Leslie Daly

Hyperhomocysteinemia: an independent risk factor for vascular disease.

BACKGROUND Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine beta-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine beta-synthase deficiency. METHODS We first established a diagnostic criterion for hyperhomocysteinemia by comparing peak serum levels of homocysteine after a standard methionine-loading test in 25 obligate heterozygotes with respect to cystathionine beta-synthase deficiency (whose children were known to be homozygous for homocystinuria due to this enzyme defect) with the levels in 27 unrelated age- and sex-matched normal subjects. A level of 24.0 mumol per liter or more was 92 percent sensitive and 100 percent specific in distinguishing the two groups. The peak serum homocysteine levels in these normal subjects were then compared with those in 123 patients whose vascular disease had been diagnosed before they were 55 years of age. RESULTS Hyperhomocysteinemia was detected in 16 of 38 patients with cerebrovascular disease (42 percent), 7 of 25 with peripheral vascular disease (28 percent), and 18 of 60 with coronary vascular disease (30 percent), but in none of the 27 normal subjects. After adjustment for the effects of conventional risk factors, the lower 95 percent confidence limit for the odds ratio for vascular disease among the patients with hyperhomocysteinemia, as compared with the normal subjects, was 3.2. The geometric-mean peak serum homocysteine level was 1.33 times higher in the patients with vascular disease than in the normal subjects (P = 0.002). The presence of cystathionine beta-synthase deficiency was confirmed in 18 of 23 patients with vascular disease who had hyperhomocysteinemia. CONCLUSIONS Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency.

Low Circulating Folate and Vitamin B6 Concentrations Risk Factors for Stroke, Peripheral Vascular Disease, and Coronary Artery Disease

BACKGROUND A high plasma homocysteine concentration is a risk factor for atherosclerosis, and circulating concentrations of homocysteine are related to levels of folate and vitamin B6. This study was performed to explore the interrelationships between homocysteine, B vitamins, and vascular diseases and to evaluate the role of these vitamins as risk factors for atherosclerosis. METHODS In a multicenter case-control study in Europe, 750 patients with documented vascular disease and 800 control subjects frequency-matched for age and sex were compared. Plasma levels of total homocysteine (before and after methionine loading) were determined, as were those of red cell folate, vitamin B12, and vitamin B6. RESULTS In a conditional logistic regression model, homocysteine concentrations greater than the 80th percentile for control subjects either fasting (12.1 micromol/L) or after a methionine load (38.0 micromol/L) were associated with an elevated risk of vascular disease independent of all traditional risk factors. In addition, concentrations of red cell folate below the lowest 10th percentile (<513 nmol/L) and concentrations of vitamin B6 below the lowest 20th percentile (<23.3 nmol/L) for control subjects were also associated with increased risk. This risk was independent of conventional risk factors and for folate was explained in part by increased homocysteine levels. In contrast, the relationship between vitamin B6 and atherosclerosis was independent of homocysteine levels both before and after methionine loading. CONCLUSIONS Lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.

Diet and 20-year mortality from coronary heart disease: the Ireland-Boston Diet-Heart Study.

In a prospective epidemiologic study of 1001 middle-aged men, we examined the relation between dietary information collected approximately 20 years ago and subsequent mortality from coronary heart disease. The men were initially enrolled in three cohorts: one of men born and living in Ireland, another of those born in Ireland who had emigrated to Boston, and the third of those born in the Boston area of Irish immigrants. There were no differences in mortality from coronary heart disease among the three cohorts. In within-population analyses, those who died of coronary heart disease had higher Keys (P = 0.06) and modified Hegsted (P = 0.02) dietary scores than did those who did not (a high score indicates a high intake of saturated fatty acids and cholesterol and a relatively low intake of polyunsaturated fatty acids). These associations were significant (P = 0.03 for the Keys and P = 0.04 for the modified Hegsted scores) after adjustment for other risk factors for coronary heart disease. Fiber intake (P = 0.04) and a vegetable-foods score, which rose with increased intake of fiber, vegetable protein, and starch (P = 0.02), were lower among those who died from coronary heart disease, though not significantly so after adjustment for other risk factors. A higher Keys score carried an increased risk of coronary heart disease (relative risk, 1.60), and a higher fiber intake carried a decreased risk (relative risk, 0.57). Overall, these results tend to support the hypothesis that diet is related, albeit weakly, to the development of coronary heart disease.

Long term effect on mortality of stopping smoking after unstable angina and myocardial infarction.

Subjects who stop smoking cigarettes after myocardial infarction have an improved rate of survival compared with those who continue, but to date it was not known whether the benefit persisted for more than six years. A total of 498 men aged under 60 years who had survived a first episode of unstable angina or myocardial infarction by two years were followed up by life table methods for a further 13 years. Mortality in those who continued to smoke was significantly higher (82.1%) than in those who stopped smoking (36.9%). These differences increased with time. Mortality in those who were non-smokers initially and who continued not to smoke was intermediate (62.1%). The adverse effect of continued smoking was most pronounced in those with unstable angina. Continuing to smoke increased the rate of sudden death to a greater degree in those with less severe initial attacks, while the effect of smoking on fatal reinfarctions was most apparent in those with a more complicated presentation. These findings suggest that stopping cigarette smoking is the most effective single action in the management of patients with coronary heart disease.

Simple SAS macros for the calculation of exact binomial and Poisson confidence limits

Statistical analysis using confidence intervals is now a preferred approach in the medical literature, and confidence limits for binomial proportions and Poisson counts are commonly required. Normal approximations of varying accuracy are often used in such situations and it is not generally realised that non-iterative exact solutions are available. This paper shows that the exact binomial and Poisson confidence limits can be expressed very simply in terms of the inverse beta and inverse gamma distributions, and describes two macros in the SAS programming language to perform the computations. The exact solutions are compared with some approximations and further applications of the techniques are described.

Stroke Associated with Atrial Fibrillation – Incidence and Early Outcomes in the North Dublin Population Stroke Study

Background: Prospective population-based studies are important to accurately determine the incidence and characteristics of stroke associated with atrial fibrillation (AF), while avoiding selection bias which may complicate hospital-based studies. Methods: We investigated AF-associated stroke within the North Dublin Population Stroke Study, a prospective cohort study of stroke/transient ischaemic attack in 294,592 individuals, according to recommended criteria for rigorous stroke epidemiological studies. Results: Of 568 stroke patients ascertained in the first year, 31.2% (177/568) were associated with AF (90.4%, i.e. 160/177 ischaemic infarcts). The crude incidence rate of all AF-associated stroke was 60/100,000 person-years (95% CI = 52–70). Prior stroke was almost twice as common in AF compared to non-AF groups (21.9 vs. 12.8%, p = 0.01). The frequency of AF progressively increased across ischaemic stroke patients stratified by increasing stroke severity (NIHSS 0–4, 29.7%; 5–9, 38.1%; 10–14, 43.8%; ≥15, 53.3%, p < 0.0001). The 90-day trajectory of recovery of AF-associated stroke was identical to that of non-AF stroke, but Rankin scores in AF stroke remained higher at 7, 28 and 90 days (p < 0.001 for all). Discussion: AF-associated stroke occurred in one third of all patients and was associated with a distinct profile of recurrent, severe and disabling stroke. Targeted strategies to increase anticoagulation rates may provide a substantial benefit to prevent severe disabling stroke at a population level.

Does the angle of episiotomy affect the incidence of anal sphincter injury

Objective  Mediolateral episiotomy is associated with lower rates of significant perineal tears than midline episiotomy. However, the relationship between precise angle of episiotomy from the perineal midline and risk of third‐degree tear has not been established. This study quantifies this relationship.

Unstable angina: Natural history and determinants of prognosis

One hundred one patients with unstable angina were treated conservatively without the routine use of beta receptor blocking agents, calcium antagonist drugs, anticoagulant agents or nitrates. Only two patients underwent arteriography and coronary arterial bypass surgery during hospitalization and one patient during the 1st year of follow-up study. The 28 day mortality rate was 4 percent and the total 1 year cardiac mortality rate 10 percent. Two patients died from carcinoma. The incidence rate of nonfatal myocardial infarction was 9 percent during the first 28 days and a further 3 percent for the 1st year. These results compare favorably with the immediate and 1 year prognosis reported from other studies using different treatment procedures, including modern intensive drug treatment and coronary arterial bypass surgery. Various factors studied during the acute stage of unstable angina were assessed in an effort to predict the immediate and long-term outcome. Only persistence of pain after admission to the hospital was found a significant indicator of an adverse prognosis. Modern medical treatment of unstable angina with beta receptor blocking agents, calcium antagonist drugs, anticoagulant agents, nitrates and antiarrhythmic agents is critically examined. The paucity of proper randomized controlled studies confirming the value of medication is underlined. There is little evidence to show that aggressive or intensive medical or surgical treatment is superior to a conservative approach to management in the coronary care unit. This approach includes bed rest until the pain has resolved, symptomatic drug treatment only, the minimal use of invasive investigations and careful risk factor intervention.

Population-Based Study of ABCD2 Score, Carotid Stenosis, and Atrial Fibrillation for Early Stroke Prediction After Transient Ischemic Attack The North Dublin TIA Study

Background and Purpose— Transient ischemic attack (TIA) etiologic data and the ABCD2 score may improve early stroke risk prediction, but studies are required in population-based cohorts. We investigated the external validity of the ABCD2 score, carotid stenosis, and atrial fibrillation for prediction of early recurrent stroke after TIA. Methods— Patients with TIA in the North Dublin city population (N=294 529) were ascertained by using overlapping hospital and community sources. The relations between individual ABCD2 items, carotid stenosis, atrial fibrillation, and early stroke were examined. Results— In confirmed TIA cases (n=443), carotid stenosis predicted 90-day stroke (hazard ratio=2.56; 95% CI, 1.27 to 5.15, P=0.003). Stroke risk rose with increasing grade of carotid stenosis, ranging from 5.4% (95% CI, 3.3% to 8.7%) with <50% stenosis to 17.2% (95% CI, 9.7% to 29.7%) with severe stenosis/occlusion (hazard ratio=3.3; 95% CI, 1.5 to 7.4, P=0.002). In confirmed TIA cases (n=443), the ABCD2 score performed no better than chance for prediction of 90-day stroke (c-statistic=0.55; 95% CI, 0.45 to 0.64), largely related to the 24.2% (8/33) of patients who experienced a recurrence and had low ABCD2 scores (0–3). However, in nonspecialist-suspected TIA cases (n=700), the predictive utility improved for stroke at 28 (c-statistic=0.61; 95% CI, 0.50 to 0.72) and 90 (c-statistic=0.61; 95% CI, 0.52 to 0.71) days. Conclusions— In a population-based TIA cohort, significant predictive information was provided by carotid stenosis. The ABCD2 score had predictive utility in patients with TIA suspected by nonspecialists. Low scores occurred in several patients with stroke recurrences, suggesting that caution is needed before using the score in isolation.

Association of symptoms with Helicobacter pylori infection in children

The aim of this study was to determine prospectively whether Helicobacter pylori-associated gastritis is associated with specific symptoms by evaluating whether these symptoms are relieved by treatment of the infection. Symptoms resolved after the eradication of H. pylori in only three of eight children with H. pylori-associated gastritis alone, in comparison with all six children with duodenal ulcer disease.