To assess the potential for therapeutic problems related to the bioavailability of oral theophylline preparations, we examined the rate and extent of absorption for various formulations in adult volunteers. Absorption of theophylline from a solution or from uncoated tablets was rapid and complete. Three of six sustained-release formulations were more slowly, but still completely and consistently, absorbed. Absorption of the other three sustained-release formulations appeared to be more erratic and less complete. Serum concentration-time curves during multiple eight-hour dosing were simulated for the bioavailable preparations. With three sustained-release formulations it was predicted that fluctuations in serum theophylline concentrations between doses would decrease, as compared with uncoated tablets, to a clinically important extent, particularly in children, in whom elimination of theophylline is generally rapid.

A study of hypertension in an industrial setting allowed us to confirm and explore an earlier retrospective finding that the labeling of patients as hypertensive resulted in increased absenteeism from work. After screening and referral, we found that absenteeism rose (mean +/- 1 S.E.) 5.2 +/- 2.3 days per year (P less than 0.025); this 80 per cent increase greatly exceeded the 9 per cent rise in absenteeism in the general employee population during this period. The main factors associated with increased absenteeism were becoming aware of the condition (P less than 0.01) and low compliance with treatment (P less than 0.001). Subsequent absenteeism among patients unaware of their hypertension before screening was not related to the degree of hypertension, whether the worker was started on therapy, the degree of blood-pressure control achieved or exposure to attempts to promote compliance. These results have major implications for hypertension screening programs, especially since absenteeism rose among those previously unaware of their condition, regardless of whether antihypertensive therapy was begun.

Seventy-one "negative" randomized control trials were re-examined to determine if the investigators had studied large enough samples to give a high probability (greater than 0.90) of detecting a 25 per cent and 50 per cent therapeutic improvement in the response. Sixty-seven of the trials had a greater than 10 per cent risk of missing a true 25 per cent therapeutic improvement, and with the same risk, 50 of the trials could have missed a 50 per cent improvement. Estimates of 90 per cent confidence intervals for the true improvement in each trial showed that in 57 of these "negative" trials, a potential 25 per cent improvement was possible, and 34 of the trials showed a potential 50 per cent improvement. Many of the therapies labeled as "no different from control" in trials using inadequate samples have not received a fair test. Concern for the probability of missing an important therapeutic improvement because of small sample sizes deserves more attention in the planning of clinical trials.

We undertook a randomized clinical trial to evaluate the efficacy of chest physiotherapy and intermittent positive-pressure breathing in the treatment of pneumonia. The diagnosis of pneumonia required a compatible clinical history and x-ray confirmation. A total of 54 patients were assigned to treatment and control groups and were similar in age, smoking history, underlying lung disease and prior antibiotic treatment. Antibiotic therapy, guided by Gram stain and sputum and blood cultures, was similar in both groups. Chest physiotherapy, consisting of postural drainage, percussion and vibration, was given concurrently with intermittent positive-pressure breathing with use of racemic epinephrine every four hours. There was no statistically significant difference in duration of fever, extent of radiographic clearing, duration of hospital stay and mortality between the control and treated groups. Chest physiotherapy and intermittent positive-pressure breathing do not hasten the resolution of pneumonia.

We performed a randomized prospective study of the effect of placement position of umbilical-artery catheters on complication rates in high-risk newborn infants. A higher complication rate (31 of 40 vs. 13 of 33) (P less than 0.005) occurred in the group with the catheter tip at the third to fourth lumbar segment, as compared to those with the tip at the seventh to eighth thoracic segment, owing to more episodes of blanching and cyanosis of the extremities. There was no difference between groups in the rate of complications requiring catheter removal. Aortography revealed thrombosis in 21 of 23 patients studied, but there was no clinical evidence of impaired circulation. In retrospect, we found that, independently of catheter position, administration of antibiotics through the catheter was associated with an increased rate of complications (63 vs. 20 per cent). Umbilical-artery catheterization entails potential risks regardless of the position of the catheter; placement of the catheter with its tip at the seventh to eighth thoracic segment may be associated with fewer complications than at lower positions.

We studied the effect of vitamin E on the development of bronchopulmonary dysplasis in neonates with respiratory-distress syndrome. Twenty infants received vitamin E administered intramuscularly during the acute phase of the syndrome, and 20 infants served as controls. Administration of vitamin E significantly increased the serum vitamin E concentration. Nine vitamin-treated and 13 control patients required supplemental oxygen for longer than 250 hours; all were treated with positive-pressure ventilation and endotracheal continuous distending airway pressure. Six of those 13 controls had x-ray changes consistent with bronchopulmonary dysplasia, and four died. None of the nine vitamin-treated patients had changes characteristic of bronchopulmonary dysplasia (P = 0.046), and all survived. Administration of vitamin E during the acute phase of the respiratory-distress syndrome appears to modify the development of bronchopulmonary dysplasis.

To investigate the efficacy of antibiotic irrigation in preventing catheter-associated urinarytract infection, we carried out a randomized controlled trial of a neomycin-polymyxin irrigant administered through closed urinary catheters. Eighteen of 98 (18 per cent) of the patients not given irrigation became infected, as compared with 14 of 89 (16 per cent) of those given irrigation, yielding a mean daily incidence of 5 per cent in each group. The distribution of organisms and their antibiotic sensitivities differed in the two groups, the organisms from the patients with irrigation being more resistant. Disconnections of the catheter junctions were associated with high rates of infection. The rate of disconnections of the junctions in the group given irrigation was almost twice that of the control group because of the presence of the extra junction on overall infection rate represents the result of two opposing phenomena: the increased entry of organisms and the suppression of a portion of them.

The role of glucagon in diabetes was studied in four patients with juvenile-type diabetes during continuous insulin infusion and a diet containing 150 g per day of carbohydrate. During insulin alone, plasma glucagon, measured at two-hour intervals, averaged 182 +/- 34 pg per milliliter, glucose 269 +/- 11 mg per deciliter, glucose excretion 52 +/- 8 g per 24 hours, ketone excretion 1.3 +/- 0.3 mmol per 24 hours, and urea nitrogen 12 +/- 2 g per 24 hours (mean +/- S.E.M.). Somatostatin (2 mg per day) lowered glucagon to 60 +/- 13 pg per milliliter, glucose to 111 +/- 17 mg per deciliter, glucose excretion to 1 +/- 0.7 g per 24 hours, ketone excretion to 0.5 +/- 0.2 mmol per 24 hours and urea nitrogen excretion to 8 +/- 2 g per 24 hours. Replacement of glucagon raised glucagon to 272 +/- 30 pg per milliliter, glucose to 202 +/- 20 mg per deciliter, glucose excretion to 14 +/- 7 g per 24 hours, ketone excretion to 0.8 mmol per 24 hours and urea nitrogen excretion to 11 +/- 2 g per 24 hours. In a subsequent study, similar improvement occurred on a diet of 30 g of carbohydrate daily, when absorption of dietary glucose was negligible. Hyperglucagonemia has an important role in diabetes; its correction reduces diabetic abnormalities to or toward normal.

Insect hypersensitivity is currently treated by immunization using whole-body extracts. We compared this regimen with immunotherapy using insect venoms or placebo in groups of 20 patients matched for history and sensitivity, as judged by venom skin test, histamine release and IgE antibody to venom. After six to 10 weeks of immunization, systemic reactions to stings occurred in seven of 12, seven of 11, and one of 18 patients treated with placebo, whole-body extract, and venom, respectively. Placebo and whole-body extract gave similar results and were significantly less effective than venom immunotherapy (P less than 0.01). The 14 patients with failure of treatment with whole-body extract and placebo were subsequently provided with venom immunotherapy; one reacted to a subsequent sting. We conclude that venom immunotherapy is clinically superior to therapy on whole-body extract or placebo.

Five hundred and eighty-five patients with threatened stroke were followed in a randomized clinical trial for an average of 26 months to determine whether aspirin or sulfinpyrazone, singly or in combination, influence the subsequent occurrence of continuing transient ischemic attacks, stroke or death. Eighty-five subjects went on to stroke, and 42 died. Aspirin reduced the risk of continuing ischemic attacks, stroke or death by 19 per cent (P less than 0.05) and also reduced risk for the "harder," more important events of stroke or death by 31 percent (P less than 0.05), but this effect was sex-dependent: among men, the risk reduction for stroke or death was 48 per cent (P less than 0.005), whereas no significant trend was observed among women. For sulfinpyrazone, no risk reduction of ischemic attacks was observed, and the 10 per cent risk reduction of stroke or death was not statistically significant. No overall synergism or antagonism was observed between the two drugs. We conclude that aspirin is an efficacious drug for men with threatened stroke.

To assess the cause of nonspecific vaginitis, we performed a prospective case-control study of vaginal flora and a randomized unblinded trial of different therapies. Haemophilus vaginalis was isolated from 17 to 18 women with signs of vaginitis but only one of 18 normal matched controls (P less than 0.002). The concentration of anaerobic bacteria in vaginal washings also was increased in patients. Clinical improvement and eradication of H. vaginalis occurred in one of seven patients given sulfonamide vaginal cream, two of 15 given oral doxycycline, nine of 27 given oral ampicillin, and 80 of 81 given oral metronidazole. On the seventh day of therapy signs of nonspecific vaginitis persisted in 31 of 31 with, and in two of 92 without, persistent H. vaginalis infection (P less than 0.001). These data suggest the causal role of H. vaginalis in nonspecific vaginitis, possibly in concert with vaginal anaerobes. The widespread use of sulfonamide creams is inappropriate. Metronidazole is effective, but its efficacy must be weighed against its possible toxicity.

We tested the hypothesis that donor blood containing antibody to hepatitis B core antigen (anti-HBc) but lacking detectable hepatitis B surface antigen (HBsAg) and antibody (anti-HBs)might transmit Type B hepatitis by examining donor and recipient serums from a Veterans Administration study of post-transfusion hepatitis. Donor blood was available from three patients with Type B hepatitis and from one patient with hepatitis B virus infection (development of anti-HBs and anti-HBc) without symptomatic disease. All four had received 1 unit of blood with high titer of anti-HBc but lacking HBsAg and anti-HBs. In contrast, no such units had been transfused into nine patients with "immunization-like" response (development of anti-HBs without anti-HBc) or into 26 control patients. These data stress the importance of anti-HBc as an indicator of hepatitis B virus infection and support the hypothesis that high-titer anti-HBc-positive blood might be infectious.

To test the feasibility and effects of incorporating concurrent quality assurance (CQA) into the concurrent utilization reviews required by PSRO's, adherence to essential criteria of medical care and attainment of expected immediate outcomes were monitored prospectively in 5604 cases of seven conditions in 24 experimental and 26 control hospitals in five PSRO areas. CQA was not consistently associated with improved documentation in records, but was associated with slightly better adherence to treatment criteria in all five PSRO areas (P less than 0.03). Adherence to pooled documentation or treatment criteria was unrelated to outcomes. However, failure to adhere to disease-specific scientifically validated treatment criteria was associated with unsatisfactory outcomes in bacterial pneumonia (P less than 0.01) and acute myocardial infarction (P less than 0.02). CQA was professionally acceptable, technically feasible and compatible with PSRO reviews. Given adequate physician support, CQA can produce slightly greater adherence to treatment criteria. If the criteria are valid, adherence may lead to improved immediate outcomes in some diseases.