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Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14–20 μg/dL). Various complications develop if the upper limit is exceeded. We present the case of a 5-year-old girl with breast development, acne, and pubic hair who was diagnosed with an adrenal mass that was subsequently excised. The pathological finding was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was recommended. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also administered. However, the patient exhibited elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty concentrating. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane level is elevated. Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by high mitotane level. The mitotane decreased to subtherapeutic level several months after its discontinuation, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient, indicating that the drug dose should be individualized with frequent monitoring of the therapeutic level.

Background: The effect of intrauterine hyperglycemia on fat mass and regional fat proportion of the offspring of mothers with gestational diabetes mellitus (OGDM) remains to be determined.Methods: The body composition of OGDM (n=25) and offspring of normoglycemic mothers (n=49) was compared using dualenergy X-ray absorptiometry at age 5 years. The relationship between maternal glucose concentration during a 100 g oral glucose tolerance test (OGTT) and regional fat mass or proportion was analyzed after adjusting for maternal prepregnancy body mass index (BMI).Results: BMI was comparable between OGDM and control (median, 16.0 kg/m2 vs. 16.1 kg/m2 ). Total, truncal, and leg fat mass were higher in OGDM compared with control (3,769 g vs. 2,245 g, P=0.004; 1,289 g vs. 870 g, P=0.017; 1,638 g vs. 961 g, P=0.002, respectively), whereas total lean mass was lower in OGDM (15,688 g vs. 16,941 g, P=0.001). Among OGDM, total and truncal fat mass were correlated with fasting and 3-hour glucose concentrations of maternal 100 g OGTT during pregnancy (total fat mass, r=0.49, P=0.018 [fasting], r=0.473, P=0.023 [3-hour]; truncal fat mass, r=0.571, P=0.004 [fasting], r=0.558, P=0.006 [3-hour]), but there was no correlation between OGDM leg fat mass and maternal OGTT during pregnancy. Regional fat indices were not correlated with concurrent maternal 75 g OGTT values.Conclusion: Intrauterine hyperglycemia is associated with increased fat mass, especially truncal fat, in OGDM aged 5 years.

BACKGROUND AND OBJECTIVE Global Lung Function Initiative (GLI) 2012 equations were developed to resolve the age-related disparity in interpreting spirometry results. Local validation of the equation is needed, especially in Northeast Asian children. This study evaluated the GLI equation in Korean children. METHODS Spirometry indices (FEV1, FVC, FEV1/FVC, and FEF25%-75%) and clinical information were gathered from three population-based birth cohorts. Predicted GLI reference values and z scores of spirometry results were calculated for 1239 healthy children. The mean, standard deviation of z scores were compared with the expected 0 and 1. Probabilities of falling below the lower limit of normal (LLN) (z score: -1.64) were compared with the expected value 5%. GLI z scores were assessed according to low ( 2) BMI z score groups. RESULTS Mean z scores significantly differed from 0 for FEV1/FVC in males (mean [95% confidence interval]: 0.18 [0.08, 0.27]) and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in females (-0.23 [-0.31, -0.15] and -0.26 [-0.36, -0.16], respectively). The standard deviation was larger than 1 for all variables in males and FVC and FEV1/FVC in females. The probability of falling below the LLN was significantly larger than 5% for FEV1 (12.13% [9.64, 14.77]), FVC (15.86% [13.06, 18.81]), and forced expiratory flow at 25%-75% of forced vital capacity (FEF25%-75%) (7.31% [5.29, 9.49]) in males and FVC (11.91% [9.40, 14.60]) in females. FEV1 and FVC z scores increased across low to high body mass index (BMI) groups, and FEV1/FVC decreased from low to high BMI groups. CONCLUSION GLI equations marginally differ from real-world values, which should be considered by pulmonologists in practice or research.

BackgroundAdverse metabolic outcomes later in life have been reported among children or young adults who were born as preterm infants. This study was conducted to examine the impact of very preterm/very low birth weight (VP/VLBW) birth and subsequent growth after hospital discharge on cardiometabolic outcomes such as insulin resistance, fasting glucose, and systolic and diastolic blood pressure (BP) among children at 6–8 years of age.MethodsThis retrospective cohort study included children aged 6–8 years and compared those who were born at n = 60) with those born at term (n = 110). Body size, fat mass, BP, glucose, insulin, leptin, adiponectin, and lipid profiles were measured. Weight-for-age z-score changes between discharge and early school-age period were also calculated, and factors associated with BP, fasting glucose, and insulin resistance were analyzed.ResultsChildren who were born VP/VLBW had significantly lower fat masses, higher systolic BP and diastolic BP, and significantly higher values of fasting glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), compared to children born at term. VP/VLBW was correlated with HOMA-IR and BPs after adjusting for various factors, including fat mass index and weight-for-age z-score changes. Weight-for-age z-score changes were associated with HOMA-IR, but not with BPs.ConclusionsAlthough children aged 6–8 years who were born VP/VLBW showed significantly lower weight and fat mass, they had significantly higher BPs, fasting glucose, HOMA-IR, and leptin levels. The associations of VP/VLBW with cardiometabolic factors were independent of fat mass and weight gain velocity.

BACKGROUND: Molecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory ((131)I-refractory) PTC. METHODS: PTC samples from 106 pediatric patients (age range: 4.3–19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983–March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison. RESULTS: We identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAF(V600E) in 41 patients, TERT(C228T) in 2 patients [1 of whom had a coexisting BRAF(V600E)], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAF(V600E) PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients

OBJECTIVE We evaluated the frequency, risk factors and the follow-up outcomes of thyroid nodules, and genetic alterations in thyroid cancer, in youth with childhood-onset Hashimoto thyroiditis (HT) residing in an iodine-sufficient country. DESIGN A retrospective cohort study. PATIENTS AND MEASUREMENTS A total of 213 patients (194 females, mean age 10.6 years at the time of HT diagnosis) were ultrasonographically evaluated. Thyroid nodules were categorized using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TI-RADS). RESULTS Thyroid nodules were detected in 40 (18.8%) patients over a median follow-up period of 3.4 years, usually after the onset of puberty. A family history of thyroid disease (hazard ratio 2.1, p = .031) was predictive of thyroid nodule detection. Papillary thyroid carcinoma (PTC) was diagnosed in 9 (4.2% of all and 22.5% of nodule-positive patients). The malignant nodules had a higher K-TIRADS or ACR-TI-RADS risk level compared with benign nodules (p

Sufficient sleep during childhood is important for cognitive functions such as learning and successful school performance. This study aimed to investigate the effects of sleep duration on the intelligence quotient (IQ) of 6-year-old children and aimed to analyze whether these effects differed by sex. The IQ of 538 6-year-old Korean participants from the cohort study, “The Environment and Development of Children,” was measured during follow-up using the Korean Educational Developmental Institute’s Wechsler Intelligence Scale for Children. The total, verbal, and performance IQ scores were evaluated. The relationship between sleep duration and IQ scores after adjusting for maternal age, maternal educational level, maternal occupation, maternal IQ, exposure to secondhand smoking, gestational age, and monthly age and birth season was also assessed. Longer sleep duration was significantly associated with improved verbal IQ measures (β 0.55; p value 0.030). After stratifying participants by sex, a significant association was observed between sleep duration and total, verbal, and performance IQ scores in boys (total IQ 2.49, p value 0.012; verbal IQ 0.75, p value: 0.037; performance IQ 0.73, p value 0.048), but not in girls. The results indicated that only boys show a significant association between IQ scores and sleep duration. These findings support the hypothesis that sleep duration is associated with IQ, in a sex dependent manner. Future studies are needed for a thorough evaluation of the connection between sleep duration and health outcome in young children.

Background: The incidence of thyroid cancer has increased worldwide. We investigated nationwide trends in the incidence and treatment course of pediatric thyroid cancer in South Korea. Methods: Usi...

Feral cats are widely considered to be leading the potential impacts on public health. This study aimed to provide estimates of vital data for feral cats relating Trap-Neuter-Return (TNR) to establish strategies effectively to manage feral cats in Pyeongtaek. Thus, this study focused on estimating feral cat population in Pyeongtaek and conducted a comparative analysis of the data for feral cats in Seoul (2013). The number of feral cats was estimated from 23,069 to 26,655 in Pyeongtaek, 2019. In relation to human population, when comparing the number of feral cats of Pyeongtaek and Seoul, it ranged from 4.57% to 5.28%, and from 1.97% to 2.55% respectively. This showed that Pyeongtaek was higher than Seoul. Fewer kittens were found in high-density areas, which the TNR project is believed to be generally effective in controlling the number of feral cats. In conclusion, in urban and rural complexes such as Pyeongtaek City, the number of feral cats compared to the population was higher than that of Seoul City, and the TNR program is believed to be somewhat effective in controlling the number of feral cats. When implementing TNR, it is necessary periodically to investigate the population and reflect them in policymaking.

The cytochrome P450 2E1 (CYP2E1) enzyme encoded by CYP2E1 plays an important role in the metabolism of organic compounds in mammalian liver cells. In this study, the plasmid pCAMBIA2300 harboring the rabbit CYP2E1 was transferred into Agrobacterium tumefaciens; this was then transferred into internodes of Ardisia pusilla. Shoot primordia, whose appearance resembles that of the in vitro protocorm-like body of orchids, regenerated from 121 of 332 internodes that were cultured in selection medium supplemented with 5 mg·L−1 kanamycin. PCR analysis confirmed that 25 of 89 putative transgenic plants (28.0%) stably harbored the CYP2E1 and NPTII genes, and Southern blot analysis revealed the presence of one to three copies of CYP2E1 within the genome of the 25 transgenic plants. The mRNA expression of the transgene was confirmed in 12 of 25 CYP2E1-transgenic plants by Northern blot analysis. Western blot analysis indicated the presence of a 53-kDa recombinant rabbit CYP2E1 protein in the 12 CYP2E1-transgenic A. pusilla plants. The aniline 4-hydroxylase activity of rabbit CYP2E1 in nine CYP2E1-transgenic A. pusilla plants was higher than that in non-transgenic A. pusilla plants. There was a statistically significant increase (5.1–6.1-fold) in the toluene removal ability of the transgenic line CYP2E1-2–2 compared to that observed in wild-type Ardisia plants at different times after exogenous toluene exposure.

OBJECTIVES: Bisphenol A (BPA) is used in the electrical, mechanical, medical, and food industries. Previous studies have suggested that BPA is an endocrine disruptor. Regulation of BPA has led to increased use of bisphenol F (BPF) and bisphenol S (BPS). However, few studies have investigated the associations of BPF and BPS with thyroid dysfunction in children. Our study investigated the associations of prenatal BPA and early childhood BPA, BPF, and BPS exposure with thyroid function in 6-year-old children.METHODS: Prenatal BPA concentrations were measured during the second trimester of pregnancy in an established prospective birth cohort. We measured urinary BPA, BPF, and BPS concentrations and thyroid hormone levels (thyroid-stimulating hormone, total T3, and free T4) in 6-year-old children (n=574). We examined the associations between urinary bisphenol concentrations and percentage change of thyroid hormone concentrations using multivariate linear regression. We also compared thyroid hormone levels by dividing the cohort according to BPA, BPF, and BPS concentrations.RESULTS: The associations between prenatal BPA and total T3 levels were statistically significant in all models, except for girls when using a crude model. The associations between urinary BPA and BPS concentrations and levels of all thyroid hormones were not statistically significant. However, we observed that lower free T4 levels (-1.94%; 95% confidence interval, -3.82 to -0.03) were associated with higher urinary BPF concentrations in girls only.CONCLUSIONS: Our findings identified significant associations between prenatal BPA exposure and total T3 levels in all children and between BPF exposure and free T4 levels in girls only.

Purpose Despite the prevalent use of insulin pump therapy worldwide, few studies have been conducted among young patients with type 1 diabetes (T1D) in Korea. We investigated the durability and effectiveness of insulin pump therapy among Korean pediatric and young adult patients with T1D. Methods This study included 54 patients with T1D diagnosed at pediatric ages (range, 1.1–14.1 years) who initiated insulin pump therapy during 2016–2019 at Seoul National University Children's Hospital and Seoul National University Bundang Hospital. Clinical and biochemical data, including anthropometric measurements, insulin dose, and glycated hemoglobin (HbA1c) levels were obtained from T1D diagnosis to last follow-up. Results Forty-four patients (81.5%) continued insulin pump therapy with a median pump use duration of 2.9 years (range, 0.2–3.5 years); 10 discontinued the therapy within 12 months (

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurobehavioral disorder in children. There are limited studies for diet or dietary supplement effects on ADHD in preschool children in Asia. This study aimed to determine the association between dietary patterns in 4-year-old children and ADHD symptoms in 6-year-old children.We estimated dietary intake in 4-year-old children using a food frequency questionnaire. Using 33 food groups, major dietary patterns were identified in relation to the consumption of sweets, vegetables, meats, and carbohydrates. Parents of 6-year-old children used the Korean version of the ADHD Rating Scale for ADHD symptom assessment.A sweet dietary pattern was associated with a higher risk of attention deficit (AD) (relative risk [RR], 1.34; confidence interval [CI], 1.17-1.55), hyperactivity (RR, 1.40; CI, 1.19-1.64), and ADHD symptoms (RR, 1.37; CI, 1.23-1.52). A vegetable dietary pattern was associated with a lower risk of ADHD symptoms (RR, 0.81; CI, 0.72-0.90). Food item analysis of the sweet dietary pattern showed that intake scores for chocolate, chips, and fruit jams positively correlated with AD, hyperactivity, and ADHD symptoms.These findings can be useful to further understand the roles of dietary factors in ADHD.

Context The levels of adrenal androgens are increased through the action of steroidogenic enzymes with morphological changes in the adrenal zona reticularis. Objective We investigated longitudinal changes in androgen levels and steroidogenic enzyme activities during early childhood. Design and Participants From a prospective children’s cohort, the Environment and Development of Children cohort, 114 boys and 86 girls with available blood samples from ages 2, 4, and 6 years were included. Outcome Measurements Serum concentrations of adrenal androgens using liquid chromatography-tandem mass spectrometry and steroidogenic enzyme activity calculated by the precursor/product ratio. Results During ages 2 to 4 years, 17,20-lyase and dehydroepiandrosterone (DHEA) sulfotransferase activities increased (P Conclusion This study supports in vivo human evidence of increased 17,20-lyase and DHEA sulfotransferase activities and decreased 3β-HSD activity during early childhood.

Background: Pediatric thyroid cancer has characteristics that are distinct from adulthood thyroid cancer. Due to its very low prevalence, little is known about the genetic characteristics of pediat...

Patients with craniopharyngioma are susceptible to autonomic dysfunction as a result of hypothalamic damage. We evaluated indices of heart rate variability (HRV) in patients with childhood-onset craniopharyngioma to investigate autonomic function and its relationship with components of the metabolic syndrome (MetS). This cross-sectional, case-only study included 53 patients (10–30 years of age). We measured the standard deviation of all normal R-R intervals (SDNN) and total power indicating overall HRV, the root-mean square of the difference of successive R-R intervals (RMSSD) and high frequency indicating parasympathetic modulation, and low frequency. These indices were compared according to the presence of the MetS. During the mean 10.8 years of follow-up, 25% of patients were diagnosed with the MetS. Patients with the MetS showed significantly lower levels of SDNN (29.0 vs. 40.6 ms), total power (416.1 vs. 1129.6 ms2), RMSSD (20.1 vs. 34.5 ms), high frequency (94.7 vs. 338.5 ms2), and low frequency (94.5 vs. 289.4 ms2) than those without (p

Background: Obesity, a chronic low-grade inflammatory state, increases the risk of cardiovascular disease. Elevated high-sensitivity C-reactive protein (hs-CRP) levels are associated with cardiovas...

Purpose: There is increasing use of modern devices in the management of patients with type 1 diabetes (T1D). We investigated temporal trends for diabetes management and outcomes in Korean pediatric...

There is a lack of studies regarding the long-term outcomes of Asian adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. We hypothesized that adults with CAH are at higher metabolic risk than their age-, and sex-matched controls. We further investigated the long-term health outcome-related factors in adults with CAH. We compared metabolic risk between adults with CAH (71 men, 93 women) and age-, and sex-matched controls (190 men, 261 women) from the Korean National Health and Nutrition Examination Survey data. The presence of obesity, testicular adrenal rest tumors (TARTs), and menstrual irregularity was assessed. Hormone status and treatment regimens were compared according to the presence of adverse outcomes. The median age was 27.0 y and 28.0 y for men and women, respectively. Adults with CAH had a higher waist circumference (88.0 vs. 82.3 cm in men, and 83.5 vs. 72.3 cm in women), and blood pressure (125.0 vs. 113.0 mmHg in men, and 120.0 vs. 104.0 mmHg in women) than age- and sex-matched controls (PPP

Per- or polyfluoroalkyl substances (PFAS), a family of synthetic polyfluorinated compounds, are widely used in consumer products. Ubiquitous exposures to PFAS, in consideration of their persistence, bioaccumulation potential, and toxicities have led to concerns regarding possible harmful effects during critical periods of development in early-life and long-term consequences on health. The potential effects of PFAS depend on various factors including the type of PFAS and the timing and level of exposure. We performed a systematic review of the epidemiologic literature to assess the effects of early-life PFAS exposure on prenatal and postnatal growth, adiposity, and puberty in children and adolescents. For birth size, most studies indicated that prenatal PFAS exposure, in particular long-chain PFAS, may impair fetal growth, albeit some reports of null associations with maternal PFAS. For growth within 2 years of age, prenatal PFAS exposure showed no associations with height and either null or negative associations with weight. However, postnatal PFAS exposures were inversely related to height and weight at 2 years in a cross-sectional study. For postnatal adiposity, prenatal PFAS may mostly have negative associations with body mass index in the first 2 years of life, but positive relationships with adiposity in childhood and adolescence, although some studies showed null associations. For puberty, the evidence for associations between early-life PFAS exposure and pubertal development or sex hormone levels were limited and inconclusive. From experimental studies, plausible mechanisms through which PFAS may affect early-life growth and puberty include PFAS-induced activation of peroxisome proliferator-activated receptor, alterations of thyroid or steroid hormone synthesis and metabolism, and their weak estrogenic or anti-androgenic properties. Although the published literature suggests possible effects of PFAS exposures on early-life growth, adiposity, and puberty, current human evidence is limited in establishing PFAS-induced effects on early-life physical development. Further investigation is warranted to clarify PFAS-induced effects on growth and physical development in consideration of the critical time-window of exposure, concomitant exposure to chemical mixtures including various PFAS types, and possible non-monotonic dose-response relationship for growth and adiposity trajectories.

Low-iodine diet (LID) is a crucial preparation for radioactive iodine (RAI) treatment or scan in thyroid cancer. The aim of this study is to analyze the influence of thyroid stimulating hormone (TSH) stimulation protocols and other clinical factors on LID adequacy. Thyroid cancer patients who underwent LID for RAI scan or treatment were retrospectively analyzed. Patients were guided to have LID for 2 weeks before RAI administration and urine iodine/creatinine ratio (UICR, μg/g Cr) was measured. TSH stimulation was conducted using either thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) injection. Adequacy of LID was classified by UICR as ‘excellent (< 50)’, ‘adequate (50–100)’, ‘inadequate (101–250)’ and ‘poor (> 250)’. A total of 1715 UICR measurements from 1054 patients were analyzed. UICR was significantly higher in case of rhTSH use than THW (72.4 ± 48.1 vs. 29.9 ± 45.8 μg/g Cr, P < 0.001). In patients who underwent LID twice using both TSH stimulation protocols alternately, UICR was higher in case of rhTSH than THW regardless of the order of method. Among clinical factors, female, old-age, and the first LID were significant factors to show higher UICR. Although the adequacy of LID was ‘adequate’ or ‘excellent’ in most patients, multivariate analysis demonstrated that THW method, male, young age, and prior LID-experience were significant determinants for achieving ‘excellent’ adequacy of LID. In conclusion, UICR was higher and the proportion of ‘excellent’ LID adequacy was lower with rhTSH than with THW. UICR was higher also in women, old-age, and LID-naïve patients. Further researches are required to suggest effective methods to reduce body iodine pool in case of rhTSH use and to validate the efficacy of such methods on outcomes of RAI treatment.

Background The GNAS gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. GNAS inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright’s hereditary osteodystrophy (AHO), and ectopic ossification. Methods This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed GNAS defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively. Results Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the GNAS gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at GNAS A/B:TSS-DMR. Conclusions Clinical and molecular characteristics of Korean patients with GNAS inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.

Purpose The aim of this study was to evaluate the prevalence and risk factors for cardiac autonomic neuropathy (CAN) in nonobese nonobese young type 1 diabetes mellitus (T1DM) patients without micro- or macrovascular complications. Methods CAN was assessed in 95 patients with T1DM, aged 18-29 years, using standard cardiovascular reflex tests - heart rate response to deep breathing, standing, and the Valsalva maneuver and blood pressure response to standing. Furthermore, power spectral analyses of overall heart rate variability (HRV), standard deviation of NN intervals (SDNN), and total power (TP) were tested with DiCAN. CAN was defined as abnormal results for at least 1 of the 4 cardiovascular reflex tests. Results The prevalence of CAN was 12.6%. The frequency of one and 2 abnormal reflex tests was 10.5% and 2.1%, respectively. No significant differences were observed in age, sex, mean hemoglobin A1c (HbA1c) level, and duration of diabetes with respect to presence of CAN. Patients with CAN exhibited lower overall HRV parameters (SDNN and TP) compared with those without CAN even though there was no statistical significance. In multivariable analyses, higher mean HbA1c level was significantly associated with lower overall HRV (β=-44.42, P=0.002 for SDNN and β=-2.82, Pl0.001 for TP). Conclusion CAN can be detected in 12.6% of young adult T1DM patients even without other micro- or macrovascular complications. Glycemic control is the main determinant to maintain overall HRV and prevent CAN.

Purpose Patients with Turner syndrome (TS) have increased risk of morbidities and mortality related to cardiovascular complications. Cardio-ankle vascular index (CAVI) is a novel method of evaluating arterial stiffness independent of changes in blood pressure. We compared arterial stiffness using CAVI between TS patients and healthy control subjects. Methods Nineteen young women with TS (mean, 26.8 years; range, 20.0-35.1 years) and 23 healthy women matched for age and body mass index (BMI) were recruited for CAVI measurements at Seoul National University Hospital between 2010 and 2013. Anthropometric parameters, fasting blood testing and measurements of CAVI were compared between the 2 groups. Results TS patients were significantly shorter (mean: 150.1 cm vs. 160.7 cm, Pl0.001) and had lower body weight (mean: 47.0 kg vs. 55.5 kg, P=0.014) than healthy controls, without difference in BMI. CAVI (6.5±0.6 vs. 6.1±0.6, P=0.039) was significantly higher in TS patients compared to healthy controls. Age was positively associated with CAVI (r=0.403, P=0.008) in univariate analysis. After adjusting for age, TS was associated with CAVI (P=0.006). Conclusion Young women with TS showed increased arterial stiffness measured by CAVI compared to healthy women after adjusting for age, suggesting inherent vasculopathy in TS patients.

Over the last decades, the onset of puberty in girls has occurred earlier, but the tempo of pubertal progression has been relatively slower, resulting in a younger age at puberty onset without a change in age at menarche. Sufficient energy availability and adiposity contribute to early pubertal development, and environmental factors, such as endocrine-disrupting chemicals (EDCs), may affect not only the control of energy balance, but also puberty and reproduction. EDCs are hormonally active substances that can perturb puberty by acting both peripherally on target organs, such as adipose tissue or adrenal glands, and/or centrally on the hypothalamic-pituitary-gonadal (HPG) axis. Depending on whether the exposure takes place earlier during fetal and neonatal life or later during early childhood, EDCs can lead to different outcomes through different mechanisms. Evidence of associations between exposures to EDCs and altered pubertal timing makes it reasonable to support their relationship. However, human epidemiologic data are limited or inconsistent and cannot provide sufficient evidence for a causal relationship between EDC exposure and changes in pubertal timing. Further investigation is warranted to determine the overall or different effects of EDCs exposure during prenatal or childhood windows on pubertal milestones and to reveal the underlying mechanisms, including epigenetic marks, whereby early-life exposure to EDCs affect the HPG-peripheral tissue axis.

Accurate investigations of adrenal hormone levels play a vital role in pediatric endocrinology for the detection of steroid-related disorders. In this study, we developed and validated a simultaneous assay for eight serum steroids, i.e., DHEA, androstenedione, testosterone, progesterone, 17‑hydroxyprogesterone, DHEA‑sulfate, pregnenolone‑sulfate and cholesterol-sulfate, using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Serum samples were prepared by liquid-liquid extraction with methyl t‑butyl ether. Quantitation by LC-MS/MS was performed in multiple reaction monitoring mode with an electrospray ionization source. The run time was 10 min. Analytical performance was evaluated, including imprecision, linearity, ion suppression, carry over and detection capabilities. Serum specimens from 59 children and 120 adults were analyzed to compare the distribution of steroid levels between the groups. All hormones were effectively extracted and separated using our method. The method was essentially free from potential interference and ion suppression. Within-run and between-run imprecision values were20%. The lower limits of quantification varied from 0.025 to 10 ng/mL. The results were generally good and correlated with those obtained using immunoassay techniques. We developed the HPLC-MS/MS method for the simultaneous measurement of free and sulfated steroid hormones. The performance of the developed method was generally acceptable. Thus, this method may provide a novel approach to steroid profiling in children of age before adrenarche.

Background Pyrethroid pesticides are reported to be the most commonly used residential insecticides worldwide. We aimed to investigate the relationship between prenatal and postnatal 3-phenoxybenzoic acid (3-PBA) concentrations, and growth and adiposity parameters in 4-year-old children. Method We obtained data from 578 children who participated in the prospective Environment and Development of Children (EDC) study at around 4 years of age (45–55 months) between August 2008 and July 2011. Anthropometric measurements were obtained at age 4 years. Prenatal and postnatal urinary 3-PBA concentration was measured in maternal urine samples at around 20 weeks of gestation, and in the 4-year-old children, respectively. Result The detection frequency of urinary 3-PBA (geometric mean concentration) was 98–99% (0.98 μg/g Cr) in maternal urine, and almost 99–100% (1.34 μg/g Cr) in 4-year-old children. Prenatal urinary3-PBA concentration was not associated with height, weight, or body mass index (BMI) z-scores at 4 years of age, regardless of sex. Postnatal urinary3-PBA concentration was not related to height z-scores, but was positively associated with weight z-scores with marginal significance among only girls (p = 0.058). Analyzed by sex, there was a significant relationship between postnatal urinary 3-PBA concentration and BMI z-scores (p = 0.015) among girls, after adjusting for covariates. Conclusion Childhood urinary 3-PBA concentration measured at 4 years of age was positively associated with BMI z-scores in 4-year-old girls, but prenatal urinary 3-PBA concentration at midterm pregnancy exhibited no association.

The pathogenic free-living amoeba Naegleria fowleri causes primary amoebic meningoencephalitis, a fatal infection, by penetrating the nasal mucosa and migrating to the brain via the olfactory nerves. N. fowleri can induce host cell death via lytic necrosis. Similar to phosphorylation, O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is involved in various cell-signaling processes, including apoptosis and proliferation, with O-GlcNAc addition and removal regulated by O-GlcNAc transferase and O-GlcNAcase (OGA), respectively. However, the detailed mechanism of host cell death induced by N. fowleri is unknown. In this study, we investigated whether N. fowleri can induce the modulation of O-GlcNAcylated proteins during cell death in Jurkat T cells. Co-incubation with live N. fowleri trophozoites increased DNA fragmentation. In addition, incubation with N. fowleri induced a dramatic reduction in O-GlcNAcylated protein levels in 30 min. Moreover, pretreatment of Jurkat T cells with the OGA inhibitor PUGNAc prevented N. fowleri–induced O-deGlcNAcylation and DNA fragmentation. These results suggest that O-deGlcNAcylation is an important signaling process that occurs during Jurkat T cell death induced by N. fowleri.

We evaluated trajectories of glycated hemoglobin (HbA1c) levels and body mass index z-scores (BMIz) for 5 years after diagnosis among Korean children and adolescents with type 1 diabetes (T1D) or type 2 diabetes (T2D) using the common data model. From the de-identified database of three hospitals, 889 patients p p p

Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels as well as leptin protein levels in whole bloods of 12 obese and 24 normal children aged 6 years. miR-328-3p, miR-1301-3p, miR-4685-3p, and miR-6803-3p were negatively associated with all obesity indicators. The four miRNAs were also associated with 3948 mRNAs, and separate 475 mRNAs (185 among 3948 mRNAs) were associated with all obesity indicators. The 2533 mRNAs (64.2%) among the 3948 mRNAs and 286 mRNAs (60.2%) among the 475 mRNAs were confirmed as targets of the four miRNAs in public databases through miRWalk 2.0. Leptin protein was associated with miR-6803-3p negatively and all obesity indicators positively. Using DAVID bioinformatics resources 6.8, top three pathways for obesity-related gene set were metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway. The top three obesity-related disease classes were metabolic, cardiovascular, and chemdependency. Our results support that childhood obesity could be developed through miRNAs-related epigenetic mechanism and, further, these obesity-related epigenetic changes could control the pathways related with the development of various diseases.

Prematurity, size at birth, and postnatal growth are important factors that determine cardiometabolic and neurodevelopmental outcomes later in life. In the present study, we aimed to investigate the associations between the size at birth and growth velocity after birth with cardiometabolic and neurodevelopmental outcomes in preterm infants. Fifty-six preterm infants born at p = 0.036) and perceptional reasoning index (β = 0.456, p = 0.003) of K-WISC-IV were positively correlated with postnatal weight gain in the neonatal intensive care unit. Although cardiometabolic outcomes were comparable in preterm SGA and AGA infants, the growth velocity at different time periods resulted in different cardiometabolic and neurocognitive outcomes. Thus, ensuring an optimal growth velocity at early neonatal period could promote good neurocognitive outcomes, while adequate growth after 1 year could prevent adverse cardiometabolic outcomes in preterm infants.

BACKGROUND: Phthalates are synthetic chemicals with endocrine-disrupting properties. They are reportedly associated with various neurotoxic outcomes. Studies on exposure to phthalates and children's autistic traits have shown inconsistent results with respect to sex and susceptible time periods. We investigated the association of phthalate exposure during the prenatal period and childhood with autistic traits over time using a birth cohort in South Korea.METHODS: Five phthalate metabolites were measured during mid-term pregnancy and children's follow-up at ages of 4, 6, and 8 years among a total of 547 mother-child pairs. The social communication questionnaire (SCQ) was used to assess autistic traits of children at each time point. The relationship between phthalate metabolites and SCQ scores were analyzed by exposure windows and sex.RESULTS: A 2.7 fold increase in di-(2-ethylhexyl) phthalate metabolite levels, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) during pregnancy was associated with increased SCQ scores at 4 years by 8.5% (95% confidence intervals [CI]: 1.9%, 15.5%) and 7.4% (95% CI: 0.3%, 15.0%), respectively, but not at the age of 6 or 8 years. Moreover, MEHHP levels at ages of 4 and 8 years were associated with increased SCQ scores at 8 years by 9.9% (95% CI: 1.8%, 18.6%) and 9.6% (95% CI: 1.3%, 18.6%), respectively. Boys showed stronger associations between phthalate exposure and SCQ scores than girls.CONCLUSION: The study suggested different susceptible time windows of phthalate exposure: exposure during pregnancy is associated with autistic traits in young children, whereas exposure during early childhood years leads to autistic traits in school-aged children, particularly boys.

Epigenetics is known to be involved in regulatory pathways through which greenness exposure influences child development and health. We aimed to investigate the associations between residential surrounding greenness and DNA methylation changes in children, and further assessed the association between DNA methylation and children’s intelligence quotient (IQ) in a prospective cohort study. We identified cytosine-guanine dinucleotide sites (CpGs) associated with cognitive abilities from epigenome- and genome-wide association studies through a systematic literature review for candidate gene analysis. We estimated the residential surrounding greenness at age 2 using a geographic information system. DNA methylation was analyzed from whole blood using the HumanMethylationEPIC array in 59 children at age 2. We analyzed the association between greenness exposure and DNA methylation at age 2 at the selected CpGs using multivariable linear regression. We further investigated the relationship between DNA methylation and children’s IQ. We identified 8743 CpGs associated with cognitive ability based on the literature review. Among these CpGs, we found that 25 CpGs were significantly associated with greenness exposure at age 2, including cg26269038 (Bonferroni-corrected p ≤ 0.05) located in the body of SLC6A3, which encodes a dopamine transporter. DNA methylation at cg26269038 at age 2 was significantly associated with children’s performance IQ at age 6. Exposure to surrounding greenness was associated with cognitive ability-related DNA methylation changes, which was also associated with children’s IQ. Further studies are warranted to clarify the epigenetic pathways linking greenness exposure and neurocognitive function.

BACKGROUND: Humans are exposed to a mixture of metals during their lifetime; however, evidence of neurotoxicity of such mixtures in critical time windows is still insufficient. We aimed to elucidate the associations of four metals mixture across multiple time points with children's intelligence quotient (IQ) in a prospective cohort study.METHODS: Prenatal exposure and exposure at age 4 and 6 years to four types of blood metals, namely lead, mercury, cadmium, and manganese were quantified in 502 pregnant women and their children who participated in the Environment and Development Cohort study. Children' s IQ scores were assessed using the Wechsler Intelligence Scale at age 6. Bayesian kernel machine regression (BKMR), quantile g-computation models, and elastic net (ENET) models were used to assess the associations of their blood metals mixture with IQ scores.RESULTS: Multivariate linear regression models indicated that postnatal blood manganese exposure at the age of 4 years was significantly negatively associated with children's IQ [β = - 5.99, 95% confidence interval (CI): -11.37 to - 0.61]. In the multi-chemical BKMR and quantile g-computation model, statistically significant inverse associations were found between the mixture of prenatal and postnatal metals and children's IQ score (Difference in children' IQ per quartile increase: -2.83; 95% CI: -5.28, -0.38). Interestingly, we found that manganese levels at both age of 4 and 6 years were contributing factors to children's IQ in the mixture models, namely, BKMR, quantile g-computation, and ENET models.CONCLUSIONS: Multi-pollutant mixtures of prenatal and postnatal exposures to four metals affected child IQ at 6 years of age. We found a relationship between manganese exposure at both age 4, and 6 years and children's IQ. Additional studies are warranted to confirm these associations and to control the exposure to different metals during pregnancy and preschool childhood.

Background: Adverse metabolic outcomes later in life have been reported among children or young adults who were born small for gestational age. This study was conducted to examine the impact of preterm birth and subsequent growth after hospital discharge on cardiometabolic risks among early school-aged children. Methods: This case-control study included school-aged children born prematurely (n = 60) and at term (n = 110). Body size, fat mass, blood pressure (BP), glucose, insulin, leptin, adiponectin, and lipid profiles were measured. Weight z-score changes between discharge and early school-age period were also calculated, and factors associated with BP and insulin resistance were analyzed.Results: Early school-aged children who were born preterm had lower fat masses, higher systolic BP and diastolic BP, and higher values of fasting glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), compared to children born at term. Preterm birth was correlated with HOMA-IR and BPs after adjusting for various factors, including fat mass index and weight z-score changes. Weight z-score changes were associated with HOMA-IR, but not with BPs. Conclusions: Although early school-aged children born prematurely showed lower weight and fat mass, they had higher BPs, fasting glucose, HOMA-IR, and leptin levels. The associations of preterm birth with cardiometabolic factors were independent of weight, fat mass and weight gain velocity.