Chenodiol is a safe and effective agent for the medical dissolution of gallstones in selected patients; however, after dissolution and cessation of treatment, gallstones recur. This study was done to determine the recurrence rate after successful medical treatment and cessation of chenodiol therapy; compare the efficacy and safety of low-dose chenodiol, as compared to placebo, for prophylaxis against recurrence; and identify factors predictive of recurrence. In a randomized, double-blind fashion, 53 patients with gallstone dissolution received either chenodiol, 375 mg/d, or placebo, for at least 2 years. Standardized oral cholecystograms were done at 6 months, 1 year, and then yearly thereafter. Routine laboratory testing was done every 6 months. The cumulative rate of recurrence (life-table) was 27% in patients followed for up to 3.5 years. Chenodiol, 375 mg/d, was ineffective in preventing the recurrence of gallstones. No demographic, clinical, roentgenographic, or biochemical characteristics were predictive of recurrence.

Risk factors for nephrotoxicity in patients treated with aminoglycosides were determined from the case records of 214 patients in two prospective, randomized clinical trials of gentamicin and tobramycin. Nephrotoxicity, defined as a 50% or greater fall in calculated creatinine clearance, developed in 30 patients (14.1%). Patients with nephrotoxicity had higher initial calculated creatinine clearances, were more often women, and were more likely to have liver disease. Using stepwise discriminant analysis, these factors were selected with the initial 1-hour post-dose aminoglycoside level, patient age, and shock. An equation was generated that was accurate in discriminating between patients with and without nephrotoxicity when validated in an independent population. Factors that did not add significantly to the equation were diabetes, dehydration, serum bicarbonate, bacteremia, urinary tract infection, gentamicin or tobramycin use, duration of therapy, total aminoglycoside dose, or the use of clindamycin, furosemide, or cephalothin.

We developed a computer-stored medical record system containing a limited set of the total clinical data base--primarily diagnostic studies and treatments. This system responds to its own content according to physician-authored reminder rules. To determine the effect of the reminder messages generated by 1490 rules on physician behavior, we randomly assigned practitioners in a general medicine clinic to study or control groups. The computer found indications for six different actions per patient in 12 467 patients during a 2-year study: 61 study group residents who received computer reminders responded to 49% of these indications; 54 control group residents, to only 29% (p less than 0.0001). Preventive care (occult blood testing, mammographic screening, weight reduction diets, influenza and pneumococcal vaccines) was affected. The intentions of the study group to use a given action for an indication predicted their response to the indications (p less than 0.03, r2 = 0.33). The intentions of the control residents did not.

Two blinded, controlled trials were done to evaluate the usefulness of fungal antigen detection for the diagnosis of invasive aspergillosis. Detection of Aspergillus fumigatus carbohydrate by radioimmunoassay was compared with antibody detection by an enzyme-linked immunosorbent assay and with diagnostic microbiologic and histopathologic procedures. In the first trial, antigenemia was detected in 4 of 6 leukemic patients with invasive pulmonary aspergillosis, but not in 8 acute leukemic controls or in 24 normal controls. Fungal antigenemia persisted for 8 to 75 days in 4 patients and seroconversion occurred at the onset of pulmonary infiltrates in 3. Antibody to A. fumigatus was detected in 2 of the 6 patients with aspergillosis, but also in 2 leukemic controls and 6 normal controls. Aspergillus species were identified in four of seven bronchoscopies done in 5 patients with invasive pulmonary aspergillosis. Prospective nasal cultures grew Aspergillus species in 4 of the 6 patients with invasive aspergillosis, but in only 1 patient was this information available before a histologic diagnosis was made. In a second trial, antigenemia was detected in 2 patients with invasive aspergillosis, and in 1 with possible invasive aspergillosis, but not in 9 controls. This study indicates that the radioimmunoassay for A. fumigatus antigen is a highly specific and moderately sensitive serodiagnostic test for invasive pulmonary aspergillosis. Prospective nasal cultures grew Aspergillus species in 4 of the 6 patients with invasive aspergillosis, but in only 1 patient was this information available before a histologic diagnosis was made. In a second trial, antigenemia was detected in 2 patients with invasive aspergillosis, and in 1 with possible invasive aspergillosis, but not in 9 controls. This study indicates that the radioimmunoassay for A. fumigatus antigen is a highly specific and moderately sensitive serodiagnostic test for invasive pulmonary aspergillosis.

Twenty-nine adult patients with acute leukemia receiving timed sequential chemotherapy participated in a randomized, double-blind, placebo-controlled trial of acyclovir prophylaxis against reactivated herpes simplex virus infection. Patients with pretreatment antibody titers of 1:16 or greater received acyclovir or placebo starting 4 days after their initial chemotherapy. Treatment was given either for 32 days or until the patients were discharged from the hospital or until a culture-positive herpes simplex virus infection was found. Culture-positive herpes simplex virus infection developed in 11 of 15 patients who received placebo. No infection appeared in 14 patients who received acyclovir (p less than 0.00005). No obvious acute drug toxicity was seen. Recurrent infection was seen in 6 of 14 patients after cessation of acyclovir when retreated with chemotherapy, suggesting no effect on viral latency in these 6 patients. Acyclovir provided highly effective prophylaxis against reactivated herpes simplex virus infections in adult patients with acute leukemia receiving timed sequential chemotherapy.

A multicenter trial compared intermittent positive pressure breathing (IPPB) therapy with compressor nebulizer therapy in 985 ambulatory patients with chronic obstructive pulmonary disease. A bronchodilator aerosol solution was administered with both treatments, the only difference being the positive pressure applied by IPPB. Patients were randomly assigned to treatment and closely followed by monthly home and quarterly clinic visits for an average of 33 months. Compliance with treatment, lung function, and quality of life were evaluated at regular intervals during follow-up, and records were kept of hospitalizations and vital status. Treatment compliance was disappointing; only half of the patients used their devices the prescribed amount of time. There was no statistically significant difference between the treatment groups in mortality, rate and duration of hospitalizations, or change in lung function or life quality with time, overall or for clinically relevant subgroups. We saw no advantage of IPPB over compressor nebulizer therapy in this large group of patients, and conclude that, if an advantage exists, it must be marginal.

The efficacy of corticosteroid treatment in the prophylaxis of the fat embolism syndrome was evaluated in a prospective, randomized, double-blind study of high-risk patients with long-bone fractures. Using a set of objective diagnostic criteria, we saw a significant difference in the incidence of the syndrome between corticosteroid- (0 of 21) and placebo-treated patients (9 of 41) (p less than 0.05). There were no complications related to corticosteroid treatment. No routine laboratory or physical findings reliably predicted the development of the fat embolism syndrome except petechial rash, which occurred only in 5 placebo-treated patients who developed the syndrome. Complement activation was present in all patients studied who had the syndrome (5 of 27) but also in many patients who did not meet our diagnostic criteria, suggesting a multifactorial cause. These data support the prophylactic value of corticosteroid treatment in patients at high risk for the fat embolism syndrome, particularly if several unfavorable predictors are present.

Sham and real trials of peritoneal dialysis were carried out in a double-blind crossover study design to test the efficacy of peritoneal dialysis as a treatment for psoriasis. The criteria for patients included having severe plaque-type psoriasis unresponsive to all conventional therapy including methotrexate. Patients were randomly assigned to 4 weeks of sham or real dialysis, 8 weeks of observation, 4 weeks of alternative real or sham dialysis and 8 weeks of observation. Topical therapy was continued during the trial. Real dialysis was done for 48 hours weekly with 1.5-hour cycle times and 2-litre exchanges by machine. Sham peritoneal dialysis was done recycling the same 2 litres of 1.5% continuous ambulatory peritoneal dialysis fluid with 1.5-hour cycle times for 48 hours weekly. After real dialysis, two patients completely cleared, two patients had greater than 75% clearing, and one patient had no substantial response. None of the five patients had a response to the sham dialysis procedure (p less than 0.01).

From 1969 to 1975, 53 patients with lupus nephritis took part in randomized trials comparing prednisone, oral azathioprine plus low-dose prednisone, and oral cyclophosphamide plus low-dose prednisone. After a mean follow-up of 85 months, cyclophosphamide appears marginally superior to prednisone for maintaining renal function (p = 0.03) and preventing end-stage renal failure (p = 0.07). Chronic change shown by renal biopsy assessed by a chronicity index was found useful in predicting renal function outcomes and response to immunosuppressive therapy. Three of 21 patients with a low chronicity index and 9 of 10 patients with a high chronicity index doubled their serum creatinine (p less than 0.00003). The probability of renal functional deterioration was not different among the treatments studied. However, in 14 patients with an intermediate chronicity index, 1 of 11 patients treated with azathioprine or cyclophosphamide doubled the serum creatinine level whereas all 3 patients treated with prednisone have progressed to end-stage renal failure (p = 0.005). The study suggests that single-drug oral immunosuppressive treatment combined with prednisone is most beneficial in lupus patients with intermediate chronic change shown by renal biopsy.

Thirty-one patients with first episodes of genital herpes were randomized in a double-blind fashion to intravenous treatment with saline placebo or acyclovir, 5 mg/kg body weight at 8-hour intervals, for 5 days. The median duration of viral shedding from genital lesions after the onset of therapy was significantly shorter for patients given acyclovir (2 days) than for those given placebo (13 days), p less than 0.001. Viral shedding from the pharynx, cervix, urethra, and urine were also shorter in acyclovir-treated patients. (p less than or equal to 0.01 for each comparison). Local and systemic symptoms were shortened by a mean of 5 days and healing of genital lesions by a mean of 12 days in acyclovir-treated patients. (p less than 0.01). Complications during treatment, such as extragenital lesions or urinary retention requiring catheterization, developed in four patients given placebo and in none given acyclovir. (p less than 0.05). Intravenous acyclovir substantially decreases the symptoms, duration of lesions, and complications of primary genital herpes.

The clinical efficacy of clindamycin was compared with that of penicillin in a randomized study of the treatment of community-acquired putrid lung abscess. After starting therapy, patients treated with clindamycin had a shorter febrile period and fewer days of fetid sputum than patients treated with penicillin (mean 4.4 versus 7.6 days and 4.2 versus 8.0 days, respectively, p less than 0.05). Four of 20 patients treated with penicillin had clinically significant pulmonary or pleural extension of their infection within 10 days after starting therapy; this was not found in any of 19 patients treated with clindamycin (p less than 0.05). Penicillin treatment failed in two additional patients after 20 days of therapy. Within 1 month after treatment, 1 of 4 patients given penicillin for 3 weeks had relapse, but none of the 13 patients given clindamycin for 3 or 6 weeks, and none of the 5 patients given penicillin for 6 weeks had relapse. Overall, only 8 of 15 patients treated with penicillin who could be followed to the end of the study were cured, whereas all 13 patients treated with clindamycin who could be followed were cured (p less than 0.01). These results suggest that penicillin may not be optimal therapy for anaerobic lung abscess.

In a randomized placebo-controlled double-blind trial, we compared flecainide to quinidine for treatment of ventricular ectopic depolarizations in 19 patients. The mean percent suppression of total ventricular ectopic depolarizations was 95% for flecainide and 56% for quinidine (p less than 0.05). A greater than 80% reduction of total ventricular ectopic depolarizations was obtained in eight of nine patients given flecainide and in five of ten patients given quinidine (p = 0.09). After the randomized protocol, the patients who had received quinidine were given flecainide; 9 of the 10 patients had greater than 80% reduction of total ventricular ectopic depolarizations. Flecainide produced 100% suppression of nonsustained ventricular tachycardia and 99.5% suppression of paired ventricular depolarizations. Flecainide prolonged the PR and QRS intervals; quinidine prolonged the PR and JTC intervals. Side effects were commoner with quinidine than flecainide (p = 0.06). Three other patients failed to complete the protocol because of serious adverse experiences.

In an effort to prevent cytomegalovirus infection among seronegative patients having marrow transplants, a globulin with high antibody levels against cytomegalovirus was given before and for 11 weeks after transplantation in a randomized trial. Among 36 patients who received no prophylactic granulocyte transfusions, globulin recipients had significantly fewer infections than controls (2 of 17 versus 8 of 19, p = 0.05 by Fisher's exact test and p = 0.03 by Mantel-Cox test). Conversely, infection rates were high and unchanged by globulin use among patients who received granulocytes from seropositive donors (7 of 8 recipients versus 6 of 7 controls). The lack of effect of the globulin among patients receiving transfusions of granulocytes from seropositive donors may suggest that the dose of antibody was insufficient or that antibody is ineffective against virus transmitted in granulocytes. We conclude that cytomegalovirus infection can be prevented by immunoprophylaxis in seronegative patients having marrow transplants who are not given granulocyte transfusions.

From a group of 108 female patients with measurable and/or evaluable metastatic breast carcinoma, 52 were randomized to receive tamoxifen and 56 to receive tamoxifen and fluoxymesterone. The fluoxymesterone dose, given orally twice a day, was 7 mg/m2 body surface area. The tamoxifen dose per patient, also given orally twice a day, ranged from 2 to 100 mg/m2 body surface area. Eighty-five percent of the patients had received previous chemotherapy and 60% previous hormone therapy. The complete and partial remission rate was better with the tamoxifen and fluoxymesterone regimen (p = 0.016), with remission rates of 15% for tamoxifen alone and 38% for the combination. The tamoxifen and fluoxymesterone regimen appeared to have higher remission rates in all subsets of pretreatment variables. Duration of remission with each regimen was similar, but the overall time to treatment failure for tamoxifen and fluoxymesterone was longer than for tamoxifen alone (180 versus 64 days, p = 0.01). Median survival with the combination was 380 days compared to 330 days for tamoxifen. No significant dose-response relationships emerged. Side effects were not different between dose levels or regimens except for the androgen effects in the tamoxifen and fluoxymesterone combination. These results suggest that there is no major dose-response effect for doses ranging from 2 to 100 mg/m2 body surface area given twice daily in this largely (94%) postmenopausal pretreated patient group, and that the tamoxifen and fluoxymesterone regimen is superior to tamoxifen alone.

The efficacy of bicozamycin, a poorly absorbable antibiotic, in the treatment of acute diarrhea was assessed in a prospective, double-blind study of 140 adults from the United States visiting Guadalajara, Mexico. Patients randomly received bicozamycin (500 mg orally four times daily) or placebo for 3 days. The mean duration of illness was shorter in the bicozamycin than the placebo treatment groups for patients with diarrhea due to Shigella (37 versus 96 hours; p = 0.01), toxigenic Escherichia coli (31 versus 60 hours; p = 0.003), and unknown pathogens (18 versus 41 hours; p = 0.02). Cramps were significantly relieved by bicozamycin in all patients. Treatment failed in significantly fewer patients treated with bicozamycin than those treated with placebo when diarrhea was associated with Shigella, Salmonella or toxigenic E. coli. Bicozamycin was well tolerated and appears to be effective therapy for acute travelers' diarrhea of diverse causes. These data show the value of an antibiotic in the therapy of toxigenic E. coli infection and indicate a need to reevaluate the clinical dictum that nonabsorbable antibiotics are ineffective against invasive enteropathogens.

We assessed serially the bone mineral loss in 37 premenopausal women for 24 months after oophorectomy and determined the dose-response for conjugated estrogen therapy in preventing this loss. Spinal cancellous bone was measured by quantitative computed tomography and measurement of appendicular cortical bone by radial photon absorptiometry and metacarpal radiogrammetry. For the placebo and low-dose treatment groups, the mean annual bone mineral losses were 7% to 9% from the vertebral spongiosum and 1% to 3% from the peripheral cortex. The correlation between axial and appendicular loss was weak (r = 0.581), precluding a reliable estimate of spinal loss from peripheral measurements. For the maximal-dose group (0.6 mg/d), the mean annual bone mineral losses were less than 0.5% from the axial and appendicular sites, and were not significant. The results indicate that spinal quantitative computed tomography provides a highly sensitive measurement of bone mineral loss after oophorectomy, that bone mineral loss is five- to sevenfold greater from the spinal spongiosum than from the appendicular cortex, and that conjugated estrogen in doses of less than 0.6 mg/d are inadequate to prevent the vertebral mineral loss.

Patients with granulocytopenia (granulocyte count less than 0.5 x 10(9)/L) and a documented infection were randomized to receive or not to receive daily granulocyte transfusions in addition to antimicrobial therapy. Thirty-four of 47 control patients responded to therapy compared to 30 of 48 transfused patients (type 2 error, pneumonia, or a soft tissue infection, respective response rates for the control and transfused patients were 11 of 11 and 11 of 16 (Yates' corrected chi-squared test, p = 0.12). Response rates for patients with gram-negative septicemia were lower but were influenced by recovery of bone marrow function. Eleven of 12 control patients and seven of seven transfused patients with recovery of marrow function survived the gram-negative septicemia. In contrast, 12 of 24 control patients and 12 of 25 transfused patients survived gram-negative septicemia and persistent granulocytopenia (type 2 error p = 0.13). Two thirds of all fatal infections were associated with an underlying disease refractory to medical therapy. Therapeutic granulocyte transfusions had no substantial benefit over optimal antimicrobial therapy alone in managing infected patients with granulocytopenia.

Single (nafcillin for 6 weeks) and combined (nafcillin for 6 weeks plus gentamicin for 2 weeks) drug regimens were compared in two separate multicenter prospective randomized trials. Forty-eight parenteral drug addicts and 30 nonaddicts with clinically and bacteriologically documented Staphylococcus aureus endocarditis were studied. In the addicts, combined therapy effected a more rapid mean clinical response (defervescence and normalization of leukocyte count) and a reduced duration of bacteremia in patients with right-sided endocarditis. In the nonaddicts, combined therapy effected more rapid clearance of bacteremia, but was associated with a higher incidence of azotemia. The addition of gentamicin did not alter morbidity or mortality in either group.

A randomized, double-blind, vaccine/placebo trial of the Merck 20-micrograms hepatitis B virus (HBV) vaccine was done among 1402 homosexual men attending venereal disease clinics in five American cities. Vaccination was followed by only minimal side effects. Two doses of vaccine induced antibody in 80% of vaccine recipients. A booster dose 6 months after the first dose induced antibody in 85% of recipients and markedly increased the proportion of recipients who produced high antibody titers. The incidence of HBV events was markedly less in the vaccine recipients compared to that in the placebo recipients (p = 0.0004). Between month 3 and 15 after the first dose, 56 more significant HBV events (hepatitis, or hepatitis B surface antigen positive, or both) occurred in the placebo group while only 11 occurred in the vaccine group. Ten of the 11 HBV events in the vaccine recipients occurred in hypo- or nonresponders to the vaccine. This vaccine appears to be safe, immunogenic, and efficacious in preventing infection with hepatitis B virus.

The treatment of cervical Chlamydia trachomatis infection in nonpregnant women was evaluated in a double-blind randomized study. Objective criteria were used to assess the response of cervicitis to therapy. Fifty patients were treated with tetracycline hydrochloride, 500 mg orally four times daily, and 50 patients were treated with rosaramicin, 250 mg orally four times daily, both for 7 days. Both agents were highly effective in eradicating C trachomatis. Both produced significant improvement in objective signs of cervicitis: eliminating mucopurulent endocervical discharge and edema of ectopy, and decreasing the clinical severity score of cervicitis. This trial shows that the 1-week course of tetracycline hydrochloride currently recommended for treatment of chlamydial urethritis in men is also highly effective for the treatment of chlamydial cervical infection in women. Rosaramicin, a macrolide antibiotic, was equally effective but produced a higher rate of gastrointestinal side effects.