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Biomedical subjects

Hitoshi Takahashi

Publications and source records attributed to Hitoshi Takahashi.

At least 73 records · Page 4Linked to original sources
PubMed2004

Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillin-resistant Staphylococcus aureus.

Neutrophils (PMN) have been described as critical effector cells in the host's antibacterial innate immunities. However, the classification of murine PMNs remains unclear. Here, we show that in addition to normal PMN (PMN-N), there are at least two distinct subsets of PMNs (PMN-I and PMN-II) distinguished as follows: (1) cytokine and chemokine production (PMN-I, IL-12/CCL3; PMN-II, IL-10/CCL2; PMN-N, no cytokine/chemokine production), (2) macrophage activation (PMN-I, classically activated macrophages; PMN-II, alternatively activated macrophages; PMN-N, no effect on macrophage activation), (3) Toll-like receptor (TLR) expression (PMN-I, TLR2/TLR4/TLR5/TLR8; PMN-II, TLR2/TLR4/TLR7/TLR9; PMN-N, TLR2/TLR4/TLR9), and (4) surface antigen expression (PMN-I, CD49d(+)CD11b-; PMN-II, CD49d(-)CD11b+; PMN-N, CD49d(-)CD11b-). PMN-I was obtained from MRSA (methicillin-resistant Staphylococcus aureus)-resistant hosts, while MRSA-sensitive hosts were a source of PMN-II. PMN-N was obtained from naive mice. Anti-MRSA innate immunities might be influenced differently by these biochemically and physically distinguished PMNs. PMN-N may convert to PMN-I or PMN-II in response to host circumstance.

Animals↗
PubMed2004

Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats.

Cytokines have been implicated in the etiology or pathology of various psychiatric diseases of developmental origin such as autism and schizophrenia. Leukemia inhibitory factor (LIF) is induced by a variety of brain insults and known to have many influences on mature and immature nervous system. Here, we assessed the neurobehavioral and pathological consequences of peripheral administration of LIF in newborn rats. Subcutaneous LIF injection induced STAT3 phosphorylation in many brain regions and increased glial fibrillary acidic protein (GFAP) immunoreactivity in the neocortex, suggesting that LIF had direct effects in the central nervous system. The LIF-treated rats displayed decreased motor activity during juvenile stages, and developed abnormal prepulse inhibition in the acoustic startle test during and after adolescence. They displayed normal learning ability in active avoidance test, however. Brain neuronal structures and startle responses were grossly normal, except for the cortical astrogliosis during neonatal LIF administration. These results indicate that LIF induction in the periphery of the infant has a significant, but discrete impact on neurobehavioral development.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Autopsy findings of a craniopharyngioma with a natural course over 60 years.

BACKGROUND: We report the histologic manifestations in an autopsy case of craniopharyngioma with an unusually long treatment-free course. CASE DESCRIPTION: A 72-year-old woman with craniopharyngioma, in whom ateliosis due to the suprasellar tumor had been identified at the age of 10 years but had not been treated, was studied postmortem. She had not acquired secondary sex characteristics. At autopsy, a hard mass 2 cm in diameter was present in the suprasellar region and invaded the anterior floor of the third ventricle. Histologically, a large proportion of the mass was replaced by wet keratin, ossified tissue, dystrophic calcification, and fatty adipose tissue: these features indicate widespread degeneration of the tumor cells. Only a few residual cell nests of craniopharyngioma-composed of squamous cells lined with a single columnar cell layer-were observed at the peripheral portion of the mass. Conspicuous reactive astrocytosis with relatively high cellularity was evident in the brain tissue adjacent to the mass. CONCLUSION: This case may represent a rare example of craniopharyngioma lacking spontaneous growth activity and consequently showing marked degeneration of the tumor cells.

Aged↗
PubMed2004

Influence of systemic inflammatory response syndrome on host resistance against bacterial infections.

OBJECTIVE: To determine the relationship between systemic inflammatory response syndrome (SIRS) and host innate immunities against bacterial infections. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male BALB/c mice, 8-10 wks of age. INTERVENTIONS: Morbidity and mortality rates of severe SIRS mice were compared with those of mild SIRS mice after infection with Enterococcus faecalis or methicillin-resistant Staphylococcus aureus (MRSA) or exposure to infectious complications induced by cecal ligation and puncture (CLP). In addition, a function of effector cells related to antibacterial innate immunities for these infections was analyzed in these two groups. Furthermore, SCIDbgMN mice (SCIDbg mice depleted of antibacterial effector cells) were reconstituted with effector cells from mild or severe SIRS mice and exposed to various infections. MEASUREMENTS AND MAIN RESULTS: Severe SIRS mice were greatly susceptible to E. faecalis, MRSA, and CLP-induced sepsis. On the other hand, as compared with normal mice, mild SIRS mice were resistant to these infections. All of SCIDbgMN mice inoculated with peritoneal macrophages (PMphi) from severe SIRS mice died after infection with E. faecalis or MRSA, whereas all SCIDbgMN mice inoculated with PMphi from mild SIRS mice survived after the same infection. SCIDbgMN mice that were inoculated with PMphi from normal mice and exposed to E. faecalis, MRSA, or CLP survived at rates of 50%, 50%, or 60%, respectively. PMphi from mild SIRS mice exhibited typical properties for classically activated macrophages (CAMphi), whereas those from severe SIRS mice exhibited typical properties for alternatively activated macrophages (AAMphi). CONCLUSIONS: Mphi-associated host antibacterial innate immunities are greatly influenced by SIRS levels. CAMphi, effector cells for the antibacterial innate immunity against E. faecalis, MRSA, and CLP-induced sepsis, are induced in mild SIRS mice. AAMphi with no antibacterial capabilities are generated in mice with severe SIRS. Induction of CAMphi may protect severe SIRS patients against infections.

Analysis of Variance↗
PubMed2004

Pathological heterogeneity in progressive supranuclear palsy and corticobasal degeneration.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative disorders of late adult life. Focal asymmetric cortical atrophy with ballooned neurons, nigral degeneration, and tau-positive neuronal and glial lesions in both the gray and white matter, especially astrocytic plaques in the affected cerebral cortex, are characteristic features of CBD. While cortical involvement may occur in PSP, ballooned neurons are sparse and limited to the limbic system, and tufted astrocytes are abundant in the precentral gyrus and striatum. The present findings suggest that PSP and CBD are distinct pathological entities. However, there exist 'atypical' cases of PSP and CBD. Severe cortical involvement or asymmetric cortical atrophy can be seen in PSP. Ballooned neurons are sparse or difficult to detect in some cases of CBD, in spite of typical cortical tau pathology. Cortical symptoms are absent or only mild in 'minimal change' CBD. Moreover, several neurodegenerative disorders can underlie CBD. This pathological heterogeneity leads to difficulty in the clinical and pathological diagnosis of both disorders.

Animals↗
PubMed2004

Prediction of antidepressant response to milnacipran by norepinephrine transporter gene polymorphisms.

OBJECTIVE: With a multitude of antidepressants available, predictors of response to different classes of antidepressants are of considerable interest. The purpose of the present study was to determine whether norepinephrine transporter gene (NET) and serotonin transporter gene (5-HTT) polymorphisms are associated with the antidepressant response to milnacipran, a dual serotonin/norepinephrine reuptake inhibitor. METHOD: Ninety-six Japanese patients with major depressive disorder were treated with milnacipran, 50-100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery-Asberg Depression Rating Scale. Assessments were carried out at baseline and at 1, 2, 4, and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants. RESULTS: Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response, whereas the A/A genotype of the NET G1287A polymorphism was associated with a slower onset of therapeutic response. In contrast, no influence of 5-HTT polymorphisms on the antidepressant response to milnacipran was detected. CONCLUSIONS: The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran.

Adrenergic Uptake Inhibitors↗
PubMed2004

Prefrontal abnormality of schizophrenia revealed by DNA microarray: impact on glial and neurotrophic gene expression.

DNA microarrays with isotope labeling from gene-specific primers enable sensitive detection of rare mRNAs, including neurotrophin and cytokine mRNAs in the brain. Using high-quality RNA from postmortem brains, gene-expression profiles covering 1373 genes were assessed in the dorsoprefrontal cortex of schizophrenic patients and compared with those of nonpsychiatric subjects. Statistical analysis of the DNA microarray data confirmed the findings of a previous GeneChip study by Hakak et al. (Proc. Natl. Acad. Sci. USA Vol. 98, pp. 4746-4751, 2001). The highest frequency of mRNA expression alterations occurred in oligodendrocyte- and astrocyte-related genes in the prefrontal cortex of schizophrenic patients, followed by the category for the genes for growth factors/neurotrophic factors and their receptors. Whether each mRNA signal represents the expression of the individual genes or homologous genes in the category remains to be determined, however. To control for potential medication effects on patients, RNA from cynomolgus monkeys that were treated with haloperidol for 3 months was also subjected to DNA microarray analysis. A few genes overlapped between the gene-expression profiles of the monkeys and patients. The present profiling study suggests a potential biological link between abnormal neurotrophic signals and impaired glial functions in schizophrenic pathology.

Aged↗
PubMed2004

DNA replication reaction in Xenopus cell-free system is suppressed by high pressure.

Previously, we demonstrated that when mouse erythroleukemia cells are exposed to a pressure of 80 MPa, the cell-cycle progression of S-phase cells is retarded. To examine the effects of high pressure on DNA replication, we used a Xenopus cell-free system. From cell-cycle progression of sperm nuclei, it was found that sperm nuclei are stable to a pressure of 80 MPa, whereas egg extracts are susceptible to high pressure. Similarly, biotin-16-dUTP was incorporated into 80 MPa-treated sperm nuclei in pressure-untreated extracts, but not into naive sperm nuclei in 80 MPa-treated extracts. These results indicate that DNA replication in Xenopus cell-free system is suppressed by the susceptibility of the extracts to a pressure of 80 MPa.

Animals↗
PubMed2004

[Development of a simple method of detecting acetaminophen using 96 well microplate readers].

Acetaminophen (APAP: N-Acetyl-p-aminophenol) has been widely used as a relatively safe antipyretic and analgesic drug. However, APAP is known as a major causative agent of fulminant hepatic failure, in a dose and a blood concentration dependent manner, in Western countries. The APAP toxicity should be expected to increase in proportion as the increasing of the clinical use in Japan. Therefore, a simplified method which determines the concentration of APAP would be valuable for clinical use. We have modified the APAP determination method developed by Yasojima. Our method enabled to measure APAP concentration with a small volume of samples by using 96-well microtiter plate, which can handle multiple samples simultaneously. From 10 microg/ml to 320 microg/ml of APAP was quantitatively measured by our method, which is suitable for diagnostics of the APAP toxicity. APAP levels below the lethal concentration of 160 microg/ml can be determined with one plate.

Acetaminophen↗
PubMed2004

[An autopsy case of systemic vasculitis associated with hepatitis C virus-related mixed cryoglobulinemia presenting severe peripheral neuropathy].

A 75-year-old man, previously diagnosed as having chronic hepatitis C virus (HCV) infection, suddenly developed left foot drop, followed by progressive motor weakness and sensory disturbance in all of the extremities. Because of an elevated level of the rheumatoid factor (RF), he had been treated with antirheumatic drugs three years before the onset of his neurological symptoms. Within two months, he became unable to walk any more, and was transferred to our hospital. Neurologic examination showed asymmetrical severe muscular weakness and atrophy of all the limbs, and a sensory deficit under the level of the wrists and knees. Livedo reticularis was also noted in bilateral legs. Nerve conduction study revealed severe sensorimotor axonal neuropathy, and muscle biopsy specimens showed necrotizing vasculitis of small arteries in the perimysium. Serological tests indicated type II cryoglobulinemia (monoclonal IgAkappa + polyclonal IgG). A diagnosis of vasculitic neuropathy associated with HCV-related mixed cryoglobulinemia was made. A high-dose intravenous immunoglobulin therapy (IVIg) and a high-dose steroid therapy were not effective, and he died of alveolar hemorrhage probably due to pulmonary vasculitis. Postmortem pathological examination revealed severe vasculitis, accompanied by fibrinoid degeneration and the infiltration of predominant mononuclear cells into the small and medium-sized vascular walls of multiple organs such as the liver, kidney, pancreas and intestine as well as the peripheral nerves and skeletal muscles. A severe loss of myelinated fibers were also observed in the multiple peripheral nerves examined. We emphasize that patients with HCV infection and mixed cryoglobulinemia may develop severe systemic vasculitis resembling polyarteritis nodosa leading to often life-threatening polyvisceral failure, particularly in patients showing progressive mononeuropathy multiplex.

Aged↗
PubMed2004

[A useful marker for differential diagnosis of Parkinson's disease--MIBG myocardial scintigraphy].

We performed [123I]-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy in 180 patients with PD, 24 patients with DLB and 73 patients with the other related diseases. The heart-to-mediastinum (H/M) ratio in PD and DLB was significantly low compared to that in MSA, PSP, CBD and AD. The H/M ratio tended to decrease with the disease progression in PD. These findings suggest that MIBG myocardial scintigraphy could be a marker for differential diagnosis of PD and DLB. We immunohistochemically examined heart tissues from patients with pathologically confirmed PD, DLB and the other related diseases using monoclonal antibody against tyrosine hydroxylase (TH). The number of TH-immunoreactive nerve fibers in the epicardium was moderate or abundant in most patients with MSA, PSP, CBD and AD as well as in the control subjects. Contrarily, the number of TH-immunoreactive nerve fibers in the epicardium had almost completely disappeared in nearly all the patients with PD and DLB. These findings suggest that postganglionic cardiac sympathetic nerve denervation occurs in PD and DLB but not in MSA, PSP, CBD and AD, which accounts for the decreased cardiac uptake of MIBG in PD and DLB, but not in the other diseases.

3-Iodobenzylguanidine↗
PubMed2003

Loss of poly(ADP-ribose) glycohydrolase causes progressive neurodegeneration in Drosophila melanogaster.

Poly(ADP-ribosyl)ation has been suggested to be involved in regulation of DNA repair, transcription, centrosome duplication, and chromosome stability. However, the regulation of degradation of poly(ADP-ribose) and its significance are not well understood. Here we report a loss-of-function mutant Drosophila with regard to poly(ADP-ribose) glycohydrolase, a major hydrolyzing enzyme of poly(ADP-ribose). The mutant lacks the conserved catalytic domain of poly(ADP-ribose) glycohydrolase, and exhibits lethality in the larval stages at the normal development temperature of 25 degrees C. However, one-fourth of the mutants progress to the adult stage at 29 degrees C but showed progressive neurodegeneration with reduced locomotor activity and a short lifespan. In association with this, extensive accumulation of poly(ADP-ribose) could be detected in the central nervous system. These results suggest that poly(ADP-ribose) metabolism is required for maintenance of the normal function of neuronal cells. The phenotypes observed in the parg mutant might be useful to understand neurodegenerative conditions such as the Alzheimer's and Parkinson's diseases that are caused by abnormal accumulation of substances in nervous tissue.

Animals↗
PubMed2003

Reciprocal accumulation of beta-synuclein in alpha-synuclein lesions in multiple system atrophy.

Alpha-Synuclein is a major component of neuronal and glial cytoplasmic inclusions in multiple system atrophy (MSA), one of the alpha-synucleinopathies. Recent studies have shown that beta-synuclein, a homolog of alpha-synuclein, inhibits alpha-synuclein aggregation in vitro. We immunohistochemically examined the MSA brain, using specific antibodies against alpha-synuclein and beta-synuclein. alpha-synuclein-positive filamentous aggregates were frequently found in neurons in the pontine and inferior olivary nuclei. No abnormal accumulation of alpha-synuclein was noted in Purkinje cells. In contrast, beta-synuclein accumulation occurred extensively in Purkinje cells, and only minimally in pontine and olivary neurons. Thus, neuronal alpha-synuclein inclusions appear to occur only rarely in neurons in which beta-synuclein accumulates. These findings support the possibility that beta-synuclein is a negative regulator of alpha-synuclein aggregation.

Aged↗
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↗