientific clarification regarding oral
environment maintenance and reconstruction of oral functions from
the perspective of patients’ quality of life.
Professor
Associate professor
Instructor
Hiroyoshi Hiratsuka, D.D.S., Ph.D.
Akihiro Miyazaki, D.D.S., Ph.D.
Yoshiki Miki, D.D.S., Ph.D.
Interests:
Interests:
Hironari Dehari, D.D.S., Ph.D.
Oral cancer, Jaw deformity
Oral cancer, Tumor immunology
Kazuhiro Ogi, D.D.S., Ph.D.
Jun-ichi Kobayashi, D.D.S., Ph.D.
Associate professor
Tomohiro Igarashi, D.D.S., Ph.D.
Itaru Nagai, D.D.S., Ph.D.
Interests:
Jaw deformity
1. Oral oncology
a) Molecular biology of oral cancer
Tumor hypoxia has a profound influence on the sensitivity
of cancer chemotherapy. We investigated the mechanism of
cisplatin (CDDP) resistance of oral squamous cell carcinoma
(OSCC) cells under hypoxia by analyzing gene expression
profiles to identify key genes and factors involved. We found
that glucose transporter protein-1 (GLUT-1) knockdown
induces cell death of OSCC. The results suggest that
knockdown of GLUT-1 inhibits sensitization of OSCC cells to
CDDP during hypoxia and that combining an anti-GLUT-1
strategy with CDDP shows promise toward improve cancer
treatment (1).
To clarify the functions of NF-κB in OSCC under hypoxia,
we examined the expression of NF-κB target genes by cDNA
plate assay analyses. We found that activation of NF-κB/p65
resulted in the proliferation of tumor cells under hypoxia, and
the function of NF-κB/p65 was more active in response to
hypoxia. The results suggest that the selective inhibition of
NF-κB activation may provide an effective approach for the
treatment of OSCC (2).
b) Tumor immunology of oral cancer
Survivin, an inhibitor of apoptosis protein (IAP), is
abundantly expressed in most malignancies, but is hardly
detectable in normal adult tissues. We reported that survivin
was an ideal cancer antigen, and that the survivin-2B peptide
could induce a cytotoxic T lymphocyte (CTL) response in the
context of HLA-A24. We performed clinical trials using the
peptide alone on patients with oral cancer (3). Results
indicated that the survivin-2B peptide vaccination was safe
and also showed therapeutic potential for inducing clinical
and immunological responses. We described a subsequent
clinical trial of the peptide administered in combination with
incomplete Freund’s adjuvant (IFA) and interferon (IFN)-α.
Results suggest that the survivn-2B peptide and IFA
vaccination in combination with IFN-α increased the frequency
of peptide specific CTL more effectively than the peptide
alone. This regimen may be useful as a new therapeutic
modality for patients with oral cancer.
Recent progress in cancer stem-like cell/cancer-initiating
cell (CSC/CIC) research indicates that CSCs are related to
metastasis. Aldehyde dehydrogenase 1 (ALDH1) and SRYrelated HMG-box gene 2 (SOX2) have recently been shown
to be putative CSC markers for several malignancies. To
determine the association of ALDH1 and SOX2 expression in
OSCC, we performed immunohistochemical staining. Results
indicated that high expression rates of ALDH1 and SOX2
diffuse staining patterns might be novel prediction markers for
OSCC lymph node metastasis (4). Furthermore, we isolated
OSCC CSCs/CICs by using the ALDEFLUOR assay. The
SPRR1B gene was expressed more highly in the ALDH1br
population than in the ALDH1low population and has a role in
OSCC cell growth by suppression of the tumor suppressor
RASSF4. Overexpression of SPRR1B might be related to
carcinogenesis of OSCC and maintenance of OSCC CICs/
CSCs (5).
97
Six-transmembrane epithelial antigen of the prostate 1
(STEAP1) is a novel cell surface protein overexpressed only
in the prostate among normal tissues and various types of
cancer. Due to its unique and restricted expression, STEAP1
is expected to be an attractive target for cancer therapy. We
showed that knockdown of STEAP1 in human cancer cells
caused the retardation of tumor growth compared with wild
type in vivo. In contrast, STEAP1 introduced in tumor cells
augmented the tumor growth compared with STEAP1
negative wild type cells. We demonstrated that STEAP1 is
involved in intercellular communication between tumor cells
and adjacent tumor stromal cells and therefore may play a
key role for the tumor growth in vivo. These data indicate the
inhibition of the STEAP1 function or expression can be a new
strategy for cancer therapy (6).
c) Case presentation
It is known that solid malignancies are rarely accompanied
by leukocytosis or other leukemoid symptoms, the
mechanisms of which are attributed to the production of
granulocyte colony-stimulating factor (G-CSF) by the tumor
cells themselves. We reported our experience in treating a
patient with a suspected G-CSF producing OSCC, which is a
rather rare entity (7).
2. Dentoalveolar surgery
We performed a retrospective study to assess the clinical
features of the inferior alveolar canal (IAC) using CT scan at
third molar surgery. We showed a significant relationship
between CT findings and inferioralveolar nerve (IAN) injury
during removal of the lower third molar (LM3). Radiographic
investigation of high-risk cases to assess cortication status
and shape of the IAC provides practical information about the
risk of IAN injury (8). Furthermore, we conducted a prospective
study to ascertain whether the shape of the IAC is a reliable
predictor for IAN injury during removal of the LM3. We showed
that cortication status and IAC shape can be considered
reliable predictors for IAN injury. Morphologic findings, such
as the presence of a dumbbell-shaped IAC, may be
reproducible predictive factors for IAN injury (9).
3. TMJ disorders
We examined 144 condyles from 78 cadavers to classify
the macroscopic shapes of the condyles into four types:
convex, flattened, angled and irregular. A convex macroscopic
form appears to be standard for human mandibular condyles.
On histological examination, we observed an increase in
cartilage cells and a decrease in cartilage cells. Increases in
cartilage cells were seen only in angled and irregular types,
whereas decreases in cartilage cells were only observed in
the flattened type. The histological findings suggest that
mandibular condyles tend to not only undergo flattening, but
also undergo progressive changes toward protrusion with age
due to increased numbers of cartilage cells. This study
suggests that there is potential for progressive alterations in
mandibular condyles in the elderly (10).
1) Shimanishi M, Ogi K, Sogabe Y, Kaneko T, Dehari H,
Miyazaki A, Hiratsuka H. Silencing of GLUT-1 inhibits
sensitization of oral cancer cells to cisplatin during
hypoxia. J Oral Pathol Med (2013) 42:382-388.
2) Anbo N, Ogi K, Sogabe Y, Shimanishi M, Kaneko T,
Dehari H, Miyazaki A, Hiratsuka H. Suppression of NFkB/p65 inhibits the proliferation in oral squamous cancer
cells. J Cancer Ther (2013) 4:891-897.
3) Miyazaki A, Kobayashi J, Torigoe T, Hirohashi Y,
Yamamoto T, Yamaguchi A, Asanuma H, Takahashi A,
Michifuri Y, Nakamori K, Nagai I, Sato N, Hiratsuka H.
Phase I clinical trial of survivin-derived peptide vaccine
therapy for patients with advanced or recurrent oral
cancer. Cancer Sci (2011) 102:324-329.
4) Michifuri Y, Hirohashi Y, Torigoe T, Miyazaki A, Kobayashi
J, Sasaki T, Fujino J, Asanuma H, Tamura Y, Nakamori K,
Hasegawa T, Hiratsuka H, Sato N. High expression of
ALDH1 and SOX2 diffuse staining pattern of oral
squamous cell carcinomas correlates to lymph node
metastasis. Pathol Int (2012) 62:684-689.
5) Michifuri Y, Hirohashi Y, Torigoe T, Miyazaki A, Fujino J,
Tamura Y, Tsukahara T, Kanaseki T, Kobayashi J, Sasaki
T, Takahashi A, Nakamori K, Yamaguchi A, Hiratsuka H,
Sato N. Small proline-rich protein-1B is overexpressed in
human oral squamous cell cancer stem-like cells and is
related to their growth through activation of MAP kinase
signal. Biochem Biophys Res Commun (2013) 439:96102.
6) Yamamoto T, Tamura Y, Kobayashi J, Kamiguchi K,
Hirohashi Y, Miyazaki A, Torigoe T, Asanuma H, Hiratsuka
H, Sato N. Six-transmembrane epithelial antigen of the
prostate-1 plays a role for in vivo tumor growth via
intercellular communication. Exp Cell Res (2013)
319:2617-26.
7) Kobayashi J, Miyazaki A, Yamamoto T, Nakamori K,
Suzuki R, Kaneko T, Suzuki N, Hiratsuka H. Granulocyte
colony-stimulating factor-producing squamous cell
carcinoma of the lower gingiva: a case report. Head Neck
Oncol (2012) 19:35.
8) Ueda M, Nakamori K, Shiratori K, Igarashi T, Sasaki T,
Anbo N, Kaneko T, Suzuki N, Dehari H, Sonoda T,
Hiratsuka H. Clinical significance of computed tomographic
assessment and anatomic features of the inferior alveolar
canal as risk factors for injury of the inferior alveolar
nerve at third molar surgery. J Oral Maxillofac Surg
(2012) 70:514-520.
9) Shiratori K, Nakamori K, Ueda M, Sonoda T, Dehari H.
Assessment of the shape of the inferior alveolar canal as
a marker for increased risk of injury to the inferior alveolar
nerve at third molar surgery: A prospective study. J Oral
Maxillofac Surg (2013) 71:2012-2019.
10) Nakai M, Abe M, Miyazaki A, Fujimiya M, Hiratsuka H.
Macroscopic and microscopic features of the mandibular
condyle in autopsied elderly individuals. Clin Anat (2013)
in press.
98
The aim of our research is to elucidate the nature and mechanisms
of cognitive dysfunction, chronic pain and disorders in various
aspects of human activities, and to develop appropriate rehabilitation
techniques to improve patients’ overall functioning. Since 2007, we
have participated as physiatrists in stem cell therapy clinical trials for
stroke.
Professor
Instructor
Masahiro Aoki, M.D.
Sumio Ishiai, M.D., Ph.D.
Megumi Toki, M.D., Ph.D.
Interests:
Interests:
Interests:
Sports rehabilitation
Neurological rehabilitation, Cognitive
Pediatric rehabilitation
dysfunction, Dementia
Yuji Hashimoto, M.D., Ph.D.
Assistant Professor
Interests:
Takanori Murakami, M.D., Ph.D.
Neurosurgical rehabilitation
Interests:
Chronic pain: neural mechanisms and
treatments
1. Rehabilitation for patients with cerebral infarction
spatial neglect in one or more of the subtests. From the
after transplantation of autologous human mesenchymal
“drawing a man or woman” subtest, 64 samples of face
stem cells
drawings were obtained in which both eyes were placed..The
We participated as physiatrists in Honmou et al.’s study
percentage deviation of the location of the eyes in the face
that was designed to assess feasibility and safety of the
outline was calculated for 46 face drawings without
transplantation of autologous human mesenchymal stem
discontinuity of the outline or severe distortion of the
cells in patients with cerebral infarction. During this study, we
construction. The percentage deviation of the location of the
looked for improvements that were distinguishable from usual
eyes was compared among the patients with neglect, right-
courses of rehabilitation. Improvements in motor function
hemisphere damaged patients without neglect and healthy
were found in rather small functional units, such as movements
control subjects. Compared with the other two groups, the
in one of the fingers, toes, or a single joint of an extremity.
patients with neglect placed the eyes with greater leftward
Brunnstrom stage may detect gross changes, while the more
deviation in the face outline. The percentage deviation of the
detailed scales were are necessary for assessment of
eyes was, however, not associated with neglect severity
recovery after transplantation of stem cells. In the investigator-
scored with the BIT conventional test. Forty-three percent of
initiated clinical trial of stem cell therapy for stroke, we plan to
the patients with neglect located the eyes leftward beyond the
include fine-grained evaluation methods and investigate the
normal range obtained from the performance of the healthy
most suitable technique of rehabilitation for patients after
subjects, while none of the patients without neglect showed
treatment.
such abnormal leftward deviation. The leftward deviation of
2. A new diagnostic measure for left unilateral spatial
the eyes in the face drawings suggests the presence but not
neglect: leftward deviation of eyes in human face drawing
the severity of left unilateral spatial neglect.
Patients with left unilateral spatial neglect draw a human
3. Rehabilitation approaches to unilateral spatial neglect
face more satisfactorily than other objects. The aim of our
The most important mechanism underlying unilateral
study was to examine the features of face drawings by
spatial neglect is a rightward bias of spatial attention following
patients with neglect and establish their meaning in the
right-hemisphere damage. Recent approaches have adopted
diagnosis of neglect. Sixty-four right-handed patients with a
unilateral sensory stimulation though the preserved route to
right hemisphere stroke underwent the conventional test of
improve neglect syndromes. Caloric stimulation, optokinetic
the Behavioral Inattention Test (BIT) and showed left unilateral
stimulation and neck muscle vibration have been reported to
99
improve neglect. However, the improvement was mostly
patient was followed for more than one year after onset. He
restricted to the duration when unilateral sensory stimulation
became able to walk with knee-ankle-foot-orthoses without
was given to patients. On the other hand, application of prism
assistance. A magnetic resonance image obtained one year
adaptation to patients with neglect has shown long-lasting
after the onset of paraplegia showed an atrophic spinal cord
improvement of their various neglect behaviors. A new visuo-
from T7-8 to the conus. The course of the neurologic findings
motor adaptation is induced while 50 to 100 reaching
and the imaging studies suggest that the pathogenesis of
movements are made with the index finger under the visual
surfer’s myelopathy may be ischemia of the anterior spinal
shift condition with prisms. Prism adaptation may modulate
artery territory induced by the abnormal trunk posture while
the cortical networks and produce some restoration of
surfing.
disordered space representation. However, the effect of prism
adaptation varies across patients and tasks, and the
List of Main Publications of from 2009 to 2013
improvement is not sufficient to recover wide aspects of
1) Seki R,Ishiai S,Seki K, Okada T. Leftward deviation of
activities of daily living. The traditional techniques and the
eyes in human face drawing: a new diagnostic measure
new approaches should be combined to improve daily
for left unilateral spatial neglect. J Neurol Sci (2010)
activities of individual patients.
297:66-70.
4. Differences between proximal and distal muscle
2) Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S,
activity of the lower limbs of community-dwelling women
Onodera R, Waxman SG, Kocsis JD.
during the 6-minute walk test
administration of auto serum-expanded autologous
Our study examined the change in the muscle activities
mesenchymal stem cells in stroke. Brain (2011)134:1790-
of the lower limbs during the 6-minute walk test to identify the
Intravenous
1807.
relationship between the change in muscle activity and
3) Ihira H, Shimada H, Suzukawa M, Furuna T, Matsuyama
physical performance of community-dwelling elderly women.
K, Ishiai S. Differences between Proximal and Distal
Twenty-three elderly women (mean age: 77.9 years) were
muscle activity of the lower limbs of community-dwelling
recruited from the community to participate. Their muscle
women during the 6-minute walk test. J Phys Ther
activities were recorded using surface electromyography of
Sci(2012) 24:205-209.
medialis,
4) Aoki M, Moriizumi S, Toki M, Murakami T, Ishiai S.
hamstrings, and gluteus medius. Additionally, muscle strength,
Rehabilitation and Long-Term Course of Nontraumatic
mobility, balance and 6-minute walking distance were
Myelopathy Associated with Surfing. Am J Phys Med
the
gastrocnemius,
tibialis
anterior,
vastus
measured. The decrease of electromyography activity during
Rehabil (2013)92:828-832
the 6-minute walk test was significantly greater in the
5) Ishiai S. Rehabilitation for patients with cerebral infarction
gastrocnemius and tibialis anterior than in the other muscles.
after transplantation of autologous human mesenchymal
The decrease of electromyography activity in the gastrocnemius
stem cells. Rinsho Shinkeigaku (2013)53:1177-1179
was correlated with the timed up-and-go time (r=-0.435) and
that of the tibialis anterior was correlated with the timed upand-go time (r=-0.530) and walking distance (r= 0.482). The
electromyogram activities of the gastrocnemius and the
tibialis anterior showed deterioration during the 6-minute walk
test, and they were correlated with gait performance. These
results suggest that muscle activity of the distal muscles plays
an important role in the walking ability of elderly women.
5. Rehabilitation and long-term course of nontraumatic
myelopathy associated with surfing.
A nontraumatic spinal cord injury related to surfing is
called surfer’s myelopathy. In our study, the case of a 26-yrold man who became paraplegic after surfing without apparent
traumatic events is described. A physical examination
revealed a spinal cord injury at T12 according to the American
Spinal Injury Association Impairment Scale A. The initial
magnetic resonance image revealed a fusiform swelling of the
spinal cord from T7-8 to the conus, which was hyperintense
on T2-weighted images. After six months of rehabilitation, the
100
5 Research institute for Frontier Medicine
Cell Science
～Research Institute for Frontier Medicine～
In 2013, we revised the name of our department from Biochemistry to
Cell Science in order to more precisely express our activities in
translational research using human basic cell biology. The analysis of
normal human cells is important for the mechanisms and therapy of
human diseases. Our department is working to elucidate the
pathological mechanisms of inflammation, allergy, virus-infection and
cancer using hTERT-transfected epithelial cells as a model of normal
epithelial cells. Additionally, we are working toward establishing
various types of drug delivery systems.
Professor
Associate Professor
Assistant Professor
Takashi Kojima, D.V.M., Ph.D.
Masahiko Taniguchi, Ph.D.
Takayuki Kohno, Ph.D.
Interests:
Interests:
Interests:
Cell biology,
Neural network formation,
Cell biology,
Culture system
Developmental biology
Molecular biology
1. Establishment of new culture system using normal
human epithelial cells
The introduction of the catalytic subunit of human
telomerase, human telomerase reverse transcriptase
(hTERT), into human somatic cells typically extends their life
span without altering their growth requirements, disturbance
of the cell-cycle checkpoints, tumorigenicity or chromosomal
abnormalities. We have established several hTERTtransfected human epithelial cells with an extended life span
including nasal, pancreatic duct, salivary gland duct and
uterus endometrial epithelial cells.
2. The pathological mechanisms and the prevention for
allergy and virus-infection in human nasal epithelial cells
The mucosal barrier of the upper respiratory tract
including the nasal cavity, which is the first site of exposure to
inhaled antigens, plays an important role in host defense in
terms of innate immunity. Various antigens are also sampled
and transported through the nasal mucosa while maintaining
the integrity of the barrier. The epithelial-derived thymic
stromal lymphopoietin (TSLP), IL-33 and IL-25, which are
master switches for allergic inflammatory diseases including
allergic rhinitis and respiratory virus-infection, affect the nasal
epithelial barrier with response of proinflammatory cytokine.
The human nasal epithelial barrier is also regulated via PPARγ
and distinct signal transduction pathways including PKC. By
using hTERT-human nasal epithelial cells, we are investigating
the pathological mechanisms of human diseases that affect
the nasal epithelial barrier and TSLP, and finding the inhibitory
agents. Furthermore, we have established a new drug delivery
system through the nasal epithelial cells.
3. The pathological mechanisms and the molecular
targeting therapy for pancreatic and uterus cancers
Pancreatic cancer is one of the most malignant diseases
in humans and there is an urgent need to develop novel
diagnostic and therapeutic strategies. Uterine endometrial
carcinoma is also one of the most common malignancies in
the female genital tract and the number of patients with this
disease has recently been growing rapidly due to increases in
life expectancy and obesity. The study of the relationship
between these cancers and obesity is being conducted using
the hTERT-human pancreatic duct or endometrial epithelial
cells.
In several human cancers, including pancreatic and
endometrial cancer, tight junction protein claudin-4, which is
the receptor of Clostridium perfringens enterotoxin (CPE), is
abnormally regulated and therefore promising molecular
targets for diagnosis and therapy using CPE. We indicate the
safety of CPE against normal epithelial cells using the hTERThuman pancreatic duct or endometrial epithelial cells.
More recently, the lipolysis-stimulated lipoprotein receptor
(LSR) has been identified as a novel molecular constituent of
tricellular contacts and is the receptor of Clostridium difficile
binary toxin (CDT). We investigate the role of LSR in the
carcinogenesis of pancreatic and uterine carcinoma and its
availability as a molecular target for therapy.
4. The pathological mechanisms and the therapy for
nonsyndromic deafness by tricellular contact proteins
LSR has two closely related proteins encoded in the
mammalian genome, immunoglobulin-like domain-containing
receptor (ILDR) 1 and ILDR2. ILDR1 is the causative gene for
familial nonsyndromic deafness and the mediated recruitment
of tricellulin is required for hearing. Notch signaling is inhibited
by a γ-secretase inhibitor selected for potency in stimulating
hair cell differentiation from inner ear stem cells. In our study,
we first investigate the role of LSR and tricellulin for
differentiation of mechanosensory hair cells using conditionally
immortalized cells that possess the potential to differentiate
into mechanosensory hair cells and the availability of
γ-secretase inhibitor against therapy of deafness by tricellular
contact proteins
5. The molecular functional analyses of semaphorin on
the neural network formation
During embryogenesis, axons reach their specific targets
correctly to form the complex neural network found in the
mature functional nervous system. The tip of the growing
axon, the growth cone, is specialized for reacting to
environmental cues during navigation. Several groups of
axon guidance molecules such as semaphorins, ephrins,
101
netrins and slits have been reported to repel or attract growing
axons that express their cognate receptors.
Semaphorins are secreted or transmembrane proteins
with a conserved sema domain of approximately 500 amino
acids, and are found in both vertebrates and invertebrates. To
date, more than 20 kinds of semaphorin genes have been
identified and semaphorin 3A (Sema3A) is the first semaphorin
to be identified in vertebrates on the basis of its ability to
induce the collapse of axonal growth cones of the dorsal root
ganglion (DRG). Sema3A-deficient mice showed a severe
abnormality in the axonal projection pattern in the peripheral
nervous system during embryogenesis. Neuropilins are
functional receptors for class 3 semaphorins and plexin-As
are co-receptors for class 3 semaphorins. Plexins are also
known as receptors for other types of semaphorins. Although
the function of semaphorins and their receptors (plexins and
neuropilins) was first acknowledged in the development of the
nervous system, these molecules are widely expressed both
inside and outside the nervous system. The involvement of
semaphorins and plexins in diverse biological processes,
such as the development of the nervous and cardiovascular
systems, the function of the immune system and pathological
processes such as tumor progression, has been extensively
reported. The main purpose of our study is the elucidation of
the molecular mechanism of semaphorins on the neural
network formation and higher brain function, such as learning
and memory. These studies are thought to be useful for
neurological disease therapy and nerve regenerative medicine.
6. The new roles of actin filaments and microtubules on
the cell surface of normal and cancer cells
Cytoskeleton assembly is instrumental in the regulation
of various biological functions. The actin filaments and
microtubules on the cell surface are important in the processes
of filopodia, lamellipodia and invadopodia. Using an EGFPlabeled probe and inhibitors of signaling transductions, we are
finding new roles of actin filaments and microtubules on the
cell surfaces in both normal and cancerous live cells.
1) Kojima T, Murata M, Yamamoto T, Lan M, Imamura M,
Son S, Takano K-i, Yamaguchi H, Ito T, Tanaka S, Chiba
H, Hirata K, Sawada N. Tight junction proteins and signal
transduction
pathways
in
hepatocytes.
Histol
Histopathol(2009)24: 1463-1472 .
enhances tight junction barrier function of human nasal
epithelial cells. Cell Tissue Res (2009) 338: 283-293.
3) Kabayama H, Nakamura T, Takeuchi M, Iwasaki H,
Taniguchi M, Tokushige N, Mikoshiba K. Ca2+ induces
macropinocytosis via F-actin depolymerization during
growth cone collapse. Mol Cell Neurosci(2009) 40: 2738.
4) Nakamura F, Ugajin K, Yamashita N, Okada T, Uchida Y,
Taniguchi M, Ohshima T, Goshima Y. Increased proximal
bifurcation of CA1 pyramidal apical dendrites in Sema3A
mutant mice. J Comp Neurol (2009)216: 360-375.
5) Yamaguchi H, Kojima T, Ito T, Kimura Y, Imamura M, Son
S, Koizumi J, Murata M, Nagayama M, Nobuoka T,
Tanaka S, Hirata K, Sawada N. Transcriptional control of
tight junction proteins via a protein kinase C signal
pathway in human telomerase reverse transcriptasetransfected human pancreatic duct epithelial cells. Am J
Pathol (2010)177: 698-712 .
6) Ogasawara N, Kojima T, Go M, Ohkuni T, Koizumi J,
Kamekura R, Masaki T, Murata M, Tanaka S, Fuchimoto
J, Himi T, Sawada N. PPARγ agonists upregulate the
barrier function of tight junctions via a PKC pathway in
human nasal epithelial cells. Pharmacol Res(2010) 61:
489-498.
7) Kohno T. Intercellular bridges for cell-cell communication.
Tumor Res.(2010) 45, 67-71
8) Takamatsu H, Takegahara N, Nakagawa Y, Tomura M,
Taniguchi M, Friedel RH, Rayburn H, Tessier-Lavigne M,
Yoshida Y, Okuno T, Mizui M, Kang S, Nojima S, Tsujimura
T, Nakatsuji Y, Katayama I, Toyofuku T, Kikutani H,
Kumanogoh A. Semaphorins guide the entry of dendritic
cells into the lymphatics via by activating myosin II.
Nature Immunol (2010)11: 594-600.
Sawada N. An NF-κB signaling pathway via PKCδ
regulates replication of respiratory syncytial virus in
polarized normal human nasal epithelial cells. Mol Biol
Cell(2011) 22: 1-13 .
10)Katsumi A, Kiyoi H, Abe A, Tanizaki R, Iwasaki T,
Kobayashi M, Matsushita T, Kaibuchi K, Senga T, Kojima
T, Kohno T, Hamaguchi M, Naoe T. FLT3/ITD regulates
leukaemia cell adhesion through α4β1 integrin and Pyk2
signalling. Eur J Haematol (2011)86, 191-198
11) Taniguchi M, Masuda T, Mikami Y, Kimura M, Yoshida T,
Mishina M, Shimizu T. Identification and characterization
of a novel zebrafish semaphorin.
Neurosci Lett
(2011)488: 215-220 .
12)Kabayama H, Takeuchi M, Taniguchi M, Kozaki S,
Mizutani A, Nakamura T, Mikoshiba K. Syntaxin 1B
suppresses macropinocytosis and Semaphorin 3A-induced
growth cone collapse. J Neurosci (2011)31: 7357-7364.
13)Kojima T, Sawada N. Regulation of tight junctions in
human normal pancreatic duct epithelial cells and cancer
cells. Ann N Y Acad Sci (2012)1257: 85-92.
14)Kojima T, Kyuno D, Sawada N. Targeting claudin-4 in
human pancreatic cancer. Expert Opinion on Therapeutic
Targets (2012)16: 881-887.
15)Hayashi M, Nakashima T, Taniguchi M, Kodama T,
Kumanogoh A, Takayanagi H.
Osteoprotection by
semaphorin 3A. Nature(2012) 485: 69-74 .
16)Masuda T, Sakuma C, Taniguchi M, Kanemoto A,
Yoshizawa M, Satomi K, Tanaka H, Takeuchi K, Ueda S,
Yaginuma H, Shiga T. Development of the dorsal ramus
of the spinal nerve in the chick embryo: A close
relationship between development and expression of
guidance cues. Brain Res (2012)1480: 30-40.
17)Kyuno D, Kojima T, Yamaguchi H, Ito T, Kimura Y,
Imamura M, Takasawa A, Murata M, Tanaka S, Hirata K,
Sawada N. Protein kinase Cα inhibitor protects against
downregulation of claudin-1 during epithelial-mesenchymal
transition of pancreatic cancer. Carcinogenesis (2013)34:
1232-1243 .
18) Obata K, Kojima T, Masaki T, Okabayashi T, Yokota S,
Hirakawa S, Nomura K, Takasawa A, Murata M, Tanaka
S, Fuchimoto J, Fujii N, Tsutsumi H, Himi T, Sawada N.
Curcumin prevents replication of respiratory syncytial
virus and the epithelial responses to it in human nasal
epithelial cells. Plos One (2013) 8: e70225.
19) Kojima T, Go M, Takano K, Kurose M, Ohkuni T, Koizumi
J, Kamekura R, Ogasawara N, Masaki T, Fuchimoto J,
Obata K, Hirakawa S, Nomura K, Keira T, Miyata R, Fujii
N, Tsutsumi H, Himi T, Sawada N. Regulation of tight
junctions in upper airway epithelium. Biomed Res Int
(2013) 947072 .
20) Masuda T, Taniguchi M, Sakuma C, Yamagishi T, Ueda S,
Kawaguchi M, Yaginuma H. Development of the dorsal
ramus of the spinal nerve in the mouse embryo:
Involvement of semaphorin 3A in dorsal muscle innervation.
Cong Anom (2013)53: 122-126 .
21) Kojima T, Ninomiya T, Konno T, Kohno T, Taniguchi M,
Sawada N. Expression of tricellulin in epithelail cells and
non-epithelial cells. Histol Histopathol (2013)1: e24894.
102
Medical Genome Sciences
Genome sequencing studies of cancer have revealed the genomic
landscapes of human cancer and have shown that the TP53 gene is
most frequently mutated in cancers among the human genes.
Our research interests are directed at the clarification of the molecular
mechanisms underlying p53 function and the understanding of the
p53 signal pathway involved in tumorigenesis. One of the major
goals is to guide the development of more effective approaches to
reducing cancer morbidity and mortality.
Professor
Associate Professor
Instructor
Takashi Tokino, Ph.D.
Yasushi Sasaki, M.D., Ph.D.
Masashi Idogawa, M.D., Ph.D.
Interest::
Interest::
Interest::
Molecular biology of human cancer,
Molecular mechanisms of human
Cancer bioinformatics and genomics,
Cancer genomics, Cancer genetics
carcinogenesis, Functional analysis of
Molecular mechanisms of cancer.
p53 family
1. Molecular genetics of human cancer
site located upstream of the E-cadherin gene. Our data
Cancer genome sequencings have revealed that genetic
suggest that FOXF1 and p53 form a portion of a regulatory
alterations are responsible for cancer. Studies in our laboratory
transcriptional network that appears to have an important role
by using a next-generation sequencer have identified a series
in cancer cell invasion and migration.
of genetic alterations which, in concert, convert a normal cell
CLCA2 was also induced by DNA damage in a p53-
to malignant one. These genetic alterations affect a specific
dependent manner. The p53 family proteins activate the
subset of oncogenes and tumor suppressor genes. The goal
CLCA2 promoter by binding directly to the conserved
of our current research include the following: (a) Identification
consensus p53-binding site present in the CLCA2 promoter.
of genes which, when mutated, contribute to human
In terms of function, ectopic expression of CLCA2 inhibited
tumorigenesis. (b) Delineation of the pathways through which
cancer cell migration. In contrast, silencing CLCA2 with siRNA
these genes function. (c) Development of targeted therapies
stimulated cancer cell migration and invasion. We also found
based on this knowledge. (d) Development of new diagnostic
that inactivation of CLCA2 enhanced the expression of focal
approaches based on the genes responsible for neoplasia.
adhesion kinase (FAK), as well as its promoter activation. A
2. p53 target genes involved in cancer cell migration and
small-molecule FAK inhibitor reduced the effect of CLCA2
invasion
siRNA on cell migration and invasion, suggesting that CLCA2
p53 is an established tumor suppressor that can activate
inhibits cancer cell migration and invasion through suppression
the transcription of multiple target genes. Recent evidence
of the FAK signaling pathway. Furthermore, there was an
suggests that p53 may contribute to the regulation of cell
inverse correlation between CLCA2 and FAK expression in
invasion and migration. We found that the forkhead box
251 human breast cancer tissues. These results strongly
transcription factor FOXF1 and the chloride channel
suggest that CLCA2 is involved in the p53 tumor suppressor
accessory-2 (CLCA2) are novel targets of the p53 gene.
network and has a significant effect on cell migration and
FOXF1 was induced upon DNA damage in a p53-
invasion.
dependent manner. Furthermore, we identified a response
3. p53 target non-coding RNAs
element located within the FOXF1 gene that is responsive to
p53 is inactivated in approximately half of human cancers.
wild-type p53, TAp73β and TAp63γ. The ectopic expression of
p53 family members execute various functions by modulating
FOXF1 inhibited cancer cell invasion and migration, whereas
transcriptional regulation. To identify direct transcriptional
the inactivation of FOXF1 stimulated cell invasion and
targets of p53 family members, we performed chromatin
migration. FOXF1 regulates the transcriptional activity of
immunoprecipitation with next-generation sequencing (ChIP-
E-cadherin (CDH1) by acting on its FOXF1 consensus binding
seq) and then searched for p53 binding motifs in the whole
103
human genome. Among the ChIP-seq peaks identified, only
M, Hosokawa M, Kusano M, Sabau SV, Tatsumi H, Imai
20.0% included a p53 motif, and approximately half were in
K, Shinomura Y, Tokino T: A novel method, digital genome
an intergenic region. Therefore, we assumed that large
scanning detects KRAS gene amplification in gastric
intergenic non-coding RNAs (lincRNAs) were major targets of
cancers: involvement of overexpressed wild-type KRAS
the p53 family. Recent reports have revealed that lincRNAs
in downstream signaling and cancer cell growth. BMC
play an important role in various biological and pathological
Cancer (2009) 9:198.
processes such as development, differentiation, stemness
5) Cheung AK, Ko JM, Lung HL, Chan KW, Stanbridge EJ,
and carcinogenesis. Through a combination of ChIP-seq and
Zabarovsky E, Tokino T, Kashima L, Suzuki T, Kwong DL,
in silico analyses, we found 22 lincRNAs that are upregulated
Chua D, Tsao SW, Lung ML: Cystein-rich intestinal
by the p53 family. Additionally, the knockdown of specific
protein 2 (CRIP2) acts as a repressor of NF-kB-mediated
lincRNAs modulated p53-induced apoptosis and promoted
proangiogenic
the transcription of a gene cluster. Our results suggest that
tumorigenesis and angiogenesis. Pros Natl Acad Sci
p53 family members and lincRNAs comprise a complex
USA (2011) 108: 8390-8395.
transcriptional network for various biological functions and
cytokine
transcription
to
suppress
tumor suppression.
M, Maruyama R, Kai M, Yamano H, Sasaki Y, Tokino T,
4. Designer microRNAs enhancing p53 therapeutic effect
Shinomura Y, Imai K, Toyota M: Genome-wide profiling of
Gene transfer involving p53 is viewed as a potentially
effective cancer therapy, but does not result in a good
microRNA genes in colorectal cancer. Cancer Res (2011)
therapeutic response in human cancers. We examined the
71: 5646-5658.
therapeutic effectiveness of a replication-deficient recombinant
7) Sasaki Y, Negishi H, Yokota I, Koyama R, Kusano M,
adenovirus (Ad-p53/miR-p21) that encoded co-cistronic p53
Suzuki H, Fujita M, Maruyama R, Toyota M, Saito T,
and artificial microRNAs (miRNAs) that targeted p21. We also
Tokino T: Negative regulation of hepatoma-derived
examined the therapeutic effectiveness of this vector in vitro
growth factor by p53. Cancer Res (2011) 71: 7038-7047.
and in vivo, and found that in colorectal and hepatocellular
8) Kashima L, Idogawa M, Mita H, Shitashige M, Yamada T,
carcinoma cells, infection with Ad-p53/miR-p21 augmented
Ogi K, Suzuki H, Toyota M, Sasaki Y, Tokino T: CHFR
apoptosis as compared to an adenovirus that expressed p53
protein regulates mitotic checkpoint by targeting PARP-1
alone (Ad-p53/miR-control). Ad-p53/miR-p21 also significantly
protein for ubiquitination and degradation. J Biol Chem
increased the chemosensitivity of cancer cells to doxorubicin.
(2012) 287: 12975-12984.
In a xenograft tumor model in nude mice, tumor volume was
9) Sasaki Y, Oshima Y, Koyama R, Tamura M, Kashima L,
significantly decreased following the direct injection of Ad-
Idogawa M, Yamashita T, Toyota M, Imai K, Shinomura Y,
p53/miR-p21 into the tumor, as compared to the injection of
Tokino T: A novel approach to cancer treatment using
Ad-p53/miR-control. Our results suggest that adenovirus-
structural hybrids of the p53 gene family. Cancer Gene
mediated transduction of p53 and p21-specific miRNAs may
Ther (2012) 19: 749-756.
be useful for gene therapy of human cancers.
10) Sasaki Y, Sugisaka J, Maruyama R, Sugisaka J, Tamura
M, Sugisaka J, Suzuki H, Idogawa M, Shinomura Y,
Tokino T: CLCA2, a target of the p53 family, negatively
1) Sasaki Y, Negishi H, Koyama R, Anbo N, Ohori K,
regulates cancer cell migration and invasion. Cancer
Idogawa M, Mita H, Toyota M, Imai K, Shinomura Y,
Tokino T: p53 family members regulate the expression of the
apolipoprotein D gene. J Biol Chem (2009) 284: 872-883.
2) Idogawa M, Sasaki Y, Suzuki H, Mita H, Imai K, Shinomura
Y, Tokino T: A single recombinant adenovirus expressing
Biol Ther (2012) 13: 1512-1521.
11) Ohashi T, Idogawa M, Sasaki Y, Suzuki H, Tokino T:
AKR1B10, a transcriptional target of p53, is downregulated
in colorectal cancers associated with poor prognosis.
Mol Cancer Res (2013) 11: 1554-1563.
p53 and p21-targeting artificial microRNAs efficiently
12) Tamura M, Sasaki Y, Koyama R, Takeda K, Idogawa M,
induces apoptosis in human cancer cells. Clinical
Tokino T: Forkhead transcription factor FOXF1 is a novel
Cancer Res (2009) 15: 3725-3732.
target of the p53 family and regulates cancer cell
3) Kashima L, Toyota M, Mita H, Suzuki H, Idogawa M, Ogi
migration and invasiveness. Oncogene (in press)
K, Sasaki Y, Tokino T: CHFR, a potential tumor suppressor,
13) Idogawa M, Ohashi T, Sasaki Y, Maruyama R, Kashima
downregulates interleukin-8 via inhibition of NF-kB.
L, Suzuki H, Tokino T: Identification and analysis of large
Oncogene (2009) 28: 2643-2653.
intergenic non-coding RNAs regulated by p53 fimily
4) Mita H, Toyota M, Aoki F, Akashi H, Maruyama R, Sasaki
Y, Suzuki H, Idogawa M, Kashima L, Yanagihara K, Fujita
members through a genome-wide analysis of p53 binding
sites. Hum Mol Genet (in press)
104
Tissue Development and Regeneration
We have focused our research on liver issues, i.e., its development,
stem/progenitor cells, regeneration and in vitro reconstruction of
hepatic tissues. Our research is mainly divided into 4 themes: 1) liver
development, particularly the biliary duct formation; 2) stem/
progenitor cells involved in normal and pathophysiological conditions
of livers; 3) cell transplantation for the treatment of liver diseases; 4)
in vitro reconstruction of hepatic tissues. To elucidate the unresolved
issues of each theme, we have conducted our research using
embryological, molecular biological and pathological methods. Our
approaches will lead to the development of new effective medicines
and treatments for intractable liver diseases and an artificial liver
device in which the reconstructed hepatic tissues are incorporated.
Professor
Assistant Professor
Instructor
Toshihiro Mitaka, M.D., Ph.D.,
Naoki Tanimizu, Ph.D.
Hiroshi Takeda, Ph.D.
Interests:
Interests:
Interests:
Hepatocytic regeneration, Hepatic
Hepatic stem cells, Liver
Cell adhesion
stem/progenitor cells, Liver
development, Epithelial
development, In vitro reconstruction
morphogenesis
of hepatic tissues.
1. Biliary duct formation
We are studying liver development by focusing on two
topics; one concerns the manners in which liver progenitor
cells differentiate and form 3-dimensional (3D) tissue
structures of bile ducts, and the other is in regard to how the
lineage plasticity of hepatocytes and cholangiocytes is
regulated during development and regeneration.
a) Formation of bile duct tubules
Epithelial tissue structures are indispensable for
physiological functions of each organ. In the liver, biliary
epithelial cells known as cholangiocytes form tubular
structures called bile ducts. The paucity of bile ducts and the
uncontrolled expansion of the ducts result in cholestasis and
polycystic disease, respectively. Therefore, it is important to
regulate the expansion of bile ducts and the proper size of the
lumen during liver development. By using the 3D culture
system of a liver progenitor cell line, HPPL, we are attempting
to understand the general mechanism regulating the formation
and maintenance of the luminal structures during
organogenesis. We have found that ECM proteins, in
particular laminin, are essential for liver progenitors to
establish apico-basal polarity and lumen formation (1).
Recently, we have identified genes specifically expressed in
cholangiocytes forming tubules. Among them, we found that a
transcription factor, grainyhead-like2 (Grhl2), regulates the
formation of the lumen by establishing a molecular network
among claudin 3, claudin 4 and Rab25 (2).
b) The lineage plasticity of liver epithelial cells
In an adult liver, three possible ways for epithelial cell
supply can be envisioned: self-duplication of mature
hepatocytes (MHs) and cholangiocytes, differentiation of
bipotential liver stem/progenitor cells (LPCs) and the lineage
conversion between MHs and cholangiocytes. To examine
lineage plasticity of cholangiocytes in different developmental
stages, we isolated EpCAM+ cholangiocytes from Glisson’s
capsule of neonatal and adult livers. We found that neonatal
but not adult cholangiocytes showed hepatocyte-like
morphology and expressed hepatocyte markers including
metabolic genes and CYPs by sequential treatment of
oncostatin M and Matrigel in vitro (3). We previously
demonstrated that Grhl2 consolidates the epithelial barrier
function of liver progenitors and thereby promotes
cholangiocyte-type morphogenesis. Interestingly, Grhl2 was
expressed in adult cholangiocytes more strongly than in
neonatal ones and overexpression of Grhl2 inhibited
hepatocytic differentiation of neonatal cells by suppressing
HNF4 and C/EBPα (3). Thus, Grhl2 is a key molecule that not
only regulates epithelial maturation of cholangiocytes but also
stabilizes its lineage.
2. Liver stem/progenitor cells and their capacity for
differentiation
It is well known that LPCs are activated when the
proliferation of MHs is inhibited by hepatotoxins. Of these
LPCs, oval cells and small hepatocytes (SHs) are well
recognized. We found that CD44 was specifically expressed
in cultured SHs and that the expression disappeared when
SHs matured (4). In galactosamine (GalN)-induced rat liver
injury, oval cells and SHs transiently appear in the initial
period of liver regeneration. To clarify the relationship between
those cells, isolated Thy1- and CD44-positive cells were used
105
as candidates for oval cells and SHs, respectively (5).
GeneChip analysis of the sorted cells and cultured Thy1+
cells suggested that hepatocytic differentiation progressed in
the order Thy1+ (GalN-D3), Thy1+ cell colony (Thy1-C) and
CD44+ (GalN-D4) cells. When Thy1+, Thy1-C and CD44+
cells were transplanted into retrorsine (Ret)/partial
hepatectomy (PH) rat livers, they could proliferate to form
hepatocytic foci in the recipient livers (6). At 30 days after
transplantation most cells forming the foci derived from
CD44+ cells possessed C/EBPα + nuclei, whereas only a few
cells derived from Thy1+ showed the positivity. When Thy1+
(GalN-D3) cells were cultured between collagen gels in a
medium with HGF+/Dex-/DMSO-, ducts/cysts consisting of
cholangiocytes appeared, whereas cells from CD44+ and
Thy1+ (GalN-D2) did not. These results suggest that the
commitment of Thy1+ cells to differentiate into hepatocytes or
cholangiocytes occurs between 2 and 3 days after GalN
treatment. Furthermore, some Thy1+ cells may differentiate
into hepatocytes via CD44+ SHs.
Although oval cells differentiate into hepatocytes through
SHs, the details of their differentiation process are not well
understood. In addition, it is not certain whether the induced
cells possess fully mature functions as MHs. Therefore, we
examined which factors could induce hepatic differentiation of
Thy1+ cells (7). EGF, basic FGF and/or HGF could trigger the
hepatocytic differentiation of the cells to form epithelial cell
colonies, and the combination of the factors stimulated the
emergence and expansion of the colonies. Cells in the Thy1+derived colonies grew more slowly than those in the CD44+derived ones in vitro and in vivo and the degree of their
hepatocytic differentiation increased with CD44 expression.
Although the induced hepatocytes derived from Thy1+ and
CD44+ cells showed similar morphology to MHs and formed
organoids from the colonies similar to those from SHs, many
hepatic differentiated functions of the induced hepatocytes
performed less well than those of mature SHs derived from
the normal liver. The results suggest that the degree of
maturation of the induced hepatocytes may not be equal to
that of normal resident ones.
3. Cell transplantation for liver diseases
Cell-based therapies as an alternative to liver
transplantation have been anticipated for the treatment of
potentially fatal liver diseases. Not only MHs but also LPCs
are considered as candidate cell sources. However, whether
the stem/progenitor cells have an advantage over MHs in
engrafting and repopulating the recipient liver has not been
comprehensively assessed. Therefore, to clarify the issue, we
transplanted Thy1+ and CD44+ cells isolated from GalNtreated DPPIV+-rat livers into the livers of DPPIV- rats with
Ret/PH (8). The growth of CD44+ cells was faster than that of
MHs until day 14. However, their repopulation efficiency in the
long term was very low, since the survival period of the
progenitor cells was much shorter than that of MHs. The short
life of the cells may be due to their replicative senescence. On
the other hand, the incorporation of sinusoidal endothelial
cells into foci and sinusoid formation were completed faster in
MH-derived foci than in CD44-derived ones. Thus, the survival
of donor cells may be closely related to not only early
integration into hepatic plates but also the differentiated state
of the cells at the time of transplantation.
Liver failure after liver resection for cirrhosis is a critical
problem, and no effective therapy other than liver
transplantation is presently available. To resolve this problem,
we examined whether hepatocyte transplantation (HT) could
reduce the post-standard liver resection mortality rate of rats
with non-alcoholic steatohepatitis (NASH)-related cirrhosis
(9). The DPPIV- recipient rats were fed a CDAA-diet for 12
weeks and were transplanted with DPPIV+ MHs 24 hours
before undergoing PH. Overall survival was significantly
longer in the HT group than in the non-HT group. Ultimately,
preoperative HT might improve the survival of rats with NASHrelated cirrhosis after PH by accelerating the growth of host
hepatocytes and preventing them from falling into apoptosis.
4. In vitro reconstruction of hepatic tissues
Development of a tissue-engineered liver is an ongoing
study for the future therapy of liver diseases. For this purpose,
it is important to reconstruct hepatic sinusoidal structures. We
investigated the role of hepatic stellate cells (HSCs) in the
sinusoid formation using SHs, HSCs and endothelial cells
(10). We clarified that quiescent stellate cells might regulate
the capillary formation of endothelial cells and maturation of
SHs.
1) Tanimizu N, Kikkawa Y, Mitaka T, Miyajima A. a1- and
a5-containing laminins regulate the development of bile
ducts via b1-intergrin signals. J Biol Chem, (2012)
287(34): 28586-28597
2) Senga K, Mostov K, Mitaka T, Miyajima A, Tanimizu N.
Grhl2 regulates epithelial morphogenesis by establishing
functional tight junctions through the organization of a
molecular network among claudin3, claudin4, and Rab25.
Mol Biol Cell, (2012) 23(15): 2845-2855
3) Tanimizu N, Nakamura Y, Ichinohe N, Mizuguchi T, Hirata
K, Mitaka T. Hepatic biliary epithelial cells acquire
epithelial integrity but lose plasticity to differentiate into
hepatocytes in vitro during development. J Cell Sci,
(2013) 126(22): 5239-5246
4) Mitaka T, Ooe H (Review). Drug Metabolism Reviews
focusing on drug transporter interactions in the liver:
Characterization of hepatic-organoid cultures. Drug
Metab Rev, (2010) 42(3): 472-481
5) Ichinohe N, Kon J, Mitaka T. Isolation of hepatic progenitor
cells from the galactosamine-treated rat liver. Methods
Mol Biol, (2012) 826:49-58
6) Kon J, Ichinohe N, Ooe H, Chen Q, Sasaki K, Mitaka T.
Thy1-positive cells have bipotential ability to differentiate
into hepatocytes and biliary epithelial cells in
galactosamine-induced rat liver regeneration. Am J
Pathol, (2009) 175(6): 2362-2371
7) Ichinohe N, Tanimizu N, Ooe H, Nakamura Y, Mizuguchi
T, Hirata K, Kon J, Mitaka T. Differentiation capacity of
hepatic
stem/progenitor
cells
isolated
from
D-galactosamine-treated rat livers. Hepatology, (2013)
57(3): 1192-1202
8) Ichinohe N, Kon J, Sasaki K, Nakamura Y, Ooe H,
Tanimizu N, Mitaka T. Growth ability and repopulation
efficiency of transplanted hepatic stem, progenitor cells,
and mature hepatocytes in retrorsine-treated rat livers.
Cell Transplant, (2012) 21(1): 11-22
9) Nakamura Y, Mizuguchi T, Tanimizu N, Ooe H, Ichinohe
N, Hirata K, Mitaka T. Preoperative hepatocyte
transplantation prevents cirrhotic rats from receiving the
fatal damage by a liver resection. Cell Transplant, in
press (2013)
10) Kasuya J, Sudo R, Mitaka T, Ikeda M, Tanishita K. Hepatic
stellate cell-mediated 3D tri-culture model of hepatocytes
and endothelial cells. Tissue Eng A, (2011) 17(3-4): 361-370
106
Molecular Medicine
Our research interests are directed at the elucidation of the molecular
mechanisms underlying disease and their applications for the better
treatment of patients. Various novel techniques of gene therapy and
regenerative medicine are developed and applied for clinical studies.
Instructor
Miki Yamaguchi, Ph.D.
Interests:
Cancer research
Hematopoietic stem cell
Transfusion medicine
1. Targeted drug delivery system (DDS) for cancer gene
therapy.
In order to determine cancer-targetable surface molecules,
we developed a unique assay system to screen monoclonal
antibodies (mAb), by utilizing a fiber-modified adenovirus with
a Z33 IgG-binding motif from Staphylococcal protein A. Mice
were immunized with various tumor cell lines, and hybridoma
libraries were prepared. After screening hundreds of
thousands of hybridomas, a total of 600 mAb was established.
In correspondence with these mAb, about 60 antigen (Ag)
molecules (without overlapping) were identified. Every targeting
mAb performed highly efficient and selective mAb-mediated
gene transductions of cancer cells. At present, there are many
applications for targeted cancer therapy using these supertargeting mAb (Staab) as DDS tools are widely open. For
example, our studies showed promising data concerning the
immunotoxins using these Staab for the treatment of cancer
patients. The DT- or PE-toxin conjugates of certain selected
Staab demonstrated remarkably augmented and specific
cytocidal activities, leading to a complete cancer cell death.
Quests for Ag/Ab sets to generate immunotoxins with a
superior performance indicate further promise.
2. Cancer-selective gene and drug delivery via monoclonal
antibodies (mAb)
For an effective therapy of advanced cancers, development
of cancer-selective gene and drug delivery methods is of
critical importance. We generated a fiber-modified adenoviral
vector, Adv-FdZ, which binds with the Fc portion of IgG,
resulting in a specific mAb-mediated infection through the
antigen (Ag) molecule. Since the FdZ vector lacked the CARbinding domain, the infection via CAR did not occur. We
established a number of mAb that achieved superb Agspecific gene transfers into cancer cells. In the presence of an
anti-EpCAM (CD326) mAb, AY12, the lacZ marker gene
transduction of HCT116 colon cancer cells was augmented
30-fold compared with the control IgG1. Various therapeutic
applications using these super-targeting mAb for cancerselective gene and drug delivery are promising. In this report,
we also report various immunotoxins, in which our mAb were
cross-linked with recombinant truncated protein toxins, e.g.,
diphtheria toxin (DT). Anti-EpCAM AY12 conjugated with DT
revealed a definite Ag-specific cytocidal effect on HCT116
cells. A selected group of molecules on the cancer surface
(including EpCAM) could be important candidates for the
treatment of advanced stage cancers.
3. EGFR-targeted selective gene therapy for non-small
cell lung cancer (NSCLC)
Therapeutic approach through virus-mediated gene
transfer is promising for cancer treatment. However,
transduction via adenoviral (Adv) vectors for normal and/or
malignant cells is neither efficient enough nor tissue-selective
for therapeutic applications. We developed a fiber-modified
Adv containing the Z33 motif from Staphylococcus protein A
(Adv-FZ33). Using an appropriate monoclonal antibody (mAb)
as a bridging tool between the FZ33 virus and target cell, the
gene transduction was highly augmented. We immunized
mice with NSCLC cell line NCI-H322, screened hybridoma
libraries by this Adv-FZ33 gene expression assay, and
established 73 hybridoma and respective mAb which revealed
extremely high transduction-increasing functions. One of the
mAb among these 73, designated AY13, recognized EGFR,
which had been recently studied as a candidate cancer
marker. EGFR was highly expressed on the cell surface of the
NSCLC cell line, i.e., NCI-H322, NCI-H2122, PC14, LCAM1
and LC2/ad. High EGFR expression was also observed in
several cell lines other than lung cancers, e.g., SKOV3
ovarian cancer, PK1 pancreatic cancer, OSC70 oral cancer
cells, U251 glioma, HCT116 colon cancer, PC3 prostate
cancer and A375 melanoma. EGFR was not expressed in
K562 myelogenous leukemia or RPMI8226 myeloma cells.
107
EGFR expression was not found in normal tissue cells
including red blood cells and platelets. By using AY13, as
high as 6.8-fold augmentation of Adv transduction efficiency
(compared with that seen in the control mAb P3) was
observed. The gene transfer was achieved in a mAb dosedependent manner, whose ED50 (at 1,000 vp/cell) was 0.16
ug of AY13/ml in our assay for the NSCLC cells (NCI-H322).
Highly augmented gene transduction was attained selectively
in EGFR-positive NSCLC cells, e.g., 47.3% for PC14 (1,000
vp/cell, AY13(10ug/mL)) and 32.5% for NCI-H322, while in the
absence of AY13 the efficiency was 5.8% for PC14 and 8.6%
for NCI-H322. Since this augmentation of gene transfer was
not only highly efficient but also strictly selective for EGFRpositive cancer cells, the method could be very promising for
therapeutic applications for NSCLC patients.
4. Generation of immunotoxins with super-targeting
mAb: superior antitumor activities with anti-TROP2 mAb
against NSCLC
We developed a unique screening system to establish
cancer-targetable antigens/antibodies sets, which utilizes a
fiber-modified adenovirus (Adv), Adv-FZ33, with a Z33 IgGbinding motif from Staphylococcal protein A. Mice were
immunized with NSCLC line NCI-H322, and hybridoma
libraries were prepared. In total, 73 mAb were obtained which
performed highly efficient and selective Adv- and IgGmediated gene transductions of NSCLC cells. By using these
super-targeting mAb, we generated various immunotoxins
conjugated with truncated diphtheria toxin (DT) or
Pseudomonas exotoxin A (PE). Toxin conjugates with antiTROP2 mAb showed highly augmented cytocidal activities
against all the NSCLC cells tested, leading to a complete cell
death. Cytotoxicities as revealed by a 72hr WST-1 assay
were present in 79.0%, 80.7% and 89.8% of the NCI-H322,
NCI-H2122 and PC14 cells, respectively. Immunotoxins using
selected super-targeting mAb could be promising for the
treatment of NSCLC patients, especially those with CNS and
meningeal metastatic involvement.
5. Generation of immunotoxins with super-targeting
mAb in the leukemia/lymphoma
We generated a recombinant fusion protein DT3C, which
contained the catalytic and translocation domain of the
truncated diphtheria toxin (DT) as well as the three IgGbinding C domains of Streptococcal protein G (3C). Fc of mAb
bound with DT3C, resulting in a mAb-DT3C complex (two
DT3C molecules conjugated with one IgG molecule). The
mAb-DT3C complex bound with the surface Ag, and was
followed by internalization and translocation into the
cytoplasm, leading to the cytocidal effect by protein synthesis
inhibition of DT. By using these, we developed a unique
screening system to establish cancer-targetable antigens/
antibodies sets. Mice were immunized with leukemia/
lymphoma cell lines (TF-1, KG1, MY, SKM1, TL-om1 and
CCRF-CEM), and hybridoma libraries were prepared. In total,
194 mAb clones were obtained which performed immunotoxin
cytocidal on AML cells. It could obtain a targeting antibody to
CD4, CD30, CD38, CD43, CD44, CD47, CD71, CD98hc,
CD107a, CD147, CD 317, MHC class I, MHC class II and
ICAM2. Our method provides an excellent way to obtain
superior Ag/Ab sets for targeted drug therapy.
1) Yamaguchi M, Fujihara M, Wakamoto S, Sakai H,
Takeoka S, Tsuchida E, Azuma H, Ikeda H. Influence of
hemoglobin vesicles, cellular-type artificial oxygen
carriers, on human umbilical cord blood hematopoietic
progenitor cells in vitro. J Biomed Mater Res A. 2009
Jan;88(1):34-42.
2) Huang J, Inoue M, Hasegawa M, Tomihara K, Tanaka T,
Chen J, Hamada H. Sendai viral vector mediated
angiopoietin-1 gene transfer for experimental ischemic
limb disease. Angiogenesis. 2009;12(3):243-9.
3) Yamaguchi M, Fujihara M, Wakamoto S, Sakai H,
Takeoka S, Tsuchida E, Hamada H, Azuma H, Ikeda H.
Biocompatibility study of hemoglobin vesicles, cellulartype artificial oxygen carriers, with human umbilical cord
hematopoietic stem/progenitor cells using an in vitro
expansion system. ASAIO J. 2009 May-Jun;55(3):200-5.
4) Sasaki M, Radtke C, Tan AM, Zhao P, Hamada H, Houkin
K, Honmou O, Kocsis JD. BDNF-hypersecreting human
mesenchymal stem cells promote functional recovery,
axonal sprouting, and protection of corticospinal neurons
after spinal cord injury. J Neurosci. 2009 Nov
25;29(47):14932-41.
5) Osaka M, Honmou O, Murakami T, Nonaka T, Houkin K,
Hamada H, Kocsis JD. Intravenous administration of
mesenchymal stem cells derived from bone marrow after
contusive spinal cord injury improves functional outcome.
Brain Res. 2010 Jul 9;1343:226-35.
6) Takenouchi M, Hirai S, Sakuragi N, Yagita H, Hamada H,
Kato K. Epigenetic modulation enhances the therapeutic
effect of anti-IL-13R(alpha)2 antibody in human
mesothelioma xenografts. Clin Cancer Res. 2011 May
1;17(9):2819-29.
7) Takahashi S, Kato K, Nakamura K, Nakano R, Kubota K,
Hamada H. Neural cell adhesion molecule 2 as a target
molecule for prostate and breast cancer gene therapy.
Cancer Sci. 2011 Apr;102(4):808-14.
8) Fujihara M, Azuma H, Ikeda H, Yamaguchi M, Hamada
H. Bone marrow stromal cell line promotes the
proliferation of mast cell progenitors derived from cord
blood CD34+ cells under serum-free conditions with a
combination of both cell-cell interaction and soluble
factors. Artif Cells Blood Substit Immobil Biotechnol. 2011
Apr;39(2):51-8.
9) Miki Yamaguchi, Kazunori Kato, Hirofumi Hamada
Kazuyasu Nakamura, Yoshiyuki Sugimoto, Tsuguo
Kubota, Masahiro Ikeda. Anti-trop-2 antibody. Patent
pending (EP 2594589 A1, US 20120237518 A1, WO
2011155579 A1. ) 2011 Jun/9
108
Biomedical Engineering
The mission of Biomedical Engineering is to combine engineering
with molecular and cellular biology to develop new approaches and
to foster research in the rapidly growing discipline.
Professor
Assistant Professor
Instructor
Yasuo Kokai, M.D., Ph.D.
Shin-ichi Imai, Ph.D.
Norio Takei, Ph.D.
Interests:
Interests:
Biomarker, Proteomics, Translational
Biomarker, Proteomics, Signal
Research
Transduction
To explore molecular targets for diagnosis and therapy,
also not fully established yet. It is apparent that study of
we employ a proteomic approach and genetic engineering of
peptidome (proteome with small molecular weight) is required
mouse embryo, in addition to molecular and cellular
to develop systems and strategies optimized for these
techniques. Using a variety of samples obtained from clinical
particular molecules. We have been working on developing
settings and experimental animal models, we are identifying a
such systems. We introduced and modified the SDS-PAGE
set of molecules useful for diagnosis and therapy. Our main
gel system containing various concentrations of urea. This gel
target for this study is proteomics of small polypeptides (2,000
system provides almost 1 pM sensitivity and good resolution
to 25,000 Da). Only limited information is available about
proteins with molecular weight between 1,000 to 30,000 Da.
these small polypeptides, though abundant polypeptides with
We are also engaged in setting up a new liquid chromatography
different classes are predicted in sera as well as in cell
system which combines reverse phase chromatography and
contents. These peptides are thought to be derived from
MALDI mass spectrometry. We hope to work with people
mostly post-translational modification of core proteins and
engaged in a wide range of clinical medicine. The system
others from the processing of large polypeptides by currently
described above is just beginning to work and must be
unknown mechanisms.
improved in many aspects.
2. Disease model of genetically engineered mice
1. Proteomics of small polypeptides
Genetic engineering of mouse embryo is powerful and
Polypeptides with small molecular weight have been
only one approach to obtain somatic information. We have
ignored for a long time, mainly due to technical limitations.
used this approach widely and have established transgenic
However, in sera for example, more than 100,000 peptides
technology. We have developed a number of genetically
actually reside with a very low concentration (at less than
altered mice with dominant positive and negative mutations.
zepto or even yocto mole). This condition indicates that there
Recently, an advance of RNA interference has opened up
is a huge amount of peptidome in sera. These peptides should
another paradigm in this field. We are currently trying to
provide a mirror of physiological and pathological conditions
develop a system with RNA interference technology. In an in
of the human body. To detect small amounts of polypeptide,
vitro system, we already achieved reasonable success and
we employed mass spectrometry that has been used by many
are now concentrating on how to manipulate gene expression
investigators. However, applications to explore molecular
in mice using RNA interference. Bone marrow transplantation
targets for diagnosis and therapy remain limited and are not
also gives us a strong route to modify cellular component of
highly established. Protein chemistry for small peptides is
mice in vivo. These approaches are useful not only in
109
modifying gene expression in vivo, but also gives us an
glial cells in the spinal cord of a model of lumbar
opportunity for studying whether molecules play a role in
radiculopathy. J Orthop Sci. (2011) 16:313–320.
disease process. In vivo study is of great convenience in that
6) Yamamoto M, Ota A, Hori T, Imai S, Sohma H, Suzuki N,
it is so straightforward in the study of pathological events and
Hatakeyama N, Inazawab N, Ito M-Y, Kimura H, Tsutsumi
useful in analyzing functions of a certain molecules relating to
H, Kokai Y. Early expression of plasma CCL8 closely
disease establishment.
correlates with survival rate of acute graft-versus-host
3. Ca2+-binding proteins and stress response in human
disease in mice. Exp Hematol. (2011) 39:1101-11112.
neurological disorder.
7) Oki G, Wada T, Iba K, Aiki H, Sasaki K, Imai S, Sohm H,
Loss of cellular Ca -homeostasis is the cause of cell
Matsumoto K, Yamaguchi M, Fujimiya M, Yamashita T,
damage in many diseases. An increase in cellular Ca2+
Kokai Y. Metalothionein deficiency in the injured
concentration induces alterations in the expression level of
peripheral nerves of complex regional pain syndrome as
several proteins. We have investigated the functional
revealed by proteomics. Pain. (2012) 153:532-539.
properties of annexin proteins, phospholipids and Ca2+-
8) Maeda N, Kokai Y, Hada T, Yoshida H, Mizushina Y. Oral
binding protein, whose expression levels increase with neural
administration of monogalactosyl diacylglycerol from
cell damage such as seen in alcohol dependence and
spinach inhibits colon tumor growth in mice. Exp Ther
Alzheimer's disease. We are continuing our study to further
Med. (2013) 5:17-22.
2+
investigate molecular markers for cell damage.
9) Sohma H, Imai S, Takei N, Honda H, Matsumoto K,
Evaluation of annexin A5 as a biomarker for Alzheimer's
1) Yamamoto M, Naishiro Y, Suzuki C, Kokai Y, Suzuki R,
disease and Dementia with Lewy bodies. Front Aging
Honda S, Abe T, Takahashi H, Shinomura Y. Proteomics
Neurosci. (2013) 5:15-23.
analysis in 28 patients with systemic IgG4-related
10) Sasaki K, Ohki G, Iba K, Kokai Y, Yamashita T, Wada
plasmacytic syndrome. Rheumatol Int. (2010) 30:565-
T. Innervation pattern at the undersurface of the extensor
568.
carpi radialis brevis tendon in recalcitrant tennis elbow. J
2) Yamaguchi M, Kokai Y, Imai S, Utusmi K, Matsumoto K,
Orthop Sci. (2013) 18:528-535.
11) Iwata K, Ikami K,Matsuno K,Yamashita T,Shiba D,Ibi M,
M-I, Kobayashi S, Hashimoto E, Saito T, Sohma H.
Matsumoto M, Katsuyama M, Cui W-H, Zhang J, Zhu K,
Investigation of Annexin A5 as a biomarker for Alzheimer's
Kokai Y, Takei N, Ohneda O, Yokoyama T, Yabe C-NY.
Deficiency of NOX1/NADPH oxidase leads to pulmonary
Neurosci Res. (2010) 88:2682-2692.
vascular remodeling. Arterioscler Thromb Vasc Biol. in
3) Hida T, Sohma H, Kokai Y, Kawakami A, Hirosaki K,
Okura M, Tosa N, YamashitaT, Jimbow K. Rab7 is a
critical mediator in vesicular transport of tyrosinaserelated protein 1 in melanocytes. J Dermatol. (2011)
38:432-441.
4) Kobayashi S, Tateno M, Woo T, Utsumi K, Sohma H, Ito
Y-M, Kokai Y, Saito T. Apolipoprotein E4 freauencies in
Japanese population with Alzheimer's disease and
dementia with Lewy bodies. PLoS ONE. (2011) 6:e18569.
5) Takahata S, Takebayashi T, Terasima Y, Tanimoto K,
Wada T, Sohma H, Kokai Y, Yamashita T. Activation of
press.
110
The Department of Neural Regenerative Medicine in the Research
Institute for Frontier Medicine at Sapporo Medical University is a
unique translational department devoted to developing innovative
treatments of neurological diseases with stem cell transplantation.
Our mission is to find seeds from basic research based on
neuroscience, conduct GCP-ICH regulated clinical trials for stroke,
spinal cord injury and other diseases, and to provide new therapies
for patients.
Professor and Chair
Assistant Professors
Osamu Honmou, M.D., Ph.D.
Masanori Sasaki, M.D., Ph.D.
Interests:
Interests:
Regeneration, Stroke, Stem cell
Neuroscience, Regeneration
Rie Onodera, Ph.D.
Interests:
Translational medicine
1. Overview
(CPC) under the Good Manufacture Practice (GMP) guidelines
The department of Neural Regenerative Medicine is a
which have much stricter regulations than conventional
translational department at Sapporo Medical University
universal academic laboratories. To guarantee high quality of
School of Medicine. The mission of our department is to
medicine, we examine our MSCs according to the GMP
improve the neural function of patients with neurological
controls.
diseases using stem cell transplantation and advance
3. Stroke
understanding of the therapeutic mechanism through the
We
integration of research, clinical practice and professional
transplantation of autologous human MSCs in 12 stroke
training.
patients and then reported on its feasibility and safety (4,10).
completed
the
Phase
I/II
clinical
study
of
We are currently proceeding with investigator initiated
Based on the positive results from this study, we are moving
trials (IIT, also called investigator sponsored trials) of stem cell
on to the Phase III investigator initiated clinical trial of
therapy for stroke (Phase III) and for spinal cord injury (Phase
autologous transplantation using MSCs cultured in a medium
II) using intravenous infusions of autologous mesenchymal
containing autologous serum on stroke patients under the
stem cells (MSCs) under the Good Clinical Practice (GCP)
GCP-ICH standards.
International Conference on Harmonization (ICH) standards.
We are also continuing various basic research projects
Our goal is to complete these trials and expand indications
for cellular transplantation to the rodent model of stroke in
based on the seeds from the basic research in our department.
order to elucidate therapeutic mechanisms of functional
2. Mesenchymal stem cells
recovery following intravenous administration of MSCs. Here,
Adult bone marrow-derived MSCs display a spectrum of
we are using a number of experimental techniques such as 7T
functional properties. We have been reporting how intravenous
Magnetic resonance imaging (MRI) for animals
transplantation of these cells improves disabilities in animal
immunohistological,
models of neurological disorders such as stroke, spinal cord
genetic and electrophysiological analyses.
behavioral,
molecular
and
biochemical,
injury via mechanisms that may include replacement of
4. Spinal cord injury
damaged cells, neuroprotective effects, induction of axonal
We have been presenting a number of studies of cellular
sprouting, and neovascularization. For our investigator
therapy providing functional recovery following experimental
initiated trials, we generate our standard operating procedures
spinal cord injury with Schwann cells, olfactory ensheathing
(SOPs) and produce the MSCs in the Cell Processing Center
cells, neural precursor/stem cells and MSCs derived from
111
adult bone marrow. We are especially focusing on how
Exp Neurol. (2011) 229: 88-98.
systemic delivery of MSCs results in therapeutic benefits in
8) Song CH, Honmou O, Furuoka H, Horiuchi M.
experimental spinal cord injury models in rodents. The
Identification of chemoattractive factors involved in the
availability of autologous MSCs in large numbers and the
migration of bone marrow-derived mesenchymal stem
potential for systemically delivering cells to target lesion areas
cells to brain lesions caused by prions. J Virol. (2011)
without neurosurgical intervention suggests the potential
85:1 1069-78.
utility of intravenous cell delivery as a prospective therapeutic
9) Matsushita T, Kibayashi T, Katayama T, Yamashita Y,
approach in acute and subacute spinal cord injury. Following
Suzuki S, Kawamata J, Honmou O, Minami M,
the initial Phase III investigator initiated trial for stroke, we
Shimohama S. Mesenchymal stem cells transmigrate
have just launched the Phase II clinical trial for spinal cord
across brain microvascular endothelial cell monolayers
injury of autologous human MSCs collaborating with clinical
through transiently formed inter-endothelial gaps.
departments at Sapporo Medical University.
Neurosci Lett. (2011) 502: 41-5.
5. Basic research projects
10) Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S,
In addition to the research projects for stroke and spinal
Onodera R, Waxman SG, Kocsis JD. Intravenous
cord injury, we are actively exploring other possibilities of the
administration of auto serum-expanded autologous
treatment for unmet medical needs to extend our therapeutic
mesenchymal stem cells in stroke. Brain. (2011) 134 (Pt
protocol using intravenous infusion of autologous human
6): 1790-807.
MSCs. Several collaborators and graduate students in our
11)Sasaki M, Lankford KL, Radtke C, Honmou O, Kocsis
medical school are extensively engaging in the basic research
JD. Remyelination after olfactory ensheathing cell
activities to test our hypotheses that our systematic infusion of
transplantation into diverse demyelinating environments.
MSCs has therapeutic efficacy for the animal models of
neurological diseases and striving to translate these into a
clinic in the near future.
Exp Neurol. (2011) 229: 88-98.
12) Osaka M, Honmou O, Murakami T, Nonaka T, Houkin K,
Hamada H, Kocsis JD. Intravenous administration of
mesenchymal stem cells derived from bone marrow after
contusive spinal cord injury improves functional outcome.
1) Lankford KL, Brown RJ, SasakiM, Kocsis JD. Olfactory
Brain Res. (2010) 1343: 226-35.
ensheathing cells, but not schwann cells, proliferate and
13) Sasaki M, Lankford KL, Brown RJ, Ruddle NH, Kocsis
migrate extensively within moderately X-Irradiated
JD. Focal experimental autoimmune encephalomyelitis
juvenile rat brain. Glia. (2014) 62: 52-63.
in the Lewis rat induced by immunization with myelin
2) Suzuki J, Sasaki M, Harada K, Bando M, Kataoka Y,
oligodendrocyte glycoprotein and intraspinal injection of
Onodera R, Mikami T, Wanibuchi M, Mikuni N, Kocsis
vascular endothelial growth factor. Glia. (2010) 58: 1523-
JD, Honmou O. Bilateral cortical hyperactivity detected
31.
by fMRI associates with improved motor function following
14) Komatsu K, Honmou O, Suzuki J, Houkin K, Hamada H,
intravenous infusion of mesenchymal stem cells in a rat
Kocsis JD. Therapeutic time window of mesenchymal
stroke model. Brain Res. (2013) 1497:15-22.
stem cells derived from bone marrow after cerebral
3) Kocsis JD, Honmou O. Bone marrow stem cells in
ischemia. Brain Res. (2010) 1334:84-92.
experimental stroke. Prog Brain Res. (2012) 201:79-98.
15) Sasaki M, Radtke C, Tan AM, Zhao P, Hamada H, Houkin
4) Honmou O, Onodera R, Sasaki M, Waxman SG, Kocsis
K, Honmou O, Kocsis JD. BDNF-hypersecreting human
JD. Mesenchymal stem cells: therapeutic outlook for
mesenchymal stem cells promote functional recovery,
stroke. Trends Mol Med. (2012) 18: 292-7.
axonal sprouting, and protection of corticospinal neurons
5) Sasaki M, Honmou O, Radtke C, Kocsis JD. Development
after spinal cord injury. J Neurosci. (2009) 29: 14932-41.
of a middle cerebral artery occlusion model in the
16)Markakis EA, Sasaki M, Lankford KL, Kocsis JD.
nonhuman primate and a safety study of i.v. infusion of
Convergence of cells from the progenitor fraction of adult
human mesenchymal stem cells. PLoS One. (2011) 6 :
olfactory bulb tissue to remyelinating glia in demyelinating
e26577.
spinal cord lesions. PLoS One. (2009) 4: e7260.
6) Radtke C, Sasaki M, Lankford KL, Gallo V, Kocsis JD.
CNPase expression in olfactory ensheathing cells. J
Biomed Biotechnol. (2011) : 608496.
7)Sasaki M, Lankford KL, Radtke C, Honmou O, Kocsis
JD. Remyelination after olfactory ensheathing cell
transplantation into diverse demyelinating environments.
112
Human Immunology
The immune system is crucial to human health, and dysregulation of
it underlies various pathological conditions, including allergy,
autoimmune diseases and cancer. Thus, understanding precisely
how the human immune system works at the cellular, genetic and
molecular levels is essential in the development of new modalities for
such immune-related disorders. To this end, this department was
established in May 2013. The scope of our research activities covers
studies of immunoregulatory mechanisms in order to develop clinical
applications.
Professor
Instructor
Shingo Ichimiya, M.D., Ph.D.
Ryuta Kamekura, M.D., Ph.D.
Interests:
Interests:
Immunology, Pathology, Oncology
Immunology, Otolaryngology, Oncology
1. Medical biology of lymphoid tissues and cells
Lymphocytes play essential roles in immune responses,
and peripheral lymphoid tissues harbor lymphocytes and a
variety of other cells. We previously established a monoclonal
antibody panel to identify specific functions of individual cells.
As assessed by immunoprecipitation and subsequent mass
spectrometric analyses, we identified the L22 antigen
preferentially expressed in non-activated B cells as
arachidonate 5-lipoxygenase (ALOX5), which is responsible
for the production of leukotrienes (1). When we examined
Alox5-gene-deficient mice, the mice normally possessed
natural antibodies except for Th1-type IgG2a, but had lost
specific antibody responses. These phenomena are probably
attributed to the dependence on ALOX5-related innate lipid
+
mediators during differentiation of naïve CD4 T cells into
effector helper T-cell subsets, including Th1 cells and follicular
helper T (Tfh) cells. Our observations were in accordance with
the recent implication of intermediate Th1/Tfh cells in their
development.
Obstructive sleep apnea (OSA) is a prevalent sleep
disorder characterized by partial or complete intermittent
obstruction of the upper airway during sleep. Accumulating
evidence suggests that 25-75% of OSA cases show serious
morbidities like cardiovascular dysfunction, hypertension and
ischemic stroke as well as neurocognitive and behavioral
disturbances. It is well recognized that OSA tonsils feature
lymphoid hyperplasia, but the immune settings of OSA tonsils
causing such histopathology remains unknown. We recently
examined a role of germinal-center-type T follicular helper
hi
cells (GC-Tfh cells, CXCR5 ) in lymphoid hyperplasia of OSA
tonsils. Results demonstrated that when comparing the age,
sex and body mass index (BMI)-matched groups of OSA and
recurrent tonsillitis (RT) patients, OSA tonsils contained 2.6
times more GC-Tfh cells of RT tonsils (P<0.001). Moreover, in
vitro experiments implied the functional importance of T-cell
immunoglobulin and the ITIM domain (TIGIT), as a negative
regulator preferentially expressed on GC-Tfh cells, which
controls the activity of B cell subsets surrounding GC-Tfh cells
in OSA tonsils.
In addition to analysis of lymphocytes in peripheral
lymphoid tissues, we are also interested in the mechanism of
+
developing CD4 T cells in the human thymus, which results
in the vast divergence of T-cell receptors to fully establish the
functional immune system. The autoimmune regulator (AIRE),
primarily discovered by pedigree analysis of a certain
autoimmune disorder, binds to p63 in epithelial cells of the
thymic medulla to regulate the surface levels of HLA class II
molecules (2). TSLP, which was originally discovered in
studies of the thymus, has a pivotal function in T-cell
development. It not only has a role in thymic selection, but
also preserves the integrity of peripheral immune tissues by
regulating stromal and dendritic antigen-presenting cells
(3,4). We have further characterized immature thymic T cells
by the expression of nonclassical class I molecules such as
HLA-E and CD1D. In this way, we hope to understand the
regulatory and developmental logic of lymphocytes in relation
to the functioning immune system and diseases.
2. Medical biology of epiimmunome
Epithelial tissues providing external and internal
interfaces act as the first line of host defense against various
pathogens, comprising a functional ‘epiimmunome.’ Their
functional alterations may result in increases in the
predisposition for infection, myriad inflammatory diseases
and cancer. Intercellular adhesive properties of epithelial
113
tissues ensure their identities in terms of formation of a barrier
as well as a scaffolding network for immunosurveillance by
antigen-presenting cells and lymphocytes, especially under
the innate stimuli sensed by TLR3 (5,6). Functional loss of
adhesive properties of epithelial tissues also influences
cellular responsiveness to inflammation and tissue repair, in
which effector cytokines and immune cells take part
sequentially. In this situation, downregulation of desmoglein-2
leads to phosphorylation and internalization of EGFR and
downstream extracellular signal-regulated kinase activation,
thereby promoting proliferation of intestinal epithelial cells (7).
Internalization of EGFR is also accompanied by endosomal
sorting by sorting nexin (SNX) family members. During a
study of the role of SNX5 in the regulation of EGFR, we found
that immunohistochemical examination of SNX5 was
particularly useful to diagnose thyrocyte-derived papillary
thyroid carcinoma, and that SNX5 regulates the levels of
expression of caspase 2 (8).
3. Approaches to study immune-related disorders
Immunology is essentially the study of complex biological
processes, as described above with regard to our research
foci, where both innate and acquired immunity are considered
and sometimes intersect with other concepts of life sciences.
Investigation of clinical specimens, including blood samples
and surgical tissues, can reveal direct evidence underlying
the pathogenesis of immune-related disorders. For instance,
juvenile dermatomyositis (JDM), an autoimmune disorder,
often shows complications such as pulmonary involvement
manifesting interstitial inflammation and diffuse alveolar
damage (DAD). Although the precise mechanism underlying
JDM is still elusive, an autoantibody against MDA5 of a DExD/
H-box-containing RNA helicase was detected at high levels in
the serum of a case of JDM with DAD (9). This implies that an
unusual acquired immune response against a molecule
engaging in innate immunity occurs in JDM. In addition to
autoimmune disorders, we are focusing on allergic diseases
like atopic dermatitis and allergic rhinitis, now widely
considered to be a national issue due to their increasing
prevalence (10).
Finally, we believe that basic knowledge and laboratory
experience will vigorously support immunological studies and
facilitate productive investigations. It is widely acknowledged
that histopathologic and cellular examinations of human
tissues of surgical specimens help to elucidate disease
orientations (11). Thus, our department lies at the intersection
of fundamental molecular and cellular sciences and clinical
research. This field provides diverse research opportunities
and will concomitantly lead to promising discoveries in human
immunology.
1) Nagashima T, Ichimiya S, Kikuchi T, Saito Y, Matsumiya
H, Ara S, Koshiba S, Zhang J, Hatate C, Tonooka A,
Kubo T, Ye RC, Hirose B, Shirasaki H, Izumi T, Takami T,
Himi T, Sato N. Arachidonate 5-lipoxygenase establishes
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
adaptive humoral immunity by controlling primary B cells
and their cognate T-cell help. Am J Pathol. (2011) 178:
222-232.
Tonooka A, Kubo T, Ichimiya S, Tamura Y, Ilmarinen T,
Ulmanen I, Kimura S, Yokoyama S, Takano Y, Kikuchi T,
Sato N. Wild-type AIRE cooperates with p63 in HLA class
II expression of medullary thymic stromal cells. Biochem
Biophys Res Commun. (2009) 379: 765-770.
Kamekura R, Kojima T, Takashima A, Koizumi J,
Ogasawara N, Go M, Takano K, Murata M, Tanaka S,
Ichimiya S, Himi T, Sawada N. Thymic stromal
lymphopoietin induces tight junction protein claudin-7 via
NF-kappaB in dendritic cells. Histochem Cell Biol. (2010)
133: 339-348.
Kamekura R, Kojima T, Koizumi J, Ogasawara N, Kurose
enhances tight-junction barrier function of human nasal
epithelial cells. Cell Tissue Res. (2009) 338: 283-293.
Ohkuni T, Kojima T, Ogasawara N, Masaki T, Fuchimoto
J, Kamekura R, Koizumi J, Ichimiya S, Murata M, Tanaka
S, Himi T, Sawada N. Poly(I:C) reduces expression of
JAM-A and induces secretion of IL-8 and TNF-α via
distinct NF-κB pathways in human nasal epithelial cells.
Toxicol Appl Pharmacol. (2011) 250: 29-38.
Ogasawara N, Kojima T, Go M, Fuchimoto J, Kamekura
R, Koizumi J, Ohkuni T, Masaki T, Murata M, Tanaka S,
Ichimiya S, Himi T, Sawada N. Induction of JAM-A during
differentiation of human THP-1 dendritic cells. Biochem
Biophys Res Commun. (2009) 389: 543-549.
Kamekura R, Kolegraff KN, Nava P, Hilgarth RS, Feng M,
Parkos CA, Nusrat A. Loss of the desmosomal cadherin
desmoglein-2 suppresses colon cancer cell proliferation
through EGFR signaling. Oncogene. (2013) in press.
Ara S, Kikuchi T, Matsumiya H, Kojima T, Kubo T, Ye RC,
Sato A, Kon S, Honma T, Asakura K, Hasegawa T, Himi T,
Sato N, Ichimiya S. Sorting nexin 5 of a new diagnostic
marker of papillary thyroid carcinoma regulates
caspase-2. Cancer Sci. (2012) 103: 1356-1362.
Sakurai N, Nagai K, Tsutsumi H, Ichimiya S. AntiCADM-140 antibody-positive juvenile dermatomyositis
with rapidly progressive interstitial lung disease and
cardiac involvement. J Rheumatol. (2011) 38: 963-934.
Kamekura R, Kojima T, Takano K, Go M, Sawada N, Himi
T. The role of IL-33 and its receptor ST2 in human nasal
epithelium with allergic rhinitis. Clin Exp Allergy. (2012)
42: 218-228.
Sugimoto K, Takasawa A, Ichimiya S, Murata M, Kimura
H, Aoyama T, Gille JJ, Kuroda N, Shimizu H, Hasegawa
T, Sawada N, Furuya M, Nagashima Y. Multifocal and
microscopic chromophobe renal cell carcinomatous
lesions associated with ‘capsulomas’ without FCLN gene
abnormality. Pathol Int. (2013) 63: 510-515.
114
6 Animal Research Center
Animal Research Center
The mechanisms of infectious diseases are the main focus of our
studies. The diseases and microorganisms studied are gastritis
induced by Helicobacter pylori, Lyme disease caused by various
Borrelia species, Leptospirosis, enterohemorrhagic Escherichia coli
and periodontal diseases. Toward that end, gene targeting as well as
transgenic animals are being studied in our research center.
Professor and Director (Affiliated)
Associate Professor
Yoshiyuki HORIO, M.D., Ph.D.
Hiroshi Isogai, D.V.M., Ph.D.
Interests:
Interests:
Aging, Protein deacetylase, Resveratrol, Heart failure,
Infectious disease, Microbiology, Experimental Animal
Muscular dystrophy
Science
1. Prof. Horio’s research and publication list appears on
examined for antibodies and nucleic acid from Borrelia by dot
Pharmacology page
blot and PCR methods. The results helped clinicians to
2. Innate Immunity
diagnose this disease in patients (2).
Animals, including human beings, have various traits that
4. E. coli O157
play protective roles against infectious microorganisms.
The lethal factors of entero hemorrhagic Escherichia coli
Cationic antimicrobial protein (CAP18) is one of the
O157; H7 (EHEC) have been studied. Our study showed that
antimicrobial proteins released from epithelial cells and
gnotobiotic mice infected with EHEC could be a useful animal
neutrophils. It exhibits strong bactericidal activity to pathogenic
model for the disease. The studies demonstrated that TNF
bacteria such as entero-hemorrhagic E. coli. Recently, we
released from intestinal tissues after infection was significantly
investigated the possibility that CAP18 exerts cytotoxic activity
related to damage of the tissues. Furthermore, this infection
against tumor cells. Interestingly, we found that CAP18 was
and tissue damage could be inhibited by pre-inoculation of
cytotoxic only to tumor cells. These results suggested that
catechins from Japanese green tea to the mice. The results
CAP18 could be used for not only prevention of infectious
indicated that the pre-inoculation or pre-treatment of catechins
diseases, but also for therapy and the prevention of tumors
was applicable to human. Because catechins can inhibit
(5-8).
bacterial growth in intestines, antibiotic treatment can be
3. Lyme disease
effective when EHEC infection occurs (3,10).
The pathogenesis and epidemiological status of Lyme
5. Oral microbial infection
disease have been studied. The studies demonstrated that
Black-pigmented Porphyromonas originating from oral
several cytokines and other biological factors affected the
cavities has been studied. Porphyromonas from animals was
pathogenesis of Lyme disease. The effects of TNF antagonists
different from that from humans. In our study, many black-
were evaluated in experimental animal studies. Our studies
pigmented Porphyromonas were isolated from the plaque of
also investigated the association of other factors, including
dogs and cats. These were examined for their biological
Interleukin-1 and interleukin-6 in the pathogenesis of Lyme
characteristics. Our study demonstrated that some strains
disease.
isolated from animals were new species (14).
Serological studies demonstrated the incidence of Lyme
6. H. pylori and disase
disease in Hokkaido and the relation of Lyme disease Borrelia
The relation between Helicobacter pylori and other
to patients with neural symptoms. About 1000 serum and
bacterial flora has been investigated using experimental mice
cerebrospinal fluid samples from patients clinically diagnosed
inoculated with H. pylori. H. pylori can grow in the stomach
with Lyme disease were accumulated. These samples were
when there is enough time for colonization. Bacterial growth
115
was easier in the stomach of germ free mice than in that of
5) Takagi S, Hayashi S, Takahashi K, Isogai H, Bai L,
microbiologically non-controlled mice. H. pylori was able to
Yoneyama H, Ando T, Ito K, Isogai E.
colonize in other tissues or organs when these existed in a
activity of a bovine myeloid antimicrobial peptide (BMAP-
microbiologically free environment. These findings indicated
28)
that H. pylori has an ability to colonize on the epithelial
resistant Staphylococcus aureus. Anim Sci J. (2012) 83,
surface. Moreover, bacterial flora on the surface of the
epithelium is effective for colonization of H. pylori.
against
methicillin-susceptible
and
Antimicrobial
methicillin-
482-486 doi: 0.1111/j.1740-0929.2011.00979.x.
6) Kuroda K, Fukuda T, Yoneyama H, Katayama M, Isogai
Additionally, we have studied the relation of Heat Shock
H, Okumura K, and Isogai E. Anti-proliferative effect of
Proteins (HSP) to tissue damage caused by H. pylori. The
the analogue peptide of human cathelicidin (hCAP18/LL-
study demonstrated that sera from patients with gastritis or
37) for the colon cancer derived cell line, HCT116 p53+/+
gastric ulcers showed high antibody titers to HSP. The results
and p53-/-, Oncology Reports, (2012), 28: 829-834
indicated that HSP and anti-HSP antibodies were associated
7) Kuroda K, Fukuda T, Okumura K, Yoneyama H, Isogai H,
with tissue destruction in the stomach of patients infected with
Savage PB, Isogai E. Ceragenin CSA-13 induces cell
this organism.
cycle arrest and anti-proliferative effects in wild-type and
7. Leptospirosis
p53 null mutant HCT116 colon cancer cells, Anti-Cancer
The
component
of
Leptospiral
lipopolysaccharide
associated with antigen determination has not been clarified.
Drugs, (2013) 24 (8) 826-834 doi: 10.1097/CAD. 0b013e
328362edc5
Our study demonstrated that a repeating unit structure
8) Takagi S, Nishimura J, Bai L, Miyagi H, Kuroda K,
including mannose was the component that determined
Hayashi S, Yoneyama H, Ando T, Isogai H, Isogai E.
antigenicity of lipopolysaccharide from Leptospira. Furthermore,
Susceptibility difference between methicillin-susceptible
our study showed that the structure was distributed widely
and methicillin-resistant Staphylococcus aureus to a
among many microorganisms, especially fungi. It is possible
bovine myeloid antimicrobial peptide (BMAP-28), Animal
that the structure can be used for vaccination against
Science Journal, (2013) doi: 10.1111/asj.12098,
9) Isogai E, Kino Y, Abe Y, Yamashiro H, Shinoda H, Fukuda
leptospirosis.
T, Fukumoto M, Kuroda K, Yoneyama H, Isogai H, Sekine
T. Distribution of radioactive cesium in Ostrich (Strutho
1) Isogai H, Mulu A, Diro E, Tekleselassie H, Kassu A,
camelus) after the Fukushima Daiichi Nuclear Power
Kimura K, Nishikawa T, Isogai E, Identification of Candida
Plant Accident. Radiation Emergency Medicine, (2013) 2
species from human immunodeficiency virus-infected
(2), 68-71,
patients in Ethiopia by combination of CHROMagar,
10)Kuroda K, Suzuki R, Ihara K, Miyagi H, Watanabe H,
Tobacco agar and PCR of amplified internally transcribed
Sato K, Hang’ombe BM, Charles Mubita, Isogai N,
rRNA spacer region. J Appl Res, (2010) 10 (1), 2-8,
Mulenga E, Moonga L, Isogai H, Fukuda T, Yoneyama H,
Isogai H, Okumura K, Hori H, Tsuruta H,
Isogai E. Detection of pathogenic genes of Escherichia
Kurebayashi Y. Tertiary structure-related activity of tick
coli and Salmonella spp. from fecal samples of Kafue
defensin (persulcatusin) in the taiga tick, Ixodes
lechwe (Kobus leche kafuensis) and pastoral cattle in the
persulcatus.
interface areas of Zambia. African J Microbiol Res ( 2013)
2) Isogai E,
Exp Appl Acar, (2011) 53, 71-77, doi:
0.1007/s10493-010-9379-3
7 (6), 504-508, (review)
3) Hang’ombe BM, Ulaya W, Mwansa JCL, Mubita C, Isogai
N, Mulenga E, Moonga L, Isogai H, Isogai E. Feasibility
of using dot blot hybridization to detect Salmonella InvA,
SpiC and SipC from clinical specimens.
African J
Microbiol Res (2011) 5(6), 582-585,
4) Nuguyen SV, Icatolo Jr FC, Nakano T, Isogai E, Hirose K,
Mizugai H, Kobayashi-Sakamoto M, Isogai H, Chiba I.
Anti-cell-associated glucosyltransferase immunoglobulin
Y suppression of salivary mutans streptococci in healthy
young adults. J Am Dent Assoc (2011) 142(8) 943-949
116
B SCHOOL OF HEALTH SCIENCES
1 Nursing
Medical and Behavioral Subjects
Our section’s staff is in charge of teaching health sciences, social
medicine and basic and clinical medicine to students of nursing,
physical therapy and occupational therapy. Research activities of
our staff members focus primarily on epidemiology of cancer (Y.N.),
and clinical epidemiology including metabolic cardiology (S.S.).
Professor
Assistant Professor
Shigeyuki Saitoh, M.D., Ph.D.
Yoshie Nagata, M.P., Ph.D.
Interests:
Interests:
Clinical epidemiology,
Epidemiology of prostate cancer
Metabolic cardiology
1. Epidemiological study on prostate cancer
Recently, there have been reports on an increased
prevalence of obese males Japan. If a link between obesity
and risk of prostate cancer could be ascertained, it would
suggest that the recent trend of increased prostate cancer
incidences in Japan has been brought about by this increased
prevalence of obese males. We investigated a case-control
study to assess the risk factors of prostate cancer with special
reference to dietary habits, obesity and family history of
cancer. Larger weight gain in adult age was significantly
associated with an increased risk of cancer (P for trend=0.041).
Moreover, a history of prostate cancer in fathers or brothers
was significantly associated with increased risk (OR=9.71,
95%CI 3.59, 26.27), as was a history of breast cancer in
mothers or sisters (OR=2.70, 95%CI 1.12, 6.49) (1).
Isoflavones contained in soy products are well-known
prevention factors in several hormone-dependent cancers
such as prostate cancer or breast cancer. On isoflavone in
particular, Equol, is believed to have a stronger protective
effect than daidzein against prostate cancer. Intestinal
bacterial flora converted to equol has been reported in a vitro
human fecal culture (2).
2. Stress and salivary alpha-amylase activity
Salivary alpha-amylase is one of the major salivary
enzymes in humans, and is secreted from the salivary glands
in response to sympathetic stimulation. It has been proposed
as an indicator for stress-induced activity of the sympathetic
nervous system.
We determined whether there are any
associations between salivary alpha-amylase activity and
lifestyles or stress-related characteristics. The salivary alphaamylase activity levels were significantly higher in males than
in females (P<0.01) and higher in subjects aged 50 years or
older than in subjects younger than 50 (P<0.01). Using
multiple linear regression analysis, scores regarding positive
stress-coping behavior and social support from relatives or
friends against stress were inversely correlated to salivary
alpha-amylase activity after being adjusted for sex and age
(P=0.02 and P=0.03, respectively). Our findings suggest that
better stress coping and social support may reduce the
psychological response to stress, as observed by the
decrease in salivary alpha amylase activity levels (3).
In a separate study, we measured salivary alpha-amylase
activity and state anxiety levels in undergraduate students
before and after fragrance inhalation of essential oils (sweet
orange oil and peppermint oil). Salivary alpha-amylase activity
levels were utilized to assess the sympathetic nervous activity.
Our research suggested that sweet orange essential oil has a
relaxation effect (4).
3. Epidemiological studies on metabolic and cardiovascular
diseases
In collaboration with the department of Internal Medicine
(II) and Public Health at Sapporo Medical University, we have
been conducting a cohort study in two towns in Hokkaido,
Japan (Tanno-Sobetsu Study) for over 35 years. We have
reported considerable data concerning relationships between
various lifestyle-related diseases and occurrence of
cardiovascular and metabolic diseases (5,7,8,9,11). Recent
results of studies are described below.
The effects of parental hypertension on longitudinal
trends of blood pressure and metabolic parameters were
examined by a mixed-effects model analysis (8). The
mechanism underlying the association of parental
hypertension with cardiovascular events in offspring remains
unclear. From 1977 to 2006, 5,198 subjects participated in the
Tanno-Sobetsu Study, and we selected 2,607 subjects (1,095
men and 1,512 women) for whom data on parental history of
hypertension were available. In both men and women with
and without parental hypertension, systolic blood pressure
117
and fasting blood glucose levels consistently increased from
the third to eighth decades of life, whereas diastolic blood
pressure and serum triglyceride levels followed biphasic
(inverted U shape) time courses during that period. However,
the relationships between the parameters and age were
significantly shifted upward (by approximately 5.3 mm Hg in
systolic blood pressure, 2.8 mm Hg in diastolic blood pressure,
0.30 mmol/L in blood glucose and 0.09 mmol/L in triglyceride)
in the group with parental hypertension compared with those
in the group without parental hypertension. Both paternal and
maternal histories of hypertension were determinants of
systolic blood pressure and diastolic blood pressure, and
there was no significant interaction between the sides of
parental history. There were no significant effects of parental
hypertension on age-dependent or body mass indexdependent changes in serum low-density lipoprotein
cholesterol or high-density lipoprotein cholesterol levels. The
present results indicate that parental hypertension has an
age-independent impact on elevation of blood pressure,
plasma glucose and triglyceride levels, which may underlie
the reported increase in cardiovascular events.
Glucagon-like peptide-1 (GLP-1) is important peptide
related to diabetes. GLP-1’s roles in extra-pancreatic tissues
remain unclear. The possible contribution of GLP-1 to blood
pressure (BP) regulation was examined (11). We recruited
128 subjects who received annual examinations and 75g-oral
glucose tolerance tests (OGTT) in the cohort. Age, plasma
glucose (PG), hemoglobin A1c (HbA1c), plasma insulin and
serum lipids were not selected as independent determinants
of fasting GLP-1 level by multiple linear regression analysis.
However, age and female sex were selected as independent
positive determinants of the area under the curve of GLP-1
level during OGTT (AUCGLP-1), an index of GLP-1 secretory
function. Multiple linear regression analysis indicated that
AUCGLP-1 was an independent negative predictor of systolic
BP (SBP). In subgroup analyses using the median of AUCGLP-1
to divide the study subjects into high and low GLP-1 response
groups, AUCGLP-1 was significantly correlated with both SBP
and diastolic BP (r=0.40 and 0.28, respectively) in the low
GLP-1 response group. These results suggest that GLP-1
secretory function is involved in prevention of BP elevation
and that the GLP-1 response to oral glucose rather increases
with aging perhaps as an adaptive phenomenon.
In addition to the above epidemiological studies, we
participate in domestic collaborative investigations such as
NIPPON DATA (National Integrated Project for Prospective
Observation of Non-communicable Disease and Its Trends in
the Aged) (10) and JALS (Japan Arteriosclerosis Longitudinal
Study) (6).
1) Mori M, Masumori N, Fukuta F, Nagata Y, Sonoda T,
Miyanaga N, Akaza H, Tsukamoto T. Weight gain and
family history of prostate or breast cancers as risk factors
for prostate cancer: results of a case-control study in
Japan. Asian Pacific J Cancer Prev (2011)12: 743-747.
2) Sugiyama Y, Masumori N, Fukuta F, Yoneta A, Hida T,
Yamashita T, Minatoya M, Nagata Y, Mori M, Tsuji H,
Akaza H, Tsukamoto T. Influence of isoflavone intake and
equol-producing intestinal flora on prostate cancer risk.
Asian Pac J Cancer Prev (2013)14: 1-4.
3) Nagata Y, Sakauchi F, Izumi H, Shang E, Ohnishi H, Mori
M. Association between salivary alpha-amylase activity
and stress-related characteristics. Sapporo Med J (2011)
80: 15-22.
4) Nagata Y, Miyashita Y, Mori M. The influence of olfactory
stimulation by essential oils on salivary alpha-amylase
activity and state anxiety level.
Japanese J of
Complementary and Alternative Medicine (2013)10(1):
39-43.
5) Akasaka H, Katsuya T, Saitoh S, Sugimoto K, Ohnishi H,
Congrain A, Ohishi M, Rakugi H, Ogihara T, Shimamoto
K. A promoter polymorphism of Lamin A/C gene is an
independ genetic predisposition to arterial stiffness in
Japanese
general
population.
J
Atheroscler
Thromb(2009)16: 404-409
6) Japan Arteriosclerosis Longitudinal Study (JALS) Group.
Four blood pressure indexes and the risk of stroke and
myocardial infarction in Japanese men and women: a
meta-analysis of 16 cohort studies. Circulation.(2009)
119: 1892-1898
7) Chiba M, Saitoh S, Ohnishi H, Akasaka H, Mitsumata K,
Furukawa T, Shimamoto K. Associations of metabolic
factors, especially serum retinol binding protein 4
(RBP4), with blood pressure in Japanese. Endocrine
Journal (2010) 57: 811-817.
8) Misumata K, Saitoh S, Akasaka H, Mitsumata K, Ohnishi
H, Akasaka H, Miura T. Effects of hypertension on
longitudinal trends in blood pressure and plasma
metabolic profile:
Mixed-effects model analysis.
Hypertens (2012) 60: 1124- 1130
9) Furugen M, Saitoh S, Ohnishi H, Akasaka H, Mitsumata
K, Chiba M, Furukawa T, Miyazaki Y, Shimamoto K,
Miura T. Matsuda-DeFronzo insulin sensitivity index is a
better predictor than HOMA-IR of hypertension in
Japanese: the Tanno-Sobetsu study. J Hum Hypertens
(2012) 26: 325-333
10) NIPPON DATA 90 Research group. HbA1c and the Risks
for All-Cause and Cardiovascular Mortality in the General
Japanese Population.
NIPPON DATA90. Diabetes
Care(2013)36:3759-3765
11) Yoshihara M, Akasaka H, Ohnishi H, Miki T, Furukawa T,
Saitoh S, Miura T. Glucagon-Like Peptide-1 Secretory
Function as an Independent Determinant of Blood
Pressure: Analysis in the Tanno-Sobetsu Study. PLoS
ONE (2013) 8(7): e67578. doi: 10. 1371/journal. pone.
0067578.
118
Fundamental and Adult Nursing
This division is composed of two parts: fundamental nursing and
adult nursing. Research projects in this division involve both basic
research and clinical investigations. Basic research deals with
nursing education and focuses on nursing technology, nursing ethics
and health education. Likewise, clinical research deals with crisis
intervention, chronic care nursing and critical care nursing. Some of
our projects are collaborative studies with researchers in other
departments and/or colleges.
Professors
Associate Professors
Assistant Professor
Terumi Ohinata, R.N., Ph.D.
Masako Momma, R.N., M.S.N.
Migiwa Nakata, R.N., P.H.N., M. S.
M.S.N.
Interests:
Interests:
Interests:
Critical care nursing, Stress and
Chronic illness trajectory
Nursing technology,
nursing
Masuko Sumikawa, R.N., P.H.N., Ph.D.
Nursing education, Nursing ethics
Masami Horiguchi, R.N., P.H.N., M.S.N.
Interests:
Mizue Shiromaru, R.N., Ph.D.
Interests:
Nursing science for lifestyle-related
Interests:
Stress and health, Nursing ethics,
diseases
Cancer care nursing,
Nursing education
Erika Shudo, R.N., P.H.N., M.S.N.
Critical care nursing
Kumiko Sato, R.N., P.H.D.
Interests:
Interests:
Nursing technology
Nursing history, Nursing education
Instructor
Natsuko Nakai, R.N., H.N.,
1. Education in nursing technologies and ethics
research was the initiation of a study aimed at building a
We examine nursing education strategies for enabling
foundation for nursing ethics. We are also examining
nursing students to acquire basic abilities in nursing practice.
educational programs that focus on the development of social
Our particular concern is to develop strategies to inculcate
and historical cognitive abilities, which are a part of the
ability in both nursing health assessment and ethical
educational contents of the nursing ethics curriculum (2).
judgments. Toward this end, we have edited a textbook on
2. Eating behaviors and stress
health assessment for beginners (Health Assessment in
Allostatic load refers to the cumulative effects of chronic
Nursing, Medical-Friend Company, 2011, in Japanese). In
stress. The aim of this study was to analyze the allostatic load
one
strategies of hand-washing
index and eating behaviors. The participants included healthy
education for nursing students. The purpose of this study was
study,
we
examined
young women, who were divided into a lean group, standard
to obtain pointers for hand-washing training in basic nursing
group, and standard body mass index (BMI) obesity group.
education. The subjects were university nursing students who
The mean of allostatic load index score in the standard BMI
received hand-washing education. We observed and analyzed
obesity group was higher than that in the lean group. There
their scrubbing actions when they washed their hands and
was a significant difference in the eating behavior scores of
fingers to determine if they were being properly washed.
the lean and standard BMI obesity groups. These findings
Results suggested that repeated practice would help to
suggest that women in the standard BMI obesity group
prevent the students from forgetting their hand-washing
experience more stress during their daily lives and have more
education (1).
unhealthy eating behaviors than women in the other two
Under a scientific research grant from the Ministry of
groups (3).
Education, Culture, Sports, Science and Technology, we have
3. Nursing History
also carried out didactic research on the development of
Nursing education in Japan today is progressing towards
nursing students’ ethical judgments skills. One result of this
raising the level of education. The situation regarding the
119
establishment of nursing colleges and graduate schools in
Instructional Sciences 26: 65-108 (2009)(in Japanese).
Japan from 1950 to the present resembles the movement
3) Horiguchi M. Maruyama R., and Tanaka G.: Analysis of
from 1860 to 1900 when modern nursing in the U.S. started.
allostatic load and eating behaviors among healthy young
Our research focuses on the early years of the creation of
women with different body types. The Journal of the
American nursing, which had a strong influence on nursing
Federation of American Societies for Experimental
education in Japan. This paper is historical research, using
Biology. 27:626.4 (2013).
the “Annual Report: U.S. Bureau of Education” as the main
4) Sato K., Okumiya A., Shiromaru M. Historical study on
source of information (4).
the formation of Visiting Nursing in the earliest of the
4. Clinical nursing for adults
Modern American Nursing. The Journal of Japan Society
To perform effective clinical nursing for adult patients and
of Nursing Hisotory.26 : 43-50(2013)(in Japanese).
their families, we have been conducting studies from the
5) Nakada M, Nakai N, Momma M, Shiromaru M. Students’
perspective of student and patient education. One of these
learning in a class on hair care for patients who experience
studies consists of a class about hair loss in patients
hair loss induced by cancer chemotherapy. Sapporo J.
undergoing cancer chemotherapy. We clarified the student-
Health Sci. 1:91-96(2012).(in Japanese)
learning outcomes throughout this class. The students
6) Sumikawa M. Nursing Care for the Patient's Daily Life
obtained practical knowledge that is useful in cancer nursing,
and Its Usefulness. HD patient support for foot care. The
and developed a greater understanding of the emotions of
Japanese Journal of Clinical Dialysis 26(12):1587-
patients who have experienced hair loss (5). Additionally, we
are conducting a clinical study to investigate the effects of
1594(2010) (in Japanese)
7) Sumikawa M..Footcare. The Journal of Japan accademy
nursing interventions aimed toward improving the self-
of rinephrology nursing 12(1): 17-24(2010) (in Japanese)
management behavior of diabetic patients who are at risk of
8) Shiromaru M ,Mizutani S, Ito T, Kadobayashi M, Sato M,
developing foot ulcers. We also conduct educational activities
Kodaira T, Honma M. Examples of using text-mining
related to clinical inference to perform appropriate nursing
techniques for exploring “research trends in breast
interventions (6-7).
cancer” and “patients’ narrative”. The Japanese Journal
5. Critical care nursing
We have been conducting research on critical care
of Nursing Research46 (5),494-502(2013) (in Japanese)
9) Murakami R, Shiromaru M, Yamane R, Hikoyama H,
nursing by focusing mainly on three themes. One is research
Sato M, Takahashi N, Yoshida S, Nakamura M, Kojima Y.
that focuses on a patient’s observed postoperative mental
Implications for better nursing practice: psychological
status and nursing practice performed between the acute and
aspects of patients undergoing post-operative wound
recovery periods. For example, using a text-mining approach,
care. Journal of Clinical Nursing 22,939-947(2012)
we analyzed a patient’s mental status based on the presence
10) Momma M, Nakai N., Kishita K. Health Survey of Nurses
or absence of metastases after breast cancer surgery, and
in Amami-Oshima Three Months after the October 2010
used the results to develop a postoperative discharge
Torrential
planning model (8). Additionally, we have clarified the mental
Experience of the Event and Relief Activities. Journal of
status of digestive system cancer patients during postoperative
Japanese Association for Emergency Nursing 15(1),12-
wound care (9). Another theme of our research centers on
Rains:
Relationship
between
Personal
20(2013) (in Japanese)
disaster nursing. Three months after the 2010 heavy rainfall
11) Nakai, N, Minegami T, Momma M. Investigation of
on Amami Oshima Island, we investigated the health status of
cumulative fatigue in nurses working in an independent
nurses affected by this disaster. Results indicated that
critical care medical center. Bulletin of School of Health
approximately 10% were at high risk of developing PTSD
Sciences, Sapporo Medical University12:9-16(2010) (in
associated with cumulative fatigue. The results suggest the
Japanese)
need of a support system for nurses (10). Finally, we also
focus on cumulative fatigue among critical care nurses (11).
1) Tano E, Ohinata T, Inaba Y: Hand Washing Behavior of
Nursing Students－Characteristics of Sophomores and
Seniors－.Bulletin of School of Health Sciences, Sapporo
Medical University 13:85-93 (2011)(in Japanese).
2) Ohinata T, Inaba Y. Examination about Contents Structure
of “Nursing Ethics” in Basic Nursing Education, Exploring
120
Maternal-Child Nursing
Our nursing section deals with maternal-child nursing. Our section’s
goal is to make a strong bridge between nursing theory and nursing
practice in order to improve the quality of nursing care. The health
care provided by nurses must be constantly evaluated and improved
based on new information.
Professor
Assistant Professor
Instructor
Miki Konno, R.N., P.H.N., D.S.N.
Hisae Tabata, R.N., P.H.N., M.S.N.
Tsuyoshi Asari, R.N., P.H.N., M.S.N.
Interests:
Interests:
Interests:
Child nursing
Child nursing
Child nursing
Tamae Ogita, R.N., C.N.M., P.H.N.,
Associate Professor
M.S.N.
Keiko Masaoka, R.N., C.N.M., P.H.N.,
Interests:
Ph.D.
Maternal nursing
Interests:
Maternal nursing
1. Maternal-child nursing
undertaking further studies to define what forms of midwifery
The birthrate in Japan is currently on the decline and the
care would be most effective in encouraging women to have a
number of nuclear families is on the rise. As a result, more
sense of control in childbirth in Japanese hospitals and clinics.
and more people become parents without prior experience of
c) Innovative approaches to learning for better understanding
dealing with infants. Bringing up children has become more
of the recipient of nursing care
difficult for new parents.
In maternal nursing lectures, the students are asked to
2. Safe and satisfactory delivery experience
interview women and parenting mothers so that they can
a) Learning process of Japanese midwives
share their stories and better understand better the recipients
Knowledge and care performance of midwives generally
of nursing care. This innovative approach has a positive
improve with experience but the number of years in itself does
feedback; the students “leant the real feelings of the mothers
not guarantee the acquisition of expert skills. A series of
that were not written in textbooks” and “became more aware
studies have been conducted to examine if there is relationship
of the role of nurses” while the mothers “felt they were doing
between the number of years in midwifery and the types of
something valuable for” and “were proud to be involved in” the
practice-based knowledge acquired from experience in labor
education of future nurses. We intend to apply similar
and delivery care. It has already been found that ten years is
initiatives to lectures focusing on the wider issue of
the watershed; midwives with ten or more years of experience
reproductive health.
had different care experience and acquired different practice-
3. Nursing care for sick children and their families
based knowledge and skills to those having less experience.
When children suffer from illness or disability, it is not only
It is our intention to develop tools that can be used to support
the children but also their families who may feel uncomfortable
midwives in their acquisition of expert knowledge and skills
in the hospital setting. We have been exploring what manners
from experience.
of nursing intervention can lessen their distress and make the
b) Midwifery care to encourage women to have a sense of
hospital experience as comfortable as possible, and also how
control in childbirth while in the hospital
nurses can teach them preventive intervention. We have
Continuous midwifery care helps parturient women
examined three study subjects regarding this matter, including
handle the childbirth process on their own initiative, but
preparation for children and smoking prevention.
providing continuous care can be a challenging task at
a) Psychological preparation of children undergoing medical
hospitals and clinics in Japan. Previous studies have indicated
intervention and their families (preparation)
that most women who give birth in clinics and hospitals are
Medical practitioners have to honor the rights of children.
satisfied with their childbirth experience. We have been
Preparation is both an ethical consideration and a practical
121
necessity because providing information about medical
Midwives. Sapporo Journal of Health Sciences. (2013) 2:
intervention (why it is necessary and what happens) to a child
27-34 (in Japanese)
in a manner appropriate to his/her assessed developmental
5) Tamae Ogita, Takayo Nakazawa, Yoko Asaka et al:
stage will help the child be in control of the situation. Even
Educational challenges and experiences of midwifery
though the idea of preparation has been known in Japan
students who performed birth reviews. Journal of Japan
since 2000, deep-rooted beliefs such as “children will not
Academy of Midwifery. (2013) 27: 72-82 (in Japanese)
understand the information/situation” and “children should be
6) Konno M, Asari T, Ebina M. Pediatric nurses’ knowledge
restrained during a procedure” remain prevalent. Our study
and attitude about smoking and encouragement given by
topics in the area of preparation include perceptions of nursing
them to family members of sick children to quit smoking
students
or to prevent them from passive smoking. The Journal of
after
lectures/exercise/practical
training
in
preparation, changes in nurses’ thoughts about preparation
after intervention and development of tools to provide effective
Child Health. (2012) 71: 851-857 (in Japanese)
7) Konno M, Asari T, Ebina M, Tabata H, Taniguchi H. Effects
preparation.
of anti-smoking class given to sixth grade elementary
b) Nursing care for preschool and school children with
school children: findings of questionnaire survey based
congenital heart disease and their families
on Kano test for social nicotine dependence for youth.
Children with congenital heart disease tend to be raised
Sapporo Journal of Health Sciences. (2012) 1: 97-104 (in
in an overprotective environment because the parents almost
Japanese)
always act on their behalf when it comes to decisions
8) Asari T, Konno M, Ebina M, Taniguchi H. Study of the
regarding treatment and procedures. It is often the case that
effectiveness of anti-smoking lessons given to children in
when these children reach adolescence, they fail to identify
secondary education- with a focus on changes in their
with the illness, become too dependent on their parents and
social nicotine dependence. Sapporo Journal of Health
therefore cannot learn self-control. Parent-child relationships
Sciences. (2012) 1: 105-110 (in Japanese)
and their interactions with those around them are therefore
9) Tamae Ogita: Types of delivery care rated highly by
even more important issues for children with congenital heart
women who gave birth at hospital. Hokkaido Journal of
disease and their families. One of our research activities
focuses on support for these children and their families.
Maternal Health. (2012) 41: 1-5 (in Japanese)
10) Miki Konno, Uemura Kouta, Ebina Michiko, et al: Student
c) Smoking prevention for children
nurse’s perception about preparation of children –
Active and passive smoking can be a big problem for
comparison of perceptions before and after classroom
families and children, affecting their physical condition and
lecture and after practical training. Journal of Japanease
health. We have been engaged in a study supported by Grant-
Society of Child Health Nursing. (2011) 20: 127-135
in-Aid for scientific research from the JSPS on the subject of
11) Keiko Masaoka, Tomoko Maruyama: Narrative Analysis
smoking intervention at school for primary and junior high
to Identify Practice-based Knowledge in Labor and
school children. One of the main focuses of the study is the
Delivery Care in Midwifery. The Japanese Journal of
role nursing has in promoting a smoke-free lifestyle for the
Health Behavioral Science. (2011) 26: 158-168 (in
good health and well being of children and their families.
Japanese)
12) Keiko Masaoka, Masako Yamaguchi, Atsuko Sugiyama:
Development of lectures to help nursing students gain a
1) Asari Tsuyoshi. Changing process of nurse’s perception
deeper understanding of women in the childbirth and
of preparation to young children hospitalized for a cardiac
parenting phase -Effects of interactive lectures with
catheter test. Sapporo Journal of Health Sciences. (2013)
mothers as guest speakers. Bulletin of School of Health
2: 19-26 (in Japanese)
Sciences Sapporo Medical University. (2011) 13: 65-69
2) Ebina M, Asari T, Konno M, Tabata H et al: Raising
(in Japanese)
awareness of preparation – Effects of mobile e-learning
13) Hisae Tabata: The Psychological State of Mothers Giving
(supported by Grant-in-Aid for scientific research (B)
Information to Their Children about Their Congenital
from JSPS for 2011/12/13/14, grant number 23390510)
Heart Disease. Journal of Japanese Society of Child
(in Japanese)
Health Nursing. (2010) 19:17-24 (in Japanese)
3) Tamae Ogita, Keiko Masaoka: Midwifery care provides
14) Keiko Masaoka, Tomoko Maruyama: Midwives’ viewpoints
women with a sense of control in childbirth at hospitals
on the connection between information and experience
and clinics. Women’s Health Society Journal of Japan.
concerning intrapartal care. Journal of Japan Academy of
(2013) 12: 57-64 (in Japanese)
Midwifery. (2009) 23: 16-25 (in Japanese)
4) Keiko Masaoka, Tomoko Maruyama, Makoto Matsuo et
al: Practice-based Knowledge of Japanese Experienced
122
Community Health, Gerontological and Psychiatric
Nursing
This division consists of three nursing specialities; community health,
gerontological and psychiatric nursing. Our primary goal is to develop
nursing assessment skills, intervention programs and evaluation
methods in response to the changing roles of nurses and changing
health care needs of our society. Both quantitative and qualitative
nursing research methods are used. Our research data contributes to
the development of nursing theories and the refinement of educational
methods.
Professor
Hisako Izumi, R.N., P.H.N., Ph.D.
Megumi Toriya, R.N., M.S.N.
Junichi Yoshino, R.N., Ph.D.
Interests:
Interests:
Interests:
Health promotion & health education,
Strokecare,
Grief care,
Community health nursing
Gerontological nursing
Psychiatric & mental health nursing
administration
Instructor
Masumi Hasegawa, R.N., Ph.D.
Naomi Okada, R.N., P.H.N., M.N.
Interests:
Assistant Professor
Delirium care,
Izumi Ueda, R.N., P.H.N., Ph.D.
Interests:
Community maternal and child health,
Associate Professor
Community health nursing
Izumi Sawada, R.N., P.H.N., Ph.D.
administration
Interests:
Terumi Kijima, R.N., P.H.N., M.S.N.
Domestic violence,
Interests:
Psychiatric & mental health nursing
Dementia care,
1. Community health nursing
Our goal is to develop high quality methods of practice
and education in community health nursing. We conduct
research on systematical scientific methods used to support
health. In particular, we investigate constructive procedural
practices that can enhance patients’ health and the health
care system as a whole.
We are interested in health promotion and nursing
intervention for the prevention of lifestyle-related diseases (1).
We are particularly interested in studying the career
development of public health nurses and education programs
for experts (2,3).
We have studied family caregiver burdens and home-visit
nursing care as they relate to the public long-term care
insurance system in Japan (4,5). We are particularly interested
in maternal and child health in communities (6-8).
2. Gerontological nursing
We have explored risk factors of delirium in elderly
patients and established a nurse education program for
preventing and managing delirium in hospitalized patients
(9,10). Additionally, we have studied about nursing care for
older adults that provides support for their physical and mental
health (11,12). We also are interested in developing
educational strategies for nursing process and interprofessional
work in health care of older adults (13,14).
3. Psychiatric and mental health nursing
We are exploring mental health nursing for families with
problems. We are particularly interested in suicide, support for
parents with mental illness, and child abuse, all of which are
becoming increasingly serious problems in Japan.
Since 1998, the number of suicides in Japan has
surpassed 30,000 every year. Thus, support for the bereaved
families to suicide has become vital. We have organized a
support group for bereaved families who lost members to
suicides (15).
Many parents of child abuse cases suffer from mental
health problem and other complex difficulties (16). We are
studying the results of a support system developed through a
nursing care program for schizophrenic mothers and their
children (17-21).
123
1) Nagata Y, Sakauchi F, Izumi H, Shang E, Ohnishi H, Mori
M: Association between salivary alpha-amylase activity
and stress-related characteristics. Sapporo Medical
Journal (2011) 80(1-6): 15-22.
2) Izumi H, Saeki K, Kawaharada M, Ueda I, Hirano M , Uza
M & Seki M: Are sense of coherence and self-assessment
of competencies associated? Investigation of participants
of a training program for public health nurse leaders in
th
Japan. The 4 International Conferences on Community
Health Nursing Research. Adelaide, Abstracts (2009):
317.
3) Ueda I, Saeki K, Kawaharada M, Hirano M, Seki M, Izumi
I: Evaluation of the effects of a leader-training program on
public health nurse leadership for staff in Japan. Open
Journal of Nursing (2012) 2: 246-253.
4) Izumi H, Oura A, Mori M, Washio M, Arai Y: The use of
social services and factors related to the care burden felt
by family caregivers of the at-home frail elderly Comparison between 2002 and 2008 in Hokkaido, Japan
- .The International Collaboration for Community Health
Nursing Research Conference 2013. Edinburgh, Poster
Abstracts. (2013): 32-33.
5) Izumi H, Matsubara M, Okada N, Namikawa K.
Comparison between visiting nursing in urban regions
and rural districts of Japan. International Conferences on
Community Health Nursing Research Biennial
Symposium 2011. Edmonton, poster and presentation
program. (2011): 2.
6) Ueda I, Saeki K, Kawaharada M, Hirano M, Izumi H,
Namikawa K. The Characteristics of Fathers Regarding
Child Abuse in Infancy based on interview cases by
Expert Public Health Nurses. International Conferences
on Community Health Nursing Research Biennial
Symposium 2011. Edmonton, poster and presentation
program. (2011): 2.
7) Okada N, Izumi H, Matsubara M, Namikawa K. The
continuous support that public health nurses links
mothers to the support. The 2nd Japan-Korea Joint
Conference on Community Health Nursing. Kobe
Abstracts. (2011): 129.
8) Ueda I: Public health nurse observations of behavioral
characteristics of fathers who contribute to the emotional
instability of mothers, as presented in cases of infant
abuse. Open Journal of nursing (2013) 3: 301-306.
9) Hasegawa M. Delirium risk factors of elderly medical
patients within three days after admission in acute care
settings. Journal of Japan Academy of Gerontological
Nursing (2010) 14: 50-59 (in Japanese).
10) Hasegawa M, Aohda T, Toriya M, Kawazato Y, Sugawara
M, Taki T. Challenge of delirium management for elderly
patients in acute hospital settings. International Council
of Nurses 25th Quadrennial Congress. (2013) Melbourne,
Australia.
11) Kijima T, Ide S. The important factors for older adults with
dementia to maintain stable living in a short-stay service
facility: Focus on the aspect of static living. Journal of
Japanese Society for Dementia Care (2011) 10(1): 28-38
(in Japanese).
12) Toriya M, Hasegawa M, Taki T. Study of a program to
support elderly males reporting their dietary habits by
using the internet. Bulletin of Tenshi college (2011) 11:
39-46 (in Japanese).
13) Kijima T, Yasukawa Y, Takeda K, Mizuno T, Okumiya A.
Effects on students’ learning and their appraisal of a
teaching strategy used for nursing process exercise
focusing on how to assess functioning of the elderly Benefits of lecture-linked nursing process exercise and
feedback. Bulletin of School of Health Sciences Sapporo
Medical University (2011) 13: 79-84 (in Japanese).
14) Hasegawa M, Kukitsu T, Taki T, Suzuki M, Takano Y,
Suzuki J. Students’ experiences during interprofessional
education in the nutrition support team in a hospital - Trial
practicum for joint team training in nursing and nutrition
departments-. The 6th International conference for
interprofessional education and collaborative practice.
(2012) Kobe, Japan.
15) Junichi Yoshino, Mutsumi Kimura. Extraction of the core
of stories used by a support group for surviving family
members of suicides to comfort themselves. Journal of
Japanese Association Group Psychotherapy (2011)
27(1): 66-73 (in Japanese).
16) Izumi Sawada: Parenting/Guardians of Abused Children
–Their Mental Health Problems and Complex Difficulties
as Revealed by case – Records of Local Child Guidance
Centre. Journal of Japan Academy of Psychiatric and
Mental health Nursing (2013) 22(3): 85-93 (in Japanese).
17)Sawada, I., Konno, M., Nomura, M., Yoshino, J.,
Miyajima, N., Hiratsuka, S., Maruyama, T. Cases of
Nursing Care for Schizophrenic Mothers during their
Pregnancy, Delivery and Parenting Provided by Health
Care Facilities in one of Japanese Prefectures.16th
International Congress of the International Society of
Psychosomatic Obstetrics and Gynecology Abstracts
(2010): CD-ROM.
18)Konno, M., Sawada, I., Nomura, M., Yoshino, J.,
Miyajima, N., Hiratsuka, S., Maruyama, T. Experiencebased Views of Nurses Midwives and Public Health
Nurses on Parenting by Schizophrenic Mothers in
Japan.16th International Congress of the International
Society of Psychosomatic Obstetrics and Gynecology
Abstracts (2010): CD-ROM.
19)Sawada, I., Kageyama, S., Ono, M,. Tsukamoto, M.
Positive Parenting program for psychiatry nursing.23th of
Japan Academy of Psychiatric and Mental health Nursing
abstract (2013): 50 (in Japanese).
20) Sawada, I. Care Guide for Schizophrenic Mothers during
their Pregnancy, Delivery and Parenting. Psychiatric
mental Health Nursing (2012) 15(6): 90-96 (in Japanese).
21) Sawada, I., Ono, M,. Tsukamoto, M. Supporting for
parents with mental illness and their families- introduction
about COPMI (Children of parents with mental illness) in
Austria. Seisinka rinshou sabisu (2013) 13(3): 341-345
(in Japanese).
124
2 Physical Therapy
First Division of Physical Therapy
Research in the 1st division of physical therapy focuses on the
application of scientific knowledge for the benefit of human health.
By learning how the musculoskeletal system adjusts to daily living,
we are able to better understand the objectives of physical therapy.
To that end, we investigate health science, physiology, neurology,
gerontology, kinesiology and exercise epidemiology. Our interests
cover neuromuscular physiology, motor control for gait and posture,
orthopedic biomechanics of the upper and lower extremities and
healthcare science.
Professor and Chair
Professor
Instructor
Taketo Furuna, R.P.T., Ph.D.
Kimiharu Inui, R.P.T., Ph.D.
Takeshi Sasaki, R.P.T., MA.
Interests:
Interests:
Interests:
Healthcare science and Motor control
Orthotics and prosthetics,
Cerebrovascular disorders,
for older adults
Proprioceptive neuromuscular
Neurophysiology, Cognitive
facilitation, Muscle physiology
science
Professor
Naoki Kozuka, R.P.T., Ph.D.
Assistant Professor
Interests:
Takashi Yamada, R.P.T., Ph.D.
Pediatric physical therapy,
Interests:
Kinesiological analysis of children
Muscle physiology and biochemistry,
with C.P., Molecular studies of
Physical agents in rehabilitation
neuromuscular disorders
1. Basic studies
a) We investigate the mechanisms underlying
1) skeletal muscle weakness in the elderly (1) and
inflammatory diseases such as myopathies (2) and
rheumatoid arthritis.
2) skeletal muscle fatigue (3,4).
3) insulin resistance in skeletal muscles (5).
b) Effects of cold-acclimation on skeletal muscles (6).
c) The role of reactive oxygen species in {beta}-adrenergic
stimulation of mouse cardiomyocytes (7).
d) Neurophysiological studies of postural control (8).
e) Studies on kinematics and physiological analyses on
childhood cerebral palsy (9-13) and molecular analyses of
hereditary neuromuscular disorders (14).
2. Applied and Clinical studies
a) Applied research about patients with neuromuscular
disease.
1) Studies on an investigation of environment of family with
disabled children (15).
2) Studies on early physical therapy intervention in NICU,
research about adult stroke patients (16) and others (17).
b) Applied research on maintaining and/or developing health
status of older adults living in communities.
1) Means of enhancing health conditions, particularly the
motor performances of older adults (18).
2) Characteristics of proximal and distal muscle activity of
lower limbs among community-dwelling older adults (19).
3) Interactional relationships between physical performance
and environment, such as falls, balance control, and
attention (20-26), among community-dwelling older and
middle aged adults (27).
List of Main Publications from 2009to 2013
1) Yamada, T., Ivarsson, N., Herrnández, A., Fahlström, A.,
Cheng, AJ., Bruton, JD., Ulfhake, B., Westerblad, H.:
Impaired mitochondrial respiration and decreased fatigue
resistance followed by severe muscle weakness in
skeletal muscle of mtDNA mutator mice. J. Physiol. 590:
6187-6197, (2012)
2) Grundtman, C., Bruton, JD., Yamada, T., Östberg, T.,
Pisetsky, DS., Erlandsson-Harris, H., Andersson, U.,
Lundberg, IE. and Westerblad, H.: Effects of HMGB1 on
in vitro responses of isolated muscle fibers and functional
aspects in skeletal muscles of idiopathic inflammatory
myopathies. FASEB. 24: 570-578, (2010)
3) Place, N., Yamada, T., Bruton, JD., and Westerblad, H.:
Muscle fatigue: from observations in humans to
underlying mechanisms studied in intact single muscle
fibres. Eur. J. Appl. Physiol. 110: 1-15, (2010)
4) Wada, M., Yamada, T., Matsunaga, S.: Characteristics
125
and mechanisms of low-frequency muscle fatigue:
alterations in skeletal muscle. Jpn. J. Phys. Fitness
Sports Med. 61: 297-306, (2012). (in Japanese)
5) Yamada, T., Zhang, SJ., Westerblad, H. and Katz, A.:
{beta}-Hydroxybutyrate inhibits insulin-mediated glucose
transport in mouse oxidative muscle. Am. J. Physiol.
Endocrinol. Metab. 299: E364-E373, (2010)
6) Bruton, JD., Aydin, J., Yamada, T., Shabalina, IG.,
Ivarsson, N., Zhang, SJ., Wada, M., Tavi, P., Nedergaard,
J., Katz, A. and Westerblad, H.: Increased fatigue
resistance linked to Ca2+-stimulated mitochondrial
biogenesis in muscle fibres of cold-acclimated mice. J.
Physiol. 588: 4275-4288, (2010)
7)Andersson, DC., Fauconnier, J., Yamada, T.,
Lacampagne, A., Zhang, SJ., Katz, A. and Westerblad,
H.: Mitochondrial production of reactive oxygen species
contributes to the {beta}-adrenergic stimulation of mouse
cardiomycytes. J. Physiol. 589: 1791-1801, (2011)
8) Sasaki T, Kozuka N, Nagamine T, Matsuyama K. Trial of
novel posturography technique for small animals
including rats and examination of its instrumental
properties. Sapporo Journal of Health Sciences. 2: 4555, (2013). (in Japanese)
9) Kozuka N, Nishibu H, Wada S, Abe H: Abnormal gait of
patient with cerebral palsy. Journal of joint surgery. 30:
85-93, (2011). ( in Japanese)
10)Osuda Y, Horimoto Y, Takada C, Suzuki A, Hisaka Y,
Kondou T, Kodama T, Takahashi N, Maeda M, Kozuka N,
Tsugawa S: Relationship between severity and thoracic
deformity in children (persons) with severe motor and
intellectual disabilities, and its characteristics. Journal of
severe motor and intellectual disabilities. 36: 471-476,
(2011). ( in Japanese)
11) Horimoto Y, Osuda Y, Takada C, Yoshida S, Miwa M,
Tsugawa S, Kozuka N: Reliability of two protocols for
measuring chestwall dimensions in the transverse plane
in individuals with severe motor and intellectual
disabilities. Journal of Physical Therapy Science. 23:
221-224, (2011)
12) Horimoto Y, Osuda Y, Takada C, Tsugawa S, Kozuka N,
Yoshida S, Otani T, Miwa M: Thoracic Deformity in the
Transverse Plane among Adults with Severe Cerebral
Palsy. Journal of Physical Therapy Science. 24. 763-766,
(2012)
13)Yokoi Y, Kozuka N, Toki M, Matsuyama T, Ishiai S:
Evaluation of the muscle tonus that used Modified Tardieu
Scale (MTS) for triceps surae of cerebral palsy: The
relationship between MTS and development/aging ,
Gross Motor Function Classification System (GMFCS).
Bull Sapporo J. Health Sci. 1: 71-77, (2012). ( in
Japanese)
14) Nakamura T, Suzuki D, Murakami G, Cho BH, Fujimiya
M, Kozuka N: Human fetal anatomy of the posterior
semimembranosus complex at the knee with special
reference to the gastrocnemio-semimembranosus bursa.
Knee. 18: 271-277, (2011)
15) Himuro N, Kozuka N, Mori M: Measurement of familycentred care: translation, adaptation and validation of the
Measure of Processes of Care (MPOC-56 and -20) for
use in Japan. Child Care Health & Development. 39: 358365, (2013)
16) Nishimura Y, Yoshio M, Matsumoto H, Kozuka N: Study
of the subjective visual vertical deviation in stroke
patients: Features of SVVD from the standpoint of
ipsilateral pushing and spatial neglect. Rigaku ryohogaku.
38: 516-523 (2011). ( in Japanese)
17) Horimoto Y, Takahashi E, Takada C, Osuda Y, Yoshida S,
Kozuka N, Miwa M: A study of measurement practices in
pediatric physical therapy -differences between education
and clinical practice-. The science and research of
physical therapy. 2: 19-25, (2011). ( in Japanese)
18)Furuna T, Makizako H,, Ihira H, Hato S, Shimada H,
Kimura M, and Mizuma M. The influence of frequency of
intervention via mail on physical and social function:
examination in community-dwelling older adults living in
rural area of northern Japan. App Gerontology, 5(1), 4049 , (2011) (in Japanese)
19) Ihira H, Shimada H, Suzukawa M, Furuna T, Matsuyama
K, Ishiai S: Differences between Proximal and Distal
Muscle Activity of the Lower Limbs of Communitydwelling Women during the 6-minute Walk Test. Journal
of Physical Therapy Science. 24: 205-209, (2012)
20) Makizako H, Furuna T, Shimada H, Ihira H, Kimura M,
Uchiyama E, Oddsson LI: Association between a history
of falls and the ability to multi-task in community-dwelling
older people. Aging Clinical And Experimental Research,
22: 427-432, (2010)
21)Shimada H, Sawyer P, Harada K, Kaneya S, Nihei K,
Asakawa Y, Yoshii C, Hagiwara A, Furuna T, Ishizaki T.
Predictive validity of the classification schema for
functional mobility tests in instrumental activities of daily
living decline among older adults. Arch Phys Med
Rehabil. 91: 241-6, (2010)
22) Shimada H, Ishizaki T, Kato M, Morimoto A, Tamate A,
Uchiyama Y, Yasumura S: How often and how far do frail
elderly people need to go outdoors to maintain functional
capacity? Archives of Gerontology and Geriatrics 50:
140–146, (2010)
23)Ishizaki T, Furuna T, Yoshida Y, Iwasa H, Shimada H,
Yoshida H, Kumagai S, Suzuki T: Declines in Physical
Performance by Sex and Age Among Nondisabled
Community-Dwelling Older Japanese During a 6-Year
Period. J Epidemiol. 21(3):176-183, (2011)
24) Kimura M, Moriyasu A, Kumagai S, Furuna T, Akita S,
Kimura S, Suzuki T: Community-based intervention to
improve dietary habits and promote physical activity
among older adults: a cluster randomized trial. BMC
Geriatrics 13:8 1471-2318, (2013)
25)Mizumoto A, Ihira H, Yasuda K, Makino K, Miyabe Y,
Saitoh S, Ohnishi H, Suzuki T and Furuna T: Associations
between Serum 25-Hydroxyvitamin D Concentration and
Physical Performance in Old-Old People Living in a
Northern Area of Japan. J Gerontol Geriatric Res 2013,
in press
26) Makizako H, Furuna T, Ihira H, Shimada H: Age-related
Differences in the Influence of Cognitive Task
Performance on Postural control Under Unstable Balance
Conditions. International Journal of Gerontology, 2013, in
press.
27)Makizako H, Kaneko F, Aoki N, Ihira H: Age-related
Differences in Reaction Time Responses under Simpleand Dual-task Conditions in Middle-aged Ski Marathon
Amateur Males. International Journal of Sport and Health
Science 11, 33-38, (2103)
126
Second Division of Physical Therapy
This division consists of our physical therapy specialties for
musculoskeletal, neurological and cardiopulmonary disorders,
including spots injuries. We have been investigating the functional
outcome of physical therapy intervention in clinical facilities and at
athletic sites, and also carrying out neurophysiologic, morphological,
kinesiological and biomechanical studies on each relative field in
laboratories.
Professor
Associate Professor
Instructor
Masaki Katayose, R.P.T., Ph.D.
Fuminari Kaneko, R.P.T., Ph.D.
Tohru Neki, R.P.T., M.S.
Interests:
Interests:
Interests:
Musculoskeletal physical therapy,
Orthopedic and sports physical
Cardiac rehabilitation and prevention
Sports physical therapy, Cardiac
therapy, Sensory motor neuroscience
Nobuhiro Aoki, R.P.T., M.S.
physical therapy
Interests:
Eiichi Uchiyama, M.D., Ph.D.
Assistant Professor
Musculoskeletal physical therapy and
Interests:
Keigo Taniguchi, R.P.T., Ph.D.
function
Biomechanics of musculoskeletal
Interests:
Erika Iwamoto, R.P.T., Ph.D.
system, Biomechanics of wheelchair
Musculoskeletal physical therapy,
Interests:
sitting
Musculoskeletal imaging
Cardiovascular and respiratory
physiology and rehabilitation
1. Sports & orthopedic physical therapy
kinesiology, such as manual therapy, mobilization and
At this laboratory, we promote the study of safe and
stretching
effective sports activities and exercise therapy not just for
In the upper extremities, we have used cadavers in
athletes, but also for all people, encompassing a wide range
evaluations of shoulder joint (5), wrist joint, and finger joint
of athletic prowess. Our main focus is the study of prevention,
kinesiology. In the lower extremities, they have been used int
physical therapy and functional diagnostic assessment for
the evaluation of hip joint and ankle joint complex (6)
trauma disorders associated with sports activities. We seek to
kinesiology.
understand mechanisms of the movement’s production and
b) We have also invesigated the kinematics, kinetics and
disorders in order to provide a scientific basis to optimize
morphology of extremities
musculoskeletal and sports-related rehabilitation and health
In the upper extremities, this includes strains of the
in the global community.
rotator cuff at the shoulder. In the lower extremities, we have
Here is a sample of our research theme:
examined instability of the ankle joint complex, dynamics of
・Three-dimensional kinematics and kinetics measured
flatfoot (7) and morphology of ligaments (8).
during movement to characterize the dynamics of sports
3. Sensorymotor science & sports neuroscience
activities.
The major goal of the SensoryMotor Science and Sports
・The activation patterns of muscles in unimpaired subjects
and in subjects with sports injuries.
NeuroScience laboratory (SMS & SNS Lab.) to contribute to
the study of neuroscience based on patient post-stroke
・Applied medical imaging experiments to determine muscle
rehabilitation and sports-neuroscience to prevent and cure
and bone geometry, measure in vivo joint motion, and
sports injuries and disorders.
characterize muscle mechanics, architecture and function.
In order to increase our knowledge about the mechanism
2. Biomechanics
of
musculoskeletal
system
and
of kinesthetic perception, associative cerebral network with
wheelchair sitting
the intention of a voluntary movement, integration of sensory
Below are purposes for which we have used fresh frozen
input and motor control, and neural plasticity, we are
cadavers in our biomechanical studies.
conducting investigations by means of various transcranial
a) We have investigated the quantitative evidence of
stimulations such as EMG, EEG and motion analysis.
127
Scientific knowledge and technical seeds are being applied to
ligaments in the hip joint: collagen fiber direction and
develop and produce innovative interventions in novel health
crimp distribution. Anat Sci Int (2012) 87, 50-55.
promotion and the rehabilitation system.
7) Izumi T, Aoki M, Tanaka Y, Uchiyama E, Suzuki D,
4. Cardiovascular & respiratory physical therapy
Miyamoto S, Fujimiya M. Stretching positions for the
Our research interest is to elucidate the cardiovascular
coracohumeral ligament: Strain measurement during
and respiratory responses in health and disease, and the
passive motion using fresh/frozen cadaver shoulders.
changes in these responses after cardiovascular and
Sports Med Arthrosc Rehabil Ther Technol (2011) 19,3,
respiratory physical therapy (e.g., exercise and heat). We use
2.
integrative approaches to test how cardiorespiratory systems
8) Fujii M, Suzuki D, Uchiyama E, Muraki T, Teramoto A,
are controlled during exercise or hypoxic stress. We are also
Aoki M, Miyamoto S. Does distal tibiofibular joint
interested in mechanisms responsible for controlling the
mobilization decrease limitation of ankle dorsiflexion?
cardiovascular system, including nerve signals, contracting
Man Ther (2010) 15,117-21.
muscles, substances in the blood, and the vessels themselves.
9) Iida, N., Kaneko, F., Aoki, N., Shibata, E.: The Effect of
Our research interests as mentioned above are related to the
Fatigued Internal Rotator and External Rotator Muscles
establishment of safe exercise procedures and management
of the Shoulder on the Shoulder Position Sense. J
of risk factors for elderly people and patients.
Here is a sample of our research themes:
・Regulation of blood flow pattern (antegrade and retrograde
blood flows) in inactive limbs (14,15).
・Cardiovascular response to the onset of acute hypoxia
during dynamic exercise (14,15).
・Coordination between pulmonary function and regulation of
the cardiovascular system (13).
・The effect of muscle metaboreflex on cardiovascular
responses in health and disease (COPD, heart failure,
diabetes).
・The cardiovascular response to static and dynamic
exercise.
Electromyogr Kinesiol (2013), in press.
10) Makizako, H., Kaneko, F., Aoki, N., Ihira, H.: Age-Related
Differences in Reaction Time Responses under Simpleand Dual-task Conditions in Middle-Aged Ski Marathon
Amateur Males. Int J Sport Health Sci (2013) 11, 33-38.
11) Shibata, E., Kaneko, F.: Kinesthetic perception based on
integration of motor imagery and afferent inputs from
antagonistic muscles with tendon vibration. Neurosci Lett
(2013) 541, 24-28.
12) Aoyama, T., Kaneko, F.: The effect of motor imagery on
gain modulation of the spinal reflex. Brain Res (2010)
1372, 41-48.
13) Iwamoto E., Taito S. et al.: The neural influence on the
occurrence of locomotor-respiratory coordination. Respir
Physiol Neurobiol (2010) 173, 23-28.
1) Yoshida M, Taniguchi K, Katayose M. Analysis of muscle
14)Iwamoto E., Katayama K. et al.: Hypoxia augments
activity and ankle joint movement during the side-hop
oscillatory blood flow in brachial artery during leg cycling.
test. J Strength Cond Res (2010) 25, 2255-2264.
Med Sci Sports Exerc (2012) 44,1035-1042.
2) Taniguchi K, Katayose M. The intra-rater and inter-rater
15) Iwamoto E., Katayama K. et al.: Retrograde blood flow in
reliability of the revised ultrasound velocity measurements
the inactive limb is enhanced during constant-load leg
in human triceps surae muscles in vivo. J JaSOU (2010)
cycling in hypoxia. Eur J Appl Physiol (2013) 113, 2565-
22, 19-23.
2575.
3) Katayose M, David J. Magee. Pre-Olympic team travel:
Logical and treatment considerations. Handbook of
Sports Medicine and Science-Sports Therapy Services:
Organization and Operations, Olympic Handbook of
Sports Medicine, Wiley-Blackwell (2012) 41-47.
4) Taniguchi K, Shinohara M, Nozaki S, Katayose, M. Acute
decrease in the stiffness of resting muscle belly due to
static stretching. Scand J Med Sci Sports (2013) in press.
5) Kamiya T, Uchiyama E, Watanabe K, Suzuki D, Fujimiya
M, Yamashita T. Dynamic effect of the tibialis posterior
muscle on the arch of the foot during cyclic axial loading.
Clin Biomech (2012) 27, 962-966.
6) Sato K, Uchiyama E, Katayose M, Fujimiya M.
Microscopic analysis of the iliofemoral and ischiofemoral
128
3 Occupational Therapy
First Division of Occupational Therapy
The scope of our research activities covers topics from occupational
sciences and kinesiology of activities of daily living to occupational
therapy for physical and psychosocial dysfunction such as hand
disorders, CVA and the elderly.
Professor
Associate Professor
Instructor
Mariko Nakamura , O.T.R., Ph.D.
Yoko Goto, O.T.R., Ph.D.
Mitsuo Nakakura, O.T.R.,.M.S.
Interests:
Interests:
Interests:
Physical dysfunction, Kinesiology of
Pulmonary rehabilitation
Physical dysfunction, Kinesiology of
hand
Mari Sakaue, O.T.R., Ph.D.
the hand
Hisaaki Ota, O.T.R., Ph.D.
Interests:
Takako Chikenji, O.T.R., Ph.D.
Interests:
Occupational science, Rehabilitation
Interests:
Neuropsychology, Cognitive
for the elderly
Hand therapy, Anatomy, Orthopedics
rehabilitation
Tomihiro Imai, M.D., Ph.D.
Interests:
Neurology, Clinical Neurophysiology
1. Kinesiological Studies of Activities of Daily Living
research on paper and pencil tasks to classify different types
Grasp and pinch are the main functions of the hand.
of USN. In addition, to ameliorate these symptoms much
When manipulating an object in ADL such as scissors, each
more effectively, we are developing new therapeutic
finger is likely to behave associatively. It is still unknown how
techniques and modifying the task procedures presented in
the associated movement of the fingers behaves during the
previous reports. Integration previous results with our own
ADL performance. To determine the strategies of associated
research may help us provide appropriate intervention
movement of the fingers, we conducted a study in which the
technique for each USN patients.
movements of the little finger were measured during precision
3. Pulmonary rehabilitation
grip with the thumb and the index finger. The results showed
Patients with severe chronic obstructive pulmonary
that the thumb and the index finger associated with the other
disease (COPD) suffer from dyspnea, which can subsequently
fingers which uninvolved in precision grip when controlling
cause a difficulty in performing routine activities of daily living
force. Among our recent studies, we have investigated the
and affect their quality of life.
five-finger prehension synergies such as grip force, joint
Pulmonary rehabilitation is medical care we provide to
movement and contact position. In contact position, we
patients that aims to improve their functional abilities and
accepted the change of the contact position of the middle
overall quality of their daily lives.
finger and ring finger by changing the weight (1). The
4. Community based rehabilitation
contributions and coordination of external finger grip forces
The transformation of the social structure (aging and
during a holding task with a precision grip using multiple
declining birthrate) in Japan affects medical care and the
fingers were also examined.
welfare system greatly. It is necessary that community based
2. Neuropsychological rehabilitation
rehabilitation hereafter makes serious efforts to address not
Patients suffering from brain damage may show
only the issue of care promotion for senior citizens and
neuropsychological symptoms. These symptoms may hinder
handicapped people, but also find ways to support the
their daily living activities and participation in society. Our
community as a whole. We analyze the health scientifically
focus of research interest centers on visuospatial cognitive
from a “Community Empowerment” viewpoint.
deficits, and mainly unilateral spatial neglect (USN). We
5. Occupational Science
developed neuropsychological tests to clarify new aspects of
Occupational Science is the study of how people’s
USN symptoms and analyzed data from previously published
engagement in their daily activities regains, develops, and
129
maintains health and well being after disease or disability.
difference between CMAP and movement-related potential.
Occupational science research has increasingly focused on
We also measured bite force using a specialized pressure-
identifying not only the nature of human occupations but also
sensitive sheet, and this enabled us to analyze the correlation
the adaptive process of constructing or re-constructing
of ECCT and bite force. ECCT was prolonged in MG patients
meaningful occupations for the clients experiencing a life
compared to normal subjects, and correlated with bite force.
crisis. Both place-making and the construction of occupations
The data supported the view that E-C coupling may be
for elderly persons with dementia are being investigated to
impaired in MG (3).
help them be able to lead meaningful and healthy lives.
Currently, the studies have shown important characteristics of
“sense of place” that influence participation in occupations,
1) Nakamura M, Katagiri K, Nakamura M: Determination
and give people the chance to experience mindfulness, which
Factors of Control Positions during Grasping the Object
is related to their experience of occupational engagement.
with Thumb and Four Fingers. Japanese Journal of
6. Basic and Clinical Research of Upper Extremity Disorder
Occupational Therapy Research (2012)15(2): 27-33 (in
Idiopathic carpal tunnel syndrome (CTS) is one of the
Japanese).
most common entrapment neuropathies, especially in
2) Tsuda E, Imai T, Hozuki T, Yamauchi R, Saitoh M,
menopausal women. Non-inflammatory fibrosis of the
Hisahara S, Yoshikawa H, Motomura M, Shimohama S.
subsynovial connective tissue (SSCT) has been determined
Correlation of bite force with excitation-contraction
to be a hallmark of CTS. The etiology of this finding and
coupling time of the masseter in myasthenia gravis. Clin
SSCT’s relationship to the development of CTS remain poorly
Neurophysiol (2010) 121: 1051-1058.
understood. To clarify the pathogenesis of the fibrosis, we are
3) Imai T, Tsuda E, Hozuki T, Yoshikawa H, Yamauchi R,
investigating the influences hormonal change has on
Saitoh M, Hisahara S, Motomura M, Kawamata J,
mesenchymal stem cells in SSCT of CTS patients. These
Shimohama S. Contribution of anti-ryanodine receptor
findings may lead to the development of a novel CTS treatment
antibody to impairment of excitation-contraction coupling
in occupational therapy.
in myasthenia gravis. Clin Neurophysiol (2012) 123:1242-
We are also interested in how upper extremity specific
1247.
disability correlates with mood and coping strategies. The
4) Chikenji T, Gingery A, Zhao C, Passe SM, Ozasa Y,
psychological factors explain a large part of the variability in
Larson D, An KN, Amadio PC. Transforming growth
disability associated with similar levels of impairment. We are
factor-β (TGF-β) expression is increased in the
investigating relations between upper extremity disability and
subsynovial connective tissues of patients with idiopathic
psychological factors such as kinesiophobia (fear of
carpal tunnel syndrome. J Orthop Res (2014) 32:116-22.
movement) and perceived partner support, depression, pain
5) Iba K, Abe Y, Chikenji T, Kanaya K, Chiba H, Sasaki K,
anxiety and catastrophic thinking. These findings can lead to
Dohke T, Wada T, Yamashita T. Delayed fracture healing
improved strategies for managing nociception, resulting in
in tetranectin-deficient mice. J Bone Miner Metab (2013)
decreases in symptoms and disability with upper extremity
31:399-408.
6) Vanhees M, Chikenji T, Thoreson AR, Zhao C, Schmelzer
disorders.
7. Clinical Neurophysiology
JD, Low PA, An KN, Amadio PC. The effect of time after
Excitation-contraction (E-C) coupling of skeletal muscles
shear injury on the subsynovial connective tissue and
has been a somewhat under-explored field in clinical
median nerve within the rabbit carpal tunnel. Hand (N Y)
neurophysiology.
(2013) 8:54-9.
It
includes
several
processes,
from
generation of a muscle action potential to muscle contraction.
7) Blangero A, Ota H, Rossetti Y, Fujii T, Ohtake H, Tabuchi
Physiologically, E-C coupling has rarely been evaluated in
M, Vighetto A, Yamadori A, Vindras P, Pisella L.
neuromuscular disorders because of the lack of appropriate
Systematic retinotopic reaching error vectors in unilateral
methods to assess E-C coupling in vivo.
optic ataxia. Cortex (2010) 46:77-93.
In 2010, we reported a novel physiologic assessment
8) Sakaue M., Reid D. Making Tea in Place: Experiences of
method of E-C coupling (2). In that study, the electrical and
Women Engaged in a Japanese Tea Ceremony. Journal
mechanical muscle responses were simultaneously recorded;
of Occupational Science (2012)19(3):283-291.
compound muscle action potentials (CMAPs) from the
masseter muscle, and jaw movement-related potentials were
measured by using an accelerometer, after which trigeminal
nerve stimulation was conducted with a needle electrode. The
E-C coupling time (ECCT) was calculated as the onset latency
130
Second Division of Occupational Therapy
We are studying analyses of disorder mechanisms and clinical
effectiveness of occupational therapy for people with developmental
or mental disorders. The current research themes of our division are
described below.
Professor
Associate Professor
Satoe Takeda, O.T.R., Ph.D.
Yasuhito Sengoku, O.T.R., Ph.D.
Sonomi Nakajima, O.T.R., Ph.D.
Interests:
Interests:
Interests:
Working memory training for patients
Sensory integration function in
Occupational therapy for children with
with dementia and schizophrenia
developmental disorders
Nozomu ikeda, O.T.R., Ph.D.
Instructor
Interests:
Assistant Professor
Mental health, Cognitive function
Yuji Nakamura, O.T.R., Ph.D
Kiyoji Matuyama, M.D., Ph.D.
Interests:
Interests:
Occupational therapy for children with
Neural mechanisms of generation,
Takafumi Morimoto, O.T.R., Ph.D.
Regulation of motor behaviors
1. Process of attentional function and cognitive function
using reaction time tasks
Reaction time tasks are known as one of the useful
methods for measuring information processing in the brain. To
analyze the process of attentional and cognitive functions, we
developed new reaction time tasks, in which spatial and/or
temporal characteristics of the visual stimuli can be
dynamically changed (1). We consider that the reaction time
tasks are valid particularly for monitoring problems in the daily
lives of people with early stage brain disorders and for
understanding cognitive functions of children with
developmental disorders (2).
2. Hokkaido birth cohort study on environment and
children’s health
The Hokkaido Study on Environment and Children’s
Health is an ongoing cohort study that began in 2002. The
study consists of two prospective birth cohorts, the Sapporo
cohort and the Hokkaido large-scale cohort. In the Sapporo
cohort, we have examined the potential negative effects
perinatal environmental chemical exposure has on infant
neurodevelopment, and the association between maternal
antenatal depression and infant development (3-5).
3. Establishment of a new objective evaluation index in
handwriting and clarification of factors contributing to
clumsiness
We developed a new handwriting assessment system
using a tablet PC that could record a pen’s trajectories and
pressures occurring during handwriting tasks. We also
investigated the usefulness of the system for assessing
clumsy children (6). In addition, we developed a quantitative
method for assessing the legibility of clumsy children. We
then examined the relationship between the results of the
subjective assessment and our quantitative method to obtain
clarity regarding the latter’s usefulness (7).
4. Support for children with cerebral palsy
We have studied for an objective evaluation method and
a seat cushion surface for cerebral palsy. Through an objective
evaluation method, using electromyography and near-infrared
spectroscopy we have been able to show the associative
reaction and visual functions of cerebral palsy patients (8).
Additionally, our research into children with cerebral palsy has
enabled us to prepare a seat cushion surface using silicon
materials, which has allowed us to examine the effects of
movement in cerebral palsy patients and healthy adults (9).
5. Effects of self-efficacy on interpersonal behavior in
people with schizophrenia
Interpersonal behavior can be a critical therapeutic target
of psychosocial rehabilitation intervention for schizophrenia
patients living in the community. A recent study proposed the
necessity of subjective assessments of people with
schizophrenia to examine their functional status. We have
investigated whether the self-efficacy of interpersonal
behavior influences real-world interpersonal behavior, and
compared this influence with the influences of other factors
that correlate with interpersonal behavior (e.g., neurocognitive
functions and psychopathological symptoms)(10).
6. Development of new working memory training
We have developed a new computerized working
memory training program. The contents of the program focus
on simulation of daily situations encountered in everyday life.
The effects of the training have been examined in patients
with dementia and schizophrenia. Results have indicated
improvements in verbal fluency, inhibition control, verbal and
spatial memory and emotional functions. We also have
investigated neuronal mechanisms of the new working
memory training through methodologies of noninvasive brain
imaging (11,12).
131
7. Survey on support systems for early onset dementia
Early onset dementia (EOD; age of onset ＜65 years)
has been recognized as a major social problem in Japan. As
it is believed to cause a different set of problems to those
associated with senile dementia, a detailed investigation of
this condition is necessary. In cooperation with the local
government, we investigated the regional prevalence of EOD,
as well as issues associated with living conditions and support
systems. (13).
8. Neurophysiology for sensorimotor and mental functions
To make proper evaluations on advantageous effects of
rehabilitation and further develop new rehabilitation strategies,
it is important to understand neural mechanisms for
sensorimotor and mental functions of the central nervous
system (CNS) because many patients who need rehabilitation
suffer dysfunction of the CNS due to damage caused by
illness or traumatic injuries. For this purpose, we have
attempted to advance understanding of neural mechanisms
responsible for the generation and regulation of motor
behaviors through animal experiments. Among the motor
behaviors, “locomotion” is one of basic motor acts that
commonly emerge in all animals and continues throughout
their entire lives. The neural control of locomotion in mammals
involves continuous interactions between various kinds of
neural subsystems that are widely distributed throughout the
CNS. Since locomotor acts belong to the category of extremely
ancient movements, the subcortical areas including the basal
ganglia, cerebellum, brainstem and spinal cord are
fundamental for locomotor function. Among these areas, the
brainstem and spinal cord are essential for the generation and
regulation of basic locomotor patterns, e.g., rhythmic
extension-flexion movements of each limb and reciprocal leftright interlimb coordination during locomotion. We have
focused our investigations mainly on the following two points:
1) morphology of spinal interneurons involved in the generation
of reciprocal left-right locomotor movements in cats, and 2)
brainstem-spinal cord mechanisms for generating hopping
locomotion in rabbits (14-16).
1) Ohyanagi T, Sengoku Y. A solution for measuring accurate
reaction time to visual stimuli realized with a programmable
microcontroller. Behav Res Methods (2010) 42(1) :242253.
2) Sengoku Y, Ohyanagi T, Nakajima S, Nakamura Y,
Kanaya F, Development of new evaluation methods for
inattention in developmental disorder. 15th International
Congress of the World Federation of Occupational
Therapists. Chile (2010).
3) Kishi R, Kobayashi S, Ikeno T, Araki A, Miyashita C, Itoh
S, Sasaki S, Okada E, Kobayashi S, Kashino I, Itoh K,
Nakajima S; The members of the Hokkaido Study on
Environment and Children’s Health. Ten years of progress
in the Hokkaido birth cohort study on environment and
children’s health: cohort profile-updated 2013. Environ
Health Prev Med. (in press) (2013).
4) Otake Y, Nakajima S, Uno A, Kato S, Sasaki S, Yoshioka
E, Ikeno T, Kishi R. Association between maternal
antenatal depression and infant development: a hospitalbased prospective cohort study. Environ Health Prev
Med. (in press) (2013).
5) Nakajima S, Kishi R. Profiling prospective birth cohort
studies on relationship between environment and
children’s health: various issues and aspects involved in
evaluating development in children. Nihon Eiseigaku
Zasshi. (2009) 64(4):765-73 (in Japanese).
6) Nakajima S, Ohyanagi T, Nakamura Y, Sakamoto K,
Sengoku Y. The assessment of handwriting performance
based on changes in pen velocity and pen pressure.
Japanese Occupational Therapy Research. (2011)
30(5):563-571 (in Japanese).
7) Ikeda C, Nakajima S, Takizawa S, Nakamura Y, Sengoku
Y. Developmental tendencies in handwriting legibility: A
quantitative evaluation of handwriting features. Japanese
Occupational Therapy Research. (2013) 32(1):14-22 (in
Japanese).
8) Nakamura Y, Sengoku Y, Nakajima S, Ohyanagi T,
Sugama K, Horimoto Y, Tachi N : Visual function
evaluation for people with severe motor and intellectual
disabilities utilizing Near-Infrared Spectroscopy, Asian J
Occup Ther. (2010) 8(1):13-19.
9) Nakamura Y, Sengoku Y, Nakajima S, Kodama T,
Kamoshita K: Sitting comfort and movements of the seat
cushion made of silicon, Japanese Journal of
Occupational Therapy in Pediatrics. (2012) 1(1): 31-38
(in Japanese).
10) Morimoto T, Matsuyama K, Ichihara-Takeda S, Murakami
R and Ikeda N. Influence of self-efficacy on the
interpersonal behavior of schizophrenia patients
undergoing rehabilitation in psychiatric day-care services.
Psychiatry and Clinical Neurosciences. (2012) 66: 203209.
11) Ichihara-Takeda S, Takeda K, Funahashi S: Reward acts
as a signal to control delay-period activity in delayedresponse tasks. Neuroreport, (2010) 21(5):367-370.
12) Ichihara-Takeda S, Yazawa S, Murahara T, Toyoshima T,
Shinozaki J, Ishiguro M, Shiraisi H, Matsuyama K,
Nagamine T: Modulation of parieto-occipital alpha activity
by distractor in visuospatial working memory task :
Magnetoencephalography study. ICCN 2010, Kobe
(2010).
13) Ikeda N, Iwabuchi A, Hirano N : Issues related to early
onset dementia in Sapporo city, Japan 15th International
Therapists. Chile (2010).
14) Matsuyama K, Ishiguro M and Takakusaki K. Descending
routes of locomotor driving signals involved in the
generation of coordinated hopping locomotion in
decerebrate rabbits. Proceedings of The 3rd International
Symposium on Mobiligence. Awaji, Japan.(2009) p255258.
15) Matsuyama K and Takakusaki K. Organizing principles of
projections of the long descending reticulospinal
pathways and their targets’ spinal commissural neurons:
with special reference to the locomotor function. (Eds.
Westland TB, Calton RN). Handbook on White Matter:
Structure, Function and Changes. (2009) pp.335-356.
Nova Science Publishers. New York.
16) Kobayashi S, Fujito Y, Matsuyama K and Aoki M. Raphe
modulation of the pre-Botzinger complex respiratory
bursts in in vitro medullary half-slice preparations of
neonatal mice. J Comp Physiol A. (2010) 196:519–528.
132
C GRADUATE COURSE IN MIDWIFERY
Graduate Course in Midwifery
This course was established in 2012. It was designed to improve the
education and midwifery practice of midwives who contribute to the
enhancement and development of maternal and child health and
perinatal care in Hokkaido. Our recent research involves the
elucidation of evidence that will form the basis of midwifery practice
and the study of more effective midwifery practices.
Professor
Assistant Professor
Instructor
Kimiharu Inui, R.P.T., Ph.D.
Kumiko Itoh, R.N., N.M., M.E.
Satoko Ebina, R.N., N.M., M.S.N.
Interests:
Interests:
Yoshika Kuno, M.D.
Orthotics and prosthetics,
Midwifery education, Women’s health
Mayuka Sasada, R.N., N.M., M.E.
Proprioceptive neuromuscular
facilitation, Muscle physiology
Yoshiko Hayashi, R.N., N.M., P.H.N.,
M.A.
Emiko Hirayama, R.N., N.M., M.A.
Interests:
Interests:
1. Midwifery practice for safety in childbirth
involves analyzing the relationship between environmental
We have focused on issues arising with the prioritization
and maternal factors and how this may affect oxidative stress.
and consolidation of obstetric institutions and the concept of
For example, in one study, measurement of oxidative stress in
health promotion to ensure safety during delivery for women
the cord blood of infants born at term revealed that fetuses
who live far from a childbirth institution. We plan to analyze
had been exposed to oxidative stress (6).
the state of pregnant women who need to travel a long
3. Supporting of breastfeeding on mother and child health
distance to reach a childbirth institution and to develop an
We hope to examine the effects of breastfeeding on
educational program based on the results (1.2). We have
maternal and child health and to clarify evidence that supports
analyzed issues that will help midwives contribute to perinatal
breastfeeding. Our investigation comparing the relationships
care in Hokkaido, where the number of obstetric institutions
between maternal blood pressure and infant weight gain with
has decreased significantly (3.4).
different modes of feeding infants revealed that feeding
2. Women, newborn and child health research
modes had lower blood pressure than those engaged in other
Environmental chemicals may contribute to numerous
modes of feeding (7.8). In the future, we plan to further
adverse health effects in fetuses and infants. We are interested
analyze the effects of breastfeeding on maternal and child
in the negative effects of perinatal environmental factors and
health, and conduct more research regarding support for
maternal lifestyles on the health of fetus and infants. Our
infants and mothers engaged in breastfeeding.
research has two main themes. The first focuses on clarifying
the effects of first trimester folic acid intake, polymorphisms in
genes involved in folate metabolism and lifestyle influences
1) Hayashi Y, Masaoka K, Ogita T. Recognition about the
on congenital abnormality onset (5). The second theme
safety of childbirth in pregnant women living a great
133
distance from any birthing institutions. Sapporo Journal
blood acid-base status and gas values on the yield of
of Health Sciences (2013) 2: 35-43 (in Japanese).
mononuclear cells and CD34+ cells. J Obstet Gynaecol
2) Hayashi Y, Masaoka K, Ogita T. Comparison of recognition
Res (2012) 38(7): 997-1003.
about childbirth safety in pregnant women from two
10) Yamaguchi S, Hirayama E. Factors influencing the self-
rd
evaluation of delivery experience. Japanese Journal of
regions living far from any birthing institution. The 3
International Nursing Research Conference of World
Academy of Nursing Science (2013). Seoul, Korea.
Maternal Health (2011) 52(1): 160-167 (in Japanese).
11)Hayashi Y, Masaoka K. Factors influencing perinatal
3) Sasaki H, Hayashi Y, Yoshimura S, Sagawa T. Research
trauma during vaginal delivery Part 1 - A comparison of
on Midwives’ service related to the merging obstetric
obstetric factors -. Bulletin of the School of Health
hospitals in Hokkaido-opinion of midwives working in the
Sciences. Sapporo Medical University (2010) 13: 53-57
intensified hospitals-. Japanese Journal of Maternal
(in Japanese).
Health (2010) 50 (4): 687-693 (in Japanese).
12)Hayashi Y, Masaoka K. Factors influencing perinatal
4) Yamakawa M, Aiba Y, Takaya Y, Nakayama E, Hayashi Y,
trauma during vaginal delivery Part 2 - A longitudinal
Sagawa T. An investigation into the actual conditions of
comparison of changing episiotomies rates -. Bulletin of
outpatient clinics by midwives in Hokkaido-A study of the
the School of Health Sciences. Sapporo Medical
methods to spread better outpatient clinics by midwives
University (2010) 13: 47-51(in Japanese).
for pregnant women-. Journal of the Hokkaido Obstetrical
13)Masaoka K, Hayashi Y, Maruyama T. Practice-based
and Gynecological Society (2010) 54 (1): 33-40 (in
Knowledge Japanese Midwives Use in Assessing the
Japanese).
Progress of Labor and their underlying experiences.
5) Kishi R, Kobayashi S, Ikeno T, Araki A, Miyashita C, Itoh
Comparison of midwives with less than ten years of
nd
S, Sasaki S, Okada E, Kobayashi S, Kashino I, Itoh K,
experiences and those with longer experience. The 2
Nakajima S.The members of the Hokkaido Study on
International Nursing Research Conference of World
Environment and Children’s Health ; Ten Years of
Academy of Nursing Science (2011). Cancun, Mexico.
Progress in the Hokkaido Birth Cohort Study on
14) Hayashi Y. The present state and problems concerning
Environment and Children’s Health Cohort Profile
health education for pregnant women in rural Morocco.
Update. Environ Health Prev Med (2013). (in press)
Journal of the Japanese Red Cross Hokkaido College of
6) Ebina S, Chiba T, Ozaki T, Kashiwakura I. Relationships
between 8-hydroxy-deoxyguanosine levels in placental /
umbilical cord blood and maternal /neonatal obstetric
factors. Exp Ther Med (2012) 4 (3): 387-390.
7) Ebina S, Kashiwakura I. Influence of breast-feeding on
maternal blood pressure at one month postpartum. Int J
Womens Health (2012) 4: 333-339.
8) Ebina S, Kashiwakura I. Relationships between feeding
modes and infant weight gain in the first months of life.
Exp Ther Med (2013) 5 (1): 28-32.
9) Ebina S, Omori A, Tarakida A, Ogasawara T, Manabe M,
Katagiri S, Kashiwakura I. Influence of umbilical cord
Nursing (2011) 11: 41-47(in Japanese).
134
D CENTER FOR MEDICAL EDUCATION
1 Admissions Research
Admissions Research
Our department studies, implements and evaluates student selection
methods in accordance with the principles of the university.
It is also in charge of publicity and external affairs related to
admissions. This involves the organization of activities such as Open
Campus initiatives, visits to high schools and the dispatch of visiting
lecturers.
Professor
Assistant Professor
Ryuichi Denno, M.D., Ph.D.
Keiji Mise, Ph.D.
Interests:
Interests:
Entrance examination, Digestive
Entrance examination, Statistics
surgery
1. Implements and evaluates student selection methods
the schools of Medicine and Health Sciences to Hokkaido
Our department studies, implements and evaluates
high school career guidance teachers. The opinions and
student selection methods in accordance with the principles
requests obtained in these sessions are important and provide
of the university to select the students who can best contribute
valuable information for the improvement of the entrance
to regional medical care in Hokkaido and conduct advanced
examinations.
international research (1-3). The characteristics we seek in
Furthermore, we help supervise the National Center Test
students are defined in the admissions policy. It is vital that the
for University Admissions every year, always striving to
selection method, criteria and analysis of exam questions are
implement appropriate examinations to the candidates.
reviewed constantly, and it is equally important to monitor
2. Public reactions and external affairs related to
students’ performances upon admission, following their
entrance examinations
progress as they develop into medical professionals.
There are many types of public relations and external
Since medical personnel are required to have not only
affairs for high schools, and their importance has been
medical knowledge and skills, but also communication skills,
increasing in recent years.
we are always striving to find ways to improve the interview
Leap, our highly regarded booklet that provides a detailed
section of the admissions process. From our research into the
introduction of the university, is edited and distributed to
group discussion method, appropriate discussion themes and
candidates every year.
evaluation criteria, we have been able to enact changes
The annual university Open Campus is conducted
adopted by both of the School of Medicine and School of
separately in both schools in August, and the number of
Health Sciences (4).
participants has increased every year since its inception.
In 2012 and 2013, we received objective assessment
Replies to questionnaires distributed to first-year students
data from high school teachers regarding the School of
confirm that many of them participated in the open campus,
Medicine’s examination. This information formed the basis of
suggesting that the event is an important factor for candidates
a report that is being used in order to improve the questions of
considering enrolling at the university (5).
subsequent examinations (private data).
Every year, we receive more than 100 requests from
Every year, questionnaires are given to university
Hokkaido high schools asking that a university representative
candidates on the day of the entrance examination, and again
visit, and introduce the university to their students. Since this
to first-year students following their admissions entrance
is an important opportunity to receive direct feedback from
ceremony. The information from these questionnaires is
high school students and teachers, we try to honor these
analyzed and used to improve both the exam and the
requests as much as possible. However, because of the
interview.
number of requests, we are unfortunately not able to respond
We also conduct briefing sessions every year to introduce
to all of them. How to rectify this situation is an important issue
135
that requires further study (6).
In recent years, requests for visiting lecturers to visit the
high schools have increased. We respond to these requests
thanks to the support of the teaching staff from both schools.
1) Denno R, Mise K, Shimada T, Miura Y, Kurahashi Y,
Segami T. The view of the measures against the influenza
(H1N1) in the entrance examination for 2010. J. Center
for Medical Education Sapporo Medical University, 2011
(2):7-13 (in Japanese)
2) Denno R, Mise K, Shimada T, Tsuchuya S, Miura Y,
Segami T, Ueno Y. Analysis of admissions based on
GPAs score for Health Science School students. J.
Center for Medical Education Sapporo Medical University.
J. Center for Medical Education Sapporo Medical
University, 2012 (3):9-14 (in Japanese)
3) Denno R, Mise K, Misumi Y. Review of the examination
system for Hokkaido community medicine. J. Center for
Medical Education Sapporo Medical University, 2013
4) Mise K, Denno R. Adoption and results of group interview
method on recommended admission test of School of
Medicine. J. Center for Medical Education Sapporo
Medical University, 2012 (3):5-8 (in Japanese)
5) Mise K, Hatate T, Sugiyama A, Kobayashi N, Ninomiya T,
Kimura Y, Akashi H, Kozuka N, Sakaue M, Ishikawa A,
Tanaka G, Denno R. Open days of the Sapporo Medical
University for high school students. J. Center for Medical
Education Sapporo Medical University, 2010 (1):33-39 (in
Japanese)
6) Mise K, Denno R. Presentation Meeting of Sapporo
Medical University for high school students. J. Center for
Medical Education Sapporo Medical University, 2011
136
2 Liberal Arts and Sciences
Philosophy and Ethics
My research is chiefly in the areas of Western philosophy and ethics,
including bioethics and medical ethics.
Assistant Professor
Interests:
Shuku Funaki, M.A., Ph.D.
Kant’s philosophy, Terminal care, Grief
care, Reproductive technologies,
Embryo research
1. Kant’s philosophy and the German Enlightenment
4. Reproductive technologies and embryos research
Kant’s philosophy and its background is one focus of my
I discuss the manners in which the issues “preimplantation
research and I have published a monograph on Kant’s
genetic diagnosis and human enhancement” are commonly
distinction between the terms “plausibility” and “probability”
viewed by researchers in bioethics (8). I also examine the
(2002) (in German). Kant attempted to distinguish these terms
ethical problems present in human embryos research (9).
on the basis of his debates with the authors of the German
Enlightenment. In the course of my research I describe how
Kant also spent his entire life dealing with how the search of
1) Funaki S. Happiness and Morality. Kant’s Study Group
power of judgment was linked with happiness and morality
(eds.), Problems of power of judgment (2009). 68-86.
(1).
Kouyo-shobo, Kyoto (in Japanese).
2. Terminal care
2) Funaki S. Decision-making in terminal care: autonomy
Among recent discussions on euthanasia and death with
vs. compassion. Journal of Mind-Body Science (2009)
dignity, there are two contrasting views. One emphasizes the
18(1): 13-20 (in Japanese).
importance of the patient’s self-determination, and the other
3) Funaki S. Rethinking the problems in euthanasia from
the importance of compassion for dependent patients. I
human relations viewpoint. Journal of Applied Ethics
discuss the question of whether and how these two manners
(2012) 6:3-14 (in Japanese).
of thought can be coordinated (2).
There are many people in the field who focus on the
subject of “euthanasia” from a human relations viewpoint. I
4) Funaki S. Biomedical ethics in a quandary between
autonomy and paternalism. Hokkaido Journal of Bioethics
(2012) 1:1-14 (in Japanese).
examine the theory that reciprocal relations among patients,
5) Funaki S. Ethical inquiry about pain-relieving treatment:
their family members and health care providers are influenced
from palliative care and negative euthanasia to active
by euthanasia policies (3).
euthanasia. Journal of Medicine and Ethics (2013) 9:28-
I am concerned with the question of whether German
36 (in Japanese).
researchers provide a basis to coordinate two contrasting
6) Funaki S. Philosophical inquiry about grief care. Journal
principles—autonomy and paternalism—from a viewpoint
of Medical Philosophy and Ethics (2011) 8:60-64 (in
differing from that of the American ethicists (4).
Japanese).
It is difficult to distinguish terminal sedation or the
7) Funaki S. Philosophical inquiry about family’s death: grief
withdrawal of life-sustaining treatment from active euthanasia.
care seen from viewpoint of human relationship. Journal
In particular, when observed from the viewpoint that death is
of Mind-Body Science (2012) 21(1): 37-45 (in Japanese).
the final result, terminal sedation combined with discontinuation
8) Funaki S. The view of human beings in bioethics today.
of hydration and nutrition closely resembles active euthanasia.
Japan Association of Synthetic Anthropology (eds.),
I explore how this issue can be evaluated from a moral
Thinking about war from a viewpoint of synthetic
standpoint (5).
anthropology (2010). 154-163. Gakubunsha, Tokyo (in
3. Grief care
Japanese).
I examine the concept of “grief” as a natural psychological
9) Funaki S. Rethinking the problem in human used embryos
reaction to the loss of a loved one and “grief care,” or more
research. Journal of Center for Medical Education,
specifically “bereavement care,” as a form of support to those
Sapporo Medical University (2012) 3:21-26 (in Japanese).
suffering (6,7).
137
Psychology
The leading aim of our department is to explore the psychophysiological
mechanisms underlying human stress reaction by adopting the
current methodology of cardiovascular psychophysiology. Our basic
research, especially on developing non-invasive new measures of
cardiovascular hemodynamics, autonomic regulation and vascular
health, has stimulated application studies orienting to the human
mind-body interaction and health promotion.
Associate Professor
Associate Professor
Instructor
Gohichi Tanaka, Ph.D.
Yoshinobu Takahashi, M.A.
Yuichi Kato, M.E.
Interests:
Interests:
Interests:
Cardiovascular psychophysiology,
Child development, Reasoning, Beliefs
Cardiovascular psychophysiology,
Behavioral medicine
about education
Cognitive neuroscience
1. Finger arterial stiffness index (FSI) as a simple measure
of small artery stiffness
Stiffening of the small artery may be the earliest sign of
arteriosclerosis. However, there is no adequate method for
directly assessing stiffness of small artery. The finger arterial
elasticity index (FEI) was defined as the parameter n that
denotes the curvilinearity of an exponential model of pressure
(P)-volume (Va) relationship [Va=a - b exp (- nP)]. For the
original estimation, FEI was calculated from a compliance
index from the finger photoplethysmogram whilst occluding
the finger. A simple estimation of FEI was devised by utilizing
normalized pulse volume instead of the compliance index
(Tanaka & Sawada 2012: Patent No. 5039123). Both
estimations yielded close agreement with the exponential
model in the healthy young participants (Study 1: n=19). Since
FEI was dependent on finger mean blood pressure, normalized
FSI was defined as the standardized residual from their
relationship: mean and SD of FSI was 50 ± 10 (Study 2:
n=174). The mean coefficient of variation of FSI for four
measurements was 5.72% (Study 3: n=6). FSI in 7 ophthalmic
patients was remarkably higher than in healthy youth: 100.0 ±
13.5 and 50.0 ± 10.0 respectively. FEI and FSI by the simple
estimation are valid and useful for arteriosclerosis research
(1).
FSI was validated subsequently for an advanced
arteriosclerosis in diabetes patients (2). Participants were 31
ophthalmic middle-aged patients who were assigned to three
groups: diabetes (DM, 7 patients), diabetes complicate
hypertension (DH, 12), and controls (CT, 12). FSI and FSI for
the high transmural pressure range (FSIH) had been
previously standardized as 50 ± 10 for a healthy young
population. FSI in DH (73.8 ± 11.3) was significantly higher
than CT (54.7 ± 11.8), while intermediate in DM (65.0 ± 14.6).
FSIH was significantly higher in DM (91.2 ± 22.9) and DH
(83.8 ± 31.1) patients than CT (61.0 ± 12.1). These findings
suggest that FSI and FSIH are associated with the stiffness of
the small artery and arteriole in the finger, respectively.
2. Finger arterial flow-mediated compliance response
(FCR) as a simple measure of small artery endothelial
function
FCR is derived from the normalized pulse volume and
compliance index (Tanaka et al. 2002) during reactive
hyperemia, which can reflect a peripheral vascular endothelial
function (Tanaka 2012: Patent application No.222570). FCR
has been validated by close agreement with a standard test of
peripheral artery tonometry Endo-PAT. Discriminant analysis
yielded a mean correct classification rate of over 95% between
diabetes patients (n=49) and healthy young students (n=40)
by combining FCR, FEI and mean blood pressure as
independent measures. A clinical study is in progress in
collaboration with the multicenter using diabetes and
hypertension patients to evaluate the diagnostic and
prognostic usefulness of the comprehensive dilatation
function in the small artery combining FCR and FSI.
3. Allostatic load (AL) as a mediator linking psychosocial
stress, personality and lifestyles to the vascular health
status
AL describes how chronic psychosocial stress relates to
health outcomes. The AL model generally describes how
psychosocial stress and lifestyle factors relate to a long-term
health outcome thorough autonomic, endocrine and immune
multisystems. Stiffening of the small artery may be useful preclinical criterion of AL indicating the earliest sign of
arteriosclerosis. We compared the association of AL with
stress-related factors between two different age groups of
Japanese asymptomatic young men: over 23 (O23: 25.5±3.4,
n=78) vs. under 22 (U22: 20.0±1.3, n=295) as one part of a
prospective cohort study that will examine the effects of
138
chronic psychosocial stress on the early signs of cardiovascular
disease in healthy young people. FSI and FSIH were tested in
terms of their relationship with AL which was defined by the
mean of standard scores for 10 variables: body mass index,
body fat, systolic (SBP) and diastolic blood pressure, highdensity lipoprotein cholesterol (HDL), total cholesterol/HDL
ratio, triglycerides, hemoglobin A1c, insulin resistance
(HOMA) and C-reactive protein. Partial correlations controlling
for age in O23 were significant for AL with FSI (r=.38), Anger
Control-Out (ACO: r=-.39), Anger Control-In (r=-.31),
Meaningfulness in Sense of Coherence (r=-.27) and exercise
(r=-.23). Those in U22 were significant for AL with ACO (r=.12), quick eating (r=.25), favoring fatty and salty meals (r=.19)
and exercise (r=-.15). Arterial stiffness indices were
significantly explained by AL measures using stepwise
regression only in the O23: FSI by SBP (standardized beta
[b]=.40) and HDL-C (b=-.33) and FSIH by age (b=.31) and
HOMA (b=.31). These findings indicate that the small vascular
health is mediated by AL that is differentially associated with
psychosocial factors for the two age groups (3-7).
4. Development of a new noninvasive blood pressure
monitoring device
In collaboration with a manufacturing company of a
biomedical device, we developed a new volume-clamp
device, MUB101 (Medisens, Tokyo). The device can achieve
a reliable measurement of a noninvasive beat-by-beat finger
blood pressure (BP) with two novel techniques: 1) a partial
open cuff-unit is employed for preventing blood from pooling
at the finger tip, and 2) an appropriate cuff position permitting
the least involvement of the finger tissue segment under the
cuff can be checked by observing the alterations of a finger
photo-plethysmographic signal along with a gradual increase
in the cuff pressure.
The long-term accuracy of the MUB 101 was examined
during anesthetized surgical operations. We obtained a total
of 91,812 paired finger and intra-radial BPs in 16 patients and
assessed their difference according to the AAMI criteria.
Results provided us with further evidence of the accuracy of
the MUB 101 (8). Our data may indicate the further potential
clinical uses of this device.
5. Development of a new physiological index to evaluate
a recovery function after stress
Biological recovery function after mental stress has to
date been proposed for the mediation process of stress into
physical health. We mathematically propose that the mean
recovery rate (MRR) is a novel method to evaluate the
recovery function. MRR is calculated as the recovery timeaveraged area under the curve (AUC) divided by the taskinduced reactivity. We measured BP of 142 men before,
during and after mental stress tasks. Compared to the
traditional indexes, our results show that MRR offers
advantages independent of the effect of the initial level of
reactivity (9,10).
Our further challenge is to explore the psychological and
behavioral factors that mediate progress in stress-related
diseases and the promotion of health. Using various measures
including the new device and indexes explained above, our
behavioral epidemiological studies are now ongoing.
1) Tanaka G, Yamakoshi K, Sawada Y, Matsumura K,
Maeda K, Kato Y, Horiguchi M, Ohguro H. A novel
photoplethysmography technique to derive normalized
arterial stiffness as a blood pressure independent
measure in the finger vascular bed. Physiol Meas (2011)
32: 1869-1883.
2)Tanaka G, Maeda K, Kato Y, Matsumura K, Miura T,
Koike G Ohguro H. Finger arterial stiffness index as a
marker of damaged small artery and arterioles in
diabetes. Jpn J Physiol Psychol & Psychophysiol (2011)
29: 217-226. (In Japanese)
3) Tanana G, Kato Y, Matsumura K, Horiguchi M, Ogasawara
H, Sawada Y. The association between chronic
psychosocial stress, allostatic load, and vascular health
in asymptomatic young men: A pilot study using a novel
finger arterial stiffness index. Jpn Psychol Res (2011)
53:140-154.
4) Tanaka G, Horiguchi M. Relationship between
psychosocial chronic stress and vascular health status in
healthy young men The International Conference of 4th
Asian Congress of Health Psychology (2010) Taipei,
Taiwan.
5) Tanaka G. Association between the eating behavior and
a chronic stress as indexed by allostatic load in healthy
young men The Second International Conference of
Indigenous and Cultural Psychology (2011) Bali,
Indonesia.
6) Tanaka G, Kato Y, Matsumura K, Horiguchi M. The
association between chronic psychosocial stress,
allostatic load, and novel finger arterial stiffness indices in
healthy young men. Society for Psychophysiological
Research, The 53th Annual Meeting, October 2-6,
Florence, Italy Psychophysiology (2013) 50;Suppl 1,
S116.
7) Ogasawara H, Tanaka G, Horiguchi M, Kawaguchi A.
Depressive states associated with risk factors for lifestylerelated diseases in medical students : association with
insulin resistance and blood pressure. Jpn J Health
Psychol (2012) 24: 42-49. (In Japanese)
8) Kato Y, et al. A Long-term accuracy of noninvasive beatby-beat blood pressure measurement under anesthesia.
American Society of Aneastheology (2010) A258.
9) Sawada Y and Kato Y. How carryover has an effect on
recovery measures related to the area under the curve:
theoretical and experimental investigations using
cardiovascular parameters. Med Biol Eng Comput (2011)
49:297–304.
10)Kato Y and Sawada Y. Novel Method for Evaluating
Recovery Function after Stress. Behavioral Science
Research (2013) 52: 57-65 (in Japanese)
139
Jurisprudence and Sociology
Associate Professor
Toshihiko Hatate, Ph.D.
Interests:
Medical ethics, Health care law, Legal Philosophy
1. Ethical, legal and social issues of organ transplantation
advisory board to each institution. I also consider how the
and regenerative medicine
community’s role in these ethics committees. I believe the
Organ transplantation encounters serious problems due
ethics committees are crucial in determining how bioethics
mainly to organ shortages. This situation is especially
can be applied to medical ethics.
applicable to Japan because even after the 2010 revisions,
the Organ transplantation Act remains extremely restrictive. I
have examined various discourses in the United States and
1) Hatate, T. Bioethics and Medical ethics(in Japanese),
Japan. In the United States, the proposition that economic
Hokkaido Bioethic Review2013,pp.15-26
incentive for organ donors should be introduced is becoming
2) Hatate, T. ch.12 reading Attitude to Biotechnology
powerful. I hae surveyed the ethical basis for the proposition,
(Japanese translation) in Gene Technology and the
and have concluded that although economic reimbursement
Public An Interdisciplinary Perspective Susanne Lundin,
remains ethical, organ sales are unethical. Also, having
Malin Ideland ed.2012
reviewed the 2010 revisions to the Japanese Transplantation
3) Hatate,T. Transplantation Act revised(in Japanese)
Act, I propose that a donor action program may be expectable.
Journal of Center for Medical Education Sapporo Medical
2. Ethical legal and social issues of regenerative medicine
University vol.2 March2011,pp.31-36
Stem cells are the main sell sources of regenerative
4) Hatate T. Public regulations of Stem Cell Research in
medicine. Among them, the embryonic stem cell and induced
Japan and U.S. THE SAPPORO MEDICAL JOURNAL
pluripotent cell are expected in clinical outcomes. I have
Vol.79, No.1-6 December2010, pp.7-12
overviewed the legislation and ethical guidelines of the United
States and the Japan. Compare to other countries’ regulations,
my conclusion is that the Japanese stem cell guidelines are
very restrictive. I am now trying to design regenerative
medicine regulations that can contribute to the life innovation
policy of the Japanese government and are also transparent
to the national public.
3. Ethics committee
In recent years, I have been committed to and participated
on research ethics committees within and outside our
institution. Each institution has several ethical committees
such as IRB(Institutional Review Board). I am now researching
the role of these ethical committees. According to may
research, ethical committees function as an educational
140
Sociology
Associate Professor
Ryoko Michinobu, Ph.D., M.P.H.
lnterests:
Medical anthropology, Multicultural health education, HIV/
AIDS prevention in the workplace, Children’s health, Medical
environment
Key words: Children, Medicine, Culture, Life, Environment
1. Medical Anthropology
I engage in research and teaching in the areas of
sociology, cultural anthropology and gender studies. My
specific research and teaching interest lies in medical
anthropological studies on HIV/AIDS (1,3,4), women’s and
children’s health (1,3,4), corporate health management (1,3,4)
and multicultural health education (2). My research and
teaching are united by a specific focus on the health and
welfare of socially vulnerable groups of people (5,10),
informed by theoretical approaches drawn from humanistic
medical anthropology as well as applied anthropology.
2. Multicultural health education
My research on multicultural health education has
critically examined the current medical and health science
curriculum offered in Japanese medical and health science
schools (6-8, 11-12). I develop a method of reasoning for
practicing cultural anthropology that is relevant to real-world
social issues, based on the multicultural medical education
theme (6, 9, 10). It is a manner of reasoning that is not defined
by the start and end points of the reasoning but rather is
continual or such reasoning that synthesizes more than one
type of reasoning at a meta level l examine such a meta
reasoning method, introducing a term,“processual reasoning”
(2).
3. HIV/AIDS prevention in the workplace
My research on HIV/AIDS in the workplace aims to
understand the situation of HIV/AIDS management in
Japanese MNCs and to explore reasons for the lack of
corporate responses or collaboration. The study is based on a
systematic review as well as long-term ethnographic case
studies conducted in Japanese-affiliated companies operating
in northern Thailand (1,3,4). Integrating cultural theory into
institutional theory, I specifically explore culturally grounded
ideas of and attitudes toward HIV/AIDS among corporate
actors, the ways in which they frame HIV/AIDS, and particular
features of the institution of HIV/AIDS management in the
Japanese companies (1,3,4).
1) Michinobu R. “HIV is irrelevant to our company”: Everyday
practices and the logic of relationships in HIV/AIDS
management by Japanese multinational corporations in
northern Thailand. Social Science and Medicine 68:941948(2009)
2) Michinobu R. Processual Reasoning in Practicing
Cultural Anthropology: A project case study of multicultural
health education in a Japanese health science school.
Bulletin of the National Museum of Ethnology 85:5376(2009)(in Japanese)
3) Michinobu R. Ethnographic approaches to HIV/AIDS
education in Japanese multinational corporations—at the
intersections of medical anthropology and global health.
An International Conference of the Society for Medical
Anthropology. Connecticut, 2009, 9
4) Michinobu R. A collaborative and participatory ethnography
in search of the best and culturally appropriate HIV/AIDS
workplace management. International Symposium on
HIV and Emerging Infectious Diseases, (Marseille, France,
March 24-26), 2010
5) Sakurai Y, Michinobu R, eds.: Social exclusion in the
modern Thailand-Seeking for the right to education,
health and social participation, Azusa publication, 2010
(in Japanese)
6) Michinobu R, et al.: On the use of photovoice for
understanding health occupations in the first-year
experience of the residential community internship
program at Sapporo Medical University. Bulletin of School
of Health Sciences, Sapporo Medical University 12: 4549, 2010 (in Japanese)
7) Michinobu R. Medical Anthropology and Global Health,
Global 30 Seminar at School of International Health/
Global Health Sciences, the University of Tokyo, Tokyo,
2011, Nov. 24, 25.
8) Michinobu R. Health, Illness, Medicine in “Cultural
Anthropology” 3rd edition, Namihira E, ed. Igaku-Shoin,
p157-189, 2011 (in Japanese)
9)Michinobu R. Let’s start a research. Hokkaido
Occupational Therapy 29(3): 118-122, 2012 (in Japanese)
10)Michinobu R. Health ethnography: A case study of
children using photovoice. Japanese Journal of
Occupational Science 6(1): 15-19, 2012 (in Japanese)
11)Michinobu R. Understanding and appreciating human
cultural diversity: Contributions of cultural anthropology
to medical and health education. Medical Education
(Japan) 2013 (in press) (in Japanese)
12)Michinobu R. Application of cultural anthropological
fieldwork to community-based experimental learning.
Medical Education (Japan) 2013 (in press) (in Japanese)
141
English
Our department has been occupied with a variety of themes involving
English that cover a wide range of specialized fields. These are
comprised of: 1) modern literary criticism with particular reference to
Victorian authors; 2) English linguistics, cognitive linguistics and
typology; and 3) plagiarism and copyright issues and Japanese
literature.
Professor
Associate Professor Assistant Professor Shin Morioka, M.A.
Kazuhiko Yamaguchi, M.A. Gregory Wheeler, M.A. Interests:
Interests:
Interests:
Victorian literature and criticism
English linguistics, Cognitive
Plagiarism and copyright issues,
linguistics, Typology
Japanese literature
1. Literary criticism
In addition to the moral issues of plagiarism, we have
We have explored the imagination and literary dimension
also examined copyright practices of Japanese universities,
in some Victorian writers from the viewpoint of their rhetoric
preparatory schools and other private companies regarding
about gender and sexuality. Our study also examines the
the use of previously published material in Japanese entrance
broader scope allowed by present-day scholarship of print
exams. Results of research toward this issue indicate that
culture for our reading of nineteenth century English literature. although the majority of universities tend to remain within the
2. English Linguistics, Cognitive Linguistics and Typology
guidelines of what is considered appropriate (or even legal)
There are two main strands to our study. First, we have
use of this material, at the same time many appear to engage
conducted data-driven analysis of capability-constructions in
in practices that approach copyright infringement. Moreover,
English (e.g. be able to, be capable of). We have carried out
the manner in which these already published works are used
an
by several of the preparatory schools and companies often
analysis
of
characteristics
of
English
capability-
constructions in the choice of source material. We have
raises legal questions.
compared the capability-constructions of English and
Japanese from a typological perspective. Second, we have
made comparisons of “acquisitive”-verbs (e.g., English get or
1) Morioka, S. Walter Pater and his sensory balance (in
Japanese morau and the semantically corresponding lexical
Japanese). The Aesthetics of Pater’s Renaissance (2012):
items in other languages) in English, Japanese, Korean and
165-182.
Chinese and proposed the possible correlation of language
2) Yamaguchi, K. On the semantic network of “acquisitive”-
types and the productivity of the uses of “acquisitive”-verbs. In
verb constructions. A report on the project of the
addition, we have proposed the cross-linguistic semantic
advancement of research. Sapporo Medical University
network of “acquisitive”-verbs.
3. Plagiarism and copyright issues
(2009): 546-564.
3) Yamaguchi, K. On the grammatical category of capability-
It has often been argued that plagiarism is a concept with
constructions. J Center for Medical Education. Sapporo
which most Japanese are unfamiliar. Differing from attitudes
Med. Univ. (2010) 1:43-54.
in the “West,” Japanese (Asians) supposedly have rather
4) Yamaguchi, K. et al. An analysis of polysemy based on
lenient views toward plagiarism and do not consider it morally
explicit characteristics—case of Hokkaido dialect -rasaru.
wrong. We have explored this so-called culture argument and
Proceeding of 141th Annual Meeting of Linguistic Society
find it to be incorrect; plagiarism is indeed considered a moral
of Japan (2010): 120-125.
issue in Japan and is not accepted nearly as readily as many
Western academics would have us believe.
5)Yamaguchi,
K.
English
and
Japanese
capability-
constructions from a typological perspective. In Nose, M
142
ed. What is revealed by contrasting Japanese and
language X. Sankeisha (2011): 174-183.
6) Yamaguchi, K. A characteristic of English in the choice of
the source material of capability-constructions. Studies in
English Literature - Regional Branches Combined Issue
(2011) 4: 91-99
7) Yamaguchi, K. On the semantic network of “acquisitive”verbs: A comparison of Japanese, Chinese, Korean, and
English. A Study on Japanese Language and Culture 2
part 1. Yan Bian University Press (2012): 281-288.
8) Yamaguchi, K. The productivity of the uses of “acquisitive”verbs and Language Type. J Center for Medical
Education. Sapporo Med. Univ. (2013) 4:21-26.
9) Wheeler, G. Examining plagiarism by Japanese university
students: truly a cultural matter? Journal of Second
Language Writing, (2009) 18(1):17-29.
10)Wheeler, G. Copyright issues concerning Japanese
university entrance exams. The Language Teacher,
(2009) 33(8):3-7.
11)Wheeler, G. Hollywood’s Japan: a study of how the
Japanese have been depicted in American movies since
the mid-1980s. Journal of Center for Medical Education
at Sapporo Medical University (2010) 1:55-66.
12) Wheeler, G. Examining how native English speakers in
Japan view Japanese physicians’ bedside manner.
Journal of Medical English Education (2011) 10(1):14-19.
13)Wheeler, G. A qualitative study of three preparatory
schools’ answers to the English writing section of a
Japanese university’s entrance exam. Journal of Center
for Medical Education at Sapporo Medical University
(2011) 2:43-48.
14)Wheeler, G. Addressing copyright concerns regarding
Japanese university entrance exams. In A. Stewart (Ed.),
JALT2010 Conference Proceedings (2011):1-6.
15) Wheeler, G. The culture argument regarding plagiarism
and how it does not apply to Japan. Journal of Center for
Medical Education at Sapporo University (2012) 3:33-40.
16) Wheeler, G. The akahon publications: Their appeal and
copyright concerns. Shiken: JALT Testing & Evaluation
SIG Newsletter; (2012) 16(1):23-26.
17)Wheeler, G. Survey on Sapporo Medical University
student attitudes regarding the necessity of citing
sources. Journal of Center for Medical Education at
Sapporo Medical University (2013) 4:27-32.
143
Exercise Science
Our laboratory has investigated the relationship between nutrition
and physical training in promoting physical fitness, improving body
composition, increasing bone formation and preventing lifestylerelated chronic diseases. Our epidemiological studies have clarified
health practices contributing to good health among the middle aged
and good ADL status in older adults as well as the prevalence of and
reasons for disordered eating among female athletes.
Associate Professor
Goroh Okano, M.S., Ph.D.
Interests:
Exercise epidemiology, Exercise physiology
1. Exercise epidemiology
fitness. a) Health promotion in middle aged and older adults
a) Health promotion in middle aged and older adults
Our epidemiological studies have clarified the importance
of physical activity for achieving and maintaining good health.
1) Okano G, Hattori M, Kawai M, Tanifuji T, Kitada M, Mori
This study is on-going and demonstrates how physical activity
M. Relationship between gait ability and past health
is one of the most effective factors toward achieving good
practices in older people living in the community.
health in the middle aged and maintaining good ADL in older
Hokkaido JPH (2009) 22:54-61 (in Japanese)
2) Okano G. Physical activity and health in middle-aged and
adults (1-4).
b) Disordered eating in athletes
elderly people. Sapporo Med J
In previous studies, we reported that Japanese athletes
Japanese)
(2011) 80 : 1-6 (in
obtained fewer nutrients and less energy than their Chinese
3) Okano G, Hattori M, Kawai M. Relationship between
counterparts, and a number of Japanese female athletes
health status and a family budget in older people living in
suffered from disordered eating resulting amenorrhea.
community. Annu Bul Res Inst Soc Sci (2012) 43:173-
Compared to the Japanese athletes, the prevalence of
181 (in Japanese)
disordered eating and amenorrhea was much lower in the
4) Kawai M, Okano G. Consideration of social effect influences
Chinese female athletes. We suggested that this could be at
implementation of woman exercise. Annu Bul Res Inst
least partially due to the differences in the socioeconomic
Soc Sci 43:183-188 (2012) (in Japanese)
factors between the two countries and/or divergent perceptions
of weight ideation for improving performance.
2. Exercise physiology
Intramuscular triglycerides are an important energy
source during prolonged exercise. Additionally, triglyceride
content in the skeletal muscles influence insulin sensitivity
and thereby carbohydrate and fat metabolism. However, the
role of intramuscular triglycerides, especially in humans, has
1
not been thoroughly elucidated. Using H-MR spectroscopy,
we have determined the triglyceride content of lower leg
muscles in term of differences in age, gender and physical
144
Physics
Our department focuses on the science of radiation protection and
medical physics. Research on radiation protection covers dosimetry,
as well as emergency radiation medicine concerning historical
nuclear disasters and present topics. Our research on medical
physics covers methodology of dosimetry for nuclear and radiation
medicine.
Professor
Assistant Professor
Jun Takada, M.S., Ph.D.
Kenichi Tanaka, M.E., Ph.D.
Interests:
Interests:
Radiation protection and dosimetry,
Medical physics, Radiation protection
Emergency radiation exposure medical care,
Medical physics
1. Science for Radiation Protection
situ dose evaluations did not suitably address health hazards.
Dosimetry of residents in nuclear hazards was previously
This study has focused on internal dosimetries of iodine-131
studied through physical methods. This entailed external and
in the thyroid and cesium-134/137 in the whole body. We have
internal doses for residents being systematically evaluated by
especially been studying radiation hygiene in cattle livestock
in-situ measurements for activities in environment, food, the
in Namie, a town located within the 20km evacuation zone
human body, environmental radiation and laboratory sample
around the Fukushima Daiichi nuclear power station. To date,
analysis. Our findings resulted in the 2005 publication of
we have found no problem regarding recovery prospects.
Nuclear Hazards in the World.
Finally, we have conducted research in China, which has
The residents around the Mayak plutonium production
had 46 nuclear explosions with yields of 20 megatons over a
complex in the former USSR were studied in situ in April-May
wide area extending to more than 1000km along the Tarim
2000. The study indicated the presence of serious internal Sr-
Basin. Field studies for radiation were conducted in and
90 exposure. Beta ray measurements on the front teeth of the
around the Taklamakan Desert by our research group in 2012.
Rongelap people carried out in 2005 showed considerable
These studies indicated there were lethal risks in the areas.
doses of internal radiation produced by Sr-90. We applied
2. Medical physics
similar tests for Sr-90 internal dosimetry on Japanese people
At present, medicine uses radiation as one of its important
in order to check for radioactive fallout from Chinese nuclear
components. Its technology is rapidly progressing, especially
explosions. The maximum evaluated dose was 7mSv.
in the past decade. Methods of delivering prescribed doses
The largest critical radiation accident to date in Japan
and accomplishing desired outputs in the radiation therapy of
occurred at the uranium conversion facilities in the village of
cancers and diagnostic applications have become more
Tokai on September 30, 1999. This accident taught us the
widespread and sophisticated. These include rapid arc
importance of dose evaluation and radiation protection,
radiation therapy, intensity modulated radiation therapy
reading available information and lectures, and psychological
(IMRT), image guided radiation therapy (IGRT) and diagnostic
care for the local population. We are studying ways in which
applications such as interventional radiology (IVR). In any
we can be better prepared in the future to deal with these
application, an essential factor is how precisely the dose is
issues. We have analyzed anisotropic radiation distribution
evaluated and also controlled. However, the accidental
and evaluated the external doses for residents involved in
radiation exposures in medicine have been remarkable, due
JCO accidents.
to mechanical, technical and/or human errors. In order to
In addition to the above, we also conducted a radiation
avoid such errors, quality assurance/quality control (QA/QC)
hygiene survey after the March 2011 Fukushima Dai-Ichi
activities have been conducted to assure and control precision
nuclear power station disaster due to the tsunami caused by
in radiation usage. In these matters, medical physics is
the enormous earthquake. Our survey has revealed that the
necessary when using radiation in medicine. In the course of
public annual dose was 10 mSv following the disaster and in
our research, we describe how radiation protection has a
145
considerable role in medical physics, especially in regard to
radiation usage safety.
(Edited by Sara Liberman et al.). (2010) .195-198.
11) Kanamori M, Suto T, Tanaka K, Takada J: A study on
Based on this background, our department is working on
medical physics research topics such as dosimetry, QA/QC
dose control for Tokaimura criticality accident termination,
Rad. Prot. Dosimetry, (2011).146: 42-45.
and related topics, dose control for patients and medical
12)Takada J. East Japan Radiation Hygiene Survey and
workers regarding various radiation diagnoses, and therapy
Rehabilitation plan in 20km area of Fukushima 1st nuke,
including, among others, brachytherapy and neutron capture
Radiation Protection Medicine 7.(2011):1-8 (in Japanese).
therapy. This research is carried out through both experiments
13) Takada J: Fukushima: Neither Chernobyl, Nor Hiroshima,
and simulation calculations. Additionally, in cooperation with
Global EnergyPolicyResearch, http://www.gepr.org/en/
the department of Radiology, our department takes part in
contents/20120220-01/ 2011.
research and education activities. This joint effort is referred
14) Tanaka K, Takada J. Development of in-situ measurement
to as the “Cancer professional training plan.”
method for 90Sr contamination, Radiation Protection
Finally, we have determined three laws that define
Medicine 7(2011).37-40 (in Japanese).
humans’ relationship with radiation: 1) Life does not exist
15) Tanaka K. Takada J. Development of in-situ measurement
without nuclear energy from the sun, 2) low dose rate radiation
for 90Sr specific activity by b ray survey meter combined
is key to staying healthy and 3) low dose rate radiation is key
with sensitivity correction by Monte Carlo calculation,
Applied Radiation and Isotopes, (2011).69: 814-817.
to staying healthy.
16) Tanaka K. Endo S. Hoshi M. Takada J. Development of
monitoring method of spatial neutron distribution in
1) Takada
J.Chinese
Nuclear
Tests.
(2009).1-158.
Iryokagakusya, Tokyo. (English and Uyghur).
2) Takada J.Hopeful Nuclear Energy Technology in Japan.
neutrons-gamma rays mixed field using imaging plate for
NCT – Depression of the field –, Applied Radiation and
Isotopes, (2011).69: 1885-1887.
Radiation Protection Medicine 5.(2009).1-8(in Japanese).
17) Tanaka K. Tateoka K. Asanuma O. Kamo K. Bengua G.
3) Takada J. Nuclear Desert and Risk on Silk road
Sato K. Ueda T. Takeda H. Takagi M. Hareyama M.
sightseeing.(2009). 1-78, Iryokagakusya, Tokyo (in
Takada J. A dosimetry study of the Oncoseed 6711 using
Japanese).
glass rod dosimeters and EGS5 Monte Carlo code in a
4) Tanaka K, Yokobori H, Endo S, Kobayashi T, Bengua G,
Saruyama I, Nakagawa Y, Hoshi M. Characteristics of
proton beam scanning dependent on Li target thickness
from the viewpoint of heat removal and material strength
for accelerator-based BNCT, Appl Rad Isot. (2009).67:
259-265.
geometry lacking radiation equilibrium scatter conditions,
Medical Physics, (2011).38: 3069-3076.
18) Takada J. Fukushima: Myth and Reality, Iryokagakusya,
(2012).1-59, Iryokagakusya, Tokyo.
19)Nakagawa Y, Takada J. Japan perish nuclear zero,
(2012).1-253, Okura, Tokyo.
5) Tanaka K, Takatsuka S, Kamo K, Takada J. Radiation
20) Takada J. Radiation hygiene survey on human and cattle
damage of semiconductor element by gamma ray
in Fukushima prefecture, No health hazards due to low
exposure, Radiation Protection Medicine 5.(2009).32-35.
doses, 1-4,The Sapporo Medical Journal, (2012).81,1-4 .
6) Takada J. Lessons of Nuclear Radiation Protection from
21) Murahashi H, Takada J. Lower mortality rate of colorectal
Nuclear Weapon Developments in the Soviet.(2010).1-
cancer in areas with higher dose rate of ultraviolet, J.
124 (in Japanese).
Center
7) Takada J. Nucleus and sword, Showa history and
struggles Heisei, Meiseisha.(2010).1-300.Meiseisha, Tokyo.
8) Kanamori M, Suto T, Tanaka K, Takada J: A Study on
Dose Evaluation for Tokaimura Criticality Accident
Termination, JAEA-Technology 2010-025.(2012)1-11.
9) Tanaka K. Endo S. Hoshi M. Measurements of neutron
for
medical
education,
Sapporo
Medical
University,(2013).4:17-20.
22) Takada J. Low Dose Radiation and No Health Risk in
Fukushima in Contrast to Chernobyl, Genes and
Environment,(2013). 35(3):69-72.
23) Tanaka K, Takada J. Development of collimator for in-situ
measurement of
90
Sr specific activity by b-ray survey
distribution in neutrons-gamma rays mixed field using
meter and Monte Carlo calculation, Applied Radiation
imaging plate for neutron capture therapy. Applied
and Isotopes, (2013).77: 1-4 .
Radiation and Isotopes, (2010) 68: 207-210.
10) Tanaka K. Endo S. Hoshi M. Takada J. Development of
monitoring method of spatial neutron distribution in
neutrons-gamma rays mixed field using imaging plate,
Challenges in Nutron Capture Therapy (Proc. of the 14th
International Congress on Neutron Capture Therapy)
24) Takada J. We cannot live without radiation. (2013).1-107,
Iryokagakusya,, Tokyo (in Japanese).
25) Takada J. Past and Present of the Silk Road.(2013).1-75,
Iryokagakusya, Tokyo (in Japanese).
Takada J. We control the nuclear power in the 21
st
century. (2013).1-281, Iryokagakusya, Tokyo (in Japanese).
146
Biophysics
Professor
Norio Matsushima, Ph.D.
Interests:
Tandem repeats, Leucine-rich repeat, Bioinformatics, System
biology, Proteomics, NMR, Small-angle x-ray scattering
1. Biology of tandem repeats in proteins
2) Nunomura W, Jinbo Y, Isozumi N, Ohki S, Izumi Y,
Tandem repeats occur in 14% of all proteins. The repeat
Matsushima N, Takakuwa Y. “Novel Mechanism of
unit lengths range from a single amino acid as in polyglutamine
Regulation of Protein 4.1G Binding Properties Through
to more than 100 residues as in spectrin and the repeat
Ca(2+)/Calmodulin-Mediated Structural Changes”
number is sometimes over 100. Leucine-rich repeats (LRRs)
Cell Biochem Biophys.(2013) 66(3):545-558.
are present in over 20,000 proteins from viruses to human.
3) Matsushima N, Miyashita H. “Leucine-rich repeat (LRR)
Most LRR proteins are involved in protein-ligand and protein-
Domains
protein interactions; these include the plant immune response
containing
intervening
motifs
in
plants”
Biomolecules, (2012) 2: 288-311.
and mammalian innate immune response. We studied the
4) Mikami T, Miyashita H, Takatsuka S, Kuroki Y, Matsushima
structures, functions and evolution of LRRs through a
N. “Molecular evolution of vertebrate Toll-like receptors:
bioinformatics approach. We also developed a new method
Evolutional rate difference between their leucine-rich
for the identification of LRR motif.
repeats and TIR domains” Gene (2012) 503(2):235-243.
a) “IRREKO” LRR: We found a nested LRR repeat in bacterial
5) Enkhbayar P, Boldgiv B, Matsushima B. “w-Helices”,
proteins. This novel LRR domain has 21 residues with the
Curr.Top. in Peptide & Protein Res. (2011)12:17-28
consensus sequence of LxxLx(L/C)xxNxLxxLDLxx(N/L/Q/x)
6) Matsushima N, Miyashita H, Mikami T, Yamada K. “A new
xx. This LRR domain is characterized by a nested periodicity.
method for the identification of leucine-rich repeats by
b) Evolution of Toll-like receptors (TLRs): TLRs that initiate an
incorporating protein secondary structure prediction” in
innate immune response contain an extracellular LRR domain
Bioinformatics:
and an intracellular Toll IL-receptor (TIR) domain. Both
Computational Biology (Renu Tuteja editor); NOVA
pairwise genetic distances and Ka/Ks values were compared
Sience Pulishers: Hauppauge, NY, USA, (2011) pp. 61-
between the LRR domain and the TIR domain of 366
88.
Genome
Bioinformatics
and
vertebrate TLRs from 96 species. In most cases, the LRR
7) Matsushima N, Miyashita H, Mikami T, Kuroki Y. “A nested
domains evolved significantly more rapidly than did the
leucine rich repeat (LRR) domain: The precursor of LRRs
corresponding TIR domains. TLR10 showed no significant
is a ten or eleven residue motif”. BMC Microbiol. (2010)
differences.
10(1):235.
2. Structural bioinformatics
a) A helix is described by several parameters: the helix axis,
8) Enkhbayar P, Boldgiv B, Matsushima N .” w-Helices in
proteins”. Protein J. (2010) 29(4):242-9.
the radius and the pitch. We developed the HELFIT program
9) Matsushima N. Mikami T. Tanaka T. Miyashita H. Yamada
for fitting helices to Ca coordinates that determine all the helix
K. Kuroki Y. Analyses of Non-Leucine Rich Repeat (Non-
parameters.
LRR) Regions Intervening Between LRRs in Proteins”
b) A modification of the a-helix, termed the w-helix, has four
residues in one turn of a helix. Through HELFIT analysis we
indicated that the w-helices actually occur in proteins.
Biochim Biophys Acta. 1790(10):1217-1237(2009)
10) Matsushima N. Tanaka T. Kretsinger RH. “Non-globular
structures of Tandem repeats”.Protein & Peptide Letters
16(11): 1297-1322 (2009)
11)Nishitani C, Takahashi M, Mitsuzawa H, Shimizu T,
1) Miyashita H, Kuroki R, Kretsinger RH, Matsushima N.
Matsushima N, Kuroki Y. “Mutational analysis of Cys88 of
Horizontal gene transfer of plant-specific leucine-rich
Toll-like receptor 4 highlights the critical role of MD-2 in
repeats between plants and bacteria” Natural Science,
cell surface receptor expression” Int Immunol. (2009)
(2013) 5(5): 580-598.
21(8):925-934.
147
Chemistry
Professor
Assistant Professor
Hirotada Fujii, Ph. D.
Youichi Yachida, Ph.D.
Interests:
In vivo detection of reactive oxygen species (ROS), free
radicals, and their biological functions
1. In vivo detection and imaging of bioradials
possibly image oxidative stress in living systems.
The challenge of developing both spin-imaging and in
vivo electron paramagnetic resonance (EPR) in living systems
requires a large number of changes in classical x-band EPR
1) Emoto CM, Yamada K, Yamato M, Fujii GH. Novel
spectroscopy. These changes are necessary in the X-band
ascorbic acid-resistive nitroxide in a lipid emulsion: An
EPR system due to the large water content of living tissue and
efficient brain imaging contrast agent for MRI of small
the large volume of the sample itself. In order to obtain free
rodents. Neuroscience Letters. (2013) 546; 11-15.
radical information from the biological system including small
2) Miyake Y, Wang X, Amasaka M, Itto K, Xu S, Arimoto H,
animals and cultured cell systems, we have been developing
Fujii H, Hirata H. Simultaneous imaging of an enantiomer
in vivo ESR spectroscopy at L-band microwave frequency
pair by electron paramagnetic resonance using isotopic
(300-1200 MHz) (1,2,4). EPR imaging instrumentation,
nitrogen labeling. Anal Chem. (2013) 85; 985-90.
enabling the performance of three-dimensional spectral-
3) Kohri, S, Fujii H. Modified oxygen radical absorbance
spatial images of free radicals, has been developed to study
capacity assay that can be implemented at low
spatially defined differences in tissue metabolism and
temperatures: A pilot study. Food Sci. Technol Res.
oxygenation. Using L-band in vivo ESR spectroscopy, we
(2013) 19; 269-276.
succeeded in detecting important bioradicals, nitric oxide
4) Fujii HG, Sato-Akaba H, Emoto MC, Itoh K, Ishihara Y,
(NO), generated in disease-model animals, seizure mice and
Hirata H. Noninvasive mapping of the redox status in
septic-shock mice (3,6).
septic mouse by in vivo electron paramagnetic resonance
imaging. Magn Reson Imag. (2013) 31; 130-138.
2. MRI as a new tool to visualize free radicals
5) Koda S, Goodwin J, Khramtsov VV, Fujii H, Hirata H.
We developed a new approach to use the NMR/MRI
Electron Paramagnetic Resonance-Based pH Mapping
method combined with the spin-trapping method to visualize
Using Spectral-Spatial Imaging of Sequentially Scanned
bioradicals generated in small animals. Free radicals captured
Spectra. Anal Chem. (2012) 84; 3833-3837.
by a spin-trapping agent, if their stability is long enough, can
6) Sueishi Y, Ishikawa M, Yoshioka D, Endoh N, Oowada
be used as contrast agents in MRI, and spatial localization of
S, Shimmei M, Fujii H, Kotake Y. Oxygen Radical
free radicals might then be visualized by MRI. We did a
Absorbance Capacity (ORAC) of cyclodextrin-solubilized
feasibility study showing that a new methodology known as
flavonoids,resveratrol and astaxanthin as measured with
the ‘MRI spin-trapping method’ can visualize NO distribution
the ORAC-EPR method. J Clin Biochem Natr (2012) 50;
in septic-shock rats (5,7). Our ultimate goal is to develop new
127-132.
approaches that couple the strengths of spin trapping with
7) Emoto M, Mito F, Yamasaki T, Yamada K, Sato-Akaba H,
methodologies that promise to overcome problems such as
Hirata H, Fujii H. A novel ascorbic acid-resistant nitroxide
radical adduct decomposition. Besides the MRI spin trapping
in fat emulsion is an efficient brain imaging probe for in
method, new complementary techniques include: 1) NMR
vivo EPR imaging of mouse. Free Radic Res. (2011) 45;
spin trapping, which monitors new NMR lines resulting from
1325-1332.
diamagnetic products of radical spin adduct degradation and
reduction, and 2) oxygen mapping by EPR imaging
methodology using oxygen-sensitive paramagnetic materials.
Although some of these approaches are in their infancy, they
are promising and versatile techniques to measure and
148
Biology
The three faculties each have their own research issues on problems
in medical or fundamental biology. The current issues of the members
are as follows: transcriptional regulation of cancer-related genes,
molecular pathology of sarcomas, molecular and cellular biology of
immune synapse, live cell imaging analysis of signaling molecules,
methodology for molecular biological microscopy, taxonomy and
ecology of nematodes. We have a course of "Molecular and Cellular
Biosciences" for graduate students.
Professor
Associate Professor
Associate Professor
Koichi Yoshida, M.S., Ph.D.
Kenji Kito, M.S., Ph.D.
Takeshi Suzuki, M.S., Ph.D.
Interests:
Interests:
Interests:
Molecular biology, Molecular oncology
Animal taxonomy, Ecology
Cell biology of signaling molecules,
Molecular and cellular immunology,
Molecular biological microscopy
1. ETS transcription factors in invasion and metastasis
may act as an oncogenic transcription factor in pathogenesis
of cancer cells
of Ewing’s sarcoma and peripheral neuroectodermal tumors.
Invasion and metastasis, major obstacles to an effective
3. Rapid attenuation of DAG in immune synapses during
cancer therapy, are complex multi-step processes. Proteolytic
productive T cell activation
enzymes including those in the matrix metalloproteinase
Membrane
(MMP) family may causally be involved in tumor cell invasion,
sustained receptor engagement activates T cells and prevents
by facilitating the breakdown of physical barriers such as
their anergy. DAG binds conserved cysteine rich C1 domains
interstitial collagen fibers. We previously showed that an ETS
in signaling proteins. Remarkably, little is known about the
transcription factor, E1AF, positively regulates transcription of
spatial-temporal regulation of DAG in immune synapses and
MMP genes and activates the Rho/Rho-associated kinase
the differential synaptic involvement of select DAG-binding
pathway to increase the malignancy potential of non-small-
proteins remains puzzling. We found that, contrary to its
cell lung cancer cells. Expression of E1AF is correlated with
expected accumulation, specific biosensors detected synaptic
malignant phenotypes in tongue squamous cell carcinoma
DAG just at the onset of intercellular antigen recognition by T
and malignant melanoma. Additionally, we showed that STAT3
cells. DAG produced by PLCγ1 was instantly consumed by
(signal transducers and activators of transcription 3) is
DGKα. Thus, physiological T cell activation is coordinated by
required for EGF induction of collagenase-1 and cell migration
robust regulated attenuation of DAG that directs essential
and invasion, as well as tumor-forming activity in nude mice.
signaling in functional immune synapses. (Manuscript in
2. Molecular pathogenesis of Ewing’s sarcoma and
preparation)
diacylglycerol
(DAG)
generated
during
peripheral neuroectodermal tumor (ES/PNET)
4. Blocking of CD28 costimulation prolonged the appearance
ES/PNET is a primitive mesenchymal tumor composed of
of DAG along the immune synapse
small round cells showing limited neural differentiation, arising
PKCθ is a key enzyme in T cells, where it plays an
within bones or soft tissue in a child or adolescent. ES/PNETs
important role in signal transduction downstream of the
contain a specific chromosomal translocation resulting in the
activated TCR and the CD28 costimulatory receptor.
fusion of the EWS gene and the ETS family gene of
Engagement of CD28 provides costimulatory signals that
transcription factors. We previously identified a fusion of the
synergize with the signals by TCR, leading to optimal
EWS and E1AF genes by a t(17;22)(q12;q12) chromosomal
activation of T cells. TCR engagement in the absence of
translocation in an undifferentiated sarcoma of infancy.
CD28 costimulation results in anergy. In this study, we
Molecular analysis provided structural characteristics of the
examined the effects of blocking of CD28 costimulation on the
EWS-E1AF gene and insight into the mechanism of
dynamics of PKCθ and DAG along the immune synapse.
chromosomal translocations. The EWS-E1AF fusion protein
Soluble CTLA4-Fc, which inhibits CD28 costimulation, did not
149
release PKCθ-GFP from the immune synapses but the
T, Yokoo S, Takata K. Function of the membrane water
membrane-bound PKCθ was spread out in the synapse
channel aquaporin-5 in the salivary gland. Acta
instead of being clustered at the center of the synapse. This
Histochem. Cytochem. 45: 251-259 (2012)
result was very similar to our previous results of inhibition
3) Aoki T, Suzuki T, Hagiwara H, Kuwahara M, Sasaki S,
experiments with R59949, which specifically inhibits DGKα.
Takata K, Matsuzaki T. Close Association of Aquaporin-2
We then localized DAG production in the presence of CTLA4-
Internalization with Caveolin-1. Acta Histochem. Cytochem.
Fc. Soluble CTLA4-Fc prolonged the appearance of DAG
along the immune synapse in the same manner as R59949.
45: 139-146 (2012)
4) Hagiwara H, Aoki T, Suzuki T, Takata K. Pre-embedding
Moreover, in the presence of CTLA4-Fc DGKα was not
immunoelectron
recruited at all to the synapse. These results indicated that
mammalian tissue culture cells. Schwartzbach and
during normal T cell activation CD28 costimulation regulates
Osafune eds., Immunoelectron microscopy, Methods in
the right timing of the recruitment of DGKα to the immune
Molecular Biology 657,145-154, Springer Science +
synapse, the transient appearance of DAG and the specific
Business Media, New York (2010)
localization of active PKCθ. (Manuscript in preparation)
microscopy
of
chemically
fixed
5) Hagiwara H, Aoki T, Suzuki T, Takata K. Double-label
5. Bio-imaging analysis in living mammalian cells
immunoelectron
microscopy
for
studying
the
Mec17/αTAT1 is a key enzyme for tubulin acetylation in
colocalization of proteins in cultured cells. Schwartzbach
mammalian cells, where it plays an important role for
and Osafune eds., Immunoelectron microscopy, Methods
stabilization of the microtubule cytoskeleton. We made a
in Molecular Biology 657, 249-257, Springer Science +
visible fluorescent probe for Mec17/αTAT1 by linking with
Business Media, New York (2010)
EGFP and induced it into the rat fibroblast 3Y1-B cells, and
6) Yamagiwa M, Ozeki Y, Omura G, Suzuki T, Kajiyama S,
analyzed the results by live cell imaging with fluorescent
Fukui K, Itoh K. Nonlinear phase imaging using two-
deconvolution microscopy. The probe was restricted to the
beam interferometry in SPE microscopy. Jpn J Appl Phys.
centrosome in resting cells of the confluent cell sheet.
48: 062501 (2009)
Conversely, the probe localized at reading edges in migrating
7) Suzuki T, Tanaka K. Visual Basic macro-program for
3Y1-B cells. These results suggested that the probe visualizes
Microsoft Word useful for planning the recombinant DNA
the site of tubulin acetylation in living mammalian cells, and
experiments. J Cent Med Edu Sapporo Med Univ. (in
that the tubulin acetylation occurs at the centrosome in resting
press) (in Japanese)
cells and reading edge in migrating cells (1). We also
8) Aryuthaka C, Kito K. Two new species of the genus
visualized the various membrane proteins such as aquaporin
Daptonema Cobb, 1920 (Nematoda: Xyalidae) found in
(2) and caveolin (3), and are investigating the methods for
the monospecific Halophila ovalis patches within an
molecular biological microscopy (4-7).
intertidal mixed-species seagrass bed on the coast of the
6. Taxonomy and ecology of free-living nematodes
Andaman Sea, Thailand. Zootaxa 3350: 34–46 (2012).
Free-living nematodes, which are found in nearly every
9) Kito K, Chatterjee T. New species of the genera
conceivable niche of the biosphere, have been taxonomically
Draconema Cobb, 1913 and Paradraconema Allen &
and ecologically studied. The main objective is to clarify the
Noffsinger, 1978 (Nematoda: Draconematidae) from the
biodiversity of marine nematodes and their role in the marine
Andaman Islands, Indian Ocean, with keys to the species.
ecosystem.
Zootaxa 3575: 78–88 (2012).
Currently, the taxonomic study of nematode
fauna has been carried out in seagrass and mangrove
10) Kagoshima H, Kito K, Aizu T, Shin-i T, Kanda H, Kobayashi
communities on the coasts of Thailand (8) and India (9).
S. Multi-decadal survival of an Antarctic nematode,
Regarding terrestrial nematodes, we evaluated the cold
Plectus murrayi, in a -20°C stored moss sample.
tolerance of Antarctic soil nematodes, using specimens
CryoLetters 33 (4), 280-288 (2012)
recovered from a -20°C stored moss sample and identified by
morphological examination and nucleotide sequencing of
ribosomal RNA loci (10).
1) Suzuki T, Nakakura T, Hagiwara H. Bio-Imaging of AlphaTubulin Acetyltransferase in Living Mammalian Cells. J
Cent Med Edu Sapporo Med Univ. 4: 11-15 (2013) (in
Japanese)
2) Matsuzaki T, Susa T, Shimizu K, Sawai N, Suzuki T, Aoki
150
Information Science
Associate Professor
Toshio Ohyanagi, D. Eng.
Interests:
Information technology for health sciences, Homecare and
remote monitoring systems, Information and communication
technologies, Physical computing
1. Information technology for health sciences
Measuring reaction time (RT) is one of the basic methods
to evaluate patients with disorders. We have been developing
new RT tasks with visual and/or auditory stimuli for both
research work and clinical applications. Before applying the
developed tasks to patients, we tested the tasks with healthy
people to accumulate data into a database and identify norms
of the tasks. We then applied the tasks to patients to
investigate whether they are effective in evaluating patients
(1-4).
Timing accuracy in measuring RTs on computer systems
has been studied by many researchers. It is known that
monitor displays, devices for responding to stimuli, operating
systems (OSs) of the computers used and software for
presenting stimuli are major technical factors influencing the
timing accuracy. We have developed a new solution for
measuring accurate reaction time (SMART) to visual stimuli.
We showed that SMART is a simple and practical solution to
accurately measure RTs in both laboratory and clinical settings
and is capable of providing both researchers and health
professionals working in clinical settings new ways of using
RT paradigms in their work (5).
We developed a new handwriting assessment system
that records the pen’s trajectories and pressures during
handwriting tasks by using a tablet PC (6). We investigated
the usefulness of the system for assessing clumsy children (7).
2. Homecare and remote monitoring system
Typical physiological monitors require clients to place
sensors in specified locations and manipulate the monitors to
send data. If patients or homecare providers have to handle
gel, adhesives and other materials, it may become impossible
to monitor physiological activities of patients in the community
and home environment. In order for physiological sensors to
be acceptable and operational, they must be wearable,
passive and operate at low power. We have been studying
remote monitoring and e-Health systems since 2002 and
have developed the WWPM (Wireless Wearable Physiological
Monitor) system (8).
1) Ohyanagi T., Kanaya K., Sengoku Y., Miyazaki M.
2)
3)
4)
5)
6)
7)
8)
Preliminary results of new reaction time tasks of detecting
velocity change of a moving stimulus to assess visual
attention skills in Occupational Therapy. Society for
Computers in Psychology 2012. (2012) p31
Ohyanagi T., Sengoku Y., Miyazaki M., Liu L. A solution
for measuring accurate reaction time to visual and
auditory stimuli and its application for assessments in
Occupational Therapy. Society for Computers in
Psychology 2011. (2011) p33
Kitajima H., Sengoku Y., Ohyanagi T., Nakajima S.,
Nakamura Y. Study on clinical application of choice
reaction time tasks using visual and auditory stimuli, 15th
International Congress of the World Federation of
Occupational Therapists. Chile (2010)
Sengoku Y., Ohyanagi T., Nakajima S., Nakamura Y.,
Kanaya F. Development of new evaluation methods for
inattention in developmental disorder, 15th International
Therapists. Chile (2010)
Ohyanagi T., Sengoku S. A solution for measuring
accurate reaction time to visual stimuli realized with a
programmable microcontroller, Behavior Research
Method. (2010) 42:242-253
Nakajima S., Ohyanagi T., Nakamura Y., Sakamoto K.,
Sengoku Y. The assessment of handwriting performance
based on changes in pen velocity and pen pressure.
Japanese Occupational Therapy Research. (2011)
30(5):563-571 (in Japanese)
Ohyanagi T., Nakajima S., Nakamura Y., Sengoku Y.
Development of new software for the assessment of
upper extremity function with handwriting tasks. Bull.
Sch. Hlth. Sci. Sapporo Med. Univ. (2010) 12:1-8 (in
Japanese)
Miyazaki M., Igras E.,Liu L., Ohyanagi T. Global health
through eHealth/Telehealth, eHealth and Remote
Monitoring (ed. Amir Hajjam) eHealth and Remote
Monitoring (2012) Chapter 1:1-16, InTech (Open access
publisher of books)
151
Mathematics
Our department has an interest in mathematical modeling related to
several kinds of natural and social phenomenon.
Associate Professor
Ken-ichi Kamo, Ph.D.
Interests:
Mathematics, Statistical analysis, Cancer epidemiology,
Environmental assessment
1. Mathematical theory
a) One focus of our research is on statistics. We have updated
several types of statistical theories. The main target is
information criteria for model selection in regression analysis
by using asymptotic expansion (1-4).
b) We also study differential equations. Here, we evaluate
quasilinear ordinary differential equations. The focus is on
asymptotic behavior of the positive proper solution, that is, the
behavior near infinity (5,6).
2. Application for mathematics
a) In our research concerning cancer epidemiology, we review
data related to cancer. Our main interest is in the
epidemiological aspect related to the longitudinal behavior or
external factor of cancer risk (7-11).
b) We have been evaluating the environmental aspect
regarding the value of forest stands. Our main focuses are on
growth analysis and risk assessment (12-15).
c) We also conduct collaboration research with other
departments. For example, we have worked closely with the
department of Hygiene, contributing mathematical analysis
for the study of infectious diseases (16,17).
1)Satoh K, Yanagihara H, Kamo K. A robust estimation
method for a growth curve model with balanced design.
J. Statist. , 2010, 3:113-124.
2)Yangihara H, Kamo K, et al. Second-order bias-corrected
AIC in multivariate normal linear models under
nonnormality. Canad. J. Statist., 2011, 39:126-146.
3)Yangihara H, Kamo K, et al. Bias-corrected AIC for
selecting variables in multinomial logistic regression
models. Linear Algebra Appl., 2012, 436:4329-4341.
4)Kamo K, et al. Bias-corrected AIC for selecting variables
in Poisson regression models. Commun. Statist., 2013,
42:1911-1921.
5)Kamo K, et al. Characterization of slowly decaying
positive solutions of second-order quasilinear ordinary
differential equations with sub-homogeneity. Bull. London
Math. Soc., 2010, 42:420-428.
6)Kamo K, et al. Nonlinear oscillations of fourth order
quasilinear ordinary differential equations. Acta Math.
Hungar., 2011, 132 : 207-222.
7)Utada M, Ohno Y, Soda M, Kamo K, Estimation of cancer
incidence in Japan with an age-period-cohort model.
Asian Pacific J. Cancer Prev., 2010, 11:1235-1240.
8) Kamo K, et al. Cancer Mortality Risk Visualization on
Age-period Plane. Proceedings of the Institute of Statist.
Math., 2011, 59:217-238 (in Japanese).
9) Qiu D, Kamo K, et al. Trends in Cancer Incidence in
Japan from 1975–2005. Proceedings of the Institute of
Statist. Math., 2011, 59:193-204 (in Japanese).
10)Matsuda T, Marugame T, Kamo K, et al. Cancer incidence
and incidence rates in Japan in 2006: based on data from
15 Population-based cancer registries in the monitoring
of cancer incidence in Japan (MCIJ) project. Jpn. J. Clin.
Oncol., 2012, 42:139-147.
11)Katanoda K, Kamo K, et al. Short-term projection of
cancer incidence in Japan using an age-period interaction
model with spline smoothing. Jpn. J. Clin. Oncol., 2014,
44:36-41.
12)Kamo K, Survival analysis and tree failure: Results from
a tree-pulling experiment. Forest Resource Manag. Math.
Modeling, 2012, 11:195-209.
13)Kamo K, et al. Comparative analysis of growth functions
based on Mallows’Cp type criterion. Forest Resource
Manag. Math. Modeling, 2013, 12:133-147.
14)Kamo K, et al. Comparative analysis on selecting growth
function. J. Forest Sci. Tech., 2013, 9:65-71.
15) Kamo K, et al. Snow damage analysis by discrete
regression models. Proceedings of the Institute of
Statistical Mathematics, (accepted) (in Japanese).
16)Sumi A, Kamo K, et al. Time series analysis of incidence
data of influenza in Japan. J. Epidemiology, 2011, 21:2129.
17)Sumi A, Kamo K, MEM spectral analysis for predicting
influenza epidemics in Japan. Environmental Health and
Preventive Medicine, 2012, 17:98-108.
152
Information Science
Our laboratory has developed the eyeball model for computer
simulation, and has studied permeability of the blood-retinal barrier.
Additionally, I am interested in analyzing computer digital images.
Toward this end, I have studied measurements of bone density and
bone mineral contents in rats depicted by soft X-ray images.
Assistant Professor
Mitsuru Kojima, M.T., Ph.D.
Interests:
Computer simulation methods,
Analysis of digital images
1. Construction of medical database system
3. Measurement of the bone density in rats using soft
We have constructed a medical database system for
X-ray images
effective and flexible application of medical quantitative data
We have developed an experimental system for analyzing
using personal computers. In this system, using data-
soft X-ray digital images of bones in male rats and tested its
compression methods we have been able to conduct high
usefulness. The objects measured were dry bones of male
time-efficiency
Wistar rats bred in various conditions. Results were as follows:
searches
and
accumulate
considerable
medical data.
(a) The induces of bone mass and density in rats with high
2. Computer Simulations and Analyses
calcium (Ca) intake were higher than those in the low Ca
a) We have conducted a computer analysis of permeability of
group.
the blood-retinal barrier (BRB) in human eyes. Analytical
(b) The relation between the image tones of each step of the
results suggest that our simulation method in conjunction with
aluminum step wedge and thickness follows the so-called
vitreous fluorophotometry can effectively estimate permeability
S-curve. We concluded that this image processing system
of BRB in human subjects.
provides acceptably accurate measurements.
b) Dynamics of local cerebral blood flow in rats was studied by
the autoradiographic diffusible tracer (14C-iodoantipyrine)
technique. We have discussed the effect of hyperglycemia on
ischemic brain damage using this technique.
c) We developed an experimental on-line system for analyzing
Placido's disk images projected by the Maloney surgical
keratometer (Keratoring), and tested its usefulness. We
concluded that this image processing system provides
acceptably accurate measurements for the radius of corneal
curvature.
153
3 Educational Development
Educational Development
Throughout the past few decades, both health care delivery and
medical education have undergone extensive changes. As a result,
our department has been actively involved in educational
development, in that we are expected to suggest strategies to reform
medical education on the basis of attainment targets. We are also
responsible for the execution of proper educational evaluation. Our
university has obtained several awards from Grant-in-Aid educational
programs supported by the Ministry of Education, Culture, Sports,
Science and Technology. Our department has been involved in the
preparation of applications, execution and assessment of these
programs.
Professor:
Hitoshi Sohma, Ph.D.
Interests:
Medical education, Interprofessional
education, Biomarker, Proteomics
Associate Professor
Masanori Shiratori, M.D., Ph.D.
Interests:
Medical education, Interstitial lung
diseases, Biomarkers
Assistant Professor:
Toshio J. Sato, M.D., Ph.D.
Interests:
Medical education, Teratology,
Occupational health
Yasuyoshi Naishiro, M.D., Ph.D.
Interests:
Medical education, Mikulicz’s disease,
IgG4-related disease
Takeshi Yamamoto, M.HSc.
Interests:
Interprofessional education, Collaborative
practice, Professionalism
To date, the university has accumulated a number of
achievements, including high recruitment and retention rates
of its graduates in the prefecture. Both schools carry out
facility and clinical training with community health care as
their primary focus.
1. Interprofessional Education (IPE)
Hokkaido Prefecture, one of the four main islands, is
located in the northern part of Japan, and covers a vast
2
geographical area. Hokkaido has an area of 83,000km ,
nearly equal to that of Austria or twice the size of the
Netherlands. The population of Hokkaido is about 5.6 million,
similar to that of Denmark or Finland. The population density
2
is 67 people/km which is very low and 1/7 of that of the entire
country, or 1/85 of that of Tokyo. Hokkaido is a cold place: the
average temperature is 9.5℃ and it is covered with snow in
winter. It is notable that Hokkaido has many remote areas
where medical resources are scarce.
To confront the medical problems in Hokkaido, we have
stressed that cooperation among various health professions
is vital and involvement of not only medical doctors but also a
wide range of medical professionals is essential. Thus, we
have conducted an interprofessional education (IPE) program
since 2005. Within the program, residential community
internship programs in remote areas are included. We have
provided our IPE goals as: 1) Strengthening students’ interest
in community health care; 2) Developing a deeper
understanding of the community, particularly in matters
concerning community health care; 3) Obtaining an
appreciation and sense of empowerment toward community
health care; 4) Developing a sense of mission driving them to
devote their energies to community health care. IPE and
Instructor:
Hiroshi Akasaka, M.D., Ph.D.
Interests:
Professional education, Epidemiology
of cardiovascular disease,
Hypertension, Cardiology
Masami Kameda, M.D.
Interests:
Medical education, Respiratory
medicine
collaborative practice can contribute to alleviating some of the
world’s most urgent health problems. Through effective
collaboration, health workers can jointly identify the key
strengths and expertise of each member, which leads to
resolving these problems.
2. Faculty Development (FD)
Increasing demands on faculty to be creative and
effective teachers, successful researchers and productive
clinicians requires the faculty to obtain new knowledge, skills,
and abilities in a relatively short period of time. Faculty
development (FD) is recognized by many medical educational
organizations as an essential support framework provided to
faculty members to assist them in responding to the challenges
of their multiple roles and evolving responsibilities. Our
department is expected to play supportive roles in organizing
FD programs such as teaching workshops and assessment,
tutor-training programs and other developmental programs.
Currently, FD programs are executed 5-6 times a year.
3. Curriculum Reform
Medical education in Japan has undergone major
changes in the last decade. Various interventions have been
introduced including problem-based learning, evidencebased approaches and clinical clerkships. Our department is
involved in curriculum reform in cooperation with the executive
committee.
4. Educational Evaluation
Educational evaluation is directly linked to the
improvement of education, increasing student motivation and
teaching effectiveness. Our department plays a central role in
conducting educational evaluation. We also aggregate
evaluation data and investigate effective evaluation methods
154
to encourage faculty self-improvement.
5. Educational Grants
Procuring educational grants supported by the Ministry of
Education, Culture, Sports, Science and Technology (MEXT)
is very important in the development of our medical education,
especially regarding community health care in Hokkaido. Our
department is involved in not only application procedures, but
also program execution after grants have been received.
We also investigate the effectiveness of evaluations
regarding the progression of program execution.
6. Medical Research
The faculty members of this department are from different
disciplines and they are also individually involved in medical
research as follows.
a) Hitoshi Sohma
2+
Loss of cellular Ca -homeostasis is the cause of cell
damage in many diseases. An increase in cellular Ca2+concentration induces alterations in the expression level of
several proteins. We have investigated the functional
2+
properties of annexin proteins, phospholipids and Ca binding proteins, whose expression levels increase with
neural cell damage such as seen in alcohol dependence and
Alzheimer’s disease. We have utilized a proteomic analysis to
further investigate molecular markers for cell damage.
b) Masanori Shiratori
Interstitial lung diseases are developed from a variety of
causes such as infection, drugs, allergic reactions, irradiation,
and connective tissue diseases. Idiopathic pulmonary fibrosis
is the most common subtype among idiopathic interstitial
pneumonias and defined as a chronic and progressive
disease resistant to any kind of medical treatment. Our focus
is on a clinical course of the disease and definition of
prognostic factors, especially biomarkers including surfactant
proteins A and D in blood, for its survival.
c) Toshio J. Sato
Many medical schools have early clinical exposure to
clinical and community settings in their curricula, usually
during the first 2 years. As this period is the preclinical phase,
students lack experience and have not yet acquired enough
knowledge and skills for such settings. Students need to be
prepared for such early exposure carefully including methods
of communication and other behavior. We explore how we
should provide the students with the knowledge, skills and
behavior for early exposure in our curricula.
d) Yasuyoshi Naishiro
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is
an immune-mediated condition that can affect multiple organs
and is now being recognized with increasing frequency. IgG4RD is characterized by a lymphoplasmacytic infiltrate
composed of IgG4+ plasma cells. The abundance of IgG4positive plasmacytes in the affected organ might be related to
the pathogenesis of the diseases; however, the pathogenesis
of IgG4-related diseases is unknown. Further investigation at
the cellular and molecular levels to make an accurate
diagnosis of IgG4-related diseases is a high priority.
e) Takeshi Yamamoto
Interprofessional Education (IPE) has spread throughout
the world in medical education. It is known that IPE has
beneficial effects on students’ knowledge, skills, attitudes and
beliefs; however the effects of IPE on collaborative practice
are virtually unknown. An evaluation tool for measuring the
effects of IPE on interprofessional collaborative practice has
not yet been developed. There is great interest in exploring
what constitutes effective collaborative practice.
f) Hiroshi Akasaka
The growing prevalence of cardiovascular disease is a
serious global problem. Treatments of cardiovascular disease
are now significantly progressing. However, the most
important point is its prevention. We have been conducting a
population-based cohort study in the towns of Tanno and
Sobetsu in Hokkaido from the viewpoint of prevention. We
have investigated and confirmed several risk factors including
genetic polymorphisms for cardiovascular disease.
g) Masami Kameda
A recent study suggests that there is a spectrum of
autoimmunity in interstitial lung disease (ILD). Since the
response to therapy and the prognosis of ILD associated with
autoimmunity is generally favorable compared to other ILD,
the presence of autoimmunity has great clinical significance.
We have investigated the characteristics and biomarkers to
predict responses to treatment and prognosis of ILD
associated with autoimmunity.
1) Takahashi H, Shiratori M. Interstitial pneumonia and SPA, SP-D (in Japanese). J Jpn Med Soc Lung Surfactant
Biol Interface 2009; 40: 99-102.
2) Sato TJ, Patten D, McLachlan JC. Cultural barriers to the
spread of clinical skills teaching methods. Int J Clin Skills
2009; 3: 95-101.
3) Sohma H, Sawada I, Konno M, Akashi H, Sato TJ,
Maruyama T, Tohse N, Imai K. Encouraging appreciation
of community health care by consistent medical
undergraduate education. Advanced Initiatives in
Interprofessional Education in Japan (Watanabe H,
Koizumi M. eds), Springer 2010; 1-12.
4) Yamaguchi M, Kokai Y, Imai S, Utsumi K, Matsumoto K,
YM, Kobayashi S, Hashimoto E, Saito S, Sohma H:
Investigation of annexin A5 as a biomarker for Alzheimer’s
Neurosci Res 2010; 88: 2682-2692.
5) Kobayashi S, Tateno M, Park TW, Utsumi K, Sohma H,
Ito YM, Kokai Y, Saito T. Apolipoprotein E4 Frequencies
in a Japanese Population with Alzheimer’s Disease and
Dementia with Lewy Bodies. PLoS ONE 2011; 6: e18569.
protein D using monoclonal antibodies. Exp Lung Res
2010; 36: 463-468.
7) Sohma H. Advanced Initiatives in Interprofessional
Education in Japan:JIPWEN Overview and Case Studies.
Symposium at the 2nd Global Forum on Human
Resources for Health. Prince Mahidol Award Conference
2011, Jan. Bangkok, Thailand.
8) Weber GF, Warren J, Sohma H, Chen T, Halim A,
Chakravarty G. Biomarkers—a pot of gold or a can of
worms? Cancer Biol Ther 2012; 10: 831-835.
9) Sohma H, Imai S, Takei N, Honda H, Matsumoto K,
Evaluation of annexin A5 as a biomarker for Alzheimer’s
disease and Dementia with Lewy bodies. Front Aging
Neurosci 2013; 5: 1-7.
10) Hashimoto E, Riederer P, Hesselbrock VM, Hesselbrock
MN, Mann K, Park TW, Ukai W, Sohma H, Schuckit MA,
Saito T. Consensus paper of the WFSBP 2011 Task
Force on Biological Markers: Biological Markers for
Alcoholics. World J Biol Psychiatry 2013; 14: 549-564..
11) Yamamoto T, Sakai I, Takahashi Y, Maeda T, Kunii Y,
Kurokochi K. Development of a new measurement scale
for interprofessional collaborative competency: A pilot
study in Japan. J Interprof Care 2013; in press.
12) Yamamoto T, Naishiro Y, Shiratori M, Takeda H, Sohma
H. Effectiveness of early-stage Interprofessional
Education (IPE) for university students through practical
training, AMEE2013. 2013 Aug; Prague.
155
E SCHOLARLY COMMUNICATION CENTER
Scholarly Communication Center
We strive to take advantage of information technology to increase
educational and research activities, resulting in the enhancement of
our university’s potential. Therefore, our research activity covers a
broad interdisciplinary area and includes multilateral projects, such
as post genome applications, multi-parallel network computing,
software programing, telemedicine, bionics and bioinformatics.
Director
Associate Professor
Instructor
Noritsugu Tohse, M.D., Ph.D.
Hirofumi Ohnishi, M.D., Ph.D.
Shintaro Takatsuka, M.E., Ph.D.
Interests:
Interests:
Interests:
Signal transduction for regulation of
Epidemiological studies on obesity,
Information, Engineering, Bionics,
ion channels, Development of cardiac
Life-style related disease,
Heart rate variability, Bioinformatics
ion channels, Excitation-contraction
Cardiovascular disease
coupling
1. Bioinformatics
1,2)
using the fitting sinusoids methods.
As a result of the human genome project and
Results indicated seeming differences in the heart rate
advancements in DNA sequencing technology, we can utilize
variability pattern between sleep apnea/hypopnea and normal
a huge amount of nucleotide sequence data and search DNA
breathing patterns. The heart rate variability difference was
sequence motifs in the whole human genome. However,
more obvious in some subjects, such as those without heart
searching motifs with the naked eye is an enormous task and
disease, for example. In specific subjects with obvious
searching throughout the whole genome is absolutely
difference, these results appear to enable us to identify heart
impossible. Therefore, we have developed a computational
rate variability patterns with sleep apnea/hypopnea based on
genome-wide analyzing system for detecting nucleotide
heart rate variability analysis using the fitting sinusoids
sequence motifs with biological significance. We have
methods.
developed computational genome-wide analyzing software
3. Receipt analysis
for calculating nucleotide sequence patterns with biological
This is the analysis of big medical receipt data that
significance.
studies the problems in Japanese community medicine and
Because such large amounts of data require considerable
health insurance caused by the aging population.
time for analysis and large storage costs, we developed both
a SPR file format that enables high compression and a new
genome browser (http://web.sapmed.ac.jp/genome/).
2. Heart Rate Variability
3)
M, Maruyama R, Kai M, Yamano HO, Sasaki Y, Tokino T,
The autonomic nerve system and respiratory frequency
Shinomura Y, Imai K, Toyota M. Genome-wide profiling of
affect heart rate variability. In general, heart rate variability
analysis is used in the assessment of autonomic nervous
MicroRNA genes in colorectal cancer. Cancer Res. 2011
system activity. Much attention has been paid to heart rate
variability analysis on bionics.
Sep 1;71(17):5646-58. Epub 2011 Jul 6.
2)Mikami T, Miyashita H, Takatsuka S, Kuroki Y, Matsushima
We try making estimates of living body information, such
N. Molecular evolution of vertebrate Toll-like receptors:
as breathing disorders and hypoglycemia, based on heart
Evolutionary rate difference between their leucine-rich
rate variability analysis. It has been possible to estimate the
repeats and their TIR domains. Gene 503 (2012) 235–
respiratory frequency of normal subjects and the breathing
243
state of sleep apnea patients. We have developed a new
3)Takatsuka S. Spectrum analysis for non-uniform sampling
algorithm for sorting out sleep apnea/hypopnea from normal
based on least squares fitting a sinusoid, AIP Conf. Proc.
breathing patterns based on heart rate variability analysis
1479, 1954 (2012)
156
F SPECIAL COURSES　Okhotsk Medical Treatment Environment
Research
Established in 2010, the goals of this course are to help community
health care professionals update their medical knowledge and to
teach retraining methods for professionals in this area. Many
members of the teaching staff at our university aim for cooperation
with the medical staff members in their various fields at Kitami Red
Cross Hospital.
Professor
Mizue Shiromaru, R.N., Ph.D.
Naoki Kozuka, R.P.T., Ph.D.
Yasuhisa Shinomura, M.D., Ph.D.
Division of Fundamental
First Division of Physical Therapy.
Department of Gastroenterology,
and Adult Nursing
Rheumatology and Clinical
Immunology
Nozomu Ikeda, O.T.R., Ph.D.
Miki Konno, R.N., P.H.N., D.S.N.
Second Division of Occupational
Division of Maternal and Child Nursing
Therapy.
Junichi Yoshino, R.N., M.S.W.
Assistant Professor
Division of Community Health,
Shin Hisahara, M.D., Ph.D.
Gerontological and Psychiatric Nursing
Department of Neurology
Sumio Ishiai, M.D., Ph.D.
Department of Rehabilitation
Wari Yamamoto, M.D., Ph.D.
Department of Community and
General Medicine
Masaki Katayose, R.P.T., Ph.D.
Second Division of Physical Therapy.
Eichi Narimatsu, M.D., Ph.D.
Department of Emergency Medicine
In the Hokkaido Okhotsk area, which is in the northeastern
improve rehabilitation services, and the establishment of a
part of Hokkaido along the Sea of Okhotsk, there is a chronic
system to educate and instruct physical therapists and
shortage of healthcare personnel such as medical doctors,
occupational therapists working at community hospitals.
nurses, physical therapists and occupational therapists. It is
Many teaching staff in different fields at our university,
important to help healthcare professionals involved in
including gastroenterology, cardiology, nephrology, hematology,
community healthcare update their knowledge and skills as
neurology, emergency medicine, rehabilitation, nursing care,
well as develop retraining systems for these professionals.
physical therapy and occupational therapy, participate in this
Kitami Red Cross Hospital is one of the core hospitals in the
course.
Okhotsk area. In August 2010, Sapporo Medical University
established the “Okhotsk Medical Treatment Environment
1. Clinical medicine
Research Course” in collaboration with the hospital. The aims
Since 2011, Professor Yasuhisa Shinomura has arranged
of this course include the following: (1) instruction about
to hold seminars at Kitami Red Cross Hospital for clinical
methods for teaching physicians to be involved in community
trainees and general physicians who work at community
medical care services so that they can obtain advanced
hospitals in the Okhotsk area. The following educational staff
medical skills and make correct diagnoses and treatments,
members from Sapporo Medical University School of Medicine
(2) the training of specialized nurses and certified nurses, and
are in charge of the seminars: Associate Professor Hiroki
the establishment of an educational system for nurses working
Takahashi (Rheumatology), Instructor Hiroshi Yasui (Hematology),
at community hospitals in order to enhance and improve
Assistant Professor Tomihiro Imai (Neurology), Instructor
nursing care, and (3) the training of specialized advisers to
Masaki Saito (Neurology), Assistant Professor Shin Hisahara
157
(Neurology), Professor Eichi Narimatsu (Emergency Medicine),
in short supply in the Okhotsk area. To manage this shortage,
Instructor Tomohisa Niiya (Anesthesiology), Instructor Shinya
the teaching staff from the department of Physical Therapy
Shimoshige (Cardiology), Assistant Professor Hideaki Yoshida
has held lectures, workshops and conferences for community
(Nephrology) and Instructor Masayo Motoya (Gastroenterology).
physical therapists at Kitami Red Cross Hospital.
Professor Wari Yamamoto held training conferences in
To improve the training in the field of cardiac rehabilitation,
2011 for clinical trainees at Kitami Red Cross Hospital. In
Instructor Satoshi Katano (Physical Therapy) visits Kitami
2012, Professor Eichi Narimatsu gave an open lecture for
Red Cross Hospital once or twice a month and trains physical
citizens on the emergency management of poisoning.
therapists for certification in cardiac rehabilitation. As a result,
Instructor Masayo Motoya and Instructor Masahiro Aoki
two therapists qualified as Registered Instructor of Cardiac
(Rehabilitation) participated in different conferences held at
Rehabilitation (RICR) and three as certificated physical
Kitami Red Cross Hospital every month during 2011–2013.
therapists in cardiovascular, pulmonary and metabolic
Instructor Masahiro Shitani (Gastroenterology) and Instructor
diseases.. We believe that these activities have improved the
Wei Zheng (Rehabilitation) have been to the Kitami Red
levels of cardiac rehabilitation in the Okhotsk area. Since
Cross Hospital each month during 2013 and have participated
2013, we have been accepting physical therapists from Kitami
in several conferences held there.
Red Cross Hospital for training in the latest medical
2. Nursing
technologies for rehabilitation.
In the Okhotsk area, there are not enough specialized
Since 2011, Professor Kozuka has been giving lectures
nurses in fields such as critical care nursing, pediatric nursing
and
or mental health nursing. Members of the teaching staff from
developmental disorders at Kitami Red Cross Hospital for
the department of Nursing at Sapporo Medical University
community physical therapists. In 2012, we also accepted
School of Health Sciences have conducted lectures,
physical therapists from Kitami Red Cross Hospital for training
workshops and conferences for the community nurses at
on physical therapy for high-risk newborns at the Neonatal
Kitami Red Cross Hospital. We believe that these activities
Intensive Unit (NICU) in Sapporo Medical University Hospital.
have contributed to advancements in the level of nursing at
To improve care in the field of occupational therapy,
not only the hospital but also in the community hospitals in the
Professors Sadako Tsubota, Nozomu Ikeda and Hisaaki Ota
Okhotsk area.
helped occupational therapists involved in community health
In the field of critical nursing, Professors Akiko Kataoka
care update their knowledge and skills. In 2010, Professor
and Mizue Shiromaru and Associate Professor Masako
Tsubota conducted workshops on exercise functional
Momma have been conducting lectures, workshops and
disorders of the upper limb. Professor Ikeda held lectures,
conferences since 2010 at Kitami Red Cross Hospital. In
workshops and conferences on mental disorders; in addition,
2013, three nurses who worked at the hospital visited Sapporo
he has been conducting collaborative research with the
Medical University Hospital and received training in critical
occupational therapists who work at Kitami Red Cross
care nursing. Additionally, our instructors have been
Hospital. Furthermore, Professor Ota has given lectures for
conducting collaborative research with the nurses who work
occupational therapists on high-order neurological dysfunction
at Kitami Red Cross Hospital.
at Kitami Red Cross Hospital since 2012. We believe that
Professors Michiko Ebina and Miki Konno conducted
these activities have improved the level of rehabilitation in the
lectures, workshops and conferences that covered the field of
Okhotsk area.
pediatric nursing at Kitami Red Cross Hospital in cooperation
with the nursing staff of the hospital. The Positive Parenting
Program—also known as the “Triple P”—is one of the most
effective evidence-based programs in the world. Our teaching
staff helped the nurses who worked at Kitami Red Cross
Hospital qualify as “Group Triple P facilitators.”
Finally, Professor Junichi Yoshino held lectures and
conferences at Kitami Red Cross Hospital that covered the
field of mental health nursing.
3. Rehabilitation
Physical therapists that work with patients who have had
a stroke or heart attack or with patients with lung disease are
conducting
workshops
on
physical
therapy
for
158
Regional Health Care and Medicine
The aim of our department is to study challenging issues of community
medicine in Hokkaido in a comprehensive manner. This includes
enhancement of the functions of regional hospitals, life-long education
for medical staff, telemedicine and education of local residents in
health care.
Professor
Takuro Wada, M.D., Ph.D.
Interests:
Orthopaedic surgery
1. Study of medical needs based on the characteristics
4. A medical check for junior baseball players
of each local area
Elbow disorders such as osteochondritis dissecance and
We performed a survey to clarify the needs for general
avulsion of the medial epicondyle are very common in youth
surgeons and orthopaedic surgeons in hospitals in local areas
baseball players. To prevent the occurrence of such disorders,
in Hokkaido prefecture. We sent the form to 129 public
we conducted medical checks using ultrasound tomography
hospitals and clinics throughout Hokkaido (except Sapporo)
for a junior baseball team in the city of Monbetsu.
and received replies from 80 (62%). Results indicated that
despite their necessity, there is a clear shortage of general
and orthopaedic surgeons in the prefecture. An increase in
1) Wada T. A roll of orthopaedic surgery in regional medical
the numbers of surgeons as well as hospitals and the
service of Hokkaido. Sekei saigai-geka 55:117,2012 (in
establishment of an effective dispatching system are required.
Japanese)
2. Life-long education for medical stuffs in regional area
2) Wada T. Restoration of regional medical service and
Since 2010, the department staff provided 21 lectures on
orthopaedic surgery. Risho seikeigeka 47:611,2012 (in
new topics in various areas of medicine for medical staff
Japanese)
members in local hospitals.
We also performed 53 teleconferences between Ko-iki
Monbetsu Hospital and Sapporo Medical University Hospital.
3. Open lectures to the public
We provided open lectures for local residences to help
them learn about the importance of understanding diseases
and their prevention. The lecture topics included metabolic
syndrome, locomotive syndrome, cardiovascular disease,
and cancer.
III INTERNATIONAL EXCHANGES
160
INTERNATIONAL EXCHANGES
Director of International Affair and Medical Exchanges
Tetsuo Himi, M.D., Ph.D
Professor
Department of Otolaryngology
１ MEDICAL EXCHANGES WITH THE NORTHERN REGION
program supports a part of the expenses needed for short-term
study abroad (two or three months) for a graduate
COUNTRIES
Sapporo Medical University has actively been promoting mutual
exchange programs with northern region countries and Asian
nations whose climate and living conditions are similar to those of
Hokkaido to improve the health and welfare of people living in
these regions. Since 1977, Sapporo Medical University has
established mutual medical exchange programs with universities
in Finland, Canada, China, U.S.A and Korea. The Catholic
University of Korea newly joined the exchange programs in 2011.
student/research (clinical) fellow.
2 VISITING RESEARCH FELLOWS
For the purposes of widening the exchange of scientific research
and contributing to the development of scientific techniques,
Sapporo Medical University, upon due consideration and deeming
it both appropriate and non-obstructive to its professors’ research,
shall make the appointment of Visiting Research Fellow, if a
person belonging to some other research institution should
express the desire to do specialized or high level scientific
FINLAND
１９７７～
University of Helsinki, University of Turku,
University of Oulu, University of Tampere,
University of Kuopio
CANADA
１９８３～
University of Alberta
research at this university for a specified length of time.
NUMBER OF FOREIGN VISITING RESEARCH FELLOWS
Fiscal year
CHINA
U.S.A
１９８４～
University of Calgary
１９８４～
２００８～
China Medical University
Jiamusi University
１９９４～
University of Massachusetts
2010
5
2011
7
2012
3
（Feb.1,2014）
2013
5
3 INTERNATIONAL CONTRIBUTIONS
With the hope of improving the health and welfare standards of
people around the world, the university participates in various
international cooperation projects to help developing countries. As
KOREA
２０１１～
The Catholic University
part of the projects, the university has actively sent its researchers
and accepted trainees from foreign countries.
◆ Faculty Member Exchange
Since the establishment of the medical exchange programs with
the above universities, many faculty members, who had a chance
4 RESEARCHERS IN OVERSEAS
NUMBER OF RESEARCHERS IN OVERSEAS
to visit the above institutions, have shared scientific knowledge,
and some have been conducting joint researches.
Fiscal year
2010
1
2011
3
（Over three months）
2012
2013
3
1
◆ Overseas Study for Undergraduate Students
Under the expanded renewal agreements made in 1999,
overseas study program for undergraduate students have started.
Sapporo Medical University has been sending our students to
English Language and Cultural Seminar at the University of
Alberta in summer. And mutual exchanges for clinical training
programs with students from China Medical University and The
Catholic University of Korea have also been conducted since
2009 and 2011, respectively.
◆ Short-term study abroad for a graduate student/research
5 SYSTEM OF INTERNATIONAL MEDICAL EXCHANGES
The Committee of International Medical Exchanges is an
advisory board for the President of Sapporo Medical University,
which promotes international medical exchanges between
Sapporo Medical University and institutions around the world.
Division of International Affairs and Medical Exchanges carries out
an executive function of dealing matters related to international
affairs in general in addition to putting decisions made by the
committee into effect.
(clinical) fellow
Sapporo Medical University is starting a new support program for
a graduate student / research (clinical) fellow from 2008. This
6 INTERNATIONAL MEDICAL EXCHANGE CENTER OF
161
Sapporo Medical University has an “International Exchange
Center” in the campus for foreign scientists, which consists of
accommodation (1 twin room & 3 single rooms) a conference
room, a small meeting room and an internet-equipped study room.
To stay in the Center, reservation must be made through the host
department in advance.
Address: South-1, West 18, Chuo-ku, Sapporo 060-8556 JAPAN
162
7 LIST OF EXCHANGES SCIENTISTS
FINLAND → SAPPORO MEDICAL UNIVERSITY
FINLAND → SAPPORO MEDICAL UNIVERSITY
NAME & TITLE
Sylvi Kassinen
Associate Professor
Dept. of Medical Microbiology
University of Oulu
Tarja H. Ruuska
Docent
Dept. of Pediatrics
University of Tampere
Pentti JA. Kiilholma
Docent
Dept. of Obstetrics &Gynecology
University of Turku
Markus EP. Rautiainen
Docent
Dept. of Otolaryngology
Kari Punnonen
Assistant Professor
Dept. of Clinical Chemistry & Hematology
University of Kuopio
Tapio Kurki
Senior Lecturer
Dept. of Obstetrics＆Gynecology
University of Helsinki
Andre Sourander
Professor
Dept. of Child Psychiatry
University of Turku
Pauli Puolakkainen
Associate Professor
Dept. of Surgery
Helsinki University Central
Janne Tapani Lehtinen
Resident
Kanta-Hame Central Hospital
Veli-Matti Kahari
Professor
Depr.of Dermatology and
Venereology
University of Turku, and
Turku University Central
Hospital
Markku Kauppi
Head of the Dept. of
Rheumatology
Rheumatism Foundation
Hospital
Juha Holopainen
Adjunct professor
Eye Hospital
Tomi Tapio Niemi
Associate Professor
Dept. of Anesthesiology ＆
Riika Lautamaki
Adjunct professor
Experimental Cardiology
Turk PET Center
Turk University Hospital
Ylermi Soini
Professor
Dept. of Pathology
University of Eastern finland
Markku Kuisma
Associate Professor
Dept. of Emergency Medicine
University of Helsinkil
Juhana Martinpoika Hakumaki
Associate Professor
Dept. of Radiology
University of Eastern finland
Hannu Juhani Aronen
Professor
Dept. of Radiology
University of Turku
NAME & TITLE
HOST DEPARTMENT
Seppo Autio
Lecturer,
Dept. of Child Neurology,
Seppo Takki
Instructor,
Dept. of Anesthesiology
Per Rosenberg
Associate Professor
Reijo Punnonen
Senior Lecturer (Docent)
Dept. of Gynecology & Obstetrics
University of Turku
Seppo Tunonen
Senior Lecturer
Consultant Pediatric Surgeon
University of Oulu
Timo Nevalainen
Professor
Dept. of Pathology
University of Turku
Dept. of
Pediatrics
Dept. of
Anesthesiology
Dept. of
Anesthesiology
PERIOD
1978.1.25
-1978.3.24
1979.8.31
-1979.11.11
1980.12.5
-1981.1.24
Dept. of
Obstetrics &
Gynecology
1982.2.4
-1982.3.31
Dept. of
Surgery (II)
1983.1.4
-1983.3.3
Dept. of
Pathology (II)
1984.1.21
-1984.3.20
Ranan Hilel Rimon
Professor
Dept. of Psychiatry
Simo Vilkki
Docent
Dept. of Orthopedic Surgery
University of Turku
Dept. of
Neuropsychiatry
Seppo Santavirta
Associate Professor
Olli Ruuskanen
Docent
Dept. of Pediatrics
University of Turku
Dept. of
Orthopedic Surgery
1986.10.2
-1986.11.27
Dept. of
Pediatrics
1988.1.19
-1988.3.15
Olof Selroos
Associate Professor
Dept. of Chest Medicine
Mikko Hallman
Professor
Dept. of Obstetrics & Gynecology
Dept. of
Internal Medicine (III)
1989.1.31
-1989.3.31
Dept. of
Biochemistry (I)
1990.3.3
-1990.3.31
Ervo Vesterinen
Docent
Jorma Paavonen
Associate Professor
Pekka-J. Klemi
Associate Professor & Senior Lecturer
Dept. of Pathology
University of Turku
Martti Vastamaki
Associate Professor
Jussi Kant
Professor
University of Turku
Kimmo T. Kyosola
Associate Professor
Dept. of Thoracic & Cardiovascular
Surgery
Dept. of
Obstetrics &
Gynecology
1991.1.15
-1991.3.23
Dept. of
Obstetrics &
Gynecology
1992.2.5
-1992.3.31
Dept. of
Pathology (II)
1993.1.31
-1993.3.31
Dept. of
Orthopedic Surgery
Dept. of
Orthopedic Surgery
Dept. of
Anesthesiology
Dept. of
Surgery (II)
1985.2.1
-1985.3.30
1986.1.27
-1986.3.25
1993.12.22
-1994.1.16
1994.6.8
-1994.7.31
1995.8.21
-1995.10.17
HOST DEPARTMENT PERIOD
Dept. of
1996.6.27
Pathology (I)
-1996.9.8
Dept. of
Pediatrics
1998. 3.14
-1998. 4.10
Dept. of
Obstetrics &
Gynecology
1999.1.31
-1999.2.27
Dept. of
Otolaryngology
2000. 1. 20
-2000. 3. 3
Dept. of
Internal Medicine (IV)
2001. 2. 4
-2001. 3. 21
Dept. of
2002.2.9
Obstetrics ＆Gynecology - 2002. 3.23
Dept. of
Neuropsychiatry
2002.8.16
- 2002.9.28
Dept. of
Surgery(I)
2004.2.26
-2004.3.30
Dept. of
Orthopedic Surgery
2005.2.5
-2005.2.28
Dept. of
Dermatology
2006.2.19
-2006.3.17
Dept. of
Internal Medicine(I)
2006.9.26
-2006.10.26
Dept. of
Ophthalmology
2008.1.5
-2008.2.23
Dept. of
Anesthesiology
2008.10.1
-2008.11.30
Dept. of
Internal Medicine(II)
2010.1.11
-2010.2.27
Dept. of
Pathology(Ⅰ)
2010.11.29
-2011.1.8
Dept. of
Traumatology and
Clitical Care Medicine
2011.11.8
-2011.12.14
Dept. of Deagnostic
Radiology
2012.10.7
-2012.11.6
Dept. of
Deagnostic
Radiology
2014.3.15
-2014.3.29
163
SAPPORO MEDICAL UNIVERSITY → FINLAND
SAPPORO MEDICAL UNIVERSITY → FINLAND
NAME & TITLE
HOST DEPARTMENT
PERIOD
NAME & TITLE
HOST DEPARTMENT
PERIOD
Mayumi Takasaki
Assistant Professor
Dept. of
Anesthesiology
1978.12.27
-1979.3.24
Takashi Nakagawa
Professor
Dept. of Ophthalmology
Dept. of
Ophthalmology
1997. 11. 4
-1997. 11. 26
Kowichi Jimbow
Associate Professor
Dept. of Dermatology
Dept. of
Dermatology
1980.2.17
-1980.3.26
Dept. of
Psychiatry
Dept. of
Anesthesiology
Dept. of
Gynecology & Obstetrics
University of Turku
1981.2.25
- 1981.4.10
Dept. of
Pediatrics
1998. 9. 13
-1998. 10. 4
Motoi Ogata
Associate Professor
Dept. of Psychiatry
Takeo Takahashi
Professor
Ryuichi Kudo
Associate Professor
Dept. of Gynecology &
Obstetrics
Shuji Nakata
Assistant Professor
Dept. of Pediatrics
Tetsuo Himi
Professor
Dept. of
Otorhinolaryngology
1999. 11. 18
-1999. 12. 2
1983.1.14
-1983.3.3
Hideaki Shirasaki
Assistant Professor
Dept. of
Otorhinolaryngology
2001. 3. 11
-2001. 4. 1
Teruhisa Kazui
Assistant Professor
Dept. of Surgery (II)
Dept. of
Surgery
1983.12.25
-1984.2.22
Toshiaki Endo
Associate Professor
Dept. of Obstetrics
＆Gynecology
Dept. of
Obstetrics＆Gynecology
2001.8.15
- 2001.9.20
Hiroyuki Matsumoto
Associate Professor
Dept. of Internal Medicine (I)
Toyoaki Akino
Professor
Dept. of Biochemistry (I)
Yutaka Yoshida
Assistant Professor
Dept. of Pathology (II)
Masamichi Usui
Associate Professor
Dept. of
Neurology
Dept. of
Pediatrics
Dept. of
Pathology
University of Turku
Dept. of
Orthopedic Surgery
1984.10.29
-1984.12.25
Naoya Masumori
Assistant Professor
Dept. of Urology
Dept. of
Urology
2002. 8.12
- 2002.9.14
Kiyofumi Morishita
Associate Professor
Dept. of Surgery(II)
Dept. of
Surgery
2003. 8.31
-2003.11.1
1987.11.2
-1987.12.31
Makoto Noguchi
Associate Professor
Dept. of Oral Surgery
2004.10.3
Dept. of
Oral & Maxillofacial Diseases -2004.11.13
Hiroshi Ajiki
Associate Professor
Dept. of
Pediatrics
University of Oulu
1988.8.1
-1988.10.2
Gen Murakami
Professor
Dept. of Anatomy(II)
Dept. of
Anatomy
University of Turku
2005.11.16
-2005.12.14
Mamoru Aoki
Professor
Dept. of Physiology (II)
Dept. of Physiology
University of Oulu
1989.1.20
-1989.7.22
Ayako Sumi
Assistant Professor
Dept. of Hygiene
Dept. of
Public Health
2006.8.31
-2006.10.27
Nobuo Maeda
Professor
Dept. of
Sociology & Economics
Dept. of Internal Medicine(II) 1990.7.30
-1990.9.3
University of Turku
Satoshi Nagoya
Associate Professor
Dept. of
Orthopedic Surgery
2007.8.30
-2007.9.24
Dept. of
Anesthesiology
Dept. of
Surgery
1992.1.2
-1992.3.10
Dept. of
Ophthalmology
2009.2.2
-2009.2.14
Hiroaki Watanabe
Associate Professor
Minoru Okazaki
Assistant Professor
Dept. of Surgery (I)
Futoshi Ishikawa
Instructor
Dept. of
Ophthalmology
Masayoshi Kawaharada
Assistant Professor
Dept.of Surgery(II)
Dept. of
2009.7.26
-2009.9.15
Shigeo Yoshida
Associate Professor
Dept. of Diagnostic
Ultrasound & Medical Electronics
Dept. of
Internal Medicine (I)
1993.8.24
-1993.10.3
Ayako Sumi
Assistant Professor
Dept.of Hygine
Dept. of
Public Health
2011.2.28
-2011.3.22
Reiko Kishi
Assistant Professor
Dept. of Public Health
Kazuo Hashi
Professor
Dept. of Neurosurgery
Dept. of
Geriatrics
Dept. of
Neurosurgery
1994.9.24
-1994.11.20
Katsutoshi Tanno
Assistant Professor
Dept.of Traumatology and
Critical Care Medicine
Dept. of
2012.2.27
Orthopaedics and Traumatology -2012.3.17
University of Oulu
Biomag laboratory, Helsinki
University Central Hospital
2012.9.29
-2012.12.1
Tetsuo Himi
Associate Professor
Dept. of
Otorhinolaryngology
1996.10.14
-1996.12.23
Syogo Yazawa
Assistant Professor
Dept.of Neuroscience
Katsutoshi Tanno
Assistant Professor
Dept.of Emergency Medicine
EMS. Helsinki University
Central Hospital
2014.2.9
-2014.2.22
1981.11.4
-1981.12.10
1985.10.23
-1985.11.21
1986.8.10
-1986.10.25
1993.1.12
-1993.2.14
1995.8.7
-1995.8.17
164
CANADA
UNIVERSITY OF ALBERTA
UNIVERSITY OF ALBERTA
→ SAPPORO MEDICAL UNIVERSITY
NAME & TITLE
HOST DEPARTMENT
PERIOD
NAME & TITLE
HOST DEPARTMENT
PERIOD
Robert S. Fraser
Acting Dean, Professor
Dept. of
Surgery (II)
1984.3.10
-1984.3.17
Colin L. Soskolne
Associate Professor
Dept. of Epidemiology
Dept. of
Public Health
1991.3.18
-1991.3.31
Thomas A. McPherson
Assistant Dean, Professor
Dept. of Pathology
Dept. of
Pathology
Cancer Research
Institute
1984.3.10
-1984.3.17
Sibrand Poppema
Professor
Dept. of Pathology
College Hospital
Laboratory Diagnosis
1992.2.14
-1992.2.27
Ronald H. Wensel
Professor
Dept. of Gastroenterology
Dept. of
1984.3.10
-1984.3.23
S. F. Paul Man
Professor
Dept. of Medicine
Dept. of
Physiology (I)
1992.2.4
-1992.3.11
Alan J. Lupin
Associate Clinical Professor
Division of Otolaryngology
Dept. of
Otolaryngology
1985.3.11
-1985.3.23
Dennis L. Modry
Associate Professor
Dept. of Surgery
Dept. of
Surgery (II)
1993.2.21
-1993.2.27
Bryan M. Longenecker
Professor
Dept. of Immunology
Dept. of Pathology (I)
1985.3.3
-1985.3.30
Stewart M. Hamilton
Professor
Dept. of Surgery
Division of
Traumatology &
1993.12.4
-1993.12.16
Wanda M. Wenman
Associate Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1985.9.29
-1985.10.12
Peter N. McCracken
Professor
Dept. of Geriatric Medicine
Dept. of
Internal Medicine (II)
1994.2.12
-1994.2.26
Neil N. Finer
Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1986.10.5
-1986.10.17
Henry F. Pabst
Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1995.1.16
-1995.1.31
Edgar G. King
Professor & Chairman
Dept. of Medicine
Dept. of
Emergency and
1987.3.24
-1987.3.31
Malcolm C. Paterson
Professor
Dept. of Medicine
Cross Cancer Institute
Dept. of
1995.3.14
-1995.3.26
George B. Frank
Professor
Dept. of Pharmacology
Dept. of
Physiology (I)
1988.1.10
-1988.2.18
Janice Lander
Professor
Dept. of Nursing
Dept. of Nursing
School of Health
Sciences
1996.3.2
-1996.3.17
Donald R. McLean
Professor
Division of Neurology
Dept. of
1988.3.11
-1988.3.25
James C. Russell
Professor
Dept. of Surgery
Dept. of
1996.11.13
-1996.11.27
Bill Johnston
Assistant Professor
Division of Orthopedic surgery
Dept. of
Orthopedic Surgery
1988.3.22
-1988.3.26
Richard Schulz
Assistant Professor
Dept. of
Pediatrics & Pharmacology
Dept. of
Pharmacology
1997.1.9
-1997.1.22
Peter M. Olley
Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1989.1.22
-1989.2.4
Paul W. Armstrong
Professor
Dept. of Medicine
Sapporo Medical
University
2000. 6. 23
-2000. 6. 26
Teresa M. Allen
Professor
Dept. of
Pharmacology
1990.1.14
-1990.2.23
1990.3.11
-1990.4.12
Gary D. Lopaschuk
Professor
Dept. of Pediatrics
＆Pharmacology
Dept. of
Pediatrics
2003.11.26
-2003.11.28
Terrence J. Montague
Professor
Dept. of Internal Medicine
Dept. of
1990.1.23
-1990.2.5
Stewart M. Hamilton
Professor
Division of
General Surgery
Dept. of
Traumatology
＆Clinical Care
Medicine
2004. 5. 19
Roderick A. Morgan
Professor
Dept. of
Ophthalmology
1991.3.14
-1991.3.24
165
UNIVERSITY OF CALGARY
UNIVERSITY OF CALGARY
NAME & TITLE
HOST DEPARTMENT
PERIOD
Norman S. Schachar
Associate Professor
Dept. of
Orthopedic Surgery
1985.11.19
-1986.2.8
NAME & TITLE
Thomas P. Hicks
Assistant Professor
Dept. of Medical Physiology
Dept. of
Pharmacology
1986.3.1
-1986.3.14
Eldon R. Smith
Professor & Head
Dept. of Medicine
Dept. of
1987.1.26
-1987.2.6
Eldon A. Shaffer
Head
Division of Gastroenterology
Dept. of Medicine
Dept. of
1987.10.12
-1987.10.25
John E. Remmers
Professor
Dept. of
1989.1.11
-1989.2.10
D. Grant Gall
Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1989.9.3
-1989.9.10
Brian A. MacVicar
Associate Professor
Dept. of Medical Physiology
Dept. of
Physiology (II)
1991.2.14
-1991.3.24
Jerry H-C. Wang
Professor
Dept. of Medical Biochemistry
Dept. of
Biochemistry (I)
1991.7.17
-1991.7.22
Nady, el-Guebaly
Professor & Head
Dept. of Psychiatry
Dept. of
Neuropsychiatry
1992.8.21
-1992.9.5
Taiki Tamaoki
Professor
Dept. of
Molecular Biology
Cancer Research
Institute
1992.9.2
-1992.10.13
Richard S. Hannah
Professor
Dept. of Anatomy
Dept. of
Anatomy (I)
1993.10.30
-1993.12.10
Norman C. Wong
Professor
Dept. of
Biochemistry (II)
1994.3.6
-1994.3.17
Clarence A. Guenter
Professor Emeritus
Dept. of
Sheldon H. Roth
Professor
Dept. of Pharmacology &
Therapeutics & Anaesthesia
Randal N. Johnston
Professor & Director
Southern Alberta Cancer
Research Center
HOST DEPARTMENT
Dept. of
PERIOD
1996.3.12
-1996.3.24
Norman S. Schachar
Professor
Dept. of Surgery
Dept. of
Orthopedic Surgery
1996.7.8
-1996.7.22
Andrew G.M. Bulloch
Professor
Dept. Medical Physiology
Dept. of
Physiology (II)
1996.9.21
-1996.10.12
Pamera A. Socol
Professor
Dept. of Microbiology &
Infectious Diseases
Dept. of
Urology
1998. 1. 22
-1998. 1. 29
Donald E. Woods
Professor
Dept. of Microbiology &
Infectious Diseases
Dept. of
Urology
1998. 1. 22
-1998. 1. 29
David L. Severson
Professor
Dept. of Pharmacology &
Therapeutics
Dept. of
1999. 2. 1
-1999. 2. 21
Peter J. Forsyth
Associate Professor
Dept. of Clinical
Neurosciences, & Medicine
Dept. of
Neurosurgery
1999. 3. 21
-1999. 4. 3
Jaques Belik
Professor
Dept. of Pediatrics
Dept. of
Pediatrics
2000. 2. 6
-2000. 2. 29
Norman C. Wong
Professor
Dept. of Medicine & Medical
Biochemistry
Dept. of
Biochemistry (I)
2000. 3. 4
-2000. 3. 31
Deborah L. Tamlyn
Professor and Dean
Faculty of Nursing
Dept. of
Nursing
2000. 6. 20
-2000. 6. 26
Johan H. van de Sande
Professor & Vice Dean
Faculty of Medicine
Dept. of
Molecular Biology
Cancer Research
Institute
2000. 6. 22
-2000. 6. 26
1994.4.20
-1994.4.27
Richard B. Hawks
Associate Dean
Graduate Science
Dept. of
Anatomy(Ⅰ)
2001. 4. 17
- 2001. 7. 28
Dept. of
Pharmacology
1994.5.20
-1994.6.3
Farshad Sepandj
Clinical Assistant professor
Division of Nephrology
Dept. of Medicine
Dept. of
Internal Medicine(Ⅱ)
2001. 7. 2
- 2001. 7. 28
Dept. of
Molecular Biology
Cancer Research
Institute
1996.2.2
-1996.2.20
Michael P. Walsh
Professor
Dept. of Biochemistry
＆ Molecular Biology
Dept. of
Physiology(I)
2004.3.7
-2004.3.28
Joseph C. Dort
Professor
Dept. of Surgery, Clinical
Neuroscience ＆ Oncology
Dept. of
Otolaryngology
2004. 4. 27
-2004. 5. 11
Sheldon Spier
Director
Dept. of Pediatric Respiratory
Alberta Children's Hospital
Dept. of
Pediatrics
2006.5.10
-2006.5.28
Samuel Song-Gu Lee
Associate Professor
Dept. of Medicine
166
SAPPORO MEDICAL UNIVERSITY → CANADA
NAME & TITLE
HOST DEPARTMENT
PERIOD
NAME & TITLE
HOST DEPARTMENT
PERIOD
Kohzoh Imai
Assistant Professor
Dept. of
Internal Medicine
1984.2.16
-1984.4.11
Susumu Chiba
Assistant Professor
Dept. of Neurology
1992.1. 31
-1992. 8. 13
Noboru Yamanaka
Assistant Professor
Dept. of
Otolaryngology
1984.2.15
-1984.4.13
Hideyuki Tsukada
Professor
Dept. of Pathology
Cancer Research Institute
1984.9.16
-1984.10.3
Akira Mizuguchi
Instructor
Dept. of
Neuropsychiatry
Dept. of
Physiology
Division of
Pulmonary Diseases
1985.1.25
-1985.3.27
Dept. of
Pediatrics
1993. 6.5
-1993. 6.22
Katsuyuki Kusajima
Assistant Professor
Shunzo Chiba
Professor
Dept. of Pediatrics
Kowichi Jimbow
Associate Professor
Dept. of
Dermatology
1985.9.29
-1985.10.6
Hidenori Yoshino
Associate Professor
Chemistry
Dept. of
1993. 9.15
-1993. 11. 15
Yoshikazu Akahonai
Associate Professor
Dept. of
Internal Medicine
1986.1.24
-1986.4.6
Atsushi Miyamoto
Associate Professor
Dept. of
Pharmacology
1994. 6. 4
-1994. 7. 19
Mamoru Aoki
Professor
Dept. of
Physiology
1986.10.20
-1986.11.3
Yukiharu Sawada
Associate Professor
Dept. of Molecular Biology
Dept. of
1994. 6. 30
-1994. 8. 26
Shoichi Tanaka
Associate Professor
Dept. of
Obstetrics & Gynecology
Dept. of
Obstetrics &
Gynecology
1987.1.13
-1987.4.5
Toshihiko Ogino
Professor
Dept. of Physical Therapy
Dept. of
Plastic Surgery
1995. 8. 11
-1995. 8. 28
Morio Akiyama
Associate Professor
Physics
Dept. of
Biochemistry
1987.9.2
-1987.10.22
Kei Fujinaga
Professor
Dept. of
1995. 8.28
-1995. 9.8
Koichi Itaya
Professor
Hospital Pharmacy
Dept. of
Pharmacology
1987.11.15
-1987.11.30
Terukatsu Sasaki
Professor
Dept. of
Medical Biochemistry &
Oncology
1996. 8. 14
-1996. 8. 24
Takashi Horikoshi
Assistant Professor
Dept. of
Dermatology
1988.7.4
-1988.11.2
Hideyo Ohshika
Professor
Dept. of
Pharmacology
1996. 10.17
-1996. 11.3
Takashi Nakagawa
Professor
Dept. of
Ophthalmology
1988.9.25
-1988.10.8
Nobuyuki Tanaka
Assistant Professor
Dept. of
Surgery
1997. 10. 30
-1997. 12. 10
Tomio Abe
Associate Professor
Dept. of
Surgery
1989.8.21
-1989.10.20
Division of
Neurosurgery
1990.3.17
-1990.3.29
Dept. of
Pediatrics
1998. 1. 17
-1998. 3. 6
Kazuo Hashi
Professor
Dept. of Neurological Surgery
Shigeto Fuse
Instructor
Dept. of Pediatrics
Hideshi Tomita
Instructor
Dept. of Pediatrics
Dept. of
Pediatrics
1990.10.1
-1990.12.31
Toshiaki Yamaki
Instructor
Dept. of
Clinical Neurosciences
1998. 3. 1
-1998. 3. 16
Yoshiaki Kumamoto
Professor
Dept. of Urology
Dept. of
Urology
1991.3.24
-1991.4.3
Toshiaki Tanaka
Assistant Professor
Dept. of
Surgery
1998. 3. 1
-1998. 3. 16
Yasufumi Asai
Associate Professor
Division of Emergency &
Division of
Emergency & Critical
Care
1991.7.1
-1991.10.2
Masato Nagashima
Assistant Professor
Dept. of Physiology (I)
Dept. of
Physiology &
Biophysics
1998. 10. 29
-1998. 11. 11
Haruyuki Tatsumi
Associate Professor
Dept. of Anatomy (I)
Dept. of
Anatomy
1991.9.10
-1991.9.27
Hiroyuki Koba
Associate Professor
Dept. of Internal Medicine (III)
Division of
Pulmonary Medicine
1999. 3. 1
1999. 3. 13
Toshihiko Yamashita
Assistant Professor
Dept. of Orthopaedic Surgery
Dept. of
Surgery
1999. 10. 24
-1999. 11. 7
1992.8.3
-1992. 10. 31
167
NAME ＆TITLE
Masaki Katayose
Instructor
HOST DEPARTMENT
PERIOD
NAME & TITLE
HOST DEPARTMENT
Faculty of
2000. 1. 13
-2000. 1. 23
Atsushi Takahashi
Assistant Professor
Dept. of Urology
Division of Urology
Dept. of Surgery
Kazumitsu Koito
Assistant Professor
Dept. of Radiology
Dept. of
Radiology
2000. 3. 16
-2000. 4. 16
Takeshi Kobayashi
Instructor
and Molecular Biology
Hisako Izumi
Instructor
Dept. of Nursing
Faculty of
Nursing
2000. 7. 28
-2000. 8. 11
Dept. of Family Medicine 2006. 2.19
Faculty of Medicine
2006. 3. 8
Takuro Wada
Assistant Professor
Dept. of Orthopaedic Surgery
Dept. of
Orthopaedic Surgery
2000. 10. 8
-2000. 10. 22
Tatsuro Morisaki
Instructor
Dept. of Community and
General Medicine
Dept. of Critical Care
Medicine
2006. 7.22
2006. 8. 6
Kanshi Komatsu
Assistant Professor
Dept. of
Surgery
2001. 2. 5
-2001. 2. 20
Hitoshi Imaizumi
Associate Professor
Dept. Traumatology and
Faculty of
2006. 8.22
2006. 9.22
Hiroshi Tanaka
Assistant Professor
Dept. of
Medicine
2001. 3. 12
-2001. 4. 1
Naoki Kozuka
Professor
Department of Physical
Therapy
Dept. of
Family Medicine
2002. 2. 9
- 2002. 3. 24
Faculty of
2008. 3.16
2008. 3.30
Hidenobu Kawabata
Instructor
Dept. of Community
＆General Medicine
Keigo Taniguchi
Instructor
Department of Physical
Therapy
Faculty of
Nursing
2002. 3 18
- 2002. 4. 2
Dept. of
Oral and Maxillofacial
Surgery
2009.2.18
-2009.3.15
Junichi Yoshino
Associate Professor
Dept. of Nursing
Yoshinori Miyazaki
Assistant Professor
Faculty of
Medicine
2001. 11.15
-2001. 11. 24
Dept. of
Biochemistry and
Molecular Biology and
Oncology
2009.10.4
-2009.10.17
Kowichi Jimbow
Professor
Dean of
School of Medicine
Masanori Someya
Instructor
Dept.of Radiology
Faculty of
Medicine
2002. 2. 18
- 2002. 3. 31
Dept. of
Palliative Medicine
2010.1.10
-2010.2.15
Atsushi Watanabe
Assistant Professor
Dept. of
Surgery (II)
Kikuko Iwamoto
Specially Appointed Instructor
Dept. of Palliative Medicine
Dept. of
Physiology
＆Biophysics
2003.1.14
-2003.2.23
Faculty of
2010.8.29
-2010.9.18
Suguru Kobayashi
Instructor
Dept. of Physiology(II)
Yuji Nakamura
Instructor
Dept. of Occupational Therapy
Dept. of
Otolaryngology
2003. 3. 2
-2003. 3. 14
Faculty of
2010.8.28
-2010.9.17
Tomoko Shintani
Assistant Professor
Sonomi Nakajima
Assistant Professor
Dept. of Occupational Therapy
Hidefumi Nishimori
Instructor
Dept. of
Surgery
2003. 8. 29
-2003. 10. 11
Mamoru Hase
Assistant Professor
Dept. of Traumatology and
Dept. of Critical Care
Medicine
2011.8.15
-2011.8.27
Ryoichi Ichikawa
Associate Professor
Dept. of Anatomy(I)
Dept. of
Cell Biology＆Anatomy
2004. 2. 27
2004. 4. 7
Masaki Katayose
Professor
Faculty of
2012.9.13
-2012.9.27
Hiroyuki Matsumoto
Professor
Dept. of Neurology
International Health
Faculty of Medicine
2004. 3. 15
-2004. 3. 21
Toshiaki Tanaka
Instructor
Dept. of Urology
Alberta Urology
Institute and Division of
Urology
2013.2.3
-2013.2.17
Erika Iwamoto
Instructor
Faculty of
2014.2.3
-2014.2.24
PERIOD
2004.11. 1
2004.11.30
2005. 2.20
2005. 3.13
168
CHINA MEDICAL UNIVERSITY
NAME & TITLE
HOST DEPARTMENT
PERIOD
NAME & TITLE
HOST DEPARTMENT
PERIOD
Li Yy-quan
Professor
Dept. of
1982.6.12
-1982.7.11
Gao Ji-yuan
Professor
Dept. of Pathology
Dept. of
Pathology (I)
1987.10.10
-1988.1.8
Tan Pu-quan
Associate Professor
Dept. of
1983.12.23
-1984.2.22
Li Yong-chang
Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1987.10.10
-1988.1.8
Xie Yu-dong
Associate Professor
Dept. of
1983.12.23
-1984.2.22
Gao Peng-yuan
Professor
Dept. of
1987.11.10
-1988.1.8
Ba Jing-yang
Associate Professor
Dept. of Obstetrics &
Gynecology
Dept. of
Obstetrics &
Gynecology
1984.9.9
-1984.11.8
Zhou Jian-ying
Professor
Dept. of Surgery
Dept. of
Surgery (I)
1987.11.10
-1988.1.8
Xia Zhen-long
Associate Professor
Dept. of Surgery
Dept. of
Surgery (I)
1984.9.9
-1984.11.8
Yijing Yao
Professor
Dept of Surgery
Dept. of
Surgery (I)
1988.9.8
-1988.11.6
Li Guang-ying
Associate Professor
Dept. of Cardiac Surgery
Dept. of
Surgery (II)
1984.10.9
-1984.12.8
Liu Zong-Han
Professor
Dept. of
Ophthalmology
1988.9.8
-1988.11.6
Piao Ying-ai
Assistant Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1984.10.9
-1984.12.8
Chun-zheng Wang
Professor
Dept. of
1988.9.8
-1988.11.6
Zhang Bing-jun
Associate Professor
Dept. of
Anesthesiology
1985.11.8
-1986.1.6
Shi Guirong
Associate Professor
Dept. of Epidemiology
Dept. of
Hygiene
1988.9.8
-1988.11.6
Sun Zhen-sheng
Associate Professor
Dept. of
Ophthalmology
1985.11.8
-1986.1.6
Li Ji
Professor
Dept. of Anatomy
Dept. of
Anatomy (I)
1989.12.8
-1990.2.5
Liang Key-I
Associate Professor
Dept. of
Otolaryngology
1985.11.8
-1986.1.6
Xia Ying-Kui
Professor
Dept. of
Dermatology
1989.12.8
-1990.2.5
Zhou Yong-de
Lecturer
Dept. of Pediatric Orthopedics
Dept. of
Orthopedic Surgery
1985.11.8
-1986.1.6
Yu Yun
Associate Professor
Dept. of
Surgery (I)
1989.12.8
-1989.2.5
Zhao Nai-cai
Professor
Dept. of
Pharmacology
1986.10.3
-1986.12.1
Qin Zhen-Yuan
Associate Professor
Dept. of Surgery
Dept. of
Anesthesiology
1989.12.8
-1990.2.5
Chen Li-ying
Associate Professor
Dept. of Radiology
Dept. of
Radiology
1986.10.3
-1986.12.1
Han Naiying
Associate Professor
Dept. of
1990.11.30
-1991.1.28
Zhao Zi-liang
Associate Professor
Dept. of Urogental Surgery
Dept. of
Urology
1986.10.3
-1986.12.1
Zhang Hui
Associate Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1990.11.30
-1992.1.28
Wang Shi-chi
Associate Professor
Dept. of
Oral Surgery
1986.10.3
-1986.12.1
Yu Qianyi
Associate Professor
Dept. of Preventive Medicine
Dept. of
Public Health
1990.11.30
-1991.1.28
169
NAME & TITLE
HOST DEPARTMENT
PERIOD
NAME & TITLE
HOST DEPARTMENT
PERIOD
Xu Fungtong
Associate Professor
Dept. of Surgery
Dept. of
Surgery (I)
1990.11.30
-1991.1.28
Song Li Chwen
Assistant Professor
Dept. of Neurology
Dept. of
Neurosurgery
1997.1.14
-1997.4.29
Lu Yun-shi
Professor
Dept. of
Dept. of
1991.11.20
Gynecology & Obstetrics -1992.1.18
Hang Ping
Associate Professor
Dept. of
1998. 1. 8
-1998. 3. 5
Wang Bao-hua
Professor
Dept. of
Otolaryngology
1991.11.20
-1992.1.18
Wang Zhenyu
Assistant Professor
Dept. of Anatomy
Dept. of
Physiology (II)
1998. 1. 8
-1998. 3. 5
Wang De-wen
Associate Professor
Dept. of
Pathological Laboratory
Dept. of
Legal Medicine
1991.11.20
-1992.1.18
Lu Yongli
Professor
Dept. of Anatomy
Dept. of
Anatomy (I)
1998. 11. 29
-1999. 2. 21
Ma Zong-sheng
Associate Professor
Dept. of
1991.11.20
-1992.1.18
Min-Jie WEI
Associate Professor
Dept. of
Pharmacology
1998. 11. 29
-1999. 2. 21
Li Xin-yuan
Associate Professor
Dept. of Pediatrics Surgery
Dept. of
Surgery (I)
1993.1.31
-1993.3.31
Kong Lingfei
Associate Professor
Dept. of
2000. 1. 23
-2000. 4. 30
Tao Jing
Associate Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1993.1.31
-1993.3.31
Xie Hui Fnag
Professor
Dept. of
2000. 6. 21
-2000. 6. 30
Liu Ying min
Professor
Dept. of
1993.1.31
-1993.3.31
Li Shengjun
Instructor
International Exchange Center
Information Center of
Computer
Communication
2000. 12. 17
-2001. 3. 31
Wang Yan-feng
Vice Director Technician
Division of
Division of
1993.1.31
-1993.3.31
Chaodong Zhang
Professor
Dept. of Neurology
Dept. of
Neurology
2002.3.6
- 2002.3.20
Shi Yu Xiu
Professor
Dept. of
Histology & Embryology
Dept. of
Anatomy (I)
1994.6.22
-1994.8.20
Chang-Qing Zheng
Professor
Dept. of
Internal Medicine(I)
2003. 3. 19
-2003. 4. 2
Sun Xin Xiang
Associate Professor
Dept. of
1994.6.22
-1994.8.20
Xindong Xue
Professor
Dept. of Pediatrics
Dept. of
Pediatrics
2004. 3. 3
-2004. 3. 17
Wang Tie
Assistant Professor
Dept. of
Otolaryngology
1995.1.16
-1995.3.31
Xiao Bai Li
Professor
Dept. of Neuropsychiatry
Dept. of
Neuropsychiatry
2008.4.19
-2008.5.3
Wang Tie
Associate Professor
Dept. of
Otolaryngology
1996.2.14
-1996.3.31
Li Changyou
Professor
Dept. of Orthopedics
Dept. of
Orthopaedic Surgery
2009.10.21
-2009.10.31
Wang Yunjie
Assistant Professor
Dept. of
Neurosurgery
Dept. of
Neurosurgery
1996.2.14
-1996.3.31
Wang Zanfeng
Assistant Professor
Dept. of Respiratory Medicine
Dept. of
Internal Medicine (Ⅲ)
2011.2.6
-2011.2.20
Zhang Lin
Associate Professor
Dept. of Surgery
Dept. of
Surgery (II)
Li Peiling
Associate Professor
Dept. of Radiology
Dept. of
2012.2.25
-2012.3.10
Ma Tao
Doctor
Dept. of Emergency Medicine
Dept. of
Emergency Medicine
2013.1.13
-2013.1.27
Chen Yan
Doctor
Dept. of Neurology
Dept. of
Neurology
2013.8.18
-2013.8.31
1997.1.14
-1997.4.29
170
→ CHINA MEDICAL UNIVERSITY
NAME & TITLE
HOST DEPARTMENT
PERIOD
NAME & TITLE
HOST DEPARTMENT
PERIOD
Morimichi Fukuda
Associate Professor
Dept. of Internal Medicine (IV)
Dept. of
Internal Medicine
1983.11.7
-1983.11.12
Akira Suzuki
Professor
Dept. of
Internal Medicine
1985.8.3
-1985.8.17
Shoichi Tanaka
Assistant Professor
Dept. of
Gynecology & Obstetrics
Dept. of
Gynecology &
Obstetrics
1983.10.31
-1983.11.12
Kokichi Kikuchi
Professor
Dept. of Pathology (I)
Dept. of
Pathology
1986.4.13
-1986.4.23
Yutaka Kohgo
Assistant Professor
Dept. of
Internal Medicine
1983.10.31
-1983.11.12
Kei Fujinaga
Professor
China Medical
University
1986.4.13
-1986.4.23
Tsuyoshi Yabana
Assistant Professor
Dept. of
Internal Medicine
1983.11.7
-1983.11.20
Kazuo Morita
Professor
Dept. of Radiology
Dept. of
Radiology
1986.9.7
-1986.9.21
Shuichi Maeda
Instructor
Dept. of
Internal Medicine
1983.11.7
-1983.11.20
Masayoshi Hashimoto
Professor
Dept. of Obstetrics &
Gynecology
Dept. of
Obstetrics &
Gynecology
1986.9.7
-1986.9.21
Sakuzo Komatsu
Professor
Dept. of
Cardiac Surgery
1984.5.18
-1984.5.30
Shuzo Chiba
Professor
Dept. of Pediatrics
Dept. of
Pediatrics
1987.10.17
-1987.10.24
Tomio Abe
Associate Professor
Dept. of
Cardiac Surgery
1984.5.18
-1984.5.30
Akikatsu Kataura
Professor
Dept. of
Otolaryngology
1987.10.17
-1987.10.24
Akira Yachi
Professor
Dept. of
Internal Medicine
1984.5.29
-1984.6.10
Morimichi Fukuda
Professor
Division of Ultrasound &
Medical Electronics
China Medical
University
1987.10.24
-1987.10.30
Takeo Wada
President
Sapporo Medical College
China Medical
University
1984.5.26
-1984.6.5
Hideyo Ohshika
Professor
Dept. of
Pharmacology
1988.9.28
-1988.10.10
Yoshikazu Narasaki
Instructor
Dept. of
Internal Medicine
1984.5.18
-1984.5.30
Kazuaki Asaishi
Assistant Professor
Dept. of
Surgery
1988.9.28
-1988.10.10
Takeshi Miki
Professor
Dept. of
Sociology & Economics
School of
Public Health
1984.5.26
-1984.6.10
1984.9.23
-1984.9.24
Kei Fujinaga
Professor
China Medical
University
1988.11.15
-1988.11.23
Tohru Nakao
Professor
Dept. of Pediatrics
Dept. of
Internal Medicine
1984.9.23
-1984.9.24
Yukiharu Sawada
Associate Professor
China Medical
University
1988.11.15
-1988.11.23
Takeo Takahashi
Professor
Dept. of
Anesthesiology
1985.8.3
-1985.8.17
Hiroaki Watanabe
Assistant Professor
Dept. of
Anesthesiology
1990.2.26
-1990.3.12
Sadatsugu Tagawa
Professor
Dept. of
Ophthalmology
1985.8.3
-1985.8.17
Masahiko Kida
Instructor
Dept. of Anatomy (II)
Dept. of
Anatomy
1990.2.26
-1990.3.12
Osamu Iimura
Professor
Dept. of Internal Medicine (II)
Dept. of
Internal Medicine
1985.8.3
-1985.8.17
Kohzoh Imai
Assistant Professor
China Medical
University
1990.5.21
-1990.5.26
171
NAME & TITLE
HOST DEPARTMENT
PERIOD
NAME & TITLE
HOST DEPARTMENT
PERIOD
Kokichi Kikuchi
President
China Medical
University
1990.10.14
-1990.10.20
Mamoru Aoki
Professor
Dept. of
Physiology
1997. 10. 17
-1997. 10. 24
Naoki Sugawara
Assistant Professor
Dept. of Public Health
Dept. of
Preventive Medicine
1991.2.28
-1991.3.13
Ryuichi Kudo
Professor
Dept. of
Dept. of
Obstetrics &
Gynecology
1997. 9. 1
-1997. 9. 7
Yoshiro Niitsu
Professor
Dept. of
Internal Medicine
1991.3.17
-1991.3.24
Ryuichi Denno
Associate Professor
Dept. of
Surgery
1998. 8. 24
-1998. 9. 6
Hideyo Yabu
Professor
Dept. of
Pharmacology
1991.10.10
-1991.10.19
Yukihiro Ibayashi
Assistant professor
Dept. of
Neurosurgery
1998. 9. 12
-1998. 9. 25
Kazuaki Shimamoto
Associate Professor
Dept. of
Internal Medicine
1992.2.29
-1992.3.8
Tomio Abe
Professor
Dept. of
Surgery
1999. 10. 24
-1999. 11. 7
Kazuo Hashi
Professor
Dept. of
Surgery
1993.1.9
-1993.1.16
Nobuyuki Ura
Associate Professor
Dept. of
Internal Medicine
1999. 9. 26
-1999. 10. 10
Haruo Takemura
Instructor
Dept. of
Pharmacology
1992.11.8
-1992.11.20
Fumio Aoki
Instructor
Information Center of
Computer Communication
International
Exchange Center
2000. 8. 6
-2000. 8. 27
Yoshiaki Kumamoto
Professor
Dept. of Urology
Dept. of
Urology
1994.3.31
-1994.4.6
Hiroyuki Matsumoto
Professor
Dept. of Neurology
Dept. of
Neurosurgery
2001. 3. 13
- 2001. 3.18
Yoshihito Ujike
Assistant Professor
Division of Traumatology &
Dept. of
Anesthesiology
1994.3.21
-1994.3.28
Akira Kihara
Professor
School of Health Science
Dept. of
Endocrinology
2001.8.1
- 2001. 8. 15
Ichiro Kurokawa
Professor
Division of Laboratory
Diagnosis
China Medical
University
1995.3.22
-1995.3.29
Kikuya Uno
Assistant Professor
Dept. of Ultrasound ＆
Medical Electronics
Dept. of
Internal Medicine
2003.3.2
-2003.3.10
Sumiyoshi Tanabe
Associate Professor
Dept. of
Neurological Surgery
1995.3.27
-1995.3.31
Center for Medical
Education
2003.11.19
-2003.12.3
Tohru Kudo
Associate Professor
Dept. of Pediatrics
Dept. of
Pediatrics
The second affiliated
hospital
1995.9.18
-1995.9.28
Shinji Kimura
Instructor
Dept. of Community ＆
General Medicine
Toshikazu Saito
Professor
China Medical
University
2007.3.25
-2007.3.30
Takafumi Ninomiya
Assistant Professor
Dept. of Anatomy (I)
Dept. of
Histology &
Embryology
1995.9.18
-1995.9.28
Wataru Ukai
Assistant Professor
Dept. of
Neuropsychiatry
2008.2.20
-2008.2.23
Seiichi Ishii
Professor
Dept. of
Orthopedic Surgery
1997.2.14
-1997.2.27
Masaru Tateno
Instructor
Dept. of
Neuropsychiatry
2009.2.18
-2009.2.26
Teiji Uede
Associate Professor
Dept. of
1997.3.1
-1997.3.14
Yasufumi Asai
Professor
Dept. of Traumatology and
Dept. of
Emergency
Medicine
2010.3.30
-2010.4.6
Naoya Yama
Instructor
Dept. of Radiology
Dept. of
Radiology
2010.10.10
-2010.10.23
Kensei Nakata
Instructor
Dept. of Radiology
Dept. of
Radiology
2012.3.3
-2012.3.16
172
JIAMUSI UNIVERSITY
→ JIAMUSI UNIVERSITY
NAME & TITLE
HOST DEPARTMENT
PERIOD
Pang Wei
Instructor
Dept. of Cerebral palsy
Dept. of
Applied Physical Therapy
2008.10.5
-2008.11.5
Sun Ying
Assistant Professor
Dept. of
Occupational and Therapeutic
Sciences
2009.10.22
-2009.11.18
Li Haihua
Associate Professor
Dept. of Rehabilitation
Dept. of
Physical Therapy
2010.11.10
-2010.12.8
NAME & TITLE
Yoko Goto
Associate Professor
Dept. of
Occupational and
Therapeutic Sciences
HOST DEPARTMENT
PERIOD
2009.8.21
-2009.8.30
Takeshi Sasaki
Instructor
Dept. of Physical
Therapy
Medicine
2010.8.28
-2010.9.12
Mari Sakaue
Associate Professor
Dept. of
Occupational
Therapy
Medicine
2011.9.5
-2011.9.11
Kimiharu Inui
Professor
Dept. of
Physical Therapy
Medicine
2012.8.23
-2012.8.31
Hisaaki Ota
Professor
Dept. of
Occpational Therapy
Medicine
2013.8.25
-2013.8.31
173
UNIVERSITY OF MASSACHUSETTS
→ UNIVERSITY OF MASSACHUSETTS
NAME & TITLE
HOST DEPARTMENT
PERIOD
Richard C. Marks
Professor
Dept. of Surgery &
Neurology
Dept. of
1996. 3. 2
-1996. 3. 31
Richard V. Aghababian
Professor
Dept. of Emergency
Medicine
Division of
Traumatology &
1996. 3. 23
-1996. 3. 31
Francis P. Renzi
Associate Professor
Dept. of Emergency
Medicine
Division of
Traumatology &
1996. 11. 3
-1996. 11. 14
Richard V. Aghababian
Professor
Dept. of Emergency
Medicine
Karin Przyklenk
Professor
Dept. of Emergency
Medicine
Dept. of
Traumatology＆Critical
Care Medicine
2004.2.12
Dept. of
Internal Medicine(II)
2004. 5.30
-2004. 6. 3
Edward T. Peskin
Associate Professor
Dept.of
Dept.of
2005.6.25
Obstetrics & Gynecology -2005.7.4
NAME & TITLE
Fumio Itoh
Instructor
Dept. of Internal Medicine(I)
HOST DEPARTMENT
Dept. of
Medicine
PERIOD
1995. 2. 20
-1995. 3. 24
Masamitsu Kaneko
Professor
Division of Traumatology＆
Satoru Sasage
Assistant Professor
Dept. of
Obstetrics ＆Gynecology
Division of
Emergency Medicine
1995. 3. 18
-1995. 3. 31
Dept. of
Obstetrics ＆
Gynecology
1996. 2. 10
-1996. 3. 16
Teruhisa Kazui
Assistant Professor
Dept. of Surgery(II)
Satoru Sagae
Assistant Professor
Dept. of Obstetrics＆Gynecology
Dept. of
Thoracic ＆Cardiac
Surgery
Dept. of
Obstetrics＆Gynecology
1996.3.17
-1996. 3.31
1996.12.11
-1997.1.17
Noritsugu Tohse
Associate Professor
Dept. of Physiology(I)
Tomio Abe
Professor
Dept. of
Physiology
1997. 3. 12
-1997. 3. 15
Division of
Cardiothoracic Surgery
1997. 10. 20
-1997. 11. 2
Osamu Honmo
Instructor
The Cancer Center
1997. 11. 1
-1997. 11. 30
Gen Murakami
Professor
Dept. of Anatomy (II)
Division of
Cell Biology &
Radiology
1998. 11. 9
-1998. 12. 23
Yasushi Itoh
Instructor
Division of Traumatology &
Dept. of
Emergency Medicine
1999. 3. 15
-1999. 3. 28
Kowichi Jimbow
Professor
Dept. of
Medicine
1999. 11. 28
-1999. 12. 4
Ken-ichiro Hirata
Dept. of
Assistant Professor
Surgery
Division of Diagnostic Ultrasound
& Medical Electronics
1999. 11. 11
-1999. 12. 29
Masayuki Morikawa
Assistant Professor
Dept. of
Surgery
2000. 11. 1
-2000. 12. 15
Tomihiro Imai
Assistant Professor
Division of Neurology
Yasufumi Asai
Professor ＆Chairman
Dept. of Traumatology
＆Critical Care Medicine
Dept. of
Neurology
2001. 3. 18
-2001. 4. 1
Dept. of
Emergency Medicine
2001. 7. 8
- 2001. 7. 22
Hidenari Akiba
Instructor
Dept. of Radiology
Yoshihiko Tsuchida
Assistant Professor
Dept. of Traumatology
＆Critical Care Medicine
Dept. of
Radiology
2003.2.11
-2003.2.27
Dept. of
Emergency Medicine
2003.2.23
-2003.3.5
Noriaki Kanaya
Assistant Professor
Dept. of
Anesthesiology
2003.11.2
-2003.11.16
Tetsuji Miura
Associate Professor
Dept. of Internal Medicine(II)
Masato Abe
Assistant
Masaaki Adachi
Associate Professor
Dept. of Internal Medicine(I)
Dept. of
Emergency Medicine
2003.11.13
-2003.11.20
Dept. of
Otolaryngology
2004.1.17
-2004.2.13
Dept. of
Molecular Biology
2008.9.1
-2008.9.15
IV INDEX(KEY WORDS)
176
Key Words
【A】
Cancer gene therapy P106
Aging P46
Cancer genetics P13
Alcohol/alcoholism P84
Cancer stem cell P40
Alzheimer disease P30
Cardioprotection P56
Alzheimer’s disease P62
Cardiovascular diseases Analysis of admissions P134
Cardiovascular medicine P24
Antibiotic resistant bacteria P44
Cardiovascular physical therapy P126
Antibody drug Conjugation P106
Cardiovascular surgery P66
Antimicrobial proteins P114
Cataract surgery P76
ARDS P25
CCL8 P74
Arterial stiffness P137
Cell polarity P42
ASIC(Acid-Sensing Ion Chanel) P28
Cell therapy P110
Atherosclerosis P56
Cerebral infarction P98
Atopic disease P78
Chemotherapy P60
Autoerotic asphyxia (AEA) P52
Children P140
Autotypic Junction P28
Chromosomal abnormality P13
Awake surgery P70
Chronic Care Nursing P118
Chronic kidney disease P56
【B】
P50, P116
Balance P124
Chronic obstructive pulmonary disease P58
Barrier function P42
Chronic psychosocial stress P137
Bile ducts P104
Circulation P88
Biodiversity P148
Clinical epidemiology P90
P139
Clinical genetics P13
P146, P155
Clinical medicine P156
P38, P54, P108
Clinical research P88
Clinical trial P110
Bioethics Bioinformatics Biomarker Biomechanics P68, P126
Biomedical Patent P12
Cochlear implant P82
Blood Pressure monitoring P137
Cognitive function P130
Bone density P152
Cognitive Linguistics P141
Bone marrow mesenchymal stem cell P30
Cognitive rehabilitation P128
Bone metabolism P68
Collection P36
BPH and lower urinary tract dysfunction P80
Community based rehabilitation Brain mapping P70
Community health care Brain-periphery axis P30
Community medicine P158
Breast cancer P50
Community oriented primary care P90
P134
Computer simulation P152
Congenital anomaly P13
Briefing sessions to high school teachers Burn P20, P94
【C】
P128
P153, P156
Congenital auricular deformity P20
Copyright Issues P141
P92
Coronary bypass grafting P66
Cancer cells P42
Crinical Care Nursing P118
Cancer Epidemiology P151
Culture P140
Cancer epigenetics P38
Curriculum reform P153
Cancer Cancer cell biology P54, P102
177
Cytoskeleton P100
【D】
Genetic variation P13
Genome P102
P36
Genomics P102
Depression P84
Genotyping of MRSA P92
Developmental disorders P130
Geriatric physical therapy P124
Diabetes mellitus P56
Gerontological nursing P122
Diabetic complication P30
GID P72
Disaster medicine P94
Glaucoma surgery P76
DNA methylation P38
GLP-1 P116
Dosimetry P144
Grief care P136
Drug dependency P52
GVHD P74
Drug information P15
DWI P22
Defensing 【E】
【H】
Hand therapy P128
Head and neck cancer P82
Embryos research P136
Health care law Emergency medicine P94
Health Promotion Endogeneus Cannabinoids P25
Heart development Endosomal sorting P112
Heart failure Endothelial function P137
Heart rate variability P155
English Linguistics P141
Heat stroke P52
Environment P140
Hematology P60
Environmental assessment P151
Hepatic organoid P104
Epidemiological study P116
Hereditary tumor P13
Epidemiology P32
P46, P56
Hokkaido P158
Epilepsy P62
Home Care P122
Epilepsy surgery P70
Host-microbe interaction P44
Epithelial cells P112
hTERT P100
EPR P147
Human higher brain function P34
Ethics committee P139
Human immunology P112
ETS transcription factor P148
Hypertension P56
Ewing’s sarcoma P148
Excitation-contraction coupling P24, P50
P139
P122, P143
P32, P128
【I】
I-131 thyroid therapy P22
External affairs P134
IAP family Extracorporeal cardiopulmonary resuscitation P94
IgG4-related disease Eyeball model P152
Immune synapse P148
Immunology P40
【F】
P92
P54, P82
Facial defect P20
Immunoregulatory molecules P112
Faculty development P153
Immunotoxins P106
Fertility preservation P72
In vivo Feuce function P42
Infection Finger function P128
Infection and inflammation
Functional neurosurgery P70
and gender identity disorder P80
Infectious disease P48
【G】
P147
P18, P44
Gastrointestinal stromal tumor P16
Inflammatory bowel disease P54
Gene P102
Info-Med(Joho-Yaku) P28
Genetic disease P78
Informatics P155
178
Information and communication technologies Innate immunity P150
P36, P44, P114
Innovative approaches to
Mental health P130
Mesenchymal stem cell P110
Metal artifact reduction technique P22
P38
learning for reproduction P120
MicroRNA Intellectual Property P12
Midwifery care for safe and satisfactory delivery P120
Interprofessional education P153
Midwifery practice P132
Interstitial lung diseases P58
Molecular diagnosis P16
Interventional Radiology P86
Molecular diagnosis for cancer P92
Iodine deficiency P74
Molecular epidemiology P48
Ion channel P32
Molecular target therapy P60
IUGR P18
Molecular targeted therapy P16
Iumbar radicular pain P32
Molecular targeting therapy P100
【K】
Monoclonal antibodies P106
Kant’s philosophy P136
Motor control Keloid P20
MRI P147
MRSA P48
【L】
P34, P124
Laparoscopic and robotic surgery P80
Mucosal Immunity of upper respiratory tract P82
Laparoscopic surgery P64
Multiple sclerosis P62
Learning process of expert midwives P120
Muscle weakness P124
Leucine-rich repeat P146
Muscular dystrophy P46
Life P140
Musculoskeletal physical therapy P126
Life-long education P158
Myasthenia gvavis P62
Live cell imaging P148
Myocardial infarction P56
Liver P104
Local flap P20
Narrative based medicine Lung cancer P27
Nasal Allergy P82
Lung MRI P22
Neural mechanisms P130
Lung transplantation P27
Neural stem cell P84
Lung tumor P58
Neurogenesis P84
Lyme disease P114
Neuroophthalmology Lymphocytes P112
Neuroscience 【M】
【N】
Neurovascularcoupling P90
P76
P70, P94
P34
Malignant melanoma P78
N-glycans P36
Marine and terrestrial nematodes P148
Nitric oxide P147
P151
Noncoding RNA P38
Non-invasive evaluation P34
Mathematics Medical education P90, P153
Medical ethics P139
Non-traumatic osteonecrosis P52
Medical management P24
Non-vascular IR P86
Medical needs P158
Normal human epithelial cells P100
Medical Oncology P60
Nursing P156
Medical physics P144
Nursing care for sick children P120
Medical professionalism P90
Nursing Education P118
Medication P15
Nursing Ethics P118
Medication safety P15
Nursing Technology P118
Medicine P140
Nutritional management P64
Melanin P78
179
【O】
Reproductive technologies P136
Occupational sciences P128
Research Course P156
Occupational therapy P150
Respiration P88
Ocular inflammation P76
Resveratrol Oncologic gene analysis P27
Rotavirus Open Campus P134
Oral oncology P96
Osteoporosis P50
Oxidative stress P60, P132
【P】
RS virus P46
P48, P74
P74
【S】
Safety in childbirth P132
Schizophrenia P84
SDMCI(Strategic Defensive
p53 P102
Pain P68, P88
Medical-Care Initiative) P28
Semaphorin P100
Palliative medicine P88
Sensorymotor science P126
Parkinson’s disease P62
Sentinel lymph node P78
Parvovirus B19 P74
Septic Shock P25
Pathogen associated molecular pattems P44
Small hepatocytes P104
Pathology P40
Small-angle x-ray scattering P146
Patient safety P15
Smoking prevention for children P120
P18, P72
Soft tissue tumor P16
P124
Soft X-ray image P152
P64, P68, P96
Spinal cord injury P98, P110
PCO Pediatric physical therapy Peptide vaccine therapy Perinatal environment P132
Sports nutrition P143
Pharmaceutical care P15
Sports physical therapy P126
Physical activity P143
Statistics P151
Placenta accrete P18
Stem cell biology P54
Plagiarism P141
Stem cell research P30
Plasticity P34
Stem/progenitor cells P104
PMX-DHP P25
Stress biology P40
Porphyromonas P114
Stress recovery P137
Postmortem computed tomogram (PMCT) P52
Stroke Preeclampsia P18
Student selection methods P134
Preparation P120
Superoxide P147
Supporting breastfeeding P132
Surfactant Protein P25
Prostate cancer Protein deacetylase P50, P116
P46
P62, P110
Surfactant proteins P58
Psychiatric nursing P122
Surgical oncology P64
Pulmonary preservation P27
Surgical pathology P16
Pulmonary regeneration P27
Synapse P28
Systems engineering P150
Proteomics P108, P146
【R】
【T】
Radiation oncology P86
Radiation Protection P144
T cell activation P148
Radiation therapy P86
Tandem repeats P146
Receipt analysis P155
Targeted drug delivery system P106
P68
Targeted therapy P54
Technical Lawsuit P12
Teleconference P158
Regeneration of spinal cord Regenerative Medicine Rehabilitation P12, P54, P64
P98, P126, P156
180
Terminal care P136
The Tanno and Sobetsu study P116
Tight junction P42
Time-series analysis P48
Trachelectomy P72
Traning methods Translational Research P156
P12, P108
Tumor hypoxia P96
Tumor immunology P96
Tumor immunotherapy P40
【U】
Unilateral spatial neglect P98
Urologic oncology P80
【V】
Vaginal surgery P72
Valve surgery P66
Vascular image P22
Vascular IR P86
Vascular surgery P66
Victorian Literature P141
Vitreoretinal surgery P76
Volatile anaesthetics P32
【W】
Walking ability P98
Working memory P130

2009-2013（PDF形式:3.46MB

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