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Biomedical subjects

M A Hayes

Publications and source records attributed to M A Hayes.

At least 37 records · Page 2Linked to original sources
PubMed1996

Modulation of bovine platelet function by C-reactive protein.

The addition of C-reactive protein (CRP) to bovine platelets suspended in homologous plasma consistently produced a reversible aggregation response following stimulation with either platelet activating factor or adenosine diphosphate while untreated control samples exhibited irreversible aggregation. This deaggregation response was independent of the amount of CRP incorporated into the platelet aggregates but did appear to be mediated through a component either present in bovine plasma or loosely bound to the exterior platelet membrane. The aggregation response of bovine platelets, separated from plasma by gel-filtration, was not affected by the addition of CRP to the platelet suspensions. It is proposed that one of the physiological actions of bovine CRP is to modulate platelet function.

Animals↗
PubMed1996

Novel drimane sesquiterpene esters from Aspergillus ustus var. pseudodeflectus with endothelin receptor binding activity.

A series of novel drimane sesquiterpene esters (1-6) was isolated from fermentations of Aspergillus ustus var. pseudodeflectus and their structures elucidated by spectroscopic methods including the HMQC, HMBC and INADEQUATE NMR experiments. The major component of the fermentation, 1, was (2'E,4'E,6'E)-6-(1'-carboxy-2',4',6'-trien)-9-hydroxydrim-7-ene-11 ,12-olide. Compounds 1, 2, 3 and 5 exhibited endothelin receptor binding inhibitory activity against rabbit endothelin-A and rat endothelin-B receptors with IC50 values in the range 20-150 microM. These compounds had similar levels of activity in assays for binding to human endothelin A and endothelin B receptors. The isolation of 9,11-dihydroxy-6-oxodrim-7-ene, 7, a probable biosynthetic precursor to the drimane esters is also reported.

Animals↗
PubMed1995

Influences of chronic cholangiohepatitis and cholestasis on hepatic metabolism of benzo[a]pyrene in white suckers (Catostomus commersoni) from industrially polluted areas of Lake Ontario.

White suckers from polluted regions of western Lake Ontario have an increased prevalence of cholangiocellular and hepatocellular and hepatocellular neoplasms associated with an idiopathic chronic cholangiohepatitis. We examined the hypothesis that bile duct obstructions and cholestasis in these fish might increase the susceptibility of liver to administered benzo[a]pyrene (B[a]P). Cytosolic glutathione S-transferase (GST) activity (CDNB) was reduced in obstructed liver to 45% of activity in adjacent unobstructed liver. At micromolar concentrations, chenodeoxycholic acid, deoxycholic acid, bilirubin and haematin each inhibited GST activity of hepatic cytosolic and S-hexylglutatione-affinity-purified GST preparations from unobstructed liver. Liver cytosol and affinity-purified hepatic GSTs from normal white sucker liver reduced DNA binding of 3H-benzo[a]-pyrene-7,8-diol-9,10-epoxide (3H-BPDE) after preincubation in vitro in the presence of 5 mM GSH. Under these conditions, cytosol from adjacent unobstructed liver had a moderately stronger protective activity against DNA binding by BPDE (16.4 +/- 1.3 pmol BPDE/mg DNA) than did cytosol from obstructed liver (20.6 +/- 1.6 pmol BPDE/mg DNA). Suckers with obstructed livers identified by laparotomy were orally administered 3H-benzo[a]pyrene (3H-B[a]P) (0.2 mmol/kg) or unlabelled B[a]P (2.0 mg/kg) and the level of B[a]P macromolecular binding was analyzed in liver tissue by liquid scintillation counting and by immunohistochemistry with antibodies to BPDE-DNA adducts. Covalent binding of 3H-B[a]P to hepatic protein was 30% less in adjacent unobstructed liver compared to obstructed liver; however, there was no significant difference in the levels of 3H-B[a]P bound to DNA in the obstructed lobes compared with non-obstructed adjacent liver. These studies demonstrate that some endogenous non-substrate ligands that accumulate during cholestasis can reduce hepatic GST activity in white suckers. While these changes are insufficient to influence total 3H-B[a]P-DNA adducts in obstructed liver, the preferential localization of BPDE-DNA adducts in GST-deficient hyperplastic biliary tracts suggests that cholangiohepatitis might increase susceptibility to cholangiolar neoplasia in fish exposed to genotoxic polycyclic aromatic hydrocarbons.

Animals↗
PubMed1995

Azaphilones with endothelin receptor binding activity produced by Penicillium sclerotiorum: taxonomy, fermentation, isolation, structure elucidation and biological activity.

A series of azaphilones produced by Penicillium sclerotiorum (Xenova culture collection number X11853) active in assays for the detection of antagonists of the endothelin-A (ETA) and endothelin-B (ETB) receptors has been identified. The series includes two novel sclerotiorin analogues, (8S,8 alpha-R)-7-deacetyl-1,O8,8,8a-tetrahydro-7-epi-sclerotiorin, 1, and its 5-dechloro analogue, 2. It also includes 5-chloroisorotiorin, 6, previously unreported as a natural product, in addition to the major product of these fermentations, (+)-sclerotiorin, 5. Data for the inhibition of endothelin-1 (ET-1) and endothelin-3 (ET-3) binding in the ETA and ETB receptor assays respectively are reported for this series. Compounds 1 and 2 were more selective for the rabbit ETA receptor than for the rat ETB receptor. The IC50 values for 1 and 2 were 9 and 28 microM respectively in an assay based on binding of ET-1 to rabbit ETA receptors. In an assay based on the binding of ET-3 to the rat ETB receptor compounds 1 and 2 exhibited IC50's of 77 and 172 microM. Members of this series of compounds demonstrated antagonist behavior in a secondary assay based on blockade of ET-1 stimulated arachidonic acid release from rabbit renal artery smooth muscle cells, when present at concentrations of > or = 30 microM.

Animals↗
PubMed1994

Computing for synchrotron radiation experiments.

Computing provision is of major concern to synchrotron radiation researchers. An overview is presented of the computing facilities for synchrotron radiation work at the Synchrotron Radiation Source, Daresbury Laboratory. Data acquisition, reduction and analysis are seen as an integrated activity essential for full utilization of beam time. We discuss the evolution of data-acquisition systems from stand-alone systems of limited computing power, to a unified project computing village using state-of-the-art equipment for combined-technique, high-data-rate experiments. A brief account of software packages for data reduction and analysis is also given.

Journal Article↗
PubMed1994

Elevation of systemic oxygen delivery in the treatment of critically ill patients.

BACKGROUND: Elevation of systemic oxygen delivery and consumption has been associated with an improved outcome in critically ill patients. We conducted a randomized trial to determine whether boosting oxygen delivery by infusing the inotropic agent dobutamine would improve the outcome in a diverse group of such patients. METHODS: On the basis of previously published recommendations, we established the following goals: a cardiac index above 4.5 liters per minute per square meter of body-surface area, oxygen delivery above 600 ml per minute per square meter, and oxygen consumption above 170 ml per minute per square meter. If these goals were not achieved with volume expansion alone, patients were randomly assigned to a treatment or control group. The treatment group received intravenous dobutamine (5 to 200 micrograms per kilogram of body weight per minute) until all three goals had been achieved. Dobutamine was administered to the control group only if the cardiac index was below 2.8 liters per minute per square meter. RESULTS: A total of 109 patients were studied. In nine patients the therapeutic goals were achieved with volume expansion alone; all nine patients survived to leave the hospital. Fifty patients were randomly assigned to the treatment group, and 50 to the control group. During treatment, there were no differences between the two groups in mean arterial pressure or oxygen consumption, despite a significantly higher cardiac index and level of oxygen delivery in the treatment group (P < 0.05). Although the predicted risk of death during hospitalization was 34 percent for both groups, the in-hospital mortality was lower in the control group (34 percent) than in the treatment group (54 percent) (P = 0.04; 95 percent confidence interval, 0.9 to 39.1 percent). CONCLUSIONS: The use of dobutamine to boost the cardiac index and systemic oxygen delivery failed to improve the outcome in this heterogeneous group of critically ill patients. Contrary to what might have been expected, our results suggest that in some cases aggressive efforts to increase oxygen consumption may have been detrimental.

Adult↗
PubMed1994

Reduced expression of glutathione S-transferase Yb2 during progression of chemically induced hepatocellular carcinomas in Fischer 344 rats.

We followed the expression of several glutathione S-transferase subunits in altered foci, liver neoplasms and metastases produced in male Fischer 344 rats by a modified Solt-Farber protocol, to determine whether components of the resistant phenotype are lost during neoplastic progression. At 6 mo after initiation, altered foci and persistent nodules displayed increased immunohistochemical expression of glutathione S-transferase subunits Yf (pi-class), Ya (alpha-class) and Yb1 (mu-class) in comparison with normal or surrounding liver tissue. However, although most altered foci exhibited little change in glutathione S-transferase Yb2 (mu-class) subunit expression, 5% of Yf-positive foci and nodules were partially or completely deficient in Yb2 expression. At 12 and 18 mo after initiation, most grossly visible hepatocellular tumors retained induced expression of glutathione S-transferase subunits Yf, Ya and Yb1, but 63% of the carcinomas, 88% of the primary metastatic carcinomas and 94% of the pulmonary metastases were deficient in Yb2 expression. These differences in glutathione S-transferase subunit expression were confirmed by quantitative analysis by reverse-phase HPLC of S-hexylglutathione affinity-purified glutathione S-transferases from advanced tumors. Cytosolic glutathione S-transferase activity for trans-4-phenyl-3-buten-2-one in advanced tumors ranged from 42% to 66% of the activity in matched surrounding liver, whereas glutathione S-transferase activities for 1-chloro-2,4-dinitrobenzene were increased by 140% to 161%. These studies demonstrate that progression of hepatocellular carcinomas in the resistant hepatocyte model of carcinogenesis in which several glutathione S-transferase subunits are induced is associated with the loss of a major constitutive mu-class hepatic glutathione S-transferase. Although the mechanism and role of the reduction or loss of glutathione S-transferase Yb2 during malignant progression are unknown, we propose that loss of glutathione S-transferase Yb2 in some preneoplastic populations of hepatocytes might be conducive to further DNA damage by presently unknown environmental or endogenous compounds that are normally detoxified preferentially by glutathione S-transferase isoenzymes containing this subunit.

Animals↗
PubMed1994

Adherence of Haemophilus somnus to tumor necrosis factor-alpha-stimulated bovine endothelial cells in culture.

Vascular thrombosis and tissue infarction is a principal lesion in Haemophilus somnus septicemia known also as thrombotic meningoencephalitis. This study was undertaken to examine whether tumor necrosis factor-alpha (TNF-alpha) can influence the adherence of H. somnus to cultured bovine aortic endothelial cells (BAEC). Confluent BAEC were exposed to 0-100 nM of human recombinant TNF-alpha for 12-48 h. Suspensions of different strains of H. somnus (approximately 1.5-3 x 10(8) labelled with [methyl-3H]-thymidine, were added to BAEC and incubated for 1.5 h. Initial studies with one pathogenic (P) strain and one non-pathogenic (NP) strain revealed that both strains adhered to normal endothelial cells but minimally to subendothelial matrix remaining after removal of BAEC. Adherence to BAEC was reduced by an excess of unlabelled H. somnus of the same strain. Adherence was enhanced for both strains by exposure of BAEC to TNF-alpha in a manner that increased with TNF-alpha concentration and with duration of exposure to TNF-alpha prior to addition of bacteria. A survey of adherence of six live P strains and six NP strains demonstrated considerable variation but no difference in adherence between P and NP strains to normal or to TNF-alpha-stimulated BAEC. However, TNF-alpha consistently increased adhesion of each strain to BAEC. Both P and NP strains caused more severe cytotoxic changes in TNF-alpha-treated BAEC. Tumor necrosis factor-alpha also increased adhesion of formalin-killed bacteria of P and NP strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Electroosmotic flow control and surface conductance in capillary zone electrophoresis.

Electroosmotic flow within capillary zone electrophoresis can be altered electronically through a mechanism modeled as surface conductance. Experimentally, a small zone of conductive silver on the outer surface of the capillary is shown to permit good control of electroosmotic flow with an applied external voltage. This control is modeled as capacitance across the capillary wall and conductance along the double layer on the inner surface. Experimental results presented agree with theory developed from this model. Surface conductance in capillary zone electrophoresis may significantly simplify electronic control of electroosmotic flow and lead to a better understanding of the effects of chemical modifications to the inner surface of the capillary.

Electrochemistry↗
PubMed1993

Effects of buffer pH on electroosmotic flow control by an applied radial voltage for capillary zone electrophoresis.

Electroosmotic flow has been shown to be controlled via an applied radial voltage. Many factors determine the effectiveness of this control, and one major factor is buffer pH. In this study the effectiveness of the applied radial voltage for controlling electroosmotic flow while varying buffer pH is examined. Previously developed theory is applied and compared to experimental results for a pH range from 1.4 to 6.32. Analysis time is dramatically reduced by applying a radial voltage for separation of a peptide mixture at pH 1.4. Theory predicts laminar flow profiles under some conditions when applying this technique. However, experimental evidence at pH 6.32 and 1.4 shows no evidence of band broadening from a laminar flow profile. Theoretical and experimental results indicate the largest range of effective electroosmotic flow control via an applied radial voltage occurs at low ph. Furthermore, a sigmoidal relationship between electroosmotic flow and applied radial voltage is clearly apparent under these conditions. In contrast, at high buffer pH ( > 6) the relationship appears to be linear and is only over a limited range of flow velocities.

Electrophoresis↗
PubMed1993

Response of critically ill patients to treatment aimed at achieving supranormal oxygen delivery and consumption. Relationship to outcome.

STUDY OBJECTIVE: To evaluate the response to therapy aimed at achieving supranormal cardiac and oxygen transport variables (cardiac index [CI] > 4.5 L/min/m2, oxygen delivery [DO2] > 600 ml/min/m2, and oxygen consumption [VO2] > 170 ml/min/m2) in a heterogenous group of critically ill patients and to assess its relationship to outcome. DESIGN: Patients were divided retrospectively into two groups. Group 1 (n = 15) achieved supranormal values for CI, DO2 and VO2 simultaneously during the first 24 h. Group 2 (n = 17) failed to achieve these goals simultaneously at any time point. SETTING: General intensive care units in a teaching and a district general hospital. PATIENTS: Thirty-two patients at risk of developing multiple organ failure were studied prospectively. INTERVENTIONS: Patients received volume expansion and then, if necessary, dobutamine (5 to 200 micrograms/kg/min) to increase CI and DO2 until all three goals were achieved simultaneously. RESULTS: In group 2, target VO2 could never be reached despite the fact that 11 (65 percent) patients achieved target CI and DO2 simultaneously. In this group, lactate levels did not fall and 16 patients died. In contrast, in group 1, attainment of all goals was associated with a significant reduction (p < 0.05) in blood lactate levels, and all but one of these patients survived. The persistently raised lactate levels in group 2 were associated with significantly higher venous oxygen saturation (SvO2) and lower oxygen extraction ratio (OER); in these patients, SvO2 rose and OER fell in response to increases in DO2. CONCLUSION: These results suggest that failure to increase VO2 was related predominantly to an inability of the tissues to extract or utilize oxygen rather than a failure to increase DO2. These findings support the hypothesis that in order to survive a critical illness, patients must achieve a high level of VO2. An inability to do so is reflected in persistently elevated blood lactate levels and an extremely poor prognosis.

Adult↗
PubMed1992

Electroosmotic flow control and monitoring with an applied radial voltage for capillary zone electrophoresis.

The control of electroosmotic flow by electronic means for capillary zone electrophoresis is presented. This is accomplished by the application of a radial voltage field with a rugged and flexible conductive polymer sheath. Fundamental theory for effect of the applied radial voltage on electroosmotic flow is developed. In addition, the effects of surface pretreatments are examined and compared to trends predicted by the theory.

Electric Conductivity↗
PubMed1992

Binding of transforming growth factor-beta 1 to methylamine-modified alpha 2-macroglobulin and to binary and ternary alpha 2-macroglobulin-proteinase complexes.

The binding of 125I-labelled transforming growth factor-beta 1 (TGF-beta 1) to human alpha 2-macroglobulin (alpha 2M) was studied by native PAGE and autoradiography. TGF-beta 1 bound preferentially to alpha 2M-methylamine and minimally, if at all, to native alpha 2M. Preparations of alpha 2M-proteinase complex were generated by incubating a standard concentration of alpha 2M (0.4 microM) with different concentrations of trypsin, chymotrypsin or neutrophil elastase (0.04-2.0 microM). The 125I-TGF-beta 1-binding activity depended on the initial ratio of active proteinase to alpha 2M, or r value, used to form the alpha 2M-proteinase complex. With all three proteinases, r values of 2 or greater yielded preparations with unchanged or decreased TGF-beta 1-binding activity relative to native alpha 2M. By contrast, r values near 1 yielded preparations with significantly increased TGF-beta 1-binding activity. The results of [3H]thymidine-incorporation studies performed in mouse keratinocytes were consistent with the 125I-TGF-beta-binding experiments. alpha 2M-trypsin and alpha 2M-chymotrypsin prepared at an r value of 1.0 counteracted the activity of TGF-beta 1, whereas the equivalent complexes prepared at an r value of 3.0 had no effect. As determined by SDS/PAGE, 125I-TGF-beta 1 binding to alpha 2M-methylamine was at least 80% non-covalent. Reaction of alpha 2M-methylamine with iodoacetamide or 5,5'-dithiobis-(2-nitrobenzoic acid) decreased the percentage of covalent binding but had no effect on total binding. Neuraminidase treatment had no effect on the binding of 125I-TGF-beta 1 to alpha 2M-methylamine. Cleavage of the 'bait regions' in alpha 2M-methylamine by prolonged treatment with trypsin also had no effect. These studies suggest that TGF-beta 1 binding to alpha 2M is enhanced by conformational change in the proteinase inhibitor resulting from reaction with proteinase or amine. If both proteinase-binding sites in a single alpha 2M molecule are occupied, TGF-beta 1-binding activity is decreased or perhaps eliminated.

Animals↗
PubMed1992

Symmetrical peripheral gangrene: association with noradrenaline administration.

The syndrome of symmetrical peripheral gangrene is characterised by distal ischaemic damage in two or more extremities, without large vessel obstruction. Four patients with bilateral pedal ischaemia are described and their haemodynamic profiles presented. In all four cases the syndrome developed in association with noradrenaline administration, sepsis and DIC, despite a high cardiac output and a low calculated systemic vascular resistance index. Early treatment with epoprostenol was instituted in the final case and was successful.

Adult↗
PubMed1991

Reaction of alpha 2-macroglobulin with plasmin increases binding of transforming growth factors-beta 1 and beta 2.

The binding of 125I-transforming growth factors-beta 1 and beta 2 (TGF-beta 1 and TGF-beta 2) to alpha 2-macroglobulin (alpha 2M) was studied before and after reaction with plasmin, thrombin, trypsin, or methylamine. Complex formation between TGF-beta and native or reacted forms of alpha 2M was demonstrated by non-denaturing polyacrylamide gel electrophoresis and autoradiography. Reaction of native alpha 2M with plasmin or methylamine markedly increased the binding of 125I-TGF-beta 1 and 125I-TGF-beta 2 to alpha 2M. The alpha 2M-plasmin/TGF-beta complexes were minimally dissociated by heparin. Reaction of alpha 2M with thrombin or trypsin reduced the binding of 125I-TGF-beta 1 and 125I-TGF-beta 2; the resulting complexes were readily dissociated by heparin. Complexes between TGF-beta 2 and native or reacted forms of alpha 2M were less dissociable by heparin than the equivalent complexes with TGF-beta 1. These studies demonstrate that the TGF-beta-binding activity of alpha 2M is significantly affected by plasmin, thrombin, trypsin and methylamine. Observations that alpha 2M-plasmin preferentially binds TGFs-beta suggest a mechanism by which alpha 2M may regulate availability of TGFs-beta to target cells in vivo.

Autoradiography↗
PubMed1991

Counteracting effects of dexamethasone and alpha 2-macroglobulin on inhibition of proliferation of normal and neoplastic rat hepatocytes by transforming growth factors-beta type 1 and type 2.

Primary cultures of hepatocytes isolated from normal F-344 rats or from F-344 rats with hepatocellular carcinomas generated by a 2-step model of chemical carcinogenesis were used to determine if dexamethasone (DEX) or alpha 2-macroglobulin (alpha 2M) modify the ability of transforming growth factors-beta type I (TGF-beta I) and type 2 (TGF-beta 2) to inhibit labelling index of hepatocytes cultured continuously with or without epidermal growth factor (EGF). Both TGF-beta 1 and beta 2 were equivalently potent inhibitors of S-phase DNA synthesis in normal and neoplastic hepatocytes as determined by 3H-thymidine autoradiography. Both DEX (1 to 100 microM) and alpha 2M (50-200 microM) partially counteracted the mito-inhibitory effect of both TGF-betas on the proliferation of normal and surrounding hepatocytes. In contrast, neoplastic hepatocytes cultured with DEX released much less immunoreactive alpha 2M and were less able to overcome the inhibitory effect of TGF-beta than normal or surrounding hepatocytes. Purified bovine alpha 2M partially counteracted the inhibition of TGF-beta 1 or beta 2 of both surrounding and neoplastic hepatocytes. Both DEX and alpha 2M were more effective against the mito-inhibitory activity of TGF-beta 2. Our data suggest that alpha 2M released by DEX-treated normal hepatocytes contributes to the counteraction of the TGF-beta effect by DEX. Our results support the hypothesis that glucocorticoids and growth-factor-binding proteins may have important roles in modulating the effects of TGF-beta on normal hepatocyte proliferation and suggest that under some conditions hepatocellular neoplasms can be more sensitive than normal hepatocytes to inhibition of proliferation by TGF-beta.

Animals↗
PubMed1991

Loss of glutathione S-transferases in pollution-associated liver neoplasms in white suckers (Catostomus commersoni) from Lake Ontario.

White suckers (Catostomus commersoni) are one of two species of bottom-feeding fish in which various liver neoplasms are more prevalent in urban/industrial sites in western Lake Ontario than in less polluted sites in the Great Lakes. Previous studies indicate that white suckers excrete metabolites of various polycyclic aromatic hydrocarbons (PAHs) in bile, and that glutathione transferase (GST)-mediated conjugation is a major detoxification pathway for the PAH benzo[alpha]pyrene. To determine whether hepatocarcinogenesis in these wild fish is associated with induced GST-dependent resistance to carcinogens, we examined the expression of immunoreactive GSTs in liver neoplasms and putatively preneoplastic altered hepatocellular foci from white suckers collected from several polluted sites in western Lake Ontario. Histological sections of liver with altered hepatocellular foci, hepatocellular adenomas, hepatocellular carcinomas, bile duct adenomas and bile duct carcinomas were examined for GST immunoreactivity by the peroxidase-antiperoxidase (PAP) technique with polyclonal antiserum specific for all major GST isoenzyme subunits found in normal liver of white suckers. All bile duct adenomas, bile duct carcinomas and hepatocellular carcinomas were markedly or completely deficient in immunoreactive GST in comparison with surrounding normal hepatocytes. The majority of the hepatocellular adenomas were also deficient. Most altered hepatocellular foci had normal GST staining, but several GST-deficient altered hepatocellular foci were observed. However, none of the preneoplastic or advanced liver neoplasms expressed induced GST, suggesting that carcinogenesis is not associated with selection for GST-dependent resistance. Loss of hepatocellular GSTs may be incidental to neoplastic progression in these fish, or might be important in increasing susceptibility of some preneoplastic populations of hepatocytes to further DNA damage by environmental or endogenous chemicals that are normally detoxified by GSTs.

Animals↗