A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women.

We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.

Psychotropic drugs as behavioral teratogens.

Three psychotropic drugs were administered to pregnant rats and were then evaluated for their behavioral and reproductive effects in the offspring. Control rats received either saline or vitamin A. Prochlorperazine had the most disruptive effects on reproduction and growth, but had the least effect on behavior. Propoxyphene had no apparent effects on reproduction or growth, but produced a variety of behavioral changes. Fenfluramine was intermediate in its effects on reproduction and growth and had behavioral effects that were revealed in tests of preweaning development. The data suggest that systematic tests of behavior add important information to evaluations of reproductive toxicity that cannot, at present, be obtained by other means.

Developmental toxicity and psychotoxicity of FD and C red dye No. 40 (allura red AC) in rats.

Adult Sprague-Dawley rats were fed diets containing FD and C red dye No. 40 for 2 weeks and were then bred. The diets were continued for the females throughout gestation and lactation and were provided continuously to their offspring thereafter. The treatment groups were: FD and C red dye No. 40 as 0.0, 2.5, 5.0 or 10.0% of the diet, and a positive control group treated with the toxin hydroxyurea on days 2-10 of life with 50 mg/kg/day given s.c. as a positive control group. Parental animals were evaluated for weight and food consumption, and females for reproductive success. The offspring were assessed on a series of tests using the Cincinnati Psychoteratogenicity Screening Test Battery. Additional measures were weight, food consumption, physical landmarks of development, and brain weight. Red-40 significantly reduced reproductive success, parental and offspring weight, brain weight, survival, and female vaginal patency development. Behaviorally, R40 produced substantially decreased running wheel activity, and slightly increased postweaning open-field rearing activity. Overall, R40 produced evidence of both physical and behavioral toxicity in developing rats at doses of up to 10% of the diet.

A classification system to evaluate weight maintainers, gainers, and losers.

OBJECTIVES: To study natural weight changes and to develop a weight classification system that can identify weight maintainers, gainers, and losers. DESIGN/OUTCOME: A prospective, observational study in which weight changes over five annual measurements were evaluated. In the weight classification system used, changes greater than 5 lb defined weight maintenance, gain, or loss. SUBJECTS/SETTINGS: Subjects were healthy, normal-weight and over weight, men and women (mean age = 44.1 +/- 14.1 years) in the Relationships of Energy, Nutrition, and Obesity to Cardiovascular Disease Risk Study. Prospective data for 385 of the original 508 subjects for whom actual weights were available for each of the 5 years (1985 to 1990) were used to classify and characterize subjects by weight-change categories. STATISTICAL ANALYSES: Cross-tabulations (with chi 2 tests) and hterarchical log-linear analyses (with partial chi 2 tests) to examine the relationships of categorical variables; analyses of variance (with F tests) for continuous measures. RESULTS: Over the 4-year interval, 46% of subjects were classified as maintainers, 34% as gainers, and 20% as losers. Over shorter 1-year epochs, more subjects were maintainers (62%) and fewer subjects were gainers (22%) or losers (16%). Maintainers had fewer and smaller magnitudes of weight fluctuations and showed fewer deleterious changes in health risk factors than gainers. APPLICATIONS: Weight changes of greater than +/-5 lb can classify a person as a weight maintainer, or loser. Although annual weight changes were used in this study, a weight change of more than 5 lb between any two points in time may suggest nonmaintenance of weight or weight instability that needs further evaluation.

A controlled study of type A behavior and psychophysiologic responses to stress in anorexia nervosa.

Adolescents and young adults meeting DSM-III criteria for anorexia nervosa (n = 13) and atypical eating disorders (n = 7) were compared with weight-recovered anorectics (n = 6) and normal weight controls (n = 11) using a type-A structured interview and a computerized stress procedure. Heart rate, blood pressure, and electrocardiographic changes were monitored. Anorexia nervosa subjects demonstrated significantly more type-A characteristics than controls. The emaciated and weight-recovered anorectics had elevated hostility scores on the type-A interview, which has been shown in recent studies of type-A behavior to be a risk factor for cardiovascular disease. This pilot study is the first to demonstrate a significant relationship between anorexia and the type-A behavioral pattern. Also the anorectic subjects showed significantly more cardiovascular reactivity than controls as measured by failure of stressed anorectic subjects to lower their systolic blood pressure to baseline levels as controls did. These results support the importance of monitoring stress reactions and personality traits as well as traditional biological measures.

Paying doctors more: use of musculoskeletal specialists and increased physician pay to decrease workers' compensation costs.

Previous studies evaluating workers' compensation care systems used retrospective controls. We performed a concurrent effectiveness study comparing a WC system that used visiting musculoskeletal specialists to assist primary care physicians with a typical discounted-fee, WC, managed-care system. In the new specialist-direct system, physicians could not profit from self-referral, but were paid 35% to 69% more per patient visit than doctors in the discounted-fee clinics. All claims filed by all employees of two hotels for 2 years were examined. Patients had self-selected either a specialist-direct or a discounted-fee clinic, and the entire cost of the claim was assigned to either system of care. Claim costs were 63% lower in the specialist-direct system (P < 0.001). Medical costs were 45% less (P < 0.014), and indemnity 85% less (P < 0.001), in this system. Claims were closed nearly 6 months faster in the specialist-direct system (P < 0.0001). Indemnity claims were more common in the discounted-fee system (P < 0.0001). Claimant and injury characteristics were not significantly different between the systems. This new care model is a cost-effective alternative to discounted WC managed care. Discounting the services of the primary treating physician may result only in cost-shifting, not cost-saving.

Dietary fat consumption in a cohort of American adults, 1985-1991: covariates, secular trends, and compliance with guidelines.

PURPOSE: To examine compliance with the guideline for dietary fat (i.e., 30% of total daily colonies) and covariates of fat intake in a cohort of adults using both 24-hour recall and food frequency questionnaire (FFQ). DESIGN: Prospective, observational cohort study over 5 years. SETTING: Community-based sample in Reno, Nevada. SUBJECTS: Equal numbers of male and female, lean and overweight adults (n = 508), recruited from 1985 to 1986, of whom 348 completed all relevant surveys. MEASURES: Subjects underwent repeated anthropometric measures and completed extensive surveys on diet, weight cycling, lifestyle, and physical activity. RESULTS: Mean fat intake by 24-hour recall declined from 36.9% to 33.6% of calories between years 1 and 5 (p < .001), while calorie intake increased (p = .2). As measured by FFQ at year 2, mean fat intake was 39.1% of calories, and only 11.8% of subjects were in compliance with the guideline for dietary fat intake. Fat intake by FFQ at year 2 was statistically higher than by 24-hour recall in year 1 for lean women (p = .02) and lean men (p = .02), but not for the overweight of either gender, and was significantly higher than the year 5 24-hour recall for all categories of gender and weight (p < .001). Calorie intake, gender, and body mass index were significant in regression models that explained less than 10% of total variability in fat intake (r2 = .08; p < .01). CONCLUSIONS: Compliance with the nationally recommended level of dietary fat intake was poor in this cohort, especially as measured by FFQ. Variability in fat intake was largely unexplained by host characteristics, including education. Further study is required to corroborate secular trends in population fat intake, elucidate the determinants of such intake, and identify cost-effective strategies for reducing the consumption of dietary fat.

Developmental toxicity and psychotoxicity of potassium iodide in rats: a case for the inclusion of behaviour in toxicological assessment.

Potassium iodide (KI) was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, at levels of 0, 0.025, 0.05 or 0.1% (w/w) of the diet. Dams in a fifth group (positive controls) were given 4 mg/kg ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation. All offspring were reared by their natural dams and were evaluated blind with respect to treatment in a battery of standardized behavioural tests between 3 and 90 days of age. KI produced no significant reductions in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality at the highest dose, and decreased weight gain at the two highest doses throughout the first 90 days after birth. Functionally, KI delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels. In rats killed on day 90 after birth KI reduced brain and body weight at a dose of 0.1% of the diet, and reduced body but not brain weight at a dose of 0.05% of the diet. No significant effect was found on absolute or relative thyroid weight at 90 days of age. Several additional behavioural effects were observed in the low-dose KI group, but because these effects were not dose-dependent, they were not regarded as reliable. 5-Azacytidine produced evidence of substantially greater developmental toxicity than KI. It was concluded that KI produced evidence of developmental toxicity consistent with a picture of impaired thyroid function. The inclusion of tests of functional development added useful evidence to the overall picture of KI developmental toxicity.

Developmental toxicity and psychotoxicity of sodium nitrite in rats.

Sodium nitrite (NaNO2) was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through day 90, at levels of 0, 0.0125, 0.025 or 0.05% (w/w) of the diet. Dams in a fifth group (positive controls) were given 4 mg/kg ip of the anti-mitotic/embryotoxic drug 5-azacytidine on day 16 of gestation. All offspring were reared by their natural dams and were evaluated blind with respect to treatment in a battery of standardized behavioural tests between 3 and 90 days of age. NaNO2 produced no significant reductions in parental body weight or food consumption, though it significantly increased offspring mortality and decreased weight gain at the two highest doses during the preweaning period. Functionally, NaNO2 delayed swimming development and decreased open-field activity. The open-field effect was not linearly dose dependent. In rats killed on day 90 after birth, NaNO2 produced no effects on brain or body weights. 5-Azacytidine produced evidence of substantially greater developmental toxicity than did NaNO2. NaNO2 produced a moderate degree of developmental toxicity, but no evidence was found to suggest that the central nervous system was the target organ for the toxic effects. The inclusion of tests of functional development added useful confirmatory evidence to the overall picture of NaNO2 toxicity.

Evaluation of the impact and acceptance of a nutrition program in an HIV community clinic.

The present paper describes the evaluation of a nutrition service and research model for human immunodeficiency virus (HIV)-positive clients within a community based HIV acquired immune deficiency syndrome (AIDS) medical clinic. This program was designed to develop an effective, practical, replicable model for the delivery of nutrition services in the ambulatory HIV care setting. The objectives of evaluating the model were to define the ways that nutrition services in HIV/AIDS impacted clients, the clinic, and referral sources, and to continually refine the model by determining what services provide greatest benefit to clients, especially in view of the changing landscape of HIV therapy. Four evaluation activities completed during the study period of 5 years are described. These included a focus group and semistructured interview with clients, a semistructured interview with workers from the local network of service referral agencies and a client satisfaction survey at study "close-out." These evaluation processes confirmed or prompted programmatic modifications that improved access, confidentiality, and the relevance of specific components for clients. Providers/stakeholder's concerns were addressed through more frequent communication about clients' specific nutrition issues, clearer and easier referral and cooperation in recruiting patients. Also, the evaluation activities provided a platform for the communication of general and specific information about the program and for outreach. Although clients' and workers' priorities differed in some details of program implementation, there was strong agreement on the value of addressing nutrition concerns in HIV. Favorable feedback about the program gave impetus to continue nutrition services in the clinic after the project period ended and supports its application in other sites and settings.

D2 dopamine receptor gene and cigarette smoking: a reward gene?

There is now growing evidence that the less prevalent allele (A1) of the D2 dopamine receptor (DRD2) gene is strongly associated with severe alcoholism. Similarly, subjects who abuse illegal drugs or who are obese also show a significantly higher prevalence of the A1 DRD2 allele compared to controls. Moreover, cigarette smokers, both past and current, demonstrate significantly higher prevalence of the A1 allele than nonsmokers. In as much as alcohol, cocaine, opiates, nicotine and food are known to increase brain dopamine levels and activate the mesocorticolimbic dopaminergic reward pathways of the brain, it is hypothesized that an inherited deficit of D2 dopamine receptor numbers in brain reward areas of A1 allelic subject predisposes them to substance abuse problems.

Phenylketonuria and complex spatial visualization: an analysis of information processing.

Recent neuropsychological studies have suggested that patients with early-treated phenylketonuria (PKU) and normal intelligence have a specific deficiency in solving complex spatial problems. In the present study a task involving the assembly of various shapes was used to compare the performance of 16 PKU patients and 11 sibling controls. Error rates generally were higher and response times slower among the PKU patients, but greater complexity did not produce differential changes in accuracy or speed in the PKU group compared to the controls. Correlations between task performance and IQ measures were significant for the PKU patients, but when IQ was controlled for the group differences vanished. The results suggest that choice of problem-solving strategy, attention span and accuracy of mental representation may be affected in PKU patients, despite efforts to maintain well-controlled phenylalanine concentrations in the blood.

Recognizing acetabular version in the radiographic presentation of hip dysplasia.

Attention to the radiographic shadow of the walls of the acetabulum seen on the anteroposterior projection of a well-centered radiograph of the pelvis is important to identify the orientation of the opening of the acetabulum. This is referred to as the acetabular version. The opening of the mouth of the acetabulum may be oriented anteriorly, which is referred to as anteverted; posteriorly, or retroverted; or when the shadow of the lips of the anterior and posterior walls terminate together on the lateral edge of the acetabular rim, neutral version. The radiographs of 153 patients with developmental hip dysplasia presenting with hip pain were reviewed to determine the frequency of retroversion of the acetabulum. In this group of patients, retroversion of the hip socket was surprisingly common, one in three hip sockets, and generally was associated with smaller values of the lateral center edge measurement. The observation is important, because it must be taken into account when planning a corrective osteotomy of the acetabulum so the abnormal horizontal orientation of socket is corrected along with the usual anterior and lateral insufficiency.