Department of
Obstetrics and Gynecology
Outline and Research Objectives
The goal we aim at is the improvement of holistic women’s health. To achieve it, we
integrate all the knowledge in the field of reproductive medicine, perinatal medicine andgynecological oncology, which has been established on the basis of our history more thanhundred years, and will develop them.

Faculties and Students
Professor and Chair
Associate Professor
Lecturer

Yuji Taketani, MD, PhD (from 1994)
Shiro Kozuma
Toshiyuki Kojima
Koji Kugu
Associate ...............................15
Postdoctoral Fellow ................2
Graduate Student....................2
Research Student ..................15
Secretary .................................2

Past Research and Major Accomplishments
Professor Taketani has led the clinical and basic
research on reproductive endocrinology in Japan.
Especially, he is the distinguished leader in the
research field of endometriosis, and has achieved
many valuable studies. He has also conducted theresearch which went into the broad range in obstetrics and gynecology by his prominent leadership inthe department. There are more than 250 papers
which he directed in these two decades.

Current Research
We have a highly organized infertility clinic, where
every patient is systemically examined and after diagnosis of underlying infertility factor(s) appropriate
treatment is performed following our protocol. Onceit turns out higher level of treatment is necessary,
ART is applied to such cases. We have been engaged
in in vitro fertilization and embryo transfer (IVF-ET)
as a main axis of ART for fifteen years. Conventional
IVF-ET is mainly indicated to cases with tubal factor,
mild male factor, immunological factor or of unexplained infertility factor. In case of severe male factor
or other fertilization disorder intracytoplasmic sperm
injection (ICSI) is performed. Now we have about 300
cases of IVF-ET every year, which conventional IVFET and ICSI share almost equally. The pregnancy rateof conventional IVF-ET is around 25% per embryo

198transfer cycle, which is comparable with that of ICSI.
Other ART techniques such as embryo cryopreservation and assisted zona hatching are also under way.
Total number of delivery cases is 426 per year.
Recently cases of obstetrical emergencies like abruptio
placentae, eclampsia and uterine ruptures transported
from neighboring hospitals have been increasing. Ourservice is an important part of Tokyo Metropolitan
Service System for Maternal Welfare and Perinatal
Medicine.
Primary care for peri/post-menopausal women is
becoming more and more important. We have alreadyestablished the primary care system for women focusing on climacteric syndrome and osteoporosis.
Hormone replacement therapy (HRT) is employed forthe purpose.
In basic research section, a couple of projects asfollows are under way, some of which have alreadyyielded interesting findings; 1) the mechanism of folliculogenesis and follicular apoptosis in the ovary, 2)
the functions of gynecologic hormones such as
gonadotropins and ovarian steroids, 3) the biochemical evaluation of early embryos and establishment of anew procedure of embryo cryopreservation, 4) thegenetic mechanism in gamete formation and development and 5) effect of sex steroid on bone metabolism.

Future Prospects
To improve the pregnancy rate in the infertility
clinic, the basic research on both the embryo and theendometrium, ovarian function and its regulatory
mechanism must be proceed. To take the precautionsin the infertility treatment, the development of thesafe protocol and secure system is also demanded.
The validity of hormone replacement therapy for
managing peri/post-menopausal women is becoming a
subject of discussion. To seek the answer this problem, we are studying on the various protocols in clinical and by experiments.
In the obstetrical field, the researches on the
immunological feto-maternal interaction are going on.

In vivo study of fetal physiology using sheep model
are in progress, expected to provide valuable knowledge for clinical field.

Research Grants
Grant-in-Aid for Scientific Research, Japan Society
for the Promotion of Science: Scientific Research (A)“Mechanism of conception in terms of embryo-maternal interaction” (1999-2001)
Grant-in-Aid for Scientific Research, Japan Society
for the Promotion of Science: Scientific Research (B)“Risk factors associated with progression and recurrence of endometriosis” (2000-2002)
Grant-in-Aid for Scientific Research, Ministry of
Health and Welfare: “Status of endometriosis in Japanin terms of reproductive health” (1998)
Grant-in-Aid for Scientific Research, Ministry of
Health, Labor and Welfare: “Strategy for reproductive
health-keeping of women with menstrual disorders”(1999-2000)
Grant-in-Aid for Scientific Research, Ministry of
Health, Labor and Welfare: “Status of reproductive
health of women with reproductive disorders in thesociety” (2001-2002)

Select Publications (most recent 50 papers)
1. Hiroi H, Momoeda M, Yamauchi N, Abe Y,
Yoshikawa H, Tsutsumi O and Taketani Y. An earlier
menopause as clinical manifestation of granulosa-celltumor: a case report. J Obstet Gynaecol Res 26, 9-12,
2000.
2. Hyodo H, Ishikawa Y, Tsuneyama H, Kashiwase K,
Toyoda C, Uchikawa M, Akaza T, Fujii T, Kozuma S,
Taketani Y and Juji T. New RhD(IVb) identified inJapanese. Vox Sang 79, 116-7, 2000.
3. Hyodo H, Ishikawa Y, Kashiwase K, Ogawa A,
Watanabe Y, Tsuneyama H, Toyoda C, Uchikawa M,
Akaza T, Fujii T, Kozuma S, Taketani Y and Juji T.
Polymorphisms of RhD(Va) and a new RhD(Va)-likevariant found in Japanese individuals. Vox Sang 78,
122-5, 2000.
4. Kamei Y, Takeda Y, Teramoto K, Tsutsumi O,
Taketani Y and Watanabe K. Human NB-2 of thecontactin subgroup molecules: chromosomal localization of the gene (CNTN5) and distinct expression
pattern from other subgroup members. Genomics 69,
113-9, 2000.
5. Koga K, Osuga Y, Tsutsumi O, Okagaki R, Momoeda
M, Yano T, Fujiwara T, Takai Y, Kugu K, Morita Y
and Taketani Y. Increased concentrations of soluble
tumour necrosis factor receptor (sTNFR) I and II inperitoneal fluid from women with endometriosis.
Mol Hum Reprod 6, 929-33, 2000.
6. Koga K, Osuga Y, Tsutsumi O, Momoeda M, Suenaga
A, Kugu K, Fujiwara T, Takai Y, Yano T and Taketani
Y. Evidence for the presence of angiogenin in humanfollicular fluid and the up-regulation of its production
by human chorionic gonadotropin and hypoxia. J
Clin Endocrinol Metab 85, 3352-5, 2000.
7. Kuroda K, Kamei Y, Kozuma S, Kikuchi A, Fujii T,
Unno N, Baba K and Taketani Y. Cephalopagus conjoined twins. Ultrasound Obstet Gynecol 16, 293,
2000.
8. Kuroda K, Kamei Y, Kozuma S, Kikuchi A, Fujii T,
Unno N, Baba K and Taketani Y. Prenatal evaluationof cephalopagus conjoined twins by means of threedimensional ultrasound at 13 weeks of pregnancy.
Ultrasound Obstet Gynecol 16, 264-6, 2000.
9. Matsumi H, Yano T, Osuga Y, Kugu K, Tang X, Xu
JP, Yano N, Kurashima Y, Ogura T, Tsutsumi O, Koji
T, Esumi H and Taketani Y. Regulation of nitricoxide synthase to promote cytostasis in ovarian follicular development. Biol Reprod 63, 141-6, 2000.
10. Matsumoto K, Yoshikawa H, Nakagawa S, Tang X,
Yasugi T, Kawana K, Sekiya S, Hirai Y, Kukimoto I,
Kanda T and Taketani Y. Enhanced oncogenicity ofhuman papillomavirus type 16 (HPV16) variants inJapanese population. Cancer Lett 156, 159-65, 2000.
11. Matsumoto K, Kawana K, Yoshikawa H, Taketani Y,
Yoshiike K and Kanda T. DNA vaccination of micewith plasmid expressing human papillomavirus 6
major capsid protein L1 elicits type-specific antibodies neutralizing pseudovirions constructed in vitro. J
Med Virol 60, 200-4, 2000.
12. Miki A, Fujii T, Ishikawa Y, Hamai Y, Yamashita T,
Tadokoro K, Kozuma S, Juji T and Taketani Y.
Immunotherapy prevents recurrent abortion without
influencing natural killer receptor status. Am J
Reprod Immunol 43, 98-106, 2000.
13. Nakagawa S, Yoshikawa H, Yasugi T, Kimura M,
Kawana K, Matsumoto K, Yamada M, Onda T and
Taketani Y. Ubiquitous presence of E6 and E7 transcripts in human papillomavirus-positive cervical carcinomas regardless of its type. J Med Virol 62, 251-8,
2000.
14. Osuga Y, Koga K, Tsutsumi O, Igarashi T, Okagaki R,
Takai Y, Matsumi H, Hiroi H, Fujiwara T, Momoeda
M, Yano T and Taketani Y. Stem cell factor (SCF)
concentrations in peritoneal fluid of women with orwithout endometriosis. Am J Reprod Immunol 44,
231-5, 2000.
15. Wang Y, Yano T, Kikuchi A, Yano N, Matsumi H,
Ando K, Kasai Y, Watanabe M, Okagaki R, Osuga Y
and Taketani Y. Comparison of the effects of addback therapy with various natural oestrogens onbone metabolism in rats administered a long-acting
gonadotrophin-releasing hormone agonist. J
Endocrinol 165, 467-73, 2000.
16. Yano T, Radulovic S, Osuga Y, Kugu K, Yoshikawa H,
Taketani Y and Schally AV. Inhibition of humanepithelial ovarian cancer cell growth in vitro bysomatostatin analog RC-160. Oncology 59 Suppl 1,
45-9, 2000.
17. Yoshida S, Unno N, Kagawa H, Shinozuka N,
Kozuma S and Taketani Y. Prenatal detection of ahigh-risk group for intrauterine growth restriction

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based on sonographic fetal biometry. Int J Gynaecol
Obstet 68, 225-32, 2000.
18. Yoshikawa H, Jimbo H, Okada S, Matsumoto K,
Onda T, Yasugi T and Taketani Y. Prevalence ofendometriosis in ovarian cancer. Gynecol Obstet
Invest 50 Suppl 1, 11-7, 2000.
19. Hiroi H, Kugu K, Hoshino H, Kozuma S and Taketani
Y. Hyperemesis gravidarum associated with thyrotoxicosis and a past history of an eating disorder.
Arch Gynecol Obstet 265, 228-30, 2001.
20. Hiroi H, Yasugi T, Matsumoto K, Fujii T, Watanabe
T, Yoshikawa H and Taketani Y. Mucinous adenocarcinoma arising in a neovagina using the sigmoid
colon thirty years after operation: a case report. J
Surg Oncol 77, 61-4, 2001.
21. Kanai T, Fujii T, Keicho N, Tokunaga K, Yamashita
T, Hyodo H, Miki A, Unno N, Kozuma S and
Taketani Y. Polymorphism of human leukocyte antigen-E gene in the Japanese population with or without recurrent abortion. Am J Reprod Immunol 45,
168-73, 2001.
22. Kanai T, Fujii T, Unno N, Yamashita T, Hyodo H,
Miki A, Hamai Y, Kozuma S and Taketani Y. Humanleukocyte antigen-G-expressing cells differently modulate the release of cytokines from mononuclear cells
present in the decidua versus peripheral blood. Am J
Reprod Immunol 45, 94-9, 2001.
23. Kanai T, Fujii T, Kozuma S, Yamashita T, Miki A,
Kikuchi A and Taketani Y. Soluble HLA-G influences
the release of cytokines from allogeneic peripheral
blood mononuclear cells in culture. Mol Hum Reprod
7, 195-200, 2001.
24. Kawana K, Kawana Y, Yoshikawa H, Taketani Y,
Yoshiike K and Kanda T. Nasal immunization ofmice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies. Vaccine 19, 1496-502, 2001.
25. Kawana Y, Kawana K, Yoshikawa H, Taketani Y,
Yoshiike K and Kanda T. Human papillomavirus type
16 minor capsid protein l2 N-terminal region containing a common neutralization epitope binds to thecell surface and enters the cytoplasm. J Virol 75,
2331-6, 2001.
26. Koga K, Osuga Y, Tsutsumi O, Yano T, Yoshino O,
Takai Y, Matsumi H, Hiroi H, Kugu K, Momoeda M,
Fujiwara T and Taketani Y. Demonstration of angiogenin in human endometrium and its enhanced
expression in endometrial tissues in the secretory
phase and the decidua. J Clin Endocrinol Metab 86,
5609-14, 2001.
27. Kugu K, Momoeda M, Sharma SS, Osuga Y, Fujiwara
T, Okagaki R, Fukushima H, Yano T, Tsutsumi O
and Taketani Y. Is an elevation in basal follicle-stimulating hormone levels in unexplained infertility predictive of fecundity regardless of age: Endocr J 48,
711-5, 2001.
28. Marumo G, Kozuma S, Ohyu J, Hamai Y, Machida Y,
Kobayashi K, Ryo E, Unno N, Fujii T, Baba K, Okai T,
Takashima S and Taketani Y. Generation of periven-

200

tricular leukomalacia by repeated umbilical cord
occlusion in near-term fetal sheep and its possible
pathogenetical mechanisms. Biol Neonate 79, 39-45,
2001.
29. Minaguchi T, Yoshikawa H, Oda K, Ishino T, Yasugi
T, Onda T, Nakagawa S, Matsumoto K, Kawana K
and Taketani Y. PTEN mutation located only outside
exons 5, 6, and 7 is an independent predictor offavorable survival in endometrial carcinomas. Clin
Cancer Res 7, 2636-42, 2001.
30. Osuga Y, Koga K, Tsutsumi O, Yano T, Kugu K,
Momoeda M, Okagaki R, Suenaga A, Fujiwara T,
Fujimoto A, Matsumi H, Hiroi H and Taketani Y.
Evidence for the presence of keratinocyte growth factor (KGF) in human ovarian follicles. Endocr J 48,
161-6, 2001.
31. Ryo E, Shiotsu H, Takai Y, Tsutsumi O, Okai T,
Taketani Y and Takeuchi Y. Effects of pulsed ultrasound on development and glucose uptake of preimplantation mouse embryos. Ultrasound Med Biol 27,
999-1002, 2001.
32. Ryo E, Yorinaga Y, Nagasaka T, Yoshikawa H and
Taketani Y. Tumor cell spillage to the vaginal cavity
and vaginal stump during the surgery of endometrial
carcinoma. Acta Obstet Gynecol Scand 80, 364-7,
2001.
33. Tsuchiya F, Ikeda K, Tsutsumi O, Hiroi H, Momoeda
M, Taketani Y, Muramatsu M and Inoue S.
Molecular cloning and characterization of mouse
EBAG9, homolog of a human cancer associated surface antigen: expression and regulation by estrogen.
Biochem Biophys Res Commun 284, 2-10, 2001.
34. Uemura H, Unno N, Osuga Y, Momoeda M, Ando K,
Marumo G, Kikuchi A, Fujii T, Kozuma S and
Taketani Y. A movable gestational sac in association
with a myometrial defect. Ultrasound Obstet
Gynecol 18, 675-7, 2001.
35. Xin CY, Matsumoto K, Yoshikawa H, Yasugi T, Onda
T, Nakagawa S, Yamada M, Nozawa S, Sekiya S,
Hirai Y, Shiromizu K, Fujii T and Taketani Y.
Analysis of E6 variants of human papillomavirus
type 33, 52 and 58 in Japanese women with cervicalintraepithelial neoplasia/cervical cancer in relation totheir oncogenic potential. Cancer Lett 170, 19-24,
2001.
36. Yoshida SH, Unno N, Kagawa H, Shinozuka N,
Kozuma S and Taketani Y. Sonographic determination of fetal size from 20 weeks of gestation onward
correlates with birth weight. J Obstet Gynaecol Res
27, 205-11, 2001.
37. Yoshino O, Osuga Y, Koga K, Tsutsumi O, Yano T,
Fujii T, Kugu K, Momoeda M, Fujiwara T, Tomita K
and Taketani Y. Evidence for the expression of interleukin (IL)-18, IL-18 receptor and IL-18 binding protein in the human endometrium. Mol Hum Reprod 7,
649-54, 2001.
38. Fujimoto A, Osuga Y, Yano T, Kusumi M, Kurosawa
T, Fujii T and Taketani Y. Ovarian hyperstimulation
syndrome complicated by peritonitis due to perforated appendicitis. Hum Reprod 17, 966-7, 2002.

39. Hashimoto K, Kato K, Imamura K, Kishimoto A,
Yoshikawa H, Taketani Y and Esumi H. 5-amino-4imidazolecarboxamide riboside confers strong tolerance to glucose starvation in a 5’-AMP-activated protein kinase-dependent fashion. Biochem Biophys Res
Commun 290, 263-7, 2002.
40. Hasumi Y, Mizukami H, Urabe M, Kohno T,
Takeuchi K, Kume A, Momoeda M, Yoshikawa H,
Tsuruo T, Shibuya M, Taketani Y and Ozawa K.
Soluble FLT-1 expression suppresses carcinomatous
ascites in nude mice bearing ovarian cancer. Cancer
Res 62, 2019-23, 2002.
41. Hiroi H, Osuga Y, Tarumoto Y, Shimokama T, Yano
T, Yokota H and Taketani Y. A case of estrogen-producing Brenner tumor with a stromal component asa potential source for estrogen. Oncology 63, 201-4,
2002.
42. Horie K, Tomida A, Sugimoto Y, Yasugi T,
Yoshikawa H, Taketani Y and Tsuruo T. SUMO-1
conjugation to intact DNA topoisomerase I amplifies
cleavable complex formation induced by camptothecin. Oncogene 21, 7913-22, 2002.
43. Kawana K, Yasugi T, Kanda T, Kawana Y, Hirai Y,
Yoshikawa H and Taketani Y. Neutralizing antibodies against oncogenic human papillomavirus as a possible determinant of the fate of low-grade cervicalintraepithelial neoplasia. Biochem Biophys Res
Commun 296, 102-5, 2002.
44. Matsumoto K, Yoshikawa H, Yasugi T, Onda T,
Nakagawa S, Yamada M, Kawana K, Minaguchi T,
Oda K, Hasumi Y and Taketani Y. Distinct lymphatic
spread of endometrial carcinoma in comparison withcervical and ovarian carcinomas. Cancer Lett 180, 839, 2002.
45. Momoeda M, Taketani Y, Terakawa N, Hoshiai H,
Tanaka K, Tsutsumi O, Osuga Y, Maruyama M,
Harada T, Obata K and Hayashi K. Is endometriosis
really associated with pain? Gynecol Obstet Invest 54
Suppl 1, 18-23, 2002.
46. Okada S, Tsuda H, Takarabe T, Yoshikawa H,
Taketani Y and Hirohashi S. Allelotype Analysis of
Common Epithelial Ovarian Cancers with Special
Reference to Comparison between Clear Cell
Adenocarcinoma with Other Histological Types. Jpn
J Cancer Res 93, 798-806, 2002.
47. Osuga Y, Yano T, Kugu K, Koga K, Fukuoka K,
Matsumi H, Wada O, Kikuchi A, Tsutsumi O and
Taketani Y. Effects of gonadotropin-releasing hormone analog treatment on skin condition. Gynecol
Endocrinol 16, 57-61, 2002.
48. Tang X, Yano T, Osuga Y, Matsumi H, Yano N, Xu J,
Wada O, Koga K, Kugu K, Tsutsumi O, Schally AV
and Taketani Y. Cellular mechanisms of growth inhibition of human epithelial ovarian cancer cell line by
LH-releasing hormone antagonist Cetrorelix. J Clin
Endocrinol Metab 87, 3721-7, 2002.
49. Xu J, Osuga Y, Yano T, Morita Y, Tang X, Fujiwara
T, Takai Y, Matsumi H, Koga K, Taketani Y and
Tsutsumi O. Bisphenol A induces apoptosis and G2-

to-M arrest of ovarian granulosa cells. Biochem
Biophys Res Commun 292, 456-62, 2002.
50. Zhang SQ, Kozuma S, Tanaka M, Ling D, Kitano Y,
Fujii T, Baba K and Taketani Y. Studies on fetal forelimb movements by using a wrist actigraph in sheep.
Psychiatry Clin Neurosci 56, 283-4, 2002.

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Department of
Gynecologic Surgery
Outline and Research Objectives
Our department was established for development of effective and safe gynecologic surgery on the basis of knowledge in reproductive medicine and gynecologic oncology.

Faculties and Students
Professor and Chair: Osamu Tsutsumi, MD, PhD (from2001)
Associate Professor: Tetsu Yano
Lecturer:
Osamu Nishii
Tomoyuki Fujii
Associate: ................................2
Postdoctoral Fellow: ...............2
Graduate Student:...................2
Research Student: ...................5
Secretary: ................................2

Past Research and Major Accomplishments
Professor Tsutsumi has been very actively working
on both clinical and basic research in our department
even before becoming Professor in 2001. In the clinical field, he conducted endoscopic surgery as the first
person in gynecology. As for the basic research, many
achievements were left so far in the embryogenesis,
the genetics and the reproductive endocrinology.

Current Research
For the benign gynecological disorders, we havebeen constantly trying to minimize surgical invasion
to patients as much as possible. With both of wellequipped instruments and well-trained expertise,
more than 90% of surgeries for benign gynecologicaldisorders are operated endoscopically, which make atotal of 300 cases per year. On the other hand, various
projects concerning treatment of gynecological malignancies and sexually transmitted viral infections areon-going. To improve the prognosis of gynecologicalmalignancy, we are conducting the studies, including
1) Prognostic significance of pelvic and paraaortic
lumphnode metastasis in the uterine cervical cancer,2) application of chemotherapy (BLM + VCR + MMC+ CDDP) for advanced or recurrent cervical cancer, 3)
incidence and distribution of PLN and PALN metastasis in endometrial cancer, 4) relationship between thepresence of estrogen and progesterone receptor andclinical course in endometrial cancer, 5) development202

of optimal surgical procedure for advanced ovariancancer, 6) impacts of aggressive debulking (including
bowel resection) on the prognosis of advanced ovariancancer, 7) analysis of long term prognosis of ovariancancer patients treated with paclitaxel containing
chemotherapy, 8) analysis of adverse effects of CDDPbased chemotherapy, focused on nephrotoxicity andneurotoxicity, 9) effect of intermittent consolidation
chemotherapy for advanced ovarian cancer, 10) evaluation of sensitivity and specificity of serum CA125level assay and ultrasonographic follow-up for diagnosis of recurrent ovarian cancer, 11) trans-arterial
chemotherapy for parenchymal liver metastasis ofovarian cancer, 12) estimation of effects of a combination chemotherapy (hydroxyurea + etoposide + DTIC)
for uterine sarcomas, 13) cohort study of low-grade
CIN.
In basic research section, the studies are on goingon the effect of endocrine disrupters on the reproductive system, embryogenesis and oncogenesis.

Future Prospects
As well as proceeding the studies mentioned
above, we are starting the project on developing vaccine against HPVs, using neutralizing epitope of HPV16 capsid proteins L1 and L2 (L1/L2 capsids).

Research Grants
1. Grant-in-Aid for Core Research for Evolutional
Science and Technology, Japan Science andThechnology Corporation: “Effect of endocrine disrupters on reproductive functions ” (1998-2003)
2. Grant-in-Aid for Scientific Research, Japan Society
for the Promotion of Science: Scientific Research (B)“Effect of endocrine disrupters on reproductive functions” (1999-2001)
3. Grant-in-Aid for Scientific Research, Japan Society
for the Promotion of Science: Scientific Research (B)“Effect of endocrine disrupters on reproductive functions” (2002-2004)
4. Grant-in-Aid for Scientific Research, Ministry of
Health, Labor and Welfare: “Effect of endocrine disrupters on reproductive health” (1998-2000)

5. Grant-in-Aid for Scientific Research, Ministry of
Health, Labor and Welfare: “Effect of endocrine disrupters on reproductive health” (2001-2002)

Select Publications
1. Tsutsumi O, Kurachi H and Oka T. A physiologicalrole of epidermal growth factor in male reproductivefunction. Science 233, 975-7, 1986.
2. Tsutsumi O, Kubota Y and Oka T. Effect of sialoadenectomy, treatment with epidermal growth factor(EGF) antiserum and replacement of EGF on the epidermis in mice. J Endocrinol 113, 193-7, 1987.
3. Tsutsumi O and Oka T. Epidermal growth factor
deficiency during pregnancy causes abortion in mice.
Am J Obstet Gynecol 156, 241-4, 1987.
4. Tsutsumi O, Tsutsumi A and Oka T. Importance of
epidermal growth factor in implantation and growthof mouse mammary tumor in female nude mice.
Cancer Res 47, 4651-3, 1987.
5. Tsutsumi O, Tsutsumi A and Oka T. A possible
physiological role of milk epidermal growth factor inneonatal eyelid opening. Am J Physiol 252, R376-9,
1987.
6. Tsutsumi O, Tsutsumi A and Oka T. Epidermal
growth factor-like, corneal wound healing substancein mouse tears. J Clin Invest 81, 1067-71, 1988.
7. Tsutsumi O, Yano T, Satoh K, Mizuno M and Kato T.
Studies of hexokinase activity in human and mouse
oocyte. Am J Obstet Gynecol 162, 1301-4, 1990.
8. Tsutsumi O, Satoh K, Taketani Y and Kato T.
Determination of enzyme activities of energy metabolism in the maturing rat oocyte. Mol Reprod Dev
33, 333-7, 1992.
9. Sadatsuki M, Tsutsumi O, Yamada R, Muramatsu M
and Taketani Y. Local regulatory effects of activin A
and follistatin on meiotic maturation of rat oocytes.
Biochem Biophys Res Commun 196, 388-95, 1993.
10. Sadatsuki M, Tsutsumi O, Sakai R, Eto Y, Hayashi N
and Taketani Y. Presence and possible function ofactivin-like substance in human follicular fluid. Hum
Reprod 8, 1392-5, 1993.
11. Tsutsumi O, Iida T, Hakuno N, Sadatsuki M, Okai T,
Taketani Y, Nagafuchi S and Nakahori Y. Y chromosome analysis and laparoscopic surgery in XY puregonadal dysgenesis: a case report and a review of literature. Asia Oceania J Obstet Gynaecol 19, 95-9,
1993.
12. Tsutsumi O, Taketani Y and Oka T. The uterine
growth-promoting action of epidermal growth factor
and its function in the fertility of mice. J Endocrinol
138, 437-44, 1993.
13. Tsutsumi O, Taketani Y and Oka T. Evidence for the
involvement of epidermal growth factor in fertility
decline in aging female mice. Horm Res 39 Suppl 1,
32-6, 1993.
14. Ayabe T, Tsutsumi O and Taketani Y. Hexokinase
activity in mouse embryos developed in vivo and invitro. Hum Reprod 9, 347-51, 1994.

15. Morita Y, Tsutsumi O and Taketani Y. In vitro treatment of embryos with epidermal growth factor
improves viability and increases the implantation
rate of blastocysts transferred to recipient mice. Am
J Obstet Gynecol 171, 406-9, 1994.
16. Tsutsumi O, Iida T, Taketani Y, Sugase M, Nakahori
Y and Nakagome Y. Intact sex determining region Y(SRY) in a patient with XY pure gonadal dysgenesis
and a twin brother. Endocr J 41, 281-5, 1994.
17. Tsutsumi O, Yano T and Taketani Y.
Phosphofructokinase activity as a measure of maturation of rat oocytes developed in vivo and in vitro.
Horm Res 41 Suppl 1, 63-7, 1994.
18. Morita Y, Tsutsumi O and Taketani Y. Successfultreatment of catamenial pneumothorax with danazol. Int J Gynaecol Obstet 51, 263-4, 1995.
19. Tsutsumi O, Iida T and Taketani Y. Laparoscopic
surgery and DNA analysis in patients with XY puregonadal dysgenesis. J Obstet Gynaecol 21, 67-74,
1995.
20. Morita Y, Tsutsumi O, Kuramochi K, Momoeda M,
Yoshikawa H and Taketani Y. Successful laparoscopic management of primary abdominal pregnancy.
Hum Reprod 11, 2546-7, 1996.
21. Takai Y, Ogawara M, Tomono Y, Moritoh C, ImajohOhmi S, Tsutsumi O, Taketani Y and Inagaki M.
Mitosis-specific phosphorylation of vimentin by protein kinase C coupled with reorganization of intracellular membranes. J Cell Biol 133, 141-9, 1996.
22. Tsutsumi O, Iida T, Nakahori Y and Taketani Y.
Analysis of the testis-determining gene SRY in
patients with XY gonadal dysgenesis. Horm Res 46
Suppl 1, 6-10, 1996.
23. Tsutsumi O and Yoshimura Y. Sex differentiationand ovarian function. An overview. Horm Res 46
Suppl 1, 1-5, 1996.
24. Kawana K, Yoshikawa H, Yokota H, Onda T,
Nakagawa K, Tsutsumi O and Taketani Y. Successfultreatment of brain metastases from ovarian cancer
using gamma-knife radiosurgery. Gynecol Oncol 65,
357-9, 1997.
25. Morita Y, Tsutsumi O and Taketani Y. Successful
hormonal treatment of pulmonary parenchymal
endometriosis. Int J Gynaecol Obstet 59, 61-3, 1997.
26. Morita Y, Tsutsumi O, Momoeda M and Taketani Y.
Cornual pregnancy successfully treated laparoscopically with fibrin glue hemostasis. Obstet Gynecol 90,
685-7, 1997.
27. Sadatsuki M, Kaneko M and Tsutsumi O. Expectant
management and methotrexate treatment of persistent ectopic pregnancy following laparoscopic salpingectomy. Int J Gynaecol Obstet 59, 49-51, 1997.
28. Tsutsumi O, Ando K and Momoeda M. Ruptured
isthmal pregnancy following laparoscopic salpingostomy in the ipsilateral tube. Int J Gynaecol Obstet
57, 187-9, 1997.
29. Uechi H, Tsutsumi O, Morita Y and Taketani Y.
Cryopreservation of mouse embryos affects laterembryonic development possibly through reduced203expression of the glucose transporter GLUT1. Mol
Reprod Dev 48, 496-500, 1997.
30. Takai Y, Tsutsumi O, Harada I, Fujii T, Kashima T,
Kobayashi K, Toda T and Taketani Y. Prenatal diagnosis of Fukuyama-type congenital muscular dystrophy by microsatellite analysis. Hum Reprod 13, 3203, 1998.
31. Tsutsumi O, Uechi H, Sone H, Yonemoto J, Takai Y,
Momoeda M, Tohyama C, Hashimoto S, Morita M
and Taketani Y. Presence of dioxins in human follicular fluid: their possible stage-specific action on thedevelopment of preimplantation mouse embryos.
Biochem Biophys Res Commun 250, 498-501, 1998.
32. Igarashi T, Osuga U, Tsutsumi O, Momoeda M,
Ando K, Matsumi H, Takai Y, Okagaki R, Hiroi H,
Fujiwara O, Yano T and Taketani Y. Expression of
Ah receptor and dioxin-related genes in human uterine endometrium in women with or without
endometriosis. Endocr J 46, 765-72, 1999.
33. Okagaki R, Osuga Y, Momoeda M, Tsutsumi O and
Taketani Y. Laparoscopic findings after ultrasoundguided transvaginal ethanol sclerotherapy for ovarian
endometrial cyst. Hum Reprod 14, 270, 1999.
34. Takai Y, Tsutsumi O, Momoeda M, Osuga Y,
Sadatsuki M, Kaibara M and Taketani Y. Non-functioning pituitary tumour after long-term treatment
with gonadotrophin-releasing hormone agonists in apatient with vaginal agenesis who underwent neovaginoplasty and cauterization of endometriosis
under laparoscopy. Hum Reprod 14, 2661-4, 1999.
35. Uechi H, Tsutsumi O, Morita Y, Takai Y and
Taketani Y. Comparison of the effects of controlledrate cryopreservation and vitrification on 2-cellmouse embryos and their subsequent development.
Hum Reprod 14, 2827-32, 1999.
36. Maruyama M, Osuga Y, Momoeda M, Yano T,
Tsutsumi O and Taketani Y. Pregnancy rates after
laparoscopic treatment. Differences related to tubal
status and presence of endometriosis. J Reprod Med
45, 89-93, 2000.
37. Morita Y, Nishii O, Kido M and Tsutsumi O.
Parvovirus infection after laparoscopic hysterectomy
using fibrin glue hemostasis. Obstet Gynecol 95,
1026, 2000.
38. Takai Y, Tsutsumi O, Ikezuki Y, Hiroi H, Osuga Y,
Momoeda M, Yano T and Taketani Y. Estrogen
receptor-mediated effects of a xenoestrogen, bisphenol A, on preimplantation mouse embryos. Biochem
Biophys Res Commun 270, 918-21, 2000.
39. Takai Y, Tsutsumi O, Harada I, Morita Y, Momoeda
M, Fukushima Y and Taketani Y. A case of XY puregonadal dysgenesis with 46,XYp-/47,XXYp- karyotype whose gonadoblastoma was removed laparoscopically. Gynecol Obstet Invest 50, 166-9, 2000.
40. Takeuchi T and Tsutsumi O. Basal leptin concentrations in women with normal and dysfunctional ovarian conditions. Int J Gynaecol Obstet 69, 127-33,
2000.
41. Tsutsumi O, Momoeda M, Takai Y, Ono M and
Taketani Y. Breast-fed infants, possibly exposed to204

dioxins in milk, have unexpectedly lower incidence
of endometriosis in adult life. Int J Gynaecol Obstet
68, 151-3, 2000.
42. Fujimoto A, Osuga Y, Tsutsumi O, Fujii T, Okagaki R
and Taketani Y. Successful laparoscopic treatment of
ileo-cecal endometriosis producing bowel obstruction. J Obstet Gynaecol Res 27, 221-3, 2001.
43. Morita Y, Tsutsumi O and Taketani Y. Regulatory
mechanisms of female germ cell apoptosis during
embryonic development. Endocr J 48, 289-301, 2001.
44. Osuga Y, Tsutsumi O, Fujiwara T, Kugu K, Fujimoto
A and Taketani Y. Usefulness of long-jaw forceps inlaparoscopic cornual resection of interstitial pregnancies. J Am Assoc Gynecol Laparosc 8, 429-32, 2001.
45. Takai Y, Tsutsumi O, Ikezuki Y, Kamei Y, Osuga Y,
Yano T and Taketan Y. Preimplantation exposure tobisphenol A advances postnatal development.
Reprod Toxicol 15, 71-4, 2001.
46. Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y and
Taketani Y. Determination of bisphenol A concentrations in human biological fluids reveals significant
early prenatal exposure. Hum Reprod 17, 2839-41,
2002.
47. Kurosawa T, Hiroi H, Tsutsumi O, Ishikawa T,
Osuga Y, Fujiwara T, Inoue S, Muramatsu M,
Momoeda M and Taketani Y. The activity of bisphenol A depends on both the estrogen receptor subtype
and the cell type. Endocr J 49, 465-71, 2002.
48. Nakagawa S, Koga K, Kugu K, Tsutsumi O and
Taketani Y. The evaluation of the sentinel node successfully conducted in a case of malignant melanomaof the vagina. Gynecol Oncol 86, 387-9, 2002.49.
Osuga Y, Koga K, Tsutsumi O, Yano T, Maruyama M,
Kugu K, Momoeda M and
49. Osuga Y, Koga K, Tsutsumi O, Yano T, Maruyama M,
Kugu K, Momoeda M and Taketani Y. Role oflaparoscopy in the treatment of endometriosis-associated infertility. Gynecol Obstet Invest 53 Suppl 1,
33-9, 2002.
50. Takeuchi T and Tsutsumi O. Serum bisphenol a concentrations showed gender differences, possibly
linked to androgen levels. Biochem Biophys Res
Commun 291, 76-8, 2002.

Department of Pediatrics /Developmental Pediatrics
Outline and Research Objectives
Department of Pediatrics was founded in 1889 and continued its activity for 113 years.
This is the oldest Pediatrics and has been the leader of Pediatrics in Japan. Many pediatricians received the training in our department and went to all over and out of Japan andworked as a leader of pediatrician in a lot of Japanese Medical School in the University, central and local hospitals and clinics.
The health problems of children and youth have changed historically in Japan. In thelate 19th century, one of five children died as infectious diseases such as dysentery, pneumonia, diphtheria, and whooping cough. Now, few children die due to the diseases. The leading causes of death for children are perinatal problems for babies, injuries, congenital anomalies, malignant neoplasms, and congenital heart diseases. Many of these diseases havegenetic background in their pathogenesis. Thus, the research objectives have greatlychanged. Now, they are to clarify the molecular pathogenesis of these difficult diseases andto find safe and effective therapies for them and to find the way to promote the body andheart health of children in our Pediatrics.
Pediatrics covers all the issues in children and youth. Thus, our department studies
almost all the issues about children and youth. Now, we have six active study groups suchas Nephrology, Hematology and Oncology, Cardiology, Immunology and Allergy,
Endocrinology and Metabolism, and Neurology. The main subjects of the research are 1)
Identification of the molecular pathogenesis of renal tubular disorders, 2) Clarification andcharacterization of the genes which cause leukemia and neuroblastoma, 3) Role of hemodynamic factors on pulmonary hypertension complicated with congenital heart diseases, 4)
Epidemiological survey and nationwide registry of primary immunodeficiency diseases andthe efficacy of immunotherapy for cancer using peripheral dendritic cells, 5) Molecular andfunctional analysis of the genes for inherited endocrine and metabolic diseases, and 6)
Pathogenesis of peroxisome biogenesis disorders. The details of the research projects aredescribed bellow.
We have been the local registration center for children’s cancer in Kantou-district. This
helps and promotes the basic research in the fields of Hematology and Oncology in ourPediatrics.

Faculties and Students
Professor and Chair Takashi Igarashi, M.D., Ph.D. (2000-)
Associate Professors Tsutomu Iwata, M.D., Ph.D.
Lecturers
Yasuhide Hayashi, M.D., Ph.D.
Masaru Takamizawa, M.D., Ph.D.
Hitoshi Kato, M.D., Ph.D.
Takashi Sekine, M.D., Ph.D.
Yoichi Sakakihara, M.D., Ph.D.
Associates .............................15
Postdoctoral Fellow ................4
Graduate student ..................18
Research student.....................3
Secretary .................................3

Past Research and Major Accomplishments
Nephrology
1) Molecular pathogenesis of Dent’s disease, proximal renal tubular acidosis and renal hypouricemia:
feedback from bench to clinics.
2) The mechanisms of post-diarrheal hemolytic uremic syndrome (HUS).
3) Molecular identification of the proximal tubulartransporters that excrete drugs from the kidney.
Hematology and Oncology
1) Identification of HOXD11, HOXA13 and HOXC11
genes as partner genes of NUP98 in t (2;11)-, t(7;11)- and t (11;12)- acute myeloid leukemias.
2) Molecular analysis of tumor suppressor genes inneuroblastoma.

205

Cardiology
1) Role of hemodynamic factors on pulmonary
hypertension complicated with congenital heartdiseases.
2) Development of coronary artery from cardiac neural crest cells.
3) Effect of epoprostenol on severe port pulmonary
hypertension complicated with biliary atresia.
4) Historical review of Kawasaki disease: When
Kawasaki disease started in Japan?
Immunology and Allergy
1) Epidemiological survey and nationwide registry ofprimary immunodeficiency diseases.
2) The efficacy of immunotherapy for cancer using
peripheral dendritic cells.
3) The effective and safe simultaneous administration of several vaccines in a short period of time
before liver transplantation and their administration under immunosuppressive conditions after
transplantation.
4) Prospective study of atopic status in infants of thecohort in Tokyo, Japan.
5) Epidemiology of bronchial asthma among children
in rural and urban area in Bangladesh.
Endocrinology and Metabolism
1) Molecular and functional analysis of the genes forseveral inherited endocrine and metabolic diseases
including the glutamate dehydrogenase gene incongenital hyperinsulinism hyperammonemia
syndrome, glucose-6-phophatase gene in glycogenstorage disease type 1a, CREB-binding protein in
Rubinstein-Taybi syndrome, hepatocyte nuclear
factor-1b in maturity-onset diabetes of the young
type 5.
Neurology
1) Pathogenesis of peroxisome biogenesis disorders:Altered lipid metabolism in peroxisome-defective
cells.
2) The genetic analysis of Japanese patients withspinal muscular atrophy.
3) The analysis of pathophysiology of epileptic syndrome and higher brain function inchildren by magnetoencephalography.
4) Development of communication tool for patientswith spinal muscular atrophy.

Current Research
Nephrology
1) Molecular and functional analysis of various ion
transporters such as Cl channels, Na +/HCO3 cotransporter, URAT1, barttin, and H+-ATPase.

2062) Molecular and functional analysis of LMX1B in
nail patella syndrome and hepatocyte nuclear factor-1 β in MODY5.
3) The mechanisms of post-diarrheal HUS.
Hematology and Oncology
1) Identification of HOXD11, HOXA13 and HOXC11
genes as partner genes of NUP98 in t (2;11)-, t(7;11)- and t (11;12)- acute myeloid leukemias.
2) Molecular analysis of tumor suppressor genes inneuroblastoma.
Cardiology
1) Role of hemodynamic factors on pulmonary
hypertension complicated with congenital heartdiseases.
2) Development of coronary artery from cardiac neural crest cells.
Immunology and Allergy
1) Epidemiological survey and nationwide registry ofprimary immunodeficiency diseases.
2) The efficacy of immunotherapy for cancer using
peripheral dendritic cells.
3) Prospective study of atopic status in infants of thecohort in Tokyo, Japan.
Epidemiology of bronchial asthma among children
in rural and urban area in Bangladesh.
5) Analysis of the function of basophils in allergic
diseases.
Endocrinology and Metabolism
1) Molecular and functional analysis of the genes forseveral inherited endocrine and metabolic diseases
including the glutamate dehydrogenase gene incongenital hyperinsulinism hyperammonemia
syndrome, glucose-6-phophatase gene in glycogenstorage disease type 1a, CREB-binding protein in
Rubinstein-Taybi syndrome, hepatocyte nuclear
factor-1b in maturity-onset diabetes of the young
type 5.
Neurology
1) Pathogenesis of peroxisome biogenesis disordersAltered lipid metabolism in peroxisome-defective
cells.
2) The analysis of pathophysiology of epileptic syndrome and higher brain function in children bymagnetoencephalography.
3) Development of communication tool for patientswith spinal muscular atrophy.

Future Prospects
Nephrology
1) Molecular and functional analysis of various renaltransporter disorders.
2) Identification of the genes for minimal change
nephrotic syndrome.
Hematology and Oncology
1) Identification and characterization of HOXD11,
HOXA13 and HOXC11 genes as partner genes of
NUP98 in t (2;11)-, t (7;11)- and t (11;12)- acute
myeloid leukemias.
2) Molecular analysis of tumor suppressor genes inneuroblastoma.
Cardiology
1) Role of hemodynamic factors on pulmonary
hypertension complicated with congenital heartdiseases.
2) Development of coronary artery from cardiac neural crest cells.
Immunology and Allergy
1) Epidemiological survey and nationwide registry ofprimary immunodeficiency diseases.
2) The efficacy of immunotherapy for cancer using
peripheral dendritic cells.
3) Prospective study of atopic status in infants of thecohort in Tokyo, Japan.
4) Epidemiology of bronchial asthma among children
in rural and urban area in Bangladesh.
5) Analysis of the function of basophils in allergic
diseases.
Endocrinology and Metabolism
1) Mutational and functional analysis of the genes
for several inherited endocrine and metabolic diseases.
Neurology
1) Pathogenesis of peroxisome biogenesis disordersAltered lipid metabolism in peroxisome-defective
cells.
2) The analysis of higher brain function by magnetoencephalography.
3) Development of communication tool for patientswith spinal muscular atrophy.
Research Grants (5 selections)
1) Igarashi T: Early diagnosis, management and treatment of intractable kidney and urinary tract diseases (Kodomokatei-H13-011). Ministry of Health,
Labor and Welfare, 16,000,000 yen in 2001-2002.

2) Iwata T: The association between Urbanization
and Childhood Asthma in Bangladesh.Nissan
Science Foundation, 4,500,000 yen in 2000-2001,
3,600,000 yen in 2002-2003.
3) Hayashi Y: Analysis of molecular mechanism ofcancer formation due to translocation gene byusing genome information and expression profile(B-2-14370242). Ministry of Education Science,
8,800,000 yen in 2002-2004.
4) Hayashi Y: Gene analysis and diagnosis of
intractable childhood leukemia and secondary
leukemia and their application to the clinics.
Ministry of Health, Labor and Welfare, 7,400,000
yen in 1996-2002.
5) Kato H: Role of hemodynamic factors on pulmonary hypertension complicated with congenital
heart diseases (No. 09470177). Ministry of Health,
Labor and Welfare, 5,300,000 yen in 1999-2001.

Select Publications
Nephrology
1. Sekine T, Cha SH, Hosoyamada M, Kanai Y,
Watanabe N, Huruta Y, Hukuda K, Igarashi T, Endou
H: Cloning, functional characterization and localization of a rat renal Na+-dicarboxylate transporter. Am
J Physiol 275 (Renal Physiol. 44): F298-F305, 1998
2. Igarashi T, Günter W, Sekine T, Inatomi J, Shiraga H,
Takahashi S, Suzuki J, Tsuru N, Yanagihara T,
Shimazu M, Jentsch TJ, Thakker RV: Functional
characterization of renal chloride channel, CLCN5,
mutations associated with Dent’s Japan disease. Kidney
Int 54:1850-1856, 1998
3. Igarashi T, Inatomi J, Sekine T, Cha SH, Kanai Y,
Kunimi M, Tsukamoto K, Satoh H, Shimadzu M,
Tozawa F, Mori T, Shiobara M, Seki G, Endou H:
Mutations in SLC4A4 cause permanent isolated
proximal renal tubular acidosis with ocular abnormalities. Nature Genet 23:264-266, 1999
4. Igarashi T, Inatomi J, Wake A, Takamizawa M,
Katayama H, Iwata T: Failure of pre-diarrheal antibiotics to prevent hemolytic uremic syndrome in serologically-proven Escherichia coli 0157:H7 gastrointestinal infection. J Pediatr 135: 768-769, 1999
5. Igarashi T, Inatomi J, Ohara T, Kuwahara T,
Shimadzu M, Thakker RV: Clinical and genetic studies of CLCN5 mutations in Japanese families with
Dent’s disease. Kidney Int 58: 520-527, 2000
6. Igarashi T, Inatomi J, Sekine T, Seki G, Shimadzu M,
Tozawa F, Takeshima Y, Takumi T, Takahashi T,
Yoshikawa N, Nakamura H, Endou H: Novel nonsense mutation in the Na+/HCO3- cotransporter gene
(SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. J
Am Soc Nephrol 12: 713-718, 2001
7. Usui T, Hara M, Satoh H, Moriyama N, Kagaya H,
Amano S, Oshika T, Ishii Y, Ibaraki N, Hara C,
Kunimi M, Noiri E, Tsukamoto K, Inatomi J,

207

Kawakami H, Endou H, Igarashi T, Goto A, Fujita T,
Araie M, Seki G: Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis. J
Clin Invest 108: 107-115, 2001
8. Kuwahara M, Iwai K, Ooeda T, Igarashi T, Ogawa E,
Katsushima Y, Shinbo I, Uchida S, Terada Y,
Fujiwara TM, Arthus MF, Lonergan M, Bicher DG,
Marumo F: Three families with autosomal dominant
nephrogenic diabetes insipidus caused by aquaporin2 mutations in the C-terminus. Am J Human
Genetics 69: 738-748, 2001
9. Norden AGW, Lapsley M, Christensen EI, Igarashi T,
Matsuyama T, Shiraga H, Kelleher CL, Lee P,
Scheinman SJ, Thakker RV, Unwin RJ, Verroust P,
Wrong O, Moestrup S: Urinary megalin deficiency
implicates abnormal tubular endocytic receptor trafficking in the Fanconi syndrome. J Am Soc Nephrol
13: 125-133, 2002
10. Chandler WL, Jelacic S, Boster D, Ciol M, Watkins S,
Igarashi T, Tarr PI: Prothrombotic coagulation abnormalities preceding the hemolytic uremic syndrome.
New Eng J Med 246: 23-32, 2002
11. Enomoto A, Kimura H, Chairoungdua A, Shigeta Y,
Jutabha P, Cha SH, Hosoyamada M, Takeda M,
Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T,
Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y,
Endou H: Molecular identification of arenal/urate/anion exchanger that regulates bloodurate levels. Nature 417: 447-452, 2002

Hematology and Oncology
12. Futatani T, Miyawaki T, Tsukada S, Hashimoto S,
Kunikata T, Arai S, Kurimoto M, Niida Y, Matsuoka
H, Sakiyama Y, Iwata T, Tsuchiya S, Tatsuzawa O,
Yoshizaki K, Kishimoto T: Deficient expression of
Bruton’s tyrosine kinase in monocytes from X-linked
agammaglobulinemia as evaluated by a flow cytometric analysis and its clinical application to carrier
detection. Blood 15:595-602, 1998
13. Ishiguro A, Ishikita T, Shimbo T, Matsubara K, Baba
K, Hayashi Y, Naritaka S, Nakahata T: Elevation ofserum thrombopoietin precedes thrombocytosis in
Kawasaki disease. Thromb Haemost 79:1096-1100,
1998
14. Kitabayashi I, Ida K, Morohoshi F, Yokoyama A,
Mitsuhashi N, Shimizu K, NomuraN, Hayashi Y,
Ohki M: The AML1-MTG8 leukemic fusion protein
forms a complex with A novel member of the MTG8
(ETO/CDR) family, MTGR1. Mol Cell Biol 18:846858, 1998
15. Miyagawa K, Kent J, Moore A, Charlieu JP, Little
MH, Williamson KA, Kelsey A, Brown KW, Hassam
S, Briner J, Hayashi Y, Hirai H, Yazaki Y, vanHeyningen V, Hastie ND: Loss of WT1 function
leads to ectopic myogenesis in Wilms’ tumour. Nat
Genet 18:15-17, 1998
16. Taki T, Shibuya N, Taniwaki M, Hanada R,
Morishita K, Bessho F, Yanagisawa M, Hayashi Y:
ABI-1, a human homolog to mouse Abl-interactor 1,

208

fuses the MLL gene in acute myeloid leukemia witht(10;11)(p11.2;q23). Blood 92:1125-1130, 1998
17. Takita J, Hayashi Y, Nakajima T, Adachi J, Tanaka T,
Yamaguchi N, Ogawa Y, Hanada R, Yamamoto K,
Yokota J: The p16 (CDKN2A) gene is involved in thegrowth of neuroblastoma cells and its expression isassociated with prognosis of neuroblastoma patients.
Oncogene 17:3137-3143, 1998
18. Yamamoto K, Hanada R, Kikuchi A, Ichikawa M,
Aihara T, Oguma E, Moritani T, Shimanuki Y,
Tanimura M, Hayashi Y: Spontaneous regression of
localized neuroblastoma detected by mass screening.
J Clin Oncol 16:1265-1269, 1998
19. Bessho F: Incidence of neuroblastoma. The Lancet
353: 70, 1999
20. Kawa K, Ohnuma N, Kaneko M, Yamamoto K, Etoh
T, Mugishima H, Ohira M, Yokoyama J, Bessho F,
Honna T, Yoshizawa J, Nakada K, Iwafuchi M,
Nozaki T, Mimaya J, Sawada T, Nakamura T, Miyata
H, Yamato K, Tsuchida Y: Long- term survivors ofadvanced neuroblastoma with MYCN amplification ;a report of 19 patients surviving disease-free formore than 66 months. J Clin Oncol 17:3216-3220,
1999
21. Taki T, Ohnishi H, Shinohara K, Sako M, Bessho F,
Yanagisawa M, Hayashi Y: AF17q25, a putative
septin family gene, fuses the MLL gene in acute
myeloid leukemia with t (11; 17)(q23; q25). Cancer
Res 59: 4261-4265, 1999
22. Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa
M, Hayashi Y: AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Pro Nat
Acad Sci USA 96: 14535-14540, 1999
23. Hayashi Y, Honma Y, Niitsu N, Taki T, Bessho F,
Sako M, Mori T, Yanagisawa M, Tsuji K, Nakahata T:
SN-1, a novel leukemic cell line with t(11:16)(q23:p13): Myeloid characteristic and resistance to retinoids and vitamin D3. Cancer Res
60:1139-1145, 2000
24. Toyoda Y, Manabe A, Tsuchida M, Hanada R, Ikuta
K, Okimoto Y, Ohara A, Ohkawa Y, Mori T,
Ishimoto K, Satoh T, Kaneko T, Maeda M,
Koike K, Shitara T, Hoshi Y, Hosoya R, Tsunematsu
Y, Bessho F, Nakazawa S, Saito T for the Acute
Lymphoblastic Leukemia Committee of the Tokyo
Children’s Cancer Study Group: Six months of maintenance chemotherapy after intensified treatment for
acute lymphoblastic leukemia of childhood. J Clin
Onco 18:1508-1516, 2000
25. Chen YZ, Soeda E, Yang HW, Takita J, Chai L, Horii
A, Inazawa J, Ohki M, Hayashi Y: Homozygous deletion in a neuroblastoma cell line defined by a highdensity STS map spanning human chromosome
band 1p36. Genes Chromosomes & Cancer 31:326332, 2001
26. Jamal R, Taketani T, Taki T, Bessho F, Hongo T,
Hamaguchi H, Horiike S, Taniwaki M, Hanada R,
Nakamura H, Hayashi Y: Co-duplication of the MLL
and FLT3 gene in patients with acute myeloid

leukemia. Genes Chromosomes & Cancer 31: 187190, 2001
27. Niitsu N, Hayashi Y, Honma Y: Downregulation of
MLL-CBP fusion gene expression is associated withdifferentiation of SN-1 cells with t (11;16)(q23;p13).
Oncogene 20: 375-384, 2001
28. Shibuya N, Taki T, Mugishima H, Chin M, Tsuchida
M, Sako M, Kawa K, Ishii E, Miura I, Yanagisawa M,
Hayashi Y: t (10; 11)-acute leukemias with MLLAF10 and MLL-ABI1 chimeric transcripts; specificexpression patterns of ABI1 gene in leukemia andsolid tumor cell lines. Genes Chromosomes & Cancer
32:1-10, 2001
29. Takita J, Yang HW, Chen YY, Hanada R, Yamamoto
K, Teitz T, Kidd V, Hayashi Y: Allelic imbalance onchromosome 2q and alterations of the caspase 8 genein neuroblastoma. Oncogene 19:4424-4432, 2001
30. Tatsumi K, Taki T, Taniwaki M, Nakamura H,
Taguchi J, Chen YZ, Bessho F, Yanagisawa M,
Hayashi Y: The CDCREL1 gene fused to MLL in denovo acute myeloid leukemia with t(11;22)(q23;q11.2) and its frequent expression in
myeloid leukemia cell lines. Genes Chromosomes &Cancer 30:230-235, 2001
31. Yang HW, Chen YZ, Takita J, Soeda E, Piao HY,
Hayashi Y: Genomic structure andmutational analysis of the human KIF1B gene which is homozygously
deleted inneuroblastoma at chromosome 1p36.2.
Oncogene 16:5075-5083, 2001
32. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T,
Takeda S, Yang HW, Terada S, Nakata T, Takei Y,
Saito M, Tsuji S, Hayashi Y, Hirokawa N: CharcotMarie-Tooth disease type 2A caused by mutation ina microtubule motor KIF1Bβ. Cell 105:587-597,
2001
33. Ono R, Taki T, Taketani T, Kawaguchi H, Taniwaki
M, Okamura T, Kawa K, Hanada R, Kobayashi M,
Hayashi Y: SEPTIN6, a human homologue to mouse
Septin6, is fused to MLL in infant acute myeloid
leukemia with complex chromosomal abnormalities
involving 11q23 and Xq24. Cancer Res 62:333-337,
2002
34. Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi
H, Hayashi Y: LCX, leukemia-associated protein witha CXXC domain, is fused to MLL in acute myeloid
leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res 62:4075-80, 2002
35. Taketani T, Taki T, Shibuya N, Ito E, Kitazawa J,
Terui K, Hayashi Y: The HOXD11 gene is fused to
the NUP98 gene in acute myeloid leukemia with thet (2;11)(q31;p15). Cancer Res 62:33-37, 2002
36. Taketani T, Taki T, Ono R, Kobayashi Y, Ida K,
Hayashi Y: The t (7;11)(p15;p15) in acute myeloid
leukemia results in fusion of the NUP98 gene with a
HOXA cluster gene, HOXA13, but not HOXA9.
Genes Chromosomes & Cancer 34:437-443, 2002
37. Uno K, Takita J, Yokomori K, Tanaka Y, Ohta S,
Shimada H, Gilles FH, Sugita K, Abe S, Sako M,
Hashizume K, Hayashi Y: Aberrations of thehSNF5/INI1 gene are Restricted to malignant rhab-

doid tumors or atypical teratoid/rhabdoid tumors inpediatric solid tumors. Genes Chromosomes &Cancer 34:33-41, 2002

Cardiology
38. Shibuya K, Bigras JL, McCrindle BW, Newman A,
Smallhorn JF: Normal values in children for myocardial ultrasonic tissue characterization by integrated
backscatter. Echocardiography 15:353-361, 1998
39. Ishiguro A, Ishikita T, Shimbo T, Matsubara K, Baba
K, Hayashi Y, Naritaka S, Nakahata T: Elevation ofserum thrombopoietin precedes thrombocytosis in
Kawasaki disease. Thromb Haemo 79:1096-1100,
1998
40. Shibuya N, Shibuya K, Kato H, Yanagisawa M:
Kawasaki disease before Kawasaki at Tokyo
University Hospital. Pediatrics 110: e17, 2002
Immunology and Allergy
41. Takamizawa M, Rivas A, Fagnoi F, Benike C, Kosek J,
Hayakawa H, Engleman EG: Dendroric cells thatprocess and present nominal antigens to naïve T
lymphocytes are derived from CD 2+ precursors. J
Immunol 158: 2134-2142, 1997
42. Cui SH, Tanabe F, Terunuma H, Iwatani Y, Nunoi H,
Agematsu K, Komiyama A, Nomura A, Hara T,
Onodera T, Iwata T, Ito M: A thiol proteinase
inhibitor, E-64-d, corrects the abnormalities in concanavalin-A cap formation and the lysosomal
enzyme activity in leucocytes from patients with
Chediak-Higashi syndrome by reversing the downregulated protein kinase C activity. Clin Exp
Immunol 125:283-290, 2001
43. Yoshimura C, Yamaguchi M, Iikura M, Izumi S, Kudo
K, Nagase H, Ishii A, Walls AF, Ra C, Iwata T,
Igarashi T, Yamamoto K, and Hirai K: Activation
markers of human basophils: CD69 expression isstrongly and preferentially induced by IL-3. J Allergy
Clin Immunol 109: 817-823, 2002
Endocrinology and Metabolism
44. Goto M, Taki T, Sugie H. Miki Y, Kato H, Hayashi Y:
A novel mutation in the glucose-6-phosphatase genein Korean twins with glycogen storage disease type1a. J Inherit Metab Dis 23:851-852, 2000
45. Miki Y, Taki T, Ohura T, Kato H, Yanagisawa M,
Hayashi Y: Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism hyperammonemia syndrome. J Pediatr
136:69-72, 2000
Neurology
46. Kobayashi K, Nakahori Y, Miyake M, Matsunuma K,
Kondo-Iida, E, Nomura Y, Segawa M, Yoshioka M,
Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka
I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga
K, Toda T: An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.
Nature 394:388-392, 1998

209

47. Kubota M, Takeshita K, Sakakihara Y, Yanagisawa
M: Magnetoencephalographic study of giant
somatosensory evoked responses in patients withrolandic epilepsy. J Child Neurol 15: 370-379, 2000
48. Kurachi Y, Oka A, Itoh M, Mizuguchi M, Hayashi M,
Takashima S: Distribution and development of CLN2
protein, the late-infantile neuronal ceroid lipofuscinosis gene product. Acta Neuropathol 102:20-26,
2001
49. Tatsumi K, Saito M, Lin B, Iwamori M, Ichiseki H,
Shimozawa N, Kamoshita S, Igarashi T, Sakakihara
Y: Enhanced expression of a-series gangliosides infibroblasts of patients with peroxisome biogenesis
disorders. Biochim Biophys Acta 1535:285-293, 2001
50. Saito M, Fukushima Y, Tatsumi K, Bei L, Fujiki Y,
Iwamori M, Igarashi T: Molecular cloning of Chinese
hamster ceremide glucosyltransferase and its
enhanced expression in peroxisome-defective
mutant Z65 cells. Arch Biochem Biophys 403:171178, 2002

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Department of PediatricSurgery / Department ofPediatric Oncology
Outline and Research Objectives
The history of Department of Pediatric Surgery is not long in University of Tokyo. It firststarted as a clinical department of University of Tokyo Hospital in 1971. In 1989 it became adepartment in The Faculty of Medicine and then transferred to The Graduate School of
Medicine as a part of the change of the system. So the duration of research in our department is not long. Also we have only few staff in our department. However, we have continued research very intensively by collaboration with other departments in The Graduate
School of Medicine, University of Tokyo, and other institutes in Japan and abroad.
Our main themes of research are in three areas, namely transplantation medicine, developmental biology of congenital anomalies and fetal surgery, and immunology of intestine.
Department of Pediatric Oncology was separated from Department of Pediatric Surgery
when the system changed, and Graduate School of Medicine became the major. Before that,studies concerning pediatric oncology was done in the Department of Pediatric Surgery andalso in the Department of Pediatrics. Now as a system, Department of Pediatrics is separated from the Department of Pediatric Oncology, the group of pediatric oncology in the
Department of Pediatrics actually works with the Department of Pediatric Oncology, andconstitutes a part of the department.
Pediatric malignancies are very special and consist only a very small part of all the malignancies considering the number of patients. However, because of their peculiarities, they havesome privileges and advantages. For example, about the theory of oncogenesis, famous “twohit theory” by Knudson was first proposed for pediatric malignancies, retinoblastoma andnephroblastoma. It is because that the mechanism of oncogenesis in these tumors is very simple compared to that of adult malignancies. Also the “multi-disciplinary treatment” of malignant diseases first successfully introduced to malignant solid tumors in infancy and children.
So the study of pediatric oncology is very important and it has possibility of break-through inthe study of oncology general. Now we mainly study oncogenes related to pediatric malignancies especially neuroblastoma, and immuno-therapy of cancer using dendritic cells.

Faculties and Students
Professor and Chair

Kohei Hashizume, M.D,,Ph.D..
(since 1997)
Lecturer
Yutaka Kanamori, M.D.,Ph.D..
(Yasuhide Hayashi, M.D.,Ph.D.)
Associates ...............................3
Graduate Students ..................4
Secretary .................................2

Past Research and Major Accomplishments
In the area of transplantation medicine, we started
clinical living-related liver transplantation with the
Department of Artifitial Organ and Transplantationand have operated about 100 pediatric cases.
Associate Professor Kawarasaki in our department
who was in charge in liver transplantation moved toJichi Medical School in 2001. So we stopped clinicalliver transplantation in pediatric cases. But we continue research in this area now. We studied immunological tolerance using rat heart transplantation model,
and found that donor specific transfusion induce
immunological tolerance. Then we analyzed rat serum
after donor specific transfusion using liquid chromatography. We found three kinds of proteins thathave a function of immunosuppression. Especially oneof those 3 protein, MAY-1 is a completely new proteinwith 234 amino acid and has a possibility of usage asa immunosuppression drug in clinical transplantation.
We studied small bowel transplantation using amodel of small bowel transplantation with a free graftof newborn intestine into the recipient’s omentum. In
this model we showed good neovascularization andhistologically mature intestine after the transplantation. We also showed the near normal motility andabsorption in this transplanted intestine. In shortboweled rats, transplantation of newborn intestine211

could restore the weight loss and could save the livesof these short-boweled rats. Also cryopreserved newborn intestine could function as good as fresh intestine after transplantation.
We also studied warm ischemia-reperfusion injury
of the liver in rat model. We showed that pretreatment of the liver with cyclosporine reduce damage tothe liver, but pretreatment with FTY720 rather prolong damage to the liver. So pretreatment withimmuno-suppressive drugs of the liver does not universally beneficial for the prevention of warm
ischemia-reperfusion injury.
In the area of developmental biology of congenital
anomalies and fetal surgery, we very intensively studied congenital diaphragmatic hernia (CDH) using rat
model induced by a drug nitrofen. CDH is one of themost difficult to treat congenital anomalies with highmortality. Until recently its experimental study wasdone using only sheep model that is made by fetal surgery. The problem is that the fetal surgery can be done
only in late phase of pregnancy, many features of thismodel is quite different from that of human CDH. We
noticed rat CDH induced by administration of nitrofen
to pregnant rat. The CDH by this method develop atvery early stage of fetal development and very similar
to human CDH. First we showed clearly that hypoplasia of the lungs develop by CDH, and spreading of
sufactant phospholipids in the alveolar cells to thelumen of alveoli is strongly impaired in fetuses with
CDH. Then we studied the effects of fetal surgery tolung hypoplasia in CDH. We developed experimental
model of tracheal ligation in rat CDH model. Using
this model, we showed that tracheal ligation can overcome the hypoplasia of the lungs induced by CDH. By
ligation of the trachea the lungs grow very rapidly, andthe weight, contents of protein and DNA of the lungs,
and histological structure normalize. By this experiment we clearly showed that tracheal ligation canovercome the hypoplasia of the lungs in CDH, andthat this simple fetal surgery can same the lives ofbabies with CDH and severe hypoplasia of the lungs
whom it is very difficult to treat after birth.
We also developed another new model of congenital
anomaly in a species of amphibian, Cynopus
pyrrhogaster. We succeeded to produce split cord malformation in Cynopus embryos experimentally incising apart of neural plate and notochord. With this procedure,
fistulae developed between endoderm and ectoderm,
and in some cases endodermal or neural cysts developed.
This experiment shed light to the cause of split notochord syndrome and also duplication of intestine.
In the area of immunology of intestine, Kanamori
first described novel lympoid tissues, cryptopatch inmurine intestinal mucosa in 1996. Then we studied
human intestinal mucosa for the existence of lymphoid tissues corresponding to the cryptopatch in212

mouse. We could not show the existence of such lymphoid tissues in human. So we turned to study thefunctions of already known lymphoid tissues inhuman if they have functions corresponding to cryptopatch in mouse and compensate the absence ofthat. Using surgical specimens of jejunum of infants,
we looked for lymphoid tissues in the mucosa of thejejunum, and examined the distribution of these tissues. We found Peyer’s patches and isolated lymphoidfollicles. Peyer’s patches distributed in antimesentericarea, but isolated lymphoid follicles distributed irregularly all through the surface of the mucosa, and inthese isolated lymphoid follicles CD19 positive andCD3 positive lympoid cells are distributed.
We introduced new synbiotics therapy to various
intestinal conditions in children, namely short bowel
syndrome, inflammatory bowel diseases, and pseudoHirschsprung disease. We administered two types ofprobiotics (Bifidobacterium brevs and Lactobacillus
casei) together with prebiotic (galactooligosaccarides)
to these patients. After the introduction of this therapy, the patients’ clinical conditions dramatically
improved. Feces became more solid and less foulsmelling, the patients got weight, abnormal dilatationof the intestine improved, and frequency of bacterialtranslocation decreased. We also showed change ofbacterial flora of feces. Those two types of probiotics
became the main flora, and the number of pathogenic
bacteria dramatically decreased.
In the area of pediatric oncology, we started ourstudy of pediatric oncology in the field of histochemistry. We studied expression of multi-drug resistance
related protein, P-glycoprotein in neuroblastoma cells.
Surprisingly, it was shown that high expression of Pglycoprotein was related to better prognosis ofpatients. It looks paradoxical, but we also found innormal adrenal medulla cells, P-glycoprotein isexpressed. So high expression of P-glycoprotein inneuroblastoma means rather well-differentiation ofthese tumors, and consequently better prognosisi.
Our result was confirmed later by other publications.
Recently we are concentrated in the study of oncogene in pediatric malignancies, especially neuroblastoma and Wilms tumor. It is well known that neuroblastomas whose cells show chromosome 1p deletion
have poor prognosis. We intensively looked for probable oncogene in this region, but it has not yet discovered. There was one great side product of this project.
In this region we found kinesin superfamily motor
protein KIF1B, and it was shown loss-of-function
mutation in the motor domain of the KIF1B genecauses Charcot-Marie-Tooth disease type 2A. We studied expression, LOH, and mutation of p73 gene that is
mapped to 1p36. We found aberrant expression of
p73 is significantly higher in advanced-stages neuroblastoma, but no homozygous deletion of p73 wasfound in any of the sample. So we conclude p73 isless involved in the development but involved in the
progression of neuroblastoma. We also studied othergenes mapped in other chromosomes because otherchromosome anomalies other than 1p deletion are
related to prognosis of neuroblastoma. For example,
17q gain is known to relate to poor prognosis. We
studied survivin mapped to 17q25, which is a memberof inhibitor of apoptosis proteins (IAPs). We foundhigh expression of survivin is a strong prognostic
indicator for the advanced stage neuroblastomas, andthere is a possibility that it is one of the candidate
genes for the 17q gain.
In the study of Wilms tumor, we found a novel
WT1 gene mutation in a patient with Wilms tumor,
male hermaphroditism, but without renal disease.
The mutation was at intron 7 in tumor cells and also
germ line cells. This mutation is thought to produce
truncated WT1 protein, and it is related to the genitourinary anomalies and genesis of Wilms tumor in thispatients. Also the clinical course of this patient was
rather atypical for Wilms tumor in general, and we
think this peculiar mutation should influence thecourse of the disease.
Other than neuroblastoma and Wilms tumor, westudied hepatoblastoma. We examined mutation ofbeta-catenin in the tumors of 68 cases of hepatoblastoma. We found mutation of beta-catenin in 44 (65%)
tumors. In these 44, 9 was point mutation, 35 wasdeletion mutation. We also studied the expression ofbeta-catenin by histochemistry. We found betacatenin is accumulated in the nuclei of tumor cells,
and in these cases with beta-catenin accumulation,
cyclin D1 was also accumulated in the nuclei. We conclude that in hepatoblastoma because of frequent
mutation of beta-catenin gene, beta-catenin protein
accumulates in the nuclei and cause activation of
cyclin D1, that results growth or progression of thetumor. We also found beta-catenin accumulation in
the nuclei of two cases of hepatic adenoma. In one ofthese 2 cases, mutation of beta-catenin gene wasfound. This is the first report of beta-catenin mutationin the case of hepatic adenoma, and we think it shedlight to the genesis of hepatic adenoma and its relation to hepatoblastoma.

Current Research
In the area of transplantation medicine, our main
themes are prevention of ischemia-reperfusion injury
in liver transplantation, and development of safer
method in transplantation of small bowel. In the former theme, we developed partioal liver transplantation model in rat, and studying the effect of gene
introduction to the graft. In the preliminary study, we
got promising effect of gene introduction. In tranplan-tation of small intestine, we have succeeded in thetransplantation of cryopreserved newborn intestine,
but found cryopreservation had no effect on antigenicity of the graft. So we are studying methods toreduce the antigenicity of the intestinal graft toimprove the survival of intestinal transplantation.
In the area of developmental biology of congenital
anomalies and fetal surgery, we are doing experimental fetal surgery of tracheal obstruction using lambs.
We developed new laryngoscope specially designed
for the obstruction of trachea of fetal lambs using balloon. We have successfully introduced balloon into
fetal trachea, and have shown growth of the lungs
after the introduction of balloon.
In the area of immunology of intestine, we are
studying the cells found in isolated lymphoid follicles
in the mucosa of infants, their characters, development, and migration. We are considering of using probiotics in wider varieties of diseases, for example
patients in PICU who receive rather intensive antibiotics therapy and are prone to develop bacterialtranslocation and sepsis.
In Pediatric Oncology Department, we continue thesearch of tumor suppressor gene of neuroblastoma suspected to reside in chromosome 1p. We have established cell line of Wilms tumor with WT1 mutation.
This cell line has morphological features of stromal celland epithelial cell. Using this cell line, we are considering to do a study concerning the factors that determine
the differentiation of the tumor. Wilms tumor shows avery wide variety of histology. In some tumors, histology is almost universally epithelial, but in other tumors,they show stroma-dominant histology with only smallpart of epithelium. Because the histological type relate
to the prognosis of the tumor, we can know the factors
related to prognosis, if we can find out factors that
determine the histological features of the tumor.
Concerning the therapy of malignant tumors inchildren, we are doing a research of immunotherapy
using dendritic cells. Immunotherapy using dendritic
cells is not studied fully in malignant tumors in children. However, it is well known that neuroblastoma
cells show strong tumor-specific antigen, and spontaneous regression of neuroblastoma is well documented. So we think immunotherapy of neuroblastoma is
promising. We found using OK-432, dendritic cells
can be activated, and CTL can be induced. We want totest this method using target of neuroblastoma cells.
Compared to neuroblastoma and Wilms tumor,
genetic and molecular study of hepatoblastoma isretarded. It is necessary to examine genes related togenesis and progression of hepatoblastoma. To examine many kind of genes, gene chip is very effective
method, and we are collaborating with ResearchCenter for Advanced Science and Technology of
University of Tokyo. Using this method and compar-

213

ing gene expression profiles of hepatoblastoma, normal liver, and cirrhotic liver, we have found some
genes that specifically expressed in hepatoblastoma.

Future Prospects
One very important aspect of study in our department is establishment of new area of medicine “fetology”. To know and to treat patients with various congenital anomalies, it is mandatory to know fetal
development of normal baby and babies with congenital anomalies. Development of imaging methods inthese ten years is enormous. However, we need not
only information of structures of fetuses, but alsofunctions of various organs during fetal life. With thedevelopment of new technology which will make itpossible, we can know the physiology of fetus and theeffects of fetal conditions to the health after birth inchildren and adults.
In this 20 years, prognosis of pediatric malignancies in general has improved dramatically. However
there are small fraction of patients whose tumors arevery resistant to standard treatment, and are apt torecur after a short period of remission. These tumors
probably has some genetic characteristics, and if we
can find out some of these characteristics, we can
improve the method of therapy and also can improve
the prognosis of these patients.

Select Publications
1. Yoshida Y, Kobayashi E, Nozawa M, Uchida H,
Fujimura A, Yamanaka T, Miyata M, Hepatic lymphocyte transplantation in hyperbilirubinemic gunnrats. Eur Surg Res 32 (4) : 223-227, 2000
2. Kitano Y, Ruchelli E, Weiner S, Adzick N S. Hepatic
Mesenchymal Hamartoma associated with mesenchymal stem villous hyperplasia of the placenta.
Fetal Diagn Therap 15 : 134-138, 2000
3. Oida T, Suzuki K, Nanno M, Kanamori Y, Saito H,
Kubota E, Kato S, Itoh M, Kaminogawa S, Ishikawa
H. Role of gut cryptopatches in early extrathymic
maturation of intestinal intraepithelial T cells. J
Immunol 164 : 3616-3626, 2000
4. Kitano Y, Flake AW, Quinn T M, Kanai M, Davies P,
Sablich T J, Schneider C, Adzick N S, von Allmen
DLung growth induced by tracheal occlusion in the
sheep is augmented by airway pressurization. J
Pediatr Surg 35 : 216-222, 2000
5. Komuro H, Makino S, Tahara K. Choledochal cyst
associated with duodenal obstruction. J Pediatr Surg
35(8) : 1259-62, 2000
6. Milner R, Kitano Y, Olutoye O, Flake A W, Adzick N
S. Radiofrequency thermal ablation (RTA): a potential treatment for hydropic fetuses with a large chest
mass. J Pediatr Surg 35 : 386-389, 2000
7. A K, Kitano Y, Kriss A, Hensley H, Bergey P, Flake
A, Hubbard A, Leigh Jr J S. In vivo, in utero micro-

214

scopic magnetic resonance imaging: application in a
rat model of diaphragmatic hernia. Magn Reson Med
44 : 331-335, 2000
8. Islam A, Kageyama H, Hashizume K, Kaneko Y,
Nakagawara A. Role of Survivin, whose gene ismapped to 17q25, in human and identification of anovel dominant-negative isoform, Survivin β/2B .
Med Pediatr Oncol 35 : 550-553, 2000
9. Kanamori Y, Suzuki K, Oida T, Ishikawa H. Gut-associated lymphoid tissue “Cryptopatches” and intraintestinal development of murine T cells. Mucosal
Immunology Update 3-5, 2000
10. Islam A, Kageyama H, Takada N, Kawamoto T,
Takayasu H, Isogai E,Ohira M, Hashizume K, Kaneko
Y, Nakagawara A. High expression of Survivin,mapped to 17q25, is significantly associated withpoor prognostic factors and promotes cell survival in
human neuroblastoma. Oncogene 19 : 617-623, 2000
11. Ohira M, Kageyama H, Mihara M, Furuda S, Machida
Y, Takayasu H, Islam A, Nakamura Y, Takahashi M,
Shishikra T, Kaneko Y, Toyota A, Sattori S, Sakaki Y,
Ohki M, Horri A, Hayashi Y, Soeda E, Inazawa J, Seki
N, Kuma H, Nozawa I, Nakagawara A. Identificationand characrerization of a 500-kb homozygously deleted region at chromosome 1p36.2 in a human neuroblastoma cell line. Oncogene 19 : 4302-4307, 2000
12. Emura T, Asashima M, Hashizume K. An
Experimental Animal Model of Split Cord
Malformation. Pediatr Neurosurg 33ÅF283-292, 2000
13. Komuro H, Makino S, Tahara K. Laparoscopic resection of an adrenal neuroblastoma detected by mass
screening that grew in size during the observation
period. Surg Endosc 14(3) : 297, 2000
14. Kawarasaki H, Hashizume K, Makuuchi M. Live
Related Pediatric Liver Transplantation. In DK Gupta(Ed.). Textbook of Neonatal Surgery, New Delhi,
Modern Publishers, 202-206, 2000
15. Uchida H, Tanaka H, Kitoh Y, Yanagisawa K, To H,
Tago K, Mizuta K,Fujimura A, Tominaga S,
Hashizume K, Kobayashi E. Mechanisms of
immunomodulation induced by bloodtransfusion:
identification of humoral factors. Transplant Proc 32(2) : 255-256, 2000
16. Ohmori M, Miyashita F, Uchida H, KitohY,Tsuruoka
S, Harada K, Sugimoto K, Fujimura A, Kobayashi E.
Effect of erythromycin on ischemia-reperfusion
injury of liver in rats. Transplant Proc 32 (4) : 811814, 2000
17. Harihara Y, Makuuchi M, Kawasaki S, Hashikura Y,
Kawarasaki H, Takayama T, Kubota K, Ito M, Mizuta
K, Yoshino H, Hirata M, Kita Y, Sano K, Hisatomi S,
Kusaka K, Hashizume K. Influence of HLA compatibility on living-related liver transplantation.
Transplant Proc 32 : 2107, 2000
18. Harihara Y, Makuuchi M, Kawarasaki H, Takayama
T, Kubota K, Ito M,Mizuta K, Yoshino H, Hirata M,
Kita Y, Sano K, Hisatomi S, Kusaka K,Miura Y, Taniai
N, Asato H, Nakatsuka T, Hashizume K. Living-related liver transplantation in adults compared with children. Transplant Proc 32 : 2160-2161, 2000

19. Harihara Y, Sano K, Makuuchi M, Kawarasaki H,
Takayama T, Kubota K, Ito M, Mizuta K, Yoshino H,
Hirata M, Kita Y, Hisatomi S, K, Miura Y, Hashizume
K. Influence of donor age on the graft function after
living-related liver transplantation. Transplant Proc
32 : 2164-2165, 2000
20. Harihara Y, Sano K, Makuuchi M, Kawarasaki H,
Takayama T, Kubota K, Ito M, Mizuta K, Yoshino H,
Hirata M, Kita Y, Hisatomi S, Kusaka K, Miura Y,
Hashizume K. Correlation between graft size and necessary tacrolimus dose after living-related liver transplantation. Transplant Proc 32 : 2166-2167, 2000
21. Hirata M, Harihara Y, Kita Y, Hisatomi S, Miura Y,
Yoshino H, Mizuta K, Ito M, Sano K, Kusaka K,
Kawarasaki H, Kubota K, Takayama T, Hashizume K,
Makuuchi M. Impact of HLA matching in livingrelated liver transplantation..Transplant Proc 32 :
2108-2109, 2000
22. Hirata M, Harihara Y, Hisatomi S, Miura Y, Yoshino
H, Mizuta K, Ito M, Sano K, Taniai N, Kusaka K, Kita
Y, Kawarasaki H, Kubota K, Takayama T, Hashizume
K, Makuuchi M. Living-related liver transplantation
for patients with primary biliary cirrhosis.
Transplant Proc 32 : 2208-2209, 2000
23. Hirata M, Harihara Y, Hisatomi S, Miura Y, Yoshino
H, Mizuta K, Ito M, Sano K, Taniai N, Kusaka K, Kita
Y, Kawarasaki H, Kubota K, Takayama T, Makuuchi
M. A case of esophageal variceal rupture following
acute portal vein thrombosis three days after livingrelated liver transplantation. Transplant Proc 32 :
2266-2268, 2000
24. Tahara K, Uchida H, Yasunaru S, Hakamata Y,
Kobayashi E. Chimeric patterns after organ transplants using green fluorescent protein-transgenic
rat.. American J transplant 1: 336, 2001
25. Kawase E, Tanaka K, Honna T, Azuma N. A case of
atypical WAGR syndrome with anterior segment
anomaly and microphthalmos. Arch Ophthalmol
119: 1855-1856, 2001
26. Utsuki T, Hashizume K, Iwamori M. Impaired spreading of surfactant phospholipids in the lungs of newborn rats with pulmonary hypoplasia as a model ofcongenital diaphragmatic hernia induced by nitrofen
27. Hakamata Y, Tahara K, Uchida H, Sakuma Y,
Nakamura M, Kume A, Murakami T,Takahashi M,
Takahashi R, Hirabayashi M, Ueda M, Miyoshi
I,Kasai N, Kobayashi E. Green fluorescent proteintransgenic rat: a tool for organ transplantation
research..Biochem Biophys Res Commun 286 (4) :779-85, 2001
28. Takayasu H, Horie H, Hiyama E, Matsunaga T,
Hayashi Y, Watanabe Y, Suita S, Kaneko M, Sasaki F,
Hashizume K, Ozaki T, Furuuchi K, Tada M,
Ohnuma N, Nakagawara Al Frequent deletions andmutations of the beta-catenin gene are associatedwith overexpression of cyclin D1 and fibronectin
and poorly differentiated histology in childhood
hepatoblastoma. Clin Cancer Res 7(4): 901-8, 2001
29. Kanamori Y, Hashizume K, Sugiyama M, Morotomi
M, Yuki N. Combination therapy with

Bifidobacterium breve, Lactobacillus casei, and galactooligosaccharides dramatically improved the intestinal function in a girl with short bowel syndrome A
novel synbiotics therapy for intestinal failure. Dig
Dis Sci 46: 2010-2016, 2001
30. Sugawara Y, Makuuchi M, Takayama T, Mizuta K,
Kawarasaki H, Imamura H, Hashizume K. Livertransplantation using a right lateral sector graft froma living donor to her granddaughter.
Hepatogastroenterology 48: 261-63, 2001
31. Sugawara Y, Makuuchi M, Takayama T, Imamura H,
Dowaki S, Mizuta K, Kawarasaki H, Hashizume K.
Small-for-size grafts in living-related liver transplantation. J Am Coll Surg 192: 510-13, 2001
32. Tahara K, Uchida H, Kawarasaki H, Hashizume K,
Kobayashi E. Experimental small bowel transplantation using newborn intestine in rats: III. Long-term
cryopreservation of rat newborn intestine. J Pediatr
Surg 36 (4) : 602-4, 2001
33. Uchida H, Tahara K, Takizawa T, Inose K, Yashiro T,
Hashizume K, Ikeda H, Takahashi M, Kobayashi E.
Experimental small bowel transplantation using
newborn intestine in rats: IV. Effect of cold preservation on graft neovascularization. J Pediatr Surg 36(12) : 1805-10, 2001
34. Sugawara Y, Mizuta K, Kawarasaki H, Takayama T,
Imamura H, Makuuchi M. Risk factors for acuterejection in pediatric living related liver transplantation: The impact of HLA matching. Liver Transpl 7:
769-73, 2001
35. Sugawara Y, Makuuchi M, Takayama T, Yoshino H,
Mizuta K, Kawarasaki H. Liver transplantation fromsitus inversus to situs inversus. Liver Transpl 7: 82930, 2001
36. Mizuta K, Kita Y, Harihara Y, Takayama T, Kubota K,
Hirata M, Inoue K, Sugawara Y, Sakamoto Y, Ito M,
Tanaka H, Inoue Y, Oka T, Kawarasaki H,
Hashizume K, Kawasaki S, Makuuchi M. Colectomy
for uncontrolled hemorrhagic cecal ulcers due to primary cytomegalovirus infection in living-related livertransplantation. Medicine of the Americas 2: 135138, 2001
37. Nakao A, Ogino Y, Tahara K, Uchida H, Kobayashi E
Orthotopic intestinal transplantation using the cuff
method in rats: a histopathological evaluation of theanastomosis. Microsurgery. 21 (1) : 12-5, 2001
38. Sakamoto J, Takata A, Fukuzawa R, Kikuchi H,
Sugiyama M, Kanamori Y, Hashizume K, Hata J. A
Novel WT1 Gene Mutation Associated with Wilms’
Tumor and Congenital Male Genitourinary
Malformation. Pediatric Research 50 : 337-344, 2001
39. Komuro H, Makino S, Momoya T, Uehara Y, Tahara
K, Momoi M: Cholangitis associated with cystic
dilatation of the intrahepatic bile ducts after antireflux valve construction in biliary atresia. Pediatr Surg
Int 17 (2-3) : 108-10, 2001
40. Hirata M, Harihara Y, Kitamura T, Hisatomi S, Kato
M, Dowaki S, Mizuta K, Sugawara Y, Kita Y, Kubota
K, Takayama T, Kawarasaki H,Hashizume K,
Makuuchi M: The influence of donor age to graft vol-215

ume increase rate in living donor Liver transplantation. Transplant Proc 33: 1416-17, 2001
41. Kanamori Y, Hashizume K, Kawarasaki H, Kitano Y,
Sugiyama M, Tanaka Y: Single vaginal ectopic ureterand renal hypoplasia associated with urogenital
sinus and abdominal muscular hypoplasia-a novel
subtype of prune-belly syndrome in a female child?
Urology 57: 975vi-ix, 2001
42. Komuro H, Makino S, Yasuda Y, Ishibashi T, Tahara
K, Nagai H. Pancreatic complications in choledochal
cyst and their surgical outcomes. World J Surg 25(12) : 1519-23, 2001
43. Tatsumi K, Taki T, Taniwaki M, Nakamura H,
Taguchi J, Chen YZ, Bessho F, Yanagisawa M,
Hayashi Y: The CDCREL1 gene fused to MLL in de
novo
acute
myeloidleukemiawitht(11;22)(q23;q11.2) and its frequent expression in
myeloid leukemia cell lines. Genes Chromosomes
Cancer 30:230-235, 2001
44. Murata T, Kurokawa R, Krones A, Tatsumi K, Ishii
M, Taki T, Masuno M, Ohashi H, Yanagisawa M,
Rosenfeld MG, Glass CK, Hayashi Y: Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP may cause RubinsteinTaybi syndrome. Hum Mol Genet 10: 1071-1076,
2001
45. Jamal R, Taketani T, Taki T, Bessho F, Hongo T,
Hamaguchi H, Horiike S, Taniwaki M, Hanada R,
Nakamura H, Hayashi Y: Co-duplication of the MLL
and FLT3 gene in patients with acute myeloid
leukemia. Genes Chromosomes Cancer 31: 187-190,
2001
46. Niitsu N, Hayashi Y, Sugita K, Honma Y:
Sensitization by 5-aza-2’-deoxycytidine of leukaemia
cells with MLL abnormalities to induction of differentiation by all-trans retinoic acid and 1α, 25-dihydroxyvitamin D3. Br J Haematol 112:315-326, 2001
47. Niitsu N, Hayashi Y, Honma Y: Downregulation of
MLL-CBP fusion gene expression is associated withdifferentiation of SN-1 cells with t(11;16)(q23;p13).
Oncogene 20: 375-384, 2001
48. Ohnishi H, Hayashi Y, Okamura T, Tabuchi K,
Kobayashi M, Bessho F: An infant witht(4;11)(q21;q23) acute lymphoblastic leukemia successfully treated using immunomagnetically purged
autologous bone marrow transplantation. Med
Pediatr Oncol 36: 388-389, 2001
49. Shibuya N, Taki T, Mugishima H, Chin M, Tsuchida
M, Sako M, Kawa K, Ishii E, Miura I, Yanagisawa M,
Hayashi Y: t(10;11)-acute leukemias with MLL-AF10
and MLL-ABI1 chimeric transcripts; specific expression patterns of ABI1 gene in leukemia and solid
tumor cell lines. Genes Chromosomes Cancer 32:110, 2001.
50. Liu M, Taketani T, Li R, Takita J, Taki T, Yang HW,
Kawaguchi H, Ida K, Matsuo Y, Hayashi Y: Loss of
p73 gene expression in lymphoid leukemia cell lines
is associated with hypermethylation. Leuk Res
25:441-447, 2001

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Department of Geriatric Medicine /Department of Aging Research
Outline and Research Objectives
The Department of Geriatrics was established in1962, as the first geriatric department inJapan.
Since elderly patients usually have multiple organ disorders, we have to take care of thepatients as whole from multiple points of view. In addition, in the elderly patients, symptoms and signs, responses to the treatment are sometimes quite different from the young.
We have to have a broad knowledge on the physiological and metabolic changes with aging
when we treat the elderly patients. Quality of life of the patients is another point of viewwhich should be emphasized.
Our sub-specialty includes respirology, cardiology, neurology, hematology, bone metabolism, besides the general geriatric internal medicine. We are trying to elucidate the pathophysiology of aging process and elderly patients from viewpoints of basic aging science
using molecular biology technique and clinical aspects using the recent advancement oftechnology and geriatric assessment.
There are 19 plus additional beds about 6 in the clinical ward, which are under thesupervision of the residents and assistant staff members. An assistant staff member withmore than 10 years experience teams up with the resident on a man-to-man basis, giving
instruction as to actual clinical decision making and procedures. The final decision making
is performed during the weekly Professor’s rounds.
We have also developed new geriatric scale such as vitality index. This is a unique index
for assessment of energy and vitality in frail elderly patients. Comprehensive geriatricassessment and critical pass applied for the treatment and care of the patients. Based onthese comprehensive approaches, both staffs of medical social service and welfare divisionof Tokyo University Hospital and we develop the new system which bridge between inpatients and out-patients in terms of maintaining a constant level of quality of life ofpatients and caregivers.
Specialized services are provided to out-patients on a daily in all areas internal medicine.
Approximately 300 new and a total of 16,000 patients visit the out-patients clinic in a year.

Faculties and Students
Professor and Chair
Lecturer

Yasuyoshi Ouchi,M.D. (1995~)
Yoshio Namba,M.D.
Takahide Nagase,M.D.
Satoshi Inoue,M.D.
Koichi Kozaki, M.D.
Associate .................................6
Postdoctoral Fellow ................4
Graduate Student....................8
Research Student ....................5
Secretary .................................6

Past Research and Major Accomplishments
Lung diseases including pneumonia are major
causes of death in the elderly. In respiratory diseases,
there are several inflammatory disorders to which no
pharmaceutical agents are currently effective. For

example, adult respiratory distress syndrome (ARDS)
is an acute lung injury and the mortality rate for
ARDS ranges from 40-70% despite of intensive careusing currently available drugs. Idiopathic pulmonary
fibrosis (IPF) is a progressive and fatal disease, whilecurrent medical intervention for IPF is only oxygentherapy except for lung transplantation. However,their mechanisms still remain to be elucidated.
Therefore, we have aimed to elucidate the pathophysiological and molecular mechanisms underlying
inflammatory diseases. Our recent studies haveshown that various mediators including cytokines,
eicosanoids or adhesion molecules are involved in thedevelopment of inflammatory lung disorders.
Especially, platelet-activating factor (PAF) and metabolites of arachidonic acid, i.e., eicosanoids, are lipid
mediators that have various biological effects. PAF is aproinflammatory phospholipid mediator that exerts
its action via activation of G-protein-coupled PAF

217

receptor (PAFR). A key enzyme for the production ofthese inflammatory mediators including eicosanoids
and PAF is cytosolic phospholipase A2 (cPLA2). To
perform this study, we used mutant mice, i.e., PAFR
transgenic mice, PAFR gene-disrupted mice, andcPLA2 gene-disrupted mice, in collaboration with
Department of Biochemistry. Our observations suggest that both PAF and cPLA2 are involved in thepathogenesis of acute lung injury and pulmonary
fibrosis. The inhibition of these pathways might provide a novel therapeutic approach to ARDS and IPF.
We have also examined the host-defense system,
especially antimicrobial peptides including defensins.
Recently, we have discovered a novel mouse betadefensin, mBD-6, predominantly expressed in skeletal
muscle. In humans and mice, we have also identified
multiple novel epididymis-specific beta-defensin isoforms. These finding suggest novel physiological rolesof this peptide family.
Cardiovascular research laboratory has been performing research of atherosclerosis. It is generally
accepted that premenopausal women are protectedfrom atherosclerotic diseases because female hormone, especially estrogen, appears to have a beneficial
effect on vascular wall. We have identified that vascular smooth muscle cells (VSMC) expressestrogen
receptor (ER) and these cells respond to estrogen fromthe evidence that estrogen inhibits endothelin-1 production and c-fos gene expression in rat aorta andestrogen inhibits migration and proliferation of vascular smooth muscle cells. We also found estrogenexerts beneficial effect in vivo by showing that estrogen inhibits intimal thickening of rat femoral arteryinduced by cuff-placement around the artery. With
respect to endothelial cells (EC), another major component constituting the vascular wall, we found that
estrogen attenuates endothelin-1 production inbovine endothelial cells via estrogen receptor and that
estrogen prevents oxidative stress-induced endothelial cell apoptosis in rats.
Besides estrogen, we have revealed that red wine
polyphenols (RWPs) have inhibitory roles in VSMC
function. RWPs inhibit VSMC proliferation, which ismediated by cyclin A downregulation. RWPs also
inhibit VSMC migration via two distinct signaling
pathways, phosphatidylinositol-3’ kinase and p38
mitogen-activated protein kinase. We also showed
potential involvement of various vasoactive substances, calcitonin gene-related peptide, parathyroid
hormone-related protein, vasopressin, and activin-A,
in the pathogenesis of atherosclerosis.
From the clinical perspective, our laboratory has auseful technique to evaluate vascular function, flowmediated vasodilatation (FMD). With this approach,we have shown that endothelium-dependent vasodilatation of the brachial artery is increased in the follic-218

ular and luteal phase of women’s menstrual cycle
when serum estradiol level is high, indicating that
endogenous estradiol is involved in menstrual cyclerelated vasodilatation. We also found that FMD is
impaired in obese men with visceral fat accumulation,
FMD negatively correlates with intima-media thickness in the carotid artery in men, long-term reduceddose hormone replacement therapy improves FMD
and intima-media thickness in the carotid artery inpostmenopausal women.
Currently, most of the research activities in neurological laboratory focus on the molecular aspects of
Alzheimer’s disease(AD). The main research topics are
elucidating the molecular mechanism underlying theaccumulation of amyloid b-protein, determining theimplications of apolipoprotein E (apoE ε4) genotype
and various risk factors in AD.
Endocrine/Metabolism Research Laboratory focuses on the clinical and basic research concerning
endocrine and metabolic diseases. We are particularlyinterested in the pathophysiological mechanisms inosteoporosis and hormone-dependent cancers.
Regarding osteoporosis, we have shown that genetic
factors are very important to develop the disease byanalyzing polymorphisms of the genes relating bonemetabolism. On the other hand, we recently haverevealed that an estrogen responsive RING finger protein Efp takes a critical role in estrogen-dependent
growth control of breast tumor, by proteolysis of acell-cycle checkpoint 14-3-3 sigma (Nature 2002, 417,
871). This finding may provide a new tool for diagnosis and treatment of breast tumor, especially of tumor
that is resistant to anti-estrogenic drugs.
We have also studied disuse syndrome as well as
the program of prevention and treatment of that.
Now we are investigating many aspects of elderly
patients by using newly developed geriatric scale.

Current Research
To further investigate the pathophysiological andmolecular mechanisms underlying inflammatory diseases, we continue to study the roles of various mediators including cytokines, eicosanoids, adhesion molecules, and CGRP family in the development of inflammatory lung disorders. Especially, CGRP family peptides including CGRP and adrenomedullin are neuropeptides that have various biological actions such as
responses to sensory stimuli, cardiovascular regulation and vasodilation. Based on their physiologicalroles, it is assumed that CGRP family might beinvolved in the pathogenesis of inflammatory diseases
including bronchial asthma. Currently, in collaboration with Department of Cardiovascular Medicine, weare studying the pathophysiological role of CGRP family using mutant mice deficient in either CGRP oradrenomedullin.
High incidence of respiratory infection including
pneumonia is a major characteristic of geriatric disease, while little is known about its mechanism. We
currently hypothesize that ageing process might affectthe expression pattern of defensins, leading to thesusceptibility to infection in the elderly. To address
this question, we are studying the ageing effects on
the expression pattern of defensins using mice. In
addition, to better understand the pathophysiologicalroles of defensins, we are now developing the mutant
mice deficient in defensins.
We are currently pursuing the differential role ofestrogen receptors, ERα and β, in VSMC function
and in other cell types utilizing adenoviral overexpression system, because we have previously shown that
estrogen has anti-proliferative and anti-migratory
effects in VSMC (Atherosclerosis. 1997). We are also
trying to overexpress each ER subtype in the aorta oflaboratory animals to identify the differential role of
ER in estrogen’s action. We are studying the role of
selective estrogen receptor modulator such as raloxifene to explore the usefulness of this new estrogenmodifying drug.
Our laboratory has been investigating vascular calcification, one of the hallmarks of vascular aging. We
have thus far found that VSMC calcify when cultured
in the presence of high inorganic phosphate, the phenomenon augmented by the addition of vitamin D3,
dexamethasone and advanced glycation end products,
attenuated by bisphosphonate and HMG CoA reductase inhibitor. We are currently studying the mechanism how VSMC calcification is regulated.
It is well known that flow-mediated vasodilatation(FMD) is under much influence by nitric oxide (NO).
Because it has been shown that an endogenous
inhibitor of NO synthase, asymmetric dimetylarginine(ADMA), and its hydrolyzing enzyme, NG,NGdimethylarginine dimethylaminohydrolase (DDAH),
are circulating in human blood, we are interested in
the role of ADMA and DDAH in such pathophysiologic conditions as pre- and post-female hormone
replacement therapy and pre- and post-treatment of
sleep apnea syndrome using nasal continuous positive
airway pressure.
The ε4 allele of apoE is a major risk factor for both
sporadic and late-onset familial AD. The apoE receptor family consists of cell-surface receptors that recognize extracellular ligands and internalize them for
degradation by lysosomes. In order to gain insightabout these receptors in the CNS, we raised a rabbit
polyclonal antibody and examined immunohistochemically human brain tissue. The immunoreactivity
was found in senile plaque in AD. These results may
suggest a role of apoE receptor in amyloid formation.
As estrogen is one of the key factors that candetermine the stages and prognosis of osteoporosis
and hormone-dependent cancers, we are particularly
studying the molecular mechanism of estrogen in its
target organs. Biochemical and genetic approaches are
utilized for the project, including analysis using
osteoblasts and tumor cell lines, characterization ofanimal models targeting estrogen receptors and estrogen-responsive genes, genetic analysis using clinicalsamples from patients.

Future Prospects
Major causes of death in the elderly include respiratory diseases including pneumonia, especially aspiration pneumonia. Furthermore, there are fatal
inflammatory disorders such as ARDS and IPF, towhich no useful drugs are currently available. We
expect that the inhibition of PAF and cPLA2 pathways might provide a novel therapeutic approach to
ARDS and IPF, leading to the development of a revolutionary medicine.
Genetic features including single nucleotide polymorphism (SNP) are potentially associated with the
etiology of asthma. The current study may suggestthat CGRP family genes could be targets for SNP
research. High incidence of respiratory infection
including pneumonia in the elderly might be
explained by the mechanism that ageing process
might alter the expression pattern of defensins, leading to the immunosupression and the susceptibility toinfection. We expect that our ongoing study related todefensins could make a contribution to the innateimmunity researches. Furthermore, novel roles ofdefensins might potentially provide a novel therapeutic approach to infectious diseases.
Because the aging process and age-related diseases
are closely associated with vascular aging, to prevent
atherosclerosis is a way to improve physical activity inthe elderly. Our laboratory keeps pursuing the mechanism of atherosclerosis, especially how hormone andits receptor regulate vascular function. We will keep
performing research as to how sex hormones or theirrelated biological materials modulate vascular function in vitro and in vivo. We will also try to elucidate
the mechanism how we can reduce vascular calcification, because vascular calcification appears tightly
linked with vascular aging, which is one of our interests.
We are studying the genetic and environmental
risk factors and prevalence, and incidence of
Alzheimer’s disease among the elderly in Japan.
Because estrogen is one of the key factors that candetermine the stages and prognosis of osteoporosis,
hormone-dependent cancers, and age-related changesof females, we are pursuing prevention and new treatment of osteoporosis and cancer. It may be contribute219

to maintain the constant level of physical and social
activity in elderly peoples. Furthermore, our basic
research focuses on novel findings of new moleculartargets for drug development concerning osteoporosis
and hormone-dependent cancers.
Based on these clinical and basic science data, weare pursuing prevention of a variety of age-related diseases and geriatric syndrome. We also propose standards for facilitation of care across the health service
continuum, care of the nursing home resident, andpalliative and hospice care.

Research Grants
Yasuyoshi Ouchi
1. Grant-in Aid (No.13557062) for Scientific Researchfrom the Minstry of Education, Science and Cultureof Japan. Elucidation of the differential role of estrogen receptor a and b in vascular lesion formation.
1999-2001 (three year research foundation grant B2).
2. Funds for Comprehensive Research on Aging and
Health, Japan Foundation for Aging and Health.
Hormone replacement therapy for elderly women.
Yasuyoshi Ouchi 1998-2000 (three year grant, H10tyojyu-007).
Nagase Takahide
1. Grant-in Aid(No. 12470134) for Scientific Researchfrom the Ministry of Education, Science, Sports andCulture of Japan. The study of molecular mechanisms underlying ARDS using genetically-engineered
mice to develop a novel treatment (three year
research foundation grant B).
2. Health Science Research Grant-in Aid forComprehensive Research on Aging and Health from
the Ministry of Health, Labour and Welfare of Japan.
The study of pathophysiological mechanisms underlying inflammatory/intractable lung diseases in theelderly: a strategic development of novel therapeutic
approaches (H14-).
Yoshio Namba
1. Health Science Research Grant-in Aid for Brain
Science from the Ministry of Health and Welfare ofJapan. Genetic and environmental risk factors for
Alzheimer’s disease (three year grant, H10-H12).

Select Publications
1. Urano T, Saito T, Tsukui T, Fujita M, Hosoi T,
Muramatsu M, Inoue S: Efp targets 14-3-3sigma forproteolysis and promotes breast tumour growth.
Nature 417, 871-875, 2002.
2. Nagase T, Uozumi N, Ishii S, Kita Y, Yamamoto H,
Ohga E, Ouchi Y, Shimizu T. A pivotal role of cytosolic phospholipase A2 in bleomycin-induced pulmonary fibrosis. Nature Med 8: 480-484, 2002.

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3. Nagase T, Ishii S, Shindou H, Ouchi Y, Shimizu T.
Airway hyperresponsiveness in transgenic mice overexpressing platelet activating factor receptor is mediated by an atropine sensitive pathway. Am J Respir
Crit Care Med 165: 200-205, 2002.
4. Hashimoto M, Miyao M, Akishita M, Hosoi T, Toba
K, Kozaki K, YoshizumiM, Ouchi Y. Effects of longterm and reduced-dose hormone replacement therapy on endothelial function and intima-media thickness in postmenopausal women. Menopause. 9:5864, 2002.
5. Iijima K, Yoshizumi M, Hashimoto M, Akishita M,
Kozaki K, Ako J, Watanabe T, Ohike Y, Son B, Yu J,
Nakahara K, Ouchi Y. Red wine polyphenols inhibit
vascular smooth muscle cell migration through two
distinct signaling pathways. Circulation. 105:24042410, 2002.
6. Kageyama A, Hirano T, Kageyama H, Osaka T,
Namba Y, Tsuji M, Adachi M, Inoue S. Distinct roleof adiposity and insulin resistance in glucose intolerance: studies in ventromedial hypothalamic-lesioned
obese rats. Metabolism. 51:716-23, 2002.
7. Kaneki M, Hedges SJ, Hosoi T, Fujiwara S, Lyons A,
Crean SJ, Ishida N, Nakagawa M, Takechi M, Sano Y,
Mizuno Y, Hoshino S, Miyao M, Inoue S, Horiki K,
Shiraki M, Ouchi Y, Orimo H: Japanese fermented
soybean food as the major determinant of the large
geographic difference in circulating levels of vitamin
K2: possible implications for hip-fracture risk.
Nutrition 17, 315-21, 2001.
8. Sudoh N, Toba K, Akishita M, Ako J, Hashimoto M,
Iijima K, Kim S, Liang YQ, Ohike Y, Watanabe T,
Yamazaki I, Yoshizumi M, Eto M, Ouchi Y. Estrogen
prevents oxidative stress-induced endothelial cell
apoptosis in rats. Circulation. 103:724-729, 2001.
9. Yamaguchi Y, Fukuhara S, Nagase T, Tomita T,
Hitomi S, Kimura S, Kurihara H, Ouchi Y. A novel
mouse beta-defensin, mBD-6, predominantly
expressed in skeletal muscle. J Biol Chem 276:
31510-31514, 2001.
10. Ishikawa M, Akishita M, Kozaki K, Toba K, Namiki
A, Yamaguchi T, Orimo H, Ouchi Y. Expression ofparathyroid hormone-related protein in human andexperimental atherosclerotic lesions: functional rolein arterial intimal thickening. Atherosclerosis.
152:97-105, 2000.
11. Inoue S, Ogawa S, Horie K, Hoshino S, Goto W,
Hosoi T, Tsutsumi O, Muramatsu M, Ouchi Y: An
estrogen receptor beta (ER beta) Isoform that lacks
exon 5 has dominant negative activity on both ER
alpha and ER beta. Biochem Biophys Res Commun
279, 814-819, 2000.
12. Miyao M, Hosoi T, Emi M, Nakajima T, Inoue S,
Hoshino S, Shiraki M, Orimo H, Ouchi Y:
Association of bone mineral density with a dinucleotide repeat polymorphism at the calsitonin (CT)locus. J Hum Genet 45: 346-350, 2000.
13. Ogawa S, Emi M, Shiraki M, Hosoi T, Ouchi Y, Inoue
S: Association of estrogen receptor beta (ESR2) gene

polymorphism with blood pressure. J Hum Genet 45:
327-330, 2000.
14. Ogawa S, Fujita M, Ishii Y, Tsurukami H,
Hirabayashi M, Ikeda K, Orimo A, Hosoi T, Ueda S,
Nakamura T, Ouchi Y, Muramatsu M, Inoue S:
Impaired estrogen sensitivity in bone by inhibiting
both estrogen receptor alpha and beta pathways. J
Biol Chem 275: 21372-21379, 2000.
15. Hoshino S, Hosoi T, Miyao M, Shiraki M, Orimo H,
Ouchi Y, Inoue S: Identification of a novel polymorphism of estrogen receptor alpha gene that is associated with calcium excretion in urine. J Bone Miner
Metab 18: 153-157, 2000.
16. Urano T, Hosoi T, Shiraki M, Toyoshima H, Ouchi Y,
Inoue S: Possible involvement of p57Kip2 gene in thebone metabolism. Biochem Biophys Res Commun
269: 422-426, 2000.
17. Miyao M, Morita H, Hosoi T, Kurihara H, Inoue S,
Hoshino S, Shiraki M, Yazaki Y, Ouchi Y: Associationof methylenetetrahydrofolate reductase (MTHFR)
polymorphism with bone mineral density in postmenopausal Japanese women. Calcif Tissue Int 66:
190-194, 2000.
18. Nagase T, Uozumi N, Ishii S, Kume K, Izumi T, Ouchi
Y, Shimizu T. Acute lung injury by sepsis and acidaspiration: a key role for cytosolic phospholipase A2.
Nature Immunol 1: 42-46, 2000.
19. Iijima K, Yoshizumi M, Hashimoto M, Kim S, Eto M,
Ako J, Liang YQ, Sudoh N, Hosoda K, Nakahara K,
Toba K, Ouchi Y. Red wine polyphenols inhibit proliferation of vascular smooth muscle cells and downregulate expression of cyclin A gene. Circulation.
101:805-811, 2000.
20. Nagano K, Toba K, Akishita M, Watanabe T, Kozaki
K, Eto M, Hashimoto M, Sudoh N, Ako J, Yoshizumi
M, Ouchi Y. Prostanoids regulate proliferation of vascular smooth muscle cells induced by arginine vasopressin. Eur J Pharmacol. 389:25-33, 2000.
21. Hashimoto M, Eto M, Akishita M, Kozaki K, Ako J,
Iijima K, Kim S, Toba K, Yoshizumi M, Ouchi Y.
Correlation between flow-mediated vasodilatation of
the brachial artery and intima-media thickness in the
carotid artery in men. Arterioscler Thromb Vasc Biol.
19:2795-2800, 1999.
22. Motoi Y, Aizawa T, Haga S, Nakamura S, Namba Y
Ikeda K. Neuronal localization of a novel mosaic
apolipoprotein E receptor, LR11, in rat and humanbrain. Brain Res: 833:209-215, 1999.
23. Namba Y, Ouchi Y, Takeda A, Ueki A Ikeda K.
bleomycin hydrolase immunoreactivity in senile
plaque in the brains of patients with Alzheimer’s disease. Brain Res: 830:200-202, 1999.
24. Namba Y, Ouchi Y, Asada T, Ueki A and Ikeda K.
Lack of association between bleomycin hydrolase
gene polymorphism and Alzheimer’s disease inJapanese people. Ann Neurol, 46:136-137, 1999.
25. Nagase T, Kurihara H, Kurihara Y, Aoki-Nagase T,
Nagai R, Ouchi Y. Disruption of ET-1 gene enhances
pulmonary responses to methacholine via functional

mechanism in knockout mice. J Appl Physiol
87:2020-2024, 1999.
26. Nagase T, Ishii S, Kume K, Uozumi N, Izumi T, Ouchi
Y, Shimizu T. Platelet-activating factor mediates acidinduced lung injury in genetically engineered mice. J
Clin Invest 104: 1071-1076, 1999.
27. Ohga E, Nagase T, Tomita T, Teramoto S, Matsuse T,
Katayama H, Ouchi Y. Increased levels of circulating
ICAM-1, VCAM-1, and L-selectin in obstructive sleep
apnea syndrome. J Appl Physiol 87: 10-14, 1999.
28. Nagase T, Kurihara H, Kurihara Y, Aoki T, Fukuchi
Y, Yazaki Y, Ouchi Y. Airway hyperresponsiveness tomethacholine in mutant mice deficient in endothelin-1. Am J Respir Crit Care Med 157: 560-564, 1998.
29. Hashimoto M, Akishita M, Eto M, Kozaki K, Ako J,
Sugimoto N, Yoshizumi M, Toba K, Ouchi Y. The
impairment of flow-mediated vasodilatation in obese
men with visceral fat accumulation. Int J Obes Relat
Metab Disord.22:477-484, 1998.
30. Akishita M, Kozaki K, Eto M, Yoshizumi M,
Ishikawa M, Toba K, Orimo H, Ouchi Y. Estrogenattenuates endothelin-1 production by bovine
endothelial cells via estrogen receptor. Biochem
Biophys Res Commun. 251:17-21, 1998.
31. Ishikawa M, Akishita M, Kozaki K, Toba K, Namiki
A, Yamaguchi T, Orimo H, Ouchi Y. Amino-terminal
fragment (1-34) of parathyroid hormone-related protein inhibits migration and proliferation of cultured
vascular smooth muscle cells. Atherosclerosis.
136:59-66, 1998.
32. Kozaki K, Akishita M, Eto M, Yoshizumi M, Toba K,
Inoue S, Ishikawa M, Hashimoto M, Kodama T,
Yamada N, Orimo H, Ouchi Y. Role of activin-A andfollistatin in foam cell formation of THP-1
macrophages. Arterioscler Thromb Vasc Biol.
17:2389-2394, 1997.
33. Akishita M, Ouchi Y, Miyoshi H, Kozaki K, Inoue S,
Ishikawa M, Eto M, Toba K, Orimo H. Estrogen
inhibits cuff-induced intimal thickening of rat
femoral artery: effects on migration and proliferationof vascular smooth muscle cells. Atherosclerosis.
130:1-10, 1997.
34. Shiraki M, Shiraki Y, Aoki C, Hosoi T, Inoue S,
Kaneki M, Ouchi Y: Association of Bone mineral density with apolipoprotein E phenotype. J Bone Miner
Res12: 1438-1445, 1997.
35. Nagano K, Toba K, Akishita M, Kozaki K, Eto M,
Hashimoto M, Sudoh N, Yoshizumi M, Ouchi Y.
Identification of arginine vasopressin mRNA in rat
aortic smooth muscle cells. Biochem Biophys Res
Commun. 231:831-834, 1997.
36. Nagase T, Ishii S, Katayama H, Fukuchi Y, Ouchi Y,
Shimizu T. Airway responsiveness in transgenic miceoverexpressing platelet activating factor receptor:
roles of thromboxanes and leukotrienes. Am J Respir
Crit Care Med 156: 1621-1627, 1997.
37. Nagase T, Aoki T, Oka T, Fukuchi Y, Ouchi Y. ETinduced bronchoconstriction is mediated via ETB
receptor in mice. J Appl Physiol 83: 46-51, 1997.

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38. Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S,
Tashiro F, Komagata Y, Maki K, Ikuta K, Ouchi Y,
Miyazaki J, Shimizu T. Role of cytosolic phospholipase A2 in allergic response and parturition. Nature
390: 618-622, 1997.
39. Akishita M, Ouchi Y, Miyoshi H, Orimo A, Kozaki K,
Eto M, Ishikawa M, Kim S, Toba K, Orimo H.
Estrogen inhibits endothelin-1 production and c-fos
gene expression in rat aorta. Atherosclerosis. 125:2738, 1996.
40. Inoue S, Hoshino S, Miyoshi H, Akishita M, Hosoi T,
Orimo H, Ouchi Y: Identification of a novel isoform
of estrogen receptor, a potential inhibitor of estrogenaction, in vascular smooth muscle cells. Biochem
Biophys Res Commun 219: 766-772, 1996.
41. Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M,
Orimo H: Association of bone mineral density withpolymorphism of the estrogen receptor gene. J Bone
Miner Res 11: 306-311, 1996.
42. Nagase T, Ohga E, Katayama H, Sudo E, Aoki T,
Matsuse T, Ouchi Y, Fukuchi Y. Roles of calcitonin
gene&#64979;related peptide (CGRP) in hyperpneainduced constriction in guinea pigs. Am J Respir Crit
Care Med 154: 1551-1556,1996.
43. Hashimoto M, Akishita M, Eto M, Ishikawa M,
Kozaki K, Toba K, Sagara Y, Taketani Y, Orimo H,
Ouchi Y. Modulation of endothelium-dependent
flow-mediated dilatation of the brachial artery by sex
and menstrual cycle.Circulation. 92:3431-3435, 1995.
44. Okuizumi K, Onodera O, Namba Y, Ikeda K,
Yamamoto T, Ueki A, Nanko S, Tanaka H,
Takahashi H, Oyanagi S, Tsuji S. Genetic associationof the very low density lipoprotein (VLDL) receptor
gene with sporadic Alzheimer’s disease. Nature
Genet, 11:207-209, 1995.
45. Ishikawa M, Ouchi Y, Akishita M, Kozaki K, Toba K,
Namiki A, Yamaguchi T, Orimo H.
Immunocytochemical detection of parathyroid hormone-related protein in vascular endothelial cells.
Biochem Biophys Res Commun.199:547-551, 1994.
46. Ishikawa M, Ouchi Y, Han SZ, Akishita M, Kozaki K,
Toba K, Namiki A, Yamaguchi T, Orimo H.
Parathyroid hormone-related protein reduces cytosolic free Ca2+ level and tension in rat aortic smoothmuscle. Eur J Pharmacol. 269:311-317, 1994.
47. Orimo A, Inoue S, Ikegami A, Hosoi T, Akishita M,
Ouchi Y, Muramatsu M, Orimo H. Vascular smoothmuscle cells as target for estrogen. Biochem Biophys
Res Commun. 195:730-736, 1993.
48. Ishikawa M, Ouchi Y, Orimo H. Effect of calcitonin
gene-related peptide on cytosolic free Ca2+ level invascular smooth muscle. Eur J Pharmacol.246:121128, 1993.
49. Namba Y, Tomonaga M, Kawasaki H, Otomo E,
Ikeda K. Apolipoprotein E immunoreactovity in cerebral amyloid deposits and neurofibrillary tangles in
Alzheimer’s disease and kuru plaque amyloid in
Creutzfeldt-Jakob disease. Brain Res, 541:163-166,
1991.

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