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Hitoshi Takahashi

Publications and source records attributed to Hitoshi Takahashi.

At least 19 recordsLinked to original sources
PubMed2003

Hepatitis C virus non-structural proteins in the probable membranous compartment function in viral genome replication.

The molecular mechanism of hepatitis C virus(HCV) RNA replication is still unknown. Recently, a cell culture system in which the HCV subgenomic replicon is efficiently replicated and maintained for a long period in Huh-7 cells has been established. Taking advantage of this replicon system, we detected the activity to synthesize the subgenomic RNA in the digitonin-permeabilized replicon cells. To elucidate how and where this viral RNA replicates in the cells, we monitored the activity for HCV RNA synthesis in the permeabilized replicon cells under several conditions. We obtained results suggesting that HCV replication complexes functioning to synthesize the replicon RNA are protected from access of nuclease and proteinase by possible cellular lipid membranes. We also found that a large part of the replicon RNA, including newly synthesized RNA, was present in such a membranous structure but a large part of each NS protein was not. A small part of each NS protein that was resistant to the proteinase action was shown to contribute sufficiently to the synthesis of HCV subgenomic RNA in the permeabilized replicon cells. These results suggested that a major subcellular site of HCV genome replication is probably compartmentalized by lipid membranes and that only a part of each NS protein forms the active replication complex in the replicon cells.

Blotting, Northern↗
PubMed2003

Baculovirus induces an innate immune response and confers protection from lethal influenza virus infection in mice.

A recombinant baculovirus expressing the hemagglutinin gene of the influenza virus, A/PR/8/34 (H1N1), under the control of the chicken beta-actin promoter, was constructed. To determine the induction of protective immunity in vivo, mice were inoculated with the recombinant baculovirus by intramuscular, intradermal, i.p., and intranasal routes and then were challenged with a lethal dose of the influenza virus. Intramuscular or i.p. immunization with the recombinant baculovirus elicited higher titers of antihemagglutinin Ab than intradermal or intranasal administration. However, protection from a lethal challenge of the influenza virus was only achieved by intranasal immunization of the recombinant baculovirus. Surprisingly, sufficient protection from the lethal influenza challenge was also observed in mice inoculated intranasally with a wild-type baculovirus, as evaluated by reductions in the virus titer, inflammatory cytokine production, and pulmonary consolidations. These results indicate that intranasal inoculation with a wild-type baculovirus induces a strong innate immune response, which protects mice from a lethal challenge of influenza virus.

Administration, Intranasal↗
PubMed2003

Some glial progenitors in the neonatal subventricular zone migrate through the corpus callosum to the contralateral cerebral hemisphere.

The great majority of glial cells of the mammalian forebrain are generated in the perinatal period from progenitors in the subventricular zone (SVZ). We investigated the migration of progenitors from the neonatal (postnatal day 0, P0) rat forebrain SVZ by labeling them in vivo with a green fluorescence protein (GFP) retrovirus and monitoring their movements by time-lapse video microscopy in P3 slices. We identified a small number of progenitors that migrated tangentially within the corpus callosum (CC) and crossed the midline. These cells retained a relatively uniform morphology: the leading process was extended toward the contralateral side but showed no process branching or turning away from the migratory direction. Net migration requires the elongation of the leading process and nuclear translocation, and the migrating cells in the CC showed both modes. We confirmed the presence of unmyelinated axon bundles within the P3 CC, but failed to detect any radially directed glial processes (vimentin- or GLAST-immunolabeled fibers) spanning through the CC. Confocal images showed a close proximity between neurofilament-immunolabeled axons and the leading process of the GFP-expressing progenitors in the CC. The destination of the callosal fibers was examined by applying DiI to the right cingulum; the labeled fibers ran throughout the CC and reached the left cingulate and motor areas. The distribution and final fates of the retrovirus-labeled cells were examined in P28 brains. A small proportion of the labeled cells were found in the contralateral hemisphere, where, as oligodendrocytes and astrocytes, they colonized predominantly the cortex and the underlying white matter of the cingulate and secondary motor areas. The distribution pattern appears to coincide well with the projection direction of the callosal fibers. Thus, glial progenitors migrate across the CC, presumably in conjunction with unmyelinated axons, to colonize the contralateral hemisphere.

Animals↗
PubMed2003

Relationship between clinical effects of fluvoxamine and the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients.

OBJECTIVES: The relationship between clinical effects of fluvoxamine (FLV) and the steady-state plasma concentrations (Css) of FLV and its major metabolite fluvoxamino acid (FLA) was studied. METHODS: The subjects were 49 Japanese patients with major depressive disorder receiving FLV 200 mg/day for 6 weeks. Depressive symptoms and side effects were evaluated by the Montgomery Asberg Depression Rating Scale (MADRS), and the UKU Side Effect Rating Scale, respectively. The Css of FLV and FLA were measured by HPLC, and the CYP2D6 genotyping was performed by PCR methods. RESULTS: The Css of FLV and FLV+FLA showed significant negative correlations with the final MADRS score. The Css of FLV, FLA and FLV+FLA were significantly higher in the responders (final MADRS score < or =10) than in non-responders. The proportion of responders was significantly higher in the patients with the Css of FLV, FLA and FLV+FLA above 150, 55 and 180 ng/ml, respectively. In the multiple regression, the Css of FLV+FLA showed a significant negative correlation with the final MADRS score. In the logistic regression, the Css of FLA had a significant effect on the differentiation of responders from non-responders. The incidence of side effects was low, and the development of nausea, the most frequent one, was not dependent on any Css. The number of mutated CYP2D6 alleles causing absent or decreased enzyme activity was not related to the therapeutic response or development of nausea. CONCLUSIONS: The present study suggests that there is a therapeutic threshold for the Css of FLV and probably also for the Css of FLA, and the Css of FLV+FLA above 180 ng/ml best predicts a good therapeutic response.

Adult↗
PubMed2003

Pathological involvement of the motor neuron system and hippocampal formation in motor neuron disease-inclusion dementia.

We report two patients with motor neuron disease-inclusion dementia, with special reference to the pathology of the motor neuron system and hippocampal formation. The ages of the patients at death were 55 and 62 years, and the disease durations were 8 and 3 years, respectively. The two patients exhibited progressive frontotemporal dementia in the absence of motor neuron signs. At autopsy, both cases exhibited frontotemporal lobar atrophy with ubiquitin-positive, and tau- and alpha-synuclein-negative neuronal inclusions. As expected from the clinical signs, in both cases, the upper and lower motor neuron systems were well preserved: no Bunina bodies or ubiquitinated inclusions were detected in the motor neurons. However, of great importance was that when visualized immunohistochemically, the Golgi apparatus and trans-Golgi network often exhibited fragmentation in the lower motor neurons (the spinal anterior horn cells). In one of the cases, a decrease in the amount of Golgi apparatus was also a frequent feature in the upper motor neurons (Betz cells in the motor cortex). Moreover, in both cases, circumscribed degeneration affecting the CA1-subiculum border zone was evident in the hippocampal formation. These findings further strengthen the idea that, pathologically, motor neuron disease-inclusion dementia is a rare phenotype of amyotrophic lateral sclerosis.

Crystallins↗
PubMed2003

Is angiomatosis an intrinsic pathohistological feature of massive osteolysis? Report of an autopsy case and a review of the literature.

We report here an autopsied patient who had died during the clinical course of massive osteolysis (MO), which is a rare chronic disease that begins insidiously and is characterized by progressive regional loss of bone. Since the original description by Gorham and Stout in 1955, vascular proliferation, e.g., hemangiomatosis, has been considered to be the characteristic feature related to the pathogenesis. However, no such vascular changes were observed in the present patient. It was also important to note that a significant number of cases of MO that showed no vascular proliferation have been described previously. Therefore, we consider that vascular proliferation is not always associated with the osteolysis in MO and that the increased vascularity, if any, may be one of the results of the disease rather than the cause.

Adult↗
PubMed2003

Primary lateral sclerosis: a rare upper-motor-predominant form of amyotrophic lateral sclerosis often accompanied by frontotemporal lobar degeneration with ubiquitinated neuronal inclusions? Report of an autopsy case and a review of the literature.

We report the autopsy findings of an 82-year-old woman who exhibited slowly progressive upper motor neuron signs (pseudobulbar palsy, muscle weakness and positive Babinski's sign) in the absence of lower motor neuron signs, which were followed by progressive dementia and frontotemporal atrophy, and who died 7 years and 4 months after onset of the disease. In this patient, the upper motor neuron system, including the precentral cortex and descending pyramidal tract, was severely degenerated, but the lower motor neurons and innervated skeletal muscles were well preserved. A few lower motor neurons were found to contain cytoplasmic inclusion bodies characteristic of amyotrophic lateral sclerosis (i.e., Bunina bodies and ubiquitin-positive skeins). However, fragmentation of the Golgi apparatus was not evident in the anterior horn cells examined. Therefore, it was considered that the lower motor neurons were also involved, but that the rate of degeneration of these neurons was very slow in the disease process. Marked frontotemporal lobar degeneration characterized by microvacuolation, and ubiquitin-positive neuronal inclusions and dystrophic neurites in cortical layer II were also observed, the precentral cortex being the most severely affected area. Similar ubiquitin-positive structures were also observed in the neostriatum. Finally, a survey of the literature based on this patient's clinical and pathological features led us to conclude that the rare clinical syndrome of primary lateral sclerosis is, in general, a rare upper-motor-predominant form of amyotrophic lateral sclerosis that is often accompanied by frontotemporal lobar degeneration with ubiquitinated neuronal inclusions.

Aged↗
PubMed2003

Milnacipran plasma levels and antidepressant response in Japanese major depressive patients.

The relationship between antidepressant effects and plasma levels of milnacipran was studied in 49 cases of major depression without psychotic features during 6 weeks of milnacipran treatment. The daily dose of milnacipran was 50 mg/day for the first week, and up to 100 mg/day thereafter. Depressive symptoms were evaluated by the Montgomery and Asberg depression rating scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of this study. Thirty-four patients (69.4%) were responders (defined as a 50% or greater decrease in the baseline MADRS score). Significant differences of MADRS scores were seen from 1 week after the beginning of this study (p=0.004, unpaired t-test) between responders and nonresponders. The mean plasma milnacipran level of responders, 82.0 +/- 29.4 ng/ml, was similar to that of non-responders, 78.6+/-23.1 ng/ml; there was no significant difference between responders and nonresponders. Neither a significant linear nor a curvilinear relationship was obtained between the final MADRS score and the plasma levels of milnacipran. Although there was no significant relationship between the plasma levels of milnacipran and the antidepressant response, milnacipran should be considered an efficacious agent in the treatment of major depressive patients.

Adrenergic Uptake Inhibitors↗
PubMed2003

A decrease in interleukin-1 receptor antagonist expression in the prefrontal cortex of schizophrenic patients.

Interleukin-1 (IL-1) mediates psychological stress responses by regulating monoamine metabolism and secretion of corticotropin-releasing factor, and is therefore, implicated in various psychiatric diseases. To evaluate the contribution of IL-1 signaling to the brain pathology of schizophrenia, we measured protein and/or mRNA levels for IL-1beta and endogenous IL-1 receptor antagonist (IL-1RA) in the postmortem brain tissues of prefrontal and parietal cortex, putamen, and hypothalamus. Both protein and mRNA levels of IL-1RA were specifically decreased in the prefrontal cortex of schizophrenic patients, whereas IL-1beta levels were not significantly altered in all the regions examined. The IL-1RA decrease was not correlated with the dose of antipsychotics given to patients. There was no influence of this illness on protein levels for IL-1 receptor type 1 in the prefrontal cortex, either. In contrast, IL-1RA serum levels were increased in schizophrenic patients, especially in drug-free patients, as reported previously. These findings suggest that chronic schizophrenia down-regulates IL-1RA production the prefrontal cortex, irrespective of its impact on the periphery. IL-1RA reduction might reflect an immunopathologic trait of the prefrontal region in schizophrenic patients.

Adult↗
PubMed2003

Proapoptotic protein glyceraldehyde-3-phosphate dehydrogenase: a possible site of action of antiapoptotic drugs.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has long been recognized as a classical glycolytic protein and has been used as a "housekeeping" gene in studies of genetic expression and regulation. However, recent advances reveal that GAPDH displays diverse nonglycolytic functions depending on its subcellular localization. Among those functions, one of the most intriguing is likely to be the induction of apoptosis. Previous works by our group and others have demonstrated that the overexpression of GAPDH and its subsequent nuclear translocation appear to be implicated in the initiation of one or more apoptotic cascades and also in the etiology of some neurological diseases. This review addresses new data demonstrating that a protein, referred to as proapoptotic protein GAPDH, with a quite mundane function in healthy cells behaves very differently during cell suicide, and summarizes emphatically the importance of this protein as a putative molecular target in developing antiapoptotic therapeutic agents for the treatment of certain neurodegenerative disorders.

Amino Acid Sequence↗
PubMed2003

Quetiapine treatment of psychotic symptoms and aggressive behavior in patients with dementia with Lewy bodies: a case series.

The authors describe here the clinical outcomes of quetiapine treatment in nine patients with dementia with Lewy bodies (DLB) who manifested psychotic symptoms and aggressive behavior. Patients who had a score of 3 or higher on any of the three items of the Neuropsychiatric Inventory (NPI), agitation/aggression, hallucinations, and delusions, were given quetiapine 25-75 mg/day. Each patient's clinical status was assessed at baseline and after 4 and 8 weeks of treatment by using the NPI, Mini-Mental State Examination (MMSE), and Simpson-Angus Scale (S-A). Five of nine patients had a positive response with a decline of more than 50% in the sum of scores for three items of the NPI. The other three patients withdrew from quetiapine treatment due to somnolence or orthostatic hypotension. The remaining patient exhibited no clinically significant change in the NPI score. The S-A scale was not affected by quetiapine treatment in any patient. These findings suggest that quetiapine may be effective in treating psychotic symptoms and disruptive behavior in some patients with DLB. Further placebo-controlled, randomized, double-blind trials with this drug are needed to confirm this observation.

Aged↗
PubMed2003

Soluble IL-4 receptor improves the skin-graft-associated cytomegalovirus infection in thermally injured mice.

The susceptibility of thermally injured mice (TI-mice) to murine cytomegalovirus (MCMV) infection is markedly influenced by burn-associated type 2 T cell responses, which are common with severe thermal injuries. In the present study, the effect of soluble IL-4 receptor (sIL-4R) on the skin-graft-associated MCMV infection was investigated. The marked growth of MCMV was demonstrated in the salivary glands of TI-mice grafted with MCMV seropositive [MCMV sero(+)] skin. However, the growth of MCMV was not demonstrated in the salivary glands of TI-mice grafted with MCMV sero(+) skin and treated with 50ng per mouse of sIL-4R. Compared with grafted normal mice, production of type 1 cytokines was markedly decreased when splenic T cells from TI-mice grafted with MCMV sero(+) skin were stimulated with anti-CD3 monoclonal antibody (mAb). The impaired type 1 cytokine production was recovered in cultures of splenic T cells from grafted TI-mice previously treated with sIL-4R. After grafting with MCMV sero(+) skin, the growth of MCMV was markedly inhibited in the salivary glands of severe combined immunodeficient (SCID) mice inoculated with T cells from TI-mice treated with sIL-4R. These results suggest that sIL-4R regulates the skin-graft-associated MCMV infection in TI-mice.

Analysis of Variance↗
PubMed2003

Therapeutic effects of IL-12 combined with benzoylmesaconine, a non-toxic aconitine-hydrolysate, against herpes simplex virus type 1 infection in mice following thermal injury.

IL-12 is an inducer of type 1 T cell responses, which are essential in host defense against herpes simplex virus type 1 (HSV-1) infection. However, type 1 T cell responses are not elicited by IL-12 in thermally injured mice (TI-mice) that routinely have a predominance of burn-associated type 2 T cell responses. In our previous studies, benzoylmesaconine (BEN, an aconitine derivative extracted from heated-Aconiti tuber) induced the generation of CD4+ T cells antagonistic to type 2 T cells (BEN-CD4+ T cells). In the present study, the effects of a combination therapy using IL-12 and BEN to treat severe HSV-1 infection in TI-mice were investigated. When TI-mice were treated with either IL-12 (500 U per mouse) or BEN (1 microg/kg) alone, they did not resist HSV-1 infection. However, 60-80% of TI-mice exposed to HSV-1 survived after they received IL-12 and BEN or BEN-CD4+ T cells in combination. After stimulation with anti-CD3 mAb in vitro, IFN- was not produced in cultures of splenic T cells from TI-mice exposed to HSV-1 and treated with either IL-12, BEN or BEN-CD4+ T cell alone. However, IFN- production was induced by the mAb stimulation in the cultures of T cells from infected mice treated with IL-12 and BEN or BEN-CD4+ T cells in combination. These results suggest that the combination therapy of IL-12 (an inducer of type 1 T cell responses) and BEN (an inhibitor of type 2 T cell responses) may protect TI-mice from severe HSV-1 infection.

Aconitine↗
PubMed2003

Lung carcinoma metastasis presenting as a pineal region tumor.

An autopsy case is reported of pineal metastasis from lung adenocarcinoma, which is a rare manifestation of the disease. A 75-year-old man who had been found to have a lesion in the lung by chest CT 2 years previously, became aware of head heaviness and then suffered consciousness disturbance. Brain MRI revealed a solitary mass in the pineal region with hydrocephalus. At autopsy a midsagittal section of the brain disclosed a well-circumscribed mass consisting of epithelial cells occupying the third ventricle. Although it should be recognized that such metastasis is very rare, the present case provides further information that might be useful for diagnosis.

Adenocarcinoma↗
PubMed2003

Effects of the CYP 2D6 genotype and cigarette smoking on the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients.

The effects of the cytochrome P450 (CYP) 2D6 genotype and cigarette smoking on the steady-state plasma concentrations (C(ss)) of fluvoxamine (FLV) and its demethylated metabolite fluvoxamino acid (FLA) were studied in 49 Japanese depressed patients receiving FLV 200 mg/d. The C(ss) of FLV and FLA were measured by HPLC, and the wild-type allele (*1) and two mutated alleles causing absent (*5) or decreased (*10) CYP 2D6 activity were identified by PCR methods. The patients were divided into three genotype groups by the number of mutated alleles: 12 cases with no (*1/*1), 27 cases with one (*1/*5 and *1/*10), and 10 cases with two (*5/*10 and *10/*10) mutated alleles. The means +/- SD of the C(ss) of FLV and FLA and the FLA/FLV ratio of all patients were 169.1 +/- 147.5 ng/mL, 83.9 +/- 52.7 ng/mL, and 0.71 +/- 0.50, respectively. The C(ss) of FLV and FLA were not significantly different among the three genotype groups. However, the FLA/FLV ratio was significantly lower in the patients with one (P < 0.05) and two (P < 0.01) mutated alleles than in those with no mutated allele. There was no significant difference between nonsmokers (n = 34) and smokers (n = 15) in these values. In the stepwise multiple regression, the C(ss) of FLA (P < 0.05) and FLA/FLV ratio (P < 0.001) showed significant negative correlations with the number of mutated alleles, and the FLA/FLV ratio was significantly (P < 0.05) lower in women than in men. The present study suggests that the CYP 2D6 genotype and cigarette smoking have no major impact on the C(ss) of FLV and FLA, though CYP 2D6 is involved in the demethylation of FLV.

Adult↗
PubMed2003

Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000.

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting adults. We studied the neuropathology and clinical correlations in 102 autopsy cases of ALS. The age at onset of the disease was significantly higher for the bulbaronset form (30 cases) than for the limb-onset form (72 cases). Dementia was confirmed in 7 cases. These 102 cases were divided into 4 pathological subgroups: typical ALS (59 cases), lower-motor-predominant ALS (23 cases), ALS with temporal lesions (18 cases), and ALS with pallido-nigro-luysian degeneration (2 cases). The age at onset was significantly higher for lower-motor-predominant ALS and ALS with temporal lesions than for typical ALS. In the lower motor neurons, Bunina bodies were detected in 88 cases, whereas ubiquitin-immunoreactive skein and/or spherical inclusions were detected in all 102 cases. Of the 100 available cases, 50 and 16 also showed ubiquitin-immunoreactive inclusions in the neostriatal and temporal small neurons, respectively. Ubiquitin-immunoreactive dystrophic neurites were also observed in the neostriatum in 3 of the 50 cases with neostriatal inclusions, and in the temporal cortex in 4 of the 16 cases with temporal inclusions. There was a significant association between the bulbar-onset form, temporal lesions, neostriatal inclusions and temporal inclusions, and between dementia, temporal lesions and temporal inclusions. Neostriatal and temporal dystrophic neurites were associated with dementia and bulbar-onset form through temporal lesions and temporal inclusions. The present findings may be helpful for designing further studies on the mechanisms underlying the development of ALS.

Age of Onset↗
PubMed2003

Monoamine oxidase A gene polymorphism, 5-HT 2A receptor gene polymorphism and incidence of nausea induced by fluvoxamine.

Selective serotonin reuptake inhibitors cause a side effect of nausea with high frequency, but there have been no accurate methods to predict its incidence. The authors first investigated whether a functional polymorphism in the monoamine oxidase A (MAOA-VNTR) and a -1438G/A polymorphism in the promoter region of the 5-HT(2A) gene were associated with the incidence of nausea induced by fluvoxamine. Fluvoxamine was administered for 6 weeks with a specific dosage plan (50-200 mg/day) in 66 Japanese major depressive patients. The frequency of MAOA-VNTR allele 1 was significantly higher in the patients without nausea than in ones with nausea in the statistical analysis including the patients whose plasma levels were below the average and who were considered to be pharmacodynamically more sensitive to nausea. This study showed that the genetic polymorphism of MAOA-VNTR might affect the incidence of nausea induced by SSRIs. If this finding is replicated in other studies with more subjects, MAOA-VNTR polymorphism would be of great clinical use to predict the incidence of nausea induced by SSRIs.

Adult↗