Implications of neural stem cells for the pathogenesis of schizophrenia : A new target for schizophrenia research

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 15209036
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: MORI Norio Hamamatsu University School of Medicine, Psychiatry and Neurology, Professor, 医学部, 教授 (00174376)
• Co-Investigator(Kenkyū-buntansha): TAKEI Noriyoshi Hamamatsu University School of Medicine, Psychiatry and Neurology, Associate Professor, 医学部, 助教授 (80206937) ; MINABE Yoshio Hamamatsu University School of Medicine, Psychiatry and Neurology, Lecturer, 医学部附属病院, 講師 (60181947) ; NAKAMURA Kazuhiko Hamamatsu University School of Medicine, Psychiatry and Neurology, Lecturer, 医学部附属病院, 講師 (80263911) ; SATO Kohji Hamamatsu University School of Medicine, Anatomy, Professor, 医学部, 教授 (80235340)
• Project Period (FY): 2003 – 2005
• Keywords: schizophrenia / neural stem cell / animal model / LIFR knockout mice / VLDLR / ApoER2 / x-irradiation / peripheral biological markers

Research Abstract

1.An animal model for schizophrenia based on hypothesis of neural stem cell dysfunction :
(1)Male Sprague-Dawley rats were irradiated to the forebrain using 6 fractions of 5 Gy. After 12 weeks, neural stem cells (BrdU positive cells) were diminished in both subventricular zone and hippocampal dentate gyrus subgranular zone. A significant increase in locomotor activity after administration of methamphetamine (MAP) (2 mg/kg i.p.) or MK-801 (0.2 mg/kg i.p.) was observed. Acoustic prepulse inhibition and social behaviors of the irradiated rats were significantly decreased. Moderate impairments of spatial working memory and reference memory assessed by Morris water maze were found in the model rats. (2)It has been reported that LIFR-deficient mice revealed a reduction in the number of adult neural stem cells. Locomotor activity induced by MAP was significantly increased in the LIFR knockout mice. However, behavioral change after MK-801 or prepulse inhibition of startle responces was not obse rved. (3)We transplanted embryonic neural precursor cells (NPCs) into the bilateral ventricles and the dentate gyri of the irradiated rats at 3 months after irradiation. The MAP-induce hyperactivity was not ameliorated at 4 weeks after the NPCs transplantation.
2.Peripheral biological markers for schizophrenia :
Reelin is a secretory protease with major roles in neurodevelopment and plasticity. A reduction of reelin expression is one of the most robust molecular findings in schizophrenia. Apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR) are reelin receptors. In search for peripheral biological markers for schizophrenia we have investigated mRNA levels of ApoER2 and VLDLR in peripheral blood lymphocytes of drug naive patients with schizophrenia, mood disorder and healthy controls. We observed a significant decrease of VLDLR mRNA levels in schizophrenia, but not those in mood disorder, compared with controls. A significant decrease in the ApoER2 mRNA level was found only in mood disorder.

Research Products

• [Journal Article] Association between polymorphisms in the promoter region of the sialyltransferase 8B (SIAT8B) gene and schizophrenia. (2006)
  • Author(s): Arai M, Yamada K, Toyota T, Obata N, Haga S, Yoshida Y, Nakamura K, Minabe Y, Ujike H, Sora I, Ikeda K, Mori N, Yoshikawa T, Itokawa M.
  • Journal Title: Biol Psychiatry. 59(7) Pages: 652-659
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A transient lesion in splenium of the corpus callosum in a patient with childhood-onset anorexia nervosa. (2006)
  • Author(s): Nishimura K, Takei N, Suzuki K, Kawai M, Sekine Y, Isoda H, Mori N.
  • Journal Title: Int J Eat Disord. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Evidence that variation in the peripheral benzodiazepine receptor (PBR) gene influences susceptibility to panic disorder. (2006)
  • Author(s): Nakamura K, Yamada K, Iwayama Y, Toyota T, Furukawa A, Takimoto T, Terayama H, Iwahashi K, Takei N, Minabe Y, Sekine Y, Suzuki K, Iwata Y, Pillai A, Nakamoto Y, Ikeda K, Yoshii M, Fukunishi I, Yoshikawa T, Mori N.
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet. 141(3) Pages: 222-226
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased rate of birth complications and small head size at birth in winter-born male patients with schizophrenia. (2006)
  • Author(s): Takagai S, Kawai M, Toulopoulou T, Tsuchiya KJ, Mori N, Takei N.
  • Journal Title: Schizophr Res. 83(2-3) Pages: 303-305
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Brain serotonin transporter density and aggression in abstinent methamphetamine abusers. (2006)
  • Author(s): Sekine Y, Ouchi Y, Takei N, Yoshikawa E, Nakamura K, Futatsubashi M, Okada H, Minabe Y, Suzuki K, Iwata Y, Tsuchiya KJ, Tsukada H, Iyo M, Mori N.
  • Journal Title: Arch Gen Psychiatry. 63(1) Pages: 90-100
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 海馬の細胞新生と統合失調症 (2005)
  • Author(s): 鈴木 勝昭
  • Journal Title: CLINICAL NEUROSCIENCE 23・1 Pages: 43-45
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 統合失調症の神経幹細胞機能異常仮説 (2005)
  • Author(s): 森 則夫
  • Journal Title: 脳21 8・1 Pages: 34-38
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 統合失調症の神経幹細胞機能異常仮説 (2005)
  • Author(s): 森 則夫
  • Journal Title: 医学のあゆみ 212・8 Pages: 768-769
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 認知機能と分子生物学(認知障害にかかわる遺伝子背景を含めて) (2005)
  • Author(s): 三辺 義雄
  • Journal Title: 分子精神医学 5 Pages: 21-27
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effective adjunctive use of pergolide with quetiapine for cognitive impairment and negative symptoms in schizophrenia. (2005)
  • Author(s): Sekine Y, Takei N, Suzuki K, Nakamura K, Tsuchiya KJ, Takebayashi K, Toulopoulou T, Mori N.
  • Journal Title: J Clin Psychopharmacol. 25(3) Pages: 281-283
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Right orbitofrontal region and obsessive-compulsive behavior : a case report. (2005)
  • Author(s): Ogai M., Iyo M., Mori N., Takei N.
  • Journal Title: Acta Psychiat Scand 111(1) Pages: 74-76
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Advanced Paternal Age Associated with an Elevated Risk for Schizophrenia in Offspring in a Japanese Population. (2005)
  • Author(s): Tsuchiya K.J., Takagai S., Kawai M., Matsumoto H., Nakamura K., Minabe Y., Mori N., Takei N.
  • Journal Title: Schizophr Res 76 Pages: 337-342
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional polymorphism of HSPA5 : Possible association with bipolar disorder. (2005)
  • Author(s): Kakiuchi C, Ishiwata M, Nanko S, Kunugi H, Minabe Y, Nakamura K, Mori N, Fujii K, Umekage T, Tochigi M, Kohda K, Sasaki T, Yamada K, Yoshikawa T, Kato T.
  • Journal Title: Biochemistry Biophysics Research Communications 336 Pages: 1136-1143
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia. (2005)
  • Author(s): Kato T, Iwayama Y, Kakiuchi C, Iwamoto K, Yamada K, Minabe Y, Nakamura K, Mori N, Fujii K, Nanko S, Yoshikawa T.
  • Journal Title: Mol Psychiatry.
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders : evidence for association of ASCU with Parkinson's disease. (2005)
  • Author(s): Ide M, Yamada K, Toyota T, Iwayama Y, Ishitsuka Y, Minahe Y, Nakamura K, Hattori N, Asada T, Mizuno Y, Mori N, Yoshikawa T.
  • Journal Title: Hum Genet.
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] No changes in serum epidermal growth factor levels in patients with schizophrenia. (2005)
  • Author(s): Hashimoto K., Shimizu E., Komatsu N., Watanabe H., Shinoda N., Nakazato M., Kumakiri C., Okada S., Takei N., Iye M.
  • Journal Title: Psychiatr.Res. 135(3) Pages: 257-260
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional polymorphism of HSPA5 : Possible association with bipolar disorder. (2005)
  • Author(s): Kakiuchi C, Ishikawa M, Nanko S, Kunugi H, Minabe Y, Nakamura K, Mori N, Fujii K, Umegaki T, Tochigi M, Kohda K, Sasaki T, Yamada K, Yoshikawa T, Kato T.
  • Journal Title: Biochemistry Biophysics Research Communications 336 Pages: 1136-1143
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association between Polymorphisms in the Promoter Region of the Sialyltransferase B (SIAT8B) Gene and Schizophrenia. (2005)
  • Author(s): Arai M, Yamada K, Toyota T, Obata N, Haga S, Yoshida Y, Nakamura K, Minabe Y, Ujike H, Sora I, Ikeda K, Mori N, Yoshikawa T, Itokawa M.
  • Journal Title: Biological Psychiatry (on-line published)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders : evidence for association of ASCL1 with Parkinson's disease. (2005)
  • Author(s): Ide M, Yamada K, Toyota T, Iwayama Y, Ishitsuka Y, Minabe Y, Nakamura K, Hattori N, Asada T, Mizuno Y, Mori N, Yoshikawa T.
  • Journal Title: Hum Genet.
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] No changes in serum epidermal growth factor levels inpatients with schizophrenia. (2005)
  • Author(s): Hashimoto K., Shimizu E., Komatsu N., Watanabe H., Shinoda N., Nakazato M., Kumakiri C., Okada S., Takei N., Iyo M.
  • Journal Title: Psychiatr.Res. 135(3) Pages: 257-260
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Stigmatisation of people with schizophrenia in Japan. (2005)
  • Author(s): Takei N, Takagai S, Mori N.
  • Journal Title: Br J Psychiatry. 187 Pages: 589-590
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B (2004)
  • Author(s): Toyota Tomoko
  • Journal Title: Human Molecular Genetics 13・5 Pages: 551-561
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genetic Expression Analysis of FZD3 in Schizophrenia (2004)
  • Author(s): Masayuki Ide
  • Journal Title: Biol Psychiatry 56・6 Pages: 462-465
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Childhood-onset schizophrenia and tryptophan hydroxylase gene polymorphism (2004)
  • Author(s): Sekizawa T., Iwata Y., Nakamura K., Matsumoto H., Suzuki A., Minabe Y., Mori N.
  • Journal Title: Am J Med Genet 128B Pages: 24-26
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Focus on psychiatry in Japan. (2004)
  • Author(s): Tsuchiya K.J., Takei N.
  • Journal Title: Br J Psychiatr 184 Pages: 88-92
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Do Jiko-shu-kyofu (a subtype of Taijin-kyofu) and olfactory reference syndrome share a common entity? (2004)
  • Author(s): Suzuki K., Takei N., Sekine Y., Tani K., Toyoda T., Ohashi Y., Kawai M., Hoshino R., Iyo M., Mori N.
  • Journal Title: Acta Psychiar Scand 109(2) Pages: 150-155
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Metabolite Alterations in Basal Ganglia Associated with Psychiatric Symptoms of Abstinent Toluene Users : A Proton MRS Study. (2004)
  • Author(s): Takebayashi K., Sekine Y., Takei N., Minabe Y., Isoda H., Takeda H., Nishimura K., Nakamura K., Suzuki K., Iwata Y., Sakahara H., Mori N.
  • Journal Title: Neuropsychopharmacol 29(5) Pages: 1019-1026
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Is inseki-jisatsu, responsibility-driven suicide, a culture-bound form of suicide? (2004)
  • Author(s): Takei N., Nakamura K.
  • Journal Title: Lancet 363(9418) Pages: 1400
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Childhood-onset schizophrenia and tryotophan hydroxylase gene polymorphism. (2004)
  • Author(s): Sekizawa T., Osada N., Iwata Y., Matsumoto H., Suzuki K., Minabe Y., Takei N., Mori N.
  • Journal Title: Am J Med Genet 128B(1) Pages: 24-26
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Poor maternal care and high maternal body mass index in pregnancy as a risk factor for schizophrenia in offspring. (2004)
  • Author(s): Kawai M., Minabe Y., Takagai S., Ogai M., Matsumoto H., Mori N., Takei N.
  • Journal Title: Acta Psychiat Scand 110(4) Pages: 257-263
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genetic and expression analyses of FDZ3 in schizophrenia. (2004)
  • Author(s): Ide M., Muratake T., Yamada K., Iwayama-Shigeno Y., Iwamoto K., Takao H., Toyota T., Kaneko N., Minabe Y., Nakamura K., Kato T., Mori N., Asada T., Someya T., Yoshikawa T.
  • Journal Title: Biol Psychiatry 56 Pages: 462-465
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 1H NMR spectroscopy show an increase in the NAAG and glutamate contents in the hippocampus of amygdaloid kindled rat. (2004)
  • Author(s): Shirayama Y., Takahashi S., Minabe Y., Ogino T.
  • Journal Title: J Neurochem 92 Pages: 1317-1326
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Augmentation of milnacipran by risperidone in treatment for major depression. (2004)
  • Author(s): Tani K., Takei N., Kawai M., Suzuki K., Sekine Y., Minabe Y., Mori N.
  • Journal Title: Int J Neuropsychopharmacol 7(1) Pages: 55-58
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers. (2004)
  • Author(s): Koizumi H., Hashimoto K., Kumakiri C., Shimizu E., Sekine Y., Ozaki N., Inada T., Harano M., Komiyama T., Yamada M., Sora I., Ujike H., Takei N., Iyo M.
  • Journal Title: Am J Med Genet 126B(1) Pages: 43-45
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Obstetric adversity and age at the first presentation in schizophrenia : evidence of a casual relationship. (2004)
  • Author(s): Kelly B.D., Feeney L., Browne R.., Byrne M.., Mulryyan N., Scully A., Morris M., Kinesella A., Takei N., McNeil T., Walsh D., Larkin C., O'Callaghan E.
  • Journal Title: Am J Psychatr 161. 161(5) Pages: 920-922
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A polydiagnostic and dimensional comparison of epileptic psychoses and schizophrenia sepctrum disorders. (2004)
  • Author(s): Matsuura M., Adachi N., Oana Y., Okubo Y., Kato M., Nakano T., Takei N.
  • Journal Title: Schizophr Res 69(2-3) Pages: 189-201
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts. (2004)
  • Author(s): Yamada K., Nakamura K., Minabe Y., Iwayama-Shigeno Y., Takao H., Toyota T., Hattori E., Takei N., Sekine Y., Suzuki K., Iwata Y., Miyoshi K., Honda A., Baba K., Katayama T., Tohyama M., Mori N., Yoshikawa T.
  • Journal Title: Biol Psychiatr 56(9) Pages: 683-690
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of FEZ1 gene-variants including Asp 123Glu with schizophrenia subset in Japan. (2004)
  • Author(s): Yamada K.#, Nakamura K.#, Minabe Y.# (#equally contributed to this work), Shigeno Y., Takao H., Toyota T., Hattori E., Takei N., Sekine Y., Suzuki K., Iwata Y., Miyoshi K., Honda A., Baba K., Katayama T., Tohyama M., Mori N., Yoshikawa T.
  • Journal Title: Biol Psychiatry 56 Pages: 583-590
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. (2004)
  • Author(s): Toyota T., Yoshitsugu K., Ebihara M., Yamada K., Ohba H., Fukasawa M., Minabe Y., Nakamura K., Sekine Y., Takei N., Suzuki K., Itokawa M., Meerabux J.M., Iwayama-Shigeno Y., Tomaru Y., Shimizu H., Hattori E., Mori N., Yoshikawa T.
  • Journal Title: Hum Mol Genet 13(5) Pages: 551-561
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers. (2004)
  • Author(s): Koizumi H., Hashimoto K., Kumakiri C., Shimizu E., Sekine Y., Ozaki N., Inada T., Harano M., Komiyama T., Yamada M., Sora I., Ujike H., Takei N., Iyo M.
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet 126(1) Pages: 43-45
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuromechanism of developing methamphetamine psychosis : a neuroimaging study. (2004)
  • Author(s): Iyo M., Sekine Y., Mori N
  • Journal Title: Ann.N.Y.Acad Sci 1025 Pages: 288-295
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• [Journal Article] Related Articles, Links Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats : an in vivo electrophysiological study. (2004)
  • Author(s): Minabe Y, Shirayama Y, Hashimoto K, Routledge C, Hagan JJ, Ashby CR Jr.
  • Journal Title: Synapse. 52(1) Pages: 20-28
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of the acute and chronic administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12- (4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on spontaneously active rat midbrain dopamine neurons : an in vivo electrophysiological study. (2004)
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• [Journal Article] Untility of neuropsychological tests to genetic studies of schizophrenia. (2004)
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• [Journal Article] Two cases of perospirone-induced mania in schizophrenia. (2004)
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  • Journal Title: J Clin Psychiatr 65 Pages: 135
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• [Journal Article] Is taijin kyofusho a culture-bound syndrome? (2003)
  • Author(s): Suzuki K, Takei N, Kawai M, Minabe Y, Mori N.
  • Journal Title: Am J Psychiatry. 160(7) Pages: 1358
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• [Journal Article] Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms. (2003)
  • Author(s): Sekine Y, Minabe Y, Ouchi Y, Takei N, Iyo M, Nakamura K, Suzuki K, Tsukada H, Okada H, Yoshikawa E, Futatsubashi M, Mori N.
  • Journal Title: Am J Psychiatry. 160(9) Pages: 1699-1701
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• [Journal Article] Auditory hallucinations and cognitive impairment in a patient with a lesion restricted to the hippocampus. (2003)
  • Author(s): Suzuki K, Takei N, Toyoda T, Iwata Y, Hoshino R, Minabe Y, Mori N.
  • Journal Title: Schizophr Res. 164(1) Pages: 87-89
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• [Journal Article] Acetaldehyde adducts in the brain of alcoholics. (2003)
  • Author(s): Nakamura K, Iwahashi K, Furukawa A, Ameno K, Kinoshita H, Ijiri I, Sekine Y, Suzuki K, Iwata Y, Minabe Y, Mori N.
  • Journal Title: Arch Toxicol. 77(10) Pages: 591-593
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• [Journal Article] Acute and chronic administration of the selective 5-HT1A receptor antagonist WAY-405 significantly alters the activity of midbrain dopamine neurons in rats : an in vivo electrophysiological study. (2003)
  • Author(s): Minabe Y, Schechter L, Hashimoto K, Shirayama Y, Ashby CR Jr.
  • Journal Title: Synapse. 50(3) Pages: 181-190
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• [Journal Article] Inseki-jisatsu, shinju (double suicide), and muri-shinju (forced suicide).
  • Author(s): Takei N., Nakamura K., Kawai M.
  • Journal Title: Brit.J.Psychatr. (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An association study between COMT gene polymorphism and methamphetamine psychotic disorder
  • Author(s): Suzuki A., Nakamura K., Sekine Y., Minabe Y., Takei N., Suzuki K., Iwata Y., Kawai M., Takebayashi K., Iyo M., Ozaki N., Inada T., Iwata N., Harano M., Komiyama T., Yamada M., Sora I., Ujike H., Mori N.
  • Journal Title: Psychiat Genet (In press)
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• [Book] Infection and Psychiatric Disoders (2005)
  • Author(s): S.H.Fatemi
  • Total Pages: 282
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  • Description: 「研究成果報告書概要(和文)」より
• [Book] Have recent studies of the seasonality of birth in schizophrenia added to our knowledge of the disease? (Infection and Psychiatric Disoders(eds.S.H.Fatemi, R.A.Machon.)) (2005)
  • Author(s): Kawai M., Takei N., Murray R.M.
  • Total Pages: 1-10
  • Publisher: Taylor & Francis
  • Description: 「研究成果報告書概要(欧文)」より