To determine whether colchicine prevents or ameliorates amyloidosis in patients with familial Mediterranean fever, we followed 1070 patients with the latter disease for 4 to 11 years after they were advised to take colchicine to prevent febrile attacks. Overall, at the end of the study, the prevalence of nephropathy was one third of that in a study conducted before colchicine was used to treat familial Mediterranean fever. Among 960 patients who initially had no evidence of amyloidosis, proteinuria appeared in 4 who adhered to the prophylactic schedule and in 16 of 54 who admitted non-compliance. Life-table analysis showed that the cumulative rate of proteinuria was 1.7 percent (90 percent confidence limits, 0.0 and 11.3 percent) after 11 years in the compliant patients and 48.9 percent (18.8 and 79.0 percent) after 9 years in the noncompliant patients (P less than 0.0001). A total of 110 patients had overt nephropathy when they started to take colchicine. Among 86 patients who had proteinuria but not the nephrotic syndrome, proteinuria resolved in 5 and stabilized in 68 (for more than eight years in 40). Renal function deteriorated in 13 of the patients with proteinuria and in all of the 24 patients with the nephrotic syndrome or uremia. We conclude that colchicine prevented amyloidosis in our high-risk population and that it can prevent additional deterioration of renal function in patients with amyloidosis who have proteinuria but not the nephrotic syndrome.

In an attempt to prevent primary cytomegalovirus infection after marrow transplantation, we randomly assigned 97 patients who were seronegative for antibody to cytomegalovirus before transplantation to receive one of the following: (1) both intravenous cytomegalovirus immune globulin and seronegative blood products (23 patients); (2) seronegative blood products alone (28 patients); (3) globulin alone (22 patients); or (4) neither treatment (24 patients). Patients not assigned to receive seronegative blood products received unscreened blood products from random donors. The incidence of cytomegalovirus infection according to study group among patients in the study for at least 62 days was 5 percent, 13 percent, 24 percent, and 40 percent, respectively. Among 57 patients with seronegative marrow donors, those who received seronegative blood products had significantly less infection (1 of 32) than those who received standard blood products (8 of 25, P less than 0.007). In contrast, the use of seronegative blood products did not appear to prevent cytomegalovirus infection among patients with seropositive marrow donors. The possibility that cytomegalovirus immune globulin as used in this study can prevent cytomegalovirus infection or ameliorate cytomegalovirus disease was not confirmed, and it cannot be recommended for routine use without additional study.

We randomly assigned 56 patients who presented within 12 hours of their first symptoms of acute myocardial infarction to treatment with either intracoronary streptokinase or coronary angioplasty. The mean (+/- SD) duration of symptoms (3.0 +/- 1.2 hours in the group treated with angioplasty vs. 3.6 +/- 1.8 in the group treated with streptokinase; P not significant) and time to recanalization (4.1 +/- 1.4 hours vs. 4.8 +/- 1.7 hours; P not significant) were similar in both groups. Coronary recanalization was achieved in 83 percent of the patients treated with angioplasty and in 85 percent of those treated with streptokinase (P not significant). Residual luminal stenosis in the coronary artery was significantly decreased after angioplasty, as compared with streptokinase therapy (43 +/- 31 percent of patients vs. 83 +/- 17; P less than 0.001). Residual stenosis of 70 percent or more was present in 4 percent of the angioplasty-treated patients and in 83 percent of the streptokinase-treated patients (P less than 0.01). Ventricular function after therapy was assessed by serial contrast ventriculograms. Increases in both global ejection fraction (8 +/- 7 percent vs. 1 +/- 6; P less than 0.001) and regional wall motion (+1.32 +/- 1.32 SD vs. +0.59 +/- 0.79 SD; P less than 0.05) were greater for the angioplasty group. We conclude that angioplasty and streptokinase produce similar rates of early coronary reperfusion during evolving transmural myocardial infarction. However, angioplasty is significantly more effective in alleviating the underlying coronary stenoses, and this may result in more effective preservation of ventricular function after therapy.

We treated 93 patients who had acute nonlymphoblastic leukemia in the first remission or chronic myelocytic leukemia in the chronic phase (median age, 30 years) with high-dose cyclophosphamide and fractionated total-body irradiation, followed by infusion of marrow from an HLA-identical sibling. To evaluate postgrafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50). All patients had evidence of sustained engraftment. A significant reduction in the cumulative incidence of grades II to IV acute graft versus host disease was observed in the patients who received both methotrexate and cyclosporine (33 percent), as compared with those who were given cyclosporine alone (54 percent) (P = 0.014). Seven patients who received cyclosporine alone acquired grade IV acute graft versus host disease, as compared with none who received both methotrexate and cyclosporine. Thirty-five of the 43 patients given both methotrexate and cyclosporine and 31 of the 50 patients given cyclosporine are alive as of this writing, at 4 months to 2 years (median, 15 months); the actuarial survival rates in the two groups at 1.5 years were 80 percent and 55 percent, respectively (P = 0.042). We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival.

Thirty-six patients with insulin-dependent diabetes mellitus who had Albustix-negative urine but elevated urinary albumin excretion (30 to 300 mg per 24 hours) were matched in pairs according to their urinary albumin level, blood glycosylated hemoglobin level, and sex and assigned randomly to either unchanged conventional treatment or continuous insulin infusion. During the next 12 months a significant improvement in glycemic control was observed in the insulin-infusion group, with a reduction in the mean glycosylated hemoglobin level from 9.5 to 7.3 percent. There was no change in the control group (9.3 to 9.2 percent). No significant change in albumin excretion was observed in either group. The mean blood pressure increased slightly in both groups (from 98 to 101 mm Hg in the insulin-infusion group and from 98 to 103 mm Hg in the control group). Kidney size was significantly reduced in all patients during insulin infusion, but no consistent change was observed in the control group. No significant change was observed in the glomerular filtration rate. Our data suggest that the pathologic processes causing microalbuminuria in early renal disease are not reversed during 12 months of strict metabolic control.

We evaluated renal function in 107 patients with active lupus nephritis who participated in long-term randomized therapeutic trials (median follow-up, seven years). For patients taking oral prednisone alone, the probability of renal failure began to increase substantially after five years of observation. Renal function was better preserved in patients who received various cytotoxic-drug therapies, but the difference was statistically significant only for intravenous cyclophosphamide plus low-dose prednisone as compared with high-dose prednisone alone (P = 0.027). The advantage of treatment with intravenous cyclophosphamide over oral prednisone alone was particularly apparent in the high-risk subgroup of patients who had chronic histologic changes on renal biopsy at study entry. Patients treated with intravenous cyclophosphamide have not experienced hemorrhagic cystitis, cancer, or a disproportionate number of major infections. We conclude that, as compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with intravenous cyclophosphamide reduces the risk of end-stage renal failure with few serious complications.

Plasma exchange has been reported to be efficacious in chronic inflammatory demyelinating polyradiculoneuropathy. We performed a prospective double-blind trial in which patients with static or worsening disease were randomly assigned to plasma exchange (n = 15) or to sham exchange (n = 14) for three weeks. After three weeks, we observed statistically significant differences in combined measurements of nerve conduction (total, motor, proximal, velocity, and amplitude) favoring patients who had received plasma exchange. Improvement to a greater degree than for any patient receiving sham exchange was detected in the neurologic-disability score in five patients (P = 0.025) and in subset scores for weakness and reflex in four patients (P less than 0.057). We conclude that for some patients with chronic inflammatory demyelinating polyradiculoneuropathy, plasma exchange has an ameliorating effect on neurologic dysfunction and nerve conduction, but in others no improvement is observed. Because plasma was replaced with normal serum albumin, a humoral factor or factors may have a role in the neurologic deficit of this disorder.

High-dose methotrexate (500 to 33,600 mg per square meter of body-surface area) with leucovorin rescue is a common component of therapy for acute lymphocytic leukemia. To increase understanding of the relation between the serum concentration and the effect of methotrexate, we conducted a randomized, prospective study of 108 children with "standard-risk" acute lymphocytic leukemia who were treated with 15 doses of methotrexate (1000 mg per square meter) that were infused over 24 hours. The median length of follow-up was 3.5 years from diagnosis for patients still in remission. Variability between patients in methotrexate clearance produced steady-state serum concentrations that ranged from 9.3 to 25.4 microM. Patients with median methotrexate concentrations of less than 16 microM (n = 59) had a lower probability of remaining in remission (P less than 0.05) than patients with concentrations of 16 microM or more (n = 49). Multivariate analyses indicated that patients with methotrexate concentrations of less than 16 microM were 3 times more likely to have any kind of relapse during therapy (P = 0.01) and 7 times more likely to have a hematologic relapse during therapy (P = 0.001). Stepwise Cox's regression identified leukemic-cell DNA content, methotrexate concentration, and hemoglobin as significant prognostic variables for hematologic relapse (P = 0.0005). We conclude that there is a concentration-effect relation for high-dose methotrexate in acute lymphocytic leukemia and that 1000 mg per square meter infused over a period of 24 hours may not be optimal for patients with relatively fast drug clearance.

We conducted a randomized, double-blind study comparing intranasal gonadotropin-releasing hormone (1.2 mg per day for 28 days) with parenteral human chorionic gonadotropin (3300 IU per week for four weeks) in the treatment of cryptorchidism in 33 boys one to five years old (29 with unilateral and 4 with bilateral cryptorchidism). Testicular descent into the scrotum occurred in 3 of the 16 patients (19 percent) treated with gonadotropin-releasing hormone and in 1 of the 17 (6 percent) treated with human chorionic gonadotropin (P = 0.23). The mean luteinizing hormone and testosterone levels were similar in both groups before treatment. During treatment, the testosterone levels were significantly increased in both groups, but higher levels occurred in the group treated with human chorionic gonadotropin (P less than 0.05). In a parallel (but uncontrolled) study of five boys with retractile testes (defined as a nonscrotal testis that could be manipulated into the bottom of the scrotum) who were originally excluded from the main protocol but were treated with the same regimen of human chorionic gonadotropin, descent into the scrotum occurred in all patients. We conclude that hormonal therapy with either gonadotropin-releasing hormone or human chorionic gonadotropin is, in most cases, ineffective in promoting testicular descent of true cryptorchid testes. However, short-term treatment with human chorionic gonadotropin is very effective in producing descent of retractile testes. These results suggest that the wide discrepancies in apparent efficacy in previous trials of hormonal therapy of cryptorchidism may have been due to inclusion in those studies of various proportions of patients with retractile testes.

After restoration of spontaneous circulation and adequate oxygenation, 262 comatose survivors of cardiac arrest were randomly assigned to receive standard brain-oriented intensive care or the same standard therapy plus a single intravenous loading dose of thiopental (30 mg per kilogram of body weight). The study was designed to have an 80 percent probability of detecting a 20 percent reduction in the incidence of permanent postischemic cerebral dysfunction. Base-line characteristics were similar in the two treatment groups. At the end of one year of follow-up, there was no statistically significant difference between treatment groups in the proportion of patients who died (77 percent of the thiopental vs. 80 percent of the standard-therapy group), survived with "good" cerebral recovery (20 percent of the thiopental vs. 15 percent of the standard-therapy group), or survived with permanent severe neurologic damage (2 percent of the thiopental vs. 5 percent of the standard-therapy group). The results of this study do not support the use of thiopental for brain resuscitation after cardiac arrest.

We randomly assigned 159 patients with non-ulcer dyspepsia, defined as chronic or recurrent epigastric pain without concomitant symptoms of the irritable bowel syndrome and with no evidence of organic disease, to treatment for three weeks with an antacid suspension one and three hours after meals, 400 mg of cimetidine twice a day, or placebo, according to a double-blind, double-dummy model. The intensity and duration of epigastric pain were recorded by the patients four times daily during a one-week period without therapy and during the three weeks of treatment. The mean reduction in pain intensity after three weeks in the placebo group was 25 percent. Neither antacid nor cimetidine treatment resulted in more than a 4 percent better effect. The reduction of pain was statistically significant (P less than 0.01) in all three groups. The time course of the pain scores in the groups receiving active drugs followed closely those in the placebo group, and there were no significant differences between the groups at any stage of the treatment. We conclude that the neutralization or suppression of gastric acid is of no clinical value in patients with this syndrome.

We compared the effects of weight reduction, metoprolol, and placebo on M-mode echocardiographic measurements of the thickness and mass of the left ventricular wall in a 21-week, randomized controlled trial that enrolled 41 young, overweight patients with hypertension. At the end of the follow-up period, the patients in the weight-reduction group had lost an average of 8.3 kg, and their blood pressure had decreased by an average of 14/13 mm Hg, as compared with 12/8 mm Hg in the metoprolol group and 9/4 mm Hg in the placebo group. In the weight-reduction group, interventricular septal and posterior-wall thickness decreased by 14 percent and 11 percent, respectively, and left ventricular mass decreased by 20 percent (16 percent when adjusted for body-surface area). Decreases in interventricular septal and posterior-wall thickness and in left ventricular mass in the weight-reduction group were significantly greater than those in the placebo group. The changes in thickness of the interventricular septum and the left ventricular mass in the weight-reduction group were also greater than those in the metoprolol group. Changes in weight, independent of changes in blood pressure, were directly associated with changes in left ventricular mass. We conclude that weight reduction decreases left ventricular mass in overweight hypertensive patients and that control of obesity is important not only for the treatment of hypertension but also for the prevention of left ventricular hypertrophy.

We conducted a randomized controlled trial to evaluate the antibody response of freshman veterinary students to intradermal human diploid-cell rabies vaccine administered concurrently with chloroquine, a drug frequently used for chemoprophylaxis against malaria. Fifty-one students who had not been vaccinated against rabies were enrolled: 26 received 300 mg of chloroquine base per week (the recommended dose for malaria prophylaxis); 25 did not receive chloroquine and served as controls. All subjects received 0.1 ml of rabies vaccine intradermally on days 0, 7, and 28. Chloroquine was administered weekly to the treatment group, beginning nine days before the first dose of vaccine and continuing until day 48. The mean rabies-neutralizing antibody titer for the chloroquine group was significantly lower than that for the control group on each day of testing--i.e., day 28 (P = 0.0094), day 49 (P = 0.0008), and day 105 (P = 0.0002)--although both groups had neutralizing antibody titers on days 49 and 105, according to the criteria of the Centers for Disease Control. The blood concentrations of chloroquine and desethylchloroquine (the major metabolite of chloroquine, which also has antimalarial properties) were negatively associated with log antibody titers. These results indicate that chloroquine taken in the dose recommended for malaria prophylaxis can reduce the antibody response to primary immunization with intradermal human diploid-cell rabies vaccine.

In an effort to prevent perinatal acquisition of Chlamydia trachomatis, we offered treatment with erythromycin ethylsuccinate (400 mg four times a day for seven days, given at 36 weeks' gestation) to 184 pregnant women with cervical chlamydial infections. Thirty-two women refused treatment; 24 of their infants were followed and served as the controls. Therapy was discontinued by 5 of 10 women who had gastrointestinal disturbances. Forty-seven women who completed therapy refused infant follow-up; in four (9 percent) of these women, therapy had failed to eradicate the infection. Sixty women and 59 infants completed the entire protocol; 55 (92 percent) of the women had negative cultures for chlamydia at follow-up. Chlamydial infection developed in 4 (7 percent) of the 59 infants of treated mothers, as compared with 12 (50 percent) of the 24 infants of untreated mothers; this difference was significant (P less than 0.001). With a success rate of 92 percent (98 of 107 patients) in treating maternal infection and with a relatively low intolerance rate (3 percent; 5 of 152), this regimen appears to be an effective, although not ideal, therapy for chlamydial infection in pregnant women. We conclude that in settings in which the prevalence of chlamydia infection is high, a routine program of screening pregnant women for cervical C. trachomatis, followed by treatment of those infected, would be cost effective and would reduce infant morbidity.

Recent studies have led to controversy about whether long-term digoxin therapy after confirmed or suspected myocardial infarction increases mortality. We analyzed the mortality experience in 903 patients enrolled in the Multicenter Investigation of Limitation of Infarct Size (MILIS). As in previous studies, the decision to treat or not to treat with digoxin was made by the patient's personal physician on the basis of the usual clinical indications. Cumulative mortality was 28 percent for the 281 digoxin-treated patients as compared with 11 percent for the 622 patients who did not receive digoxin (P less than 0.001; follow-up interval, six days to 36 months; mean, 25.1 months). However, patients treated with digoxin had more base-line characteristics predictive of mortality than did their counterparts. Adjustment for these differences with two separate applications of the Cox method yielded P values of 0.14 and 0.34 for tests of difference in mortality, providing no evidence for a significant excess mortality associated with digoxin. Thus, the findings in the MILIS population do not support the assertion that digoxin therapy is excessively hazardous after infarction, but the existence of an undetected harmful effect can only be excluded with a randomized study. Until the results of such a study are available, we recommend careful consideration of whether any treatment of ventricular dysfunction is actually needed, consideration of alternatives to digoxin therapy, and restriction of digoxin use to the subgroup of patients (with severe chronic congestive failure and a dilated left ventricle) previously shown to have a beneficial clinical response.