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Biomedical subjects

N Takei

Publications and source records attributed to N Takei.

At least 19 recordsLinked to original sources
PubMed2005

ErbB1 receptor ligands attenuate the expression of synaptic scaffolding proteins, GRIP1 and SAP97, in developing neocortex.

Scaffolding proteins containing postsynaptic density-95/discs large/zone occludens-1 (PDZ) domains interact with synaptic receptors and cytoskeletal components and are therefore implicated in synaptic development and plasticity. Little is known, however, about what regulates the expression of PDZ proteins and how the levels of these proteins influence synaptic development. Here, we show that ligands for epidermal growth factor receptors (ErbB1) decrease a particular set of PDZ proteins and negatively influence synaptic formation or maturation. In short-term neocortical cultures, concentrations of epidermal growth factor and amphiregulin (2-9 pM) decreased the expression of glutamate receptor interacting protein 1 (GRIP1) and synapse-associated protein 97 kDa (SAP97) without affecting postsynaptic density-95 (PSD-95) levels and glial proliferation. In long-term cultures, epidermal growth factor treatment resulted in a decrease in the frequency of pan-PDZ-immunoreactive aggregates on dendritic processes. A similar activity on the same PDZ proteins was observed in the developing neocortex following epidermal growth factor administration to rat neonates. Immunoblotting revealed that administered epidermal growth factor from the periphery activated brain ErbB1 receptors and decreased GRIP1 and SAP97 protein levels in the neocortex. Laser-confocal imaging indicated that epidermal growth factor administration suppressed the formation of pan-PDZ-immunoreactive puncta and dispersed those structures in vivo as well. These findings revealed a novel negative activity of ErbB1 receptor ligands that attenuates the expression of the PDZ proteins and inhibits postsynaptic maturation in developing neocortex.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A right orbitofrontal region and OCD symptoms: a case report.

OBJECTIVE: To discuss the relationship between obsessive-compulsive symptoms and a right orbitofrontal lesion. METHOD: Single case report. RESULTS: A 59-year-old man developed obsessive-compulsive disorder (OCD) symptoms after his head injury. Magnetic resonance imaging brain scans showed a small contusion in the right orbitofrontal region, and single-photon emission computed tomography revealed hypoperfusion in blood flow at the same region. CONCLUSION: The OCD symptoms that developed in the present case may be attributable primarily to hypofunction in the lesion localized to the right orbitofrontal area. Although caution is needed for interpretation of the observation because of our experience of only a single case, it suggests that the right orbitofrontal region may be important in forming OCD symptoms.

Brain Concussion↗
PubMed2004

Do olfactory reference syndrome and jiko-shu-kyofu (a subtype of taijin-kyofu) share a common entity?

OBJECTIVE: Olfactory reference syndrome (ORS) in the Western literature is characterized as preoccupation with the idea that the body emits a foul odor. Japanese patients with a feature similar to ORS have long been recognized as jiko-shu-kyofu, which is believed to be a culture-bound syndrome and specific to Japan. The aim of the study was to clarify the relationship between the two separate syndromes that had independently been recognized in culturally different settings. METHOD: The phenomenology and treatment of seven patients with jiko-shu-kyofu were described. A feature of jiko-shu-kyofu was then compared with that of ORS. RESULTS: In our cases, clinical characteristics of jiko-shu-kyofu such as symptomatology, insight, and pharmacotherapy response were found identical to those of ORS except for the onset at relatively younger ages. CONCLUSION: Jiko-shu-kyofu and ORS may share a common clinical entity, hence the former is not a culturally distinctive disorder.

Adolescent↗
PubMed2004

Poor maternal care and high maternal body mass index in pregnancy as a risk factor for schizophrenia in offspring.

OBJECTIVE: We investigated whether antenatal factors in mothers would increase the risk of schizophrenia in the offspring, and also examined any relationship between these factors and histories of obstetric complications (OCs). METHOD: Using the Mother and Child Health Handbooks of 52 patients with schizophrenia and 284 healthy subjects, we evaluated the risk-increasing effects of the frequency of antenatal care visits and mothers' body mass index (BMI) at both early and late pregnancy. RESULTS: In logistic regression analysis, there was a significant association between the number of antenatal care visits and the risk of the disorder; an increase in a unit of visits corresponds to a reduction of the risk by 12%. We also found a 24% increase in the risk with a one-unit increase of BMI at the early pregnancy, and a 19% increase at the late pregnancy. These antenatal factors were found to contribute, in part, to an excess of OCs in individuals with schizophrenia. CONCLUSION: Poor maternal care during pregnancy and comparatively high maternal BMI especially at early pregnancy may cause a predisposition to schizophrenia in the offspring.

Adolescent↗
PubMed2004

[Schizophrenia and ocular misalignment: phenotypic and genetic association analysis].

The increased incidence of minor physical anomalies (MPAs) in schizophrenia is the fundamental basis for the neurodevelopmental hypothesis of schizophrenia etiology. Ocular misalignment falls into the category of MPAs, but this phenotype has not been assessed in schizophrenia. This study reveals that constant exotropia displays marked association with schizophrenia. To assess the genetic mechanisms, we examined the transcription factor genes ARIX and its paralogue, PMX2B. We identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PMX2B, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia. The polymorphisms were also associated with overall schizophrenia and more specifically with schizophrenia manifesting strabismus. These results suggest a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes. This study also highlights the unique nature of the polyalanine length variations found in PMX2B.

Exotropia↗
PubMed2003

Transforming growth factor-alpha changes firing properties of developing neocortical GABAergic neurons by down-regulation of voltage-gated potassium currents.

Transforming growth factor-alpha (TGFalpha), a member of the epidermal growth factor family, has neurotrophic actions on postmitotic neurons. We examined the chronic effects of TGFalpha on the electrophysiological properties of one type of GABAergic neuron, identified by its bipolar morphology, in neocortical primary culture. Approximately 85% of the bipolar neurons were GABA-immunoreactive. In response to depolarizing current injection, the bipolar neurons usually showed tonic firing of action potential under control conditions. After treatment with TGFalpha (20 ng/ml) for 2 days, these neurons failed to generate trains of action potentials. Furthermore, the treatment altered the action potential waveforms of the bipolar neurons, including the duration and amplitude of the fast after-hyperpolarization, which implies a reduction in voltage-gated potassium currents. In contrast, TGFalpha did not affect the firing properties of pyramidal-shaped non-GABAergic neurons. Voltage-clamp recordings from the bipolar neurons indicated that chronic treatment with TGFalpha markedly decreased the current densities of slow delayed rectifier (IK) and transient voltage-gated potassium currents, whereas the treatment had no effect on voltage-gated sodium current and fast delayed rectifier potassium current densities. Reverse transcription-polymerase chain reaction analysis of potassium channel mRNA in the bipolar neurons revealed that the reduction in the IK current density was caused by Kv2.2 mRNA down-regulation. Thus, chronic treatment with TGFalpha down-regulated slow delayed rectifier and transient voltage-gated potassium currents, and in parallel, suppressed repetitive generation of action potentials in the cortical GABAergic neurons.

4-Aminopyridine↗
PubMed2003

Brain-derived neurotrophic factor upregulates and maintains AMPA receptor currents in neocortical GABAergic neurons.

The regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors is implicated in synaptic plasticity. Although we have found that brain-derived neurotrophic factor (BDNF) triggers surface translocation of AMPA receptor proteins, the physiological significance of the BDNF effect remained to be determined. The present immunohistochemical studies revealed that cortical GABAergic neurons exhibited the most striking response to BDNF. Accordingly, we monitored AMPA-triggered currents through GABAergic neurons: Chronic BDNF treatment increased the AMPA-triggered currents but not NMDA-triggered currents in culture. In parallel, the amplitude, but not frequency, of spontaneous miniature excitatory postsynaptic currents (mEPSCs) was elevated in GABAergic neurons. In agreement, BDNF enhanced GABA release triggered by AMPA compared to the amount triggered by high potassium. Conversely, there was a significant decrease in the mEPSC amplitude of GABAergic neurons in heterozygous BDNF-knockout mice. These findings indicate that the neurotrophin enhances the input sensitivity of GABAergic neurons to facilitate their inhibitory function in the neocortex.

Animals↗
PubMed2003

Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation.

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity such as long-term potentiation (LTP), a form of synaptic correlate of learning and memory. BDNF is also implicated in learning and memory. We have demonstrated that radial arm maze training in rats for spatial learning and memory results in a significant increase in the BDNF mRNA expression in the hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only acquisition, but also maintenance and/or recall of spatial memory in the maze. Although these results suggest a role of BDNF for spatial memory processes, the signal transduction mechanisms that mediate the actions of BDNF remain unknown. Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI3-K) and Akt, a target of PI3-K, in the hippocampus increased in parallel with spatial memory formation. Moreover, an activation of translational processes was suggested in the hippocampus after the maze training. When spatial learning was inhibited by antisense BDNF oligodeoxynucleotide, the activation was diminished. Chronic treatment with PI3-K inhibitor wortmannin impaired spatial learning. Our findings suggested that activation of TrkB/PI3-K and protein synthesis signaling pathway by BDNF in the hippocampus is important for spatial memory.

Androstadienes↗
PubMed2003

Pregnancy and birth complications in patients with schizophrenia in Trinidad and London.

It has been shown that an excess of pregnancy and birth complications (PBCs) does not contribute to the excess rates of schizophrenia reported for the population of Caribbean origin in Britain compared with the native Caucasian British population. We therefore attempted to compare the rate of PBCs between a sample of schizophrenics in Britain with that of a sample from Trinidad where some of the Caribbean migrants to Britain originated. First contact patients with schizophrenia according to the CATEGO system diagnosis were identified in Trinidad and London. Their mothers, where available, were interviewed using the Lewis-Murray scale for pregnancy and birth complications. Data from Trinidad and Tobago concerning 56 patients were compared with those of the Caucasian (n = 61) and African-Caribbean (n = 50) patients in London. The rate of PBCs was similar for the Caucasian British patients (24.6%) and the patients in Trinidad and Tobago (21.7%). The rates were lowest in the African-Caribbean patients in London (14.0%), though this difference was not statistically significant. These findings suggest that pregnancy and birth complications are a risk factor for a substantial minority of patients with schizophrenia in Trinidad and London. It also confirms that the excess rates of schizophrenia reported for the Caribbean population in Britain are not due to these complications.

Adolescent↗
PubMed2002

Hemophagocytic syndrome as the primary clinical symptom of Hodgkin's disease.

It is now well recognized that hemophagocytic syndrome (HPS) is occasionally associated with malignant lymphomas. However, its association with Hodgkin's disease has been only rarely reported. We present here a 72-year-old woman manifesting with HPS as the primary and solitary clinical symptom of Hodgkin's disease. She had been suffering from high-grade fever and anemia for more than a month. Based on the findings in bone marrow aspirates, she was diagnosed as having HPS. In spite of extensive surveys including various cultures, serological tests for collagen disease, abdominal and cardiac sonography, chest computed tomography (CT), and renal biopsy, the origin of the fever was not determined. She was treated with steroid pulse therapy and then referred. Radiological studies revealed only mild hepatosplenomegaly and small lymph node swellings around celiac and common hepatic arteries. Reevaluation of the bone marrow specimen revealed the infiltration of small numbers of CD30-, CD15-, and EBER-1-positive large-sized lymphocytes with bizarre nucleus. Under the diagnosis of Hodgkin's disease, she was treated with combination chemotherapy containing pirarubicin, cyclophosphamide, vincristine, and prednisolone. However, it was not effective and she died of rapidly progressive hepatic failure on the 5th day of the chemotherapy. Autopsy was performed, which showed proliferation of lymphoma cells in para-aortic lymph nodes. We believe that diagnostic survey to rule out the underlying lymphoma should be vigorously performed for patients with hemophagocytic syndrome of unknown origin.

Aged↗
PubMed2002

Neurotrophins induce BDNF expression through the glutamate receptor pathway in neocortical neurons.

Neurotrophins jointly exert various functions in the nervous system, including neuronal differentiation, survival, and regulation of synaptic plasticity. However, the functional interactions of neurotrophins or mechanisms through which neurotrophins regulate each other are still not clear. In the present study, brain-derived neurotrophic factor (BDNF) mRNA expression is induced by neurotrophin-4/5 (NT-4/5) and by BDNF itself in neocortical neurons. K252a, a specific tyrosine kinase (Trk) inhibitor, completely suppresses BDNF- and NT-4/5-enhanced BDNF mRNA expression. NT-4/5 significantly augments BDNF protein production, which is also reversed by K252a. When neurons are incubated with neurotrophin-3 (NT-3) or nerve growth factor (NGF), there are no significant changes in BDNF mRNA or protein expression. Interestingly, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or the N-methyl-D-aspartate (NMDA) receptor blocker AP-5 completely suppresses NT-4/5-enhanced BDNF protein production, while tetrodotoxin (TTX) only suppresses NT-4/5-enhanced BDNF production by 50%. Additionally, the mitogen activated protein (MAP) kinase inhibitor PD98059 enhances BDNF-induced glutamate receptor-1 (GluR1) protein expression, but a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 strongly reduces BDNF-induced GluR1 protein expression. Taken together, glutamate receptors are important for the regulation of BDNF expression by neurotrophins, and MAP and PI3K kinases differentially modulate AMPA receptor expression in the cortical neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2002

Fatal reactivation of hepatitis B virus following cytotoxic chemotherapy for acute myelogenous leukemia: fibrosing cholestatic hepatitis.

Hepatitis B virus (HBV) is a well known pathogen that sometimes causes fulminant hepatitis in patients undergoing cytotoxic chemotherapy. Fibrosing cholestatic hepatitis (FCH) is a recently recognized unique variant of viral hepatitis, which has been occasionally reported in HBV-infected recipients of liver, renal, or bone marrow transplantation. We present here a 48-yr-old male in whom HBV was reactivated during post-remission chemotherapy for acute myelogenous leukemia, which resulted in rapidly fatal outcome. He manifested with deterioration of liver function in association with enormous replication of HBV. Liver biopsy showed marked ballooning of hepatocytes, cholestasis, and periportal fibrosis with minimum infiltrates. Immunostaining revealed that hepatocytes were strongly positive for hepatitis B surface antigen. Under the diagnosis of FCH, he was treated with lamivudine and interferon beta, which was not effective. Autopsy showed severe atrophy of the liver and marked degeneration of hepatocytes. Hematologists should be aware that FCH is a fatal complication that can develop under post-chemotherapy immunosuppressed conditions. Although there is no convincing evidence, prophylactic administration of lamivudine seems to be a reasonable strategy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Effect of social class at birth on risk and presentation of schizophrenia: case-control study.

OBJECTIVES: To examine if low parental social class increases children's risk of subsequently developing schizophrenia or modifies the presentation. DESIGN: Case-control study with historical controls. SETTING: Geographically defined region in south Dublin. PARTICIPANTS: 352 patients with first presentation of schizophrenia matched with the next registered same sex birth from the same birth registration district. MAIN OUTCOME MEASURES: Social class at birth. Age at presentation to psychiatric services, admission to hospital, and diagnosis of schizophrenia. RESULTS: Risk of schizophrenia was not increased in people from lower social classes. There was a slight excess risk among people in highest social classes (odds ratio 0.59, 95% confidence interval 0.40 to 0.85). However, the mean age at presentation was 24.8 years for patients whose parents were in the highest social class compared with 33.1 years for those in the lowest social class at birth. CONCLUSIONS: Although social class of origin does not seem to be an important risk factor for schizophrenia, it partially determines the age at which patients receive treatment. The relation between low social class at birth and poor outcome may be at least partially mediated through treatment delay.

Adult↗
PubMed2001

PACAP has a neurotrophic effect on cultured basal forebrain cholinergic neurons from adult rats.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal polypeptide gene family (VIP) that was originally isolated from rat hypothalamus. The high affinity PACAP receptor, PAC1, is expressed in the basal forebrain area of adult, as well as developing rat brain. Hippocampus, a targeting area of basal forebrain cholinergic neurons, contains PACAP. Thus, hippocampal-derived PACAP may have an effect on basal forebrain cholinergic neurons. Indeed, we have reported that PACAP showed neurotrophic effects on these neurons in embryonic and early postnatal culture. Here we report that PACAP has a neurotrophic effect on adult cholinergic neurons in culture. PACAP increases the number of choline acetyltransferase immunoreactive neurons about 2-fold. A similar effect was observed on treatment with cAMP analogue but not nerve growth factor. PACAP also improved the survival and neurite outgrowth of total neurons. These results indicate that PACAP acts as a neurotrophic factor even on adult neurons in vitro.

Age Factors↗
PubMed2001

Brain-derived neurotrophic factor triggers a rapid glutamate release through increase of intracellular Ca(2+) and Na(+) in cultured cerebellar neurons.

We reported previously that BDNF induced glutamate release was dependent on intracellular Ca(2+) but not extracellular Ca(2+) in cerebellar neurons (Numakawa et al., 1999). It was revealed that the release was through a non-exocytotic pathway (Takei et al., 1998; Numakawa et al., 1999). In the present study, we monitored the dynamics of intracellular Ca(2+) and Na(+) in cerebellar neurons, and investigated the possibility of reverse transport of glutamate mediated by BDNF. As reported, BDNF increased the intracellular Ca(2+) level. We found that the Ca(2+) increase induced by BDNF was completely blocked by xestospongin C, an IP(3) receptor antagonist, and U-73122, a PLC-gamma inhibitor. Xestospongin C and U-73122 also blocked the BDNF-dependent glutamate release, suggesting that the BDNF-induced transient increase of Ca(2+) through the activation of the PLC-gamma/ IP(3) pathway was essential for the glutamate release. We found that BDNF induced a Na(+) influx. This was blocked by treatment with TTX. U-73122 and xestospongin C blocked the BDNF-induced Na(+) influx, suggesting that the Na(+)influx required the BDNF-induced Ca(2+) increase. Next, we examined the possibility that a co-transporter of Na(+) and glutamate was involved in the BDNF-induced glutamate release. BDNF-induced glutamate release was blocked by L-trans-pyrollidine-2,4-dicalboxylic acid (t-PDC), a glutamate transporter inhibitor, whereas neither the 4-aminopyridine (4AP)- nor high potassium (HK(+))-induced release was blocked by t-PDC. In addition, DL-threo-beta-benzyloxyaspartate (DL-TBOA) also blocked the BDNF-mediated glutamate release, suggesting that reverse transport of glutamate may be involved. All the results therefore suggest that Na(+)-dependent reverse transport contributes to BDNF-mediated transmitter release through the PLC-gamma/IP(3)-mediated Ca(2+) signaling.

Amino Acid Transport System X-AG↗
PubMed2001

Brain-derived neurotrophic factor enhances neuronal translation by activating multiple initiation processes: comparison with the effects of insulin.

The effects of neurotrophic factors on translational activation were investigated in cortical neurons. Brain-derived neurotrophic factor (BDNF) increased protein synthesis within 30 min, whereas insulin produced a weaker enhancement of protein synthesis. BDNF-triggered protein synthesis was inhibited by LY294002, PD98059, and rapamycin, whereas the effect of insulin was unaffected by PD98059. To explore the mechanisms underlying this effect, the protein phosphorylation cascades that lead to the activation of translation initiation in neurons were examined. BDNF induced the phosphorylation of both eukaryote initiation factor (eIF) 4E and its binding protein (eIF4E-binding protein-1). The former reaction was inhibited by PD98059, whereas the latter was inhibited by LY294002 or rapamycin. In agreement, BDNF induced the phosphorylation of mammalian TOR (target of rapamycin) and enhanced its kinase activity toward eIF4E-binding protein-1. In contrast, insulin failed to activate MAPK and did not induce the phosphorylation of eIF4E. Since BDNF and insulin increased the activity of eIF2B and eIF2, the only difference between them was eIF4E phosphorylation. Thus, this may explain the lower activity of insulin in potentiating neuronal protein synthesis. These results suggest strongly that BDNF simultaneously activates multiple signaling cascades consisting of phosphatidylinositol 3-kinase, mammalian TOR, and MAPK to enhance translation initiation in neurons.

Animals↗