Biomedical subjects

K Tominaga

Publications and source records attributed to K Tominaga.

At least 19 recordsLinked to original sources

PubMed1992

Ischemia-induced impairment of 2-deoxyglucose uptake and CA1 field potentials in rat hippocampal slices: protection by 5-HT1A receptor agonists and 5-HT2 receptor antagonists.

Various in vitro models have been developed to study ischemia and/or hypoxia. In the present experiment, we examined whether hypoxia/hypoglycemia (ischemia) in rat hippocampal slices reduced the 2-deoxyglucose (2-DG) uptake and CA1 field potentials evoked by stimulation of Schaffer collaterals. Autoradiograms revealed that ischemia for 15 or 20 min reduced 2-DG uptake in the stratum radiatum of the CA1 and the dentate gyrus. Similarly, the CA1 field potentials of slices exposed to ischemia for 15 and 20 min decreased by about 70 and 90% after a 6-h washout. In the second experiment, we evaluated the neuroprotective effect of the 5-HT1A receptor agonists 8-OH-DPAT and buspirone, and the 5-HT2 receptor antagonists cyproheptadine, mianserin and ketanserin on deficits of 2-DG uptake and Schaffer-CA1 field potentials induced by ischemia. The 5-HT1A receptor agonists and 5-HT2 receptor antagonists exhibited significant neuroprotective actions against ischemia-induced deficits. Therefore, impairments of 2-DG uptake and CA1 field potentials induced by ischemia may be good markers of ischemia-induced functional deficits. The attenuating action of 5-HT1A receptor agonists and 5-HT2 receptor antagonists were assessed using this model of ischemia.

Animals↗

PubMed1992

Effect of substance P on circadian rhythms of firing activity and the 2-deoxyglucose uptake in the rat suprachiasmatic nucleus in vitro.

The suprachiasmatic nuclei (SCN) have been identified as a pacemaker for many circadian rhythms in mammals. Although substance P (SP) fibers from retina are found to terminate the SCN, the physiological role of this peptide is uncertain. The 2-deoxyglucose (2-DG) uptake and firing activity in the SCN show a robust circadian change. SP causes an increase in 2-DG uptake by SCN during the subjective night but not during subjective day. SP-induced increase in 2-DG uptake is blocked by co-treatment with the SP receptor antagonist, spantide. Treatment with SP produces phase shifts of circadian rhythm in spontaneous neural activity in SCN neurons with a phase-response curve that is similar to the effect of light pulses to animals under constant darkness. SP-induced phase change is also blocked by pretreatment with spantide. SP-induced increase in 2-DG uptake and phase changes in firing activity occur only during subjective night, at circadian times when photic phase shifting of activity occurs. The present results suggest that SP may be an important transmitter for conveying environmental light-dark information from retina to the SCN.

Action Potentials↗

PubMed1992

Neuroprotective effect of protein kinase C inhibitors on oxygen/glucose free-induced decreases in 2-deoxyglucose uptake and CA1 field potentials in rat hippocampal slices.

Staurosporine, a protein kinase C inhibitor, was found to produce a neuroprotective effect against an ischemic insult in both gerbils and rats in vivo. We have demonstrated that rat hippocampal slices exposed to oxygen/glucose-free medium showed decreases in 2-deoxyglucose (2-DG) uptake and CA1 field potentials elicited by the stimulation of Schaffer collaterals. Therefore we examined the effect of protein kinase C inhibitors on oxygen/glucose free-induced impairments of 2-DG uptake and CA1 field potentials. Pretreatment with staurosporine, K252a and H-7 attenuated decreases in 2-DG uptake and CA1 field potentials. Treatment with phorbol ester, a protein kinase C activator, for a long period (90 min) was found to induce a down-regulation of protein kinase C activity. Therefore we examined the effect of pretreatment with phorbol ester for 90 min on oxygen/glucose free-induced decreases in 2-DG uptake and CA1 field potentials. These decrements were not attenuated by 5-min treatment with phorbol ester but were attenuated by 90-min treatment. The present results suggest that the treatment which decreases protein kinase C activity shows a neuroprotective action against oxygen/glucose free-induced deficits of metabolic and synaptic activity in hippocampal slices.

Alkaloids↗

PubMed1992

Assessment of the role of adrenoceptor function in ischemia-induced impairment of 2-deoxyglucose uptake and CA1 field potential in rat hippocampal slices.

The release of catecholamines, dopamine and noradrenaline has been suggested to play a role in mediating ischemic damage in susceptible brain regions, the hippocampus and striatum. We now provide evidence that suggests a role for adrenoceptors in the deficit of 2-deoxyglucose uptake and CA1 field potential induced in hippocampal slices by hypoxia/hypoglycemia (ischemia). Treatment with alpha 1- or beta-adrenoceptor agonists or cAMP potentiated an ischemia-induced decline of both 2-deoxyglucose uptake and CA1 field potential in hippocampal slices, whereas alpha 1- or beta-adrenoceptor antagonists, or alpha 2-adrenoceptor agonists produced a remarkable neuroprotective action against these deficits. The results indicate that stimulation of adrenoceptors may play a detrimental role in the development of ischemic damage, and suggest a neuroprotective action for adrenoceptor antagonists, which may lessen the functional deficits induced by ischemia.

Action Potentials↗

PubMed1992

Effect of muscarinic cholinergic drugs on ischemia-induced decreases in glucose uptake and CA1 field potentials in rat hippocampus slices.

To clarify the role of muscarinic acetylcholine receptors in the hypoxia/hypoglycemia (ischemia)-induced functional deficit in hippocampal neurons, we examined the effect of cholinergic drugs on ischemia-induced impairments of glucose uptake and CA1 field potentials in hippocampus slices. Muscarinic receptors were subdivided into M1 (high affinity for pirenzepine) and M2 (low affinity for pirenzepine) subtypes. The M1 receptor subtype is coupled to an increase in phosphoinositide hydrolysis and the M2 receptor subtype is associated with inhibition of adenylate cyclase. The greater potency of carbachol in stimulating phosphoinositide hydrolysis resulted in exacerbated ischemia-induced deficits. Treatment with the muscarinic receptor antagonists scopolamine and pirenzepine (M1 receptor-selective antagonist) had a strong dose-dependent protective effect against ischemia-induced deficits. Oxotremorine and McN-A-343, weak stimulators of phosphoinositide hydrolysis and strong inhibitors of adenylate cyclase, had a weak neuroprotective action against ischemia-induced deficits. These results suggest that stimulation of M1 muscarinic receptors coupled with an increase in phosphoinositide hydrolysis may play a facilitatory role in ischemia-induced deficits. Stimulation of M2 muscarinic receptors may play an inhibitory role in ischemia-induced neuronal deficits.

Acetylcholine↗

PubMed1992

A neuroprotective effect of adenosine A1-receptor agonists on ischemia-induced decrease in 2-deoxyglucose uptake in rat hippocampal slices.

The effects of adenosine (A) receptor agonists on ischemia-induced impairment of 2-deoxyglucose (2-DG) uptake by rat hippocampal slices was evaluated. Hippocampal slices were exposed to 20-min hypoxia + hypoglycemia (ischemia) and then returned to oxygenated and glucose-containing Krebs-Ringer solution for 6 h. Ischemia reduced 2-DG uptake in the hippocampal slices. The ischemia-induced reduction in 2-DG uptake was attenuated by pretreatment with A1 receptor agonists but not with A2 receptor agonists. 8-Phenyltheophylline, an A1 receptor antagonist, exacerbated the ischemia-induced decrease. The A1 receptor agonist-induced neuroprotective effect was blocked by co-treatment with 8-phenyltheophylline. The present study suggests that the A1 receptor-mediated function has a protective role in ischemia-induced decreases in glucose metabolism in hippocampal slices.

Adenosine↗

PubMed1992

Histogenesis of diffuse small cleaved cell lymphoma. An immunohistochemical and molecular genetic (bcl-2 gene) study with comparison to follicular small cleaved cell lymphoma and mantle zone lymphoma.

Immunohistochemical and molecular genetic (bcl-2 gene) studies were performed on specimens from 24 patients with follicular small cleaved cell lymphoma (FSCCL), 24 patients with diffuse small cleaved cell lymphoma (DSCCL) and 4 patients with mantle zone lymphoma (MZL) to determine the cellular origin of the disease and whether or not DSCCL represents the diffuse counterpart of FSCCL. Two patients with FSCCL, 22 patients with DSCCL, and all of the patients with MZL had a phenotype of mantle zone (MZ) B-lymphocytes (SIgD+, Leu-1+, Leu-8+, positive alkaline phosphatase [ALPase+], and negative common acute lymphoblastic leukemia antigen [CALLA-]), and all the tested patients (2 patients with FSCCL, 13 patients with DSCCL, and 4 patients with MZL) had germlines of bcl-2 gene. Fourteen patients with FSCCL and 1 patient with DSCCL had a phenotype of follicular center cells (FCC) (CALLA+, SIgD-, Leu-1-, Leu-8- and negative ALPase), and 11 patients with FSCCL had bcl-2 gene rearrangements. These results indicate that FSCCL are almost always derived from FCC, whereas some FSCCL, most DSCCL, and all MZL are derived from MZ B-lymphocytes, and these lymphomas should be included in the same category as MZ B-lymphocyte-derived lymphomas. Histologically diagnosed DSCCL often may represent a diffuse counterpart of MZ B-lymphocyte-derived lymphoma. MZ B-lymphocyte-derived lymphomas histologically show a follicular (nodular), a follicular MZ, or a diffuse growth pattern and clinically show a high incidence of peripheral blood (PB) involvement or bone marrow (BM) involvement.

Adult↗

PubMed1992

An in vitro circadian rhythm of protein synthesis in the rat suprachiasmatic nucleus under tissue culture conditions.

Because inhibitors of protein synthesis produce changes in the circadian rhythm of wheel-running activity in rodents, we examined the circadian changes of in vitro protein synthesis by the rat suprachiasmatic nucleus (SCN). We demonstrated a robust circadian rhythm of [14C]leucine incorporation as well as [3H]2-deoxyglucose (2DG) uptake by the SCN. The peak time of 2DG uptake was around circadian time 6-9 h (CT6-CT9). In contrast to 2DG uptake, the maximum rate of leucine incorporation occurred around CT22-CT0. Thus, the leucine incorporation rate preceded 2DG uptake by 6-9 h. Leucine incorporation was inhibited by protein synthesis inhibitors, but not by tetrodotoxin. Since a robust circadian rhythm of leucine incorporation by the SCN was detected in vitro by using our method, this procedure may be useful to study the circadian clock function of the SCN.

Animals↗

PubMed1992

Effects of inhibitory and excitatory drugs on the metabolic rhythm of the hamster suprachiasmatic nucleus in vitro.

In order to elucidate the role of excitatory and inhibitory transmitters within the suprachiasmatic nucleus (SCN) in the circadian change of 2-deoxyglucose (2-DG) uptake in this nucleus, the effects of 8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT), muscimol, flurazepam, pentobarbital and glutamate on uptake of 2-DG by hamster SCN were examined in hypothalamic slice preparations. 2-DG uptake in the SCN was high during the subjective day and low during the subjective night. The high uptake of 2-DG in the SCN during the daytime was inhibited by the superfusion of 8-OH-DPAT, muscimol, flurazepam and pentobarbital in a dose-dependent manner, but the low uptake of 2-DG during the night was unaffected. The low uptake during the night was significantly increased by treatment with glutamate, whereas 2-DG uptake during the day was unaffected. In contrast to the above results, 20 mM KCl and 1 microM tetrodotoxin increased and decreased 2-DG uptake during both the day and night, respectively. The present results strongly suggest that agonists of 5-HT1A receptors and GABAA-benzodiazepine-barbiturate complex receptors regulate the function of the SCN through their inhibitory action on 2-DG uptake during the day, and that glutamate also regulates SCN function through it stimulatory action on 2-DG uptake during the night.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Upstream region of a genomic gene for human mitochondrial transcription factor 1.

A genomic gene for human mitochondrial transcription factor 1 was cloned from a human genomic library and its 5' flanking region was sequenced. No typical TATA and three consensus sequences for potential Sp1 binding site were found in its 5' flanking region of 2 kilobase pairs. There were, at least, four common sequences among some nuclear genes for mitochondrial-related proteins.

Amino Acid Sequence↗

PubMed1992

Phase-resetting effect of 8-OH-DPAT, a serotonin1A receptor agonist, on the circadian rhythm of firing rate in the rat suprachiasmatic nuclei in vitro.

The 5-HTergic neurons in the mesencephalic raphe nuclei provide a robust projection to the hypothalamic suprachiasmatic nucleus (SCN), the site of a putative neuronal circadian pacemaker. Although it has been suggested that 5-HT neurons may play a role in the circadian timing system, this role has not yet been specified. Prosser et al. (Brain Res., 534 (1990) 336-339) reported that 1 h treatments with quipazine induce robust phase shifts in vitro, and that this effect depends upon the circadian time of treatment. However, quipazine is a non-specific 5-HT agonist. Besides, it is reported that the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetraline hydrobromide (8-OH-DPAT) affected a circadian rhythm of hamster wheel-running activity. In the present study we investigated whether the 5-HT1A agonist 8-OH-DPAT can reset the phase of the SCN clock when it is isolated in vitro. The present results show that 1 h treatments with 8-OH-DPAT induce robust phase advances in vitro when it was administered during the subjective day. This result suggests that 5HT1A receptor functioning may play a role in modulating the phase of SCN clock, especially during the subjective day.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Excitatory effect of N-methyl-D-aspartate and kainate receptor on the 2-deoxyglucose uptake in the rat suprachiasmatic nucleus in vitro.

The suprachiasmatic nuclei (SCN) have been identified as a pacemaker for many circadian rhythms in mammals. The previous findings indicate the excitatory amino acid (EAA) receptors play an important role in the transmission of light information from the retina to the circadian clocks. The 2-deoxyglucose (2DG) uptake shows a robust circadian change; high uptake during subjective day and low uptake subjective night. To determine whether EAA agonists regulate 2DG uptake in the SCN, we have measured 2DG uptake in the rat SCN in vitro. We report that, during the subjective night, glutamate, N-methyl-D-aspartate (NMDA) and kainic acid (KA) cause an increase in 2DG uptake and that NMDA- or KA-induced increase of 2DG uptake is blocked by co-treatments with competitive and non-competitive NMDA or KA receptor antagonists. EAA receptor agonist-induced increase in 2DG uptake occurs only during subjective night, at circadian times when photic phase shifting of activity occurs. Taken together, those data suggest that EAA may be an important transmitter of light information from retina to the SCN.

Animals↗

PubMed1992

Effects of 5-HT1A receptor agonists on the circadian rhythm of wheel-running activity in hamsters.

The effects of 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone on wheel-running activity in hamsters were investigated in comparison with those of GABAA receptor agonist muscimol and benzodiazepine triazolam. Intraperitoneal administration of 8-OH-DPAT, buspirone, ipsapirone, muscimol and triazolam at circadian time (CT) 8 (CT 12; onset of activity) induced a significant phase advance of wheel-running activity under constant light conditions. However, administration of these drugs at other CT points did not induce phase changes. The administration of trifluoromethylphenylpiperazine (TFMPP), a 5-HT1B receptor agonist, at CT8 produced a small phase advance. The phase advance induced by 8-OH-DPAT was blocked by pretreatment with (-)-pindolol, a 5-HT1A receptor antagonist. In addition, 8-OH-DPAT, buspirone and SM3997 accelerated the rate of re-entrainment to an 8-h phase advance in the light-dark cycle. These observations suggest that 5-HT1A receptors in the brain participate in the regulation of the circadian rhythm of wheel-running activity in hamsters.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Establishment and characterization of a human T-cell lymphoblastic lymphoma cell line (HT-1) carrying an inversion of chromosome 14.

A new human lymphoblastic lymphoma cell line was established (designated HT-1) from the pleural fluid lymphoma cells of a patient with lymphoblastic lymphoma of T-cell type. The HT-1 cells expressed CD1, CD2, CD3, CD4, CD5, CD7, CD8, CD57, and terminal deoxynucleotidyl transferase (TdT) but lacked B-cell-associated antigens and myeloid-associated antigens. In addition, HT-1 cells had rearranged T-cell receptor (TCR) beta-chain gene and gamma-chain gene but retained germlines of immunoglobulin (Ig) heavy chain gene. These findings indicate that HT-1 cell line represents a common thymocyte in the T-cell lineage. Cytogenetic studies revealed that HT-1 cells carry an inversion (inv) of the long arm of chromosome 14. This cell line is the second T-cell line carrying inv(14) chromosome and may be useful for the molecular investigation of the cytogenetic break points of inv(14).

Adult↗

PubMed1992

Characterization and comparison of two newly established Epstein-Barr virus (EBV)-negative and EBV-positive Burkitt's lymphoma cell lines. EBV-negative cell line with a low level of expression of ICAM-1 molecule and EBV-positive cell line with a high level of expression of ICAM-1 molecule.

Two human Burkitt's lymphoma cell lines (HBL-4 and HBL-5) were established individually from two patients with small noncleaved cell lymphoma (Burkitt's type). The HBL-4 cell line is Epstein-Barr virus (EBV)-negative, and the HBL-5 cell line is EBV-positive. Cytogenetically, both cell lines had the same chromosomal translocation, t(8;14)(q24;q32) as those observed in the primary malignant cells from individual patients. Morphologic, immunophenotypic, cytogenetic, and molecular studies confirmed that both cell lines were derived from the primary lymphoma cells in vivo. HBL-4 cells lacked CD23(H107), CD11a(LFA-1), and latent membrane protein (LMP) but expressed CD54(ICAM-1) at low levels, whereas HBL-5 cells showed the high level of expression of CD54 and faint expression of LMP but lacked CD11a. In addition, the EBV-positive lymphoblastoid cell line (LCL) expressed CD11a, CD23, CD54, and LMP at high levels. Therefore, an HBL-5 phenotype with expression of CD54 and LMP tends toward an LCL phenotype, and the augmentation of CD54 on the HBL-5 cells in comparison with primary lymphoma cells is likely to be upregulated by LMP, probably resulting from the EBV infection. There was little difference in the BrdUrd uptake in vivo and in vitro, doubling time, tumorigenicity, and dynamics of tumor growth in athymic nude mice between both cell lines. These findings indicate that the potentiality of cell growth and tumorigenicity of these two cell lines are unlikely to be related with EBV.

Adult↗

PubMed1992

Phase II study of cisplatin as a 5-day continuous infusion with vindesine plus recombinant human granulocyte-colony-stimulating factor in the treatment of advanced non-small-cell lung cancer.

A total of 36 patients with advanced non-small-cell lung cancer (NSCLC) were treated with a combination of 5-day continuous i.v. infusion of cisplatin (25 mg/m2 daily), bolus infusion of vindesine (3 mg/m2) on days 1 and 8, and s.c. injection of recombinant human granulocyte-colony-stimulating factor (2 micrograms/kg daily) on days 6-21. Treatment was repeated every 3-4 weeks. Responding patients with stage IIIA or IIIB disease received chest radiation therapy (50-60 Gy) after this treatment. One complete response and 23 partial responses were observed, for an overall response rate of 66.7% (24/36; 95% confidence limits, 51.3%-82.1%). The median duration of response was 5.7 months and the median overall survival was 10.1 months. WHO grade 3 or 4 leukopenia and neutropenia occurred in 22 (61%) and 27 (75%) patients, respectively, but the mean duration of leukopenia (< 2,000/mm3) and neutropenia (< 1,000/mm3) was 3.4 and 3.5 days, respectively, and there was no instance of life-threatening infection. Thrombocytopenia and anemia of grade 3 or 4 occurred in 28% and 36% of our subjects, respectively. Grade 2 nausea and vomiting occurred in 47% of the patients. Elevated serum creatinine levels (> 1.5 mg/dl) were observed in 3 (8%) of the 36 patients. One patient died of acute renal failure induced by hemorrhage of a gastric ulcer. This regimen is effective in the treatment of NSCLC and further studies of this combination are warranted.

Actuarial Analysis↗

PubMed1992

The use of granulocyte colony-stimulating factor to shorten the interval between cycles of mitomycin C, vindesine, and cisplatin chemotherapy in non-small-cell lung cancer.

We investigated the possibility of shortening the interval between courses of the commonly prescribed 28-day MVP (mitomycin C, vindesine, and cisplatin) regimen in patients with non-small-cell lung cancer (NSCLC). We conducted a nonrandomized phase II study using recombinant human granulocyte colony-stimulating factor (G-CSF, Chugai) to explore the possibility of shortening the cycle length to 21 days and compared the results with those obtained in historical controls who had received the standard 28-day regimen. A total of 40 patients, 37 of whom were evaluable, were entered in the 21-day treatment group of the trial and were compared with 38 historical controls who had received standard 28-day cycles of MVP at our institution. Patients in the 21-day group received mitomycin C at 8 mg/m2 on day 1, vindesine at 3 mg/m2 on days 1 and 8, and cisplatin at 80 mg/m2 on day 1, with the schedule being repeated every 21 days. Controls had received the same regimen, albeit at 28-day intervals. G-CSF was given s.c. to the patients in the 21-day group at a daily dose of 2 micrograms/kg from day 2 to day 21 of every MVP cycle. The administration of G-CSF to these patients accelerated neutrophil recovery as compared with that observed in the historical controls. Significant differences were found between the two groups in terms of mean neutrophil nadirs (2666/microliters in the first cycle and 1369/microliters in the second for the G-CSF group vs 416/microliters in the first cycle and 685/microliters in the second cycle for the control group; P < 0.0001) and the mean duration of neutropenia (< or = 1000/microliters; 1.0 day in the first cycle and 1.7 days in the second for the G-CSF group vs 8.0 days in the first cycle and 6.9 days in the second for the control group; P < 0.0001). This enabled 32 (86%) of 37 patients in the G-CSF group to complete > or = 2 cycles on schedule. In 10 patients, the bone marrow aspirates taken after G-CSF administration showed increases in band neutrophil and myelocyte percentages. In conclusion, MVP treatment of patients with NSCLC at 21-day intervals is possible with the support of G-CSF.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

Rapid, sensitive, specific, and quantitative detection of human T-cell leukemia virus type 1 sequence in peripheral blood mononuclear cells by an improved polymerase chain reaction method with nested primers.

Improving on the nested double polymerase chain reaction (PCR) described previously, we have developed a new two-step PCR (TS-PCR) method for detecting more specifically the human T-cell leukemia virus type 1 (HTLV-1) proviral sequences in peripheral blood mononuclear cells (PBMC). In our TS-PCR method, the point of modification is to use optimal concentrations of primers in the first amplification step in the range of 0.01-0.025 microM. This increases sensitivity and specificity enough to detect from 1 to 10(5) copies of template DNA without radioisotopes. This method is rapid because of completion in 1 day and is also applicable for quantitative detection of clinical specimens. The data show that the quantitative detection of HTLV-1 proviral sequences by this method correlates with the anti-HTLV-1 antibody titers from serologic analysis of seropositive healthy carriers. Moreover, the TS-PCR method using each specific primer was also attempted for successful detection of other viral genomes; therefore, the principle of this method is widely suitable for routine detection of genomes in the basic and clinical microbiological fields.

Base Sequence↗