Biomedical subjects

T Kitamoto

Publications and source records attributed to T Kitamoto.

At least 37 records · Page 2Linked to original sources

PubMed2000

p300 mediates functional synergism between AF-1 and AF-2 of estrogen receptor alpha and beta by interacting directly with the N-terminal A/B domains.

Estrogen receptor (ER) alpha and beta mediate estrogen actions in target cells through transcriptional control of target gene expression. For 17beta-estradiol-induced transactivation, the N-terminal A/B domain (AF-1) and the C-terminal E/F domain (AF-2) of ERs are required. Ligand binding is considered to induce functional synergism between AF-1 and AF-2, but the molecular mechanism remains unknown. To clarify this synergism, we studied the role of reported AF-2 coactivators, p300/CREB binding protein, steroid receptor coactivator-1/transcriptional intermediary factor-2 (SRC-1/TIF2) family proteins and thyroid hormone receptor-associated protein-220/(vitamin D3 receptor-interacting protein- 205-(TRAP220/DRIP205) on the AF-1 activity in terms of synergism with the AF-2 function. We found that neither any of the SRC-1/TIF2 family coactivators nor TRAP220/DRIP205 is potent, whereas p300 potentiates the AF-1 function of both human ERalpha and human ERbeta. Direct interactions of p300 with the A/B domains of ERalpha and ERbeta were observed in an in vitro glutathione S-transferase pull-down assay in accordance with the interactions in yeast and mammalian two-hybrid assays. Furthermore, mutations in the p300 binding sites (56-72 amino acids in ERalpha and 62-72 amino acids in ERbeta) in the A/B domains caused a reduction in ligand-induced transactivation functions of both ERalpha and ERbeta. Thus, these findings indicate that ligand-induced functional synergism between AF-1 and AF-2 is mediated through p300 by its direct binding to the A/B regions of ERalpha and ERbeta.

Animals↗

PubMed2000

Isolation and characterization of mutants for the vesicular acetylcholine transporter gene in Drosophila melanogaster.

The Drosophila vesicular acetylcholine transporter gene (Vacht) is nested within the first intron of the choline acetyltransferase gene (Cha). To isolate Vacht mutants, we performed an F(2) genetic screen and identified mutations that failed to complement Df(3R)Cha(5), a deletion lacking Cha and the surrounding genes. Of these mutations, three mapped to a small genomic region where Cha resides. Complementation tests with a Cha mutant allele and rescue experiments using a transgenic Vacht minigene have revealed that two of these three mutations are nonconditional lethal alleles of Vacht (Vacht(1) and Vacht(2) ). The other is a new temperature-sensitive allele of Cha (Cha(ts3) ). Newly isolated Vacht mutants were used to reexamine the existing Cha mutations. We found that all deficiencies uncovering Cha also lack Vacht function, reflecting the nested organization of the two genes. The effective lethal phase for Vacht(1) is the embryonic stage, whereas that for Vacht(2) is the larval stage. Viable first-instar larvae homozygous for Vacht(2) showed reduced motility. Adult flies heterozygous for Vacht mutations were found to have defective responses in the dorsal longitudinal muscles following high-frequency brain stimulation. Since cholinergic synapses have been shown to be involved in the giant fiber pathway that mediates this response, the result suggested that reduction in the Vacht activity to 50% causes an abnormality in cholinergic transmission when stressed by a high-frequency stimulus.

Alleles↗

PubMed2000

Proton magnetic resonance spectroscopy of a patient with Gerstmann-Straussler-Scheinker disease.

A 23-year-old woman with Gerstmann-Straussler-Scheinker disease (GSS) was investigated by 1H-magnetic resonance spectroscopy (1H-MRS). She developed gait ataxic at 22 years. The diagnosis was confirmed by DNA analysis showing a proline-to-leucine point mutation at codon 102 of the prion protein. On 1H-MRS, she showed a remarkable reduction of the N-acetylaspartate/creatine ratio in the frontal lobe, cerebellar hemisphere and vermis and putamen. MRI revealed mild atrophy of the cerebellar hemispheres and vermis and cerebral cortex, but single-photon emission computed tomography (SPECT) with 99mHMPAO showed normal perfusion in the cerebellum. The imaging studies suggest that MRS might be superior to MRI or SPECT for detection of early neuronal degeneration.

Adult↗

PubMed2000

Epidemiologic features of 65 Creutzfeldt-Jakob disease patients with a history of cadaveric dura mater transplantation in Japan.

A total of 65 cases of Creutzfeldt-Jakob disease with a history of cadaveric dura transplantation in Japan were analysed to clarify the epidemiologic features of such patients and to explore whether other such patients will appear in the future. The age at transplantation averaged 44.4 years with a standard deviation of 14.4 years. The age at onset had an average of 53.0 years with a standard deviation of 14.1 years. The shortest latent period was 14 months, and the longest was 218 months with an average of 103.1 months and a standard deviation of 49.9 months. From the relationship between the calendar year at transplantation and the latent period, other such patients will appear in the near future. The current data suggested that several patients with Creutzfeldt-Jakob disease will occur from those receiving cadaveric dura mater grafts in the near future.

Adolescent↗

PubMed2000

Creutzfeldt-Jakob disease.

It is valuable to summarize the milestone study of prion diseases done in Japan for review in the journal Neuropathology in 2000. Many studies done in Japan promote world prion research activity, and also influence further research projects in other groups abroad. In this review the author focuses on the transmission experiment, the discovery of abnormal prion protein localization in the synaptic structures or follicular dendritic cells, and the genetic analysis of prion protein gene for the establishment of familial prion diseases.

Creutzfeldt-Jakob Syndrome↗

PubMed2000

A case-control study of Creutzfeldt-Jakob disease in Japan: transplantation of cadaveric dura mater was a risk factor.

A case-control study was conducted to reveal the relative risk of cadaveric dura mater graft transplantation for Creutzfeldt-Jakob disease. Fifty-two cases with Creutzfeldt-Jakob disease that were reported to the surveillance of the disease, and 102 age- and sex-matched hospital controls were selected. Information on family history, occupations, and medical history was collected. Eight cases and no control had a history of cadaveric dura mater graft transplantation. Surgical operations without the dura mater graft, blood transfusion, and acupuncture did not elevate the risk.

Acupuncture Therapy↗

PubMed2000

[Prion diseases].

Explore the source record for details and available documents.

Humans↗

PubMed1999

An inherited prion disease with a PrP P105L mutation: clinicopathologic and PrP heterogeneity.

OBJECTIVE: To clarify a clinical and neuropathologic phenotype of an inherited prion disease associated with a missense mutation at codon 105 in the prion protein (PrP) gene that was originally described as a variant of Gerstmann-Sträussler-Scheinker disease demonstrating spastic paraparesis. METHODS: Two siblings from a Japanese family are described. PrP gene analyses, neuropathologic studies with immunohistochemistry, and Western blot analysis of the PrP were performed. RESULTS: Both patients showed a missense (proline-->leucine) mutation at codon 105 and a methionine/valine polymorphism at codon 129 of the PrP gene. Clinically, Patient 1 presented with progressive spastic paraparesis, ataxia, and dementia. Patient 2, the sister of Patient 1, showed prominent action myoclonus and dementia. Neuropathologically, multiple PrP-positive amyloid plaques and diffuse PrP deposition in the deep cortical layers were found in the cerebral cortex with primarily frontal dominant atrophy in both patients. Tau-positive pathologic structures including neurofibrillary tangles, neuropil threads, and dystrophic neurites around the plaques were abundant in the brain of Patient 2. In contrast, the tau pathology was scarce in Patient 1. Western blot analysis of the brain showed different patterns of detergent-insoluble PrP fragments between the patients. CONCLUSIONS: Despite the identical codon 105 mutation and codon 129 polymorphism of the PrP gene, remarkable clinical and neuropathologic differences, and PrP heterogeneity were present between the affected siblings. The phenotypic variability might be related to PrP heterogeneity.

Amino Acid Substitution↗

PubMed1999

Wernicke encephalopathy-like symptoms as an early manifestation of Creutzfeldt-Jakob disease in a chronic alcoholic.

A case of Creutzfeldt-Jakob disease (CJD) with presenting Wernicke encephalopathy (WE)-like symptoms and severe insomnia is presented. An 80-year-old alcoholic man with a 6 month history of tremors, ataxia, memory loss and confabulation, developed profound insomnia, confusion, and delirium with vivid hallucinations. Polysomnography revealed a marked reduction of sleep time, with central-type sleep apnea. Neither myoclonus nor periodic synchronous discharge (PSD) was observed. An autopsy revealed diffuse spongiform changes and astrocytosis throughout the cerebral gray matter, with severe involvement of the mammillary bodies and thalamus. Prion protein (PrP) immunostaining was positive in kuru plaques in the cerebellum, PrP polymorphism at codon 129 was heterozygous Met/Val, and proteinase K resistant PrP (PrP(res)) was demonstrated by Western blotting. The lack of necrotizing lesions in the mammillary bodies, thalamus, and periaqueductal gray matter could rule out WE. The data suggest that the present case of CJD is consistent with PrP(res) type 2 (CJD M/V 2), but was unique in the lack of some typical CJD signs and the presence of signs of WE and sleep abnormalities.

Aged↗

PubMed1999

Creutzfeldt-Jakob disease with florid-type plaques after cadaveric dura mater grafting.

BACKGROUND: Many reported cases of iatrogenic Creutzfeldt-Jakob disease (CJD) developed after grafting cadaveric dura mater contaminated with CJD prions (dura-associated CJD). They are known to be clinicopathologically similar to sporadic CJD. We report herein 2 autopsy cases of dura-associated CJD with atypical clinicopathological features. PATIENTS: Two patients presented with progressive ataxia and mental deterioration 10 or 11 years after neurosurgical treatment with cadaveric dural grafting, which led to their deaths at 8 and 17 months, respectively, after onset. RESULTS: The cases were clinically atypical in exhibiting no or late occurrence of myoclonus and periodic synchronous discharges on electroencephalographic studies. They were pathologically unique in several aspects. The most striking feature was the presence of many prion protein (PrP) plaques in multiple areas in the brain. Some of them were the "florid" type surrounded by a zone of spongiform changes known to be a hallmark for the new variant CJD. The distribution of spongiform degeneration was also unique in that it was intense in the thalamus, basal ganglia, and the dentate nuclei of the cerebellum but milder in the cerebrum. There were no mutations in the PrP gene of the patients. There was no major difference in the size and glycoform pattern between the abnormal isoform of PrP extracted from the brain tissue from the dura-associated cases of CJD and that from a sporadic case of CJD. CONCLUSIONS: These 2 cases are clinicopathologically distinct from typical dura-associated cases of CJD. They may be a subtype with florid-type plaques in dura-associated CJD.

Aged↗

PubMed1999

Variant Gerstmann-Sträussler syndrome with the P105L prion gene mutation: an unusual case with nigral degeneration and widespread neurofibrillary tangles.

We present here a case of variant Gerstmann-Sträussler syndrome (GSS) with a codon 105 mutation of the prion protein gene. A 57-year-old woman developed dementia and gait disturbance dissimilar to the spastic paraparesis that is observed in most cases with codon 105 mutation. The clinical course of the disease in this case was 12 years. The brain weighed 900 g, and the frontal lobe, pallidum and thalamus were markedly atrophic. Severe neuronal loss was observed in the deep layer of the frontal and temporal cortices, and fibrillary gliosis and a marked loss of neurons was observed in the globus pallidus, thalamus and substantia nigra. Many amyloid plaques and some ballooned neurons were present in the frontal, temporal and parietal cortices. However, no spongiform changes were seen. The cerebellum was relatively well preserved. Numerous neurofibrillary tangles (NFTs) were recognized in the cerebral cortices, and scattered NFTs were observed in the basal nucleus of Meynert, thalamus, substantia nigra, periaqueductal gray matter, raphe nuclei and locus ceruleus. The case presented here indicates the presence of variations in the pathological findings of cases with codon 105 mutation, and that the formation of cortical and brain stem NFTs might have something to do with the duration of illness and/or the degree of brain tissue destruction that had occurred.

Brain↗

PubMed1999

Interaction of aluminum with PHFtau in Alzheimer's disease neurofibrillary degeneration evidenced by desferrioxamine-assisted chelating autoclave method.

To demonstrate that aluminum III (Al) interacts with PHFtau in neurofibrillary degeneration (NFD) of Alzheimer's disease (AD) brain, we developed a "chelating autoclave method" that allows Al chelation by using trivalent-cationic chelator desferrioxamine. Its application to AD brain sections before Morin histochemistry for Al attenuated the positive fluorescence of neurofibrillary tangles, indicating Al removal from them. This method, applied for immunostaining with phosphorylation-dependent anti-tau antibodies, significantly enhanced the PHFtau immunoreactivity of the NFD. These results suggest that each of the phosphorylated epitopes in PHFtau are partially masked by Al binding. Incubation of AD sections with AlCl(3) before Morin staining revealed Al accumulation with association to neurofibrillary tangles. Such incubation before immunostaining with the phosphorylation-dependent anti-tau antibodies abolished the immunolabeling of the NFD and this abolition was reversed by the Al chelation. These findings indicate cumulative Al binding to and thereby antigenic masking of the phosphorylated epitopes of PHFtau. Al binding was further documented for electrophoretically-resolved PHFtau on immunoblots, indicating direct Al binding to PHFtau. In vitro aggregation by AlCl(3) was observed for PHFtau but was lost on dephosphorylation of PHFtau. Taken together, phosphorylation-dependent and direct PHFtau-Al interaction occurs in the NFD of the AD brain.

Aluminum↗

PubMed1999

Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo.

BACKGROUND/AIMS: During hepatic fibrosis, hepatic stellate cells (HSCs) transform into myofibroblastic cells and lose their intracellular droplets of retinyl esters, the storage form of vitamin A. Recently, we have demonstrated that 9,13-di-cis-retinoic acid (RA), a geometric isomer identified as a stable and major metabolite of vitamin A in circulation, stimulates the synthesis of plasminogen activator (PA) and induces PA/plasmin-dependent latent transforming growth factor (TGF)-beta activation in HSC cultures, probably via induction and activation of RA receptor (RAR) alpha. The aim of the present study was to address a potential link between the loss of retinyl esters to increased formation of RA(s), which might play a role in facilitating TGF-beta-mediated liver fibrogenesis in vivo. METHODS: We examined the effect of 9,13-di-cis-RA on transactivating activity of RARalpha in HeLa cells as well as its effect on PA- and TGF-beta-dependent collagen synthesis in rat and human HSC cultures. We measured the changes in 9,13-di-cis-RA levels both during activation of rat HSCs in vitro and during porcine serum-induced rat hepatic fibrosis in vivo and correlated this with RAR alpha/beta, PA, TGF-beta and type I procollagen mRNA expression in the fibrotic liver. RESULTS: 9,13-di-cis-RA transactivated RARalpha, and provoked PA/plasmin and TGF-beta-dependent procollagen synthesis in HSCs. 9,13-di-cis-RA levels were increased both in activated HSCs in vitro and in fibrotic liver accompanying the enhanced expression of RAR alpha/beta, PA, TGF-beta and procollagen in vivo. CONCLUSIONS: These findings suggest a potential link between 9,13-di-cis RA formation and hepatic fibrosis via formation of TGF-beta in vivo, and thus provide further insight into the biologic role of retinoids during hepatic fibrogenesis.

Animals↗

PubMed1999

Drosophila choline acetyltransferase temperature-sensitive mutants.

We used the reverse transcription-polymerase chain reaction (RT-PCR) to amplify choline acetyltransferase (ChAT) mRNA fragments from two temperature-sensitive alleles of Drosophila melanogaster, Cha(ts1) and Cha(ts2). Single base substitutions in the mutants (T1614A in Cha(ts1) and G1596A in Cha(ts2)) would result in amino acid changes for ChAT protein (Met403Lys in Ch(ts1) and Arg397His in Cha(ts2)). These base substitutions were confirmed in mRNA extracted from homozygous mutants using a Single Nucleotide Primer Extension assay (SNuPE) and are sufficient to produce thermolabile enzyme. Our results indicate that these temperature-sensitive mutants are point mutations in the structural gene for ChAT. Using a quantitative SNuPE assay we also show that similar levels of Cha(ts) and wild type transcripts are present in heterozygous flies (Cha(ts1)/+ and Cha(Ts2)/+) at both restrictive and permissive temperatures. This contrasts with RNase protection assays of ChAT mRNA in homozygous mutant animals where the levels of mutant mRNA decrease at restrictive temperature.

Alleles↗

PubMed1999

Urocortin expression in the human central nervous system.

OBJECTIVE AND STUDY DESIGN: Urocortin is a recently identified neuropeptide of the corticotrophin-releasing factor (CRF) family in the mammalian brain and has been demonstrated to stimulate ACTH secretion from pituitary cells, but its expression in human brain tissue including the hypothalamus has not been examined. In this study, we first examined urocortin expression in the hypothalamus (20 cases) and pituitary stalks (17 cases) of human brain obtained from autopsy using immunohistochemistry and mRNA in situ hybridization. RESULTS: Neither urocortin immunoreactivity nor mRNA hybridization signals were detected in the hypothalami and pituitary stalks while CRF immunoreactivity was detected in the paraventricular nuclei of the hypothalami in 10/20 cases and in nerve fibres of the stalks in 17/17 cases. These results indicate that urocortin does not act on the hypothalamo-pituitary-adrenal axis, at least not in the same manner as CRF in humans. We then examined urocortin expression in various portions of the brain in 7 cases. Both urocortin immunoreactivity and mRNA hybridization were detected in Purkinje cells of the cerebellum and anterior horn cells of the spinal cord in specimens examined. Urocortin expression was, however, variably seen in superior olivary nuclei (two out of six cases examined) and in the Edingar-Westphal nuclei (one out of three cases examined). CONCLUSIONS: The distribution of urocortin in the human central nervous system suggests that urocortin may work as a neurotransmitter like other neuropeptides in the human.

Adolescent↗

PubMed1999

A chicken monoclonal antibody with specificity for the N-terminal of human prion protein.

Chickens were immunized with human prion protein (PrP) peptide H25 (amino acid residues 25-49) coupled to keyhole limpet hemocyanin. From a fusion experiment using the chicken fusion partner cell line MuH1 and immune spleen cells, one mAb, HUC2-13, was generated which reacted with the peptide. HUC2-13 was specific for a pentapeptide (RPKPG) of the N-terminal of the peptide H25. In Western blotting analysis, the mAb reacted with PrP materials from a human Creutzfeldt-Jakob disease (CJD) case and the membrane fraction from normal murine brain, but not with the same materials pretreated with proteinase K. When compared with the HUC2-13 and the conventional mouse mAb 3F4, the background stainings using the HUC2-13 were minimal. In immunohistochemistry, the HUC2-13 stained positively with kuru plaques in brain sections from patients with Gerstmann-Straussler syndrome (GSS), and also reacted with synaptic structures of the CJD patients. However, any immunolabelings using the HUC2-13 were not observed in the section from a patient with amyotrophic lateral sclerosis (ALS) as CJD-negative control. These results indicate that the mAb HUC2-13 is a suitable tool for immunological and diagnostic analyses of prion disease in humans and other mammals.

Amino Acid Sequence↗

PubMed1999

A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein.

A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype) has two features never observed in subjects carrying the pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype): (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2 protease-resistant prion protein (PrP(res)). This observation further underlines the role of codon 129 on the mutated PRNP allele in modulating the phenotype of familial prion diseases.

Aged↗

PubMed1999

[Diffusion images on brain MRI in Creutzfeldt-Jakob disease].

We report a 72-year-old man with Creutzfeldt-Jakob disease. He showed a progressive dementia, myoclonus, and other neurological symptoms. DNA analysis showed a normal variation of prion gene (codon 129, Met/Met: codon 219, Glu/Glu). He had periodic synchronous discharge on electroencephalogram and brain atrophy on CT scan and MRI. Diffusion images on his brain MRI revealed a marked increase in signal intensity in the caudate nuclei, putamen, and cerebral cortices. These changes may represent spongy changes of the brain and seem to be a feature of brain MRI in Creutzfeldt-Jakob disease.

Aged↗