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.

We evaluated the effect of treatment of gonorrhea on simultaneous Chlamydia trachomatis infection by randomly assigning 293 heterosexual men and 246 heterosexual women with gonorrhea to receive one of the following treatment regimens: (1) 4.8 million units of aqueous procaine penicillin plus 1 g of probenecid, (2) nine tablets of trimethoprim-sulfamethoxazole daily for three days, or (3) 500 mg of tetracycline four times a day for five days. Among the men, gonococcal infection was cured in 99 per cent given penicillin plus probenecid, 96 per cent given trimethoprim-sulfamethoxazole, and 98 per cent given tetracycline. Among the women, only 90 per cent given tetracycline were cured, in contrast to 97 per cent given penicillin plus probenecid and 99 per cent given trimethoprim-sulfamethoxazole. Chlamydial infection, present in 15 per cent of the men and 26 per cent of the women, was cured in 30 of 32 patients given trimethoprim-sulfamethoxazole and 27 of 29 given tetracycline, but in only 10 of 23 given penicillin plus probenecid. Among chlamydia-positive patients, postgonococcal urethritis in men and cervicitis in women occurred more often in patients given penicillin plus probenecid. Salpingitis developed in 6 of 20 women given penicillin plus probenecid, but in only 1 of 26 given trimethoprim-sulfamethoxazole and in none of 24 given tetracycline. We conclude that the use of penicillin plus probenecid alone for gonorrhea in heterosexual patients carries an unacceptably high risk of postgonococcal chlamydial morbidity. Trimethoprim-sulfamethoxazole and tetracycline were highly effective against both pathogens and were well tolerated in men, but both drugs caused frequent side effects in women. The failure of tetracycline to cure gonorrhea in 10 per cent of women argues against its use alone; treatment with penicillin followed by tetracycline has been recommended for further trial.

Because leptospirosis has been an important cause of morbidity in U.S. soldiers training in the Republic of Panama, we conducted a randomized, double-blind, placebo-controlled field trial during the fall of 1982 to determine whether doxycycline was an effective chemoprophylactic agent against this infection. Doxycycline (200 mg) or placebo was administered orally on a weekly basis and at the completion of training to 940 volunteers from two U.S. Army units deployed in Panama for approximately three weeks of jungle training. Twenty cases of leptospirosis occurred in the placebo group (an attack rate of 4.2 per cent), as compared with only one case in the doxycycline group (attack rate, 0.2 per cent, P less than 0.001), yielding an efficacy of 95.0 per cent. This study demonstrated the value of doxycycline as a prophylactic drug against leptospirosis.

We compared the weight-reducing effect of diet and gastroplasty with that of diet alone in a randomized trial in 60 morbidly obese patients followed for two years. Initial median body weight was 120 kg in patients randomly assigned to gastroplasty plus diet and 115 kg in those assigned to diet alone. Maximum weight losses did not differ significantly between the groups (26.1 kg in the gastroplasty group and 22.0 kg in the group treated with diet alone, P greater than 0.05). The risk of a Type II error with a true difference larger than 9.5 kg was less than 5 per cent. However, the group treated with diet alone regained significantly more weight after maximum weight loss had been achieved, so that the gastroplasty group had a more favorable net outcome at two years (P less than 0.05).

We investigated whether the glomerular synthesis of prostacyclin modulates the renal blood flow and glomerular filtration rate in chronic glomerular disease. The urinary excretion of 6-keto-prostaglandin F1 alpha, a stable breakdown product of prostacyclin, was significantly (P less than 0.01) reduced in 20 women with chronic glomerular disease, as compared with 19 controls, whereas excretion of urinary prostaglandin E2 was unchanged. In 10 patients randomly assigned to one week of treatment with ibuprofen, excretion of urinary 6-keto-prostaglandin F1 alpha and prostaglandin E2 was reduced by 80 per cent, the level of serum creatinine was increased by 40 per cent, and creatinine and para-aminohippurate clearances were reduced by 28 and 35 per cent, respectively. The reduction of both clearances was inversely related (P less than 0.01) to the basal urinary excretion of 6-keto-prostaglandin F1 alpha but not of prostaglandin E2. No functional changes were detected in five healthy women, despite a similar suppression of renal prostacyclin synthesis by ibuprofen. In contrast, one week of treatment with sulindac did not affect renal prostacyclin synthesis or renal function in the other 10 patients, despite a marked inhibition of extrarenal cyclooxygenase activity. We conclude that in patients with mild impairment of renal function, the renal blood flow and glomerular filtration rate are critically dependent on prostacyclin production. In such patients sulindac may be a safe substitute for other nonsteroidal antiinflammatory drugs.

Survival after out-of-hospital cardiac arrest is poor in communities served only by basic ambulance services, but conventional advanced prehospital care is not an option for most rural communities. Ambulance technicians in 18 small communities (average population, 10,400) were trained to recognize and defibrillate ventricular fibrillation. Neither endotracheal intubation nor medication was used. Twelve additional communities of similar size where such early defibrillation was not attempted provided control data. In the communities where early defibrillation was available, 12 of 64 patients (19 per cent) who were found in ventricular fibrillation were resuscitated and discharged alive from the hospital; this was true of only 1 of 31 such patients (3 per cent) in the control communities, where only basic life support was available (P less than 0.05). Ten (83 per cent) of the long-term survivors received electrical shocks administered solely by the technicians. Early defibrillation by minimally trained ambulance technicians is an effective approach to emergency cardiac care in rural communities.