We conducted a randomized trial in seven Australian hospitals of the efficacy and safety of three immunosuppressive regimens after first transplantation of a cadaver kidney: long-term cyclosporine, short-term (three months) cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine. Patients assigned to long-term cyclosporine (n = 138) or short-term cyclosporine followed by azathioprine and prednisolone (n = 141) had similar actuarial 12-month survival (98.4 vs. 96.4 percent) and graft survival (83.9 vs. 82.1 percent). Patients assigned to receive only azathioprine and prednisolone (n = 138), with optional use of antithymocyte globulin, had a significantly poorer survival rate (91.3 percent, P = 0.015) because of deaths from cardiac causes and infection, but their graft survival of 76.0 percent (P = 0.31) did not differ significantly from that of either group receiving cyclosporine. After the switch from cyclosporine to azathioprine and prednisolone, 15 percent of patients had reversible rejection episodes, but the frequency of rejection and graft loss did not differ from that in the long-term cyclosporine group. After the change to azathioprine and prednisolone, serum creatinine levels declined in nearly all patients, so that after three months they were comparable to those in the group receiving azathioprine and prednisolone only, and significantly lower than those in the group receiving long-term cyclosporine therapy (P less than 0.003). We conclude that the two cyclosporine regimens result in comparable patient and graft survival, but that changing to azathioprine and prednisolone at three months improves graft function.

We studied the metabolic effects of stearic acid (18:0) on plasma lipoprotein levels in 11 subjects during three dietary periods of three weeks each. The three liquid-formula diets, which were used in random order, were high in palmitic acid (16:0), stearic acid, and oleic acid (18:1), respectively. Caloric intakes were the same during the three periods. As compared with the values observed when the subjects were on the high-palmitic-acid diet, plasma total cholesterol decreased by an average of 14 percent during consumption of the high-stearic-acid diet (P less than 0.005) and by 10 percent during consumption of the high-oleic-acid diet (P less than 0.02). Low-density lipoprotein cholesterol levels fell by 21 percent in subjects on the high-stearic-acid diet (P less than 0.005) and by 15 percent in subjects on the high-oleic-acid diet (P less than 0.005). No significant differences were observed in the plasma levels of triglycerides or high-density lipoprotein cholesterol among the three diets. Measurements of the intestinal absorption of palmitic, stearic, and oleic acids revealed essentially complete absorption of each during the three dietary periods. The oleic acid content of plasma triglycerides and cholesteryl esters increased significantly during the high-stearic-acid period, suggesting that stearic acid is rapidly converted to oleic acid. We conclude that stearic acid appears to be as effective as oleic acid in lowering plasma cholesterol levels when either replaces palmitic acid in the diet.

Enterotoxigenic Escherichia coli is a common cause of traveler's diarrhea. Prophylaxis against traveler's diarrhea has been associated with side effects from bismuth subsalicylate and the development of resistance to antimicrobial agents. We undertook a double-blind controlled trial in which a bovine milk immunoglobulin concentrate with high titers of antibodies against enterotoxigenic E. coli was used as prophylaxis against E. coli challenge in volunteers. Lyophilized milk immunoglobulins were prepared from the colostrum of cows immunized with several enterotoxigenic E. coli serotypes and fimbria types, E. coli heat-labile enterotoxin, and cholera toxin. As a control, an immunoglobulin concentrate with no anti-E. coli activity was prepared. Ten volunteers received buffered immunoglobulin concentrate against enterotoxigenic E. coli, and 10 received the control immunoglobulin concentrate, dissolved in water, three times a day. No side effects were observed. On the third day of immunoglobulin prophylaxis, the volunteers were given 10(9) colony-forming units of enterotoxigenic E. coli H10407 (O78:H11). This strain produces colonization factor antigen I and heat-labile and heat-stable enterotoxins. None of the 10 volunteers receiving the immunoglobulin concentrate against E. coli had diarrhea, but 9 of the 10 controls did (P less than 0.0001). All volunteers excreted E. coli H10407. We conclude from these preliminary results that milk immunoglobulin concentrate may be an effective prophylaxis against traveler's diarrhea.

Although wide surgical excision is the accepted treatment for thin malignant melanomas, there is reason to believe that narrower margins may be adequate. We conducted a randomized prospective study to assess the efficacy of narrow excision (excision with 1-cm margins) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. The major prognostic criteria were well balanced in the two groups. The mean thickness of melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the wide-excision group. The subsequent development of metastatic disease involving regional nodes and distant organs was not different in the two groups (4.6 and 2.3 percent, respectively, in the narrow-excision group, as compared with 6.5 and 2.6 percent in the wide-excision group). Disease-free survival rates and overall survival rates (mean follow-up period, 55 months) were also similar in the two groups. Only three patients had a local recurrence as a first relapse. All had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that narrow excision is a safe and effective procedure for such patients.

We conducted a study of the effectiveness of an educational intervention designed to modify risk factors associated with coronary heart disease among 3388 children in 37 schools in two demographically dissimilar areas (the Bronx and Westchester County) in and around New York City. Schools within each area were randomly assigned to either intervention or nonintervention groups. In schools targeted for intervention, children in the fourth through eighth grades were taught a teacher-delivered curriculum focusing on diet, physical activity, and cigarette smoking. Risk-factor levels were measured in all schools at base line and at four follow-up points. A total of 1769 of the children qualified for analysis of the intervention effect. After five years, the net mean change in plasma levels of total cholesterol was -1.7 mg per deciliter per year (-0.04 mmol per liter) (95 percent confidence interval, -2.7 to -0.7 mg per deciliter [-0.07 to -0.02 mmol per liter]) in the Westchester County schools, or -8.5 mg per deciliter (-0.22 mmol per liter) (5.1 percent) over a period of five years. In the schools in the Bronx, the net mean change was -1.0 mg per deciliter per year (-0.03 mmol per liter) (95 percent confidence interval, -2.3 to +0.3 mg per deciliter [-0.06 to +0.01 mmol per -2.3 to +0.3 mg per deciliter [-0.06 to +0.01 mmol per liter]), or -5.0 mg per deciliter (-0.13 mmol per liter) (2.9 percent) over a period of five years. Favorable trends in dietary intake and health knowledge were also observed, whereas the other targeted risk factors were not significantly altered. If these findings can be replicated, this will suggest that educational programs to modify coronary risk factors are feasible and may have a favorable (albeit small) effect on blood levels of cholesterol in children.

To evaluate the feasibility and cost savings of hospital discharge three days after acute myocardial infarction, we screened 507 consecutive patients prospectively for clinical complications and exercise-test performance. Of 179 patients whose condition was classified as uncomplicated (no angina, heart failure, or arrhythmia 72 hours after admission), 126 underwent early exercise testing and 90 had no provocable myocardial ischemia. Eighty of these patients were randomly assigned to early (day 3) or conventional (days 7 to 10) hospital discharge. Seventy-six of them had received coronary reperfusion therapy (thrombolysis, angioplasty, or both). At six months of follow-up, there were no deaths or new ventricular aneurysms, and the early-discharge and conventional-discharge groups had similar numbers of hospital readmissions (6 and 10), reinfarctions (none and 5), and patients with angina (3 and 8). In the early-discharge group, 25 of 29 previously employed patients returned to work 40.7 +/- 21.9 days (mean +/- SD) after admission, as compared with 25 of 27 patients in the conventional-discharge group, who returned to work after a mean of 56.9 +/- 30.3 days (P = 0.054). The mean cumulative hospital and professional charges were $12,546 +/- 3,034 in the early-discharge group, as compared with $17,868 +/- 3,688 in the conventional-discharge group (P less than 0.0001). In carefully selected patients with uncomplicated myocardial infarction, hospital discharge after three days is feasible and leads to a substantial reduction in hospital charges. Before this strategy can be widely recommended, however, its safety must be confirmed in larger prospective clinical trials.

We discontinued anticonvulsant drugs in 92 patients who had been free of seizures during two years of treatment with a single drug. All the patients had epilepsy that had previously been untreated, and had been randomly assigned to receive carbamazepine, phenytoin, or sodium valproate. Thirty-one patients relapsed, and 61 remained free of seizures. The mean duration of the follow-up in the patients remaining free of seizures was 35 months (range, 6 to 62). There was no significant difference between the relapse rate among adults (35 percent) and that among children (31 percent). Our results suggest that the number of seizures a patient had before control was achieved, the number of drugs tried as single-drug therapy, and the type of treatment withdrawn all influenced the outcome. Among the various types of seizures, complex partial seizures with secondary generalization carried the worst prognosis. In comparison, the risk of relapse was 65 percent lower in patients with generalized seizures and 97 percent lower in patients with complex or simple partial seizures in the absence of secondary generalized attacks. Among the four electroencephalographic classes, class 4 (abnormal before treatment and unchanged before withdrawal) carried the worst prognosis. The risk of relapse was 94 to 99 percent lower in patients in the other three electroencephalographic classes. Among the three anticonvulsants, withdrawal of sodium valproate carried the worst prognosis. In comparison, the odds of relapsing were 28 percent lower after withdrawal of phenytoin and 85 percent lower after withdrawal of carbamazepine. We conclude that withdrawal of anticonvulsant medication should be considered in patients free of seizures for two years.

We randomly assigned 95 patients with large esophageal varices (Grade 3 or 4) who had not previously had upper gastrointestinal tract bleeding to two groups: 49 received intravariceal sclerotherapy, and 46 were followed as controls. Over a mean follow-up of 13 months there was no difference between the sclerotherapy group and the control group in mortality (24.4 percent) or any significant difference in average hospital stay per month (3.0 vs. 2.6 days). Sclerotherapy was associated with significantly more episodes of upper gastrointestinal bleeding (26 vs. 10 episodes, P less than 0.05); 75 percent of deaths in the sclerotherapy group were related to bleeding, as compared with 18 percent in the control group. An additional 54 patients with cirrhosis who did not qualify for the study were also followed--20 with small varices and 34 with none. Mortality was 20 and 15 percent, respectively; no deaths were due to bleeding. We conclude that prophylactic sclerotherapy does not provide clinical benefit to patients with large esophageal varices.

Legislatively mandated programs for early intervention on behalf of handicapped infants often stipulate the inclusion of physical therapy as a major component of treatment for cerebral palsy. To evaluate the effects of physical therapy, we randomly assigned 48 infants (12 to 19 months of age) with mild to severe spastic diplegia to receive either 12 months of physical therapy (Group A) or 6 months of physical therapy preceded by 6 months of infant stimulation (Group B). The infant-stimulation program included motor, sensory, language, and cognitive activities of increasing complexity. Masked outcome assessment was performed after both 6 and 12 months of therapy to evaluate motor quotient, motor ability, and mental quotient. After six months, the infants in Group A had a lower mean motor quotient than those in Group B (49.1 vs. 58.1, P = 0.02) and were less likely to walk (12 vs. 35 percent, P = 0.07). These differences persisted after 12 months of therapy (47.9 vs. 63.3, P less than 0.01, and 36 vs. 73 percent, P = 0.01, respectively). We noted no significant differences between the groups in the incidence of contractures or the need for bracing or orthopedic surgery. Group A also had a lower mean mental quotient than Group B after six months of therapy (65.6 vs. 75.5, P = 0.05). The routine use of physical therapy in infants with spastic diplegia offered no short-term advantage over infant stimulation. Because of the limited scope of the trial, our conclusions favoring infant stimulation are preliminary. The results suggest that further study of the effects of both physical therapy and infant stimulation is indicated.

We evaluated the use of silver nitrate drops and tetracycline ointment for the prophylaxis of ophthalmia neonatorum in a controlled trial involving 2732 newborns in Nairobi, Kenya. The overall rates of prevalence of intrapartum maternal gonococcal and chlamydial infection were 6.4 and 8.9 percent, respectively. After prophylaxis with silver nitrate, the incidence rates of gonococcal, chlamydial, and nongonococcal, nonchlamydial ophthalmia neonatorum were 0.4, 0.7, and 6.2 percent, respectively, whereas after prophylaxis with tetracycline, the rates were 0.1, 0.5, and 4.5 percent. The attack rates of gonococcal ophthalmia neonatorum in newborns exposed to Neisseria gonorrhoeae at birth were 7.0 percent in those receiving silver nitrate and 3.0 percent in those receiving tetracycline (95 percent confidence interval for the difference in rates, -3.4 to 11.4 percent). As compared with historical controls, the incidence of gonococcal ophthalmia neonatorum decreased 83 percent among infants treated with silver nitrate and 93 percent among those treated with tetracycline. Failure of prophylaxis was associated with postpartum maternal endometritis (P = 0.05). Among newborns exposed to maternal infection with Chlamydia trachomatis, chlamydial conjunctivitis developed in 10.1 percent given silver nitrate and in 7.2 percent given tetracycline (95 percent confidence interval for the difference in rates, -4.7 to 10.5 percent), yielding reductions in the incidence of chlamydial ophthalmia of 68 and 77 percent, respectively, as compared with the historical controls. We conclude that tetracycline is as effective as silver nitrate in preventing gonococcal ophthalmia neonatorum.

To test our previous observation that methotrexate reduces corticosteroid requirements of patients with severe asthma, we studied 14 patients with corticosteroid-dependent bronchial asthma in a 24-week randomized double-blind crossover trial comparing a low dosage of methotrexate (15 mg per week) with placebo. At base line the mean dosage of prednisone was 173.5 mg per week (range, 70 to 420). On the average, 36.5 percent less prednisone was required when patients received methotrexate than when they received placebo (P = 0.01). Measurement of forced vital capacity and forced expiratory volume in one second showed that there was no deterioration in the condition of patients in whom the dosage of prednisone was reduced. The patients' subjective assessment of breathing ability indicated significant improvement (P = 0.01). The adverse effects of methotrexate were limited to transient nausea in three patients and an evanescent rash in one patient. Nine patients are still receiving methotrexate 3 to 10 months after the study's conclusion. The dosages of steroids have been further reduced in each of these patients, and prednisone has been discontinued in four. We conclude from this preliminary study that the use of methotrexate allows a significant reduction in the use of corticosteroids in patients with severe asthma without deterioration of pulmonary function.

Treatment with nafarelin, a gonadotropin-releasing hormone agonist, reversibly inhibits ovarian function and induces hypoestrogenemia. To determine the efficacy of such hormonal manipulation in the treatment of endometriosis, we randomly assigned 213 patients with laparoscopically confirmed endometriosis to receive, for six months, either nafarelin by nasal spray (400 or 800 micrograms per day) or oral danazol (800 mg per day). Placebo nasal spray and placebo tablets were used to double blind the study. Pretreatment and post-treatment laparoscopies were compared by means of the American Fertility Society's scoring system. More than 80 percent of the patients in each treatment group had a reduction in the extent of disease as assessed by laparoscopy. The mean laparoscopic scores decreased from 21.9 to 12.6 with 800 micrograms of nafarelin, from 20.4 to 11.7 with 400 micrograms of nafarelin, and from 18.4 to 10.5 with danazol (P = 0.0001 within each group; there were no statistically significant differences between the groups). The percentage of women with severely painful symptoms of endometriosis decreased from about 40 percent to 5 to 10 percent, whereas the percentage with no or minimal discomfort rose from 25 to 70 percent. Of the 149 patients who tried to become pregnant, 58 (39 percent) succeeded after the completion of treatment; similar rates of pregnancy applied to the three treatment groups. Danazol use decreased high-density lipoprotein levels and increased low-density lipoprotein levels. These changes were not observed in nafarelin users, but a higher percentage of them reported hot flashes and decreased libido. We conclude that nafarelin is an effective agent for treating endometriosis and has few side effects other than hypoestrogenism.

Thromboembolic disease has long been recognized as a complication of cancer. Recent reports have suggested that drugs used in the treatment of cancer, including chemotherapeutic agents and hormones, may contribute to this risk, but it has not been possible to separate the effect of these drugs from that of the cancer. We performed a randomized trial comparing 12 weeks of chemohormonal therapy (using cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, doxorubicin, and tamoxifen) with 36 weeks of chemotherapy (using cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone) in patients with Stage II breast cancer. Among 205 patients randomly assigned to treatment, there were 14 episodes of thrombosis (6.8 percent). These 14 episodes occurred during 979 patient-months of chemotherapy; by comparison, there were no events during 2413 patient-months without therapy. During the first 12 weeks of the study, five patients in the 12-week group and four patients in the 36-week group had thrombosis. During the subsequent 24 weeks, when only patients in the 36-week group were still receiving chemotherapy, there was no thrombosis in the 12-week group, but there were five additional events in the 36-week group (P = 0.03). These findings suggest that chemotherapy contributes to thrombosis in patients with breast cancer.

Heterotopic prosthetic ventricles were used to support the circulation in 29 candidates for heart transplantation who were expected to die before procurement of a donor heart. Twenty-one of these patients (average age, 36 years) underwent successful transplantation after 8 hours to 31 days of circulatory support. The other eight patients died because their condition could not be stabilized for transplantation, despite restoration of blood flow. Fourteen patients received biventricular support; 15 received only left ventricular support, with pharmacologic assistance of right heart function. Before transplantation, blood flow from the left prosthetic ventricle averaged 2.8 +/- 0.4 liters per minute per square meter of body-surface area, and from the right prosthesis 2.4 +/- 0.4 liters, as compared with an average flow of 1.6 +/- 0.5 liters per minute per square meter before implantation. Of the 21 patients who received heart transplants, 20 were discharged from the hospital after a median of 31 days. Nineteen patients were alive at 7 to 39 months, and 11 of the first 12 were alive at one year. We conclude that heterotopic placement of prosthetic ventricles as a bridge to transplantation provides an effective method of temporarily supporting cardiac function in critically ill patients without removing the natural heart. The early survival rate after transplantation is similar to that with elective cardiac transplantation.