Prophylactic blood transfusion has come to be regarded as necessary in the treatment of patients with sickle cell disease during pregnancy. Because of the risks associated with blood products and reports of successful outcomes without the use of blood transfusion, we conducted a prospective randomized controlled study of this issue. Seventy-two pregnant patients with sickle cell anemia were randomly assigned to one of two treatment groups: 36 received prophylactic transfusions of frozen red cells, and 36 received red-cell transfusions only for medical or obstetric emergencies. Twenty-eight patients with sickle cell anemia who did not qualify for randomization (mainly because they had other medical disorders), 66 with sickle cell-hemoglobin C disease, and 23 with sickle cell-beta-thalassemia were also followed and received transfusions only for emergencies. There was no significant difference in perinatal outcome between the offspring of mothers with sickle cell disease who were assigned to treatment with prophylactic transfusions and those who were not (15 vs. 5 percent). The occurrence of a perinatal death in a previous pregnancy and the presence of twins in the present pregnancy were two major risk factors for an unfavorable outcome; when they were present, perinatal mortality was 50 percent. Perinatal mortality was somewhat higher in the two groups that were randomized than in the three groups that were not. Prophylactic transfusion significantly reduced the incidence of painful crises of sickle cell disease (P less than 0.01) and substantially reduced the cumulative incidence of other complications of this disorder (P = 0.07). Other medical and obstetric complications occurred with nearly equal frequency in the two randomized groups. Increases in costs, the number of hospitalizations, and the risk of alloimmunization were disadvantages of prophylactic transfusion. We conclude that the omission of prophylactic red-cell transfusion will not harm pregnant patients with sickle cell disease or their offspring.

To evaluate the safety and cost of outpatient cardiac catheterization, we conducted a randomized trial at three hospitals of outpatient (n = 192) as compared with inpatient (n = 189) cardiac catheterization in low-risk patients. Outpatients had the following complication rates as compared with inpatients: hematoma, 12 versus 8.5 percent; numbness or weakness of extremity, 0.5 versus 1.6 percent; cold or blue extremity, 1.6 versus 1.1 percent; and acute myocardial infarction, 1.6 versus 0.5 percent. None of these differences were statistically significant. No deaths or strokes occurred in either group. Twenty-three patients (12 percent) assigned to the outpatient group required hospitalization because of complications of catheterization. In the outpatient group, the relative risk for hematoma was 1.42 (95 percent confidence interval, 0.77 to 2.29), and the relative risk for myocardial infarction within one week was 2.95 (95 percent confidence interval, 0.3 to 28.1). There were no significant differences between the two groups in whether they resumed normal activities or in the rates of rehospitalization within one week of the procedure. Total catheterization-related charges per patient were $679 lower for outpatients, with a savings in total hospital charges (including charges for subsequent therapeutic procedures) of $885 per patient. We conclude that elective cardiac catheterization as an outpatient procedure for selected patients is feasible and safe. Given the small size of our sample, however, we urge caution in interpreting these findings, since they do not exclude a small increase in complication rates with outpatient cardiac catheterization.

We studied separately the influence of two methods for losing fat weight on the levels of plasma lipids and lipoproteins in overweight sedentary men--decreasing energy intake without increasing exercise (diet), and increasing energy expenditure without altering energy intake (exercise, primarily running)--in a one-year randomized controlled trial. As compared with controls (n = 42), dieters (n = 42) had significant loss of total body weight (-7.8 +/- 0.9 kg [mean +/- SE]), fat weight (-5.6 +/- 0.8 kg), and lean (non-fat) weight (-2.1 +/- 0.5 kg) (P less than 0.001 for each variable), and exercisers (n = 47) had significant loss of total body weight (-4.6 +/- 0.8 kg) and fat weight (-3.8 +/- 0.7 kg) (P less than 0.001 for both variables) but not lean weight (-0.7 +/- 0.4 kg). Fat-weight loss did not differ significantly between dieters and exercisers. All subjects were discouraged from altering their diet composition; however, dieters and exercisers had slight reductions in the percentage of kilojoules derived from fat. As compared with the control group, both weight-loss groups had significant increases (P less than 0.01) in plasma concentrations of high-density lipoprotein (HDL) cholesterol (diet vs. exercise, 0.13 +/- 0.03 vs. 0.12 +/- 0.03 mmol per liter), HDL2 cholesterol (0.07 +/- 0.02 vs. 0.07 +/- 0.02 mmol per liter), and HDL3 cholesterol (0.07 +/- 0.02 vs. 0.06 +/- 0.02 mmol per liter) and significant decreases (P less than 0.05) in triglyceride levels (diet vs. exercise, -0.35 +/- 0.14 vs. -0.24 +/- 0.12 mmol per liter). Levels of total and low-density lipoprotein cholesterol were not significantly changed, relative to values in controls. None of these changes were significantly different between dieters and exercisers. Thus, we conclude that fat loss through dieting or exercising produces comparable and favorable changes in plasma lipoprotein concentrations.

We tested the usefulness of aspirin (325 mg twice daily), heparin (1000 units per hour by intravenous infusion), and a combination of the two in the early management of acute unstable angina pectoris in a double-blind, randomized, placebo-controlled trial involving 479 patients. The patients entered the study as soon as possible after hospital admission (at a mean [+/- SD] of 7.9 +/- 8.0 hours after the last episode of pain), and the study was ended after 6 +/- 3 days, when definitive therapy had been selected. Major end points--refractory angina, myocardial infarction, and death--occurred in 23, 12, and 1.7 percent of the 118 patients receiving placebo, respectively. Heparin was associated with a decrease in the occurrence of refractory angina (P = 0.002). The incidence of myocardial infarction was significantly reduced in the groups receiving aspirin (3 percent; P = 0.01), heparin (0.8 percent; P less than 0.001), and aspirin plus heparin (1.6 percent, P = 0.003), and no deaths occurred in these groups. There were too few deaths overall to permit evaluation of the effect of treatment on this end point. The combination of aspirin and heparin had no greater protective effect than heparin alone but was associated with slightly more serious bleeding (3.3 vs. 1.7 percent). We conclude that in the acute phase of unstable angina, either aspirin or heparin treatment is associated with a reduced incidence of myocardial infarction, and there is a trend favoring heparin over aspirin. Heparin treatment is also associated with a reduced incidence of refractory angina.

We assessed two antibiotic regimens--vancomycin, ticarcillin, and amikacin, as compared with a vancomycin placebo, ticarcillin-clavulanate, and amikacin--as initial empirical therapy for febrile, neutropenic children with cancer. In a randomized, double-blind clinical trial, the planned 10-day treatment was unsuccessful in 15 percent of the vancomycin, ticarcillin, and amikacin group (n = 53), as compared with 38 percent of the group receiving ticarcillin-clavulanate and amikacin (n = 48) (P = 0.010). Of 10 episodes of breakthrough bacteremia, 9 (1 fatal) occurred in patients treated with ticarcillin-clavulanate and amikacin (P = 0.006). Each of the 10 microbial isolates was a gram-positive bacterium with similar susceptibilities to vancomycin and ticarcillin-clavulanate in vitro. Both regimens were well tolerated. None of the patients had detectable renal dysfunction, but those receiving vancomycin, ticarcillin, and amikacin were more likely to have twofold increases in serum hepatic-enzyme activity. Rashes consistent with the "red-man" syndrome occurred in three patients upon the infusion of vancomycin and in three others who received a placebo. We conclude that the combination of vancomycin, ticarcillin, and amikacin is more effective than ticarcillin-clavulanate and amikacin as empirical antibiotic therapy in clinical settings in which gram-positive bacteremias are a serious problem.

We enrolled 200 infants and older children with bacterial meningitis in two prospective double-blind, placebo-controlled trials to evaluate the efficacy of dexamethasone therapy in addition to either cefuroxime (Study 1) or ceftriaxone (Study 2). Altogether, 98 patients received placebo and 102 received dexamethasone (0.15 mg per kilogram of body weight every six hours for four days). At the beginning of therapy, the clinical and demographic characteristics of the patients in the treatment groups were comparable. The mean increase in the cerebrospinal fluid concentration of glucose and the decreases in lactate and protein levels after 24 hours of therapy were significantly greater in those who received dexamethasone than in those who received placebo (glucose, 2.0 vs. 0.4 mmol per liter [36.0 vs. 6.9 mg per deciliter], P less than 0.001; lactate, 4.0 vs. 2.1 mmol per liter [38.3 vs. 19.8 mg per deciliter], P less than 0.001; and protein, 0.64 vs. 0.25 g per liter [64.0 vs. 25.3 mg per deciliter], P less than 0.05). One patient in the placebo group in Study 1 died. As compared with those who received placebo, the patients who received dexamethasone became afebrile earlier (1.6 vs. 5.0 days; P less than 0.001) and were less likely to acquire moderate or more severe bilateral sensorineural hearing loss (15.5 vs. 3.3 percent; P less than 0.01). Twelve patients in the two placebo groups (14 percent) had severe or profound bilateral hearing loss requiring the use of a hearing aid, as compared with 1 (1 percent) in the two dexamethasone groups (P less than 0.001). We conclude that dexamethasone is beneficial in the treatment of infants and children with bacterial meningitis, particularly in preventing deafness.

In a double-blind study, we randomly assigned 84 patients with chronic lymphocytic leukemia who were judged to be at increased risk of bacterial infection to receive intravenous immunoglobulin G (400 mg per kilogram of body weight) or a placebo every three weeks for one year. Eligible patients had hypogammaglobulinemia, a history of infection, or both. The patients receiving immunoglobulin had significantly fewer bacterial infections during the study period than those receiving placebo (23 vs. 42; P = 0.01). This reduction was most striking in the patients who completed a full year of treatment (14 vs. 36; P = 0.001). The period from study entry to the first serious bacterial infection was significantly longer in the patients receiving immunoglobulin (P = 0.026). There was no significant difference between the two groups in the incidence of nonbacterial infection. Immunoglobulin therapy was tolerated well; there were no serious adverse reactions, and the incidence of minor reactions was low. We conclude that selected patients with chronic lymphocytic leukemia who are at risk of bacterial infection can be substantially protected from this complication by the regular intravenous administration of immunoglobulin.

We compared a high-carbohydrate diet with a high-fat diet (specifically, a diet high in monounsaturated fatty acids) for effects on glycemic control and plasma lipoproteins in 10 patients with non-insulin-dependent diabetes mellitus (NIDDM) receiving insulin therapy. The patients were randomly assigned to receive first one diet and then the other, each for 28 days, in a metabolic ward. In the high-carbohydrate diet, 25 percent of the energy was in the form of fat and 60 percent in the form of carbohydrates (47 percent of the total energy was in the form of complex carbohydrates); the high-monounsaturated-fat diet was 50 percent fat (33 percent of the total energy in the form of monounsaturated fatty acids) and 35 percent carbohydrates. The two diets had the same amounts of simple carbohydrates and fiber. As compared with the high-carbohydrate diet, the high-monounsaturated-fat diet resulted in lower mean plasma glucose levels and reduced insulin requirements, lower levels of plasma triglycerides and very-low-density lipoprotein cholesterol (lower by 25 and 35 percent, respectively; P less than 0.01), and higher levels of high-density lipoprotein (HDL) cholesterol (higher by 13 percent; P less than 0.005). Levels of total cholesterol and low-density lipoprotein (LDL) cholesterol did not differ significantly in patients on the two diets. These preliminary results suggest that partial replacement of complex carbohydrates with monounsaturated fatty acids in the diets of patients with NIDDM does not increase the level of LDL cholesterol and may improve glycemic control and the levels of plasma triglycerides and HDL cholesterol.

To determine whether infection with Loa loa could be prevented in temporary residents of endemic areas, we conducted a randomized, double-blind, placebo-controlled trial of diethylcarbamazine as a chemoprophylactic agent. Diethylcarbamazine (300 mg) or placebo was taken orally once a week by Peace Corps volunteers serving in Gabon, Cameroon, and the Central African Republic. The participants were assessed clinically and with serologic and parasitologic testing before and yearly during their two years of service. One hundred one persons satisfactorily completed the study. In Gabon (where exposure to the parasite was heaviest), 6 of 20 volunteers (30 percent) in the placebo group had clinical disease, as compared with none of 16 (0 percent) in the diethylcarbamazine-treated group (P less than 0.02). Of those taking placebo, 10 of 20 (50 percent) became seropositive for antifilarial IgG antibody, as compared with 2 of 16 (12 percent) in the drug-treated group (P less than 0.02). Exposure to the parasite appeared to be much lower among the 65 Peace Corps volunteers in Cameroon and the Central African Republic. No volunteer in either group in these countries had overt loiasis; 2 of 40 (5 percent) in the placebo groups in Cameroon and the Central African Republic seroconverted, as compared with none of 25 (0 percent) of those receiving diethylcarbamazine. Occasional nausea was the only symptom significantly associated with the prophylactic drug regimen. We conclude that diethylcarbamazine given orally once weekly can be an effective, acceptable chemoprophylactic agent to prevent loiasis in temporary residents of regions of Africa where Loa loa is endemic.

Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC + ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference). Eleven patients on the FDC + ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC + ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions.

To determine the safety and benefit of n-3 fatty acid therapy in the prevention of early restenosis after coronary angioplasty, we conducted a randomized, unblinded study comparing a conventional antiplatelet regimen (325 mg of aspirin and 225 mg of dipyridamole per day; control group) with a similar regimen supplemented with 3.2 g of eicosapentaenoic acid per day (treatment group). Treatment began seven days before angioplasty and continued for six months afterward. All angiographic analyses were blinded and performed by a method that was validated by comparison with quantitative coronary angiography. In 82 male patients, 103 coronary lesions were dilated. Both groups had similar base-line clinical and angiographic characteristics. The incidence of early vessel restenosis, as determined on a second angiogram three to four months after angioplasty, was 36 percent in the control group and 16 percent in the treatment group (P = 0.026). The incidence of restenosis per patient was also significantly lower in the treatment group (46 vs. 19 percent). Both multiple logistic regression and Mantel-Haenszel statistical analyses demonstrated a significant independent benefit of treatment with n-3 fatty acids. No important bleeding complications developed in the treated patients. These results, in a male population at relatively high risk for restenosis, suggest that a dietary supplement of n-3 fatty acids, administered for one week before and for six months after coronary angioplasty, is safe and reduces the occurrence of early restenosis after that procedure. Whether this beneficial effect also applies to other populations is unknown.

We studied the timing and duration of adjuvant chemotherapy for operable breast cancer with axillary-node involvement in a randomized trial including 1229 patients divided into three treatment groups. One group received a single perioperative course of adjuvant combination chemotherapy beginning within 36 hours of mastectomy; a second received six cycles of conventionally timed adjuvant chemotherapy starting 25 to 32 days after operation; and a third received both the perioperative cycle and the conventionally timed regimen. The chemotherapy consisted of cyclophosphamide, methotrexate, and fluorouracil. Tamoxifen was added to the conventionally timed regimen in postmenopausal women. At a median follow-up of 42 months, the estimated four-year disease-free survival was 40 percent for the single perioperative cycle, 62 percent for the longer, conventionally timed regimen, and 60 percent for the combined program (P less than 0.0001). Overall survival differences also favored the longer treatments (P = 0.011). We conclude that a single perioperative cycle of adjuvant combination chemotherapy is less effective than prolonged therapy in patients with operable breast cancer and involved axillary nodes. Furthermore, starting the prolonged therapy perioperatively is no more effective than starting treatment four weeks after mastectomy.

We randomly assigned 46 patients (mean age, 11.7 years; range, 4.5 to 32.8) with newly diagnosed insulin-dependent diabetes mellitus within two weeks of beginning insulin to receive either corticosteroids for 10 weeks plus daily azathioprine for one year or no immunosuppressive therapy. Half the 20 immunosuppressed patients completing the one-year trial had satisfactory metabolic outcomes (hemoglobin A1c less than 6.8 percent; stimulated peak C peptide greater than 0.5 nmol per liter; insulin dose less than 0.4 U per kilogram of body weight per day) as compared with only 15 percent of the controls. Three of 20 immunosuppressed patients, but no controls, were insulin independent at one year. Two of these continue to receive azathioprine without insulin after more than 27 months of follow-up. The response to immunosuppression correlated with older age, better initial metabolic status, and lymphopenia (less than 1800 lymphocytes per cubic millimeter) resulting from immunosuppression. The side effects of azathioprine included vomiting in one patient and mild hair loss in several others. Prednisone use resulted in a transient cushingoid appearance, weight gain, and hyperglycemia. The growth rate remained normal in all patients. We conclude that early immunosuppression with short-term use of corticosteroids plus daily azathioprine can improve metabolic control in some patients with insulin-dependent diabetes mellitus, but results from this unblinded study are preliminary and require further confirmation and long-term follow-up.

Encephalitis caused by Japanese encephalitis virus occurs in annual epidemics throughout Asia, making it the principal cause of epidemic viral encephalitis in the world. No currently available vaccine has demonstrated efficacy in preventing this disease in a controlled trial. We performed a placebo-controlled, blinded, randomized trial in a northern Thai province, with two doses of monovalent (Nakayama strain) or bivalent (Nakayama plus Beijing strains) inactivated, purified Japanese encephalitis vaccine made from whole virus derived from mouse brain. We examined the effect of these vaccines on the incidence and severity of Japanese encephalitis and dengue hemorrhagic fever, a disease caused by a closely related flavivirus. Between November 1984 and March 1985, 65,224 children received two doses of monovalent Japanese encephalitis vaccine (n = 21,628), bivalent Japanese encephalitis vaccine (n = 22,080), or tetanus toxoid placebo (n = 21,516), with only minor side effects. The cumulative attack rate for encephalitis due to Japanese encephalitis virus was 51 per 100,000 in the placebo group and 5 per 100,000 in each vaccine group. The efficacy in both vaccine groups combined was 91 percent (95 percent confidence interval, 70 to 97 percent). Attack rates for dengue hemorrhagic fever declined, but not significantly. The severity of cases of dengue was also reduced. We conclude that two doses of inactivated Japanese encephalitis vaccine, either monovalent or bivalent, protect against encephalitis due to Japanese encephalitis virus and may have a limited beneficial effect on the severity of dengue hemorrhagic fever.

There is reason to believe that diabetic neuropathy may be related to the accumulation of sorbitol in nerve tissue through an aldose reductase pathway from glucose. Short-term treatment with aldose reductase inhibitors improves nerve conduction in subjects with diabetes, but the effects of long-term treatment on the neuropathologic changes of diabetic neuropathy are unknown. To determine whether more prolonged aldose reductase inhibition reverses the underlying lesions that accompany symptomatic diabetic peripheral polyneuropathy, we performed a randomized, placebo-controlled, double-blind trial of the investigational aldose reductase inhibitor sorbinil (250 mg per day). Sural-nerve biopsy specimens obtained at base line and after one year from 16 diabetic patients with neuropathy were analyzed morphometrically in detail and compared with selected electrophysiologic and clinical indexes. In contrast to patients who received placebo, the 10 sorbinil-treated patients had a decrease of 41.8 +/- 8.0 percent in nerve sorbitol content (P less than 0.01) and a 3.8-fold increase in the percentage of regenerating myelinated nerve fibers (P less than 0.001), reflected by a 33 percent increase in the number of myelinated fibers per unit of cross-sectional area of nerve (P = 0.04). They also had quantitative improvement in terms of the degree of paranodal demyelination, segmental demyelination, and myelin wrinkling. The increase in the number of fibers was accompanied by electrophysiologic and clinical evidence of improved nerve function. We conclude that sorbinil, as a metabolic intervention targeted against a specific biochemical consequence of hyperglycemia, can improve the neuropathologic lesions of diabetic neuropathy.