A double-blind, placebo-controlled trial of interferon prophylaxis against viral infections was conducted in renal-transplant recipients receiving standard immunosuprressive therapy with or without antithymocyte globulin. Interferon was administered for six weeks, beginning on the day of transplantation. Cytomegalovirus excretion began earlier and viremia was more frequent in placebo-treated than in interferon-treated patients. Cytomegalovirus viremia correlated with clinical syndromes was more frequent in recipients of antithymocyte globulin. In contrast, neither interferon nor antithymocyte globulin altered excretion of herpes simplex virus. Reversible leukopenia and thrombocytopenia occurred in seven interferon recipients. Patient and graft survival were comparable in interferon and placebo groups. There preliminary results suggest that a six-week course of prophylactic interferon delays shedding of cytomegalovirus and decreases the incidence of viremia after transplantation. In contrast, antithymocyte globulin appears to increase the severity of infection from cytomegalovirus among these patients.

Two double-blind, crossover trials comparing the antiemetic effectiveness of nabilone, a new synthetic cannabinoid, with that of prochlorperazine were conducted in patients with severe nausea and vomiting associated with anticancer chemotherapy. Of 113 patients evaluated, 90 (80 per cent) responded to nabilone therapy, whereas only 36 (32 per cent) responded to prochlorperazine (P less than 0.001). Complete relief of symptoms was infrequent, occurring only in nine patients (8 per cent) given nabilone. When both drugs were compared, both nausea (P less than 0.01) and vomiting episodes (P less than 0.001) were significantly lower in patients given nabilone. Moreover, patients clearly favored nabilone for continued use (P less than 0.001). Predominant side effects noted by patients were similar for both agents and included somnolence, dry mouth and dizziness but were about twice as frequent and more often severe in patients receiving nabilone. In addition, four patients (3 per cent) taking nabilone had side effects (hallucinations in three, hypotension in one) that required medical attention. Euphoria associated with nabilone was infrequent (16 per cent) and mild.

The ability of topical 10 per cent adenine arabinoside 5'-monophosphate to decrease the severity and frequency of recurrent herpes simplex labialis was evaluated in a double-blind, randomized study of 233 patients at three collaborating institutions. Nine clinical and four virologic measurements were used to evaluate drug efficacy during a single episode. No statistically significant improvement in any measurement was seen in the drug-treated patients. Analyses according to institution and age, stage and size of lesion before therapy also indicated no benefit attributable to the drug. There was no effect of the drug on the rate of recurrence of herpes simplex labialis. We conclude that, despite activity against herpes simplex virus infection in tissue culture and in some laboratory animal models, topical use of the drug is ineffective against recurrent herpes simplex labialis. This may be due to failure of the drug to penetrate the skin.

We observed the frequent occurrence of persistent middle-ear effusion in children with acute otitis media and followed them according to standard procedures for otologic diagnosis. We performed a life-table analysis to identify risk factors for such persistent disease. Sixty-two patients were free of middle-ear effusion at one or more clinic visits two to 13 weeks after presentation and were considered cured; 45 had effusion at all clinic visits during this period and were defined as having persistent effusion. The life-table analysis showed that the relative risk for persistence was 3.8 times higher in children less than 24 months of age as compared with children 24 months of age or older (P less than 0.001) and that this risk was 2.8 times greater for white as compared with black children (P less than 0.01). Other factors examined were not identified as significant risk factors. Persistent middle-ear effusion may be associated with impaired hearing and appears to be the most important sequela of otitis media.

We compared the immediate effects of five beta-adrenoreceptor-blocking agents in 16 patients with stable angina pectoris. Acute dose-response studies showed that all five drugs improved exercise tolerance and reduced ST-segment depression, heart rate and blood pressure by a similar degree in comparison with a placebo (P less than 0.01). Near maximum improvement in exercise tolerance occurred when the acute cumulative oral dose had reached 160 mg for propranolol and oxprenolol, 200 mg for metoprolol and tolamolol and 400 mg for practolol. When these drugs were administered as a single doses, increase in walking time before the development of angina and reduction in ST-segment depression, heart rate and systolic blood pressure all occurred within one hour and persisted for eight hours--effects markedly different from the response to a placebo (P less than 0.01). These data show that non-cardioselective agents (propranolol and oxprenolol), cardioselective agents (practolol, metoprolol and tolamolol), as well as drugs with intrinsic sympathomimetic activity (oxprenolol and practolol), were equally effective in the treatment of angina pectoris.

Because high concentrations of ascorbic acid (0.57 mM) lower the free (nonprotein) cystine content of cultured cystinotic skin fibroblasts by over 50 per cent, we did a double-blind clinical trial to establish whether this drug would benefit cystinotic children. Sixty-four patients were randomized into the study; 32 received ascorbic acid (200 mg per kilogram of body weight per day), and 32 placebo. The study was terminated after approximately two years because there was no indication that vitamin C was beneficial and accumulating evidence that it might be harmful. Of 11 patients who left the study because of death or the requirement for dialysis or renal transplantation, eight were receiving ascorbic acid. The estimated relative risk (treatment vs. control) of an adverse event was R = 2.7, with a 90 per cent confidence interval of (0.8, 11.5). The serum creatinine concentration increased 0.53 mg per deciliter per year in patients receiving vitamin C and 0.24 mg per deciliter per year in patients receiving placebo (P = 0.08).

Penicillamine has an effect on immune complexes and immunoglobulins both in vivo and in vitro. We therefore studied the effect of penicillamine on immune complexes and immunoglobulins in primary biliary cirrhosis. Twenty-eight patients were randomly allocated into a treatment group receiving 600 to 900 mg of penicillamine, or a control group, and followed for a maximum of 24 months. After 12 and 24 months, serum immune complexes had fallen significantly in treated patients as compared to controls (P less than 0.05, P less than 0.01). Treatment reduced IgA, IgG and IgM concentrations, with IgM being significantly different from controls at six, 12 and 24 months (P less than 0.01). Over 24 months, serum aspartate transaminase levels fell in treated patients but rose in controls (P less than 0.01). Bilirubin concentrations increased at a slower rate in treated patients. Penicillamine may favorably influence the course of primary biliary cirrhosis by its immunologic action in addition to its copper-chelating action.

To evaluate the effects of coronary-artery bypass, 100 patients with stable, disabling angina were randomized to medical (49) or surgical (51) therapy. There was no statistical difference in major cardiac events after three years (death in five medical vs. four surgical, infarction in eight vs. 10, and unstable angina requiring operation or reoperation in eight vs. three cases). Surgical patients with three-vessel disease had fewer major events (P less than 0.05) than the comparable medical group and less unstable angina requiring operation (P less than 0.02). All unstable angina was less frequent in the surgical group (15 vs. six, P less than 0.01). Functional classification improved more in surgical patients at six months (P less than 0.01) and at late followup examination (P less than 0.05). After six months, surgical patients achieved significantly higher exercise work loads (P less than 0.01), exercise heart rates (P less than 0.05), maximum paced heart rates (P less than 0.01) and myocardial lactate extraction (P less than 0.01). On the basis of this interim report of a relatively small group of patients, we conclude that bypass results in greater functional improvement and less unstable angina than medical therapy. The likelihood of death and myocardial infarction is unchanged by operation.

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

Twenty patients with chronic oral candidiasis were assigned by random allocation to a two-week course of either 10-mg clotrimazole buccal troches or placebo taken five times daily in a double-blind clinical trial. Each of the 10 recipients of clotrimazole had marked regression of symptoms and mucosal lesions, and in nine patients potassium hydroxide preparations and cultures of mucosal scrapings gave no evidence of candidiasis. In contrast, only one of the 10 patients receiving placebo showed any improvement. The clinical outcome in the clotrimazole-treated group was significantly more favorable (P less than 0.001) than in the group receiving placebo. No adverse reactions to the drug were observed. After the blind phase of their trial, 15 patients were treated with clotrimazole troches in an open trial. One to three troches per day were found adequate to sustain remissions. We conclude that clotrimazole is highly effective treatment for chronic oral candidiasis.

To evaluate the effectiveness of cyclophosphamide in the treatment of lupus nephritis, we designed a prospective study of patients with diffuse proliferative lupus nephritis. Twenty-six patients received prednisone (average dose, 40 mg per day) and 24 combined prednisone (average dose, 29 mg per day) and cyclophosphamide (average dose, 107 mg per day) for six months. Thereafter, all patients received maintenance doses of prednisone. Most of the patients improved (84 per cent) after six months of initial treatment with either program. Early progression of disease, ending mainly in end-stage renal disease, was equally frequent in the two treatment groups in patients with already advanced disease. In a four-year follow-up study there was a higher incidence (P approximately 0.04) and average rate (P approximately 0.02) of clinical recurrence of nephritis in the group initially given only steroid than in the group initially given both drugs. However, the proportion of patients alive after four years with stable or improved renal function was similar in the two treatment groups.

A study of hypertension in an industrial setting allowed us to confirm and explore an earlier retrospective finding that the labeling of patients as hypertensive resulted in increased absenteeism from work. After screening and referral, we found that absenteeism rose (mean +/- 1 S.E.) 5.2 +/- 2.3 days per year (P less than 0.025); this 80 per cent increase greatly exceeded the 9 per cent rise in absenteeism in the general employee population during this period. The main factors associated with increased absenteeism were becoming aware of the condition (P less than 0.01) and low compliance with treatment (P less than 0.001). Subsequent absenteeism among patients unaware of their hypertension before screening was not related to the degree of hypertension, whether the worker was started on therapy, the degree of blood-pressure control achieved or exposure to attempts to promote compliance. These results have major implications for hypertension screening programs, especially since absenteeism rose among those previously unaware of their condition, regardless of whether antihypertensive therapy was begun.

Seventy-one "negative" randomized control trials were re-examined to determine if the investigators had studied large enough samples to give a high probability (greater than 0.90) of detecting a 25 per cent and 50 per cent therapeutic improvement in the response. Sixty-seven of the trials had a greater than 10 per cent risk of missing a true 25 per cent therapeutic improvement, and with the same risk, 50 of the trials could have missed a 50 per cent improvement. Estimates of 90 per cent confidence intervals for the true improvement in each trial showed that in 57 of these "negative" trials, a potential 25 per cent improvement was possible, and 34 of the trials showed a potential 50 per cent improvement. Many of the therapies labeled as "no different from control" in trials using inadequate samples have not received a fair test. Concern for the probability of missing an important therapeutic improvement because of small sample sizes deserves more attention in the planning of clinical trials.

We undertook a randomized clinical trial to evaluate the efficacy of chest physiotherapy and intermittent positive-pressure breathing in the treatment of pneumonia. The diagnosis of pneumonia required a compatible clinical history and x-ray confirmation. A total of 54 patients were assigned to treatment and control groups and were similar in age, smoking history, underlying lung disease and prior antibiotic treatment. Antibiotic therapy, guided by Gram stain and sputum and blood cultures, was similar in both groups. Chest physiotherapy, consisting of postural drainage, percussion and vibration, was given concurrently with intermittent positive-pressure breathing with use of racemic epinephrine every four hours. There was no statistically significant difference in duration of fever, extent of radiographic clearing, duration of hospital stay and mortality between the control and treated groups. Chest physiotherapy and intermittent positive-pressure breathing do not hasten the resolution of pneumonia.

We performed a randomized prospective study of the effect of placement position of umbilical-artery catheters on complication rates in high-risk newborn infants. A higher complication rate (31 of 40 vs. 13 of 33) (P less than 0.005) occurred in the group with the catheter tip at the third to fourth lumbar segment, as compared to those with the tip at the seventh to eighth thoracic segment, owing to more episodes of blanching and cyanosis of the extremities. There was no difference between groups in the rate of complications requiring catheter removal. Aortography revealed thrombosis in 21 of 23 patients studied, but there was no clinical evidence of impaired circulation. In retrospect, we found that, independently of catheter position, administration of antibiotics through the catheter was associated with an increased rate of complications (63 vs. 20 per cent). Umbilical-artery catheterization entails potential risks regardless of the position of the catheter; placement of the catheter with its tip at the seventh to eighth thoracic segment may be associated with fewer complications than at lower positions.

To investigate the efficacy of antibiotic irrigation in preventing catheter-associated urinarytract infection, we carried out a randomized controlled trial of a neomycin-polymyxin irrigant administered through closed urinary catheters. Eighteen of 98 (18 per cent) of the patients not given irrigation became infected, as compared with 14 of 89 (16 per cent) of those given irrigation, yielding a mean daily incidence of 5 per cent in each group. The distribution of organisms and their antibiotic sensitivities differed in the two groups, the organisms from the patients with irrigation being more resistant. Disconnections of the catheter junctions were associated with high rates of infection. The rate of disconnections of the junctions in the group given irrigation was almost twice that of the control group because of the presence of the extra junction on overall infection rate represents the result of two opposing phenomena: the increased entry of organisms and the suppression of a portion of them.

Insect hypersensitivity is currently treated by immunization using whole-body extracts. We compared this regimen with immunotherapy using insect venoms or placebo in groups of 20 patients matched for history and sensitivity, as judged by venom skin test, histamine release and IgE antibody to venom. After six to 10 weeks of immunization, systemic reactions to stings occurred in seven of 12, seven of 11, and one of 18 patients treated with placebo, whole-body extract, and venom, respectively. Placebo and whole-body extract gave similar results and were significantly less effective than venom immunotherapy (P less than 0.01). The 14 patients with failure of treatment with whole-body extract and placebo were subsequently provided with venom immunotherapy; one reacted to a subsequent sting. We conclude that venom immunotherapy is clinically superior to therapy on whole-body extract or placebo.

Five hundred and eighty-five patients with threatened stroke were followed in a randomized clinical trial for an average of 26 months to determine whether aspirin or sulfinpyrazone, singly or in combination, influence the subsequent occurrence of continuing transient ischemic attacks, stroke or death. Eighty-five subjects went on to stroke, and 42 died. Aspirin reduced the risk of continuing ischemic attacks, stroke or death by 19 per cent (P less than 0.05) and also reduced risk for the "harder," more important events of stroke or death by 31 percent (P less than 0.05), but this effect was sex-dependent: among men, the risk reduction for stroke or death was 48 per cent (P less than 0.005), whereas no significant trend was observed among women. For sulfinpyrazone, no risk reduction of ischemic attacks was observed, and the 10 per cent risk reduction of stroke or death was not statistically significant. No overall synergism or antagonism was observed between the two drugs. We conclude that aspirin is an efficacious drug for men with threatened stroke.