Yoshihiro Fukui

Publications (69)96.73 Total impact

• Article: Prenatal ethanol exposure impairs passive avoidance acquisition and enhances unconditioned freezing in rat offspring.

  Ken-ichi Ohta, Hiromi Sakata-Haga, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: Previous studies have suggested that ethanol exposure during brain development affects responses to fear and anxiety after maturity. To clarify in detail the impaired behavior related to fear and anxiety seen in rat offspring prenatally exposed to ethanol, their behaviors were observed using an elevated T-maze (ETM) test, which allows assessment of passive avoidance acquisition and one-way escape separately, and an elevated open platform (EOP) test for the assessment of unconditioned freezing against innate fear. The ETM test revealed that acquisition of passive avoidance was significantly inhibited in prenatally ethanol-exposed rats, while their escape behavior was not altered. In the EOP test, the duration of the freezing behavior was significantly elongated in prenatally ethanol-exposed offspring. Thus, we concluded that prenatal ethanol exposure could impair acquisition of passive avoidance, while it could facilitate a response related to unconditioned fears in rat offspring.
  Behavioural brain research 07/2012; 234(2):255-8. · 3.22 Impact Factor
• Article: Fetal gyrification in cynomolgus monkeys: a concept of developmental stages of gyrification.

  Kazuhiko Sawada, Katsuhiro Fukunishi, Masatoshi Kashima, Shigeyoshi Saito, Hiromi Sakata-Haga, Ichio Aoki, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: Our article summarizes a series of studies about fetal gyrification and its relation to cerebral growth in cynomolgus monkeys. Based on the cerebral growth (i.e., brain weight, cerebral volume, and frontooccipital length of the cerebral hemisphere) and the developmental pattern of gyrification in each sulcus of cynomolgus monkeys, we divided the gyrification process into four stages: Stage 1. Demarcation of cerebral lobes and limbic gyri; Stage 2. Demarcation of neocortical gyri; Stage 3. Emergence of secondary and tertiary sulci; and Stage 4. Growth of sulcal length and depth. Each stage of those gyrification processes was influenced by different developmental events, such as the emergence of corticocortical long-associative fiber tracts, cortical maturations, and subcortical white-matter development. This is the first report to systematically propose gyrification processes closely related to the order of phyologenetical development of the cerebral cortex in primates.
  The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 05/2012; 295(7):1065-74. · 1.47 Impact Factor
• Article: Neuroanatomic and magnetic resonance imaging references for normal development of cerebral sulci of laboratory primate, cynomolgus monkeys (Macaca fascicularis).

  Kazuhiko Sawada, Katsuhiro Fukunishi, Masatoshi Kashima, Noritaka Imai, Shigeyoshi Saito, Hiromi Sakata-Haga, Ichio Aoki, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: Cynomolgus monkey (Macaca fascicularis) is a popular laboratory primate belonging to Old World monkeys, which are the group most closely related to humans except for the apes. This paper summarizes a series of our studies regarding the development of cerebral sulci and gyri in this primate, and the stated possibility of evaluation of the sulcal development for assessing the developmental toxicity testing. The cerebrum of cynomolgus monkeys experienced a regular sequence of emergence of sulci and gyri on gross observation while such timetables corresponded to those obtained by magnetic resonance imaging (MRI) with a lag time of 10-30 days. When the timetables for the emergence of anatomically identical primary sulci and gyri were compared between cynomolgus monkeys and humans, their chronological sequences were comparable, while some sulci and gyri located on the phylogenetically newer cortical region in humans emerged earlier in monkeys. The present paper further indicates brief procedures for evaluating cerebral abnormalities and/or maturity using brain specimens without MRI measurements. The primary sulcal lengths measured by the 'cotton thread' method were a brief index of the degree of regional gyrification. As the development of a calcarine sulcus was closely correlated with morphological maturation of the lateral ventricle, which changed drastically during embryonic days (EDs) 90-100, the cerebral maturity on ED 100 could be evaluated by the infolding of that sulcus. Thus, the present paper provides gross anatomical and MRI references and brief procedures for investigating the normality of the development of cerebral sulci and gyri of laboratory primates, cynomolgus monkeys.
  Congenital Anomalies 03/2012; 52(1):16-27.
• Article: Sexual dimorphism of sulcal length asymmetry in the cerebrum of adult cynomolgus monkeys (Macaca fascicularis).

  Noritaka Imai, Kazuhiko Sawada, Katsuhiro Fukunishi, Hiromi Sakata-Haga, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: The present study aimed to quantitatively clarify the gross anatomical asymmetry and sexual dimorphism of the cerebral hemispheres of cynomolgus monkeys. While the fronto-occipital length of the right and left cerebral hemispheres was not different between sexes, a statistically significant rightward asymmetry was detected in the cerebral width at the perisylvian region in females, but not in males (narrower width of the left side in the females). An asymmetry quotient of the sulcal lengths revealed a rightward asymmetry in the inferior occipital sulcus and a leftward asymmetry in the central and intraparietal sulci in both sexes. However, the laterality of the lengths of other sulci was different for males and females. The arcuate sulcus was directed rightward in males but there was no rightward bias in females. Interestingly, the principle sulcus and lateral fissure were left-lateralized in the males, but right-lateralized in the females. The results suggest that lateralization patterns are regionally and sexually different in the cerebrum of cynomolgus monkeys. The present results provide a reference for quantitatively evaluating the normality of the cerebral cortical morphology in cynomolgus monkeys.
  Congenital Anomalies 12/2011; 51(4):161-6.
• Article: Correlation between formation of the calcarine sulcus and morphological maturation of the lateral ventricle in cynomolgus monkey fetuses.

  Katsuhiro Fukunishi, Kazuhiko Sawada, Masatoshi Kashima, Shigeyoshi Saito, Hiromi Sakata-Haga, Takayuki Sukamoto, Ichio Aoki, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: In the present study developmental changes in the cerebral sulci and volumes of subcortical and archicortical structures of the cerebrum in cynomolgus monkey fetuses were examined with T(1)-weighted magnetic resonance (MR) images in 3D. On the embryonic day (ED) 90, the lateral ventricle had still an immature vesicular shape in the occipital region of the cerebrum, and it dramatically closed its lumen by ED 100. In that period the calcarine sulcus progressively infolded from the medial surface of the cerebral hemisphere narrowing the lumen of the lateral ventricle in the occipital region. Volume of the lateral ventricle decreased in the period ED 90-100, increasing afterwards in spite of increasing volumes of subcortical and archicortical structures such as the caudate nucleus, putamen, globus pallidus, amygdala and hippocampal formation. During the same time, the volume of the germinal matrix around lateral ventricles decreased to disappear completely by ED 120. These results suggest that the morphological maturation of lateral ventricle is linked to the development of calcarine sulcus in cynomolgus monkey fetuses. The degree of infolding of calcarine sulcus on ED 100 would be useful as a gross anatomical landmark for evaluating the cerebral maturation in cynomolgus monkey fetuses.
  Acta neurobiologiae experimentalis 01/2011; 71(3):381-6. · 2.11 Impact Factor
• Article: Alternating array of tyrosine hydroxylase and heat shock protein 25 immunopositive Purkinje cell stripes in zebrin II-defined transverse zone of the cerebellum of rolling mouse Nagoya.

  Kazuhiko Sawada, Hiromi Sakata-Haga, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: The present study examined the spatial organization of tyrosine hydroxylase (TH) immunopositive Purkinje cells in the cerebellum of rolling mouse Nagoya with reference to the distribution pattern of the cerebellar compartmentation antigen, heat shock protein 25 (HSP25). Whole-mount immunostaining revealed a striking pattern of parasagittal stripes of TH staining in the rolling mouse cerebellum but not in the control cerebellum. Although the TH stripes resembled the zebrin II stripes in the rolling cerebellum, these two distributions did not completely overlap. The TH stripes were present in the lobules VI and VII (central zone), the lobule X (nodular zone), and the paraflocculus, where zebrin II immunostaining was uniformly expressed. Double immunostaining revealed that TH stripes were aligned in an alternative fashion with HSP25 stripes within the caudal half of lobule VIb, lobules IXb and X, and paraflocculus. Some, but not all, TH stripes shared boundaries with HSP25 stripes. These results revealed an alternating array of TH immunopositive Purkinje cell subsets with HSP25 immunopositive Purkinje cells in the zebrin II-defined transverse zone of the rolling mouse cerebellum. The constitutive expression of HSP25 may prevent the ectopic expression of TH in zebrin II immunopositive Purkinje cell subsets.
  Brain research 05/2010; 1343:46-53. · 2.46 Impact Factor
• Article: Alteration in anxiety-related behaviors and reduction of serotonergic neurons in raphe nuclei in adult rats prenatally exposed to ethanol.

  Ken-ichi Ohta, Hiromi Sakata-Haga, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: It is known that the developing serotonergic system is one of the targets of ethanol teratogenicity. Because serotonin has multiple functions in both mature and immature brains, disturbance of the serotonergic system by ethanol exposure in utero can be cause of a wide range of psychiatric problems in adulthood. In the present study, we observed serotonergic neurons in the midbrain raphe nuclei and anxiety-like behaviors which would be affected by an altered serotonergic system in adult rats prenatally exposed to ethanol. Pregnant rats were fed a liquid diet containing 2.5-5.0% (w/v) ethanol on gestational days 10-21. Their offspring were examined at 60-70 days of age. A significant decrease in the number of serotonergic cells in the midbrain raphe nuclei was shown in prenatally ethanol-exposed offspring. In an open field test, they spent more time in a central area compared to controls. Also in an elevated plus maze test, prenatally ethanol-exposed offspring spent more time on the open arms than controls. These behavioral results suggested that prenatally ethanol-exposed rats were less sensitive to anxiety. However, 44% of prenatally ethanol-exposed offspring exhibited freezing behavior on the open arms of the elevated plus maze, causing strong anxiety, compared with 0% in intact control and 12.5% in isocaloric sucrose-fed control groups. These findings suggest that prenatal ethanol exposure decreases both susceptibility and resistance of anxiety. Insufficient serotonergic actions caused by reduced serotonergic neurons in the raphe nuclei might contribute to the alterations in anxiety-related behaviors observed in our prenatally ethanol-exposed rats.
  Congenital Anomalies 02/2010; 50(2):105-14.
• Article: Embryonic exposure to ethanol disturbs regulation of mitotic spindle orientation via GABA(A) receptors in neural progenitors in ventricular zone of developing neocortex.

  Shiro Tochitani, Hiromi Sakata-Haga, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: Neural progenitors in the ventricular zone of the developing neocortex divide oriented either parallel or perpendicular to the ventricular surface based on their mitotic spindle orientation. It has been shown that the cleavage plane orientation is developmentally regulated and plays a crucial role in cell fate determination of neural progenitors or the maintenance of the proliferative ventricular zone during neocortical development. We tested if fetal exposure to ethanol, the most widely used psychoactive agent and a potent teratogen that may cause malformation in the central nervous system, alters mitotic cleavage orientation of the neural progenitors at the apical surface of the ventricular zone in the developing neocortex. Fetal exposure to ethanol on E10.5 and 11.5 increased the occurrence frequency of a horizontal cleavage plane that is parallel to the ventricular surface on E 12.5. Administration of picrotoxin, a GABA(A) receptor antagonist, prior to ethanol administration canceled the effect of ethanol with the frequency of horizontal division similar to the control level, although picrotoxin itself did not show any effect on cleavage plane orientation. Phenobarbital, a GABA(A) receptor agonist, induced horizontal cleavage to an extent similar to that induced by ethanol administration. (+)MK801, an antagonist of NMDA receptor that is another major target of ethanol in neural cells, did not affect the cleavage plane of dividing progenitors. These results suggest that fetal ethanol exposure induced alterations in the cleavage plane orientation of neural progenitors in the ventricular zone of the neocortex via the enhancement of the function of GABA(A) receptors.
  Neuroscience Letters 02/2010; 472(2):128-32. · 2.11 Impact Factor
• Source

  Available from: Kazuhiko Sawada

  Article: Zebrin II expressing Purkinje cell phenotype-related and -unrelated cerebellar abnormalities in Cav2.1 mutant, rolling mouse Nagoya.

  Kazuhiko Sawada, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: Rolling mouse Nagoya is an ataxic mutant mouse that carries a mutation in a gene encoding for the alpha 1A subunit of the voltage-gated P/Q-type Ca2+ channel (Cav2.1). This report summarizes our studies and others concerning cerebellar abnormalities in rolling mice based on chemical neuroanatomy. While there are no obvious cerebellar deformations in this mutant mouse, the altered functions of Purkinje cells can be revealed as a reduced expression of type 1 ryanodine receptor (RyR1) in all Purkinje cells uniformly throughout the cerebellum, and as an ectopic expression of tyrosine hydroxylase (TH) in the Purkinje cell subsets with the zebrin II-immunopositive phenotype. As the mutated Cav2.1 channel is expressed at uniform levels in all Purkinje cells, its copresence with RyR1 staining suggests that a Cav2.1 channel dysfunction links with the expression of RyR1 in Purkinje cells of rolling mice. However, an ectopic expression of TH in the Purkinje cells is topologically related to the projection of corticotrophin-releasing factor-immunopositive climbing fibers rather than expression of the mutated Cav2.1 channel. On the other hand, increased levels of serotonin (5-HT) in 5-HTergic fibers were revealed immunohistochemically in Purkinje cells of the vermis of rolling cerebellum. Thus, to determine whether or not cerebellar abnormalities are related to Purkinje cell populations revealed by zebrin II expression is essential for enhancing our understanding of the pathogenesis of hereditary cerebellar ataxic mutants such as rolling mice.
  TheScientificWorldJOURNAL 01/2010; 10:2032-8. · 1.66 Impact Factor
• Article: Developments of sulcal pattern and subcortical structures of the forebrain in cynomolgus monkey fetuses: 7-tesla magnetic resonance imaging provides high reproducibility of gross structural changes.

  Kazuhiko Sawada, Xue-Zhi Sun, Katsuhiro Fukunishi, Masatoshi Kashima, Hiromi Sakata-Haga, Hiroshi Tokado, Ichio Aoki, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: The aim of this study was to spatio-temporally clarify gross structural changes in the forebrain of cynomolgus monkey fetuses using 7-tesla magnetic resonance imaging (MRI). T(1)-weighted coronal, horizontal, and sagittal MR slices of fixed left cerebral hemispheres were obtained from one male fetus at embryonic days (EDs) 70-150. The timetable for fetal sulcation by MRI was in good agreement with that by gross observations, with a lag time of 10-30 days. A difference in detectability of some sulci seemed to be associated with the length, depth, width, and location of the sulci. Furthermore, MRI clarified the embryonic days of the emergence of the callosal (ED 70) and circular (ED 90) sulci, which remained unpredictable under gross observations. Also made visible by the present MRI were subcortical structures of the forebrain such as the caudate nucleus, globus pallidus, putamen, major subdivisions of the thalamus, and hippocampal formation. Their adult-like features were formed by ED 100, corresponding to the onset of a signal enhancement in the gray matter, which reflects neuronal maturation. The results reveal a highly reproducible level of gross structural changes in the forebrain using a high spatial 7-tesla MRI. The present MRI study clarified some changes that are difficult to demonstrate nondestructively using only gross observations, for example, the development of cerebral sulci located on the deep portions of the cortex, as well as cortical and subcortical neuronal maturation.
  Brain Structure and Function 03/2009; 213(4-5):469-80. · 5.63 Impact Factor
• Source

  Available from: Kazuhiko Sawada

  Article: Striking pattern of Purkinje cell loss in cerebellum of an ataxic mutant mouse, tottering.

  Kazuhiko Sawada, Abul Kalam Azad, Hiromi Sakata-Haga, Nam-Seob Lee, Young-Gil Jeong, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: Tottering mouse is an ataxic mutant that carries a mutation in a gene encoding for the apha1A subunit of P/Q-type Ca2+ channel (Cav2.1). This study revisited to examine whether a Purkinje cell loss occurred in the cerebellum of tottering mice. In tottering mice, Calbindin D-28k negative gaps were apparent in the vermis but not in the hemisphere. Calbindin D-28k immunofluorescence with DAPI staining demonstrated the absence of Purkinje cells in the Calbindin D-28k negative gaps. The Purkinje cell loss seemed to be observed prominently in the zebrin II negative compartments of the anterior vermis, but in the zebrin II positive compartments of the posterior vermis. Quite consistent with the histopathological observations, quantitation of the density of Calbindin D-28k and zebrin II immunopositive Purkinje cells in the tottering cerebellum revealed that the Purkinje cells were selectively lost in the zebrin II immunonegative compartments of the lobules I and II but in the zebrin II immunopositive compartments in the lobule IX. Those results predict that the susceptibility to the Cav2.1 gene defect is different among Purkinje cell phenotypes of the tottering cerebellum rather than the expression pattern of mutated Cav2.1 channels. This may result in the reproducible parasagittal pattern of Purkinje cell loss.
  Acta neurobiologiae experimentalis 02/2009; 69(1):138-45. · 2.11 Impact Factor
• Article: Protective effect of taurine against nitrosative stress in the stomach of rat with water immersion restraint stress.

  Ning Ma, Takeshi Sasaki, Hiromi Sakata-Haga, Ken-ichi Ohta, Ming Gao, Shosuke Kawanishi, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: In the present study, we examined by immunohistochemistry the formation and distribution of 8-nitroguanine, a sensitive marker of nitrosative DNA damage, in rat stomach of rats subjected to water immersion restraint stress (WIR). WIR induced an increase in 8-nitroguanine content of gastric gland epithelium. 8-Nitroguanine immunoreactivity, which was observed mainly in the nuclei of stomach epithelium, increased with the severity of inflammation. Expression of iNOS was also observed in the inflammatory cells of lamina propria. Therefore, it is logical that iNOS-mediated nitrosative stress must participate in the development of ulcers through apoptotic cell death linked to the formation of 8-nitroguanine during chronic inflammation. Taurine administration attenuated stress-induced gastric mucosal injury. These results demonstrate that nitrosative stress participates in stress-mediated ulcer formation. Taurine exerts a prophylactic effect against mucosal lesions of the stomach caused by stress. This effect of taurine may have a potential clinical benefit in preventing gastritis associated with stress.
  Advances in experimental medicine and biology 02/2009; 643:273-83. · 1.09 Impact Factor
• Article: Intrauterine environment-genome interaction and children's development (1): Ethanol: a teratogen in developing brain.

  Yoshihiro Fukui, Hiromi Sakata-Haga
  [show abstract] [hide abstract]
  ABSTRACT: Exposure to ethanol during prenatal development can have devastating consequences on developing fetuses, the so-called fetal alcohol spectrum disordres (FASD). Among FASD, cases that exhibit all of three criterion; 1) central nervous system dysfunction, 2) prenatal and postnatal growth deficiency, and 3) characteristic cranial/facial abnormalities, referred as fetal alcohol syndrome (FAS). Children born to drinking mothers may suffer from severe brain damage that is expressed by a variety of behavioral alterations. We examined the effects of ethanol exposure during brain development on brain morphogenesis and circadian rhythm using a rat model. Pregnant Sprague-Dawley (SD) rats were fed a liquid diet containing 2.5-5.0% (w/v) ethanol during gestational days 10 to 21. Mean daily ethanol consumption by these dams was 11.53 +/- 2.54 g/kg/day. In rats prenatally exposed to ethanol, ectopias on the cerebral cortex, aberrant distribution of hippocampal mossy fibers, and fusion of cerebellar folia were found. Rats exposed to ethanol during the prenatal or postnatal period suffered from a fragile synchronizing system of circadian rhythms in adulthood. Although the prevalence of FAS in Japan is lower than in the United States, the increasing number of Japanese women with the drinking habit are cause for great concern. However, the preventive action of FAS/FASD has been advanced recently, and now alcoholic beverages carry labels warning of the risk of drinking during pregnancy and breastfeeding of babies. Although little is still known about how ethanol affects brain development, the only and most certain way to prevent FAS/FASD is total abstinence from alcohol during pregnancy and breastfeeding.
  The Journal of Toxicological Sciences 01/2009; 34 Suppl 2:SP273-8. · 1.52 Impact Factor
• Article: Spatial distribution of corticotropin-releasing factor immunopositive climbing fibers in the mouse cerebellum: analysis by whole mount immunohistochemistry.

  Kazuhiko Sawada, Yoshihiro Fukui, Richard Hawkes
  [show abstract] [hide abstract]
  ABSTRACT: This study examined the spatial organization of corticotropin-releasing factor (CRF) immunopositive climbing fibers in the mouse cerebellum by whole mount immunohistochemistry. A striking pattern of parasagittal stripes of CRF staining was revealed. Cryosections of whole mount CRF stained cerebellum showed that anti-CRF immunostaining is restricted to climbing fibers in the molecular layer and does not penetrate deeper into the granular layer. The array of CRF stripes was reminiscent of zebrin II immunopositive Purkinje cell stripes in the anterior vermis and the hemispherical lobules. However, a direct comparison of the two distributions showed that the CRF-defined parasagittal stripes and transverse zones in the posterior vermis are different from those defined by the expression of zebrin II: in particular, CRF immunostaining revealed a transverse boundary between lobules VIb and VII and the presence of four CRF-immunopositive climbing fiber stripes in lobule VIII. Furthermore, an array of CRF stripes was seen in lobule X, the flocculus and the paraflocculus, despite uniform zebrin II expression in these areas. In these cases some, but not all, CRF-immunopositive stripes shared boundaries with Purkinje cell stripes that were visualized by the expression of heat shock protein 25. The results reveal a reproducible pattern of CRF-immunopositive climbing fiber innervation in the mouse cerebellum that bears a complex relationship to the stripes delineated by Purkinje cell compartmentation antigens.
  Brain Research 08/2008; 1222:106-17. · 2.73 Impact Factor
• Article: Reactive nitrogen species-dependent DNA damage in EBV-associated nasopharyngeal carcinoma: the relation to STAT3 activation and EGFR expression.

  Ning Ma, Michiko Kawanishi, Yusuke Hiraku, Mariko Murata, Guang-Wu Huang, Yuanjiao Huang, Dian-Zhong Luo, Wei-Guang Mo, Yoshihiro Fukui, Shosuke Kawanishi
  [show abstract] [hide abstract]
  ABSTRACT: Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. Recently, reactive nitrogen and oxygen species are considered to participate in inflammation-related carcinogenesis through DNA damage. In our study, we obtained biopsy and surgical specimens of nasopharyngeal tissues from NPC patients in southern China, and performed double immunofluorescent staining to examine the formation of 8-nitroguanine, a nitrative DNA lesion and 8-oxo-7,8-dihydro-2'-deoxyguanosine, an oxidative DNA lesion, in these specimens. Strong DNA lesions were observed in cancer cells and inflammatory cells in stroma of NPC patients. Intensive immunoreactivity of iNOS was detected in the cytoplasm of 8-nitroguanine-positive cancer cells. DNA lesions and iNOS expression were also observed in epithelial cells of EBV-positive patients with chronic nasopharyngitis, although their intensities were significantly weaker than those in NPC patients. In EBV-negative subjects, no or little DNA lesions and iNOS expression were observed. EGFR and phosphorylated STAT3 were strongly expressed in cancer cells of NPC patients, but NF-kappaB was not expressed, suggesting that STAT3-dependent mechanism is important for NPC carcinogenesis. IL-6 was expressed mainly in inflammatory cells of nasopharyngeal tissues of EBV-infected patients. EBV-encoded RNAs (EBERs) and latent membrane protein 1 (LMP1) were detected in cancer cells from all EBV-infected patients. In vitro cell system, nuclear accumulation of EGFR was observed in LMP1-expressing cells, and IL-6 induced phosphorylated STAT3 and iNOS. These data suggest that nuclear accumulation of EGFR and STAT3 activation by IL-6 play the key role in iNOS expression and resultant DNA damage, leading to EBV-mediated NPC.
  International Journal of Cancer 07/2008; 122(11):2517-25. · 5.44 Impact Factor
• Article: A quantitative study of the optic nerve in diabetic mutant, Otsuka Long‐Evans Tokushima Fatty (OLETF) rats

  Kazuhiko Sawada, Sachiko Nitta, Hiromi Sakata‐Haga, Takamasa Ohnishi, Yoshihiro Fukui
  [show abstract] [hide abstract]
  ABSTRACT: ABSTRACT  Optic nerves of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of non-insulin dependent diabetes mellitus, were examined using quantitative stereological procedures. At 67 weeks of age, OLETF rats showed a mild hyperglycemia: their blood glucose level was 196 ± 93 mg/dl, significantly higher than that of non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats (110 ± 24 mg/dl). However, there were no differences in the cross sectional area of optic nerves (the mean minimum diameter), the total number and mean diameter of both myelinated and non-myelinated fibers, or the thickness of the myelin sheath between OLETF and LETO rats. The results suggested that a mild hyperglycemia in OLETF rats could not cause any morphological changes in the optic nerve.
  Congenital Anomalies 06/2008; 41(4):307 - 311.
• Article: Strain Difference in Effects of Ethanol Treatment on Fetal Development in C57BL and DBA Mice

  Yoshihiro FUKUI, Ichiro NARUSE, Kiyoshi HOSHINO, Yoshiro KAMEYAMA, Yoshiki TAKEUCHI
  [show abstract] [hide abstract]
  ABSTRACT: Pregnant C57BL and DBA mice were treated with i. p. injection twice of 25% ethanol (3.97 g/kg × 2), four hours apart, on day 7, 8, 9, 10, 11, 12 or 13 of gestation. They were killed on day 18 of gestation, and the fetuses were examined for external and skeletal malformations. In order to determine the blood ethanol levels, nonpregnant animals were treated with the same dose of ethanol and then killed at 0.5-16 hours after injection.Fetal mortalities of DBA mice were higher than those of C57BL mice. The body and brain growth retardations were severer and the incidence of malformations was higher in C57BL mice than in DBA mice. The most frequently observed malformations were microphthalmia and digital malformations in C57BL mice, and open eyelids in DBA mice. Blood ethanol reached the maximum level within half an hour after the second injection in both strains, and was significantly higher in DBA mice than in C57BL mice 2–15 hours after the second injection. It is difficult to explain the strain difference of embryotoxicity between C57BL and DBA mice on the basis of only the difference in blood ethanol level in the present study.
  Congenital Anomalies 05/2008; 30(3):177 - 186.
• Article: Midkine, A New Heparin‐Binding Growth/Differentiation Factor: Expression and Distribution during Embryogenesis and Pathological Status

  Xue-Zhi SUN, Yoshihiro FUKUI
  [show abstract] [hide abstract]
  ABSTRACT: Midkine (MK) is a 13 kDa heparin-binding growth factor found as a product of a retinoic acid-responsive gene. MK is rich in basic amino acids and cysteine and its sequence is not homologous with any other proteins so far reported, so it is a new family of heparin-binding growth factor. It has been found that MK exerts variety of biological activities such as neurite-promoting, neuronal cell survival and differentiation-inducing activities. MK is strictly expressed during the mouse embryogenesis; among the adult organs, it is detected only in the kidney. MK is also strongly expressed in a number of human carcinomas and specifically localized in senile plaques in the brain of patients with Arzheimer disease. More recently, it has been reported that MK is an important molecule regulating inflammation response and tissue repair. These results demonstrated that the relevance of MK not only in normal development, but also in processes leading to tissue repair or diseases. Increased MK gene expression is a common phenomenon observed in many human carcinomas, therefore MK is of significant interest in cancer biology. As a new growth/differentiation factor, many issues including the detailed sites and the precise time of MK expression, the exact cellular source which synthesizes and secretes MK, the signal transducing receptors for MK, the mechanisms underlying those developmentally regulated expression and its potential clinical significance still remain unknown. To elucidate the molecular mechanisms of MK action will lead not only to a deeper understanding of developmental processes, but also to the ultimate obtaining a key to diagnose and treat human carcinomas.
  Congenital Anomalies 05/2008; 38(1):25 - 38.
• Article: Abnormal Cerebral Vascularity in Mice with Histogenetic Disorders of the Cerebral Cortex and Postnatal Manifestation of Hydrocephalus

  Shoko KIMURA, Yoshihiro FUKUI, Yoshiro KAMEYAMA
  [show abstract] [hide abstract]
  ABSTRACT: Abstract Pregnant mice were exposed to 60Co gamma-irradiation on day 13 of gestation, and the offspring after birth were examined in histological sections and microvascular specimens with India ink, in order to know the pathological changes leading to postnatal manifestation of hydrocephalus. The cerebrospinal fluid pressure was also measured.The offspring from birth to 12 days of age showed microcephaly or dysgenetic hydrocephaly with severely deranged cerebral cortical architecture. The microvascular specimens of these brains showed a deranged vascular pattern and poor vascular network in the brain mantle. Its severity was in proportion to that of the disorder of the cortical architecture. These brains were involved with blood congestion and perivascular hemorrhage in the periventricular white matter, and consequently with cystic degeneration and pseudoventricle formation, which changes became evident at 7 to 10 days of age. The cerebrospinal fluid pressure was not different from that of non-treated control mice until 12 days of age. Around 14 days of age, the pressure began to increase concurrently with an external appearance of vaulted skull, indicating a transformation from degenerative ex vacuo type of hydrocephaly to progressive high-pressure hydrocephalus.These results suggested that histogenetic disorders of the cerebral cortex caused abnormal vascular formation in the brain mantle and that the consequent intracerebral circulatory disturbance played a significant role for degenerative changes of the brain tissue and a failure of the cerebrospinal fluid dynamics at the time of brain growth spurt.
  Congenital Anomalies 05/2008; 28(2):93 - 102.
• Article: Cerebellar Abnormalities Induced by Intracisternal Injection of Cytosine Arabinoside in Neonatal Mice

  Yoshihiro FUKUI, Kiyoshi HOSHINO, Yoshiro KAMEYAMA
  [show abstract] [hide abstract]
  ABSTRACT: Abstract In order to examine the direct effects of cytosine arabinoside (Ara-C) on cerebellar development, Slc:ICR mice were treated intracisternally with a single dose of 160 μ Ara-C on day 0, 1, 2, 4, 5, 7 or 10 after birth. The mice in each group were killed at 30 days of age. Cerebellar weight was heavily reduced, but body and total brain weights were only slightly reduced in all Ara-C-treated groups. In mice treated on day 0, 1 or 2, derangement of the layered structure of the vermis was evident in the anterior folia. In the immunohistochemical examinations with GFAP and S-100 protein, Bergmann glial fibers ran tortuously and not perpendicular to the pia mater in the disarranged area. Bergmann glial cell bodies were scattered in the cerebellar cortex and not always adjacent to Purkinje cells. In the group treated on day 4 or later, the layered structure of the vermis was well preserved.
  Congenital Anomalies 05/2008; 27(4):475 - 482.