Biomedical subjects

Yuko Saito

Publications and source records attributed to Yuko Saito.

At least 19 recordsLinked to original sources

PubMed2006

Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia.

Anti-glutamic acid decarboxylase antibody is associated with the development of progressive cerebellar ataxia and slowly progressive insulin-dependent diabetes mellitus. Previously, the neurophysiological characteristics of IgG in the cerebrospinal fluid of a patient with anti-glutamic acid decarboxylase antibody-associated progressive cerebellar ataxia and slowly progressive insulin-dependent diabetes mellitus were reported. Using a voltage-gated whole-cell recording technique, it was observed that the IgG in the cerebrospinal fluid of the patient selectively suppressed the inhibitory postsynaptic currents in the Purkinje cells. The patient died from aspiration pneumonia. Postmortem examination showed almost complete depletion of the Purkinje cells with Bergmann gliosis. Therefore, the main cause of cerebellar ataxia observed in this case may be attributed to the near-complete depletion of the Purkinje cells. In this paper, the pathomechanisms underlying Purkinje cell damage are discussed.

Aged↗

PubMed2006

Clinical validity of the Japanese version of the Functional Assessment of Cancer Therapy-Anemia Scale.

GOALS OF WORK: The purpose of this study was to reveal the clinical validity of the Japanese version of the Functional Assessment of Cancer Therapy-Anemia scale (FACT-An) in relation to hemoglobin level. We also analyzed patients' scores for the related FACT-General scale (FACT-G), the FACT Anemia subscale, and the FACT Trial Outcome Index-Anemia scale (FACT TOI-An) to determine which was the most sensitive to anemia measurements. MATERIALS AND METHODS: Throughout Japan, we recruited 227 patients (mean+/-SD, 59+/-12.1 years old) diagnosed with a variety of cancers. We correlated the severity of anemia, as measured by hemoglobin levels, to scores on the FACT-An and on the other scales at baseline and at 3 months. MAIN RESULTS: The questionnaire completion rate was more than 98% at both time points. The FACT-An had high internal consistency (Cronbach's alpha coefficient >0.8). FACT-An scores were significantly and positively correlated with hemoglobin levels both at baseline (r=0.24; 95% CI=0.12 to 0.36; n=225) and at 3 months (r=0.24; 95% CI=0.10 to 0.36; n=204). FACT-G, FACT Anemia subscale, and FACT TOI-An scores also successfully discriminated between patients with lower (Hb <11.0 g/dl) and higher (Hb > or =11.0 g/dl) hemoglobin levels. Moreover, the changes of these FACT scores over 3-months could discriminate changes in hemoglobin level. CONCLUSION: The Japanese version of the FACT-An has higher clinical validity and can be used to appropriately assess health-related quality of life among Japanese cancer patients with anemia.

Adult↗

PubMed2006

Characterization of the protease activity that cleaves the extracellular domain of beta-dystroglycan.

Dystroglycan (DG) complex, composed of alphaDG and betaDG, provides a link between the extracellular matrix (ECM) and cortical cytoskeleton. Although the proteolytic processing of betaDG was reported in various physiological and pathological conditions, its exact mechanism remains unknown. In this study, we addressed this issue using the cell culture system of rat schwannoma cell line RT4. We found that the culture medium of RT4 cells was enriched with the protease activity that degrades the fusion protein construct of the extracellular domain of betaDG specifically. This activity was suppressed by the inhibitor of matrix metalloproteinase-2 (MMP-2) and MMP-9, but not by the inhibitors of MMP-1, MMP-3, MMP-8, and MMP-13. Zymography and RT-PCR analysis showed that RT4 cells secreted MMP-2 and MMP-9 into the culture medium. Finally, active MMP-2 and MMP-9 enzymes degraded the fusion protein construct of the extracellular domain of betaDG. These results indicate (1) that RT4 cells secrete the protease activity that degrades the extracellular domain of betaDG specifically and (2) that MMP-2 and MMP-9 may be involved in this process.

Animals↗

PubMed2006

Autotaxin expression is enhanced in frontal cortex of Alzheimer-type dementia patients.

We searched for genes differentially expressed in the frontal cortices of Alzheimer-type dementia (ATD) patients compared with those of non-ATD controls using DNA microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses. Here we show that the expression level of the autotaxin (also called lysophospholipase D or ecto-nucleotide pyrophosphatase/phosphodiesterase 2) gene was significantly greater in ATD cortices than in non-ATD cortices. In both ATD and non-ATD groups, the expression levels were greater in patients with the apoE epsilon3/epsilon4 genotype than in patients with the apoE epsilon3/epsilon3 genotype, although the differences were not statistically significant. These observations suggest that expression of the autotaxin gene and cell signaling by lysophosphatidic acid may be involved in the pathology of ATD, and that this cell signaling pathway may be a potential target of treatments for ATD.

Aged↗

PubMed2006

Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease.

Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case-control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case-control populations, we found that a SNP in alpha-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0 x 10(-10)). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D'>0.9) spanning approximately 120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0 x 10(-9)-1.7 x 10(-11)). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.

Adult↗

PubMed2006

Pathology of the sympathetic nervous system corresponding to the decreased cardiac uptake in 123I-metaiodobenzylguanidine (MIBG) scintigraphy in a patient with Parkinson disease.

Decreased cardiac uptake in (123)I-metaiodobenzylguanidine (MIBG) scintigraphy has been adopted as one of the most reliable diagnostic tests for Parkinson disease (PD) in Japan. To investigate the morphological basis for this finding, we performed a detailed neuropathological study of the cardiac sympathetic nervous system of a 71-year-old autopsy-proven PD patient, who presented with a marked decrease in cardiac uptake of MIBG, just 1 year prior to death. We carefully examined the intermediolateral column at several levels of the thoracic spinal cord, the sympathetic trunk and ganglia, and the nerve plexus of the anterior wall of the left ventricle and compared the findings with those of five age-matched controls. We found that the cardiac plexus was more heavily involved than the sympathetic ganglia in this patient with PD. Our study may provide further evidence that the markedly decreased cardiac uptake of MIBG observed in PD cases represents preferential involvement of the cardiac sympathetic nerve plexus in this disorder.

3-Iodobenzylguanidine↗

PubMed2006

Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease.

Development of neurofibrillary tangles (NFTs) is a pathological hallmark in various neurodegenerative disorders including Alzheimer's disease (AD). Recently, we identified a granular tau oligomer having a pre-filamentous structure. To determine the role of this oligomer in NFT formation, we quantified the amount of granular tau oligomer in 21 frontal cortex samples, each displaying varying degrees of Braak-staged NFT pathology. Here we report that granular tau oligomer levels in frontal cortex were significantly increased, even in brains displaying Braak-stage I neuropathology, a stage at which clinical symptoms of AD and NFTs in frontal cortex are believed to be absent. This suggests that increases in granular tau oligomer levels occur before NFTs form and before individuals manifest clinical symptoms of AD. Increased granular tau oligomer levels, therefore, may lead to NFT formation in frontal cortex, eventually leading to the development of AD. Thus, increases in granular tau oligomer levels may represent a very early sign of NFT formation and AD.

Aged↗

PubMed2006

Standard organ weights among elderly Japanese who died in hospital, including 50 centenarians.

The present study was conducted to determine standard organ weights among the elderly, because little has been reported on this subject. To analyze the human aging process in terms of organ weights, age-associated changes and correlations among organ weights and the contributions of age and nutrition to organ weights were also examined. The subjects included 1615 consecutive autopsy cases of patients aged 60-99 years who died between 1995 and 2003, and cases of 50 centenarians who died between 1973 and 2005. The weights of nine organs were measured before formalin fixation. If affected by serious diseases, such as cancer, the organs were excluded from the study. Values beyond 99% of the bilateral measurement limits were also excluded. In this manner the standard organ weights were obtained. The organ weights decreased significantly according to age in all organs except for the heart in men and the lungs in both genders. Undernutrition strongly contributed to organ weight except for the hypophysis, and was especially apparent in the heart and liver. In conclusion, the standard organ weights of elderly patients who died while hospitalized were determined. Undernutrition contributed significantly to a reduction in organ weights.

Aged↗

PubMed2006

[A case of recurrent esophageal cancer with lung metastases successfully treated with docetaxel-combination chemotherapy].

We report a case of a 67-year-old woman diagnosed with advanced esophageal cancer. She was treated with chemo-radiotherapy (5-FU/CDDP therapy and irradiation) initially, and primary lesion was well controlled. Two and a half years after first treatment, a chest CT showed multiple lung metastasis, which were confirmed by thoraco-laparoscopy. We chose docetaxel/CDDP combination chemotherapy, because of severe side effects due to the first treatment. After 3 courses, lung metastatic lesions were reduced. The following courses combining docetaxel-nedaplatin were done as ambulatory treatment. These regimens could be one choice for recurrent esophageal cancer, especially FP therapy-resistant or intolerant cases.

Aged↗

PubMed2006

[Brain bank].

Explore the source record for details and available documents.

Alzheimer Disease↗

PubMed2005

Beta-site APP cleaving enzyme 1 (BACE1) is increased in remaining neurons in Alzheimer's disease brains.

Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid beta protein (Abeta) in the brain cortex. Abeta is produced from beta-amyloid precursor protein (APP) by beta-secretase and gamma-secretase. beta-Secretase has been identified as beta-site APP cleaving enzyme1 (BACE1). We produced rabbit polyclonal antibodies against the amino and the carboxyl terminals of BACE1. Using these antibodies, BACE1 was characterized in temporal lobe cortices by Western blotting and immunohistochemistry. Immunohistochemical studies employing anti-GFAP and anti-MAP2 antibodies as well as anti-BACE1 antibodies showed that BACE1 was expressed exclusively in neurons but not in glial cells. Brain samples were directly extracted by 0.5% SDS and analyzed by Western blotting and densitometer. Although the mean level of BACE1/mg protein in AD brains was not increased, the ratio of BACE1 to MAP2 or to NSE was significantly increased compared with that in control brains. Taken together, these findings suggest that those neurons that survive in AD brains might generate more BACE1 than normal neurons in control brains, indicating that increased BACE1 activity could be one of the causes of AD. This could justify the development of anti-BACE1 drugs for AD treatment.

Alzheimer Disease↗

PubMed2005

An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains.

Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. By positional cloning, we have identified the gene strongly associated with a form of degenerative ataxia (chromosome 16q22.1-linked ADCA) that clinically shows progressive pure cerebellar ataxia. Detailed examination by use of audiogram suggested that sensorineural hearing impairment may be associated with ataxia in our families. After restricting the candidate region in chromosome 16q22.1 by haplotype analysis, we found that all patients from 52 unrelated Japanese families harbor a heterozygous C-->T single-nucleotide substitution, 16 nt upstream of the putative translation initiation site of the gene for a hypothetical protein DKFZP434I216, which we have called "puratrophin-1" (Purkinje cell atrophy associated protein-1). The full-length puratrophin-1 mRNA had an open reading frame of 3,576 nt, predicted to contain important domains, including the spectrin repeat and the guanine-nucleotide exchange factor (GEF) for Rho GTPases, followed by the Dbl-homologous domain, which indicates the role of puratrophin-1 in intracellular signaling and actin dynamics at the Golgi apparatus. Puratrophin-1--normally expressed in a wide range of cells, including epithelial hair cells in the cochlea--was aggregated in Purkinje cells of the chromosome 16q22.1-linked ADCA brains. Consistent with the protein prediction data of puratrophin-1, the Golgi-apparatus membrane protein and spectrin also formed aggregates in Purkinje cells. The present study highlights the importance of the 5' untranslated region (UTR) in identification of genes of human disease, suggests that a single-nucleotide substitution in the 5' UTR could be associated with protein aggregation, and indicates that the GEF protein is associated with cerebellar degeneration in humans.

5' Untranslated Regions↗

PubMed2005

Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer's disease.

Citrullinated proteins are the products of a posttranslational process in which arginine residues undergo modification into citrulline residues when catalyzed by peptidylarginine deiminases (PADs) in a calcium ion-dependent manner. In our previous report, PAD2 expressed mainly in the rat cerebrum became activated early in the neurodegenerative process. To elucidate the involvement of protein citrullination in human neuronal degeneration, we examined whether citrullinated proteins are produced during Alzheimer's disease (AD). By Western blot analysis with antimodified citrulline antibody, citrullinated proteins of varied molecular weights were detected in hippocampal tissues from patients with AD but not normal humans. Two of the citrullinated proteins were identified as vimentin and glial fibrillary acidic protein (GFAP) by using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. Interestingly, PAD2 was detected in hippocampal extracts from AD and normal brains, but the amount of PAD2 in the AD tissue was markedly greater. Histochemical analysis revealed citrullinated proteins throughout the hippocampus, especially in the dentate gyrus and stratum radiatum of CA1 and CA2 areas. However, no citrullinated proteins were detected in the normal hippocampus. PAD2 immunoreactivity was also ubiquitous throughout both the AD and the normal hippocampal areas. PAD2 enrichment coincided well with citrullinated protein positivity. Double immunofluorescence staining revealed that citrullinated protein- and PAD2-positive cells also coincided with GFAP-positive cells, but not all GFAP-positive cells were positive for PAD2. As with GFAP, which is an astrocyte-specific marker protein, PAD2 is distributed mainly in astrocytes. These collective results, the abnormal accumulation of citrullinated proteins and abnormal activation of PAD2 in hippocampi of patients with AD, strongly suggest that PAD has an important role in the onset and progression of AD and that citrullinated proteins may become a useful marker for human neurodegenerative diseases.

Aged↗

PubMed2005

Possibility for neurogenesis in substantia nigra of parkinsonian brain.

Recent studies of enhanced hippocampal neurogenesis by antidepressants suggest enhancement of neurogenesis is a potentially effective therapy in neurodegenerative diseases. In this study, we evaluated nigral neurogenesis in animals and autopsy brains including patients with Parkinson's disease (PD). First, proliferating cells in substantia nigra were labeled with retroviral transduction of green fluorescent protein, which is an efficient method to label neuronal stem cells. Subsequent differentiation of labeled cells was followed; many transduced cells became microglia, but no differentiation into tyrosine hydroxylase-positive neurons was detected at 4 weeks after injection, in both intact rodents and those treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Second, polysialic acid (PSA)-like immunoreactivity, indicative of newly differentiated neurons, was detected in the substantia nigra of rodent, primate, and human midbrains. A large number of PSA-positive cells were detected in the substantia nigra pars reticulata of some patients with PD. In rats and a macaque monkey, the dopamine-depleted hemispheres showed more PSA staining than the intact side. A small number of tyrosine hydroxylase-positive cells were PSA-positive. Our results suggest enhanced neural reconstruction in PD, which may be important in the design of new therapies against the progression of PD.

Aged↗

PubMed2005

Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease.

Niemann-Pick disease type C (NP-C) is an autosomal recessive neurovisceral storage disease with neurodegeneration caused by mutations in either the NPC-1 or NPC-2 gene. The murine ortholog of NPC-1 is mutated in BALB/c npc(nih) and this mutant mouse shows equally conspicuous neurodegeneration and loss of neurons. However, the molecular mechanisms causing neurodegeneration in NP-C remain elusive. Here, we report the presence of apoptotic cells detected by both TUNEL staining and electron microscopy in the cerebrum and cerebellum of human patients and the mouse model. Moreover, we found that with progression of the disease process leading to neuronal cell death, an up-regulation of genes involved in the TNF-alpha death pathway caspase-8, FADD, TNFRp55, TRADD, and RIP-by an RNA protection assay. Furthermore, RT-PCR showed that TNF-alpha mRNA expression level also increased up to 30-50-fold in the cerebellum of 7- and 9-week-old NP-C mice compared with wild-type mice. Elevated expression of TNF-alpha was detected in both neurons and astrocytes with TNF-alpha-expressing astrocytes distributed in the affected brain regions. Collectively, our results suggest that the cell death in the brain of NP-C disease occurs through apoptosis and it is mediated by the TNF receptor superfamily pathway.

Animals↗

PubMed2005

Visualization of newly deposited tau in neurofibrillary tangles and neuropil threads.

Neurofibrillary tangles (NFTs) and neuropil threads (NTs), the major hallmark of Alzheimer disease (AD), are composed of the microtubule-associated protein tau that has undergone posttranslational modifications, including deamidation and isomerization on asparaginyl or aspartyl residues. Because such modifications represent protein aging, we generated 2 antibodies, TM4, specific for Asp-387 of tau, and iD387, specific for isoAsp-387 of tau, to investigate the evolution of NFTs and NTs. On Western blots of Sarkosyl-insoluble fractions, TM4 strongly labeled paired helical filament-tau (PHF-tau), whereas iD387 preferentially labeled PHF smear. Thus, it is reasonable to postulate that TM4-labeled tau (unmodified tau species) represents more recent deposition, and iD387-labeled tau (modified tau species) represents earlier deposition. Unexpectedly, TM4 immunostained even highly evolved NFTs, suggesting that deposition of newly produced tau continues until neuronal death. iD387 labeled the whole profile of NFTs up to distal dendritic branches, whereas TM4 staining was localized to particular portions of NFTs in proximal dendrites and neuronal perikarya. In NTs, TM4 preferentially labeled the outer portion, whereas iD387 intensely labeled the core portion. Based on TM4-positive NFT counts and total NFT counts, we speculate that NFTs in the human hippocampus are produced at a constant rate irrespective of the disease stage.

Alzheimer Disease↗

PubMed2005

Unique tauopathy in Fukuyama-type congenital muscular dystrophy.

Fukuyama-type congenital muscular dystrophy (FCMD) is characterized by muscular dystrophy and cortical dysgenesis of the cerebrum and cerebellum. We investigated the extent and nature of tauopathy in the brains of 7 postfetal (14-34 years of age) and 2 fetal (18- and 20-week gestational age) FCMD cases. In all postfetal cases, tauopathy was found in the areas of cortical dysgenesis in the cerebrum, in addition to predictable sites such as the hippocampus. In fetal cases, the neuropil of malformed cerebral cortex was diffusely immunostained with anti-aberrantly phosphorylated tau antibodies. By immunoelectron microscopy, the epitope of the antibodies was associated with microtubule-like bundles within cellular processes protruding through disrupted glia limitans. In Western blot analysis, a unique 50-kDa band of tau was detected in a fetal and a postfetal case. In addition, 3 to 4 tau bands of 60 to 68 kD, similar to tau in Alzheimer disease, were also detected in the latter. After dephosphorylation, the insoluble tau from the fetal and the postfetal cases showed highly similar immunoblotting patterns. This anomalous phosphorylation of tau may be related to the development of the cortical dysgenesis in FCMD and may shed light on the biologic function of tau in the development of the central nervous system.

Adolescent↗

PubMed2005

[Establishment of brain bank for aging research].

We have established a brain bank for the prevention and treatment of aging-related movement and cognitive disturbances, as a joint project between a rural care hospital and a research institute. The resources of the bank are to be used for collaborative studies approved by the bank's committee. The collaborative investigators should also be qualified by the institute to conduct the research jointly. The collaborative studies require authorization by the institutional review board (IRB) of the institute, the hospital and each facility involved in collaborative studies. The bank continues to have the responsibility for the resources, after the transfer of the resources to the facilities of collaborative investigators, pursuant to Article 18 of the Cadaver Autopsy and Preservation Act Thus, the status of resource utilization and outcomes from their use in studies will be monitored periodically (every 6 months). We shared the philosophy with the brain banks in the United States that the resources of the bank, donated on the basis of a charitable spirit, belong to the public domain and are regarded as public resources to be used to contribute to promoting public welfare.

Aging↗