Pediatric Obesity: Influence on Drug Dosing and Therapeutics

Obesity is an ongoing global health concern and has only recently been recognized as a chronic disease of energy homeostasis and fuel partitioning. Obesity afflicts 17% of US children and adolescents. Severe obesity (³120% of the 95th percentile of BMI-for-age, or a BMI of ³35 kg/m2) is the fastest growing subgroup and now approaches 6% of all US youth. Health consequences (e.g., type 2 diabetes, coronary heart disease) are related in a dose-dependent manner to severity of obesity. Since therapeutic interventions are less effective in severe obesity, prevention is a high priority. Treatment plans involving combinations of behavioral therapy, nutrition and exercise achieve limited success. Only one drug, orlistat, is FDA-approved for long-term obesity management in adolescents 12 years and older. As part of comprehensive medication management, clinicians should consider the propensity for a given drug to aggravate weight gain and to consider alternatives that minimize weight impact. Medication management must take into account developmental changes as well as pathophysiology of obesity and comorbidities. Despite expanding insight into obesity pathophysiology, there are gaps in its translation to therapeutic application. The historical construct of obesity as simply a fat storage disorder is fundamentally inaccurate. The approach to adjusting doses based solely on body size and extrapolating from therapeutic knowledge of adult obesity may be based on assumptions that are not fully substantiated. Classes of drugs commonly prescribed for comorbidities associated with obesity should be prioritized for clinical research evaluations aimed at optimizing dosing regimens in pediatric obesity

Autism Spectrum Disorder and the Child\u27s Weight–Related Behaviors: A Parents\u27 Perspective

Purpose To explore parent perspectives of how the attributes of their child\u27s autism spectrum disorder(ASD) impact nutrition, physical activity, screen time behaviors and risk for obesity. Secondarily, we examined the parent\u27s perception of the healthcare providers (HCP) influence on these weight-related behaviors. Design and method We conducted and audio-recorded telephone interviews with parents of children with ASD (n = 8) using a structured question guide. Data were transcribed and thematic analysis was conducted. Issues surrounding weight-related behaviors and parental strategies used were reported. Results Two overarching themes with eight subthemes emerged: (1) Challenges related to features of ASD (subthemes included fixation on food, sensory issues/rigidity, developmental factors, impaired social skills, and medication effects) and (2) Challenges related to the care of children with ASD (subthemes included lack of individualized care planning, picking your battles and the impact of ASD on family). Conclusion Strategies extracted from the parent narratives promoted both healthy and unhealthy weight-related behaviors. The key finding in this study is that some parents did not follow HCP guidance when they perceived that the HCP did not understand their particular situation. Practice Implications Implementation of healthy weight-related behaviors can be optimized when providers consider the child\u27s challenging ASD behaviors, affirm the difficulties encountered by the family and provide guidance that builds on the individual child/family strengths

A Pilot Study Investigating the Feasibility and Acceptability of a Parent-Only Behavioral Weight-Loss Treatment for Children with Autism Spectrum Disorder.

Evidence-based weight-loss treatments for children with autism spectrum disorder (ASD) are lacking. Therefore, a parent-based weight-loss treatment for children with ASD (PBT-ASD) was developed. A pilot study was conducted to test the initial efficacy, feasibility, and acceptability of this intervention. Parents of 20 children with ASD and overweight/obesity (mean age = 9.90 (SD = 2.31) years; 90% male; 40% Hispanic) participated in a 16-session PBT-ASD. The PBT-ASD program was found to be feasible and acceptable. Both children and parents lost weight from pre- to post-treatment (p's < .05). Parent-reported child physical activity and vegetable consumption increased at post-treatment (p's < .05). This pilot study provides a proof-of-concept for PBT-ASD. Randomized controlled trials with larger samples and follow-up are needed

Predictors of slow colonic transit in children

PURPOSE: Slow transit constipation (STC) and functional fecal retention (FFR) are two forms of severe intractable constipation in childhood diagnosed by nuclear transit studies (NTS). This retrospective study aims to identify the predicting factors for STC and FFR by looking at the association with neuropsychiatric disorders (NPD), obesity, family history of constipation and atopic disease. PATIENTS AND METHODS: A retrospective chart review was conducted on children with intractable constipation referred for NTS between 1st April 2003 and 1st April 2014. Comparisons were made between STC, FFR and normal transit patients with regards to NPD, obesity (BMI z score >95th percentile), family history of constipation in first and second-degree relatives and atopic disease which included food allergy, asthma and eczema. RESULTS: Between 2003 and 2014, 97 patients were referred for a NTS. Out of 36 patients with NPD, 21 (58.3 %) had STC and 13 (36.1 %) had FFR (p < 0.05). 15.8 % of patients with constipation were obese, compared to 6.4 % in the general Australian paediatric population (p < 0.05). There was no significant association between constipation and atopic disease or family history. CONCLUSION: Neuropsychiatric disorders, in particular autism, are useful predictors of STC and FFR in children. Obesity may be associated with a higher risk of developing chronic constipation

Maternal BMI as a predictor of methylation of obesity-related genes in saliva samples from preschool-age Hispanic children at-risk for obesity.

BackgroundThe study of epigenetic processes and mechanisms present a dynamic approach to assess complex individual variation in obesity susceptibility. However, few studies have examined epigenetic patterns in preschool-age children at-risk for obesity despite the relevance of this developmental stage to trajectories of weight gain. We hypothesized that salivary DNA methylation patterns of key obesogenic genes in Hispanic children would 1) correlate with maternal BMI and 2) allow for identification of pathways associated with children at-risk for obesity.ResultsGenome-wide DNA methylation was conducted on 92 saliva samples collected from Hispanic preschool children using the Infinium Illumina HumanMethylation 450 K BeadChip (Illumina, San Diego, CA, USA), which interrogates &gt;484,000 CpG sites associated with ~24,000 genes. The analysis was limited to 936 genes that have been associated with obesity in a prior GWAS Study. Child DNA methylation at 17 CpG sites was found to be significantly associated with maternal BMI, with increased methylation at 12 CpG sites and decreased methylation at 5 CpG sites. Pathway analysis revealed methylation at these sites related to homocysteine and methionine degradation as well as cysteine biosynthesis and circadian rhythm. Furthermore, eight of the 17 CpG sites reside in genes (FSTL1, SORCS2, NRF1, DLC1, PPARGC1B, CHN2, NXPH1) that have prior known associations with obesity, diabetes, and the insulin pathway.ConclusionsOur study confirms that saliva is a practical human tissue to obtain in community settings and in pediatric populations. These salivary findings indicate potential epigenetic differences in Hispanic preschool children at risk for pediatric obesity. Identifying early biomarkers and understanding pathways that are epigenetically regulated during this critical stage of child development may present an opportunity for prevention or early intervention for addressing childhood obesity.Trial registrationThe clinical trial protocol is available at ClinicalTrials.gov ( NCT01316653 ). Registered 3 March 2011

Stress and social support in normal weight and overweight/obese prepubertal children

Background: Overweight and obesity in children are public health problems. Understanding the risk factors is essential in order to develop effective interventions. Besides the more classical known risk factors, the impact of stress either caused by major life events or by repetitive daily hassles has been proposed to be a more novel important risk factor. Social support is often considered a protective factor concerning the negative effects of stress. Objectives: This cross-­‐sectional study aimed at comparing normal weight and overweight/obese children with regards to their stress exposure (number of stressful major life events and chronic daily hassles), their stress perception, and the level of social support Methods: For this part of the study, 50 normal weight and overweight/obese children aged 7 to 10 years old were recruited. Upon arrival, anthropometric measures of children were taken while parents filled out questionnaires about family major life events (including recent life events and early separation), their perceived stress, chronic daily hassles (including socioeconomic status, migrant status, parental worries and parenting practices), and their social support. Results: There were no group differences with regards to serious life events, recent life events or early separation (all p=NS). In contrast, chronic daily hassles in the form of lower socioeconomic, migrant status and certain unfavourable parenting practices such as corporal punishment occurred more frequently in overweight/obese children than in normal weight children (all p ≤0.06) and parents of overweight/obese children had a tendency to be more worried (p=0.08). Finally, there was no difference in social support between the two groups. Conclusion: In this more clinical sample of children, we found no differences in major life events or social support between normal weight and overweight/obese children, but the latter experienced more chronic daily hassles. Our results highlight the importance and influence of a child's environment on his weight and thus show that actions should be undertaken to treat childhood obesity on different levels. Further research is needed to study the interplay of the determinants influencing childhood overweight in a more epidemiological setting

Genetic factors of obesity and eating disorders: Copy number variations (CNV) involving SH2B1

Context : It is now clearly shown that genetic factors in association with environment play a key role in obesity and eating disorders. This project studies the clinical symptoms and molecular abnormalities in patients carrying a strong hereditary predisposition to obesity and eating behavior disorders. We have previously published the association between the 16:29.5-30.1 deletion and a very penetrant form of morbid obesity and macrocephaly. We have also demonstrated the association between the reciprocal 16:29.5-30.1 duplication and underweight and small head circumference. These 2 studies demonstrate that gene dosage of one or several genes in this region regulates BMI as well as brain growth. At present, there are no data pointing towards particular candidate genes. We are currently investigating a second non-overlapping recurrent CNV encompassing SH2B1, upstream of the aforementioned rearrangement. SNPs in this gene have been associated with BMI in GWAS studies and mice models confirmed this association. Bokuchova et al have reported an association between deletions encompassing this gene and severe early onset obesity, as well as insulin resistance. We are currently collecting and analyzing data to fully characterize the phenotype and the transcriptional patterns associated with this rearrangement. Aims : 1. Identify carriers of any CNVs in the greater 16p11.2 region (between 16:28MB and 32MB) in the EGG consortium. 2. Perform association studies between SNPs in the greater 16p11.2 region (16:28-32MB) and anthropometric measures with adjusted "locus-wide significance", to identify or prioritize candidate genes potentially driving the association observed in patients with the CNVs (and thus worthy of further validation and sequencing). 3. Explore associations between GSV genome-wide and brain volume. 4. Explore relationship between brain volumes (whole brain and regional for those who underwent brain MRI), head circumference and BMI. 5. Extrapolate this procedure to other regions covered by the Metabochip. Methods : - Examine and collect clinical informations, as well as molecular informations in these patients. - Analysis of MRI data in children and adults with BMI &gt; 2SD. Compare changes to MRI data obtained in patients with monogenic forms of obesity (data from Lausanne study) and to underweight (BMI&lt;-2SD) individuals from EGG. - Test whether opposite extremes of the phenotypic distribution may be highly informative Expected results : This is a highly focused study, pertaining to approximately 1 0/00 of the human genome. Yet it is clear that if successful, the lessons learned from this study could be extrapolated to other segments of the genome and would need validation and replication by additional studies. Altogether they will contribute to further explore the missing heritability and point to etiologic genes and pathways underlying these important health burdens

The role of maternal obesity in the risk of neuropsychiatric disorders

Recent evidence indicates that perinatal exposure to maternal obesity, metabolic disease, including diabetes and hypertension, and unhealthy maternal diet has a long-term impact on offspring behavior and physiology. During the past three decades, the prevalence of both obesity and neuropsychiatric disorders has rapidly increased. Epidemiologic studies provide evidence that maternal obesity and metabolic complications increase the risk of attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, anxiety, depression, schizophrenia, eating disorders (food addiction, anorexia nervosa, and bulimia nervosa), and impairments in cognition in offspring. Animal models of maternal high-fat diet (HFD) induced obesity also document persistent changes in offspring behavior and impairments in critical neural circuitry. Animals exposed to maternal obesity and HFD consumption display impairments in hyperactivity, impairments in social behavior, increased anxiety-like and depressive-like behaviors, substance addiction, food addiction, and diminished cognition. During development, these offspring are exposed to elevated levels of nutrients (fatty acids, glucose), hormones (leptin, insulin), and inflammatory factors (C-reactive protein, interleukin, and tumor necrosis factor). Such factors appear to permanently change neuroendocrine regulation and brain development in offspring. In addition, inflammation of the offspring brain during gestation impairs the development of neural pathways critical in the regulation of behavior, such as serotoninergic, dopaminergic, and melanocortinergic systems. Dysregulation of these circuits increases the risk of mental health disorders. Given the high rates of obesity in most developed nations, it is critical that the mechanisms by which maternal obesity programs offspring behavior are thoroughly characterized. Such knowledge will be critical in the development of preventative strategies and therapeutic interventions

Current changes in the occurrence of Autism Spectrum Disorders in Stockholm

The overall objective of this thesis is to estimate recent changes in and current prevalence of autism spectrum disorders (ASD) among young people in Stockholm County. An additional objective is to explore potential risk factors for ASD in view of the increasing occurrence in the population. For this purpose, a register-based total population study was set up and ASD case ascertainment validated as a means and research model for achieving the overall objective. All studies were based on the Stockholm Youth Cohort (SYC), a longitudinal total population study of 0-17 year olds resident in Stockholm County at any time since 2001. Prospectively compiled data for this population were merged from regional and national registers. In study I, we found that 96.0% of clinical case notes from randomly sampled ASD cases in the SYC were consistent with a diagnosis of ASD. Furthermore, we confirmed ASD in 82.5% of affected twins in the SYC by means of cross-validation against a twin study. In study II, we reported that ASD prevalence at the end of 2011 was 1.5% among 0-27 year olds (N=735,096), of whom 25.9% had a registered diagnosis of ID. The ASD prevalence was highest among teenagers at 2.4%. The male: female prevalence ratio for ASD decreased with age (from 3.3:1 among 0-12 year olds, to 1.9:1 among 18-27 year olds), particularly for ASD without ID. Between 2001 and 2011, the prevalence of ASD increased almost 3.5 fold among 2-17 year olds, mainly due to an eightfold increase of ASD without ID. In contrast, the prevalence of ASD with ID increased only slightly during this period. The recent increase in ASD prevalence has attracted research interest toward risk factors for ASD that have increased in a parallel manner, such as parental age and weight. In study III, we found that higher parental age increased the risk of offspring ASD as well as stronger parental age effects for ASD with, than without, ID. We found the risk of ASD to be greater for offspring of older mothers than for those of older fathers. Furthermore, the paternal age effect on ASD risk was only evident among offspring to mothers aged 35 years or younger, while maternal age increased the risk of ASD regardless of paternal age. In the population- based analysis of study IV, we found that maternal overweight increased the risk of ASD, while no such effect was evident in the sibling analysis. In addition to the finding that too much weight gain during pregnancy increases the risk of offspring ASD, this study was the first to report that too little weight gain also constitutes a risk. In conclusion, the prevalence of identified ASD without comorbid ID has increased substantially between 2001 and 2011 in Stockholm, and ASD currently affects more than 2% of teenagers, with important implications for the planning of health and educational services. Changes in diagnostic practice and awareness are likely to be the main drivers of the rise, but an actual true increase in ASD incidence cannot be ruled out. Collectively, these studies confirm the relevance of categorizing ASD according to ID. Finally, the SYC, with its extensive register-based data as well as a valid and thorough ASD case ascertainment constitutes an important resource for ASD research