To assess the value of simple protective isolation, we prospectively compared it with standard hospital care in 43 episodes of severe granulocytopenia, most occurring in patients with acute nonlymphocytic leukemia. Sterilized food and prophylactic oral antibiotics were not used. Twenty episodes in 17 patients were randomized to simple protective isolation (437 days), and 23 episodes in 20 patients to standard care (611 days). No statistically significant differences were observed in the overall incidence of infection, time to onset of first infection, or days with fever. Twenty-seven infections occurred in recipients of standard care (4.42 per 100 days), and 28 infections in isolated patients (6.41 per 100 days). Except for a threefold higher rate of bacteremia in patients in isolation (2.06 vs. 0.65 per 100 days), the profile of infection was similar in the two groups. Neither response to antileukemic therapy nor survival was improved by isolation. We conclude that protective isolation alone, as practiced in most hospitals, appears not to benefit granulocytopenic patients.

In studies to determine the optimal treatment for polycythemia vera, 431 previously untreated patients whose disease met established diagnostic criteria were entered into a prospective, randomized controlled trial between 1967 and 1974. Three treatment regimens were used: phlebotomy alone, chlorambucil supplemented by phlebotomy, or radioactive phosphorus supplemented by phlebotomy. Despite minor differences in age and sex, the three groups were comparable in initial hematocrit, white-cell and platelet counts, and disease-related symptoms. The median duration of follow-up is now more than 6 1/2 years. As of February 15, 1980, there were no statistically significant differences in survival among the groups. However, the risk of acute leukemia in patients given chlorambucil was 2.3 times that in patients given radioactive phosphorus and 13 times that in patients treated with phlebotomy alone. The increased incidence of leukemia during chlorambucil treatment is statistically significant (P less than or equal to 0.002); accordingly, the Polycythemia Vera Study Group has discontinued the use of chlorambucil in the treatment of polycythemia vera.

To study the efficacy of corticosteroids in chronic active hepatitis (CAH) positive for hepatitis B surface antigen (HBsAg), we pair-randomized 51 patients to receive either 15 to 20 mg of prednisolone per day or a placebo. After initial remission, the maintenance dosage of prednisolone was 10 mg per day, and the patients were prospectively followed for up to 3 1/2 years. Prednisolone decreased serum bilirubin (P < 0.05) and globulin (P < 0.01) at three months; it delayed other biochemical remission occurring after the second month of medication (P < 0.001); it hastened biochemical relapse (P < 0.0001); and it increased the frequency of complications (P < 0.0001) and the death rate (P < 0.01). We conclude that prednisolone has an overall harmful effect in patients with HBsAg-positive CAH.

We examined the value of maintenance theophylline at serum concentrations of 10 to 20 micrograms per milliliter in a placebo-controlled, randomized, double-blind trial of 33 children with steroid-dependent chronic asthma. Patients were free of all symptoms 63 +/- 6 per cent of the days (mean +/- S.E.M.) when taking theophylline as compared with 42 +/- 6 per cent when taking placebo (P < 0.01). Inhaled metaproterenol was required twice as often with placebo (P < 0.01), and additional daily corticosteroids were needed more than three times as often with placebo (P = 0.02). Daily peak flow measurements improved with theophylline (P < 0.01) as did monthly spirometric measurements and residual volume measured by plethysmography. Theophylline was associated with a 50 per cent increase in the number of patients able to complete an exercise test (P = 0.01) and with a smaller decrease in forced expiratory volume in one second among patients completing the exercise (P < 0.02). We conclude that maintenance bronchodilator therapy with theophylline can provide clinically important benefit for patients with chronic steroid-dependent asthma.

Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

We studied the therapeutic efficacy of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid in nine patients with Crohn's disease and in 23 patients with ulcerative colitis. In a randomized, controlled trial, we treated 11 patients for six weeks with 1 g of sulfasalazine three times a day, seven patients with 0.5 g of sulfapyridine three times a day, and 14 patients with 0.5 g of 5-aminosalicylic acid suppositories three times a day. The clinical state of the disease was characterized by an activity index, quality of stool, and remission rate. In addition, we monitored plasma levels of sulfapyridine, 5-aminosalicylic acid, and their acetylated metabolites. The initial activity index (mean +/- S.D.) was significantly reduced by sulfasalazine (from 245 +/- 129 to 100 +/- 71; P < 0.001) and by 5-aminosalicylic acid (from 251 +/- 65 to 90 +/- 93; P < 0.0001), but sulfapyridine was without benefit. Stool quality was also improved by sulfasalazine (82 per cent of the cases) and by 5-aminosalicylic acid (79 per cent). The highest remission rate was achieved with 5-aminosalicylic acid (86 per cent), followed by sulfasalazine (64 per cent) and sulfapyridine (14 per cent). Our investigations show that 5-aminosalicylic acid is the active moiety of sulfasalazine and that this effective metabolite may be an alternative to sulfasalazine in inflammatory bowel disease.

Within three weeks of definitive surgical intervention, 467 patients with histologically proved malignant glioma were randomized to receive one of four treatment regimens: semustine (MeCCNU), radiotherapy, carmustine (BCNU) plus radiotherapy, or semustine plus radiotherapy. We analyzed the data for the total randomized population and for the 358 patients in whom the initial protocol specifications were met (the valid study group). Observed toxicity included acceptable skin reactions secondary to radiotherapy and reversible leukopenia and thrombocytopenia due to chemotherapy. Radiotherapy used alone or in combination with a nitrosourea significantly improved survival in comparison with semustine alone. The group receiving carmustine plus radiotherapy had the best survival, but the difference in survival between the groups receiving carmustine plus radiotherapy and semustine plus radiotherapy was not statistically significant. The combination of carmustine plus radiotherapy produced a modest benefit in long-term (18-month) survival as compared with radiotherapy alone, although the difference between survival curves was not significiant at the 0.05 level. This study suggests that it is best to use radiotherapy in the post-surgical treatment of malignant glioma and to continue the search for an effective chemotherapeutic regimen to use in addition to radiotherapy.

To evaluate the treatment of advanced islet-cell carcinoma, we randomly assigned 84 patients to streptozocin alone or streptozocin plus fluorouracil. Each regimen was given in five-day courses. The most frequent toxic effects were nausea and vomiting, mild and reversible renal toxicity, and bone-marrow depression with the combination regimen. The combination had advantages over streptozocin alone in overall rate of response (63 vs. 36 per cent) and in rates of complete response (33 vs. 12 per cent). There was no evidence of a preferential response among types of functional tumors. Objective responses were generally of long duration (median, 17 months) and of substantive clinical benefit. Treatment with the combination also yielded a survival advantage over treatment with streptozocin alone (medians, 26 and 16 1/2 months), but this difference is not statistically significant. In spite of gastrointestinal side effects, streptozocin combined with fluorouracil appears to be a valuable treatment for advanced islet-cell carcinoma.

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.

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.

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.

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.

Patients with cardiac failure have a generalized sympathetic vasoconstriction that may impair cardiac function and exercise tolerance. The ability of long-term alpha-receptor blockade and vasodilation with trimazosin (TMZ) to improve exercise capacity was studied in patients with chronic, stable heart failure of varying severity (functional exercise classes B to D). Exercise performance was monitored by respiratory gas exchange and air flow before and after patients were randomized to placebo (13 patients) or TMZ were then followed on treatment for up to 52 weeks. Significant (P less than 0.05) and sustained increases in exercise capacity, oxygen uptake, and oxygen pulse were observed with TMZ treatment in each Class B or C patient and in six of nine Class D patients, and were not observed during treatment with placebo.

Two hundred fifty-eight patients with suspected sepsis were treated with tobramycin or gentamicin in a prospective, randomized, double-blind trial. One hundred forty-six patients received nine or more doses, had serial determinations of serum creatinine, and were evaluated for nephrotoxicity; 91 were able to cooperate with audiometry and were evaluated for auditory toxicity. Auditory toxicity developed in five of 47 (10 per cent) given gentamicin and five of 44 (11 per cent) given tobramycin. Nephrotoxicity developed in 19 of 72 (26 per cent) given gentamicin and nine of 74 (12 per cent) given tobramycin (P less than 0.025). The severity of the nephrotoxicity was not different; the mean increase in creatinine was 1.3 mg per 100 ml (114.9 mumol per liter) in both groups. Both the tobramycin and gentamicin groups had a similar mean age, initial serum creatinine level, total dose, serum aminoglycoside level, and duration of therapy. We conclude that tobramycin causes nephrotoxicity less frequently than does gentamicin.

To test the effectiveness of 6-mercaptopurine (6-MP) in the treatment of Crohn's disease, we entered 83 chronically ill patients into a two-year double-blind study comparing 6-MP with placebo. Crossover data showed that improvement occurred in 26 of 39 courses of 6-MP (67%) as compared with three of 39 courses of placebo (8%) (P less than 0.001). Non-crossover data likewise confirmed the superiority of 6-MP. The drug was more effective than placebo in closing fistulas (31 vs 6%) and in permitting discontinuation or reduction of steroid dosage (75 vs. 36%) (P less than 0.001). The onset of response to 6-MP was often delayed, with 32% of patients taking longer than three months to respond, and 19% taking longer than four months. Adverse side effects to 6-MP occurred in 10% of patients and were uniformly reversible. We conclude that 6-MP is an effective and useful agent in the management of Crohn's disease.

To examine the effects of the Leboyer method of delivery, we randomly assigned 56 women to either a Leboyer or a conventional delivery and used a variety of clinical and behavioral measures to assess the outcome in mother and child. No differences were noted in maternal or newborn morbidity, in infant behavior in the first hour of life, at 24 or 72 hours post partum, or at eight months of age; or in maternal perceptions of her infant and the experience of giving birth, except that eight months after delivery, mothers who had used the Leboyer method were more likely to say that the event had influenced their child's behavior (P = 0.05). Women who expected a Leboyer delivery had shorter active labors (P = 0.03), suggesting that psychologic factors (expectations) influence physical outcomes in perinatal medicine. Our results suggest that the Leboyer procedure has no advantage over a gentle, conventional delivery in influencing infant and maternal outcomes.