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.

To study the prevention of occlusion of aortocoronary-artery bypass grafts, we concluded a prospective, randomized, double-blind trial comparing long-term administration of dipyridamole (begun two days before operation) plus aspirin (begun seven hours after operation) with placebo in 407 patients. Results at one month showed a reduction in the rate of graft occlusion in patients receiving dipyridamole and aspirin. At vein-graft angiography performed in 343 patients (84 per cent) 11 to 18 months (median, 12 months) after operation, 11 per cent of 478 vein-graft distal anastomoses were occluded in the treated group, and 25 per cent of 486 were occluded in the placebo group. The proportion of patients with one or more distal anastomoses occluded was 22 per cent of 171 patients in the treated group and 47 per cent of 172 in the placebo group. All grafts were patent within a month of operation in 94 patients in the placebo group and 116 patients in the treated group; late development of occlusions was reduced from 27 per cent in the placebo group to 16 per cent in the treatment group. The results show that dipyridamole and aspirin continue to be effective in preventing vein-graft occlusion late after operation, and we believe that such treatment should be continued for at least one year.

Using a retrospective analysis we compared 79 recipients of cadaveric renal allografts who were treated with cyclosporine as the sole initial immunosuppressant and 29 concurrent transplant recipients treated with conventional immunosuppressants. The cyclosporine-treated group had a slightly higher actuarial patient survival at four years (86 per cent v. 76 per cent). Actuarial graft survival at four years was 70 per cent in the cyclosporine group, as compared with 62 per cent in the conventionally immunosuppressed group. The incidence of acute rejection episodes was 62.1 per cent in the former and 65.5 per cent in the latter. Nephrotoxicity was managed either by reduction of the dose of cyclosporine or by conversion to conventional immunosuppression. Monitoring of trough serum levels of cyclosporine facilitated its administration. Serum creatinine levels have been higher in cyclosporine-treated patients with functioning grafts, but graft deterioration has not occurred after more than three years. Cyclosporine provides adequate immunosuppression for patients with renal allografts. At four years, the rates of patient and graft survival remain superior to those with conventional immunosuppression. In 41 per cent of patients the use of steroids was completely avoided. The longer-term results of this powerful immunosuppressive agent are not yet known.

We compared high-dose dexamethasone (initial dose, 3 mg per kilogram of body weight) with placebo in a randomized, double-blind trial involving 38 patients with culture-positive, specifically defined severe typhoid fever. The patients in the two treatment groups ranged in age from 5 to 54 and were comparable at the outset. All patients received chloramphenicol. The case-fatality rate of 10 per cent (2 of 20 patients) in the dexamethasone group was significantly lower than the fatality rate of 55.6 per cent (10 of 18) in the placebo group (P = 0.003). There was no significant difference in the incidence of complications among the survivors in either group. Delirium, obtundation, and stupor were grave prognostic signs that were useful for predicting which patients were at high risk of dying before they became comatose or went into shock. Dexamethasone is unnecessary for most patients with typhoid but is recommended for all patients with suspected typhoid fever who are delirious, obtunded, stuporous, comatose, or in shock.

One hundred forty-four patients admitted to the hospital within four hours after onset of symptoms of myocardial infarction were randomly assigned to either intravenous timolol treatment or to placebo. Timolol was given intravenously for the first 24 hours and orally thereafter for the duration of hospitalization. Infarct evolution was assessed by continuous vectorcardiography and creatine kinase release. The timolol group had reduced myocardial ischemia and infarct size as measured by an accelerated reduction of ST-vector magnitude, a significant reduction of maximal cumulative creatine kinase release (29.5 per cent), and significantly smaller changes in QRS-vector variables (20 to 25 per cent). Furthermore, the predicted creatine kinase release and maximal QRS-vector change for a given initial ST-vector magnitude was significantly reduced in the timolol group. Timolol was also associated with significant reductions in pain and need for analgesics and was well tolerated overall. This study supports the use of intravenous timolol in the early phase of suspected myocardial infarction to limit infarct size.

We performed three oral glucose-tolerance tests and three muscle biopsies over a period of approximately three years in 41 asymptomatic patients with chemical diabetes. At base line, 13 (32 per cent) had an increased capillary basement-membrane width in muscle. Twenty-three patients received glipizide, a new oral hypoglycemic compound, and 18 received placebo. In the patients receiving placebo the mean width of the muscle capillary basement membrane increased from 135.9 +/- 9.0 nm (S.E.M.) to 169.3 +/- 9.5 nm (P = 0.01), but in those receiving glipizide the value decreased to a level no different from that in subjects without diabetes: from 152.9 +/- 2.9 to 127.5 +/- 5.1 nm (P = 0.01). These findings suggest that microangiopathy, as indicated by an increased capillary basement-membrane width in muscle, may be present in a considerable number of patients with asymptomatic diabetes and that the changes can be reversed by early drug treatment.

We conducted a prospective randomized trial of propranolol for the prevention of recurrent variceal bleeding in 48 patients with cirrhosis of the liver. During a follow-up period of up to 21 months, 12 of 26 patients in the propranolol group and 11 of 22 in the control group had rebleeding from esophageal varices. There was no significant difference in rebleeding between the two groups. This contrasts with a previous report of the efficacy of propranolol in preventing recurrent gastrointestinal bleeding in alcoholic cirrhosis. The difference in results may be due to the inclusion in our study of patients with other causes of cirrhosis and more severe liver disease. Propranolol may not be indicated for the prophylaxis of variceal rebleeding in such patients, and we advocate that its use be limited at present to controlled clinical trials.

Two hundred fifty patients were enrolled in a multicenter, community-based study of the efficacy of intracoronary streptokinase thrombolysis in acute myocardial infarction; 134 were randomly assigned to streptokinase therapy and 116 were controls. All patients underwent left ventricular angiography and coronary arteriography before the random assignment. The mean time from the onset of symptoms to hospitalization was 134 +/- 144 minutes (S.D), and the mean time to random assignment was 276 +/- 185 minutes. Coronary reperfusion was achieved in 68 per cent of the streptokinase-treated group. The overall 30-day mortality was 18 (7.2 per cent); there were five deaths in the streptokinase-treated group (3.7 per cent) and 13 in the control group (11.2 per cent, P less than 0.02). Fifteen of the 18 deaths occurred in patients with anterior infarction. Intracoronary streptokinase therapy resulted in a nearly threefold reduction in the 30-day mortality after hospitalization for acute myocardial infarction.

Over a two-year period we obtained monthly urine samples from all noncatheterized male residents on two geriatric wards to determine the occurrence and optimal management of bacteriuria in this population. Among 88 men the prevalence of bacteriuria was 33 per cent, and the incidence was 45 infections per 100 patients per year. Outcomes after single-dose therapy for asymptomatic bacteriuria with 43 courses of trimethoprim/sulfamethoxazole and 23 of tobramycin included 15 cures, 40 relapses, and 11 treatment failures. Thirty-six residents who had a relapse or in whom single-dose therapy failed were randomly assigned to receive therapy to eradicate bacteriuria or to receive no therapy. All 20 residents who received no therapy remained bacteriuric. The 16 residents who received therapy had fewer months of bacteriuria after randomization, but at the end of the study only one remained free of bacteriuria. Mortality and infectious morbidity after randomization were similar in the two groups. These data suggest that asymptomatic bacteriuria is common in elderly institutionalized men and that therapy is neither necessary nor effective.

Does free medical care lead to better health than insurance plans that require the patient to shoulder part of the cost? In an effort to answer this question, we studied 3958 people between the ages of 14 and 61 who were free of disability that precluded work and had been randomly assigned to a set of insurance plans for three or five years. One plan provided free care; the others required enrollees to pay a share of their medical bills. As previously reported, patients in the latter group made approximately one-third fewer visits to a physician and were hospitalized about one-third less often. For persons with poor vision and for low-income persons with high blood pressure, free care brought an improvement (vision better by 0.2 Snellen lines, diastolic blood pressure lower by 3 mm Hg); better control of blood pressure reduced the calculated risk of early death among those at high risk. For the average participant, as well as for subgroups differing in income and initial health status, no significant effects were detected on eight other measures of health status and health habits. Confidence intervals for these eight measures were sufficiently narrow to rule out all but a minimal influence, favorable or adverse, of free care for the average participant. For some measures of health in subgroups of the population, however, the broader confidence intervals make this conclusion less certain.

To determine whether epinephrine-induced hypokalemia is due to beta2-adrenoceptor stimulation, and whether hypokalemia can occur at physiologic concentrations of the agonist, epinephrine was infused into six normal volunteers at a rate of 0.1 microgram per kilogram of body weight per minute. The circulating epinephrine concentration was increased to 1.74 +/- 0.65 ng per milliliter, plasma potassium was reduced by 0.82 +/- 0.19 meq per liter, plasma insulin fell by 12 +/- 4 mU per liter, plasma renin activity was elevated, and tachycardia occurred. Isoproterenol infused at 0.02 micrograms per kilogram per minute caused similar tachycardia (25 beats per minute) and elevation in plasma renin activity (6.0 to 6.5 ng per milliliter per hour), but no hypokalemia. The difference in responses to the two catecholamines was ascribed to the relative beta2-selectivity of epinephrine. This hypothesis was tested in six subjects given infusions of epinephrine (0.05 micrograms per kilogram per minute) after administration of either 2.5 or 5 mg of ICI 118551--a selective beta2-receptor antagonist--or placebo. After placebo, epinephrine infusion elevated the circulating epinephrine concentration and reduced plasma potassium; hypokalemia was prevented by the beta2-antagonist. This drug only partially inhibited the rises in plasma renin and glucose and the shortening of systolic time intervals; there was no tachycardia. Fifteen-fold to 30-fold increases in circulating epinephrine concentration appear to cause hypokalemia by a specific beta2-receptor effect distinct from other actions of epinephrine. This phenomenon may be of physiologic importance after severe myocardial infarction, when similar increases in plasma epinephrine have occurred.

Controlled clinical trials of the treatment of acute myocardial infarction offer a unique opportunity for the study of the potential influence on outcome of bias in treatment assignment. A group of 145 papers was divided into those in which the randomization process was blinded (57 papers), those in which it may have been unblinded (45 papers), and those in which the controls were selected by a nonrandom process (43 papers). At least one prognostic variable was maldistributed (P less than 0.05) in 14.0 per cent of the blinded-randomization studies, in 26.7 per cent of the unblinded-randomization studies, and in 58.1 per cent of the nonrandomized studies. Differences in case-fatality rates between treatment and control groups (P less than 0.05) were found in 8.8 per cent of the blinded-randomization studies, 24.4 per cent of the unblinded-randomization studies, and 58.1 per cent of the nonrandomized studies. These data emphasize the importance of keeping those who recruit patients for clinical trials from suspecting which treatment will be assigned to the patient under consideration.

The presence of estrogen receptors in breast cancers is now accepted as a predictor of extended disease-free survival, but the relative value of progesterone receptors for this purpose has not been established. We have examined both receptors along with other risk factors in 189 patients receiving adjuvant therapy for Stage II breast cancer. The presence of either estrogen receptors or progesterone receptors was positively correlated with disease-free survival when analyzed separately, whether or not the adjuvant regimen included an endocrine component. However, when estrogen receptors and progesterone receptors were analyzed together in multivariate models, the presence of progesterone receptors was more significant than that of estrogen receptors for predicting time to recurrence, regardless of what other variables were included in the model. These data suggest that determination of the progesterone-receptor concentration is of equal or greater value than determination of the estrogen-receptor concentration for predicting the disease-free survival of patients with breast cancer. Future trials should include measurement of progesterone receptors.

Sleep behavior is modulated by serotonergic neurons within the brain, and the synthesis and release of serotonin by such neurons is thought to be influenced by the availability of tryptophan, the amino acid precursor of serotonin. We investigated the effects on the sleep patterns of newborn infants of variations in diet designed to affect tryptophan availability. Twenty healthy newborns (two to three days of age) were randomly assigned to receive a feeding consisting either of tryptophan in 10 per cent glucose or valine in 5 per cent glucose (valine competes with tryptophan for entry into the brain). Sleep patterns during the three hours after this feeding were compared with those after a feeding of routine formula (Similac). The infants fed tryptophan entered active sleep 14.1 minutes sooner than they did after Similac, and entered quiet sleep 20 minutes sooner. Those fed valine entered active sleep 15.8 minutes later than they did after Similac, and entered quiet sleep 39 minutes later. The differences between the tryptophan and valine groups were significant (P less than 0.01 for active sleep and P less than 0.005 for quiet sleep). We conclude that variations in the composition of the diet may influence sleep behavior in newborns.