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Objective: To develop criteria for interpreting results of the metyrapone test for the differential diagnosis of the adrenocorticotropin (ACTH)-dependent Cushing syndrome and to compare its diagnostic accuracy with that of the high-dose dexamethasone suppression test.Design: Retrospective cohort study.Setting: Inpatient research ward.Patients: 186 patients believed to have the ACTH-dependent Cushing syndrome who had the metyrapone test, the dexamethasone test, and a surgical procedure to remove the source of excessive ACTH.Measurements: The sensitivity, specificity, and diagnostic accuracy were determined for the metyrapone test using urine excretion of hydroxysteroid and plasma levels of 11-deoxycortisol. For the dexamethasone suppression test, urine excretions of 17-hydroxysteroid (17-OHS) and free cortisol were used.Main Results: 156 patients had pituitary disease, 15 had ectopic ACTH secretion, and 15 had no diagnosis after pituitary surgery. Of those 15 patients, 14 were ultimately classified as having pituitary disease on the basis of follow-up, and 1 was found to have ACTH-independent Cushing syndrome. After administration of metyrapone, stimulation of 17-OHS excretion greater than 70% or of a plasma 11-deoxycortisol level greater than 400-fold did not result in the misclassification of any of the patients with surgically confirmed cases of ectopic ACTH secretion. When these criteria were combined, the percentage of correct predictions (122 of 186 [71%; 95% CI, 62% to 79%]) was higher than that for either steroid alone (116 of 186 [62%; CI, 52% to 71%]) for excretion of 17-OHS and that for plasma 11-deoxycortisol (82 of 186 [44%; CI, 34% to 54%]). When the criteria for both the metyrapone test and the dexamethasone test were combined, the percentage of correct predictions (153 of 186 [82%; CI, 75% to 87%]) was higher than that obtained when the criteria for either test alone were used (P = 0.001). Similar results were found when the 15 patients with indeterminate surgery were assigned to the appropriate group on the basis of follow-up. When the criteria for both the metyrapone and dexamethasone tests were combined to identify patients with the pituitary Cushing syndrome, the sensitivity and diagnostic accuracy improved to 88% and 89%, respectively.Conclusions: The metyrapone test, which can be done in 48 hours, has a sensitivity and specificity for the diagnosis of the Cushing syndrome identical to that of the standard 6-day high-dose dexamethasone suppression test. Combining both tests results in greater accuracy than that obtained with either test alone. [ABSTRACT FROM AUTHOR]

Discusses advances in obesity research. How more than 50 percent of United States adults are overweight; Reasons for obesity, including genetic factors; Role of leptin in weight gain and loss; Importance of a healthy diet and exercise; Need for more research to learn how to treat obesity successfully.

Background: It is commonly asserted that the average American gains 5 lb (2.3 kg) or more over the holiday period between Thanksgiving and New Year's Day, yet few data support this statement.Methods: To estimate actual holiday-related weight variation, we measured body weight in a convenience sample of 195 adults. The subjects were weighed four times at intervals of six to eight weeks, so that weight change was determined for three periods: preholiday (from late September or early October to mid-November), holiday (from mid-November to early or mid-January), and postholiday (from early or mid-January to late February or early March). A final measurement of body weight was obtained in 165 subjects the following September or October. Data on other vital signs and self-reported health measures were obtained from the patients in order to mask the main outcome of interest.Results: The mean (+/-SD) weight increased significantly during the holiday period (gain, 0.37+/-1.52 kg; P<0.001), but not during the preholiday period (gain, 0.18+/-1.49 kg; P=0.09) or the postholiday period (loss, 0.07+/-1.14 kg; P=0.36). As compared with their weight in late September or early October, the study subjects had an average net weight gain of 0.48+/-2.22 kg in late February or March (P=0.003). Between February or March and the next September or early October, there was no significant additional change in weight (gain, 0.21 kg+/-2.3 kg; P=0.13) for the 165 participants who returned for follow-up.Conclusions: The average holiday weight gain is less than commonly asserted. Since this gain is not reversed during the spring or summer months, the net 0.48-kg weight gain in the fall and winter probably contributes to the increase in body weight that frequently occurs during adulthood. [ABSTRACT FROM AUTHOR]

Background: Although the medical determinants of mortality in patients with end-stage renal disease (ESRD) treated with hemodialysis (HD) are well appreciated, the contribution of immunologic parameters to survival in such patients is unclear, especially when variations in age, medical comorbidity and nutrition are controlled. In addition, although dysregulation of cytokine metabolism has been appreciated in patients with ESRD, the association of these parameters with outcomes has not been established. Recently, the type of dialyzer used in patients' treatment has been associated with survival, but the mechanisms underlying these findings, including their immune effects, have not been established. We conducted a prospective, cross-sectional, observational multicenter study of urban HD patients to determine the contribution of immunological factors to patient survival. We hypothesized increased proinflammatory cytokines would be associated with increased mortality, and that improved immune function would be associated with survival.Methods: Patients were assessed using demographic and anthropometric indices, Kt/V, protein catabolic rate (PCR) and immunologic variables including circulating cytokine [interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-12, IL-13 and tumor necrosis factor (TNF)-alpha] levels, total hemolytic complement activity (CH50), and T cell number and function. A severity index, previously demonstrated to be a mortality marker, was used to grade medical comorbidity. A Cox proportional hazards model, controlling for patients' age, severity index, level of serum albumin concentration, dialyzer type and dialysis site was used to asses relative survival risk.Results: Two hundred and thirty patients entered the study. The mean (+/- SD) age of the population was 54.4 +/- 14.2 years, mean serum albumin concentration was 3.86 +/- 0.47 g/dl, mean PCR was 1.1 +/- 0.28 g/kg/day, and mean Kt/V 1.2 +/- 0.3. Patients' serum albumin concentration was correlated with levels of Kt/V and PCR, and their circulating IL-13 and TNF-alpha levels, but negatively with their circulating IL-2 levels, T-cell number and T-cell antigen recall function. T-cell antigen recall function correlated negatively with PCR, but not Kt/V. There was no correlation of any other immune parameter and medical or demographic factor. Immune parameters, were all highly intercorrelated. Mean level of circulating cytokines in HD patients were in all cases greater than those of a normal control group. There were few differences in medical risk factors or immune parameters between patients treated with different types of dialyzers. After an almost three-year mean follow-up period, increased IL-1, TNF-alpha, IL-6, and IL-13 levels were significantly associated with increased relative mortality risk, while higher levels of IL-2, IL-4, IL-5, IL-12, T-cell number and function, and CH50 were associated with improved survival. The difference in survival between patients treated with unmodified cellulose dialyzers and modified or synthetic dialyzers approached the level of statistical significance, but there were no differences in levels of circulating cytokines between these two groups.Conclusions: Higher levels of circulating proinflammatory cytokines are associated with mortality, while immune parameters reflecting improved T-cell function are associated with survival in ESRD patients treated with HD, independent of other medical risk factors. These factors may serve as markers for outcome. The mechanism underlying the relationship of immune function and survival, and the effect of interventions to normalize immune function in HD patients should be studied. [ABSTRACT FROM AUTHOR]

Aim: Maximal oxygen uptake (VO(2max)), the gold standard for measurement of cardiorespiratory fitness, is frequently difficult to assess in overweight individuals due to physical limitations. Reactance and resistance measures obtained from bioelectrical impedance analysis (BIA) have been suggested as easily obtainable predictors of cardiorespiratory fitness, but the accuracy with which ht(2)/Z can predict VO(2max) has not previously been examined in overweight adolescents., Methods: The impedance index was used as a predictor of VO(2max) in 87 overweight girls and 47 overweight boys ages 12 to 17 with mean BMI of 38.6 + or - 7.3 and 42.5 + or - 8.2 in girls and boys respectively. The Bland Altman procedure assessed agreement between predicted and actual VO(2max)., Results: Predicted VO(2max) was significantly correlated with measured VO(2max) (r(2)=0.48, P<0.0001). Using the Bland Altman procedure, there was significant magnitude bias (r(2)=0.10; P<0.002). The limits of agreement for predicted relative to actual VO(2max) were -589 to 574 mL O(2)/min., Conclusions: The impedance index was highly correlated with VO(2max) in overweight adolescents. However, using BIA data to predict maximal oxygen uptake over-predicted VO(2max) at low levels of oxygen consumption and under-predicted VO(2max) at high levels of oxygen consumption. This magnitude bias, along with the large limits of agreement of BIA-derived predicted VO(2max), limit its usefulness in the clinical setting for overweight adolescents.

Background and Purpose: Little is known about the methods used to assess the physical fitness of adolescents who are overweight. We investigated the relationship between walk/run performance and cardiorespiratory fitness in adolescents who are overweight., Subjects: Eight African-American adolescents (5 female, 3 male) and 10 Caucasian adolescents (5 female, 5 male) who were overweight (mean age=14.5 years, SD=2.0, range=12-17; mean body mass index [BMI]=42.9 kg/m2, SD=11.5) participated in this study., Methods: Subjects performed a 12-minute walk/run test. The distances traveled at both 9 minutes (D9) and 12 minutes (D12) were recorded, and the distance traveled between 9 and 12 minutes (D9-12) was calculated. Subjects also completed a maximal cycle ergometry test, during which peak oxygen uptake (VO2peak), anaerobic threshold (AT), peak power (Wpeak), and power at the anaerobic threshold (WAT) were determined. Body composition was determined by air displacement plethysmography., Results: The mean percentage of body fat was 48.6% (SD=5.3%, range=40.3%-60.4%). Percentage of body fat and BMI were each inversely related to D9, D12, and VO2peak (all P<.005). Peak oxygen uptake (r=.72, P=.0001), VO2peak/kg lean body mass (r=.60, P<.005), Wpeak (r=.88, P<.0001), and WAT (r=.72, P=.0007) were all related to D12, with greater r values than for D9. If D9-12was included in regression analyses, D9 did not account for additional variance in any of the cycle ergometry variables., Discussion and Conclusion: These results suggest that an easily obtained measurement of physical performance (distance traveled during a 12-minute walk/run test) is related to cardiorespiratory fitness and to body composition in adolescents who are overweight. The 12-minute walk/run distance is more predictive of cycle ergometry test results than the 9-minute distance.

Objective: African American children have earlier pubertal and skeletal maturation and a higher body mass index (BMI) than Caucasian children. We tested the hypothesis that advanced bone age in African American children is accounted for by their greater adiposity., Study Design: We studied 252 African American (n = 97) and Caucasian (n = 155) children aged 5 to 12 years. Skeletal age was determined by a radiologist blinded to clinical details. The difference between bone age (BA) and chronological age (CA) (noted as BA - CA) and the ratio of bone age to chronological age (BA/CA) were determined. Analysis of covariance was used to adjust skeletal maturation for the effects of adiposity, as measured by BMI, BMI standard deviation score (BMI SDS), and fat mass by dual energy x-ray absorptiometry (DXA)., Results: African American children were significantly heavier than Caucasians (BMI SDS 2.7 +/- 3.4 vs 1.7 +/- 2.4, P <.05). Both BA - CA (0.75 +/- 1.46 vs 0.28 +/- 1.38, P <.05) and BA/CA (1.09 +/- 0.17 vs 1.03 +/- 0.16, P <.05) were significantly greater in African Americans than Caucasians. BA - CA and BA/CA were significantly correlated with lean body mass, BMI, BMI SDS, and DXA fat mass (all r > 0.46, P <.001). Neither BA - CA nor BA/CA of African Americans and Caucasians were significantly different after correction for lean body mass and measures of adiposity, including BMI, BMI SDS, or DXA fat mass., Conclusion: Skeletal age is more advanced in African American than Caucasian children and is significantly related to body mass. In large measure, the advancement in skeletal maturation of prepubertal and early pubertal African American children can be accounted for by their greater adiposity.

Background: Large-volume lipoplasty changes body composition during a single surgical intervention by selectively decreasing subcutaneous adipose tissue. Positive health benefits, previously reported for a cohort of 14 women at 4 months after surgery, include significant decreases in weight, systolic blood pressure, and fasting insulin levels., Objective: In the present study, we sought to determine whether the benefits of altering body composition by large-volume liposuction observed at 4 months are sustained over longer periods of time., Methods: Subjects were seen for an additional follow-up visit approximately 1 year (range 10 to 21 months) after surgery. Fasting insulin levels were measured in the 8 patients who had preoperative fasting insulin levels higher than 12 muU/mL. Weight, systolic and diastolic blood pressure, heart rate, and body circumferences were measured in all 14 subjects., Results: Compared with data obtained before surgery and 4 months after surgery, results at 10 to 21 months after lipoplasty showed that the improvements in body weight, systolic blood pressure, and fasting insulin levels observed 4 months after the procedure had been maintained., Conclusions: Should these results be confirmed in larger studies, lipoplasty may prove to be a valuable tool for reducing some of the co-morbid conditions associated with obesity. (Aesthetic Surg J 2001;21:527-531.).

Pediatric obesity can be defined as BMI > 95th percentile for age and sex from large surveys that were carried out in the past. Using these cut points, over 10% of all children and adolescents are obese, and another 10% are overweight (BMI > 85th percentile). Obesity in childhood is associated with many immediate consequences, including orthopedic, neurologic, pulmonary, gastroenterologic, endocrinologic, metabolic, and cardiovascular disorders. Psychosocial and economic problems also are seen in obese adolescents. Long-term consequences of pediatric obesity include risks for cardiovascular disease and death that are independent of adult body weight. The differential diagnosis of pediatric obesity includes many multi-system genetic syndromes and a limited number of endocrine disorders that include abnormalities in the leptin signaling pathway, but most children with excess body weight do not have an established diagnosis. Treatment is best carried out at specialized centers, and usually involves a program of behavioral modification, caloric restriction, increased activity, and decreased sedentary behaviors. Medication for pediatric obesity cannot be recommended at present outside the context of clinical trials. Gastric bypass surgery is effective, but should be considered a last resort for the child with life-threatening complications of obesity.

The purpose of this study was to determine the ability of air displacement plethysmography (ADP) to estimate body fatness in prepubertal and early pubertal African American and white children. One hundred nineteen nonoverweight and overweight boys (N = 56) and girls (N = 63), age (mean +/- SD) 9.8 +/- 1.7 y, body mass index 25.9 +/- 7.6 kg/m2 (range, 14.2-47.0 kg/m2), and mean percent body fat (%BF) by dual-energy x-ray absorptiometry (DXA) 39.2 +/- 11.7% (range, 12.2-57.5%), were studied. %BF by ADP was compared with DXA %BF estimates and with body fat by several field methods: skinfold thicknesses using the Slaughter et al. equations (Hum Biol 60: 709-723, 1988), bioelectrical impedance analysis (BIA) using the Houtkooper et al. equation (J Appl Physiol 72: 366-373, 1992), and a predictive equation using skinfold thicknesses, BIA, and weight (Goran et al.: Am J Clin Nutr 63: 299-305, 1996). All methods used to estimate %BF were significantly correlated with DXA (all p < 0.0001), with r2 ranging from 0.85 (skinfold measurements) to 0.95 (ADP). ADP using the Siri equation underestimated %BF by -1.9% (p < 0.001); the Bland-Altman limits of agreement (defined as +/-2 SD) were +/-7.4%. %BF by ADP-Siri underestimated %BF by DXA by 3.0% for girls (p < 0.001) and by 0.6% for boys (NS). Agreement between body fat estimation by ADP and DXA did not vary with age, race, or pubertal stage. Application of the age-adjusted Lohman model to ADP significantly increased the magnitude of the underestimation to -6.9% (p < 0.0001). Prediction of %BF by the Slaughter skinfold thickness equation showed no significant mean bias for the overall data, but significantly underestimated %BF in girls (-3.7%) while overestimating %BF in boys (+2.4%) with wide limits of agreement (+/-17.7%, p < 0.01 versus ADP). %BF by the Houtkooper BIA equation or Goran model underestimated %BF to a significantly greater degree than ADP (Houtkooper, -8.1%; Goran, -10.1%; both p < 0.0001 versus DXA or ADP). Determination of %BF from ADP using the Siri model slightly underestimates %BF as determined by DXA in girls, but appears to be superior to existing field methods both in accuracy and limits of agreement. Because of the ease with which it can be performed, ADP may prove useful for investigations of adiposity in children.

The intensive therapies that have been used to treat pediatric and adolescent obesity include very-low-calorie diets, pharmacotherapy, and bariatric surgery. None of these approaches have been reported in sufficient numbers of subjects who have taken part in well-designed experiments with long-term follow-up to demonstrate convincingly their true value for the treatment of pediatric obesity. As the potency of the therapy increases, so does its possible adverse consequences. Of the intensive approaches, only bariatric surgery can be said to have even small studies supporting its ability to induce long-lasting (> 1 year) effects on body weight in severely obese adolescents. The risks and benefits of intensive weight-management therapies should be weighed carefully before they are used with pediatric-aged patients. Until further controlled trials become available, intensive therapies for pediatric obesity should be considered only for children who have not responded to conventional weight-management programs but have significant complications of their obesity. Intensive approaches generally should be restricted to specialized centers that have experience with those treatments and should be carried out in the context of a comprehensive weight-management program.

In this study, the authors investigated the physiologic effects of the altered body composition that results from surgical removal of large amounts of subcutaneous adipose tissue. Fourteen women with body mass indexes of greater than > 27 kg/m2 underwent measurements of fasting plasma insulin, triglycerides, cholesterol, body composition by dual-energy x-ray absorptiometry (DXA), resting energy expenditure, and blood pressure before and after undergoing large-volume ultrasound-assisted liposuction. There were no significant intraoperative complications. Body weight had decreased by 5.1 kg (p < 0.0001) by 6 weeks after liposuction, with an additional 1.3-kg weight loss (p < 0.05) observed between 6 weeks and 4 months after surgery, for a total weight loss of 6.5 kg (p < 0.00006). Body mass index decreased from (mean +/- SEM) 28.8 +/- 2.3 to 26.8 +/- 1.5 kg/m2 (p < 0.0001). This change in body weight was primarily the result of decreases in body fat mass: as assessed by DXA, lean body mass did not change (43.8 +/- 3.1 kg to 43.4 +/- 3.6 kg, p = 0.80), whereas DXA total body fat mass decreased from 35.7 +/- 6.3 to 30.1 +/- 6.5 kg (p < 0.0001). There were significant decreases in fasting plasma insulin levels (14.9 +/- 6.5 mIU/ml before liposuction versus 7.2 +/- 3.2 mIU/ml 4 months after liposuction, p < 0.007), and systolic blood pressure (132.1 +/- 7.2 versus 120.5 +/- 7.8 mmHg, p < 0.0002). Total cholesterol, high-density lipoprotein cholesterol, plasma triglycerides, and resting energy expenditure values were not significantly altered after liposuction. In conclusion, over a 4-month period, large-volume liposuction decreased weight, body fat mass, systolic blood pressure, and fasting insulin levels without detrimental effects on lean body mass, bone mass, resting energy expenditure, or lipid profiles. Should these improvements be maintained over time, liposuction may prove to be a valuable tool for reducing the comorbid conditions associated with obesity.

Objectives: Acanthosis nigricans (AN) has been proposed as a reliable marker of hyperinsulinemia, but its utility for predicting hyperinsulinism has not been systematically evaluated in overweight children. We examined the relationship of AN to hyperinsulinemia and body adiposity., Study Design: One hundred thirty-nine children underwent physical examination for AN, body composition studies, an oral glucose tolerance test, and a hyperglycemic clamp., Results: Thirty-five children (25%) had AN. AN was more prevalent in African Americans (50.1%) than in white subjects (8.2%, P < .001). Independent of race, children with AN had greater body weight and body fat mass (P < .001); greater basal and glucose-stimulated insulin levels during oral glucose tolerance test (P < .001); greater first-phase, second-phase, and steady-state insulin levels (P < .001); and lower insulin sensitivity (P < .001) during the hyperglycemic clamp. After adjusting for body fat mass and age, none of these differences remained significant. When categorized by fasting insulin, 35% with fasting insulin levels > 20 microU/mL and 50% with fasting insulin levels > 15 microU/mL did not have AN. Eighty-eight percent of children with fasting insulin levels > or = 15 microU/mL had a body mass index SD score > or = 3.0., Conclusions: AN is not a reliable marker for hyperinsulinemia in overweight children. Children with a race-, sex-, and age-specific body mass index SD scores > or = 3.0 should be screened for hyperinsulinemia, whether or not they have AN.

The purpose of the study was to develop ethnic-specific equations for fat-free mass (FFM) from selected anthropometric dimensions and bioelectrical impedance measures of resistance (R) and reactance (Xc) for use in the NHLBI Growth and Heath Study. Using dual-energy X-ray absorptiometry measures of body composition as the dependent variable and field measures of body composition by anthropometry and bioelectrical impedance as the explanatory variables, ethnic-specific prediction equations were developed on a sample of girls representing a wide range of ages and BMI. The equations were cross-validated using (1) the Prediction of Sum of Squares (PRESS) statistic and (2) an independent sample of 20 girls of each race from a study conducted at the National Institute of Child Health and Human Development (NICHD). Subjects were 65 White and 61 Black girls 6-17 years of age. The best race-specific equations for FFM each explained 99% and 97% of the variance in the White and Black girls, respectively. Root mean square errors (RMSE) ranged from 1.14 to 1.95 kg. The equation for Black girls used Stature2/Resistance (R), weight, and reactance (Xc) as predictor variables; the equation for White girls used Stature2/R, weight, and triceps skinfold thickness. The results indicate that (1) equations to predict FFM in girls should be ethnic-specific and that (2) accurate values for TBF and %BF can be calculated from the predicted FFM.

Objective: To evaluate the effect of growth hormone (GH) therapy on pubertal onset, pubertal pace, adult testicular function, and adrenarche in boys with non-GH-deficient short stature., Study Design: Randomized, double-blind, placebo-controlled trial. GH (0.074 mg/kg, subcutaneously, 3 times per week) or placebo treatment was initiated in prepubertal or early pubertal boys and continued until near final height was reached (n = 49). Statistical significance was assessed by survival analysis, repeated-measures analysis of variance, and Student t test., Results: GH therapy did not affect the age at pubertal onset, defined either by testicular volume >4 mL or by testosterone concentration >1.0 nmol/L (30 ng/dL). GH treatment also did not affect the pace of puberty, defined either by the rate of change in testicular volume or testosterone concentration during the 4 years after pubertal onset. In boys followed up to age > or =16 years during the study, there were no significant differences in final testicular volume or in plasma testosterone, luteinizing hormone, or follicle-stimulating hormone concentrations. The pace of adrenarche, assessed by change in dehydroepiandrosterone sulfate levels over time, also did not differ significantly between the GH and placebo groups., Conclusion: Our findings suggest that GH treatment does not cause testicular damage, alter the onset or pace of puberty, or alter the pace of adrenarche in boys with non-GH-deficient short stature.

Objectives: African American children have greater bone mineral density (BMD) and bone mineral content (BMC) than white children. We examined the hypothesis that differences in insulin-like growth factors (IGFs) are important determinants of BMD during childhood., Methods: We measured IGFs and IGF binding proteins in 59 African American and 59 white girls matched for age, body mass index, socioeconomic status, and pubertal stage. BMD and BMC were determined by dual emission x-ray absorptiometry., Results: African American girls had greater total BMD (P <.001), BMC (P <.01), total IGF-1 (P <.001), and free IGF-1 (P <.01) than white girls. IGFBP-1, IGFBP-2, and IGFBP-3 were similar in both groups or lower in African Americans. IGF-1 was positively correlated with IGF-2 in white girls (P =.012) but was negatively correlated with IGF-2 in African Americans (P =.015). IGF-1 and free IGF-1 were positively correlated with BMD/BMC. Multiple regression analyses showed 80% of the variance in BMC could be accounted for by the use of body weight, height, and IGF-1 in the model. When IGF-1 was included as a factor, race did not add to the model's predictive power., Conclusion: IGF-1 and free IGF-1 are greater in African American than in white girls and may contribute to the greater BMD of African Americans.

Background: HAART has been associated with metabolic abnormalities (hyperlipidemia, insulin resistance, alterations in cortisol metabolism) and fat redistribution., Setting: A prospective study of 26 Caucasian men (median age 43.5 years) with HIV-1 viral loads < 500 copies/ml for 12 months while on highly active antiretroviral therapy (HAART) who interrupted treatment for a median of 7.0 weeks (range 4.9-10.3 weeks). Seventeen (65.4%) patients reported at least one fat redistribution symptom at baseline., Method: Serum lipids, glucose and insulin levels during an oral glucose tolerance test, 24-h urinary free cortisol and 17-hydroxycorticosteroids, and anthropometric parameters were measured before HAART cessation and prior to its reinstitution., Results: When baseline values were compared with those obtained after HAART interruption (means +/- SD), there was a significant decrease in total cholesterol (194+/-47.3 versus 159+/-29.3 mg/dl; P < 0.0001), low density lipoprotein (LDL) cholesterol (114+/-32.6 versus 96+/-24.7 mg/dl; P = 0.0013), triglycerides (261+/-244.3 versus 185+/-165.4 mg/dl; P = 0.008), and 24-hour urinary 17-hydroxycorticosteroids (15+/-7.9 versus 5+/-2.5 mg/24 h, P < 0.0001) and a significant increase in 24-hour urinary free cortisol (45+/-34.1 versus 62+/-32.2 microg/24 h; P = 0.016). There were no significant changes in glucose or insulin levels or in anthropometric measurements., Conclusions: A relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and triglyceride levels. No changes were observed in insulin resistance profiles or anthropometric measurements, perhaps because of the brief duration of HAART interruption. These results suggest that hyperlipidemia and alterations in corticosteroid metabolism in the setting of HAART are a direct drug effect that reverses with drug withdrawal. However, glucose metabolism and fat redistribution do not change over the short term.

Background: Little is known about genes that affect childhood body weight., Objective: The objective of this study was to examine the association between alleles of the mitochondrial uncoupling protein 2 (UCP2) gene and obesity because UCP2 may influence energy expenditure., Design: We related UCP2 genotype to body composition and resting energy expenditure in 105 children aged 6-10 y. Overweight children and nonoverweight children of overweight parents were genotyped for a 45-base pair deletion/insertion (del/ins) in 3'-untranslated region of exon 8 and for an exon 4 C to T transition., Results: Eighty-nine children were genotyped for the exon 8 allele: 50 children had del/del, 33 had del/ins, and 6 had ins/ins. Mean (+/-SD) body mass index (BMI; in kg/m(2)) was greater for children with del/ins (24.1 +/- 5.9) than for children with del/del (20.4 +/- 4.8; P < 0.001). BMI of ins/ins children (23.7 +/- 7.8) was not significantly different from that of del/ins children. A greater BMI in del/ins children was independent of race and sex. Body composition was also different according to UCP2 genotype. All body circumferences and skinfold thicknesses examined were significantly greater in del/ins than in del/del children. Body fat mass as determined by dual-energy X-ray absorptiometry was also greater in del/ins than in del/del children (P < 0.005). For 104 children genotyped at exon 4, no significant differences in BMI or body composition were found among the 3 exon 4 genotypes. Neither resting energy expenditure nor respiratory quotient were different according to UCP2 exon 4 or exon 8 genotype., Conclusions: The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity. The UCP2/UCP3 genetic locus may play a role in childhood body weight.

Orlistat, a weight-loss agent with a novel mechanism of action, recently was approved by the Food and Drug Administration for the treatment of obesity. It inhibits gastric and pancreatic lipases in the lumen of the gastrointestinal tract to decrease systemic absorption of dietary fat. In several trials lasting up to 2 years, orlistat was more effective than diet alone for weight reduction and maintenance of lost weight. Orlistat treatment also results in modest improvements in total cholesterol, low-density lipoprotein, blood pressure, and fasting glucose and insulin concentrations. The major adverse effects are gastrointestinal, usually occur early in therapy, and tend to decrease with continued treatment. Because orlistat may decrease the absorption of fat-soluble vitamins, a standard multiple-vitamin supplement is recommended daily during therapy to prevent abnormalities in vitamin serum concentrations. The potential for severe gastrointestinal discomfort and the modest degree of weight loss may limit the agent's clinical utility. Its long-term safety and effectiveness for weight maintenance, cost-effectiveness of treatment, and overall reduction in obesity-related morbidity and mortality remain to be determined.

Vitamin A deficiency and excess both cause abnormalities in mammalian longitudinal bone growth. Because all-trans retinoic acid (RA) is synthesized from vitamin A, we hypothesized that RA regulates growth plate chondrogenesis. Consistent with this hypothesis, a single oral dose of RA reduced the height of the rat proximal tibial growth plate. To determine whether RA acts directly on growth plate, fetal rat metatarsal bones were cultured in the presence of RA. In this system, RA inhibited longitudinal bone growth by three mechanisms: 1) decreased chondrocyte proliferation, (assessed by 3H-thymidine incorporation), particularly in the proliferative zone of the growth plate; 2) decreased matrix synthesis (assessed by 35SO4 incorporation into glycosaminoglycans); and 3) decreased cell hypertrophy (determined histologically). The growth-inhibiting effects of RA were completely reversed by a retinoic acid receptor (RAR) antagonist. In the absence of exogenous RA, this antagonist accelerated bone growth, as did an RA-specific neutralizing antibody, suggesting that endogenous RA negatively regulates growth plate chondrogenesis. We conclude that RA, acting through RARs, negatively regulates longitudinal bone growth by inhibiting growth plate chondrocyte proliferation, chondrocyte hypertrophy, and matrix synthesis.

Multidrug antiretroviral regimens that include human immunodeficiency virus-1 (HIV-1) protease inhibitors are associated with distinct lipodystrophy, hypertriglyceridemia, hyperinsulinemia, and deposition of visceral abdominal adipose tissue. To determine whether these findings are related to abnormalities of adrenal function, we compared the hypothalamic-pituitary-adrenal axes of HIV-positive patients who had evidence of protease inhibitor-associated lipodystrophy (PIAL), control volunteers (CON), and patients with Cushing's syndrome (CS). To elucidate the metabolic consequences of the observed lipodystrophy, we measured basal serum lipids and compared glucose and insulin concentrations during an oral glucose tolerance test. Spontaneous plasma cortisol showed normal diurnal variation in PIAL. Cortisol levels were similar in CON and PIAL, and levels in these groups were less than those in CS at all times of the night or day (P < 0.005). Ovine CRH-stimulated morning plasma cortisol levels were similar in PIAL and CON. ACTH was significantly greater in PIAL than CON (P < 0.05) at 0, 15, and 30 min after CRH stimulation. Urinary free cortisol in PIAL (mean +/- SD, 76 +/- 51 nmol/day) was significant lower than those in CON (165 +/- 64 nmol/day; P < 0.001) and CS (1715 +/- 1203 nmol/day; P < 0.001). However, 17-hydroxycorticosteroid excretion was significantly greater in PIAL (43 +/- 23 micromol/day) than in CON (17 +/- 8 micromol/day; P < 0.001), although lower than that in CS (74 +/- 47 micromol/day; P < 0.01). Scatchard analysis revealed normal glucocorticoid receptor number and affinity in PIAL. Serum triglycerides were significantly greater in PIAL (6.57 +/- 5.63 mmol/L) than in CS (1.78 +/- 0.83 mmol/L; P < 0.001) or CON (1.36 +/- 0.84 mmol/L; P < 0.001). Although triglyceride levels were significantly correlated with body mass index for CON and CS, these were not correlated for PIAL. During an oral glucose tolerance test, similar glucose and insulin values were found in PIAL and CS that were greater (P < 0.05) than CON values at 30, 60, 90, and 120 min. We conclude that the lipodystrophy associated with use of HIV-1 protease inhibitors is a syndrome of increased intraabdominal adiposity with concomitant dyslipidemia and insulin resistance, but without total body weight gain and is distinct from any known form of hypercortisolism. Although urinary cortisol disposition seems to be altered in HIV-infected patients who are being treated with multidrug regimens that include protease inhibitors, the decreased free cortisol and increased 17-hydroxycorticosteroid excretion appear to be unlikely explanations for the observed lipodystrophy. The cause remains to be elucidated.