Multiple events case-control study in a prospective cohort to identify systemic, cellular, and molecular biomarkers of obesity-induced accelerated aging in 30-years-olds: the ObAGE study protocol.

BACKGROUND: Aging is characterized by a progressive loss of capacities linked to fundamental alterations/damage in multiple cellular and molecular pathways. It is the most significant risk factor for all non-communicable diseases (NCDs). Another contributing factor to the rise in NCDs is obesity. It has been suggested that obesity not only accelerates the onset of metabolic imbalances but also decreases lifespan and impacts cellular and molecular processes in a manner similar to aging. Obesity might accelerate the pace of aging. Guided by a lifecourse approach, we will explore how exposure to obesity in critical developmental stages disrupt homeostatic resilience mechanisms that preserve physiological integrity, inducing an early expression of aging phenotypes. Also, we will determine whether exposure to early psychosocial adversity influences vulnerability to obesity as a risk factor for accelerated aging. METHODS: Multiple events case-control study embedded in a prospective cohort of Chileans at 30-31y, 50% females, of low- to-middle socioeconomic status, who participated in nutrition research since birth. At 23y, 25% had obesity and cardiometabolic risk was high. We will use a multi-layer approach including: anthropometric assessment; DXA scan for body composition; abdominal ultrasound of the liver; stool samples collection and sequencing of the ribosomal RNA 16S gene to characterize the gut microbiome; determination of age-related pro-inflammatory cytokynes and anti-inflammatory miokynes. For the first time in Chile, we will address age-related epigenetic changes using the Horvath´s epigenetic clock. In a subset we will conduct a controlled physical challenge to characterize physical resilience (autophagy). DISCUSSION: ObAGE is in an excellent position to: approach aging as a process whose expression involves multiple factors from the early stages of a person's life; understand how longitudinal changes in health trajectories impact the biological mechanisms of aging; identify potential resilience mechanisms that help prevent unhealthy aging. Because SLS participants are still young, our research setting combined with advanced scientific techniques may identify individuals or groups at risk of early onset health issues. Results from ObAGE may pave the way to address the contribution of obesity to aging through lifespan from cells to systems and might be instrumental to developing interventions to improve health span in the Chilean population. TRIAL REGISTRATION: The proposed study does not consider any health care intervention on human participants.

Ferritin levels throughout childhood and metabolic syndrome in adolescent stage.

BACKGROUND AND AIM: Increased ferritin levels have been widely associated with cardiovascular risk in adults. Whether ferritin levels and their changes during childhood are related to metabolic syndrome (MetS) at adolescence is unknown. We aimed to evaluate these associations using levels of ferritin at 5, 10 and 16 years and their linear increases and patterns of sustained increased levels across childhood. METHODS AND RESULTS: There were four samples evaluated according to non-missing values for study variables at each stage (5 years: 562; 10 years: 381; and 16 years: 567 children; non-missing values at any stage: 379). MetS risk was evaluated as a continuous Z score. Patterns of sustained increased ferritin (highest tertile) and slope of the change of ferritin per year across the follow-up were calculated. Ferritin levels in the highest versus lowest tertile at five and 16 years were significantly positively associated with MetS risk Z score at adolescence in boys and these associations were unaffected by adjustment for covariates. Having high, compared to low/moderate ferritin level at 2 or more time periods between 5 and 16 years was related to higher Mets Z-score in boys only [e.g. 5-10 years adjusted-beta (95 %CI):0.26 (0.05-0.48),P < 0.05]. In girls, ferritin Z score at 10 and 16 years was positively and independently associated with HOMA-IR Z score. In girls, the slope of ferritin per year in the highest tertile was positively associated with MetS risk Z-score [adjusted-beta (95 %CI):0.21 (0.05-0.38),P < 0.05]. CONCLUSIONS: Ferritin levels throughout childhood are positively related to cardiometabolic risk in adolescence, with associations varying by sex.

Eating in the Absence of Hunger and Obesity Among Adolescents in Santiago, Chile.

In reports among mostly, US, white, preschool and young school-age children eating in the absence of hunger (EAH) has been positively related to adiposity, with some support for a sex-specific relationship. There is considerable interest in EAH and obesity in populations at risk for obesity-like populations of countries that have undergone rapid development. We assessed adolescents (n = 679) after an overnight fast with anthropometry and an EAH paradigm beginning with an ad lib pre-load meal. Participants reported satisfaction and perceived ability to eat more food, and then proceeded to a room with freely available snacks where they were permitted to eat ad lib for 20 min. Adolescents were 16.8 years old, 52% male, and 14% with obesity. Median preload meal kcal consumption was 602 (IQR 474-746). Additional calories were consumed at the EAH snack by 47.6%. Among those who ate snack, 155 additional calories were consumed (IQR 78-283). Adolescents with obesity had 0.61 (95% CI 0.37-0.99) reduced odds of eating at the EAH snack adolescents without obesity. Adolescents with obesity were also less likely to eat above the median total calories compared to adolescents without obesity (OR = 0.59, 95% CI 0.36-0.96). A sex by obesity interaction term was not significant in any model. Obesity was related to eating behavior in our sample of Chilean adolescents, however not in the direction we hypothesized. Adolescents with obesity were less likely to eat additional calories in the EAH paradigm and ate fewer total calories compared to adolescents without obesity.

Understanding self-assessment in undergraduate dental education.

The clinical teaching of undergraduate dentistry is based on a curriculum of desired learning outcomes and competencies in all domains such that graduates can practice autonomously. This report will consider how self-assessment (SA) fits into the continuum of assessment and its use by students and teachers in undergraduate dental education. The purpose of the report is to identify the process of SA. The literature is explored and uses, pitfalls and perceived benefits considered.

Greater early weight gain and shorter breastfeeding are associated with low adolescent adiponectin levels.

BACKGROUND: Early life factors can programme future risk for cardiovascular disease. OBJECTIVES: We explored associations between adolescent adiponectin levels and concomitant metabolic alteration and also looked at the association between early life factors and adolescent adiponectin levels. METHODS: We studied a longitudinal cohort of low-income to middle-income Chilean adolescents who were enroled in an infancy iron-deficiency anaemia preventive trial and follow-up studies at the Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile. In the 577 adolescents who were assessed as part of the 16-year follow-up, we evaluated independent associations between adiponectin levels and metabolic disturbances during adolescence. We also assessed the association between early life factors [short breastfeeding {<6 months} and infancy weight gain] and adolescent adiponectin levels. RESULTS: Participants were 16.8 years old (16.4-18.1), 48% female and 38% overweight/obese. Adolescent adiponectin levels were inversely associated with metabolic disturbances: altered homeostatic model assessment of insulin resistance and high-density lipoprotein cholesterol [odds ratios {95% confidence interval} = 0.87 {0.79-0.95}, p-value = 0.002, and 0.90 {0.87-0.94}, p-value < 0.001, respectively], adjusting for sex and fat mass index. Early life factors were independently associated with adolescent adiponectin levels, which decreased 0.88 ug mL-1 per each unit increase in weight-for-age z-score between 0 and 6 months and was 1.58 ug mL-1 lower among participants with short breastfeeding. CONCLUSIONS: Higher adolescent adiponectin levels were independently associated with lower odds of metabolic disturbances. Greater weight gain during infancy and shorter breastfeeding were associated with lower adolescent adiponectin levels, supporting research indicating early life as a window of opportunity for prevention of later cardiovascular alterations. © 2017 World Obesity Federation.

Breastfeeding as the sole source of milk for 6 months and adolescent bone mineral density.

Little is known regarding the relationship between early life factors and bone mineral density (BMD). We found a positive association between breastfeeding for at least 6 months, without formula supplementation, and whole body adolescent BMD z-score. INTRODUCTION: The aim of the study is to assess the role of breastfeeding BF on adolescent bone mineral density (BMD) in a cohort prospectively followed since infancy. METHODS: We studied 679 participants from an infancy iron deficiency anemia preventive trial in Santiago, Chile, followed to adolescence. Breast and bottle feeding were ascertained weekly from 4 to 12 months. At 16 years, whole body BMD was assessed by DEXA. Using linear regression, we evaluated associations between BF duration and BF as the sole source of milk and adolescent BMD z-score, adjusting for possible infancy, adolescent, and background confounders. RESULTS: Mean birth weight and length were 3.5 (0.3) kg and 50.7 (1.6) cm. For at least 6 months, BF was the sole source of milk for 26.3% and with supplementation for 36.7%. For 37%, BF was provided for less than 6 months. Mean 16-year BMD z-score was 0.25 (1.0). Covariates included male sex, birth length, and gestational age. BF as the sole source of milk ≥6 months, compared to BF < 6 months, was associated with higher adolescent BMD z-score adjusting for covariates (ß = 0.29, p < 0.05). Mixed BF was not significantly related to adolescent BMD z-score (ß = 0.06, p = 0.47). For every 30 days of BF as the sole source of milk, adolescent BMD z-score increased by 0.03 (p = 0.01). CONCLUSION: BF without formula supplementation for at least 6 months was associated with higher adolescent BMD z-score and a suggestive trend in the same direction for BMD suggests that exclusivity and duration of BF may play a role in adolescent bone health.

Low muscle mass is associated with cardiometabolic risk regardless of nutritional status in adolescents: A cross-sectional study in a Chilean birth cohort.

BACKGROUND: Increased cardiometabolic risk (CMR) is documented in obese and non-obese adolescents with low muscular fitness. However, the association of low muscle mass (LMM) with CMR, independent of weight status, has not been examined. We analyzed the relationship of LMM with CMR in adolescents, regardless of their weight status. MATERIALS AND METHODS: Observational study in 660 adolescents. BMI, waist circumference (WC), arterial blood pressures (ABP) were measured. Total fat mass (TFM), total lean tissue (TLT), and appendicular skeletal muscle mass (ASM) were estimated (DXA). Fasting lipid profile, glucose, and insulin were measured. HOMA-IR was estimated. Metabolic Syndrome (MetS) was diagnosed (AHA/NHLBI/IDF). ROC analysis was performed to find the optimal cutoffs of TLT percentage for MetS diagnosis. Values below these cutoffs defined LMM. ANCOVA examined the association of LMM with selected cardiometabolic biomarkers. RESULTS: In both sexes, TLT showed better sensitivity and specificity than ASM for MetS diagnosis. In males and females, TLT of 66.1% and 56.3%, respectively, were the optimal cutoff for MetS diagnosis. In the sample, 17.3% of males and 23.7% of females had LMM. In both sexes, adolescents with LMM had significantly higher values of WC, ABP, TG, TC/HDL, HOMA-IR, and MetS z-score than non-LMM participants. Adolescents with LMM, regardless nutritional status, had significantly increased values of MetS z-score, ABP, TG, TC/HDL-chol, and HOMA-IR than non-obese non-LMM adolescents. Adolescents having both obesity and LMM had the unhealthiest CMR profile. CONCLUSION: In adolescents, LMM was associated with higher CMR, regardless of nutritional status. In obese adolescents, LMM increased obesity-associated CMR.

Healthy Chilean Adolescents with HOMA-IR ≥ 2.6 Have Increased Cardiometabolic Risk: Association with Genetic, Biological, and Environmental Factors.

OBJECTIVE: To determine the optimal cutoff of the homeostasis model assessment-insulin resistance (HOMA-IR) for diagnosis of the metabolic syndrome (MetS) in adolescents and examine whether insulin resistance (IR), determined by this method, was related to genetic, biological, and environmental factors. METHODS: In 667 adolescents (16.8 ± 0.3 y), BMI, waist circumference, glucose, insulin, adiponectin, diet, and physical activity were measured. Fat and fat-free mass were assessed by dual-energy X-ray absorptiometry. Family history of type 2 diabetes (FHDM) was reported. We determined the optimal cutoff of HOMA-IR to diagnose MetS (IDF criteria) using ROC analysis. IR was defined as HOMA-IR values above the cutoff. We tested the influence of genetic, biological, and environmental factors on IR using logistic regression analyses. RESULTS: Of the participants, 16% were obese and 9.4 % met criteria for MetS. The optimal cutoff for MetS diagnosis was a HOMA-IR value of 2.6. Based on this value, 16.3% of participants had IR. Adolescents with IR had a significantly higher prevalence of obesity, abdominal obesity, fasting hyperglycemia, and MetS compared to those who were not IR. FHDM, sarcopenia, obesity, and low adiponectin significantly increased the risk of IR. CONCLUSIONS: In adolescents, HOMA-IR ≥ 2.6 was associated with greater cardiometabolic risk.

Satiety responsiveness and eating behavior among Chilean adolescents and the role of breastfeeding.

OBJECTIVE: To determine patterns of satiety responsiveness and its relationship to eating in the absence of hunger (EAH), in a cohort of adolescents. We also assessed whether sex, body mass index and duration of breastfeeding, during infancy, predicted satiety responsiveness and eating behavior at 16 years. METHODS: Adolescents (n=576) from a longitudinal cohort, which began as an iron deficiency anemia preventive trial, participated in an unlimited breakfast after an overnight fast, and reported satiety response on a visual analog scale after the meal, followed by an EAH procedure. Height, weight and body composition were measured before breakfast. Latent profile analysis generated profiles that captured individual differences in satiety responsiveness. Multivariable regressions, adjusted for potential confounders, evaluated the association between: (1) satiety responsiveness and EAH, and (2) breastfeeding in infancy, satiety responsiveness and EAH in adolescence. RESULTS: Participants were on average 16.7-year old, 48% female, 37% overweight/obese and 76% were breastfed as the sole source of milk for <6 months. We found three latent profiles of satiety responsiveness: 1: 'responsive' (49%); 2: 'not responsive' (41%); 3: 'still hungry' (10%). Participants in the 'not responsive' or 'still hungry' profile were more likely to eat during the EAH procedure (odds ratio (OR)=2.5, 95% confidence interval (CI)=1.8-3.6). Being breastfed for <6 months was related to higher odds of being in the 'not responsive' or 'still hungry' profile (OR=1.8, 95% CI=1.2-2.6) and EAH (OR=2.2, 95% CI=1.4-3.3). Satiety responsiveness was not influenced by sex and overweight/obesity. CONCLUSION: After an ad libitum meal, we found varied satiety responses, which related to EAH. Furthermore, shorter breastfeeding duration was associated with poorer satiety response and higher consumption during an EAH procedure. Understanding if breastfeeding influences the development of satiety responsiveness and eating behavior may be important in an era characterized by abundant calorie-dense foods and a plethora of environmental cues promoting consumption.

Melanocortin-4 receptor gene variants in Chilean families: association with childhood obesity and eating behavior.

OBJECTIVE: To screen for mutations in the coding region of the melanocortin-4 receptor (MC4R) gene and to assess the association between the rs17782313 variant near MC4R with childhood obesity and eating behavior. SUBJECTS AND METHODS: A cross-sectional sample of 221 obese Chilean children and 268 parents were incorporated in the study to assemble 134 case-parent trios. We performed direct sequencing of the MC4R coding region while the rs17782313 variant was genotyped by a Taqman assay. Eating behavior scores were calculated using the Child Eating Behavior and Three Factor Eating Questionnaires adapted for Chilean families. RESULTS: A low frequency of genetic variation in the coding region of MC4R was found in Chilean obese children (Thr150Ile mutation and polymorphisms Ile251Leu and Val103Ile). The rs17782313 variant is possibly associated with satiety responsiveness (P = 0.01) and enjoyment of food scores (P = 0.03). CONCLUSION: The rs17782313 variant may influence eating behavior in obese children.

Melanocortin-3 receptor gene variants: association with childhood obesity and eating behavior in Chilean families.

OBJECTIVE: To evaluate the association between melanocortin-3 receptor common genetic polymorphisms with childhood obesity and eating behavior in Chilean families. METHODS: Two hundred twenty-nine obese children (6-12 y old, body mass index >95th percentile of Centers for Disease Control and Prevention/National Center for Health Statistics, 2000) and 270 parents were selected. Genotypes for MC3R genetic markers -239A>G, 17C>A (Thr6Lys), 241G>A (Val81Ile), +2138InsCAGACC, and microsatellite D20s32e were determined. Eating behavior scores were computed using the Child Eating Behavior Questionnaire and a shorter version of the Three Factor Eating Questionnaire adapted for evaluating eating inclinations in children. Genotype-obesity associations were assessed by the Transmission Disequilibrium Test. Non-parametric tests were used to compare eating behavior scores across study groups. RESULTS: Allelic frequencies of -239G, 17A, 241A, and +2138InsCAGACC were estimated as 4.5%, 5.9%, 5.6%, and 17.6%, respectively, in obese children. The Transmission Disequilibrium Test in case-parent trios revealed no significant associations between childhood obesity and genetic markers, including the microsatellite D20s32e. In girls, we found significantly higher scores of the emotional eating subscale in carriers of the +2138InsCAGACC compared with non-carriers (P=0.04). In boys, carriers of 17A and 241A showed lower scores for the emotional eating subscale (P=0.01), whereas carriers of +2138InsCAGACC showed significantly lower scores for the enjoyment of food subscale compared with non-carriers (P=0.04). CONCLUSIONS: There is not sufficient evidence to support the contribution for common melanocortin-3 receptor variants in childhood obesity. However, our results are concordant for a role of melanocortin-3 receptor variants in some dimensions of eating behavior such as emotional eating and enjoyment of food.

The guinea-pig tracheal potential difference as an in vivo model for the study of epithelial sodium channel function in the airways.

BACKGROUND AND PURPOSE: The epithelial sodium channel (ENaC) is a key regulator of airway mucosal hydration and mucus clearance. Negative regulation of airway ENaC function is predicted to be of clinical benefit in the cystic fibrosis lung. The aim of this study was to develop a small animal model to enable the direct assessment of airway ENaC function in vivo. EXPERIMENTAL APPROACH: Tracheal potential difference (TPD) was utilized as a measure of airway epithelial ion transport in the guinea-pig. ENaC activity in the trachea was established with a dose-response assessment to a panel of well-characterized direct and indirect pharmacological modulators of ENaC function, delivered by intra-tracheal (i.t.) instillation. KEY RESULTS: The TPD in anaesthetized guinea-pigs was attenuated by the direct ENaC blockers: amiloride, benzamil and CF552 with ED(50) values of 16, 14 and 0.2 microg kg(-1) (i.t.), respectively. 5-(N-Ethyl-N-isopropyl) amiloride, a structurally related compound but devoid of activity on ENaC, was without effect on the TPD. Intra-tracheal dosing of the Kunitz-type serine protease inhibitors aprotinin and placental bikunin, which have previously been demonstrated to inhibit proteolytic activation of ENaC, likewise potently attenuated TPD in guinea-pigs, whereas alpha(1)-antitrypsin and soya bean trypsin inhibitor were without effect. CONCLUSIONS AND IMPLICATIONS: The pharmacological sensitivity of the TPD to amiloride analogues and also to serine protease inhibitors are both consistent with that of ENaC activity in the guinea-pig trachea. The guinea-pig TPD therefore represents a suitable in vivo model of human airway epithelial ion transport.

Statistical modelling of biochemical pathways.

The usefulness of Bayesian statistical methods for the modelling of biochemical reactions is examined. With simulated data, it is shown that these methods can effectively fit mechanistic models of sequences of enzymatic reactions to experimental data. These methods have the advantages of being relatively easy to use and producing probability distributions for the model parameters rather than point estimates, allowing more informative inferences to be drawn. Three Markov Chain Monte Carlo algorithms are used to fit models to data from a sequence of four enzymatic reactions. The algorithms are evaluated with respect to the goodness-of-fit of the fitted models and the time to completion. It is shown that the algorithms produce essentially the same parameter distributions, but the time to completion varies.

Effect of glycemic index on whole-body substrate oxidation in obese women.

BACKGROUND: Glycemic index is hypothesized to determine fuel partitioning through serum plasma insulin modifications induced by dietary carbohydrates, thereby modulating fat accretion or oxidation. OBJECTIVE: To assess the glycemic effects on postprandial fuel oxidation and blood response. DESIGN: In all, 12 obese women were fed on a randomized crossover design with two test meals (breakfast+lunch). High- or low-glycemic meals were provided on separate days. Energy intake on high-glycemic meal was 7758+/-148 kJ and for low-glycemic meal was 7806+/-179 kJ. Carbohydrates supplied were 273+/-5 and 275+/-6 g, respectively. Macronutrient distribution was 55% carbohydrates, 30% fat and 15% protein. Fuel oxidation was measured continuously in a respiratory chamber for 10 h. Serum glucose, free fatty acids (FFA), insulin and glucagon samples were taken for 5 h after breakfast. RESULTS: Glucose AUC changed significantly in response to different glycemic breakfast. Low- vs high-glycemic breakfast was 211+/-84 and 379+/-164 mmol/l (P<0.05). Similarly, insulin changed from 94+/-37 and 170+/-87 nmol/l (P<0.05), respectively. The rate of increment for serum glucose and insulin reached by the high- vs low-glycemic meal was 1.8 times more with the high-glycemic breakfast. Serum FFA were similarly suppressed by both meal types by 3 h after meal intake, but then raised significantly more with the low-glycemic meal by the fourth and fifth hour (P<0.05). Plasma glucagon did not show a significant variation with glycemic index. Carbohydrate and fat oxidation was not modified by glycemic meal characteristics, being virtually the same for low- vs high-glycemic comparisons in the 5 h following breakfast and lunch (P=NS). CONCLUSION: This study demonstrates that dietary glycemic characteristics were unable to modify fuel partitioning in sedentary obese women.

The utilisation of engineered invert traps in the management of near bed solids in sewer networks.

Large existing sewers are considerable assets which wastewater utilities will require to operate for the foreseeable future to maintain health and the quality of life in cities. Despite their existence for more than a century there is surprisingly little guidance available to manage these systems to minimise problems associated with in-sewer solids. A joint study has been undertaken in the UK, to refine and utilise new knowledge gained from field data, laboratory results and Computational Fluid Dynamics (CFD) simulations to devise cost beneficial engineering tools for the application of small invert traps to localise the deposition of sediments in sewers at accessible points for collection. New guidance has been produced for trap siting and this has been linked to a risk-cost-effectiveness assessment procedure to enable system operators to approach in-sewer sediment management pro-actively rather than reactively as currently happens.