We compared the efficacy of intravenous gamma globulin plus aspirin with that of aspirin alone in reducing the frequency of coronary-artery abnormalities in children with acute Kawasaki syndrome in a multicenter, randomized trial. Children randomly assigned to the gamma globulin group received intravenous gamma globulin, 400 mg per kilogram of body weight per day, for four consecutive days; both treatment groups received aspirin, 100 mg per kilogram per day, through the 14th day of illness, then 3 to 5 mg per kilogram per day. Two-dimensional echocardiograms were interpreted blindly and independently by two or more readers. Two weeks after enrollment, coronary-artery abnormalities were present in 18 of 78 children (23 percent) in the aspirin group, as compared with 6 of 75 (8 percent) in the gamma globulin group (P = 0.01). Seven weeks after enrollment, abnormalities were present in 14 of 79 children (18 percent) in the aspirin group and in 3 of 79 (4 percent) in the gamma globulin group (P = 0.005). No child had serious adverse effects from receiving gamma globulin. We conclude that high-dose intravenous gamma globulin is safe and effective in reducing the prevalence of coronary-artery abnormalities when administered early in the course of Kawasaki syndrome.

Fifty-three recipients of bone marrow transplants were monitored prospectively for urinary excretion of human polyomaviruses by enzyme-linked immunosorbent assays of urinary supernatants and DNA hybridization assays of urinary cells. Excretion of BK virus was demonstrated in 47 percent of the transplant recipients and was the result of the reactivation of latent virus. Hemorrhagic cystitis of long duration (greater than or equal to 7 days) was associated with BK viruria. The disease occurred four times more frequently in patients who excreted BK virus than in those who did not, and the virus was identified in 55 percent of the urine specimens during episodes of cystitis as compared with 8 to 11 percent of the specimens during cystitis-free periods. BK viruria often preceded or coincided with the onset of the disease. Among 19 patients with BK viruria lasting seven days or longer, hemorrhagic cystitis occurred in 15. Occurrence of the disease was related to the source of marrow. The disease occurred in 50 percent of 38 recipients of allogeneic marrow and in 7 percent of 15 recipients of syngeneic or autologous marrow. Among recipients of allogeneic marrow, the disease was observed in 71 percent of the 21 patients excreting BK virus and in 24 percent of the 17 not excreting the virus. An association of BK virus with hemorrhagic cystitis was demonstrated in 16 of the 18 cases of the disease that were adequately characterized. We conclude that reactivation of BK virus may account for a substantial proportion of late-onset, long-lasting hemorrhagic cystitis in recipients of bone marrow transplants.

To study the duration of antibody persistence and protection provided by the hepatitis B vaccine, we followed 773 homosexual men for five years after completion of vaccination. Among the 635 participants in whom antibody levels above 9.9 sample ratio units (SRU) developed after vaccination, 15 percent lost antibody altogether, and in another 27 percent, antibody levels declined below 10 SRU within five years. The extent of the maximal antibody response strongly predicted the persistence of protective antibody. Hepatitis B infection occurred in 55 men; 8 of these infections were clinically important (characterized by the presence of the hepatitis B surface antigen and elevation of liver-enzyme levels), and two of the patients became hepatitis B virus carriers. The long-term risk of hepatitis B infection was inversely related to the maximal antibody response to vaccine. Most severe infections occurred among those who responded poorly or had no response to the vaccination. The risk of late infection with hepatitis B in those with an initially adequate vaccine response increased markedly when antibody levels decreased below 10 SRU, but only 1 of 34 late infections resulted in viremia and liver inflammation. A second series of vaccinations induced a moderate antibody response in 50 percent of the subjects who initially had no response or a poor response; however, the persistence of antibody was poor. Both antibody loss and the risk of severe disease should be considered when booster-dose strategies for the hepatitis B vaccine are being designed.

We studied 25 patients with acute nonlymphocytic leukemia in second remission (20 patients) or third remission (5 patients) in whom autologous bone marrow transplantation was performed with use of marrow incubated ex vivo with the alkylating agent 4-hydroperoxycyclophosphamide. Patients received intensive cytoreductive therapy with busulfan and cyclophosphamide or cyclophosphamide and total body irradiation, followed by an infusion of marrow that had been collected in remission, treated with 4-hydroperoxycyclophosphamide, and cryopreserved. Four patients died from bacterial or fungal sepsis within the first month after transplantation, and one patient with persistent marrow hypoplasia died from gram-negative sepsis 155 days after infusion with autologous marrow. In the remaining patients, peripheral-blood levels of neutrophils in excess of 0.5 X 10(9) per liter and platelet counts over 50 X 10(9) per liter were attained at median intervals of 29 and 57 days after transplantation, respectively. Nine patients had leukemic relapses at 73 to 316 days (median, 182 days) after infusion of autologous marrow, for an actuarial relapse rate of 46 percent. Eleven patients (eight in second remission and three in third) remained in remission at a median of more than 400 days (range, greater than 230 to greater than 1653 days) after transplantation. The observed disease-free survival after transplantation with autologous marrow treated with 4-hydroperoxycyclophosphamide compares favorably with the results of syngeneic or allogeneic transplantation in similar groups of patients.

We conducted a five-year prospective controlled study of prophylaxis of Staphylococcus aureus nasal carriage and infection among patients in a hemodialysis unit. Carriers tended to have chronic colonization with a single phage type. S. aureus infections occurred significantly more frequently in carriers than in noncarriers and, in 93 percent of the infected carriers, were caused by the same phage type as that carried in the nares. Neither intravenous vancomycin nor topical bacitracin was found to be efficacious in eradicating nasal carriage. However, oral rifampin given for five days decreased S. aureus carriage over a one-month follow-up period, but within three months colonization of the nares recurred in most carriers, often with an S. aureus of the original phage type. Carriers were then randomly assigned to receive either rifampin or no prophylaxis. Rifampin was readministered at three-month intervals if culture of the anterior nares yielded S. aureus. Infections with S. aureus occurred significantly more frequently in carriers given no prophylaxis than in those given a full course of rifampin. S. aureus resistant to rifampin was isolated from the anterior nares of four patients, but these isolates were not implicated in any infections. The incidence of infection at the dialysis access site, skin, and soft tissue of patients on hemodialysis can be decreased by interventions directed at nasal carriage of S. aureus.

Most cases of neonatal group B streptococcal disease with early onset have an intrapartum pathogenesis. Attack rates are increased substantially in infants born to mothers with prenatal group B streptococcal colonization and various perinatal risk factors (premature labor, prolonged membrane rupture, or intrapartum fever). In a randomized controlled trial, we studied the effect of selective intrapartum prophylaxis with ampicillin in 160 such high-risk women. In infants born to mothers who received intravenous ampicillin during labor, as compared with controls who received no treatment, neonatal colonization with group B streptococci was present in 8 of 85 (9 percent) versus 40 of 79 (51 percent; P less than 0.001), colonization at multiple (greater than or equal to 3) sites was observed in 3 of 85 (4 percent) versus 24 of 79 (30 percent; P less than 0.001), and bacteremia occurred in none of 85 versus 5 of 79 (6 percent; P = 0.024). The side effects of ampicillin were limited to a single episode of urticaria in a mother who had no history of penicillin allergy. We conclude that intrapartum ampicillin prophylaxis in women with positive prenatal cultures for group B streptococci who have certain perinatal risk factors can prevent early-onset neonatal group B streptococcal disease.

We conducted a multicenter randomized double-blind clinical trial among 626 men with mild to moderate hypertension to determine the effects of captopril, methyldopa, and propranolol on their quality of life. Hydrochlorothiazide was added if needed to control blood pressure. After a 24-week treatment period, all three groups had similar blood-pressure control, although fewer patients taking propranolol required hydrochlorothiazide. Patients taking captopril alone or in combination with a diuretic were least likely to withdraw from treatment because of adverse effects (8 percent vs. 20 percent for methyldopa and 13 percent for propranolol). The treatment groups were similar in scores for sleep dysfunction, visual memory, and social participation. However, patients taking captopril, as compared with patients taking methyldopa, scored significantly higher (P less than 0.05 to less than 0.01) on measures of general well-being, had fewer side effects, and had better scores for work performance, visual-motor functioning, and measures of life satisfaction. Patients taking propranolol also reported better work performance than patients taking methyldopa. Patients taking captopril reported fewer side effects and less sexual dysfunction than those taking propranolol and had greater improvement (P less than 0.05 to less than 0.01) on measures of general well-being. Our findings show that antihypertensive agents have different effects on the quality of life and that these can be meaningfully assessed with available psychosocial measures.

We conducted a randomized controlled trial to determine whether intensive multi-agent adjuvant chemotherapy improves the chances of relapse-free survival in patients with nonmetastatic high-grade osteosarcoma of the extremity, as compared with concurrent controls. After undergoing definitive surgery, 36 patients were randomly assigned to adjuvant chemotherapy or to observation without adjuvant treatment. At two years the actuarial relapse-free survival was 17 percent in the control group, similar to that found in studies before 1970, and 66 percent in the adjuvant-chemotherapy group (P less than 0.001). Similar results were observed among 77 additional patients who declined to undergo randomization but who elected observation or chemotherapy. We conclude that the natural history of osteosarcoma of the extremity has remained stable over the past two decades, that adjuvant chemotherapy increases the chances of relapse-free survival of patients with high-grade osteosarcoma, and that it should be given to all such patients.

Children with sickle cell anemia have an increased susceptibility to bacterial infections, especially to those caused by Streptococcus pneumoniae. We therefore conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether the regular, daily administration of oral penicillin would reduce the incidence of documented septicemia due to S.pneumoniae in children with sickle cell anemia who were under the age of three years at the time of entry. The children were randomly assigned to receive either 125 mg of penicillin V potassium (105 children) or placebo (110 children) twice daily. The trial was terminated 8 months early, after an average of 15 months of follow-up, when an 84 percent reduction in the incidence of infection was observed in the group treated with penicillin, as compared with the group given placebo (13 of 110 patients vs. 2 of 105; P = 0.0025), with no deaths from pneumococcal septicemia occurring in the penicillin group but three deaths from the infection occurring in the placebo group. On the basis of these results, we conclude that children should be screened in the neonatal period for sickle cell hemoglobinopathy and that those with sickle cell anemia should receive prophylactic therapy with oral penicillin by four months of age to decrease the morbidity and mortality associated with pneumococcal septicemia.

We evaluated the reorganization of a general medical clinic into several group practices, using equivalent groups of patients and physicians in a randomized controlled trial. The group practice, unlike the traditional clinic, provided decentralized registration, clinic coverage five days a week, and telephone coverage at night and on weekends. Residents worked in small groups with an attending physician, nurse practitioner, and receptionist. All financial activity involving a sample of 2299 patients was followed during the 11-month intervention. The total hospital charges per patient were 26 percent lower for the patients seen in the group practice than for those seen in the traditional clinic (P = 0.003). This difference was primarily attributable to inpatient charges, which were 27 percent lower per patient hospitalized (P = 0.004). The mean length of stay was 8.3 days among group-practice patients and 10.5 days among traditional-clinic patients (P = 0.011). We conclude that organizational changes to improve outpatient access and to integrate inpatient and outpatient services can decrease medical charges.

To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.

Within six hours after the onset of symptoms of myocardial infarction, we randomly assigned 1741 patients up to 75 years of age to a one-hour intravenous infusion of 1.5 million IU of streptokinase or placebo. At 21 days mortality was 6.3 percent in the streptokinase group and 7.1 percent in the placebo group. Of those treated within three hours of the onset of symptoms, 5.2 percent died in the streptokinase group (n = 477), as compared with 6.5 percent in the placebo group (n = 463). These differences were not significant. The time to peak serum levels of creatine kinase of myocardial origin (CK-MB) after the onset of symptoms was significantly shorter (13.9 vs. 19.2 hours), and the integrated area under the CK-MB curve (CK-MB infarct size) was significantly smaller, in the streptokinase group (P less than 0.02). Angiograms obtained in 848 patients three to four weeks after infarction revealed that the streptokinase group had higher global ejection fractions (56.8 vs. 53.9 percent, P less than 0.005) and regional ejection fractions (all patients in group, P less than 0.005; patients with anterior or inferior infarctions, P less than 0.05). We conclude that beginning intravenous streptokinase infusion early after the onset of myocardial infarction limits the size of the infarct regardless of its localization. There was, however, only a trend toward reduced mortality at 21 days.

Bleeding after cardiopulmonary bypass remains a cause for concern, requiring reexploration of the chest in approximately 3 percent of patients who have had operations on the heart. We examined the possibility that this problem might be alleviated by desmopressin acetate (DDAVP), which increases the plasma level of von Willebrand factor and improves hemostasis in mild hemophilia and other conditions associated with defective platelet function. In a double-blind, prospective, randomized trial, we studied the effect of intraoperative desmopressin acetate in 70 patients undergoing various cardiac operations requiring cardiopulmonary bypass. Patients undergoing uncomplicated primary coronary-artery bypass grafting were not included. The drug significantly reduced mean operative and early postoperative blood loss (1317 +/- 486 ml in the treated group vs. 2210 +/- 1415 ml in the placebo group); of the 14 patients whose 24-hour blood loss exceeded 2000 ml, 11 had received the placebo. Plasma levels of von Willebrand factor were higher after desmopressin acetate than after placebo. Patients with the most bleeding had relatively low levels of von Willebrand factor before operation, suggesting a role for this factor in the hemorrhagic tendency induced by extracorporeal circulation. There were no untoward side effects of desmopressin acetate. We conclude that the administration of desmopressin acetate can be recommended to reduce blood loss in patients undergoing complex cardiac operations. The beneficial effect of the drug on hemostasis after cardiopulmonary bypass may be related to its effect on von Willebrand factor.

The per capita expenditure for health care of patients with multiple physical symptoms but no apparent physical disease (somatization disorder) is up to nine times the average per capita amount. We conducted a randomized controlled trial to determine whether psychiatric consultation would reduce the medical costs of these patients, without effecting a substantial change in patient outcome. Thirty-eight patients were randomly assigned to treatment or control groups and studied prospectively for 18 months. Treatment consisted of a psychiatric consultation and suggestions on management given to primary physicians. After nine months, the control group was crossed over to receive treatment with the same intervention. After the psychiatric consultation, the quarterly health care charges in the treatment group declined by 53 percent (P less than 0.05). In contrast, the charges in the control group showed wide variations but no overall change. The quarterly charges in the control group were significantly higher than those in the treatment group (P less than 0.05). After the control group was crossed over to receive treatment, their quarterly charges declined by 49 percent (P less than 0.05). The reductions in expenditures in both groups were due largely to decreases in hospitalization. We conclude that psychiatric consultation in the care of patients with somatization disorder reduced subsequent health care expenditures without inducing changes in health status or patients' satisfaction with their health care.

To determine whether sulfonylureas and exogenous insulin have different effects on insulin action, we studied eight patients with non-insulin-dependent diabetes mellitus before and after three months of treatment with tolazamide and exogenous semisynthetic human insulin, using a randomized crossover design. Therapy with tolazamide and therapy with insulin resulted in similar improvement of glycemic control, as measured by a decrease in mean glycosylated hemoglobin (+/- SEM) from 9.4 +/- 0.7 percent to 7.7 +/- 0.5 percent with tolazamide and to 7.1 +/- 0.2 percent with exogenous insulin (P less than 0.01 for both comparisons). Therapy with either tolazamide or exogenous insulin resulted in a similar lowering (P less than 0.05) of postabsorptive glucose-production rates (from 2.3 +/- 0.1 to 2.0 +/- 0.2 and 1.8 +/- 0.1 mg per kilogram of body weight per minute, respectively) but not to normal (1.5 +/- 0.1 mg per kilogram per minute). Both tolazamide and exogenous insulin increased (P less than 0.05) glucose utilization at supraphysiologic insulin concentrations (from 6.2 +/- 0.7 to 7.7 +/- 0.6 mg per kilogram per minute with tolazamide and to 7.8 +/- 0.6 mg per kilogram per minute with exogenous insulin) to nondiabetic rates (7.9 +/- 0.5 mg per kilogram per minute). Neither agent altered erythrocyte insulin binding at physiologic insulin concentrations. We conclude that treatment with sulfonylureas or exogenous insulin results in equivalent improvement in insulin action in patients with non-insulin-dependent diabetes mellitus. Therefore, the choice between these agents should be based on considerations other than their ability to ameliorate insulin resistance.

One hundred sixty-two children with severe juvenile rheumatoid arthritis were entered in a randomized, double-blind, placebo-controlled 12-month clinical trial designed to establish the efficacy and safety of two slower-acting antirheumatic drugs, penicillamine and hydroxychloroquine. The study was a cooperative effort of the United States and the Soviet Union. One group of subjects received 10 mg of penicillamine per kilogram of body weight per day, another group received 6 mg of hydroxychloroquine per kilogram daily, and a third group received placebo. All three groups were allowed a single concurrent nonsteroidal antiinflammatory drug, but no other antirheumatic medications, including corticosteroids. All three groups had dramatic improvement in many of the clinical and laboratory outcome variables after one year of study. There were no significant differences in efficacy between the penicillamine and placebo groups. Pain on movement was the only index of articular disease that was alleviated more by hydroxychloroquine than by placebo. Serious adverse drug reactions attributable to the active agents were rare. We were unable to demonstrate that, in the presence of a nonsteroidal antiinflammatory drug, either penicillamine or hydroxychloroquine is superior to placebo in the treatment of children with juvenile rheumatoid arthritis.

In a multicenter trial we investigated the effect of immunosuppressive therapy on graft and patient survival, renal function, and complications in 291 recipients of cadaveric renal transplants. One hundred forty-two patients were randomly assigned to treatment with cyclosporine and prednisone, and 149 to control immunosuppressive therapy (azathioprine and prednisone, with or without antilymphocyte globulin). At three years graft survival was 69 percent in the cyclosporine-treated patients and 58 percent in the controls (P = 0.05). The number of episodes of graft rejection was similar in the two groups, but the severity of rejection was significantly worse among the controls. Patients survival after three years was 90 percent in the cyclosporine group and 82 percent in the control group (P = 0.04). Acute tubular necrosis was an important risk factor for graft loss in both groups. Risk factors for death included diabetes and older age of the recipient. Renal function as indicated by the serum creatinine concentration or creatinine clearance was poorer in the cyclosporine-treated patients than in the controls, but has remained stable in both groups since the sixth month after transplantation. We conclude that, among recipients of cadaveric renal transplants, those treated with cyclosporine, despite having poorer (but stable) renal function, have better graft and patient survival at three years than those treated with alternative forms of immunosuppressive therapy.