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Biomedical subjects

M Okada

Publications and source records attributed to M Okada.

At least 595 records · Page 33Linked to original sources
PubMed1997

The anti-human tumor effect and generation of human cytotoxic T cells in SCID mice given human peripheral blood lymphocytes by the in vivo transfer of the Interleukin-6 gene using adenovirus vector.

Interleukin-6 (IL-6) was found to function as a late-acting killer helper factor in the differentiation of CTLs. In the model of tumor-bearing mice, the systemic administration of recombinant IL-6 was found to mediate the antitumor effect on the immunogenic murine tumors via the in vivo induction of murine CTLs but not on the poorly immunogenic murine tumors in our previous study. However, an in vivo experimental model capable of analyzing the anti-human tumor effect via the in vivo induction of human CTLs has not yet been established. Therefore, in the present study, severe combined immunodeficient mice were given human peripheral blood lymphocytes (SCID-PBL/hu), and thereafter human tumor cells were administered i.p. into these SCID-PBL/hu mice as a model of human patients with cancer. When these SCID-PBL/hu mice bearing allogeneic human CESS B blastoid tumor cells were treated in vivo with recombinant adenovirus vector expressing IL-6 cDNA, both the induction of CD8+ human CTLs against CESS cells in the spleen cells and peritoneal exudate cells and a prolongation in the survival of these mice were observed. Furthermore, SCID-PBL/hu mice were given peripheral blood lymphocytes from patients with cancer (gastric or rectal cancers) and autologous human tumor cells. The in vivo administration of recombinant adenovirus vector expressing IL-6 cDNA induced CD8+ human CTLs specific for autologous human tumor cells from human precursor T cells. The in vivo injection of the IL-6 gene also inhibited growth and metastasis in autologous human cancers. Based on the above findings, the experimental model using SCID-PBL/hu mice and the IL-6 gene delivered in vivo by an adenovirus vector might therefore provide a new strategy capable of analyzing an anti-human tumor effect and the in vivo induction of human CTLs by cytokine gene therapy without using the human body.

Adenoviridae↗
PubMed1997

Effect of byakko-ka-ninjin-to on the efferent activity of the autonomic nerve fibers innervating the sublingual gland of the rat.

The effect of intraduodenal infusion of Byakko-ka-ninjin-to (BN) on the efferent activity of the autonomic outflow to the sublingual gland was observed in the anesthetized rat. Intraduodenal infusion of BN (50-200 mg/kg) resulted in a dose-related increase in efferent activity. The enhancement of the nerve activity following administration of 200 mg/kg BN lasted longer than three hours. It was observed that the suppressive effect on efferent activity due to i.v. administration of hypertonic saline was antagonized by intraduodenal infusion of BN. From these observations it is suggested that Byakko-ka-ninjin-to acts as a facilitatory agent on salivary secretion.

Adrenergic alpha-Agonists↗
PubMed1997

Determination of the effects of caffeine and carbamazepine on striatal dopamine release by in vivo microdialysis.

The effects of carbamazepine and caffeine on adenosine receptor subtypes were determined using in vivo microdialysis in an attempt to elucidate their different psychotropic mechanisms of action. Adenosine and a selective adenosine A1 receptor agonist decreased the striatal extracellular dopamine level, whereas caffeine, carbamazepine and a selective adenosine A1 receptor antagonist increased it, but neither an adenosine A2 receptor agonist nor an antagonist affected it. Under conditions of adenosine A1 receptor blockade, adenosine, carbamazepine and a selective adenosine A2 receptor agonist increased the striatal extracellular dopamine level, whereas caffeine and a selective adenosine A2 receptor antagonist decreased it. These results suggest that adenosine A1 receptor stimulation reduces the striatal extracellular dopamine level, and that adenosine A2 receptor stimulation under conditions of adenosine A1 receptor blockade increases it. Therefore, caffeine is an antagonist of both adenosine A1 and A2 receptor subtypes, and carbamazepine is an adenosine A1 receptor antagonist as well as an adenosine A2 receptor agonist. These properties support the hypothesis that the central actions of both carbamazepine and caffeine result from effects on both adenosine A1 and A2 receptors.

Adenosine↗
PubMed1997

Megakaryocytopoietic activity of a truncated variant of mouse thrombopoietin.

Thrombopoietin (TPO) is a hemopoietic cytokine that specifically stimulates the growth and development of megakaryocytes. In addition to full-length TPO (corresponding to TPO-1), cDNAs of three truncated variants (TPO-2 to 4) have been isolated. However, whether or not these variants have biological activities has not been clarified presumably because of poor secretion into extracellular milieu. To examine the biological significance of the shortest variants, TPO-4, we prepared two fusion cDNAs of TPO-1 and TPO-4, each of which was combined with the finger-growth factor-kringle 1 (FGK1) domains of tissue plasminogen activator (tPA) as a tag and transfected them into baby hamster kidney (BHK) cells. An immunodetection assay for FGK1 antigen revealed that the amount of secreted TPO-4-FGK1 fusion protein was about 2% of that of TPO-1-FGK1. These fusion proteins after affinity purification had comparable activities on a molar basis in both megakaryocyte colony stimulating activity towards mouse bone marrow cells and growth promotion activity towards the TPO-responsive cell line UT-7/GM. These results indicate that the TPO-4 is biologically active in vitro, although its primary structure of the C-terminal half after the 111th amino acid residues is completely different from authentic TPO-1 due to frame shift.

Animals↗
PubMed1997

Glutathione S-transferase-pi expression and glutathione concentration in ovarian carcinoma before and after chemotherapy.

BACKGROUND: To clarify the role of glutathione (GSH) in the chemotherapy resistance of ovarian carcinoma, the authors examined the expression of glutathione S-transferase-pi (GST-pi) and the concentration of glutathione in tumors before and after chemotherapy in the same patients. METHODS: The cohort for this study comprised 20 patients with ovarian carcinoma who had residual disease after primary surgery. These patients received two to three courses of postoperative chemotherapy, then underwent surgery for a second time. Chemotherapy consisted of 50 mg/m2 cisplatin, 40 mg/m2 doxorubicin, and 400 mg/m2 cyclophosphamide. The expression of GST-pi in tumors was determined by immunohistochemical staining and Western blot analysis. GSH concentration was measured by an enzymatic assay. RESULTS: Of the 20 patients, 10 responded to chemotherapy and 10 did not. Immunohistochemical staining for GST-pi was positive in 3 tumors among the 10 responders and in 7 tumors among the 10 nonresponders, but Western blot analysis detected GST-pi expression in all tumors. Among the responders, GST-pi after chemotherapy increased in one patient, was unchanged in two patients, and decreased in seven patients. Among nonresponders, GST-pi increased in six patients, was unchanged in one patient, and decreased in three patients. The ratio of GST-pi density in tumors after chemotherapy to GST-pi density before chemotherapy was significantly higher in nonresponders than in responders (2.0 +/- 1.1 vs. 0.6 +/- 0.4). The concentration of GSH in tumors was widely distributed, but it was found that the ratio of GSH concentration in each tumor after chemotherapy to GSH concentration before chemotherapy was significantly higher for nonresponders than for responders (3.0 +/- 1.3 vs. 0.6 +/- 0.3). CONCLUSIONS: Increased levels of GST-pi expression after chemotherapy are linked to drug resistance in patients with ovarian carcinoma.

Aged↗
PubMed1997

Csk overexpression reduces several monokines and nitric oxide productions but enhances prostaglandin E2 production in response to lipopolysaccharide in the macrophage cell line J774A.1.

The catalytic activity of src-family protein tyrosine kinases (src-PTK) is suppressed when a C-terminal tyrosine is phosphorylated by an intracellular PTK, C-terminal Src kinase (Csk). In the present report, to study the regulatory functions of the Csk in cells of monocyte/macrophage lineage, we transfected a eukaryotic expression vector containing rat csk cDNA in a macrophage cell line, J774A.1, and examined alterations of the response to lipopolysaccharide (LPS) in the transfectants which overexpressed Csk. Csk overexpression resulted primarily in a down-regulation of Fgr activity, an src-PTK expressed in J774A.1, and hyperphosphorylation of several cellular proteins of 35, 57, 66, 97 and 120-130 kDa. Furthermore, in these Csk transfectants, production of interleukin (IL)-1alpha, IL-6, tumor necrosis factor-alpha, and nitric oxide (NO) following LPS stimulation were reduced compared with those in parental J774A.1 or J774A.1 transfected with the vector alone. The extent of reduction paralleled the amounts of Csk proteins expressed in the Csk-transfected J774A.1. The reduced NO production in these cells was associated with low levels of mRNA of inducible NO synthetase. On the other hand, an enhancement of prostaglandin E2 production was observed in the Csk-transfected J774A.1 cells upon stimulation with LPS, which appeared to result from the high level of prostaglandin-H synthetase in the transfectants. The present findings indicate that overexpression of Csk has differential effects on the regulation of production of chemical mediators and monokines, probably via modulation of signal transduction downstream of LPS-mediated signals.

Animals↗
PubMed1997

Plasma levels of the monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 are elevated in patients with acute myocardial infarction.

Cardiac inflammatory responses appear to play a pivotal role in scar formation after acute myocardial infarction. Monocyte chemotactic and activating factor (MCAF) monocyte chemoattractant protein-1 (MCP-1) is a cytokine with chemotactic activity for mononuclear phagocytes, but also for NK cells, T cells, mast cells, and basophils. To investigate the possible involvement of MCAF/MCP-1 in the pathogenesis, its course was studied in patients with acute myocardial infarction. Twenty-three consecutive patients with acute myocardial infarction and 18 patients with angina pectoris were studied. Cytokines were measured by enzyme-linked immunosorbent assay. Plasma levels of interleukin IL-1alpha, IL-1beta, and IL-2 were below the detection limit of our method. IL-6 and interferon-gamma were detected in 17.4%, and tumor necrosis factor-alpha in 13.0% of patients with acute myocardial infarction, but the frequency was not statistically significantly different from that in angina pectoris. The plasma level of MCAF/MCP-1 in myocardial infarction tended to increase at 3 h after the onset of chest pain (133 +/- 19 pg/ml, P= 0.06) and was significantly elevated at 9 h (143 +/- 20 pg/ml) when compared with that in angina pectoris (87 +/- 6 pg/ml, P<0.05). The MCAF/MCP-1 level remained increased during the 24-hours observation period (P<0.01), and maximum level (168 +/- 13 pg/ml) was seen at 24 hour. The level of MCAF/ MCP-1 correlated significantly with the plasma level of another chemokine, IL-8, at 12 h after the onset of chest pain (r=0.51, P<0.05), suggesting that common stimuli mediate the release of both cytokines in myocardial infarction. The identification of MCAF/MCP-1 as an inflammatory mediator in acute myocardial infarction suggests that mononuclear phagocytes may play an important role in the early stage of the disease.

Adult↗
PubMed1997

Colonic cancer in a patient with primary sclerosing cholangitis and long-standing ulcerative colitis.

A 27-year-old woman with a 9-year history of ulcerative colitis involving the entire colon was admitted to our hospital in August 1992 because of bloody stools and left lower abdominal pain. She had been treated with sulfasalazine since 1983 and the colitis had been clinically quiescent or mild for 7 years. She had also been diagnosed as having primary sclerosing cholangitis (PSC) 4 years prior to this admission, based on the clinical, laboratory, and cholangiographic findings. A barium enema and colonoscopy showed an irregular mass obstructing the bowel lumen in the distal portion of the descending colon. Biopsy specimens taken from the mass revealed moderately differentiated adenocarcinoma, and a subtotal colectomy was performed. Histologic examination of the mass lesion showed moderately differentiated adenocarcinoma invading the pericolic adipose tissue. She is currently alive 3 years after surgery. PSC has recently been reported as a risk factor for colonic neoplasia in patients with long-standing ulcerative colitis. In Japan, however, colorectal cancer associated with PSC and ulcerative colitis has rarely been reported. The present case suggests that the risk of colonic cancer is higher in patients with ulcerative colitis and PSC than in patients with ulcerative colitis alone.

Adenocarcinoma↗
PubMed1997

Enhanced pain management for postgastrectomy patients with combined epidural morphine and fentanyl.

PURPOSE: To determine whether clinical advantages could be demonstrated by epidural fentanyl given in addition to epidural morphine for postgastrectomy analgesia. METHODS: One-hundred and twenty two patients undergoing elective gastrectomy were prospectively studied in a randomised, double-blind fashion. All patients received epidural lidocaine 1.5% with epinephrine (1:200,000) followed by light general anaesthesia for surgical anaesthesia. They were assigned to four groups according to the combinations of each epidural opioid: 2 mg morphine alone, 2 mg morphine + 100 micrograms fentanyl, 4 mg morphine alone, and 4 mg morphine + 100 micrograms fentanyl. Morphine and fentanyl were given epidurally approximately 60 and 15 min, respectively, before the completion of surgery. RESULTS: Addition of epidural fentanyl to both doses of morphine not only decreased intensity of pain associated with coughing during the early postoperative period, but also prolonged the time until the first analgesic request at each morphine dose studied. Of the combination doses, 4 mg morphine + 100 micrograms fentanyl provided the longest time to the first request for analgesic, and was associated with least amount of postoperative analgesic supplement and best patient satisfaction without increasing incidence of side effects. CONCLUSION: The addition of 100 micrograms fentanyl to 2 mg or 4 mg epidural morphine provides clinical advantages over morphine alone for post-gastrectomy analgesia.

Analgesia, Epidural↗
PubMed1997

Restriction of viral population by intravaginal infection of simian immunodeficiency viruses in macaque monkeys.

In order to examine whether the viral population is affected by intramucosal transmission, we analyzed the viral genotypes first detected in peripheral blood mononuclear cells (PBMCs) after intravaginal inoculation, before virus antibodies were detectable, and compared them with those in the inoculum. Three female cynomolgus macaques were inoculated intravaginally and a fourth was inoculated intravenously with polyclonal simian immunodeficiency viruses (SIVmac32H). The provirus genomes which first appeared in PBMC were sequenced in the V1 to V2 region of the SIV envelope gene. A comparison of the sequences obtained from each monkey revealed a homogeneous or heterogeneous viral population depending on the infection route. In the intravenously inoculated monkey, the viral population was heterogenous and was similar to that in the virus inoculum. On the other hand, in the intravaginally inoculated monkeys, single genotypes (in two monkeys) and one genotype with a slight variation (in one monkey) were found, but they were different from each other, having no characteristic sequences in the V1 to V2 region in common. None of the genotypes found in the PBMC were major genotypes in the virus inoculum. These results suggest that some selective mechanism, which differs among individuals, restricts the viral population during mucosal transmission.

Amino Acid Sequence↗
PubMed1997

Open distal anastomosis in retrograde cerebral perfusion for repair of ascending aortic dissection.

BACKGROUND: In patients with aortic dissection, a patent distal false lumen at long-term follow-up leads to complications. We investigated the feasibility of performing an open distal anastomosis using retrograde cerebral perfusion. METHODS: Over a 10-year period, 41 patients with acute type A aortic dissection underwent 43 surgical repairs. In 1991, an open distal anastomosis using retrograde cerebral perfusion (group 2) was introduced to replace the standard aortic cross-clamp method (group 1). The mean retrograde cerebral perfusion time was 47.3 minutes (range, 22 to 67 minutes), and there were no neurologic sequelae in surviving patients. RESULTS: The operative mortality rate was 18.5% in group 1 and 18.7% in group 2. At long-term follow-up, dilatation of the false lumen (more than 50 mm in diameter) occurred in 9 of 18 patients (50%) in group 1, and 2 patients died of aortic rupture. There were no deaths in group 2, and dilatation of the distal false lumen occurred in only 15.4% of patients (p < 0.05). CONCLUSIONS: The use of retrograde cerebral perfusion in patients with acute aortic dissection provides adequate time to perform a safe, open, distal anastomosis, and could decrease significantly the rate of enlarged, patent, false lumina.

Acute Disease↗
PubMed1997

Effects of 17 beta-estradiol and progesterone on migration of human monocytic THP-1 cells stimulated by minimally oxidized low-density lipoprotein in vitro.

OBJECTIVE: Many epidemiological studies have shown that postmenopausal hormone replacement therapy (HRT) has a beneficial effect on atherosclerotic cardiovascular disease. The aim of this study was to investigate the effects of estrogen and progestin on the migration of monocytes induced by minimally oxidized low-density lipoprotein (m-ox-LDL) in vitro. METHODS: Human monocytic THP-1 cells were used for the study. Migration assay was performed using a modified Boyden chamber. RESULTS: The presence of estrogen receptors was determined in THP-1 cells by Western and Northern blot analysis. Although native LDL had no significant effects on the migration of THP-1 cells, m-ox-LDL increased the migration of THP-1 cells in a dose-dependent manner. Although 17 beta-estradiol (E2, 10(-9)-10(-6) M) inhibited the 10 micrograms/ml-induced migration of THP-1 cells in a dose-dependent manner, estrone (E1), estriol (E3) and progesterone (P) had no significant effects. The combination of P (10(-9)-10(-6) M) did not show any effect on the inhibitory effect of 10(-7) M E2. Preincubation of THP-1 cells with the anti-estrogenic agent, tamoxifen (10(-6) M), significantly antagonized the inhibitory effect of 10(-7) M E2. m-ox-LDL stimulated MCP-1 secretion from THP-1 cells, which was reduced by E2. Anti-human MCP-1 neutralizing antibody inhibited the migration of THP-1 cells stimulated by m-ox-LDL. E2 also inhibited the 10 ng/ml MCP-1-induced migration of THP-1 cells in a dose-dependent manner. CONCLUSIONS: These findings suggest that the inhibitory effect of E2 on the migration of monocytes might be one of the factors involved in the decreased incidence of atherosclerotic cardiovascular disease in premenopausal women and postmenopausal HRT.

Adult↗
PubMed1997

LpA-I levels do not reflect pre beta1-HDL levels in human plasma.

High-density lipoprotein (HDL) containing apo A-I but no apo A-II (LpA-I) can promote cholesterol efflux from cells, while HDL containing apo A-I and apo A-II can not. Pre beta1-HDL, a minor fraction of LpA-I, is the initial acceptor of cellular cholesterol. To determine whether the pre beta1-HDL:LpA-I ratio is constant in human plasma, we measured LpA-I levels by differential electroimmunoassay, and HDL subfraction levels by nondenaturing 2-dimensional gel electrophoresis in 26 subjects. We found that the pre beta1-HDL:LpA-I ratio was higher in hypercholesterolemia (0.21+/-0.09; n = 11, P < 0.05), coronary artery disease (0.26+/-0.13; n = 5, P = 0.08) and hypertriglyceridemia (0.39+/-0.22; n = 3, P = 0.16) than in normolipidemia (0.11+/-0.03, n = 5). LpA-I levels were significantly correlated with HDL2b (r = 0.771, P=0.000001), HDL2a (r = 0.438, P < 0.01), and pre beta2-HDL levels (r = 0.496, P < 0.005) but not with pre beta1-HDL or HDL3 levels. In conclusion, the pre beta1-HDL:LpA-I ratio is not constant in human plasma. These findings strongly suggest that size distribution of LpA-I may change in various disorders.

Adult↗
PubMed1997

Antitumor effects of internal iliac arterial infusion of platinum compounds in a rabbit cervical cancer model.

OBJECTIVE: To compare three platinum compounds for their antitumor effects on cervical cancer after systemic and intra-arterial infusion. METHODS: Adult female rabbits with squamous cell carcinoma of the uterine cervix received infusions of 1.7 mg/kg cisplatin, 10 mg/kg carboplatin, or 6 mg/kg cis-diammine (glycolato)platinum (254-S) via the internal iliac artery or ear vein. Platinum concentrations in the tumor and tumor size were measured after internal iliac arterial or intravenous (i.v.) infusion with these platinum compounds. RESULTS: The platinum concentration in the tumor after intra-arterial infusion was significantly higher than that after i.v. infusion for cisplatin. However, the tumor concentrations of platinum for carboplatin and 254-S did not differ between the infusion methods. The platinum concentration 20 minutes after i.v. infusion was significantly higher for 254-S than for cisplatin or carboplatin. The platinum concentration 7 days after intra-arterial infusion was significantly higher with cisplatin than with carboplatin or 254-S. Tumor size 7 days after intra-arterial infusion was significantly smaller than that after i.v. infusion for cisplatin (1.85 +/- 0.54 versus 5.60 +/- 2.60 cm2; P < .05). Tumor size was significantly smaller with 254-S than with cisplatin or carboplatin using the i.v. infusion method (2.40 +/- 0.21 cm2 for 254-S, 5.60 +/- 2.60 cm2 for cisplatin, and 5.13 +/- 1.59 cm2 for carboplatin, P < .05. CONCLUSIONS: Intra-arterial infusion seems to be a suitable route of administration for cisplatin, whereas i.v. infusion appears to have an advantage for 254-S in the treatment of cervical cancer.

Animals↗
PubMed1997

Kainate excitotoxicity is mediated by AMPA- but not kainate-preferring receptors in embryonic rat hippocampal cultures.

We investigated kainate-induced excitotoxicity in embryonic rat hippocampal cells cultured in a chemically defined medium. Treatment with kainate for 24 h resulted in neuronal death, as assessed by the release of lactate dehydrogenase into the culture media. This neurotoxic effect was kainate dose- and culture age-dependent. EC50 of kainate was 127 +/- 11 microM. 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (f)quinoxaline (NBQX) completely blocked the toxicity, while MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, also blocked it but not completely. Furthermore, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) attenuated the kainate injury, while the selective and noncompetitive AMPA-preferring receptor antagonist 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzo-diazepine (GYKI 52466) blocked it completely. Concanavalin A (ConA), which potentiates the response to kainate at kainate-preferring receptors, had little effect on kainate toxicity. Further, AMPA alone induced little toxicity, but produced remarkable toxicity when cyclothazide was used to block the desensitization of AMPA-preferring receptors. These results indicate that kainate excitotoxicity in hippocampal cultures is mediated by AMPA- but not kainate-preferring receptors, and that it involves NMDA-receptor-mediated toxicity. The non-desensitizing response at AMPA-preferring receptors may play an important role in kainate-induced excitotoxicity.

Animals↗
PubMed1997

Dual mode of N-methyl-D-aspartate-induced neuronal death in hippocampal slice cultures in relation to N-methyl-D-aspartate receptor properties.

Hippocampal slices prepared from neonatal rats were cultured for several weeks, and excitotoxicity induced in CA1 pyramidal neurons by N-methyl-D-aspartate was evaluated at different culture stages. CA1 neurons cultured for one week exhibited cell death predominantly within 1-3 h after a 15-min N-methyl-D-aspartate insult (early death), whereas those cultured for three weeks showed cell death mainly a few hours to 24 h after the insult (delayed death). CA1 neurons cultured for two weeks were in a transitional state, expressing only weak early and delayed forms of cell death in response to N-methyl-D-aspartate. The N-methyl-D-aspartate-induced early cell death observed in the one-week group depended on external Cl- but did not require external Ca2+; rather, early cell death was enhanced in Ca2+-free solution. This early cell death was accompanied by cell swelling, but cell swelling alone produced by osmotic changes failed to induce cell death. There was no evidence that CA1 neurons in the one-week group were more responsive to N-methyl-D-aspartate than those in the two other groups. Delayed cell death examined in the three-week group depended on external Ca2+ but was independent of Cl-. The density of N-methyl-D-aspartate-induced whole-cell currents recorded from CA1 neurons in Mg2+-free solution remained unchanged during three weeks of culture. However, the N-methyl-D-aspartate receptor channel in the three-week group was more resistant to Mg2+ block than that in the one- or two-week group. The incidence of N-methyl-D-aspartate-induced delayed cell death was higher in the three-week group than in the two-week group in normal solution but not in Mg2+-free solution. Thus, Mg2+ block-resistant properties of the N-methyl-D-aspartate receptor channel acquired during prolonged culture may account for the high incidence of N-methyl-D-aspartate-induced delayed cell death in the three-week group. However, the N-methyl-D-aspartate receptor subunits expressed in the CA1 subfield did not show any feature specific to the three-week group. These results show that two mechanistically distinct modes of N-methyl-D-aspartate-induced neuronal death are manifested differentially at different culture stages, depending on the intrinsic neuron properties (i.e. early cell death) and on the properties or the responsiveness of the N-methyl-D-aspartate receptor (i.e. delayed cell death).

Animals↗