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Biomedical subjects

N Arai

Publications and source records attributed to N Arai.

At least 73 records · Page 4Linked to original sources
PubMed1999

Can secondary degeneration accelerate the formation of neurofibrillary tangles? A case of hemispheric infarction showing asymmetric degeneration of the substantia nigra, red nuclei, inferior olivary nuclei and dentate nuclei with concomitant changes of progressive supranuclear palsy.

A case of hemispheric infarction involving the territory of the right middle cerebral artery and the thalamus showed conspicuous asymmetric degeneration in the substantia nigra, red nuclei, inferior olivary nuclei and dentate nuclei with concomitant changes of progressive supranuclear palsy (PSP). The right substantia nigra and red nucleus showed loss of neurons and proliferation of astrocytes. The right olivary nucleus was hypertrophic, while the neuronal loss and astrocytosis in the dentate nucleus were predominant on the contralateral side. Modified Gallyas-Braak staining revealed the extensive distribution of neurofibrillary tangles (NFTs), threads and intraglial argyrophilic structures in the globus pallidus, subthalamic nuclei, cerebral cortex and dentate nuclei, as well as in the affected brain stem nuclei, with a distinct predominance on the affected side. In this case, the one-sided predominance of the extended degeneration in these brain stem and cerebellar areas is considered, in addition to the PSP changes, to be due to secondary retrograde degeneration via the nigrostriatal and dentato-rubro-thalamic pathways following the hemispheric infarction, and to also be the result of disruption of the dentato-olivary fiber connections. In addition, because of the predominant distribution of NFTs on the more degenerated side, it is surmised that the formation of NFTs may be accelerated by secondary degeneration.

Aged↗
PubMed1999

Interictal hyperperfusion observed in infants with cortical dysgenesis.

We investigated increases of interictal regional cerebral blood flow (rCBF) in patients with intractable epilepsy caused by cortical dysgenesis. Using single photon emission computed tomography, we measured interictal rCBF of epileptic foci in 24 patients with cortical dysgenesis who achieved Engel Class I or II outcomes at least 1 year after surgical intervention. The patients included 14 males and ten females, ranging in age from 2 months to 34 years (mean 6 years and 5 months). In the interictal period, dysplastic areas showed hyperperfusion in four patients (17%), hypoperfusion in 15 (62%), and isoperfusion patterns in five (21%). Interictal hyperperfusion was found in four infants aged 3-4 months; three with focal cortical dysplasia and one with hemimegalencephaly. Our results suggest that interictal hyperperfusion may indicate the presence of an active epileptic focus in infants with cortical dysgenesis, but not in older children or adults with the same disorder. Given the risk of misinterpreting the normal side as hypoperfused, the phenomenon of interictal hyperperfusion in the epileptogenic area should be taken into account when diagnosing pediatric epilepsy caused by cortical dysgenesis.

Adolescent↗
PubMed1999

Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells.

Stat6 is critical for IL-4-mediated Th2 cell development, but its molecular mechanism remains unclear. Here we constructed Stat6:ER, a Stat6-estrogen receptor fusion protein that can be activated by 4-hydroxy-tamoxifen, independently of IL-4 and endogenous Stat6. Retrovirus-mediated introduction of Stat6:ER into developing Th1 cells induced Th2-specific cytokines and suppressed IFNgamma production in a 4-HT-dependent manner and in the absence of IL-4. It also induced GATA-3 and c-maf expression and downregulated IL-12Rbeta2 chain expression. Its decreased ability to induce the Th2 phenotype with progressing Th1 cell commitment correlated with a decreased induction of GATA-3 and c-maf. This study indicates that Stat6 functions upstream of GATA-3 and c-Maf to induce Th2 development.

Animals↗
PubMed1999

Syndrome of inappropriate secretion of antidiuretic hormone associated with amyotrophic lateral sclerosis in respiratory failure.

A 65-year-old man who had muscle weakness and dysarthria was admitted for investigation of motor neuron disease. He had lost 12 kg of weight in 6 months. Neurological findings disclosed upper and lower motor neuron disturbances with normal sensory nerve function, and needle electromyography showed a neurogenic pattern. Laboratory findings on admission demonstrated dilutional hyponatraemia due to an excessive secretion of antidiuretic hormone (ADH). Based on these findings, the patient was diagnosed as having the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with amyotrophic lateral sclerosis (ALS). During the night of first hospital day, the patient complained of severe dyspnoea, and mechanical ventilation was commenced. Following the mechanical ventilation, plasma ADH levels and serum sodium concentration were normalized. We propose that respiratory failure secondary to the atrophy of respiratory muscle might be responsible for the development of SIADH.

Aged↗
PubMed1999

Identification of cytochromes P450 involved in human liver microsomal metabolism of ecabapide, a prokinetic agent.

1. In vitro studies identified the hepatic cytochrome P450 (CYP) enzyme(s) involved in the major metabolism of ecabapide in human. 2. Ecabapide mainly underwent N-dealkylation to form M1 and 6-hydroxylation of the benzamide moiety to form M6. 3. The rates of formation of the major metabolites M1 and M6 were significantly correlated with CYP3A-selective testosterone 6beta-hydroxylase activities in 14 different human liver microsomes. The formation of both metabolites was markedly decreased by ketoconazole, miconazole or troleandomycin (TAO), CYP3A-selective inhibitors, and also was inhibited by anti-CYP3A antibodies. 4. These results strongly indicate that CYP3A is the predominant isozyme responsible for the major metabolism of ecabapide in human liver microsomes. 5. Marginal inhibition of the formation of M1 and M6 by nifedipine, a substrate of CYP3A with a Ki > 100 microM, suggested that nifedipne has a limited potential to inhibit the major metabolic pathways of ecabapide.

Anti-Ulcer Agents↗
PubMed1999

Surgical treatment of a case of early infantile epileptic encephalopathy with suppression-bursts associated with focal cortical dysplasia.

We report a surgically treated case of early infantile epileptic encephalopathy (EIEE) with suppression-bursts associated with focal cortical dysplasia. Tonic-clonic seizures followed by a series of spasms occurred about a hundred times a day at a few days of age. Interictal electroencephalogram (EEG) revealed a suppression-burst pattern that was predominant in the left hemisphere. Magnetic resonance imaging (MRI) suggested focal cortical dysplasia in the left prefrontal area. Combination therapies with antiepileptic treatments showed only partial efficacy. The patient underwent lesionectomy at age 4 months, after which he gradually showed psychomotor development and a decrease of spasms to 0-2 series daily. In cases of EIEE with focal cortical dysplasia, surgical treatment may have beneficial effects on both psychomotor development and seizure control.

Adrenocorticotropic Hormone↗
PubMed1999

An aggressive desmoid tumor in a patient with familial adenomatous polyposis: immunohistochemical findings.

A case of an aggressive desmoid tumor in a patient with familial adenomatous polyposis is described. The lesion rapidlyenlarged with compression of adjacent structures including the ureter and small bowel, and the patient died because of small bowel perforation and hydronephrosis 3 years after detection of small desmoid tumors at the time of a prophylactic coloproctectomy for a colon carcinoma. Immunohistochemically, proliferating cell nuclear antigen (PCNA), p21WAF1/CIP1 and cathepsin D indices, but not the bcl-2 index, which were defined as the numbers of immunoreactive tumor cells per 1000 tumor cells, increased in line with tumor progression. The tumor did not show staining for collagen IV, but was characterized by intense staining for basic fibroblast growth factor (bFGF). Accordingly, tumor aggression was related to increases in both cell proliferation and protease activity, as well as an enhanced expression of bFGF. In addition, the desmoid tumor showed deregulation between PCNA and p21WAF1/CIP1 because the normal inverse relation between these two was not apparent.

Adenomatous Polyposis Coli↗
PubMed1999

Reactive oxygen intermediates stimulate interleukin-6 production in human bronchial epithelial cells.

Reactive oxygen intermediates (ROIs) play an important role in the initiation and progression of lung diseases. In this study, we investigated whether ROIs were involved in the induction of interleukin (IL)-6 in human bronchial epithelial cells. We exposed normal human bronchial epithelial cells as well as a human bronchial epithelial cell line, HS-24, to ROIs. We measured the amount of IL-6 in the culture supernatants using ELISA and the IL-6 mRNA levels using RT-PCR. Superoxide anions (O-2), but not hydrogen peroxide (H2O2), increased IL-6 production. To examine whether it is a cell type-specific mechanism of airway epithelial cells, the experiments were also performed in human lung fibroblasts, WI-38-40. In WI-38-40 cells, neither O-2 nor H2O2 increased IL-6 production. In contrast, tumor necrosis factor (TNF)-alpha (200 U/ml) induced IL-6 at the protein and mRNA levels in both airway epithelial cells and lung fibroblasts. This cytokine-induced IL-6 production was significantly suppressed by several antioxidants, including dimethyl sulfoxide (DMSO), in airway epithelial cells. In WI-38-40 cells, DMSO was not able to suppress IL-6 production induced by TNF-alpha. Pretreatment with DMSO recovered the TNF-alpha-induced depletion of intracellular reduced glutathione in HS-24 cells. These findings indicate that oxidant stress specifically induces IL-6 production in human bronchial epithelial cells and that in these cells ROIs may be involved in IL-6 production after stimulation with cytokines such as TNF-alpha. Presumably, ROIs participate in the local immune response in lung diseases via IL-6 release from bronchial epithelial cells.

Antioxidants↗
PubMed1999

[A DOPA antagonist, DOPA cyclohexyl ester inhibits transient brain ischemia-induced release of glutamate and delayed neuronal cell death in striatal and hippocampal region of in vivo rats].

We have previously obtained evidence that DOPA is probably involved in an upstream process of mechanisms for in vivo neuronal cell death in striatum. We attempted to clarify whether or not this is also the case in hippocampal region of conscious Wistar rats. Four vessels were occluded for 5 min during microdialysis of hippocampus. DOPA, dopamine and glutamate (Glu) in perfusates collected every 10 min were measured by HPLC-ECD and spectrophotometer. Delayed neuronal cell death in hippocampus was evaluated 96 hr after ischemia. Five-min transient brain ischemia induced Glu release, with the peak being 2.5-fold of a basal release at the fraction immediately after ischemia. The release of DOPA and dopamine was not consistently detectable, but an increase was sometimes observed during and after ischemia. Delayed neuronal cell death was slight to moderate with 5-min ischemia. Intrastriatal perfusion of DOPA cyclohexyl ester (DOPA CHE) at 100 nM, a novel stable potent competitive DOPA antagonist, almost completely inhibited the ischemia-induced glutamate release, and protected hippocampal neurons from delayed cell death. Endogenously released DOPA itself seems to act on its recognition site and to behave as a causal and/or deteriorating factor on glutamate release and resultant delayed neuronal cell death by transient ischemia in rats.

Animals↗
PubMed1999

Meiotic contraction of CAG repeats in Saccharomyces cerevisiae.

Several human neurodegenerative disorders are caused by expansion of CAG repeats that occurs during meiosis or gametogenesis. We anticipated that the CAG repeats cloned in a plasmid of Saccharomyces cerevisiae might undergo a change in the number of repeats during meiosis and sporulation. To test this possibility, we devised a new method to change in vitro the number of CAG repeats and constructed plasmids carrying (CAG)39, (CAG)65 or (CAG)123 from a plasmid carrying (CAG)18. We monitored the number of colonies showing an altered length of the repeat tracts during mitosis and meiotic growth. Contraction of long CAG repeat was found to occur frequently, whereas a few cases of expansion were observed. The contraction was equally enhanced in both orientations when the host cells grew through meiosis. Thus, our results suggest that long CAG repeats are destabilized during meiosis or gametogenesis in S. cerevisiae.

Base Sequence↗
PubMed1999

Enhanced epithelial cell turnover associated with p53 accumulation and high p21WAF1/CIP1 expression in ulcerative colitis.

To cast light on accelerated epithelial cell turnover as an important risk factor of dysplasia and carcinoma development in patients with long-standing ulcerative colitis (UC), we examined cell proliferation and cell death, as well as expression of apoptosis-related markers, including p53 and p21WAF1/CIP1, in a series of cases. Biopsy specimens (n = 176; 84, active phase; 92, remission) were endoscopically obtained from 25 Japanese patients with UC. As controls, 68 biopsy specimens of normal mucosa were also examined from 27 Japanese patients with colon polyps. We counted the numbers of mitoses, apoptotic bodies, Ki-67-immunoreactive cells, and p21WAF1/CIP1-immunoreactive cells per 1000 crypt cells and the numbers of p53-positive cells per crypt. All of the indices in active UC were significantly higher than in either remitting UC cases or normal cases (mean mitotic index = 0.52, 0.28, and 0.15%, respectively; apoptotic index = 5.40, 2.91, and 1.30%, respectively; Ki-67 labeling index = 39.5, 28.3, and 26.8%, respectively; p21WAF1/CIP1 labeling index = 33.6, 20.0, and 19.0%, respectively; p53 labeling index = 0.66, 0.13, 0.13 per crypt, respectively). In addition, the mitotic, apoptotic, and Ki-67 labeling indices were increased in remitting UC of more than 10 years' duration, in comparison with those of less than 10 years' duration or the normal group. Immunostaining of serial sections revealed a small number of crypt cells coexpressing p53 and p21WAF1/CIP1. Increases in both epithelial cell proliferation and cell death, partially associated with p53 accumulation and high p21WAF1/CIP1 expression, are thus characteristic of active phase UC, as well as in remission of long-standing UC. Accelerated epithelial cell turnover caused by chronic inflammation and epithelial damage might predispose the mucosa to DNA damage, resulting in an elevated risk of mutation in line with dysplasia and carcinoma development in patients with UC.

Adult↗
PubMed1998

Carboxyl-terminal 15-amino acid sequence of NFATx1 is possibly created by tissue-specific splicing and is essential for transactivation activity in T cells.

NFAT regulates transcription of a number of cytokine and other immunoregulatory genes. We have isolated NFATx, which is one of four members of the NFAT family of transcription factors and is preferentially expressed in the thymus and peripheral blood leukocytes, and an isoform of NFATx, NFATx1. Here we provide evidence showing that 15 amino acids in the carboxyl-terminal end of NFATx1 are required for its maximum transactivation activity in Jurkat T cells. A fusion between these 15 amino acids and the GAL4 DNA binding domain was capable of transactivating reporters driven by the GAL4 DNA binding site. Interestingly, this 15-amino acid transactivation sequence is well conserved in NFAT family proteins, although the sequences contiguous to the carboxyl-terminal regions of the NFAT family are much less conserved. We also report three additional isoforms of NFATx, designated NFATx2, NFATx3, and NFATx4. This transactivation sequence is altered by tissue-specific alternative splicing in newly isolated NFATx isoforms, resulting in lower transactivation activity in Jurkat T cells. NFATx1 is expressed predominantly in the thymus and peripheral blood leukocyte, while the skeletal muscle expressed primarily NFATx2. In Jurkat cells, transcription from the NFAT site of the IL-2 promoter is activated strongly by NFATx1 but only weakly by NFATx2. These data demonstrate that the 15-amino acid sequence of NFATx1 is a major transactivation sequence required for induction of genes by NFATx1 in T cells and possibly regulates NFAT activity through tissue-specific alternative splicing.

Alternative Splicing↗
PubMed1998

A conditionally active form of STAT6 can mimic certain effects of IL-4.

Binding of IL-4 to its cognate receptor leads to the activation of a number of signaling pathways within the cell. Activation of the transcription factor STAT6 by JAK family protein tyrosine kinases has been shown to be essential for the full response of cells to IL-4. To elucidate the role of STAT6 in IL-4 signaling, we have constructed and expressed in cells a conditionally active form of the protein (STAT6:ER*) by fusing STAT6 to a modified form of the hormone-binding domain of the estrogen receptor. Activation of STAT6:ER* by 4-hydroxytamoxifen leads to specific activation of STAT6-regulated gene expression including the activation of a STAT6 reporter construct and induction of CD23 in B cell lines. Interestingly, in contrast to native STAT6, activation of STAT6:ER* occurs in the absence of detectable tyrosine phosphorylation of the fusion protein. This type of conditional system will be helpful in dissecting the mechanisms and specificity of transcriptional regulation by the STAT family of transcription factors.

Animals↗
PubMed1998

Interleukin-18 activates the IRAK-TRAF6 pathway in mouse EL-4 cells.

The pleiotropic biological activities of interleukin-18 (IL-18) are mediated by IL-18 receptor (IL-18R). When the ligand binds to the IL-18R, IL-18R initiates a signaling cascade that results in the activation of nuclear factor kappa B (NF-kappa B). When mouse EL-4 cells were exposed to IL-18, IL-1 receptor-associated kinase (IRAK) was recruited to IL-18R and was phosphorylated. In addition, tumor necrosis factor receptor-associated factor-6 (TRAF6) was associated with IRAK. Therefore, we concluded that IL-18/IL-18R-mediated signaling may share the IRAK/TRAF6 pathway through NF-kappa B activation with the IL-1/IL-1 receptor system.

Animals↗
PubMed1998

Distinct NFAT family proteins are involved in the nuclear NFAT-DNA binding complexes from human thymocyte subsets.

The nuclear factor of activated T cells (NFAT) is involved in the transcriptional induction of cytokine and other immunoregulatory genes during an immune response. Among four distinct NFAT family members identified to date, mRNAs of NFAT1, NFATc, and NFATx are expressed in the thymus. Here, we report the distribution of these three NFAT family members in human fetal thymocyte subsets and in peripheral mature T cells. We show that NFATx mRNA was expressed in all T lymphocyte subsets tested and was highest in CD4+CD8+ double positive (DP) thymocytes. Conversely, NFAT1 mRNA was preferentially expressed in the mature CD4+ single positive (SP) populations. NFATc mRNA was present at low levels in all subsets but strongly induced upon treatment with phorbol ester and calcium ionophore. Interestingly, we detected NFAT-DNA binding complexes in DP thymocytes, albeit at lower levels than in CD4 SP cells. Corresponding to the mRNA expression, we observed that NFATx was responsible for the NFAT-DNA binding in DP thymocytes. Moreover, this DNA binding was inhibited by cyclosporin A, indicating that NFATx nuclear translocation was regulated by the calcineurin phosphatase in DP thymocytes. For the CD4 SP populations, NFAT1 and NFATc, and to some extent NFATx, were responsible for the NFAT-DNA binding complexes. These results indicate that NFAT family members are differentially regulated during the development of T cells, and that NFATx may play a distinct role in calcineurin-dependent signaling in DP thymocytes.

Cell Nucleus↗
PubMed1998

Characterization of cis-regulatory elements and nuclear factors conferring Th2-specific expression of the IL-5 gene: a role for a GATA-binding protein.

Expression of the IL-5 gene is restricted to the Th2 subset of helper T cells. We have previously defined four cis-regulatory elements of the IL-5 promoter responding to PMA and cAMP in EL-4 cells. We now report that the 1.2-kb region of the IL-5 promoter directs expression of the IL-5 gene in a Th2 clone but not a Th1 clone, indicating that transcription from the IL-5 promoter is Th2 specific. For the functioning of the IL-5 promoter in a Th2 clone, IL-5C and IL-5CLE0 were critical. IL-5CLE0 interacted with both constitutive and inducible nuclear factors (designated NFIL-5CLE0), which existed in both Th1 and Th2 clones, whereas IL-5C interacted with a constitutive nuclear factor (designated NFIL-5C), which was found only in Th2 but not in Th1 clones. Th2 specificity of NFIL-5C was also confirmed using in vitro-differentiated Th1 and Th2 cells derived from TCR-transgenic mice. The sequence for NFIL-5C binding bears homology with GATA-binding sites. The NFIL-5C complex was supershifted by an anti-GATA-3 Ab and inhibited by an oligonucleotide containing GATA-binding sites. We showed preferential expression of GATA-3 in Th2 cells. Finally, we demonstrated that in vitro-translated GATA-3 bound to IL-5C and overexpression of GATA-3 augmented stimulation-dependent IL-5 promoter activity in EL-4 cells. Taken together, our results provide evidence that GATA-related factors may be involved in Th2-specific expression of the IL-5 gene.

Animals↗