Search PubMed⌕ Search

Biomedical subjects

J M Sutton

Publications and source records attributed to J M Sutton.

At least 19 recordsLinked to original sources
PubMed2001

Tyrosine-1290 of tetanus neurotoxin plays a key role in its binding to gangliosides and functional binding to neurones.

Tetanus toxin acts by blocking the release of glycine from inhibitory neurones within the spinal cord. An initial stage in the toxin's action is binding to acceptors on the nerve surface and polysialogangliosides are a component of these acceptor moieties. Using site-directed mutagenesis, we identify tyrosine-1290 of tetanus toxin as a key residue that is involved in ganglioside binding. This residue, which is located at the centre of a shallow pocket on the beta-trefoil domain of the tetanus H(c) fragment, is also shown to play a key role in the functional binding of tetanus toxin to spinal cord neurones leading to the inhibition of neurotransmitter release.

Animals↗
PubMed1999

Effects of calcium and protons on the secondary structure of the nodulation protein NodO from Rhizobium leguminosarum biovar viciae.

NodO, a 30-kDa nodulation protein secreted by Rhizobium leguminosarum biovar viciae, belongs to a family of proteins produced by Gram-negative bacteria containing a variable number of glycine/aspartates nonapeptides. In some instances, these are organized into a parallel beta-roll structure and bind Ca(2+) (one ion per repeat). To gain insight into NodO's secondary and tertiary structures, and their dependence upon Ca(2+) binding, we performed fluorescence experiments and FTIR spectroscopy. We found that calcium binds to the protein, promoting about a 10% increase in beta-structure mainly to the expense of random-coil. Protons can also induce a reversible change in NodO structure, as indicated by quenching of intrinsic tryptophan fluorescence and binding of ANS, albeit probably via a different mechanism. Tb(3+), a trivalent lanthanide, can compete with Ca(2+) for the same binding sites, but with higher affinity. The number of Ca(2+) binding sites, estimated by FTIR spectroscopy, was found to be consistent with the number of predicted repeats.

Anilino Naphthalenesulfonates↗
PubMed1998

Usefulness of technetium-99m sestamibi infarct size in predicting posthospital mortality following acute myocardial infarction.

In this multicenter study, 249 patients who underwent tomographic technetium-99m sestamibi infarct size measurement at hospital discharge were followed up for a median duration of 7 months. Infarct size was significantly associated with mortality (chi-square = 5.8, p = 0.02) and could stratify patients into lower and higher risk subsets: 1-year mortality 2% for infarct size < 14% versus 8% for infarct size > or = 14% of the left ventricle.

Aged↗
PubMed1997

First chronic platelet glycoprotein IIb/IIIa integrin blockade. A randomized, placebo-controlled pilot study of xemilofiban in unstable angina with percutaneous coronary interventions.

BACKGROUND: Clinical studies have demonstrated the efficacy of intravenous administration of agents that block platelet glycoprotein IIb/IIIa receptors in the setting of percutaneous coronary revascularization. Although the optimal duration of treatment has not been determined, more prolonged receptor blockade has been associated with increased efficacy. Orally active glycoprotein IIb/IIIa receptor antagonists may be advantageous and required for chronic therapy. METHODS AND RESULTS: Thirty patients with unstable angina who were undergoing percutaneous coronary interventions were randomized to placebo or Xemilofiban 35 mg orally before and 20 to 25 mg TID for 30 days after angioplasty. Bleeding events, platelet aggregation, and pharmacokinetic and hematologic parameters were assessed during hospitalization and at 2 and 4 weeks after drug initiation. Xemilofiban produced a rapid, sustained, marked inhibition of platelet aggregation. ADP-induced platelet aggregation at 2 hours after the initial dose at 2 and 4 weeks was 15%, 8%, and 11% in the Xemilofiban group compared with 80%, 68%, and 69% in the placebo group. Among 20 patients randomized to Xemilofiban there was 1 death after emergency coronary bypass surgery complicated by severe bleeding diathesis, and 3 patients had major bleeding events. Patients on Xemilofiban for 30 days reported episodes of mild mucocutaneous bleeding. CONCLUSIONS: Xemilofiban, an orally active glycoprotein IIb/ IIIa receptor inhibitor, produced rapid, sustained, extensive inhibition of platelet aggregation for a period of up to 30 days. At the dose initially tested, however, acute major bleeding and mucocutaneous bleeding during chronic administration were encountered.

Adult↗
PubMed1997

Effects of thrombolytic regimen, early catheterization, and predischarge angiographic variables on six-week left ventricular function. The TAMI Investigators. Thrombolysis and Angioplasty in Acute Myocardial Infarction.

The Thrombolysis and Angioplasty in Acute Myocardial Infarction phase 5 (TAMI-5) trial randomized patients to 1 of 3 thrombolytic regimens (alteplase, urokinase, or both), then further randomized them to acute or deferred catheterization. The group of patients randomized to acute catheterization had improved infarct zone but not global left ventricular function on predischarge left ventriculography. To better explore the late effects of these strategies on global and regional left ventricular function, a subset of patients (n = 296) were prospectively evaluated at 6 weeks by multiple uptake gated acquisition (MUGA) radionuclide ventriculography scan. Of these patients, 219 had interpretable studies with paired predischarge and late left ventriculographic data for comparison. At 6 weeks, choice of thrombolytic regimen had no impact on either global or infarct-zone left ventricular function. Further, catheterization strategy (acute vs deferred) did not influence global or infarct-zone function at 6 weeks. In patients randomized to acute catheterization, those undergoing rescue angioplasty had worse infarct-zone wall motion at 6 weeks than patients with a patent infarct vessel not requiring rescue angioplasty (p = 0.002). The early benefit on regional left ventricular function of triage to acute catheterization after thrombolysis for acute myocardial infarction did not persist at 6 weeks, which is most likely attributable to a high incidence of reocclusion. The worse infarct-zone regional wall motion in patients undergoing rescue angioplasty in the acute-catheterization group likely reflects failed reperfusion and illustrates the difficulty in identifying and consequences of early thrombolytic failures.

Aged↗
PubMed1997

Positive screening tests for gonorrhea and chlamydial infection fail to lead consistently to treatment of patients attending a sexually transmitted disease clinic.

BACKGROUND AND OBJECTIVES: Patients attending sexually transmitted disease (STD) clinics are frequently screened for gonorrhea and chlamydial infection. To determine the efficiency of these screening efforts as a component of STD control, we evaluated treatment outcomes of patients with positive cultures who had not received presumptive treatment at their initial visit. GOALS: To determine the treatment outcomes of patients screened for STDs who have positive test results. STUDY DESIGN: Retrospective chart review of the computerized medical record. RESULTS: Between January 1, 1994 and June 30, 1995, 24,823 patients were tested for gonorrhea, of whom 19.3% (4791) had positive cultures. Of patients with positive gonorrhea cultures, 564 (11.8%) had positive screening cultures and did not receive therapy at the time of evaluation. Similarly, screening chlamydial cultures were positive in 1539 (10.9%) of 14,162 patients screened for chlamydial infection. Forty-four percent (677) of these did not receive presumptive treatment for chlamydial infection at their initial visit. Overall, 20% of patients with positive cultures failed to return to the clinic for treatment within 30 days of screening. Of those who did return, 30% did so only after at least 2 weeks had elapsed. CONCLUSIONS: A substantial proportion of patients with positive screening tests for gonorrhea and chlamydial infection fail to comply with follow-up recommendations and thus are likely to remain infectious. Methods must be sought to enhance patient compliance with follow-up of test results and treatment if indicated.

Aftercare↗
PubMed1996

Randomized, double-blind, placebo-controlled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty.

OBJECTIVES: The objectives of this double-blind, placebo-controlled, randomized dose-ranging study were 1) to examine the safety and tolerability of tirofiban (MK-383), a new nonpeptide platelet IIb/IIIa receptor antagonist, on a background of intravenous heparin and aspirin therapy; 2) to study the pharmacodynamics and pharmacokinetics of tirofiban; and 3) to evaluate the incidence of adverse cardiac outcomes (urgent repeat revascularization, myocardial infarction and death) with tirofiban versus placebo in a high risk subset of patients undergoing coronary angioplasty. BACKGROUND: Abrupt vessel closure complicates 4% to 8% of angioplasty procedures. Recent data have suggested that agents that antagonize the platelet glycoprotein IIb/IIIa receptor may reduce the incidence of adverse ischemic outcomes after coronary angioplasty. METHODS: Seventy-three patients received tirofiban in three sequential dose panels and 20 patients received placebo. Patients within each panel were randomized to receive either tirofiban or placebo in a 3:1 randomization design. Bolus doses of 5, 10 and 10 microg/kg and continuous infusion (16 to 24 h) doses of 0.05, 0.10 and 0.15 microg/kg per min were administered in panels I, II and III, respectively. Patients received concomitant heparin and aspirin for the angioplasty procedure. Data on patients receiving placebo (heparin and aspirin only) were pooled across panels for comparisons. The pharmacodynamic effect of tirofiban on ex vivo platelet aggregation to 5 micromol/liter adenosine diphosphate (ADP) and bleeding times were measured. Clinical outcomes were assessed in all patients, but the power to detect clinically meaningful differences (a one-third reduction in clinical events) between groups was limited (5%). RESULTS: Tirofiban was associated with a dose-dependent inhibition of ex vivo ADP-mediated platelet aggregation that was sustained during intravenous infusion and resolved rapidly after drug cessation. Adverse bleeding events, largely related to vascular access site hemorrhage, were slightly increased at the highest dose. Adverse clinical outcomes were infrequent in all patients and were not different among the small number of patients within each group. CONCLUSIONS: This study establishes a rational and generally well tolerated dosing regimen for administration of tirofiban as adjunctive therapy in high risk angioplasty patients. The impact of tirofiban on adverse clinical outcomes after angioplasty awaits definition by a larger clinical trial.

Angioplasty, Balloon, Coronary↗
PubMed1996

Azabicyclic indole esters as potent 5-HT4 receptor antagonists.

The synthesis of a series of azabicyclic indole esters is described and their potency reported as 5-HT4 receptor antagonists. Optimization of the most potent compound (19) by preparing the corresponding oxazino[3,2-a]indole ester afforded 34, which had a pIC50 of 9.5 in the guinea pig distal colon longitudinal muscle myenteric plexus preparation.

Animals↗
PubMed1996

Analysis of the C-terminal secretion signal of the Rhizobium leguminosarum nodulation protein NodO; a potential system for the secretion of heterologous proteins during nodule invasion.

We used deletions to analyze the domains required for secretion of the Rhizobium leguminosarum bv. viciae nodulation protein, NodO, by the sec-independent pathway. Deletion of the C-terminal 24 amino-acids (residues 261 to 284) reduced secretion by at least 95%. A monoclonal antibody that recognizes the C-terminal domain of NodO was used to identify four nested deletions that retained the C-terminal 24 residues of NodO but had lost up to 133 residues (amino acids 128 to 259); all four proteins were secreted into the growth medium with an efficiency between 50 and 90% of normal. A deleted derivative of NodO that retained residues 1 to 21 and 167 to 284 (and therefore lacked most of the N-terminal Ca(2+)-binding domain) was secreted at around 80% of normal efficiency. Taken together, these observations indicate that the C-terminal 24 amino acids are sufficient for NodO secretion although the region adjacent to this domain appears to affect secretion efficiency. A derivative of the Escherichia coli alkaline phosphatase (phoA) gene was cloned into two derivatives of nodO such that PhoA (lacking the N-terminal transit peptide) was in-frame at both ends, with the C terminus fused to either the last 24 or 50 amino acids of NodO. These fusion proteins were secreted at 40 and 80% of the wild-type level, respectively, and the larger of the two retained alkaline phosphatase activity. A hybrid protein, containing E. coli beta-glucuronidase (GUS) fused to the N terminus of NodO, was not secreted, and it reduced the levels of wild-type NodO secreted by R. leguminosarum bv. viciae. The nature of the NodO C-terminal secretion signal is discussed with regard to its use as a delivery system for heterologous proteins useful for investigating the Rhizobium-legume interaction.

Amino Acid Sequence↗
PubMed1995

Rhizobium leguminosarum NodT is related to a family of outer-membrane transport proteins that includes TolC, PrtF, CyaE and AprF.

Cells containing a protein fusion consisting of the Rhizobium leguminosarum bv. viciae nodulation protein, NodT, fused to PhoA, produced alkaline phosphatase activity, indicating that the N terminus of NodT could translocate PhoA across the inner membrane. Cellular fractionation suggested that the NodT::PhoA fusion is targetted to the outer membrane. NodT resembles a family of bacterial outer membrane proteins including TolC, PrtF, CyaE and AprF, which are involved in secretion. By analogy, NodT (together with the inner membrane putative transport proteins NodI and NodJ) is proposed to be involved in the secretion of nodulation factors.

Amino Acid Sequence↗
PubMed1995

Adjunctive selectin blockade successfully reduces infarct size beyond thrombolysis in the electrolytic canine coronary artery model.

BACKGROUND: An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia-reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia-reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model. METHODS AND RESULTS: A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 micrograms/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503-treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7 +/- 8.4% versus 21.8 +/- 13.6%; P = .008) and a marked reduction in myeloperoxidase activity (0.014 +/- 0.009 versus 0.0370 +/- 0.025 U/min per gram; P = .02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias. CONCLUSIONS: Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia-reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia-reperfusion injury.

Animals↗
PubMed1994

The nodulation-signaling protein NodO from Rhizobium leguminosarum biovar viciae forms ion channels in membranes.

The secreted nodulation-signaling protein NodO was purified from the supernatant of cultures of Rhizobium leguminosarum biovar viciae. The native protein has a M(r) of approximately 67,000, suggesting that it exists as a dimer since the DNA sequence predicts a M(r) of 30,002. Pure NodO protein had no protease, pectinase, or cellulase activity, and no binding was observed to lipooligosaccharide nodulation factors. Although NodO is relatively hydrophilic, it appeared to insert into liposomes and was protected by liposomes from proteolytic cleavage. When added to planar lipid bilayers, NodO formed cation-selective channels that allowed the movement of monovalent cations (K+ and Na+) across the membrane. NodO is a Ca(2+)-binding protein; in the presence of high concentrations of Ca2+, channel activity was reduced. We hypothesize that NodO plays a role in nodulation signaling by stimulating uptake of nodulation factors or by forming cation-specific channels that function synergistically with the proposed lipooligosaccharide-induced depolarization of the plasma membrane of leguminous plants.

Bacterial Proteins↗
PubMed1994

Major clinical events after coronary stenting. The multicenter registry of acute and elective Gianturco-Roubin stent placement. The Gianturco-Roubin Intracoronary Stent Investigator Group.

BACKGROUND: Abrupt vessel closure and early reocclusion remain the principal vascular events underlying early recurrent ischemia complicating elective percutaneous transluminal coronary angioplasty (PTCA). Intracoronary stenting has been used to circumvent emergency bypass surgery after acute vessel closure and as an adjunct for the elective treatment of restenosis. The initial multicenter experience with the Gianturco-Roubin stent is presented, and predictors for early recurrent ischemic events are identified. METHODS AND RESULTS: Data accrued from 639 serial patients undergoing emergency stenting for abrupt closure (n = 415; 65%) or elective deployment for restenosis (n = 224; 35%) from October 1989 through May 1991 were analyzed. The incidence of subsequent ischemic events, including death, nonfatal myocardial infarction, and bypass surgery referral within 90 days of the procedure, was higher after acute deployment (20%) compared with elective stenting (9%; P = .0004). Although mortality within the two cohorts was the same (3%; P = NS), there were significant differences in the incidence of nonfatal myocardial infarction (5% versus 0.5%; P = .002) and bypass surgery (12% versus 6%; P = .02) between the acutely and electively stented patients, respectively. These events were significantly more common when the stent was undersized to the target vessel diameter (stent:artery ratio for event, 0.95 +/- 0.14 versus no event, 1.04 +/- 0.22; P = .0001) or when there was less expansion of the lesion by the deployed device (stent-to-lesion diameter ratio for event, 6.6 +/- 9.2 versus no event, 11.0 +/- 21.4; P = .0001). In a stepwise logistic regression model, acute stenting (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.3 to 2.4), multivessel disease (OR, 1.4; CI, 1.1 to 1.8), larger target lesion diameter (OR, 2.1; CI, 1.4 to 3.2), larger target vessel (OR, 2.9; CI, 1.7 to 4.7), and smaller stent size (OR, 6.1; CI, 3.0 to 12.3) were independent predictors of early, recurrent ischemic events. The presence of thrombus was associated with a higher event rate after elective stenting (OR, 2.3; CI, 1.06 to 5.4) but was not associated with a higher early event rate after acute stenting. CONCLUSIONS: Early ischemic events are more common after acute stenting for abrupt or threatened closure than after elective deployment. These events may be avoided with careful attention to morphometric characteristics to avoid undersizing the stent to the target vessel and ensure adequate lesion expansion.

Angioplasty, Balloon, Coronary↗
PubMed1992

Six-year survival after coronary thrombolysis and early revascularization for acute myocardial infarction.

Six-year follow-up was conducted in a consecutive series of 192 patients receiving thrombolytic therapy for acute myocardial infarction (AMI) with ST-segment elevation. Cardiac catheterization was performed within a day, and patients with an open infarct artery routinely had early revascularization: 99 (67%) underwent coronary bypass surgery and 18 (12%) coronary angioplasty. With this treatment strategy, 6-year cardiac mortality was 14.5%, 6% (12 patients) in hospital and 9% (16 patients) for survivors of hospitalization. Multivariate analysis showed that predictors of cardiac death among survivors of hospitalization were a closed infarct artery at catheterization (p less than 0.01), diabetes (p less than 0.01) and anterior myocardial infarction (p = 0.01). A subset of 146 patients underwent radionuclide angiography before hospital discharge; for them, predictors of mortality were a closed infarct artery at catheterization (p less than 0.01), anterior wall AMI (p = 0.02), and Killip class III to IV on admission (p less than 0.06). Left ventricular ejection fraction was not a significant predictor of mortality for this subset of patients.

Aged↗
PubMed1991

Significance of a negative exercise thallium test in the presence of a critical residual stenosis after thrombolysis for acute myocardial infarction.

BACKGROUND: After thrombolytic therapy for acute myocardial infarction, increasing emphasis is placed on early submaximal exercise testing, with further intervention advocated only for demonstrable ischemia. Although significant residual coronary artery lesions after successful thrombolysis are common, many patients paradoxically have no corresponding provokable ischemia. METHODS AND RESULTS: The relation between significant postthrombolytic residual coronary artery disease and a negative early, submaximal exercise thallium-201 tomogram was studied among 101 consecutive patients with uncomplicated myocardial infarction and at least 70% residual stenosis of the infarct artery. A negative test occurred in 49 (48.5%) patients with a mean 88% residual infarct artery stenosis. Further characteristics of the group were as follows: mean time to treatment was 3.1 hours; mean age was 54 +/- 10 years; 80% were male; 47% had anterior infarction; 39% had multivessel disease; mean left ventricular ejection fraction was 53 +/- 14%; and mean peak creatine kinase level was 3,820 +/- 3,123 IU/ml. A similar group of 52 (51.5%) patients, treated within 3.3 hours from symptom onset, with a mean postthrombolysis stenosis of 90%, had a positive exercise test. Characteristics of this group were as follows: age was 58 +/- 10 years; 92% were male; 56% had anterior infarction; 40% had multivessel disease; and mean left ventricular ejection fraction was 54 +/- 15%. The peak creatine kinase level associated with the infarction, however, was lower: 2,605 +/- 1,805 IU/ml (p = 0.04). There was no difference in performance at exercise testing with respect to peak systolic pressure, peak heart rate, or time tolerated on the treadmill between the two groups. By multivariate logistic regression, only peak creatine kinase level predicted a negative stress result in the presence of a significant residual stenosis (odds ratio, 4.2; 95% confidence interval, 1.1-16.3). CONCLUSIONS: The explanation for the relatively frequent finding of a negative early stress 201Tl tomogram after apparently successful reperfusion appears to be more extensive myocardial necrosis and not delay in therapy or inadequate exercise performance.

Creatine Kinase↗
PubMed1990

Usefulness of coronary artery angioplasty strategies in acute myocardial infarction.

The usefulness of percutaneous transluminal coronary angioplasty (PTCA) as an adjunct to thrombolytic therapy for acute myocardial infarction is the focus of intense clinical investigation. With an angiographically significant residual stenosis present in the infarct vessel in at least 70% of cases, PTCA has the potential to resolve residual ischemia of surviving myocardium; provide a route for nutrient influx to promote healing and reorganization by leukocytes and fibroblasts; and maintain ventricular wall integrity. Additionally, the residual lesion may interfere with flow to collateral vessels supplying other diseased vascular territories, or inhibit the delivery of inotropic or antiarrhythmic agents to a problematic peri-infarct region. Various angioplasty strategies have been devised to define the optimal timing of PTCA in several clinical settings. Although the impact on resting left ventricular performance has been disappointing except in cases of cardiogenic shock, an approach involving early angiography with thoughtful triage to PTCA when feasible, has been associated with improved survival at one- to three-year follow-up, compared with a 'thrombolysis only' approach. The results of clinical trials investigating the role of PTCA as a direct method of revascularization; as a 'rescue' procedure following failed thrombolysis; as an empiric, immediate or deferred strategy; or as an elective adjunct to thrombolytic therapy only in the presence of subsequent ischemia are reviewed in detail.

Angioplasty, Balloon, Coronary↗