Biomedical subjects

T Kakiuchi

Publications and source records attributed to T Kakiuchi.

At least 73 records · Page 4Linked to original sources

PubMed1997

Activation of the prefrontal, occipital and parietal cortices during go/no-go discrimination tasks in the monkey as revealed by positron emission tomography.

The regions of the monkey brain involved in cognito-behavioral tasks were mapped using the H2(15)O positron emission tomography (PET) activation technique. Monkeys performed hand movements in an asymmetrically rewarded go/no-go reaction-time task with discrimination between green (go) and red (no-go) light signals. Regional cerebral blood flow (rCBF) was measured during the go/no-go task and a control task in which only go signals were presented. In the go/no-go task, when compared with the control, a significant increase in rCBF was noted in the following regions: (1) the principal sulci; (2) the anterodorsal frontal pole; (3) the anterior part of the inferior occipital sulcus which appeared to be the V4; and (4) the parieto-occipital region. The increase in the principal sulci may be related to the no-go decision and motor suppression in the area, as interpreted in our previous electrophysiological studies. The present results appear to support electrophysiological observations on visual perception and motor suppression and reflect a mode of their functional integration.

Animals↗

PubMed1997

Regulation of cerebral blood flow response to somatosensory stimulation through the cholinergic system: a positron emission tomography study in unanesthetized monkeys.

The effects of scopolamine, a muscarinic cholinergic receptor antagonist and physostigmine, a cholinesterase inhibitor, on the regional cerebral blood flow (rCBF) response to vibrotactile stimulation of the forepaw were studied in the brain of unanesthetized monkeys using 15O-labeled water and high resolution positron emission tomography. Before scopolamine administration, vibrotactile stimulation produced a significant increase in the rCBF response in the contralateral somatosensory cortex of the monkey brain. Intravenous administration of scopolamine at doses ranging from 1 to 500 microg/kg resulted in a dose-dependent reduction of the rCBF response. The rCBF response abolished by scopolamine (50 microg/kg) was recovered by administration of physostigmine (10 microg/kg). On the other hand, the regional cerebral metabolic rate of glucose (rCMRglc) response, measured with [18F]-2-fluoro-2-deoxy-D-glucose, to the same stimulation was unchanged by administration of either scopolamine and/or physostigmine. These results suggested that cholinergic mechanisms might be involved in regulation of the coupling between neuronal activity and rCBF response, not between the activity and rCMRglc response.

Animals↗

PubMed1997

Genetic defect in T lymphocyte-specific homing into peripheral lymph nodes.

Lymphocytes circulating in the bloodstream home into lymph nodes (LN). T cells predominate in peripheral LN (PLN) and B cells in spleen or mucosal tissue, e.g. Peyer's patches (PP). DDD/1 mice are unique in marked paucity of LN cells, especially T cells. T cell frequency in PLN was 20-40% in this strain, compared to 60-80% in others. Immunohistochemistry confirmed the low density of T cells in the subcortical area but normal colonization of B cells in cortical area in PLN of DDD/1. In contrast, the T cell content of peripheral blood and spleen was higher in DDD/1 but that in PP was not significantly different compared to other strains. It was thus concluded that this abnormality in DDD/1 results from a homing defect of T cells into PLN but not from lymphopenia. Genetical analysis showed that the defect in T cell-specific homing was regulated by a single autosomal recessive gene, tentatively designated plt (paucity of lymph node T cells). Reciprocal bone marrow transplantation indicated that the plt phenotype may arise from some defect in PLN stroma but not in lymphocytes. An in vivo homing assay using fluorescence-labeled lymphocytes demonstrated that the homing defect was specific for T cells but not for B cells. A Stamper-Woodruff assay revealed that the binding between lymphocytes and PLN high endothelial venules was normal and that L-selectin and its ligand, peripheral node vascular addressin (PNAd), were expressed and functioned normally in DDD/1. These results taken together indicate that the T cell-specific homing into PLN is disturbed at a post-adhesion stage in DDD/1. The product of the plt locus may play a pivotal role at this stage.

Animals↗

PubMed1997

Enhancement of antigen-presenting ability of B lymphoma cells by partial inhibition of protein synthesis through inducing B7-1 expression.

During the investigation of the role of protein synthesis in antigen-presenting cell (APC) function of A20-HL B lymphoma cells, we found that partial inhibition of protein synthesis enhanced their APC function. The treatment of A20-HL cells with 0.313-2.5 microM emetine, an irreversible inhibitor of protein synthesis, decreased protein synthesis by 60-70%, and enhanced their APC function to stimulate I-Ad/OVA323-339-specific T cells to produce interleukin-2 in response to ovalbumin (OVA). The emetine-treated and paraformaldehyde-fixed A20-HL cells required only 20 nM OVA323-339 peptide to stimulate the T cells, whereas those untreated and fixed required 200 nM peptide. This enhancement of APC function was mostly because of the induction of B7-1 expression on A20-HL cells by the emetine treatment, since B7-1 molecules were detected on the emetine-treated A20-HL cells, but only negligibly, if at all, on the untreated cells, and an anti-B7-1 monoclonal antibody, 1G10, inhibited the enhanced APC function of the emetine-treated A20-HL cells. The emetine-treatment also increased B7-1 mRNA expression in A20-HL cells, suggesting that the induction of B7-1 expression was due to the increase in the accumulation of mRNA and the translation with residual ability to synthesize protein. Thus, partial inhibition of protein synthesis in A20-HL cells increases B7-1 mRNA accumulation and its expression on the cell surface, which results in the enhancement of their APC function.

Antigen Presentation↗

PubMed1997

MHC class I presentation of an exogenous polypeptide antigen encoded by the murine AIDS defective virus.

Peptides derived from endogenous proteins are presented by MHC class I molecules, whereas those derived from exogenous proteins are presented by MHC class II molecules. This strict segregation has been reconsidered in recent reports in which exogenous antigens are shown to be presented by MHC class I molecules in the phagocytic pathway. In this report, the presentation pathway of an exogenously added highly antigenic polypeptide encoded by the murine AIDS (MAIDS) defective virus gag p12 gene is investigated. A 25-mer polypeptide (P12-25) encoded within the gag p12 region of the MAIDS defective virus was found to be effective in stimulating unprimed B6 (H-2b) CD8+ T cells in vitro. The presentation of P12-25 is sensitive to cytochalasin B and D, brefeldin A and gelonin, a ribosome-inactivating protein synthesis inhibitor, but less sensitive or resistant to lactacystin, a highly specific inhibitor of the proteasome. Interestingly, CA-074, a selective inhibitor of cathepsin B, inhibited presentation of the polypeptide, indicating its involvement in the degradation of the P12-25 polypeptide. In fact, when P12-25 was digested with purified cathepsin B in vitro, a highly antigenic 11-mer peptide containing the class I (H-2Db)-binding motif was obtained. Our results favor the phagosome/macropinosome-to-cytosol-to-endoplasmic reticulum (ER)-to-cell surface pathway for exogenous antigens presented by MHC class I molecules. These findings may be relevant to exploiting peptide vaccines that specifically elicit CD8+ T cell immunity in vivo.

Acetylcysteine↗

PubMed1997

[The effect of cerebral perfusion pressure on cerebral blood flow in the rhesus monkey during sevoflurane anesthesia].

The effect of cerebral perfusion pressure on cerebral blood flow (CBF) was studied under the normocapnic condition in the rhesus monkey under sevoflurane anesthesia. CBF was measured by means of positron emission tomography technique. After the measurement of CBF at 0.5% sevoflurane as control, the measurement was repeated at 2.0% sevoflurane (1 MAC), when blood pressure was kept at a half of the control value. The measurement was also repeated at the same sevoflurane concentration, when the mean blood pressure was restored with the infusion of angiotensin II. Average CBF as well as regional CBFs were compared between two different mean blood pressures at 2.0% sevoflurane. Average CBF increased significantly (+35%), when the mean arterial pressure was increased by the angiotensin II infusion. All the regional CBFs except at frontal cortex increased significantly (+ about 30%) in response to the increase in the mean arterial pressure. The increase in occipital CBF was greatest (+52%). We conclude that CBF during sevoflurane anesthesia up to 2.0% might become dependent on the cerebral perfusion pressure, indicating the compromised autoregulation of CBF in the rhesus monkey.

Anesthesia, Inhalation↗

PubMed1997

[The effect of sevoflurane on regional cerebral metabolism and cerebral blood flow in rhesus monkeys].

The effects of sevoflurane on cerebral metabolism and hemodynamics were studied in rhesus monkeys. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMR O2) as well as their regional changes were measured by means of positron emission tomography technique. After the measurement of regional CBFs and CMR O2s at 1.5% sevoflurane as control, the measurement was repeated at 3.0% sevoflurane and at the same sevoflurane concentration with the infusion of angiotensin II to restore mean arterial pressure. Regional CBFs and CMR O2s were compared among three different conditions. At 3.0% sevoflurane, regional CBFs increased significantly in response to the increase in the mean arterial pressure, suggesting the inhibition of autoregulation of CBF. However, regional CBF/CMR O2 ratio was not significantly different among the cerebral regions with each condition. It could be concluded that CBF during sevoflurane anesthesia up to 3.0% might become dependent on the cerebral perfusion pressure and the changes in regional CBFs varied among the regions. On the other hand, the ratio of oxygen consumption and delivery was well maintained throughout the brain regions.

Anesthesia, Inhalation↗

PubMed1997

Functional activation of cerebral blood flow abolished by scopolamine is reversed by cognitive enhancers associated with cholinesterase inhibition: a positron emission tomography study in unanesthetized monkeys.

The effects of somatosensory stimulation on the regional cerebral blood flow (rCBF) response were studied in unanesthetized monkeys before and after treatment with scopolamine and three cognitive enhancers (physostigmine, E2020 and tacrine) that inhibit cholinesterase, using 15O-labeled water and high-resolution positron emission tomography. Under control conditions, somatosensory stimulation induced a significant increase in the rCBF response in the contralateral somatosensory cortex of monkey brain. Intravenous administration of scopolamine (50 microg/kg) resulted in abolishment of the rCBF response to stimulation. The rCBF response abolished by pretreatment with scopolamine was recovered by administration of physostigmine (1 or 10 microg/kg), E2020 (10 or 100 microg/kg) or tacrine (100 or 1000 microg/kg), in a dose-dependent manner. The effect of E2020 (100 microg/kg) on the rCBF response lasted for >4 hr, whereas the effects of physostigmine and tacrine were of shorter duration. These findings suggest that these compounds reversed the scopolamine-abolished rCBF response to somatosensory stimulation via enhancement of cholinergic neurotransmission, which was mainly induced by cholinesterase inhibition.

Animals↗

PubMed1996

Effects of binge pattern cocaine administration on dopamine D1 and D2 receptors in the rat brain: an in vivo study using positron emission tomography.

The aim of the present study was to determine the effect of "binge" pattern cocaine administration on dopamine D1 and D2 receptors in the rat brain. Male Sprague Dawley rats were injected three times at 1 hr intervals with saline or cocaine (15 mg/kg) each day for 2, 7, or 14 d. The in vivo binding of [11C]SCH23390 (dopamine D1 receptor antagonist) and [11C]N-methylspiperone (NMSP; dopamine D2 receptor antagonist) in the striatal region was measured by a high-resolution positron emission tomography at 1 and 3.5 hr, respectively, after the last cocaine or saline injection. Acute (2 d) binge cocaine administration did not change the in vivo binding potential of [11C]SCH23390 or the binding of [11C]NMSP in the striatum. After 7 d of binge cocaine administration, a significant decrease in the binding potential of [11C]SCH23390 was observed, whereas no change in the binding of [11C]NMSP was found. After 14 d of binge cocaine administration, the in vivo binding was significantly reduced for both [11C]SCH23390 and [11C]NMSP. Separate saturation experiments indicated that the observed alterations of in vivo binding were attributable mainly to apparent alterations in the affinity and not the number of binding sites. These results suggest that both dopamine D1 and D2 receptors may have altered physiologically available binding sites after binge pattern cocaine administration.

Animals↗

PubMed1996

Deletion of peripheral V beta 14+ T cells by Mtv-2-encoded viral superantigen preceded by blastogenesis and DNA synthesis but not by specific expansion.

Exogenous and endogenous mouse mammary tumor viruses encode superantigen (SAG) in the 3' long terminal repeat. We investigated the immune response of lymph node cells to the viral SAG encoded by endogenous Mtv-2 (vSAG-2) by i.v. injecting splenocytes from Mtv-2+ mice into Mtv-2- congenic counterparts. vSAG-2 stimulation induced blastogenesis and DNA synthesis but not subsequent specific expansion of V beta 14+CD4+ or CD8+ T lymphocytes. Instead, immediate deletion of these T cells progressed after vSAG-2 stimulation, and it was more prominent in both rapidity and degree in CD4+ than CD8+ population and in I-E+ than I-E- mice. vSAG-7 stimulation caused specific expansion of V beta 6+ T cells prior to their deletion as reported. vSAG-7 but not vSAG-2 induced IL-2R expression in the specific T cells. Moreover, the percentage of 5-bromo-2'-deoxyuridine-incorporated cells was about twofold higher in Vbeta6+ T cells stimulated with vSAG-7 than in V beta 14+ T cells stimulated with vSAG-2. The results suggest that vSAG-2 may be a weak mitogen against specific T cells and that T cells weakly activated by SAG may die without preceding expansion. In addition, proliferation of lymphocytes, especially B cells, and enhancement of the expression of IL-2, IL-4, and IFN-gamma messenger RNA were observed. Thus, V beta 14+ T cells stimulated with vSAG-2 were activated to produce cytokines and depleted quickly.

Animals↗

PubMed1996

Compartment analysis of cerebral glucose metabolism and in vitro glucose-metabolizing enzyme activities in the rat brain.

To clarify the relationship between cerebral glucose metabolic rate constants and glucose-metabolizing enzyme activities in the cerebral cortex, we evaluated the cerebral metabolic rate of glucose (CMRGlu), metabolic rate constants of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) and related enzyme activities in the frontal cortex under normal and glucose metabolism-suppressed conditions. Applying a three-compartment four-parameter model, metabolic rate constants were obtained by dynamic positron emission tomography with FDG, and CMRGlu was calculated based on these rate constants. The glycolytic enzyme activities were determined by in vitro biochemical assay. Three days after ibotenic acid injection into the basal forebrain, CMRGlu was decreased in the ibotenic acid-treated frontal cortex as well as k3* (phosphorylation), while K1* (plasma to brain) showed no remarkable change. No significant reductions of the enzyme activities except for hexokinase activity were found in the frontal cortex. Regression analysis showed a significant positive correlation between k3* and the hexokinase activity. These results suggested that k3* in the compartment analysis reflects hexokinase activity.

Analysis of Variance↗

PubMed1996

Inflammatory cytokines in the herniated disc of the lumbar spine.

STUDY DESIGN: Tissues in the area of herniated lumbar discs were examined for inflammatory cytokines to elucidate the causes of sciatic pain in lumbar disc herniation. OBJECTIVES: To determine the role of inflammatory cytokines in the stimulation of sciatic pain in lumbar disc herniation. SUMMARY OF BACKGROUND DATA: It is postulated that in addition to mechanical compression of lumbar nerve roots and sensory root ganglia by herniated discs, there is a chemical stimulus to the production of sciatic leg pain. The exact mechanisms of chemical stimulation are not clearly defined. METHODS: During surgery, cases of lumbar disc herniation in 77 patients were classified macroscopically into protrusion, extrusion, and sequestration types. Tissues adjacent to nerve roots at the herniation were excised and analyzed biochemically and immunohistochemically for the presence of inflammatory cytokines and for the production of these cytokines and prostaglandin E2 in vitro. RESULTS: The homogenates of samples were analyzed for interleukin-1 alpha, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and granulocyte-macrophage colony stimulating factor, which were detectable. Most of the cytokine-producing cells were histiocytes, fibroblasts, or endothelial cells in extrusion and sequestration types, and chondrocytes in protrusion type. The secretion of these cytokines and prostaglandin E2 was decreased by the addition of betamethasone. The prostaglandin E2 production was dramatically enhanced by additional interleukin-1 alpha, but decreased by the addition of tumor necrosis factor-alpha. CONCLUSION: The results demonstrate that at the site of lumbar disc herniation, inflammatory cytokines such as interleukin-1 alpha are produced, which increases prostaglandin E2 production. Further studies are required to elucidate the role of inflammatory cytokines in causing sciatic pain.

Dinoprostone↗

PubMed1996

[A case of hemolysis induced by lansoprazole].

Hemolytic anemia and possible aplastic crisis with symptoms including jaundice, general fatigue and dark urine developed in a man being treated only by lansoprazole. Five days later, he was treated with antibiotics. The next day, he was admitted to our hospital because of jaundice. On admission, the hemoglobin was 14.0 g/dl, reticulocyte count 8/1000, platelets 79 x 10(9)/l and total bilirubin 12.4 mg/dl (indirect bilirubin 9.5 mg/dl). The above medications were discontinued. The direct Coombs antiglobulin test was positive. Examination of the complement revealed a C3 fiter at the upper limit of normal and an increased C4 and CH50. Three days after admission, he had a severe anemia. The hemoglobin was 3.3 g/DL. We thought it possible that aplastic crisis had followed the hemolytic anemia induced by lansoprazole. He was treated with blood transfusions and corticosteroids. He recovered from anemia within three weeks. Exhaustive studies to identify the cause of the hemolytic anemia were undertaken with negative results. We detected IgG antibody to lansoprazole. We believe that the hemolytic anemia was induced by lansoprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1995

Real-time PET analysis of metastatic tumor cell trafficking in vivo and its relation to adhesion properties.

Although a number of studies have indicated that highly metastatic cells tend to adhere more to target endothelium in vitro than low or non-metastatic cells, direct evidence about the correlation between cellular adhesiveness and organ disposition of the cells has not been obtained. Using positron emission tomography (PET), we have developed a novel technique that enables the non-invasive detection of the real-time tumor cell trafficking. The present study shows the correlation between trafficking of murine large cell lymphoma RAW117 and the adhesion properties of the cells in vitro. Cells accumulated in the liver time-dependently, and accumulation of RAW117-H10, liver metastatic subline cells, was more intense than that of RAW117-P, the parental cells, indicating that the metastatic potential is correlated with the in vivo accumulation of the cells in the target tissue. To examine whether the adhesion properties of the cell membrane determine the cell trafficking, we performed PET analysis after altering the adhesion properties on the cell membrane by means of cellular protein kinase C modulation, since the modulation of this enzyme is known to alter the surface adhesion molecules, i.e., those of the integrin superfamily. The treatment of RAW117-P with 12-O-tetradecanoylphorbol 13-acetate, which caused augmentation of adhesion to hepatic sinusoidal microvessel endothelial cells (HSE) in vitro, enhanced the hepatic accumulation of the cells in vivo. On the contrary, treatment of RAW117-H10 with the protein kinase C inhibitor H-7, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, which reduced the adhesion activity of the cells to HSE, suppressed their accumulation in the liver, although the suppression was observed only during the first 30 min after administration of the cells. These data suggest that the adhesion properties of metastatic lymphoma cells are critical for the accumulation of these cells in the target tissue.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1995

Role of newly synthesized MHC class II molecules in antigen-specific antigen presentation by B cells.

Using a B lymphoma, A20-HL, bearing IgM receptors for TNP, we have shown that presentation of an Ag taken up through the receptors is highly sensitive, whereas that of an Ag taken up nonspecifically is resistant to inhibition of protein synthesis or protein transport from the endoplasmic reticulum. To analyze the difference, we have examined the effect of protein synthesis inhibition on A20-HL cells in terms of internalization and fragmentation of a specific Ag, TNP-OVA, and distribution of MHC class II molecules. Inhibition of protein synthesis in A20-HL cells with emetine, an irreversible protein synthesis inhibitor, did not decrease the surface expression of anti-TNP receptors, or the kinetics of internalization of 125I-TNP-OVA. To detect fragmentation of TNP-OVA, A20-HL cells were incubated at 37 degrees C in the presence of 125I-TNP-OVA, and the cell lysate was analyzed in SDS-PAGE. The number of detectable fragments increased with the incubation period, and inhibition of protein synthesis did not change the electrophoretic pattern. Expression of MHC class II molecules on the surface of A20-HL cells was not affected by inhibition of protein synthesis. However, intracellular MHC class II molecules markedly decreased in amount in the emetine-treated cells. Thus, presentation of an Ag taken up through Ag receptors seems to be dependent on intracellular MHC class II molecules, whereas that of an Ag taken up nonspecifically does not, suggesting that the Ag-processing pathway in B cells for a specific Ag is different from that for a nonspecific one, at least partly.

Antigen Presentation↗

PubMed1995

Differential sensitivity to antigenic competition in antigen-specific and -nonspecific antigen presentation by B cells.

We have previously shown that a specific Ag presentation by B cells is different from a nonspecific one in the sensitivity to protein synthesis inhibition. In the present study we have compared the sensitivity of these Ag presentations to antigenic competition. A20-HL cells expressing TNP-specific IgM were pulsed with anti-mouse IgM goat IgG (aMGG) or trinitrophenylated goat IgG (TNP-NGG) as an Ag internalized through Ag receptor or NGG as an Ag internalized by fluid-phase pinocytosis. The pulsed cells induced IL-2 production by NGG-specific cloned T cells. The presence of dog IgG during pulsing A20-HL cells severely inhibited the presentation of NGG but not of aMGG or TNP-NGG. The presence did not decrease the internalization of 125I-NGG into A20-HL cells, suggesting that the inhibition was localized into the complex formation of antigenic peptides with MHC class II molecules. Thus, a specific Ag presentation by A20-HL cells is different from a nonspecific one in its sensitivity to antigenic competition.

Animals↗

PubMed1995

Concanamycin B inhibits the expression of newly-synthesized MHC class II molecules on the cell surface.

We screened natural chemical compounds which inhibit the expression of newly-synthesized MHC class II molecules on the cell surface. IFN-gamma stimulates Colo 205 adenocarcinoma cells to induce the expression of MHC class I, MHC class II, and ICAM-1 molecules on the cell surface. We show here that concanamycin B inhibits the expression of MHC class II molecules on Colo 205 cells, whereas it does not affect the expression of MHC class I and ICAM-1 molecules. Concanamycin B also abrogates the enhancement of the MHC class II expression by IL-4 on mouse lymphocytes. Furthermore, concanamycin B suppresses the antigen presentation by MHC class II molecules.

Animals↗

PubMed1994

Brain activation study by use of positron emission tomography in unanesthetized monkeys.

A system for the measurement of brain activity in conscious monkeys by positron emission tomography (PET) was established in the present study. The signal/noise ratio was maximal around 40 s for data acquisition in the PET scan with 15O-labeled water. When the monkey was stimulated by vibration and subtraction images of the data sets from regional cerebral blood flow (rCBF) changes in paired stimulation and control were superimposed on magnetic resonance images obtained from the same specimens, a somatotopic map corresponding to the sites stimulated was clearly demonstrated. Visual stimulation with a photic stimulator activated the corresponding regions of the primary visual cortex. Comparison of the activated sites and extents under the conscious state with those under anesthesia assured that the study is controllable; there was little unpredictable activation due to unlimited subject movement or to psychological effects.

Animals↗