Department of MolecularPreventive Medicine
Outlines and Research objectives
This department originates from The Department of Hygiene which was first established by Prof. Masanori Ogata in 1885. Prof. Ogata is the first Japanese bacteriologist who
was trained by Prof. Pettenkofer in Munich. The Department of Microbiology was separated
in 1920. I (K.M.) am the 8th professor of this department.
Main current research interests are as follows:
1. Molecular pathogenesis of inflammatory and immune diseases focusing on chemokinesand dendritic cells, and development of novel therapeutics for inflammatory andimmune diseases.
2. Molecular mechanism of leukocyte trafficking in vivo and chemotaxis in vitro.
3. Development of novel, effective ways of dendritic cells(DC)-based vaccination for infectious and inflammatory diseases as well as cancer.
4. Identification of novel targets for intervention therapy and prevention of inflammatory
and immune diseases through completing comprehensive gene expression profiling of
human leukocyte subsets.

Faculties and Students
Professor and Chair

Kouji Matsushima MD and PhD(1996 appointed)
Associated Professor Sho Ishikawa MD and PhD
Associate .................................2
Assistant .................................1
Postdoctoral Fellows...............2 (JSP) 1 (SORST, JST)
Graduate Students ..................9
Graduate Students from outside ....8
Visiting Scientists ...................5
Technical Assistants ..........1+1 (SORST, JST)
Secretary .................................1 (SORST, JST)

Past Major Accomplishments
Chemokine, chemotactic cytokine family now consists of over 40 and is subdivided into four subfamilies
based on the location of the very conserved first two cysteine residues. Interleukin 8 (IL 8), which was purified
based on in vitro neutrophil chemotactic activity andmolecularly cloned by me in collaboration with Teizo
Yoshimura in 1987, is a prototype of CXC chemokines.
On the other hand, MCAF/MCP-1, which was purified
based on monocyte chemotactic activity and molecularlycloned by me and Teizo Yoshimura independently in
1989, is a prototype of CC chemokines.
From the beginning of the 1990’s we and several
other groups initiated the studies to establish thepathophysiological roles of chemokines in various animal inflammation models using specific blocking antibodies against chemokines. We reported the essential

138

involvement of IL 8 in recruiting neutrophils in acuteinflammation models such as LPS/IL-1 induced dermatitis, immune-complex induced acute glomerulonephritis, lung reperfusion injury, acute respiratory
distress syndrome and brain infarct; and that intervention of IL 8 leads to the prevention of neutrophil infiltration-associated tissue injury. We also revealed thepivotal role of MCAF/MCP-1 in recruiting monocytes/macrophages in chronic inflammatory diseases
through working on chronic glomerulonephritis
caused by anti-glomerular basement membrane antibody, thickening of endothelium after carotid arteryinjury as an athelosclerosis model, and monocrotalineinduced pulmonary hypertension model in rats. Later,
the pivotal role of IL 8 and MCAF/MCP-1 in recruiting
neutrophils and monocytes, respectively was essentially confirmed by other groups analyzing gene targeted
mice for IL 8 receptor homologue, and JE (murine
homologue of MCAF/MCP-1) and its receptor CCR2.
Recent discovery of numerous novel chemokines
by others through signal sequence trap method and
EST data base, most of which are chemoattractantsfor immune cells such as subclasses of T lymphocytes,
B lymphocytes and DC, has changed our understanding of the role of chemokines in host defense responses. For example, CD4+CD45RA+naive T lymphocytes
express CCR7. CD4+CD45RO+memory T lymphocytes express CXCR3 and CCR5 on Th1 subset andCCR4 on Th2 subset. We generated a monoclonal
antibody against human CCR4 and established thatabout 20% of CD4+ memory T lymphocytes in the circulation of normal individuals express CCR4 andFigure 1: Peripheral and regional DC-Th cell clusters as the sites of Th1 cell generation regulatedby DC-derived chemokinesthese cells are committed Th2 population producing
preferentially Th2 cytokines without any cultures topolarize into Th2 cells in vitro and the percentage ofthis population is much increased in atopic diseases
such as atopic dermatitis and asthma. We also reported a pivotal role of the ligands for CCR4, TARC and
MDC in causing and regulating atopic diseases inmurine models.
Molecular pathogenesis of inflammatory andimmune diseases
Chemokines in a murine model of bacteria-induced
fulminant heapatitis
Propionibacterium acnes (P.acnes) is the most probable causing bacterium of sarcoidosis. In this model,
administration of P.acnes causes numerous granuloma
formation in the sinusoidal area of the liver, and subsequent challenge of the mice with low dose of LPS
induces massive hepatic injury around granuloma. We
first revealed that Th1 type immune response dominates in granuloma formation in terms of
chemokine/chemokine receptor expression as well as
cytokine production, whereas dramatic shift to Th2
response occurs immediately after LPS administration.
Administration of the antibody against TARC (a ligandof CCR4, Th2 chemokine receptor) significantly inhibited liver injury. This is the first presentation that the
rapid local shift from Th1 to Th2 by chemokines leads
to severe tissue injury. We next identified TARC producing cells at the granuloma sites to be DC. We, thenextensively analyzed the mechanism of granuloma formation, and revealed that numerous CCR1/5+DC-precursors appear shortly after P.acnes administration in
the circulation and rapidly migrate into sub-sinusoidal
area (Disse’s space) in response to MIP1a produced by
Kupffer cells to participate in the initial granuloma formation. Antigen-laden DC matured at the granuloma
sites start to express CCR7, and subsequently migrate
to portal area and the draining lymph nodes(hepatic/celiac lymph nodes) in response to SLC produced by lymphatic endothelium. We revealed that thefirst immune response occurs at the portal area andinflammation-associated lymphoid tissue appears at

the portal area which we termed “portal tract-associated lymphoid tissue, PALT. We also showed directlythat Th1 polarization occurrs at the draining lymphnodes by visualizing IFN-gamma producing CD4+T cells
clustered with DC in the paracortex of lymph nodes.
We provided evidence that IP-10 produced by migrated mature DC in the hepatic lymph nodes regulates
DC-Th1 cluster formation and controls the exit ofmemory/effector T cells from the lymph nodes tohome to the liver to complete granuloma formation(Figure 1). This is the first report describing the existence of DC at the granuloma sites and the identification of inflammation-associated DC precursors in thecirculation. This implies that even the exit/release ofmemory/effector T cells from the peripheral lymph
nodes is regulated by chemokines. This study has provided a new concept that chemokine-recruited DC
tightly link inflammation (innate immunity) andacquired immunity. Inflammation and immunity
should not be conceptually separated any more, andgranuloma formation is not a mere end-point of chronic inflammation, rather a very active immune site.
1; Initiation and induction of DC-naive T cell clusters by ELC(CCL19) or SLC(CCL21). 2; Amplificationof DC-nonpolarized T cell clusters by MDC(CCL22). 3;
Promotion and retention of DC-Th1 cell clusters (thisstudy). These clusters may develop in the given
spaces of the paracortex called “cytokine fields”. DCderived chemokines may regulate T cell traffic
depending on their state of activation between thesegiven spaces to magnify the effective immune
responses. After leaving the LNs, Th1 cells migrate
into the liver through the circulation and 4. re-form
clusters with peripheral tissue-resided inflammatory
DCs (granuloma formation) possibly by MIP1a(CCL3)
or Mig(CXCL9). Th1 cells can further proliferate andproduce higher amount of IFN-γ at the periphery of
the granulomas to complete polarization. HEV, highendothelial venule.

Current Research
DC migration pathway so far described is limited139

to the idea that tissue immature DC such as
Langerhans cells mature after antigen capturing andstart to express CCR7 to be recruited to draining
lymph nodes through afferent lymphatics. There isneither direct presentation of DC precursor migration
into any organs nor evidence of the entry of DC into
secondary lymph nodes through HEV (high endothelial venule) directly from the circulation. We have now
identified DC precursors which rapidly appear in thecirculation in inflammation. We are currently studying the following issues:
Mechanism of rapid release of DC precursors frombone marrow---identification of chemokine(s)involved.
Heterogeneity of the identified DC precursors andfate of DC precursors after administering into normal
and inflamed mice. Most of cells are
CD11c+CD11b+myeloid type DC, but some of thecells express L-selectin and B220. Therefore, some ofthese cells may directly enter peripheral lymph nodes
through HEV to act as tolerance-inducing DC.
Identification of homing molecules to the lymph
nodes.
Examination of the possible usefulness of theidentified DC precursors for vaccination and antigenspecific tolerance induction.
Future Prospective: Investigation of “lymph nodehoming” circulating DC precursors may provide a clue
to the mechanism of systemic tolerance induction andan approach to establish effective way of DC-based
vaccination to cancer and microbes. We will further
examine the role of chemokines in Th2 polarization,
CTL generation and the recruitment and maintainance of memory state of CD4/8 T lymphocytes.
We will also establish the critical role of TARC/MDC
to recruit CCR4+CD4+CD25+ so called regulatory T
cells in cancer and chronic infection models. The clinical development of humanaized monoclonal antibody
against human CCR4 will be tried in a collaboration
with a pharmaceutical. This antibody is expected toeliminate by ADCC CCR4+cells such as Th2, regulatory T cells and adult leukemia cells in a few hours invivo. Therefore, this antibody treatment may be useful for the treatment of various atopic diseases. This
antibody may also be useful to recover patients from
immune-suppression to respond more to DC-based
vaccination. This antibody may also become an effective drug for curing ATL patients.

Research Grants
Research Grants from JSP
1996
27,600,000 JPY
1997
11,100,000 JPY
2001
7,000,000 JPY

140

2002
20,300,000 JPY
Core Research of Evolutional Science and Technology(CREST, JST)
1996-2001 Total 600,000,000 JPY (about 5 million USD)
Solution Oriented Research for Science and Technology(SORST, JST)
15,000,000 JPY (about 120,000 USD)
70,000,000 JPY (about 500,000 USD)

50 Select Publications
1. Kimura H, Kasahara Y, Kurosu K, Sugito K, Takiguchi
Y, Terai M, Mikata A, Natsume M, Mukaida N,
Matsushima K, Kuriyama T. Alleviation of monocrotaline-induced pulmonary hypertension by antibodies to monocyte chemotactic and activating
factor/monocyte chemoattractant protein-1. Lab
Invest. 1998;78:571-581
2. Kuno K, Matsushima K. ADAMTS-1 protein anchorsat the extracellular matrix through the thrombospondin type I motifs and its spacing region. J Biol
Chem. 1998;273:13912-13917
3. Sonoda Y, Mukaida N, Wang JB, Shimada-Hiratsuka
M, Naito M, Kasahara T, Harada A, Inoue M,
Matsushima K. Physiologic regulation of postovulatory neutrophil migration into vagina in mice by a C-XC chemokine(s). J Immunol. 1998;160:6159-6165
4. Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata
K, Kataoka Y, Kitamura Y, Matsushima K, Yoshida N,
Nishikawa S, Kishimoto T, Nagasawa T. The
chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature.
1998;393:591-594
5. Wang J, Harada A, Matsushita S, Matsumi S, Zhang Y,
Shioda T, Nagai Y, Matsushima K. IL-4 and a glucocorticoid up-regulate CXCR4 expression on humanCD4+ T lymphocytes and enhance HIV-1 replication.
J Leukoc Biol. 1998;64:642-649
6. Yoneyama H, Harada A, Imai T, Baba M, Yoshie O,
Zhang Y, Higashi H, Murai M, Asakura H,
Matsushima K. Pivotal role of TARC, a CC
chemokine, in bacteria-induced fulminant hepatic
failure in mice. J Clin Invest. 1998;102:1933-1941
7. Zhang Y, Harada A, Wang JB, Zhang YY, Hashimoto S,
Naito M, Matsushima K. Bifurcated dendritic cell differentiation in vitro from murine lineage phenotypenegative c-kit+ bone marrow hematopoietic progenitor cells. Blood. 1998;92:118-128
8. Hashimoto S, Suzuki T, Dong HY, Nagai S, Yamazaki
N, Matsushima K. Serial analysis of gene expression
in human monocyte-derived dendritic cells. Blood.
1999;94:845-852
9. Hashimoto S, Suzuki T, Dong HY, Yamazaki N,
Matsushima K. Serial analysis of gene expression inhuman monocytes and macrophages. Blood.
1999;94:837-844
10. Imai T, Nagira M, Takagi S, Kakizaki M, Nishimura
M, Wang J, Gray PW, Matsushima K, Yoshie O.
Selective recruitment of CCR4-bearing Th2 cells
toward antigen-presenting cells by the CC

chemokines thymus and activation-regulated
chemokine and macrophage-derived chemokine. Int
Immunol. 1999;11:81-88
11. Kuno K, Terashima Y, Matsushima K. ADAMTS-1 isan active metalloproteinase associated with theextracellular matrix. J Biol Chem. 1999;274:1882118826
12. Murai M, Yoneyama H, Harada A, Yi Z, Vestergaard
C, Guo B, Suzuki K, Asakura H, Matsushima K.
Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J Clin Invest. 1999;104:49-57
13. Ogata M, Zhang Y, Wang Y, Itakura M, Zhang YY,
Harada A, Hashimoto S, Matsushima K. Chemotactic
response toward chemokines and its regulation bytransforming growth factor-beta1 of murine bonemarrow hematopoietic progenitor cell-derived different subset of dendritic cells. Blood. 1999;93:32253232
14. Tsuji H, Mukaida N, Harada A, Kaneko S, Matsushita
E, Nakanuma Y, Tsutsui H, Okamura H, Nakanishi
K, Tagawa Y, Iwakura Y, Kobayashi K, Matsushima
K. Alleviation of lipopolysaccharide-induced acuteliver injury in Propionibacterium acnes-primed IFNgamma-deficient mice by a concomitant reduction of
TNF-alpha, IL-12, and IL-18 production. J Immunol.
1999;162:1049-1055
15. Vestergaard C, Yoneyama H, Murai M, Nakamura K,
Tamaki K, Terashima Y, Imai T, Yoshie O, Irimura T,
Mizutani H, Matsushima K. Overproduction of Th2specific chemokines in NC/Nga mice exhibiting
atopic dermatitis-like lesions. J Clin Invest.
1999;104:1097-1105
16. Zhang Y, Zhang YY, Ogata M, Chen P, Harada A,
Hashimoto S, Matsushima K. Transforming growth
factor-beta1 polarizes murine hematopoietic progenitor cells to generate Langerhans cell-like dendritic
cells through a monocyte/macrophage differentiation
pathway. Blood. 1999;93:1208-1220
17. Hashimoto SI, Suzuki T, Nagai S, Yamashita T,
Toyoda N, Matsushima K. Identification of genes
specifically expressed in human activated andmature dendritic cells through serial analysis of gene
expression. Blood. 2000;96:2206-2214.
18. Inadera H, Sekiya T, Yoshimura T, Matsushima K.
Molecular analysis of the inhibition of monocyte
chemoattractant protein-1 gene expression by estrogens and xenoestrogens in MCF-7 cells.
Endocrinology. 2000;141:50-59
19. Onai N, Zhang Y, Yoneyama H, Kitamura T,
Ishikawa S, Matsushima K. Impairment of lymphopoiesis and myelopoiesis in mice reconstituted
with bone marrow-hematopoietic progenitor cells
expressing SDF-1-intrakine. Blood. 2000;96:20742080.
20. Sekiya T, Miyamasu M, Imanishi M, Yamada H,
Nakajima T, Yamaguchi M, Fujisawa T, Pawankar R,
Sano Y, Ohta K, Ishii A, Morita Y, Yamamoto K,
Matsushima K, Yoshie O, Hirai K. Inducible expression of a Th2-type CC chemokine thymus- and acti-

vation-regulated chemokine by human bronchial
epithelial cells. J Immunol. 2000;165:2205-2213
21. Shindo T, Kurihara H, Kuno K, Yokoyama H, Wada
T, Kurihara Y, Imai T, Wang Y, Ogata M, Nishimatsu
H, Moriyama N, Oh-hashi Y, Morita H, Ishikawa T,
Nagai R, Yazaki Y, Matsushima K. ADAMTS-1: ametalloproteinase-disintegrin essential for normal
growth, fertility, and organ morphology and function. J Clin Invest. 2000;105:1345-1352.
22. Suzuki T, Hashimoto S, Toyoda N, Nagai S,
Yamazaki N, Dong HY, Sakai J, Yamashita T, Nukiwa
T, Matsushima K. Comprehensive gene expression
profile of LPS-stimulated human monocytes by
SAGE. Blood. 2000;96:2584-2591
23. Tokuda A, Itakura M, Onai N, Kimura H, Kuriyama
T, Matsushima K. Pivotal role of CCR1-positive
leukocytes in bleomycin-induced lung fibrosis inmice. J Immunol. 2000;164:2745-2751
24. Vestergaard C, Bang K, Gesser B, Yoneyama H,
Matsushima K, Larsen CG. A Th2 Chemokine,
TARC, Produced by Keratinocytes May Recruit
CLA+CCR4+ Lymphocytes into Lesional Atopic
Dermatitis Skin. J Invest Dermatol. 2000;115:640646
25. Wada T, Furuichi K, Sakai N, Iwata Y, Yoshimoto K,
Shimizu M, Takeda SI, Takasawa K, Yoshimura M,
Kida H, Kobayashi KI, Mukaida N, Naito T,
Matsushima K, Yokoyama H. Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitiallesions of human diabetic nephropathy. Kidney Int.
2000;58:1492-1499
26. Wada T, Furuichi K, Sakai N, Iwata Y, Yoshimoto K,
Shimizu M, Kobayashi K, Mukaida N, Matsushima K,
Yokoyama H. A new anti-inflammatory compound,
FR167653, ameliorates crescentic glomerulonephritis
in Wistar-Kyoto rats. J Am Soc Nephrol.
2000;11:1534-1541
27. Yamamoto J, Adachi Y, Onoue Y, Adachi YS, Okabe
Y, Itazawa T, Toyoda M, Seki T, Morohashi M,
Matsushima K, Miyawaki T. Differential expressionof the chemokine receptors by the Th1- and Th2type effector populations within circulating CD4+ T
cells. J Leukoc Biol. 2000;68:568-574.
28. Zhang Y, Wang Y, Ogata M, Hashimoto S, Onai N,
Matsushima K. Development of dendritic cells in
vitro from murine fetal liver-derived lineage phenotype-negative c-kit(+) hematopoietic progenitor cells.
Blood. 2000;95:138-146
29. Furuichi K, Wada T, Iwata Y, Sakai N, Yoshimoto K,
Shimizu M, Kobayashi K, Takasawa K, Kida H,
Takeda S, Matsushima K, Yokoyama H. Upregulationof fractalkine in human crescentic glomerulonephritis. Nephron. 2001;87:314-320.
30. Ishikawa S, Sato T, Abe M, Nagai S, Onai N,
Yoneyama H, Zhang Y, Suzuki T, Hashimoto S,
Shirai T, Lipp M, Matsushima K. Aberrant highexpression of B lymphocyte chemokine(BLC/CXCL13) by C11b+CD11c+ dendritic cells inmurine lupus and preferential chemotaxis of B1 cells
towards BLC. J Exp Med. 2001;193:1393-1402.

14131. Itakura M, Tokuda A, Kimura H, Nagai S, Yoneyama
H, Onai N, Ishikawa S, Kuriyama T, Matsushima K.
Blockade of secondary lymphoid tissue chemokine
exacerbates Propionibacterium acnes-induced acutelung inflammation. J Immunol. 2001;166:2071-2079.
32. Kawasaki S, Takizawa H, Yoneyama H, Nakayama T,
Fujisawa R, Izumizaki M, Imai T, Yoshie O, Homma
I, Yamamoto K, Matsushima K. Intervention of thymus and activation-regulated chemokine attenuates
the development of allergic airway inflammation andhyperresponsiveness in mice. J Immunol.
2001;166:2055-2062.
33. Takayama T, Morelli AE, Onai N, Hirao M,
Matsushima K, Tahara H, Thomson AW.
Mammalian and viral IL-10 enhance C-C chemokine
receptor 5 but down-regulate C-C chemokine receptor 7 expression by myeloid dendritic cells: impact
on chemotactic responses and in vivo homing ability.
J Immunol. 2001;166:7136-7143.
34. Wada T, Furuichi K, Sakai N, Hisada Y, Kobayashi K,
Mukaida N, Tomosugi N, Matsushima K, Yokoyama
H. Involvement of p38 mitogen-activated protein
kinase followed by chemokine expression in crescentic glomerulonephritis. Am J Kidney Dis.
2001;38:1169-1177.
35. Yamashita T, Kaneko S, Hashimoto S, Sato T, Nagai
S, Toyoda N, Suzuki T, Kobayashi K, Matsushima K.
Serial analysis of gene expression in chronic hepatitis C and hepatocellular carcinoma. Biochem Biophys
Res Commun. 2001;282:647-654.
36. Yokochi S, Hashimoto H, Ishiwata Y, Shimokawa H,
Haino M, Terashima Y, Matsushima K. An antiinflammatory drug, propagermanium, may target
GPI-anchored proteins associated with an MCP-1
receptor, CCR2. J Interferon Cytokine Res.
2001;21:389-398.
37. Yoneyama H, Matsuno K, Zhang Y, Murai M, Itakura
M, Ishikawa S, Hasegawa G, Naito M, Asakura H,
Matsushima K. Regulation by chemokines of circulating dendritic cell precursors, and the formation of
portal tract-associated lymphoid tissue, in a granulomatous liver disease. J Exp Med. 2001;193:35-49.
38. Higashi N, Fujioka K, Denda-Nagai K, Hashimoto S,
Nagai S, Sato T, Fujita Y, Morikawa A, Tsuiji M,
Miyata-Takeuchi M, Sano Y, Suzuki N, Yamamoto K,
Matsushima K, Irimura T. The macrophage C-type
lectin specific for galactose/N-acetylgalactosamine isan endocytic receptor expressed on monocytederived immature dendritic cells. J Biol Chem.
2002;277:20686-20693.
39. Inadera H, Dong HY, Matsushima K. WISP-2 is asecreted protein and can be a marker of estrogen
exposure in MCF-7 cells. Biochem Biophys Res
Commun. 2002;294:602-608.
40. Ishikawa S, Nagai S, Sato T, Akadegawa K,
Yoneyama H, Zhang YY, Onai N, Matsushima K.
Increased circulating CD11b+CD11c+ dendritic cells(DC) in aged BWF1 mice which can be matured by
TNF-alpha into BLC/CXCL13-producing DC. Eur J
Immunol. 2002;32:1881-1887.

142

41. Kuno K, Baba C, Asaka A, Matsushima C,
Matsushima K, Hosono R. The Caenorhabditis elegans ADAMTS family gene adt-1 is necessary formorphogenesis of the male copulatory organs. J Biol
Chem. 2002;277:12228-12236.
42. Kurachi M, Hashimoto S, Obata A, Nagai S, Nagahata
T, Inadera H, Sone H, Tohyama C, Kaneko S,
Kobayashi K, Matsushima K. Identification of
2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive genes
in mouse liver by serial analysis of gene expression.
Biochem Biophys Res Commun. 2002;292:368-377.
43. Narumi S, Kaburaki T, Yoneyama H, Iwamura H,
Kobayashi Y, Matsushima K. Neutralization of IFNinducible protein 10/CXCL10 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol.
2002;32:1784-1791.
44. Onai N, Kitabatake M, Zhang YY, Ishikawa H,
Ishikawa S, Matsushima K. Pivotal role of CCL25(TECK)-CCR9 in the formation of gut cryptopatches
and consequent appearance of intestinal intraepithelial T lymphocytes. Int Immunol. 2002;14:687-694.
45. Sekiya T, Yamada H, Yamaguchi M, Yamamoto K,
Ishii A, Yoshie O, Sano Y, Morita A, Matsushima K,
Hirai K. Increased levels of a TH2-type CC
chemokine thymus and activation-regulated
chemokine (TARC) in serum and induced sputum ofasthmatics. Allergy. 2002;57:173-177.
46. Uekusa Y, Yu WG, Mukai T, Gao P, Yamaguchi N,
Murai M, Matsushima K, Obika S, Imanishi T,
Higashibata Y, Nomura S, Kitamura Y, Fujiwara H,
Hamaoka T. A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced byinterleukin 12 treatment in tumor-bearing mice.
Cancer Res. 2002;62:3751-3758.
47. Ueno T, Hara K, Willis MS, Malin MA, Hopken UE,
Gray DH, Matsushima K, Lipp M, Springer TA, Boyd
RL, Yoshie O, Takahama Y. Role for CCR7 ligands inthe emigration of newly generated T lymphocytes
from the neonatal thymus. Immunity. 2002;16:205218.
48. Wang Y, Zhang Y, Yoneyama H, Onai N, Sato T,
Matsushima K. Identification of CD8alpha(+)
CD11c(-) lineage phenotype-negative cells in the
spleen as committed precursor of CD8alpha(+) dendritic cells. Blood. 2002;100:569-577.
49. Yoneyama H, Narumi S, Zhang Y, Murai M,
Baggiolini M, Lanzavecchia A, Ichida T, Asakura H,
Matsushima K. Pivotal role of dendritic cell-derived
CXCL10 in the retention of T helper cell 1 lymphocytes in secondary lymph nodes. J Exp Med.
2002;195:1257-1266.
50. Yoshie O, Fujisawa R, Nakayama T, Harasawa H,
Tago H, Izawa D, Hieshima K, Tatsumi Y,
Matsushima K, Hasegawa H, Kanamaru A, Kamihira
S, Yamada Y. Frequent expression of CCR4 in adult
T-cell leukemia and human T-cell leukemia virus
type 1-transformed T cells. Blood. 2002;99:15051511.

Department of
Public Health
Outline and Research Objectives
Public health departments in medical schools in Japan were introduced after the WorldWar II, following the model of the U.S. system of medical education. The Department of
Public Health was established in 1948, in the Faculty of Medicine, University of Tokyo. In
1995, the Department became a part of the Division of Social Medicine, Graduate School of
Medicine, as the result of the shift to a graduate school system in University of Tokyo.
The objectives of the Department are both education and research of public health. The
Department trains graduate and undergraduate students through lectures, seminars, fieldpractice, and laboratory work in public health and occupational medicine, for the degrees ofMedical Doctor (MD), Master of Medical Sciences (MSc), and Doctor of Medical Sciences(DMSc). The Department also provides those lectures related to public health and occupational medicine for undergraduate students in the School of Health Sciences and Nursing.
The Department has conducted research on a wide variety of public health issues,
including health policy and economics, occupational medicine, environmental health, community and clinical epidemiology, behavioral medicine, and so on. In addition, the staff
members of the Department have offered public and occupational health services to the central and local governments, industries, and local communities.
Currently, the Department comprises a professor and chair, an associate professor, a lecturer, an associate, a research resident, several part-time lecturers, and several visiting
research fellows, all of who take part in the education and/or the research of the
Department.

Faculties and Students;
Professor and Chair

Yasuki Kobayashi, MD, DMSc
(since April 2001)
Associate Professor Kazuhito Yokoyama, MD, DMSc
Lecturer
Hajime Sato, MD, MPH, DMSc, DPH
Associate .................................1
Research Resident...................1
Postdoctoral Fellow ................1
Graduate Students ................10 (including 3 entrusted
students)
Research Students...................4
Secretary .................................2

Past Research and Major Accomplishments
1) Health policy and economics
We are interested in the topics of health care system and economics in general. We have performed
and published those studies related to supply anddemand sides of health services in Japan; such as supply and distribution of physicians, the separation ofpharmaceutical dispensing and prescribing in medical
practice, cost studies of outpatient and inpatient services, and the efficiency and equity of the Japan’s
health insurance system.
For the issues of physician supply, we examined

and analyzed the impact of physician manpower policy in the 1970s and 1980s in Japan, through both economic and statistical methods, and showed that geographic mal-distribution of physicians did not
improve despite the growing number of physician
during the period. Also, we projected future demandof physicians by specialty in Japan, since this issue
brought a constant debate among the government,
medical schools, medical providers, and patients. Our
projections could facilitate these arguments.
For Japan’s insurance system, we first showed that
it would be cost-beneficial if an electronic claiming
system were introduced to the system. On the other
hand, the financing system for the elderly health careis really a global issue worldwide, and we also havetackled the issue. Since the late 1980s, we haveshown the effectiveness and efficiency of home carefor the elderly in terms of their quality of life. In thelate 1990s, there have been wide and continuous
debates on the matter nationwide, and finally the
new insurance system, namely the Long-term Care
Insurance for the Elderly has been introduced toJapan since the year 2000. Our study results have definitely facilitated these discussions.
We have examined what factors are relevant toearly discharge of elderly patients. We did a follow-up
survey of hospitalized patients with cerebrovascular143

diseases (CVD) in almost all the hospitals in a prefecture. The study showed that the caregiver’s conditions, including economic ones, as well as thepatient’s conditions, were closely related to earlier
home discharge of the CVD patients.
We have carried on several policy studies in thehealth and environmental fields, especially those frominternational comparative perspectives, such as tobacco smoking control, and patient isolation policy for
Hansen’s disease. These studies have been publishedin some international policy journals.
Overall, we have contributed to the evidence based
health policy in Japan, through numerous empiricalstudies using the methods of epidemiology and healtheconomics.

3) Community and clinical epidemiology
We have done several epidemiological studies incommunity, occupational, or clinical settings, such asactive life expectancy for the elderly, quality of life
assessment in RA patients, work-related diseases, andoutcome studies for various kinds of treatments. Mostof these studies have been carried on in collaboration
with local communities, industries, or clinical departments, and published in various journals.

ceuticals has progressed, however, our study has suggested that the separation itself would not necessarily
lead to the cost containment of pharmaceuticals
because physicians tend to prescribe bland-namepharmaceuticals. Therefore, we suggest that such a
separation policy should be combined with a policy
encouraging the use of generics.
In addition, we study the methods and guidelines
by which health insurance claim data will be used forresearch with securing the patients’ privacy. Such a
study would facilitate expanding the volume of andimproving the quality of health services research inJapan, consequently lead to the improvement of quality of health services in Japan.
For the issues of the financing system worldwide,
we have recently began to study a system for providing the effective treatment for people with HIV/AIDS
in developing countries, since the issue is a global andurgent one both in terms of health and economics.
We have conducted a cost study of providing highly
active antiretroviral therapy (HAART) to AIDS
patients in Khon Kaen Province, Thailand. As a result,
we indicate that a substantial increase of resources
would be necessary to provide HAART to all the adult
AIDS patients under the current universal coveragesystem in Khon Kaen province, and we suggest possible solutions for this financial obstacle. This type ofanalysis would be also useful to assess the financial
implications of providing HAART for public healthsystems worldwide.
For the issues of environmental pollution andhealth effects of chemicals, we have recently started
an international collaborative study on pesticide problem in Malaysia. In the study, the health effects ofpesticide in relation to occupational safety behavior
are studied among tobacco-growing farmers in
Kelantan, Malaysia. So far, the following results are
obtained; (i) Organophosphate and dithiocarbamate
pesticides affect peripheral nerve conduction, whereas
pyrethroid affects postural balance system. (ii)
Nonsmoking while spraying, good-sprayer condition,and changing clothes immediately after spraying prevents occurrence of acute symptoms just after pesticide spray in male farmers; in female farmers, wearing
a hat while spraying significantly prevents the symptoms. These results suggest that sub-clinical healtheffects are caused by pesticide use; the effects could
be prevented by safety handling of pesticides so that
health education would be effective.

Current Research

Future Prospects

Most of the above mentioned research topics aretackled at present, with new perspectives andmethodologies. For the insurance system, recently theseparation of prescribing and dispensing of pharma-

Our empirical studies on the health insurance system and health manpower policy in Japan are unique,and our strength. Therefore, we should continue toexpand these kinds of studies and to train profession-2) Occupational medicine and environmental
healthWe have tackled the issues of neurotoxicologic
effects of lead and other heavy metals and solvents,
sarin poisoning, particulate matter monitoring, andhealth effects of pesticides in developing countries aspart of the Alliance for Global Sustainability project.
We have been also interested in the issues of behavioral medicine, such as socioeconomic and psychological aspects of drinking and traffic accidents. For theabove purposes, the Department conducted international collaborative studies in the Faeroes islands ofDenmark (methyl-mercury), Seoul of Korea (lead,chromium and mercury poisonings) and Kota Bahr of
Malaysia (pesticide poisoning). Also, the former chairman of the Department (Araki), as Chairman of the
Scientific Committee on Neurotoxicology andPsychophysiology of the International Commission on
Occupational Health (ICOH), promoted symposia at
the ICOH 2000 Congress in Singapore. The
Department also held the 48th Annual Meeting of theJapanese Society of Occupational Medicine andTraumatology in Tokyo in November 2000.

144

als in such fields, and hope to facilitate and contributeto improving our health care system. Furthermore,international collaborative studies for pubic health arealso a tradition of the Department as well as its
strength in terms of research. We would also like tocontinue such collaborative studies on health of andhealth care for disadvantaged people, such as thepoor, the frail elderly, people with HIV/AIDS, andunderprivileged workers. In addition, since there are
growing needs for epidemiological studies in occupational and clinical settings, we should expand outcome studies and clinical epidemiology, in collaboration with clinical departments. In order to maintainand promote health for all the people in Japan and in
the world, it is essential to promote both theoreticaland empirical studies in public health. The
Department is making every effort for this purpose
through domestic, international and interdisciplinary
collaborative researches.

Research Grants
1. 2001-03 Research Grants from Ministry of Education,
Culture, and Sports. Study on payment system forthe checking functions preventing adverse events ofpharmaceuticals in the separation of prescribing anddispensing. (Kobayashi Y)
2. 2001-03 Health Sciences Research Grants (Researchon Policy Planning and Evaluation) from the Ministryof Health, Labor and Welfare of Japan. Study on use
and security of insurance claim data in Japan’s healthinsurance system. (Kobayashi Y)
3. 2001-04 Grant for Health Cooperation Research from
the Ministry of Health, Labor and Welfare of Japan.
Study on a financing system for providing the effective treatment for people with HIV/AIDS in developing countries. (Kobayashi Y)
4. 2001-03 Research Grants from Ministry of Education,
Culture, and Sports. Study on risk assessment ofsubclinical neuro-behavioral effects of environmental
pollutants. (Yokoyama K)
5. 2001-04 Research Grants from Ministry of Education,
Culture, and Sports. International collaborative study
on health effects of pesticides and their safe use.
(Yokoyama K)

Select Publications
Health policy and economics
1 Kobayashi Y, Yano E. Structure, process, effectiveness and efficiency of the check and review system
in Japan’s health insurance. Health Policy 19: 229244, 1991.
2 Kobayashi Y, Takaki H. Geographic distribution ofphysicians in Japan. Lancet 340: 1391-1393, 1992.

3

Kobayashi Y, Reich MR. Health care financing for theelderly in Japan. Social Science & Medicine 37: 343353, 1993.
4 Kobayashi Y, Chiba Y, Hikita K, Kusumoto K.
Collaboration between Japan and China towards
poliomyelitis eradication [letter]. Lancet 1995; 345:
455.
5 Tamiya, N., Araki, S., Kobayashi, Y., Yamashita, K.,
Murata, K., Yano, E.: Gender difference in the utilization and use’s characteristics of community rehabilitation programs for cerebrovascular disease patientsin Japan. International Journal for Quality in HealthCare 8: 359-366,1996.
6 Ishizaki T, Kobayashi Y, Tamiya N. The role of geriatric intermediate care facilities in long-term care forthe elderly in Japan. Health Policy 43:141-151, 1998.
7 Sato, H.: Policy and politics of smoking control inJapan. Social Science & Medicine 49: 581-600, 1999.
8 Sato, H.: The advocacy coalition framework and thepolicy process analysis: The case of smoking control
in Japan. Policy Studies Journal 27: 28-44, 1999.
9 Sato, H., Araki, S.: Yields and daily consumption ofcigarettes in Japan in 1969-1996. Journal of
Epidemiology 10: 7-15, 2000.
10 Sato, H., Araki, S., Yokoyama, K.: Policy functions ofsmoking control in Japan: Government and social
interests in smoking control in Japan. Environmental
Health and Preventive Medicine 4 : 156-164, 2000.
11 Voorhees, A.S., Araki, S., Sakai, R., Sato, H.: An ex
post cost-benefit analysis of the nitrogen dioxide air
pollution control program in Tokyo. Journal of the
Air & Waste Management Association 50: 391-410,
2000.
12 Sato, H., Araki, S., Yokoyama, K.: Influence ofmonopoly privatization and market liberalization on
smoking prevalence in Japan: Trends of smoking
prevalence in Japan in 1975-1995. Addiction 95:
1089-1098, 2000.
13 Voorhees, A. S., Sakai, R., Araki, S., Sato, H., Otsu,
A.: Cost benefits analysis of nitrogen dioxide control
programmes: A case study of Chiyoda-ku, Tokyo.
Journal of Environmental Planning and Management
44 : 149-165, 2001.
14 Asano, N., Kobayashi, Y., Kano, K.: Issues of interventions aimed at preventing prospective surplus ofphysicians in Japan. Medical Education 35: 488-494,
2001.
15 Tamiya, N., Kobayashi, Y., Murakami, S., Sasaki, J.,
Yoshizawa, K., Otaki, J., Kano, K.: Factors related tohome discharge of cerebrovascular disease patients,
one-year follow-up interview survey of caregivers of
hospitalized patients in 53 acute care hospitals inJapan. Archives of Gerontology and Geriatrics 33:
109-121, 2001.

(2) Occupational medicine and environmental
health16 Hayashi T, Kobayashi Y, Yamaoka K, Yano E. Effectof overtime work on 24-hour ambulatory blood pres-145

sure. Journal of Occupational and Environmental
Medicine 38: 1007-1011, 1996.
17 Tanigawa, T., Araki, S., Nakata, A., Araki, T.,
Sakuraai, S.: Decreases in subpopulations of T lymphocytes and natural killer cells in the blood ofretired chromate workers. International Journal of
Occupational and Environmental Health 2: 222225,1996.
18 Sata, F., Araki, S.,: Adjustment of creatinine-adjusted
value to urine flow rate in lead workers. Archives ofEnvironmental Health 51: 329-333, 1996.
19 Kawakami, N., Araki, S., Kawashima, M., Masumoto,T., Hayashi, T.: Effects of work-related stress reduction on depressive symptoms among Japanese bluecollar workers. Scandinavian Journal of Work,
Environment Health 23: 54-59, 1997.
20 Yokoyama, K., Araki, S., Murata, K., Morita, Y.,
Katsuno, N., Tanigawa, T.,Mori, N., Yokota, J., Ito,
A., Sakata, E.: Subclinical vestibulo-cerebellar, anterior cerebellar lobe and spinocerebellar effects in lead
workers in relation to concurrent and past exposure.
Neurotoxicology 18: 371-380, 1997.
21 Yokoyama, K., Araki, S., Murata, K., Nishikitani, M.,
Nakaaki, K., Yokota, J., Ito, A., Sakata, E.: Postural
sway frequency analysis in workers exposed to nhexane, xylene, and toluene: Assessment of subclinical cerebellar dysfunction. Environmental Research
74: 110-115, 1997.
22 Sata, F., Araki, S., Sakai, T., Nakata, A., Yamashita,K., Morita, Y., Tanigawa, T., Miki, A.: Immunologicaleffects of CaEDTA injection: Observations in twolead workers. American Journal of Industrial
Medicine 32: 674-680, 1997.
23 Grandjean, P., Weihe, P., White, R.F., Debes, F.,
Araki, S., Yokoyama, K., Murata, K., SÉ”rensen, N.,
Dahl, R., JÉ”rgensen, P.J.: Cognitive deficit in 7-yearold children with prenatal exposure to methylmercury. Neurotoxicology and Teratology 19: 417-428,
1997.
24 Murata, K., Araki, S., Yokoyama, K., Okumura, T.,
Ishimatsu, S., Takasu, N., White, R.F.:
Asymptomatic sequelae to acute sarin poisoning in
the central and autonomic nervous system 6 months
after the Tokyo subway attack. Journal of Neurology
244: 601-606, 1997.
25 Yokoyama, K., Araki, S., Murata, K., Nishikitani, M.,
Okumura, T., Ishimatsu, S., Takasu, N.: A preliminary study on delayed vestibulo-cerebellar effects ofTokyo subway sarin poisoning in relation to genderdifference: Frequency analysis of postural sway.
Journal of Occupational and Environmental Medicine
40:17-21, 1998.
26 Yokoyama, K., Araki, S., Murata, K., Nishikitani, M.,
Okumura, T., Ishimatsu, S., Takasu, N., White, R.F.:
Chronic neuro-behavioral effects of Tokyo subway
sarin poisoning in relation to posttraumatic stressdisorder. Archives of Environmental Health 53: 249256, 1998.
27 Yokoyama, K., Araki, S., Aono, H., Murata, K.:
Calcium disodium ethylene-diaminetetraacetate-146

chelated lead as a predictor for subclinical lead neurotoxicity: Follow-up study on gun-metal foundry
workers. International Archives of Occupational andEnvironmental Health 71: 459-464, 1998.
28 Kim, J.M., Araki, S., Kim, D.J., Takasuka, N.,
Babatoriyama, H., Nir,Z., Khachik, F., Shimizu, N.,
Tanaka, Y., Osawa, T., Nishino,H., Tsuda, H.:
Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2dimethylhydrazine initiation. Carcinogenesis 19: 8185, 1998.
29 Murata, K., Weihe, P., Renzoni, A., Debes, F.,
Vasconcelos, R,. Zino, F., Araki, S., JÉ”rgensen, P.J.,
White, R. F., Grandjean, P.: Delayed evoked potentials in children exposed to methylmercury fromseafood. Neurotoxicology and Teratology 21: 343348, 1999.
30 Zhang, J., Araki, S., Sato, H., Yokoyama, K.:
Psychobehavioral effects of divorced mother-headed
one-child families on children in China.
Environmental Health and Preventive Medicine 4:
135-139, 1999.
31 Park, S.H., Araki, S., Nakata, A., Kim, Y.H., Park,
J.A., Tanigawa, T., Yokoyama, K., Sato, H.: Effects ofoccupational metallic mercury vapor exposure on
suppressor-inducer (CD4+CD45RA+) T lymphocytes
and CD59+CD16+ natural killer cells. International
Archives of Occupational and Environmental Health73: 537-542, 2000.
32 Kawakami, N., Akaki, K., Shimizu, H., Haratani, T.,
Kobayashi, F., Ishizaki, M., Hayashi, T., Fujita, O.,
Aizawa, Y., Miyazaki, S., Hiro, H., Hashimoto, S.,
Araki, S.: Job strain, social support in the workplace,and hemoglobin A1c in Japanese men. Occupational
and Environmental Medicine 57: 805-809, 2000.
33 Kitamura, F., Araki, S., Suzuki, Y., Yokoyama, K.,
Tanigawa, T., Iwasaki, R. : Assessment of the mutation of the p53 suppressor gene and Ha-and Ki-ras
oncogenes in malignant mesothelioma in relation toasbestos exposure: A study of 12 American patients.
Industrial Health 40: 175-181, 2002.
34 Nordin, R., Araki, S., Sato, H., Yokoyama, K., Muda,
W., Kyi, D. W.: Effects of safety behaviors of pesticide use on occurrence of acute symptoms in maleand female tobacco-growing Malaysian farmers.
Industrial Health 40: 182-190, 2002.
35 Yokoyama, K., Araki, S., Yamashita, K., Murata, K.,
Nomiyana, K., Nomiyama, H., Tao, Y- X., Liu, S-J.,
Sato, H.: Subclinical cerebellar anterior lobe, vestibulo-cerebellar and spinocerebellar afferente effects inyoung female lead workers in China: Computerized
posturography with sway frequency analysis andbrainstem auditory evoked potentials. Industrial
Health 40: 245-253, 2002.

(3) Community and clinical epidemiology
36 Kawakami, N., Iwata, N., Tanigawa, T., Ohga, H.,
Araki, S., Fujikhara, S., Kitamura, T.: Prevalence ofmood and anxiety disorders in working population

in Japan. Journal of Occupational and Environmental
Medicine 38: 899-905, 1996.
37 Yamada, K., Araki, S., Tamura, M., Sakai, I.,
Takahashi, Y., Kashihara, H., Kono, S.: Case-control
study of colorectal carcinoma in situ and cancer in
relation to cigarette smoking and alcohol use inJapan. Cancer Causes and Control 8: 780-785, 1997.
38 Yokoyama, K., Araki, S., Nishikitani, M.: Reasons fordrinking in relation to problem drinking behavior ina sample of Japanese high school students.
International Journal of Behavioral Medicine 6: 135149, 1999.
39 Kawakami, N., Araki, S., Takatsuka, N., Shimizu, H.,
Ishibashi, H.: Overtime, psychosocial working conditions, and occurrence of non-insulin dependent diabetes mellitus in Japanese men. Journal of
Epidemiology and Community Health 53: 359-363,
1999.
40 Yokoyama, K., Araki, S., Matsuoka, K., Mori, N.,
Sato, H., Nakao, M.: Socioeconomic factors affecting
alcohol consumption in Japan. Alcoholism 35: 13-22,
1999.
41 Hotta, Y., Araki, S., Sato, H., Yokoyama, K.: Social
life factors for the mortality from motor vehicle accident. Japanese Journal of Occupational Medicine andTraumatology 48: 483-489, 2000.
42 Ishizaki T, Kobayashi Y, Kai I. Functional transitionsin instrumental activities of daily living among older
Japanese. Journal of Epidemiology 10: 249-254, 2000.
43 Suematsu, Y., Sato, H., Ohtsuka, T., Kotsuka, Y.,
Araki, S., Takamoto, S.: Predictive risk factors ofdelayed extubation in patients undergoing coronary
bypass grafting. Heart and Vessels 15 : 214-220,
2000.
44 Sato, H., Hashimoto, A., Araki, S., Nishibayashi, Y.,
Hoshi, K., Kutsuna, T., Shiino, Y., Ishihara, Y.,
Tsuboi, S., Fujimori, J., Kondo, H., Akizuki, M.,
Moroi, Y., Yoshida, S., Yokoyama, K.: Validity andreliability of a revised Japanese version of the arthritis impact measurement scales version 2 (AIMS2).
Modern Rheumatology 10: 247-255, 2001.
45 Shibata, K., Takamoto, S., Kotsuka, Y., Miyairi, T.,
Morota, T., Ueno, K., Sato, H.: Doppler ultrasonographic identification of the critical segmental arteryfor spinal cord protection. European Journal of
Cardio-Thoracic Surgery 20 : 527-532, 2001.
46 Lee JS, Kawakubo K, Sato H, Kobayashi Y, Haruna Y.
Relationship between total and regional bone mineral density and menopausal state, body compositionand life style factors in overweight Japanese women.
International Journal of Obesity 25: 880-886, 2001.
47 Lee JS, Kawakubo K, Kobayashi Y, Mori K, Kashihara
H, Tamura M. Effects of ten year body weight variability on cardiovascular risk factors in Japanese middle-aged men and women. International Journal of
Obesity 25: 1063-1067, 2001.
48 Ishizaki T, Kai I, Kobayashi Y, Imanaka Y. Functionaltransitions and active life expectancy for older
Japanese living in a community. Archives ofGerontology and Geriatrics 35: 107-120, 2002.

49 Shibata, K., Takamoto, S., Kotsuka, Y., Sato, H.:
Effectiveness of combined blood conservation measures in thoracic aortic operations under deep
hypothermic circulatory arrest. Annals of Thoracic
Surgery 73: 739-743, 2002.
50 Ohyama T, Kobayashi Y, Mori K, Kano K, Sakurai K,
Sato Y. Factors affecting complete resection of gastrictumors by the endoscopic mucosal resection procedure. Journal of Gastroenterology and Hepatology
17:844-848, 2002.

147

Department of
Forensic Medicine
Outline and Research Objectives
Since Professor Kunika Katayama founded our department first in Japan on 1888, we
have performed10258 autopsies by September 30th, 2002. Our precursors have devoted toso many outstanding cases that were paid social attentions. Research objectives are bloodDNA typing, serology, toxicology, forensic pathology, etc. as described below.

Faculties and Students
Professor
Ken-ichi Yoshida, M.D (1999)
Associate Professor Hirotaro Iwase, M.D. (2001)
Associate .................................2
Graduate students...................6
Technical persons ...................4
Secretary .................................2

Past Research and Major Accomplishment
Besides the research on forensic pathology anddetermination of death cause, there have been outstanding accomplishments in basic medical field since
Professor Mita, S., the founder of the Department of
Immunology. Professor Furuhata, T. was outstanding
in the study on the inheritance of ABO blood group.
Professor Ueno, S. discovered complements, while hestudied on medical law. Professor Miki was famousfor blood typing. Professor Ishiyama introduced DNA
typing in the forensic practice, while encouraged
forensic pathology. Professor Takatori, T. was famousin the autopsy and research on the Sarin murdercases, while his research on lipid has been inherited
today.

Current Research
1) Reactive oxygen generation, and Lipid peroxidation and their implication in the pathogenesis:
We identified several lipid species that are generated in the presence of heme-proteins and associatedwith peroxidation. These lipids may be associatedwith the pathogenesis caused by oxidative stresses
that are caused by ischemia-reperfusion (myocardialor brain infarction) or various drugs or toxins(amphetamines, carbon monoxide, agricultural medicines etc.). We undertake to clarify the molecularmechanism of the injury or the cell death due to thesepathogens with reference to lipid peroxidation. Of
these, 4-hydroxynonenal (HNE) is rapidly induced in
the endothelium and sarcolemma of the infarcted

148

myocardium.
Carbon monoxide (CO) is the most common causeof death due to intoxication, and is often supposed toaggravate fatality due to ischemic heart diseases (IHD)or cause delayed neuronal death. CO protects cardiomyogenic cells against ischemia and alleviates reactive oxygen (ROS) generation. By contrast, in the invivo experiments in the rat, CO plus hypoxia induces
necrotic cortical neuronal death, which is associatedwith the enhanced production of lipid peroxide.
Hypothermia reduced the neuronal injury and lipid
peroxide generation, suggesting the implication oflipid peroxidation in the neuronal death induced byCO.
2) The molecular mechanism of the injury and cell
death of myocardium or brain after ischemiareperfusion or toxic substances.
More than two thirds of the causes of unusual
death are ischemic heart or brain diseases. Most ofsuch death occurs within an hour of the onset of thesymptoms. Because it takes more than several hours
from the onset of symptoms for the myocardium toshow distinct histological changes (coagulation necrosis), it is mandatory to establish a diagnostic method
for the early ischemia. To this end, we have to understand the molecular basis of the evolution of theischemic heart or brain disease. We have clarified on
the roles of proteases or intracellular signaling molecules in the pathogenesis of ischemic diseases andtoxic cell injuries. 1) Brief ischemic (e.g. 10min) followed by reperfusion induces proteolysis of cytoskeletal proteins fodrin and ankyrin by Ca2+-dependent
protease calpain, which causes contractile dysfunctionin the isolated heart. This is the earliest irreversible
change so far documented. 2) Protein Kinase C (PKC)
isoforms translocate to membrane or nucleus during
ischemia. Nitric oxide (NO) mediates the translocationof PKC-α, δ, and ε, which protects myocardium
against reperfusion injury. 3) Ischemia-reperfusioncauses sequential activation of PI3 kinase-PKC-ζ-MEKMAP kinase- c-fos , thereby preventing apoptotic
death. This study disclosed that MAP kinase translo-

cates to the nucleus independent of phosphorylation,
but is activated by phosphorylation through MEK activation during postischemic reperfusion in the nucleus,in contrast with the paradigm. 4) Hypoxia under normoglycemia causes autophagic cell death through acidosis through PI3 kinase-mediated activation of glycolysis, explaining the myocardial death under pulmonary hypoventilation or hypoxic hypoxia. 5)
Angina attacks often attenuate the injury due to subsequent myocardial infarction (MI). This phenomenon, ischemic preconditioning (IP), is reproduced in
rat coronary occlusion model of acute MI. IP induces
endothelial NO synthase (eNOS) and collateral vasodilation in the early MI, whereas IP induces angiogenesis in late MI through PKC- ε activation and VascularEndothelium Growth Factor (VEGF) up-regulation.
The both salvage myocardium in MI. 6) Connexin(Cx)-43 undergoes proteolysis during early MI
through lysosomal and proteasomal proteases independently of calcineurin-mediated proteolysis. IP
attenuates the Cx43 proteolysis in early MI. Thesefinding explain the arrhythmias in early MI and its
prevention by IP. 7) Emotional stress evoked byimmobilization of rat causes activation of MAP
kinase-c-fos pathway. 8) Methamphetamine (MAH)
induces hyperthermia through symphathetico-adrenal
activation and enhanced skeletal muscle metabolism,
which is blocked by a sarcoplasmic reticulum Ca2+release blocker dantrolene. Repeated intermittent
administration of MAH causes enhanced cardiovascular, thermal, and behavioral responses to MAH or
emotional stress. We are willing to apply the findingsof the experimental studies to exploit a new method
for the diagnosis of ischemic or other disease states.
3) The study on the legal aspects of forensic medicine.
Forensic practices are associated with various legal
or social problems that ought to be solved, though
there have been research on such issues. On the other
hand, those who provide expert opinion in the civil orlegal litigation were far less than those required.
There is dissociation in the thought-ways between
medical doctors and lawyers, which can seriously violate the human right of persons concerned as well as
causes the shortage of the expert witnesses. The
courts have made effort to increase the numbers ofexpert witnesses for the litigation, though no adequate. On the other hand, the expression or the wayof the expert witness may affect the judgment in thelitigation or prosecution, as suggested by the questionnaire study.
The "reportable unusual deaths" in the guideline
proposed by Japanese Society of Legal Medicine
includes the unexpected death during or shortly after
any medical practice. According to the Doctorﾕs Act

in Japan, doctors must report unusual death cases tothe police. The police (prosecutors) demand autopsy
under the guidance of superintendents. In England,coroners request autopsy after inquiry with the police,
relatives and forensic pathologists. Medical accidents
are largely autopsied in England whereas, in Japan,
medical accidents are rarely reported nor. In Tokyoand few other districts, medical examiners decide
autopsy of 1/4~1/3 of unusual deaths, but autopsies inother districts are mostly conducted by police judgment in search for a possible crime. It should be
reminded that death cause tells criminality and the
responsibility only if the cause is diagnosed exactly by
autopsy performed under proper judgment and that
autopsy is often effective to clarify the cause of unexpected deaths. Recently in Japan, unexpected deaths
in hospitals have come to be increasingly suspected as
caused by malpractice. For lack of a proper system toanswer for complaints from patientsﾕ side, the relatives sometimes go to the police. Though most cases
are asked only for civil liability, the police investigate
the hospital in question and this makes doctors hesitate to report. Prosecutors judge criminality on autopsy operatorﾕs expert opinion, whereas they insist that
autopsy results should not be disclosed to protect privacy of investigation. Thus, an insufficient information on patientﾕs side explains to a great extent why
nearly 700 relatives sue doctors every year in Japan.
In 2001, Japan Surgical Society announced to the public and Society of Legal Medicine that patientsﾕ death
during or shortly after operations should not be
accounted as an unusual death reportable to thepolice, but to the independent authority, if required.
Though many cases are unavoidable and not problematic, doctors sometimes neither inform the patientﾕs
side enough to get satisfactory consent for the practice nor explain the necessity of autopsy to clarify
death cause. As accepted in U.K., there should only bereasonable cause to suspect for "unusual death".
Accordingly, although deaths in medical accident may
be sometimes inevitable or unrelated to the malpractice, the doctorﾕs explanation as such for an unexpected death can be hardly accepted by patientﾕs side.
Therefore, independent investigation and autopsy are
required in medical accidents in order to determineand explain the cause of death to patientﾕs side andto disclose and improve the medical practice by doctors. We are willing to devote to set up valid system
for the death investigation in the medical accident
cases.
4) Forensic pathology.
Because each case is unique and diversity is a
important determinant of the death, we try to perform microscopic analyses in as many cases as possible. We undertake to take the advantage of the above-149

mentioned studies in the immunohistochemical
method for the diagnosis of our autopsy cases.

Future Prospective
The correct and fair determination of deathcause in the medico-legal autopsy cases has been themost important mission of us. We must accept very
difficult and socially notable victims and requirementsof expert opinion. We must play this important role
carefully and impatiently, and train young forensic
pathologists.
There has been not so much evolution in theforensic practice except for the DNA identification
technology. This may be the cause of the low overall
activity in the forensic medicine. To open the window
to the future of forensic medicine, we must do every
effort to find new directions of forensic medicine andlet them known to the public as well as medical field.
Actually, there are many medico-legal issues in theclinical medicine, which have manifested as the growing criticisms from the society on the medical malpractice, inadequate risk management of the medical
accidents, etc. In Japan, the death investigation system for the medical accidents and the unexpected
death in hospitals is quite immature, so that it is very
important and urgent to set up an independent organization for the death investigation for such cases. As
forensic pathologists, we have autopsied such cases
and recognize the problems to be addressed. We aregoing to take part in such activity in cooperation withclinicians and civil servants to find and build up thegood system. Additionally, the education on theseissues to the clinicians, citizens, as well as medical
and law students are very important.
The legal systems for death investigation of"unusual death", prosecution and litigation haveinherent drawbacks, which require improvement. We
have taken effort to inform on the problems to persons concerned, but it is far from what is ought to be.
The 15~20% of total deaths are "unusual deaths",
which requires death investigation. The misdiagnosesof the "unusual deaths" by clinicians, and police surgeons, are police officers have been manifested due tothe inherent inadequacy of the system and poor education of those who investigate. Because there aresome typical patterns of misdiagnoses and poor management of those cases, we must educate on theseissues to students, medical service personnel, and thesociety.

Research Grant
Grant-in-aid from Monbusho (B) for Yoshida et al.
1) A survey for the myocardial proteins and genes
induced by ischemia or psychological stress and its

150

application to the forensic practices (1998~1999)
10,200,000 yen
2) Identification and path-physiological study of novel
peroxidized fatty acids formed in the tissue after
ischemia or various intoxication and the exploitationof the new diagnostic method (2000~2001)
14,800,000 yen
3) Research on the mechanism of cellular injury due tonitric oxide or carbon monoxide in tissues undergoing ischemia or shock (2002) 14,000,000 yen

Grant-in-aid from Monbusho (C) for Uemura,
Yoshida et al.
4) Research on the intracellular stress response in theamphetamine-induced neuro-degeneration (1999~
2000) 2,500,000 yen
5) Research on the molecular mechanism of promotion
and protection of cell death by carbon monoxide(2002) 2,700,000 yen

Select Publications
1. Yoshida K, Inui M, Harada K, Saido TC, Sorimachi Y,
Ishihara T, Kawashima S, Sobue K. Reperfusion of
rat heart after brief ischemia induces proteolysis ofcalspectin(nonerythroid spectrin or fodrin) by calpain. Circ Res. 77, 603-10, 1995.
2. Sorimachi Y, Harada K, Yoshida K. Involvement of
calpain in postmortem proteolysis in the rat brain.
Forensic Sci Int. 15, 81, 165-74.
3. Yoshida K, Hirata T, Akita Y, Mizukami Y,
Yamaguchi K, Sorimachi Y, Ishihara T, Kawashiama
S. Translocation of protein kinase C-alpha, delta andepsilon isoforms in ischemic rat heart. Biochim
Biophys Acta. 1996 Oct 7;1317(1):36-44.
4. Sorimachi Y, Harada K, Saido TC, Ono T, Kawashima
S, Yoshida K. Downregulation of calpastatin in rat
heart after brief ischemia and reperfusion. J Biochem(Tokyo). 1997 Oct;122(4):743-8.
5. Kitakaze M, Funaya H, Minamino T, Node K, Sato
H, Ueda Y, Okuyama Y, Kuzuya T, Hori M, Yoshida
K. Role of protein kinase C-alpha in activation ofecto-5 -nucleotidase in the preconditioned canine
myocardium. Biochem Biophys Res Commun 1997
Oct 9;239(1):171-5
6. Fukuda S, Harada K, Kunimatsu M, Sakabe T,
Yoshida K. Postischemic reperfusion induces alphafodrin proteolysis by m-calpain in the synaptosome
and nucleus in rat brain. J Neurochem. 1998
Jun;70(6):2526-32.
7. Yoshida K, Harada K. Proteolysis of erythrocyte-type
and brain-type ankyrins in rat heart after postischemic reperfusion. J Biochem (Tokyo). 1997
Aug;122(2):279-85.
8. Harada K, Fukuda S, Kunimoto M, Yoshida K.
Distribution of ankyrin isoforms and their proteolysis after ischemia and reperfusion in rat brain. J
Neurochem. 1997 Jul;69(1):371-6.
9. Harada K, Sorimachi Y, Yoshida K. Proteolysis ofankyrin and Na+/K+-ATPase in postmortem rat brain:

is calpain involved? Forensic Sci Int. 1997 Apr
18;86(1-2):77-85.
10. Mizukami Y, Yoshioka K, Morimoto S, Yoshida K. A
novel mechanism of JNK1 activation. Nuclear
translocation and activation of JNK1 during ischemia
and reperfusion. J Biol Chem. 1997 Jun
27;272(26):16657-62.
11. Mizukami Y, Yoshida K. Mitogen-activated protein
kinase translocates to the nucleus during ischaemia
and is activated during reperfusion. Biochem J. 1997
May 1;323 ( Pt 3):785-90.
12. Mizukami Y, Hirata T, Yoshida K. Nuclear translocation of PKC zeta during ischemia and its inhibition
by wortmannin, an inhibitor of phosphatidylinositol
3-kinase. FEBS Lett. 1997 Jan 20;401(2-3):247-51.
13. Kawamura S, Yoshida K, Miura T, Mizukami Y,
Matsuzaki M. Ischemic preconditioning translocates
PKC-delta and -epsilon, which mediate functional
protection in isolated rat heart. Am J Physiol. 1998
275(6 Pt 2):H2266-71.
14. Kawata Y, Mizukami Y, Fujii Z, Sakumura T, Yoshida
K, Matsuzaki M. Applied pressure enhances cell proliferation through mitogen-activated protein kinase
activation in mesangial cells. J Biol Chem. 1998 Jul
3;273(27):16905-12.
15. Makisumi T, Yoshida K, Watanabe T, Tan N,
Murakami N, and Morimoto A. Sympatho-adrenal
involvement in methamphetamine-induced hyperthermia through skeletal muscle hypermetabolism.
Eur J Pharmacol 363, 107-112, 1998.
16. Shama KMA, Suzuki A, Harada K, Fujitani N,
Kimura H, Ohno S, Yoshida K. Transient up-regulation of myotonic dystrophy protein kinase-binding
protein, MKBP, and HSP27 in the neonatal myocardium.Cell Struct Funct 1999; 24; 1-4.
17. Yoshida K, Mizukami Y, Kitakaze M. Nitric oxide
mediates protein kinase C isoform translocation in
rat heart during postischemic reperfusion. Biochim
Biophys Acta 1999; 1453; 230-8.
18. Harada K, Ichiyama T, Ikeda H, Yoshida K. A fatalcase of oral ingestion of benzine. Am J Forensic
Med Pathol 1999; 20; 84-9.
19. Harada K, Maekawa T, Shama KMA, Yamashima T,
Yoshida K. Translocation and down-regulation ofprotein kinase C-α,-β, and -γisoforms during
ischemia-reperfusion in rat brain. J Neurochem 1999;
72; 2556-64.
20. Yoshida K, Aki T, Harada K, Shama KMA, Kamoda
Y, Suzuki A, Ohno S. Translocation of HSP27 and
MKBP in ischemic heart. Cell Struct Funct 1999; 24;
181-5.
21. Harada K, Asa K, Imachi T, Yamaguchi Y, Yoshida K.
Centipede inflicted postmortem injury. J Forensic Sci
1999; 44; 849-50.
22. Ueyama T, Yoshida K, Senba E. Emotional stressinduces immediate-early gene expression in rat
heart via activation of alpha- and beta-adrenoceptors.
Am J Physiol 1999; 277; H1553-61.
23. Sakurada K, Iwase H, Takatori T, Nagao M,
Nakajima M, Niijima H, Matsuda Y, Kobayashi M.

Identification of cis-9,10-methylenehexadecanoic
acid in submitochondrial particles of bovine heart.
Biochim Biophys Acta 1999; 1437; 214-22.
24. Niijima H, Nagao M, Nakajima M, Takatori T,
Matsuda Y, Iwase H, Kobayashi, M. Sarin-like,soman-like organophosphorous agents activate PLC
gamma in rat brains. Toxicol Appl Pharmacol 1999;
156; 64-9.
25. Kobayashi M, Takatori T, Nakajima M, Saka K,
Iwase H, Nagao M, Niijima H, Matsuda Y. Does thesequence of onset of rigor mortis depend on the proportion of muscle fiber types and on intra-muscularglycogen content? Int J Legal Med 1999; 112; 167-71
26. Kobayashi M, Sakurada K, Nakajima M, Iwase H,
Hatanaka K, Matsuda Y, Ikegaya H, Takatori T. A
keyhole lesion gunshot wound in an adipocere
case. Legal Med 1999; 1; 170-3.
27. Ikegaya H, Iwase H, Hatanaka K, Sakurada K,
Matsuda Y, Kobayashi M, Takatori, T: Postmortem
changes in cytochrome c oxidase activity in variousorgans of the rat and in human heart. Forensic Sci
Int 108, 181-186, 2000
28. Mizukami, Y, Kobayashi, S, Uberall, F, Hellbert, K,
Kobayashi, N and Yoshida, K.: Nuclear mitogen-activated protein kinase activation by protein kinase C
zeta during reoxygenation after ischemic hypoxia. J
Biol Chem, 275, 19921-19927, 2000.
29. Ueyama, T, Yoshida, K and Senba, E.: Stress-induced
elevation of the ST segment in the rat electrocardiogram is normalized by an adrenoceptor blocker.
Clinical Exp Pharmacol Physiol, 27, 384-386, 2000.
30. Iwase, H., Sakurada, K., Hatanaka, K., Kobayashi, M.
and Takatori, T.: Effect of cytochrome c on thelinoleic acid-degrading activity of porcine leukocyte
12-lipoxygenase. Free Radical Biol Med, 28, 912-919,
2000.
31. Nakajima, M., Nagao, M., Iwasa, M., Monma-Ohtaki,J., Maeno, Y., Koyama, H., Seko-Nakamura, Y., Isobe,
I. and Takatori, T.: Related Articles：Purificationand characterization of diquat (1, 1 -ethylene-2,
2 -dipyridylium)- metabolizing enzyme fromparaquat-resistant rat liver cytosol. Toxicology, 154,
55-66, 2000.
32. Shiraishi, K, Naito, K. and Yoshida, K. Inhibition of
calpain but not caspase protects the testis against
injury after experimental testicular torsion of rat.
Biol. Reproduct, 63, 1538-1548, 2000.
33. Tsuji T, Ohga Y, Yoshikawa Y, Sakata S, Abe T,
Tabayashi N, Kobayashi S, Kohzuki H, Yoshida KI,
Suga H, Kitamura S, Taniguchi S, Takaki M. Rat cardiac contractile dysfunction induced by Ca2+ overload: possible link to the proteolysis of alphafodrin.Am J Physiol Heart Circ Physiol 2001
281(3):H1286-9
34. Uemura K, Harada K, Sadamitsu D, Tsuruta R,
Takahashi M, Aki T, Yasuhara M, Maekawa T,
Yoshida K. Apoptotic and necrotic brain lesions in a
fatal case of carbon monoxide poisoning. Forensic
Sci Int 2001; 116, 213-9.

15135. Uemura K, Yoshida K. Seat belt induced transectionof trachea in a child held on laps of adult upon car
diving. J Forensic Sci 2001; 46, 714-6.
36. Sanada S, Kitakaze M, Papst PJ, Hatanaka K,
Asanuma H, Aki T, Shinozaki Y, Ogita H, Node K,
Takashima S, Asakura M, Yamada J, Fukushima T,
Ogai A, Kuzuya T, Mori H, Terada N, Yoshida K,
Hori M. Role of phasic dynamism of p38 mitogenactivated protein kinase activation in ischemic preconditioning of the canine heart. Circ Res. 2001 Feb
2;88(2):175-80.
37. Kawata H, Yoshida K, Kawamoto A, Kuroiwa H,
Takase E, Sasaki Y, Hatanaka K, Kobayashi M,
Ueyama T, Hashimoto T, Dohi K. Ischemic preconditioning upregulates vascular endothelial growth factor mRNA expression and neovascularization via
nuclear translocation of protein kinase C e in the rat
ischemic myocardium. Circ Res 2001; 88: 696-704.
38. Hatanaka K, Ikegaya H, Takase I, Kobayashi M,
Iwase H, Yoshida K. Immobilization stress-induced
thymocyte apoptosis in rats. Life Sci 2001; 69: 15565.
39. Ikegaya H, Iwase H, Hatanaka K, Sakurada K,
Yoshida K, Takatori T. Diagnosis of cyanide intoxication by measurement of cytochrome c oxidase activity. Toxicol Lett. 2001; 119: 117-23.
40. Yamada Y, Kobayashi M, Takatori T, Nagao M, Ohira
H, Yamamoto I, Ohtani S. Possibility of paternity
testing using RFLP analysis of a very small amountof material. J Forensic Odontostomatol 2001; 19: 1-4.
41. Yamada Y, Takatori T, Nagao M, Iwase H, Kuroda N,
Yanagida J, Shinozuka T. Expression of paraoxonase
isoform did not confer protection from acute sarin
poisoning in the Tokyo subway terrorist attack. Int J
Legal Med. 2001; 115: 82-4.
42. Aki T, Mizukami Y, Oka Y,Yamaguchi Y, Uemura K,
Fujimiya T, Yoshida K. Phosphoinositide 3-kinase
accelerates necrotic cell death during hypoxia.
Biochem J 2001; 358, 481-7.
43. Kudo R, Adachi J, Uemura K, Maekawa T, Ueno Y,
Yoshida K. Lipid peroxidation in the rat brain after
CO inhalation is temperature dependent. Free
Radical Biol Med 2001; 31, 1417-23.
44. Iwase H, Kobayashi M, Nakajima M, Takatori T. The
ratio of insulin to C-peptide can be used to make aforensic diagnosis of exogenous insulin overdosage.
Forensic Sci Int 2001; 115: 123-7.
45. Iwase H, Kobayashi M, Kurata A, Inoue S. Clinicallyunidentified dissection of vertebral artery as a causeof cerebellar infarction. Stroke 2001; 32: 1422-4.
46. wase H, Sakurada K, Ikegaya H, Hatanaka K,
Takeichi H, Kobayashi M, Yoshida K. Thiol-oxidizing
agent diamide and acidic pH enhance lipid peroxidation of rat heart mitochondria and cardiolipincytochrome c complex. IUBMB Life 2001; 51: 39-43.
47. Kobayashi M, Ikegaya H, Takase I, Hatanaka K,
Sakurada K, Iwase H. Development of rigor mortis is
not affected by muscle volume. Forensic Sci Int 2001;
117: 213-9.

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48. Shiraishi K, Naito K, Yoshida K. Vasectomy impairs
spermatogenesis through germ cell apoptosis mediated by p53-Bax pathway in the rat. J Urology 2001;
166: 1565-1568.
49. Shiraishi K, Yoshida K, Fujimiya T, Naito K.
Activation of mitogen activated protein kinases andapoptosis of germ cells after vasectomy in the rat. J
Urology 2002; 168: 1273-1278.
50. Yoshida K, Kuroki H, Takeichi H, Kawai K. Deathduring surgery in Japan. The Lancet 2002; 360: 805.

Department of Medical
Informatics and Economics
Outline and Research Objectives
In 1983, the Department of Hospital Information Management(Hospital Computer
Center) was established as one of central facilities in the University of Tokyo Hospital. The
major roles have been designing, implementing, and maintaining the hospital information
management system based on up-to-date information technology and improving functionsof clinical information management required in the university hospital. The University
Medical Information Network Center(UMIN Center) was opened in the department as acooperate organization for national medical schools in Japan. The purposes of the UMIN
Center are to provide up-to-date communication environment to healthcare professionals
via the Internet. In 1997, according to the reconstruction of Graduate School, theDepartment of Medical Informatics and Economics was established in the Division of Social
Medicine, Graduate School of Medicine, and the functions of research and education andthe staffs were formally moved from the hospital to the department in the Graduate Schoolof Medicine. However, all the administrative works for providing various services of hospital information management have been conducted by the same staffs as before.
From the responsibilities of the hospital described as above, most of the researches havebeen based on practical development, integration, and implementation of hospital information systems using an innovative information technology. The scope covers standardizationof medical information exchange, evaluation of new technologies for distributed hospital
information systems, development of electronic medical record systems(EMRS) and medical
decision support systems(MDSS), application of the Internet technology in healthcare fields,
and method of knowledge discovery from clinical database. The goal is to contribute toimprovement of quality of care using information technology

Faculties and Students
Professor and Chair Kazuhiko Ohe, M.D., Ph.D. (1997-)
Associate Professors Takahiro Kiuchi, M.D., Ph.D. (forUMIN Center)
Graduate student ....................9
Research student.....................2

Past Research and Major Accomplishments
1) Development and evaluation of a hospital
information system using open standard and HL7(1993-Current)
Although the Health Level Seven(HL7) Version 2.1
was the only proposal for connecting distributed
information systems in a hospital around 1993, it was
no so-called “standard” protocol. Because it was essential for developers of develop large-scale hospital
information systems(HISs) to introduce a standard
communication protocol that could be generally usedin different departmental computer systems and theirterminals, an experience and evaluation of real implementation of HL7 in a large-scale HIS were needed in
the field of medical informatics in the early ‘90s. Ohe

designed a new architecture of client-server-type HIS
using HL7-based messaging protocol between client
terminals and the server over TCP/IP network, which
had never been used in Japan. The innovative HIS
was successfully implemented based on this newarchitecture in the University of Tokyo Hospital in
1995 and the good performance was proved in this
implementation[7]. This first experience of implementing the standard communication protocol or HL7
contributed to move most HISs in Japan from thevender proprietary systems into multi-vender distributed systems using open standard. Subsequent activities related to the open standard brought about foundation of the Association of HL7 Japan(Ohe is thevice-chair of the technical committee), foundation ofJapan Health Information and Communication
Standards Board (HELICS Board; Ohe is the Chair of
the Board),
2) Modeling a semantic structure of clinical information using object-oriented approach and development of HIS using OODB and CORBA(1996Current)
Analyzing and Modeling a semantic structure ofclinical information in terms of information science153are essential tasks to develop both multi-purpose
EMR systems and future intelligent decision support
systems. Object-oriented analysis(OOA) and modeling(OOM) were proposed in the ‘90s as powerful
methods to model a semantic relationship among
information objects in a target domain and they were
gradually applied in various fields as well as medical
information. We recognized the importance of the
OOA/OOM at the early stage, and focused on applying the approach to developing a future intelligent
clinical information systems. At first we analyzed andmade a model of data of ECG, and implemented aretrievalsystemusing
Object-Oriented
Database(OODB)[5,6,10]. The research proved the feasibility and realization of OOA/OOM and OODB system to develop multi-media clinical information systems.
Based on this result, we proposed a new architecture for managing distributed medical information
using OODB and CORBA(Common Objects Request
Broker Architecture). This approach aimed to shareinter-hospital distributed clinical information forimprovement of quality of care and quality of multiinstitutional large-scale clinical researches. In thisresearch, we have been developing CORBA-based
EMR systems in the University of Tokyo
Hospitals[12,18,21].
3) Standardization of medical informationexchange and terminology (1997-Current)
Ohe and the collaborative researchers in otherinstitutes have been concurrently developing a new
standard protocol for exchanging medical informationelectronically among hospitals in collaboration with
the Association of HL7-USA /Japan and related working group of ISO/TC215, in which Ohe is the delegateof Japan of WG3; concept representation). We proposed a protocol named “MML(Medical Markup
Language)” based on XML(eXtensible Markup
Language) in the early stage of the work[8], and later
we proposed a new protocol named “MERIT-9” basedon integration of XML, HL7, DICOM, and other defacto standard through our experiences of implementing the previous protocol[14,16]. This new protocol isin the stage of evaluation in several hospitals in Japan.
In the domain of medical terminology, Japan had
double standards of Japanese clinical disease terminology and all of hospitals in Japan have not decided touse which of them for a long time. Ohe and Kaihara,
who was a former professor of this department, proposed a method of integrating these two Japanesestandard into one unified standard terminology thatis available for general-purpose clinical information
systems and EDI(Electronic Data Interchange) systemof health insurance claim reimbursement. Each termin the unified disease terminology is linked to an ICD-

154

10 code and semantic relations among the terms.
Further a new standard methods to access to a database of the terminology was developed and published
as a open software in 2001 by Ohe and the colleagues.
Most large-scale university hospitals has been moving
to introduce the standard disease terminology since
2002 and Japan Ministry of Health, Labor, andWelfare announced that all of the hospitals must use
this terminology including the codes in EDI.
4) Application of the Internet technology to medical field by the UMIN
Application of the Internet technology to medical
field by the UMIN has been the major topic of theresearches[13,15,17,]. Associate Professor Kiuchi isthe director of the UMIN Center and he has beendeveloping and managing the nation-wide medical
information network sponsored by the Ministry of
Education, Culture, Science, Sports and Technology(MEXT). Using this infrastructure, Kiuchi and his colleagues proposed a standard method of on-line
abstract and paper entry and developed a system forJapanese academic medical societies. Hundreds of thesocieties have been adopting this system and as aresult this methods and the system has become thede-facto standard in Japan. Kiuchi and his colleagues
also developed Internet-based data collection system
for nation-wide clinical and epidemiological research.
The system have been enhancing the scale and theefficiency of such research[22].

Current Research
Most of the researches described above is continuing and currently expanded toward the next stage.
1) Enhancing Standardization of electronic representation of medical information:
Revising and evaluating the “MERIT-9” standard
protocol in harmonization with HL7 ver.3 that is proposed to cover comprehensive clinical information
systems.
2) Implementing large-scale EMR system integrated with order entry system using distributed
object technology:
Based on the evaluation study of CORBA-based
HIS, we are preparing and developing large-scale EMR
system that will be operated from Apr. 2003 in the
University of Tokyo Hospital.
3) Trial of knowledge discovery from large-scale
medical database created by HIS for futureIntelligent decision support system:
We are investigating a method of data mining andknowledge discovery from large-scale medical database[23].

Future Prospects
We will shift to develop an intelligent decision
support system that uses both large-scale clinical database and real-time knowledge discovering process,and for the purpose a new method of data mining
including both natural language processing and temporal data processing should be created. Further, wewant to focus on a method of creating an practical
ontology that is specific to healthcare domain. In
other words, integration of management of clinicaldata and handling of electronic medical knowledge isthe next objectives for our goals.

Research Grants
five recent grants selected:
1) 2000F.Y.-2001F.Y. Health and Labor Sciences
Research Grants of MHLW, Research on HealthTechnology Assessment, Research on developmentof formal electronic representation of logics of Japan
medical fee payment system and a standard softwareof source-code generator for calculating medical fee.
Head Researcher.
2) 2002F.Y Health and Labor Sciences Research Grants of
MHLW, Research on Policy Planning and Evaluation,
Investigation of DRG for inpatients with acute diseases. Co-researcher.
3) 2001F.Y.-2002F.Y. Grants-in-Aid for Scientific
Research of MEXT, Scientific Research-C,
Development of a method to discover similar cases
from clinical database using semantic relationshipamong medical terms, Head researcher.
4) 2001F.Y-2002F.Y. Health and Labor Sciences Research
Grants of MHLW, Research on Policy Planning and
Evaluation, A study on roles of Health Insurance
Agency, Head researcher.
5) 1999F.Y.-2001F.Y. Health and Labor Sciences
Research Grants of MHLW, Research on HealthTechnology Assessment, A study on modeling
healthcare information domain. Head Researcher.

Select Publications
1) Ohe,K., Kaihara,S.: An Object -Oriented Model ofPhysicians’ Strategy at First Encounters - An
Approach to sharing Distributed Knowledge-bases.
K.C.Lun et al.(eds), Elsevier Science Publishers,
B.V.(North-Holland), MEDINFO92: 434-439, 1992.
2) Kaihara S., Ohe K., Sakurai T. and Kiuchi T.: HIS andResearch. Hospital Information Systems: ScopeDesign-Architecture, A.R. Bakker et al. (eds), Elsevier
Science Publishers B.V.(North-Holland), 97-101,
1992.
3) T. Koyama, K. Ohe: Building a Common Knowledge
Base for Internal Medicine. Proceedings ofKorea/Japan Joint Conference on Expert Systems:
876-888,Seoul (Korea), 1993.
4) K.Ohe, S.Kaihara, K.B.Ishikawa, T.Hishiki, T.Nagase,
T.Sakurai: Hospital Information system and theInternet. K.Chon (ed), Proceedings of theInternational Networking Conference INET’95, 10331036, Internet Society, 1995.
5) C.Wang, K.Ohe, T.Sakurai, T.Nagase, S.Kaihara: An
ECG Storage and Retrieval System Embedded in
Client Server HIS Utilizing Object-Oriented DB.
Journal of Medical Systems, 20(1), 35-43, 1996.
6) C.Wang, K.Ohe, T.Sakurai, T.Nagase, S.Kaihara:
Object-oriented Analysis and Design of an ECG
Storage and Retrieval System Integrated with an HIS.
Methods of Information in Medicine, 35(1), 35-40,
1996.
7) K.Ohe, S.Kaihara: Implementation of HL7 to ClientServer Hospital Information System(HIS) in the
University of Tokyo Hospital. Journal of Medical
Systems, 197-205, Vol.20, No.4, 1996.
8) Yoshihara H., Ohe K., Ohashi K., Yamamoto R.,
Yamazaki S., Hirose Y., et.al.: Standardization of
Exchange Procedures of Clinical Information, and an
Experiment of Clinical Data Exchange Using Medical
Markup Language (MML). Journal of Japan Medical
Informatics, 17(3)Suppl., 203-207,1997.
9) Hishiki T.,Ohe K., Kaihara S.: Extraction of Clinical
Information from Narrative Medical Records Using
Natural Language Processing Journal of Japan
Medical Informatics, 17(3)Suppl.,1997.
10) Wang C, Ohe K, Kaihara S: Dynamic link between
ECG and clinical data by a CORBA-based query
engine and temporal mapping. Proceedings of AMIA
Annual Fall Symposium,27-31,1997.
11) K.Miyo, K.Ohe: SGML-based Construction andAutomatic Organization of Comprehensive Medical
textbook on the Internet. Proceedings of MEDINFO98, B.Cesnik etal.(Eds), Amsterdam:IOS press,145149,1998.
12) K.Ohe: A Hospital Information System based on
Common Object Request Broker Architecture(CORBA) for Exchanging Distributed Medical Objects- an approach to future environment of sharing
healthcare information. Proceedings of MEDINFO98,
B.Cesnik etal.(Eds), Amsterdam:IOS press,962964,1998.
13) T. Kiuchi, T. Sakurai, K. Ohe, Y. Ohashi, S. Kaihara:
University Medical Information Network - Past,
Present, and Future. Proceedings of MEDINFO98,
B.Cesnik etal.(Eds), Amsterdam:IOS press,420424,1998.
14) M. Kimura, K.Ohe, H. Yoshihara, Y. Ando, F.
Kawamata, T. HIshiki, et.al.: Patient Information
Exchange Guideline MERIT-9 using Medical Markup
Language MML. Proceedings of MEDINFO98,
B.Cesnik etal.(Eds), Amsterdam:IOS press,433437,1998.
15) H． Yamakami， T.Kiuchi, T.Nagase， K.Ohe,
S.Kaihara, T.Sakurai: Development and Trial operation of a World Wide Web-based data entry system

155

for the collection of statistical data on the management of the national university hospitals in Japan.
Medical Informatics,23(1),19-29,1998.
16) M. Kimura, K. Ohe, H. Yoshihara, Y. Ando, F.
Kawamata, T. Hishiki, et.al.: MERIT-9; a patient
information exchange guideline using MML, HL7,
and DICOM. International Journal of Medical
Informatics, 59-68,51(1),1998.
17) T.Kiuchi, K.Ohe, S.Kaihara: Using WWW-based Mail
User Agent for Secure Electronic Mail Service for
HealthCare Users, Methods of Information in
Medicine,37,247-253,1998.
18) C.Wang, K.Ohe: A CORBA-based Object Frameworkwith Patient Identification Translation and Dynamic
Linking-Methods for Exchanging Patient Data,Method of information in Medicine,38(1),5665,1999.
19) D. Koide, K. Ohe, Dennis Ross-Degnan, S.Kaihara:
Computerized reminders to monitor liverfunction to
improve the use of etretinate. International Journalof Medical Informatics,57(2000),11-19, 2000.
20) E.Hanada, Y.Antoku, S.Tani, M.Kimura,
A.Hasegawa, S.Urano, K Ohe, Member, IEEE,
M.Ymaki, Y.Nose: Electromagnetic interference on
medical equipment by low-power mobile telecommunication systems. IEEE TRANSACTIONS ON ELECTROMAGNETIC COMPATIBILITY, 42(4),470-476,
2000.
21) K. Ohe, K.Miyo, Y.Onogi, K.Ueda, M.Takada,T.Chihara: Implications of a General data model for
implementing OODB/CORBA-based computerized
patient record system. Proceedings of MEDINFO2001, V.Patel etal.(Eds), Amsterdam:IOS
press,789,2001.
22) T.Kiuchi,K. Ohe,T.Sakurai: UMIN-Key information
infrastructure for the Japanese Medical Community.
Proceedings of MEDINFO2001, V.Patel etal.(Eds),
Amsterdam:IOS press,1359-1363,2001.
23) D.Koide,K. Ohe: Applying data mining to detectionof adverse drug reactions. Proceedings of MEDINFO2001, V.Patel etal.(Eds), Amsterdam:IOS
press,1421,2001.
24) S.Kataoka, K. Ohe, M.Mochizuki, S.Ueda: Developing
and integrating an adverse drug reaction reporting
system with the hospital information system. YAKUGAKU ZASSHI,122(1),113-116, 2002.
25) Y.Ohyama, K.Funao, E.Kawabe, D.Hayashi,
T.Yamazaki, T.Iga, D.Koide, K. Ohe, K.Kubota：
Calcium channel blockers and myocardial infarction:
A case-control study in a Japanese hospital. PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, 2002,
11, 487-492, 2002.

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