Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central ...hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.
Severe obesity is often associated with co-morbid conditions such as diabetes mellitus, hypertension, and obstructive sleep apnea. Successful weight loss can result in remission of these conditions. ...The authors retrospectively examined the co-morbidity profiles of pre-operative gastric sleeve adult patients from the MBSAQIP database with subjects from our adolescent bariatric program. Five conditions were compared: hypertension (HTN), type 2 diabetes mellitus (T2DM), dyslipidemia (DL), obstructive sleep apnea (OSA), and gastroesophageal reflux disease (GERD). Patients were matched by gender and body mass index (BMI). The prevalence of each condition was statistically more significant in the adult cohort. Successful weight loss at an earlier age may reduce the prevalence of these co-morbid conditions.
Objective: Our objective was to formulate practice guidelines for the treatment and prevention of pediatric obesity.
Conclusions: We recommend defining overweight as body mass index (BMI) in at least ...the 85th percentile but < the 95th percentile and obesity as BMI in at least the 95th percentile against routine endocrine studies unless the height velocity is attenuated or inappropriate for the family background or stage of puberty; referring patients to a geneticist if there is evidence of a genetic syndrome; evaluating for obesity-associated comorbidities in children with BMI in at least the 85th percentile; and prescribing and supporting intensive lifestyle (dietary, physical activity, and behavioral) modification as the prerequisite for any treatment. We suggest that pharmacotherapy (in combination with lifestyle modification) be considered in: 1) obese children only after failure of a formal program of intensive lifestyle modification; and 2) overweight children only if severe comorbidities persist despite intensive lifestyle modification, particularly in children with a strong family history of type 2 diabetes or premature cardiovascular disease. Pharmacotherapy should be provided only by clinicians who are experienced in the use of antiobesity agents and aware of the potential for adverse reactions. We suggest bariatric surgery for adolescents with BMI above 50 kg/m2, or BMI above 40 kg/m2 with severe comorbidities in whom lifestyle modifications and/or pharmacotherapy have failed. Candidates for surgery and their families must be psychologically stable and capable of adhering to lifestyle modifications. Access to experienced surgeons and sophisticated multidisciplinary teams who assess the benefits and risks of surgery is obligatory. We emphasize the prevention of obesity by recommending breast-feeding of infants for at least 6 months and advocating that schools provide for 60 min of moderate to vigorous daily exercise in all grades. We suggest that clinicians educate children and parents through anticipatory guidance about healthy dietary and activity habits, and we advocate for restricting the availability of unhealthy food choices in schools, policies to ban advertising unhealthy food choices to children, and community redesign to maximize opportunities for safe walking and bike riding to school, athletic activities, and neighborhood shopping.
Pediatric obesity can lead to concurrent co-morbidities. Intensive lifestyle modification remains the primary treatment. Carefully selected patients with severe co-morbidities may benefit from the addition of pharmacotherapy and/or bariatric surgery. Because treatment is difficult, prevention is the ultimate goal.
Background
Laparoscopic adjustable gastric banding (LAGB) is used to treat obesity in adults. Less is known about long-term results of the procedure in adolescents.
Objectives
To evaluate LAGB 5-year ...outcomes in teenagers with severe obesity.
Setting
Children’s hospital, USA.
Methods
Adolescents (14–18 years) underwent LAGB in an FDA-approved observational clinical trial. Outcomes including anthropometric measurements, comorbid conditions, complications, and band retention were collected through 60 months.
Results
One hundred thirty-seven subjects underwent LAGB (94 female, 43 male; 43% white, 37% Hispanic, 17% black; 4% other). Mean age and body mass index (BMI) pre-operatively were 17.0
+
1.2 years and 48.3
+
8.2 kg/m
2
, respectively. Comorbidities were present in 71%. Maximum weight loss occurred by 36 months (mean % excess weight loss (EWL) 40.6
+
35.2, mean % excess BMI loss (EBMIL) 41.6
+
34.9) and was maintained through 5 years for most subjects. There were no significant differences in weight loss by gender. Twenty-three (18%) of 127 adolescents reporting at 60 months achieved 50% excess weight loss. Postoperative heartburn and emesis occurred in 70% and 32%, respectively. Complications requiring additional surgery occurred 80 times in 63 patients. Thirty-three (26%) of 127 subjects contacted at 5 years had undergone band removal.
Conclusion
In this study, fewer than 20% of adolescents with severe obesity lost > 50% of their excess weight following LAGB. Nearly 50% of patients required additional surgery. With reports of success following sleeve gastrectomy and gastric bypass, we believe that LAGB is not a preferred choice to treat adolescents with obesity.
Objective
To understand the regulation of adipocyte size and adipokine expression in relation to gender, anatomic location, adiposity, and metabolic risk factors in adolescents with morbid obesity.
...Methods
Adipocyte size and adipokine expression in paired abdominal subcutaneous (SAT) and omental (VAT) surgical adipose tissues were related to gender, anatomic location, adiposity, and metabolic risk factors in a group of morbidly obese adolescents.
Results
Significant depot‐ and/or gender‐related differences in adipocyte size and adipokine expression were detected. Adjusted for body mass index, adipocyte size in both depots was larger in males than in females and was a major predictor of mRNA levels of leptin, plasminogen activator inhibitor‐1, and adiponectin. Gender, but not adipocyte size, was significantly correlated with proinflammatory cytokine expression. Body mass index and waist circumference were correlated positively with VAT adipocyte size and negatively with SAT adipocyte size. VAT adiponectin and interleukin‐6 expression levels were major predictors of high‐density lipoprotein cholesterol concentrations, independent of gender, adiposity, and insulin sensitivity.
Conclusions
Adipose tissue morphology and function in obese adolescents are influenced by gender and anatomic location; the pattern of gender‐ and depot‐related differences in adipocyte size and adipokine expression suggests that adolescent males, relative to the females, are at increased risk for obesity‐related metabolic comorbidities.
Objectives To characterize associations among psychosocial well-being, physical phenotype, and sex hormones in a sample of youth with Klinefelter syndrome (KS). We hypothesized that KS physical ...traits (phenotype) are associated with adverse psychosocial health measures and that testosterone levels are associated with adverse psychosocial health. Study design Forty-three boys with KS (ages 8-18 years) participated in a cross-sectional study. Participants underwent physical examination, hormone analyses, and psychosocial health questionnaires. Results Using an investigator-developed Klinefelter Phenotype Index Scale, the number of KS physical traits ranged from 1-13 (mean 5.1 ± 1.9). Pubertal boys presented with more KS traits compared with prepubertal boys (5.6 vs 4.2, P = .01). Boys diagnosed prenatally had a milder phenotype compared with those diagnosed postnatally. Gonadotropins were elevated without androgen deficiency in 45%. Psychosocial health scores indicated adverse quality of life (QOL) (67%), low self-esteem (38%), poor self-concept (26%), and risk for depression (16%) without a difference between pubertal groups. Linear regression showed that 22% of the variance in QOL ( P = .0001) was explained by phenotype. Testosterone level was not associated with psychosocial health measures. Conclusions Depending on the degree of phenotypic abnormality, boys with KS may be at risk for impaired QOL. Testosterone levels were not shown to influence psychosocial health. The Klinefelter Phenotype Index Scale may be a useful tool to characterize KS features in boys.
Recruiting pediatric samples for research may be challenging due to parental mistrust of the research process, privacy concerns, and family time constraints. Recruitment of children with chronic and ...genetic conditions may further complicate the enrollment process.
In this paper, we describe the methodological challenges of recruiting children for research and provide an exemplar of how the use of information technology (IT) strategies with social networking may improve access to difficult-to-reach pediatric research participants.
We conducted a cross-sectional descriptive study of boys between the ages of 8 and 18 years with Klinefelter syndrome. This study presented unique challenges for recruitment of pediatric participants. These challenges are illustrated by the report of recruitment activities developed for the study. We reviewed the literature to explore the issues of recruiting children for research using conventional and IT approaches. Success rates of conventional recruitment approaches, such as brochures, flyers in medical offices, and physician referrals, are compared with IT-based outreach. The IT approaches included teleconferencing via a Klinefelter syndrome support group, services of a Web-based commercial recruitment-matching company, and the development of a university-affiliated research recruitment website with the use of paid advertising on a social networking website (Facebook).
Over a 3-month period, dissemination of over 150 recruitment brochures and flyers placed in a large urban hospital and hospital-affiliated clinical offices, with 850 letters to physicians and patients were not successful. Within the same period, face-to-face recruitment in the clinical setting yielded 4 (9%) participants. Using Web-based and social networking approaches, 39 (91%) agreed to participate in the study. With these approaches, 5 (12%) were recruited from the national Klinefelter syndrome advocacy group, 8 (19%) from local and teleconference support groups, 10 (23%) from a Web-based research recruitment program, and 16 (37%) from the university-affiliated recruitment website. For the initial 6 months, the university website was viewed approximately 2 to 3 times per day on average. An advertisement placed on a social networking site for 1 week increased website viewing to approximately 63 visits per day. Out of 112 families approached using all of these methods, 43 (38%) agreed to participate. Families who declined cited either travel distance to the study site (15, 22%) or unwillingness to disclose the Klinefelter syndrome diagnosis to their sons (54, 78%) as the reasons for nonparticipation.
Use of Web-based technologies enhances the recruitment of difficult-to-reach populations. Of the many approaches employed in this study, the university-affiliated recruitment website supported by a Facebook advertisement appeared to be the most successful. Research grant budgets should include expenses for website registration and maintenance fees as well as online advertisements on social networking websites. Tracking of recruitment referral sources may be helpful in planning future recruitment campaigns.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Type 2 diabetes mellitus is a complex and under-treated disorder closely intertwined with obesity. Adolescents with severe obesity and type 2 diabetes have a more aggressive disease compared to ...adults, with a rapid decline in pancreatic β cell function and increased incidence of comorbidities. Given the relative paucity of pharmacotherapies, bariatric surgery has become increasingly used as a therapeutic option. However, subsets of this population have sub-optimal outcomes with either inadequate weight loss or little improvement in disease. Predicting which patients will benefit from surgery is a difficult task and detailed physiological characteristics of patients who do not respond to treatment are generally unknown. Identifying physiological predictors of surgical response therefore has the potential to reveal both novel phenotypes of disease as well as therapeutic targets. We leverage data assimilation paired with mechanistic models of glucose metabolism to estimate pre-operative physiological states of bariatric surgery patients, thereby identifying latent phenotypes of impaired glucose metabolism. Specifically, maximal insulin secretion capacity, σ, and insulin sensitivity, S
, differentiate aberrations in glucose metabolism underlying an individual's disease. Using multivariable logistic regression, we combine clinical data with data assimilation to predict post-operative glycemic outcomes at 12 months. Models using data assimilation sans insulin had comparable performance to models using oral glucose tolerance test glucose and insulin. Our best performing models used data assimilation and had an area under the receiver operating characteristic curve of 0.77 (95% confidence interval 0.7665, 0.7734) and mean average precision of 0.6258 (0.6206, 0.6311). We show that data assimilation extracts knowledge from mechanistic models of glucose metabolism to infer future glycemic states from limited clinical data. This method can provide a pathway to predict long-term, post-surgical glycemic states by estimating the contributions of insulin resistance and limitations of insulin secretion to pre-operative glucose metabolism.
The known markers of insulin resistance in obese children are well studied. However, they require serial measurements and complicated calculations. The objective is to study IGFBP-1 and its relation ...with other known risk measures.
The study included 98 New York City school students of diverse ethnic/racial backgrounds (57 males and 41 females), 11-15 years of age. Subjects were enrolled in a cross-sectional study, and anthropometric measures were collected. They underwent fasting intravenous glucose tolerance tests (IVGTT), and glucose, insulin, lipids, IGFBP-1, adiponectin and inflammatory markers were collected.
The subjects were stratified into 3 groups based upon the BMI Z-score. Out of all the subjects, 65.3% were in the group with a BMI Z-score <1 SDS, 16.3% subjects were in the group with a BMI Z-score of 1 to 2 SDS, and 18.4% of the subjects were in the group with a BMI Z-score of more than 2 SDS. The group with a BMI Z-score of more than 2 SDS had increased waist circumference (WC), body fat, increased fasting insulin, and triglycerides (TG). This group had decreased levels of adiponectin and HDL and low IGFBP-1 as compared to the group with BMI <1 SDS. The group with a BMI Z-score of 1 to 2 SDS had a decreased level of IGFBP-1 as compared to the group with a BMI Z-score less than 1 SDS. IGFBP-1 inversely correlated with age, WC, BMI, body fat, TG, and insulin levels. IGFBP-1 positively correlated with adiponectin and HDL levels.
IGFBP-1 in children can identify the presence of insulin resistance in the group with BMI 1 to 2 SDS, even before the known markers of insulin resistance such as elevated triglycerides and even before decreased HDL and adiponectin levels are identified.
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