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Background Neonatal adiposity has many determinants and may be a risk factor for future obesity. Epigenetic regulation of metabolically important genes is a potential contributor. Objectives The objective of the study is to determine whether methylation changes in the LEP gene in cord blood DNA are impacted by the maternal environment or affect neonatal adiposity measures. Methods A cross-sectional study of 114 full-term neonates born to healthy mothers with normal glucose tolerance was performed. Cord blood was assayed for leptin and genome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariate linear regression models and semi-partial correlation coefficients were used to analyze associations. False discovery rate was estimated to account for multiple comparisons. Results Maternal pre-pregnancy BMI was associated with decreased methylation at five CpG sites near the LEP transcription start site in an adjusted model (false discovery rate <0.022 for each site). The association between maternal BMI and cord blood leptin approached significance ( r = 0.18, p = 0.054). Cord blood leptin was positively correlated with neonatal adiposity measures including birth weight ( r = 0.45, p < 0.001), fat mass ( r = 0.47, p < 0.001) and percent body fat ( r = 0.44, p < 0.001). Conclusions Maternal pre-pregnancy BMI is strongly associated with decreased cord blood LEP gene methylation and may mediate the well-known association between maternal pre-pregnancy BMI and neonatal adiposity. [ABSTRACT FROM AUTHOR]

Purpose: The most common indications for total thyroidectomy (TT) in children are malignancy and thyrotoxicosis due to Graves' disease (GD). However, the incidence of patients with GD among patients undergoing TT is unknown. This study aims to examine trends in pediatric TT., Materials and Methods: The US Agency for Health Research and Quality Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID) was queried to identify patients who underwent TT between 1997 and 2019. Weighted national estimates were obtained. Statistical analysis was completed using univariate logistic regression and one-sided Mann-Kendall Test., Results: An estimated 4803 pediatric patients underwent TT within the study years. GD was the indication in 25 % of cases. Mann-Kendall testing showed a trend toward an increasing proportion of TT for GD without reaching statistical significance (z = 1.3609, S = 12, p = 0.0688). Statistically significant univariate associations were found among those who underwent thyroidectomy for GD compared to other indications, as they were more likely to be female (β = 0.286, 95 % CI [0.058, 0.514], p = 0.014), Black, or Hispanic (β = 1.392 [1.064, 1.721], p < 0.001; and β = 0.562 [0.311, 0.814], p < 0.001, respectively). Additionally, they were less likely to have private insurance (β = -0.308 [-1.076, -0.753], p = 0.002) and more likely to live in a ZIP code associated with a median household income below the 50th percentile (β = 0.190 [0.012, 0.369], p = 0.036). The associations with the female sex, Black race, and Hispanic race persisted in multivariate analysis., Conclusion: GD appears to be an increasingly prevalent indication for TT. Patient characteristics differ from those who undergo TT for other diagnoses., Competing Interests: Declaration of competing interest The authors have no disclosures or conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Dolutegravir (DTG)-based antiretroviral therapy is the World Health Organization's preferred first-line regimen for all persons with HIV, including pregnant women. While DTG has been implicated as an obesogen associated with greater weight gain compared to other antiretrovirals, there is a paucity of data in pregnant women and their children. The Obesogenic oRigins of maternal and Child metabolic health Involving Dolutegravir (ORCHID) study is investigating associations between DTG, weight gain, and metabolic outcomes in the context of HIV., Materials & Methods: ORCHID is a prospective observational study taking place in Cape Town, South Africa (NCT04991402). A total of 1920 pregnant women with and without HIV infection are being followed from ≤18 weeks gestational age to 24 months postpartum with their children. Participants attend eleven study visits: 3 antenatal, delivery, and 7 postnatal visits. Several embedded sub-studies address specific scientific aims. Primary outcome measurements in mothers include anthropometry, blood pressure, body composition, dysglycemia, insulin resistance (IR), and dyslipidemia. Other maternal measures include demographics, resting energy expenditure, viral load, physical activity, dietary intake, hepatic steatosis, and repository specimens. Sub-study measurements include markers of adipose inflammation, gut integrity, and satiety/hunger, subcutaneous adipose tissue morphology and mitochondrial function, and metabolomics. Primary outcome measurements in children include anthropometry, adipose tissue mass, dysglycemia, IR, and dyslipidemia. Other variables include fetal growth, birth outcomes, medical/breastfeeding history, caloric intake, neurodevelopment, and repository specimens. Sub-study measurements include metabolites/lipid subspecies in umbilical cord blood, as well as breast milk composition and DTG exposure., Discussion: ORCHID will play a pivotal role in defining obesogenic mechanisms and clinical consequences of DTG use in pregnancy in women with HIV and their children. It will provide insights into metabolic disease risk reduction in the context of HIV/DTG, identify intervention targets, and inform public health approaches to diminish chronic metabolic co-morbidities for women and children., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Abrams et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Lifestyle choices, metformin, and dietary supplements may prevent GDM, but the effect of intervention characteristics has not been identified. This review evaluated intervention characteristics to inform the implementation of GDM prevention interventions., Methods: Ovid, MEDLINE/PubMed, and EMBASE databases were searched. The Template for Intervention Description and Replication (TIDieR) framework was used to examine intervention characteristics (who, what, when, where, and how). Subgroup analysis was performed by intervention characteristics., Results: 116 studies involving 40,940 participants are included. Group-based physical activity interventions (RR 0.66; 95% CI 0.46, 0.95) reduce the incidence of GDM compared with individual or mixed (individual and group) delivery format (subgroup p-value = 0.04). Physical activity interventions delivered at healthcare facilities reduce the risk of GDM (RR 0.59; 95% CI 0.49, 0.72) compared with home-based interventions (subgroup p-value = 0.03). No other intervention characteristics impact the effectiveness of all other interventions., Conclusions: Dietary, physical activity, diet plus physical activity, metformin, and myoinositol interventions reduce the incidence of GDM compared with control interventions. Group and healthcare facility-based physical activity interventions show better effectiveness in preventing GDM than individual and community-based interventions. Other intervention characteristics (e.g. utilization of e-health) don't impact the effectiveness of lifestyle interventions, and thus, interventions may require consideration of the local context., (© 2024. The Author(s).)

Background: Precision prevention involves using the unique characteristics of a particular group to determine their responses to preventive interventions. This study aimed to systematically evaluate the participant characteristics associated with responses to interventions in gestational diabetes mellitus (GDM) prevention., Methods: We searched MEDLINE, EMBASE, and Pubmed to identify lifestyle (diet, physical activity, or both), metformin, myoinositol/inositol and probiotics interventions of GDM prevention published up to May 24, 2022., Results: From 10347 studies, 116 studies (n = 40940 women) are included. Physical activity results in greater GDM reduction in participants with a normal body mass index (BMI) at baseline compared to obese BMI (risk ratio, 95% confidence interval: 0.06 [0.03, 0.14] vs 0.68 [0.26, 1.60]). Combined diet and physical activity interventions result in greater GDM reduction in participants without polycystic ovary syndrome (PCOS) than those with PCOS (0.62 [0.47, 0.82] vs 1.12 [0.78-1.61]) and in those without a history of GDM than those with unspecified GDM history (0.62 [0.47, 0.81] vs 0.85 [0.76, 0.95]). Metformin interventions are more effective in participants with PCOS than those with unspecified status (0.38 [0.19, 0.74] vs 0.59 [0.25, 1.43]), or when commenced preconception than during pregnancy (0.21 [0.11, 0.40] vs 1.15 [0.86-1.55]). Parity, history of having a large-for-gestational-age infant or family history of diabetes have no effect on intervention responses., Conclusions: GDM prevention through metformin or lifestyle differs according to some individual characteristics. Future research should include trials commencing preconception and provide results disaggregated by a priori defined participant characteristics including social and environmental factors, clinical traits, and other novel risk factors to predict GDM prevention through interventions., (© 2023. Springer Nature Limited.)

Objective: To identify variables that are associated with poor compliance to thyroid hormone replacement therapy in children after total thyroidectomy., Method: A retrospective cohort study of children who underwent total thyroidectomy by high-volume pediatric otolaryngologists between 1/2014 and 9/2021. Postoperative poor compliance was characterized by at least three separate measurements of high TSH levels not associated with radioactive iodine treatment., Results: There were 100 patients, ages 3-20 years old who met inclusion criteria; 44 patients underwent thyroidectomy for cancer diagnosis, and 56 for Graves' disease. The mean follow-up time was 36.5 months (range 3.0-95.6 months). Overall, 42 patients (42%) were found to have at least three measurements of high TSH during follow-up, and 29 patients (29%) were diagnosed with clinical hypothyroidism. Sex, race, income, insurance type, and benign versus malignant etiology for thyroidectomy were not associated with adherence to therapy. Multivariate regression analysis identified patients with Graves' disease and hyperthyroidism at the time of surgery and Hispanic ethnicity to be associated with postoperative clinical hypothyroidism (OR 9.38, 95% CI 2.16-49.2, p = 0.004 and OR 6.15, 95% CI 1.21-36.0, p = 0.033, respectively)., Conclusions: Preoperative hyperthyroidism in patients with Graves' disease and Hispanic ethnicity were predictors of postoperative TSH abnormalities. Preoperative counseling for patients and their families on the implications of total thyroidectomy and the need for life-long medications postoperatively is necessary. Efforts should be made to evaluate and improve adherence to therapy pre-and postoperatively in patients with Graves' disease., Level of Evidence: 4 Laryngoscope, 133:2402-2406, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Maternal metabolites influence the size of newborns independently of maternal body mass index (BMI) and glycemia, highlighting the importance of maternal metabolism on offspring outcomes. This study examined associations of maternal metabolites during pregnancy with childhood adiposity, and cord blood metabolites with childhood adiposity using phenotype and metabolomic data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study. The maternal metabolites analyses included 2324 mother-offspring pairs, while the cord blood metabolites analyses included 937 offspring. Multiple logistic and linear regression were used to examine associations between primary predictors, maternal or cord blood metabolites, and childhood adiposity outcomes. Multiple maternal fasting and 1 hr metabolites were significantly associated with childhood adiposity outcomes in Model 1 but were no longer significant after adjusting for maternal BMI and/or maternal glycemia. In the fully adjusted model, fasting lactose levels were negatively associated with child BMI z-scores and waist circumference, while fasting urea levels were positively associated with waist circumference. One-hour methionine was positively associated with fat-free mass. There were no significant associations between cord blood metabolites and childhood adiposity outcomes. Few metabolites were associated with childhood adiposity outcomes after adjusting for maternal BMI and glucose, suggesting that maternal BMI accounts for the association between maternal metabolites and childhood adiposity.

Background: Hashimoto's thyroiditis (HT) affects 1-2 % of the pediatric population. In adults with HT, thyroidectomy is considered challenging and prone to postoperative complications due to the chronic inflammatory process. However, the complications of thyroidectomy among children with HT have not been established. The objective of our study was to evaluate whether children with HT undergoing total thyroidectomy for presumed thyroid cancer have higher complication rates than children without HT., Methods: A retrospective cohort study of children who underwent total thyroidectomy by high-volume pediatric otolaryngologists between 2014 and 2021., Results: 111 patients met inclusion criteria, 15 of these were diagnosed with HT preoperatively. Operative time and length of admission were similar among the groups. Postoperatively, patients with HT were more likely to have low levels of parathyroid hormone (60 % vs 26 %, p = 0.014) and transient hypocalcemia compared to non-HT patients, present with symptomatic hypocalcemia (67 % vs 27 %, p = 0.006), demonstrate EKG changes (20 % vs 6.3 %, p = 0.035) within 24 h of surgery, and to require both oral and intravenous calcium supplements (80 % vs 35 %, p = 0.001 and 60 % vs 22 % p = 0.004 respectively). Persistent hypocalcemia at 6 months follow-up, and recurrent laryngeal nerve paralysis rates were similar between groups. Parathyroid tissue was found in the thyroid specimen of 9 (60 %) HT patients vs 34 (35 %) non-HT patients (p = 0.069)., Conclusions: The risk of permanent complications among children with HT following thyroidectomy is low. However, patients with HT are more likely to develop symptomatic transient hypocalcemia and to require oral and intravenous calcium supplements in the immediate post-operative period compared to non-HT patients. Tailoring a perioperative treatment protocol to optimize calcium levels may be considered for children with HT., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest and that this study did not receive financial support. All authors have seen and approved the manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Graves' disease (GD) is the most common cause of childhood hyperthyroidism. Surgery is often chosen as a treatment modality given the high relapse rates and side effects of antithyroid drugs and has shown to be safe and efficacious. The goal of our study was to evaluate whether hyperthyroidism at time of thyroidectomy is associated with higher intra and postoperative complication rates., Methods: A retrospective cohort study of children who underwent thyroidectomy for GD by high-volume pediatric otolaryngologists between 2014 and 2021., Results: 64 patients met inclusion criteria. Patients with hyperthyroidism (defined as free T4≥1.63 ng/dL) were more likely to be treated with beta-blocker preoperatively compared to the euthyroid group (20/24 patients (83%) vs 23/40 patients (58%) respectively, p = 0.035). Twenty (83%) patients with hyperthyroidism and 39 euthyroid patients (98%) were treated with methimazole prior to surgery. Intraoperative tachycardia was noted in 5% of euthyroid patients and 20.8% of patients with hyperthyroidism. The mean peak heart rate intra-operatively and the number of patients with heart rate ≥120bmp were significantly higher for patients with hyperthyroidism (96.5 ± 16.2 vs 87.6 ± 22.1bpm, p = 0.02). Two patients required administration of esmolol during surgery for heart rate control, both with hyperthyroidism. Intra-operative peak systolic blood pressure, operative time, estimated blood loss, persistent hypocalcemia, length of admission and recurrent laryngeal nerve paralysis rates were similar among groups., Conclusions: Hyperthyroidism at surgery is associated with increased heart rate intraoperatively, with no increased risk for other complications. While optimizing thyroid hormone levels before surgery should be pursued in all children, our data suggest that hyperthyroidism should not delay the surgery., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Maternal prepregnancy body mass index (BMI) represents a surrogate marker of fetal exposures to the maternal metabolism during pregnancy. Yet, it remains poorly understood whether this marker indicates risk of altered trajectories in postnatal growth and development in children born preterm. This study aimed to determine whether maternal prepregnancy BMI is associated with altered growth and development in children born preterm., Study Design: A retrospective cohort study evaluated prepregnancy BMI as the exposure for childhood outcomes using linear regression and mixed effects models. The 38 children included in this follow-up evaluation originally participated in a prospective, observational cohort study to determine longitudinal levels of lipid species in preterm human milk expressed by women who delivered prior to 32 weeks. Childhood outcomes in this study were anthropometric measures during hospitalization ( n  = 38), after discharge through 36 months ( n  = 34) and Bayley-III developmental scores through 18 months corrected age ( n  = 26)., Results: In 38 children born prior to 32 weeks, higher maternal prepregnancy BMI was independently associated with higher preterm infant growth velocity during hospitalization, but not associated with in-hospital change in length or head circumference and/or postdischarge growth. In univariate linear regression models, higher maternal BMI was associated with lower cognitive scores at 18 months corrected age. This significant association remained in an adjusted model accounting for relevant influences on early childhood development., Conclusion: Increasing maternal prepregnancy BMI may reflect risk of altered growth and cognitive development in children born preterm., Key Points: · Maternal BMI was associated with early preterm infant weight gain.. · Maternal BMI was not associated with postdischarge growth.. · Increased maternal BMI may be associated with lower cognitive function scores in offspring.., Competing Interests: None declared., (Thieme. All rights reserved.)

Human milk samples were prospectively obtained from women who delivered prior to the 32nd week of gestation [1]. The 36 preterm human milk samples analysed in this dataset were collected at week 1 and week 4 of lactation. Samples were categorized as being from women with normal pre-pregnancy body mass index (BMI 18-24.9 kg/m 2 ) versus overweight/obese (BMI ≥25). Whole milk samples were frozen at -80 Celsius without prior processing and shipped for analysis on dry ice. Untargeted metabolomic and lipidomic platforms using UPLC-MS/MS and infusion-MS analysis for select lipids were performed by Metabolon. Lipidomic analysis included detection of complex lipids found in the milk fat globule membrane. Data were categorized by maternal BMI, week of lactation as well as gestational age at delivery. Data sheets are separated based on whether they report metabolomics versus lipidomics, as well as whether they report output from samples collected at week 1 versus week 4 of lactation. These data allow calculating relationships between clinical variables and human milk components. As an illustrative example, correlations between pre-pregnancy BMI and total milk fatty acids were calculated for this report using the Spearman correlation. These data will inform scientists of variability in milk composition attributable to maternal pre-pregnancy BMI as well as changes in milk composition as milk matures during lactation from week 1 to week 4. These data may best be used for generating hypotheses and justification of future work investigating whether maternal pre-pregnancy body mass index impacts preterm human milk composition., Competing Interests: None., (© 2020 The Authors.)

Background: Mother's milk is the recommended source of nutrition for all newborns. Preterm infants may be further compromised by maternal factors that impede successful lactation and alter milk composition., Purpose: To review and summarize the state of the science regarding implications of maternal overweight and obesity on successful lactation and associated alterations in preterm mother's milk composition., Methods/search Strategy: PubMed, EMBASE, and Web of Science searches were performed using relevant key words to identify references addressing maternal overweight or obesity, prematurity, human milk, and lactation., Findings/results: In the United States, more than half of women enter pregnancy with an overweight or obese body mass index. These women have increased risk of adverse pregnancy outcomes and obstetric complications that can undermine successful initiation and continuation of lactation, including preterm birth. Maternal overweight and obesity are also associated with alterations in mother's milk composition., Implications for Practice: Mother-preterm infant dyads affected by maternal overweight and obesity are at risk for barriers to initiation and continuation of lactation. Support for early initiation of milk expression is needed. Continued support, especially during the first weeks of lactation, can facilitate sustained milk production., Implications for Research: Considerable knowledge gaps remain in this area of human milk science. Future research is needed to facilitate more comprehensive understanding of differences in milk composition associated with maternal overweight and obesity and their impact on clinical outcomes in the preterm infant.

Introduction: Technology-enhanced antenatal diet and lifestyle intervention could prevent excess gestational weight gain and benefit mother and child., Study Design: A randomized clinical trial., Setting/participants: Overweight and obese ethnically diverse pregnant women in Chicago, Illinois, were enrolled between October 2012 and December 2015, with antenatal data collection completed by July 2016. Analysis was completed June 2017., Intervention: Participants were randomized when their fetus was gestational age 16 weeks to dietitian-led Dietary Approaches to Stop Hypertension diet and physical activity coaching that was received as three individual and six group counseling sessions by phone and webinar. A commercially available smartphone application was used for self-monitoring diet and physical activity. Telephone, text message prompts, and e-mail reminders encouraged adherence and website viewing. Usual-care, "web-watcher" participants were e-mailed biweekly newsletters and publicly available maternity website links., Main Outcome Measures: The primary outcome was gestational weight gain measured at baseline, 24 weeks, and 35.0-36.6 weeks. Secondary outcomes included weekly rate of gestational weight gain, newborn anthropometrics, maternal diet quality, physical activity, and blood pressure., Results: Among 281 participants randomized (n=140 in intervention, n=141 in usual care, BMI 25 to <40, and age range 18-40 years), 37% were non-white and 274 completed antenatal data collection (n=139 in the intervention group and n=135 in the usual-care group). Gestational weight gain differed significantly by intervention group (difference, 1.7kg, p=0.01) and rate of weight gain was 0.4 (SD=0.2) vs 0.5 (SD=0.2) kg/week. No significant differences were noted in birth weight, percentage body fat, or adverse pregnancy outcomes, but more cesarean sections (55 [40%] vs 37 [27%]) occurred among the intervention group., Conclusions: Technology-enhanced Dietary Approaches to Stop Hypertension diet and lifestyle intervention resulted in significantly less total gestational weight gain over 35 weeks with no adverse infant outcomes. Nutrient quality improved without an adverse impact on rate of prematurity. Increased cesarean delivery requires further exploration. The National Academy of Medicine goals were not achieved by the majority of participants. Obesity prevention preconception is needed., Trial Registration: This study is registered at www.clinicaltrials.gov NCT01631747., (Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Context: Elevated levels of the phosphate-regulating hormone, fibroblast growth factor-23 (FGF-23) are associated with skeletal and cardiovascular disease. Levels of FGF-23 are elevated in neonates, but the mechanisms are poorly understood. Iron deficiency is a recently described stimulus for FGF-23 production., Objective: To test the hypothesis that lower fetal iron status, as measured by lower cord blood ferritin, is independently associated with elevated FGF-23 levels in neonates., Design and Participants: This is a cross-sectional study of 64 full-term, healthy neonates., Setting: This study took place in a university-based, tertiary care center., Main Outcome Measures: Plasma levels of second generation C-terminal FGF-23 (cFGF-23) and intact FGF-23 (iFGF-23)., Results: Levels of cFGF-23 ranged from 108 to 7508 reference units (RU)/ml (median, 824 RU/ml), and iFGF-23 from undetectable (<8.5) to 135.4 pg/ml (median, <8.5 pg/mL). Ferritin ranged from 58 to 719 ng/ml (mean, 203 ng/ml). Lower cord blood ferritin levels were associated with higher cFGF-23 (r = −0.320; P = .014), but not iFGF-23 levels (r = −0.222; P = .082). In multivariate analyses adjusted for glycemic indices, maternal race, and parity, lower ferritin levels remained independently associated with higher cFGF-23 levels (B = −0.261, P = .01). In the full models, higher cord blood glucose and C-peptide levels were also independently associated with higher cFGF-23 levels., Conclusions: cFGF-23, but not iFGF-23 levels, are elevated in cord blood of healthy term neonates and independently associated with lower serum ferritin and higher glycemic indices.

Insulin-like growth factor 2 (IGF-2) is necessary for adequate human growth. Overexpression of the IGF2 gene is associated with fetal overgrowth and may play a role in the intrauterine programming of adipose tissue. As obesity in children is a major public health problem associated with early onset of comorbid metabolic diseases, identifying early life markers of obesity may serve as useful tool for counseling and implementation of preventive efforts before obesity develops. The relationship between IGF-2 and body composition is an emerging field of study and existing data are conflicting. In this review, we discuss the IGF2 gene and its function, highlight the proposed mechanisms for the effects of IGF-2 on adiposity, and examine the current literature studying the relationships between IGF-2 levels, changes within the IGF2 gene, weight, and adiposity. With additional study, IGF-2 may emerge as a useful marker of future obesity risk in infants.

Objective: To describe the clinical manifestations of growth hormone (GH) excess in children with optic pathway tumors (OPT)., Study Design: Descriptive case series of 5 children with OPT, 3 with associated neurofibromatosis type 1, referred for evaluation of accelerated linear growth. GH excess was evaluated by oral glucose tolerance tests with frequent sampling of GH levels. Precocious puberty was evaluated by basal luteinizing hormone and sex steroid hormone levels. Stimulation testing with leuprolide acetate (20 μg/kg subcutaneously) was conducted in patients with normal baseline testing., Results: All patients had OPT involving both the hypothalamus and optic chiasm. All patients had elevated levels of the growth factor insulin-like growth factor 1 and on stimulation testing demonstrated an inability to suppress GH levels to < 1.0 ng/mL, indicating the presence of unregulated GH secretion. Additionally, all patients displayed biochemical evidence of precocious puberty., Conclusions: GH excess may be an under-recognized occurrence in the setting of neurofibromatosis type 1 and OPT. GH excess in such patients may contribute to continued brain tumor growth. Given the potential adverse consequences of unrestrained GH excess, all children with chiasmal or hypothalamic tumors who have rapid growth should be evaluated for both precocious puberty and GH excess., (Copyright © 2011 Mosby, Inc. All rights reserved.)

A progressive decline in islet function is a major obstacle to success of islet transplantation. The cause of this decline is islet function is unclear, but immunosuppressive agents may contribute. Insulin-like growth factor-I (IGF-I) and betacellulin are important for islet cell survival and/or proliferation. In the present study, we performed studies of IGF-I and betacellulin on progression of islet cells through the cell cycle and the impact of immunosuppressive agents. Treatment of INS-1 cells for 24 hours with 20 ng/mL betacellulin or 50 ng/mL IGF-1 increased cells in S phase by ~2-fold. Treatment of INS-1 cells with IGF-I or betacellulin also increased cyclin D1 expression and nuclear exclusion of the cyclindependent kinase inhibitors p21(Cip1) and p27(Kip1). In INS-1 cells and islets, betacellulin- and IGF-I increased the increase in p70(s6 kinase) phosphorylation stimulated by betacellulin- and IGF-I in INS-1 cells. Rapamycin also inhibited betacellulin- and IGF-I IN IGF-1 cells. Rapamycin also inhibited betacellulin- and IGF-I-induced entry of cells into S phase and 5'-Bromo-2'-deoxyuridine incorporation as well as the effect of betacellulin and IGF-I on cyclin D1 expression and nuclear exclusion of p21(Cip1) and p(27Kip1). Together, these data suggest that the effect of betacellulin and IGF-I on islet cell growth and proliferation is mediated, in part, via signaling through mammalian target of rapamycin. As rapamycin is used to treat islet transplant recipients, these results suggest that rapamycin could have deleterious effects on islet proliferation and function over time.

The incidence of thyroid nodules in children is estimated to be 1 to 1.5% based on clinical examination. Children with thyroid nodules, compared to adults with thyroid nodules, have a fourfold greater risk of developing malignant thyroid disease. Differentiated thyroid carcinoma is the most common pediatric endocrine tumor, constituting 0.5-3% of all childhood malignancies. The thyroid is one of the most frequent sites of secondary neoplasm in children who receive radiation therapy for other malignancies. Thyroid carcinoma has been studied extensively in adults. However, the pediatric literature on this subject is much less complete, owing to the rarity of its diagnosis. This article reviews the predisposing factors, genetics, pathology, pathogenesis , clinical presentation, detailed treatment and follow-up management of children with thyroid carcinoma. Additionally, a discussion regarding the controversial aspects of radioiodine therapy in children is included.