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1.  Impact of Ketamine on Learning and Memory Function, Neuronal Apoptosis and Its Potential Association with miR-214 and PTEN in Adolescent Rats 
PLoS ONE  2014;9(6):e99855.
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is used as a general pediatric anesthetic and anti-depressive drug. Recent studies suggest that ketamine enhances neuronal apoptosis in developing rats. The goal of this study is to explore whether ketamine could result in learning and memory impairment and neurodegeneration in adolescent rats, and if so, whether the effects of ketamine are associated with miR-214 and PTEN expression. Fifty-day-old SD rats were randomly divided into three groups receiving ketamine at 30, or 80 mg/kg, i.p. or saline for seven consecutive days. Twenty-four hours after the last treatment, learning and memory function were tested by the Morris water maze. The rats were then decapitated, and the brains were isolated for detection of neuronal apoptosis and protein PTEN expression by TUNEL and immunohistochemistry respectively. Expression levels of the miR-214 and PTEN in the hippocampus were measured by qRT-PCR and western blot analysis respectively. Ketamine administered to the adolescent rats at a dose of 80 mg/kg rather than the lower dose of 30 mg/kg caused learning and memory impairment, increased the number of apoptotic cells in the hippocampal CA1 region, cerebral cortex and subcortical region, decreased the miR-214 levels and increased PTEN protein expression in hippocampus. The results suggest that ketamine at a dose of 80 mg/kg in the adolescent rats is able to induce the learning and memory impairment and neurodegeneration, in which the down-regulation of miR-214 and high expression of PTEN protein may be involved.
doi:10.1371/journal.pone.0099855
PMCID: PMC4051782  PMID: 24914689
2.  Prepregnancy body mass index and risk of preterm birth: association heterogeneity by preterm subgroups 
Background
To evaluate the association between prepregnancy body mass index (BMI) is associated with early vs. late and medically-induced vs. spontaneous preterm birth (PTB) subtypes.
Methods
Using data from the Boston Birth Cohort, we examined associations of prepregnancy BMI with 189 early (<34 completed weeks) and 277 late (34–36 completed weeks) medically-induced PTBs and 320 early and 610 late spontaneous PTBs vs. 3281 term births (37–44 weeks) in multinomial regression. To assess for mediation by important pregnancy complications, we performed sequential models with and without hypertensive disorders of pregnancy, chorioamnionitis, and gestational diabetes.
Results
Prevalence of prepregnancy obesity (BMI ≥ 30.0 kg/m2) was 28% among mothers with medically-induced PTBs, 18% among mothers with spontaneous PTBs, and 18% among mothers with term births (p = <0.001). After adjustment for demographic and known risk factors for PTB, prepregnancy obesity was associated with higher odds of both early [OR 1.78 (1.19, 2.66)] and late [OR 1.49 (1.09, 2.04)] medically-induced PTB. These effect estimates were attenuated with inclusion of hypertensive disorders of pregnancy and gestational diabetes. For spontaneous deliveries, prepregnancy obesity was associated with decreased odds of PTB (0.76 [0.58, 0.98]) and underweight was nearly associated with increased odds of PTB (1.46 [0.99, 2.16]).
Conclusion
Prepregnancy obesity is associated with higher risk of medically-induced, but not spontaneous PTB. Hypertensive disorders of pregnancy and gestational diabetes appear to partially explain the association between prepregnancy obesity and early and late medically-induced PTB.
doi:10.1186/1471-2393-14-153
PMCID: PMC4022544  PMID: 24779674
Maternal obesity; Prepregnancy BMI; Medically-induced preterm birth; Spontaneous preterm birth; Late preterm birth
3.  The Longitudinal Trajectory of Vitamin D Status from Birth to Early Childhood on the Development of Food Sensitization 
Pediatric research  2013;74(3):321-326.
Background
Increasing evidence supports the immunomodulatory effect of vitamin D on allergic diseases. The combined role of prenatal and postnatal vitamin D status in the development of food sensitization (FS) and food allergy remains under-studied.
Methods
460 children in the Boston Birth Cohort had plasma 25(OH)D measured at birth and early childhood, and were genotyped for rs2243250 (C-590T) in the IL4 gene. We defined FS as specific IgE ≥0.35kUA/L to any of eight common food allergens; and persistently low vitamin D status as cord blood 25(OH)D <11ng/ml and postnatal 25(OH)D <30ng/ml.
Results
We observed a moderate correlation between cord blood 25(OH)D at birth and venous blood 25(OH)D measured at 2–3 years (r=0.63), but a weak correlation at <1 year (r=0.28). There was no association between low vitamin D status and FS at any single time point alone. However, in combination, persistence of low vitamin D status at birth and early childhood increased the risk of FS (OR=2.03, 95%CI:1.02–4.04), particularly among children carrying the C allele of rs2243250 (OR=3.23, 95%CI:1.37–7.60).
Conclusions
Prenatal and early postnatal vitamin D levels, along with individual genetic susceptibility, should be considered in assessing the role of vitamin D in the development of FS and food allergy.
doi:10.1038/pr.2013.110
PMCID: PMC3773018  PMID: 23797532
4.  IgE but not IgG4 Antibodies to Ara h 2 Distinguish Peanut Allergy from Asymptomatic Peanut Sensitization 
Allergy  2012;67(12):1538-1546.
Background
There are no available clinical tests that can accurately predict peanut allergy (PA) and/or anaphylaxis. This study is aimed at evaluating whether the component-resolved diagnostic (CRD) IgE and IgG4 tests can 1) distinguish PA from asymptomatic peanut sensitization; and 2) differentiate anaphylactic vs. non-anaphylactic PA.
Methods
This study included 20 non-atopic controls, 58 asymptomatically peanut-sensitized children, 55 non-anaphylactic and 53 anaphylactic PA cases from the Chicago Food Allergy Study. IgE and IgG4 to 103 allergens were measured using the ImmunoCAP ISAC technology, and were compared among each group of children. The random forest test was applied to estimate each allergen’s ability to predict PA and/or peanut anaphylaxis.
Results
PA cases (with or without anaphylaxis) had significantly higher IgE reactivity to Ara h 1–3 (peanut allergens) and Gly m 5–6 (soy allergens) than asymptomatically-sensitized children (p<0.00001). Similar but more modest relationships were found for IgG4 to Ara h 2 (p<0.01). IgE to Ara h 2 was the major contributor to accurate discrimination between PA and asymptomatic sensitization. With an optimal cutoff point of 0.65 ISU-E, it conferred 99.1% sensitivity, 98.3% specificity, and a 1.2% misclassification rate in the prediction of PA, which represented a higher discriminative accuracy than IgE to whole peanut extract (p=0.008). However, none of the IgE and/or IgG4 tests could significantly differentiate peanut anaphylaxis from non-anaphylactic PA.
Conclusions
IgE to Ara h 2 can efficiently differentiate clinical PA from asymptomatic peanut sensitization, which may represent a major step forward in the diagnosis of PA.
doi:10.1111/all.12047
PMCID: PMC3499645  PMID: 23094689
Ara h 2; Component-resolved diagnostics; Diagnostic performance; Peanut allergy; Peanut anaphylaxis
5.  Placental Weight Mediates the Effects of Prenatal Factors on Fetal Growth: the Extent Differs by Preterm Status 
Obesity (Silver Spring, Md.)  2013;21(3):10.1002/oby.20254.
Elevated pre-pregnancy body mass index (BMI), excessive gestational weight gain (GWG), and gestational diabetes (GDM) are known determinants of fetal growth. The role of placental weight is unclear. We aimed to examine the extent to which placental weight mediates the associations of pre-pregnancy BMI, GWG, and GDM with birthweight-for-gestational age, and whether the relationships differ by preterm status. We examined 1035 mother-infant pairs at birth from the Boston Birth Cohort. Data were collected by questionnaire and clinical measures. Placentas were weighed without membranes or umbilical cords. We performed sequential models excluding and including placental weight, stratified by preterm status. We found that 21% of mothers were obese, 42% had excessive GWG, and 5% had GDM. 41% were preterm. Among term births, after adjustment for sex, gestational age, maternal age, race, parity, education, smoking and stress during pregnancy, birthweight-for-gestational age z-score was 0.55 (0.30, 0.80) units higher for pre-pregnancy obesity vs. normal weight. It was 0.34 (0.13, 0.55) higher for excessive vs. adequate GWG, 0.67 (0.24, 1.10) for GDM vs. no DM, with additional adjustment for pre-pregnancy BMI. Adding placental weight to the models attenuated the estimates for pre-pregnancy obesity by 20%, excessive GWG by 32%, and GDM by 21%. Among preterm infants, GDM was associated with 0.67 (0.34, 1.00) higher birthweight-for-gestational age z-score, but pre-pregnancy obesity and excessive GWG were not. Attenuation by placental weight was 36% for GDM. These results suggest that placental weight partially mediates the effects of pre-pregnancy obesity, GDM and excessive GWG on fetal growth among term infants.
doi:10.1002/oby.20254
PMCID: PMC3418379  PMID: 23592670
pre-pregnancy BMI; gestational weight gain; gestational diabetes; placental weight; fetal growth; birth weight z-score
6.  Genetic and Environmental Contributions to Phenotypic Components of Metabolic Syndrome: A Population-based Twin Study 
Obesity (Silver Spring, Md.)  2009;17(8):1581-1587.
The increasing prevalence of metabolic syndrome (MS) poses a serious public health problem worldwide. Effective prevention and intervention require improved understanding of the factors that contribute to MS. We analyzed data on a large twin cohort to estimate genetic and environmental contributions to MS and to major MS components and their inter-correlations: waist circumference, systolic and diastolic blood pressure, fasting plasma glucose, triglycerides, and high density lipoprotein cholesterol. We applied structural equation modeling to determine genetic and environmental structure of MS and its major components, using 1,617 adult female twin pairs recruited from rural China. The heritability estimate for MS was 0.42 (95% CI: 0.00–0.83) in this sample with low MS prevalence (4.4%). For MS components, heritability estimates were statistically significant and ranged from 0.13 to 0.64 highest for WC, followed by TG, SBP, DBP, HDL-C, and FPG. HDL-C was mainly influenced by common environmental factors (0.62, 95%CI: 0.58–0.62), while the other five MS components were largely influenced by unique environmental factors (0.32–0.44). Bivariate Cholesky decomposition analysis indicated that the clinical clustering of MS components may be explained by shared genetic and/or environmental factors. Our study underscores the importance of examining MS components as inter-correlated traits, and to carefully consider environmental and genetic factors in studying MS etiology.
doi:10.1038/oby.2009.125
PMCID: PMC3766632  PMID: 19407809
metabolic syndrome; twin study; heritability; Chinese
7.  Serum Folate and DDT Isomers and Metabolites Are Inversely Associated in Chinese Women: A Cross-Sectional Analysis 
Background
Vitamin nutritional status may influence some xenobiotic metabolism or vice versa.
Methods
This analysis examines the relationship between B-vitamin concentrations and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDT) isomers and metabolites in healthy women. Serum pp′DDT, pp′DDE, pp′DDD, op′DDT, op′DDE, and serum folate, cysteine, and vitamins B6 and B12 were measured in 296 nonsmoking female textile workers (21–34 yr) in Anhui, China. Mean (SD) age and body mass index of this cohort were 24.9 (1.5) y and 19.7 (2.0) kg/m2, respectively.
Results
Median pp′DDT, pp′DDE, pp′DDD, op′DDT, and op′DDE were 1.5, 29.2, 0.22, 0.17, and 0.09 ng/g, respectively. Median folate and cysteine were 9.2 and 200.0 nmol/L, respectively. Folate was significantly inversely associated with pp′DDT and pp′DDE: β (95% confidence interval [CI]) = −0.23 (−0.39, −0.07) and −0.20 (−0.36, −0.05), respectively, and it was marginally associated with pp′DDD. Cysteine was significantly inversely associated with pp′DDT, β (95% CI) = −0.69 (−1.00, −0.37); pp′DDE, β (95% CI) = −0.32 (−0.62, −0.02); pp′DDD, β (95% CI) = −0.31 (−0.59, −0.03); and op′DDT, β (95% CI) = −0.35 (−0.68, −0.02).
Conclusions
Folate and cysteine are independently inversely associated with DDT isomers, adjusting for vitamins B6 and B12, age, and body mass index. These nutrients may play a role in DDT metabolism; however, it is also possible that DDT may exert a negative impact on folate and cysteine levels. Longitudinal studies are needed to ascertain the direction of this association.
PMCID: PMC3763738  PMID: 20368376
DDT isomers/metabolites; folate; cysteine; vitamin B6; vitamin B12
8.  Early Life Precursors, Epigenetics, and the Development of Food Allergy1 
Seminars in immunopathology  2012;34(5):655-669.
Food allergy (FA), a major clinical and public health concern worldwide, is caused by a complex interplay of environmental exposures, genetic variants, gene-environment interactions, and epigenetic alterations. This review summarizes recent advances surrounding these key factors, with a particular focus on the potential role of epigenetics in the development of FA. Epidemiologic studies have reported a number of non-genetic factors that may influence the risk of FA, such as timing of food introduction and feeding pattern, diet/nutrition, exposure to environmental tobacco smoking, prematurity and low birthweight, microbial exposure, and race/ethnicity. Current studies on the genetics of FA are mainly conducted using candidate gene approaches, which have linked more than 10 genes to the genetic susceptibility of FA. Studies on gene-environment interactions of FA are very limited. Epigenetic alteration has been proposed as one of the mechanisms to mediate the influence of early-life environmental exposures and gene-environment interactions on the development of diseases later in life. The role of epigenetics in the regulation of the immune system and the epigenetic effects of some FA-associated environmental exposures are discussed in this review. There is a particular lack of large-scale prospective birth cohort studies that simultaneously assess the inter-relationships of early life exposures, genetic susceptibility, epigenomic alterations and the development of FA. The identification of these key factors and their independent and joint contributions to FA will allow us to gain important insight into the biological mechanisms by which environmental exposures and genetic susceptibility affect the risk of FA, and will provide essential information to develop more effective new paradigms in the diagnosis, prevention and management of FA.
doi:10.1007/s00281-012-0323-y
PMCID: PMC3439840  PMID: 22777545
Genetics; Environmental Exposure; Epigenetics; Food allergy
9.  Maternal Smoking during Pregnancy, Prematurity and Recurrent Wheezing in Early Childhood 
Pediatric pulmonology  2012;47(7):666-673.
Summary
Background
Prenatal maternal smoking and prematurity independently affect wheezing and asthma in childhood.
Objective
We sought to evaluate the interactive effects of maternal smoking and prematurity upon the development of early childhood wheezing.
Methods
We evaluated 1448 children with smoke exposure data from a prospective urban birth cohort in Boston. Maternal antenatal and postnatal exposure was determined from standardized questionnaires. Gestational age was assessed by the first day of the last menstrual period and early prenatal ultrasound (preterm<37 weeks gestation). Wheezing episodes were determined from medical record extraction of well and ill/unscheduled visits. The primary outcome was recurrent wheezing, defined as ≥ 4 episodes of physician documented wheezing. Logistic regression models and zero inflated negative binomial regression (for number of episodes of wheeze) assessed the independent and joint association of prematurity and maternal antenatal smoking on recurrent wheeze, controlling for relevant covariates.
Results
In the cohort, 90 (6%) children had recurrent wheezing, 147 (10%) were exposed to in utero maternal smoke and 419 (29%) were premature. Prematurity (odds ratio [OR] 2.0; 95% CI, 1.3-3.1) was associated with an increased risk of recurrent wheezing, but in utero maternal smoking was not (OR 1.1, 95% CI 0.5-2.4). Jointly, maternal smoke exposure and prematurity caused an increased risk of recurrent wheezing (OR 3.8, 95% CI 1.8-8.0). There was an interaction between prematurity and maternal smoking upon episodes of wheezing (p=0.049).
Conclusions
We demonstrated an interaction between maternal smoking during pregnancy and prematurity on childhood wheezing in this urban, multiethnic birth cohort.
doi:10.1002/ppul.22501
PMCID: PMC3756665  PMID: 22290763
Smoking; Prematurity; Wheeze
10.  Gestational Diabetes, Atopic Dermatitis and Allergen Sensitization in Early Childhood 
Background
The relationship between the prenatal environment, maternal-fetal interaction, and allergic disease in the offspring remains understudied.
Objective
We sought to determine whether gestational diabetes modifies the risk of early childhood atopic manifestations including atopic dermatitis and allergen sensitization.
Methods
This study includes 680 children from the Boston Birth Cohort. Mother-child dyads were recruited at birth and followed prospectively to a mean age of 3.2±2.3 years with study visits aligned with the pediatric primary care schedule. The primary outcomes were physician diagnosed atopic dermatitis on standardized medical record abstraction and allergen sensitization based on Immunocap to 7 common foods and 5 common aeroallergens (sIgE≥0.10 kUA/L, Phadia). Gestational diabetes was determined by standardized medical record review. Logistic regression analysis, stratified by term/preterm status, evaluated the association of gestational diabetes with atopic dermatitis and allergen sensitization respectively, controlling for maternal pre-pregnancy BMI, fetal growth, and pertinent covariates.
Results
Of the 680 children, 488 were term and 192 were preterm (<37 weeks gestation). Overall, 4.9% of the mothers developed gestational diabetes. Among the 680 children, 34.4% developed atopic dermatitis and 51% developed allergen sensitization. In term births, gestational diabetes was significantly associated with atopic dermatitis (OR, 95%CI=7.2, 1.5-34.5) and allergen sensitization (OR, 95%CI=5.7, 1.2-28.0). Adjusting for fetal growth had little effect. The association with sensitization was driven primarily by food sensitization (OR, 95%CI=8.3, 1.6-43.3). The above associations were not observed in preterm births.
Conclusions
In term births, gestational diabetes increased the risk of atopic dermatitis and early childhood allergen sensitization, independent of maternal pre-pregnancy BMI and fetal growth.
doi:10.1016/j.jaci.2009.06.052
PMCID: PMC3756674  PMID: 19733904
atopic dermatitis; eczema; food allergen sensitization; gestational diabetes
11.  Gender-Specific Association of Sleep Duration with Blood Pressure in Rural Chinese Adults 
Sleep medicine  2011;12(7):693-699.
Background
There are limited data about the role of gender on the relationship between sleep duration and blood pressure (BP) from rural populations.
Methods
We conducted a cross-sectional rural population-based study. This report includes 1,033 men and 783 women aged 18–65 years from a cohort of twins enrolled in Anhui, China, between 2005 and 2008. Sleep duration was derived from typical bedtime, wake-up time, and sleep latency as reported on a standard sleep questionnaire. Primary outcomes included measured systolic blood pressure (SBP) and diastolic blood pressure (DBP). High blood pressure (HBP) was defined as SBP≥130 mmHg, DBP ≥85 mmHg, or physician diagnosed hypertension. Linear and logistic regression models were used to assess gender-specific associations between sleep duration and BP or HBP, respectively, with adjustment for known risk factors including adiposity and sleep-related disorder risk from the questionnaires. Generalized estimating equations were used to account for intra-twin pair correlations.
Results
Compared with those sleeping 7 to less than 9 hours, women sleeping <7 hours had a higher risk of HBP (odds ratios [ORs] 3.0, 95% confidence interval [CI], 1.4–6.6); men sleeping ≥9 hours had a higher risk of HBP (ORs=1.5, 95%CI: 1.1–2.2).
Conclusions
Among rural Chinese adults, a gender-specific association of sleep duration with BP exists such that HBP is associated with short sleep duration in women and long sleep duration in men. Longitudinal studies are needed to further examine the temporal relationship and biological mechanisms underlying sleep duration and BP in this population. Our findings underscore the potential importance of appropriate sleep duration for optimal blood pressure.
doi:10.1016/j.sleep.2010.12.019
PMCID: PMC3755492  PMID: 21764369
sleep duration; high blood pressure; gender difference; rural Chinese
12.  Cord Blood 8-Isoprostane in the Preterm Infant 
Early Human Development  2012;88(8):683-689.
Background
Cord blood 8-isoprostane (8-IP) is a marker of lipid peroxidation in the peripartum period. The independent association with degree of prematurity is not well-described.
Objective
To identify patterns of lipid peroxidation among early, moderate and late preterm infants, and to understand how cord blood 8-IP varies with gestational age (GA) and related covariates.
Study Design
Mother-infant pairs from 237 preterm births were studied as part of a longitudinal birth cohort study. GA subgroups were defined as extremely (≤28w), moderately (29-33w), and late (34-36w) preterm. Cord blood 8-IP was measured using EIA. Elevated 8-IP (4th quartile) was the primary outcome for multivariate logistic regression models, which were adjusted for maternal age/race, multiple gestation and infant gender, as well as other relevant covariates.
Results
Elevated 8-IP was associated with extremely preterm birth (OR=4.31; 95% CI=1.90, 9.76), and was inversely associated with increasing GA (OR=0.88; 95% CI=0.80, 0.97). Elevated 8-IP was also associated with decreasing birth weight (BW), clinical chorioamnionitis, fetal inflammatory response of the placenta (FIR), and signs of perinatal depression. The GA on 8-IP association appeared to be modified by several maternal disease and fetal-infant factors. Lastly, the indirect associations between log-transformed 8-IP, GA and BW appeared to be most prominent for GA<30w and for BW<2000 grams.
Conclusion
Lipid peroxidation in preterm birth, and the relative influence of accompanying peripartum factors, varies according to degree of prematurity. These findings have important implications for the developmental regulation of antioxidant defense and its impact on neonatal outcomes.
doi:10.1016/j.earlhumdev.2012.02.002
PMCID: PMC3380152  PMID: 22425039
premature infant; low birth weight; oxidant stress; cord blood; placenta
13.  Methylation and aberrant expression of the Wnt antagonist secreted Frizzled-related protein 1 in bladder cancer 
Oncology Letters  2012;4(2):334-338.
The aims of this study were to determine the methylation and expression status of secreted Frizzled-related protein 1 (SFRP1) in bladder cancer, to explore the mechanisms involved and to study the role of SFRP1 in the pathogenesis of bladder cancer. SFRP1 mRNA was detected by reverse transcription PCR (RT-PCR). The DNA methylation status was determined by methylation-specific PCR and protein was detected using western blotting. The results of the present study demonstrated that SFRP1 was methylated in the bladder cancer cell lines T24 and 5637, but not in SCaBER cells. After treating T24 and 5637 cells with a demethylating agent, the cells expressed SFRP1 mRNA and protein. Among the 45 patients with bladder cancer, methylation of SFRP1 was detected in 28 patients (62.2%). Of the matched cancer-adjacent tissues, 6 (13.3%) were found to have methylated SFRP1. The result is statistically significant (P<0.01). In conclusion, SFRP1 is downregulated in certain bladder cancer patients as a consequence of methylation. SFRP1 methylation may be involved in the pathogenesis of bladder cancer via excessive activation of the Wnt signaling pathway.
doi:10.3892/ol.2012.713
PMCID: PMC3402742  PMID: 22844380
secreted Frizzled-related protein 1; methylation; bladder cancers; Wnt signaling pathway
14.  Sleep, School Performance, and a School-Based Intervention among School-Aged Children: A Sleep Series Study in China 
PLoS ONE  2013;8(7):e67928.
Background
Sufficient sleep during childhood is essential to ensure a transition into a healthy adulthood. However, chronic sleep loss continues to increase worldwide. In this context, it is imperative to make sleep a high-priority and take action to promote sleep health among children. The present series of studies aimed to shed light on sleep patterns, on the longitudinal association of sleep with school performance, and on practical intervention strategy for Chinese school-aged children.
Methods and Findings
A serial sleep researches, including a national cross-sectional survey, a prospective cohort study, and a school-based sleep intervention, were conducted in China from November 2005 through December 2009. The national cross-sectional survey was conducted in 8 cities and a random sample of 20,778 children aged 9.0±1.61 years participated in the survey. The five-year prospective cohort study included 612 children aged 6.8±0.31 years. The comparative cross-sectional study (baseline: n = 525, aged 10.80±0.41; post-intervention follow-up: n = 553, aged 10.81±0.33) was undertaken in 6 primary schools in Shanghai. A battery of parent and teacher reported questionnaires were used to collect information on children’s sleep behaviors, school performance, and sociodemographic characteristics. The mean sleep duration was 9.35±0.77 hours. The prevalence of daytime sleepiness was 64.4% (sometimes: 37.50%; frequently: 26.94%). Daytime sleepiness was significantly associated with impaired attention, learning motivation, and particularly, academic achievement. By contrast, short sleep duration only related to impaired academic achievement. After delaying school start time 30 minutes and 60 minutes, respectively, sleep duration correspondingly increased by 15.6 minutes and 22.8 minutes, respectively. Moreover, intervention significantly improved the sleep duration and daytime sleepiness.
Conclusions
Insufficient sleep and daytime sleepiness commonly existed and positively associated with the impairment of school performance, especially academic achievement, among Chinese school-aged children. The effectiveness of delaying school staring time emphasized the benefits of optimal school schedule regulation to children’s sleep health.
doi:10.1371/journal.pone.0067928
PMCID: PMC3707878  PMID: 23874468
15.  Association of Adiposity Trajectories With Insulin Sensitivity and Glycemic Deterioration 
Diabetes Care  2012;35(7):1506-1512.
OBJECTIVE
To evaluate associations between adiposity trajectories over time and insulin sensitivity and glucose deterioration in a Chinese twin cohort.
RESEARCH DESIGN AND METHODS
This study focused on 341 males and 292 females aged 20–50 years at baseline who had physical clinical examinations and oral glucose tolerance test at two time points with an average of 6 years apart. BMI, waist circumference, percent body fat (PBF), and percent trunk fat (PTF) trajectories were classified into five track groups based on age- and sex-specific tertiles at each visit. We calculated the odds of the insulin sensitivity index(0,120) [ISI(0,120)] or glycemic deterioration at follow-up among five defined trajectories (tertilebaseline → tertilefollow-up) using generalized estimate equation models. Additionally, we applied structural equation models to examine genetic and environmental influences on adiposity, adiposity change over time (ACO), ISI(0,120), and the interrelationships among them.
RESULTS
Participants with stable adiposity (BMI, waist circumference, PBF, and PTF) in the highest tertile or shifting to the highest tertile tended to have the lowest ISI(0,120) at follow-up or experience glycemic deterioration. Genetic factors exerted the major influence on adiposity, but environmental factors unique to each twin contributed more strongly to ISI and ACO. Correlations between adiposity/ACO and insulin sensitivity were mainly due to environmental influences.
CONCLUSIONS
When adiposity stays or becomes high, insulin sensitivity falls and risk of glycemic deterioration rises. Additionally, we found that genetic factors exerted the major influence on adiposity, while environmental factors played the principal role for ACO and insulin sensitivity.
doi:10.2337/dc11-2060
PMCID: PMC3379613  PMID: 22596174
16.  Individual variation and longitudinal pattern of genome-wide DNA methylation from birth to the first two years of life 
Epigenetics  2012;7(6):594-605.
Prenatal development and early childhood are critical periods for establishing the tissue-specific epigenome, and may have a profound impact on health and disease in later life. However, epigenomic profiles at birth and in early childhood remain largely unexplored. The focus of this report is to examine the individual variation and longitudinal pattern of genome-wide DNA methylation levels from birth through the first two years of life in 105 Black children (59 males and 46 females) enrolled at the Boston Medical Center. We performed epigenomic mapping of cord blood at birth and venous blood samples from the same set of children within the first two years of life using Illumina Infinium Humanmethylation27 BeadChip. We observed a wide range of inter-individual variations in genome-wide methylation at each time point including lower levels at CpG islands, TSS200, 5′UTR and 1st Exon locations, but significantly higher levels in CpG shores, shelves, TSS1500, gene body and 3′UTR. We identified CpG sites with significant intra-individual longitudinal changes in the first two years of life throughout the genome. Specifically, we identified 159 CpG sites in males and 149 CpG sites in females with significant longitudinal changes defined by both statistical significance and magnitude of changes. These significant CpG sites appeared to be located within genes with important biological functions including immunity and inflammation. Further studies are needed to replicate our findings, including analysis by specific cell types, and link those individual variations and longitudinal changes with specific health outcomes in early childhood and later life.
doi:10.4161/epi.20117
PMCID: PMC3398988  PMID: 22522910
CpG; DIP test; DNA Methylation; empirical bayes; genome-wide; normal mixture
17.  Urine and Serum MicroRNA-1 as Novel Biomarkers for Myocardial Injury in Open-Heart Surgeries with Cardiopulmonary Bypass 
PLoS ONE  2013;8(4):e62245.
MicroRNA-1 (miR-1) is a cardio-specific/enriched microRNA. Our recent studies have revealed that serum and urine miR-1 could be a novel sensitive biomarker for acute myocardial infarction. Open-heart surgeries with cardiopulmonary bypass (CPB) are often accompanied with surgery injury and CPB-associated injury on the hearts. However, the association of miR-1 and these intra-operative and post-operative cardiac injures is unknown. The objective of this study was to test the hypothesis that urine and serum miR-1 might be a novel biomarker for myocardial injuries in open-heart surgeries with CPB. Serum and urine miR-1 levels in 20 patients with elective mitral valve surgery were measured at pre-surgery, pre-CPB, 60 min post-CBP, and 24h post-CBP. Serum cardiac troponin-I (cTnI) was used as a positive control biomarker for cardiac injury. Compared with these in pre-operative and pre-CPB groups, the levels of miR-1 in serum and urine from patients after open-heart surgeries and CPB were significant increased at all observed time points. A similar pattern of serum cTnI levels and their strong positive correlation with miR-1 levels were identified in these patients. The results suggest that serum and urine miR-1 may be a novel sensitive biomarker for myocardial injury in open-heart surgeries with CPB.
doi:10.1371/journal.pone.0062245
PMCID: PMC3632512  PMID: 23630629
18.  Gene-Vitamin D Interactions on Food Sensitization: A prospective birth cohort study 
Allergy  2011;66(11):1442-1448.
Background
It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine if cord blood VDD is associated with FS and if such association can be modified by genetic variants in a prospective birth cohort.
Methods
This study included 649 children who were enrolled at birth and followed from birth onward at the Boston Medical Center. We defined VDD as cord blood 25(OH)D < 11ng/ml, and FS as specific IgE ≥ 0.35kUA/L to any of eight common food allergens in early childhood. We genotyped potentially functional single nucleotide polymorphisms (SNPs) in 11 genes known to be involved in regulating IgE and 25(OH)D concentrations. Logistic regressions were used to test the effects of VDD on FS individually and jointly with SNPs.
Results
Among the 649 children, 44% had VDD and 37% had FS. When examined alone, VDD was not associated with FS. When examined jointly with SNPs, a significant interaction between IL4 gene polymorphism (rs2243250) and VDD (pinteraction=0.003, pFDR=0.10) was found: VDD increased the risk of FS among children carrying CC/CT genotypes (OR=1.79, 95%CI: 1.15–2.77). Similar but weaker interactions were observed for SNPs in MS4A2 (rs512555), FCER1G (rs2070901), and CYP24A1 (rs2762934). When all four SNPs were simultaneously considered, a strong gene-VDD interaction was evident (pinteraction=9×10−6).
Conclusions
Our data demonstrate that VDD may increase the risk of FS among individuals with certain genotypes, providing evidence of gene-vitamin D interaction on FS.
doi:10.1111/j.1398-9995.2011.02681.x
PMCID: PMC3189275  PMID: 21819409
cord blood plasma 25(OH)D; food sensitization; gene-vitamin D deficiency interaction; SNP
19.  Role of African Ancestry and Gene-Environment Interactions in Predicting Preterm Birth 
Obstetrics and gynecology  2011;118(5):1081-1089.
Objective
To estimate whether African ancestry, specific gene polymorphisms, and gene-environment interactions could account for some of the unexplained preterm birth variance within blacks.
Methods
We genotyped 1,509 African ancestry informative markers, cytochrome P-450 1A1 (CYP1A1) and glutathione S-transferases Theta 1 (GSTT1) variants in 1,030 self-reported black mothers. We estimated the African ancestral proportion using the ancestry informative markers for all 1,030 self-reported black mothers. We examined the effect of African ancestry and CYP1A1 and GSTT1 smoking interactions on preterm birth cases as a whole and within its subgroups: very preterm birth (gestational age less than 34 weeks); and late preterm birth (gestational age greater than 34 and less than 37 weeks). We applied logistic regression and receiver operating characteristic (ROC) curve analysis, separately, to evaluate if African ancestry and CYP1A1- and GSTT1-smoking interactions could make additional contributions to preterm birth beyond epidemiological factors.
Results
We found significant associations of African ancestry with preterm birth (22% vs. 31%, OR=1.11; 95%CI: 1.02–1.20) and very preterm birth (23% vs. 33%, OR=1.17; 95%CI: 1.03–1.33), but not with late preterm birth (22% vs. 29%, OR=1.06; 95%CI: 0.97–1.16). In addition, the ROC curve analysis suggested that African ancestry and CYP1A1- and GSTT1-smoking interactions made substantial contributions to very preterm birth beyond epidemiologic factors.
Conclusion
Our data underscore the importance of simultaneously considering epidemiological factors, African ancestry, specific gene polymorphisms and gene-environment interactions to better understand preterm birth racial disparity and to improve our ability to predict preterm birth, especially very preterm birth.
doi:10.1097/AOG.0b013e31823389bb
PMCID: PMC3218119  PMID: 22015876
20.  Race, Ancestry, and Development of Food-Allergen Sensitization in Early Childhood 
Pediatrics  2011;128(4):e821-e829.
OBJECTIVE:
We examined whether the risk of food-allergen sensitization varied according to self-identified race or genetic ancestry.
METHODS:
We studied 1104 children (mean age: 2.7 years) from an urban multiethnic birth cohort. Food sensitization was defined as specific immunoglobulin E (sIgE) levels of ≥0.35 kilo–units of allergen (kUA)/L for any of 8 common food allergens. Multivariate logistic regression analyses were used to evaluate the associations of self-identified race and genetic ancestry with food sensitization. Analyses also examined associations with numbers of food sensitizations (0, 1 or 2, and ≥3 foods) and with logarithmically transformed allergen sIgE levels.
RESULTS:
In this predominantly minority cohort (60.9% black and 22.5% Hispanic), 35.5% of subjects exhibited food sensitizations. In multivariate models, both self-reported black race (odds ratio [OR]: 2.34 [95% confidence interval [CI]: 1.24–4.44]) and African ancestry (in 10% increments; OR: 1.07 [95% CI: 1.02–1.14]) were associated with food sensitization. Self-reported black race (OR: 3.76 [95% CI: 1.09–12.97]) and African ancestry (OR: 1.19 [95% CI: 1.07–1.32]) were associated with a high number (≥3) of food sensitizations. African ancestry was associated with increased odds of peanut sIgE levels of ≥5 kUA/L (OR: 1.25 [95% CI: 1.01–1.52]). Similar ancestry associations were seen for egg sIgE levels of ≥2 kUA/L (OR: 1.13 [95% CI: 1.01–1.27]) and milk sIgE levels of ≥5 kUA/L (OR: 1.24 [95% CI: 0.94–1.63]), although findings were not significant for milk.
CONCLUSIONS:
Black children were more likely to be sensitized to food allergens and were sensitized to more foods. African ancestry was associated with peanut sensitization.
doi:10.1542/peds.2011-0691
PMCID: PMC3182844  PMID: 21890831
food allergy; sensitization; racial disparities; genetic ancestry
21.  Short Sleep Duration Is Associated with Insulin Resistance Independent of Adiposity in Chinese Adult Twins 
Sleep medicine  2011;12(9):914-919.
Objective
To investigate the association between sleep duration and insulin resistance in rural Chinese adults and examine whether any such associations are independent of adiposity.
Methods
This is a cross-sectional analysis of 854 men and 640 women aged 20 to 70 years from the Anqing Twin Cohort. The following measures were obtained for each subject: Body mass index (BMI) and percentage of trunk fat (%TF), fasting plasma glucose, homeostatic model assessment of insulin resistance index (HOMA-IR), self-reported sleep duration, and measures of snoring and sleep disturbance from the Pittsburgh Sleep Quality Indices (PSQI) questionnaire modified for a Chinese population. Multivariate linear regressions were applied to examine the association of sleep duration with HOMA-IR, with and without adjustment for adiposity variables, along with other relevant covariates.
Results
In this sample of relatively lean rural Chinese adults, short sleep duration was associated with HOMA-IR in women but not in men. In women, short (≤7 hrs/night) sleep duration was associated with a higher HOMA-IR (p=0.003) compared with normal sleep duration (>7 to ≤8 hrs/night) after adjustment for all the covariates except adiposity. Further adjustment for BMI or %TF attenuated the sleep-HOMA-IR association, but the association remained significant upon adjustment for BMI (p=0.013); and upon adjustment for %TF (p=0.026). Long sleep duration (>8 hrs/night) was not significantly associated with HOMA-IR.
Conclusion
In this rural Chinese cohort, short sleep duration is independently associated with increased insulin resistance among women only, even after adjusting for adiposity and other potential confounders.
doi:10.1016/j.sleep.2011.04.006
PMCID: PMC3210935  PMID: 21940204
sleep duration; insulin resistance; adiposity; gender; rural; adults
22.  Prevalence and Associated Factors of Diabetes and Impaired Fasting Glucose in Chinese Hypertensive Adults Aged 45 to 75 Years 
PLoS ONE  2012;7(8):e42538.
Objective
This study examined the prevalence of impaired fasting glucose (IFG) and diabetes and their associated factors in 17,184 Chinese hypertensive adults aged 45–75 years.
Methods
A cross-sectional investigation was carried out in a rural area of Lianyungang, China. Previously undiagnosed diabetes [fasting plasma glucose (FPG) ≥7.0mmol/l] and IFG (6.1–6.9mmol/l) were defined based on FPG concentration. Previously diagnosed diabetes was determined on the basis of self-report. Total diabetes included both previously diagnosed diabetes and previously undiagnosed diabetes.
Results
The prevalence of previously diagnosed diabetes, undiagnosed diabetes, and IFG were 3.4%, 9.8%, and 14.1%, respectively. About 74.2% of the participants with diabetes had not previously been diagnosed. In the multivariable logistic-regression model, older age, men, antihypertensive treatment, obesity (BMI ≥25kg/m2), abdominal obesity (waist circumference ≥90cm for men and ≥80cm for women), non-current smoking, a family history of diabetes, higher heart rate, lower physical activity levels, and inland residence (versus coastal) were significantly associated with both total diabetes and previously undiagnosed diabetes. Furthermore, methylene- tetrahydrofolate reductase (MTHFR) 677 TT genotype was an independent associated factor for total diabetes, and current alcohol drinking was an independent associated factor for previously undiagnosed diabetes. At the same time, older age, men, abdominal obesity, non-current smoking, current alcohol drinking, a family history of diabetes, higher heart rate, and inland residence (versus coastal) were important independent associated factors for IFG.
Conclusion
In conclusion, we found a high prevalence of diabetes in Chinese hypertensive adults. Furthermore, about three out of every four diabetic adults were undiagnosed. Our results suggest that population-level measures aimed at the prevention, identification (even if only based on the FPG evaluation), and treatment of diabetes should be urgently taken to overcome the diabetes epidemic in Chinese hypertensive adults.
doi:10.1371/journal.pone.0042538
PMCID: PMC3411819  PMID: 22880024
23.  Association of Antenatal Steriod Use with Cord Blood Immune Biomarkers in Preterm Births 
Early human development  2011;87(8):559-564.
Objectives
To evaluate the effect of maternal administration of antenatal steroids (ANS) on cord blood cytokine levels at birth in preterm infants.
Methods
Cord blood cytokine concentrations were measured for pro-inflammatory cytokines (IL-1β, IL-6, IL-8); anti-inflammatory cytokines (IL-4, IL-10 and TGF β); and neurotrophic cytokines (BDNF, NT-3, and NT-4) in two hundred preterm infants. Data were analyzed using multivariable linear regression to model the independent and joint effects of ANS and inflammation on mean log cord blood cytokine concentrations adjusted for gestational age and Apgar scores.
Results
Exposure to ANS had no significant effect on the cord blood concentrations of cytokines measured in this study. All three pro-inflammatory cytokines levels and levels of IL-10 were significantly increased and cord blood levels of TGF-β and NT-3 were significantly decreased in infants with placental inflammation.
Conclusion
Although exposure to ANS did not have any significant effect on cord blood levels of cytokines, there was a trend toward the attenuation of inflammatory response and higher levels of neurotrophic cytokines in infants born to mothers with placental inflammation and exposure to ANS compared to infants born to mothers with placental inflammation and no ANS exposure.
doi:10.1016/j.earlhumdev.2011.04.013
PMCID: PMC3140537  PMID: 21576006
24.  Gene Polymorphisms, Breastfeeding and Development of Food Sensitization in Early Childhood 
Background
The impact of breastfeeding on the development of allergic disease is uncertain. There are no data that show whether this relationship varies by individual genotypes.
Objective
To evaluate the effect of breastfeeding and gene-breastfeeding interactions on food sensitization (FS) in a prospective U.S. birth cohort.
Methods
This study included 970 children who were prospectively followed since birth. Breastfeeding history was obtained from a standardized questionnaire interview. FS was defined as specific IgE ≥0.35 kUA/L to any of eight common food allergens. Eighty-eight potentially functional SNPs were genotyped from 18 genes involved in innate immunity or TH1/TH2 balance. Logistic regression models were used to test the effects of breastfeeding and gene-breastfeeding interactions on FS, with adjustment for pertinent covariates.
Results
Children who were ever breastfed (n=739), including exclusively breastfed children, were at a 1.5 (95%CI=1.1-2.1, p=0.019) times higher risk of FS than never breastfed children (n=231). This association was significantly modified by rs425648 in the IL12RB1gene (pinteraction=0.0007): breastfeeding increased the risk of FS (OR=2.0, 95%CI=1.4-3.1, p= 0.0005) in children carrying the GG genotype but decreased the risk (OR=0.6, 95%CI=0.3-1.4, p=0.252) in children carrying the GT/TT genotype. Similar interactions were observed for SNPs in the TLR9 (rs352140) and TSLP (rs3806933) genes. The interaction between the combined genotypes of the three SNPs and breastfeeding on FS was even stronger (pinteraction<10-5).
Conclusion
Our data suggest that the effect of breastfeeding on FS was modified by SNPs in the IL12RB1, TLR9, and TSLP genes both individually and jointly. Our findings underscore the importance of considering individual genetic variations in assessing this relationship.
doi:10.1016/j.jaci.2011.05.007
PMCID: PMC3149737  PMID: 21689850
Breastfeeding; food sensitization; gene-environment interaction
25.  Association between Short Sleep Duration and the Risk of Sensitization to Food and Aero Allergens in Rural Chinese Adolescents 
Background
Both long and short sleep duration have been associated with obesity, cardiovascular disease, and diabetes. However, there have been no previous studies investigating the potential relationship between altered sleep duration and allergen sensitization.
Objective
To explore the association between sleep duration and sensitization to food and aeroallergens.
Methods
This study includes 1534 rural Chinese adolescent twins aged 12 to 21 years who completed standard sleep questionnaires and skin prick tests (SPTs) to 9 food and 5 aeroallergens. Total sleep time was defined as the interval from bedtime to wake-up time minus sleep latency. Sensitization was defined as having at least one positive SPT.
Results
Compared to individuals with the highest (3rd) tertile of sleep duration, those who slept less were more likely to be sensitized to any food allergen with odds ratios (ORs) of 1.9 (95% confidence interval(CI):1.3–2.7) and 1.4 (95%CI:1.0–1.9) for the 1st and 2nd tertiles (trend test Ptrend=3×10−4), respectively. The corresponding ORs for sensitization to any aeroallergen were 1.5 (95%CI: 1.1–2.0) and 1.3 (95%CI:1.0–1.7) (Ptrend=8×10−3). These associations were independent of percent body fat. In addition, we observed a significant dose-response association between the number of positive SPTs and percentage of shortest sleep duration (1st tertile) (Ptrend=1×10−3).
Conclusions and Clinical Relevance
In this sample of relatively lean rural Chinese adolescents, we found that short sleep duration was associated with increased risk of sensitization to food and aeroallergens, independent of percent body fat. Longitudinal studies are needed to further determine the temporal and causal relationships. If short sleep duration indeed is one of the risk factors for allergic sensitization, the global burden of allergic diseases could be dramatically reduced by providing appropriate guidance on sleep duration for youth.
doi:10.1111/j.1365-2222.2010.03677.x
PMCID: PMC3056931  PMID: 21255141
sleep duration; skin prick test; allergen; sensitization; adolescent

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