Biomedical subjects

Takashi Nishimura

Publications and source records attributed to Takashi Nishimura.

50 records · Page 3Linked to original sources

PubMed2004

Community discharge of patients with schizophrenia: a Japanese experience.

In Japan, admission to a psychiatric facility for people with schizophrenia is usually for life. We developed a rehabilitation program aimed at discharging these patients into the Tokyo community. This paper describes the results for the 224 patients. Using an inpatient ward at the Tokyo Musashino Hospital, patients were enrolled in the program and subsequently discharged into the community with an assigned worker. The results indicate for the majority (79%) re-integration into the community was successful. The success of this program in a metropolitan city like Tokyo argues for the efficacy of such programs.

Adult↗

PubMed2003

Functional expression of the TrkC gene, encoding a high affinity receptor for NT-3, in antigen-specific T helper type 2 (Th2) cells.

Neurotrophins, including nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 (NT-3) are essential factors for the development of the nervous system. In this report, we demonstrate gene expression of neurotrophins and their receptors in T helper 1 (Th1) and T helper 2 (Th2) cells induced from naïve CD4+ CD45RB+ T cells of ovalbumin-specific DO11.10 T cell receptor transgenic mice. Interestingly, the TrkC gene, which encodes a high affinity receptor for NT-3, was expressed in Th2 cells, but not in Th1 and naïve CD4+ T cells. Expression of the TrkC gene was markedly augmented by addition of anti-IFN-gamma monoclonal antibody (mAb) into the culture, whereas it was blocked by anti-IL-4 mAb. Moreover, NT-3 synergistically enhanced anti-CD3 mAb-induced IL-4 production by Th2 cells, but did not affect IFN-gamma production by Th1 cells. These data suggest that NT-3, through its receptor TrkC, plays a critical role in regulating the Th1/Th2 balance.

Animals↗

PubMed2003

CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth.

Axon growth during neural development is highly dependent on both cytoskeletal re-organization and polarized membrane trafficking. Previously, we demonstrated that collapsin response mediator protein-2 (CRMP-2) is critical for specifying axon/dendrite fate and axon growth in cultured hippocampal neurons, possibly by interacting with tubulin heterodimers and promoting microtubule assembly. Here, we identify Numb as a CRMP-2-interacting protein. Numb has been shown to interact with alpha-adaptin and to be involved in endocytosis. We found that Numb was associated with L1, a neuronal cell adhesion molecule that is endocytosed and recycled at the growth cone, where CRMP-2 and Numb were colocalized. Furthermore, expression of dominant-negative CRMP-2 mutants or knockdown of CRMP-2 message with small-interfering (si) RNA inhibited endocytosis of L1 at axonal growth cones and suppressed axon growth. These results suggest that in addition to regulating microtubule assembly, CRMP-2 is involved in polarized Numb-mediated endocytosis of proteins such as L1.

Animals↗

PubMed2003

Successful elimination of memory-type CD8+ T cell subsets by the administration of anti-Gr-1 monoclonal antibody in vivo.

During investigating the expression of Gr-1 antigen on various subsets of mouse spleen cells, we found that Gr-1 was expressed on memory-type CD8(+)CD44(high)CD62L(high) T cells in addition to granulocytes. Intraperitoneal administration of anti-Gr-1 mAb caused almost complete elimination of Ly-6C(+) memory-type CD8(+) T cells as well as Ly-6G(+) granulocytes. Anti-Gr-1 mAb-treated mouse spleen cells exhibited greatly reduced IFN-gamma production in response to anti-CD3 mAb both in vitro and in vivo. This reduced cytokine production appeared to be derived from elimination of IFN-gamma-producing Gr-1(+)CD8(+) T cells. Indeed, CD8(+) T cells with IFN-gamma-producing activity and cytotoxicity were generated from isolated Gr-1(+)CD8(+) cells but not from Gr-1(-)CD8(+) T cells. We also demonstrated that therapeutic effect of MBL-2 tumor-immunized spleen cells was greatly reduced by anti-Gr-1 mAb-treatment. Thus, we initially demonstrated that anti-Gr-1 mAb might become a good tool to investigate a precise role for memory-type CD8(+) T cells in vivo.

Animals↗

PubMed2003

Differential regulation of VLA-2 expression on Th1 and Th2 cells: a novel marker for the classification of Th subsets.

We found that T(h)1 cells derived from ovalbumin (OVA)-specific TCR transgenic (DO11.10) mice showed significantly higher levels of VLA-2 (CD49b/CD29) expression than T(h)2 cells. In the early days (until 6 days) during induction of T(h)1 or T(h)2 cells, the expression of VLA-2 was gradually increased on both T(h) subsets. Thereafter, VLA-2 expression was further up-regulated on T(h)1 cells until 13 days, while a significant decrease of VLA-2 was observed in T(h)2 cells, resulting in a marked difference of expression at day 13. Up-regulation of VLA-2 on T(h)1 cells was not impaired in IFN-gamma(-/-) T(h) cells nor blocked by anti-IL-12 mAb treatment on wild-type T(h) cells, suggesting that up-regulation of VLA-2 on T(h)1 cells occurs in an IFN-gamma- and IL-12-independent manner. In contrast, T(h) cells cultured under IL-4-depleted T(h)2 conditions abrogated the down-regulation of VLA-2 expression, suggesting that down-regulation of VLA-2 expression on T(h)2 cells was dependent on IL-4. The finding that STAT6(-/-) T(h)2 cells did not show any down-regulation of VLA-2 expression and expressed the same levels of VLA-2 as T(h)1 cells indicated a critical role for the IL-4 receptor/STAT6 signaling pathway in IL-4-dependent down-regulation of VLA-2 on T(h)2 cells. Stimulation of T(h)1 cells by VLA-2 ligands such as collagen type I or agonistic mAb provided co-stimulation for anti-CD3 mAb-induced IFN-gamma production. However, these ligations had little effect on the IL-4 production of T(h)2 cells. Together, these results indicate that VLA-2 is a novel functional marker that dissociates T(h)1 from T(h)2 cells, and thus might be useful for therapeutic monitoring of T(h)1-dependent immune diseases such as rheumatoid arthritis or Crohn's disease.

Animals↗

PubMed2003

A novel tumor-vaccine cell therapy using bone marrow-derived dendritic cell type 1 and antigen-specific Th1 cells.

Dendritic cell (DC)-based tumor-vaccine therapy is a rational strategy for tumor immunotherapy. However, using this protocol, it is still difficult to induce long-term regression in established tumor-bearing mice. To overcome this problem we developed a novel tumor-vaccine therapy, combining inactivated tumor cells with bone marrow-derived DC type 1 (BMDC1) and antigen-specific T(h)1 cells. BALB/c mice were intradermally inoculated with A20-OVA tumor cells expressing ovalbumin (OVA) as a model tumor antigen. After A20-OVA tumor mass became palpable (6-8 mm), mice were treated with DC-based vaccine therapy in various protocols. A complete cure of tumor-bearing mice was induced only when mice were repeatedly vaccinated with inactivated A20-OVA cells, OVA-pulsed BMDC1 and OVA-specific T(h)1 cells. Regression of tumor cells was associated with induction of T(h)1/T(c)1-dominant antitumor immunity. Removal of one of these cellular components during vaccination resulted in failure to completely cure tumor-bearing mice. Moreover, BMDC2 cells could not replace the therapeutic effect of BMDC1 cells combined with T(h)1 cells. Thus, we propose a novel tumor-vaccine cell therapy using DC1 and T(h)1 cells.

Animals↗

PubMed2003

Critical role of the Th1/Tc1 circuit for the generation of tumor-specific CTL during tumor eradication in vivo by Th1-cell therapy.

Th1 and Th2 cells obtained from OVA-specific T cell receptor transgenic mice completely eradicated the tumor mass when transferred into mice bearing A20-OVA tumor cells expressing OVA as a model tumor antigen. To elucidate the role of Tc1 or Tc2 cells during tumor eradication by Th1- or Th2-cell therapy, spleen cells obtained from mice cured of tumor by the therapy were re-stimulated with the model tumor antigen (OVA) for 4 days. Spleen cells obtained from mice cured by Th1-cell therapy produced high levels of IFN-gamma, while spleen cells from mice cured by Th2-cell therapy produced high levels of IL-4. Intracellular staining analysis demonstrated that a high frequency of IFN-gamma-producing Tc1 cells was induced in mice given Th1-cell therapy. In contrast, IL-4-producing Tc2 cells were mainly induced in mice after Th2-cell therapy. Moreover, Tc1, but not Tc2, exhibited a tumor-specific cytotoxicity against A20-OVA but not against CMS-7 fibrosarcoma. Thus, immunological memory essential for CTL generation was induced by the Th1/Tc1 circuit, but not by the Th2/Tc2 circuit. We also demonstrated that Th1-cell therapy is greatly augmented by combination therapy with cyclophosphamide treatment. This finding indicated that adoptive chemoimmunotherapy using Th1 cells should be applicable as a novel tool to enhance the Th1/Tc1 circuit, which is beneficial for inducing tumor eradication in vivo.

Animals↗

PubMed2003

An efficient method to prepare T cell receptor gene-transduced cytotoxic T lymphocytes type 1 applicable to tumor gene cell-therapy.

Genes encoding 2C T cell receptor (TCR) alpha, beta chains from H-2(b)-restricted L(d)-specific CD8(+) cells were successfully transduced into polyclonally activated CD8(+) cells by retroviral modification to generate antigen-specific cytotoxic T lymphocytes (CTL). Antigen-nonspecific CD8(+) T cells polyclonally expanded in the presence of interleukin (IL)-2, Th1 cytokines (interferon (IFN)-gamma and IL-12) and anti-IL-4 monoclonal antibody showed neither cytokine production nor cytotoxicity in response to L(d)-expressing P815 tumor cells. However, 2C-TCR gene-modified CD8(+) T cells exhibited both IFN-gamma production and cytotoxicity in response to P815 tumor cells. The antitumor activity of TCR gene-modified Tc1 cells was also demonstrated in vivo by Winn's assay. Thus, we have developed an efficient method to induce TCR gene-modified antigen-specific Tc1 cells that exhibit antitumor activity both in vitro and in vivo.

Animals↗

PubMed2003

Augmentation of Actinobacillus actinomycetemcomitans invasion of human oral epithelial cells and up-regulation of interleukin-8 production by saliva CD14.

It has recently been shown that human salivary glands constitutively express CD14, an important molecule in innate immunity, and that a soluble form of CD14 is secreted in saliva. The concentration of CD14 in parotid (a serous gland) saliva was comparable to that in normal serum and 10-fold the amount in whole saliva, although the physiological function of saliva CD14 remained unclear. Actinobacillus actinomycetemcomitans is a periodontopathic bacterium and is able to invade oral epithelial cells. The present study showed that upon exposure to live A. actinomycetemcomitans Y4 for 2 h, human oral epithelial HSC-2 cells produced interleukin-8 (IL-8) for a further 24 h and whole saliva augmented the production induced by A. actinomycetemcomitans Y4. Parotid saliva showed a more pronounced effect on the production of IL-8 than whole saliva. Neither saliva preparation itself had IL-8-inducing activity. Parotid saliva exhibited antibacterial activity against a low concentration of A. actinomycetemcomitans Y4, but recombinant CD14 did not show the activity. The internalization of A. actinomycetemcomitans Y4 into HSC-2 cells was inhibited by cytochalasin B, indicating that the process was actin dependent, and depletion of CD14 from parotid saliva inhibited the invasion and, as a consequence, inhibited production of IL-8. Furthermore, human recombinant CD14 augmented invasion and IL-8 production. These results suggest that saliva CD14 promoted the invasion of oral epithelial cells by A. actinomycetemcomitans and consequently augmented the production of IL-8, playing an important role in innate immunity in the oral cavity.

Adult↗

PubMed2002

Glucose-insulin-potassium solution improves left ventricular mechanics in diabetes.

BACKGROUND: The mechanism by which glucose-insulin-potassium solutions enhance recovery of left ventricular function after myocardial ischemia in diabetic patients is not well understood. We evaluated the effect of glucose-insulin-potassium on ventriculoarterial coupling and left ventricular mechanics in a chronic ovine model of diabetes. METHODS: Diabetes was induced in 6 sheep with streptozotocin. After 6 months of diabetes, the response of the left ventricular pressure-volume relationship to 60 minutes of intravenous glucose-insulin-potassium solution (1,000 mL of 5% dextrose in water, 100 IU of regular insulin, 90 mmol of KCl at 1.5 mL x kg(-1) x h(-1)) was determined. RESULTS: Glucose-insulin-potassium solution increased end-systolic elastance 68% (p = 0.01) and improved ventriculoarterial coupling (1.7+/-0.3 to 1.0+/-0.1; p < 0.01). Potential energy decreased 35% (p = 0.01), and pressure-volume area decreased 20% (p = 0.01). However, stroke work did not change; therefore stroke work efficiency increased from 50.1%+/-3.5% to 60.2%+/-5.1% (p = 0.01). CONCLUSIONS: Glucose-insulin-potassium solution improves left ventricular contractility and ventriculoarterial coupling in diabetes. Left ventricular mechanics is improved by decreasing total mechanical work without significantly affecting stroke work, resulting in improved stroke work efficiency. Improved efficiency facilitates understanding of the enhanced tolerance to myocardial ischemia afforded by glucose-insulin-potassium solution.

Animals↗

PubMed2002

Left ventricular oxygen utilization efficiency is impaired in chronic streptozotocin-diabetic sheep.

OBJECTIVE: Energy metabolism is altered in the diabetic heart. However, direct in vivo evidence that diabetes impairs energetics at the chamber level is lacking. Therefore, we investigated the effect of diabetes on left ventricular (LV) energetics in a chronic ovine model. METHODS: Diabetes was induced in Merino-cross sheep with streptozotocin. Experiments were performed in five animals following 12 months untreated diabetes and six animals served as controls. Open-chest anesthetized sheep were instrumented to determine the LV pressure-volume relationship, oxygen consumption and free fatty acid uptake. RESULTS: Diabetes impaired LV contractility (1.5+/-0.5 vs. 2.3+/-0.5 mmHg/ml, P<0.01). Stroke work was preserved but stroke work efficiency (stroke work/pressure-volume area) deteriorated (52+/-4 vs. 58+/-3%, P<0.01). Plasma free fatty acid levels increased (1885+/-1078 vs. 354+/-203 mmol/l, P<0.01) as did LV free fatty acid uptake (312+/-278 vs. 90+/-47 micromol/beat per 100 g LV, P=0.04). Contractile efficiency decreased (31.9+/-1.4 vs. 50.0+/-8.7%, P<0.01) while unloaded oxygen consumption did not change significantly. Therefore, LV oxygen utilization efficiency (stroke work/LV oxygen consumption) was compromised in the diabetic heart (14.9+/-2.8 vs. 24.3+/-4.0%, P<0.001). CONCLUSION: This is the first study to demonstrate that diabetes alters ventricular energetics in vivo. LV oxygen utilization efficiency is impaired as a consequence of decreased contractile efficiency and stroke work efficiency. Impaired efficiency of oxygen utilization may explain in part the increased sensitivity of the diabetic heart to ischemia and the accelerated deterioration of ventricular function in diabetic patients.

Animals↗

PubMed2002

CRMP-2 binds to tubulin heterodimers to promote microtubule assembly.

Regulated increase in the formation of microtubule arrays is thought to be important for axonal growth. Collapsin response mediator protein-2 (CRMP-2) is a mammalian homologue of UNC-33, mutations in which result in abnormal axon termination. We recently demonstrated that CRMP-2 is critical for axonal differentiation. Here, we identify two activities of CRMP-2: tubulin-heterodimer binding and the promotion of microtubule assembly. CRMP-2 bound tubulin dimers with higher affinity than it bound microtubules. Association of CRMP-2 with microtubules was enhanced by tubulin polymerization in the presence of CRMP-2. The binding property of CRMP-2 with tubulin was apparently distinct from that of Tau, which preferentially bound microtubules. In neurons, overexpression of CRMP-2 promoted axonal growth and branching. A mutant of CRMP-2, lacking the region responsible for microtubule assembly, inhibited axonal growth and branching in a dominant-negative manner. Taken together, our results suggest that CRMP-2 regulates axonal growth and branching as a partner of the tubulin heterodimer, in a different fashion from traditional MAPs.

Animals↗

PubMed2002

[Genetically engineered mice and its application to bioindustry].

More than 2 decades have past since the first transgenic mouse was created. In this review we will focus on recent technologies in the field of mouse genetic engineering and on its application to bioindustry. The most important milestone in this field was the invention of the gene targeting technique. Recent improvement of this technique to conditional gene targeting together with the Cre/IoxP system further encouraged the generation of mutant mice. It is obvious that there will be a great demand for some mutant mice as experimental models of human disease or as resources of experimental material for basis biological research. Thus, creation of such mice would be a rewarding challenge for a biological enterprise.

Animals↗

PubMedDate not supplied

Air pollution by concrete dust from the Great Hanshin Earthquake.

Air pollution in the areas affected by the Great Hanshin Earthquake (Hyogo, Japan) of 17 Jan. 1995 was quite serious. We performed three investigations of dust. In the first investigation, we measured the total suspended particulate (TSP) concentration in the greatly damaged areas, located around the Sannomiya Station where a few hundred thousand people walked by during the daytime of 3 February. The maximum concentration at five points reached 150 microg/m3. In the second investigation, eight samples, which were classified into three groups (concrete, mortar, and soil dusts) as sources, were analyzed elementally by X-ray fluorescence. The elements found in concrete dust (Ca and S) were similar to those found in mortar dust. These differed from those found in soil dust (Ti, Fe, and Zr). The elements found in soil dust were important from the viewpoint of heavy metal contamination. In the third investigation, the alkalinity of concrete dust was observed by dissolution. This solution was equivalent to pH 11 to 12 and electrical conductivity 20 to 30 microS/m. We suspect that the alkaline component in the dust from debris in all the devastated areas was approximately comparable with the alkaline solution by which the acid rain falling over the Hanshin district of Osaka Megalopolis in one year could be neutralized into water of pH 7.0.

Air Pollutants↗