Patients with frequently recurring genital herpes were enrolled in a double-blind placebo-controlled trial comparing 200-mg acyclovir capsules, given five or two times daily, with placebo. Of 47 placebo recipients, 44 (94 per cent) had recurrences during the 120-day treatment period, compared with 13 (29 per cent) of 45 patients treated with acyclovir five times daily and 18 of 51 (35 per cent) treated with acyclovir twice daily (P less than 0.001 for each regimen compared with placebo). The median time to the first clinical recurrence was 18 days in placebo recipients, compared with over 120 days in both acyclovir-treated groups (P less than 0.001 for both groups compared with placebo). The mean monthly recurrence rate during the medication period was 0.86 in placebo recipients, compared with 0.13 in patients treated with acyclovir five times daily and 0.14 in patients treated with acyclovir twice daily (P less than 0.001 for both groups compared with placebo). While receiving therapy, 86 of 96 acyclovir-treated patients had over a 50 per cent reduction in their pretreatment recurrence rate. Breakthrough recurrences in acyclovir recipients were of shorter duration and associated with a lower frequency of viral shedding than recurrences in placebo recipients. After medication was discontinued, the subsequent recurrence rate returned to pretreatment frequencies. Daily oral acyclovir was well tolerated. We conclude that oral acyclovir given for four months markedly reduces but does not completely prevent recurrences of genital herpes and does not influence the long-term natural history of the disease.

We studied 35 otherwise healthy adults with frequently recurring genital herpes (greater than or equal to 1 episode per month), in a double-blind trial comparing oral acyclovir with placebo capsules for suppression of recurrent infection. The patients were treated for 125 days unless herpes recurred. Among 32 evaluable patients, there were significantly fewer recurrences during acyclovir treatment (4 of 16) than during placebo treatment (16 of 16, P less than 0.001). The mean duration of therapy was significantly longer for patients receiving acyclovir than for those receiving placebo (114.9 vs. 24.8 days, P less than 0.001). Of 19 patients who had recurrences in the blind trial, only 2 had recurrences when given acyclovir in a second, open-study phase. All patients had recurrences after completing acyclovir treatment. The therapy was well tolerated, with minimal gastrointestinal upset and one hypersensitivity reaction. Studies of the viral isolates demonstrated that lesions developing in patients receiving acyclovir contained drug-resistant virus. Later recurrences in these patients were associated with drug-sensitive virus. We conclude that oral acyclovir suppresses genital herpes in patients with frequent recurrences, but the potential for problems with drug resistance and the long-term safety need to be more fully explored.

Does a prepaid group practice deliver less care than the fee-for-service system when both serve comparable populations with comparable benefits? To answer this question, we randomly assigned a group of 1580 persons to receive care free of charge from either a fee-for-service physician of their choice (431 persons) or the Group Health Cooperative of Puget Sound (1149 persons). In addition, 733 prior enrollees of the Cooperative were studied as a control group. The rate of hospital admissions in both groups at the Cooperative was about 40 per cent less than in the fee-for-service group (P less than 0.01), although ambulatory-visit rates were similar. The calculated expenditure rate for all services was about 25 per cent less in the two Cooperative groups (P less than 0.01 for the experimental group, P less than 0.05 for the control group). The number of preventive visits was higher in the prepaid groups, but this difference does not explain the reduced hospitalization. The similarity of use between the two prepaid groups suggests that the mix of health risks at the Cooperative was similar to that in the fee-for-service system. The lower rate of use that we observed, along with comparable reductions found in non-controlled studies by others, suggests that the style of medicine at prepaid group practices is markedly less "hospital-intensive" and, consequently, less expensive.

Forty patients with Type I membranoproliferative glomerulonephritis were treated for one year with dipyridamole, 225 mg per day, and aspirin, 975 mg per day, in a prospective, randomized, double-blind, placebo-controlled study. At the base line, the half-life of 51Cr-labeled platelets was reduced in 12 of 17 patients. The platelet half-life became longer and renal function stabilized in the treated group, as compared with the placebo group, suggesting a relation between platelet consumption and the glomerulopathy. The glomerular filtration rate, determined by iothalamate clearance, was better maintained in the treated group (average decrease, 1.3 ml per minute per 1.73 m2 of body-surface area per 12 months) than in the placebo group (average decrease, 19.6). Fewer patients in the treated group than in the placebo group had progression to end-stage renal disease (3 of 21 after 62 months as compared with 9 of 19 after 33 months). The data suggest that dipyridamole and aspirin slowed the deterioration of renal function and the development of end-stage renal disease.

We conducted a double-blind, placebo-controlled efficacy trial of the live attenuated Oka/Merck varicella vaccine among 956 children between the ages of 1 and 14 years, with a negative clinical history of varicella. Of the 914 children who were serologically confirmed to be susceptible to varicella, 468 received vaccine and 446 received placebo. The vaccine produced few clinical reactions and was well tolerated. There was no clinical evidence of viral spread from vaccinated children to sibling controls. Approximately eight weeks after vaccination, 94 per cent of the initially seronegative children who received vaccine had detectable antibody to varicella. During the nine-month surveillance period, 39 clinically diagnosed cases of varicella, 38 of which were confirmed by laboratory tests, occurred among study participants. All 39 cases occurred in placebo recipients; no child who received vaccine contracted varicella. The vaccine was 100 per cent efficacious in preventing varicella in this population of healthy children (P less than 10(-9).

Each year 1.5 million patients are admitted to coronary-care units (CCUs) for suspected acute ischemic heart disease; for half of these, the diagnosis is ultimately "ruled out." In this study, conducted in the emergency rooms of six New England hospitals ranging in type from urban teaching centers to rural nonteaching hospitals, we sought to develop a diagnostic aid to help emergency room physicians reduce the number of their CCU admissions of patients without acute cardiac ischemia. From data on 2801 patients, we developed a predictive instrument for use in a hand-held programmable calculator, which requires only 20 seconds to compute a patient's probability of having acute cardiac ischemia. In a prospective trial that included 2320 patients in the six hospitals, physicians' diagnostic specificity for acute ischemia increased when the probability value determined by the instrument was made available to them. Rates of false-positive diagnosis decreased without any increase in rates of false-negative diagnosis. Among study patients with a final diagnosis of "not acute ischemia," the number of CCU admissions decreased 30 per cent, without any increase in missed diagnoses of ischemia. The proportion of CCU admissions that represented patients without acute ischemia dropped from 44 to 33 per cent. Widespread use of this predictive instrument could reduce the number of CCU admissions in this country by more than 250,000 per year.

To determine whether cigarette smoking affects the results of drug treatment for angina, we studied 10 cigarette smokers with angina who were given placebo, nifedipine (60 mg per day), propranolol (240 mg per day), and atenolol (100 mg per day), each for one week. The four-week double-blind study was repeated with the same randomly determined order of drug sequences, after all 10 subjects had stopped smoking. Before and after the subjects stopped smoking, all three drugs significantly reduced the frequency of angina, as measured with angina diaries, and improved the results of maximal exercise testing and 48-hour ambulatory monitoring of ST segments (P less than 0.01). However, during the nonsmoking phase of the study, there was an overall decline in the frequency of angina and an improvement in performance on exercise testing (P less than 0.05) as compared with the smoking period, although the results of 48-hour ambulatory monitoring remained unchanged. The improvement after patients stopped smoking was greater during treatment with nifedipine than during administration of the other two drugs or placebo. Blood levels of propranolol were increased when patients stopped smoking; levels of nifedipine and atenolol were unchanged. Our data show that smoking had direct and adverse effects on the heart and interfered with the efficacy of all three anti-anginal drugs, but with nifedipine the most.

Sixty-seven adults with idiopathic membranous nephropathy and the nephrotic syndrome were randomly assigned to symptomatic treatment only or to a six-month course of methylprednisolone alternated with chlorambucil every other month. Patients were followed for one to seven years. At the end of follow-up (mean of 31.4 +/- 18.2 months for the treated group and 37.0 +/- 22.0 for the control group) 23 of 32 treated patients were in complete or partial remission, as compared with 9 of 30 control patients (P = 0.001). Twelve of the treated patients were in complete remission, as compared with only two of the controls. In the treated group there were no changes in renal function during follow-up, whereas in the control group the reciprocal of the plasma creatinin level, which is proportional to the creatinine clearance, decreased significantly (P = 0.00017) after two years of follow-up. Side effects were minimal in all treated patients except two, who were dropped from the study because of peptic ulcer and gastric intolerance to chlorambucil. We conclude that steroid and chlorambucil treatment for six months favors remission of the nephrotic syndrome in adults with idiopathic membranous nephropathy and can preserve renal function for at least some years.

High-density lipoproteins (HDL) in plasma may be divided into two subfractions: less dense HDL2, the concentration of which appears to be negatively associated with coronary heart disease, and more dense HDL3, which is reportedly unrelated to coronary disease. Alcohol consumption correlates with both reduced coronary heart disease and increased plasma HDL cholesterol concentrations; however, the relation of moderate alcohol intake to HDL2 and HDL3 is obscure. To study the effect of alcohol on these HDL subfractions, we randomly assigned 24 men who were moderate drinkers to an abstention group (n = 12) or a control drinking group (n = 12). After six weeks, concentrations of HDL cholesterol and HDL3 mass were decreased in abstainers but not in drinkers (P less than or equal to 0.05), whereas HDL2 mass was unchanged. Resumption of drinking increased the levels of HDL cholesterol and HDL3 mass (P less than or equal to 0.05) without affecting HDL2 mass. These data suggest that the association of alcohol with coronary disease is not mediated by increases in plasma HDL2 levels. Furthermore, the HDL3 fraction may not be "inert" with respect to coronary heart disease, or the association of alcohol with coronary disease may operate through mechanisms unrelated to HDL.

The long-term benefit of coronary bypass surgery in terms of longevity and prevention of major ischemic events in patients who have mild angina is not well defined. The randomized Coronary Artery Surgery Study (CASS) was designed to evaluate this issue; it consists of 780 patients who were considered operable and who had mild stable angina pectoris or who were free of angina after infarction. As a result of the randomization process there were no significant differences in base-line variables between patients randomly assigned to medical and to surgical therapy. The likelihood of death in the five-year period after randomization was only 8 per cent in the medical cohort, as compared with 5 per cent in the surgical cohort (not significant). The likelihood of nonfatal Q-wave myocardial infarction was 11 and 14 per cent, respectively (not significant). The five-year probability of remaining alive and free of infarction was 82 per cent in the patients assigned to medical therapy and 83 per cent in the patients assigned to surgery (not significant). There were no statistically significant differences in the survival rate or in the myocardial-infarction rate between subgroups of patients randomly assigned to medical and to surgical therapy when they were analyzed according to initial group assignment, number of diseased vessels, or ejection fraction. Therefore, as compared with medical therapy, coronary bypass surgery appears neither to prolong life nor to prevent myocardial infarction in patients who have mild angina or who are asymptomatic after infarction in the five-year period after coronary angiography.

After curative surgical resection, 621 patients with modified Dukes' stage B2, C1, or C2 colon carcinoma were randomly assigned to one of four treatment programs. These included chemotherapy with fluorouracil and semustine, immunotherapy with methanol extraction residue of bacillus Calmette-Guérin (BCG), combination therapy with fluorouracil, semustine, and immunotherapy, or close follow-up without adjuvant treatment. Treatment continued for 70 weeks. After a median of 51/2 years of follow-up, no significant differences were noted in either recurrence or survival rates among the four treatment programs. Leukemia developed in seven patients, all of whom had received fluorouracil and semustine. The results of this study do not support the use of chemotherapy with fluorouracil and semustine, immunotherapy with methanol extraction residue of BCG, or their combination as an adjuvant treatment program for patients at high risk for recurrent colon carcinoma. The data do, however, demonstrate the necessity for an untreated control group in a trial of adjuvant therapy for colon cancer.

Acute mountain sickness is a syndrome that occurs when unacclimatized persons ascend rapidly to high altitudes. It is postulated that cerebral edema causes its symptoms. Since dexamethasone is useful in treating some forms of cerebral edema, we investigated its role in the prevention of acute mountain sickness. Using a double-blind crossover design, we exposed eight young men to a simulated altitude of 4570 m (15,000 ft) on two occasions. By random assignment, each subject received dexamethasone (4 mg every 6 hours) or placebo for 48 hours before and throughout the 42-hour exposure. The presence of symptoms of acute mountain sickness was established by two methods: a questionnaire and an interview by a physician. Dexamethasone significantly reduced the symptoms of acute mountain sickness. During dexamethasone treatment, the cerebral-symptom score (mean +/- S.E.) decreased from 1.09 +/- 0.18 to 0.26 +/- 0.08, and the respiratory-symptom score decreased from 0.64 +/- 0.09 to 0.31 +/- 0.06 (both, P less than 0.05). As judged by the interviewing physician, the symptom score decreased from 1.10 +/- 0.11 to 0.28 +/- 0.07 (P = 0.01). We conclude that dexamethasone may be effective in preventing the symptoms of acute mountain sickness.