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.

In a prospective, randomized trial, we compared intravenous acyclovir and vidarabine in the treatment of varicella-zoster virus infection in severely immunocompromised patients who presented within 72 hours of onset of the infection. Eleven patients were treated in each group. Cutaneous dissemination of infection occurred in none of the 10 acyclovir recipients and in 5 of the 10 vidarabine recipients who had presented with localized dermatomal disease (P = 0.016). As compared with vidarabine, acyclovir treatment shortened the median periods during which cultures were positive for the virus (four vs. seven days, P = 0.004) and new lesions formed (three vs. six days, P = 0.03). Acyclovir also shortened the median interval until the first decrease in pain (4 vs. 7 days, P = 0.005), the pustulation of all lesions (4 vs. 7 days, P = 0.0004), the crusting of all lesions (7 vs. 17 days, P = 0.0003), and the complete healing of lesions (17 vs. 28 days, P = 0.003). In addition, acyclovir reduced the incidence of fever (two vs. eight patients, P = 0.015). We conclude that acyclovir is better than vidarabine for the treatment of varicella-zoster infection in immunocompromised patients.

Ninety-seven acutely ill patients with bronchial asthma were enrolled in a double-blind, placebo-controlled, randomized trial of intravenous methylprednisolone (125 mg), given on presentation in the emergency room in addition to standard emergency treatments for asthma. Subjective and spirometric indexes of the severity of the asthma were similar on entry into the study in all patients, but only 9 of 48 patients (19 percent) treated with methylprednisolone required hospital admission, as compared with 23 of 49 patients (47 percent) in the control group (P less than 0.003). Our results suggest that prompt use of glucocorticoids in the emergency treatment of severe asthma can prevent significant morbidity, reduce the number of hospitalizations, and effect substantial savings in health care costs.

We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis.

We conducted a randomized, placebo-controlled, double-blind study to determine whether intranasal alpha 2-interferon could prevent respiratory illnesses in healthy contacts of ill family members. Beginning within 48 hours of the onset of illness in a family member, contacts self-administered interferon (5 X 10(6) IU) or placebo spray once daily for seven days. Respiratory illness developed during the eight-day period, starting with the second day of spraying, in 52 of 222 persons in the placebo group as compared with 32 of 226 in the interferon group (P = 0.02; efficacy, 39 percent). Among persons exposed to laboratory-documented rhinovirus colds, illness developed in 2 of 27 interferon recipients as compared with 12 of 34 placebo recipients (P = 0.02; efficacy, 79 percent). During the two-week period during and after spraying, rhinovirus colds developed in 1.3 percent of those spraying with interferon and in 15.1 percent of those spraying with placebo (P = 0.003; efficacy, 88 percent). Blood-tinged mucus or nasal mucosal bleeding or both were detected in 7.7 percent of placebo and 13.6 percent of interferon users (P = 0.04), but no evidence of cumulative nasal toxicity was found. We conclude that postexposure prophylaxis with intranasal interferon may in some cases provide an effective strategy for controlling the spread of natural colds, especially those caused by rhinoviruses.

In a double-blind evaluation of alpha 2-interferon as prophylaxis against naturally acquired respiratory infections, 120 adult members of 46 Australian families used 325 courses of intranasal spray during a six-month period, applying 5 million IU to the anterior nasal mucosa daily for seven days when respiratory symptoms developed in another member of the family. Used in this way, the alpha 2-interferon was well tolerated, and the rate of minor nasal bleeding (12 percent) did not increase with repeated courses. By comparison with the control group of 109 members of 49 families who used 319 seven-day courses of placebo spray, the users of alpha 2-interferon experienced 33 percent fewer days with nasal symptoms and 41 percent fewer episodes of "definite" respiratory illness. The users of alpha 2-interferon who were exposed to rhinovirus infections experienced 76 percent fewer days with symptoms and 86 percent fewer "definite" illnesses than their counterparts who used placebo. All of the observed clinical benefits, which suggested prevention of 6.8 "definite" respiratory illnesses per 100 courses of medication used, could be explained by a protective effect against illness associated with rhinoviruses that was not demonstrated for influenza A or B or coronavirus 229E.

We describe here the preliminary results of the systemic administration of autologous lymphokine-activated killer (LAK) cells and the recombinant-derived lymphokine interleukin-2 to patients with advanced cancer. This regimen was based on animal models in which the systemic administration of LAK cells plus interleukin-2 mediated the regression of established pulmonary and hepatic metastases from a variety of murine tumors in several strains of mice. We treated 25 patients with metastatic cancer in whom standard therapy had failed. Patients received both 1.8 to 18.4 X 10(10) autologous LAK cells, generated from lymphocytes obtained through multiple leukaphereses, and up to 90 doses of interleukin-2. Objective regression of cancer (more than 50 per cent of volume) was observed in 11 of the 25 patients: complete tumor regression occurred in one patient with metastatic melanoma and has been sustained for up to 10 months after therapy, and partial responses occurred in nine patients with pulmonary or hepatic metastases from melanoma, colon cancer, or renal-cell cancer and in one patient with a primary unresectable lung adenocarcinoma. Severe fluid retention was the major side effect of therapy, although all side effects resolved after interleukin-2 administration was stopped. Further development of this approach and additional patient follow-up are required before conclusions about its therapeutic value can be drawn.

We performed a randomized, double-blind, placebo-controlled trial in 555 patients with unstable angina who were hospitalized in coronary care units. Patients received one of four possible treatment regimens: aspirin (325 mg four times daily), sulfinpyrazone (200 mg four times daily), both, or neither. They were entered into the trial within eight days of hospitalization and were treated and followed for up to two years (mean, 18 months). The incidence of cardiac death and nonfatal myocardial infarction, considered together, was 8.6 per cent in the groups given aspirin and 17.0 per cent in the other groups, representing a risk reduction with aspirin of 51 per cent (P = 0.008). The corresponding figures for either cardiac death alone or death from any cause were 3.0 per cent in the groups given aspirin and 11.7 per cent in the other groups, representing a risk reduction of 71 per cent (P = 0.004). Analysis by intention to treat yielded smaller risk reductions with aspirin of 30 per cent (P = 0.072), 56 per cent (P = 0.009), and 43 per cent (P = 0.035) for the outcomes of cardiac death or nonfatal acute myocardial infarction, cardiac death alone, and all deaths, respectively. There was no observed benefit of sulfinpyrazone for any outcome event, and there was no evidence of an interaction between sulfinpyrazone and aspirin. Considered together with the results of a previous clinical trial, these findings provide strong evidence for a beneficial effect of aspirin in patients with unstable angina.

To determine whether the onset of myocardial infarction occurs randomly throughout the day, we analyzed the time of onset of pain in 2999 patients admitted with myocardial infarction. A marked circadian rhythm in the frequency of onset was detected, with a peak from 6 a.m. to noon (P less than 0.01). In 703 of the patients, the time of the first elevation in the plasma creatine kinase MB (CK-MB) level could be used to time the onset of myocardial infarction objectively. CK-MB-estimated timing confirmed the existence of a circadian rhythm, with a three-fold increase in the frequency of onset of myocardial infarction at peak (9 a.m.) as compared with trough (11 p.m.) periods. The circadian rhythm was not detected in patients receiving beta-adrenergic blocking agents before myocardial infarction but was present in those not receiving such therapy. If coronary arteries become vulnerable to occlusion when the intima covering an atherosclerotic plaque is disrupted, the circadian timing of myocardial infarction may result from a variation in the tendency to thrombosis. If the rhythmic processes that drive the circadian rhythm of myocardial-infarction onset can be identified, their modification may delay or prevent the occurrence of infarction.

We randomized 81 postmenopausal women with advanced breast cancer, whose tumors were rich in estrogen receptors or of unknown estrogen-receptor status, to receive either estrogen therapy alone or estrogen therapy combined with chemotherapy. An additional 31 patients, whose tumors were poor in estrogen receptors, were randomized to receive either chemotherapy alone or estrogen combined with chemotherapy. The median duration of follow-up was 87 months. In the receptor-rich group, the survival of the 21 patients receiving combined therapy was significantly longer than that of 19 patients receiving estrogen as initial therapy (followed by chemotherapy after failure or relapse). The median survivals were 72 and 29 months, respectively (P = 0.05 by the generalized Wilcoxon method). Among 41 patients with tumors of unknown receptor status, a survival advantage from combined therapy over chemotherapy was seen in the first two years and then disappeared. The survival in 31 patients with receptor-poor tumors was uniformly short regardless of the therapeutic method. We conclude that combined therapy offers a survival advantage in postmenopausal patients with receptor-rich tumors.

To determine whether bypass surgery would benefit patients with symptomatic atherosclerotic disease of the internal carotid artery, we studied 1377 patients with recent hemisphere strokes, retinal infarction, or transient ischemic attacks who had atherosclerotic narrowing or occlusion of the ipsilateral internal carotid or middle cerebral artery. Of these, 714 were randomly assigned to the best medical care, and 663 to the same regimen with the addition of bypass surgery joining the superficial temporal artery and the middle cerebral artery. The patients were followed for an average of 55.8 months. Thirty-day surgical mortality and major stroke morbidity rates were 0.6 and 2.5 per cent, respectively. The postoperative bypass patency rate was 96 per cent. Nonfatal and fatal stroke occurred both more frequently and earlier in the patients operated on. Secondary survival analyses comparing the two groups for major strokes and all deaths, for all strokes and all deaths, and for ipsilateral ischemic strokes demonstrated a similar lack of benefit from surgery. Separate analyses in patients with different angiographic lesions did not identify a subgroup with any benefit from surgery. Two important subgroups of patients fared substantially worse in the surgical group: those with severe middle-cerebral-artery stenosis (n = 109, Mantel-Haenszel chi-square = 4.74), and those with persistence of ischemic symptoms after an internal-carotid-artery occlusion had been demonstrated (n = 287, chi-square = 4.04). This study thus failed to confirm the hypothesis that extracranial-intracranial anastomosis is effective in preventing cerebral ischemia in patients with atherosclerotic arterial disease in the carotid and middle cerebral arteries.

In a randomized controlled study examining the value of an intramuscular injection of lidocaine in the prehospitalization phase of suspected acute myocardial infarction, paramedics used an automatic injector to administer 400 mg of the drug into the patient's deltoid muscle before transport to the hospital. In a 33-month period, 7026 patients with acute chest pain were seen. Of the 6024 patients randomized (2987 to the lidocaine group and 3037 to the control group), 1935 (32 per cent) proved to have an acute myocardial infarction. In the entire 60-minute period of observation by continuous electrocardiography, primary ventricular fibrillation was observed in 8 treated and 17 control patients (P = 0.08). However, from 15 minutes after randomization onward, when plasma lidocaine levels were in the therapeutic range, only 2 cases of ventricular fibrillation occurred in the treated group, as compared with 12 in the control group (P less than 0.01). Ventricular tachycardia terminated a mean of 10 minutes after injection in six of nine lidocaine-treated patients with acute myocardial infarction but in none of five control patients with infarction (P less than 0.02). Mean plasma lidocaine levels were 3 micrograms per milliliter 11 to 20 minutes after injection in 369 consecutive patients. In 65 patients, levels were below 2 micrograms per milliliter, and in 15 patients, levels were above 6 micrograms per milliliter. Side effects were rare and did not contribute to mortality. We conclude that intramuscular lidocaine may be useful if given by a paramedic, another person, or the patient himself when acute myocardial infarction is suspected outside the hospital.

The original Norwegian Multicenter Study on Timolol after Myocardial Infarction was a double-blind, randomized study comparing the effect of timolol with that of placebo for up to 33 months after acute myocardial infarction. The initial results showed that the cumulated mortality rate was 39.4 per cent lower among 945 patients randomly assigned to timolol treatment than among 939 patients randomly assigned to placebo (P = 0.0003). After the end of the double-blind period the majority of participating patients in the timolol group continued to receive beta-adrenergic blockade, whereas the majority of placebo-treated patients continued without such blockade. During an extended follow-up of participating patients up to 72 months after randomization, the mortality curves of the two groups continued to rise in parallel. Cumulated mortality rates were 32.3 per cent in the placebo group and 26.4 per cent in the timolol group (P = 0.0028). We conclude that the previously observed early beneficial effect of beta-adrenergic blocking therapy is maintained for at least six years after infarction.