The pathogenesis of the antiphospholipid syndrome.
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Antibody Specificity↗
Biomedical subjects
I Ford
Publications and source records attributed to I Ford.
Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
BACKGROUND: Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. METHODS: We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. RESULTS: Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). CONCLUSIONS: Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.
Anticholesteremic Agents↗
Model inconsistency, illustrated by the Cox proportional hazards model.
We consider problems involving the comparison of two or more treatments where we have the opportunity to adjust for relevant covariates either conditionally in a regression model or implicitly in repeated measures data, for example, in crossover trials. It is seen that for data arising from non-Normal distributions there is the possibility that models adjusting for covariates and those not adjusting for covariates will be inconsistent, that is, at most one of the models can be valid. Alternatively, even if conditional and unconditional models are valid, parameters in each model may have different interpretations. We note that this presents difficulties for the specification and interpretation of the analysis. It is also clear that model validation is critical. Specific attention is paid to survival data analysed by the Cox proportional hazards model.
Analysis of Variance↗
Commentary and opinion: III. Some nonontological and functionally unconnected views on current issues in the analysis of PET datasets.
Strother et al. (1995) and Friston (1995) both raise important issues and provide useful reviews of various aspects of PET data analysis. Statisticians would not assume that any single piece of methodology would answer all questions about a type of data in a variety of experimental and observational contexts. The fundamental importance of hypothesis-driven inference, based on well designed experiments, cannot be overestimated for its ability to progress scientific understanding in an orderly manner. However, hypothesis-generating experiments are also vital in their own right. In practice, we generally do not have the luxury of both types of experiment, and we should note Strother et al.'s comment on the importance of extracting as much information as possible from each dataset. Friston (1995) also sees formal testing methods and exploratory methods such as principal components analysis as complementary. The correct approach would therefore seem to be (a) to select methods for formal and exploratory data analysis from the rich existing tool kit of statistical procedures, (b) to modify these as necessary to deal with special PET problems such as multiplicity, (c) to be aware of the assumptions underlying the methods being used and to investigate the problems that can arise if these assumptions fail to hold, (d) to appreciate the complexity of both PET data and of the potential questions that can be asked of it, and (e) to be aware of the limitations of any statistical analysis and the need for caution in interpreting conclusions not based on any predefined hypothesis.
Analysis of Variance↗
Does the exercise protocol matter when assessing the anti-anginal effects of drug therapy?
Four exercise test protocols (Bruce, Balke, Ellestad and Steep) were compared in 16 patients with proven coronary artery disease in demonstrating the anti-anginal effects of sublingual glyceryl trinitrate in a randomization double-blind trial. Glyceryl trinitrate significantly improved the time, heart rate and rate pressure product to peak exercise, onset of angina and 1 mm ST segment depression in all four protocols (P < 0.05) (except rate pressure product to angina in the Balke protocol). The increase in exercise time was greatest for the Balke protocol at peak exercise (188.1 +/- 187.1) (mean +/- SD in s), at onset of angina (251.9 +/- 247.1) and at 1 mm ST depression (233.6 +/- 243.8), followed by the Steep and Bruce protocols, and was lowest for the Ellestad protocol 41.9 +/- 42.4, 96.5 +/- 65.8, 82.6 +/- 74.0, respectively. Increase in time to peak exercise with glyceryl trinitrate was significantly greater for the Balke protocol in comparison with the other three protocols and for the Bruce and Steep protocols when compared to the Ellestad protocol. Time to 1 mm ST depression with treatment was significantly greater on the Balke and Bruce protocols than the Ellestad protocol, and to onset of angina for the Balke compared to other three protocols. There were no significant differences between the Bruce and Steep protocols for any of the endpoints. The magnitude of treatment effect in the different protocols was accompanied by correspondingly greater inter-patient variability such that no protocol was more, or less, sensitive than another in detecting treatment effect. Changes in heart rate and rate pressure product with treatment were generally similar between the different protocols. In conclusion, a protocol with small and frequent increments (Balke), although able to show greater increase in exercise duration with glyceryl trinitrate than more aggressive protocols, is no more sensitive at detecting treatment effect.
Adult↗
The South African Pilot Hospital Accreditation Programme.
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Accreditation↗
Cardiorespiratory and symptomatic variables during maximal and submaximal exercise in men with stable effort angina: a comparison of atenolol and celiprolol.
Celiprolol is a novel beta 1 selective adrenoreceptor blocker with partial beta 2 agonism and direct vasodilator activity. These ancillary properties may reduce symptomatic breathlessness and fatigue and modify respiration during exercise. To test this hypothesis 20 men with stable effort angina were enrolled in a double-blind crossover study to investigate the effects of atenolol 100 mg once daily (A) and celiprolol 400 mg once daily (C) on cardiorespiratory and symptomatic variables during maximal and submaximal exercise. Total exercise time on a modified Bruce protocol was similar on both treatments: C12.5 min, A 13.1 min. During steady state submaximal exercise at 60-75% (mean 68%) of maximum work capacity, minute ventilation (C33.81 min-1, A 33.51 min-1), oxygen uptake (C14.6 ml.kg-1.min-1, A15.1 ml.kg-1.min-1), respiratory exchange ratio (C 0.89, A 0.87), ratio of VE/VCO2 (C 33.6, A 33.4), ratio of VE/VO2 (C 2.34, A 2.72), Borg perceived exertion score (C 11.2, A 10.9) and visual analogue scores for breathlessness (C 29.5, A 25.9) and muscle fatigue (C 28.9, A 26.0) were all similar on both treatments. At maximal exercise capacity on the modified Bruce protocol, minute ventilation (C 58.31 min-1, A 60.41 min-1), oxygen uptake (C 21.3 ml.kg-1.min-1, A 21.7 ml.kg-1.min-1), respiratory exchange ratio (C 1.02, A.1.05), ratio VE/VCO2 (C 34.8, A 35.9), and ratio VE/VO2 (C 2.80, A 2.83) were also similar on both drugs. Over a 10 day period anginal attacks (C 10.1 +/- 10.4, A 5.4 +/- 5.9) and sublingual GTN use (C 5.9 +/- 10.3, A 4.4 +/- 9.8) were both more frequent on celiprolol).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
PET assessment of brain metabolic recovery in aphasia.
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Aphasia↗
Statistical methods in neuroimaging with particular application to emission tomography.
We review statistical methods being applied in four key areas connected with PET and SPECT neuroimaging: (i) image reconstruction (briefly); (ii) tracer-kinetic, or compartmental, modelling; (iii) inference from region-of-interest data; (iv) inference at the pixel or voxel level. Under the last heading, we pay particular attention to the analysis of data from serial scans. We conclude by identifying some topics for future statistical research.
Algorithms↗
Changes in haematological indices, blood viscosity and inhibitors of coagulation during treatment of endometriosis with danazol.
The effects of treatment with danazol (600 mg daily) on haemostatic and haematological function were investigated in 18 pre-menopausal women with endometriosis. Blood samples were taken at 2 pre-treatment visits, at 6, 12 and 24 weeks on treatment, and at 6 weeks after discontinuation of the drug. Haemoglobin, red cell count, haematocrit and platelet count all rose significantly during treatment with danazol (p < 0.01 vs. baseline). Plasma fibrinogen levels fell significantly (p < 0.01), while whole blood viscosity increased during treatment and remained significantly elevated at follow-up. The prothrombin time shortened, but remained within normal limits, and there were no significant changes in factor VII:C, VIIa, or fibrinopeptide A. No significant changes were found in platelet function. Plasma B-beta 15-42 increased significantly. Functional levels of protein C, protein S, and antithrombin III, all rose significantly, above the normal range, while C4b-binding protein levels fell. We conclude that the observed changes in coagulation inhibitors and fibrinolytic activity may be considered beneficial in the context of venous thromboembolism. The rheological effects, however, indicate a degree of caution in the use of the drug in individuals considered to be at risk from arterial cardiovascular disease.
Adult↗
Quantification of primary and secondary lesions in severe head injury.
The current trend is to classify brain damage due to non-missile head injury as focal or diffuse. Quantitative findings will be discussed and reference will be made to both human and experimental non-human primate.
Adolescent↗
Mechanisms of platelet aggregation by Streptococcus sanguis, a causative organism in infective endocarditis.
The ability of certain strains of Streptococcus sanguis to aggregate human platelets in vitro may be related to their virulence in the pathogenesis of infective endocarditis. We have studied the mechanisms of aggregation of human platelets by S. sanguis strain NCTC 7863. Platelet aggregation follows incubation of S. sanguis cells with platelet-rich plasma from normal, healthy adults, after a lag of 7-19 min. Platelet aggregation was accompanied by 5-hydroxytryptamine release and thromboxane B2 production. Aggregation was prevented by aspirin and by EDTA. Platelets from two patients with Glanzmann's thrombasthenia did not respond to bacteria. Fixed, washed platelets resuspended in normal plasma were not agglutinated by S. sanguis. Blocking the glycoprotein Ib receptor with a monoclonal antibody inhibited aggregation of PRP. However, S. sanguis did not induce von Willebrand factor (vWF) binding to platelets; nor did the bacteria prevent ristocetin-induced platelet agglutination or vWF binding. The aggregation response was not related to plasma vWF activity levels in normal subjects or in patients with von Willebrand's disease. The platelet response to S. sanguis therefore resembles true aggregation, requiring the cyclo-oxygenase pathway and the presence of glycoprotein IIb/IIIa. The mechanism also involves glycoprotein Ib, but not apparently through irreversible binding of vWF.
Agglutination↗
Early treatment with captopril after acute myocardial infarction.
OBJECTIVES: To determine the effects of early treatment with captopril on haemodynamic function, neuroendocrine biochemistry, left ventricular structure, clinical outcome, and exercise capacity over one year from acute myocardial infarction. DESIGN: Randomised, double blind, placebo controlled comparison of captopril and placebo. SETTING: Coronary care units and cardiology departments of two university teaching hospitals in Glasgow. PATIENTS: 99 haemodynamically stable patients with acute myocardial infarction, selected on clinical grounds as being at risk of late ventricular dilatation. INTERVENTION: Captopril or identical placebo started between six and 24 hours after start of symptoms and continued for 12 months. Target maintenance dose was 25 mg three times a day. MAIN OUTCOME MEASURES: (a) Acute haemodynamic effects of treatment; (b) neuroendocrine biochemistry from admission to two months; and (c) change in echocardiographic measures of left ventricular size, clinical outcome, and exercise capacity after 12 months of treatment with a separate analysis of the effects of one month of treatment withdrawal on left ventricular volumes. RESULTS: Captopril caused acute reductions in mean (SEM) pulmonary artery pressure (2.48 (0.69) mm Hg) and systemic vascular resistance (260 (103)) dyn.s.cm-5). Over the first 10 hours captopril reduced mean arterial pressure by 12.1 (2.4) mm Hg compared with 3.8 (1.9) mm Hg in the placebo group. No patient had to be withdrawn from the captopril group because of hypotension. From day 1 onwards systolic and diastolic arterial pressures in the captopril treated group were slightly but not significantly lower than on placebo. There was no difference in the incidence of ventricular or supraventricular arrhythmia with treatment. Captopril prevented the day 3 peak in angiotensin II that occurred in the placebo group (peak concentration (interquartile range): 10.1 (4.8-19.4) pg/ml v 16.8 (4.3-46.3) pg/ml)) but had no effect on atrial natriuretic factor, arginine vasopressin, or catecholamines. Plasma atrial natriuretic factor remained above normal in both groups at two months after infarction. After one year left ventricular volume indices had increased less on captopril than on placebo: left ventricular end systolic volume index 5.4 ml/m2 v 14.7 ml/m2 (95% confidence interval (95% CI) of difference -14.6 to -3.9; p = 0.0011); left ventricular end diastolic volume index 8.4 ml/m2 v 19.0 ml/m2 (95% CI of difference, -17.0 to -4.2; p = 0.0016). Withdrawal of captopril for one month did not affect ventricular volumes. There was no difference in exercise capacity. CONCLUSIONS: Captopril started between six and 24 hours after acute myocardial infarction is not associated with significant hypotension. It suppresses activation of the renin angiotensin system but has no effect on plasma concentrations of other neurohormones. Atrial natriuretic factor remains raised at two months after myocardial infarction. Captopril significantly decreases left ventricular dilatation. This effect is not lost after one month of treatment withdrawal and is thus due to an alteration of left ventricular structure and not to a short lived haemodynamic action of captopril. Long-term treatment with captopril does not result in improved aerobic exercise capacity after acute myocardial infarction.
Adult↗
Clinical trials in silent ischaemia: lessons from TIBET.
The Total Ischaemic Burden European Trial (TIBET) affords the opportunity to investigate the prognostic value of both exercise testing and ambulatory monitoring on and off medical treatment; 682 patients were followed for two years. Patients with < 1 mm ST segment depression on exercise testing have very low risk indeed of an important end point in a two year period, and this effect is partially obscured by the presence of medical treatment. Ambulatory monitoring showed that the presence of silent ischaemia had little prognostic impact in this group of patients.
Aged↗
Relationships between haemostatic factors and capillary morphology in human diabetic neuropathy.
We have examined haemostatic factors in 15 diabetic patients with peripheral neuropathy and 10 diabetic patients without clinical complications. Plasma and blood viscosity, fibrinogen, factor VIIIc, von Willebrand factor activity, spontaneous platelet aggregation and fibrinolytic activity were not significantly different between diabetic patients without clinical complications and diabetic patients with peripheral neuropathy. Platelet aggregation was enhanced in diabetic patients with neuropathy compared with those without complications. In the 15 patients with neuropathy and 3 without complications, who underwent biopsy of sural nerve, skin and muscle, associations were found between haemostatic variables and measures of nerve capillary pathology, notably: plasma fibrinogen and nerve capillary basement membrane thickness (r = 0.70, p < 0.001); thromboxane B2 production and nerve capillary basement membrane thickness (r = -0.61, p < 0.01); plasma fibrinolytic activity and endoneurial capillary lumen size (r = 0.60, p < 0.01) and endothelial cell outer perimeter (r = 0.65, p < 0.01). The main associations of skin and muscle capillary abnormalities were with measures of in vitro platelet aggregation, and the correlations found with nerve capillary measurements were not echoed in the overlying muscle and skin. The results are supportive of the involvement of haemostatic abnormalities in the pathogenesis of diabetic neuropathy.
Adult↗
Effects of early captopril administration on infarct expansion, left ventricular remodeling and exercise capacity after acute myocardial infarction.
In a double-blind study, 99 patients (82 men, age range 40 to 75 years) with acute myocardial infarction (AMI) were randomly assigned to receive captopril or placebo. Treatment began within 24 hours of admission. Serial echocardiographic measurements of endocardial segment lengths and left ventricular (LV) volumes, and ejection fractions were obtained. The 2 groups were matched at baseline except for an excess of previous AMI in the placebo group (13 of 50 vs 2 of 49 patients, p = 0.002). The increase in anterior segment length, from baseline to 2 months, was significantly less in the captopril than in the placebo group (2.8 +/- 1.6 vs 10.4 +/- 2.4mm, 95% confidence interval [CI] -13.5 to -1.7, p = 0.01). The increase in posterior segment length was also less in the captopril group, but the difference was not significant (3.2 +/- 1.2 vs 7.0 +/- 1.8mm, 95% CI -8.0 to 0.5, p = 0.08). Fewer patients in the captopril group demonstrated increases in segment length greater than 2 standard deviations of the measurement error (14 of 70 [20%] vs 29 of 72 [40%] patients, p = 0.009). In patients with anterior AMI, the infarct-containing anterior segment length increased by 4.5 +/- 2.3 mm in the captopril versus 12.4 +/- 3.1 mm in the placebo group (95% CI -15.7 to -0.2, p = 0.046), and fewer patients in the captopril group demonstrated infarct expansion (6 of 20 [30%] vs 13 of 21 [62%] patients, p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Multivariate analysis of spect images with illustrations in Alzheimer's disease.
Modern neuroimaging techniques such as positron emission tomography and single photon emission computed tomography (SPECT) often generate datasets consisting of a large number of variables measured on a small number of subjects. In addition, the data contain large 'subject effects' which must be adjusted for in any statistical analysis. This paper illustrates the dangers inherent in naive univariate analysis and proceeds to demonstrate the application of multivariate methods such as Hotellings T2-test, canonical correlation analysis and discriminant analysis. The issues and statistical methods are illustrated using a dataset from a SPECT study of groups of normal control subjects and subjects with a clinical diagnosis of Alzheimer's disease.
Alzheimer Disease↗
Submaximal, but not maximal, exercise testing detects differences in the effects of beta-blockers during treadmill exercise: a study of celiprolol and atenolol. II.
Celiprolol is a new-generation beta-blocker with ancillary properties that include partial beta 2-agonism and direct vasodilating activity. The effects of atenolol and celiprolol on maximal exercise capacity and on both respiratory variables and subjective indices of breathlessness and fatigue during submaximal exercise were compared in a placebo-controlled crossover study of 12 trained volunteers. Both atenolol and celiprolol equally and significantly reduced exercise capacity and maximal oxygen consumption. During constant submaximal exercise at 70% maximal oxygen uptake, however, differences emerged between the two beta-blockers. Atenolol was associated with a significantly higher minute ventilation than placebo. In contrast, values for minute ventilation and respiratory exchange ratio with celiprolol were similar to values with placebo. During the early stages of exercise, treatment with atenolol was also associated with higher scores for the subjective indices of breathlessness and fatigue. Thus submaximal exercise, which may be physiologically more relevant to the everyday activities of patients, may demonstrate potentially useful differences between drugs that are not seen during maximal exercise testing.
Adrenergic beta-Antagonists↗