Biomedical subjects

R Hashimoto

Publications and source records attributed to R Hashimoto.

At least 19 recordsLinked to original sources

PubMed2006

Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population.

We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.

Alleles↗

PubMed2006

A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity.

Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles ('A1' allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5-5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.

Adult↗

PubMed2006

Effect of antipsychotic drugs on DISC1 and dysbindin expression in mouse frontal cortex and hippocampus.

Altered expression of Disrupted-In-Schizophrenia-1 (DISC1) and dysbindin (DTNBP1), susceptibility genes for schizophrenia, in schizophrenic brain has been reported; however, the possible effect of antipsychotics on the expression levels of these genes has not yet been studied. We measured the mRNA expression levels of these genes in frontal cortex and hippocampus of mice chronically treated with typical and atypical antipsychotics by a real-time quantitative RT-PCR method. We found that atypical antipsychotics, olanzapine and risperidone, in a clinically relevant dose increased DISC1 expression levels in frontal cortex, while a typical antipsychotic, haloperidol, did not. No significant effect on dysbindin expression levels was observed in either brain region. These data suggest that prior evidence of decreased expression of dysbindin in postmortem brain of schizophrenics is not likely to be a simple artifact of antemortem drug treatment. Our results also suggest a potential role of DISC1 in the therapeutic mechanisms of certain atypical antipsychotics.

Actins↗

PubMed2005

Association study of the frizzled-3 (FZD3) gene with schizophrenia and mood disorders.

Two research groups have recently reported a significant association between schizophrenia and genetic variants of Frizzled-3 (FZD3) gene. We examined a possible association in a Japanese sample of schizophrenia, bipolar disorder, unipolar depression and controls with four single nucleotide polymorphisms (SNPs), tested in previous reports. We failed to find significant association in the four SNPs or haplotype analysis. The FZD3 gene might not play a role in conferring susceptibility to major psychosis in our sample.

Adult↗

PubMed2005

Characterizing kinetics of transport and transformation of selenium in water-sediment microcosm free from selenium contamination using a simple mathematical model.

This study developed a seven-compartment model for predicting the fate of selenium (Se) in an aquatic environment containing a water-sediment boundary. Speciation of Se in water-sediment microcosms under microaerobic conditions was measured to evaluate first-order kinetics of Se transportation and transformation. The microcosm consisted of a 10-ml solution containing 1mM soluble Se as selenate (Se6+) or selenite (Se4+) and 8 g wet sediment that was free from Se contamination, sampled from the Senri, Yamato, or Yodo Rivers in Osaka, Japan. Stepwise reaction coefficients describing transportation and transformation were determined using an inverse method on this model which includes: selenate (Se(W)6+) and selenite (Se(W)4+) in ponded water; selenate (Se(S)6+) and selenite (Se(S)4+), elemental Se (Se0), organic Se (Se2-) in sediment; and gaseous Se (DMSe). During this 1-month experiment, soluble Se was transported from ponded water to the sediment and Se was transformed sequentially to other Se species through biochemical reactions. Experimental and kinetic analyses indicated quantitatively that the Yamato River microcosm, with its high organic matter content, had a high adsorption rate of soluble Se. The Yodo River microcosm had a low adsorption rate for Se6+ and a low Se reduction rate. The Senri River microcosm had an apparent high volatilization rate of DMSe. The model developed in this study is extremely useful for predicting fate of Se in aquatic environment in the field.

Biological Transport↗

PubMed2004

High frequency Agrobacterium-mediated transformation and plant regeneration via direct shoot formation from leaf explants in Beta vulgaris and Beta maritima.

We have developed a new procedure for Agrobacterium-mediated transformation of plants in the genus Beta using shoot-base as the material for Agrobacterium infection. The frequency of regeneration from shoot bases was analyzed in seven accessions of sugarbeet ( Beta vulgaris) and two accessions of B. maritima to select materials suitable for obtaining transformed plants. The frequency of transformation of the chosen accessions using Agrobacterium strain LBA4404 and selection on 150-mg/l kanamycin was found to be higher than that in previously published methods. Genomic DNA analysis and beta-glucuronidase reporter assays showed that the transgene was inherited and expressed in subsequent generations. In our method, shoot bases are prepared by a simple procedure, and transformation does not involve the callus phase, thus minimizing the occurrence of somaclonal variations.

Agrobacterium tumefaciens↗

PubMed2004

Association analysis of the -308G>A promoter polymorphism of the tumor necrosis factor alpha (TNF-alpha) gene in Japanese patients with schizophrenia.

Two research groups have thus far reported a significant association between schizophrenia and a promoter polymorphism (-308G > A) of the gene encoding tumor necrosis factor alpha (TNF-alpha), while contradictive negative results have also been reported. We examined the possible association in a Japanese sample of 297 schizophrenia cases and 458 controls. Allele frequencies of both the patients and controls were very low (1.5% and 0.8%, respectively), and the difference was not statistically significant. We conclude that the effect of the -308G > A polymorphism on the development of schizophrenia is, if any, weak and the majority of Japanese schizophrenics are unrelated to the -308G > A polymorphism of the TNF-alpha gene.

Adenine↗

PubMed2004

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia.

Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls-GAPDH, cyclophilin, and beta-actin-were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia.

Autopsy↗

PubMed2004

Analysis of enhancer activity of a dinucleotide repeat polymorphism in the neurotrophin-3 gene and its association with bipolar disorder.

Growing evidence has implicated the possible involvement of neurotrophins in the pathogenesis of functional psychoses such as schizophrenia and bipolar disorder. Previous studies reported a significant association of a dinucleotide repeat polymorphism of the neurotrophin-3 (NTF3) gene with schizophrenia. The aims of the present study were to examine whether this polymorphism is associated with bipolar disorder and whether the polymorphic region has an enhancer/silencer effect on transcriptional activity in an allele-dependent manner. In an association analysis between the polymorphism and bipolar disorder in a Japanese sample of 88 patients and 98 controls matched for age, sex, and ethnicity, the distribution of alleles did not differ significantly between the two groups. pGL3-promoter luciferase reporter vectors containing the polymorphic region increased luciferase activity relative to empty pGL3-promoter vector in HeLa, IMR-32 (neuroblastoma) and Hs683 (glioma) cell lines; however, no significant difference was detected between alleles for either cell line. Our results suggest that the examined polymorphism has no major role in giving susceptibility to bipolar disorder. Although the polymorphic region may have an enhancer-like effect on transcriptional activity, we obtained no evidence for allele-dependent differential effects.

Alleles↗

PubMed2004

Changes in the concentrations of tetrahydrobiopterin, the cofactor of tyrosine hydroxylase, in blood under physical stress and in depression.

This paper studies changes in the concentrations of tetrahydrobiopterin (BH4), the cofactor of tyrosine hydroxylase, in blood under physical stress and in depression. BH4 was found to be transiently released from the sympathetic nerves under severe physical stress but continuously released in depression with an increased oxidation rate of BH4 to B.

Adolescent↗

PubMed2003

Lithium stimulates progenitor proliferation in cultured brain neurons.

The number of neurons in the brain is controlled by production of new neurons and neuronal death. Neural progenitor proliferation in the developing and adult brain plays a prominent role in the production of new neurons. Here, we examined the effects of lithium, a mood-stabilizing drug, on neuronal proliferation in rat primary neuronal cultures. The incorporation of 5-bromo-2'-deoxyuridine (BrdU) into replicating DNA was used to label proliferating cells. BrdU incorporation was detected by immunocytochemistry in cerebellar granule cells prepared from postnatal rats and cerebral cortical cultures prepared from embryonic rats. Quantification of BrdU incorporation into cultures was performed by counting BrdU-positive cells and BrdU-coupled enzyme-linked immunosorbent assay. Both methods revealed that lithium increased BrdU incorporation in cerebellar granule cells and cerebral cortical cultures. Most BrdU-positive cells colocalized with nestin, a neuroblast cell marker, in cerebral cortical cultures. Blockade of DNA replication by cytosine arabinoside almost completely abolished BrdU incorporation, suggesting that lithium-induced BrdU incorporation was mainly due to enhanced DNA replication. Glutamate, glucocorticoids and haloperidol were found to markedly reduce neural progenitor proliferation in cerebellar granule cells. The presence of lithium prevented the loss of proliferation induced by these agents. Lithium-induced neural progenitor proliferation in vitro suggests that similar effects might occur in vivo and this action could also be related to its clinical efficacy. Cultured brain neurons may provide a valuable model for studying the molecular mechanisms underlying lithium-induced up-regulation of neural proliferation.

Animals↗

PubMed2001

Hydrogen peroxide and hydroxyl radical involvement in the activation of caspase-3 in chemically induced apoptosis of HL-60 cells.

Apoptosis of HL-60 cells induced by actinomycin D, H7, or daunorubicin was shown to involve the activation of caspase-3-like protease, 2 h after the addition of these drugs, based on microassay of enzyme activity by high-performance liquid chromatography. Catalase and a spin trap, N-t-butyl-alpha-phenylnitrone, which effectively inhibited the apoptosis induced by these drugs, also inhibited the activation of caspase-3-like protease. These results suggest that hydrogen peroxide and the hydroxyl radical are common mediators of caspase-3 activation caused by these chemicals, with apparently different functional mechanisms. Based on mitochondrial activity determined by oxygen consumption, complexes I, II, and IV were inhibited by actinomycin D. H7 inhibited complexes I and IV, 1 and 1.5 h respectively, after the addition of the drug to HL-60 cells. Daunorubicin inhibited complex IV, 1.5 h after the addition of the drug to HL-60 cells. Inhibition of complex IV by actinomycin D, H7, and daunorubicin were almost fully restored by the addition of cytochrome c. The release to the cytosol of cytochrome c by these drugs was also demonstrated by Western blot analysis. Addition of catalase inhibited the depression of complex IV activity induced by actinomycin D and H7. These observations indicate a direct relationship between hydrogen peroxide and the release of cytochrome c during apoptosis caused by actinomycin D, H7, and daunorubicin.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2001

Sentence processing in the cerebral cortex.

Human language is a unique faculty of the mind. It has been the ultimate mystery throughout the history of neuroscience. Despite many aphasia and functional imaging studies, the exact correlation between cortical language areas and subcomponents of the linguistic system has not been established. One notable drawback is that most functional imaging studies have tested language tasks at the word level, such as lexical decision and word generation tasks, thereby neglecting the syntactic aspects of the language faculty. As proposed by Chomsky, the critical knowledge of language involves universal grammar (UG), which governs the syntactic structure of sentences. In this article, we will review recent advances made by functional neuroimaging studies of language, focusing especially on sentence processing in the cerebral cortex. We also present the recent results of our functional magnetic resonance imaging (fMRI) study intended to identify cortical areas specifically involved in syntactic processing. A study of sentence processing that employs a newly developed technique, optical topography (OT), is also presented. Based on these findings, we propose a modular specialization of Broca's area, Wernicke's area, and the angular gyrus/supramarginal gyrus. The current direction of research in neuroscience is beginning to establish the existence of distinct modules responsible for our knowledge of language.

Brain Mapping↗

PubMed2001

Visual stimulation-induced phosphorylation of neurofilament-L in the visual cortex of dark-reared rats.

In dark-reared animals, visual exposure is expected to induce drastic changes in both the physiology and anatomy of the cortical neurons, including the rearrangement of their cytoskeletal structures. Phosphorylation of neurofilament-L (NF-L) is probably associated with relatively short-term structural plasticity in vivo, because the assembly and disassembly of the filaments are regulated by phosphorylation of the head domain of NF-L. Thus, by using a series of site- and phosphorylation state-specific antibodies against NF-L, we examined how visual activation induces the phosphorylation of NF-L in the rat brain. We found no specific immunoreactivity for phosphorylated NF-L in the brain of naive rats, whereas one-hour ambient light exposure after dark rearing for ten weeks from birth induced marked phosphorylation of NF-L selectively. Also, the NF-L phosphorylation was found to be localized in the primary and secondary visual cortical areas. These findings suggest that the selective phosphorylation of NF-L plays an important role in the structural plasticity related to the visual experience.

Amino Acid Sequence↗

PubMed2000

Phosphorylation of neurofilament-L during LTD.

We recently reported that CaMKII-dependent phosphorylation of the neurofilament-L (NF-L) head domain was induced in the apical dendrites during long-term potentiation. Long-term depression (LTD) is another cellular model for neuronal plasticity. In the present study, we examined the phosphorylation of NF-L during hippocampal LTD using a series of phospho-specific antibodies against the NF-L head domain. During LTD, these antibodies visualized NF-L phosphorylation at Ser57 in the apical dendrites of the hippocampal pyramidal neurons. The assembly and disassembly of NF-L filaments are regulated by phosphorylation of its head domain. Thus, our results indicated that NF-L phosphorylation might be associated with alterations of the neuronal structure during LTD.

Animals↗

PubMed2000

Cardiac fibrosis in mice lacking brain natriuretic peptide.

Cardiac fibrosis, defined as a proliferation of interstitial fibroblasts and biosynthesis of extracellular matrix components in the ventricles of the heart, is a consequence of remodeling processes initiated by pathologic events associated with a variety of cardiovascular disorders, which leads to abnormal myocardial stiffness and, ultimately, ventricular dysfunction. Brain natriuretic peptide (BNP) is a cardiac hormone produced primarily by ventricular myocytes, and its plasma concentrations are markedly elevated in patients with congestive heart failure and acute myocardial infarction. However, its precise functional significance has been undefined. In this paper, we report the generation of mice with targeted disruption of BNP (Nppb(-/-) mice). We observed multifocal fibrotic lesions in the ventricles from Nppb(-/-) mice. No signs of systemic hypertension and ventricular hypertrophy are noted in Nppb(-/-) mice. In response to ventricular pressure overload, focal fibrotic lesions are increased in size and number in Nppb(-/-) mice, whereas no focal fibrotic changes are found in wild-type littermates (Nppb(+/+) mice). This study establishes BNP as a cardiomyocyte-derived antifibrotic factor in vivo and provides evidence for its role as a local regulator of ventricular remodeling.

Animals↗

PubMed2000

Amnesic confabulatory syndrome after focal basal forebrain damage.

A 73-year-old woman developed amnesic confabulatory syndrome after a right focal basal forebrain hemorrhage. The confabulation, despite persistent antegrade amnesia, gradually subsided with improvement of the frontal executive function. The lesion appeared to disrupt connections of the medial and lateral limbic circuits important for memory. Simultaneous dysfunctioning of the two circuits involving the medial temporal and frontal lobes may be necessary for the development of this syndrome.

Aged↗

PubMed2000

Unusually high reactivity of apolipoprotein B-100 among proteins to radical reactions induced in human plasma.

Relative reactivities of proteins to radical reactions caused in human plasma were studied for the first time utilizing an immunoblotting assay. When radical reactions were caused by Cu(2+), apolipoprotein B-100 (apoB) underwent extensive fragmentation concurrently with the decrease in alpha-tocopherol, while human serum albumin (HSA) and transferrin (TF) were not decreased at all. When radical reactions were initiated by Cu(2+) with hydrogen peroxide or 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH), alpha-tocopherol and apoB were also decreased steadily but HSA and TF were not decreased. These observations indicate that apoB is extremely reactive, even comparable to alpha-tocopherol, towards radical reactions. These results also suggest that the radical reaction of apoB is a possible process in vivo and it is involved in atherogenesis along with low density lipoprotein lipid peroxidation, which has been studied extensively.

Amidines↗