Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth.

The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.

Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors.

Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors by-passed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.

Solid anthropomorphic infant whole-body DXA phantom: design, evaluation, and multisite testing.

BACKGROUND: Dual-energy X-ray absorptiometry (DXA) requires phantoms for quality control and cross-calibration. No commercially available phantoms are designed specifically for whole-body scanning of infants. METHODS: We fabricated a phantom closely matching a 7-kg human infant in body habitus using polyvinyl chloride (PVC), nylon mix, and polyethylene for bone, lean tissue, and fat, respectively, for evaluating the comparability of instruments used in studies on infant body composition. We scanned the phantom multiple times for short- and long-term repeatability and then shipped it to six other sites for comparison scans. All instruments were Hologic Delphi or Discovery models. Scan analyses were in-house procedures (Hologic V12.1). RESULTS: Short- and long-term results were not significantly different. Nylon mix underrepresented expected lean mass values by 5%, PVC underrepresented bone by 12%, and polyethylene overrepresented fat by 30%. Precision values were as follows: lean mass ≈ 3%; bone ≈ 3.5%; and fat = 5.5-7.5%. Instruments differed significantly for bone mineral content and density results in most instances. Three instruments differed in fat and lean mass. The two Hologic models differed significantly in all compartments except bone density. CONCLUSION: The phantom design came close to emulating bone, lean tissue, and fat and showed good reproducibility. Significant differences among various DXA instruments highlight the necessity of cross-calibration for any multicenter studies.

Effect of soy isoflavone supplementation on menopausal quality of life.

OBJECTIVE: The purpose of this study was to assess the effect of soy isoflavone supplementation on quality of life in postmenopausal women. METHODS: A multicenter, randomized, double-blind, placebo-controlled 24-month trial was conducted to assess the effect of 80 or 120 mg of daily aglycone hypocotyl soy isoflavone supplementation on quality of life in 403 postmenopausal women using a validated Menopause-Specific Quality of Life questionnaire. RESULTS: Menopause-Specific Quality of Life domain scores at 1 year and 2 years were similar to baseline. There were no differences in domain scores among treatment groups. CONCLUSIONS: Soy isoflavone supplementation offers no benefit to quality of life in postmenopausal women.

Assessment of bone mineral status in children with Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with skeletal involvement. It is caused by mutations in fibrillin1 (FBN1) gene resulting in activation of TGF-ß, which developmentally regulates bone mass and matrix properties. There is no consensus regarding bone mineralization in children with MFS. Using dual-energy X-ray absorptiometry (DXA), we evaluated bone mineralization in 20 children with MFS unselected for bone problems. z-Scores were calculated based on age, gender, height, and ethnicity matched controls. Mean whole body bone mineral content (BMC) z-score was 0.26±1.42 (P=0.41). Mean bone mineral density (BMD) z-score for whole body was -0.34±1.4 (P=0.29) and lumbar spine was reduced at -0.55±1.34 (P=0.017). On further adjusting for stature, which is usually higher in MFS, mean BMC z-score was reduced at -0.677±1.37 (P=0.04), mean BMD z-score for whole body was -0.82±1.55 (P=0.002) and for lumbar spine was -0.83±1.32 (P=0.001). An increased risk of osteoporosis in MFS is controversial. DXA has limitations in large skeletons because it tends to overestimate BMD and BMC. By adjusting results for height, age, gender, and ethnicity, we found that MFS patients have significantly lower BMC and BMD in whole body and lumbar spine. Evaluation of diet, exercise, vitamin D status, and bone turnover markers will help gain insight into pathogenesis of the reduced bone mass. Further, larger longitudinal studies are required to evaluate the natural history, incidence of fractures, and effects of pharmacological therapy.

Decreased bone mineralization in children with Noonan syndrome: another consequence of dysregulated RAS MAPKinase pathway?

INTRODUCTION: Noonan syndrome (NS) is a disorder of RAS- mitogen activated protein kinase (MAPK) pathway with clinical features of skeletal dysplasia. This pathway is essential for regulation of cell differentiation and growth including bone homeostasis. Currently, limited information exists regarding bone mineralization in NS. MATERIALS AND METHODS: Using dual-energy X-ray absorptiometry (DXA), bone mineralization was evaluated in 12 subjects (mean age 8.7 years) with clinical features of NS. All subjects underwent genetic testing which showed mutations in PTPN11 gene (N=8) and SOS1 gene (N=1). In a subgroup of subjects with low bone mass, indices of calcium-phosphate metabolism and bone turnover were obtained. RESULTS: 50% of subjects had low bone mass as measured by DXA. Z-scores for bone mineral content (BMC) were calculated based on age, gender, height, and ethnicity. Mean BMC z-score was marginally decreased at -0.89 {95% CI -2.01 to 0.23; p=0.1}. Mean total body bone mineral density (BMD) z-score was significantly reduced at -1.87 {95% CI -2.73 to -1.0; p=0.001}. Mean height percentile was close to - 2 SD for this cohort, thus total body BMD z-scores were recalculated, adjusting for height age. Adjusted mean total body BMD z-score was less reduced but still significant at -0.82 {95% CI -1.39 to -0.25; p=0.009}. Biochemical evaluation for bone turnover was unremarkable except serum IGF-I and IGF-BP3 levels which were low-normal for age. DISCUSSION: Children with NS have a significantly lower total body BMD compared to age, gender, ethnicity and height matched controls. In addition, total BMC appears to trend lower in children with NS compared to controls. We conclude that the metabolic bone disease present resulted from a subtle variation in the interplay of osteoclast and osteoblast activity, without clear abnormalities being defined in the metabolism of either. Clinical significance of this finding needs to be validated by larger longitudinal studies. Also, histomorphometric analysis of bone tissue from NS patients and mouse model of NS may further elucidate the relationship between the RAS-MAPK pathway and skeletal homeostasis.

Ethnic bias in anthropometric estimates of DXA abdominal fat: the TIGER study.

BACKGROUND/INTRODUCTION: The purpose of this study was to examine the race/ethnicity bias of using waist circumference (WC) to estimate abdominal fat. METHODS: A total of 771 females and 484 males (17-35 yr) were tested one to three times during a prescribed 30-wk aerobic exercise program. The race/ethnicity distribution for women was non-Hispanic white, 29%; Hispanic, 25%; African American (AA), 35%; Asian Indian, 3%; and Asian, 8%. The distribution for men was non-Hispanic white, 37%; Hispanic, 26%; AA, 22%; Asian Indian, 5%; and Asian, 10%. Abdominal fat (L1-L5) was estimated from whole-body scanning using dual-energy x-ray absorptiometry (DXA Abd-Fat). RESULTS: DXA Abd-Fat varied by race/ethnicity after accounting for WC and height in both women and men. The increase in DXA Abd-Fat per increase in WC was lower in the Asian and Asian-Indian women than that in the other women. The increase in DXA Abd-Fat per increase in WC was higher in the AA men and lower in the Asian-Indian men than that in the other men. These differential race/ethnicity effects were most notable when WC exceeded ≍90 cm in the women and ≍100 cm in the men, values which are consistent with current definitions of abdominal obesity in the United States. CONCLUSIONS: Prediction equations for abdominal fat using WC that do not account for race/ethnicity group provide biased estimates. These results may affect assessment of disease risk from abdominal obesity among racial/ethnic groups.

Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women.

BACKGROUND: Soy isoflavones are naturally occurring phytochemicals with weak estrogenic cellular effects. Despite numerous clinical trials of short-term isoflavone supplementation, there is a paucity of data regarding longer-term outcomes and safety. OBJECTIVE: Our aim was to evaluate the clinical outcomes of soy hypocotyl isoflavone supplementation in healthy menopausal women as a secondary outcome of a trial on bone health. DESIGN: A multicenter, randomized, double-blind, placebo-controlled 24-mo trial was conducted to assess the effects of daily supplementation with 80 or 120 mg aglycone equivalent soy hypocotyl isoflavones plus calcium and vitamin D on the health of 403 postmenopausal women. At baseline and after 1 and 2 y, clinical blood chemistry values were measured and a well-woman examination was conducted, which included a mammogram and a Papanicolaou test. A cohort also underwent transvaginal ultrasound measurements to assess endometrial thickness and fibroids. RESULTS: The baseline characteristics of the groups were similar. After 2 y of daily isoflavone exposure, all clinical chemistry values remained within the normal range. The only variable that changed significantly was blood urea nitrogen, which increased significantly after 2 y (P = 0.048) but not after 1 y (P = 0.343) in the supplementation groups. Isoflavone supplementation did not affect blood lymphocyte or serum free thyroxine concentrations. No significant differences in endometrial thickness or fibroids were observed between the groups. Two serious adverse events were detected (one case of breast cancer and one case of estrogen receptor-negative endometrial cancer), which was less than the expected population rate for these cancers. CONCLUSION: Daily supplementation for 2 y with 80-120 mg soy hypocotyl isoflavones has minimal risk in healthy menopausal women. This trial was registered at clinicaltrials.gov as NCT00665860.

Chronic parenteral nutrition induces hepatic inflammation, steatosis, and insulin resistance in neonatal pigs.

Prematurity and overfeeding in infants are associated with insulin resistance in childhood and may increase the risk of adult disease. Total parenteral nutrition (TPN) is a major source of infant nutritional support and may influence neonatal metabolic function. Our aim was to test the hypothesis that TPN induces increased adiposity and insulin resistance compared with enteral nutrition (EN) in neonatal pigs. Neonatal pigs were either fed enteral formula orally or i.v. administered a TPN mixture for 17 d; macronutrient intake was similar in both groups. During the 17-d period, we measured body composition by dual-energy X-ray absorptiometry scanning; fasting i.v. glucose tolerance tests (IVGTT) and hyperinsulinemic-euglycemic clamps (CLAMP) were performed to quantify insulin resistance. On d 17, tissue was collected after 1-h, low-dose CLAMP for tissue insulin signaling assays. TPN pigs gained less lean and more body fat and developed hepatic steatosis compared with EN pigs. After 7 and 13 d, IVGTT showed evidence of insulin resistance in the TPN compared with the EN group. Fasting plasma glucose and insulin also were higher in TPN pigs. CLAMP showed that insulin sensitivity was markedly lower in TPN pigs than in EN pigs. TPN also reduced the abundance of the insulin receptor, insulin receptor substrate 1, and phosphatidylinositol 3 kinase in skeletal muscle and liver and the proliferation of total pancreatic cells and ß-cells. Hepatic proinflammatory genes as well as c-Jun-N-terminal kinase 1 phosphorylation, plasma interleukin 6, and tumor necrosis factor-α were all higher in TPN pigs than in EN pigs. The results demonstrate that chronic TPN induces a hepatic inflammatory response that is associated with significant insulin resistance, hepatic steatosis, and fat deposition compared with EN in neonatal pigs. Further studies are warranted to establish the mechanism of TPN-induced insulin resistance and hepatic metabolic dysfunction and whether there are persistent metabolic consequences of this lifesaving form of infant nutritional support.

Exposing college students to exercise: the Training Interventions and Genetics of Exercise Response (TIGER) study.

OBJECTIVE: The Training Interventions and Genetics of Exercise Response (TIGER) study is an exercise program designed to introduce sedentary college students to regular physical activity and to identify genetic factors that influence response to exercise. PARTICIPANTS: A multiracial/ethnic cohort (N = 1,567; 39% male), age 18 to 35 years, participated in the study. METHODS: Subjects underwent 30 weeks of exercise training, 3 days/week, for 40 minutes at 65% to 85% of age- and gender-predicted maximum heart rate reserve. Multiple measures of body size/composition, heart rate, and blood pressure were obtained. RESULTS: A total of 1,567 participants, (39% male), age 18 to 35 years, participated in the TIGER study. The prevalence of overweight/obesity in participants was 48.0%/19.3% in non-Hispanic Whites, 55.3%/24.2% in Hispanic Whites, 54.9%/25.4% in African Americans, and 38.3%/11.3% in Asians. Average within-semester retention was 68%, but overall retention (30 weeks, 2 semesters) was 20%. CONCLUSIONS: The TIGER study represents an efficacious strategy for introducing college-aged individuals to regular aerobic exercise.

Generalized equations for estimating DXA percent fat of diverse young women and men: the TIGER study.

PURPOSE: Popular generalized equations for estimating percent body fat (BF%) developed with cross-sectional data are biased when applied to racially/ethnically diverse populations. We developed accurate anthropometric models to estimate dual-energy x-ray absorptiometry BF% (DXA-BF%) that can be generalized to ethnically diverse young adults in both cross-sectional and longitudinal field settings. METHODS: This longitudinal study enrolled 705 women and 428 men (aged 17-35 yr) for 30 wk of exercise training (3 d·wk(-1) for 30 min·d(-1) of 65%-85% predicted V˙O2max). The distribution of ethnicity was as follows: 37% non-Hispanic white, 29% Hispanic, and 34% African-American. DXA-BF%, skinfold thicknesses, and body mass index (BMI) were collected at baseline and after 15 and 30 wk. RESULTS: Skinfolds, BMI, and race/ethnicity were significant predictors of DXA-BF% in linear mixed model regression analysis. For comparable anthropometric measures (e.g., BMI), DXA-BF% was lower in African-American women and men but higher in Hispanic women compared with non-Hispanic white. Addition of BMI to the skinfold model improved the SEE for women (3.6% vs 4.0%), whereas BMI did not improve prediction accuracy of men (SEE = 3.1%). CONCLUSIONS: These equations provide accurate predictions of DXA-BF% for diverse young women and men in both cross-sectional and longitudinal settings. To our knowledge, these are the first published body composition equations with generalizability to multiple time points, and the SEE estimates are among the lowest published in the literature.

Body composition in infancy: impact on health later in life.

From retrospective studies, there is substantial evidence that birthweight and the rate of weight gain during early infancy are associated with increased risk for adverse health outcomes later in life. Birthweight is the marker of the integrative effects of the prenatal environment, while the rate of weight gain after birth reflects both genetic potential and external postnatal influences. The adulthood-to-infancy associations constitute the basis for the 'fetal origins' and 'catch-up growth' hypotheses for some diseases. However, these findings are based on the assumption that anthropometric-based indices reflect body composition during both time periods, with the body mass index (weight/stature2) being the most frequently used index. More direct measures of body composition were simply not available at the time of the births of the adults participating in these studies. Nowadays, there are a number of in vivo techniques that can be used to examine body composition in infancy. In particular, what does the body mass index reflect in terms of body composition for the infant? Is it an adequate index?

A comparison of the growth responses following intramuscular GHRH plasmid administration versus daily growth hormone injections in young pigs.

The efficacy of daily porcine growth hormone (GH) injections versus plasmid-driven porcine GH-releasing hormone (pGHRH) production to promote growth was assessed. Ten-day-old piglets were injected intramuscularly with 0.1, 1, or 3 mg pGHRH, or a control plasmid followed by electroporation. Plasmid constructs were driven by a synthetic muscle-specific promoter. A fifth group received daily injections of GH [0.15 mg/(kg.day)]. Control and pGHRH-treated pigs were pair-fed to GH-treated pigs. Body composition was assessed by dual-energy X-ray absorptiometry (DXA). Weight gains of GH- and pGHRH-treated pigs were greater than of controls (P < 0.001) due to greater lean mass accretion; fat accretion was similar across all treatments. Weight gain of pGHRH- and GH-treated pigs was similar for 6 weeks, but over the final 10 days, only pigs administered the highest plasmid dose maintained higher growth rates. Serum insulin-like growth factor-I (IGF-I) levels were two- to threefold higher in GH- and pGHRH-treated pigs than in controls after 4 weeks (P = 0.05), but subsequently decreased to control levels in the pGHRH-treated group. Organ weights were greater in GH- than pGHRH-treated and control piglets (P < 0.02). These results demonstrate that pGHRH transfer is effective for promoting growth and avoids the need for the frequent injections necessitated with peptide hormone use.

Soy isoflavone supplementation and bone mineral density in menopausal women: a 2-y multicenter clinical trial.

BACKGROUND: Isoflavones are naturally occurring plant estrogens that are abundant in soy. Although purported to protect against bone loss, the efficacy of soy isoflavone supplementation in the prevention of osteoporosis in postmenopausal women remains controversial. OBJECTIVE: Our aim was to test the effect of soy isoflavone supplementation on bone health. DESIGN: A multicenter, randomized, double-blind, placebo-controlled 24-mo trial was conducted to assess the effects of daily supplementation with 80 or 120 mg of soy hypocotyl aglycone isoflavones plus calcium and vitamin D on bone changes in 403 postmenopausal women. Study subjects were tested annually and changes in whole-body and regional bone mineral density (BMD), bone mineral content (BMC), and T scores were assessed. Changes in serum biochemical markers of bone metabolism were also assessed. RESULTS: After study site, soy intake, and pretreatment values were controlled for, subjects receiving a daily supplement with 120 mg soy isoflavones had a statistically significant smaller reduction in whole-body BMD than did the placebo group both at 1 y (P < 0.03) and at 2 y (P < 0.05) of treatment. Smaller decreases in whole-body BMD T score were observed among this group of women at 1 y (P < 0.03) but not at 2 y of treatment. When compared with the placebo, soy isoflavone supplementation had no effect on changes in regional BMD, BMC, T scores, or biochemical markers of bone metabolism. CONCLUSION: Daily supplementation with 120 mg soy hypocotyl isoflavones reduces whole-body bone loss but does not slow bone loss at common fracture sites in healthy postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00665860.

Body mass index bias in defining obesity of diverse young adults: the Training Intervention and Genetics of Exercise Response (TIGER) study.

The BMI cut-score used to define overweight and obesity was derived primarily using data from Caucasian men and women. The present study evaluated the racial/ethnic bias of BMI to estimate the adiposity of young men and women (aged 17-35 years) using dual-energy X-ray absorptiometry (DXA) determination of percentage body fat (DXA-BF%) as the referent standard. The samples were 806 women and 509 men who were tested from one to three times over 9 months providing 1300 observations for women and 820 observations for men. Linear mixed models (LMM) regression showed that with age and BMI controlled, DXA-BF% of African-American (AA) men and women, Asian-Indian men and women, Hispanic women and Asian women significantly differed from non-Hispanic white (NHW) men and women. For the same BMI of NHW women, the DXA-BF% of AA women was 1.76 % lower, but higher for Hispanic (1.65 %), Asian (2.65 %) and Asian-Indian (5.98 %) women. For the same BMI of NHW men, DXA-BF% of AA men was 4.59 % lower and 4.29 % higher for Asian-Indian men. Using the recommended BMI cut-scores to define overweight and obesity systematically overestimated overweight and obesity prevalence for AA men and women, and underestimated prevalence for Asian-Indian men and women, Asian women and Hispanic women. The present study extends the generalisability of research documenting the racial/ethnic bias of the universal overweight and obesity BMI cut-scores.

Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study.

PURPOSE: We studied the relationship between doxorubicin pharmacokinetics and body composition in children with cancer. PATIENTS AND METHODS: Children between 1 and 21 years of age, receiving doxorubicin as an infusion of any duration <24 h on either a 1-day or 2-day schedule were eligible if they had no significant abnormality of liver function tests, their dose of doxorubicin was not based on ideal body weight or otherwise "capped," and they weighed > or =12 kg. Body composition was measured by dual-energy X-ray absorptiometry. Doxorubicin and doxorubicinol concentration in plasma were measured by high pressure liquid chromatography. NONMEM was used to perform pharmacokinetic model fitting and S-PLUS was used to perform a post hoc analysis to examine the effect of body composition on pharmacokinetic parameters. RESULTS: Twenty-two subjects (16 male; 10 Hispanic, 10 Caucasian, 2 Asian) completed the study. The median age was 15.0 years (range 3.3-21.5), median weight was 51.5 kg (range 12.4-80), median BMI was 19.7 (range 13.2-30.0), and median body fat was 25% (range 15-36). The population mean clearance of doxorubicin was 420 ml/min/m(2). Doxorubicinol but not doxorubicin clearance was lower in patients with body fat greater than 30%. CONCLUSIONS: Doxorubicinol clearance is decreased in children with >30% body fat. This finding is potentially important clinically, because doxorubicinol may contribute significantly to cardiac toxicity after doxorubicin administration. Further study of the body composition on doxorubicin and doxorubicinol pharmacokinetics and on clinical outcomes is warranted.

Cross-validation of generalised body composition equations with diverse young men and women: the Training Intervention and Genetics of Exercise Response (TIGER) Study.

Generalised skinfold equations developed in the 1970s are commonly used to estimate laboratory-measured percentage fat (BF%). The equations were developed on predominately white individuals using Siri's two-component percentage fat equation (BF%-GEN). We cross-validated the Jackson-Pollock (JP) generalised equations with samples of young white, Hispanic and African-American men and women using dual-energy X-ray absorptiometry (DXA) as the BF% referent criterion (BF%-DXA). The cross-sectional sample included 1129 women and men (aged 17-35 years). The correlations between BF%-GEN and BF%-DXA were 0.85 for women and 0.93 for men. Analysis of measurement error showed that BF%-GEN underestimated BF%-DXA of men and women by 1.3 and 3.0 %. General linear models (GLM) confirmed that BF%-GEN systematically underestimated BF%-DXA of Hispanic men and women, and overestimated BF%-DXA of African-American men. GLM were used to estimate BF%-DXA from the JP sum of skinfolds and to account for race/ethnic group bias. The fit statistics (R and standard error of the estimate; see) of the men's calibration model were: white, R 0.92, see 3.0 %; Hispanic, R 0.91, see 3.0 %; African-American, R 0.95, see 2.6 %. The women's statistics were: white and African-American, R 0.86, see 3.8 %; Hispanic, R 0.83, see 3.4 %. These results showed that BF%-GEN and BF%-DXA were highly correlated, but the error analyses documented that the generalised equations lacked accuracy when applied to these racially and ethnically diverse men and women. The inaccuracy was linked to the body composition and race/ethnic differences between these Training Intervention and Genetics of Exercise Response (TIGER) study subjects and the men and women used to develop the generalised equations in the 1970s and using BF%-DXA as the referent criterion.

Bone mineral content and bone mineral density are lower in older than in younger females with Rett syndrome.

Although bone mineral deficits have been identified in Rett syndrome (RTT), the prevalence of low bone mineral density (BMD) and its association with skeletal fractures and scoliosis has not been characterized fully in girls and women with RTT. Accordingly, we measured total body bone mineral content (BMC) and BMD using dual energy x-ray absorptiometry in a cross-sectional group of 50 females, aged 2-38 y, with RTT. Methyl-CpG-binding 2 (MECP2) mutations, skeletal fractures, and scoliosis were documented. The prevalence of BMC and BMD z scores < or-2 SD was 59 and 45%, respectively. Although absolute BMC and BMD increased significantly with increasing age, BMC, and BMD z scores were significantly lower in older than in younger females. The prevalence of fractures and scoliosis was 28 and 64%, respectively. Low BMD z scores were positively associated with fractures and scoliosis. Deficits in BMD were identified across a broad range of MECP2 mutations. This study identified associations among low BMD, fractures, and scoliosis, and underscored the need for better understanding of the molecular mechanisms of MECP2 in the regulation of bone mineral metabolism.

DXA: can it be used as a criterion reference for body fat measurements in children?

OBJECTIVE: Dual-energy X-ray absorptiometry (DXA) is often cited as a criterion method for body composition measurements. We have previously shown that a new DXA software version (Hologic Discovery V12.1) will affect whole-body bone mineral results for subjects weighing <40 kg. We wished to reanalyze pediatric whole-body scans in order to assess the impact of the new software on pediatric soft-tissue body composition estimates. METHODS AND PROCEDURES: We reanalyzed 1,384 pediatric scans (for ages 1.7-17.2 years) using Hologic software V12.1, previously analyzed using V11.2. Regression analysis and ANCOVA were used to compare body fat (total body fat (TBF), percentage fat (%BF)), and non-bone lean body mass (LBM) for the two versions, adjusting for gender, age and weight. RESULTS: Software V12.1 yielded values that were higher for TBF, lower for LBM, and unchanged for DXA-derived weight in subjects weighing <40 kg. Body composition values for younger, smaller subjects were most affected, and girls were more affected than boys. Using the new software, 14% of the girls and 10% of the boys were reclassified from the "normal" %BF range to "at risk of obesity," while 7 and 5%, respectively, were reclassified as obese. DISCUSSION: Hologic's newest DXA software has a significant effect on soft-tissue results for children weighing <40 kg. The effect is greater for girls than boys. Comparison of TBF estimates with previous studies that use older DXA instruments and software should be done with caution. DXA has not yet achieved sufficient reliability to be considered a "gold standard" for body composition assessment in pediatric studies.

Generalized metabolic bone disease in Neurofibromatosis type I.

Skeletal abnormalities are a recognized component of Neurofibromatosis type I (NF1) but a generalized metabolic bone defect in NF1 has not been fully characterized thus far. The purpose of this study was to characterize at the densitometric, biochemical and pathological level the bone involvement in NF1 patients. Using dual energy X-ray absorptiometry (DXA) we analyzed bone status in 73 unselected NF1 subjects, 26 males and 47 females, mainly children and adolescents (mean age: 16.6 years). In a subgroup of subjects with low bone mass, we measured indices of calcium-phosphate metabolism, bone turnover, and bone density before and after vitamin D and calcium treatment. We found statistically significant and generalized reduction in bone mass with the mean lumbar bone mineral density (BMD) z-score being -1.38+/-1.05 (CI 95% -1.62 to -1.13), and whole body bone mineral content (BMC) z-score -0.61+/-1.19 (CI 95% -0.94 to -0.29), both significantly reduced compared to normal controls (p<.001). PTH was moderately elevated and after 4 months of supplemental therapy with calcium and vitamin D, it decreased to the normal range. However, BMD z-scores did not significantly improve after 2 years of follow-up. Histological analysis of bone samples from NF1 patients revealed substantial alteration of bone microarchitecture due mainly to reduced trabecular bone. Our observations are consistent with a generalized bone metabolic defect due to loss of the function of neurofibromin. Early identification of patients with osteoporosis may permit more timely and aggressive treatments to prevent the likely substantial morbidity associated with increased fracture risk later in life.