Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation.
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Biomedical subjects
Publications and source records attributed to R J Gibbons.
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AIMS: We examined the clinical characteristics and outcome of patients with early (<2 h), intermediate (2-4 h) and late (>4 h) presentation treated by primary angioplasty or thrombolytic therapy for acute myocardial infarction. METHODS AND RESULTS: We studied 2635 patients enrolled in 10 randomized trials of primary angioplasty (n=1302) vs thrombolytic therapy (n=1333) in acute myocardial infarction, and baseline characteristics of the two groups were comparable. Increase in presentation delay is associated with older age, female gender, diabetes and an increased heart rate. We classified the patients according to the time delay from symptom onset to presentation into three categories: early presentation (<2 h), intermediate presentation (2-4 h), and late presentation (>or=4 h). At 30 days the combined rate of death, non-fatal reinfarction and stroke in patients presenting early was 5.8% in the angioplasty group vs 12.5% in the thrombolysis group, in patients with intermediate presentation, 8.6% vs 14.2%, respectively, and in patients presenting late 7.7% vs 19.4%, respectively. With increasing time from symptom onset to presentation, all major adverse cardiac event rates show a trend to a larger increase in the thrombolysis group compared to the angioplasty group, both at 30 days and at 6 months after the acute event. CONCLUSIONS: Major adverse cardiac event rates are lower after angioplasty compared to thrombolysis, irrespective of time to presentation. With increasing time to presentation major adverse cardiac event rates increase after thrombolysis but appear to remain relatively stable after angioplasty.
Rest (201) Tl imaging has been used for detecting viability, but the ideal timing for imaging after injection to maximally estimate viability is not well established. Thirty patients with fixed or incompletely reversible defects on 4 h redistribution SPECT imaging after thallium rest injection underwent 24 h imaging. Global redistribution was subjectively rated none, minimal or meaningful by two experienced observers. Fourteen patients had no meaningful redistribution at either 4 h or 24 h. Ten patients had meaningful redistribution at 4 h only. Six patients had no meaningful redistribution at 4 h but did at 24 h. Defect size was quantified using a 70% threshold. For the total group, defect size was smaller at 4 h compared to immediate imaging (38+/-18% vs 41+/-19%, P=0.06) and smaller still at 24 h (36+/-16% vs 38+/-18%, P=0.02). Later (24 h) redistribution images detected additional redistribution in 30% of the patients who did not have meaningful redistribution on early (4 h) images, and in 8% of the segments which were abnormal at 4 h. It is concluded that, in patients who have incompletely reversible defects on early redistribution imaging at 4 h, late redistribution imaging after 24 h will demonstrate additional redistribution in 30% of the patients.
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BACKGROUND: Inhibition of leukocyte adhesion can reduce myocardial infarct size in animals. This study was designed to define the safety and efficacy of a recombinant, humanized, monoclonal antibody to the CD18 subunit of the beta2 integrin adhesion receptors (rhuMAb CD18), in reducing infarct size in patients treated with a thrombolytic agent. METHODS AND RESULTS: The Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction Study (LIMIT AMI) was a randomized, double-blind, placebo-controlled, multicenter study conducted in 60 centers in the United States and Canada. A total of 394 subjects who presented within 12 hours of symptom onset with ECG findings (ST-segment elevation) consistent with AMI were treated with recombinant tissue plasminogen activator and were also given an intravenous bolus of 0.5 or 2.0 mg/kg rhuMAb CD18 or placebo. Coronary angiography was performed at 90 minutes, 12-lead ECGs were obtained at baseline, 90, and 180 minutes, and resting sestamibi scans were performed at >/=120 hours. Adjunctive angioplasty and use of glycoprotein IIb/IIIa antiplatelet agents at the time of angiography were discretionary. There were no treatment effects on coronary blood flow, infarct size, or the rate of ECG ST-segment elevation resolution, despite the expected induction of peripheral leukocytosis. A slight trend toward an increase in bacterial infections was observed with rhuMAb CD18 (P=0.33). CONCLUSIONS: RhuMAb CD18 was well tolerated but not effective in modifying cardiac end points.
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The transcription factor TFIIH is involved in both basal transcription and DNA repair. Mutations in the XPD helicase component of TFIIH can result in the diverse clinical features associated with xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). It is generally believed that the multi-system abnormalities associated with TTD are the result of a subtle deficiency in basal transcription. However, to date, there has been no clear demonstration of a defect in expression of any specific gene in individuals with these syndromes. Here we show that the specific mutations in XPD that cause TTD result in reduced expression of the beta-globin genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene have the haematological features of beta-thalassaemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All these parameters were normal in three patients with XP. These findings provide the first evidence for reduced expression of a specific gene in TTD. They support the hypothesis that many of the clinical features of TTD result from inadequate expression of a diverse set of highly expressed genes.
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The dual aims of treating patients with chronic stable angina are 1) to reduce morbidity and mortality and 2) to eliminate angina with minimal adverse effects and allow the patient to return to normal activities. In the absence of contraindications, beta-blockers are recommended as initial therapy. All beta-blockers seem to be equally effective. If the patient has serious contraindications to beta-blockers, unacceptable side effects, or persistent angina, calcium antagonists should be administered. Long-acting dihydropyridine and nondihydropyridine agents are generally as effective as beta-blockers in relieving angina. Long-acting nitrates are considered third-line therapy because a nitrate-free interval is required to avoid developing tolerance. All long-acting nitrates seem to be equally effective. Patients with angina should take 75 to 325 mg of aspirin daily unless they have contraindications. Such risk factors as smoking, elevated low-density lipoprotein cholesterol level, diabetes, and hypertension should be treated appropriately. Coronary revascularization has not been shown to improve survival for most patients with chronic angina but may be required to control symptoms. However, coronary artery bypass grafting (CABG) is often indicated for symptomatic patients with left-main disease, three-vessel disease, or two-vessel disease including proximal stenosis of the left anterior descending coronary artery; it improves their survival. Percutaneous transluminal coronary angioplasty is an alternative to CABG for patients with normal left ventricular function and favorable angiographic features. Coronary artery bypass grafting is initially more effective in relieving angina than medical therapy, but the two procedures yield similar results after 5 to 10 years. Eighty percent of patients who undergo CABG remain angina-free 5 years after surgery. In low-risk patients, percutaneous transluminal coronary angioplasty seems to control angina better than medical therapy, but recurrent angina and repeated procedures are more likely than with CABG. Patient education is an important component of management. Long-term follow-up should be individualized to ascertain clinical stability at regular intervals and to reassess prognosis when warranted.
Patients with suspected chronic stable angina can be evaluated in three stages. In stage one, the clinician uses information from the history, physical examination, laboratory tests for diabetes and hyperlipidemia, and resting electrocardiography to estimate the patient's probability of coronary artery disease (CAD). In stage two, additional testing for patients with a low probability of CAD focuses on diagnosing noncoronary causes of chest pain. Patients with a high probability of CAD have stress tests to assess their risk from CAD, and patients with an intermediate probability of CAD have stress tests to estimate the probability of CAD and assess their risk from CAD. Most patients with new-onset angina can start stress testing with exercise electrocardiography. The initial stress test should be a stress imaging procedure for patients with rest ST-segment depression greater than 1 mm, complete left bundle-branch block, ventricular paced rhythm, preexcitation syndrome, or previous revascularization with percutaneous coronary angioplasty or coronary artery bypass grafting. Patients who cannot exercise can have an imaging procedure with stress induced by pharmacologic agents. In stage three, patients with a predicted average annual cardiac mortality rate between 1% and 3% should have a stress imaging study or coronary angiography with left ventriculography. Those with a known left ventricular dysfunction should have cardiac catheterization. Patients with CAD who have an estimated annual mortality rate greater than 3% should have cardiac catheterization to determine whether their anatomy is suitable for revascularization. Patients with an estimated annual mortality rate less than 1% can begin to receive medical therapy.
Maximal benefits of coronary reperfusion after acute myocardial infarction (AMI) with ST-segment elevation may be attenuated by neutrophil-mediated reperfusion injury. Inflammatory mediators released from potentially viable myocytes cause activation of neutrophils, which traverse the endothelium and enter the myocardium. This process involves interaction between the neutrophil-expressed CD11/CD18 and endothelial-expressed intercellular adhesion molecule-1 (ICAM-1). Preclinical studies have shown that monoclonal antibodies (MAb) to CD18 can limit infarct size and preserve left ventricular function. We sought to determine the initial clinical safety and tolerability of Hu23F2G (LeukArrest), a humanized MAb to CD11/CD18, in patients with AMI who underwent percutaneous transluminal coronary angioplasty (PTCA). Sixty patients with AMI were randomized to low- (0.3 mg/kg) or high-dose (1.0 mg/kg) Hu23F2G or to placebo immediately before PTCA. We found no clinically significant differences in vital signs, physical examination, laboratory evaluation, or need for subsequent cardiac interventions. In Hu23F2G treatment groups, serum concentration of Hu23F2G increased rapidly to 3,234 +/- 1,298 microg/L (low-dose group) and 15,558 +/- 4409 microg/L (high-dose group) between 5 and 60 minutes, then declined over 72 hours to near-baseline values. Myocardial single-photon emission computed tomographic imaging 120 to 260 hours after PTCA showed no statistically significant differences in final left ventricular defect size. Hu23F2G was well tolerated, with no increase in adverse events, including infections. Thus, Hu23F2G appears safe and well tolerated in patients undergoing PTCA for AMI.
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The exercise electrocardiogram (ECG) is widely believed to be less accurate in women, primarily due to a high prevalence of false-positive tests. The purpose of this study was to examine the relative accuracy of the exercise ECG in women versus men in 8,671 patients (3,213 women, 5,458 men) using myocardial perfusion imaging as the reference standard. More women (14%) than men (10%) had a false-positive ECG (p <0.001), but the absolute difference was relatively small. The false-negative rate was considerably lower in women (17% vs 32%, p <0.001). Compared with men, women had lower test sensitivity (30% vs 42%, p <0.001) and positive predictive value (34% vs 70%, p <0.001) but higher specificity (82% vs 78%, p = 0.002), negative predictive value (78% vs 52%, p <0.001), and accuracy (69% vs 58%, p <0.001). In patients with a false-negative exercise ECG, "high-risk" scans were less prevalent in women (12% vs 19%, p <0.001). In the smaller subset of patients referred for coronary angiography (205 women, 838 men), the false-positive electrocardiographic rate was again higher in women (13% vs 7%, p = 0.003), but neither specificity (69% vs 74%, p = NS) nor accuracy (60% vs 66%, p = NS) was different between the sexes. Thus, the percentage of patients with a false-positive exercise ECG was higher in women than men but low in absolute terms (<15%) for both sexes. Test specificity was not lower in women. These results suggest that gender should not be a major determinant for selecting stress imaging over standard treadmill testing.
BACKGROUND: Left ventricular ejection fraction (LVEF) is a recognized determinant of survival in patients with coronary artery disease. In major trials comparing surgical and percutaneous revascularization approaches, the long-term effect of the coronary revascularization strategy on LVEF has not been reported. METHODS AND RESULTS: In the NHLBI-sponsored Bypass and Angioplasty Revascularization Investigation (BARI) randomized trial comparing angioplasty and bypass surgery as initial treatment strategies, 1220 (75%) of the 1617 surviving randomized patients had their EF measured by radionuclide ventriculography 5 years after study entry. For the total study group, the 5-year EF in the CABG group (n=623) was 55.8+/-12.3, compared with 55.7+/-12.7 in PTCA group (n=597, P:=0.82). There was no significant difference in measured EF between the CABG group and the PTCA group within multiple subgroups determined by the presence or absence of diabetes, 3-vessel disease, complete revascularization, or prior myocardial infarction. In a multiple linear regression model developed to predict 5-year EF, treatment assignment to PTCA or CABG was not significant (P:=0.95). If an EF of 0 was imputed for patients who were dead and missing EF data, however, there was a higher EF in the CABG group (P:=0.0018) among diabetic patients only. CONCLUSIONS: In the BARI randomized trial, initial treatment assignment to angioplasty was not associated with any difference in long-term ventricular function compared with initial treatment assignment to surgery. These results apply, however, only to patients who were alive at 5 years.
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OBJECTIVES: We sought to evaluate the prognostic impact of right ventricular (RV) myocardial involvement in patients with inferior myocardial infarction (MI). BACKGROUND: There is uncertainty regarding the risk of major complications in patients with inferior MI complicated by RV myocardial involvement. Whether these complications are related to RV myocardial involvement itself or simply to the extent of infarction involving the left ventricle (LV) is also unknown. METHODS: We examined the incidence of death and mechanical and electrical complications in patients with (n = 491) and without (n = 638) RV myocardial involvement and in patients with anterior MI (n = 971) in an analysis from the Collaborative Organization for RheothRx Evaluation (CORE) trial. Left ventricular infarct size was assessed by technetium-99m-sestamibi single-photon emission computed tomography and peak creatine kinase, and LV function was assessed by radionuclide angiography. We also performed a meta-analysis in which we pooled the results of our study with previous smaller studies addressing the same question. RESULTS: Six-month mortality was 7.8% in inferior MI compared with 13.2% in anterior MI. Among patients with inferior MI, serious arrhythmias were significantly more common in patients with RV myocardial involvement who also had a trend toward higher mortality, pump failure and mechanical complications. However, this was not associated with a difference in LV infarct size or function. A meta-analysis of six studies (n = 1,198) confirmed that RV myocardial involvement was associated with an increased risk of death (odds ratio [OR] 3.2, 95% confidence interval [CI] 2.4 to 4.1), shock (OR 3.2, 95% CI 2.4 to 3.5), ventricular tachycardia or fibrillation (OR 2.7, 95% CI 2.1 to 3.5) and atrioventricular block (OR 3.4, 95% CI 2.7 to 4.2). CONCLUSIONS: Patients with inferior MI who also have RV myocardial involvement are at increased risk of death, shock and arrhythmias. This increased risk is related to the presence of RV myocardial involvement itself rather than the extent of LV myocardial damage.
OBJECTIVE: The objective of this study was to evaluate the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for exercise testing (EXT) after successful coronary revascularization (CR) using the Bypass Angioplasty Revascularization Investigation experience. BACKGROUND: The ACC/AHA guidelines state that EXT within three years of successful CR is not useful. METHODS: The 1,678 patients randomized to CR by either angioplasty or bypass surgery were required to take symptom-limited treadmill tests one, three and five years after revascularization. RESULTS: Patients who took the test at each specified time had a much lower subsequent two-year mortality than those who did not (1.9% vs. 9.4%, 3.5% vs. 12.6% and 3.3% vs. 11.0% at one, three and five years, respectively, after CR [p < 0.0001 for each]). Exercise parameters at the one- and three-year test did not improve a multivariable model of survival after including clinical parameters. Exercising to Bruce stage 3 or generating a Duke score >-6 were independently predictive of two-year survival after the five-year test. ST depression on the one-year test was associated with more revascularizations (relative risk = 1.6; p < 0.001). CONCLUSIONS: Patients with stable multivessel coronary disease who took a protocol-mandated exercise test at one, three and five years after revascularization were at low risk for mortality in the two years subsequent to each test. Exercise parameters did not improve prediction of mortality in the two years after the one- and three-year tests. The ACC/AHA guidelines on exercise testing after CR (no value for routine testing in stable patients for three years after revascularization) are supported by these results.