A better index of body adiposity.

Obesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)(1.5))-18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the "BetaGene" study, to develop the new index of body adiposity. %Body fat, as measured by the dual-energy X-ray absorptiometry (DXA), was used as a "gold standard" for validation. Hip circumference (R = 0.602) and height (R = -0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the "Triglyceride and Cardiovascular Risk in African-Americans (TARA)" study of African Americans. Correlation between DXA-derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.

Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial.

OBJECTIVE: Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant. RESEARCH DESIGN AND METHODS: This study was a randomized double-blind placebo-controlled trial consisting of 100 severely obese (mean BMI 34.6 ± 6.6 kg/m(2)) insulin-resistant children aged 6-12 years, randomized to 1,000 mg metformin (n = 53) or placebo (n = 47) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program. RESULTS: Eighty-five percent completed the 6-month randomized phase. Children prescribed metformin had significantly greater decreases in BMI (difference -1.09 kg/m(2), CI -1.87 to -0.31, P = 0.006), body weight (difference -3.38 kg, CI -5.2 to -1.57, P < 0.001), BMI Z score (difference between metformin and placebo groups -0.07, CI -0.12 to -0.01, P = 0.02), and fat mass (difference -1.40 kg, CI -2.74 to -0.06, P = 0.04). Fasting plasma glucose (P = 0.007) and homeostasis model assessment (HOMA) insulin resistance index (P = 0.006) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17%. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score; those treated continuously with metformin did not significantly change BMI Z score further. CONCLUSIONS: Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program.

The stability of metabolic syndrome in children and adolescents.

CONTEXT: Some studies suggest the presence of metabolic syndrome before adulthood may identify those at high risk for later cardiovascular morbidity, but there are few data examining the reliability of pediatric metabolic syndrome. OBJECTIVE: To examine the short- and long-term stability of pediatric metabolic syndrome. DESIGN: Metabolic syndrome was defined as having at least three of the following: waist circumference, blood pressure, and fasting serum triglycerides in the 90th or higher percentile for age/sex; high-density lipoprotein-cholesterol 10th or lower percentile for age/sex; and fasting serum glucose of at least 100 mg/dl. Short-term metabolic syndrome stability (repeated measurements within 60 d) was assessed in obese youth ages 6-17 yr. Long-term metabolic syndrome stability (repeated measurements more than 1.5 yr apart) was studied in 146 obese and nonobese children age 6-12 yr at baseline. PATIENTS AND SETTING: Convenience samples of obese and nonobese youth ages 6-17 yr participating in research studies were collected at a clinical research hospital. RESULTS: Short-term metabolic syndrome stability (repeat measurements performed 19.7 +/- 13.1 d apart) was assessed in 220 children. The diagnosis of metabolic syndrome was unstable in 31.6% of cases. At their short-term follow-up visit, incidence of metabolic syndrome among participants who did not have metabolic syndrome at baseline was 24%. In the long term (repeat measurements performed 5.6 +/- 1.9 yr apart), the diagnosis of metabolic syndrome was unstable in 45.5% of cases. CONCLUSIONS: Cutoff-point-based definitions for pediatric metabolic syndrome have substantial instability in the short and long term. The value of making a cutoff-point-based diagnosis of metabolic syndrome during childhood or adolescence remains in question.

Effects of calcium supplementation on body weight and adiposity in overweight and obese adults: a randomized trial.

BACKGROUND: Some data suggest that increasing calcium intake may help prevent weight gain. OBJECTIVE: To test the hypothesis that calcium supplementation can prevent weight gain in persons who are overweight or obese. DESIGN: Randomized, placebo-controlled trial. Randomization was computer-generated, and allocation was assigned by pharmacy personnel who prepared intervention and placebo capsules. Participants, providers, and those who assessed outcomes were blinded to study group assignment. SETTING: Single research center. PARTICIPANTS: 340 overweight (body mass index [BMI], 25 to <30 kg/m(2)) and obese (BMI > or =30 kg/m(2)) adults (mean age, 38.8 years [SD, 10.5]). INTERVENTION: Calcium carbonate (elemental calcium, 1500 mg/d) (n = 170) or placebo (n = 170) with meals for 2 years. MEASUREMENTS: Changes in body weight and fat mass (primary outcomes). RESULTS: Seventy-five percent of participants completed the trial (78% received calcium; 73% received placebo). There were no statistically or clinically significant differences between the calcium and placebo groups in change in body weight (difference, 0.02 kg [95% CI, -1.64 to 1.69 kg]; P = 0.98), BMI (difference, 0.32 kg/m(2) [CI, -0.41 to 1.02 kg/m(2)]; P = 0.39), or body fat mass (difference, 0.39 kg [CI, -1.04 to 1.92 kg]; P = 0.55). Parathyroid hormone concentrations decreased in the calcium group compared with the placebo group (difference, -0.71 pmol/L [CI, -1.28 to -0.13 pmol/L]). LIMITATION: The study took place at a research center, and its sample was mostly women. CONCLUSION: Dietary supplementation with elemental calcium, 1500 mg/d, for 2 years had no statistically or clinically significant effects on weight in overweight and obese adults. Calcium supplementation is unlikely to have clinically significant efficacy as a preventive measure against weight gain in such patients.

Bone mineral density in estrogen-deficient young women.

CONTEXT: Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density. OBJECTIVE: The aim of the study was to assess bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model. DESIGN AND SETTING: We conducted a cross-sectional study at a tertiary care research center. PARTICIPANTS: We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353). PRIMARY OUTCOME MEASURE: We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry. RESULTS: Patients on average had 2-3% lower BMD at L1-L4, femoral neck, and total hip (P < 0.01 at all sites). The modifiable risk factors for BMD below the expected range for age (Z-score <-2) were: more than 1-yr delay in diagnosis of estrogen deficiency (P = 0.018), low (<32 ng/ml) vitamin D levels (P = 0.002), estrogen replacement nonadherence (P = 0.002), low calcium intake (P = 0.005), and lack of exercise (P = 0.005). As compared to Caucasians, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have Z-scores below -2 (P = < 0.0001 for both). Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density. CONCLUSIONS: Women with POI have lower bone density compared to regularly menstruating women. Compared to Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy.

Recruitment to a physical activity intervention study in women at increased risk of breast cancer.

BACKGROUND: Physical activity is being studied as a breast cancer prevention strategy. Women at risk of breast cancer report interest in lifestyle modification, but recruitment to randomized physical activity intervention studies is challenging. METHODS: We conducted an analysis of recruitment techniques used for a prospective, randomized pilot study of physical activity in women at risk of breast cancer. We evaluated differences in proportion of eligible patients, enrolled patients, and successful patients identified by each individual recruitment method. The Fisher-Freeman-Halton test (an extension of Fisher's exact test from 2 x 2 tables to general row by column tables) was used to compare the success of different recruitment strategies. RESULTS: We received 352 inquiries from women interested in participating, of whom 171 (54%) were eligible. Ninety-nine women completed a baseline activity evaluation, and 58 (34% of eligible; 16% of total inquiries) were randomized. Recruitment methods fell into three broad categories: media techniques, direct contact with potential participants, and contacts with health care providers. Recruitment strategies differed significantly in their ability to identify eligible women (p = 0.01), and women who subsequently enrolled in the study (p = 0.02). CONCLUSION: Recruitment techniques had varying success. Our data illustrate the challenges in recruiting to behavior modification studies, and provide useful information for tailoring future recruitment efforts for lifestyle intervention trials. TRIAL REGISTRATION NO(S): CDR0000393790, NCI-04-C-0276, NCI-NAVY-B05-001.

Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity.

We describe the clinical features of 28 patients with juvenile dermatomyositis (JDM) and 1 patient with adult-onset dermatomyositis (DM), all of whom developed lipodystrophy (LD) that could be categorized into 1 of 3 phenotypes, generalized, partial, or focal, based on the pattern of fat loss distribution. LD onset was often delayed, beginning a median of 4.6 years after diagnosis of DM. Calcinosis, muscle atrophy, joint contractures, and facial rash were DM disease features found to be associated with LD. Panniculitis was associated with focal lipoatrophy while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more associated with generalized LD. Specific LD features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with LD, in a gradient of frequency and severity among the 3 sub-phenotypes. Metabolic studies frequently revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial LD. Regional fat loss from the thighs, with relative sparing of fat loss from the medial thighs, was more frequent in generalized than in partial LD and absent from DM patients without LD. Cytokine polymorphisms, the C3 nephritic factor, insulin receptor antibodies, and lamin mutations did not appear to play a pathogenic role in the development of LD in our patients. LD is an under-recognized sequela of JDM, and certain DM patients with a severe, prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for the development of this complication. High-risk JDM patients should be screened for metabolic abnormalities, which are common in generalized and partial LD and result in much of the LD-associated morbidity. Further study is warranted to investigate the pathogenesis of acquired LD in patients with DM.

Adiponectin and leptin in African Americans.

OBJECTIVE: African Americans (AAs) have less visceral and more subcutaneous fat than whites, thus the relationship of adiponectin and leptin to body fat and insulin sensitivity in AA may be different from that in whites. METHODS AND PROCEDURES: Sixty-nine non-diabetic AA (37 men and 32 women), aged 33 +/- 1 year participated. The percent fat was determined by dual-energy X-ray absorptiometry, abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume by computerized tomography (CT), and insulin sensitivity by homeostasis model assessment (HOMA). RESULTS: VAT was greater in men (1,619 +/- 177 cm(3) vs. 1,022 +/- 149 cm(3); P = 0.01); women had a higher percentage of body fat (34.1 +/- 1.4 vs. 24.0 +/- 1.2; P < 0.0001), adiponectin (15.8 +/- 1.2 microg/ml vs. 10.4 +/- 0.8 microg/ml; P = 0.0004) and leptin (23.2 +/- 15.8 ng/ml vs. 9.2 +/- 7.2 ng/ml; P < 0.0001). SAT and HOMA did not differ because of the sex. Adiponectin negatively correlated with VAT (r = -0.41, P < 0.05) in men, and with VAT (r = -0.55, P < 0.01), and SAT (r = -0.35, P < 0.05) in women. Adiponectin negatively correlated with HOMA in men (r = -0.38, P < 0.05) and women (r = -0.44, P < 0.05). In multiple regression, sex (P = 0.02), HOMA (P = 0.03) and VAT (P = 0.003) were significant predictors of adiponectin (adj R (2) = 0.38, P < 0.0001). Leptin positively correlated with VAT, SAT, percent fat and HOMA in men (r = 0.79, r = 0.86, r = 0.89, and r = 0.53; P < 0.001) and women (r = 0.62, r = 0.75, r = 0.83, and r = 0.55; P < 0.01). In multiple regression VAT (P = 0.04), percent body fat (P < 0.0001) and sex (P = 0.01), but not HOMA were significant predictors of serum leptin (adj R (2)= 0.82, P < 0.0001). DISCUSSION: The relationship of adiponectin and leptin to body fat content and distribution in AA is dependent on sex. Although VAT and insulin sensitivity are significant determinants of adiponectin, VAT and percent body fat determine leptin.

Determining the waist circumference in african americans which best predicts insulin resistance.

Total body size and central fat distribution are important determinants of insulin resistance. The BMI and waist circumference (WC) thresholds in African Americans that best predict insulin resistance are unknown. Our goal was to determine the BMI and WC values in African Americans, which optimally predict insulin resistance. The subjects were African Americans (68 men, 63 women), aged 35 +/- 8 years (mean +/- s.d.), with a BMI of 30.9 +/- 7.5, in the range of 18.5-54.7 kg/m(2), and with a WC of 98 +/- 18, in the range of 69-173 cm. Insulin resistance was defined by the lowest tertile of the insulin sensitivity index (S(I)). The Youden index was calculated to determine the WC and BMI thresholds that predict insulin resistance with an optimal combination of sensitivity and specificity. In men the thresholds that optimally predicted insulin resistance were a BMI > or =30 kg/m(2) or a WC > or =102 cm. For women, insulin resistance was best predicted by a BMI > or =32 kg/m(2) or a WC > or =98 cm. In African Americans, insulin resistance (in men) was best predicted by a WC > or =102 cm, and in women by a WC > or =98 cm, or by a BMI value that fell in the obese category (men: > or =30 kg/m(2), women: > or =32 kg/m(2)).

Obesity-related hypoferremia is not explained by differences in reported intake of heme and nonheme iron or intake of dietary factors that can affect iron absorption.

Hypoferremia is more prevalent in obese than nonobese adults, but the reason for this phenomenon is unknown. To elucidate the role dietary factors play in obesity-related hypoferremia, the intake of heme and nonheme iron and the intake of other dietary factors known to affect iron absorption were compared cross-sectionally from April 2002 to December 2003 in a convenience sample of 207 obese and 177 nonobese adults. Subjects completed 7-day food records, underwent phlebotomy for serum iron measurement, and had body composition assessed by dual-energy x-ray absorptiometry, during a 21-month period. Data were analyzed by analysis of covariance and multiple linear regression. Serum iron (mean+/-standard deviation) was significantly lower in obese than nonobese individuals (72.0+/-61.7 vs 85.3+/-58.1 microg/dL [12.888+/-11.0443 vs 15.2687+/-10.3999 micromol/L]; P<0.001). The obese cohort reported consuming more animal protein (63.6+/-34.5 vs 55.7+/-32.5 g/day; P<0.001) and more heme iron (3.6+/-2.8 vs 2.7+/-2.6 mg/day; P<0.001). Groups did not differ, however, in total daily iron consumption, including supplements. Obese subjects reported consuming less vitamin C (77.2+/-94.9 vs 91.8+/-89.5 mg/day; P=0.01), which may increase absorption of nonheme iron, and less calcium (766.2+/-665.0 vs 849.0+/-627.2 mg/day; P=0.038), which may decrease nonheme iron absorption, than nonobese subjects. Groups did not significantly differ in intake of other dietary factors that can impact absorption of iron, including phytic acid, oxalic acid, eggs, coffee, tea, zinc, vegetable protein, or copper. After accounting for demographic covariates and dietary factors expected to affect iron absorption, fat mass (P=0.007) remained a statistically significant negative predictor of serum iron. This cross-sectional, exploratory study suggests that obesity-related hypoferremia is not associated with differences in reported intake of heme and nonheme iron or intake of dietary factors that can affect iron absorption.

Low bone mass in premenopausal women with depression.

BACKGROUND: An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder (MDD), mostly women. METHODS: Study recruitment was conducted from July 1, 2001, to February 29, 2003. We report baseline BMD measurements in 89 premenopausal women with MDD and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual-energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women. We defined MDD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). RESULTS: The prevalence of low BMD, defined as a T score of less than -1, was greater in women with MDD vs controls at the femoral neck (17% vs 2%; P = .02) and total hip (15% vs 2%; P = .03) and tended to be greater at the lumbar spine (20% vs 9%; P = .14). The mean +/- SD BMD, expressed as grams per square centimeters, was lower in women with MDD at the femoral neck (0.849 +/- 0.121 vs 0.866 +/- 0.094; P = .05) and at the lumbar spine (1.024 +/- 0.117 vs 1.043 +/- 0.092; P = .05) and tended to be lower at the radius (0.696 +/- 0.049 vs 0.710 +/- 0.055; P = .07). Women with MDD had increased mean levels of 24-hour proinflammatory cytokines and decreased levels of anti-inflammatory cytokines. CONCLUSIONS: Low BMD is more prevalent in premenopausal women with MDD. The BMD deficits are of clinical significance and comparable in magnitude to those resulting from established risk factors for osteoporosis, such as smoking and reduced calcium intake. The possible contribution of immune or inflammatory imbalance to low BMD in premenopausal women with MDD remains to be clarified.

Validation of three food frequency questionnaires to assess dietary calcium intake in adults.

OBJECTIVE: To assess the accuracy of three self-administered food frequency questionnaires (FFQs) to measure dietary calcium intake in healthy adults. DESIGN: Estimates of dietary calcium intake from one previously validated and two recently developed FFQs were compared with those from 7-day food records. SUBJECTS/SETTING: Healthy adults enrolled in an outpatient study of calcium supplementation completed the 36-page Dietary History Questionnaire (DHQ), a 3-page Calcium Questionnaire, and a 1-page Short Calcium Questionnaire. Subjects then completed a 7-day food record. MAIN OUTCOME MEASURES: Differences between calcium intake reported on FFQs and calcium intake from food records were compared. STATISTICAL ANALYSES: Spearman correlations were used to measure associations among variables; Bland-Altman pairwise comparisons were conducted to assess systematic and magnitude biases. RESULTS: We studied 341 subjects, 74.5% female, mean (+/-standard deviation) age of 38+/-11 years and body mass index (calculated as kg/m(2)) of 31.8+/-7.1. Mean (+/-standard deviation) food record calcium intake was 896+/-380 mg/day; data from all three FFQs were positively related to food record calcium intake, but accounted for <40% of the variance in food record dietary calcium intake (DHQ: r(2)=0.21; Calcium Questionnaire: r(2)=0.33; Short Calcium Questionnaire: r(2)=0.37; all P<0.001). The DHQ underestimated daily calcium intake (systematic bias: -94 mg/day, P<0.001; magnitude bias r=-0.40; P<0.001), whereas the Calcium Questionnaire overestimated calcium intake (systematic bias +177 mg/day, P<0.001), but had no significant magnitude bias (r=-0.09; P=0.11). The Short Calcium Questionnaire showed minimal systematic bias (+34 mg/day, P=0.09), but had magnitude bias (r=-0.33; P<0.001). CONCLUSIONS: All three FFQs performed reasonably well at estimating dietary calcium intake compared to food records; each may be appropriate for use in select clinical and research settings.

The prevalence of hypovitaminosis D and secondary hyperparathyroidism in obese Black Americans.

CONTEXT: Both obesity (body mass index, BMI > or = 30 kg/m2) and Black race are associated with a higher risk of vitamin D deficiency and secondary hyperparathyroidism. We hypothesized the risk of hypovitaminosis D would therefore be extraordinarily high in obese Black adults. OBJECTIVE: To study the effects of race and adiposity on 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (iPTH). DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of 379 Black and White adults from the Washington D.C. area. BMI ranged from 19.9 to 58.2 kg/m2. MAIN OUTCOME MEASURES: Prevalence of hypovitaminosis D [25(OH)D < 37.5 nmol/l] and secondary hyperparathyroidism [25(OH)D < 37.5 nmol/l with iPTH > 4.2 pmol/l]. RESULTS: Obese Black subjects had lower mean 25(OH)D, 40.3 (SD, 20.3) nmol/l, compared with obese Whites, 64.5 (29.7), P < 0.001, nonobese Blacks, 53.3 (26.0), P = 0.0025 and nonobese Whites, 78.0 (33.5), P < 0.001. The prevalence of hypovitaminosis D increased with increasing BMI, and was greater (P < 0.001) in Blacks than Whites within all BMI categories examined. Among subjects with BMI > or = 35 kg/m2, 59% of Blacks vs 18% of Whites had hypovitaminosis D (odds ratio 6.5, 95% confidence interval 3.0-14.2). iPTH was negatively correlated with 25(OH)D (r = -0.31, P < 0.0001), suggesting those with hypovitaminosis D had clinically important vitamin D deficiency with secondary hyperparathyroidism. For secondary hyperparathyroidism 35.2% of Blacks met the criteria, compared to 9.7% of Whites (OR 3.6, CI 1.5-98.8). CONCLUSIONS: Obese Black Americans are at particularly high risk for vitamin D deficiency and secondary hyperparathyroidism. Physicians should consider routinely supplementing such patients with vitamin D or screening them for hypovitaminosis D.

Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity.

Both human linkage studies and MC3R knockout mouse models suggest that the MC3R may play an important role in energy homeostasis. Here we show that among 355 overweight and nonoverweight children, 8.2% were double homozygous for a pair of missense MC3R sequence variants (Thr6Lys and Val81Ile). Such children were significantly heavier (BMI and BMI SD score: P < 0.0001), had more body fat (body fat mass and percentage fat mass: P < 0.001), and had greater plasma leptin (P < 0.0001) and insulin concentrations (P < 0.001) and greater insulin resistance (P < 0.008) than wild-type or heterozygous children. Both sequence variants were more common in African-American than Caucasian children. In vitro expression studies found the double mutant MC3R was partially inactive, with significantly fewer receptor binding sites, decreased signal transduction, and less protein expression. We conclude that diminished MC3R expression in this double MC3R variant may be a predisposing factor for excessive body weight gain in children.

Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk.

Major depressive disorder (MDD) is one of the most common psychiatric illnesses in the adult population. It is often associated with an increased risk of cardiovascular disease. We measured body fat distribution as well as plasminogen activator inhibitor-1 (PAI-1) concentration and factor VIII (fVIII) activity at 8:00 am and 8:00 pm in 45 premenopausal women with MDD vs 28 healthy controls (age, 37 +/- 6.8 vs 35 +/- 6.5; weight [kg], 75.3 +/- 17.2 vs 67.9 +/- 10.2; mean +/- SD] participating in a prospective study of bone turnover, the POWER Study. At the time of evaluation, women with MDD were mildly depressed and mostly in clinical remission on antidepressants. After adjusting for body weight, women with MDD had greater waist circumference and abdominal fat as well as significantly higher evening (8:00 pm) PAI-1 and fVIII levels than controls. Even when age-, race-, and body mass index-matched subsets were compared, the MDD group continued to exhibit statistically higher PAI-1 and fVIII levels. The observed alterations in body fat distribution (increased abdominal fat) and prothrombotic factors (increased PAI-1 and fVIII) may be in part responsible for the increased risk of cardiovascular disease reported in association with major depression.

Use of nitisinone in patients with alkaptonuria.

Alkaptonuria, a rare autosomal recessive disorder caused by mutations in the HGD gene and deficiency of homogentisate 1,2 dioxygenase, is characterized by ochronosis, arthritis, and daily excretion of gram quantities of homogentisic acid (HGA). Nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, can drastically reduce urinary excretion of HGA in individuals with alkaptonuria. We investigated the safety and the HGA-depleting efficacy of nitisinone in an open-label, single-center study of 9 alkaptonuria patients (5 women, 4 men; 35-69 years of age) over the course of 3 to 4 months. Each patient received nitisinone in incremental doses, 0.35 mg bid followed by 1.05 mg bid, and remained on this dosage and a regular diet for 3 months. Nitisinone reduced urinary HGA levels from an average of 4.0 +/- 1.8 (SD) g/day to 0.2 +/- 0.2 g/day ( P < .001). The average plasma tyrosine concentration, initially 68 +/- 18 mmicro mol/L, rose to 760 +/- 181 micro mol/L ( P < .001). During the final week of the study, 5 patients adhered to a protein-restricted diet (40 g/day), and their mean plasma tyrosine level fell from 755 +/- 167 to 603 +/- 114 mu mol/L. Six of the 7 patients who received nitisinone for more than 1 week reported decreased pain in their affected joints. Weekly ophthalmologic examinations showed no signs of corneal toxicity. Adverse events included the passing of kidney stones, the recognition of symptoms related to aortic stenosis, and elevation of liver transaminase levels. We conclude that low-dose nitisinone effectively reduced urinary HGA levels in patients with alkaptonuria. Future long-term clinical trials are planned to determine the benefits of nitisinone in preventing joint deterioration and providing pain relief, and its long-term side effects.

Both subcutaneous and visceral adipose tissue correlate highly with insulin resistance in african americans.

OBJECTIVE: The contribution of visceral adipose tissue (VAT) to insulin resistance is well-established; however, the role of subcutaneous abdominal adipose tissue (SAT) in insulin resistance remains controversial. Sex may determine which of these two components of abdominal obesity is more strongly related to insulin resistance and its consequences. The aim of this study was to determine whether both VAT and SAT contribute to insulin resistance in African Americans and to examine the effects of sex on this relationship. RESEARCH METHODS AND PROCEDURES: This was a cross-sectional study of 78 nondiabetic African-American volunteers (44 men, 35 women; age 33.8 +/- 7.3 years; BMI 30.9 +/- 7.4 kg/m2). VAT and SAT volumes were measured using serial computerized tomography slices from the dome of the diaphragm to the iliac crest. The insulin sensitivity index (SI) was determined from the minimal model using data obtained from the frequently sampled intravenous glucose tolerance test. RESULTS: In men, both VAT and SAT were negatively correlated with SI (r for both correlations = -0.57; p < 0.01). In women, the correlation coefficient between VAT and SI was -0.50 (p < 0.01) and between SAT and SI was -0.67 (p < 0.01). In women, the correlation coefficient for SI with SAT was significantly greater than the correlation coefficient with VAT (p = 0.02). DISCUSSION: Both SAT and VAT are strongly correlated with insulin resistance in African Americans. For African-American women, SAT may have a greater effect than VAT on insulin resistance.

Comparison of methods to assess change in children's body composition.

BACKGROUND: Little is known about how simpler and more available methods to measure change in body fatness compare with criterion methods such as dual-energy X-ray absorptiometry (DXA) in children. OBJECTIVE: Our objective was to determine the ability of air-displacement plethysmography (ADP) and formulas based on triceps skinfold thickness (TSF) and bioelectrical impedance analysis (BIA) to estimate changes in body fat over time in children. DESIGN: Eighty-six nonoverweight and overweight boys (n = 34) and girls (n = 52) with an average age of 11.0 +/- 2.4 y underwent ADP, TSF measurement, BIA, and DXA to estimate body fatness at baseline and 1 +/- 0.3 y later. Recent equations were used to estimate percentage body fat by TSF measurement (Dezenberg equation) and by BIA (Suprasongsin and Lewy equations). Percentage body fat estimates by ADP, TSF measurement, and BIA were compared with those by DXA. RESULTS: All methods were highly correlated with DXA (P < 0.001). No mean bias for estimates of percentage body fat change was found for ADP (Siri equation) compared with DXA for all subjects examined together, and agreement between body fat estimation by ADP and DXA did not vary with race or sex. Magnitude bias was present for ADP relative to DXA (P < 0.01). Estimates of change in percentage body fat were systematically overestimated by BIA equations (1.37 +/- 6.98%; P < 0.001). TSF accounted for only 13% of the variance in percentage body fat change. CONCLUSION: Compared with DXA, there appears to be no noninvasive and simple method to measure changes in children's percentage body fat accurately and precisely, but ADP performed better than did TSF or BIA. ADP could prove useful for measuring changes in adiposity in children.

Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome.

Recombinant methionyl human leptin (r-metHuLeptin) therapy has shown clear efficacy in the treatment of severe insulin resistance associated with lipodystrophy syndromes and low leptin levels. We treated two siblings with Rabson-Mendenhall syndrome (severe insulin resistance and presumed insulin receptor mutations). The brother and sister, aged 13 and 11 yr, respectively, had severe acanthosis nigricans, insulin resistance, and diabetes. Both were taking 2000 mg metformin and 2 mg rosiglitazone daily; the brother was also taking 300 U regular insulin daily. In contrast to our lipoatrophic patients treated with r-metHuLeptin, these two patients had a higher percent body fat and low-normal fasting triglycerides [42 mg/dl (0.37 mmol/liter), male sibling, and 33 mg/dl (0.47 mmol/liter), female sibling]. The siblings were treated with r-metHuLeptin therapy for 10 months and demonstrated a 40-60% decrease in fasting serum glucose and insulin levels and improved glycosylated hemoglobin. There was corresponding improvement in glucose and insulin tolerance during leptin therapy. This is the first report of a partial, but significant, effect of r-metHuLeptin administration in patients with extreme insulin resistance with a presumed insulin receptor mutation and low serum triglyceride levels.

Efficacy of orlistat as an adjunct to behavioral treatment in overweight African American and Caucasian adolescents with obesity-related co-morbid conditions.

This pilot study compared the efficacy of orlistat as an adjunctive treatment for obesity between African American and Caucasian adolescents. Twenty obese adolescents with obesity-related co-morbid conditions underwent measurements of body composition, glucose homeostasis by frequently sampled intravenous glucose tolerance test (FSIGT), and fasting lipids before and after 6 months treatment with orlistat 120 mg tid in conjunction with a comprehensive behavioral program. Weight (p < 0.05), BMI (p < 0.001), total cholesterol (p < 0.001), LDL cholesterol (p < 0.001), fasting insulin (p < 0.02) and fasting glucose (p < 0.003) were lower after treatment. Insulin sensitivity, measured during the FSIGT, improved significantly (p < 0.02), as did fasting indices such as the homeostasis model assessment for insulin resistance (p < 0.01). African American subjects exhibited significantly less improvement in weight (p < 0.05), BMI (p < 0.01), waist circumference (p = 0.03), and insulin sensitivity (p = 0.05). Improvements in cholesterol were not significantly different between African Americans and Caucasians. We conclude that Caucasians lost more weight and had greater improvements in insulin sensitivity than African Americans, but both exhibited improvements in plasma lipids. The true benefit of orlistat treatment over a comprehensive behavioral program remains to be determined in placebo-controlled trials.