In a randomized double-blind study (N = 562), a traditional treatment schedule, starting antihypertensive treatment in elderly hypertensive patients (60 to 75 years old) with 25 mg of hydrochlorothiazide once daily and doubling the dose if a satisfactory response was not achieved, was compared with antihypertensive treatment of 100 mg of metoprolol once daily, adding 12.5 mg of hydrochlorothiazide for patients whose response was not satisfactorialy achieved with metoprolol alone. Systolic and diastolic blood pressure was significantly reduced with both regimens. The frequency rates of responders (diastolic blood pressure, less than or equal to 95 mm Hg) in the metoprolol group and the hydrochlorothiazide group were 50% and 47% after four weeks and 65% and 61% after eight weeks, respectively. There were no significant differences in total symptom score or single symptoms between the regimens, but significantly more patients had hypokalemia and hyperuricemia with the hydrochlorothiazide regimen. Thus, we conclude that beginning antihypertensive treatment with 100 mg of metoprolol once daily and adding a small dose of hydrochlorothiazide (12.5 mg) in patients whose response is not satisfactory with metoprolol alone appears to be effective and safe in elderly hypertensive patients.

In a prospective randomized study, contamination rates of disposable pressure transducers changed every two days (n = 81) were compared with those changed at four (n = 26) or eight days (n = 50); the mean daily incidence of contamination was 3% for each group. After four days of use, the cumulative prevalences of contamination were similar. However, after eight days, the cumulative prevalence was significantly higher in transducers used without change (6.9%) than in those changed every two days (2.9%). Gram-negative bacilli were present in 63% of contaminated transducers; over half were from the patients' own flora. The only definite transducer-related bacteremia occurred on a day of initial contamination and should have been unaffected by the interval of change. Routine use of disposable transducers can be safely extended to four days, even in a busy intensive care unit.

Loperamide hydrochloride was compared with bismuth subsalicylate for the treatment of acute nondysenteric travelers' diarrhea in 219 students visiting seven countries in Latin America. Subjects whose condition was not improved with therapy could elect to take trimethoprim-sulfamethoxazole. Persons receiving loperamide passed fewer unformed stools when compared with the bismuth subsalicylate group during the first four hours of therapy, from four to 24 hours, and from 24 to 48 hours after therapy was initiated. Among subjects with disease due to enterotoxigenic Escherichia coli, Shigella sp, other pathogens, and unknown agents, fewer unformed stools were passed by the loperamide-treated subjects than the bismuth subsalicylate-treated subjects for all time periods studied. No significant prolongation of disease was seen in subjects with shigellosis treated with loperamide. Eight of the loperamide-treated subjects experienced constipation compared with one in the bismuth subsalicylate-treated group; otherwise, there was no difference in minor side effects experienced between both treatment groups. We conclude that loperamide is a safe and effective alternative to bismuth subsalicylate for the treatment of nondysenteric travelers' diarrhea.

Improved perinatal outcome is associated with the prevention of hyperglycemia during pregnancy in diabetic women. To determine whether the method of insulin administration influences the degree of diabetic control obtained, we randomized 22 pregnant diabetic women to intensive conventional insulin therapy (N = 11) and insulin pump therapy (N = 11). Frequent outpatient visits; home glucose monitoring, at least six times daily; and frequent telephone contact were offered to all subjects. Patients were hospitalized in the inpatient clinical research center each trimester for a 24-hour metabolic profile. There were no differences between the two treatment groups with respect to outpatient mean glucose levels, symptomatic hypoglycemia, or glycosylated hemoglobin levels, or with respect to inpatient mean glucose level, glycemic excursions, chemical hypoglycemia, or hyperglycemia. Excellent metabolic control was achieved with both treatment methods.

Evidence is sparse concerning the value of the "educational" materials that physicians receive in the mail. We conducted a randomized trial of a mailed continuing education program on hypertension for primary care physicians. Although formal pretesting documented that the program led to significant improvements in physician knowledge over the short term, the current study showed no lasting effect on physician knowledge (mean scores on an end-of-study questionnaire were 50% and 52% for study and control physicians, respectively) and no influence on performance in lowering the blood pressures of patients referred from screening (mean blood pressure drop for study patients, 12.2/10.4 mm Hg vs 13.0/10.6 mm Hg for control patients). The chance that we missed a difference in diastolic blood pressure as great as 3 mm Hg is less than 5%. Resources spent on instructional materials mailed to physicians may be wasted.

Within 48 hours of variceal hemorrhage, 82 patients were randomly assigned to conventional treatment including balloon tamponade or to conventional treatment supplemented by sclerotherapy. The prerandomization general clinical characteristics of the two groups were similar. Seventy-nine percent of patients were alcoholic and 57% were in Child's class C. In the sclerotherapy group of 44 patients, sclerotherapy was performed twice in 28 patients and thrice in 13 patients over the two weeks of follow-up. The number of patients who rebled was significantly lower in the sclerotherapy group than in the group treated conventionally (23% vs 53%). The number of bleeding episodes also was significantly lower in the sclerotherapy group (15 vs 32). Moreover, blood transfusion requirements were significantly decreased in the sclerotherapy group. This was true even for patients who were bleeding at the time of randomization or who were in Child's class C, but this primarily was because fewer patients who underwent sclerotherapy (10 of 24 vs 18 of 23) required transfusions. Although there was no difference in survival between the two groups, we conclude that sclerotherapy is better than conventional treatment in the acute management of variceal bleeding.

Forty patients with serum antibody against herpes simplex virus (HSV) were enrolled in a randomized, placebo-controlled, double-blind investigation of acyclovir given orally in a low dosage as prophylaxis against recurrent HSV infection after renal transplantation. During 30 postoperative days of medication, 14 of 21 placebo-treated and one of 19 acyclovir-treated patient(s) developed reactivation of HSV infection. Eleven of the former, but not the latter, had herpetic lesions. The protection against active infection with HSV during the period of prophylaxis with acyclovir is statistically highly significant. From 30 to 90 days after transplantation when no antiviral medicine was given, 60% (3/5) of the remaining placebo recipients and 44% (7/16) of the acyclovir patients developed active HSV infections. Herpetic lesions occurred in two of three and two of seven of infected people in the respective groups. No adverse effects of the drug were observed. The results show that HSV infections in immunosuppressed renal allograft recipients can be safely prevented, deferred, and ameliorated by an initial period of prophylaxis with a low dose of oral acyclovir.

In a randomized five-year multifactorial primary prevention trial of vascular diseases, hyperlipidemias, hypertension, smoking, obesity, and abnormal glucose tolerance of the high-risk test group (n = 612 men) were treated with dietetic-hygienic measures and hypolipidemic (mainly probucol and clofibrate) and antihypertensive (mainly diuretics and beta-blockers) agents. A matched high-risk control group (n = 610) and a low-risk control group (n = 593) were not treated. The program markedly improved the risk factor status, yet the five-year coronary incidence tended to be higher in the intervention group than in the control group (3.1% vs 1.5%), while the stroke incidence was significantly reduced (1.3% vs 0%). The coronary events tended to be accumulated in subgroups treated with beta-blocking agents or clofibrate, but there were few in those receiving probucol or diuretics. Thus, the intervention program significantly reduced development of stroke, but the occurrence of cardiac events was not prevented. Possible adverse drug effects offsetting the probable benefit of improved risk profile are not excluded.

The relationship of white blood cell count (WBC) to fatal and nonfatal coronary heart disease (CHD) incidence and all-cause and cancer mortality was assessed in a subset of participants in the Multiple Risk Factor Intervention Trial (MRFIT). For this group of 6,222 middle aged men, total WBC count was found to be strongly and significantly related to risk of CHD, independent of smoking status. Change in WBC count from baseline to the annual examination just prior to the CHD event was found to be a significant and independent predictor of CHD risk. For each decrease in WBC count of 1,000/cu mm the risk for CHD death decreased 14%, controlling for baseline WBC count and other CHD risk factors (smoking, cholesterol level, diastolic blood pressure). The WBC count was strongly related cross-sectionally to cigarette smoking and smoking status as indicated by serum thiocyanate concentration. Smokers on average had a WBC count of 7,750/cu mm compared with 6,080/cu mm for nonsmokers. The WBC count was also significantly associated with cancer death, independent of reported smoking and serum thiocyanate levels.

In a prospective, single-blind, randomized study, a single 2-g dose of metronidazole was compared with a seven-day course of 500 mg given twice daily in the treatment of symptomatic vaginal discharge associated with Gardnerella vaginalis. Based on resolution of symptoms and on cultures negative for G vaginalis, 86% (40/46) of women treated with the single dose and 97% (35/36) of women treated with the seven-day course were considered cured at seven to ten days after treatment. Evaluation at 21 days after treatment, however, indicated that only 46% (16/34) of patients treated with the single 2-g dose were considered cured compared with 86% (26/30) of those treated with the seven-day course. Treatment of sexual contacts did not significantly improve cure rates in either group.

Seventy-nine children were enrolled in a study to compare seven vs ten days of ceftriaxone therapy for bacterial meningitis. On the basis of a computer-generated list of therapy assignments, 35 children with Haemophilus, pneumococcal, or group B streptococcal meningitis each were assigned to seven- or ten-day treatment regimens; nine children with meningococcal meningitis received seven days of therapy. The population characteristics and etiologic agents were similar for the two treatment groups, as were also the findings on examination and culture of cerebrospinal fluid at completion of therapy. There were no significant differences in the frequency and types of neurological complications between the two treatment groups; four patients in each group had two or more neurological abnormalities. The rates of nosocomial infections and prolonged and secondary fever were similar in those who received seven days of therapy compared with patients treated for the conventional ten days. Diarrhea occurred in 44% of those receiving the drug. Patients treated with the seven-day regimen were discharged from the hospital approximately two days earlier than those with the ten-day regimen.

The large number of participants (5,485 patients) in the Hypertension Detection and Follow-Up Program, Stepped Care, form the largest group to date on which detailed surveillance of long-term antihypertensive therapy and drug side effects has been reported. Over a five-year period, among all hypertensive persons (mild, moderate, and severe combined) who were not taking antihypertensive medications at the beginning of the study and who attended the clinic at least once during the five-year trial, a total of 9.3% had definite or probable side effects severe enough to cause discontinuation of the drug treatment in question. An additional 23.4% had drug treatment discontinued due to possible side effects. Within the mild, moderate, and severe hypertension categories, 8.6%, 11%, and 12%, respectively, had definite or probable side effects. The incidence of side effects declined over the five years in all race-sex groups. Five-year incidence of total side effects was 29.8% in those aged 60 to 69 years at entry and 38.0%, 36.8%, and 34.1%, respectively, in those aged 50 to 59, 40 to 49, and 30 to 39 years. Sexually related side effects required discontinuation of treatment in 8.3% of male participants. However, less than 1% of active participants required hospitalization for side effects. No death that could be attributed to side effects was detected. Thus, the Hypertension Detection and Follow-up Program data, which have previously demonstrated the beneficial effects of antihypertensive therapy, confirm the relative safety of such therapy.

High serum concentrations of apolipoprotein (apo) A-I are associated with a decreased risk of coronary heart disease. To study the effect of alcohol intake on serum apo A-I and A-II concentrations, 24 healthy male drinkers (37.8 +/- 13.9 mL [1.3 +/- 0.5 oz] of ethanol per day, mean +/- SD) were randomized into treatment and control groups after a three-week baseline period. The treatment group abstained from all intake of alcohol for the six weeks following randomization and then reverted to its usual level of intake for a five-week period. The control group continued its usual level of drinking throughout the trial. The concentrations of apo A-I and apo A-II of abstainers decreased significantly compared with the corresponding changes in controls. After drinking was resumed, apo A-I and apo A-II concentrations were significantly increased in the treatment group compared with the corresponding changes in the control group. These results suggest that the association between moderate alcohol intake and reduced risk of coronary heart disease may be mediated in part by increased levels of serum apo A-I or apo A-II, or both.

Terminal cancer patients were randomly assigned to receive comprehensive hospice care or traditional medical care. Patients were followed up for two years or until death. Pain was measured by the McGill Pain Scale. Frequency and intensity of cancer-related symptoms were also noted. Over the course of the study, 34% of hospice patients and 21% of control patients never reported pain. No significant differences between the two groups could be detected in either the proportion of patients with pain at any time or the intensity of pain. Neither were there differences in the intensity or frequency of cancer-related symptoms. The presence of pain was associated with the presence of other symptoms; a significant correlation was found between the levels of depression and anxiety and pain scores.

Thermodilution cardiac output measurements are commonly employed in the management of critically ill patients. Serial measurements often show significant variation, and poor reproducibility limits their clinical utility. There are no clinical studies revealing when to perform thermodilution cardiac output measurements in relation to the respiratory cycle. We prospectively studied 32 patients in a randomized scheme comparing three thermodilution cardiac output measurements at peak-inspiration, at end-exhalation, or randomly in spontaneously breathing and mechanically ventilated patients. Saline injections initiated at peak-inspiration or end-exhalation resulted in cardiac output measurements with much smaller standard deviations than those seen with random injections. Thermodilution cardiac output measurements performed at random times in the respiratory cycle should be avoided, and we recommend initiating these measurements at end-exhalation.

Three hundred five patients with advanced pancreatic and gastric carcinoma were randomly assigned to treatment with fluorouracil, fluorouracil plus doxorubicin (Adriamycin) (FA), or fluorouracil plus doxorubicin plus mitomycin (mitomycin C) (FAM). All regimens were equivalent with regard to patient survival. There is no reasonable likelihood that either the FA or FAM regimen could produce a meaningful survival advantage over fluorouracil alone. Interval to disease progression, objective response rates, and palliative effects (improved performance, body weight, or symptoms) were essentially equivalent among the three regimens. With regard to toxicity, the FAM regimen produced more anorexia, nausea, vomiting, leukopenia, thrombocytopenia, and cumulative bone marrow suppression. Fluorouracil alone produced more stomatitis and diarrhea. Because of a failure to produce improved survival or palliation, unrewarded toxicity, and excessive cost, neither the FA nor FAM regimen can be recommended for the treatment of advanced pancreatic or gastric cancer.

At the conclusion of a double-blinded, randomized clinical trial of propranolol hydrochloride, but before unblinding, the patients and clinic personnel were asked to guess the treatment group assignment of each patient. While 79.9% of the patients receiving propranolol correctly identified their treatment group assignment, 57.2% of the patients receiving placebo incorrectly guessed that they were also in the propranolol group. No specific mechanism was identified to explain why more patients receiving propranolol were better able to guess their group assignment. Clinic physicians correctly identified the group assignment of 69.9% of the patients receiving propranolol and 68.8% of the patients receiving placebo. Clinic coordinators correctly identified the group assignment of 67.1% of the patients receiving propranolol and 70.6% of the patients receiving placebo. For clinic personnel, heart rate level and heart rate change seem to be the mechanisms employed to identify their patients' treatment assignment.

Thirty-two adults were enrolled in a randomized, placebo-controlled double-blind trial of intramuscular injections of gel-sustained adenosine monophosphate (AMP) given three times a week for up to four weeks for acute herpes zoster. Adenosine monophosphate moderately reduced the pain soon after the start of treatment, decreased desquamation time, and promoted faster healing of the skin than placebo treatment. Adenosine monophosphate treatment reduced virus shedding and cleared the virus faster than in placebo-treated subjects. At the end of the initial four-week treatment period, 88% of AMP-treated patients were pain free, as opposed to only 43% in the placebo group. After four weeks, all patients who had not recovered from pain started receiving AMP treatment without breaking the code. All these patients recovered from pain within three weeks after initiation of treatment. No recurrence of pain or lesions was experienced from three to 18 months after the end of treatment. Adenosine monophosphate, a natural cellular metabolite, showed no side effects or toxicity during and after the treatment.

Forty-four children with a clinical diagnosis of streptococcal pharyngitis had throat cultures performed at the initial evaluation and were assigned by randomization to receive either oral penicillin or a placebo for 72 hours. The treating physician, who remained blind to the treatment regimen, recorded the child's temperature and assessed the presence and severity of other signs and symptoms initially and at 24, 48, and 72 hours. The throat culture was positive for group A beta-hemolytic streptococci in 26 (59%) of the initial study group, and most of these children developed a fourfold or greater titer rise in antistreptococcal antibodies in their serum, confirming the diagnosis of streptococcal pharyngitis. Statistically significant clinical improvement was observed in the group of 11 children who were later shown to have been taking penicillin compared with the group of 15 who had taken the placebo. Significant differences in the presence and degree of fever and severity of symptoms persisted in the placebo-treated group for 48 hours. We conclude that early penicillin treatment of children with streptococcal pharyngitis significantly alters the acute clinical course of the disease.