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ContextAdults with cerebral palsy (CP) display a higher prevalence of cardiometabolic disease compared with the general population. Studies examining cardiometabolic disease risk in children with CP are limited.ObjectiveThe purpose of this study was to determine if children with CP exhibit higher cardiometabolic risk than typically developing children, and to examine its relationship with visceral adiposity and physical activity.MethodsThirty ambulatory children with CP and 30 age-, sex-, and race-matched typically developing control children were tested for blood lipids, glucose, and the homeostatic model assessment of insulin resistance (HOMA-IR). Visceral fat was assessed using dual-energy x-ray absorptiometry. Physical activity was assessed using accelerometer-based monitors.ResultsChildren with CP had higher total cholesterol, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol (non-HDL-C), glucose, prevalence of dyslipidemia, prevalence of prediabetes, and visceral fat mass index (VFMI) and lower physical activity than controls (all P < .05). In the groups combined, non-HDL-C and glucose were positively related to VFMI (r = 0.337 and 0.313, respectively, P < .05), and non-HDL-C and HOMA-IR were negatively related to physical activity (r = −0.411 and −0.368, respectively, P < .05). HOMA-IR was positively related to VFMI in children with CP (r = 0.698, P < .05), but not in controls. Glucose was not related to physical activity in children with CP, but it was negatively related in controls (r = −0.454, P < .05).ConclusionChildren with CP demonstrate early signs of cardiometabolic disease, which are more closely related to increased visceral adiposity than decreased physical activity.

OBJECTIVE To evaluate the efficacy and safety of tin mesoporphyrin (SnMP) in neonates with hyperbilirubinemia (HB) due to hemolysis. STUDY DESIGN This multicenter, placebo-controlled phase 2b study (NCT01887327) randomized newborns (35-42 weeks) with hemolysis started on phototherapy (PT) to placebo (Ctrl), SnMP 3.0 mg/kg, or SnMP 4.5 mg/kg given once IM within 30 min of initiation of PT. RESULTS In all, 91 patients were randomized (Ctrl: n = 30; 3 mg/kg SnMP: n = 30; 4.5 mg/kg SnMP: n = 31). At 48 h TSB significantly increased in Ctrl by 17.5% (95% CI 5.6-30.7; p = 0.004) and significantly decreased by -13% (95% CI -21.7 to -3.2; p = 0.013) in the 3.0 mg/kg and by -10.5% (95% CI -19.4 to -0.6; p = 0.041) in the 4.5 mg/kg group. Decreases in SnMP groups were significant (p

Background Important disparities in the treatment and outcomes of women and men with atrial fibrillation are well recognized. Whether introduction of direct oral anticoagulants has reduced disparities in treatment is uncertain. Methods All patients who had an incident hospitalization from 2010 to 2019 with non-valvular atrial fibrillation in Scotland were included in this cohort study. Community drug dispensing data were used to determine prescribed oral anticoagulation therapy and comorbidity status. Logistic regression modelling was used to evaluate patient factors associated with treatment with vitamin K antagonists and direct oral anticoagulants. Results A total of 172,989 patients (48% women [82,833/172,989]) had an incident hospitalization with non-valvular atrial fibrillation in Scotland between 2010 and 2019. The proportion of patients with thromboembolic risk factors (CHA2DS2VASc score >0 in men and >1 in women) treated with oral anticoagulation therapy increased from 36.8% to 66.3% over this 10-year period. By 2019, factor Xa inhibitors accounted for 83.6% of all oral anticoagulants prescribed, while treatment with vitamin K antagonists and direct thrombin inhibitors declined to 15.9% and 0.6%, respectively. Women were less likely to be prescribed any oral anticoagulation therapy compared to men (adjusted odds ratio, aOR 0.68 [95% CI, CI 0.67–0.70]). This disparity was mainly attributed to vitamin K antagonists (aOR 0.68 [95% CI 0.66–0.70]), whilst there was less disparity in use of factor Xa inhibitors between women and men (aOR 0.92 [95% CI 0.90–0.95]). At 1 year following hospitalization with atrial fibrillation, patients not prescribed oral anticoagulation therapy were more likely to have subsequent major adverse cardiovascular events compared to those prescribed with oral anticoagulation therapy (38.8% [15,380/39,608] versus 17.0% [6,761/39,671] in women and 35.2% [12,977/36,868] versus 16.4% [7,395/45,093] in men). Conclusions Women with non-valvular atrial fibrillation were significantly less likely to be prescribed vitamin K antagonists compared to men. Most patients admitted to hospital in Scotland with incident non-valvular atrial fibrillation are now treated with factor Xa inhibitors and this is associated with less treatment disparities between women and men. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This study was supported by the British Heart Foundation through a Clinical Research Training Fellowship (FS/18/25/33454), Intermediate Clinical Research Fellowship (FS/19/17/34172), Senior Clinical Research Fellowship (FS/16/14/32023) and a Research Excellence Award (RE/18/5/34216), and a research grant to NHS Lothian from Bristol Myers Squibb Pharmaceuticals Ltd and Pfizer UK Ltd.

Background Perinatal growth has important implications for cardiac development. Low birth weight is associated with cardiovascular (CV) events and mortality, and animal studies have shown that fetal growth restriction is associated with cardiac remodeling in the perinatal period leading to a permanent loss of cardiomyocyte endowment and compensatory hypertrophy. Aims To determine associations of birthweight (BW) and multiple proportionality indexes (body mass index (BMI); weight/length2 and Ponderal index (PI); weight/length3) at birth on one hand, with left ventricular (LV) structure and function during adolescence. Subjects 379 healthy adolescents aged 14–18 years in Augusta, Georgia. Outcome measures LV structure and function parameters, including intraventricular septal thickness in diastole (IVSd), LV internal dimension in diastole (LVIDd), LV internal diameter in systole (LVIDs), LV posterior wall thickness in diastole (LVPWd), relative wall thickness (RWT), midwall fractional shortening (MFS), and ejection fraction, were assessed by echocardiography. Results When associations of birthweight, birth BMI, and birth PI with LV structure and function parameters were separately evaluated with linear regression adjusting for age, sex, race, Tanner stage, socioeconomic status, and physical activity, significant positive associations of BW with LVIDd (P = 0.004), birth BMI with LV mass index (P = 0.01), and birth PI with IVSd (P = 0.02), LVPWd (P = 0.03), and LV mass index (P = 0.002) were identified. When LV structure and function parameters were compared across PI tertiles, a significant U-shaped trend for LV mass index (Pquadratic = 0.04) was identified. Conclusions Our adolescent data suggest that proportionality at birth may identify associations between perinatal growth and cardiac remodeling independent of birthweight alone.

Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Introduction Atrial Fibrillation (AF) is an important cause of mortality and morbidity. The major risk of AF is stroke, which can be reduced through anticoagulation. The burden of stroke, and AF-related stroke, is particularly high in Scotland. It is often reported that AF-related stroke is associated with poorer outcomes than other stroke types, it is also thought to lead to an increased institutionalisation. Data supporting these observations are historic, but major advances in AF assessment and treatment could have changed outcome patterns. Real world evidence on outcomes, collected at scale, can give a useful measure of contemporary AF stroke outcomes. Purpose To assess whether stroke patients, with and without AF on admission, differ in terms of al-cause mortality, recurrence of stroke, and care home admission using contemporary large-scale observational data. Methods A retrospective cohort study linking national hospital, prescribing, care home and stroke audit data was conducted. The cohort, comprising patients ≥18 years of age with incident ischemic stroke between 2009 and 2017, was divided into three groups: AF-related stroke prescribed oral anticoagulant (OAC) pre-stroke event (AF-OAC Group); AF-related stroke not prescribed anticoagulant pre-stroke event (AF-noOAC Group); stroke with no prevalent or incident AF and no anticoagulation (comparator) (noAF-noOAC Group). Time-to-event analyses (adjusted for demographic and clinical characteristics) were conducted to estimate hazard ratios for recurrent stroke, all-cause mortality, and care-home admission with a follow-up time of two years. Results From a cohort of 64,159 incident ischemic strokes, 4,418 and 15,124 patients with AF were identified for groups AF-OAC and AF-noOAC, respectively. The remaining 44,617 patients belonged to group noAF-noOAC. An increasing number of incident strokes was observed with increasing age in each group up to 80–84 years. The risk of recurrent stroke was significantly greater in groups AF-OAC (HR 1.12 [95% CI 1.08,1.17]) and AF-noOAC (HR 1.05 [95% CI 1.03,1.08]) compared to noAF-noOAC group. An increased risk of all-cause mortality was observed in groups AF-OAC (HR 1.52 [95% CI 1.39,1.66]) and AF-noOAC (HR 1.59 [95% CI 1.51,1.68]) compared to the noAF-noOAC group. Patients in group AF-noOAC were more likely to be discharged to a care home following stroke (HR 1.37 [95% CI 1.23,1.52]) compared to patients in the other groups. Conclusion AF-related stroke is associated with poor outcomes, with significantly higher risks of recurrent stroke and all-cause mortality for patients with AF compared to non-AF stroke. Despite advances in AF care, our data suggest there is still potential to prevent a substantial proportion of disabling strokes through better identification and treatment of AF. These results must be interpreted with caution, as data take no account of treatment adherence, dosing or rationale for individual patient level prescribing decisions. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Bristol-Myers Squibb Research and Development

BackgroundA previous real-world study has reported the characteristics, treatment patterns and clinical outcomes of patients with rheumatoid arthritis (RA) who received abatacept in UK clinical practice.1,2 However, many of the eligible population received abatacept monotherapy rather than as indicated. A subgroup analysis of patients treated with abatacept in combination with methotrexate (ABA + MTX) was therefore undertaken to explore the treatment effect in this specific patient population.ObjectivesPresent a subgroup analysis describing the clinical outcomes of patients with RA treated with ABA + MTX in UK real-world clinical practice.MethodsA multi-centre, retrospective observational study was undertaken in patients with RA treated with abatacept at any line of therapy between 1 January 2013 and 31 December 2017, across four UK centres. Data were collected from patient medical records from index date, defined as the date of first bDMARD initiation, to most recent RA clinic visit, death or end of study (31 December 2017). Clinical outcomes (disease activity and response to treatment) were measured using the 28-joint Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) and European League Against Rheumatism (EULAR) response criteria. Patients that received abatacept outside indication (i.e., without concomitant methotrexate) were retrospectively excluded from the analysis dataset. Statistical analyses for the ABA + MTX subgroup were repeated in line with the methodology previously reported.1,2ResultsThis subgroup analysis included 133 patients, of 213 patients included in the original study, with RA that received ABA + MTX (mean age 54.6 years, 77.4% female, 7.5 years mean duration of RA at index date). At index date, 64.8% of patients were positive for both anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), where data were available. In total, 77.8% of patients were categorised with high disease activity at index, with mean DAS28-ESR of 6.2 (SD 1.1).Irrespective of line of treatment (LOT), patients tended to have a more favourable distribution of good/moderate/no EULAR response when receiving ABA + MTX (31.8%/34.1%/34.1%; n=44) compared with receipt of other bDMARDs (12.7%/36.4%/50.9%; n=55) at 6 months. Similarly, a favourable distribution of good/moderate/no EULAR response in favour of those receiving ABA + MTX compared with other bDMARDs was observed at 12 months (30.6%/41.7%/27.8% versus 20.0%/35.0%/45.0%, respectively).Patients receiving ABA + MTX remained on treatment for significantly longer than patients in receipt of other bDMARDs as first LOT (median time on treatment 53.4 vs 18.1 months; pConclusionPatients with RA who received treatment with any bDMARDs, including ABA + MTX, experienced reduced disease activity. However, those receiving ABA + MTX persisted with treatment significantly longer than when receiving other bDMARDs.References[1]Choy, E. et al. Outcomes in rheumatoid arthritis patients treated with abatacept: a UK multi-centre observational study. BMC Rheumatology5, 3, doi:10.1186/s41927-020-00173-0 (2021).[2]Henning, S. et al. AB0295 CHANGE IN DISEASE ACTIVITY AND TREATMENT RESPONSE AFTER ABATACEPT TREATMENT FOR RHEUMATOID ARTHRITIS: REAL-WORLD EVIDENCE FROM THE UK. Annals of the Rheumatic Diseases79, 1446-1447, doi:10.1136/annrheumdis-2020-eular.1069 (2020).AcknowledgementsThis analysis was supported by Bristol-Myers Squibb.Disclosure of InterestsErnest Choy Speakers bureau: Abbvie, Amgen, Bristol Myer Squibbs, Chugai Pharma, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Consultant of: Abbvie, Amgen, Biogen, Biocon, Chugai Pharma, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm and Sanofi, Grant/research support from: Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi and UCB, Sadie Henning Shareholder of: Bristol Myers Squibb, Employee of: Yes, Bristol Myers Squibb, Marie Brazil Shareholder of: Bristol Myers Squibb, Employee of: Currently an employee of Bristol Myers Squibb, Kevin Pollock Shareholder of: Yes - Bristol Myers Squibb, Speakers bureau: Yes - Merck Sharp & Dohme and Glaxo Smith Kline, Consultant of: Yes - Merck Sharp & Dohme, Employee of: Yes – currently employed by Bristol Myers Squibb, Lara Groves Grant/research support from: I am an employee of Health Economics and Outcomes Research Ltd., Cardiff, UK, who received fees from Bristol Myers Squibb in relation to this study, Daniel Sugrue Grant/research support from: I am an employee of Health Economics and Outcomes Research Ltd., Cardiff, UK, who received fees from Bristol Myers Squibb in relation to this study, John Houghton Grant/research support from: I am an employee of Health Economics and Outcomes Research Ltd., Cardiff, UK, who received fees from Bristol Myers Squibb in relation to this study

Background: Associations between childhood vitamin K consumption and cardiac structure and function have not been investigated. Objective: We determined associations between phylloquinone (vitamin K-1) intake and left ventricular (LV) structure and function in adolescents. Methods: We assessed diet with three to seven 24-h recalls and physical activity (PA) by accelerometry in 766 adolescents (aged 14–18 y, 50% female, 49% black). Fat-free soft tissue (FFST) mass and fat mass were measured by dual-energy X-ray absorptiometry. LV structure [LV mass (g)/height (m)2.7 (LV mass index) and relative wall thickness] and function [midwall fractional shortening (MFS) and ejection fraction] were assessed by echocardiography. Associations were evaluated by comparing the LV structure and function variables across tertiles of phylloquinone intake. Prevalence and OR of LV hypertrophy (LV mass index >95th percentile for age and sex) were also assessed by phylloquinone tertiles. Results: The prevalence of LV hypertrophy progressively decreased across tertiles of phylloquinone intake (P-trend < 0.01). Multinomial logistic regression—adjusting for age, sex, race, Tanner stage, systolic blood pressure, FFST mass, fat mass, socioeconomic status, PA, and intakes of energy, fiber, calcium, vitamin C, vitamin D, and sodium—revealed that compared with the highest phylloquinone intake tertile (reference group), the adjusted OR for LV hypertrophy was 3.3 (95% CI: 1.2, 7.4) for those in the lowest phylloquinone intake tertile. When LV structure variables were compared across phylloquinone intake tertiles adjusting for the same covariates, there were significant linear downward trends for LV mass index (6.5% difference, tertile 1 compared with tertile 3) and relative wall thickness (9.2% difference, tertile 1 compared with tertile 3; both P-trend ≤ 0.02). Conversely, significant linear upward trends across phylloquinone intake tertiles were observed for MFS (3.4% difference, tertile 1 compared with tertile 3) and ejection fraction (2.6% difference, tertile 1 compared with tertile 3; both P-trend < 0.04). Conclusion: Our adolescent data suggest that subclinical cardiac structure and function variables are most favorable at higher phylloquinone intakes.

A wide-band vertical instability feedback control system in development at CERN requires 1–1.5 GHz of bandwidth for the entire processing chain, from the beam pickups through the feedback signal digital processing to the back-end power amplifiers and kicker structures. Dispersive effects in cables, amplifiers, pickup and kicker elements can result in distortions in the time domain signal as it proceeds through the processing system, and deviations from linear phase response reduce the allowable bandwidth for the closed-loop feedback system. We have developed an equalizer analog circuit that compensates for these dispersive effects. Here we present a design technique for the construction of an analog equalizer that incorporates the effect of parasitic circuit elements in the equalizer to increase the fidelity of the implemented equalizer. Finally, we show results from the measurement of an assembled backend equalizer that corrects for dispersive elements in the cables over a bandwidth of 10–1000 MHz.

IGF-I is a pivotal hormone in pediatric musculoskeletal development. Although recent data suggest that the role of IGF-I in total body lean mass and total body bone mass accrual may be compromised in children with insulin resistance, cortical bone geometric outcomes have not been studied in this context. Therefore, we explored the influence of insulin resistance on the relationship between IGF-I and cortical bone in children. A secondary aim was to examine the influence of insulin resistance on the lean mass-dependent relationship between IGF-I and cortical bone. Children were otherwise healthy, early adolescent black and white boys and girls (ages 9 to 13 years) and were classified as having high (n = 147) or normal (n = 168) insulin resistance based on the homeostasis model assessment of insulin resistance (HOMA-IR). Cortical bone at the tibia diaphysis (66% site) and total body fat-free soft tissue mass (FFST) were measured by peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA), respectively. IGF-I, insulin, and glucose were measured in fasting sera and HOMA-IR was calculated. Children with high HOMA-IR had greater unadjusted IGF-I (p

Whole-body vibration (WBV) has gained attention as a potential exercise mimetic, but direct comparisons with the metabolic effects of exercise are scarce. To determine whether WBV recapitulates the metabolic and osteogenic effects of physical activity, we exposed male wild-type (WT) and leptin receptor–deficient (db/db) mice to daily treadmill exercise (TE) or WBV for 3 months. Body weights were analyzed and compared with WT and db/db mice that remained sedentary. Glucose and insulin tolerance testing revealed comparable attenuation of hyperglycemia and insulin resistance in db/db mice following TE or WBV. Both interventions reduced body weight in db/db mice and normalized muscle fiber diameter. TE or WBV also attenuated adipocyte hypertrophy in visceral adipose tissue and reduced hepatic lipid content in db/db mice. Although the effects of leptin receptor deficiency on cortical bone structure were not eliminated by either intervention, exercise and WBV increased circulating levels of osteocalcin in db/db mice. In the context of increased serum osteocalcin, the modest effects of TE and WBV on bone geometry, mineralization, and biomechanics may reflect subtle increases in osteoblast activity in multiple areas of the skeleton. Taken together, these observations indicate that WBV recapitulates the effects of exercise on metabolism in type 2 diabetes., We compared the effects of exercise and whole-body vibration in obese and nonobese mice. The results indicate that whole-body vibration mimics the effects of exercise on metabolism in obese mice.

Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC50 values of 2.71μM and 1.86μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86.

Additional file 1. The ACTION trial.

BACKGROUND It is unknown to what extent higher maternal blood pressure (BP) in early postpartum impacts the relationship between higher maternal weight status and greater infant weight gain in early postpartum. OBJECTIVE To evaluate the mediating role of higher maternal BP at 1 month postpartum on the association between higher maternal weight status at 1 month postpartum and greater infant weight gain over 6 months postpartum. METHODS Participants were 169 Hispanic mother-infant pairs. Maternal body mass index (BMI) and BP were assessed at 1 month postpartum. Infant weight was measured at 1 and 6 months postpartum to calculate weight-for-age z scores (WAZ). Multiple linear regression models were used for prediction, and Sobel test was used to determine mediation. RESULTS Controlling for maternal pre-pregnancy BMI, age, delivery mode, infant sex, and infant birth weight revealed that both maternal BMI (β = .29) and BP (β = .32) predicted infant WAZ gain (both P ≤ .03). However, the relationship between infant WAZ gain and maternal BMI was no longer significant after further adjustment for maternal BP, which remained significant (P < .05). Maternal BP explained 23.6% (Sobel T = 2.01) of the association between maternal BMI at 1 month and infant WAZ gain over 6 months. CONCLUSION Our data suggest that higher maternal weight status at 1 month postpartum is related to greater infant weight gain over 6 months postpartum, and this relationship is mediated by higher maternal BP at 1 month postpartum.

Introduction Childhood obesity and inactivity are associated with cardiovascular risk. Evidence is limited for exercise effects on arterial health in children. Methods One hundred seventy-five inactive children with overweight or obesity (8–11 years, ≥85th percentile BMI, 61% female, 87% Black, 73% with obesity) were randomized to an 8-month daily after-school aerobic exercise program (40 min/d, n=90) or a sedentary control condition (n=85). Carotid-femoral pulse wave velocity (PWV, primary outcome, arterial stiffness), fitness, adiposity, blood pressure (BP), glucose, insulin resistance, lipids, and C-reactive protein were measured at baseline and posttest (8 months). Adiposity, fitness, and BP were measured again at follow-up, 8–12 months later. Intent-to-treat analyses were conducted using mixed models. Results The study had 89% retention, with attendance of 59% in exercise and 64% in the control condition, and vigorous exercise participation (average heart rate 161±7 beats/min). Compared to controls, the exercise group had twice the improvement in fitness (VȮ2 peak, 2.7 (95% CI 1.8, 3.6) vs. 1.3 (0.4, 2.3) ml/kg/min) and adiposity (−1.8 (−2.4, −1.1) vs. −0.8 (−1.5, -0.1)%), each p=0.04, and a large improvement in HDL-cholesterol (0.13 (0.075, 0.186) vs. -0.028 (−0.083, 0.023) mmol/l, p

IGF-1 promotes bone growth directly and indirectly through its effects on skeletal muscle. Insulin and IGF-1 share a common cellular signaling process; thus, insulin resistance may influence the IGF-1-muscle-bone relationship.We sought to determine the effect of insulin resistance on the muscle-dependent relationship between IGF-1 and bone mass in premenarcheal girls.This was a cross-sectional study conducted at a university research center involving 147 girls ages 9 to 11 years.Glucose, insulin, and IGF-1 were measured from fasting blood samples. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin. Fat-free soft tissue (FFST) mass and bone mineral content (BMC) were measured by dual-energy x-ray absorptiometry. Our primary outcome was BMC/height.In our path model, IGF-1 predicted FFST mass (b = 0.018; P = .001), which in turn predicted BMC/height (b = 0.960; P.001). IGF-1 predicted BMC/height (b = 0.001; P = .002), but not after accounting for the mediator of this relationship, FFST mass. The HOMA-IR by IGF-1 interaction negatively predicted FFST mass (b = -0.044; P = .034). HOMA-IR had a significant and negative effect on the muscle-dependent relationship between IGF-1 and BMC/height (b = -0.151; P = .047).Lean body mass is an important intermediary factor in the IGF-1-bone relationship. For this reason, bone development may be compromised indirectly via suboptimal IGF-1-dependent muscle development in insulin-resistant children.

Background: Data have shown that healthy children and adolescents have an inadequate intake of zinc, an essential nutrient for growth. It is unclear whether zinc supplementation can enhance bone health during this rapid period of growth and development. Objective: The primary aim of this study was to determine the effect of zinc supplementation on biochemical markers of bone turnover and growth in girls entering the early stages of puberty. The secondary aim was to test moderation by race, body mass index (BMI) classification, and plasma zinc status at baseline. Methods: One hundred forty seven girls aged 9–11 y (46% black) were randomly assigned to a daily oral zinc tablet (9 mg elemental zinc; n = 75) or an identical placebo (n = 72) for 4 wk. Fasting plasma zinc, procollagen type 1 amino-terminal propeptide (P1NP; a bone formation marker), carboxy-terminal telopeptide region of type 1 collagen (ICTP; a bone resorption marker), and insulin-like growth factor I (IGF-I) were assessed at baseline and post-test. Additional markers of bone formation (osteocalcin) and resorption (urinary pyridinoline and deoxypyridinoline) were also measured. Results: Four weeks of zinc supplementation increased plasma zinc concentrations compared with placebo [mean change, 1.8 μmol/L (95% CI: 1.0, 2.6) compared with 0.2 μmol/L (95% CI: −0.3, 0.7); P < 0.01]. Zinc supplementation also increased serum P1NP concentrations compared with placebo [mean change, 23.8 μmol/L (95% CI: −14.9, 62.5) compared with −31.0 μmol/L (95% CI: −66.4, 4.2); P = 0.04). There was no effect from zinc supplementation on osteocalcin, ICTP, pyridinoline, deoxypyridinoline, or IGF-I. There was no moderation by race, BMI classification, or plasma zinc status at baseline. Conclusions: Our data suggest that 4 wk of zinc supplementation increases bone formation in premenarcheal girls. Further studies are needed to determine whether supplemental zinc can improve childhood bone strength. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT01892098","term_id":"NCT01892098"}}NCT01892098.

Investigations in older individuals suggest that adequate nutrition and physical activity are particularly important to skeletal muscle health; however, data in adolescents are scant and equivocal. The objective was to determine the associations among diet, physical activity and skeletal muscle mass in adolescents.We assessed diet with four to seven 24-h recalls and physical activity by accelerometry in 640 adolescents. Using total body measures of fat-free soft tissue mass and fat mass assessed by dual-energy X-ray absorptiometry, the skeletal muscle mass index (SMMI) was derived by adjusting fat-free soft tissue mass for fat mass in addition to height.Skeletal muscle mass index (SMMI) was negatively associated with consumption of sugar-sweetened beverages (standardized beta coefficient [β] = -0.10, P = 0.001) and saturated fats (β = -0.28, P 0.001). SMMI was positively associated with physical activity (moderate + vigorous) (β = 0.20, P 0.001). In further analysis, we observed a significant interaction between physical activity and sugar-sweetened beverage intake on SMMI (P = 0.002).Our study in adolescence suggests that physical activity and consumption of both sugar-sweetened beverages and saturated fats are associated with skeletal muscle mass. More importantly, our findings suggest that sugar-sweetened beverage intake may attenuate the beneficial effects of physical activity on skeletal muscle mass.

Purpose The combretastatins (CAs) are known to exhibit anti-tumour activity but the underlying mechanism remains to be fully elucidated. Inflammation plays a critical role in altering the function of cancer cells and evasion of cell death and increased proliferation are characteristics of transformed malignancies. Many of the proteins involved in these pathways are regulated by the transcription factor NF-κB which can be activated by tumour necrosis factor (TNF-α), a pro-inflammatory cytokine released by both malignant and immune cells within the tumour microenvironment. In this study, we examined the ability of combretastatin A-4 (CA-4) and its novel, cis-restricted analogue CA-432 to target the NF-κB signalling pathway in T cells. Methods Effects of the CAs on the viability of DND-41 leukaemia and Jurkat lymphoma T-cell lines was assessed by the alamar blue assay. Induction of apoptosis and effects on expression levels of key apoptotic proteins was established though flow cytometry and western blotting. Modulation of the NF-κB signalling pathway was determined through western blotting and through assessment of NF-κB reporter gene activity. Results CA-4 and CA-432 reduced cell viability and induced apoptosis in DND-41 and Jurkat T cells and sensitised the cells to TNF-α-induced apoptosis through inhibition of the NF-κB signalling pathway. Suppression of the NF-κB pathway downregulated NF-κB-dependent gene products involved in cell survival (IAPs, Bcl-2 and Mcl-1), proliferation (cyclin D1) and inflammation (COX-2). Furthermore, both CA-4 and CA-432 inhibited TNF-α-induced NF-κB activation through the inhibition of IκBα degradation and p65 nuclear translocation and decreased NF-κB reporter gene activity. Conclusions Our data indicate that the anti-cancer properties of comebretastatins may be mediated in part through targeting the NF-κB pathway. This study provides new insights into the molecular mechanisms of CA compounds and a potential application of combretastatins for inflammatory diseases such as cancers, which are associated with abnormal NF-κB activation.

BACKGROUND Matrix Gla protein (MGP) is a vascular calcification inhibitor dependent upon vitamin K for activation. Evidence suggests that elevated plasma inactive MGP levels (desphospho-uncarboxylated MGP, dp-ucMGP; indicating poorer vascular vitamin K status) are associated with greater cardiovascular disease (CVD) risk. Despite African Americans experiencing highest rates of kidney failure and CVD events, relationships between dp-ucMGP and CVD risk markers have not been examined in this population. We investigated vascular vitamin K status (via plasma dp-ucMGP) between African American hemodialysis (HD) patients and healthy controls, and the associations of dp-ucMGP with arterial stiffness and endothelial function in HD patients only. METHODS In 37 African American HD patients and 37 age- and race-matched controls, plasma dp-ucMGP was measured by enzyme immunoassay as a marker of vascular vitamin K status. Carotid-femoral pulse wave velocity (PWV; arterial stiffness measurement) and brachial artery flow-mediated dilation (FMD; endothelial function measurement) were assessed by applanation tonometry and ultrasound, respectively, in HD patients only. RESULTS Mean dp-ucMGP levels were 5.6 times higher in HD patients vs. controls (2,139 +/- 1,102 vs. 382 +/- 181 pmol/l, P < 0.01). Multiple linear regression, adjusting for age, sex, dialysis vintage, diabetes mellitus, CVD history, body mass index, and blood pressure, revealed that dp-ucMGP was independently related to PWV (standardized beta = 0.49) and FMD (standardized beta = -0.53) (both P < 0.01). CONCLUSIONS Our data suggest that the higher plasma dp-ucMGP concentrations found in African American HD patients may be associated with greater arterial stiffness and endothelial dysfunction.

Though still a topic of debate, the position that skeletal health is compromised with obesity has received support in the pediatric and adult literature. The limited data relating specifically to trabecular bone microarchitecture, however, have been relatively inconsistent. The aim of this pilot cross-sectional case-control study was to compare trabecular bone microarchitecture between obese (OB) and normal-weight (NW) late-adolescent females. A secondary aim was to compare diaphyseal cortical bone outcomes between these two groups. Twenty-four non-Hispanic white females, ages 18–19 years, were recruited into OB (n = 12) or NW (n = 12) groups based on pre-specified criteria for percent body fat (≥32 vs. 90th vs. 20th–79th, respectively), and waist circumference (≥90th vs. 25th–75th, respectively). Participants were also individually matched on age, height, and oral contraceptive use. Using magnetic resonance imaging, trabecular bone microarchitecture was assessed at the distal radius and proximal tibia metaphysis, and cortical bone architecture was assessed at the mid-radius and mid-tibia diaphysis. OB versus NW had lower apparent trabecular thickness (radius and tibia), higher apparent trabecular separation (radius), and lower apparent bone volume to total volume (radius; all P < 0.050). Some differences in radius and tibia trabecular bone microarchitecture were retained after adjusting for insulin resistance or age at menarche. Mid-radius and mid-tibia cortical bone volume and estimated strength were lower in the OB compared to NW after adjusting for fat-free soft tissue mass (all P

The capacity of T-lymphocytes to migrate and localise in tissues is important in their protective function against infectious agents, however, the ability of these cells to infiltrate the tumour microenvironment is a major contributing factor in the development of cancer. T-cell migration requires ligand (ICAM-1)/integrin (LFA-1) interaction, activating intracellular signalling pathways which result in a distinct polarised morphology, with an actin-rich lamellipodium and microtubule (MT)-rich uropod. Combretastatin (CA)-4 is a MT-destabilising agent that possesses potent anti-tumour properties. In this study, the effect of CA-4 and its novel analogue CA-432 on human T-cell migration was assessed. Cellular pretreatment with either of CA compounds inhibited the migration and chemotaxis of the T-cell line HuT-78 and primary peripheral blood lymphocyte (PBL) T-cells. This migration-inhibitory effect of CA compounds was due to the disruption of the MT network of T-cells through tubulin depolymerisation, reduced tubulin acetylation and decreased MT stability. In addition, both CA compounds induced the RhoA/RhoA associated kinase (ROCK) signalling pathway, leading to the phosphorylation of myosin light chain (MLC). Furthermore, the siRNA-mediated depletion of GEF-H1, a MT-associated nucleotide exchange factor that activates RhoA upon release from MTs, in T-cells prevented CA-induced phosphorylation of MLC and attenuated the formation of actin-rich membrane protrusions and cell contractility. These results suggest an important role for a GEF-H1/RhoA/ROCK/MLC signalling axis in mediating CA-induced contractility of T-cells. Therapeutic agents that target cytoskeletal proteins and are effective in inhibiting cell migration may open new avenues in the treatment of cancer and metastasis.

Although animal studies suggest that adenovirus 36 (Ad36) infection is linked to obesity and systemic inflammation, human data are scant and equivocal.Associations of Ad36 infection with total body adiposity and inflammatory-related markers were determined in 291 children aged 9-13 years (50% female, 49% black).Fasting blood samples were measured for presence of Ad36-specific antibodies and TNF-α, IL-6, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1). Fat mass and fat-free soft tissue mass were measured by dual-energy X-ray absorptiometry.The overall prevalence of Ad36 seropositivity [Ad36(+)] was 42%. There was a higher percentage of Ad36(+) children in the highest tertiles of TNF-α and IL-6 compared with their respective middle and lowest tertiles (both P.03). There was also a trend toward a higher prevalence of Ad36(+) children in the highest tertile of VEGF compared with tertiles 1 and 2 (P = .05). Multinomial logistic regression, adjusting for age, race, sex, and fat-free soft tissue mass, revealed that compared with children with the lowest TNF-α, IL-6, and VEGF levels (tertile 1), the adjusted odds ratios for Ad36(+) were 2.2 [95% confidence interval (CI) 1.2-4.0], 2.4 (95% CI 1.4-4.0), and 1.8 (95% CI 1.0-3.3), respectively, for those in the highest TNF-α, IL-6, and VEGF levels (tertile 3). No association was observed between Ad36(+) and greater levels of fat mass or MCP-1 (all P.05).In children, our data suggest that Ad36(+) may be associated with biomarkers implicated in inflammation but not with greater levels of fat mass.

OBJECTIVES: To determine the relationships of sodium intake with adiposity and inflammation in healthy adolescents. METHODS: A cross-sectional study involved 766 healthy white and African American adolescents aged 14 to 18 years. Dietary sodium intake was estimated by 7-day 24-hour dietary recall. Percent body fat was measured by dual-energy x-ray absorptiometry. Subcutaneous abdominal adipose tissue and visceral adipose tissue were assessed using magnetic resonance imaging. Fasting blood samples were measured for leptin, adiponectin, C-reactive protein, tumor necrosis factor-α, and intercellular adhesion molecule-1. RESULTS: The average sodium intake was 3280 mg/day. Ninety-seven percent of our adolescents exceeded the American Heart Association recommendation for sodium intake. Multiple linear regressions revealed that dietary sodium intake was independently associated with body weight (β = 0.23), BMI (β = 0.23), waist circumference (β = 0.23), percent body fat (β = 0.17), fat mass (β = 0.23), subcutaneous abdominal adipose tissue (β = 0.25), leptin (β = 0.20), and tumor necrosis factor-α (β = 0.61; all Ps < .05). No relation was found between dietary sodium intake and visceral adipose tissue, skinfold thickness, adiponectin, C-reactive protein, or intercellular adhesion molecule-1. All the significant associations persisted after correction for multiple testing (all false discovery rates < 0.05). CONCLUSIONS: The mean sodium consumption of our adolescents is as high as that of adults and more than twice the daily intake recommended by the American Heart Association. High sodium intake is positively associated with adiposity and inflammation independent of total energy intake and sugar-sweetened soft drink consumption.

Human clinical trials targeted at preventing gains in body weight using soy protein and isoflavones are limited to adults and yield conflicting results. We hypothesized that daily intake of soy protein/isoflavones would attenuate gains in body weight to a greater extent than a casein-based control in 18 to 19 year-old females. To test this hypothesis, we conducted a randomized, double blind, placebo-controlled trial over 16 weeks to examine the effects of a soy protein/isoflavone-based meal replacement (experimental group) versus a casein-based meal replacement (control group) on body weight and body composition variables in female college freshmen (N = 120). Fat mass (FM), fat-free soft tissue mass (FFST), and percent body fat (%BF) were measured using dual energy X-ray absorptiometry (DXA; Delphi A). Repeated measures mixed models were used to determine the effects of treatment on anthropometric and body composition variables (body weight, waist circumference, FM, FFST, and %BF). No significant group×time interactions were observed, even when body mass index was controlled for in the analysis. Over 16 weeks, body weight, FM, FFST, and %BF significantly increased in both groups (P < .05). Our findings show that female college freshmen gained a significant amount of weight over the course of the 16-week study. Gains in body weight and FM were similar among participants assigned to the soy protein/isoflavone- and the casein-based meal replacements. Future research is warranted to determine the effects of soy protein/isoflavone- and casein-based meal replacements versus a non-intervention (i.e., non-protein based) control.

Animal studies indicate that osteocalcin (OC), particularly the undercarboxylated isoform (unOC), affects insulin sensitivity and secretion, but definitive data from humans are lacking.The objectives of the study were to determine whether total OC and unOC are independently associated with insulin sensitivity and β-cell response in overweight/obese adults; whether glucose tolerance status affects these associations; and whether the associations are independent of bone formation, as reflected in procollagen type 1 amino propeptide (P1NP).This was a cross-sectional study conducted at a university research center involving 63 overweight/obese adults with normal (n = 39) or impaired fasting glucose (IFG; n = 24).Serum concentrations of total/undercarboxylated OC and P1NP were assessed by RIA; insulin sensitivity was determined by iv glucose tolerance test (S(I)-IVGTT), liquid meal test (S(I) meal), and homeostasis model assessment of insulin resistance; β-cell response to glucose [basal β-cell response to glucose; dynamic β-cell response to glucose; static β-cell response to glucose; and total β-cell response to glucose] was derived using C-peptide modeling of meal test data; and intraabdominal adipose tissue was measured using computed tomography scanning.Multiple linear regression, adjusting for intraabdominal adipose tissue and P1NP, revealed that total OC was positively associated with S(I)-iv glucose tolerance test (P.01) in the total sample. OC was not associated with S(I) meal or homeostasis model assessment of insulin resistance. In participants with IFG, unOC was positively associated with static β-cell response to glucose and total β-cell response to glucose (P.05), independent of insulin sensitivity.In overweight/obese individuals, total OC may be associated with skeletal muscle but not hepatic insulin sensitivity. unOC is uniquely associated with β-cell function only in individuals with IFG. Further research is needed to probe the causal inference of these relationships and to determine whether indirect nutrient sensing pathways underlie these associations.

BACKGROUND: Metabolic abnormalities in obesity can overstimulate the renal epithelial sodium channel (ENaC) and subsequently lead to blood pressure (BP) elevation. Prostasin, a membrane-bound/secretive serine protease, is thought to activate ENaC via the proteolytic cleavage of the channel. Our specific aim was to explore whether there is a relationship between adiposity and urinary prostasin excretion at the population level.METHODS: In 271 African-American adolescents, urinary prostasin concentrations were determined by enzyme-linked immunosorbent assay and normalized by urinary creatinine.RESULTS: Urinary prostasin excretion increased in the overweight/obese group (n = 110, 38.2 +/- 4.0 ng/mg) vs. the normal-weight group (n = 161, 20.7 +/- 1.2 ng/mg, P = 0.03). Urinary prostasin excretion was significantly correlated with BMI percentiles (r = 0.14, P = 0.02), waist circumference (r = 0.13, P = 0.05), total body fat mass (r = 0.20, P CONCLUSION: Our data for the first time suggest that adiposity plays a role in urinary prostasin excretion, and its association's with aldosterone and BP appear to be modulated by adiposity. Whether urinary prostasin excretion is a biomarker/mechanism underlying obesity-related hypertension deserves further investigations.

Background: Zinc is a micronutrient involved in the production of, and peripheral sensitivity to, pancreatic β cell-derived insulin. To our knowledge, the effect of zinc supplementation on insulin outcomes, and potential risk of diabetes, in otherwise healthy children in the United States has not been investigated.Objective: The objective of this study was to determine the influence of zinc supplementation on insulin outcomes in black and white girls in the early stages of adolescence. A secondary objective was to determine relations between baseline zinc concentrations and insulin outcomes.Methods: Healthy black and white girls aged 9-11 y were randomly assigned to daily supplementation of zinc (9 mg elemental Zn/d; n = 75; blacks: n = 35) or placebo (n = 72; blacks: n = 32) for 4 wk. Fasting serum insulin, glucose, and C-peptide were assessed at baseline and at 4 wk. C-peptide and glucose values were used to calculate the computer model-derived homeostatic model assessment of insulin resistance (HOMA2-IR). Changes in outcome measures were compared by using repeated-measures, mixed-model ANOVA.Results: Baseline plasma zinc was not correlated with C-peptide (r = -0.07), insulin (r = -0.06), or HOMA2-IR (r = -0.09) (all P > 0.05) after controlling for race and age. Treatment × time interactions for C-peptide and HOMA2-IR were not significant (both P > 0.05). Although the treatment × race × time interactions for C-peptide and HOMA2-IR were not significant (both P = 0.08), black girls who received the placebo experienced slight increases in C-peptide (15.7%) and HOMA2-IR (17.7%) (P = 0.06).Conclusions: Four weeks of zinc supplementation had no effect on insulin outcomes in healthy black and white early-adolescent girls, although C-peptide and HOMA2-IR tended to increase in black girls who received placebo. Additional trials that are appropriately powered should further explore the effect of zinc on markers of diabetes risk, and whether race affects this relation. This trial was registered at clinicaltrials.gov as NCT01892098.

In the last decade, the number of children with life-limiting and life-threatening conditions in England has almost doubled, and it is estimated that worldwide, there are 1.2 million children with palliative care needs. Families and professionals caring for children with life-limiting conditions are likely to face a number of difficult treatment decisions and develop plans for future care over the course of the child's life, but little is known about the process by which these decisions and plans are made.The purpose of this review is to synthesize findings from qualitative research that has investigated decision-making and future planning for children with life-limiting conditions. A systematic search of six online databases was conducted and identified 887 papers for review; five papers were selected for inclusion, using predefined criteria. Reference list searching and contacting authors identified a further four papers for inclusion.Results sections of the papers were coded and synthesized into themes. Nineteen descriptive themes were identified, and these were further synthesized into four analytical themes. Analytical themes were 'decision factors', 'family factors', 'relational factors' and 'system factors'.Review findings indicate that decision-making and future planning is difficult and needs to be individualized for each family. However, deficits in understanding the dynamic, relational and contextual aspects of decision-making remain and require further research.

The link between adolescent fiber consumption, inflammation, and body fat distribution has not been investigated.This study investigated associations of dietary fiber intake with inflammatory-related biomarkers and robust measures of total and central adiposity in a sample of 559 adolescents aged 14-18 yr (49% female, 45% Black).Fasting blood samples were measured for leptin, adiponectin, resistin, C-reactive protein, and fibrinogen. Diet was assessed with four to seven 24-h recalls, and physical activity was determined by accelerometry. Fat-free soft tissue mass and fat mass were measured by dual-energy x-ray absorptiometry. Visceral adipose tissue was assessed using magnetic resonance imaging.Multiple linear regression, adjusting for age, race, Tanner stage, fat-free soft tissue mass, energy intake, and physical activity, revealed that dietary fiber intake was inversely associated with fat mass and serum leptin in males (all P0.03) but not in females. In both genders, dietary fiber intake was negatively associated with visceral adipose tissue, plasma C-reactive protein, and plasma fibrinogen and positively associated with plasma adiponectin (all P0.05). No relations were found between dietary fiber intake and plasma resistin in either males or females.Our adolescent data suggest that greater consumption of dietary fiber is associated with lower visceral adiposity and multiple biomarkers implicated in inflammation.

OBJECTIVE Low vitamin D status is common among healthy black and white adolescents residing at southern U.S. latitudes with a year-round sunny climate. Thus we aimed to study the relationships between circulating 25-hydroxyvitamin D [25(OH)D] and cardiometabolic risk factors in this population. RESEARCH DESIGN AND METHODS 25(OH)D concentrations were measured with liquid chromatography tandem mass spectroscopy in 701 girls and boys (14–18 years old, 54% blacks, 49% females). Cardiometabolic risk was indexed by adipokines, inflammatory markers, fasting glucose, homeostatic model assessment-insulin resistance (HOMA-IR), lipid profile, and blood pressure (BP). RESULTS Controlling for age, sex, race, sexual maturation, season, physical activity, and percent body fat, 25(OH)D concentrations were significantly correlated with adiponectin (r = 0.06, P = 0.05), leptin (r = −0.32, P < 0.01), fibrinogen (r = −0.05, P = 0.03), glucose (r = −0.16, P = 0.02), HOMA-IR (r = −0.17, P < 0.01), HDL cholesterol (r = 0.14, P = 0.02), systolic BP (r = −0.10, P = 0.02), and diastolic BP (r = −0.21, P < 0.01). When 25(OH)D concentrations were stratified into increasing tertiles, there were significant linear upward trends for adiponectin (P = 0.01) and HDL cholesterol (P = 0.04), but significant linear down trends for glucose (P < 0.01), HOMA-IR (P < 0.01), and systolic BP (P < 0.01), after adjusting for the above covariates. CONCLUSIONS Circulating 25(OH)D concentrations are associated with various adverse cardiometabolic risk factors, independent of adiposity. Clinical trials addressing the effects of vitamin D supplementation on cardiometabolic risk are warranted in adolescents irrespective of their geographical regions.

The properties of hydrogenated amorphous germanium (a-Ge:H) are studied as a function of near-substrate plasma density and hydrogen partial pressure at fixed temperature. Near substrate plasma density is varied by using an unbalanced magnetron and an external magnetic field, and characterized using a guard ring flat probe and a cylindrical Langmuir probe. Films are characterized by infrared absorption, optical transmission, dark conductivity, activation energy, and photoconductivity. A major effect of increasing the near-substrate plasma density is to increase the dihydride component content of the films. The photoconductivity of these films is lower than those whose hydrogen content is increased by increasing the hydrogen partial pressure during deposition, implying a degradation in film properties with increasing near-substrate plasma density. These results show that chemical effects, as well as ion bombardment effects, need to be considered in the plasma-based deposition of a-Ge:H.

BACKGROUND AND OBJECTIVES Investigations in older individuals suggest that adequate nutrition and physical activity are particularly important to skeletal muscle health; however, data in adolescents are scant and equivocal. The objective was to determine the associations among diet, physical activity and skeletal muscle mass in adolescents. METHODS We assessed diet with four to seven 24-h recalls and physical activity by accelerometry in 640 adolescents. Using total body measures of fat-free soft tissue mass and fat mass assessed by dual-energy X-ray absorptiometry, the skeletal muscle mass index (SMMI) was derived by adjusting fat-free soft tissue mass for fat mass in addition to height. RESULTS Skeletal muscle mass index (SMMI) was negatively associated with consumption of sugar-sweetened beverages (standardized beta coefficient [β] = -0.10, P = 0.001) and saturated fats (β = -0.28, P

OBJECTIVES: The objectives were to characterize the vitamin D status of black and white adolescents residing in the southeastern United States (latitude: ∼33°N) and to investigate relationships with adiposity. METHODS: Plasma 25-hydroxyvitamin D levels were measured with liquid chromatography-tandem mass spectroscopy for 559 adolescents 14 to 18 years of age (45% black and 49% female). Fat tissues, physical activity, and cardiovascular fitness also were measured. RESULTS: The overall prevalences of vitamin D insufficiency ( CONCLUSIONS: Low vitamin D status is prevalent among adolescents living in a year-round sunny climate, particularly among black youths. The relationships between 25-hydroxyvitamin D levels, adiposity, physical activity, and fitness seem to be present in adolescence.

Despite adolescent black females experiencing the highest rates of obesity, the effect of excess fat mass on bone structure and strength in this population is unknown. Our findings in postadolescent black females suggest that excess weight in the form of fat mass may adversely influence cortical bone structure and strength. Although adolescent obesity has been associated with reduced bone structure and strength in white females, this relationship has not been studied in adolescent black females, a population experiencing the highest rates of obesity. Our objective was to compare bone structure and strength between postadolescent black females with normal and high levels of adiposity. Black females with ≤32% body fat were classified as normal body fat (NF; n = 33, aged 19.3 ± 1.3 years); females exceeding this cutoff were classified as high body fat (HF; n = 15, aged 19.0 ± 1.1 years). Using peripheral quantitative computed tomography, tibial and radial bones were scanned at the 4% (trabecular) and 20% (cortical) sites from the distal metaphyses. Fat-free soft-tissue mass (FFST) and %body fat were assessed by dual-energy X-ray absorptiometry. After controlling for either FFST or body weight, the HF vs. NF group had lower total cross-sectional area (CSA; 9–17%), cortical CSA (6–15%), and strength–strain index (SSI; 13–24%) at the cortical site of the tibia (all p

The Julia Creek dunnart (Sminthopsis douglasi) is an endangered carnivorous marsupial belonging to the family Dasyuridae. This study investigated the oestrous cycle of this species in terms of its reproductive physiology and behaviour to explore more efficient methods of oestrus detection. Ten sexually mature captive female dunnarts were monitored daily at David Fleay Wildlife Park, Burleigh Heads, Australia, from mid September to late December 2006 for changes in urogenital cytology within the urine (0, 1+, 2+ and 3+), running wheel activity, body weight, uneaten food, faecal steroid metabolites (progesterone and oestradiol) and pouch development. Periods of increased running wheel activity were associated (p=0.004) with an increase in the proportion of cornified urogenital epithelial cells found in the urine; periods of decreasing weight (p0.001) and uneaten food (p0.001) were also associated with changes in urogenital cytology but not to the point where they would be useful for oestrus detection. Between 60.3% and 92.0% of peak distances (confidence interval 95%) occurred when the epithelial cell index was 2+ or 3+. Only 15.5-37.5% of peak weights (CI: 95%) and 28.1-49.9% of incidences of uneaten food (CI: 95%) occurred when the epithelial cell index was 2+ or 3+. There was no significant difference in the mean length of the oestrous cycle when measured by urogenital cytology (mean+/-SD: 25.0+/-5.7 days; n=20) or peak distance travelled (mean+/-SD: 25.4+/-5.7 days; n=20). Changes in the concentration of oestradiol metabolites in Julia Creek Dunnart faeces were not useful in characterising the oestrous cycle. Wheel running activity declined markedly with increased faecal progestagen concentration. The majority of the pouch variables examined showed maximum development during the inter-oestrus period but as there was considerable variation between animals, the pouch was not considered a useful index of oestrus.

Animal models have proven valuable for elucidating the effects of body fat on bone metabolism, and this review highlights recent findings relevant for better understanding the relationship between adiposity and bone mass. Genetically obese mice and rats with altered leptin signaling consistently show reduced bone mass, demonstrating that leptin deficiency can contribute directly to osteopenia; however, the effect of leptin on bone is concentration dependent, such that relatively low doses of leptin stimulate bone formation, whereas high concentrations of leptin suppress bone formation and increase bone resorption. The hyperleptinemia associated with obesity and leptin receptor downregulation is therefore likely to have a negative impact on bone modeling and adaptation. Likewise, diets high in fat and sugar have been observed to increase bone fragility and decrease the accumulation of bone mineral in growing rodents. In vitro studies reveal that increasing concentrations of glucose and lipid can inhibit osteogenic differentiation of mesenchymal stem cells (MSCs), and instead direct these precursors toward the adipocyte lineage. Taken together, the evidence from animal studies indicates that excess body fat and obesogenic diets may attenuate the accretion of skeletal mass in growing animals, suggesting that low bone mass (relative to body weight) may be a potential side-effect of pediatric obesity.

The C-KIT receptor tyrosine kinase is constitutively activated in the majority of gastrointestinal stromal tumours (GIST). Imatinib (IM) a selective inhibitor of C-KIT, is indicated for the treatment of KIT-positive unresectable and/or metastatic GIST, and has tripled the survival time of patients with metastatic GIST. However, the majority of patients develop IM-resistance and progress. Although IM elicits strong antiproliferative effects, it fails to induce sufficient levels of apoptosis; acquired IM-resistance and disease recurrence remain an issue, a more effective drug treatment is greatly needed. We examined the effect of a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-15 in combination with IM on GIST cells. PBOX-15 decreased viability and in combination with IM synergistically enhanced apoptosis in both IM-sensitive and IM-resistant GIST cells, decreased the anti-apoptotic protein Mcl-1, and enhanced activation of pro-caspase-3 and PARP cleavage. The combination treatment also led to an enhanced inhibition of C-KIT-phosphorylation and inactivation of C-KIT-dependent signalling in comparison to either drug alone; CDC37, a key regulator of C-KIT in GIST was also dramatically decreased. Furthermore, PBOX-15 reduced CKII expression, an enzyme which regulates the expression of CDC37. In conclusion, our findings indicate the potential of PBOX-15 to improve the apoptotic response of IM in GIST cells and provide a more effective treatment option for GIST patients.

Background: Whereas excess adiposity is presumed to be advantageous for the skeleton, studies investigating relations between bone strength and fat during youth have been equivocal. Objectives: Relations of percentage body fat (BF) and bone strength indexes were assessed in late adolescent females, taking into consideration surrogates of muscle force [ie, muscle cross-sectional area (MCSA) and bone length]. Bone measurements in the normal- and high-fat groups were also compared. Design: Late adolescent females (n 115; aged 18.2 0.4 y) participated in this cross-sectional study. Fat-free soft tissue mass, fat mass, and percentage BF were measured with the use of dualenergy X-ray absorptiometry. Tibial and radial peripheral quantitative computed tomography measurements were taken at the 4% (trabecular bone), 20% (cortical bone), and 66% (for measurement of MCSA) sites from the distal metaphyses. Results: Percentage BF was inversely related to radial cortical bone area, total bone cross-sectional area (CSA), cortical bone mineral content (BMC), periosteal circumference, and strength-strain index (SSI) (20% site; all P 0.05). After control for MCSA and limb length, negative relations remained between percentage BF and radial measurements and were also observed at the tibia (20% site). Unadjusted bone measures were not different between groups. After control for MCSA, the high- compared with the normal-fat group had lower bone measures at the 20% site (cortical bone area and cortical BMC at the tibia, total bone CSA at the radius, and SSI at both the tibia and radius; P 0.05 for all). Conclusion: Excess weight in the form of fat mass does not provide additional benefits, and may potentially be negative, for adolescent bone. Am J Clin Nutr 2007;86:1530 – 8.