Department of International
Community Health
Outline and Research Objectives
The mission of our department is to seek equity and equality in health and health care,and social justice within and across the nations with caring, sharing and compassionate
spirit, by the people, with the people and for the people, by means of comprehensive andintegrated scientific research and education on health and health care, and social development in collaboration with other related institutes of various disciplines including universities, governmental and non-governmental organizations and private sectors.
Our aim is to bring together the clinical, public health and social science research toaddress the broad issues of health and health care.
The goals are: 1) to investigate how to change the status quo by improving health statusof the most vulnerable, the most underprivileged and the poorest of the poor; 2) to undertake research on the influences of ‘globalization’ and ‘free market’ system on health andsocial development; 3) to investigate the mechanisms to reduce inequalities between andwithin nations on health and development and 4) to develop the mechanisms to link theabove three goals with individual research activities described below.
Focusing on the followings:
1. Target diseases or topics: 1) HIV/AIDS (prevention and health care services), 2)
Tuberculosis control, 3) Leprosy control, 4) Appropriate treatment and prevention ofcommon diseases and injuries including traffic accidents in Japan and developing countries, 5) Public health aspects of Stroke, 6) Health care services for international migrant
workers in Japan, 7) Maternal and Child Health Care (issues on contraceptives excluded).
2. Site/Field: 1) Aral Sea area, 2) Cambodia, 3) Bangladesh, 4) Nepal, 5) Nicaragua and 5)
Japan.
3. Research topics are related to Epidemiology, prevention and health care service delivery.

Faculties and Students
Professor and Chair Susumu Wakai, MD, PhD (1999-)
Lecturer
Nasamine Jimba, MD, PhD
Associate .................................2
Graduate student ..................20
Research student.....................1
Secretary .................................2

Past Research and Major Accomplishments
Please refer to the Select Publications related to
Research on International Health including Advocacy
papers (number 1 to 31)

Current Research
1) Injury prevention in Japan and developing countries2) HIV/AIDS prevention and care among migrant
workers living in Japan
3) Leprosy and tuberculosis control in Asian countries

4) Environmental degradation and people’s health:Aral Sea region and elsewhere
5) Epidemiology of Stroke and its prevention
6) Maternal and child healthIn each six research field a concerted effort has
been made with the Faculty members and Graduate
students to contribute for improving people’s healthstatus in developing countries but in developed countries including Japan as well.

Future Prospects
We continue focusing our research efforts on the 6
major research fields described above. We utilize deferent tools such as Epidemiological, medical.
Quantitative and Qualitative research methods. We
also need human resource development for continuing such research efforts by mobilizing Graduate students.

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Research Grants
Ministry of Education and Science
1. FY 1999 5.5 million Yen: S Wakai, K Pyo.
Mechanisms of spondylotic changes of the spine.
2. FY 2001~2002: 3.4 million Yen: S Yanagisawa andS Wakai. Health reform in Cambodia and its
effects on people’s health seeking behavior
3. FY 2002-2003: 8 million Yen: J Okumura and S
Wakai Ministry of Health and Welfare
4. FY 2000-2002: 21.5 million Yen: S Wakai. Healthsystem building for supporting people with
HIV/AIDS from overseas.

Select Publications
Research on International Health including
Advocacy paper
1. Wakai S: Primary health care projects and social
development. Lancet 345:1241, 1995
2. Wakai S: Sanctions against Iraq. Lancet 347: 200,
1996
3. Wakai S: Access to the Internet. Science 271: 1347,
1996
4. Kunii O, Wakai S, Honda T, Tsujimoto K: Role ofexternal medical volunteers after disasters. Lancet
347: 1411, 1996
5. Wakai S. Role of neurosurgeons in Japan. Lancet 349:
140, 1997
6. Yoshimoto Y, Wakai S: Unruptured intracranial vertebral artery dissection: clinical course and serial radiographic imagings. Stroke 28:370-374, 1997
7. Wakai S: Global health care and neurosurgeons.
Neurol Med Chir 37:483-490, 1997
8. Wakai S: Scourge of Japanese encephalitis in southwestern Nepal. Lancet 351:759, 1998
9. Wakai S: Health care in Burma. Lancet 352: 1230,
1998
10. Wakai S: Surgical treatment for incidentally discovered intracranial aneurysms. Lancet 1999; 353:19751976
11. Barua S, Wakai S, Shwe T, Umenai T: Leprosy elimination through integrated basic health services in
Myanmar: the role of midwives in the pre- and postelimination phases. Leprosy Rev 70:174-179, 1999
12. Yoshimoto Y, Wakai S: Cost-effectiveness analysis ofscreening for asymptomatic, unruptured intracranial
aneurysms: A mathematical model. Stroke 30: 16211627 1999
13. Inaoka E, Wakai S, Nakamura Y, Babily YA,
Saghayroun AAR. Correlate of visit regularity amongfamily planning clients in urban Yemen. Adv
Contraception 1999; 15: 257-274
14. Wakai S. Pysicians for peace. Lancet 2000; 355: 13651366
15. Wakai S. Life after sanctions: the fate of Iraq. Lancet
2000; 356: 685

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16. Kuroiwa C, Vongphrachanh P, Chosa T, Murakami
H, Hashizume M, Wakai S, Tanaka M. Risk ofpoliomyelitis importation and reemergence in Laos.
Lancet 2000; 356: 1487-88.
17. Toyama N, Wakai S, Nakamura Y, Andryansyah
Arifin. Mother’s working status and nutritional status of children under the age of five in urban lowincome community, Surabaya, Indonesia. J Trop
Pedatr 2001; 47: 179-181
18. Jimba M, Wakai S. Is Gandhi’s philosophy of nonviolence dead in Nepal? Lancet 2001:358;1018- 2.
19. Nakahara S, Wakai S. Underreporting of traffic
injuries involving children in Japan. Injury
Prevention 2001;7: 242-244
20. Sase E, Wakai S. A world war against terrorism.
Lancet 2001:358;1365
21. Ichikawa M, Nakahara S, Wakai S. Death withunbeled passengers. Lancet 2002:359;43-44
22. Ichikawa M, Okumura J, Wakai S. Two decisions ofJapanese court on detaind Afghan asylum seekers.
Lancet 2002:359;448
23. Saengdidtha B, Lapparat G, Torugsa K, Suppadit W,
Wakai S. Sexual Behavior and HIVInfection Among
Thai Army Conscripts between 1992 and 1998.
Military Med 2002: 167(4):272-6
24. Nakahara S, Wakai S. Differences between Japanesepre-school and school-age pedestrian mortality andmoridity trends. Public Health 2002:116;1-7
25. Kunii O, Nakamura S, Abdur R, Wakai S. The Impact
on Health and Risk Factors of the Diarrhoea
Epidemics in the 1998 Bangladesh Floods. Public
Health 2002:116; 68-74
26. Okumura J, Wakai S, Umenai T. Drug utilisation
practice at household focusing self-medication inrural communities in Vietnam. Soc Sci Med
2002:54;1875-1886
27. Md. Akramul Islam, Susumu Wakai, Nobukatsu
Ishikawa, A.M.R. Chowdhury, J. Patrick Vaughan:
Tuberculosis control by community health workers
inBangladesh: are they more cost-effective? Bull
WHO 2002:80;445-450
28. Phoxay C, Okumura J, Nakamura Y, Wakai S.
Influence of Women’s Knowledge and HealthSeeking Behaviour on Maternal Health Care
Utilization in Southern Laos. Asia-Pacific J Public
Health 2001:13;13-18
29. Flores FP, Umenai T, Wakai S. Shoud communitymanaged drugstores be phased out? Asia-Pacific J
Public Health 2001:13;9-12
30. Wakai S. Mobilization of Cuban doctors in developing countries. Lancet 2002: 360;92
31. Miura S, Kunii O, Wakai S. Home Gardening in
Urban Poor Communities of the Philippines. Int J
Food Sci Nutrition 2002 (in print)
32. M Hashizume,1 O Kunii,1 S Sasaki,2 T Shimoda,3 S
Wakai1 and M Chiba. Anemia and Anthropometrical
Status of School-age Children in the Aral Sea Region,
Kazakhstan. J Trop Pediatr (in press)

Clinical Research and Epidemiology
33. Wakai S, Fukushima T, Furihata T, Sano K:
Association of cerebral aneurysm with pituitary adenoma. Surg Neurol 12:503-507, 1979
34. Wakai S, Fukushima T, Teramoto A, Sano K:
Pituitary apoplexy: its incidence and clinical significance. J Neurosurg 55:187-193, 1981
35. Sano K, Wakai S, Ochiai C, Takakura K:
Characteristics of intracranial meningiomas in childhood. Child’ Brain 8:98-106, 1981
36. Wakai S, Yamakawa K, Mananka S, Takakura K:
Spontaneous intracranial hemorrhage caused bybrain tumor: its incidence and clinical significance.
Neurosurgery 10:437-444, 1982
37. Segawa H, Wakai S, Tamura K, Yoshimasu N,
Kakamura O, Ohta M: Computed tomographic measurement of local cerebral blood flow by Xenon
enhancement. Stroke 14:356-362, 1983
38. Wakai S, Narita J, Hashimoto K, Nagai M: Dermoid
cyst communicating with the subarachnoid spaceand lateral ventricle: demonstration by metrizamide
computed
tomographic
cisternography.
Neurosurgery 13:696-698, 1983
39. Wakai S, Arai T, Nagai M: Congenital brain tumors.
Surg Neurol 21:597-609, 1984
40. Wakai S, Nagai M: Ventricular diverticulum. J Neurol
Neurosurg Psychiatry 47:514-517, 1984
41. Wakai S, Ueda Y, Inoh S, Nagai M: Angiographicallyoccult angiomas: A report of thirteen cases withanalysis of the cases documented in the literature.
Neurosurgery 17:549-556, 1985
42. Wakai S, Nagai M: Histological verification of
microaneurysms as a cause of cerebral haemorrhage
in surgical specimens. J Neurol Neurosurg Psychiatry
52:595-599, 1989
43. Wakai S, Hashimoto K, Watanabe N, Inoh S, Ochiai
C, Nagai M: Efficacy of closed-drainage system intreating chronic subdural hematoma: A prospective
comparative study. Neurosurgery 26:771-773, 1990
44. Iwanaga H, Wakai S, Ochiai C, Narita J, Inoh S, Nagai
M: Ruptured cerebral aneurysms missed by initialangiography. Neurosurgery 27:45-51, 1990
45. Wakai S, Kumakura N, Nagai M: Lobar intracerebral
hemorrhage: A clinical, radiographic and pathologic
study of 29 consecutive operated cases with negative
angiography. J Neurosurg 76: 231-238, 1992

extracellular space of the brain. Neurosurgery
18:548-554, 1986
50. Wakai S, Meiselman SE, Brightman MW: Focal circumvention of blood-brain barrier with grafts ofmuscle, skin and autonomic ganglia. Brain Res
386:209-222, 1986

Biomedical Research
46. Wakai S, Hirokawa N: Development of the bloodbrain barrier to horseradish peroxidase in the chickembryo. Cell Tiss Res 195:195-203, 1978
47. Wakai S, Matsutani M, Mizutani H, Sano K: Tight
junctions in choroid plexus papillomas. Acta
Neuropathol 45:159-160, 1979
48. Wakai S, Hirokawa N: Development of blood-cerebrospinal fluid barrier to horseradish peroxidase in
the avian choroidal epithelium. Cell Tiss Res
214:271-278, 1981
49. Wakai S, Meiselman SE, Brightman MW: Muscle
grafts as entries for blood-borne proteins into the339

Department of
Human Genetics
Outline and Research Objectives
The Department of Human Genetics was established in April 1992 as one of the departments at the newly established School of International Health. The department educates
students at the Graduate School of International Health with courses covering basic principles as well as clinical applications of human genetics. A series of lectures on human genetics are also provided to the first year students at the School of Medicine (compulsory). In
addition, for undergraduate students at the School of Health Sciences, a series of lectures
are given to each of the sophomore (Human Genetics I, compulsory) and junior (Human
Genetics II, elective) classes.
The major research projects in the department are: (1) Search for susceptibility genes torheumatic diseases and other autoimmune diseases, (2) Search for susceptibility genes toclinical subsets of malaria, (3) Genome diversity of Asia-Pacific populations, (4) Search forsusceptibility genes to behavioral disorders, and (5) Analysis of gene expression profiles in
inflammatory tissues and cell differentiation.

Faculties and Students
Professor and Chair Katsushi TOKUNAGA, DSc
Associate Professors Naoyuki TSUCHIYA, MD, DMSc
Associate
Jun OHASHI, DHSc
Postdoctoral Fellow ................2
Graduate student ..................12
Research student.....................3
Research Technician ...............7
Secretary .................................2

Past Research and Major Accomplishments(1) By means of extensive variation screening of anumber of candidate genes followed by association analyses with complex diseases including
rheumatic diseases, malaria and narcolepsy, several disease-gene associations have been newly
found as follows.
- Rheumatoid arthritis (RA): LIR1(ILT2),
BLYS/BAFF-R, TNFR2, FCGR3A/HLA-DRB1- Systemic lupus erythematosus (SLE): TNFR2,
CD19, FCGR2B, FCGR3A
Cerebral malaria (in Thailand): HLA-B, TNFA, CD36
Severe malaria (in Thailand): HLA-DRB1, iNOS
Narcolepsy: TNFA, TNFR2
ANCA-associated vasculitis: HLA-DRB1(2) Studies on HLA gene and haplotype distribution in
East Asian and Pacific populations have demonstrated genetic affinities and clustering of the populations, multiple migration and dispersal routesof ancestral populations, and the genetic link
between Asians and Native Americans.

340(3) Gene expression profiling in synovia from RA
patients demonstrated several up-regulated genes
including ID family genes. Also a number of upregulated and down-regulated genes including
TNF-TNFR family were identified in the differentiation of monocytes into dendritic cells.

Current Research(1) Establishment of Human SNP (single nucleotide
polymorphism) Typing Center for large scale SNP
typing (goal: 1,000,000 typing/year).
(2) Continue the search for susceptibility genes torheumatic diseases, malaria subsets, and narcolepsy mainly by means of candidate gene approach.
(3) Screening of novel candidate regions for susceptibility genes to SLE and narcolepsy by means ofwhole genome association studies.
(4) Analyses of linkage disequilibrium blocks on chromosome 1 for the determination of primary genes.
(5) Functional analyses of disease-associated SNPs andID family genes.

Future Prospects(1) High-throughput SNP typing in the Human SNP
Typing Center will contribute to the identificationof susceptibility genes to various complex diseases
including allergy, diabetes, hypertension, andinfectious diseases.
(2) Using the new strategy of the whole genome association analyses, several candidate regions for SLE
and narcolepsy will be newly found.

(3) Extensive studies on linkage disequilibrium blocks
will contribute to effective search of disease associated genes.
(4) Further development of new high-throughput SNP
typing technologies.

Research Grants<Only the grants of more than 10,000,000
yen/year are listed below>
1. “Medical Genome Science”, Grant-in-Aid for
Scientific Research on Priority Areas, Grant-in-Aid
for Scientific Research by The Ministry of Education,
Culture, Sports, Science and Technology: Human
SNP Typing Center. 2001-2004.
2. “Medical Genome Science”, Grant-in Aid for
Scientific Research on Priority Areas, Grant-in Aid
for Scientific Research by The Ministry of Education,
Culture, Sports, Science and Technology:
Susceptibility genes to rheumatic diseases.
28,000,000 yen/year. 2000-2004.
3. “Genome Informatics Research and Technology
Development”, by the New Energy and Industrial
Technology Development Organization (NEDO):Development of DNA capillary array. 10,000,000
yen/year. 1999-2002.
4. “Genome Diversity Project”, by the New Energy andIndustrial Technology Development Organization(NEDO): Genome-wide association studies onrheumatoid arthritis. 10,000,000 yen/year. 20012004.

Select Publications
1. Tokunaga K, Araki C, Juji T, and Omoto K: Genetic
polymorphism of the complement C2 in Japanese.
Hum. Genet. 58: 213-216, 1981.
2. Tokunaga K, Omoto K, Juji T, and Itoh T:
Polymorphism of BF, C2 and GLO in Japanesepatients with insulin-dependent diabetes mellitus:
Confirmation of an increase of BF*FT. Hum. Genet.
62: 86-88, 1982.
3. Tokunaga K, Yukiyama Y, and Omoto K:
Polymorphism of the complement C6 in Japanese. J.
Immunogenet. 10: 419-424, 1983.
4. Tokunaga K, Omoto K, Yukiyama Y, Sakurai M, SajiH, and Maruya E: Further study on a BF silent allele.
Hum. Genet. 67: 449-451, 1984.
5. Matsuki K, Juji T, Tokunaga K, Naohara T, Satake M,
and Honda Y: Human histocompatibility leukocyte
antigen (HLA) haplotype frequencies estimated fromthe data on HLA class I, II, and III antigens in 111
Japanese narcoleptics. J. Clin. Invest. 76: 2078-2083,
1985.
6. Tokunaga K, Dewald G, Omoto K, and Juji T: Family
study on the polymorphisms of the sixth and seventh components (C6 and C7) of human complement: Linkage and haplotype analyses. Am. J. Hum.
Genet. 39: 414-419, 1986.

7. Matsuki k, Juji T, Tokunaga K, Mochizuki M,
Hayashi K, Fujino Y, Numaga J, and Yamashita H:
HLA antigens in Behcet’s disease with refractoryattacks. Tissue Antigens 29: 208-213, 1987.
8. Tokunaga K, Sauerecker G, Kay P, Christiansen F,
Anand R, and Dawkins RL: Extensive deletions andinsertions in different MHC supratypes detected bypulsed field gel electrophoresis. J. Exp. Med. 168:933-940, 1988.
9. Watanabe Y, Tokunaga K, Matsuki K, Takeuchi F,
Matsuta K, Maeda H, Omoto K, and Juji T: Putative
amino acid sequence of HLA-DRB chain contributing
to rheumatoid arthritis susceptibility. J. Exp. Med.
169: 2263-2268, 1989.
10. Matsuki K, Juji T, Tokunaga K, Takamizawa M,
Maeda H, Soda M, Nomura Y, and Segawa M: HLA
antigens in Japanese patients with myasthenia
gravis. J. Clin. Invest. 86: 392-399, 1990.
11. Tokunaga K, Jin F, Mauff G, Nishimukai H, Simeoni
E, Suzuki K, Weber W: C6 reference typing report.
Complement Inflamm. 7: 234-239, 1990.
12. Kuwata S, Tokunaga K, Jin F, Juji T, Sasaki T, andHonda Y: Analysis of HLA-DRB gene in narcolepsy.
N. Engl. J. Med. 324: 271-272, 1991.
13. Tokunaga K, Zhang WJ, Christiansen FT, andDawkins RL: The genomic structure of two ancestral
haplotypes carrying C4A duplications. Immunogenet.
34: 247-251, 1991.
14. Uchigata Y, Kuwata S, Tokunaga K, Eguchi Y,
Takayama-Hasumi S, Miyamoto M, Omori Y, Juji T,
and Hirata Y: Strong association of insulin autoimmune syndrome with HLA-DR4. Lancet 339: 393394, 1992.
15. Mitsunaga S, Kuwata S, Tokunaga K, Uchikawa C,
Takahashi K, Akaza T, Mitomi Y, and Juji T: Family
study on HLA-DPB1 polymorphism: Linkage analysis
with HLA-DR/DQ and two “new” alleles. Hum.
Immunol. 34: 203-211, 1992.
16. Bannai M, Mazda T, Tokunaga K, and Juji T: DNA
single-strand conformation polymorphism method
to distinguish DR4 alleles. Lancet 341: 769, 1993.
17. Lin L, Tokunaga K, Ogawa A, Ishikawa Y, Kashiwase
K, Akaza T, Tadokoro K, and Juji T: Genotyping andassociation analysis of HLA-B61 in Japanese. Hum.
Immunol. 37: 95-100, 1993.
18. Wang L, Juji T, Tokunaga K, Takahashi K, Kuwata S,
Uchida S, Tadokoro K, and Takai K: Polymorphic
microsatellite markers for the diagnosis of graft-versus-host disease. N. Engl. J. Med. 330: 398-401, 1994.
19. Oka T, Matsunaga H, Tokunaga K, Mitsunaga S, JujiT, and Yamane A: A simple method for detecting
single base substitutions and its application to HLADPB1 typing. Nucleic Acid Research 22: 1541-1547,
1994.
20. Tokunaga K, Sideltseva EW, Tanaka H, Uchikawa C,
Nieda M, Sideltsev VV, Zhuravleva E, Imanishi T,
Itoh K, Akaza T, Takahashi K, Khalturin V, Alexeev
LP, and Juji T: Distribution of HLA antigens and haplotypes in the Buryat population in Siberia. Tissue
Antigens 45: 98-102, 1995.

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21. Yoshida M, Ohtsuka R, Nakazawa M, Juji T, andTokunaga K: HLA-DRB1 frequencies of nonAustronesian-speaking Gidra in South New Guinea
and their genetic affinities with Oceanian populations. Am. J. Phys. Anthrop. 96: 177-181, 1995.
22. Uchigata Y, Tokunaga K, Nepom G, Bannai M,
Kuwata S, Dozio N, Benson EA, Ronningen KS,
Spinas GA, Tadokoro K, Hirata Y, Juji T, and Omori
Y: Differential immunogenetic determinants of polyclonal insulin autoimmune syndrome (Hirata’s
Disease) and monoclonal insulin autoimmune syndrome. Diabetes 44: 1227-1232, 1995.
23. Suto Y, Tokunaga K, Watanabe Y, and Hirai M:
Visual demonstration of the organization of thehuman complement C4 and 21-hydroxylase genes byhigh-resolution fluorescence in situ hybridization.
Genomics 33: 321-324, 1996.
24. Lin L, Tokunaga K, Tanaka H, Nakajima F, Imanishi
T, Kashiwase K, Bannai M, Mizuno S, Akaza T,
Tadokoro K, Shibata Y, and Juji T: Further moleculardiversity in the HLA-B15 group. Tissue Antigens 47:
265-274, 1996.
25. Ogasawara K, Yabe R, Uchikawa M, Saitou N, Bannai
M, Nakata K, Takenaka M, Fujisawa K, Ishikawa Y,
Juji T and Tokunaga K: Molecular genetic analysis ofvariant phenotypes of the ABO blood group system.
Blood 88: 2732-2737, 1996.
26. Fujiwara K, Isa K, Oka T, Maekawajiri S, Yamase A,
Akaza T, Tadokoro K, Juji T, Shibata Y, andTokunaga K: Large-scale DNA typing for humanplatelet alloantigens by PCR-PHFA (preferential
homoduplex formation assay). Brit. J.Haematol. 95:
198-203, 1996.
27. Bannai M, Tokunaga K, Tanaka H, Lin L, Kashiwase
K, Tokunaga K, and Juji T: Five HLA-B22 group alleles in Japanese. Tissue Antigens 49: 376-382, 1997.
28. Miyake M, Nakahori Y, Matsushita I, Kobayashi K,
Mizuno K, Hirai M, Kanazawa I, Nakagome Y,
Tokunaga K, and Toda T: YAC and cosmid contigs
encompassing the Fukuyama-type congenital muscular dystrophy (FCMD) candidate region on 9q31.
Genomics 40: 284-293, 1997.
29. Watanabe Y, Tokunaga K, Geraghty DE, Tadokoro K,
and Juji T: Large scale comparative mapping of MHC
class I region of predominant haplotypes in Japanese.
Immunogenet. 46: 135-141, 1997.
30. Tokunaga K, Ishikawa Y, Ogawa A, Wang H,
Mitsunaga S, Moriyama S, Lin L, Bannai M,
Watanabe Y, Kashiwase K, Tanaka H, Akaza T,
Tadokoro K, and Juji T: Sequence-based association
analysis of HLA class I and II alleles in Japanese supports conservation of common haplotypes.
Immunogenet. 46: 199-205, 1997.
31. Tsuchiya N, Shiota M, Moriyama S, Ogawa A,
Komatsu-Wakui M, Mitsui H, Geraghty ED, andTokunaga K: MICA allele typing of HLA-B27 positive
Japanese patients with seronegative spondylarthropathies and healthy individuals: Differential
linkage disequilibrium with HLA-B27 subtypes.
Arthritis Rheum. 41: 68-73, 1998.

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32. Ogawa A, Tokunaga K, Lin L, Kashiwase K, Tanaka
H, Herrero MJ, Vilches C,Park MH, Jia GJ, Chimge NO, Sideltseva EW, Ishikawa Y, Akaza T, Tadokoro K,
and Juji T: Diversity of HLA-B61 alleles and haplotypes in East Asians and Spanish Gypsies. Tissue
Antigens 51:356-366, 1998.
33. Kobayashi K, Nakahori Y, Miyake M, Matsumura K,
Kondo-lida E, Nomura Y, Segawa M, Yoshioka M,
Saito K, Osawa M, Hamano K, Sakakibara Y, Nonaka
I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga
K, and Toda T: An ancient retrotransposal insertion
causes Fukuyama-type congenital muscular dystrophy. Nature 394: 388-392, 1998.
34. Wuerzer R, Witzel-Schloemp K, Tokunaga K, Fernie
BA, Hobart MJ, and Orren A: Reference typing reportfor complement components C6, C7, and C9 including mutations leading to deficiencies. Exp. Clin.
Immunogenet. 15: 268-285, 1998.
35. Komata T, Tsuchiya N, Matsushita M, Hagiwara K,
and Tokunaga K: Association of tumor necrosis factor receptor 2 (TNFR2) polymorphism with susceptibility to systemic lupus erythematosus. Tissue
Antigens 53(6): 527-533, 1999.
36. Komatsu-Wakui M, Tokunaga K, Ishikawa Y,
Kashiwase K, Moriyama S, Tsuchiya N, Ando H,
Shiina T, Geraghty DE, Inoko H, and Juji T: MIC-A
polymorphism in Japanese and a MIC-A-MIC-B null
haplotype. Immunogenet. 49(7/8): 620-628, 1999.
37. Hatta Y, Ohashi J, Imanishi T, Kamiyama H, Iha M,
Shimabukuro T, Ogawa A, Tanaka H, Akaza T,
Gojobori T, Juji T, and Tokunaga K: HLA genes andhaplotypes in Ryukyuan suggest a recent gene flow
to the Okinawa islands. Hum. Biol. 71(3): 353-365,
1999.
38. Chida S, Hohjoh H, and Tokunaga K: Molecularanalyses of the possible RNA-binding protein genelocated in the human leukocyte antigen (HLA)-DR
subregion. Gene 240: 125-132 1999.
39. Bannai M, Ohashi J, Harihara S, Takahashi Y, Juji T,
Omoto K, and Tokunaga K: Analysis of HLA genes
and haplotypes in Ainu (from Hokkaido, northern
Japan) supports the premise that they descent from
Upper Paleolithic populations of East Asia. Tissue
Antigens 55 (2):128 -139, 2000.
40. Keicho N, Ohashi J, Tamiya G, Nakata K, Taguchi Y,
Azuma A, Ohishi N, Emi M, Park MH, Inoko H,
Tokunaga K, and Kudoh S: Fine localization of amajor disease-susceptibility locus for diffuse panbronchiolitis. Am. J. Hum. Genet. 66 (2): 501-507,
2000.
41. Shibue T, Tsuchiya N, Komata T, Matsushita M,
Shiota M, Ohashi J, Wakui M, Matsuta K, andTokunaga K: Tumor necrosis factorα 5’-flanking
region, TNF receptor ll, and HLA-DRB1 polymorphisms in the Japanese patients with rheumatoid
arthritis. Arthritis Rheum. 43 (4): 753-757, 2000.
42. Ohashi J, Yamamoto S, Tsuchiya N, Hatta Y, Komata
T, Matsushita M, and Tokunaga K: Comparison of
statistical power between 2×2 allele frequency andallele positivity tables in case-control studies of com-plex diseases genes. Ann. Hum. Genet. 65(2): 197206, 2001.
43. Ogasawara K, Yabe R, Uchikawa M, Nakata K,
Watanabe J, Takahashi Y, and Tokunaga K:
Recombination and gene conversion-like events may
contribute to ABO gene diversity causing various
phenotypes. Immunogenet. 53(3): 190-199, 2001.
44. Sakurai D, Yamaguchi A, Tsuchiya N, Yamamoto K,
and Tokunaga K: Expression of ID family genes inthe synovia from patients with rheumatoid arthritis.
Biochem. Biophys. Res. Commun. 284(2): 436-442,
2001.
45. Lapteva N, Ando Y, Nieda M, Hohjoh H, Okai M,
Kikuchi A, Dymshits G, Ishikawa Y, Juji T, andTokunaga K. Profiling of genes expressed in humanmonocytes and monocyte-derived dendritic cells
using cDNA expression array. Br. J. Haematol.
114(1): 191-197, 2001.
46. Tokunaga K, Ohashi J, Bannai M, and Juji T: Genetic
link between Asians and Native Americans:
Evidence from HLA genes and haplotypes. Hum.
Immunol. 62(9): 1001-1008, 2001.
47. Sirikong M, Tsuchiya N, Chandanayingyong D,
Bejrachandra S, Suthipinittharm S, Luangtrakool K,
Srinak D, Thongpradit R, Siriboonrit U, andTokunaga K: Association of HLA-DRB1*1502DQB1*0501 haplotype with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens
59 (2): 113-117, 2002.
48. Kyogoku C, Dijstelboem M.H, Tsuchiya N, Hatta Y,
Kato H, Yamaguchi A, Fukazawa T, Jansen D.M,
Hashimoto H, Winkel G.J. J, Kallenberg G.M. C, andTokunaga K: Fcg receptor gene polymorphisms inJapanese patients with systemic lupus erythematosus: Contribution of FCGR2B to genetic susceptibility. Arthritis Rheum. 46(5): 1242-1254, 2002.
49. Ohashi J, Naka I, Patarapotikul J, Hananantachai H,
Looareesuwan S, and Tokunaga K: Significant association of longer forms of CCTTT microsatellite repeat
in inducible nitric oxide synthase (iNOS) promoterwith severe malaria in Thailand. J. Infect. Dis.186:
578-581, 2002.
50. Kuroki K, Tsuchiya N, Tsao B, Grossman J, Fukazawa
T, Hagiwara T, Kano H, Takazoe M, Iwata T,
Hashimoto H, and Tokunaga K: Polymorphisms ofhuman CD19 gene: Possible association with susceptibility to systemic lupus erythematosus in Japanese.
Genes. Immun. (in press)(Number of the other original papers in English: 229)

343

Department of Developmental
Medical Sciences
Outline and Research Objectives
In 1996, the Department of Mother and Child Health was formed at the University ofTokyo. In Japan, it was the first division in International Health, which specifically focusedon maternal and child health issues. Maternal and child health involves all activities tomaintain and promote psychological and physiological health of mothers and children. The
field of maternal and child health covers (1) countermeasure for infectious diseases, (2)maternal and child nutrition, (3) prevention of diseases, and (4) protection of mothers andchildren from environmental unhealthy factors.
The study of maternal and child health not only covers research areas where clinicalintervention is possible but also it is beneficial for studying diseases where intervention isdifficult and abnormalities cannot be prevented. Maternal and child health research helps
administration and health policy makers to develop policies and to take decisions that are
in accordance with the current problems and are in the best interest of the communities.
Since 1998, in order to broaden its vision in research, scope of work and teaching activities
the division changed its name to “Developmental Medical Sciences”. Aging, human andenvironment, and their related items are newly added to our theme. This comes underInternational Biomedical Sciences, which is a division of Institute of International Health.
Since then, our research scope and work have expanded to foreign countries, mainly in Asia

Faculties and Students
Professor

Hiroshi Ushijima, M.D., Ph.D.
(1995 - to date)
Associate Professor Hideoki Fukuoka, M.D., Ph.D.
Associate .................................2
Postdoctoral Fellow ................3
Graduate student ..................20
Research student.....................4
Secretary .................................2

Past Research and Major Accomplishments
Background
After graduation from medical university andobtaining license of medical doctor, I first worked at
Tokyo University Hospital and related hospitals as apediatrician. At the same time, I studied clinicalresearch regarding pediatric infection, pediatricimmunology, and pediatric neurology. My research
produced results, which were related to clinical medicine. Following that I had an opportunity to study in
the United States as a virologist (Research fellow) atState University of Alabama for about 2 years. My
major was molecular study of Bunyaviruses, which
infect humans as well as animals. Some of the viral344

strains caused emerging diseases. During my research,
I discovered reassortant viruses and non-structure
proteins in the family. After returning to Japan, in
addition to being a pediatrician I also worked as a
researcher on molecular epidemiology, diagnosis anddevelopment of medicine for diarrhea caused by viruses and HIV at National Institute of Infectious Diseases(NIID) and National Institute of Public Health (NIPH)
as a chief and director, respectively. After that, I
moved to the University of Tokyo in 1995. Since then,I have been engaged in various researches in topics
ranging from infection, nutrition, maternal and childhealth in the world, with a special focus in Asia.
Followings are few researches, which I had carriedout and supervised in the University of Tokyo. The
researches include basic and field studies.
Diarrheal viruses
Rotavirus disease is an important diarrheal disease
especially in children. More than 500,000 children die
every year especially in developing countries. In thedeveloped countries, almost all infants have viral disease within 2 years after birth. My experience inworking on molecular epidemiology of rotavirus in
Japan expands over a period of a little more than 20
years. Besides, in the past four years, extensive collaboration has been done with researchers, microbiolo-

gists and pediatricians in countries like Korea, China,
Vietnam and Thailand. It has been done with similar
themes of epidemiological studies of diarrheal viruses.
These studies are important to develop vaccines
because serotypes and genotypes sometimes change
and the most appropriate vaccines are needed.
Major diarrheal viruses are rotavirus, astrovirus,
adenovirus, Norwalk virus and Sapporo virus.
Currently, we study all of them up to molecular level.
Immunodeficient persons discharge the viruses forlong time. Through research we have highlighted
complications of encephalopathy, hepatitis and others, which were caused by these viruses. Stool samples, slightly over 10,000 were collected for more than
20 years in five areas in Japan. Besides Japan, stool
samples were also collected in Asian countries. In
complicated cases, cerebrospinal fluids, bloods andliver tissues are also examined at times.
I have the honor of pioneering the concept anddeveloping molecular epidemiology of diarrheal viruses in Japan. During the process, I established particulars about diarrheal viruses causing encephalopathy
and other complications in humans. Due to seasonalchanges and serotype distribution, detail analyses of
all the viruses were done during the past 20 years.
Reassortment and recombination were also discovered. The changes in serotypes or genotypes wereaffected principally by time and also by geographic
distributions across the countries. We established thefacts about Norwalk virus spreading in early winterand rotavirus spreading in late winter in Japan.
However the detail of mode of spread of viruses isstill largely unknown, except for outbreaks of foodpoisoning and outbreaks at institutes. We alsobrought forward the fact that rotavirus infection
starts at the same time all over Japan. We have established a research system in Japan and nowadays weare examining the shellfishes and sewerages regularly.
The results of the research will contribute to thehealth policy and decision-making in Japan.
We newly developed RT-PCR, enzyme immunoassay, immunochromatography and latex agglutination
tests for rapid, easy and sensitive diagnosis. Anti-diarrheal virus agents are examined by in vitro assay. We
found that tea extracts, pine seed extracts and poly IC
were effective on rotavirus infection. This method isuseful to find anti-viral agents in vitro. In vivo assays
by using mouse model are also used. Mouse pups
born to and nursed by dams fed Bifidobacterium
breve and immunized orally with rotavirus were morestrongly protected against rotavirus-induced diarrhea
than those born to and nursed by dams immunizedwith rotavirus only.

tant areas of research not only in Asia in general but
also in Japan in particular. It is now an establishedfact that HIV, hepatitis B and C viruses cause motherto child infection. Transportation of such sample safely across different countries has always been a problem. To transport HIV samples safely from foreigncounties, we introduced the use of filter paper method
for blood and saliva. New primers were designed for
subtyping of HIV subtype B and E. We succeeded todetermine HIV from several countries. Now we aredeveloping primers for all subtypes. The PCR was useful for the samples from blood, saliva and breast milk.
Basic research of HIV infection was also done throughcollaboration with Prof. Muller in Germany; it was
found that exposure to gp120 of HIV induces apoptosis in neuronal cell culture. Moreover, I am still amember of National research group to find anti-HIV
candidate drugs. For the said purpose we screen antiHIV drugs distributed from pharmaceutical companies. We have found some effective chemicals in vitro.
Molecular Epidemiology of hepatitis B has been done
through the collaboration with Dr. Abe, NIH Japan.
Our results revealed that there was high prevalence of
HBV pre-S mutant in Asia, where there are highendemic regions of HBV, except for Japan. The
appearance of HBV mutation seemed to be correlated
to duration of persistent infection and genotypes of
HBV. In fact, we found higher prevalence of HBVmutation in hepatocellular carcinoma patients andgenotypes B and C. Mode of transmission of hepatitis
C infection in Japan is different to that in Asia. The
patients in most countries in Asia are due to co-infection with HIV but the majority of the patients inJapan are due to misuse of syringes.
Field studies
The field study of maternal and child health is also
integral part of our department. One project is “maternal and child health in minority groups in Asian countries”. Dr. Li Y, a researcher from Yunnan, China, hasconducted a project in rural minority area of Yunnan.
An interview of 2019 rural mother was conducted.
We found that maternal child-rearing behaviors differed significantly among ethnic groups as well as
between urban and rural areas. The behaviors weresignificantly associated with maternal education level,family type, family income, maternal age at delivery,
and number of children in the family. We continued
this project and found the malnutrition was especially
due to vitamin B1 deficiency. The main reason waseating too much polished rice, deficiency of vegetables
and longer time for cooking.

HIV and hepatitis viruses
HIV and hepatitis infections have become impor-345Current Research
Viruses
We have continued epidemiological studies of diarrheal viruses, HIV and hepatitis, especially in children. It will help achieve the final goal of decreasingmortality and morbidity caused by these diseases.
Enzyme immunoassay, (RT-) PCR, sequence analysis
and other methods are used for the diagnosis.
Immunochromatographic method is useful for diagnosis in outpatient clinics because of simplicity andrapidity.
We are trying to develop;(1) Diarrheal virus detection kit for rotavirus, entericadenovirus, astrovirus and Norwalk virus,(2) Hepatitis virus detection kit for hepatitis A, B, C
and E, and TTV.
To make antibodies for immunochromatograph,
we culture the viruses that grow in vitro, make synthetic peptides and make virus like particles withgenetic engineering. Rapid detection kit using gene
amplification is also proceeding.
Field research
Asia: As further activity in Yunnan, we conductedtraining course of maternal and child health for about
60 health workers and physicians who belong tominority areas. Education session focused on proper
cooking methodology, general physical examination,knowledge about HIV and other diseases. We madepamphlets and CD. Then, the health workers andphysicians teach the caregivers by using them.
Vitamin B1 is used in the area as a treatment. In addition, we used rapid methods of detecting viruses in
the areas.
A student from Vietnam, who worked before at
NGO GROUP, is studying in minority group in rural
mountain areas in north part of Vietnam. Physicalconditions of infants and attitudes of caregivers are
examined every 3 months after birth for 2 years. In
2003, a student will come from Laos. She will also
conduct similar research in Laos. Maternal and childhealth in minority groups in the border areas in
China, Thailand, Laos and Vietnam are examined andintervention is planned.
Japan: We are conducting a project of maternaland child health in ethnic minority in Japan. This
project started in 2001. Due to globalization, childrenof ethnic minority group have increased in Japan in
the last 10 years. However health check system, medical care and health insurance system are not enoughfor them. In addition, education of mother and child,communication among health workers and residents
are sometimes not sufficient for them. We have multipronged approach for the research. It includes (a)Ask

346

3000 local health workers about their activities onmother and child health in ethnic minority groups,(b)Interview health workers, physicians, NGO members and administrators deeply at two local areas how
they succeeded in high quality of health care forminority groups. (c)Some families stay in Japan over
the time than officially allowed. They do not receive
enough medical care. To improve the situation, we
examine it and make proposals for their better living.
(d)Lack of communication among themselves andwith health workers causes anxiety among them.
Proper and efficient communication system andhealth service system will be suggested. (e)In addition
to health care, education of mother and child is alsoneeded. Both are related and necessary for their better
health. All minorities in high class, middle class andlower class should be improved irrespective of ethnicity, religion or country of origin.
OthersOther activities are concurrently carried out in mydepartment are such as relation between developmentof voice / sucking and growth, mother’s
relaxation/infant development and touch care, maternal mortality and obesity in developed and developing countries. Moreover, other staffs in the division
have their own projects. We regularly communicate,
help and discuss together on our research agendas.

Future Prospects
21 st century has started in the wake of social
chaos. World has become a global village and emerging and reemerging infectious diseases are gaining
importance. While, exchanges of people and information are rapidly increasing via various modes of transportation and internet service. Under these circumstances, the health of mother, child, and elderly isespecially important. Our research of health in children among ethnic minority groups will become highly valuable. The results will contribute in making evidence based decision as regards maternal and childhealth.
In order to keep environment safe, a decrease ininfection diseases and malnutrition are equally important. Our diagnostic methods are useful to for theabove said cause and thus help fight against diseases.
Further development of vaccine, medicine and molecular epidemiological survey of infection is the need of
the time, to make the future safe for our generationsin the times to come.
Followings are schema of our research of past,present and future.

Research Grants
a: Health-welfare and labor science research(1) Maternal and child heath in multi-racial culturalsociety, a project of “general research on child andfamily” (2001-2004) 11,000,000 yen/3years(2) Research of survey of microorganism contamination in foods and evaluation of safety, a project of“general research on safety of food and chemicals”(2001-2004) 1,000,000 yen/year
b: Basic research supported by the ministry ofeducation and science(1) Diagnosis, molecular epidemiology, pathology, prevention and treatment of diarrheal viruses. (20022005) 18,891,000 yen(2002)(2) Molecular epidemiological study of maternal andchild infection in Asia. (2001-2004) 4,200,000
yen(2002)
c: Others(1) Research for gravity and infection supported by
space development project. 520,000 yen(2002)(2) Research for Nano-technology supported byhuman science foundation. Other small grants are
not shown. 7,500,000 yen/year

Select Publications
1. Ushijima H, Nishio O, Klocking R, Schroder HC,
Perovic S, Muller WEG: Exposure to gp120 of HIV-1
induces an increase release of aranchidonic acid in
rat neuronal cells followed by NMDA receptor-mediated neurotoxity. Eur J Neuroscience 7:13531359,1995.
2. Kakizawa J, Ushijima H, Ando S, Yamamoto Y, Oka
S, Ikeda Y, Muller WEG: Detection of HIV-1 RNA
and DNA in saliva by RT-PCR and PCR under different condition. Acta Paediatrica Japonica 38 : 218-223,
1996.

3. Yasui H, Kiyoshima J, Ushijima H. Passive protection
against rotavirus-induced diarrhea of pups born toand nursed by dams fed Bifidobacterium breve
YIT4064 J Infect Dis 172: 403-409, 199
4. Schroder HC, Ushijima H, Theis C, Seve A-P, HubertJ, Muller WEG. Expression of nuclear lectin carbohydrate-binding protein 35 in human immunodeficiency virus type 1-infected Molt-3 cells J AIDS 9:340348, 1995.
5. Saito K, Ushijima H, Nishio O, Oseto M, Motohiro H,
Ueda Y, Takagi M, Nakaya S, Ando T, Glass R,
Zaiman K. Detection of astroviruses from stool samples in Japan using reverse transcription and polymerase chain reaction amplification. Microbiology
and Immunology 39:825-828, 1995.
6. Wen L, Ushijima H, Kakizawa J, Fang Z-Y, Nishimura
S, Nishio O, Morokawa S, Motohiro T. Genetic variation in VP7 gene of human rotavirus serotype 2 (G2type) isolated in Japan, China, and Pakistan.
Microbiology and Immunology 39;911-915, 1995.
7. Ushijima H, Morikawa S, Mukoyama A, Nishio O.
Characterization of VP4 and VP7 of a murine
rotavirus (YR-1) isolated in Japan. Jpn. J. Med. Sci.
Biol. 48: 237-247, 1995.
8. Kakizawa J, Ushijima H, Morishita Y, Oka S, Ikeda Y,
Muller WEG. Diversity of HIV type 1 envelope V3loop region in saliva. Human retrovirus and AIDS,
12: 561-563, 1996.
9. Nakayama M, Ueda Y, Kawamoto H, Yue HJ, Saio K,
Nishio O, Ushijima H. Detection and sequencing of
Norwalk-like viruses from stool samples in Japan
using RT-PCR. Microbiology and Immunology 40:
317-320, 1996.
10. Yue Han-Jun, Hiroshi Ushijima. Detection and genotyping of astroviruses by RT-PCR and sequencing J.
Jap Assoc Infect Dis 70: 1220-1226, 1996
11. Perovic S, Schroder HC, Pergande G, Ushijima H,
Muller WEG. Downregulation of Bcl-2 and glutationelevel in neuronal cells in vitro treated with the prion
protein fragment (PrP106-126): Prevention by flupirtine Experimental Neurology 147:518-524, 1997.
12. Akihara S, Nakayama M, Kakizawa J, Bosu K, Izumi
K, Ushijima H. An outbreak of Norwalk-like virus347infection in Tokyo and Saitama in late 1995. J. Jap.
Assoc. Infect. Dis. 70: 840-841, 1996.
13. Wen L, Nakayama M, Yamanishi Y, Nishio O, Fang
Z-Y, Nakagomi O, Araki K, Nishimura S, Hasegawa
A, Muller WEG, Ushijima H. Genetic variation in the
VP7 gene of human rotavirus serotype 3 (G3 Type)isolated in China and Japan. Arch Virol 142:14811489,1997.
14. Kakizawa J, Ushijima H, Wen L, Ikeda Y, Oseto K.
Genetic analysis of the capsid region of human astrovirus serotype 3 isolated in Japan. Microbiol
Immunol 41: 637-640, 1977.
15. Schroder HC, Perovic S, Ushijima H, Muller WEG.
Mechanisms of prionｓｃ- and HIV-1 gp120 induced
neuronal cell death. Neuro Toxicology 19,683-688,
1998.
16. Kato H, Horino A, Sakurai S, Ushijima H, Komuro K,
Uchida T: Inhibition of tumor cell growth by murine
splenic adherent cells stimulated with IFN-ganma Int
Arch Allergy Immunol 115:115-120, 1998.
17. Hakamada-Taguchi R, Kato T, Ushijima H, Murakami
M, Uede T, Nariuchi H. Expression and co-stimulatory function of B7-2 on murine CD4+ T cells. Eur J
Immunol 28:865-873, 1998.
18. Matsui M, Ushijima H, Hachiya M, Kakizawa J,
Leying Wen, Oseto M, Morooka K, Kurz JB.
Detection of serotypes of astroviruses by reverse
transcription-polymerase chain reaction and homologies of the types by the sequencing of Japanese
Isolates. Microbiol. Immunol. 42: 539-547, 1998.
19. Cao X-R, Akihara S, Fang Z-Y, Nakagomi O, Ushijima
H. Genetic variation in the VP4 gene and the NSP4
gene of human rotavirus serotype 3 (G3 type) isolated in China and Japan. Microbiol Immunol 43(2):171175,1999.
20. Adhikary AK,Zhou Y, Kakizawa J, Numaga J, Akihara
S, Fang ZY, Ushijima H. Distribution of rotavirus VP4
genotype and VP7 serotype among Chinese Children.
Acta Paediatrica Japonica 40:641-643, 1998.
21. Abe T, Kobayashi M, Araki K, Ushijima H. Viral
infection-new concepts and treatment -infantile convulsion and viral infection- Brain and Development,
20:392-393, 1998.
22. Li Y, Liu J, Liu F, Guo G, Anme T, Ushijima H.
Maternal child-rearing behaviors correlates in rural
minority areas of Yunnan, China. Developmental andbehavioral pediatrics 21: 114-122, 2000
23. Li Y, Guo G, Shi A, Li Y, Anme T, Ushijima H.
Prevalence and correlates of Malnutrition among
Children in Rural Minority Areas of China. Pediatrics
International 41:549-556, 1999
24. Li Y, Kong L,Hotta M, Wongkhomthong S, Ushijima
H. Breat feeding in Bangkok, Thailand: the Current
Status, Maternal Knowledge, Attetude and Social
Support. Pediatrics International 41:648-654, 1999
25. Nishiwaki M, Yasumizu T, Hoshi K, Ushijima H. The
effect of pregnancy, lactation, and weaning on thebone mineral density of rats determined by dualenergy X-ray absorptionmetry. Endocrine Journal 46:
711-716, 1999.

348

26. Sakamoto T，Wang Q-H， Akihara S，KimＢ，
Nishimura S，Kaneshi K，Nakaya S，Ueda Y，
Sugita K，Motohiro T，Nishimura T，Ushijima H．
Molecular epidemiology of astrovirus in Japan from1995 to 1998 by RT-PCR with serotype-specificPrimers (1to 8) J Med Virol 61:326-331,2000.
27)Hachiya M, Matsui M, Sanogo M, Oseto M,
Morooka K, Ushijima H. Genetic variation in the capsid region of human astrovirus serotype 4 isolated inJapan. Microbiol Immunol 43(11),1067-1070,1999.
28. Ushijima H, Perovic S, Leuck J, Rytik P, Muller WEG,
HC Scroder.: Suppression of PrPsc- and HIV-1 gp120
induced neuronal cell death by sulfated colominic
acid. J Neurovirology 5:289-299, 1999.
29. Tanaka N,Shimoike T, Ishii K, Suzuki R, Suzuki T,
Ushijima H, Matsuura Y, Miyamura T. Selective
binding of hepatitis C virus core protein to synthetic
oligonucleotides corresponding to the 5’untranslated
region of the viral genome. Virology 270; 229-236,
2000.
30. Konishi K, Gu Y, Hatano I, Ushijima H. Effect of colominic acid on enteric-virus (rotavirus, poliovirus andCozsackievirus) infection in vitro. Japanese Journal of
Infectious Diseases. Jpn J Infect Dis 53:62-66, 2000.
31. Muller WEG, Laplanche JL, Ushijima H, Schroder
HC. Novel approaches in diagnosis and therapy of
Creutzfeldt-Jakob disease. Mechanisms of aging anddevelopment 31:116(2-3) 193-218, 2000 32 Ushijima
H. Rotavirus infection in Asia. Pediatrics
International. 42:392-394,2000
33. Kohno H, Akihara S, Nishio O, Ushijima H.
Development of a simple and rapid latex test for
rotavirus in stool. Pediatrics International 42:395400, 2000
34. Maneekarn N, Ushijima H. Epidemiology ofrotavirus infection in Thailand. Pediatrics
International 42:415-421, 2000
35. Nishio O, Matsui K, Lan DTP, Ushijima H, Isomura
S. Rotavirus infection among infants with diarrhea in
Vietnam. Pediatric International 42: 422-424, 2000
36. Zhou Y, Li L, Kim B, Kaneshi K, Nishimura S,
Kuroiwa T, Nishimura T, Sugita K, Ueda Y, Nakaya
T, Ushijima H. Rotavirus infection in children in
Japan. Pediatric International. 42:428-439, 2000
37. Gu Y, Gu Q, Kodama H, Muller WEG, Ushijima H.
Development of anti-rotavirus agents in Asia.
Pediatric International 42:440-447, 2000.
38. Wang QH, Kakizawa J, Wen L, Simizu M, Nishio O,
Fang Z, Ushijima H. Genetic Analysis of the Capsid
Region of Astroviruses. J Med Virol 64:245-255,2001.
39. Jonassen CM, Jonassen TO, Saif YM, Snodgrass DR,
Ushijima H, Shimizu M, Grinde B. Comparison ofcapsid sequences from human and animal astroviruses. J Gen Virol. 82:1061-1067, 2001.
40. Abe T, Kobayashi M, Araki K, Kodama H, Fujita Y,
Shinozaki T, Ushijima H. Infantile convulsions withmild gastroenteritis. Brain & Development 22:301306, 2000.
41. Adhikary AK, Numaga J, Kaburaki T, Kawashima H,
Kato S, Araike M, Miyata K, Simizu H, Suzuki E,

Yagyu F, Ushijima H. Rapid detection and typing of
oculopathogenic strain of subgenus D adenovirusesby fiber based PCR and restriction enzyme analysis.
Investigative ophthalmology & visual science. 42:
2010-2015, 2001.
42. Li Y, Shi A, Wan Y, Hotta M, Ushijima H. Childbehavior problems: Prevalence and correlates in rural
minority areas of China. Pediatrics International.
43:651-661, 2001.
43. Tani H, Nishimura M, Ushijima H, Miyamura T,
Matsuura Y. Characterization of cell-surface determinants important for baculovirus infection. Virology
279: 343-353, 2001.
44. Kudo S, Zhou Y, Cao XR, Yamanishi S, Nakaya S,
Ushijima H. Molecular characterization in the VP7,
VP4 and NSP4 genes of human rotavirus serotype 4(G4) isolated in Japan and Kenya. Microbiol Immunol
45 : 167-171, 2001.
45. Gu Y, Kodama H, Murata Y, Mochizuki D, Yanagawa
Y, Ushijima H, Shiba T, Lee CC. Mutations in the
ATP7A gene and copper metabolism in patients with
Menkes disease and occipital horn syndrome.
American Journal of Medical Genetics 99:217-222,
2001.
46. Kakizawa J, Nitta Y, Yamashita T, Ushijima H, Katow
S. Mutations of rubella virus vaccine TO-336 strain
occurred in the attenuation process of wild promotor
virus. Vaccine 19: 2793-2802, 2001.
47. Yamaguchi K, Ushijima H, Hisano M, Inoue Y,
Shimamura T, Hirano T, Muller WEG.
Immunomodulatory effect of gold sodium thiomalateof murine acquired immunodeficiency Syndrome.
Microbiol Immunol 45:549-555, 2001.
48. Zhou Y, Supawadee J, Khawan C, Tonusin S,
Peerakome S, Kim B, Kaneshi K, Ueda Y, Nakaya S,
Akatani K, Maneekarn N, Ushijima H.
Characterization of human rotavirus serotype G9 isolated in Japan and Thailand 1995 to 1997. J Med
Virol 65:619-628,2001.
49. Yagyu F, Ikeda Y, Sugiura W, Wongkhomthong SA,
Masuda M, Ushijima H. Differentiation of serotypes
B and E of human immunodeficiency virus type 1 bypolymerase chain reaction using novel env geneprimers. J Virol Methods;10: 11-20. 2002
50. Li Luibai, Thi Phuong Lan D, Hoa NT. Prevalence ofbreast-feeding and its correlates in Ho Chi Minh
City, Vietnum. Pediatrics International 44: 4754,2002. Other 20 English papers from 1995 to 2002.
(Total 70 papers)
10 majors are No.1, No.3, No.22, No.26, No..28, No.32,
No.38, No.40, No.41, No.48 and No.49.

349

Department of
Human Ecology
Outline and Research Objectives
In 1965, our department was established in the School of Health Sciences. From 1966 to
1972, however, there was no full-time professor in our department and thus its scientificactivities were limited. Between 1972 and 1976, Professor Akira Koizumi took the office andmade efforts for founding the bases in this new field, focusing on environmental health andpopulation analysis. For three years from 1976 when Professor Koizumi transferred to
Department of Public Health in our university, however, there was no professor again. In
1979, Professor Tsuguyoshi Suzuki transferred from Tohoku University, and since thenresearch activities of our department have flourished; in this period, particularly in the later
half, I fully assisted Professor Suzuki as an associate professor. In 1992, when I took hisplace, our department was reorganized as one of six departments in the newly established
School of International Health.
Regarding the research objectives, human ecology is unique in elucidating health andsurvival of humans at the individual and population levels, particularly from the relations orinteractions with their environment (not only the natural components but also the sociocultural components). Thus, the research of human ecology aims to integrate various aspects,
i.e. biomedical, environmental and sociocultural, as far as possible.
Since 1972 and particularly since 1979, the staff and students in our department haveconducted fieldworks and experimental works, with special interest in the linkage between
them. For the former, various populations in the Asia-Oceania region have been investigated, focusing on food-producing and consuming activities, nutritional and health status, population dynamics including births, deaths and migrations, and infectious and chronic degenerative (lifestyle-related) diseases; my own major contributions were related to the fieldworks. For the latter, toxicological and nutritional examinations have been conducted forbiological specimens (i.e. urine, blood and hair) and environmental samples (i.e. water andfoods), most of which were collected in our fieldworks; in addition, the associated animal
experiments have also been carried out.

Faculties and Students (in October 2002)
Professor and Chair Ryutaro Ohtsuka, D.Sc., since 1992.
Associate Professor Chiho Watanabe, Ph.D.
Associates ...............................2
Postdoctoral Fellow ................1 (foreigner).
Graduate Students ................13 (including 3 foreigners).
Research Students...................5 (including 3 foreigners).
Secretaries ...............................3 (1 full-time and 2 parttime).

Past Research and Major Accomplishments
It is reasonable to review the whole research activities of our department from the 1980s to the recent
past since I, as an associate professor from 1981 to
1992, actively participated in most of them, while
assisting, and collaborating with, the then Professor
T. Suzuki. For convenience, the major research fociare shown in Table 1, separately for the 1st period (up350

to 1992, when I became a professor) and the 2nd period (up to the late 1990s); in the same table, those in
the current and future periods are also mentioned. It
is noted that this table does not include the common
themes, such as nutritional adaptation, behavioral
adaptation and population dynamics, which havealways been pursued.
The most important goal of my research (withProfessor T. Suzuki and other staff) in the 1980s wasto establish the research framework of human ecology, focusing on human population ecology. Briefly, thesignificance of human population ecology or humanpopulation biology, which aims to elucidate humanadaptation at the population level not only in the
short term, e.g. within a year, but also in the longterm, e.g. through generations, had long been pointed
out by many human ecologists and human biologists
worldwide, but its systematic studies had been
lacked. For this purpose, my efforts were devoted tothe collaborative research in the Gidra-speaking popu-Table 1. The major research items, broken down into four periods
1st
2nd
3rd
4th
(-1992) (1990s) (current) (future)
Establishment of research framework++

Developments/Innovations of methodologies*
Human activity+
Nutritional/health status+++
Energy expenditure+++
Microdemography++
Specific themes**
Infectious diseases
Toxic elements
Lifestyle-related diseases
Harmonized development

*
**

+

++
+
+

+
+
+

(?)
(?)
(?)
(?)

+
++
+
+

+
+
++
++

Including only fieldwork-based methodologies.
The common themes are not included.
Infectious diseases: mostly, malaria in the earlier stages
and schistosomiasis in the later stages.
Toxic elements: mostly, mercury in the 2nd period andarsenic in the 3rd and 4th periods.
Lifestyle-related diseases: mostly, obesity, hypertension
and cardiovascular disorders.

lation in Papua New Guinea. The Gidra people aresuited to this purpose since they have maintained thebasic characteristics of a population, forming a unit ofmarriages and thus a unit of gene pool, despite thesmall number, i.e. about 2,000 in total, but theirmicroenvironmental conditions differ from village tovillage, e.g. inland, riverine and coastal terrains fromthe natural settings and in the degree of modernization from the sociocultural settings.
Our Gidra studies were characterized by the following two points. First, long-term field investigations were repeatedly conducted, based on observation, measurements and interviews, for the people’s
daily activity pattern, especially food procurements
and intakes, nutritional and health status and population dynamics. Second, biological specimens (blood,urine and hair) and environmental samples (foods andwater) were systematically collected for laboratory
analyses.
In tandem with the establishment of the researchframework, my efforts were directed to the developments and innovations of various biological, behavioral and microdemographic methods applicable tofield investigations. The major achievements included
1) genealogical-demographic analysis which has been
useful for reconstruction of long-term change in fertility, mortality and increase rates, 2) heart rate-monitoring method for estimation of energy expenditure
which has now become popular in human ecologicalfieldworks and 3) determination of sodium, potassium and urea nitrogen concentrations from urine samples, using filter papers, which has also been widely
used.
Following the findings from the Gidra studies,most of which were based on the combined efforts offieldwork and laboratory analysis, more than 40 original papers were published in international journals. In
addition, I, with Professor T. Suzuki, collected theimportant papers to edit a book in English, titled
Population Ecology of Human Survival: BioecologicalStudies of the Gidra in Papua New Guinea (No. 15 inSelect Publications), which has been distributed
worldwide to not only human ecologists but also scientists in the related fields. The 20 chapters of thisbook are categorized into four parts: “The ecology offood production,” “The ecology of food consumption,”“Nutrition and health” and “Population structure anddynamics.” Among various findings, some contributed
to the health promotion plans of the national andprovincial governments of Papua New Guinea: for
instance, disadvantageous effects of dietary modernization due to reduced intakes of essential micronutrients (e.g. zinc and potassium) and less effects of ironsupplementation to the anemia patients in malaria
endemic areas because their anemic states werecaused not by inadequate iron intake but by malariainduced haemolysis and dyserythropoiesis.
Since the late 1980s, I have increased the study
populations for more generalized understanding of
the people’s health and survival, based on the
research framework which was established. For
instance, our studies revealed an extraordinarily highmercury levels (in hair) among the Lake Murry population under artificially nonpolluted environment due
to large consumed amounts of fish in which mercury
was accumulated through biological concentration.
For another instance, our studies in the most modernized rural population, called Balopa, disclosed that
their prevalence rates of obesity and hypertension
were higher than those in many other populations
even in developed countries, mostly due to their lessenergy-consuming activity pattern and large amounts
of intake of fat-rich purchased foods.
Aside from the studies in Papua New Guinea, bothfield research and toxicological and nutritional experiments were conducted for various Japanese popula-351

tions, though only a few of them are listed in the
Select Publications.

Current Research
Since the late 1990s, my research foci have extended to clarify the effects of modernization on humanhealth and survival on the one hand, and on theother, the effects of some specific harmful environmental factors on human health and their mitigations.
In Papua New Guinea, our major efforts have been
devoted to the comparative analysis of rural (homeland) dwellers and rural-urban migrants of the same
populations, particularly the Huli and the Balopa,
whose genetic backgrounds markedly differ. For thispurpose, we have conducted research in both environments, the homelands and Port Moresby, i.e. the capital city, focusing on energy and nutrient intakes, energy expenditure and the prevalence of obesity, hypertension and other cardiovascular diseases and havedisclosed the significance of lifestyle change on them;protein status has been improved while obesity,
hypertension and many other cardiovascular risks
have been worsened. Furthermore, the comparison
between the two rural-urban migrant populations inPort Moresby revealed difference in the trigger factor,
obesity for the Balopa (an Austronesian group) andhigh lipoprotein-a level for the Huli (a NonAustronesian group).
Concurrently, I began research projects in several
Asian countries. Of them, the study for Bangladeshi
populations under arsenic hazards has been the major
target in the last several years. Despite that 35-50 million Bangladeshi people are recognized as a risk population of arsenic poisoning, systematic analyses, thedose-response relationships in particular, have seldom
been conducted. Our research contributed to concrete
elucidation for the interrelations among arsenic concentration of drinking water, urinary arsenic concentration and the extents of skin lesions (i.e. keratosis
and melanosis as the major symptoms of arsenic poisoning), in collaboration with dermatologists in our
University Hospital. Furthermore, in this research
project headed by me, many colleagues of different
disciplines, such as water chemists and public healthengineers from Switzerland and Japan and hydrologists from USA, have collaborated to seek integrated
ways for mitigation of arsenic hazards and sustainable
water supply systems in arsenic affected areas.
Energetics, i.e. the balance between energy intake
and energy expenditure, has been one of the important research themes in our department. The recent
studies have clarified its particularly significant roles
on degradation of health status in modernization
process among populations in Papua New Guinea,
Thailand and Bangladesh.

352

Finally, I began a biosocial research, which seeks
harmonized ways of community development andenvironmental conservation in the Asia-Oceania
region. The major reason why I organized this projectcame from my judgment that the basic idea of humanecology is useful for this issue. In this project, I
recruited not only biomedical scientists but rathersociocultural scientists from Japan and some other
Asian and Oceanian countries. At the beginning stage,
our findings have still been limited mostly due to difficulties in data collection by means of sociocultural
methods, but I will continue this research in the
future.

Future Prospects
My term of professor is not long, and thus I willconcentrate in the three research projects: the arsenic
hazards in Asian countries (not only Bangladesh but
several countries) and the harmonized community
development with environmental conservation in the
Asia-Oceania region, both which have already commenced, and a new project which has begun in theyear 2002 and will continue for three years. This new
project aims to elucidate the causes of markedly different prevalence of lifestyle-related diseases among
Asian, Melanesian and Polynesian populations. Basedon my previous research findings and in collaboration
with the staff in our school, particularly those from
Department of Human Genetics (headed by Professor
K. Tokunaga), the effects of both genetic factors andenvironmental (mostly lifestyle) factors will be simultaneously clarified.
My intentions for these three projects, with special
interest in collaborations with scientists of other disciplines, are as follows. The arsenic project, which has
been and will be sponsored by the Alliance for Global
Sustainability (the joint programs of Massachusetts
Institute of Technology in USA, Swiss Federal
University of Technology and our university), is
expected to contribute our human ecology research tothe integrated efforts for solution/mitigation of thisenvironmental issue, recognized very serious forhuman health and survival in several Asian countries.
The genetico-ecological project for lifestyle-related diseases aims at development of collaborative works
with many colleagues, particularly, those from
Departments of Human Genetics, Biomedical
Chemistry and Developmental Medical Sciences (all ofwhich belong to a large Department called
International Biomedical Sciences, together with ourdepartment). The harmonized development project is
expected to broaden human ecology aspects throughcollaboration with scientists of social medicine andsocial ecology in our school, i.e. a large Department ofInternational Social Medicine) and some others.

Research Grants
1. (as the Cluster Sub-leader, with many colleagues
from many countries) “People, land management andenvironmental change” organized by the United
Nations University and sponsored by the Global
Environmental Facility through the United Nations
Environmental Programme: 1998-99; 7,816,860 Yen(in total, for my own team).
2. (as the Leader, with 15 colleagues from Japan, USA,
Switzerland, Bangladesh and Nepal) “Mitigation ofgroundwater-derived arsenic hazards and sustainable
water supply system in Asian countries” sponsoredby the Alliance for Global Sustainability Programs;
1999-2002; 29,420,518 Yen (in total).
3. (as the Leader, with 30 colleagues from Japan, China,
Solomon Islands and Nepal) “Influences of development on local communities and their mitigations”
sponsored by the Japan Society for Promotion of
Science: 1999-2002; 184,000,000 Yen (in total).
4. (as the Leader, with 15 colleagues from Japan,
Solomon Islands and Indonesia) “Genetico-ecologicalstudies for high risks of lifestyle-related diseases in
Oceanian populations” sponsored by the
Monbukagaku-sho, Japan (Grant-in-Aid for Scientific
Research); 2002- 2004; 29,300,000 Yen (in total).
5. (as the Leader, with 10 colleagues from Japan, Papua
New Guinea, Malaysia and Nepal) “Application ofhigh-quality satellite images to analyses of land use
and environmental change” sponsored by the
Monbukagaku-sho, Japan (Grant-in-Aid for Scientific
Research); 2002-2005; 15,800,000 Yen (in total).

Select Publications
1. Ohtsuka, R. Oriomo Papuans: Ecology of Sago-Eatersin Lowland Papua. University of Tokyo Press, Tokyo,
1983.
2. Ohtsuka R, Kawabe T, Inaoka T, Suzuki T, Hongo T,
Akimichi T, Sugahara T. Composition of local andpurchased foods consumed by the Gidra in lowland
Papua. Ecology of Food and Nutrition, 15, 159-169,
1984.
3. Ohtsuka R, Kawabe T, Inaoka T, Akimichi T, Suzuki
T. Inter- and intra-population migration of the Gidrain lowland Papua. Human Biology, 57, 33-45, 1985.
4. Ohtsuka R, Inaoka T, Kawabe T, Suzuki T, Hongo T,
Akimichi T. Diversity and change of food consumption and nutrient intake among the Gidra in lowland
Papua. Ecology of Food and Nutrition, 16, 339-350,
1985.
5. Kawabe T, Ohtsuka R, Inaoka T, Akimichi T, Suzuki
T. Visual acuity of the Gidra in lowland Papua New
Guinea. Journal of Biosocial Science, 17, 361-369,
1985.
6. Ohtsuka R, Hongo T, Kawabe T, Suzuki T, Inaoka T,
Akimichi T, Sasano H. Mineral content of drinking
water in lowland Papua. Environment International,
11, 505-508, 1985.

7. Ohtsuka R. Low rate of population increase of theGidra Papuans in the past: A genealogical-demographic analysis. American Journal of Physical
Anthropology, 71, 13-23, 1986.
8. Inaoka T, Suzuki T, Ohtsuka R, Kawabe T, Akimichi
T, Takemori K, Sasaki N. Salt consumption, body fatness and blood pressure of the Gidra in lowland
Papua. Ecology of Food and Nutrition, 20, 55-66,
1987.
9. Suzuki T, Ohtsuka R. [Eds.] Human Ecology ofHealth and Survival in Asia and the South Pacific.
University of Tokyo Press, Tokyo, 1987.
10. Ohtsuka R, Suzuki T, Morita M. Sodium-rich tree ash
as a native salt source in lowland Papua. Economic
Botany, 41, 55-59, 1987.
11. Suzuki T, Watanabe S, Hongo T, Kawabe T, Inaoka
T, Ohtsuka R, Akimichi T. Mercury in scalp hair ofPapuans in the Fly estuary, Papua New Guinea.
Asia-Pacific Journal of Public Health, 2, 39-47, 1988.
12. Ohtsuka, R. Hunting activity and aging among theGidra Papuans: A biobehavioral analysis. American
Journal of Physical Anthropology, 79, 31-39, 1989.
13. Hongo T, Suzuki T, Ohtsuka R, Kawabe T, Inaoka T,
Akimichi T. Element intake of the Gidra in lowland
Papua: Inter-village variation and the comparison
with contemporary levels in developed countries.
Ecology of Food and Nutrition, 23, 293-309, 1989.
14. Hongo T, Suzuki T, Ohtsuka R, Kawabe T, Inaoka T,
Akimichi T. Hair element concentrations of theGidra in lowland Papua: The comparison withdietary element intakes and water element concentrations. Ecology of Food and Nutrition, 24, 167-179,
1990.
15. Ohtsuka R, Suzuki T. [Eds.] Population Ecology of
Human Survival: Bioecological Studies of the Gidra in
Papua New Guinea . University of Tokyo Press,
Tokyo, 1990.
16. Yoshinaga J, Minagawa M, Suzuki T, Ohtsuka R,
Kawabe T, Hongo T, Inaoka T, Akimichi T. Carbon
and nitrogen isotopic characterization for Papua New
Guinea foods. Ecology of Food and Nutrition, 26,
17-25, 1991.
17. Yoshinaga J, Suzuki T, Ohtsuka R, Kawabe T, Hongo
T, Imai H, Inaoka T, Akimichi T. Dietary selenium
intake of the Gidra, Papua New Guinea. Ecology ofFood and Nutrition, 26, 27-36, 1991.
18. Yoshinaga J, Suzuki T, Hongo T, Minagawa M,
Ohtsuka R, Kawabe T, Inaoka T, Akimichi T.
Mercury concentration correlates with the nitrogenstable isotope ratio in the animal food of Papuans.
Ecotoxicology and Environmental Safety, 24, 37-45,
1992.
19. Hongo T, Ohtsuka R, Nakazawa M, Kawabe T,
Inaoka T, Akimichi T, Suzuki T. Serum mineral andtrace element concentrations in the Gidra of lowland
Papua New Guinea: Inter-village variation and comparison with the levels in developed countries.
Ecology of Food and Nutrition, 29, 307-318, 1993.
20. Hongo T, Abe T, Ohtsuka R, Komai M, Okiyama T,
Amano K, Toyo-oka T, Suzuki T. Urinary mercury

353

monitoring of university staff and students occasionally exposed to mercury vapor. Industrial Health, 32,
17-27, 1994.
21. Ohtsuka R. Subsistence ecology and carrying capacity in two Papua New Guinea populations. Journal of
Biosocial Science, 26, 395-407, 1994.
22. Nakazawa M, Ohtsuka R, Kawabe T, Hongo T,
Suzuki T, Inaoka T, Akimichi T, Kano S, Suzuki M.
Differential malaria prevalence among villages of theGidra in lowland Papua New Guinea. Tropical andGeographical Medicine, 46, 350-354, 1994.
23. Hongo T, Ohtsuka R, Inaoka T, Kawabe T, Akimichi
T, Kuchikura Y, Suda K, Tohyama C, Suzuki T.
Health status comparison by urynalysis (dipsticktest) among four populations in Papua New Guinea.
Asia-Pacific Journal of Public Health , 7, 165-172,
1994.
24. Yoshida M, Ohtsuka R, Nakazawa M, Juji T,
Tokunaga K. HLA-DRB1 frequencies of
Non-Austronesian-speaking Gidra in south New
Guinea and their genetic affinities with Oceanian
populations. American Journal of Physical
Anthropology, 96, 177-181, 1995.
25. Ohtsuka R, Inaoka T, Umezaki M, Nakada N, Abe T.
Long-term subsistence adaptation to the diversified
Papua New Guinea environment: Human ecologicalassessments and prospects. Global Environmental
Change, 5, 347-353, 1995.
26. Abe T, Ohtsuka R, Hongo T, Suzuki T, Tohyama C,
Nakano A, Akagi H, Akimichi T. High hair and urinary mercury levels of fish eaters in the nonpolluted
environment of Papua New Guinea. Archives ofEnvironmental Health, 50, 367-373, 1995.
27. Yoshinaga J, Minagawa M, Suzuki T, Ohtsuka R,
Kawabe T, Inaoka T, Akimichi T. Stable carbon andnitrogen isotopic composition of diet and hair of
Gidra-speaking Papuans. American Journal of
Physical Anthropology, 100, 23-34, 1996.
28. Dejima Y, Fukuda S, Ichijoh Y, Takasaka K, Ohtsuka
R. Cold-induced salt intake in mice and catecholamine, renin and thermogenesis mechanisms.
Appetite, 26, 203-220, 1996.
29. Nakazawa M, Ohtsuka R, Kawabe T, Hongo T,
Inaoka T, Akimichi T, Suzuki T. Iron nutrition andanaemia in a malaria-endemic environment:
Haematological investigation of the Gidra-speaking
population in lowland Papua New Guinea. British
Journal of Nutrition, 76, 333-346, 1996.
30. Inaoka T, Ohtsuka R, Kawabe T, Hongo T, Suzuki T.
Emergence of degenerative diseases in Papua New
Guinea islanders. Environmental Sciences, 4, 79-93,
1996.
31. Nakazawa M, Ohtsuka R. Analysis of completed parity using microsimulation modeling. Mathematical
Population Studies, 6, 173-186, 1997.
32. Umezaki M, Ohtsuka R. Impact of rural-urban migration on fertility: A population ecology analysis in the
Kombio, Papua New Guinea. Journal of Biosocial
Science, 30, 411-422, 1998.

354

33. Ohtsuka R, Abe T, Umezaki M. Environmentally
Sound Agricultural Development in Rural Societies:
A Comparative View from Papua New Guinea andSouth China. UNESCO, Paris, 1998.
34. Sudo N, Ohtsuka R. Sleep patterns and sleep disorders among female shift workers in a computer factory of Japan. Journal of Human Ergology, 28, 39-47,
1999.
35. Umezaki M, Ishimaru H, Ohtsuka R. Daily timebudgets of long-distance commuting workers inTokyo Megalopolis. Journal of Biosocial Science, 31,
71-78, 1999.
36. Murayama N, Ohtsuka R. Seasonal fluctuation inenergy balance among farmers in Northeast
Thailand: The lack of response of energy intake tothe change of energy expenditure. European Journalof Clinical Nutrition, 53, 39-49, 1999.
37. Umezaki M, Yamauchi T, Ohtsuka R. Diet among the
Huli in Papua New Guinea Highlands when they
were influenced by the extended rainy period.
Ecology of Food and Nutrition, 37, 409-427, 1999.
38. Murayama N, Ohtsuka R. Heart rate indicators forassessing physical activity level in the field.
American Journal of Human Biology, 11, 647-657,
1999.
39. Natsuhara K, Inaoka T, Umezaki M, Yamauchi T,
Hongo T, Nagano M, Ohtsuka R. Cardiovascular risk
factors of migrants in Port Moresby from the highlands and island villages, Papua New Guinea.
American Journal of Human Biology, 12, 655-664,
2000.
40. Nakazawa M, Ohtsuka R, Hongo T, Inaoka T,
Kawabe T, Suzuki T. Serum biochemical data of theGidra in lowland Papua New Guinea: Considerationof their normal ranges. Journal of Nutrition andEnvironmental Medicine, 10, 153-162, 2000.
41. Ohashi J, Yoshida M, Ohtsuka R, Nakazawa M, Juji
T, Tokunaga K. Analysis of HLA-DRB1 polymorphism in the Gidra of Papua New Guinea. Human
Biology, 72, 337-347, 2000.
42. Yamauchi T, Ohtsuka R. Basal metabolic rate andenergy costs at rest and during exercise in rural- andurban-dwelling Papua New Guinea Highlanders.
European Journal of Clinical Nutrition, 54, 494-499,
2000.
43. Yamauchi T, Umezaki M, Ohtsuka R. Energy expenditure, physical exertion and time allocation among
Huli-speaking people in the Papua New Guinea
Highlands. Annals of Human Biology, 27, 571-585,
2000.
44. Umezaki M, Kuchikura Y, Yamauchi T, Ohtsuka R.
Impact of population pressure on food production:
An analysis of land use change and subsistence pattern in the Tari basin in Papua New Guinea
Highlands. Human Ecology, 28, 359-381, 2000.
45. Yamauchi T, Umezaki M, Ohtsuka R. Influence ofurbanisation on physical activity and dietary changes
in Huli-speaking population: A comparative study ofvillage dwellers and migrants in urban settlements.
British Journal of Nutrition, 85, 65-73, 2001.

46. Yamauchi T, Umezaki M, Ohtsuka R. Physical activity and subsistence pattern of the Huli, a Papua New
Guinea Highland population. American Journal of
Physical Anthropology, 114, 258-268, 2001.
47. Umezaki M, Natsuhara K, Ohtsuka R. Protein content and amino acid scores of sweet potatoes in
Papua New Guinea Highlands. Ecology of Food andNutrition, 40, 471-480, 2001.
48. Watanabe C, Inaoka T, Kadono T, Nagano M,
Nakamura S, Ushijima K, Murayama N, Miyazaki K,
Ohtsuka R. Males in rural Bangladeshi communities
are more susceptible to chronic arsenic poisoning
than females: Analyses based on urinary arsenic.
Environmental Health Perspectives, 109, 1265-1270,
2001.
49. Sudo N, Ohtsuka R. Nutrient intake among female
shift workers in a computer factory in Japan.
International Journal of Food Sciences and Nutrition,
52, 367-378, 2001.
50. Umezaki M, Yamauchi T, Ohtsuka R. Time allocation
to subsistence activities among the Huli in rural andurban Papua New Guinea. Journal of Biosocial
Science, 34, 133-137, 2002.

355

Department of
Biomedical Chemistry
Outline and Research Objectives
Aim of our department is to contribute to global health and welfare from basic research.
Our department, formerly named Biochemistry and Nutrition was renamed on April 1st,
1996 to The Department of Biomedical Chemistry as newly affiliating with Biomedical
Science Division of International Health, Graduate School of Medicine, The University ofTokyo. Prof. Kita has moved from The Institute of Medical Science, The University of Tokyo
on March 1st, 1998. Therefore, we are quite new and all of our members are highly motivated.

Faculties and Students
Professor and Chair

KITA Kiyoshi, Dr. of Pharmacy(1998-)
Lecturer
WATANABE Yoh-ichi, Dr. ofTechnology
Associate .................................3
Postdoctoral Fellow ................2
Graduate student ..................12
Research student.....................4
Secretary .................................1

Past Research and Major Accomplishments
Energy metabolism is essential for the survival,continued growth and reproduction of living organisms. From the standpoint of biological adaptation,
we have been studying on the molecular mechanismof energy transducing systems such as mitochondrialand bacterial respiratory chain. Because energy metabolisms of pathogenic organisms such as bacteria andparasites are quite different from that of mammalianhost and these unique aspects of pathogens would bepromising targets for chemotherapy.
For the first step to understand a mechanism ofadaptation to the change of oxygen availability, composition and its change during aerobic growth ofEscherichia coli was studied. Finally, we found two
different terminal oxidases, cytochrome bo and bd
complexes. Cytochrome bo complex is expressed inearly log phase and possesses proton-pumping activity, while cytochrome bd complex is expressed fromlate log phase to stationary phase with higher affinity
to oxygen than cytochrome bo complex. Thus, wefound that E. coli keep their energy supply by changing the respiratory chain during their growth.
Then, we have started our research on the biological strategy to adapt to different oxygen availability ineukaryotes. Purpose of this project is multiple. We

356

would like to know the common strategy to maintainenergy supply in different environments and also tounderstand unique feature of energy metabolism inpathogenic organisms. If we could understand themechanism clearly, it would be quite important information to fight against infectious diseases caused bybacteria and parasites in addition to the basic knowledge on the molecular mechanism of biological adaptation. As a model system, we selected Ascaris suum
which is a parasitic nematode resides in our small
intestine where oxygen tension is quite limited,
because 1) they are rather large in size allowing biochemical study, 2) their life cycle has been well characterized and 3) they are closely related to
Caenorhabditis elegans which is well known free-living nematode, of which whole genome sequence has
been reported.

Current Research
I. Human mitochondria
1) succinate dehydrogenase2) mitochondrial myopathy
Succinate-ubiqinone oxidoreductase (complex II
and/or SQR) is an important enzyme complex in boththe tricarboxylic acid cycle and the aerobic respiratory
chains of eukaryotic mitochondria and prokaryotic
cells. Complex II catalyzes the oxidation of succinate
to fumarate (succinate dehydrogenase: SDH) andtransfers its reducing equivalent to ubiquinone. To
elucidate the molecular basis of a mitochondrial disease caused by a deficiency in the SDH activity ofcomplex II, we cloned the cDNAs for all four subunitsof human liver complex II. During this study, we
found two isoforms of complex II containing Fp subunits of liver type and heart type.
Then we have mapped large (CybL) and small(CybS) subunits of cytochrome b in complex II ofhuman mitochondria to chromosome 1q21 and
11q23, respectively. Recently, the human SDHD geneencoding CybS was cloned and characterized. The
gene comprises four exons and three introns extending over 19 kb. Sequence analysis of the 5’ promoter
region showed several motifs for the binding of transcription factors including nuclear respiratory factors
NRF-1 and NRF-2 at positions -137 and -104, respectively. In addition to this gene, six pseudogenes of
CybS were isolated and mapped on the chromosome.
II. Ascaris suum and Caenorhabditis elegans
1) molecular mechanism of adaptation to low oxygen
tension (regulation of gene expression of mitochondrial proteins)2) mitochondrial quinol-fumarate reductase (structure-function relationship, enzyme evolution)3) C. elegans as a model system of parasitic nematodes and ageing (expression of foreign genes,
gene knockout, oxygen stress)
Parasites have developed a variety of physiological
functions necessary for existence within the specialized environment of the host. Regarding energy
metabolism, which is an essential factor for survival,
parasites adapt to low oxygen tension in host mammals using metabolic systems that are very different
from that of the host. The majority of parasites does
not use the oxygen available within the host, but
employ systems other than oxidative phosphorylation
for ATP synthesis.
In addition, all parasites have a life cycle. In manycases, the parasite employs aerobic metabolism during
their free-living stage outside the host. In such systems, parasite mitochondria play diverse roles. In particular, marked changes in the morphology and components of the mitochondria during the life cycle arevery interesting elements of biological processes suchas developmental control and environmental adaptation. Recent our research on adult A. suum has shownthat the stage-specific mitochondrial complex II plays
an important role in the anaerobic energy metabolismof parasites inhabiting hosts, by acting as quinolfumarate reductase (QFR). Sequence analysis of thesubunits in the enzyme revealed that mitochondrial
QFR is new enzyme evolved by “reverse evolution” of
SQR rather than direct evolution from bacterial QFR.
We have been studying free-living nematode, C.
elegans as a control nematode living in an aerobic
condition. In addition, we also have been studying
ageing by using C. elegans. Our study on long-lived
clk-1 mutants of C. elegans demonstrated that biosynthesis of UQ is dramatically altered in mutant mitochondria. Demethoxy ubiquinone (DMQ), that accumulates in clk-1 mutants in place of UQ, may contribute to the extension of life span. We proposed thepossible mechanisms of life span extension in clk-1
mutants, with particular emphasis on the electrochemical property of DMQ. On the other hand, in the
short-lived mev-1 mutant, a point of mutation glycine
71 of CybL in SQR results in hypersensitivity tooxidative stress. We demonstrated the production ofreactive oxygen species (ROS) was higher in the
mutant complex II than wild type, indicating ROS is
responsible for the short life span of mev-1 mutant.

III. Malaria and Trypanosome (Plasmodium falciparum, Trypanosoma brucei,Trypanosoma cruzi)
1) characterization of mitochondria as a target for thechemotherapy2) molecular biology of mitochondrial DNA3) structure based drug design (SBDD)
The mitochondria of parasitic protozoa that havebeen most studied are those of Trypanosoma brucei,
which is the causative agents of African trypanosomiasis in human and nagana in cattle. Parasitic protozoa
living within a mammalian host do not generally use
oxygen, and instead synthesize ATP via the glycolytic
pathway. In comparison to research on helminthes,
research on mitochondrial electron transfer of protozoa during the developmental stage within the host islacking. However, mitochondria have become a focusof chemotherapy, and researches, particularly on
mitochondria of the malaria parasite and trypanosomes are currently progressing.
To study the unique properties of Plasmodium
complex II, we have cloned and characterized thegenes for the flavoprotein subunit (Fp) and the ironsulfur protein subunit (Ip) subunits of complex II.
This is the first report of the primary structure of protozoan complex II. Interestingly, a P. falciparum-specific insertion and a unicellular organism-specific deletion were found in the amino acid sequence of Fp.
Despite the fact that Fp and Ip are generally well-conserved subunits, the structure of both subunits in themalaria parasite clearly differs considerably from thatof the host.
Cyanide-insensitive trypanosome alternative oxidase (TAO) is the terminal oxidase of the respiratory
chain of long slender bloodstream forms of theAfrican trypanosome. TAO is a cytochrome-independent, cyanide-insensitive quinol oxidase. These characteristics are distinct from those of the bacterial quinoloxidase, a protein that belongs to the heme-copper
terminal oxidase superfamily. TAO has been targeted
for the development of anti-trypanosomal drugs
because it does not exist in the host. We found themost potent inhibitor of TAO to date, ascofuranone, acompound isolated from phytopathogenic fungus,
Ascochyta visiae. The inability to purify stable TAO
has severely hampered biochemical studies of the357

alternative oxidase family. Recently, we were able topurify recombinant TAO to homogeneity from E. coli
membranes using the detergent digitonin. Kinetic
analysis of the purified TAO revealed that ascofuranone is a competitive inhibitor of ubiquinol oxidase
activity.
IV. Escherichia coli
1) succinate dehydrogenase complex (mechanism ofmolecular assembly, electron transport mechanismin the complex)2) regulation of energy supply

E. coli is one of the useful model systems to investigate biological reactions common to living organisms. In order to investigate the role of the heme in
the assembly of complex II, we used a hemH (encodes
ferrochelatase) mutant of E. coli lacking the ability toinsert iron into the porphyrin ring. The hemH mutant
failed to synthesize functional complex II in the cytoplasmic membrane and the catalytic portion of complex II, Fp and Ip, was localized in the cytoplasm of
the cell. In contrast, complex II was assembled in themembrane of a heme-permeable and hemH double
mutant when hemin was present in the culture. Onlya small amount of succinate-ubiquinone reductase(SQR) activity was found in the membrane whenhemin was replaced by non-iron metalloporphyrins;
Mn-, Co-, Ni-, Zn-, Cu-protoporphyrin IX or protoporphyrin IX. These results indicate the indispensabilityof iron of heme for the functional assembly of complex II in the cytoplasmic membrane of E. coli, andadd a new aspect to the biological role of heme in themolecular assembly of the multi-subunit enzyme complex.

Future Prospects
Dynamic rearrangement of the respiratory chain
during parasite life cycle that we found is a key element of their adaptation to different environments. In
the case of mammals, cells are able to sense decreased
oxygen and activate response systems, including
hypoxia-inducible factor-1 (HIF-1)–mediated transcriptional activation of several genes. Quite recently,
HIF-β and a homologue of HIF-1α were found in thefree-living nematode C. elegans. Although it is notknown whether such a pathway exists in the parasites, A. suum shows a very clear transition between
larval and adult metabolic systems. Thus, A. suum is
an excellent model system for studying the regulationof transcription by the oxygen level in the environment.
Current research on C. elegans including our result
has revealed that oxygen concentration, its availability, and oxidative stress can produce a variety of inter-358

esting phenotypes such as modified life spans. As
described above, in the long-lived C. elegans mutant
clk-1, UQ biosynthesis is altered so that mitochondria
do not possess detectable levels of UQ-9 but instead
contain the UQ biosynthesis intermediate DMQ-9. On
the other hand, in the short-lived mev-1 mutant, apoint of mutation glycine 71 of CybL in SQR results in
hypersensitivity to oxidative stress. These findings
indicate that the respiratory chain plays an importantrole in sensing and responding to the oxygen level inthe environment. Consistent with this, recent reportssuggest that complex II functions as an oxygen sensor
in human. We would like to understand a molecularmechanism of biological adaptation to the change ofoxygen availability by using these nematodes andhuman systems. Diversity of complex II was also
found in human complex II. Studies on the humanrespiratory chain will be achieved from the viewpointof physiological role of energy supply and related diseases.
It remains unclear which critical factor determines
the catalytic direction of electron transfer in complex
II. Biochemical and molecular biological studies
showed that both the properties and the primarystructures of mitochondrial and bacterial quinolfumarate reductase (QFR) differ significantly.
Identification of the amino acid residues of mitochondrial QFR responsible for the directional specificity of
its catalysis should help to clarify the molecular mechanism of this “new” parasite enzyme. Furthermore,investigations of the molecular pathways of parasite
survival may provide insight into general mechanismsof biological adaptation.
Finally, we would like to develop anti-parasitic
drugs which should be used in endemic areas. As
described in “Current Research”, the parasite metabolic system is an attractive target for chemotherapy
because it is different than the host metabolic systemand because it is essential for parasite survival. TAO
in trypanosome mitochondria and its specificinhibitor, ascofuranone are excellent examples in thisregard. As pointed out by Dr. Opperdoes, ascofuranone is the most potent TAO inhibitor to date.
Because of its high selectivity and low toxicity, ascofuranone is a potential candidate for the next generation of anti-trypanosomal agents. Indeed, current
studies are examining the molecular mechanism of
ascofuranone and ways of improving its efficacy invivo. We already have started a trial by using goat in
Africa. One problem that must be solved is that glycerol must be administered along with ascofuranone,
to inhibit the reverse reaction of glycerol kinase.
Although glycerol is not toxic, it is not practical to
give the large dose (3g /kg) required, and an inhibitorof the reverse reaction of glycerol kinase is expected
to be more useful. Fortunately, glycerol kinase hasbeen cloned and the recombinant enzyme can be overexpressed. We are now trying to screen and find a
specific inhibitor of glycerol kinase.
Thus, we would like to contribute to global healthand welfare from basic research and train young scientists to be thoughtful and powerful colleagues.

Research Grants
1. “Molecular and biochemical studies on Plasmodium
mitochondria” from a Grant-in-aid for scientificresearch on priority areas from the Ministry of
Education, Science, Culture and Sport, Japan
40,000,000 yen (2001-)
2. “Crystalization of parasite proteins and molecular
design of anti-parasitic drugs” from Pilot Applied
Research Project for the Industrial Use of Space” ofthe National Space Development Agency of Japan(NASDA) and Japan Space Utilization Promotion
Center (JSUP).
30,000,000 yen (2000-)
3. “New anti-trypanosome drug, ascofuranone” from a
Grant for research on emerging and re-emerging
infectious diseases from the Ministry of Health andWelfare120,000,000 yen (1999-2001)
4. “Molecular structure and role of mitochondrial
fumarate reductase from Ascaris suum ” from a
Grant-in-aid for scientific research on priority areasfrom the Ministry of Education, Science, Culture andSport, Japan
13,200,000 yen (1999-2000)
5. “Molecular properties of Plasmodium mitochondria
in the erythrocytic stages” from a Grant-in-aid for scientific research on priority areas from the Ministryof Education, Science, Culture and Sport, Japan
28,000,000 yen (1997-2000)

Select Publications
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2. Kita, K., Kasahara, M., and Anraku, Y. Formation ofa membrane potential by reconstituted liposomes
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3. Kita, K., Konishi, K., and Anraku, Y. Terminal oxidases of Escherichia coli aerobic respiratory chain. I.
Purification and properties of cytochrome b 562- ocomplex from cells in the early exponential phase of
aerobic growth. J. Biol. Chem. 259, 3368-3374, 1984,
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cells grown with limited oxygen and evidence ofbranched electron carrying systems. J. Biol. Chem.
259, 3375-3381, 1984.

4. Kita, K., Takamiya, S., Furushima, R., Ma, Y., andOya, H. Complex II is a major component of the respiratory chain in the muscle mitochondria of Ascaris
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6. Hata-Tanaka, A., Kita, K., Furushima, R., Oya, H.,
and Itoh, S. ESR studies on iron-sulfur clusters ofcomplex II in Ascaris suum mitochondria which
exhibits strong fumarate reductase activity. FEBS
Lett. 242, 183-186, 1988.
7. Kita, K., Vibat, C., Meinhardt, S., Guest, J., andGennis, R. One-step purification from Escherichia
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8. Kita, K., Oya, H., Gennis, R., Ackrell, B.A.C., andKasahara, M. Human complex II (succinateubiquinone oxidoreductase): cDNA cloning of ironsulfur (Ip) subunit of liver mitochondria. Biochem.
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9. Furushima, R., Takamiya, S., Okochi, I., Kita, K.,
Aoki, T., and Oya, H. A comparative study of theeffects of phebrol on the respiratory chains of rat
liver, Biomphalaria glabrata and Oncomelania
nosophora. Comp. Biochem. Physiol. 99C, 191-199,
1991.
10. Kita, K. Electron-transfer complexes of mitochondria
in Ascaris suum. Parasitol. Today 8, 155-159, 1992.
11. Hirawake, H., Wang, H., Kuramochi, T., Kojima, S.,
and Kita, K. Human Complex II (succinateubiquinone oxidoreductase): cDNA cloning of theflavoprotein (Fp) subunit of liver mitochondria. J.
Biochem. 116, 221-227, 1994.
12. Kuramochi, T., Hirawake, H., Kojima, S., Takamiya,S., Furushima, R., Aoki, T., Komuniecki, R., and Kita,
K. Sequence comparison between the flavoprotein
subunit of the fumarate reductase (Complex II) of theanaerobic parasitic nematode, Ascaris suum and thesuccinate dehydrogenase of the aerobic, free-living
nematode, Caenorhabditis elegans. Mol. Biochem.
Parasitol. 68, 177-187, 1994.
13. Watanabe, Y., Tsurui, H., Ueda, T., Furushima, R.,
Takamiya, S., Kita, K., Nishikawa, K., and Watanabe,
K. Primary and higher order structures of nematode(Ascaris suum) mitochondrial tRNAs lacking either
the T or D stem. J. Biol. Chem. 269, 22902-22906,
1994.
14. Saruta, F., Kuramochi, T., Nakamura, K., Takamiya,S., Yu, Y., Aoki, T., Sekimizu, K., Kojima, S., andKita, K. Stage-specific isoforms of ComplexII (succinate-ubiquinone oxidoreductase) in mitochondria
from the parasitic nematode, Ascaris suum. J. Biol.
Chem. 270, 928-932, 1995.
15. Kuramochi, T., Kita, K., Takamiya, S., Kojima, S., andHayasaki, M. Comparative study and cDNA cloning359

of the flavoprotein subunit of mitochondrial complex
II (succinate-ubiquinone oxidoreductase: fumarate
reductase) from the dog heartworm, Dirofilaria
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1995.
16. Nakamura, K., Yamaki, M., Sarada, M., Nakayama,S., Vibat, C.R.T., Gennis, R.B., Nakayashiki, T.,
Inokuchi, H., Kojima, S., and Kita, K. Two hydrophobic subunits are essential for the heme b ligation andfunctional assembly of complex II (succinateubiquinone oxidoreductase) from Escherichia coli. J.
Biol. Chem. 271, 521-527, 1996.
17. Takamiya, S., Hirawake, H., Kuramochi, T., Aoki, T.,
Kojima, S., and Kita, K. cDNA cloning for mitochondrial cytochrome c and its adult-specific isoform
from Ascaris suum. Mol. Biochem. Parasitol. 76, 293297, 1996.
18. Ohtsuki, T., Kawai, G., Watanabe, Y., Kita, K.,
Nishikawa, K., and Watanabe, K. Preparation of biologically active Ascaris suum mitochondrial
tRNAMet with a TV-replacement loop by ligation ofchemically synthesized RNA fragments. Nucleic
Acids Res. 24, 662-667, 1996.
19. Noor Rain, A., Furuta, T., Radzan, T., Kita, K.,
Kojima, S., and Mak, J.W. Development of a new
diagnostic method for Plasmodium falciparum infection using a reverse transcriptase-polymerase chain
reaction. Am. J. Trop. Med. Hyg. 54, 162-163, 1996.
20. Saruta, F., Hirawake, H., Takamiya, S., Ma, Y-C.,
Aoki, T., Sekimizu, K., Kojima, S., and Kita, K.
Cloning of a cDNA encoding the small subunit ofcytochrome b558 (cybS) of mitochondrial fumarate
reductase (Complex II) from adult Ascaris suum .
Biochim. Biophys. Acta 1276, 1-5, 1996.
21. Minagawa, N., Yabu, Y., Kita, K., Ohta, N., Meguro,
K., Sakajo, S., and Yoshimoto,A. An antibiotic,
Ascofuranone, specifically inhibits respiration and invitro growth of long slender bloodstream forms of
Trypanosoma brucei brucei. Mol. Biochem. Parasitol.
81, 127-136, 1996.
22. Lim, P.K.C., Watanabe, Y., Tan, S.K., Furuta, T.,
Aoki, T., Kojima, S., Kita, K., Sharma, Y.D., and Mak,
J.W. Cytochrome c oxidase III (COIII) gene of
Plasmodium vivax: Complete coding sequence andits expression in the erythrocytic stage of the parasite. Jpn. J. Parasitol. 45, 373-383, 1997.
23. Nara, T., Tanabe, K., Mahakunkijcharoen, Y., Osada,Y., Matsumoto, N., Kita, K., and Kojima, S. The B cell
epitope of paramyosin recognized by a protective
monoclonal IgE antibody to Schistosoma japonicum.
Vaccine 15, 79-84, 1997.
24. Watanabe, Y., Tsurui, H., Ueda, T., Furushima, R.,
Takamiya, S., Kita, K., Nishikawa, K., and Watanabe,
K. Primary sequence of mitochondrial tRNAArg of anematode Ascaris suum: occurrence of unmodified
adenosine at the first position of the anticodon.
Biochim. Biophys. Acta 1350, 119-122, 1997.
25. Kita, K., Hirawake, H., and Takamiya, S.
Cytochromes in the respiratory chain of helminth
mitochondria. Int. J. Parasitol. 27, 617-630, 1997.

360

26. Hirawake, H., Kita, K., and Sharma, Y.D. Variation in
the C-terminal repeats of the knob-associated histidine-rich protein of Plasmodium falciparum .
Biochim. Biophys. Acta 1360, 105-108, 1997.
27. Isobe, K., Kishino, S., Inoue, K., Takai, D., Hirawake,
H., Kita, K., Miyabayashi, S., and Hayashi, J.
Identification of inheritance modes of mitochondrial
diseases by introduction of pure nuclei from mtDNAless HeLa cells to patient-derived fibroblasts. J. Biol.
Chem. 272, 12606-12610, 1997.
28. Watanabe, Y., Kita, K., Ueda, T., and Watanabe, K.
cDNA sequence of a translational elongation factor
Ts homologue from Caenorhabditis elegans: mitochondrial factor-specific features found in the nematode homologue peptide. Biochim. Biophys. Acta
1353, 7-12, 1997.
29. Hirawake, H., Taniwaki, M., Tamura, A., Kojima, S.,
and Kita, K. Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of
the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC)and small (SDHD) subunits to 1q21 and 11q23.
Cytogenet. Cell Genet. 79, 132-138, 1997.
30. Vibat, C.R.T., Cecchini, G., Nakamura, K., Kita, K.,
and Gennis, R.B. Localization of histidine residues
responsible for heme axial ligation in cytochromeb556 of complex II (succinate:ubiquinone oxidoreductase) in Escherichia coli. Biochemistry 37, 4148-4159,
1998.
31. Fukai, Y., Amino, H., Hirawake, H., Yabu, Y., Ohta,
N., Minagawa, N., Sakajo, S., Yoshimoto, A., Nagai,
K., Takamiya, S., Kojima, S., and Kita, K. Functional
expression of the ascofuranone-sensitive
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32. Hirawake, H., Taniwaki, M., Tamura, A., Amino, H.,
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33. Amino, H., Wang, H., Hirawake, H., Saruta, F.,
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34. Takeo, S., Kokaze, A., Ng, C. S., Mizuchi, D.,
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35. Omura, S., Miyadera, H., Ui, H., Shiomi, K.,
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Namikoshi, M., Miyoshi, H., Sakamoto, K., and Kita,
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