Computer programs that automatically review decisions can help physicians provide better patient care. In the Netherlands, the ELIAS computer information system has replaced paper medical records in some general practices. We have written a computer program called 'HyperCritic' that audits general practitioners' management of patients with essential hypertension by taking patient-specific data from the ELIAS system. We investigated whether the computer-based medical records contain sufficient information to generate critiques, and compared the limitations of audit by hypercritic with those of review by a panel of eight physicians. Hypercritic and the physicians independently reviewed the medical records of 20 randomly selected patients with hypertension and commented on the decisions made at each of 243 patient visits. Of 468 comments on patient management, 260 were judged correct by six or more of the physicians; hypercritic also made 118 of these 260 comments. The main reasons why the program did not produce the other 142 comments were: insufficient data in the computer-based medical record; absence of sufficient medical consensus; and omissions in the database of hypercritic. Calculation of an "index of merit" ([sensitivity + specificity] - 1) for individual reviewers showed that hypercritic performed better (index of merit 0.62) in its limited domain than did physician reviewers (0.3-0.56). At least in hypertension management, automated review of computer-based medical records compares favourably with review by physicians. Further development of computer-aided clinical audit requires the introduction of computer-based medical records that capture the reasoning of physicians, and of widely accepted practice guidelines.

The combined effects of negative intrathoracic pressure swings during obstructive sleep apnoeas (OSAs) and increased sympathetic nervous system tone associated with hypoxia and sleep arousal may lead to pulmonary oedema or left-ventricular hypertrophy. Therefore, we have done a study of patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy to see whether OSA could contribute to impaired left-ventricular function and to assess nasal continuous positive airway pressure (NCPAP) for treatment. Eight men (aged 29-69 years) took part in the study; all were obese. Left-ventricular ejection fraction (LVEF) was measured while on stable medication and then 4 weeks after the start of nocturnal NCPAP. NCPAP was associated with abolition of OSA (mean [SE] number of apnoeas and hypopnoeas per hour of sleep 54.1 [7.2] and 1.0 [0.4] for pretreatment and NCPAP nights, respectively, p less than 0.0001). Mean (SE) LVEF increased from 37 (4)% pretreatment to 49 (5)% after four weeks' NCPAP therapy (p less than 0.0001). Withdrawal of NCPAP for 1 week in four patients was associated with a reduction in LVEF from 53 (6)% to 45 (5)% (p less than 0.001). OSA may contribute to impaired left-ventricular function in some patients with dilated cardiomyopathy of otherwise unknown origin, and reversal of OSA by NCPAP can lead to significant improvement in LVEF.

The role of stressful life events in the onset of Graves' disease (toxic diffuse goitre) is controversial. However, the numerous early clinical reports that supported such an association were not adequately controlled and specificity of the diagnosis could be questioned. Later studies have not shown a causal relation, but these studies were small, did not have proper controls, or epidemiological methods were inappropriate. To assess possible associations between life events, heredity, social support, and Graves' disease, we have done a population-based case-control study in a defined area with about 1 million inhabitants. Over 2 years, 208 (95%) of 219 eligible patients with newly-diagnosed Graves' disease and 372 (80%) of all selected matched controls answered an identical mailed questionnaire about marital status, occupation, drinking and smoking habits, physical activity, familial occurrence of thyroid disease, life events, social support, and personality. Compared with controls, patients claimed to have had more negative life events in the 12 months preceding the diagnosis, and negative life-event scores were also significantly higher (odds ratio 6.3, 95% confidence interval 2.7-14.7, for the category with the highest negative score). Individuals who had relatives with thyroid disease (especially first-degree and second-degree relatives) were more likely to have Graves' disease (3.6, 2.2-5.9). Slightly more patients than controls were divorced (1.8, 1.0-3.3) and reported a less frequent intake of alcohol (0.4, 0.2-0.8). When results were adjusted for possible confounding factors in multivariate analyses, risk estimates were almost unchanged. These findings indicate that negative life events and hereditary factors may be risk factors for Graves' disease.

Interleukin-1 (IL-1) has been implicated in the pathogenesis of sepsis. IL-1-receptor antagonist (IL-1ra) is a naturally occurring inhibitor of IL-1 activity that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We induced endotoxaemia in 9 healthy human volunteers by injection of Escherichia coli endotoxin, and measured plasma concentrations of IL-1 and IL-1ra by radioimmunoassay during the next 24 h. Peak plasma concentrations of IL-1ra were about a hundred-fold greater than those of IL-1 beta. No IL-1 or IL-1ra were detectable in the plasma of 4 volunteers injected with saline. Our results suggest that the predominant natural response to endotoxin in man is the production of antagonist rather than agonist.

Sunlight exposure is reported by some patients to precede onset of recurrent herpes labialis. Ultraviolet (UV) B light is known to be a stimulus for the reactivation of herpes simplex virus (HSV) infections. We assessed the effect of a sunblocking agent on UV-light-induced reactivation of recurrent herpes labialis in a double-blind, placebo-controlled crossover trial. 38 patients were exposed on two separate occasions to four minimum erythema doses of UV light at an area of previous labial herpes recurrence. A solution containing sunscreen was applied to the lips before one exposure and a matched placebo before the other. After placebo and UV exposure, herpes labialis developed in 27 (71%) of the 38 patients, with a mean time to recurrence of 2.9 (SEM 0.2) days. In contrast, when sunscreen was applied before UV exposure, no lesions developed, but 1 of the 35 patients shed virus at the exposure site. We conclude that UV light is a potent stimulus for inducing reactivation of herpes labialis, and that application of sunscreen may be effective in the prevention of sunlight-induced recurrent infection.

Although platelet characteristics have an important influence on ischaemic heart disease, the nature of the association of platelet size and platelet count with death and reinfarction after an index heart attack is unknown. Mean platelet volume (MPV), a determinant of platelet reactivity, was measured in 1716 men six months after myocardial infarction (MI). Deaths and recurrent ischaemic heart disease events were then assessed at two years. MPV was greater in 126 men who had a further ischaemic event (fatal or non-fatal) than in the 1590 men who had no further MI (p less than 0.001). In addition, the MPV was larger in men who died than in those who did not (p less than 0.001). There was no difference in platelet count between these groups. When analysed by quartiles, consistent trends of increasing age-adjusted relative odds of death and recurrent ischaemic events were noted for MPV. MPV did not correlate with known ischaemic heart disease risk factors such as blood pressure, blood lipids, fibrinogen, white cell count, or plasma viscosity. We believe that MPV is a further independent risk factor for recurrent MI.

Erythropoietin significantly, reversibly, and reproducibly increased in-vitro whole-blood spontaneous platelet aggregation in 15 patients on haemodialysis. During erythropoietin treatment, spontaneous platelet aggregation was significantly higher in these subjects than in non-uraemic controls; concomitant treatment with 300 mg aspirin daily reversed platelet hyperaggregability. Erythropoietin may promote thrombosis by an effect on platelet function.

Coeliac disease may remain undiagnosed because of the non-specific nature of the presenting symptoms. Several antibody tests are claimed as markers for this condition but a direct comparison of the available tests has not been reported. The probands and healthy first-degree relatives of 42 families with coeliac disease were studied. Histological examination of biopsy specimens revealed jejunal mucosal villous atrophy compatible with coeliac disease in 13 of 122 relatives. Reticulin-antibody-positive relatives with or without jejunal mucosal atrophy were genetically similar to the probands of the families (DR3 gene frequencies 55.3%-60.0%). Gliadin-antibody-positive relatives with normal mucosa were genetically different from the probands (DR3 gene frequency 16.7% versus 55.3%). IgA reticulin and endomysium antibodies detected 92.3% of subjects with silent coeliac disease. The only case that was missed had selective IgA deficiency and was positive for IgG-class reticulin antibodies. By contrast, gliadin antibodies detected only half of the cases. Follow-up of the 7 reticulin-antibody-positive relatives with normal mucosa revealed 2 further cases of coeliac disease and 1 of dermatitis herpetiformis during the next three years. Our family study shows that healthy reticulin-antibody-positive first-degree relatives of coeliac disease patients, irrespective of the state of the jejunal mucosa, are genetically similar to known coeliac disease patients. Reticulin-antibody positivity is an indicator of both silent and latent coeliac disease.

The efficacy of aspirin in daily doses of 300 mg and more as secondary prophylaxis after cerebrovascular events is well established. Since much lower doses of aspirin can inhibit platelet function, and carry a lower risk of adverse effects, the Swedish Aspirin Low-dose Trial (SALT) was set up to study the efficacy of 75 mg aspirin daily in prevention of stroke and death after transient ischaemic attack (TIA) or minor stroke. 1360 patients entered the study 1-4 months after the qualifying event: 676 were randomly assigned to aspirin treatment and 684 to placebo treatment. The median duration of follow-up was 32 months. Compared with the placebo group, the aspirin group showed a reduction of 18% in the risk of primary outcome events (stroke or death; relative risk 0.82, 95% confidence interval 0.67-0.99; log-rank analysis p = 0.02), and reductions of 16-20% in the risks of secondary outcome events (stroke; stroke or two or more TIAs within a week of each other necessitating a change of treatment; or myocardial infarction). Adverse drug effects were reported by 147 aspirin-treated and 123 placebo-treated patients Gastrointestinal side-effects were only slightly more common in the aspirin-treated patients, but that group had a significant excess of bleeding episodes (p = 0.04). Thus, we have found that a low dose (75 mg/day) of aspirin significantly reduces the risk of stroke or death in patients with cerebrovascular ischaemic events.

To assess the safety and immunogenicity of a Pseudomonas aeruginosa octavalent O-polysaccharide-toxin A conjugate vaccine, 22 patients (mean age 7 years) with cystic fibrosis who had no history of colonisation with P aeruginosa were immunised with the vaccine. Adverse reactions were mild and self-limiting. IgG antibody concentrations to all vaccine antigens were significantly raised after vaccination and remained so for 12 months. Immunisation produced opsonic and toxin A neutralising antibodies. A booster dose given at 12 months led to an anamnestic response. There was no significant change in clinical status after vaccination. Further work to assess efficacy in patients with cystic fibrosis can now be considered since our findings support the safety and immunogenicity of the vaccine.

Increased parasympathetic tone does not fully explain the night-time bronchoconstriction responsible for nocturnal cough and wheezing in asthmatic subjects. The overnight variation in function of the other neural pathway innervating bronchial smooth muscle--the non-adrenergic, non-cholinergic (NANC) system--was thus examined. NANC function was tested after parasympathetic and beta-adrenergic blockade in 12 normal subjects and 12 patients with mild asthma by comparing the bronchodilator effect (measured as oscillatory resistance, Ros) of capsaicin (an NANC stimulant) at 0400 h with that at 1600 h. The order in which capsaicin or diluent was given was randomised, and observers were blind as to which substance had been inhaled. Bronchodilatation was greater at 1600 h than at 0400 h in both the normal subjects (mean decrease in Ros 1-3 min after capsaicin at 1600 h 9% [SEM 1], at 0400 h -2% [1]; p less than 0.001) and the asthmatic group (1% [1], -7% [2]; p = 0.001). The results suggest that inhibition of NANC function in the early morning may contribute to overnight bronchoconstriction.