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Biomedical subjects

S Sakamoto

Publications and source records attributed to S Sakamoto.

At least 505 records · Page 28Linked to original sources
PubMed1989

Expression of Lewisa, Lewisb, Lewisx, Lewisy, siayl-Lewisa, and sialyl-Lewisx blood group antigens in human gastric carcinoma and in normal gastric tissue.

A panel of 6 mouse monoclonal antibodies detecting blood group antigens of the Lewis systems and their sialylated derivatives have been used to define the immunoanatomic distribution of these antigenic structures within the normal human gastric mucosa and in gastric cancer tissues. The reagents employed detect the following blood group specificities: Lewisa, Lewisb, Lewisx, Lewisy, sialylated Lewisa, and sialylated Lewisx. We have analyzed the presence of these antigens in histologically normal gastric mucosa and in gastric carcinoma from 61 patients by the immunoperoxidase method. In addition, we simultaneously examined the blood group and secretor status in 31 of the 61 individuals studied. Immunohistochemical analysis revealed that these antigenic systems are differentially expressed in cell types and cell layers of the normal gastric epithelium. Major differences were observed in surface epithelia and in deep glands including Brenner's gland of the gastroduodenal junction, mainly in the pronounced expression of Lewisa and Lewisb antigens in the former and the expression of Lewisx and Lewisy in the latter. In secretor individuals, Lewisb was the dominant antigen in the surface epithelium, and in nonsecretors, Lewisa was observed in the surface epithelium, Lewisx and Lewisy were both detected in the deep glands and in Brenner's glands regardless of the secretor status. The expression of sialylated derivatives in normal gastric tissues was considerably reduced but was consistent with the expression of their precursors in normal gastric epithelium. In gastric cancers, more pronounced expression of Lewisa and sialylated Lewisa was observed in secretor individuals and acted as a tumor-associated antigen. Comparison of the plasma level of sialylated Lewisa and its tissue expression demonstrated that the shedding of the antigen into interstitial stroma correlated with the detection of the antigen in serum. These studies confirmed the importance of blood group antigens as normal differentiation antigens. Examination of secretor status clarified the mechanism of Lewisa and Lewisb antigen expression in gastric surface epithelium. Alterations in the expression of these antigens and an increase of sialylated derivatives in gastric cancers demonstrated that these blood group antigens are useful tools for the analysis of histogenesis and organogenesis in the stomach and its neoplastic and nonneoplastic diseases.

Antibodies, Monoclonal↗
PubMed1989

[Effects of neo-adjuvant chemotherapy with UFT (a combination of tegafur and uracil) on DNA-synthesizing enzyme activities in human colorectal carcinomas].

Thymidylate synthetase (TS) and thymidine kinase (TK) are known to catalyse the methylation of dUMP for the de novo synthesis of dTMP and the phosphorylation of thymidine for the salvage synthesis of dTMP in the pyrimidine pathway, respectively. High TS and TK activities have been observed in rapidly proliferating tissues such as foetal tissue, regenerating liver and carcinomas. TS and TK activities were measured in histologically normal colon mucosa and colorectal carcinomas with or without neo-adjuvant chemotherapy of an antitumor drug UFT (a combination of tegafur and uracil) in humans. In colorectal carcinomas, 5-FU and uracil levels were increased to 2.6- and 3.2-fold, respectively, those in normal colon mucosa by neo-adjuvant chemotherapy of UFT. In colorectal carcinomas, TS and TK activities were both increased to approximately 2- and 3-fold, respectively, those in normal colon mucosa without UFT treatment. In normal colon mucosa and colorectal carcinomas with neo-adjuvant chemotherapy of UFT, TS activities were reduced to approximately 50% and 40%, respectively, those without UFT treatment. These results indicate that neo-adjuvant chemotherapy with UFT may prevent dissemination of cancer cells during operation, and local recurrence and distant metastasis after operation, inhibiting DNA synthesis via the de novo pathway of pyrimidine synthesis in carcinomas.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Kinetic analysis of the elimination process of human epidermal growth factor (hEGF) in rats.

Pharmacokinetic study of human epidermal growth factor (hEGF) in rats was performed in vivo. The hepatic extraction ratio (EH) of [125I]hEGF, determined from the difference between the artery and the hepatic vein plasma concentrations at steady state, was 0.19. The hepatic clearance (CLH:7.56 ml/min/kg body wt), calculated by multiplying EH by the hepatic plasma flow rate (QP,H), was approximately 70% of the total body clearance (CLtot: 10.8 ml/min/kg body wt), which was determined from the steady-state arterial plasma concentration and the infusion rate. These results indicated that the liver is the main organ responsible for the removal of [125I]hEGF from the systemic circulation in rats. The renal extraction ratio (ER) of [125I]hEGF was half of that of [14C]inulin; this may have resulted from the plasma protein binding of [125I]hEGF, which was approximately 50% as determined by the charcoal adsorption method and the equilibrium gel-filtration method. The renal clearance (CLR:2.65 ml/min/kg body wt), calculated by multiplying ER by the renal plasma flow rate (QPR), was approximately 17% of the CLtot (15.6 ml/min/kg body wt), indicating a minor contribution of CLR to CLtot compared with that of CLH to CLtot. The CLR of [125I]hEGF calculated from the urinary excretion data was one-tenth of that calculated from the plasma concentration difference between the femoral artery and the renal vein at steady state. These results suggest that the bulk of [125I]hEGF cleared from the plasma by the kidney may have been metabolized further in the renal tubules before appearing in the urine.

Animals↗
PubMed1989

Analysis of the methylation state of the T cell receptor beta chain gene in T cells and large granular lymphocytes.

We have evaluated the methylation state of the T cell receptor beta chain gene (TcR beta) in freshly isolated human large granular lymphocyte (LGL) and T cell DNA in order to investigate the relationship between LGL and T cells with regard to methylation of this region of genomic DNA. In addition, we wished to determine whether hypomethylation of specific regions of the beta chain gene DNA might account for the production of only a nonfunctional 1.0-kilobase (kb) TcR beta mRNA transcript in LGL. Our analysis indicates that the heterogeneous pattern of methylation seen in LGL DNA lies predominantly in the J beta 1 region of the TcR beta DNA structure. The CCGG sequences located at the beginning of the HTF island (CG-rich region) in the J beta 2 region are nonmethylated in both LGL and at least half of the T cell DNA, suggesting that the HTF island is nonmethylated in both LGL and T cell DNA. In addition, specific methylation differences between T cell and LGL DNA can be detected 0.7 kb 3' to the last exon of C beta 1, just 5' to the first exon and within the second exon of the C beta 2 region. The heterogeneous methylation state of the TcR beta J beta 1 region in LGL DNA may be due to and a result of the differential use of the J beta 1 segment for generation of the nonfunctional 1.0-kb mRNA in LGL. These results and our previous studies (Sakamoto, S., Ortaldo, J. R., and Young, H. A. (1988) J. Immunol. 140, 654-660 and Sakamoto, S., and Young, H. A. (1988) Nucleic Acid Res. 16, 2149-2163) indicate that DNA methylation may be one method by which functional gene expression is controlled in specific lymphoid cell populations.

DNA↗
PubMed1989

The methylation state of the T cell antigen receptor beta chain gene in subpopulations of mouse thymocytes.

Previous analyses of T cell receptor beta chain (TcR beta) genomic DNA from subsets of human peripheral blood leukocytes suggested that the TcR beta methylation pattern might reflect distinct differentiation pathways. The studies presented here, using murine thymocyte subsets, have specifically addressed the question of whether methylation of TcR beta DNA is related to the cellular maturity and type of TcR beta mRNA expressed in the different subsets. We have observed that the DNA isolated from either CD4+ or CD8+ thymocytes, the more mature thymic subsets, is less methylated in the TcR beta region than DNA isolated from the CD4-CD8-, double-negative population containing the more immature thymocytes. In addition, this pattern of DNA methylation is directly related to the ratio of 1.3-kb to 1.0-kb TcR beta mRNA seen in these different cell types. Although a quantitative difference in the level of TcR beta mRNA was noted for the two mature subsets, no qualitative difference in the ratio of 1.3-kb to 1.0-kb mRNA was detected. Furthermore, these DNA methylation patterns appear to be lineage related, because the TcR beta region of genomic DNA isolated from mouse macrophages is heavily methylated.

Animals↗
PubMed1989

Antithrombin III in children with various renal diseases.

Levels of antithrombin III (AT-III) activity and antigen in plasma and urine in children with renal diseases, and their correlation with the light microscopic findings of kidney tissue and the fluorescence of glomeruli, were investigated. AT-III activity in plasma was reduced slightly during the acute stage of acute glomerulonephritis and moderately in the relapse stage of nephrotic syndrome, whereas a small increase of AT-III antigen level in urine was noted in the acute stage of glomerulonephritis and considerably more was observed during the relapse stage of nephrotic syndrome. During the acute stage of glomerulonephritis or in some primary persistent glomerulonephritis (IgA nephritis, non-IgA nephritis), Henoch-Schönlein purpura nephritis and nephrotic syndrome, localization of small amounts of AT-III was noted on the capillary walls of glomeruli. These findings were in parallel with the proliferative changes of glomeruli. However, the AT-III localization did not change in parallel with the light microscopic findings or degree of the fluorescence of the fibrinogen/fibrin-related antigen. It was thought that the existence of AT-III antigen on the capillary walls of the glomeruli might be associated with the inhibition of excessive fibrin formation by AT-III.

Acute Disease↗
PubMed1989

The effect of substrate composition and condition on resorption by isolated osteoclasts.

Osteoclasts isolated from 10-day-old rabbits were studied in a cell culture system to obtain further insight into the possible mechanisms involved in the process of bone resorption. Osteoclasts were cultured on the surfaces of devitalized mammalian bones, a composite of polycrystalline synthetic hydroxyapatite and geological single crystal hydroxyapatite. The structural interaction of osteoclasts with these various substrates was morphologically characterized by using a scanning electron microscope. Viable osteoclasts were observed to adhere and extend pseudopodia and filopodia for all cases of calcium-phosphate surfaces. However, actual resorbing process was only observed in devitalized bone surfaces. Resorption pits of various sizes were found in multiple series and showed a preference for mineral-exposed area over collagen-exposed area. The difference observed between resorption of those areas of bone surface and the failure of osteoclasts to resorb non-tissue substrates are discussed in relation to current theories of the mechanisms of mineral dissolution and resorption in mammalian calcified tissues.

Animals↗
PubMed1989

Effects of pinacidil on myocardial blood flow and infarct size after acute left anterior descending coronary artery occlusion and reperfusion in awake dogs with and without a coexisting left circumflex coronary artery stenosis.

To determine whether partial stenosis of a second major coronary artery promoted vasodilator-induced coronary steal and increased infarct size after acute coronary artery occlusion, we produced acute myocardial infarction by 4-h left anterior descending coronary artery occlusion and 20-h reperfusion in awake dogs with and without a mild to moderate stenosis (33-72%) of the proximal left circumflex coronary artery. Dogs were randomized to receive intravenous (i.v.) normal saline or pinacidil, a new antihypertensive agent with a marked coronary dilator property, beginning 40 min after onset of coronary artery occlusion and continuing throughout the occlusion and the first hour of reperfusion. Pinacidil was titrated to decrease mean aortic pressure 25 mm Hg, which resulted in an increase in heart rate (HR), cardiac output (CO), and left ventricular (LV) dP/dt and LVdP/dt/P. Saline infusion had no effects. Blood flows to ischemic and remote myocardium did not differ between dogs with and without coronary stenosis. Pinacidil increased blood flow threefold in normal myocardium, but had no effect on infarct zone myocardial blood flow or infarct size (58 +/- 4% of region at risk vs. 56 +/- 4% in animals receiving normal saline) in dogs without coronary stenosis. In contrast, similar administration of pinacidil in dogs with coronary stenosis reduced infarct size zone myocardial blood flow and increased infarct size (69 +/- 3% vs. 55 +/- 5% in the saline group, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effects of the in vivo administration of recombinant human granulocyte colony-stimulating factor following cytotoxic chemotherapy on granulocytic precursors in patients with malignant lymphoma.

We examined the effects of the in vivo administration of recombinant granulocyte colony-stimulating factor (rhG-CSF) on granulocytic precursors in the bone marrow of 4 patients with malignant lymphoma who received chemotherapy. Patients were treated with rhG-CSF at doses of 100-800 micrograms/m2/day intravenously for 14 days only in the first course of chemotherapy (G-CSF course) followed by the second course of chemotherapy without rhG-CSF which was used as a control course. In the G-CSF course, white blood cell counts (WBCs) demonstrated a biphasic response consisting of a first peak observed within a few days after the initiation of rhG-CSF administration, and a second peak observed on the last day of rhG-CSF injection or the day after. In the second peak, the incidence of granulocyte-macrophage colony-forming units (CFU-GM) in mononucleated bone marrow cells did not change significantly after treatment with rhG-CSF as compared with a control. However, since the number of nucleated cells in the bone marrow increased, the absolute number of CFU-GM in the bone marrow increased. The number of mature and immature granulocytes in the bone marrow increased. These findings suggest that G-CSF stimulates the proliferation and differentiation of granulocytic precursors in the bone marrow in granulocytopenic patients who received cytotoxic drugs and causes mature granulocytes to be released from the bone marrow.

Adult↗
PubMed1989

Treatment of multiple myeloma with carboquone-prednisolone.

18 previously untreated patients with multiple myeloma were entered in a clinical study of a combination chemotherapy, carboquone (CQ) and prednisolone (P) (CQ-P). Response was observed in 44% of patients treated with CQ-P judged by the criteria for response to chemotherapy. The median survival time was 33 months. Serious toxic reactions seldom occurred. The results suggest that the combination of CQ-P has efficacy in the treatment of multiple myeloma and could have a role among primary chemotherapeutic regimens for the disease. Further clinical trials should be conducted to establish a new drug combination in which CQ is included.

Aged↗
PubMed1989

Behenoyl cytosine arabinoside, aclacinomycin A, 6-mercaptopurine, and prednisolone combination therapy for acute non-lymphocytic leukaemia in adults.

38 consecutive, previously untreated adult patients with acute non-lymphocytic leukaemia (ANLL) were treated with BHAC-AMP (N4-behenoyl-1-beta-D-arabinofuranosyl-cytosine, aclacinomycin A, 6-mercaptopurine, and prednisolone) therapy between March 1980 and February 1985. 25 patients (65.8%) achieved complete remission (CR). Median CR duration and median survival of patients who achieved CR were 14, and 24 months, respectively. The Kaplan-Meier analysis revealed a probability for remaining in CR of 18.0% at 5 years. Analysis of failure cases revealed that most of them were due to resistant disease. Major toxicities were infection, diarrhoea, liver dysfunction, nausea and vomiting but these were acceptable. The results indicate that BHAC-AMP therapy is comparable to the regimen with daunorubicin and cytosine arabinoside and a further clinical trial is necessary for previously untreated adult patients with ANNL.

Aclarubicin↗
PubMed1989

Opiate receptor inhibition improves the blunted baroreflex function in conscious dogs with right-sided congestive heart failure.

The endogenous opiate system is activated in congestive heart failure. because endogenous opioids are known to depress the baroreflex function, we conducted studies to determine whether the increased endogenous opioids play a role in causing the reduced baroreflex function that occurs in heart failure. Right-sided congestive heart failure was produced in 16 dogs by tricuspid avulsion and progressive pulmonary artery constriction. Seven sham-operated dogs were included for comparison. Baroreflex function was measured in the conscious dogs after pretreatment with either normal saline or an opiate-receptor antagonist by bolus administration of phenylephrine. The slope of the regression line relating systolic blood pressure to cardiac cycle (R-R) interval was taken as an index of baroreflex sensitivity. Plasma beta-endorphin was elevated in the dogs with heart failure (15.3 +/- 2.5 pmol/l) compared with the sham-operated dogs (4.2 +/- 0.4 pmol/l, p less than 0.001). The dogs with heart failure also exhibited a reduced baroreflex sensitivity (3.84 +/- 0.19 msec/mm Hg) after saline pretreatment when compared with the sham-operated dogs (10.86 +/- 1.20 msec/mm Hg, p less than 0.001). Administration of naloxone hydrochloride increased the baroreflex sensitivity of dogs with heart failure to 5.16 +/- 0.26 msec/mm Hg (p less than 0.01) but produced no significant effects in sham-operated dogs (11.36 +/- 1.42 msec/mm Hg). To further study the site of action for the effect of naloxone, we measured baroreflex sensitivity in the dogs with heart failure after pretreatment with naloxonazine, a selective mu-receptor antagonist, with ICI 154,129, a selective delta-receptor antagonist, or with naloxone methobromide, a quaternary analogue of naloxone that does not penetrate the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Opiate receptor antagonism in right-sided congestive heart failure. Naloxone exerts salutary hemodynamic effects through its action on the central nervous system.

Opiate receptor inhibition causes adrenergic receptor-mediated increases in aortic pressure, cardiac output, and left ventricular contractile function in right heart failure. To study whether the effects of opiate receptor inhibition are mediated by means of an action on the central opiate system, we administered equimolar doses of naloxone hydrochloride and naloxone methobromide (MeBr) and normal saline to heart failure dogs. Chronic stable right heart failure was produced by progressive pulmonary artery constriction and tricuspid valve avulsion. Naloxone hydrochloride caused an increase in mean aortic pressure, cardiac output, left ventricular dP/dt and dP/dt/P, plasma catecholamines, and regional blood flows to the myocardium, quadriceps muscle, kidneys, and splanchnic beds. Plasma beta-endorphin and adrenocorticotropin also increased. In contrast, neither normal saline nor naloxone MeBr (which does not cross the blood-brain barrier) affected the systemic or regional hemodynamics or neurohormones. Naloxone hydrochloride was also administered to anesthetized heart failure dogs. Pentobarbital anesthesia removed cortical perception of nociceptive stimulation, reduced the increase in plasma epinephrine, and abolished vasodilation in skeletal muscle that occurred in conscious dogs after naloxone hydrochloride administration but had no major effects on responses of plasma norepinephrine, systemic hemodynamics, or other regional blood flows to opiate receptor inhibition. Naloxone hydrochloride had no effect in sham-operated dogs. The results indicate that the hemodynamic effects of naloxone are mediated by an action within the central nervous system. Furthermore, since pentobarbital anesthesia did not markedly alter the hemodynamic responses to naloxone hydrochloride, the acute salutary effects of opiate receptor inhibition probably are not caused by removal of the antinociceptive effect of endogenous opioids in heart failure.

Anesthesia↗
PubMed1989

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

The reduction of myocardial beta-adrenoceptor density in congestive heart failure has been thought to be caused by agonist-induced homologous desensitization. However, recent evidence suggests that excessive adrenergic stimulation may not produce myocardial beta-receptor downregulation unless there is an additional defect in the local norepinephrine (NE) uptake mechanism. To investigate the association between beta-adrenoceptor regulation and NE uptake activity, we carried out studies in 30 dogs with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary artery constriction and 23 sham-operated control dogs. We determined NE uptake activity by measuring accumulation of [3H]NE in tissue slices, NE uptake-1 carrier density by [3H]mazindol binding and beta-adrenoceptor density by [3H]dihydroalprenolol binding. Compared with sham-operated dogs, RHF dogs showed a 26% decrease in beta-adrenoceptor density, a 51% reduction in NE uptake activity, and a 57% decrease in NE uptake-1 carrier density in their right ventricles. In addition, right ventricle beta-receptor density correlated significantly with NE uptake activity and NE uptake-1 carrier density. In contrast, neither NE uptake activity nor beta-receptor density in the left ventricle and renal cortex was affected by RHF. Thus, the failing myocardium is associated with an organ- and chamber-specific subnormal neuronal NE uptake. This chamber-specific loss of NE uptake-1 carrier could effectively reduce local NE clearance, and represent a local factor that predisposes the failing ventricle to beta-adrenoceptor downregulation.

Animals↗
PubMed1989

A sensitive enzyme immunoassay for human epidermal growth factor. Determination of hEGF in human serum and urine and pharmacokinetics in mouse.

A sensitive enzyme immunoassay for human epidermal growth factor (hEGF) is described. The anti-hEGF antibody was prepared by immunizing rabbits with hEGF, which was synthesized by Escherichia coli using the genetic engineering technique. The present assay system was based on the sandwiching of an antigen between anti-hEGF F(ab')2 precoated on a 96-well polystyrene plate and beta-D-galactosidase-labeled anti-hEGF Fab'. The range of measurable hEGF by this assay was 0.1-100 pg/well. Recoveries of hEGF added to serum and urine ranged between 94 and 108%. The intra- and inter-assay coefficients of variation were less than 6 and 8%, respectively. The results obtained by this assay method correlated well with those obtained by the radioimmunoassay method. By using this assay, the time course of serum hEGF levels in mice after the various administrations were also examined.

Animals↗
PubMed1989

Stability of recombinant human epidermal growth factor in various solutions.

The stability of recombinant human epidermal growth factor (hEGF) in various solutions was examined. hEGF degraded spontaneously and temperature-dependently to several degradation products in phosphate buffered saline or in 0.1 N acetic acid. The enzymatic degradation was observed in human serum or in pepsin/HCl solution. The structure and biological activities of these compounds were examined. The results suggest that the Asp11 and Trp50 residues are important for the receptor binding.

Chromatography, High Pressure Liquid↗