Doug Hayden

Effects of Testosterone and Progressive Resistance Training in Eugonadal Men with AIDS Wasting: A Randomized, Controlled Trial

Substantial loss of lean body and muscle mass occur among HIV-infected patients with relatively preserved body weight (1); these changes are associated with reduced functional status and strength (2). Protease inhibitor therapy has not been shown to increase muscle mass in patients with AIDS wasting (3), suggesting the need for successful anabolic strategies in these patients. Testosterone therapy and progressive resistance training increase lean body mass in hypogonadal men with AIDS wasting (4-6). However, most men with AIDS wasting have normal testosterone levels (7). We assessed the independent effects of progressive resistance training and testosterone in eugonadal men with AIDS wasting. Baseline (2) and screening data (7) from a subset of participants were previously reported. Methods Patients From 1997 to 1999, 54 HIV-infected men with AIDS-related wasting (weight<90% ideal body weight or self-reported weight loss>10%) and a normal serum level of free testosterone (>42 pmol/L) were recruited through community advertisements and contact with physicians in the multidisciplinary HIV practice at the Massachusetts General Hospital, Boston, Massachusetts, and other community clinics. Exclusion criteria were new opportunistic infection diagnosed within 6 weeks of the study; other contraindication to exercise; use of a new antiretroviral agent within 8 weeks of the study; abnormal prostate-specific antigen level; symptomatic prostatism; prostate malignancy; bipolar disorder; use of parenteral nutrition, megestrol acetate, glucocorticoids, androgen, estrogen, growth hormone or other anabolic agent within 3 months of the study; hemoglobin value less than 90 g/L or greater than 170 g/L; platelet count less than 50 000 cells/mm3; or serum creatinine concentration greater than 177 mol/L (2.0 mg/dL). All patients gave written consent, and the study was approved by the Human Studies Committee of the Massachusetts General Hospital. Protocol Eligible patients were stratified for weight less than 90% of ideal body weight or 90% or greater than ideal body weight. Using a 2 2 factorial design, we randomly assigned patients to receive intramuscular injections of testosterone enanthate (200 mg/wk; Bio-Technology General Corp., Iselin, New Jersey) or placebo and to progressive resistance training (three times per week) or no training for 12 weeks. The study statistician used a permuted-block algorithm with blocks of 8 to perform randomization; the code was available only to the hospital pharmacy that bottled the study drug. Placebo contained sesame oil with chlorobutanol as a preservative and matched testosterone enanthate in color and consistency. Compliance with drug therapy was confirmed by history, outpatient injection records, and vial counts. Patients assigned to training participated in supervised progressive strength training and aerobic conditioning three times per week for 12 weeks. During each session, patients began by performing 20 minutes of aerobic exercise on a stationary bicycle at a target heart rate of 60% to 70% of their age-predicted maximum, in accordance with American College of Sports Medicine recommendations (8). A cool-down period of 15 minutes and normalization of heart rate preceded resistance training. Training was performed isotonically on the following computerized equipment (Life Fitness, Franklin Park, Illinois): leg extension, leg curl, leg press, latissimus dorsi pull-down, arm curl, and triceps extension. A one-repetition maximum weight was established at baseline for each patient on each machine in the best of three efforts. Patients increased resistance as follows: weeks 1 and 2, 2 sets, 8 repetitions/set, 60% one-repetition maximum; weeks 3 through 6, 2 sets, 8 repetitions/set, 70% one-repetition maximum; weeks 7 through 12, 3 sets, 8 repetitions/set, 80% one-repetition maximum. Patients were asked to refrain from exercise for 2 weeks before the baseline visit and to refrain from any exercise or activity beyond normal daily activity during the study. Food intake was ad libitum; caloric intake was determined by using a 4-day food record (Nutrition Data System for Research, version 12A/2.91, Nutrition Coordinating Center, University of Minnesota, Minneapolis, Minnesota). Resting and predicted energy expenditure were calculated (VMAX 29N, SensorMedics, Inc., Loma Linda, California). Clinical End Points Clinical end points were assessed at baseline and 12 weeks. Lean body mass and fat mass were measured by using dual-energy x-ray absorptiometry (QDR-4500 Densitometer, Hologic, Inc., Waltham, Massachusetts) with a precision error of 1.5% for fat-free mass (9). Cross-sectional muscle areas of the leg and arm were assessed by performing computed tomography of the midfemur and humerus (General Electric High Speed Helical CAT Scanner, Milwaukee, Wisconsin; SE 3% for arm muscle area and 1% for leg muscle area). The location of the midfemur and humerus were determined from the scout image. Upper- and lower-extremity muscle strength were measured by using the quantitative muscle function test (10, 11). Peak isometric force of shoulder flexion, shoulder extension, elbow flexion, elbow extension, knee flexion, knee extension, dorsiflexion, and grip were measured on the best of two repetitions (10, 12). Z scores were calculated for upper- and lower-extremity strength (MVCT Computer Analysis Software, Boston, Massachusetts) by standardizing to a group of healthy male controls (11, 12). Serum levels of total and free testosterone were measured by using a radioimmunoassay kit (Diagnostics Products Corp., Los Angeles, California) (4). CD4 cell counts were measured by using flow cytometry (Becton-Dickinson Immunocytochemistry Systems, San Jose, California); viral load was measured by using the Amplicor HIV-1 Monitor (Roche Molecular Systems, Branchburg, New Jersey). Other tests were done according to published methods (13). A digital prostate examination was performed at each visit. Statistical Analysis The effects of training and testosterone were simultaneously assessed in the same factorial model. In the primary analysis, we used analysis of covariance to assess change from baseline at 3 months simultaneously in the testosterone arm (testosterone recipients vs. placebo recipients) and the training arm (trained patients vs. nontrained patients), controlling for baseline values. To test for an interaction between testosterone and training, we used analysis of covariance with an interaction term. Change in lean body mass was the primary clinical end point for the effect of testosterone, and change in cross-sectional muscle area was the primary end point for the effect of resistance training. Change from baseline was also determined within each individual treatment group and was compared with zero change by using analysis of covariance. The t- test was used to compare treatment groups at baseline. All available data are included in the analysis. Results are reported as the mean SD. Results No patient withdrew from the study because of an adverse event or side effect; dropout rates did not differ by group (Appendix Figure). Patients had lost significant weight but were not severely ill or low weight at study entry (Table 1). Seventy-six percent of patients were receiving antiretroviral therapy and 72% were receiving highly active antiretroviral therapy. Seventy-six percent of patients had previously had an opportunistic infection. Appendix Figure. Flow of participants through the study. Table 1. Results of Factorial Analysis Changes in response to testosterone therapy and training are shown in Table 1. Lean body mass and muscle area increased significantly in response to training and testosterone therapy. Muscle strength on elbow flexion and shoulder extension and overall upper-extremity Z score increased in response to testosterone therapy. The change in muscle area correlated with the change in muscle strength (R =0.48; P =0.001 for mid-thigh muscle area and strength on knee extension). No interaction was found between testosterone therapy and training. Levels of high-density lipoprotein (HDL) cholesterol increased in response to training but decreased in response to testosterone therapy. Levels of total and free testosterone increased in response to testosterone therapy, and levels of gonadotropin and sex hormonebinding globulin decreased. Caloric intake did not change significantly between the groups. The CD4 count did not change significantly in response to training or testosterone therapy (P >0.2). Viral load decreased in testosterone-treated patients. Use of antiretroviral therapy did not change in any study group. Levels of aspartate aminotransferase or prostate-specific antigen did not change significantly (P >0.2). No patient developed new prostate nodules. Three patients developed breast tenderness or gynecomastia (two were receiving testosterone and one was receiving placebo). Compliance with the training program was 78% among patients who completed the study; compliance with testosterone therapy was 98%. Discussion Previous studies suggest that testosterone therapy, alone (4, 5) and in combination with resistance training, increases lean body mass in hypogonadal men with AIDS wasting (6). However, recent data indicate that androgen levels are normal in most HIV-infected men (7), and the independent effects of testosterone and supervised exercise in eugonadal men with AIDS wasting are not known. The patients in our study generally had normal body weight and a normal Karnofsky score but had lost substantial weight. Most patients had a history of opportunistic infection, and although they were not cachectic or malnourished, they had reduced muscle mass (2). Previous studies have shown that resistance training in combination with testosterone or anabolic steroid therapy increases lean body mass (6, 14, 15). In contrast, we found that training had a significant effect (increase of 2.3 kg) on lean bod

Clinical and Cost Outcomes of Medical Nutrition Therapy for Hypercholesterolemia: A Controlled Trial

OBJECTIVE To compare the results and cost-effectiveness of a cholesterol lowering protocol implemented by registered dietitians with cholesterol lowering advice by physicians. DESIGN Six month randomized controlled trial, cost-effectiveness analysis. Subjects included 90 ambulatory care patients (60 men, 30 women), age range 21 to 65 years, with hypercholesterolemia and not taking hypolipidemic drugs. Patients were randomly assigned to receive medical nutrition therapy (MNT) from dietitians using a NCEP based lowering protocol or usual care (UC) from physicians. Outcome measures were plasma lipid profiles, dietary intake, weight, activity, patient satisfaction, and costs of MNT. Changes from baseline for each variable of interest were compared between treatment groups using analysis of covariance controlling for baseline value of the variable and gender. RESULTS MNT achieved a 6% decrease in total and LDL cholesterol levels at 3 and 6 months compared with a 1% increase and a 2% decrease in both values at 3 and 6 months with UC (P<.001 and P<.05, respectively). Weight loss (1.9 vs 0 kg, P<.001) and dietary intake of saturated fat (7% of energy vs 10%, P<.001) were better in the MNT than the UC group. The additional costs of MNT were

A double‐blind, placebo‐controlled trial of sibutramine for clozapine‐associated weight gain

217 per patient to achieve a 6% reduction in cholesterol and

Metabolic effects of adjunctive aripiprazole in clozapine-treated patients with schizophrenia.

98 per patient to sustain the reduction. The cost-effectiveness ratio for MNT was

Validation of the riboleukogram to detect ventilator-associated pneumonia after severe injury.

36 per 1% decrease in cholesterol and LDL level. APPLICATIONS/CONCLUSIONS MNT from registered dietitians is a reasonable investment of resources because it results in significantly better lipid, diet, activity, weight, and patient satisfaction outcomes than UC.

Medical nutrition therapy for hypercholesterolemia positively affects patient satisfaction and quality of life outcomes

Objective:  This study sought to examine the effectiveness of sibutramine, a weight loss agent, on clozapine‐associated weight gain.

Building primary care practitioners' attitudes and confidence in mental health skills in a post-conflict society: a Cambodian example.

Fan X, Borba CPC, Copeland P, Hayden D, Freudenreich O, Goff DC, Henderson DC. Metabolic effects of adjunctive aripiprazole in clozapine‐treated patients with schizophrenia.

Cost-effectiveness of Medical Nutrition Therapy in the Treatment of Hypercholesterolemia.

Objective:We hypothesized that circulating leukocyte RNA profiles or “riboleukograms” detect ventilator-associated pneumonia after blunt trauma. Summary Background Data:A pilot microarray study of 11 ventilator-associated pneumonia (VAP) patients suggested that 85 leukocyte genes can be used to diagnose VAP. Validation of this gene set to detect VAP was tested using data from an independent patient cohort. Methods:A total of 158 intubated blunt trauma patients were enrolled at 5 centers, where 57 (36%) developed VAP. Patient age was 34.2 ± 11.1 years; 65% were male. Circulating leukocyte GeneChip U133 2.0 expression values were measured at time 0.5, 1, 4, 7, 14, 21, and 28 days after injury. DChip normalized leukocyte transcriptional profiles were analyzed using repeated measures logistic regression. A compound covariate model based on leukocyte gene transcriptional profiles in a training subset of patients was tested to determine predictive accuracy for VAP 4 days prior to clinical diagnosis in the test subset. Results:Using gene expression values measured on each study day at an FDR <0.05, 27 (32%) of the 85 genes were associated with the diagnosis of VAP 1 to 4 days before diagnosis. However, the compound covariate model based on these 85-genes did not predict VAP in the test cohort better than chance (P = 0.27). In contrast, a compound covariate model based upon de novo transcriptional analysis of the 158 patients predicted VAP better than chance 4 days before diagnosis with a sensitivity of 57% and a specificity of 69%. Conclusion:Our results validate those described in a pilot study, confirming that riboleukograms are associated with the development of VAP days prior to clinical diagnosis. Similarly, a riboleukogram predictive model tested on a larger cohort of 158 patients was better than chance at predicting VAP days prior to clinical diagnosis.

Clozapine, Diabetes Mellitus, Weight Gain, and Lipid Abnormalities: A Five-Year Naturalistic Study

Following a heart-healthy diet to lower cholesterol levels is often assumed to be difficult, to be burdensome, and to have a negative impact on quality of life (QOL). The purpose of this study was to evaluate the impact of medical nutrition therapy (MNT) versus usual care (UC) for hypercholesterolemia on patient satisfaction and QOL. Ninety ambulatory care patients (6 men and 30 women), age 28 to 66, were randomly assigned to receive either MNT from dietitians using a National Cholesterol Education Program-based protocol or UC from their physicians. Patients who received MNT reported no difference in QOL related to the taste or enjoyment of food compared with UC patients. However, the MNT group reported initial improvements in QOL related to the convenience and cost of following a low-fat diet when compared with the UC group. The MNT group also reported significant and lasting improvements in perceived QOL related to self-care compared with the UC group. MNT patients were more satisfied with the interaction at visits, knowledge and ability to manage their cholesterol, eating habits, appearance, time spent exercising, and life in general. Moreover, MNT patients did not report any negative impact related to following a low-fat diet in regard to feeling restricted by diet; interference with lifestyle activities; or difficulty planning, purchasing, or preparing meals or eating away from home. Contrary to popular belief, there is no apparent reduction but rather an improvement in some measures of QOL and patient satisfaction with MNT for hypercholesterolemia.

A Placebo-Controlled Trial of D-Cycloserine Added to Conventional Neuroleptics in Patients With Schizophrenia

Our program attempted to integrate community mental health in primary care settings in Cambodia and to evaluate the effects of training on local providers. The training program underwent an extensive evaluation to determine its impact on the mental health knowledge, confidence in performing medical and psychiatric procedures, skills and attitudes of its trainees. One hundred four Cambodian primary care practitioners (PCPs) were trained in a primary care setting in Siem Reap, Cambodia, over a 2-year period. There was a significant improvement in PCPs’ confidence in all clusters of medical and psychiatric procedures (counseling, medical evaluation, prescribing medications, psychiatric diagnosis, assessing risk for violence, traditional treatments, and treating trauma victims) comparing baseline to posttraining and baseline to 2-year follow-up (p < 0.05). Only confidence in prescribing psychotropic medications improved from posttraining to 2-year follow-up. This study supports the feasibility of training PCPs in a culturally effective manner in a postconflict society.