ABSTRACT
Besides the well-recognized influence of maternal health on fetal in utero development, recent epidemiological studies appoint paternal pre-conception metabolic health as a significant factor in shaping fetal metabolic programming and subsequently offspring metabolic health; however, mechanisms behind these adaptations remain confined to animal models. To elucidate the effects of paternal obesity (P-OB) on infant metabolism in humans, we examined mesenchymal stem cells (MSCs) which give rise to infant tissue, remain involved in mature tissue maintenance, and resemble the phenotype of the offspring donor. Here, we assessed mitochondrial functional capacity, content, and insulin action in MSC from infants of fathers with overweight (BMI 25-30kg/m2) (P-OW) or obesity (BMI≥30kg/m2) (P-OB), while controlling for maternal intrauterine environment. Compared to P-OW, infant MSCs in the P-OB group had lower intact cell respiration, OXPHOS, and electron transport system capacity, independent of any changes in mitochondrial content. Furthermore, glucose handling, insulin action, and lipid content and oxidation were similar between groups. Importantly, infants in the P-OB group had a greater weight-to-length ratio, which could be in part due to changes in MSC metabolic functioning which precedes and therefore influences infant growth trajectories. These data suggest that P-OB negatively influences infant MSC mitochondria.
ABSTRACT
Pantoprazole is a proton pump inhibitor indicated for the treatment of gastroesophageal reflux disease, a condition that disproportionately affects children with obesity. Appropriately dosing pantoprazole in children with obesity requires understanding the body size metric that best guides dosing, but pharmacokinetic (PK) trials using traditional techniques are limited by the need for larger sample sizes and frequent blood sampling. Physiologically-based PK (PBPK) models are an attractive alternative that can account for physiologic-, genetic-, and drug-specific changes without the need for extensive clinical trial data. In this study, we explored the effect of obesity on pantoprazole PK and evaluated label-suggested dosing in this population. An adult PBPK model for pantoprazole was developed using data from the literature and accounting for genetic variation in CYP2C19. The adult PBPK model was scaled to children without obesity using age-associated changes in anatomical and physiological parameters. Lastly, the pediatric PBPK model was expanded to children with obesity. Three pantoprazole dosing strategies were evaluated: 1 mg/kg total body weight, 1.2 mg/kg lean body weight, and US Food and Drug Administration-recommended weight-tiered dosing. Simulated concentration-time profiles from our model were compared with data from a prospective cohort study (PAN01; NCT02186652). Weight-tiered dosing resulted in the most (>90%) children with pantoprazole exposures in the reference range, regardless of obesity status or CYP2C19 phenotype, confirming results from previously published population PK models. PBPK models may allow for the efficient study of physiologic and developmental effects of obesity on PK in special populations where clinical trial data may be limited.
ABSTRACT
Maternal obesity is associated with lower infant resting energy expenditure (REE), predisposing them to more rapid weight and adiposity gain through early infancy. Maternal exercise (ME) decreases infant adiposity and risk for childhood obesity; however, it remains unknown if this is in part mediated by changes in infant energy expenditure. Thus, we measured REE in 1-month-old infants from pregnant individuals who performed moderate-intensity exercise during pregnancy and compared it to infants from non-exercising controls. We observed higher oxygen respiratory rates (p = 0.003 for VO2 and p = 0.007 for VCO2) and REE (p = 0.002) in infants exposed to exercise in utero, independent of any differences in infant body composition. Furthermore, maternal BMI was significantly and inversely associated with infant REE in the control (r = -0.86, R2 = 0.74, p = 0.029), but not the exercise group (r = 0.33, R2 = 0.11, p = 0.473). Together, these findings associate ME with increasing infant energy expenditure which could be protective of subsequent infant adiposity gain. Clinical Trial: ClinicalTrials.gov Identifier: NCT03838146 and NCT04805502.
ABSTRACT
Maternal exercise (ME) has been established as a useful non-pharmacological intervention to improve infant metabolic health; however, mechanistic insight behind these adaptations remains mostly confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to infant tissues (e.g., skeletal muscle), and remain involved in mature tissue maintenance. Importantly, these cells maintain metabolic characteristics of an offspring donor and provide a model for the investigation of mechanisms behind infant metabolic health improvements. We used undifferentiated MSC to investigate if ME affects infant MSC mitochondrial function and insulin action, and if these adaptations are associated with lower infant adiposity. We found that infants from exercising mothers have improvements in MSC insulin signaling related to higher MSC respiration and fat oxidation, and expression and activation of energy-sensing and redox-sensitive proteins. Further, we found that infants exposed to exercise in utero were leaner at 1 month of age, with a significant inverse correlation between infant MSC respiration and infant adiposity at 6 months of age. These data suggest that infants from exercising mothers are relatively leaner, and this is associated with higher infant MSC mitochondrial respiration, fat use, and insulin action.
Subject(s)
Body Composition , Exercise , Insulin , Mesenchymal Stem Cells , Mitochondria , Humans , Female , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/physiology , Exercise/physiology , Mitochondria/metabolism , Insulin/metabolism , Infant , Pregnancy , Male , Body Composition/physiology , Adult , Infant, Newborn , Adiposity/physiologyABSTRACT
Sugar-sweetened beverage (SSB) consumption remains a major target for interventions to treat severe obesity in children. Understanding how total energy consumption is divided among different types of beverages remains unclear. This study retrospectively examined how the consumption of beverage calories (kcal) from 100% fruit juice and SSBs, and body mass index, assessed as a percent of the 95th sex- and age-specific percentile (%of 95BMI), changed during the treatment of children with obesity aged 2-18 years. Treatment was provided by an integrative multi-disciplinary team, comprising a physician, a dietician/ nutritionist and a behavioralist employing motivational interviewing and a small change approach to promote improved sustainable health habits and induce a net negative energy balance. The sample included 155 patients, with 341 visits. The median age was 11 years, 60% were girls, and there was a median follow-up of 3.1 months. At baseline, the median %of 95BMI was 135 and the median kcal/day intake was 436 from juice and 263 from SSB. For each additional 100 kcal consumed/day from SSB and juice, the %of 95BMI increased by 1.4 percentage points. In the follow-up, each additional month was associated with 7 fewer kcal/day from SSB and juice combined, with a 0.5 percentage point increase in %of 95BMI. Children in this treatment program consumed fewer calories from SSB over time, although the %of 95BMI did not decrease. SSBs other than soda accounted for the majority of beverage kcal intake, therefore potentially providing a targeted direction for interventions.
Subject(s)
Pediatric Obesity , Female , Humans , Child , Male , Pediatric Obesity/therapy , Retrospective Studies , Beverages , Carbonated Beverages , Energy Intake , Dietary SucroseABSTRACT
To estimate half-lives for novel fluoroethers, the GenX Exposure Study obtained two serum measurements for per- and polyfluoroalkyl substances (PFAS) for 44 participants of age 12-86 years from North Carolina, collected 5 and 11 months after fluoroether discharges into the drinking water source were controlled. The estimated half-lives for these compounds were 127 days (95% confidence interval (95% CI) = 86, 243 days) for perfluorotetraoxadecanoic acid (PFO4DA), 296 days for Nafion byproduct 2 (95% CI = 176, 924 days), and 379 days (95% CI = 199, 3870 days) for perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA). Using these estimates and the literature values, a model was built that predicted PFAS half-lives using structural properties. Three chemical properties predicted 55% of the variance of PFAS half-lives based on 15 PFAS. A model with only molecular weight predicted 69% of the variance. Some properties can predict the half-lives of PFAS, but a deeper understanding is needed. These fluoroethers had biological half-lives longer than published half-lives for PFHxA and PFHpA (30-60 days) but shorter than those for PFOA and PFOS (800-1200 days). These are the first and possibly only estimates of human elimination half-lives of these fluoroethers.
Subject(s)
Alkanesulfonic Acids , Fluorocarbons , Water Pollutants, Chemical , Humans , Child , Adolescent , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , Ethers , Water Pollutants, Chemical/analysis , Caprylates , Fluorocarbons/analysisABSTRACT
In 2017, people living in New Hanover County, North Carolina, learned that for â¼40 years they were unknowingly exposed to per- and polyfluoroalkyl substances (PFAS) through drinking water sourced by the Cape Fear River. Using data from the GenX Exposure Study, which measured serum PFAS levels in county residents, we aimed to understand questionnaire-measured factors associated with serum PFAS levels. Because most residents were served by the same municipal water source, we focused on surrogate factors of drinking water exposure that may contribute to variability in PFAS levels. Our analysis included 335 participants aged 6 and older. We included seven chemicals detected in ≥75% of the study population: four well-studied perfluoroalkyl acids (PFOA, PFOS, PFNA, PFHxS) and three understudied fluoroethers (Nafion byproduct 2, PFO4DA, PFO5DoA). For each PFAS, we evaluated associations of variables with serum PFAS levels adjusting for key demographic characteristics. Additionally, we developed predictive models for each PFAS. We used years of residence in the lower Cape Fear Region as a surrogate for water consumption. Duration of drinking water exposure was associated with higher serum levels of all seven PFAS. Drinking municipal water treated by home filters or other sources of water (non-city) were associated with lower PFAS concentrations for all seven PFAS compared to drinking municipal water without additional filtration. Males had higher levels of well-studied PFAS, but there was no difference for fluoroethers. For six PFAS, the predictive models explained ≥30% of the variance in serum PFAS levels. While some factors were significantly associated with levels of individual PFAS, their relative importance to overall prediction was low, such as microwave popcorn consumption. Consistently, water consumption-related variables were important for both the association and predictive investigations. These analyses provide additional evidence that drinking water is a primary source for serum PFAS concentrations among New Hanover County residents.
Subject(s)
Alkanesulfonic Acids , Drinking Water , Environmental Pollutants , Fluorocarbons , Water Pollutants, Chemical , Male , Humans , Drinking Water/chemistry , North Carolina , Water Pollutants, Chemical/analysis , Alkanesulfonic Acids/analysis , Environmental Pollutants/analysisABSTRACT
The community of Pittsboro, North Carolina has been documented to have extensive per- and polyfluoroalkyl substances (PFAS) contamination in its drinking water source, the Haw River, over the last 20 years. However, a detailed exposure assessment has never been conducted. In this study, we sought to characterize the PFAS in paired drinking water and blood samples collected from a small cohort of Pittsboro residents (n = 49). Drinking water and serum from blood were collected from adults in late 2019 and early 2020 and were analyzed to quantify 13 PFAS analytes. In order to explore potential health effects of PFAS exposure, serum was further analyzed for clinical chemistry endpoints that could be potentially associated with PFAS (e.g., cholesterol, liver function biomarkers). PFAS were detected in all serum samples, and some serum PFAS concentrations were 2 to 4 times higher than the median U.S. serum concentrations reported in the general U.S. population. Of the 13 PFAS in drinking water, perfluorohexanoic acid (PFHxA) was measured at the highest concentrations. PFAS levels in the current drinking water were not associated with current serum PFAS, suggesting that the serum PFAS in this cohort likely reflects historical exposure to PFAS with long half-lives (e.g., PFOS and PFOA). However, one PFAS with a shorter half-life (PFHxA) was observed to increase in serum, reflecting the temporal variability of PFHxA in river and drinking water. Statistical analyses indicated that serum PFOA and PFHxS were positively associated with total cholesterol and non-HDL cholesterol. No serum PFAS was associated with HDL cholesterol. In the clinical chemistry analyses, serum PFHxA was found to be negatively associated with electrolytes and liver enzymes (e.g., AST and ALT), and serum PFOS was found to be positively associated with the ratio of blood urea nitrogen to creatinine (BUN:Cre). While small in size, this study revealed extensive exposure to PFAS in Pittsboro and associations with clinical blood markers, suggesting potential health impacts in community residents.
Subject(s)
Alkanesulfonic Acids , Drinking Water , Fluorocarbons , Water Pollutants, Chemical , Adult , Humans , Drinking Water/chemistry , North Carolina , Alkanesulfonic Acids/analysis , Water Pollutants, Chemical/analysis , Caprylates/analysis , Fluorocarbons/analysisABSTRACT
Following the 2016 US Presidential election, immigration enforcement became more aggressive, with variation by state and region depending on local policies and sentiment. Increases in enforcement created an environment of risk for decreased use of health care services among especially among Latino families. of Hispanic ethnicity and/or from Latin American origin (as a group subsequently referred to as Latino). For Latino children with chronic health conditions, avoidance of routine health care can result in significant negative health consequences such as disease progression, avoidable use of acute health care services, and overall increased costs of care. To investigate for changes in visit attendance during the periods before and since increased immigration enforcement, we extracted data on children followed by subspecialty clinics of one healthcare system in the US state of North Carolina during 2015-2019. For each patient, we calculated the proportion of cancelled visits and no-show visits out of all scheduled visits during the 2016-2019 follow-up period. We compared patient characteristics (at the 2015 baseline) according to whether they cancelled or did not show to any visits in subsequent years by clinic and patient factors, including ethnicity. Data were analyzed using multinomial logistic regression of attendance at each visit, including an interaction between visit year and patient ethnicity. Among 852 children 1 to 17 years of age (111 of Latino ethnicity), visit no-show was more common among Latino patients, compared to non-Latino White patients; while visit cancellation was more common among non-Latino White patients, compared to Latino patients. There was no significant interaction between ethnicity and trends in visit no-show or cancellation. Although differences in pediatric specialty clinic visit attendance by patient ethnicity were seen at study baseline, changing immigration policy and negative rhetoric did not appear to impact use of pediatric subspecialty care.
ABSTRACT
BACKGROUND: Residents of Wilmington, North, Carolina, were exposed to drinking water contaminated by fluoroethers and legacy per- and polyfluoroalkyl substances (PFAS), such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), with fluoroether exposure occurring from 1980 to 2017. PFOA and PFOS have previously been associated with metabolic dysfunction; however, few prior studies have examined associations between other PFAS and lipid levels. OBJECTIVES: We measured the association between serum fluoroether and legacy PFAS levels and various cholesterol outcomes. METHODS: Participants in the GenX Exposure Study contributed nonfasting blood samples in November 2017 and May 2018 that were analyzed for 20 PFAS (10 legacy, 10 fluoroethers) and serum lipids [total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides] and calculated non-HDL cholesterol. We estimated covariate-adjusted associations between quartiles of exposure to each of the PFAS measures (as well as the summed concentrations of legacy PFAS, fluoroethers, and all 10 targeted PFAS) and lipid outcomes by fitting inverse probability of treatment weighted linear regressions. RESULTS: In this cross-sectional study of 326 participants (age range 6-86 y), eight PFAS were detected in >50% of the population. For PFOS and perfluorononanoic acid (PFNA), non-HDL cholesterol was approximately 5mg/dL higher per exposure quartile increase: [PFOS: 4.89; 95% confidence interval (CI): 0.10, 9.68 and PFNA: 5.25 (95% CI: 0.39, 10.1)], whereas total cholesterol was approximately 6mg/dL higher per quartile [PFOS: 5.71 (95% CI: 0.38, 11.0), PFNA: 5.92 (95% CI: 0.19, 11.7)]. In age-stratified analyses, associations were strongest among the oldest participants. Two fluoroethers were associated with higher HDL, whereas other fluoroether compounds were not associated with serum lipid levels. DISCUSSION: PFNA and PFOS were associated with higher levels of total and non-HDL cholesterol, with associations larger in magnitude among older adults. In the presence of these legacy PFAS, fluoroethers appeared to be associated with HDL but not non-HDL lipid measures. https://doi.org/10.1289/EHP11033.
Subject(s)
Alkanesulfonic Acids , Drinking Water , Environmental Pollutants , Fluorocarbons , Adolescent , Adult , Aged , Aged, 80 and over , Child , Cholesterol , Cross-Sectional Studies , Humans , Lipids , Middle Aged , Young AdultABSTRACT
Factors related to adolescents and sleep are understudied. We evaluate the relationship between bedtime technology use (TU), TV in bedroom, weight, and socioeconomic status in seventh graders (N = 3956) enrolled in a school-based wellness intervention. Sleep quantity was dichotomized to insufficient (<8 hours) or sufficient (≥8 hours); high TU before sleep was defined by use "a few nights each week" or "every, or almost every night." Insufficient sleep (38.7%), having TV in bedroom (72.9%), and high TU (83.1%) were commonly reported. The likelihood of sufficient sleep was lower for those with high TU (odds ratio [OR] = 0.529 [0.463-0.605]), obese students (OR = 0.815 [0.700-0.949]), and those with a TV in the bedroom (OR = 0.817 [0.703-0.950]). Also, attending a school with higher percent low socioeconomic status students was also associated with insufficient sleep (P = .026). Interventions to reduce TU may be important for improving sleep quantity, especially for some vulnerable populations.
Subject(s)
Body Mass Index , Circadian Rhythm , Pediatric Obesity/epidemiology , Sleep Wake Disorders/prevention & control , Adolescent , Adolescent Behavior , Humans , Sleep , Social Class , Time FactorsABSTRACT
BACKGROUND: Although maternal systemic inflammation is hypothesized to link maternal pre-pregnancy obesity to offspring metabolic dysfunction, patient empirical data are limited. OBJECTIVES: In this study, we hypothesized that pre-pregnancy obesity alters systemic chemo/cytokines concentrations in pregnancy, and this alteration contributes to obesity in children. METHODS: In a multi-ethnic cohort of 361 mother-child pairs, we measured prenatal concentrations of plasma TNF-α, IL-6, IL-8, IL-1ß, IL-4, IFN-γ, IL-12 p70 subunit, and IL-17A using a multiplex ELISA and examined associations of pre-pregnancy obesity on maternal chemo/cytokine levels, and associations of these cytokine levels with offspring body mass index z score (BMI-z) at age 2-6 years using linear regression. RESULTS: After adjusting for maternal smoking, ethnicity, age, and education, pre-pregnancy obesity was associated with increased concentrations of TNF-α (P = .026) and IFN-γ (P = .06). While we found no evidence for associations between TNF-α concentrations and offspring BMI-z, increased IFN-γ concentrations were associated with decreased BMI-z (P = .0002), primarily in Whites (P = .0011). In addition, increased maternal IL-17A concentrations were associated with increased BMI-z in offspring (P = .0005) with stronger associations in African Americans (P = .0042) than Whites (P = .24). CONCLUSIONS: Data from this study are consistent with maternal obesity-related inflammation during pregnancy, increasing the risk of childhood obesity in an ethnic-specific manner.
Subject(s)
Cytokines/blood , Obesity, Maternal , Pediatric Obesity , Black or African American , Body Mass Index , Child , Child, Preschool , Cohort Studies , Female , Humans , Obesity, Maternal/epidemiology , Pediatric Obesity/epidemiology , Pregnancy , White PeopleABSTRACT
A variety of endocrine disrupting chemicals (EDCs), including some known to be obesogenic, can be found in household wastewater. Many are only partially treated by wastewater treatment and drinking water purification systems and can enter municipal drinking water supplies. We evaluated drinking water consumption habits in a cohort of obese pediatric patients to determine the percentage that might avoid exposure to EDCs from drinking municipal tap water. Obese (BMI ≥ 95th percentile) children presenting to an obesity clinic serving a largely poor and rural population were studied. Self-reported race/ethnicity, insurance status and details concerning type and volume of water consumed were obtained from their medical records. Most homes were supplied with municipal, rather than private well water (90.6% vs. 9.4%, respectively). A majority (76.4%) of patients with municipal water as their water supply only drank bottled water. "Taste" and "Health Concerns" were the most commonly endorsed reasons for eschewing tap water. Bottled water consumption among low socioeconomic status patients may reduce their risk for exposure to EDCs in municipal tap water. Further studies are needed to confirm the generalizability of this observation.
ABSTRACT
INTRODUCTION: Family based interventions are the standard for pediatric weight management programs (PWMPs), yet the details of how to involve additional family members, when youth are part of blended families (i.e., step families) or reside in multiple households is not well understood. The objective of this study is to describe how providers involve blended families and multiple households in PWMPs. METHOD: A cross-sectional exploratory survey was conducted of providers at PWMPs in the United States and Canada. The survey questions included had both multiple choice and open-ended responses. Univariate analyses were conducted. RESULTS: 71 providers participated, representing 47 centers/clinics. The majority (96%) reported assessing multiple households, most often during the medical history. Providers reported including the primary caretakers at all known residences (59%), but not immediate family members beyond the primary caretakers. Providers reported adapting dietary (88%) and physical activity (77%) recommendations to accommodate multiple households. The most frequent adaptations included the goals at each family/household, adjustments on a per family basis or based on family resources, and making materials available to all family members. The most frequent challenges in extending treatment plans to multiple households included one caretaker/household not willing to participate or being present at visits, and inconsistency between households. Despite providers reporting that they assess multiple households, they did not have a formal interview template or form to use in assessments (27%). DISCUSSION: Providers recognize the challenges and complexity that blended families present with in obesity treatment. Further research is need to increase provider assessment and involvement of blended families and the extension of goals and treatment plans to multiple homes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Subject(s)
Body Weight Maintenance , Family Relations/psychology , Parents/education , Canada , Cross-Sectional Studies , Family/psychology , Family Characteristics , Health Personnel , Humans , Parents/psychology , Pediatric Obesity/psychology , Pediatric Obesity/therapy , Surveys and Questionnaires , United StatesABSTRACT
BACKGROUND AND AIMS: Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation. METHODS: Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6-17 years; n = 40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM®). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios. RESULTS: A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC0-∞)] within ranges previously reported as therapeutic, without over- or under-prediction for obese children. CONCLUSIONS: Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC0-∞ remained using this dosing approach.
Subject(s)
2-Pyridinylmethylsulfinylbenzimidazoles/pharmacokinetics , Models, Biological , Obesity/complications , Proton Pump Inhibitors/pharmacokinetics , 2-Pyridinylmethylsulfinylbenzimidazoles/administration & dosage , Administration, Oral , Adolescent , Area Under Curve , Body Weight , Child , Female , Humans , Male , Metabolic Clearance Rate , Pantoprazole , Prospective Studies , Proton Pump Inhibitors/administration & dosageABSTRACT
OBJECTIVE: To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. STUDY DESIGN: A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula. Ten post-dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole. RESULTS: Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower (P < .05) and systemic exposure significantly higher (P < .01) in obese vs nonobese children. When normalized per kg LBW, these differences were not evident in children ≥12 years of age and markedly reduced in children <12 years of age. CONCLUSIONS: LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age-related changes in CYP2C19 activity), appear to affect pantoprazole PK in children <12 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02186652.
Subject(s)
Gastroesophageal Reflux/drug therapy , Pantoprazole/pharmacokinetics , Pediatric Obesity/drug therapy , Proton Pump Inhibitors/pharmacokinetics , Administration, Oral , Adolescent , Area Under Curve , Body Weight , Child , Cytochrome P-450 CYP2C19/genetics , Drug Dosage Calculations , Female , Gastroesophageal Reflux/complications , Genotype , Humans , Male , Pantoprazole/administration & dosage , Pediatric Obesity/complications , Pediatric Obesity/genetics , Prospective Studies , Proton Pump Inhibitors/administration & dosageABSTRACT
Effects of ZnO NPs and ionic Zn on germline apoptosis and the regulation of genes in the apoptosis pathway were investigated in vivo using the model organism Caenorhabditis elegans.Age synchronized Bristol N2 worms were exposed to ZnO NPs and ZnCl2 at concentrations of 6.14 × 10-1, 61.4, and 614 µM form larval stage 1 (L1) to early adulthood. Possible ZnO nanoparticles were observed under the worm cuticle and also in the gonadal region by transmission electron microscopy (TEM). ZnO NPs and ZnCl2 both significantly increased the number of apoptotic cells as compared with controls in the 61.4 and 614 µM treatment groups (P < .05). However, ZnO NPs induced more apoptotic cells in the 61.4 µM treatment than ZnCl2 (P < .05), suggesting ZnO NP is more potent in inducing apoptosis at specific exposure concentration. Findings using the MD701 (bcIs39 [(lim-7)ced-1p::GFP + lin-15(+)]) strain further confirmed the observations in N2 strain. Genes involved in the apoptosis pathway (ced-13, ced-3, ced-4, ced-9, cep-1, dpl-1, efl-1, efl-2, egl-1, egl-38, lin-35, pax-2, and sir-2.1) were in general upregulated in response to ZnO NP exposure. The cep-1/p53 gene was up-regulated in gene expression assay. In the cep-1 loss of function mutant, no significant increase in apoptosis was observed. Therefore, the increased apoptosis resulting from ZnO NPs exposure is likely cep-1/p53 dependent. This study provides evidence that ZnO nanoparticles affect germ cell apoptotic machinery as a potential mechanism of reproductive toxicity.
Subject(s)
Apoptosis/drug effects , Caenorhabditis elegans/drug effects , Chlorides/pharmacology , Germ Cells/drug effects , Metal Nanoparticles , Zinc Compounds/pharmacology , Zinc Oxide/pharmacology , Animals , Apoptosis/genetics , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/geneticsABSTRACT
OBJECTIVE: The objective of this study was to investigate the effect of baseline sleep on baseline weight status and weight-loss responsiveness in obese adolescents. METHODS: Twenty-five obese adolescents who participated in a 19-day summer camp-based immersion treatment (IT) program completed pre-intervention measures of sleep duration and quality, and pre- and post-intervention body mass index z-scores (zBMI) and waist circumference (WC) assessments. Objective measures of sleep were obtained by actigraphy for a random subset of six participants for 1 week pre- and post-intervention. RESULTS: Shorter weekday sleep durations and more sleep debt were related to higher pre-intervention WCs (r = -0.54, p = 0.01 and r = -0.56, p = 0.01), and lower subjective sleep quality was related to higher pre-intervention zBMIs (r = -0.49, p = 0.02). Longer weekend sleep durations and more sleep debt were related to smaller reductions in pre- to post-intervention zBMIs (r = -0.47, p = 0.04 and r = -0.51, p = 0.03). For the subgroup of adolescents who wore actigraphs pre- and post-intervention, an increase in their sleep durations (d = -0.25) and a reduction in their sleep latencies (d = 0.52), zBMIs (d = 0.31), and WCs (d = 0.20) were observed. CONCLUSIONS: These results provide further evidence linking poor sleep patterns and obesity in adolescence, and suggest that sleep patterns may impact the effectiveness of pediatric obesity interventions and that IT programs may improve sleep in obese adolescents. Overall, they provide support for addressing sleep problems as part of obesity interventions.
Subject(s)
Pediatric Obesity/therapy , Sleep Wake Disorders/complications , Weight Loss , Weight Reduction Programs , Actigraphy , Adolescent , Body Mass Index , Child , Female , Humans , Life Style , Male , Pediatric Obesity/complications , Pilot Projects , Risk Factors , Treatment Outcome , Waist CircumferenceABSTRACT
Attrition is a significant problem for health care providers working with youth and parents involved in childhood obesity treatment. Barriers for families in childhood obesity treatment have been explored, but less is known about factors that may be associated with follow-up attendance. The purpose of this study is to explore youth and parent variables, pediatrician's evaluations of youth and parents' likelihood to change (LTC), and their association with attendance at follow-up. One hundred ninety-three youth and parent dyads were included in the sample; slightly more than half of the sample did not return for a follow up visit. Descriptive statistics, paired and independent t tests, and correlations were used to determine associations between youth and parent demographic factors, attendance at follow-up, and pediatricians' evaluation of likelihood to change. Evaluations of LTC and demographic factors did not significantly associate with follow-up appointment attendance. Single parents were more likely to be rated by pediatricians as likely to make changes. Implications for future research and clinical practice are discussed.