PubMed Health⌕ Search

Biomedical subjects

S Worley

Publications and source records attributed to S Worley.

8 recordsLinked to original sources
PubMed2001

pH-induced structural changes regulate histidine decarboxylase activity in Lactobacillus 30a.

Histidine decarboxylase (HDC) from Lactobacillus 30a produces histamine that is essential to counter waste acids, and to optimize cell growth. The HDC trimer is active at low pH and inactive at neutral to alkaline pH. We have solved the X-ray structure of HDC at pH 8 and revealed the novel mechanism of pH regulation. At high pH helix B is unwound, destroying the substrate binding pocket. At acid pH the helix is stabilized, partly through protonation of Asp198 and Asp53 on either side of the molecular interface, acting as a proton trap. In contrast to hemoglobin regulation, pH has a large effect on the tertiary structure of HDC monomers and relatively little or no effect on quaternary structure.

Binding Sites↗
PubMed1997

Rapid assessment of platelet function with a modified whole-blood aggregometer in percutaneous transluminal coronary angioplasty patients receiving anti-GP IIb/IIIa therapy.

BACKGROUND: The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (c7E3 Fab, ReoPro) is approved for use in high-risk percutaneous transluminal coronary angioplasty (PTCA). At present, no "point of care" exists for measuring pharmacological GP IIb/IIIa blockade. To address this need, the Chrono-log Whole Blood Aggregometer, which measures platelet aggregation by electrical impedance, was adapted to test platelet function at the bedside. METHODS AND RESULTS: GP IIb/IIIa receptor blockade, impedance (5 microg/mL collagen), and turbidimetric aggregation (5 and 20 micromol/L ADP) measurements were obtained on 14 PTCA patients who received the standard bolus plus a 12-hour infusion of abciximab. During abciximab administration, mean GP IIb/IIIa receptor blockade was > 91%, and both impedance and turbidimetric aggregation were inhibited by > or = 90%. At 12 hours after abciximab treatment, the mean inhibition of turbidimetric platelet aggregation to 5 and 20 micromol/L ADP was 65+/-20% and 49+/-14%, respectively, and inhibition of impedance aggregation was 69+/-12%. GP IIb/IIIa receptor blockade was 67+/-8%. At 36 hours after abciximab treatment (n=8), the mean inhibition of turbidimetric platelet aggregation to 5 and 20 micromol/L ADP was 44+/-21% and 30+/-14%, respectively, whereas impedance aggregation was inhibited by 60+/-14%. GP IIb/IIIa receptor blockade was 57+/-7%. CONCLUSIONS: During and at 12 hours after abciximab therapy, impedance and turbidimetric platelet aggregation to 5 micromol/L ADP were comparable and closely correlated with GP IIb/IIIa receptor blockade. However, at 36 hours after abciximab treatment, impedance platelet aggregation more closely paralleled GP IIb/IIIa receptor blockade and indicated a slower recovery of platelet function than turbidimetric aggregometry.

Abciximab↗
PubMed1994

Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. The EPIC Investigators.

Restenosis after coronary angioplasty occurs in at least 30% of patients in the first six months and, as yet, there is no known treatment to decrease this event. We tested a monoclonal antibody Fab fragment (c7E3) directed against the platelet glycoprotein IIb/IIIa integrin, the receptor mediating the final common pathway of platelet aggregation, to see whether it reduced the frequency of clinical restenosis. Patients who had unstable angina, recent or evolving myocardial infarction, or high-risk angiographic morphology, were randomised to receive c7E3 bolus and a 12 hour infusion of c7E3 (708 patients), c7E3 bolus and placebo infusion (695 patients), or placebo bolus and placebo infusion (696 patients). With maintenance of the double-blind state, patients were followed-up for at least 6 months to determine the need for repeat angioplasty or surgical coronary revascularisation and the occurrence of ischaemic events. By 30 days, 12.8% of placebo bolus/placebo infusion patients had had a major ischaemic event (death, myocardial infarction, urgent revascularisation), compared with 8.3% of c7E3 bolus/c7E3 infusion patients, yielding a 4.5% difference (35% reduction, p = 0.008). At 6 months, the absolute difference in patients with major ischaemic event or elective revascularisation was 8.1% between placebo bolus/placebo infusion and c7E3 bolus/c7E3 infusion patients (35.1% vs 27.0%; 23% reduction p = 0.001). The favourable long-term effect was mainly due to less need for bypass surgery or repeat angioplasty in patients with an initial successful procedure, since need for repeat target vessel revascularisation was 26% less for c7E3 bolus/c7E3 infusion than for placebo treatment (16.5% vs 22.3%; p = 0.007). The c7E3 bolus/placebo infusion group had an intermediate outcome which was not significantly better than that of the placebo bolus/placebo infusion group. These results extend the benefit of c7E3 bolus/c7E3 infusion from reducing abrupt closure and acute-phase adverse outcomes to a diminished need for subsequent coronary revascularisation procedures. Because this therapy carries a risk of bleeding complications and has been studied only in high-risk angioplasty patients, further evaluation is needed before it can be applied to other patient groups.

Angioplasty, Balloon, Coronary↗
PubMed1993

Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group.

OBJECTIVES: This study was designed to assess outcome in patients with diabetes who received thrombolytic therapy and to determine whether differences in angiographic characteristics may account for the worse outcome observed in diabetic patients. BACKGROUND: Patients with diabetes are known to have a worse outcome after acute myocardial infarction than that of patients without diabetes. METHODS: Clinical and angiographic characteristics of the 148 patients with diabetes and the 923 patients without diabetes in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trials were examined and analyzed. RESULTS: Patients with diabetes tended to be older (median age 59 vs. 56 years) and to have a higher incidence of hypertension and hyperlipidemia and a lower incidence of cigarette smoking. Patients with diabetes had significantly more severe anatomic disease (66% vs. 46% had multivessel disease, p < 0.0001), similar global left ventricular ejection fraction (49% vs. 51%) and worse noninfarct zone ventricular function (-0.13 vs. 0.32 SD/chord, p = 0.02) than that of nondiabetic patients. Angiographic patency rates at 90 min after thrombolytic therapy were similar in patients with and without diabetes (initial 90-min patency 71% vs. 70%). Diabetic patients had nearly twice the in-hospital mortality rate (11% vs. 6%, p < 0.02) and a higher incidence of pulmonary edema (11% vs. 4%, p = 0.001). Diabetic women had an especially high in-hospital mortality rate (21%). No retinal hemorrhages were observed. Although diabetes as an unadjusted variable was predictive of in-hospital (p < 0.02) and long-term (p = 0.003) mortality, after adjustment for baseline clinical and angiographic characteristics, diabetes was not found to have an independent influence on mortality. CONCLUSIONS: Patients with diabetes after myocardial infarction have a worse outcome than that of patients without diabetes despite similar rates of infarct vessel patency. However, diabetes was not found to be an independent risk factor for increased mortality. These findings suggest that diabetes itself is not a major risk factor for poor early outcome after thrombolytic therapy for myocardial infarction; rather, the secondary effects such as more extensive coronary artery disease account for the worse outcome.

Aged↗
PubMed1991

Device interaction--antitachycardia pacemakers and defibrillators for sustained ventricular tachycardia.

We evaluated the combined use of permanent automatic antitachycardia pacemakers and implanted defibrillators in ten patients with recurrent monomorphic sustained ventricular tachycardia (VT). Pacemaker programming was VVI-T automatic burst in eight patients, VVI-T magnet mode in one patient, and VVI in one patient. Device interactions occurred in four patients, requiring changes in pacemaker programming. These included defibrillator multiple counting during pacing, inappropriate pacemaker bursts initiating VT, inappropriate reset of the pacemaker antitachycardia mode by defibrillation, defibrillator discharge after pacemaker VT termination, and defibrillator VT reinitiation. Two patients required pacemaker programming out of the antitachycardia mode, and two required a change in antitachycardia pacing parameters. Seven patients remain in automatic VVI-T and three in VVI modes. Mean follow-up is 13 months and all patients are alive. Thus, although pacemaker/defibrillator combinations function well for patients with more than one VT rate, device interactions occur frequently and may require pacemaker reprogramming or elimination of the overdrive mode. Combined use of these devices should be cautiously considered when single device therapy is unsatisfactory. Devices that combine both pacing and defibrillation features may reduce adverse interaction.

Algorithms↗
PubMedDate not supplied

Structural analysis of ricin and implications for inhibitor design.

Ricin is a potent cytotoxin with experimental and clinical uses; it has also been used as a poison. There is considerable interest in identifying or designing inhibitors of the toxin that could be administered as antidotes. The X-ray structure of ricin A-chain is known and a plausible mechanism of action has been proposed. This provides a structural and chemical framework around which inhibitors could be designed; such a structure-based project is underway. Computer programs such as DOCK, GRID, SYBYL, and CHEMX have been used to map the ricin A-chain binding site and to search for potential inhibitors. Inhibitor candidates can be assayed kinetically in a protein synthesis assay and binding can be observed crystallographically. Taken together, a workable search algorithm has been developed and initial tests indicate that at least one ricin A-chain inhibitor, pteroic acid, has been identified.

Animals↗