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Biomedical subjects

J Mathew

Publications and source records attributed to J Mathew.

At least 19 recordsLinked to original sources
PubMed1992

Cardiopulmonary bypass induces leukocyte-platelet adhesion.

Cardiopulmonary bypass (CPB) has been demonstrated to activate platelets, producing an increased number of circulating platelets that have undergone alpha-granule release and express granule membrane protein-140 (GMP-140) on their surface. In vitro, GMP-140 mediates activated platelet adhesion to neutrophils (PMN) and monocytes, causing the formation of leukocyte-platelet conjugates. Using a newly developed assay that measures the percentage of circulating leukocyte-platelet conjugates in whole blood, we studied 17 patients undergoing CPB and have determined that (1) monocyte-platelet conjugates increased significantly during CPB, from 18% +/- 1.5% to 44% +/- 4.5% (mean +/- SEM) by the end of CPB, while PMN-platelet conjugates increased only slightly and lymphocyte-platelet conjugates decreased; (2) the time course of the increase in monocyte- and PMN-platelet conjugates paralleled that of the increase in circulating activated platelets, as determined by the presence of surface GMP-140; and (3) monocyte activation, as assessed by increased surface expression of CD11b, showed a gradual increase similar to the increase in monocyte-platelet conjugates, while PMN surface CD11b peaked immediately after the start of CPB. We conclude that CPB, through increased platelet GMP-140 expression, causes formation of monocyte-platelet, and to a lesser extent, PMN-platelet conjugates. The activation of monocytes and PMN on CPB, as evidenced by CD11b expression, occurs with differing time courses.

Blood Platelets↗
PubMed1992

Activity and distribution of phosphoinositidase C in rat sciatic nerve.

The hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) by rat sciatic nerve cytosolic phosphoinositidase C [phosphoinositide-specific phospholipase C (PIC)] was studied at neutral pH and at ionic concentrations that approximate intracellular conditions. The principal water-soluble product formed was shown to be inositol trisphosphate by anion exchange chromatography. The maximum hydrolysis rate (2.5 nmol/min/mg protein) was achieved at less than 100 nM Ca2+. Hydrolysis was markedly increased to 15 nmol/min/mg protein by inclusion of K+ in the reaction mixture. In the presence of 200 mM K+, the optimum Ca2+ was increased to approximately 600 nM. Higher Ca2+ concentrations progressively inhibited PIP2 hydrolysis. Mg2+ also inhibited the reaction, but the presence of equimolar amounts of ATP and Mg2+ had no effect. Appreciable degradation of phosphatidylinositol-4-phosphate (PIP) also occurred in the nanomolar Ca2+ range, whereas breakdown of phosphatidylinositol (PI) required millimolar Ca2+. The presence of PIP but not PI inhibited PIP2 hydrolysis. Upon subcellular fractionation of nerve, more than 50% of recovered PIC activity was in the cytosol and about 20% was located in a myelin-enriched fraction. Using PIP2 as substrate, PIC activities in nerves from normal and streptozotocin-induced diabetic animals were not different. However, the myelin-associated enzyme from diabetic animals was more labile to freezing and thawing.

Animals↗
PubMed1992

c-erbB-2 oncogene expression in hepatocellular carcinoma and cholangiocarcinoma.

The c-erbB-2 proto-oncogene encodes a transmembrane protein which is homologous to the epidermal growth factor receptor. This protein can be localized immunohistochemically in formalin-fixed paraffin-embedded material using a monoclonal antibody NCL-CB11; positive membrane staining correlates with gene amplification and protein overexpression in breast cancer. Using this technique we have shown that only 2/26 (8%) of hepatocellular carcinomas, 0/10 (0%) of cholangiocarcinomas and 0/2 (0%) hepatoblastomas overexpressed c-erbB-2 as evidenced by membrane staining. Moreover c-erbB-2 mRNA was not detected in seven hepatocellular carcinomas examined by Northern blot analysis. c-erbB-2 overexpression is, therefore, unlikely to be contributing to the malignant phenotype in hepatocellular carcinoma and cholangiocarcinoma.

Adenoma, Bile Duct↗
PubMed1992

Glutathione S-transferases in neonatal liver disease.

AIMS: To investigate the distribution of alpha and pi class glutathione S-transferases (GST) in normal fetal, neonatal, and adult liver; and to examine changes in GST expression in neonatal liver disease. METHODS: alpha and pi class GST were immunolocalised in sections of formalin fixed liver tissue obtained from human fetuses (n = 21), neonates (n = 8), young children (n = 9) and adults (n = 10), and from neonates with extrahepatic biliary atresia (n = 15) and neonatal hepatitis (n = 12). Monospecific rabbit polyclonal antibodies were used with a peroxidase-antiperoxidase method. RESULTS: Expression of pi GST was localised predominantly within biliary epithelial cells of developing and mature bile ducts of all sizes from 16 weeks' gestation until term and in neonatal and adult liver. Coexpression of pi and alpha GST was seen in hepatocytes of developing fetal liver between 16 and 34 weeks' gestation. Although pi GST was seen in occasional hepatocytes up to six months of life, this isoenzyme was not expressed by hepatocytes in adult liver. By contrast, alpha GST continued to be expressed by hepatocytes in adult liver; this isoenzyme was also seen in some epithelial cells of large bile ducts in adult liver. No change was observed in the distribution of alpha GST in either neonatal hepatitis or extrahepatic biliary atresia. However, aberrant expression of pi GST was identified in hepatocytes of all but one case of extrahepatic biliary atresia but in only two cases of neonatal hepatitis. CONCLUSIONS: The phenotypic alterations noted in extrahepatic biliary atresia may result from the effect of cholate stasis. Evaluation of the pattern of pi and alpha GST distribution by immunohistochemical staining may provide valuable information in distinguishing between these two forms of neonatal liver disease.

Adult↗
PubMed1991

Obliterative otosclerosis.

An analysis of 420 consecutive cases of obliterative otosclerosis seen in the Christian Medical College Hospital, Vellore is presented. The proportion of truly obliterative otosclerosis is 33.09 per cent (139 ears). Our male to female ratio in truly obliterative otosclerosis is 1.48:1, while in the non-obliterative group it is 1.34:1. The mean age at onset in the obliterative group was 19.14 while in the non-obliterative group it was 25.60. This is statistically significant (P less than 0.001). The age at presentation was 25.90 in the obliterative group while in non-obliterative group it was 30.86; this is also statistically significant (P less than 0.001). However the time interval between the age at onset and the age at presentation is not statistically significant.

Adolescent↗
PubMed1991

EDTA and EGTA stimulate 36Cl- uptake into rat brain synaptoneurosomes.

Addition of EDTA (0.5-10 mM) to rat brain synaptoneurosomes stimulated rapid, concentration-dependent uptake of 36C1-. Chloride uptake stimulated by EDTA was additive with the 36C1- uptake induced by the GABAA agonist, muscimol, and was not blocked by the GABA-antagonist, picrotoxin, the glycine antagonist, strychnine or the loop diuretic, furosemide. However, the chloride transport inhibitor DIDS completely antagonized 36C1- uptake. EDTA-induced 36C1- uptake varied across brain regions as follows: Striatum greater than hippocampus greater than cerebellum greater than tectum greater than cerebral cortex greater than brain stem greater than hypothalamus. EDTA-induced 36C1- uptake was also present in liver tissues. EDTA analogues, EGTA and CDTA, also stimulated uptake. Although the effect of EDTA was dependent on the presence of extravesicular Ca2+ (0.01-10 mM) this action did not appear to be due to Ca2+ chelation since BAPTA, arsenazo III and citrate were ineffective. These results suggest that EDTA stimulates 36C1- uptake into brain synaptoneurosomes by a picrotoxin-insensitive, calcium-dependent mechanism that may involve a DIDS sensitive anion exchanger or ion channel.

Animals↗
PubMed1989

Differences in susceptibility of rat liver and brain sialidases to ethanol and gangliosides.

Based on reports that ethanol can decrease the level of sialic acid (SA) (neuraminic acid) in several tissues, we tested the hypothesis that ethanol promotes SA cleavage by enhancing the activity of sialidases (neuraminidases). We also investigated whether brain and liver sialidases have the same response to ethanol and gangliosides, especially since our prior studies have demonstrated that gangliosides could antagonize ethanol-induced behavior. Experiments were conducted on homogenates of brain and liver and of liver slices of adult rats. In liver slices, cleavage of SA did not fall in proportion to the ethanol-induced inhibition of sialidase; in fact, at 0.1 M ethanol, free SA increased, even though sialidase was inhibited. Brain sialidase activity on endogenous sialoglycoconjugates was much more resistant to ethanol than liver sialidase and was fully active even in concentrations as high as 1 M. When gangliosides were incubated with liver slices in the absence of ethanol, sialidase was markedly stimulated. The ethanol-induced inhibition of sialdase in liver slices was mimicked by sorbitol, suggesting that the inhibition may be caused by a shift in redox state as a result of increased NADH. The ethanol metabolite, acetaldehyde, does not seem to be a factor, because sialidase inhibition still occurred when slices were incubated with ethanol containing pyrazole. The results indicate that ethanol promotes the accumulation of free SA in liver without stimulating sialdase; our other work suggests that the cause is an increase in accessibility to sialoglycoconjugates rather than decreased utilization of SA. Brain and liver sialidases clearly respond differently to both ethanol and gangliosides.

Animals↗
PubMed1989

Ethanol-induced hydrolysis of brain sialoglycoconjugates in the rat: effect of sialic acid in antagonizing ethanol intoxication.

Several reports indicate that acute ethanol promotes the cleavage of brain sialoglycoconjugates (SGC). We attempted to confirm this effect by monitoring cleavage of sialic acid (SA) that had been radiolabeled by pretreatment with the specific precursor of SA, N-[3H]acetyl-D-mannosamine, injected intracerebroventricularly into rats 20 h prior to ethanol injection (2 or 3 g/kg, given four times in a simulated "binge drinking" protocol). Analysis of the residual labeled material revealed a significant reduction of radiolabel (p less than 0.01), as compared to saline controls. A dose of 3 g/kg diminished the total labeled SGC by half. Brain sialidase activity was not affected by the ethanol treatment. Since ethanol intoxication is associated with enhanced SA cleavage, one hypothesis needing testing is that loss of SA might help to cause intoxication. If so, pretreatment with SA might antagonize intoxication, presumably by offsetting loss due to cleavage of SA. Consistent with our earlier results, we found that when sialic acid was given i.p. (25 mg/kg), 1, 6, or 24 h prior to ethanol injection (4 g/kg, i.p.), the sleep time was reduced by 35-40% and the performance on rotorod was significantly enhanced (p less than 0.01). When ethanol was replaced by pentobarbital (40 mg/kg), the sleep time was increased (approximately 30%) at 6 h after injection with either 25 or 100 mg/kg sialic acid, whereas at the 24 h postinjection it was decreased (approximately 20%) at both doses. The results suggest that sialic acid is a key component in mediating ethanol effects and perhaps also, in a different way, anesthetic effects.

Alcoholic Intoxication↗
PubMed1988

Gangliosides, or sialic acid, antagonize ethanol intoxication.

Because ethanol elicits a dose-dependent hydrolysis of brain sialogangliosides, we tested the possibility that injected gangliosides might antagonize intoxicating doses of ethanol. Clear anti-intoxication effects were seen at 24 hr post-injection of mixed mouse-brain gangliosides at 125-130 mg/kg, but not at lower or higher doses. Sleep time was reduced on the order of 50%, and roto-rod agility was significantly enhanced. Sialic acid (SA) similarly antagonized ethanol; however, the precursor of SA, N-acetyl-D-mannosamine, as well as ceramide and asialoganglioside did not.

Alcohol Deterrents↗
PubMed1986

Inactivation of gamma-aminobutyric acid aminotransferase by (S,E)-4-amino-5-fluoropent-2-enoic acid and effect on the enzyme of (E)-3-(1-aminocyclopropyl)-2-propenoic acid.

(S,E)-4-Amino-5-fluoropent-2-enoic acid (6) is synthesized in six steps starting from the known gamma-aminobutyric acid aminotransferase (gamma-Abu-T) inactivator, (S)-4-amino-5-fluoropentanoic acid (1). Compound 6 is a mechanism-based inactivator of gamma-Abu-T: time-dependent inactivation is saturatable and protected by substrate; thiols do not protect the enzyme from inactivation; no enzyme activity returns upon dialysis. This compound (6) binds 50 times more tightly to gamma-Abu-T than does the saturated analogue (1). No transamination of 6 occurs prior to inactivation. However, five molecules of 6 are required to inactivate the enzyme with concomitant release of five fluoride ions. Therefore, four molecules are being converted to product for each inactivation event. (E)-3-(1-Aminocyclopropyl)-2-propenoic acid is synthesized in seven steps from 1-aminocyclopropanecarboxylic acid. It is prepared as a cyclopropyl derivative of the proposed intermediate in the inactivation of gamma-Abu-T by 6. The cyclopropyl derivative, however, is a noncompetitive inhibitor and does not inactivate the enzyme. This study shows the usefulness and hazards of incorporation of a trans double bond into potential gamma-Abu-T inactivators.

4-Aminobutyrate Transaminase↗
PubMed1974

Paul Schatzki.

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Australia↗