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Biomedical subjects

N Miyasaka

Publications and source records attributed to N Miyasaka.

At least 91 records · Page 5Linked to original sources
PubMed1998

[A refractory case of relapsing polychondritis].

We report here a case of relapsing polychondritis (RPC), who responded to salazosulfapyridine (SASP) after 1.5 years of active disease. A 15-year-old girl having chondritis of bilateral auricles, nose and respiratory tract, ocular inflammation, cochlear and vestibular dysfunction and seronegative polyarthritis was diagnosed as RPC, and oral corticosteroid was initially effective. She was admitted to our hospital with obstructive tract chondritis and was refractory to any of the treatment such as intravenous (i.v.) pulse steroid therapy, i.v. pulse cyclophosphamide (CPA), oral intermittent methotrexate (MTX) and high dose i.v. gamma globulin. Although she was partly responsive to oral cyclosporine A (CsA), but clinical symptoms did not completely subside. SASP, initiated in combination with oral corticostreroid and CsA, however, was successful not only to show steroid sparing effect but also to induce complete remission. SASP might be useful to refractory case of RPC.

Adolescent↗
PubMed1998

Expression and function of CD40 in rheumatoid arthritis synovium.

OBJECTIVE: To determine the involvement of CD40 in chronic activation of rheumatoid arthritis (RA) synovial monocytes. METHODS: CD40 expression on RA synovial monocytes was examined by immunostaining. Involvement of CD40 in tumor necrosis factor-alpha (TNF-alpha) secretion from RA synovial fluid mononuclear cells (SFMC) was examined by blocking with anti-CD40 antibody. RESULTS: CD40 was expressed on RA synovial monocytes. TNF-alpha secretion from RA SFMC was enhanced by CD40 ligand stimulation. Spontaneous secretion of TNF-alpha from RA SFMC was inhibited by anti-CD40 antibody. CONCLUSION: CD40 was involved in the activation of RA synovial monocytes that leads to TNF-alpha production.

Adult↗
PubMed1997

Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells.

The present study demonstrates that erythropoietin (Epo) and IL-3 induce tyrosine phosphorylation of the SH2/SH3-containing adapter protein CrkL and its transient association with tyrosine-phosphorylated SHP-2, Shc, and Cbl in a murine IL-3-dependent cell line, 32D, expressing the Epo receptor (EpoR). In these cells, CrkL was constitutively complexed with the guanine nucleotide exchange factor C3G, which was found to coimmunoprecipitate with Shc from Epo- or IL-3-stimulated cells. Studies using cells expressing mutant EpoRs showed that the Epo-induced tyrosine phosphorylation of CrkL is dependent on the membrane-proximal EpoR cytoplasmic region involved in the activation of Jak2 as well as the C-terminal 145 amino acid region which is required for tyrosine phosphorylation of SHP-2 and Shc. It was further revealed that CrkL is recruited to the tyrosine-phosphorylated EpoR, most likely through its interaction with tyrosine-phosphorylated Shc and SHP-2. These results suggest that CrkL is involved in the signaling pathways from the receptors for Epo and IL-3, most likely by modulating the activity of the Ras family GTPases through its interaction with C3G.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Anticoagulant effects of synthetic retinoids mediated via different receptors on human leukemia and umbilical vein endothelial cells.

We recently found that retinoic acids (RAs) exert anticoagulant effects by upregulating thrombomodulin (TM) and downregulating tissue factor (TF) expression in acute promyelocytic leukemia (APL) cells and monoblastic leukemia cells. Two classes of nuclear RA receptors, termed retinoic acid receptors (RARs) and retinoid X receptors, have been identified. Each receptor class consists of three subtypes. In the present study, we have used several synthetic retinoids to determine which receptor subtypes are involved in the regulation of TM and TF expression in NB4 APL cells, U937 monoblastic leukemia cells, and human umbilical vein endothelial cells (HUVECs). Am80, which has no binding affinity for RAR gamma, and Ch55, which does not bind to cytoplasmic retinoic acid binding protein (CRABP), upregulated TM and downregulated TF in NB4 and U937 cells, similar to all-trans RA (ATRA). A specific RAR alpha antagonist, Ro41-5253, significantly suppressed the upregulation of TM by ATRA and Am80 in NB4 cells, U937 cells, and HUVECs. In contrast, only with preincubation with both RAR alpha and RAR beta antagonists was downregulation of TF by retinoids suppressed in NB4 cells. These findings indicate that the mechanism of transactivation and transrepression functions of RARs are distinct and also elucidate the major role of RAR alpha in TM upregulation by retinoids in leukemic cells and HUVECs and the cooperation of RAR alpha and RAR beta in TF downregulation by retinoids. They also indicate that binding to CRABP is not required for the anticoagulant effect of retinoids and that synthetic retinoids will prove very useful in controlling distinct targets, the TM and TF genes, at the level of transcription, and will permit the development of retinoids with a new type of anticoagulant effect.

Anticoagulants↗
PubMed1997

Disruption of the Bcl6 gene results in an impaired germinal center formation.

The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, and its products are expressed highly in germinal center (GC) B cells. To investigate the function of Bcl6 in lymphocytes, we have generated RAG1-deficient mice reconstituted with bone marrow cells from Bcl6-deficient mice (Bcl6(-/-)RM). Lymphogenesis in primary lymphoid tissues of Bcl6(-/-)RM is normal, and Bcl6(-/-)RM produced control levels of primary IgG1 antibodies specific to T cell-dependent antigens. However, GCs were not found in these mice. This defect was mainly due to the abnormalities of B cells. Therefore, Bcl6 is essential for the differentiation of GC B cells.

Animals↗
PubMed1997

Erythropoietin induces tyrosine phosphorylation of the interleukin-3 receptor beta subunit (betaIL3) and recruitment of Stat5 to possible Stat5-docking sites in betaIL3.

The receptors for erythropoietin (Epo) and interleukin-3 (IL-3) both induce the ligand-dependent activation of the Jak2 tyrosine kinase. Activated Jak2 then phosphorylates these receptors and thereby recruits various signaling molecules containing the Src homology (SH)-2 domain, including Stat5, to the tyrosine phosphorylated receptors. In the present study, we demonstrate that Epo stimulation induces unidirectional cross-phosphorylation of the IL-3 receptor beta subunit (betaIL3) on tyrosines and its rapid and transient association with Stat5 in murine IL-3-dependent cell lines engineered to express the Epo receptor (EpoR). Using cell lines expressing various EpoR mutants, it was demonstrated that the Epo-induced tyrosine phosphorylation of betaIL3 is dependent on the membrane-proximal EpoR cytoplasmic region involved in the activation of Jak2, but not on the extracellular and transmembrane regions or on the carboxy-terminal 145 amino acid region containing all the intracellular tyrosine residues. It was also shown that IL-3 induces rapid and dose-dependent association of Jak2 with betaIL3. However, Epo failed to induce any detectable association of betaIL3 with Jak2 or the EpoR. The present study also demonstrates that in IL-3-stimulated cells, an ovine Stat5 mutant harboring a substitution of Tyr694 to Phe, which abolishes the tyrosine phosphorylation required for activation, fails to dimerize with endogenous Stat5, shows sustained binding with tyrosine-phosphorylated betaIL3, and inhibits the tyrosine phosphorylation of endogenous Stat5. These results suggest that betaIL3 may have Stat5 docking sites, similar to those found in the EpoR, that facilitate the activation of Stat5 by Jak2 and raise the possibility that Epo may cross-activate or transmodulate the IL-3 receptor signaling pathways.

Animals↗
PubMed1997

Binding sequence of STAT4: STAT4 complex recognizes the IFN-gamma activation site (GAS)-like sequence (T/A)TTCC(C/G)GGAA(T/A).

Studies of transcriptional activation by interferons and various cytokines have led to the identification of a family of proteins that serve as signal transducers and activators of transcription (STAT). STAT4 is phosphorylated following interleukin (IL)-12 stimulation and is required for IL-12 signal transduction. By immunoprecipitation and PCR amplification, a specific consensus sequence for DNA binding of the STAT4 complex was determined. The binding sequence of the STAT4 complex, (T/A)TTCC(C/G)GGAA(T/A), proved to be palindromic and similar to the IFN-gamma activated site (GAS)-like sequence. The first (T/A) and last (T/A) sites of the consensus sequence were critical for the binding affinity of the STAT4 complex.

Amino Acid Sequence↗
PubMed1997

Nitric oxide and inflammatory arthritides.

Nitric oxide (NO), first identified as endothelium-derived relaxing factor (EDRF), is a free radical synthesized from L-arginine by NO synthases (NOS). NO plays vital roles in biological responses, including regulation of vascular tone, neurotransmission, anti-viral defense and immune response. There are two isoforms in NOS; constitutive NOS (cNOS) and inducible NOS (iNOS). Inflammatory cytokines such as interleukin-1(IL-1), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) induce iNOS expression in various cells including macrophages. NO production is increased in inflammatory arthritides both in rodent models and human. Enhanced NO production is observed in various compartment in vivo but inflammatory synovium and cartilage are the major source of NO. The onset of arthritis in rodent models is successfully blocked by the NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA). These data suggest a possible involvement of NO in the pathogenesis and tissue destruction in arthritis, and the significance of up-regulated NO production is discussed.

Animals↗
PubMed1997

An immortalized septal cell line that expresses trkA mRNA in response to basic fibroblast growth factor.

Cells dissociated from embryonic rat septum were transfected with SV40 large T antigen gene by the calcium phosphate precipitation method. One of the cloned lines (EG6) had a flat morphology and expressed nestin gene, a marker of neural stem cells. Upon stimulation with basic fibroblast growth factor (bFGF), morphological changes of EG6 cells were induced, e.g. shrinkage of cell body and extension of neuritic processes. Furthermore, bFGF induced expression of the high affinity NGF receptor (trkA) gene. EG6 cell line thus will be useful for studies of roles of bFGF in the developing CNS as well as for studies of the regulation of trkA gene expression.

Animals↗
PubMed1997

HLA-dependent peripheral T cell receptor (TCR) repertoire formation and its modification by rheumatoid arthritis (RA)

Our previous studies have disclosed that the peripheral T cell receptor beta (TCRB) gene repertoires of RA monozygotic twins were similar. This suggested that the TCRBV repertoire is controlled primarily by genetic factors. Here, we examine how the combination of HLA and presence of RA influence the peripheral TCRB repertoire. Peripheral blood mononuclear cells from six pairs of healthy monozygotic twins, six pairs of monozygotic twins discordant for RA, and nine siblings of a large family, including three RA patients, were examined for their TCRB gene repertoires. Among healthy twins and siblings, the BV repertoires between HLA-identical pairs were significantly more similar than those of HLA-non-identical pairs. When RA-affected members were included, the repertoires of the HLA-identical pairs discordant for RA were dissimilar compared with those of healthy pairs. TCRBV-BJ combination repertoire analysis of CD4 and CD8 T cell subsets from the twins showed that the dissimilarity was primarily confined to CD8 T cells in the healthy identical twins, whereas it was seen in both CD4 and CD8 T cell subsets in the RA-discordant twins. These results suggest (i) the presence of RA modifies the genetically controlled TCR repertoire of peripheral T cells, and (ii) the RA-associated alterations appear to occur more frequently in CD4 T cells than in CD8 T cells.

Arthritis, Rheumatoid↗
PubMed1997

Gastrointestinal autonomic nerve tumor with giant abscess. A case report and literature review.

We report a gastrointestinal autonomic nerve tumor of the stomach with a giant abscess. The patient had fever and pain and was found to have anemia and an abdominal mass. X-ray and endoscopic examination showed a gastric submucosal tumor with a fistula to the gastric lumen. Partial gastrectomy was performed and no metastasis was found. On gross examination, the excised tumor was seen to be a submucosal solid tumor with a giant abscess. Alpha streptococci and anaerobic gram-negative rods were cultured from the pus of the abscess. The tumor resembled a gastric myogenic tumor composed of spindle cells, partly showing storiform and epithelioids. Tumor cells showed positive staining for vimentin and neuron-specific enolase but were negative for desmin, alpha-smooth muscle actin, and S-100 protein. Ultrastructural examination showed remarkable interdigitation of cytoplasmic processes with neurosecretory granules between the tumor cells. This lesion was similar to previously described gastrointestinal autonomic nerve tumors. Gastrointestinal autonomic nerve tumors are a rare, distinct subtype of gastrointestinal stromal tumors; although several cases of focally necrotic tumors have been reported, there has been only one report of the tumor with an abscess, as in our case.

Abscess↗
PubMed1997

Double-negative BV8S3 T cells expanded in MRL lpr/lpr lymph nodes conserve TCRBJ gene usage of single-positive BV8S3 T cells.

Enlarged lymph nodes of mice with lpr mutation consist predominantly of CD4- CD8- (double-negative: DN) T cells. Among them, TCRBV8S3 (V beta 8.3) T cells are overrepresented as compared to those in single-positive (SP) T cells. To address the question of whether the expansion of oligoclonal T cells is responsible for the increase in TCRBV8S3 cells, we examined the TCRBJ gene repertoires of BV8S3 DN and SP T cells from multiple MRL lpr/lpr mice. The BJ repertoires of BV3 (V beta 3), BV8S1 (V beta 8.1) and BV8S2 (V beta 8.2) were studied for comparison with those of BV8S3 T cells. The employed method, which was based on a PCR-ELISA technique, was newly developed and allowed us to make a precise quantitation of TCRBJ gene usage of the multiple lymphocyte samples. The results showed that there were no biases of the BJ gene usage by BV8S3 DN T cells as well as other BV T cells. Furthermore, the BJ gene usage of CD4 and CD8 BV8S3 T cells was conserved by the DN T cells. It is suggested that the BV8S3 DN T cells were not expanded by specific antigens. The expansion may result from aberrant regulation specific to the BV8S3-expressing T cells.

Animals↗
PubMed1997

cDNA cloning, expression and chromosome mapping of the human STAT4 gene: both STAT4 and STAT1 genes are mapped to 2q32.2-->q32.3.

Studies of transcriptional activation by interferons and a variety of cytokines have led to the identification of a family of proteins that serve as signal transducers and activators of transcription (STAT). STAT4 is phosphorylated following interleukin (IL)-12 stimulation and is essential for IL-12 signal transduction. The human STAT4 cDNA was cloned, and both STAT4 and STAT1 genes were mapped to human chromosome bands 2q32.2-->q32.3 by fluorescence in situ hybridization. These results suggest that STAT4 and STAT1 may have arisen via a tandem gene duplication. However, human STAT1 is expressed ubiquitously, whereas human STAT4 is expressed in several tissues including spleen, heart, brain, peripheral blood cells, and testis.

Base Sequence↗
PubMed1997

Enhanced expression of nucleobindin in lymphatic organs of lupus-prone mice.

Nucleobindin (Nuc) was originally identified as a 55 kDa protein that enhanced anti-DNA antibody production in cultures of autoimmune MRL/lpr mouse spleen cells. cDNA cloning and the production of recombinant protein (rNuc) have revealed that rNuc binds to DNA and Ca2+ by means of leucine zipper and EF-hand motif structures. In vitro and in vivo effects of rNuc to induce autoantibodies including anti-dsDNA antibody in normal mice have been demonstrated; however, whether Nuc is involved in the state of autoimmunity occurred in MRL/lpr, C3H/gld and male BXSB mice has not been elucidated. Here we report that the expression of Nuc mRNA is upregulated with age in the lymphatic organs and is positively correlated to the serum levels of Nuc in these lupus-prone strains of mice. Upon immunization with KLH in Freund's complete adjuvant, normal BALB/c mice also showed an elevated level of Nuc in their serum and elevated Nuc mRNA in their lymphatic organs. In addition, in vitro stimulation of BALB/c splenocytes with Con A or LPS remarkably enhanced Nuc mRNA expression. These results suggest that upregulation of Nuc mRNA in lymphatic organs and serum Nuc of lupus-prone mice is related to spontaneous activation of immunocompetent cells; the present data are also consistent with our previous hypothesis on the role of Nuc in the induction or enhancement of autoimmunity in lupus models of mice.

Animals↗
PubMed1997

Transcatheter neodymium-yttrium-aluminum-garnet laser coagulation of canine ventricle using a balloon-tipped cardioscope.

The feasibility of transcatheter laser ablation of the canine left ventricle (LV) was tested using a newly developed cardioscope. In 17 anesthetized dogs, a combined laser-endoscope catheter, consisting of an endoscope encased in a 7-French flexible catheter with an inflatable and transparent balloon at the distal end, was introduced into the LV via the carotid artery. A 1064-nm neodymium-yttrium-aluminum-garnet (Nd:YAG) laser was delivered by laser optic fiber, which was introduced through the transport channel and positioned inside the saline-filled balloon. In 16 of 17 dogs, the endocardial surface of the LV was clearly observed. Laser energy totaling 500-5,000 J was applied sequentially in 13 dogs and laser irradiation was completed in all but 2 of the dogs. The excised hearts revealed well-demarcated oval-shaped lesions 2.5-9.5 mm deep in 7 of 11 dogs. Histologic sections revealed coagulation necrosis surrounded by a rim of contraction band necrosis. Thus, transballoon laser photocoagulation of the beating LV is feasible. The newly combined laser-endoscope catheter, which is still in its preliminary stages and needs to be improved to increase the success rate of photocoagulation, appears to be a promising alternative modality for catheter ablative therapy for ventricular tachycardia.

Animals↗
PubMed1997

[A refractory case of adult-onset Still's disease].

We report here a case of adult-onset Still's disease (AOSD), who finally responded to a combination of cyclophosphamide (CPA) and gold sodium thiomalate (GST) after two years of active disease. A 23-year-old man having continuous high fever with skin rash, polyarthralgia and increased serum ferritin, was diagnosed as AOSD, and oral corticosteroid was initially effective. His symptoms recurred one year later without clinical improvement to increased dosage of steroid. He was admitted to our hospital with pericarditis and pleural effusion but did not respond to either intravenous (i.v.) pulse steroid therapy, methotrexate (MTX) or high dose i.v. gamma-globulin. He was partly responsive to monthly i.v. injection of CPA, but clinical symptoms did not completely subside and hyperferritinemia persisted. GST, initiated in combination with CPA, however, was successful to induce complete remission. MTX has recently been reported to be efficacious to steroid-resistant AOSD, but CPA and gold compounds might be useful to refractory case of AOSD.

Adult↗
PubMed1997

Estimated prevalence and incidence of adult Still's disease: findings by a nationwide epidemiological survey in Japan.

To estimate prevalence and incidence of adult Still's disease in Japan, and to describe the epidemiological features of the patients, a nationwide epidemiological survey was conducted in 1994. The study consisted of two questionnaires which were distributed to the heads of the relevant departments, randomly sampled, in hospitals throughout Japan. Following major epidemiological findings emerged from the study: (a) The total annual number of patients treated for adult Still's disease was estimated as 1,100 in 1993 in Japan. The estimated crude prevalence among those aged 16 years or older were calculated as 0.73 and 1.47 per 100,000 population for males and females, respectively, with the corresponding crude incidence rate of 0.22 and 0.34. (b) The sex ratio (female to male) of the reported patients was 2.1. This female predominance might be specific to Japan, though additional surveys in other countries will be warranted. The mean age of the patients was 38.1 years, and female patients tended to be older than male ones; 50% of the female patients aged 40 years or older, while so did only 28% of the male patients.

Adolescent↗