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T Uchiyama

Publications and source records attributed to T Uchiyama.

At least 163 records · Page 9Linked to original sources
PubMed1999

[Abnormal respiratory regulation in myotonic dystrophy].

The abnormal respiratory regulation as well as respiratory muscle degeneration are thought to be involved in the pathogenesis of alveolar hypoventilation in myotonic dystrophy (MD). In the present study we recorded changes in oxygen saturation resulting from exercise and hyperventilation in MD, Duchenne muscular dystrophy (DMD) patients and healthy volunteers by pulse oxymetry. Following are the results obtained in this study. (1) In DMD individuals showing preexisting mild desaturation around 90-95%, mild muscle exercise such as drawing a picture always caused further desaturation, which is presumably due to an increase in oxygen demand. On the other hand the MD patients with the same level of desaturation often showed paradoxical improvement in oxygen saturation up to 95-97% after a similar mild exercise, however, they showed obvious desaturation by a harder exercise such as propelling wheelchair. (2) There was a fluctuation of oxygen saturation at rest in MD, while this was not apparent in DMD patients and normal volunteers. (3) In MD and normal individuals, a strenuous hyperventilation is always followed by an oxygen desaturation through ventilatory suppression probably caused by hypocapnea resulting from the hyperventilation. This desaturation phase is much more prolonged in MD patients than in normal control subjects. The above data indicate further evidence of abnormal ventilatory regulation in MD.

Adult↗
PubMed1999

Muscle activity-torque-velocity relations in human elbow extensor muscles.

With the aid of an artificial neural network technique, we investigated relationships between the torque and extending velocity of an elbow at constant muscle activation in healthy volunteers. Each subject sat on a chair and was able to move his upper- and forearm on a shoulder-high horizontal plane. First, with the gravitational force of a weight hanging from a pulley, the subject's wrist was pulled to flex the elbow. Next, the subject was instructed to extend his elbow joint at a constant velocity. Integrated electromyograms (IEMGs), elbow joint angle and torque were measured while the elbow was being extending. Then the relationships among these three variables were modeled using an artificial neural network where IEMGs, joint angle and velocity were the inputs, and torque was the output. After back propagation learning, we presented various combinations of IEMGs, elbow joint angle and velocity to the model, and estimated the elbow joint torque to obtain the torque-velocity relationship for constant muscle activation. The torque decreased in a nearly linear manner as the velocity increased. This was caused by slow extending velocity and was explained by Hill's equation at slow velocity.

Adult↗
PubMed1999

Rhabdomyolysis and aggravation of arthritis in a rheumatoid arthritis patient as a result of sepsis due to Staphylococcus aureus infection of a rheumatoid nodule; a catastrophic outcome.

A 63-year-old man with rheumatoid arthritis presented with rhabdomyolysis and intractable arthritis of acute onset. He was diagnosed to have sepsis due to Staphylococcus aureus infection through of an ulcerated rheumatoid nodule. Staphylococcus aureus isolated from pus in the ulcerated rheumatoid nodule and a blood sample obtained from the heart post-mortem produced the toxic shock syndrome toxin-1 (TSST-1). The TSST-1 and/or unmethylated CpG motifs in the oligonucleotides present in a bacterium, Staphylococcus aureus in this case, might be implicated in the induction of rhabdomyolysis and intractable arthritis.

Arthritis, Rheumatoid↗
PubMed1998

Thrombopoietin potentiates the protein-kinase-C-mediated activation of mitogen-activated protein kinase/ERK kinases and extracellular signal-regulated kinases in human platelets.

The thrombopoietin (TPO) receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. We investigated the effect of TPO on the extracellular signal-regulated kinase (ERK) activation pathway in human platelets. TPO by itself did not activate ERK1, ERK2 and protein kinase C (PKC), whereas TPO directly enhanced the PKC-dependent activation of ERKs induced by other agonists including thrombin and phorbol esters, without affecting the PKC activation by those agonists. TPO did not activate the mitogen-activated protein kinase/ERK kinases, MEK1 and MEK2, but activated Raf-1 and directly augmented the PKC-mediated MEK activation, suggesting that TPO primarily potentiates the ERK pathway through regulating MEKs or upstream steps of MEKs including Raf-1. The MEK inhibitor PD098059 failed to affect not only thrombin-induced or phorbol ester-induced aggregation, but also potentiation of aggregation by TPO, denying the primary involvement of ERKs and MEKs in those events. ERKs and MEKs were located mainly in the detergent-soluble/non-cytoskeletal fractions. ERKs but not MEKs were relocated to the cytoskeleton following platelet aggregation and actin polymerization. These data indicate that TPO synergizes with other agonists in the ERK activation pathway of platelets and that this synergy might affect functions of the cytoskeleton possibly regulated by ERKs.

Adult↗
PubMed1998

HLA-DRB1 and tumor necrosis factor gene polymorphisms in Japanese patients with multiple sclerosis.

We studied genetic polymorphisms in the tumor necrosis factor (TNF) region as well as HLA-DRB1 of 42 patients with Western-type multiple sclerosis (MS) and 38 with Asian-type MS in Japan. The sex ratio (Female:Male) was significantly higher in Asian than in Western type MS (3.8 vs. 1.3, P = 0.038). The frequency of HLA-DRB1 * 1501 allele in the Western-type MS group increased significantly compared with the control group, while Asian-type MS and control groups showed similar distribution in the frequencies of HLA-DRB1 alleles. No significant differences existed in the TNF region, however, including TNF-a microsatellite alleles. The results suggest that MS in Asians may present two different clinical and immunogenetic manifestations.

Adult↗
PubMed1998

OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T cells into high IL-4-producing effectors.

Th2 cell development is critically dependent on the presence of interleukin-4 (IL-4) at priming. The cellular origin and the mechanisms regulating this early production of IL-4 at the site of naive T-cell priming are extensively investigated. We previously reported that anti-CD3-activated and CD28-costimulated naive human CD4(+) T cells themselves release very low but sufficient levels of IL-4 to support their development into high IL-4-producing cells. We show here that ligation of OX40 Ag, a member of the tumor necrosis factor receptor (TNF-R) family, on activated umbilical cord blood CD4(+) T cells upregulates IL-4 production at priming and thereby promotes their development into effector cells producing high levels of the type 2 cytokines IL-4, IL-5, and IL-13. OX40 ligation increases four times the expression of IL-4 mRNA after 48 hours of anti-CD3/B7.1 activation and significantly augments the release of IL-4 and IL-13 in primary cultures. The effects of OX40 costimulation on Th cell differentiation are observed in the presence of optimal and suboptimal CD28 stimulation. Because OX40 ligand is expressed on dendritic cells, the OX40 costimulation pathway may be involved in the physiological regulation of Th cell development by augmenting the differentiation of IL-4-producing cells.

CD28 Antigens↗
PubMed1998

Parathyroid hormone-related protein-induced hypercalcemia in SCID mice engrafted with adult T-cell leukemia cells.

Parathyroid hormone-related protein (PTHrP) is considered to be one of the main causes of hypercalcemia associated with adult T-cell leukemia (ATL). To clarify the role of PTHrP and bone remodeling in the development of hypercalcemia in ATL, we examined the SCID mouse model of ATL that has previously been shown to mimic the disease in humans. Using this model, we found clear elevations in serum levels of calcium and C-terminal PTHrP (C-PTHrP). PTHrP mRNA was highly expressed in ATL cells proliferating in vivo. After the development of hypercalcemia, ATL mice were killed and bone histomorphometric analysis was performed. Bone volume was clearly decreased in the ATL mice. In comparison to control SCID mice, bone formation indices were very low in the ATL mice. Surprisingly, no significant difference was detected between the ATL mice and the control SCID mice in eroded surface/bone surface (ES/BS), a parameter of bone resorption. To our knowledge, the model presented here is the first animal model of ATL with humoral hypercalcemia. This is in contrast to previously reported, well-characterized animal models of human solid tumors associated with humoral hypercalcemia of malignancy (HHM). Furthermore, this model not only provides us with the opportunity to study the mechanisms underlying development of elevated calcium levels in ATL, but also allows us to test new therapeutic agents designed to treat hypercalcemia.

Animals↗
PubMed1998

Exanthematous disease induced by toxic shock syndrome toxin 1 in the early neonatal period.

BACKGROUND: We have seen a number of patients who developed systemic exanthema and thrombocytopenia in the first week of life. Although nearly 100% of the patients were carriers of meticillin-resistant Staphylococcus aureus (MRSA), no clear link between MRSA and this exanthematous disease has yet been made. METHODS: 20 neonates with exanthema and thrombocytopenia were selected for study. To see whether superantigenic exotoxins from MRSA are involved in the pathogensis of the exanthematous disease, we studied the production of these exotoxins by MRSA isolates from the neonates. We studied the expression of T-cell-receptor Vbeta and CD45RO in T cells taken from four of the neonates. We also analysed the DNA sequences of 16 cloned Vbeta2-positive T-cell-receptor-chain genes taken from two of the neonates. FINDINGS: Although most of the patients recovered within 5 days of onset of the exanthematous disease without any active treatment, two preterm infants died in the recovery phase. All patients showed colonisation by MRSA. The MRSA produced toxic shock syndrome toxin-1 (TSST-1). The number of T cells positive for T-cell-receptor Vbeta2, reactive to TSST-1, was increased in the four patients studied (p<0.0001), and these T cells expressed CD45RO (p=0.0185). None of the Vbeta2 clones had the same junctional sequences. INTERPRETATION: The polyclonal expansion of Vbeta2-positive T cells in patients colonised by TSST-1-producing MRSA suggests that the pathogenic micro-organism of this neonatal exanthematous disease is S aureus, mainly MRSA, and that in its pathogenesis it activates T cells by TSST-1. Although the pathogenesis of both this exanthematous disease and toxic shock syndrome are fundamentally the same, a diagnosis of toxic shock syndrome cannot be made in this case, based on the clinical criteria for toxic shock syndrome. We propose neonatal toxic-shock-syndrome-like exanthematous disease (NTED) as the name for this disease.

Bacterial Toxins↗
PubMed1998

Hemophagocytic syndrome in five patients with Epstein-Barr virus negative B-cell lymphoma.

BACKGROUND: The recent recognition of the association of Epstein-Barr virus (EBV) with T-cell/natural killer cell (T/NK-cell) lymphoma has documented that particular types of EBV-containing T/NK-cell lymphoma are frequently complicated by hemophagocytic syndrome (HPS). This observation suggests that both EBV and proliferating T/NK-lymphoma cells play significant roles in the development of HPS. Cytokines released from neoplastic T cells are presumed to account for the activation of macrophages, which is followed by a complex cascade of cytokine production, resulting in full-blown HPS. Five patients with B-cell lymphoma complicated by HPS were studied for elevated serum cytokines, the association of EBV, and CD25 expression of lymphoma cells; the aim of this study was to verify whether the mechanisms of HPS development hypothesized for T/NK-cell lymphoma also operate in B-cell lymphoma. METHODS: Sera were analyzed for the presence of inflammatory and immunoregulatory cytokines. Flow cytometry, immunohistology (IH), in situ hybridization (ISH), polymerase chain reaction (PCR), and Southern blot analysis were performed using bone marrow aspirates, biopsy specimens, and autopsy specimens. RESULTS: Immunophenotypic and Southern blot studies verified that the lymphoma cells of all five patients were of B-cell lineage. Bone marrow aspirates demonstrated histiocytosis with extensive hemophagocytic activity. Marked elevation of serum cytokines and expression of CD25 were observed in all five patients. However, the results of PCR, ISH using EBER1 probe, and IH for latent membrane protein indicated that these lymphoma cells were free of EBV infection. CONCLUSIONS: In patients with B-cell lymphoma, EBV infection is not necessarily required for the initiation of HPS. In this article, the pathogenesis of HPS assumed to be operative in B-cell lymphoma is discussed with reference to T/NK-cell lymphoma complicated by HPS.

Aged↗
PubMed1998

IL-4 induces functional cell-surface expression of CXCR4 on human T cells.

Here we report that IL-4 specifically enhances cell surface expression of CXCR4 on resting peripheral and cord blood T cells. Whereas polarized Th2 clones express variable levels of CXCR4, expression of this receptor is undetectable on polarized Th1 clones but can be induced on the latter cells as well, following short-term culture in the presence of IL-4. The IL-4-induced CXCR4 is functional since interaction with its ligand, stromal-derived factor (SDF)-1, activates the p42 MAP-kinase ERK-2. In addition, although CXCR4 expression is down-regulated following stimulation of T cells and T cell clones via CD28 or CD3 and CD2 cell surface molecules, respectively, it is re-induced by IL-4. These data indicate an important role for IL-4 in rendering CD4+ T cells susceptible to infection with HIV via CXCR4, as well as in promoting SDF-1-induced migration of these cells.

CD4-Positive T-Lymphocytes↗
PubMed1998

Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation.

We investigated the intracellular signaling of OX40, a member of the tumor necrosis factor receptor family. Activation of NF-kappaB in OX40-transfected HSB-2 cells was detected by electrophoretic mobility shift assay within 30 min after the binding of the ligand gp34. In vitro binding experiments showed that tumor necrosis factor receptor-associated factor (TRAF) 1, TRAF2, TRAF3, and TRAF5 but not TRAF4 associated with glutathione S-transferase-OX40 fusion protein. The cotransfection experiments using human embryo kidney cell derived HEK 293T cells showed that TRAF2, TRAF3, and TRAF5 associated with OX40 in vivo. Studies with OX40 deletion mutants demonstrated that the cytoplasmic portion consisting of amino acid sequence 256-263 (GGSFRTPI) was required for the association with TRAFs and NF-kappaB activation. The introduction of the dominant negative mutants of TRAF2 and TRAF5 into HSB-2-OX40 cells suppressed NF-kappaB activation in a dose-dependent manner. In addition, the introduction of TRAF3 together with the dominant negative mutants of TRAF2 or TRAF5 further reduced NF-kappaB activation. These results indicate that the NF-kappaB activation resulting from OX40 stimulation is mediated by both TRAF2 and TRAF5, and is likely to be negatively modulated by TRAF3.

Antigens, Surface↗
PubMed1998

Expression of a soluble form of LFA-1 and demonstration of its binding activity with ICAM-1.

The interaction between lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is of importance in a number of cellular events, including antigen-specific T cell activation and emigration of leukocytes into sites of inflammation. We describe here the first use of a recombinant soluble form of human LFA-1 (sLFA-1) for the measurement of the binding between LFA-1 and ICAM-1. sLFA-1 has been successfully expressed and purified. The expressed sLFA-1 was shown to be functionally active by their binding to ICAM-1. Binding of sLFA-1 to ICAM-1 was observed by receptor binding assay. Both monomeric (soluble ICAM-1 or the first two domains of ICAM-1) and dimeric ICAM-1 (IgG chimera of each ICAM-1 fragment) showed inhibitory activity on assay with IC50 values of 400 nM and 40 nM, respectively. These results suggest that the soluble constructs would be useful tools for molecular analysis of ICAM-1/LFA-1 interaction as well as in screening for ICAM-1/LFA-1 antagonists.

CD18 Antigens↗
PubMed1998

Human T-cell leukemia virus type 1 Tax protein induces the expression of lymphocyte chemoattractant SDF-1/PBSF.

We investigated the mechanism of lymphocyte infiltration into tissues infected with human T-cell leukemia virus type 1 (HTLV-1). The cytokine SDF-1/PBSF is a highly efficient chemoattractant for lymphocytes. Reverse transcription-PCR analysis showed that among various human T-cell lines, those infected with HTLV-1 selectively expressed the SDF-1 gene. Expression of the viral protein Tax in a human T-cell line induced the expression of the SDF-1 gene, indicating that the constitutive expression of SDF-1 in virus-infected cell lines is at least in part mediated by Tax. HTLV-1-infected T-cell lines also expressed CXCR-4, a receptor for SDF-1. Moreover, chemotaxis assay showed that a HTLV-1-infected cell line migrated toward synthetic SDF-1. Thus, HTLV-1-infected cells are themselves responders for SDF-1. Our results suggest that SDF-1 induced by Tax may alter the distribution of HTLV-1-infected cells in vivo; hence it may contribute to their infiltration into affected tissues in HTLV-1-associated inflammatory diseases.

Animals↗
PubMed1998

The upregulation of p27Kip1 by rapamycin results in G1 arrest in exponentially growing T-cell lines.

An immunosuppressant Rapamycin (Rap) has been reported to cause G1 arrest by inhibiting p70 S6 kinase and G1 cyclin/cdks kinase activities when added to quiescent cells with mitogens. However, antiproliferative effects of Rap on exponentially growing cells have been poorly investigated. We examined the intracellular events after the treatment of Rap in exponentially growing T cells and found that Rap upregulated a cdks inhibitor, p27Kip1 at both mRNA and protein levels in Rap-sensitive cells. Antiproliferative effect of Rap was mainly ascribed to the inhibition of cyclin E/cdk2 kinase activity through the formation of cyclin E/cdk2-p27Kip1 complex rather than inhibition of p70 S6 kinase activity. Furthermore, we showed that Rap-sensitive cells with elevated p27Kip1 expression lost sensitivity to Rap when antisense p27Kip1 was introduced, which indicates that the basal level of p27Kip1 is one of the limiting factors that determine the sensitivity to Rap in already cycling cells. These data suggest the presence of a putative threshold level of p27Kip1 at late G1 phase in already cycling cells. Rap may cause G1 arrest by upregulating the amount of p27Kip1 beyond the threshold in some Rap-sensitive cells that are exponentially growing.

CDC2-CDC28 Kinases↗
PubMed1998

V3 loop of human immunodeficiency virus type 1 reduces cyclin E expression and induces G1 arrest in interleukin 2-dependent T cells.

We previously described that V3 loop derived from the HTLV-III BH10 clone V3-BH10 markedly suppressed IL-2-driven T cell proliferation and produced G1 arrest of the cells. Here, we tested the effect of V3-BH10 on the molecules that are involved in transition from the G1 to S phase of the cell cycle. The effect of V3-BH10 on the IL-2-induced expression of G1 cyclins, Cdk inhibitors, and phosphorylation of retinoblastoma protein (pRb) was tested by immunoblotting, using the IL-2-dependent CD4-positive cell line Kit 225. Furthermore, IL-2-dependent kinase activity of the cyclin E-Cdk2 complex was investigated with histone H1 as a substrate. V3-BH10 reduced the IL-2-dependent expression of cyclin E, but not that of cyclin D and Cdk inhibitors such as p21 and p27. As the result of reduction of cyclin E, histone H1 kinase activity of the cyclin E-Cdk2 complex was markedly reduced even in the presence of rIL-2, followed by incomplete phosphorylation of pRb. The reduction in hyperphosphorylation of pRb by V3-BH10 led to G1 arrest of the cell cycle. Thus, V3-BH10 induced G1 arrest in IL-2-dependent cell cycle progression by reducing cyclin E expression, which may be one of the mechanisms underlying the dysfunction of T cells in HIV-1-infected people.

Blotting, Western↗
PubMed1998

Post-thymic maturation of migrating human thymic single-positive T cells: thymic CD1a- CD4+ T cells are more susceptible to anergy induction by toxic shock syndrome toxin-1 than cord blood CD4+ T cells.

To determine whether human CD4+ T cells undergo post-thymic maturation, we compared the susceptibility to anergy induction in human thymic CD1a- CD4+ single-positive (CD4+), cord blood (CB) CD4+, and adult peripheral blood (APB) CD4+ T cells by stimulation with toxic shock syndrome toxin-1 (TSST-1). Most TSST-1-induced T cell blasts derived from either T cell preparation expressed TCR Vbeta2, which determines the potential reactivity to TSST-1. Most thymic CD4+ T cell blast preparations exhibited little or no production of IL-2 and IL-4 after restimulation with TSST-1 and only marginal responses after stimulation with rIL-2 or a combination of PMA and calcium ionophore, while the APB CD4+ T cell blasts showed high responses to these stimuli. The responses of CB CD4+ T cell blasts to these stimuli varied, ranging from minimal to relatively high. Studies of DNA fragmentation showed that there was no significant cell death of thymic CD4+ T cell blasts. Most thymic CD1a- CD4+ and CB CD4+ T cells were CD38 positive. APB CD4+ T cell blasts derived from the CD38+ fraction and from the CD38- fraction exhibited equally high responses to restimulation with TSST-1. These results indicate that thymic CD1a- CD4+ and CB CD4+ T cells are inherently highly susceptible to anergy induction by bacterial superantigens and that thymic CD1a- CD4+ T cells are less mature than CB CD4+ T cells, suggesting that post-thymic maturation in thymic T cells migrating to the periphery is required for acquisition of full reactivity to antigenic stimulation.

ADP-ribosyl Cyclase↗
PubMed1998

Detection and delineation of CXCR-4 (fusin) as an entry and fusion cofactor for T-tropic [correction of T cell-tropic] HIV-1 by three different monoclonal antibodies.

A chemokine receptor, CXCR-4, has been identified as an entry cofactor for T cell line-tropic (T-tropic) HIV-1. To detect expression of CXCR-4 at the single cell level and dissect postbinding events of HIV-1 infection, we generated three mAbs against human CXCR-4. These mAbs inhibited SDF-1-induced intracellular Ca2+ mobilization, and one of the mAbs immunoprecipitated a specific 47-kDa component from CXCR-4+ cells. Flow cytometric analysis showed that most human cell lines examined expressed CXCR-4. A fraction of normal PBMC expressed CXCR-4, but neutrophils were negative. Two-color analysis revealed that the majority of T cells, virtually all B cells, and all monocytes expressed CXCR-4, while it was only weakly present on NK cells. Thus, expression of CXCR-4 is not ubiquitous but cell type specific in hemopoietic cells. The three mAbs were shown to suppress cell fusion mediated by envelope proteins of a T-tropic NL432 virus but not by those of an M-tropic JRCSF virus Likewise, they suppressed infection of NL432 but not that of an M-tropic NL162 virus. In both cases it was noted that the suppressive activity varied considerably among the mAbs. These data confirmed that CXCR-4 is directly involved in env-mediated entry and fusion of T-tropic HIV-1 and suggest that the epitopes on CXCR-4 recognized by the three mAbs may have different roles in interaction with the envelope proteins of T-tropic HIV-1.

Animals↗