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Biomedical subjects

T Yamaguchi

Publications and source records attributed to T Yamaguchi.

At least 865 records · Page 48Linked to original sources
PubMed1996

The competitive NMDA antagonist, CGS-19755, improves postischemic hypoperfusion in selectively vulnerable regions in gerbils.

We attempted to clarify the effects of an NMDA antagonist on postischemic hypoperfusion in gerbils with 10 min forebrain ischemia and to relate it to postischemic metabolic recovery. We administered 10 mg/kg of CGS-19755, a competitive NMDA antagonist, or the same volume of saline intraperitoneally 30 min before the vascular occlusion. In 26 gerbils, we measured local cerebral blood flow (LCBF) 60 min after the reperfusion using [14C]iodoantipyrine autoradiography. In 20 gerbils, the effects on metabolic recovery were determined by serial measurements of intracellular pH, adenosine triphosphate (ATP) and the ratio between phosphocreatine and inorganic phosphate (PCr/Pi) until 60 min after reperfusion using 31P-magnetic resonance spectroscopy. In another group of 24 gerbils, we determined histopathological damage 24 h after the ischemia. The LCBF autoradiograms in the control group consistently demonstrated a typical postischemic hypoperfusion, i.e. homogeneous 50-75% reduction of blood flow in all forebrain structures. In contrast, CGS-19755 pretreatment animals showed highly heterogeneous LCBF declines, and significantly higher LCBF values were observed in the frontoparietal cortex and thalamus both of which were the most vulnerable area in this model. No significant LCBF change was observed in sham operated animals with or without CGS-19755 pretreatment. The postischemic recovery of PCr/Pi in gerbils pretreated with CGS-19755 was significantly better than that in the control animals. No significant differences in the recovery of ATP and intracellular pH were observed. The histological damage in the CGS-19755-treated group was less extensive than those in the saline-treated group. CGS-19755 pretreatment improved postischemic hypoperfusion and PCr/Pi recovery in the 10-min forebrain ischemia model in gerbils. The improvement of postischemic hypoperfusion in selectively vulnerable regions suggests that the activation of NMDA receptors may be related to the mechanism of developing postischemic hypoperfusion.

Animals↗
PubMed1996

Indeloxazine hydrochloride improves impairment of passive avoidance performance after fluid percussion brain injury in rats.

We studied behavioral and histological changes after fluid percussion brain injury and the effects of indeloxazine hydrochloride, a cerebral activator, on these post-traumatic changes in rats. An acquisition trial in passive avoidance task was conducted on the 3rd day after injury. The latency of step-through in injured rats was significantly (p < 0.05) shorter than that in sham-operated rats on the 4th, 10th and 14th days after the operation. There were injury-induced neurological deficits on days 1-4 post-injury. Histological changes were observed in the peripheral area of the cortical lesion at the impact site and in the thalamus but not in the hippocampus on the 14th day. Indeloxazine (10 and 20 mg/kg, p.o.) administered once a day from the 3rd (30 min prior to the acquisition trial) to the 9th day after injury significantly (p < 0.05) improved the impairment of the passive avoidance performance without affecting locomotor activity. Indeloxazine showed no significant effects on either neurological deficits or the cortical lesion area. These results suggest that impairment of passive avoidance performance occurs without apparent histological damage in the hippocampus after fluid percussion brain injury and is attenuated by post-traumatic treatment with indeloxazine.

Animals↗
PubMed1996

A research to develop a predicting system of mammalian subacute toxicity. II. Single dose detailed toxicity studies.

"Single dose detailed toxicity study" in rats was conducted with 6 chemical substances to establish a predicting system of subacute toxicity of non-congeneric industrial chemicals. In the detailed examinations, new and previously reported biological parameters were developed and utilized for the establishment and confirmation of the correlations for both qualitative and quantitative prediction of target organs and effects in repeated dose toxicity studies of non-congeners; the new parameters were concerned with liver, kidneys and blood and the established relating equations for prediction had a correlation coefficient of 0.83 (liver), 0.49 (kidneys) and 0.94 (blood), while the old parameters effectively confirmed the previous correlations. The serial changes in the study gave a biological explanation to the established relationships between acute and subacute toxicities in terms of extrapolation.

Animals↗
PubMed1996

A research to develop a predicting system of mammalian subacute toxicity. I. Prediction of subacute toxicity using the biological parameters of acute toxicities.

Predicting equations of subacute toxicity were developed by analyzing rat acute and subacute toxicity data of 56 chemicals of various structures. Minimum or 10% effect level in acute or subacute toxicity was estimated as a "biological parameter". Good regression equations were established between the geometrical means ("combined parameters") of any two of the parameters of acute and subacute toxicities and introduction of log P to the equations improved the correlations with a statistically significant multiple regression coefficient. The lowest predicted effect level of the subacute toxicity, which is selected from the data calculated by the above several correlations, can predict the upper limit of the no observed effect level. In recent years, for research and development of new chemical substances, it becomes one of the important factors that these have a lower environmental load in nature. Eventually, it becomes essential to evaluate not only their acute effects on human or environments, but also their chronic influences when they are to be exposed for a long period of time, and the cost for such verification is becoming a breaking factor for research and development. Thus, the development of a new technique which estimates the environmental load of a chemical substance including toxic effects on human with lower cost is now being attempted. For example, the development of in vitro new alternative methods using cultured cells, the utilization of a data base or software which relates mammalian and environmental toxicities and so on are internationally carried forwards. As for the latter, quantitative structure-activity relationship (QSAR) techniques have been applied practically to decide appropriate toxicity tests needed for regulatory purposes by EPA/TSCA, ITC/TSCA and FDA/FDAA in the USA. In addition, it was concluded recently in a joint meeting of EU and US-EPA that the approach by QSAR techniques was useful to specify the new chemical substances which are to be required toxicological examinations. In these QSAR techniques, however, while there are some considerations about common mechanisms of toxicity among chemicals with a similar structure (Congeneric chemicals, Congeners) for establishing of correlation formulas, for chemicals with various structures (Non-congeneric chemicals, Non-congeners) there often lack such common considerations. In addition, biological or physiological factors which are basic toxic indices are often ignored. In a previous study, we researched acute and subacute oral toxicities of industrial common chemicals in rats and reported the followings; 1) their subacute toxicological spectrum in target organs/tissues and morphologic changes was very limited and specific, 2) the important targets were liver, kidneys, blood (spleen) and stomach and these are considered the sites of dominant exposure due to the kinetics of chemical substances, 3) the morphological changes were hepatocellular hypertrophy, deposition of substance in renal tubules, extramedullary hematopoiesis in spleen and mucous lesion in stomach, and these are implying adaptation such as induction of drug-metabolizing enzymes, overload to renal function, anemia from erythrocyte destruction, and direct reaction, respectively, 4) there seems to occur a series of direct and adaptive reactions to exclude the "foreign compounds" which do not show any specific biological activities, 5) it is also considered that there is a possibility to establish a correlation between toxicological findings or target organs/tissues of both acute and subacute toxicities by their continuity. Therefore, in the present study, a predicting equation of subacute (28-day repeated dose) toxicity is attempted to develop from acute (single dose) toxicity data by considering both common mechanisms and biological factors for non-congeneric industrial chemical substances.

Animals↗
PubMed1996

Induction of IFN-gamma and IL-1 alpha production in macrophages stimulated with phosphopolysaccharide produced by Lactococcus lactis ssp. cremoris.

The induction of interferon (IFN) and interleukin-1 (IL-1) production in murine macrophages by a phosphopolysaccharide, produced by a dairy lactic acid bacteria, Lactococcus lactis ssp. cremoris, was investigated. When the phosphopolysaccharide was added into macrophage cultures at concentrations from 1 to 200 micrograms/ml, substantial IFN titers (6.2-79.2 IU/ml) were detected. Using the reverse transcription-polymerase chain reaction (RT-PCR), the expression of mRNA encoding IFN-gamma was verified in spleen macrophage cultures. Macrophages stimulated with the phosphopolysaccharide also produced IL-1 alpha at a concentration of 50 micrograms/ml. This study showed for the first time that phosphopolysaccharide derived from a dairy lactic acid bacterium can induce IFN-gamma and IL-1 alpha production in macrophages. These findings strongly suggest that the phosphopolysaccharide is a type of 'biological response modifier' and the fermented dairy foods containing Lactococcus lactis ssp. cremoris can be designated as a physiologically functional food.

Animals↗
PubMed1996

Effect of endothelin on angiotensin converting enzyme activity in cultured vascular smooth muscle cells.

We evaluated the effect of endothelin-1 (ET) on the angiotensin converting enzyme (ACE) activity in rat aortic smooth muscle cells (VSMCs). ACE activity was determined by radioimmunoassay of the amount of angiotensin II generated after the addition of angiotensin I (500 pg/ml) to cultured VSMCs. The antibody used had less than 0.1% cross-reactivity with angiotensin I. ACE activity increased 1.9-fold 5 hr after the addition of 10(-6) M ET under serum-free conditions. This stimulatory effect of ET on ACE activity in VSMCs was completely inhibited by 10(-7) M captopril. Results suggested that the ACE present in SMCs is stimulated by ET.

Angiotensin II↗
PubMed1996

Safety and feasibility of continuous monitoring of coronary flow velocity in acute myocardial infarction by Doppler guide wire.

We investigated the safety and limitations of the Doppler guide wire for continuous monitoring of coronary flow velocity outside the catheterization laboratory in 17 patients with acute myocardial infarction. After direct angioplasty, patients were taken to the coronary care unit with the Doppler guide wire positioned within the artery. Flow velocity was continuously monitored. Heparin was titrated to an active clotting time > 200 seconds. Clinical outcome and angiographic analyses were evaluated. Flow velocity monitoring was conducted with an 88.2% success rate and lasted for 16 +/- 5 hours. Monitoring failed in 2 of the 4 right coronary artery cases. Small amounts of thrombus were seen to adhere to the Doppler guide wire at the end of monitoring. No complications were related to the procedure. No deterioration of angiographic findings was observed. This preliminary study confirmed the safety of the Doppler guide wire for continuous monitoring of coronary flow in patients with acute myocardial infarction.

Aged↗
PubMed1996

Distal coronary flow velocity immediately after direct angioplasty for acute myocardial infarction.

To evaluate coronary flow dynamics after direct angioplasty and to define the determinants of flow-velocity variables in the infarct artery, we measured coronary flow velocity in 36 infarct arteries and 64 normal coronary arteries by using a Doppler guide wire. Flow-velocity variables in the infarct arteries did not return to normal even after successful direct angioplasty, and phasic coronary flow in infarct arteries varied considerably. Normal phasic flow was calculated as the ratio of diastolic to systolic flow ratio (DSVR) of greater than or equal to mean DSVR - 1 SD in normal coronary arteries. Infarct-related arteries were divided into two groups: normal DSVR (n = 28) and low DSVR (n = 8). Reduced diastolic peak velocity with a relative preservation of systolic velocity contributed to a low DSVR flow. Angiographic slow flow and late recanalization were significantly related to low DSVR flow. Thus the extent of disturbed microcirculation can be evaluated by assessing phasic flow after direct angioplasty for acute infarction.

Aged↗
PubMed1996

Prognostic evaluation of preoperative combined treatment for advanced cancer in the lower rectum with radiation, intraluminal hyperthermia, and 5-fluorouracil suppository.

BACKGROUND: Since 1977, we have studied preoperative treatments using 5-fluorouracil (5-FU) suppositories alone or in combination with radiation to reduce local recurrence and improve survival of patients with rectal cancer. PATIENTS AND METHODS: We developed a novel preoperative therapy combining radiation, intraluminal hyperthermia, and 5-FU suppositories. Thirty-five patients with rectal cancer underwent surgery after this treatment, and 41 patients underwent surgery without pretreatment. RESULTS: The patients who underwent preoperative combination treatment showed significant tumor reduction; 2 achieved microscopically complete regression. In comparison with the patients who underwent surgery without pretreatment, the preoperative treatment group had a 16.7% lower local recurrence rate (10.4% versus 27.1%) and an improved survival rate (81.8% versus 67.6%). CONCLUSIONS: Preoperative combination therapy is a promising modality for the patients with respectable advanced cancer in the lower rectum.

Adult↗
PubMed1996

Effects of competitive blood flow on arterial graft patency and diameter. Medium-term postoperative follow-up.

To identify predictors of arterial graft patency, we followed up 30 internal thoracic arterial grafts and 23 right gastroepiploic arterial grafts in situ with patency documented during postoperative angiography. After 24 months of follow-up on average, repeat angiography detected that one internal thoracic artery and two gastroepiploic arteries were anatomically occluded and that the other three gastroepiploic arteries were nonfunctioning. The logistic regression model identified a relationship between graft patency and competitive flow, which was detected as stenosis in the recipient coronary arteries (coefficients, p < 0.05; model, Hosmer-Lemeshow chi2 statistic 3.59, p = 0.89). The linear regression model demonstrated that changes in graft luminal diameter correlated with competitive flow (p < 0.01), smoking history (p < 0.05), and type of arterial grafts (p < 0.001) (R2 = 0.40, adjusted R2 = 0.36). The findings suggest a temporal relationship between competitive flow and prognosis of arterial graft.

Abdominal Muscles↗
PubMed1996

Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity.

YM992, (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride, exhibited the biochemical profile of a selective serotonin (5-HT) reuptake inhibitor (SSRI) with 5-HT2A receptor antagonistic activity. YM922 showed the same high affinity as fluoxetine against the 5-HT reuptake site (Ki = 21 nM) and a similar affinity to that of crazodone against the 5-HT2A receptor (Ki = 86 nM). In other receptor binding studies, an affinity for the adrenergic alpha 1 receptor (Ki = 200 nM) and 5-HT2C receptor (Ki = 680 nM) was observed. In a monoamine uptake study, YM992 showed a selective 5-HT uptake inhibition (IC50 = 0.15 microM), but only very weakly inhibited both noradrenaline (NA) and dopamine (DA) uptake (IC50 = 3.1 microM (NA), > 10 microM (DA)). YM992 was also found to potently inhibit the aggregation of human platelets (IC50 = 1.9 microM), revealing antagonistic activity for the 5-HT2A receptor in vitro. Enhanced serotonergic neurotransmission, in particular that mediated by the 5-HT1A receptor, has recently been reported to be important in the long-term treatment of depressive disorders with antidepressants. In addition, some 5-HT1A receptor-mediated responses are known to be potentiated by co-administration of 5-HT2A receptor antagonists. Thus, YM992, having both selective 5-HT reuptake inhibition and 5-HT2A antagonistic activity, might show potent therapeutic activity as a novel antidepressant in comparison with conventional SSRIs.

Animals↗
PubMed1996

End results of simultaneous splenectomy in patients undergoing total gastrectomy for gastric carcinoma.

BACKGROUND: Splenectomy often is performed simultaneously with total gastrectomy for gastric carcinoma to facilitate dissection of splenic hilar lymph nodes. Splenectomy, however, should be avoided as frequently as possible because of its important role in the reticuloendothelial system and because of its sometimes severe complications. We evaluated the end results of simultaneous splenectomy with total gastrectomy. METHODS: The effect of splenectomy on survival was examined by retrospective analysis of 245 patients undergoing total gastrectomy for gastric carcinoma. Of these, 154 underwent splenectomy, and 91 did not. Prognostic factors for patients undergoing total gastrectomy were determined. The relationship to postoperative complications also was analyzed. RESULTS: No significant differences overall were found between the 5-year survival of the patients undergoing total gastrectomy with or without splenectomy. No correlation to any prognostic factor was seen with splenectomy. In contrast, splenectomy was independently associated with postoperative complications. CONCLUSIONS: In this retrospective study simultaneous splenectomy at total gastrectomy for gastric cancer did not have an effect on the survival rate of patients undergoing total gastrectomy, and it sometimes caused severe complications.

Female↗
PubMed1996

Research to develop a predicting system of mammalian subacute toxicity, (3). Construction of a predictive toxicokinetics model.

A new predictive toxicokinetics model was developed to estimate subacute toxicity (target organs, severity, etc.) of non-congeneric industrial chemicals, where the chemical structures and physico-chemical properties are only available. Thus, a physiological pharmacokinetics model, which consists of blood, liver, kidney (these were experimentally found as major toxicological targets), muscle and fat compartments, was established to simulate the chemical concentrations in organs/tissues with pharmacokinetic parameters by means of Runge-Kutta-Gill algorithm. The pharmacokinetic parameters, i.e. absorption rate, absorption ratio, hepatic extraction ratio of metabolism and renal clearance were calculated by using separately established Quantitative Structure-Pharmacokinetics Relationship equations. The developed predictive model was then applied to simulations of 43 non-congeneric industrial chemicals. The chemical concentrations in organs/tissues after single oral administration were simulated, and their maximum concentrations (Cmax's) and area under the concentration-time curves (AUC's) were calculated. Fast Inverse Laplace Transform was newly applied for the purpose of simulation of 28-day repeated dose toxicity. Simulated concentrations of 28 days repeated dose were, however, found to be the same as those of simple repetitions of a single administration per day because of the short half-lives of non-congeneric industrial chemicals. A comparison of subacute toxicity data with Cmax's and AUC's in a single dose scenario suggested that the organs/tissues with relatively high concentrations of tested chemical substances were the most sensitive targets within a chemical. Chemical concentrations in liver, for instance, were correlated with the severity of hepatotoxicity among the chemicals. It was also suggested that to improve and widen the present approach, data of metabolite and reactivity of non-congeneric industrial chemicals to organs/tissues, receptors, etc. should be incorporated into the model.

Adipose Tissue↗
PubMed1996

Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis.

gp130 is a common signal transducer for the interleukin-6-related cytokines. To delineate the gp130-mediated growth signal, we established a series of pro-B cell lines expressing chimeric receptors composed of the extracellular domain of the granulocyte colony-stimulating factor receptor and the transmembrane and cytoplasmic domains of gp130. The second tyrosine (from the membrane) of gp130, which was required for the tyrosine phosphorylation of SHP-2, its association with GRB2, and activation of a MAP kinase, was essential for mitogenesis, but not for anti-apoptosis. On the other hand, the tyrosine in the YXXQ motifs essential for STAT3 activation was required for bcl-2 induction and anti-apoptosis. Furthermore, dominant-negative STAT3 inhibited anti-apoptosis. These data demonstrate that two distinct signals, mitogenesis and anti-apoptosis, are required for gp130-induced cell growth and that STAT3 is involved in anti-apoptosis.

Animals↗
PubMed1996

Retrospective study on the usefulness of radius and lumbar bone density in the separation of hemodialysis patients with fractures from those without fractures.

We measured bone mineral density (BMD) at the lumbar spine (LS-BMD), 1/3 radius (1/3R-BMD), and ultradistal radius (UDR-BMD) in 59 men (4 with spine fractures and 4 with nonspine fractures) and 65 women (10 with spine fractures and 9 with nonspine fractures), all receiving maintenance hemodialysis (HD). The BMD at each site expressed absolutely in g/cm2 was significantly lower in women than in men (p = 0.0001). In men, the absolute and age-matched values of both 1/3R- and UDR-BMD were inversely and significantly correlated with the duration of HD, and with serum alkaline phosphatase and parathyroid hormone levels (p < 0.05), whereas such relationships were obscure in women. On the other hand, the absolute values of BMD at each site in women but not in men were inversely and significantly correlated with patient age (p < 0.001). In both sexes, R-BMD was significantly lower in both the spine and nonspine fracture groups than in the nonfracture group (p < 0.05 and p < 0.01, respectively), whereas the only significant difference in LS-BMD was that it was lower in women with spine fractures than in women without fractures, when expressed as its absolute value (p < 0.05). By receiver operating characteristic analyses, both the absolute and age-matched values of R-BMD were better than LS-BMD as a determinant of non-spine fracture histories, and were similar to absolute LS-BMD as a determinant of spine fracture histories. We conclude that R-BMD is more valuable than LS-BMD for discriminating HD patients with all types of fractures from those without fractures.

Adult↗
PubMed1996

Synthetic nucleosides and nucleotides. 37. Antisense oligodeoxynucleotides bearing 5-(phenylethyl)-2'-deoxyuridylate at the 3'-terminus: exonuclease-resistant molecule with natural phosphodiester backbone.

5-(Phenylethyl)-2'-deoxyuridine has been incorporated into an oligodeoxynucleotide (ODN) by using normal cyanoethyl phosphoramidite chemistry on a DNA synthesizer. For introduction of the modified residue at the 3'-end position of the ODN, we designed and synthesized a new nucleoside phosphoramidite derivative, which connected the 3'-hydroxyl group and phosphoramidite moiety by an alkaline-labile linker. The 3'-end could be substituted in ODNs by using commercially available supports as a starting material following standard NH4OH treatment. The ODN carrying 5-(phenylethyl)-2'-deoxyuridine at the 3'-end position showed about 3-fold resistance to nucleolytic degradation in human plasma without precluding its specific base-pairing activity.

Deoxyuridine↗
PubMed1996

In vivo ESR studies on pharmacokinetics and metabolism of parenteral lipid emulsion in living mice.

PURPOSE: We applied non-invasive and real-time method with in vivo ESR spectroscopy to determining pharmacokinetics and metabolism of lipid emulsion as a drug carrier in living mice. METHODS: A spin-labeled triglyceride (SL-TG) was newly synthesized and lipid emulsion containing SL-TG was prepared. In vivo ESR spectra in mice were observed after intravenous administration of the lipid emulsion. RESULTS: In vivo ESR spectra consisted of three components, coinciding with the in vitro spectra of SL-TG particles, free and immobilized fatty acids. The amount of the components depended on both the observing domain and the period after administration. In the chest, all three components were observed, while SL-TG particle was lacking in the abdomen. The half-life of the lipid particles in the chest was 2 hr. CONCLUSIONS: Non-invasive and real-time analysis of drug carriers in living animal is successfully accomplished using an in vivo ESR method.

Animals↗