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.

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.

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 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.

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.

We evaluated the risk of acute nonlymphocytic leukemia, acute myelodysplastic syndrome, and preleukemia in 3633 patients with gastrointestinal cancer who were treated in nine randomized clinical trials. Among 2067 patients given semustine (methyl-CCNU) as adjuvant therapy, leukemic disorders developed in 14, whereas only one leukemic disorder (acute nonlymphocytic leukemia) occurred among 1566 patients given other therapies (relative risk = 12.4; 95 per cent confidence interval = 1.7 to 250). The six-year cumulative mean risk (+/- S.E.) of acquiring a leukemic disorder after treatment with semustine was 4.0 +/- 2.2 per cent; the incidence rate was 2.3 cases per 1000 persons per year. Risk increased significantly with time after treatment. The risk of leukemic disorders did not differ according to sex, race, age at treatment, or initial tumor type, nor was it enhanced by concomitant radiotherapy or immunotherapy. In addition, no excess of acute nonlymphocytic leukemia was seen in 44,370 patients treated for gastrointestinal cancer in Connecticut during the period 1935 to 1974, before the advent of nitrosourea chemotherapy. This study provides quantitative evidence that nitrosoureas are leukemogenic in human beings and confirms previous observations that adjuvant chemotherapy with alkylating agents may increase the risk of leukemia.

Venous thromboembolism after total hip replacement continues to be a serious problem. We conducted a study to determine whether adjustment of the dose of subcutaneous heparin to yield partial thromboplastin times in the high-normal range results in a greater reduction of postoperative deep-vein thrombosis than fixed doses of heparin. Seventy-nine patients undergoing elective hip arthroplasty were randomly divided into two groups two days before surgery. Group 1 (41 patients) received a fixed dose of 3500 IU of heparin subcutaneously ever eight hours; 16 of the 41 (39 per cent) had deep-vein thrombosis diagnosed by venography. Group 2 (38 patients) was started on the same dose, which was then adjusted to keep the activated partial thromboplastin time between 31.5 and 36 seconds. From the day of operation to the eighth postoperative day these patients needed progressively more heparin to maintain the activated partial thromboplastin time in the prescribed range. Only 5 of the 38 (13 per cent) had deep-vein thrombosis (P less than 0.01), and the number of thrombi in proximal veins was also lower in this group (P = 0.003). The number of units of blood transfused, the frequency of postoperative wound hematomas, and the drop in hemoglobin levels were identical in the two groups. Adjusted low-dose heparin prophylaxis appears to be a safe and efficacious method to reduce the frequency of deep-vein thrombosis in patients undergoing total hip replacement.

In a randomized multicenter trial, 209 recipients of cadaveric renal transplants were treated either with cyclosporine and prednisone or with standard therapy that included azathioprine and prednisone. Predicted graft survival at one year was 80.4 per cent in patients receiving cyclosporine and 64.0 per cent in those receiving standard therapy (P = 0.003). Predicted patient survival at one year was 96.6 per cent in patients given cyclosporine and 86.4 per cent in those given standard therapy. A detrimental effect on predicted graft survival at one year was seen in patients treated with cyclosporine if they received kidneys that were perfused by machine for longer than 24 hours (70 vs. 88 per cent, P = 0.005) or if the time used to perform the surgical anastomosis was longer than 45 minutes (60 vs. 89 per cent, P = 0.002). In the group receiving standard therapy, predicted graft survival was better in patients who had had five or more blood transfusions than in those who had had two to four transfusions (77 vs. 55 per cent, P = 0.05). Serum creatinine was 2.6 mg per deciliter in patients receiving cyclosporine 90 days after transplantation and 2.0 mg per deciliter in those receiving standard therapy (P = 0.03). Lymphoma developed in one patient receiving cyclosporine. We conclude that cyclosporine is preferable to azathioprine in preventing renal transplant rejection. Further studies will be required to determine the optimal regimen with this agent.

We conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina (625 taking aspirin and 641 placebo). The principal end points were death and acute myocardial infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on electrocardiograms. The incidence of death or acute myocardial infarction was 51 per cent lower in the aspirin group than in the placebo group: 31 patients (5.0 per cent) as compared with 65 (10.1 per cent); P = 0.0005. Nonfatal acute myocardial infarction was 51 per cent lower in the aspirin group: 21 patients (3.4 per cent) as compared with 44 (6.9 per cent); P = 0.005. The reduction in mortality in the aspirin group was also 51 per cent--10 patients (1.6 per cent) as compared with 21 (3.3 per cent)--although it was not statistically significant; P = 0.054. There was no difference in gastrointestinal symptoms or evidence of blood loss between the treatment and control groups. Our data show that aspirin has a protective effect against acute myocardial infarction in men with unstable angina, and they suggest a similar effect on mortality.