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1.  Sugar-Sweetened Beverages and Weight Gain in 2- to 5-Year-Old Children 
Pediatrics  2013;132(3):413-420.
BACKGROUND AND OBJECTIVE:
Although sugar-sweetened beverage (SSB) consumption has been tightly linked to weight status among older children, the data regarding these relationships in children aged 2 to 5 years have been mixed. Our objective was to evaluate longitudinal and cross-sectional relationships between SSB consumption and weight status among children aged 2 to 5 years.
METHODS:
We assessed SSB consumption and BMI z scores among 9600 children followed in the Early Childhood Longitudinal Survey—Birth Cohort, using linear and logistic regression and adjusting for race/ethnicity, socioeconomic status, mother’s BMI, and television viewing.
RESULTS:
Higher rates of SSB consumption were associated with higher BMI z scores among children age 4 (P < .05) and 5 (P < .001) but not yet at 2 years. Children aged 5 years who drank SSB regularly (compared with infrequent/nondrinkers) had a higher odds ratio for being obese (1.43, confidence interval 1.10–1.85, P < .01). In prospective analysis, children drinking SSB at 2 years (compared with infrequent/nondrinkers) had a greater subsequent increase in BMI z score over the ensuing 2 years (P < .05).
CONCLUSIONS:
Similar to what is seen among older children, children aged 2 to 5 years drinking SSB demonstrate both prospective and cross-sectional correlations with higher BMI z score. Pediatricians and parents should discourage SSB consumption to help avoid potential unhealthy weight gain in young children. From a public health standpoint, strong consideration should be made toward policy changes leading to decreases in SSB consumption among children.
doi:10.1542/peds.2013-0570
PMCID: PMC3876761  PMID: 23918897
sugar sweetened beverages; weight gain; obesity; preschool
2.  Delays in Puberty, Growth and Accrual of Bone Mineral Density in Pediatric Crohn’s Disease: Despite Temporal Changes in Disease Severity, the Need for Monitoring Remains 
The Journal of pediatrics  2013;163(1):17-22.
doi:10.1016/j.jpeds.2013.02.010
PMCID: PMC3692567  PMID: 23522861
Inflammatory bowel disease; inflammation; cytokines; adolescent
3.  Ethnic Differences in the Link Between Insulin Resistance and Elevated ALT 
Pediatrics  2013;132(3):e718-e726.
BACKGROUND:
Nonalcoholic fatty liver disease (NAFLD) exhibits tight links with insulin resistance (IR) and the metabolic syndrome (MetS), a cluster of cardiovascular risk factors. Compared with non-Hispanic whites, non-Hispanic black adolescents have more IR but a lower prevalence of NAFLD and MetS. Our hypothesis was that IR would be a better predictor of alanine aminotransferase (ALT) elevations than is MetS among non-Hispanic blacks.
METHODS:
We analyzed data from 4124 adolescents aged 12 to 19 years in the 1999 to 2010 NHANES, using unexplained elevations in ALT (>30 U/L) to characterize presumed NAFLD and using a pediatric adaptation of the Adult Treatment Panel III definition of MetS.
RESULTS:
Prevalence of elevated ALT varied by race/ethnicity (Hispanics 13.7%, non-Hispanic white 8.6%, non-Hispanic blacks 5.4%, P < .0001). Among non-Hispanic whites and Hispanics, a classification of MetS performed well in identifying adolescents with elevated ALT (odds ratios [ORs] 9.53 and 5.56, respectively), as did MetS-related indices. However, among non-Hispanic blacks, the association between MetS and ALT elevations was smaller in magnitude and technically nonsignificant (OR = 3.24, P = .051). Furthermore, among non-Hispanic blacks, the presence of IR and elevated waist circumference performed more poorly at identifying ALT elevations (ORs 3.93 and 2.28, respectively: significantly smaller than ORs for non-Hispanic whites, P < .05), with triglyceride elevations being a better predictor (OR = 4.44).
CONCLUSIONS:
Non-Hispanic black adolescents exhibit a lower relationship between IR and elevated ALT, supporting racial/ethnic differences in the link between MetS and NAFLD. These data may have implications regarding triggers for screening for NAFLD among non-Hispanic black adolescents, focusing particularly on those with triglyceride elevations.
doi:10.1542/peds.2012-3584
PMCID: PMC3876752  PMID: 23940240
metabolic syndrome; visceral obesity; inflammation; racial/ethnic difference
4.  Low sensitivity of the metabolic syndrome to identify adolescents with impaired glucose tolerance: an analysis of NHANES 1999–2010 
Background
The presence of impaired glucose tolerance (IGT) and metabolic syndrome (MetS) are two risk factors for Type 2 diabetes. The inter-relatedness of these factors among adolescents is unclear.
Methods
We evaluated the sensitivity and specificity of MetS for identifying IGT in an unselected group of adolescents undergoing oral glucose tolerance tests (OGTT) in the National Health and Nutrition Evaluation Survey 1999–2010. We characterized IGT as a 2-hour glucose ≥140 mg/dL and MetS using ATP-III-based criteria and a continuous sex- and race/ethnicity-specific MetS Z-score at cut-offs of +1.0 and +0.75 standard deviations (SD) above the mean.
Results
Among 1513 adolescents, IGT was present in 4.8%, while ATP-III-MetS was present in 7.9%. MetS performed poorly in identifying adolescents with IGT with a sensitivity/specificity of 23.7%/92.9% for ATP-III-MetS, 23.6%/90.8% for the MetS Z-score at +1.0 SD and 35.8%/85.0 for the MetS Z-score at +0.75 SD. Sensitivity was higher (and specificity lower) but was still overall poor among overweight/obese adolescents: 44.7%/83.0% for ATP-III-MetS, 43.1%/77.1% for the MetS Z-score at +1.0 SD and 64.3%/64.3% for MetS Z-score at +0.75 SD.
Conclusion
This lack of overlap between MetS and IGT may indicate that assessment of MetS is not likely to be a good indicator of which adolescents to screen using OGTT. These data further underscore the importance of other potential contributors to IGT, including Type 1 diabetes and genetic causes of poor beta-cell function. Practitioners should keep these potential causes of IGT in mind, even when evaluating obese adolescents with IGT.
doi:10.1186/1475-2840-13-83
PMCID: PMC4000320  PMID: 24755002
Insulin resistance; Metabolic syndrome; Impaired glucose tolerance; Type 2 diabetes; Adolescents
5.  The impoverished gut—a triple burden of diarrhoea, stunting and chronic disease 
More than one-fifth of the world’s population live in extreme poverty, where a lack of safe water and adequate sanitation enables high rates of enteric infections and diarrhoea to continue unabated. Although oral rehydration therapy has greatly reduced diarrhoea-associated mortality, enteric infections still persist, disrupting intestinal absorptive and barrier functions and resulting in up to 43% of stunted growth, affecting one-fifth of children worldwide and one-third of children in developing countries. Diarrhoea in children from impoverished areas during their first 2 years might cause, on average, an 8 cm growth shortfall and 10 IQ point decrement by the time they are 7–9 years old. A child’s height at their second birthday is therefore the best predictor of cognitive development or ‘human capital’. To this ‘double burden’ of diarrhoea and malnutrition, data now suggest that children with stunted growth and repeated gut infections are also at increased risk of developing obesity and its associated comorbidities, resulting in a ‘triple burden’ of the impoverished gut. Here, we Review the growing evidence for this triple burden and potential mechanisms and interventions that must be understood and applied to prevent the loss of human potential and unaffordable societal costs caused by these vicious cycles of poverty.
doi:10.1038/nrgastro.2012.239
PMCID: PMC3617052  PMID: 23229327
6.  Obesity, systemic inflammation, and increased risk for cardiovascular disease and diabetes among adolescents: A need for screening tools to target interventions 
Cardiovascular disease (CVD) and type 2 diabetes mellitus have their roots in childhood, particularly in obese children and adolescents, raising important opportunities for early lifestyle intervention in at-risk individuals. However, not all obese individuals are at the same risk for disease progression. Accurate screening of obese adolescents may identify those in greatest need for intensive intervention to prevent or delay future disease. One potential screening target is obesity-related inflammation, which contributes to insulin resistance, metabolic syndrome, and CVD. In adults, the inflammatory marker high-sensitivity C-reactive protein (hsCRP) has utility for risk stratification and treatment initiation in individuals of intermediate CVD risk. In adolescents, hsCRP shares many of the associations of hsCRP in adults regarding the degree of insulin resistance, metabolic syndrome, and carotid artery media thickness. However, long-term data linking increased hsCRP levels—and increased insulin or decreased adiponectin—in childhood to adult disease outcomes are lacking at this time. Future efforts continue to be needed to identify childhood clinical and laboratory characteristics that could be used as screening tests to predict adult disease progression. Such tests may have utility in motivating physicians and patients' families toward lifestyle changes, ultimately improving prevention efforts.
doi:10.1016/j.nut.2012.07.003
PMCID: PMC3578702  PMID: 23022122
Obesity; Metabolic syndrome; Insulin resistance; Risk; Adolescents; Inflammation; High-sensitivity C-reactive protein; Adiponectin
7.  Racial/Ethnic and Gender Differences in the Relationship between Uric Acid and Metabolic Syndrome in Adolescents: An Analysis of NHANES 1999–2006 
Metabolism  2011;61(4):554-561.
Background
Among adolescents uric acid is associated with insulin resistance, hypertension and the metabolic syndrome (MetS) and in adults high uric acid levels are an independent risk factor for cardiovascular disease and diabetes.
Objective
Determine whether the relationship of uric acid with MetS varies in adolescents by race/ethnicity and gender.
Methods
We used linear regression to evaluate associations between uric acid and other MetS-associated clinical and laboratory measures among 3,296 non-Hispanic-white, non-Hispanic-black and Hispanic adolescents age 12–19y participating in the National Health and Nutrition Evaluation Survey (1999–2006).
Results
Overall, non-Hispanic-white males and females had the highest uric acid levels among the three racial/ethnic groups. In each racial/ethnic group there were higher uric acid levels for those adolescents with vs. without MetS. However, the extent of the MetS-related increase in uric acid level varied by race and gender. Among males, MetS was associated with the greatest increases in uric acid among non-Hispanic whites. However, among females, the MetS-related increase in uric acid was greatest among non-whites. Non-Hispanic-white females exhibited the lowest degrees of correlation between levels of uric acid and MetS-associated variables. Uric acid levels did not correlate with insulin levels in non-Hispanic-white females.
Conclusions
These data suggest the relationship between uric acid and MetS varies by race/ethnicity and gender. In particular, non-Hispanic-white males exhibit a strong relationship and non-Hispanic-white females exhibit a relatively poor correlation between uric acid and MetS-related factors. These data may have implications for the use of uric acid as a marker of future risk among adolescents.
doi:10.1016/j.metabol.2011.09.003
PMCID: PMC3262070  PMID: 22000606
obesity; insulin resistance; hypertension
8.  Low Sensitivity for the Metabolic Syndrome to Detect Uric Acid Elevations in Females and Non-Hispanic-Black Male Adolescents: An Analysis of NHANES 1999-2006 
Atherosclerosis  2011;220(2):575-580.
Background
Uric acid is tightly linked to the metabolic syndrome (MetS) and among adults higher uric acid levels are associated with future risk for diabetes, cardiovascular disease, hypertension and renal disease.
Objective
Evaluate the sensitivity of MetS to identify adolescents with elevated uric acid levels on a race/ethnicity and gender-specific basis.
Methods
We evaluated 3,296 males and female adolescents 12-19y participating in the National Health and Nutrition Evaluation Survey ‘99-’06, comprised of 67.6% non-Hispanic whites, 15.1% non-Hispanic blacks, and 17.3% Hispanics. We used a definition of MetS modified for use in adolescents and evaluated the sensitivity of a diagnosis of MetS to identify individuals with uric acid elevations (approximately the 95th percentile of uric acid by gender among normal-weight adolescents).
Results
When used as a screening test to identify individuals with uric acid elevations MetS performed more poorly among females (18.0%) than among males (37.0%)(p<0.001). Among males, MetS exhibited a lower sensitivity among non-Hispanic blacks (17.8%) compared to Hispanics (45.9%)(p<0.01) and non-Hispanic whites (37.4%)(p<0.05). There were no race/ethnicity differences in detecting elevated uric acid levels among females (non-Hispanic-white 15.5%, non-Hispanic-black 19.4%, Hispanic 26.5%, p>0.05).
Conclusion
Current criteria to diagnose MetS exhibit racial/ethnic and gender differences in the ability to identify adolescents with elevated uric acid levels, performing poorly among non-Hispanic-black males and among females. Given emerging data regarding the ability of uric acid elevations for predicting future disease, these data may have implications regarding the use of MetS as a marker of risk among all gender and racial/ethnic groups.
doi:10.1016/j.atherosclerosis.2011.11.033
PMCID: PMC3321243  PMID: 22178428
metabolic syndrome; uric acid; adolescents; insulin resistance; cardiovascular disease risk
9.  Early childhood growth failure and the developmental origins of adult disease: Do enteric infections and malnutrition increase risk for the metabolic syndrome? 
Nutrition reviews  2012;70(11):642-653.
Hypotheses regarding the developmental origins of health and disease postulate that developing fetuses–and potentially young children—undergo adaptive epigenetic changes with longstanding effects on metabolism and other processes. Ongoing research explores whether these adaptations occur during early life following malnutrition. In the developing world there remains a high degree of nutritional stunting—linear growth failure due to inadequate calories that may be exacerbated by inflammation from ongoing infections. In areas with poor sanitation children experience vicious cycles of enteric infections and malnutrition, resulting in poor nutrient absorption from intestinal mucosa changes now termed “environmental enteropathy.” Emerging evidence links early childhood diarrhea and/or growth failure with increased CVD risk factors in later life, including dyslipidemia, hypertension and glucose intolerance. The mechanisms for these associations remain poorly understood and may relate to epigenetic responses to poor nutrition, increased inflammation or both. Given increases in CVD in developing areas of the world, associations between childhood malnutrition, early life infections and increased CVD risk factors underscore further reasons to improve nutrition and infection-related outcomes for young children worldwide.
doi:10.1111/j.1753-4887.2012.00543.x
PMCID: PMC3493112  PMID: 23110643
Nutrition; diarrhea; stunting; cardiovascular disease; environmental enteropathy; Fetal Origins Hypothesis
10.  Racial/ethnic and sex differences in the ability of metabolic syndrome criteria to predict elevations in fasting insulin in adolescents 
The Journal of pediatrics  2011;159(6):975-981.e3.
Objective
To evaluate racial/ethnic and sex differences in the relationship between metabolic syndrome (MetS) diagnosis and fasting insulin among adolescents.
Study design
We analyzed data from the National Health and Nutrition Evaluation Survey 1999–2008 for 3,693 non-Hispanic-white, non-Hispanic-black and Hispanic adolescents (12–19y). We used linear regression to evaluate differences in fasting insulin between those with and without an adolescent adaptation of ATPIII-MetS in a sex- and race/ethnicity-specific basis.
Results
Females had higher insulin levels than males and non-Hispanic blacks and Hispanics had higher levels than non-Hispanic whites. Adolescents with MetS had higher insulin levels than those without MetS. The difference in insulin levels between those with and without MetS was greater among non-Hispanic blacks compared with non-Hispanic whites (p<0.05) but not Hispanics (p=0.10). The sensitivity of MetS for detecting elevated insulin levels was lower among non-Hispanic blacks and females compared with other ethnicities and males, respectively. Correlations between insulin and individual MetS components were similar among ethnicities.
Conclusion
MetS diagnosis performed more poorly in predicting elevated insulin levels among non-Hispanic blacks and among females. These data support the hypothesis that non-Hispanic blacks do not meet current criteria for MetS until they have reached a more advanced degree of insulin resistance.
doi:10.1016/j.jpeds.2011.05.023
PMCID: PMC3202665  PMID: 21784441
Metabolic syndrome; ethnicity; insulin resistance; adolescents
11.  Use of Ghrelin as a Treatment for Inflammatory Bowel Disease: Mechanistic Considerations 
Inflammatory bowel diseases (IBD)—and in particular Crohn's disease—are immune-mediated processes that result in denuded intestinal mucosa and can produce decreased appetite, weight loss, and systemic inflammation. Current treatments include anti-inflammatory medications, immunomodulators, and feeding interventions. Ghrelin is an endogenous orexigenic hormone that directly stimulates growth hormone release, increases gut motility, and has cardiovascular and anti-inflammatory properties. Although ghrelin levels are elevated in active IBD, administration of ghrelin in most (but not all) animal models of colitis has produced improvements in disease activity and systemic inflammation. The mechanism for these effects is not known but may relate to decreased inflammation, increased motility, increased appetite, and increased colonic blood flow. Human trials have not been performed, however, and more research is clearly needed.
doi:10.1155/2011/189242
PMCID: PMC3154487  PMID: 21845198
12.  Diagnosis of the Metabolic Syndrome Is Associated With Disproportionately High Levels of High-Sensitivity C-Reactive Protein in Non–Hispanic Black Adolescents 
Diabetes Care  2011;34(3):734-740.
OBJECTIVE
Whereas it is known that the metabolic syndrome (MetS) has a paradoxically lower prevalence in non–Hispanic black adolescents than in non–Hispanic whites or Hispanics, the relative severity of MetS by race/ethnicity is unknown. Inflammation, indicated by high-sensitivity C-reactive protein (hsCRP), is a key factor linking MetS to cardiovascular disease and type 2 diabetes. Our goal was to determine whether elevations of hsCRP vary by race/ethnicity among adolescents with MetS.
RESEARCH DESIGN AND METHODS
We used the National Health and Nutrition Examination Survey (1999–2008) and evaluated adolescents (age 12–19 years) using a pediatric/adolescent adaptation of the ATP III definition of MetS. We used linear regression to evaluate the interaction between MetS status and ethnicity with respect to hsCRP concentration.
RESULTS
For male and female adolescents, MetS was associated with elevated hsCRP levels compared with adolescents without MetS. However, the elevation in hsCRP between adolescents with and without MetS was greater in non–Hispanic blacks compared with that in non–Hispanic whites (P = 0.04) but not that in Hispanics (P = 0.18). hsCRP concentrations correlated with individual MetS components similarly among all ethnicities. In an evaluation of adolescents diagnosed with MetS, non–Hispanic blacks had higher BMI and more hypertension than other ethnicities but there were no other racial/ethnic differences in the features of MetS.
CONCLUSIONS
Non–Hispanic black adolescents have a greater differential in hsCRP between those with and those without MetS than the differential in non–Hispanic whites but not that in Hispanics. Therefore, even though MetS has a low prevalence in non–Hispanic blacks, MetS is a particularly good indicator of inflammation in non–Hispanic black adolescents.
doi:10.2337/dc10-1877
PMCID: PMC3041218  PMID: 21285387
13.  Increased systemic inflammation overnight correlates with insulin resistance among children evaluated for obstructive sleep apnea 
Purpose
Obstructive sleep apnea (OSA) in children is associated with obesity, insulin resistance, and elevated baseline inflammation as measured by high-sensitivity C-reactive protein (hsCRP). Our goal was to evaluate whether inflammation increases overnight among children suspected of having OSA and to determine whether worsened inflammation is associated with the degree of OSA severity, obesity, and/or insulin resistance.
Methods
Twenty-three children with clinical suspicion of OSA underwent a sleep study. Levels of hsCRP were tested the evening before and morning after the sleep study. Fasting insulin and glucose levels were measured from which the homeostasis model of insulin resistance (HOMA-IR) was calculated. Linear correlations were performed to evaluate relationships between hsCRP levels at baseline and change overnight (ΔhsCRP) vs. HOMA-IR, body mass index (BMI) z-score, and sleep study parameters related to O2 saturation and the apnea-hypopnea index (AHI).
Results
Among children with OSA and the entire cohort, hsCRP values were correlated with HOMA-IR and BMI z-scores. HOMA-IR but not BMI z-score correlated with ΔhsCRP overnight in the entire cohort. Sleep study parameters, including AHI mean O2 saturation overnight, REM O2 nadir, and non-REM O2 nadir were not correlated with hsCRP or ΔhsCRP overnight.
Conclusion
Among children being evaluated for OSA, degree of insulin resistance may be an important determinant of increased systemic inflammation overnight. Sleep study markers did not correlate with ΔhsCRP, leaving uncertain the role of OSA in increasing inflammation overnight. Further studies are needed to explore these associations and their potential mechanisms.
doi:10.1007/s11325-011-0499-8
PMCID: PMC3253221  PMID: 21360253
Obstructive sleep apnea; Inflammation; hsCRP; Obesity; Insulin resistance; Oxygen desaturation; Adolescents
14.  Puberty Is Delayed in Male Mice With Dextran Sodium Sulfate Colitis Out of Proportion to Changes in Food Intake, Body Weight, and Serum Levels of Leptin 
Pediatric research  2011;69(1):34-39.
In boys, inflammatory bowel disease often results in delayed puberty associated with decreased bone mineral density and decreased linear growth. Our goal was to investigate whether pubertal timing and levels of leptin differed between prepubertal male mice with colitis and food-restricted (FR) mice maintained at a similar weight. We induced colitis in 32-d-old male mice using dextran sodium sulfate (DSS), resulting in 10 d of worsening colitis. We followed up these mice for separation of the prepuce from the glans penis as a marker of pubertal progression. Compared with free-feeding control mice, DSS and FR mice had significantly lower weight on d 7–10 of treatment. DSS mice had later puberty than control and FR mice. DSS mice also had smaller testes, lower FSH levels, increased systemic cytokines, and increased colonic inflammation by histology. Leptin levels were similar between DSS and FR mice, whereas both had decreases in leptin compared with controls. We conclude that DSS colitis causes delayed puberty in sexually immature male mice beyond what is seen among FR mice of similar weight, food intake, and leptin levels. These experiments provide support for the hypothesis that pubertal delay in colitis is influenced by factors beyond poor weight gain alone.
doi:10.1203/PDR.0b013e3181ffee6c
PMCID: PMC3039692  PMID: 20940665
15.  Changes in inflammation and quality of life after a single dose of infliximab during on-going treatment: Differences between patients with and without IBD symptoms at time of administration 
Background
Infliximab is used increasingly as maintenance therapy for inflammatory bowel disease (IBD); however the effects of a single maintenance dose of infliximab are unclear with respect to quality of life and hormones related to growth and puberty.
Objective
Determine the time course of inflammatory, hormonal and quality-of-life changes following a single dose of infliximab in the context of on-going therapy, as related to presence of IBD symptoms at time of administration.
Methods
Children and adolescents with IBD receiving on-going therapy with infliximab for clinical indications were recruited. Pediatric Crohn’s Disease Activity Index (PCDAI) was determined at baseline and laboratory measures of hsCRP and hormones of growth and puberty were determined on Days 0, 2 and 14. IBD-related quality of life (IMPACT-III questionnaire) was tested on Days 0 and 14. Subjects who had symptoms of IBD were compared to asymptomatic subjects.
Results
Subjects overall and in the symptomatic group exhibited improved hsCRP by Day 2 following treatment. Symptomatic subjects had higher PCDAI scores and lower quality-of-life scores than asymptomatic subjects on Day 0, while at Day 14 there were no significant differences in quality-of-life scores between the two groups.
Conclusions
Even in the context of on-going treatment, a single dose of infliximab results in decreased hsCRP an improvement that is particularly noted among subjects who are symptomatic at the time of treatment. While randomized trials are needed, these observational data may assist clinicians, patients and families regarding expectations about timing and extent of these changes following a single treatment dose.
doi:10.1097/MPG.0b013e3182382ee3
PMCID: PMC3297691  PMID: 21946833
Inflammatory bowel disease; infliximab; inflammation; quality of life; adolescent
16.  Ability Among Adolescents for the Metabolic Syndrome to Predict Elevations in Factors Associated with Type 2 Diabetes and Cardiovascular Disease: Data from the National Health and Nutrition Examination Survey 1999–2006 
Objective
The aim of this study was to compare currently proposed sets of pediatric metabolic syndrome criteria for the ability to predict elevations in “surrogate” factors that are associated with metabolic syndrome and with future cardiovascular disease and type 2 diabetes mellitus. These surrogate factors were fasting insulin, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (hsCRP), and uric acid.
Methods
Waist circumference (WC), blood pressure, triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting glucose, fasting insulin, HbA1c, hsCRP, and uric acid measurements were obtained from 2,624 adolescent (12–18 years old) participants of the 1999–2006 National Health and Nutrition Examination Surveys. We identified children with metabolic syndrome as defined by six commonly used sets of pediatric metabolic syndrome criteria. We then defined elevations in the surrogate factors as values in the top 5% for the cohort and calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each set of metabolic syndrome criteria and for each surrogate factor.
Results
Current pediatric metabolic syndrome criteria exhibited variable sensitivity and specificity for surrogate predictions. Metabolic syndrome criteria had the highest sensitivity for predicting fasting insulin (40–70%), followed by uric acid (31–54%), hsCRP (13–31%), and HbA1c (7–21%). The criteria of de Ferranti (which includes children with WC >75 th percentile, compared to all other sets including children with WC >90 th percentile) exhibited the highest sensitivity for predicting each of the surrogates, with only modest decrease in specificity compared to the other sets of criteria. However, the de Ferranti criteria also exhibited the lowest PPV values. Conversely, the pediatric International Diabetes Federation criteria exhibited the lowest sensitivity and the highest specificity.
Conclusions
Pediatric metabolic syndrome criteria exhibit moderate sensitivity for detecting elevations in surrogate factors associated with metabolic syndrome and with risk for future disease. Inclusion of children with more modestly elevated WC improved sensitivity.
doi:10.1089/met.2010.0008
PMCID: PMC3046372  PMID: 20698802
17.  Ability Among Adolescents for the Metabolic Syndrome to Predict Elevations in Factors Associated with Type 2 Diabetes and Cardiovascular Disease: Data from the National Health and Nutrition Examination Survey 1999–2006 
Abstract
Objective
The aim of this study was to compare currently proposed sets of pediatric metabolic syndrome criteria for the ability to predict elevations in “surrogate” factors that are associated with metabolic syndrome and with future cardiovascular disease and type 2 diabetes mellitus. These surrogate factors were fasting insulin, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (hsCRP), and uric acid.
Methods
Waist circumference (WC), blood pressure, triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting glucose, fasting insulin, HbA1c, hsCRP, and uric acid measurements were obtained from 2,624 adolescent (12–18 years old) participants of the 1999–2006 National Health and Nutrition Examination Surveys. We identified children with metabolic syndrome as defined by six commonly used sets of pediatric metabolic syndrome criteria. We then defined elevations in the surrogate factors as values in the top 5% for the cohort and calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each set of metabolic syndrome criteria and for each surrogate factor.
Results
Current pediatric metabolic syndrome criteria exhibited variable sensitivity and specificity for surrogate predictions. Metabolic syndrome criteria had the highest sensitivity for predicting fasting insulin (40–70%), followed by uric acid (31–54%), hsCRP (13–31%), and HbA1c (7–21%). The criteria of de Ferranti (which includes children with WC >75th percentile, compared to all other sets including children with WC >90th percentile) exhibited the highest sensitivity for predicting each of the surrogates, with only modest decrease in specificity compared to the other sets of criteria. However, the de Ferranti criteria also exhibited the lowest PPV values. Conversely, the pediatric International Diabetes Federation criteria exhibited the lowest sensitivity and the highest specificity.
Conclusions
Pediatric metabolic syndrome criteria exhibit moderate sensitivity for detecting elevations in surrogate factors associated with metabolic syndrome and with risk for future disease. Inclusion of children with more modestly elevated WC improved sensitivity.
doi:10.1089/met.2010.0008
PMCID: PMC3046372  PMID: 20698802
18.  Predictors of Retention and BMI Loss or Stabilization in Obese Youth Enrolled in a Weight Loss Intervention 
Objective
To evaluate predictors for intervention dropout and successful reduction of metabolic syndrome risk factors among obese children enrolled in a short-term, clinic-based weight-loss intervention.
Design, Setting, Subjects
Retrospective database review of 1080 children 8 months-17 y.o. seen a a pediatric obesity clinic.
Interventions
Behavior modification counseling to induce change in dietary and exercise choices.
Main Outcome Measures
1). Pre-/post-intervention change in body mass index (BMI), waist circumference, blood pressure, glucose, insulin, and cholesterol (LDL, HDL, & total). 2) Predictors of successful decrease in BMI and clinic drop-out.
Analysis
Paired t-tests for pre-/post-intervention comparisons. Linear regression to assess predictors of success and predictors of drop-out, with adjustment for age, gender, race, insurance status, and service area.
Results
Among children evaluated, adolescent females were most likely to achieve successful decrease in BMI, insulin level, and LDL cholesterol post-intervention. Nearly 40% of children dropped out early in the intervention. Predictors of drop out included age <6y, public insurance status, follow-up scheduled during summer months, and residence in a tertiary service area.
Conclusions
Clinic-based weight loss interventions can lead to successful improvements in BMI and other metabolic parameters in pediatric populations and may be more likely among adolescent females than in younger children or males. Drop-out is common, particularly among younger children, children with public insurance and children scheduled for follow-up in the summer. Identification of these drop-out predictors in individual patients may help in targeting children likely to succeed in short-term, clinic-based, weight-loss interventions.
doi:10.1016/j.orcp.2011.08.157
PMCID: PMC3501750  PMID: 23181148
obesity; weight loss; child; adolescent
19.  High Rate of Obesity-Associated Hypertension among Primary Schoolchildren in Sudan 
Cardiovascular disease (CVD) frequently has roots in childhood, including following childhood-onset hypertension. Incidence of CVD has increased in developing countries in East Africa during recent urbanization. Effects of these shifts on childhood hypertension are unclear. Our objectives were to (1) Determine the prevalence of hypertension among primary schoolchildren in Khartoum, Sudan; (2) Determine whether hypertension in this setting is associated with obesity. We performed a cross sectional study of 6-12y children from two schools randomly selected in Khartoum, Sudan. Height, weight, BMI, BP and family history of hypertension were assessed. Age-, height- and gender-specific BP curves were used to determine pre-hypertension (90–95%) and hypertension (>95%). Of 304 children, 45 (14.8%) were overweight; 32 (10.5%) were obese; 15 (4.9%) were pre-hypertensive and 15 (4.9%) were hypertensive. Obesity but not family history of hypertension was associated with current hypertension. In multiple logistic regression, adjusting for family history, children who were obese had a relative-risk of 14.7 (CI 2.45-88.2) for systolic hypertension compared to normal-weight children. We conclude that overweight and obesity are highly prevalent among primary schoolchildren in urban Sudan and are strongly associated with hypertension. That obesity-associated cardiovascular sequelae exist in the developing world at young ages may be a harbinger of future CVD in sub-Saharan Africa.
doi:10.4061/2011/629492
PMCID: PMC3014717  PMID: 21234364
20.  A confirmatory factor analysis of the metabolic syndrome in adolescents: an examination of sex and racial/ethnic differences 
Objective
The metabolic syndrome (MetS) is a cluster of clinical indices that signals increased risk for cardiovascular disease and Type 2 diabetes. The diagnosis of MetS is typically based on cut-off points for various components, e.g. waist circumference and blood pressure. Because current MetS criteria result in racial/ethnic discrepancies, our goal was to use confirmatory factor analysis to delineate differential contributions to MetS by sub-group.
Research Design and Methods
Using 1999–2010 data from the National Health and Nutrition Examination Survey (NHANES), we performed a confirmatory factor analysis of a single MetS factor that allowed differential loadings across sex and race/ethnicity, resulting in a continuous MetS risk score that is sex and race/ethnicity-specific.
Results
Loadings to the MetS score differed by racial/ethnic and gender subgroup with respect to triglycerides and HDL-cholesterol. ROC-curve analysis revealed high area-under-the-curve concordance with MetS by traditional criteria (0.96), and with elevations in MetS-associated risk markers, including high-sensitivity C-reactive protein (0.71), uric acid (0.75) and fasting insulin (0.82). Using a cut off for this score derived from ROC-curve analysis, the MetS risk score exhibited increased sensitivity for predicting elevations in ≥2 of these risk markers as compared with traditional pediatric MetS criteria.
Conclusions
The equations from this sex- and race/ethnicity-specific analysis provide a clinically-accessible and interpretable continuous measure of MetS that can be used to identify children at higher risk for developing adult diseases related to MetS, who could then be targeted for intervention. These equations also provide a powerful new outcome for use in childhood obesity and MetS research.
doi:10.1186/1475-2840-11-128
PMCID: PMC3489601  PMID: 23062212
Metabolic syndrome; Factor analysis, Statistical; Insulin resistance; Pediatrics; Adolescents; Epidemiology; Clinical studies; Obesity; Risk factors
21.  Ghrelin and cachexia: Will treatment with GHSR-1a agonists make a difference for patients suffering from chronic wasting syndromes? 
Cachexia is a syndrome of wasting and anorexia that worsens the prognosis of many chronic diseases including cancer, chronic kidney disease, chronic heart disease and chronic obstructive pulmonary disease. Properties of the orexigenic hormone ghrelin—including appetite-stimulation, weight-gain production and increased cardiac output—make it a logical treatment for cachexia. While endogenous ghrelin levels are increased in the setting of cachexia, treatment with ghrelin and other GHSR-1a agonists in animal models of cachexia and in humans with cachexia have demonstrated consistent effects of increased appetite and improved weight gain. These positive effects occur in multiple underlying diseases associated with cachexia and appear to be sustained over treatment duration of up to 12 weeks. The mechanism of action in producing these effects is likely related to stimulation of central appetite centers such as the central melanocortin system and to increased growth hormone release, though ghrelin’s effects may also relate to decreased systemic inflammation and other direct and indirect actions. Questions regarding the long-term safety of ghrelin treatment are still unanswered, as is the important question of whether successful treatment of cachexia will improve the prognosis of the underlying disease itself.
doi:10.1016/j.mce.2011.02.012
PMCID: PMC3114250  PMID: 21354462
22.  What can anorexia nervosa teach us about appetite regulation? 
doi:10.1016/j.nut.2011.02.001
PMCID: PMC3062266  PMID: 21392703
23.  Ethnicity, obesity and the metabolic syndrome: implications on assessing risk and targeting intervention 
Pediatric obesity threatens the future health of a growing number of children worldwide. An added challenge in identifying the patients at greatest need for intervention due to their elevated risk for future disease is that pediatric obesity and the associated metabolic syndrome manifest differently among different ethnic groups. African–Americans and Hispanics are more likely to exhibit obesity and insulin resistance and are at a higher risk for developing Type 2 diabetes. Nevertheless, using current criteria, African–American adolescents are much less likely to be diagnosed with metabolic syndrome, largely owing to lower rates of dyslipidemia. Further development is needed in ethnicity-inclusive means of risk identification among adolescents to accurately target treatment toward children at highest risk for future disease and to motivate adolescent patients and their families towards lifestyle improvement. Effective targeting and intensive treatment efforts may help in avoiding future sequelae of obesity among all ethnicities.
doi:10.1586/eem.11.17
PMCID: PMC3105461  PMID: 21643518
adolescent; cardiovascular disease; ethnicity; insulin resistance; metabolic syndrome; race; Type 2 diabetes mellitus
24.  Underdiagnosis of Metabolic Syndrome in Non-Hispanic Black Adolescents: A Call for Ethnic-Specific Criteria 
Childhood obesity is a risk factor for the development of both type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). One marker that can be used to predict T2DM is the metabolic syndrome (MetS). MetS, a cluster of cardiovascular factors associated with insulin resistance, is defined by central obesity, impaired fasting glucose, hypertension, elevated triglycerides (TG), and low levels of high-density lipoprotein cholesterol. Some have advocated using a diagnosis of MetS to trigger increased intervention in children. However, ethnic differences in MetS may hamper identification of at-risk children. For example, non-Hispanic blacks are diagnosed with MetS less frequently than non-Hispanic whites, despite having higher rates of T2DM and CVD. These differences in MetS are predominantly due to a low frequency of hypertriglyceridemia in non-Hispanic blacks. Compared with non-Hispanic whites and Mexican Americans, non-Hispanic blacks have lower TG levels at baseline but exhibit worsening insulin resistance with increasing TG. Therefore “normal” TG levels appear to be falsely reassuring among insulin-resistant non-Hispanic blacks. Ethnic-specific tools may be needed to more accurately predict risk for T2DM and CVD in minorities.
doi:10.1007/s12170-010-0104-x
PMCID: PMC3046404  PMID: 21379366
Metabolic syndrome; Insulin resistance; Ethnic differences; Inflammation; Cardiovascular disease; Diabetes
25.  Colitis causes delay in puberty in female mice out of proportion to changes in leptin and corticosterone 
Journal of gastroenterology  2010;45(3):277-284.
Background
Inflammatory bowel disease that begins prior to puberty frequently causes a delay in puberty resulting in losses of growth, bone mineralization, and self-esteem. A major cause of this pubertal delay is likely due in part to the effect of decreased levels of leptin on the function of the hypothalamic–pituitary–gonadal axis, though systemic inflammation is also thought to play a role.
Methods
To investigate further whether low leptin levels alone were responsible for delayed puberty in colitis, we induced colitis in 23-day-old female mice using 3% dextran sodium sulfate (DSS), resulting in 10 days of worsening colitis. These mice were compared to controls that were free-feeding and food-restricted (FR) mice that were given only enough food to keep them the same weight as the DSS group. All groups were followed for the timing of vaginal opening until 33 days old, when they were euthanized and their serum collected.
Results
DSS-treated mice exhibited later timing of vaginal opening relative to both of the other groups, as well as increased colonic inflammation by cytology and increased serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. The difference in the timing of vaginal opening between the DSS and FR groups occurred despite equivalent serum levels of leptin between the groups and despite an increase in corticosterone in the FR group relative to both of the other groups.
Conclusions
We conclude that DSS colitis causes delay in puberty in sexually immature mice beyond what would be expected from decreases in weight and leptin levels.
doi:10.1007/s00535-009-0192-x
PMCID: PMC2850610  PMID: 20072791
Colitis; Puberty; Leptin; Inflammation

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