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2.  Systemic inflammation, growth factors, and linear growth in the setting of infection and malnutrition 
Objectives
Deficits in weight gain and linear growth are seen frequently among children in areas where malnutrition and recurrent infections are common. Although both inflammation and malnutrition can result in growth hormone (GH) resistance, the interrelationships of infection, inflammation, and growth deficits in developing areas remain unclear. The aim of this study was to evaluate relationships between low levels of systemic inflammation, growth factors, and anthropometry in a case–control cohort of underweight and normal weight children in northern Brazil.
Methods
We evaluated data from 147 children ages 6 to 24 mo evaluated in the MAL-ED (Interactions of Malnutrition and Enteric Disease) case–control study following recruitment from a nutrition clinic for impoverished families in Fortaleza, Brazil. We used nonparametric tests and linear regression to evaluate relationships between current symptoms of infections (assessed by questionnaire), systemic inflammation (assessed by high-sensitivity C-reactive protein [hsCRP]), the GH insulin-like growth factor-1 (IGF-1) axis, and measures of anthropometry. All models were adjusted for age and sex.
Results
Children with recent symptoms of diarrhea, cough, and fever (compared with those without symptoms) had higher hsCRP levels; those with recent diarrhea and fever also had lower IGF-1 and higher GH levels. Stool myeloperoxidase was positively associated with serum hsCRP. hsCRP was in turn positively associated with GH and negatively associated with IGF-1 and IGF-binding protein-3 (IGFBP-3), suggesting a state of GH resistance. After adjustment for hsCRP, IGF-1 and IGFBP-3 were positively and GH was negatively associated with Z scores for height and weight.
Conclusions
Infection and inflammation were linked to evidence of GH resistance, whereas levels of GH, IGF-1, and IGFBP-3 were associated with growth indices independent of hsCRP. These data implicate complex interrelationships between infection, nutritional status, GH axis, and linear growth in children from a developing area.
Highlights
•Among children in this developing area, symptoms of illness correlated with high-sensitivity C-reactive protein (hsCRP).•hsCRP correlated positively with growth hormone (GH) and negatively with insulin-like growth factor (IGF)-1 and IGF-binding protein-3 (IGFBP-3).•IGF-1 and IGFBP-3 correlated positively with height.•These data are consistent with a model of inflammation-induced GH resistance.
doi:10.1016/j.nut.2016.06.013
PMCID: PMC5193489  PMID: 27712965
Nutrition; Diarrhea; Growth; Stunting; IGF-1
3.  Severity of Metabolic Syndrome as a Predictor of Type 2 Diabetes Between Childhood and Adulthood: The Princeton Lipid Research Cohort Study 
Diabetologia  2015;58(12):2745-2752.
Aim
Determine the long-term associations of a sex- and race/ethnicity-specific MetS-severity Z-score from childhood and adulthood with future diagnosis of type 2 diabetes mellitus (T2DM).
Methods
We performed a prospective cohort study with evaluations from the Lipids Research Clinic (LRC) 1973–1976 and Princeton Follow-up Study (PFS) 1998–2003 and further disease status from Princeton Health Update (PHU) 2010–2014. We assessed MetS severity as a predictor of incident T2DM among 629 cohort participants assessed at both LRC and PFS and 354 participants at PHU.
Results
Cohort participants had a mean age of 12.9y at baseline (LRC), 38.4y at PFS and 49.6y at most recent follow-up. Childhood MetS-Z-scores were associated with adult MetS-Z-scores (p<0.01). Compared to individuals disease-free at all time points, those who developed T2DM by 1998–2003 and 2010–2014 had higher MetS severity scores in childhood (p<0.05). For every 1-unit elevation in childhood MetS-Z-score, the OR of future T2DM was 2.7 for incident disease by mean age 38.5y (p<0.01) and 2.8 for incident disease by mean age 49.6y (p<0.05). In assessing associations with the change in Z-score from childhood to adulthood, for every 1-unit increase in MetS-Z-score over time, the OR of incident T2DM by mean age 49.6 was 7.3 (p<0.01).
Conclusions
The severity of MetS in childhood was associated with incidence of adult T2DM and the degree of increase in this severity also predicted future disease. This provides evidence of potential clinical utility in assessing MetS severity to detect risk and follow clinical progress over time.
doi:10.1007/s00125-015-3759-5
PMCID: PMC4734129  PMID: 26380985
insulin resistance; metabolic syndrome; risk; type 2 diabetes mellitus
4.  The Severity of the Metabolic Syndrome Increases over Time within Individuals, Independent of Baseline Metabolic Syndrome Status and Medication Use: The Atherosclerosis Risk in Communities Study 
Atherosclerosis  2015;243(1):278-285.
Background and Aims
The severity of the metabolic syndrome (MetS) is linked to future cardiovascular disease. However, it is unclear whether MetS severity increases among individuals followed over time.
Methods
We assessed changes in a sex- and race/ethnicity-specific MetS severity Z-score over a 10-year period (visits 1–4) among 9,291 participants of the Atherosclerosis Risk in Communities study cohort. We compared sex- and racial/ethnic subgroups for the rate of change in the MetS severity score and MetS prevalence as assessed using traditional ATP-III MetS criteria. We further examined effects of use of medications for hypertension, diabetes and dyslipidemia.
Results
Over the 10 years of follow-up, MetS severity Z-scores increased in 76% of participants from an overall mean of 0.08 ± 0.77 at baseline to 0.48 ± 0.96 at visit 4 with the greatest progression in scores observed among African-American women. Baseline MetS severity scores predicted the time until ATP-III MetS diagnosis, with a model-predicted 77.5% of individuals with a visit 1 MetS severity score of 0.75 progressing to ATP-III MetS within 10 years. The rate of increase in MetS severity score was higher among those younger at baseline but was independent of baseline MetS status or the use of medications to treat blood pressure, lipids and diabetes.
Conclusion
The severity of metabolic derangements as measured using this MetS severity score increases over time within individuals and predicts diagnosis of ATP-III MetS. These data may have implications for tracking MetS related risk within individuals over time.
doi:10.1016/j.atherosclerosis.2015.09.025
PMCID: PMC4734118  PMID: 26409627
Metabolic syndrome x; cardiovascular disease; type 2 diabetes mellitus; minority health
5.  Depressive symptoms are associated with worsened severity of the metabolic syndrome in African American women independent of lifestyle factors: A consideration of mechanistic links from the Jackson heart study 
Psychoneuroendocrinology  2016;68:82-90.
Background
Depression and the metabolic syndrome (MetS) are both risk factors for cardiovascular disease and type 2 diabetes mellitus. Prior studies in predominantly White populations demonstrated that individuals with depressive symptoms at baseline are more likely to develop future MetS. We tested the hypothesis that depressive symptoms would contribute to a more pronounced increase in MetS severity among African Americans in the Jackson Heart Study (JHS).
Methods
We used repeated-measures modeling among 1743 JHS participants during Visits 1–3 over 8 years of follow-up to evaluate relations between depressive symptom score (Center for Epidemiologic Survey-Depression (CES-D)) at baseline and a sex- and race/ethnicity-specific MetS severity Z-score at each visit.
Results
20.3% of participants had a CES-D score ≥16, consistent with clinically-relevant depressive symptoms. Higher depressive-symptom scores were associated with higher MetS severity in women but not men (p = 0.005 vs. p = 0.490). There was no difference by depressive symptom score with rate of change in MetS severity over time. Both depressive-symptom score and MetS severity Z-score were associated with lower levels of physical activity and higher levels of C-reactive protein; however, addition of these to the regression model did not attenuate the association between depressive symptoms and MetS severity.
Conclusion
African American women but not men in the JHS exhibit relationships between baseline depressive symptoms and MetS severity over an 8-year period. These data may have implications for targeting of MetS-associated lifestyle changes among individuals with depressive symptoms.
doi:10.1016/j.psyneuen.2016.02.030
PMCID: PMC5105331  PMID: 26963374
Depression; Metabolic syndrome; Risk
7.  Progression of Metabolic Syndrome Severity During the Menopausal Transition 
Background
After menopause, women exhibit a higher prevalence of the metabolic syndrome (MetS) and higher risk of cardiovascular disease. However, the timing of changes in MetS severity over the menopausal transition and whether these changes differ by racial/ethnic group remain unclear.
Methods and Results
We assessed data from 1470 women from the Atherosclerosis Risk in Communities cohort who experienced transition in menopausal status over 10 years (visits 1–4). We used linear mixed models to evaluate changes by menopausal status (premenopause, perimenopause, and postmenopause) in a MetS severity Z‐score and in the individual MetS components. While there were gradual increases in MetS severity over time across menopause stages, black women in particular exhibited more rapid progression in MetS severity during the premenopausal and perimenopausal periods than during the postmenopausal period. In the postmenopausal period (compared with prior periods), white women exhibited unfavorable decreases in high‐density lipoprotein, while black women exhibited favorable alterations in the rate of change for waist circumference, triglycerides, high‐density lipoprotein, and glucose, contributing to the slowed progression of MetS severity. These changes were all observed after adjusting for hormone replacement treatment.
Conclusions
During menopausal transition, women exhibited rapid increases in MetS severity during the premenopausal and perimenopausal periods, with black women having significant reductions in this increase in severity during the postmenopausal period. These data suggest that the higher prevalence of MetS in postmenopausal women may be caused more by changes during the menopausal transition than by postmenopause. These findings may thus have implications regarding the timing of cardiovascular risk relative to menopause.
doi:10.1161/JAHA.116.003609
PMCID: PMC5015287  PMID: 27487829
cardiovascular disease risk factors; menopause; metabolic syndrome; race and ethnicity; type 2 diabetes mellitus; Cardiovascular Disease; Risk Factors; Race and Ethnicity; Obesity; Diabetes, Type 2
9.  Recent Advances in Understanding the Long-term Sequelae of Childhood Infectious Diarrhea 
Worldwide, early childhood infectious diarrhea continues to be a significant concern. Diarrheal illness affects the world’s youngest and most vulnerable citizens disproportionately. Estimates are that over 70% of the deaths from diarrhea occur in people younger than 24 months of age. Diarrhea and environmental enteropathy have been associated with growth failure and stunting. In addition, the burden of enteric disease also leads to cognitive and academic losses, thus resulting in loss of human capital and economic productivity. While considerable progress has been made on preventing and treating childhood diarrheal illness, the mortality and morbidity still remain unacceptably high. This paper seeks to review the recent (mainly from 2013) publications surrounding the global burden of childhood diarrhea and the implications for long-term sequelae.
doi:10.1007/s11908-014-0408-y
PMCID: PMC4157332  PMID: 24819871
Enteric disease; early childhood infectious diarrhea; long-term sequelae; malnutrition; environmental enteropathy; cognitive development; early childhood development; pediatric infectious disease; environmental enteric dysfunction
10.  Longitudinal evaluation of milk type consumed and weight status in preschoolers 
Archives of disease in childhood  2013;98(5):335-340.
Objective
Evaluate relationships between type of milk consumed and weight status among preschool children.
Design
Longitudinal cohort study.
Setting
Early Childhood Longitudinal Study–Birth Cohort, a representative sample of U.S. children.
Participants
10,700 U.S. children examined at age 2 and 4 years.
Main Outcome Measures
BMI z-score and overweight/obese status as a function of milk type intake.
Results
The majority of children drank whole or 2% milk (87% at 2 years, 79.3% at 4 years). Across racial/ethnic and SES subgroups 1%/skim-milk drinkers had higher BMI z-scores than 2%/whole-milk drinkers. In multivariable analyses, increasing fat content in the type of milk consumed was inversely associated with BMI z-score (p<0.0001). Compared to those drinking 2%/whole milk, 2- and 4-year-old children drinking 1%/skim milk had an increased adjusted odds of being overweight (age 2 OR 1.64, p<0.0001; age 4 OR 1.63 p<0.0001) or obese (age 2 OR 1.57 p<0.01; age 4 OR 1.64, p<0.0001). In longitudinal analysis, children drinking 1%/skim milk at both 2 and 4 years were more likely to become overweight/obese between these time points (adjusted OR 1.57, p<0.05).
Conclusions
Consumption of 1%/skim milk is more common among overweight/obese preschoolers, potentially reflecting the choice of parents to give overweight/obese children low-fat milk to drink. Nevertheless, 1%/skim milk does not appear to restrain body weight gain between 2–4 years in this age range, emphasizing a need for weight-targeted recommendations with a greater evidence basis.
doi:10.1136/archdischild-2012-302941
PMCID: PMC4439101  PMID: 23508869
11.  Early childhood diarrhea and cardiometabolic risk factors in adulthood: The Institute of Nutrition of Central America and Panama (INCAP) Nutritional Supplementation Longitudinal Study 
Annals of epidemiology  2013;23(6):314-320.
Background
Nutritional deficits in early life have been associated with a higher prevalence of metabolic syndrome (MetS) in adulthood. Early childhood diarrhea contributes to under-nutrition and may potentially increase the risk for adult non-communicable diseases. Our objective was to examine associations between early childhood diarrhea burden and later development of MetS.
Methods
We studied individuals who participated in the Institute of Nutrition of Central America and Panama Nutritional Supplementation Longitudinal Study (1969–1977) and were followed up in 2002–04. We used logistic regression to determine associations of diarrhea burden at ages 0–6 mo, 6–12 mo, and 12–24 mo with odds of MetS and elevations in its components as adults.
Results
Among 389 adults age 25–42 years at follow-up the prevalence of MetS was 29%. Adjusting for several confounders including adult BMI, each absolute 1% increase in diarrhea burden at age 0–6 mo (but not at other time periods) was associated with increased odds of MetS (odds ratio 1.03; 95% CI 1.01–1.06). This was attributable primarily to associations with elevated BP (OR 1.03, 1.00–1.06) and waist circumference (OR 1.03, 1.00–1.06).
Conclusions
Childhood diarrhea burden 0–6 months is associated with MetS in adulthood after controlling for childhood growth parameters and adult BMI.
doi:10.1016/j.annepidem.2013.03.012
PMCID: PMC4431615  PMID: 23608305
metabolic syndrome; enteric disease; infection; malnutrition; early origins of adult disease
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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