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Biomedical subjects

N Miyasaka

Publications and source records attributed to N Miyasaka.

At least 19 recordsLinked to original sources
PubMed2006

Reliability of recalled self-report on headache intensity: investigation using ecological momentary assessment technique.

Recalled evaluation of headache intensity is often affected by several factors. Recently, computerized ecological momentary assessment (EMA) has been developed to avoid such problems as recall bias. Here, we compared recalled headache intensity with momentary headache intensity using EMA in tension-type headache (TTH). Forty patients with TTH wore watch-type computers for 1 week to record momentary headache intensity and also rated their headache intensities by recall. We calculated intraclass correlation coefficients between recalled headache intensity and indices from EMA recordings in the whole study population and in two subgroups divided by variability of momentary headache intensity. The results showed that consistency and agreement of momentary and recalled headache intensity were low, and this was especially marked in the subjects whose headache varied widely. These observations suggested that variability of headache intensity may affect recall of headache intensity and this should be taken into consideration in both clinical and research settings.

Adult↗
PubMed2003

Recovery of apparent diffusion coefficient after embolic stroke does not signify complete salvage of post-ischemic neuronal tissue.

BACKGROUND AND PURPOSE: It has been shown in previous studies that recovery of apparent diffusion coefficient (ADC) of water is not necessarily associated with a reversal of tissue damage. We examined the relationships between temporal ADC change and histological outcome after embolic stroke in rat using an experimental MRI scanner. SUBJECTS AND METHODS: Male Wistar rats underwent embolization of the right middle cerebral artery with autologous clot. ADC and relative cerebral blood flow (rCBF) were measured consecutively for 3 hours after embolization. The brains were prepared for histological examination. RESULTS: Transient decline of ADC was observed during the initial 2 hours after embolization. In these areas, serial rCBF measurement revealed incomplete recovery. In some other areas, ADC decrease without rCBF recovery was observed during 3 hours postischemia. Histological examination revealed infarction in areas with persistent ADC decrease. Scattered neuronal death was noticeable in areas with a transient--in some areas less than 0.5 hour--ADC decrease. CONCLUSION: Consecutive MRI analysis demonstrated postischemic transient ADC decrease in an embolic stroke model of rat. The normalization of ADC does not signify normalization of postischemic tissue, since the areas often evolve postischemic neuronal death at a later time.

Animals↗
PubMed2003

Temporal evolution of apparent diffusion coefficient and T2 value following transient focal cerebral ischemia in gerbils.

We examined the time course of apparent diffusion coefficient (ADC) and T2 values in gerbils subjected to transient focal cerebral ischemia and compared them with histopathologic changes. Ten gerbils were subjected to two times 10-min occlusions of the left common carotid artery and examined with diffusion-weighted and T2-weighted MR imaging, at the interocclusion period and 1 hour, 2 hours. 1 day, 2 days, 4 days, and 7 days after the second occlusion. Immediately after the last MR imaging, their brains were examined histopathologically. ADC values decreased 1 hour after the second occlusion and continued to decrease up to 1 or 2 days later. ADC values remained lowered up to 4 days and slightly recovered at 7 days. T2 values were normal at 1 and 2 hours and began to increase at 1 day. T2 values began to recover at 4 days. Histopathologically, infarction was confined in the fronto-parietal cortex, dorsolateral caudate nucleus and dorsolateral thalamus, and neuronal necrosis was found in the pyramidal cell layer of the hippocampus. This study indicates that sequential ADC and T2 studies of gerbils subjected to transient focal cerebral ischemia provide a useful tool for evaluating temporal evolution of ischemic brain injury and edema, including cytotoxic and vasogenic edema.

Animals↗
PubMed2003

Dipeptidyl peptidase IV on activated T cells as a target molecule for therapy of rheumatoid arthritis.

The extracellular domain of the T cell co-stimulatory molecule CD26 possesses dipeptidyl peptidase IV (DP IV) enzyme activity. Activated T cells are known to increase expression of cell surface DP IV and some specific inhibitors of this enzyme have been reported to suppress T cell function. Previously we have identified a DP IV inhibitor, designated TMC-2, found in culture supernatant of Aspergillus oryzae. Administration of TMC-2 to rats with adjuvant arthritis caused marked suppression of paw swelling. To elucidate the mechanism of TMC-2 antiarthritic activity, we have studied its effects on T cell function. Here we show that TMC-2 inhibited DP IV activity of CD26 immunoprecipitated from T cell lysates, and also inhibited proliferative responses of T cells to specific antigen or anti-CD3 antibody. Suppression of IL-2 production was demonstrated at both the mRNA and protein levels. TMC-2 did not alter the PTPase activity of pure CD45, but when this molecule was co-precipitated from T cell lysates together with associated CD26, its PTPase was virtually completely abolished by TMC-2. These results suggest that modulation of CD45 PTPase activity might be responsible for functional suppression of T cells by TMC-2. Because the effects of TMC-2 on T cells were reversible and it was not toxic at the concentrations used, TMC-2 may be a candidate novel therapeutic agent for rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed2001

Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by proliferation of synoviocytes that produce inflammatory cytokines and chemokines. The expressed chemokines are thought to be involved in the migration of inflammatory cells into the synovium. In this study we show that CCL2/monocyte chemotactic protein-1, CCL5/RANTES, and CXCL12/stromal cell-derived factor-1 enhanced IL-6 and IL-8 production by fibroblast-like synoviocytes (FLS) from patients with RA, and their corresponding receptors, CCR2, CCR5, and CXCR4, respectively, were expressed by RA FLS. The chemokines stimulated RA FLS more effectively than skin fibroblasts. Culture with CCL2 enhanced phosphorylation of extracellular signal-related kinase 1 (ERK1) and ERK2, but not phosphorylation of p38 or Src. Moreover, activation of ERK1/2 was inhibited by pertussis toxin, a G(i)-coupled protein inhibitor, and RS-504393, CCR2 antagonist, suggesting that ERK1/2 was activated by CCL2 via CCR2 and G(i)-coupled protein. On the other hand, CCL2, CCL5, and CXCL12 were expressed on RA FLS, and their production was regulated by TNF-alpha, IL-1beta, and TGF-beta1. Our results indicate that the chemokines not only play a role in inflammatory cell migration, but are also involved in the activation of FLS in RA synovium, possibly in an autocrine or paracrine manner.

Arthritis, Rheumatoid↗
PubMed2001

Clonal biases of peripheral CD8 T cell repertoire directly reflect local inflammation in polymyositis.

Polymyositis (PM) involves destruction of striated muscles by autoaggressive CD8 T cells, which accumulate and secrete cytotoxic effector molecules in the affected muscles. Previous studies of peripheral T cell repertoires from normal individuals and patients with viral infections have shown that primed CD8 T cells, unlike CD4 T cells, are prone to expand clonally and persist as large populations in the peripheral blood. These facts made us assume that autoaggressive myocytotoxic CD8 T cells would expand clonally in the peripheral blood from patients with PM. By clonal analyses of peripheral T cells from patients and age-matched controls, we show here that clonal expansion of CD8 T cells was more frequent in patients. This was not significant in CD4 T cells. In analogy to virus-specific T cells, the expanded T cells persisted as large populations over time. Analysis of the muscle biopsy specimens revealed that some of the expanded clones were infiltrating in the affected muscles from the same patients. These results provide the first evidence that local autoimmune reaction directly elicits significant biases in peripheral T cell repertoire. The expanded cells, which should be candidate autoaggressive T cells, were readily isolated from the peripheral blood for analysis of expressed genes including perforin. Thus, our findings should give us an immediate clue to analysis of the pathogenic T cells in PM.

Adult↗
PubMed2001

Rac is activated by tumor necrosis factor alpha and is involved in activation of Erk.

Tumor necrosis factor alpha (TNFalpha) activates various signal transduction pathways including those involving phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinases (Erk), c-Jun N-terminal protein kinases (JNK), and p38 kinases. Using the Rac binding domain of PAK (PAK-RBD) as an activation-specific probe, here we demonstrate that TNFalpha very rapidly and transiently activates the Rho family GTPase Rac in L929 cells. The PI3K inhibitor LY294002 significantly inhibited TNFalpha activation of Rac as well as Erk and abolished that of the PI3K target Akt, without showing any inhibitory effects on JNK and p38 activation. Furthermore, TNFalpha activation of Erk was abolished by a dominant negative Rac mutant, Rac17N, or by an activated Rac mutant, Rac12V. These findings suggest that Rac is activated by a mechanism that is at least partly dependent on PI3K in TNFalpha stimulated cells and plays a critical role in activation of the Erk signaling pathway.

Animals↗
PubMed2001

CrkL is recruited through its SH2 domain to the erythropoietin receptor and plays a role in Lyn-mediated receptor signaling.

The erythropoietin (Epo) receptor transduces its signals by activating physically associated tyrosine kinases, mainly Jak2 and Lyn, and thereby inducing tyrosine phosphorylation of various substrates including the Epo receptor (EpoR) itself. We previously demonstrated that, in Epo-stimulated cells, an adapter protein, CrkL, becomes tyrosine-phosphorylated, physically associates with Shc, SHP-2, and Cbl, and plays a role in activation of the Ras/Erk signaling pathway. Here, we demonstrate that Epo induces binding of CrkL to the tyrosine-phosphorylated EpoR and SHIP1 in 32D/EpoR-Wt cells overexpressing CrkL. In vitro binding studies showed that the CrkL SH2 domain directly mediates the EpoR binding, which was specifically inhibited by a synthetic phosphopeptide corresponding to the amino acid sequences at Tyr(460) in the cytoplasmic domain of EpoR. The CrkL SH2 domain was also required for tyrosine phosphorylation of CrkL in Epo-stimulated cells. Overexpression of Lyn induced constitutive phosphorylation of CrkL and activation of Erk, whereas that of a Lyn mutant lacking the tyrosine kinase domain attenuated the Epo-induced phosphorylation of CrkL and activation of Erk. Furthermore, Lyn, but not Jak2, phosphorylated CrkL on tyrosine in in vitro kinase assays. Together, the present study suggests that, upon Epo stimulation, CrkL is recruited to the EpoR through interaction between the CrkL SH2 domain and phosphorylated Tyr(460) in the EpoR cytoplasmic domain and undergoes tyrosine phosphorylation by receptor-associated Lyn to activate the downstream signaling pathway leading to the activation of Erk and Elk-1.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Characteristic changes in T(2)-value, apparent diffusion coefficient, and ultrastructure of substantia nigra evolving exofocal postischemic neuronal death in rats.

To correlate the magnetic resonance (MR) imaging characteristics of exofocal postischemic neuronal death (EPND) in the substantia nigra (SN) with associated histologic changes, we occluded the left middle cerebral artery of rats for 1, 4, 7, or 12 days. Day 1 (post-occlusion) T(2)-weighted images revealed high signal intensity indicative of infarction in the ipsilateral caudate nucleus, putamen, and cortex but not the SN. Diffusion-weighted images (DWIs) on day 1 similarly failed to reveal any changes in the SN. However, on day 4, DWIs revealed high signal intensity in the ipsilateral SN, in which the apparent diffusion coefficient (ADC) transiently decreased (P<0.05) while the T(2)-value increased (P<0.05). These measures returned to and remained at control levels on days 7 and 12. Histologic examination on day 4 revealed dark-staining neurons, markedly swollen perivascular astrocytic end-feet, many swollen neurons with cytoplasmic microvacuoles that mainly originated in the rough endoplasmic reticulum, and strongly roughed neuropils. Reactive astrocytes and dark neurons most frequently appeared on days 7 and 12. The severity of cellular swelling paralleled the change in the ADC. These results demonstrate that a transient high-intensity signal on DWIs, indicative of a decrease in the ADC, is predictive of EPND in the SN.

Animals↗
PubMed2001

Activation of autoreactive T cells that help nucleobindin-injected mice produce anti-DNA antibodies.

Nucleobindin (Nuc) is a DNA- and calcium-binding protein that was originally identified as an anti-DNA antibody-enhancing factor in MRL/MpJ-lpr/lpr (MRL/lpr) mice. In MRL/lpr mice, both expression of Nuc mRNA in enlarged lymph nodes and serum concentration of Nuc protein are shown to increase as disease progresses. Administration of recombinant (r) Nuc to young MRL/MpJ-+/+ and normal BALB/c mice leads to augmentation or induction of IgG anti-double-stranded (ds) DNA autoantibodies. In this study, spleen cells prepared from MRL/lpr mice were found to show a proliferative response to rNuc, indicating existence of T cells that are specific to this autoantigen in peripheral lymphoid tissues. Furthermore, CD4+ T cell lines were generated from a BALB/c mouse that had been producing anti-dsDNA antibodies as a result of repeated injections of rNuc. These T cell lines were confirmed to be autoreactive, because they proliferated in culture with syngeneic but not with allogeneic spleen cells without addition of any exogenous antigens. Their proliferation was enhanced by rNuc, and inhibited by an anti-MHC class II monoclonal antibody. Upon in vivo inoculation, these T cells provided help for rNuc-injected BALB/c mice to produce anti-DNA antibodies. These results suggest that Nuc is able to activate autoreactive peripheral T cells through an MHC-class II pathway leading to acceleration or induction of anti-DNA antibody production when it is excessively produced in lupus-prone mice or experimentally administered into normal mice.

Animals↗
PubMed2001

The GOR gene product cannot cross-react with hepatitis C virus in humans.

GOR (GOR47--1) is an epitope thought to be a host-derived antigen cross-reactive with hepatitis C virus (HCV) since it was isolated from a cDNA library of host animals reactive with sera of HCV-positive patients. An enzyme immunosorbent assay (ELISA) using this epitope as antigen is of sufficient sensitivity and specificity for screening patients with HCV. However, the relationship between GOR47--1 epitope and autoimmune phenomena associated with HCV infection or autoimmune hepatitis is controversial. Here we isolated the human GOR gene and found that the GOR47--1 epitope was not translated in humans due to a single base replacement from chimpanzee. Furthermore, we found some patients who had antibodies against another epitope, which is translated (GOR1--125) in humans, although there was no correlation between the existence of anti-GOR47--1 or anti-GOR1--125 Ab and autoimmune phenomena. Serum IgG levels did not influence the titres of these antibodies. Taken together with the results of several other studies, our finding that the GOR47--1 epitope cannot be translated into a protein suggests that there is little relationship between autoimmunity and the GOR gene product in human beings. We also discuss here the possible mechanism of cross-reactivity between HCV and the GOR gene product.

Amino Acid Sequence↗
PubMed2001

Suppression of arthritis by forced expression of cyclin-dependent kinase inhibitor p21(Cip1) gene into the joints.

Rheumatoid synovial fibroblasts (RSF) express cyclin-dependent kinase (CDK) inhibitors p16(INK4a) and p21(Cip1) when they are growth-inhibited in vitro. The induction of p16(INK4a) is characteristic of RSF and intra-articular p16(INK4a) gene therapy has been shown to suppress adjuvant arthritis (AA) of rats. The other inducible CDK inhibitor, p21(Cip1), has multiple functions depending on the cell type. They include inhibition of CDK as well as promotion of active CDK complex formation and induction of apoptosis. This study is to discern the biological effects of p21(Cip1) gene transfer into RSF and its therapeutic effects on AA. A recombinant adenovirus containing a human p21(Cip1) gene and control adenoviruses were prepared. RSF infected with these viruses were examined for their cell growth. Apoptotic cell death was evaluated by nuclear staining and DNA fragmentation analysis. In vivo gene therapy of rat AA was carried out by intra-articular injection of the viruses. Severity of the arthritis was clinically scored. The treated joints were examined histologically and proliferating cell nuclear antigens (PCNA) were detected immunohistochemically. The adenoviral p21(Cip1) gene transfer inhibited growth of RSF without inducing apoptosis. p21(Cip1) gene therapy suppressed AA clinically and histologically. The effects were comparable to p16(INK4a) gene therapy. PCNA expression was reduced in the p21(Cip1)-treated joints. The adenoviral gene transfer of p21(Cip1) ameliorated rat AA. The effect was attributable to inhibition of proliferation. Because p21(Cip1) is induced more easily by many chemicals than p16(INK4a), it also appears to be a feasible target in developing anti-rheumatic drugs.

Adenoviridae↗
PubMed2001

[A case of sarcoidosis characterized by a nasopharyngeal tumor and neurological lesions].

A 20-year-old man was admitted to a hospital complaining a slight fever lasting for 3 months associated with a dull headache and weight loss. A tumor was found in the nasopharynx of which biopsy specimen revealed granulomas with Langhans' giant cells. He was given antituberculous agents without symptomatic improvement, and transferred to our hospital. Serum levels of soluble IL-2 receptor and lysozyme were increased, and a significant uptake was observed by Ga scintigraphy at the nasopharynx and bilateral hilar lymphnodes. Furthermore, spinal fluid contained increased number of mononuclear cells, and T2-weighted MRI scans showed an enhanced lesion at the pituitary stalk. The specimen of both TBLB and repeated biopsy of the nasopharyngeal tumor showed granulomas without caseous necrosis. Taken together with these findings, a diagnosis of sarcoidosis with CNS involvement was finally made, and he made a favorable progress by treatment with prednisolone. This is an unique case which emphasizes importance of differential diagnosis of nasopharyngeal tumors with neurological manifestations in the clinicalsetting of rheumatology.

Adult↗