We conducted a randomized double-blind trial of levamisole versus placebo as adjuvant therapy for surgical treatment of melanoma. Of 203 patients entered into the study, 104 received levamisole and 99 placebo. The distribution of prognostic variables was similar in both groups, indicating the efficacy of the randomization and the absence of bias. Three end points were analyzed: disease-free interval, time to appearance of visceral metastasis, and survival. There was no statistically significant difference between the groups regarding any of these end points. In patients with Stage I disease, there was a trend in favor of levamisole regarding time to first visceral recurrence and survival (P = 0.07). We conclude that levamisole has no benefit, as compared with placebo, as adjuvant therapy for malignant melanoma.

Because the formation of sickle cells is dependent on the intracellular concentration of deoxyhemoglobin S, we investigated the possibility of altering or preventing sickle-cell crises by reducing serum sodium so as to cause red cells to swell. In three patients with sickle-cell anemia who had been disabled by recurrent painful crises, sustained dilutional hyponatremia was induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in combination with a high fluid intake. Mean corpuscular hemoglobin concentration fell, and the degree of sickling at low partial oxygen pressure was reduced, as determined by morphologic criteria and by increased oxygen affinity of blood. Chronic hyponatremia (serum sodium, 120 to 125 mmol per liter) reduced the frequency of painful crises, whereas acutely induced hyponatremia abbreviated the duration of crises. These results, although preliminary, are encouraging enough to warrant further study of the safety and effectiveness of induced hyponatremia in the prevention and treatment of sickle-cell crises.

The Coronary Drug Project was carried out to evaluate the efficacy and safety of several lipid-influencing drugs in the long-term treatment of coronary heart disease. The five-year mortality in 1103 men treated with clofibrate was 20.0 per cent, as compared with 20.9 per cent in 2789 men given placebo (P = 0.55). Good adherers to clofibrate, i.e., patients who took 80 per cent of more of the protocol prescription during the five-year follow-up period, had a substantially lower five-year mortality than did poor adherers to clofibrate (15.0 vs. 24.6 per cent; P = 0.00011). However, similar findings were noted in the placebo group, i.e., 15.1 per cent mortality for good adherers and 28.3 per cent for poor adherers (P = 4.7x10-16). These findings and various other analyses of mortality in the clofibrate and placebo groups of the project show the serious difficulty, if not impossibility, of evaluating treatment efficacy in subgroups determined by patient responses (e.g., adherence or cholesterol change) to the treatment protocol after randomization.

We performed a prospective, double-blind study of the incidence of thrombocytopenia in 149 patients randomly assigned to treatment with one of three heparin preparations--from bovine lung from intestinal-mucosa A, or from intestinal-mucosa O. Thrombocytopenia developed in 21 patients (platelets, < 100 x 10(9) per liter): 13 of the 50 receiving bovine lung heparin, four of 45 receiving intestinal-mucosa-A heparin, and four of 54 receiving intestinal-musoca-O heparin (P < 0.005). There was a significantly increased incidence of thrombocytopenia in the bovine-lung group (P < 0.002); estimated incidence rates after nine days of treatment were 24 per cent in this group and 7 per cent in the combined intestinal-mucosa A and O groups. Thrombocytopenia appeared in the bovine-lung group on days 3 to 16, in the intestinal-mucosa-A groups on Days 4 to 12, and in the intestinal-mucosa-O group on Days 3 to 7; it disappeared in all groups three to eight days after discontinuation of heparin. A total of 121 patients were subsequently given warfarin for four to six months, and thrombocytopenia was not observed.

To compare the effects of heparin thrombolytic agents in pulmonary thromboembolic disease, we randomly assigned 40 patients with pulmonary emboli but without other clinical cardiopulmonary disease either to heparin followed by oral anticoagulants (21 patients) or to urokinse or streptokinase followed by heparin and then by oral anticoagulants (19 patients). The effects on pulmonary-capillary blood volume and diffusing capacity were compared at two weeks and at one year. The pulmonary-capillary blood volume (in milliliters per square meter of body-surface area) was abnormally low (30 +/- 2.4) [+/- S.E.]; normal, 47 +/- 1.5) in the heparin-treated group at two weeks and remained unchanged at one year. In contrast, it was normal (45 +/- 2.5) in the group receiving thrombolytic agents, both at two weeks and at one year (P < 0.001). The pulmonary diffusing capacity was reduced to 69% of the predicted value in the heparin group at two weeks and 72% at one year, whereas it was 85% of the predicted value in the thrombolytic group at two weeks and 93% at one year (P < 0.001). These results indicate that thrombolytic agents allow more complete resolution of thromboemboli than do heparin and anticoagulants and that they improve capillary perfusion and diffusion.

We assessed the efficacy of an inactivated hepatitis B vaccine in a placebo-controlled, randomized, double-blind trial in 1083 homosexual men known to be at high risk for hepatitis B virus infection. The vaccine was found to be safe and the incidence of side effects was low. Within two months, 77% of the vaccinated persons had high levels of antibody against the hepatitis B surface antigen. This rate increased to 96% after the booster dose and remained essentially unchanged for the duration of the trial. For the first 18 months of follow-up, hepatitis B or subclinical infection developed in only 1.4 to 3.4% of the vaccine recipients as compared with 18 to 27% of placebo recipients (P < 0.0001). The reduction of incidence in the vaccinees was as high as 92.3%; none of the vaccinees with a detectable immune response to the vaccine had clinical hepatitis B or asymptomatic antigenemia. A significant reduction of incidence was already seen within 75 days after randomization; this observation suggests that the vaccine may be efficacious even when given after exposure.

A scleroderma-like illness developed in a patient treated with L-5 hydroxytryptophan (L-5HTP) and carbidopa for intention myoclonus. The patient had high plasma kynurenine levels that remained high when the L-5HTP-carbidopa combination was discontinued, However, levels rose futher on drug rechallenge, suggesting that the drug unmasked an abnormality in one of the enzymes that catabolize kynurenine. Plasma kynurenine was also determined to be high in seven of 15 patients wth idiopathic scleroderma, but not in eight patients with intention myoclonus treated with L-5HTP and a decarboxylase inhibitor and in whom scleroderma did not develop or in 10 patients with Parkinson's disease treated wth L-dopa and carbidopa. Our data and studies in the literature suggest that two factors may be important in the pathogenesis of some scleroderma-like illness: high plasma serotonin and the abnormality associated with elevated kynurenine.

Neonatal Group B streptococcal infections may not respond to antimicrobial therapy and have been associated with case fatality rates of 50 per cent or greater. We evaluated the effect on colonization and disease rates of a single intramuscular dose of aqueous penicillin G given at birth in a prospectively controlled study of 18,738 neonates during a 25-month period. The colonization rate in the mothers was 26.6 per cent, with 50 per cent concordance in the untreated infants and 12.2 per cent in the penicillin-treated infants (P < 0.001). There was a significant decrease in the incidence of disease caused by all penicillin-susceptible organisms in the penicillin group (0.64 vs. 2.26 cases per thousand live births, P = 0.005). Disease caused by penicillin-resistant pathogens was increased in the penicillin-treated group during the first year of the study but was unaffected during the second year. Routine administration of parenteral penicillin at birth cannot be recommended until the effect on the incidence of disease caused by penicillin-resistant pathogens is fully defined.

We administered phenytoin (diphenylhydantoin) by mouth to 17 unselected patients to assess its ability to reduce blistering in recessive dystrophic epidermolysis bullosa (RDEB). Therapeutic response was correlated with blood levels of the drug. Although there was a decrease in blistering of 53 +/- 6 per cent (mean +/- S.E.) among all patients at levels of more than 8 microgram of phenytoin per milliliter, the response was variable, with 12 of 17 patients having a decrease in blistering of more than 40 per cent. Since increased collagenase in human skin has been implicated in the pathogenesis of blistering in RDEB, we examined the effect of phenytoin on this enzyme. Although the drug did not inhibit collagenase activity directly, its addition to human-skin explant and fibroblast cultures produced a 50 to 60 per cent decrease in collagenase activity and immunoreactive protein concentrations. These in vitro studies suggest that phenytoin inhibits synthesis or secretion of collagenase of both, and that the favorable clinical response can be explained by this inhibition.

We studied the effects of a supportive lay woman ("doula") on the length of labor and on mother-infant interaction after delivery in healthy Guatemalan primigravid women. Initial assignment of mothers to the experimental (doula) or control group was random, but controls showed a higher rate (P less than 0.001) of subsequent perinatal problems (e.g. cesarean section and meconium staining). It was necessary to admit 103 mothers to the control group and 33 to the experimental group to obtain 20 in each group with uncomplicated deliveries. In the final sample, the length of time from admission to delivery was shorter in the experimental group (8.8 vs. 19.3 hours, P less than 0.001). Mothers who had a doula present during labor were awake more after delivery (P less than 0.02) and stroked (P less than 0.001), smiled at (P less than 0.009), and talked to (P less than 0.002) their babies more than the control mothers. These observations suggest that there may be major perinatal benefits of constant human support during labor.

Trials of pneumococcal vaccine in healthy young adult populations suggest 75 to 95 per cent type-specific efficacy. Trials have not been done, however, in groups for which pneumococcal vaccine is currently recommended in the United States. To assess efficacy in the immunocompromised groups now receiving the vaccine, we compared serotypes of 35 isolates of Streptococcus pneumoniae isolated from blood or cerebrospinal fluid one month or longer after the patient had received commercially available pneumococcal vaccine with serotypes of 392 isolates from unvaccinated persons surveyed in a study of the nationwide distribution of pneumococcal serotypes. Proportions of infections with vaccine serotypes were unexpectedly similar. An alternative approach to estimation of vaccine efficacy suggested an average efficacy of 36 per cent in persons of all ages. The estimated efficacy was lowest in children two to 10 years old (less than or equal to 0 per cent) and in persons with preexisting diseases that are thought to predispose to pneumococcal disease (less than or equal to 0 per cent), and highest in the group over 10 years old (60 per cent). The possibility that efficacy is low in high-risk, immunocompromised populations makes it important to evaluate clinical efficacy and not just serum antibody responses in such groups.

The therapeutic efficacy of prothrombin-complex concentrates in patients with hemophilia and inhibitors (antibodies) to factor VIII has been increasingly debated. We therefore entered 51 hemophiliacs with factor VIII inhibitors into a double-blind randomized crossover study to compare two commercial prothrombin-complex concentrates (Konyne and Proplex) and an albumin placebo. Acute hemarthrosis of the elbow, knee, or ankle was treated with a single dose of a test preparation and assessed six hours later with objective and subjective criteria. In all measurements the concentrates were significantly more effective than the placebo. The data indicate that although prothrombin-complex concentrates, when used in a single dose, are only partially effective in the treatment of joint hemorrhage in hemophiliacs with inhibitors, their continued use for acute hemarthrosis is justified in the absence of any other effective and readily available therapy for this disorder.