bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health-Related Quality of Life in Cushing Disease: Discrepancy Between Parent and Child Reports
Authors: Keil Margaret F , Leahu Adela , Stratakis Constantine A 
Published: May 2021

Abstract
Background: Previously we reported impairment in quality of life (QoL) measures in children with Cushing disease (CD) by parent proxy; however, little is known about QoL measures from the affected child’s perspective. Method: Prospective study of 48 (26 females, Age:11.5±3.0 yr.) children diagnosed with CD. Prior to treatment, the Child Health Questionnaire (CHQ) was used to assess QoL by parent (proxy) and child report. Results: In children with active CD, there was a discrepancy between parent and child responses for mental health and self-esteem subscales. Child responses were significantly lower than parent responses (lower scores indicate poorer function) for mental health (56 ± 2 vs. 67 ± 2, p&lt0.001) and self-esteem (32.8 ±3 vs. 60.5 ±3, p&lt0.001). No significant differences were found between parent vs.child report for other subscale scores of the CHQ. Conclusion: This is the first study to compare child vs. parent report of health-related quality of life children with active CD. Parent reports underestimated the impact of CD on quality of life measures for mental health and self-esteem. It is important for clinicians to obtain information about health-related quality of life from the child’s perspective in order to guide management and take precautionary measures to alleviate negative outcomes.
Prevalence and Risk Factors of Hypothalamic-Pituitary Dysfunction in Infant and Toddler Brain Tumor Survivors
Authors: Lebbink Chantal A , Ringers Tiara P , Schouten-van Meeteren Antoinette Y N , van Iersel Laura , Clement Sarah C , Boot Annemieke M , Claahsen-van der Grinten Hedi L , Janssens Geert O R , van Vuurden Dannis G , Michiels Erna M , Han K Sen , van Trotsenburg A S Paul , Vandertop W Peter , Kremer Leontien C M , van Santen Hanneke M 
Published: May 2021

Abstract
Background: Childhood brain tumor survivors (CBTS) are at risk for hypothalamic-pituitary (HP) dysfunction, mainly caused by radiation exposure or tumor involvement of the HP-region. The risk for HP dysfunction (HPD) may vary between different age groups due to maturation of the brain and differences in oncologic treatment protocols. The aim of this study was to determine the prevalence and risk factors of HPD in infant (IBTS) and toddler brain tumor survivors (TBTS) compared to older childhood brain tumor survivors (OCBTS).
Patients and Methods: A retrospective analysis in a nationwide cohort of CBTS was performed. Prevalence and risk factors for HPD were compared between IBTS (aged 0-1 years at diagnosis), TBTS (aged 1-3 years at diagnosis) and OCBTS (aged &gt;3-18 years at diagnosis).
Results: In 718 included CBTS, with a median follow-up time of 7.9 years, overall no differences in percentage of HPD were found between the three age groups. Treatment with radiotherapy (RT) (OR 15.41; 95%CI 8.33 to 28.48), suprasellar tumor location (OR 46.62; 95%CI 19.64 to 110.66) and younger age (OR 1.09; 95%CI 1.02 to 1.15) were associated with HP dysfunction. Because IBTS were significantly less often treated with RT, subanalyses were performed for all CBTS not treated with radiation (n=459). In non-irradiated CBTS, IBTS and TBTS were significantly more frequently diagnosed with TSH-, ACTH- and ADH deficiency, compared to ECBTS. IBTS and TBTS showed significantly more weight gain (p&lt;0.0001) and smaller height SDS (p=0.001) during follow-up.
Conclusion: Infant and toddler brain tumor survivors seem to be more vulnerable to develop HP dysfunction than when compared to older children. These results emphasize the importance of special infant and toddlers brain tumor treatment protocols and endocrine surveillance in children treated for a brain tumor at young age.
The Association of Insulin-Like Growth Factor-1 With Bone Mineral Density in Survivors of Childhood Acute Leukemia
Authors: Ahn Moon Bae , Kim Sung Eun , Lee Na Yeong , Kim Seul Ki , Kim Shin Hee , Cho Kyoung Soon , Kyoung Cho Won , Ho Jung Min , Suh Byung-Kyu 
Published: May 2021

Abstract
Background: The purpose of the current study is to investigate bone mineral deficit of children in survivors of childhood acute leukemia and examine the association of insulin-like growth factor-1 (IGF-1) with bone mineral density (BMD) status and the presence of osteoporosis. Methods: In a cross-sectional study of children diagnosed with different types of acute leukemia at age between 6 months and 18 years, serum IGF-1 and IGFBP-3, were assessed in relation to lumbar spine BMD (LSBMD) by using dual-energy x-ray absorptiometry and non-traumatic vertebral fracture by lateral thoracolumbar spine radiographs. Standard deviation scores (SDS) were calculated based on the age- and gender-adjusted population mean. Results: Among 189 children after completion of acute leukemia treatment, 22 (11.6%) children had LSBMD SDS less than -2.0 while 80 (42.3 %) children were diagnosed with osteoporosis. Mean areal BMD and LSBMD SDS of the subjects were 0.862±0.197 g/cm2 and -0.6±1.6, respectively. IGF-1 and IGFBP-3 were lower in children with LSBMD lower than -2.0 (P&lt;0.05) and those with osteoporosis (P&lt;0.05). LSBMD SDS showed linear correlation with serum IGF-1 (P=0.041). Low serum IGF-1 level (OR=0.724, P=0.042) and elder age of leukemia diagnosis (OR=1.089, P=0.023) were suggested risk factor of the occurrence of osteoporosis. Conclusions: Substantial number of survivors from childhood acute leukemia undergo bone mineral deficits, and serum IGF-1 status could be a prognostic factor associated with bone mass acquisition and future occurrence of osteoporosis.
The Impact of Cannabinoid Exposure on Glucocorticoid Receptor Signaling in Neural Stem Cells
Authors: Gill Nikki , Burale Suban , Silswal Neerupma , DeFranco Donald Benedict , Monaghan-Nichols Paula 
Published: May 2021

Abstract
Preterm birth-birth before 37 weeks of pregnancy-can cause many short- and long-term complications in newborns, including respiratory distress syndrome (RDS). RDS results from incomplete lung development and a surfactant deficiency, and it is a major factor of pre-term mortality. Synthetic glucocorticoids (sGCs) such as Betamethasone or Dexamethasone (Beta, Dex) are administered prenatally to women at risk of pre-term birth to prevent preterm complications. While sGCs are known to improve outcome, they also cause alterations in brain development and neural stem cell biology that are associated with long-term neurological defects.
One common recreational drug used during pregnancy is cannabis. Some of the active components of cannabis include cannabinoids, which interact with the endocannabinoid receptor pathway in cells. Cannabinoids have been shown to induce proliferation and differentiation of embryonic neural stem cells (NSCs). We hypothesized that maternal cannabis use activates cannabinoid signaling pathways and leads to changes in glucocorticoid signaling in the developing brain. The purpose of this study was to determine whether cannabis use leads to a better or worse neurological outcome for children born pre-term and treated with sGCs for RDS.
Neural stem cell neurospheres (NSCs) were isolated from the cerebral cortex of mice and treated with Vehicle (ethanol), Dex, cannabinoid receptor agonist WIN-55,212-2 (Win), or a combination WinDex. The transcriptional profile induced by exposure to Vehicle, Dex, and WinDex RNA were analyzed using microarray analyses examining the complete expressed genome. Gene Chip profiles indicated that both glucocorticoids and cannabinoids induce distinct transcriptional responses in E14.5 NSCs. The genes involved in proliferation-including S100a11, Jun, and Bex2-were repressed by Dex whereas WinDex rescued some of these expression profiles. Some genes encoding microRNA that inhibit our top target coding genes implicated in proliferation showed a greater induction by Dex compared to WinDex.
Quantitative Polymerase Chain Reaction (qPCR) was performed to validate our genes of interest, including Adm, which has been shown to induce neural stem cell proliferation and differentiation. The biological impact of Winn on Dex-induced changes in NSC function were examined by in-vitro proliferation and differentiation studies using antibodies to Tuj1 (neurons), GFAP (glia), and CNPase (immature oligodendrocytes). The experiments indicate that Dex increased neuronal and oligodendrocyte differentiation, while WinDex appeared to reverse this phenotype in neurons.
These studies suggest that cannabis use during pregnancy may limit the biological impact sGCs for preterm birth and lead to distinct cellular responses.
The Relationship Between Iodine Status and Thyroid Function in Congenital Hypothyroidism With Eutopic Thyroid Gland
Authors: Lee Yun Jeong , Heo You Joung , Choe Yunsoo , Park Sang Hee , Ko Jung Min , Shin Choong Ho , Lee Young Ah 
Published: May 2021

Abstract
Background: We investigated the relationship between iodine status and thyroid function in children with congenital hypothyroidism (CH) with eutopic gland. We also evaluated whether the presence of iodine organification defect (IOD) or pathogenic genetic variants affects the association between iodine status and thyroid function. Methods: A total of 31 children (14 boys) with CH participated in the study, who repeatedly underwent thyroid function test and urine iodine concentration (UIC) without levothyroxine (LT4) medication after 3 years of age (1-5 times per patient). After confirming eutopic gland, IOD was demonstrated by the positive perchlorate discharge test with a discharge rate &gt;10%. Genetic analysis was performed using targeted gene sequencing including 23 genes. Results: We identified likely pathogenic or pathogenic variants in 14 cases (45.2%): 1 case with triallelic (digenic) variants (DUOX2 and TSHR), 4 cases with biallelic variants (3 DUOX2 and 1 TSHR), and 9 cases with monoallelic variants (7 DUOX2, 1 DUOXA2, and 1 TSHR). Among 26 cases treated with LT4 from neonatal period, thyroid function after LT4 discontinuation was euthyroid (n = 7), subclinically hypothyroid (n=15), and overtly hypothyroid requiring LT4 (n = 3). The other 5 cases without LT4 treatment remained subclinical hypothyroid. After excluding 2 cases with TSHR, 29 cases (with 72 samples) were included to analyze the relationship between iodine status and log-transformed TSH (log-TSH) using generalized estimating equation models. The positive IOD (n = 17) was not associated with presence of DUOX2/DUOXA2 variants (n = 12). Iodine status of urine samples was categorized into adequate (UIC &lt; 300 μg/L, n = 25), mild excessive (UIC = 300-599 μg/L, n = 14), and severe excessive (UIC ≥ 600 μg/L, n = 33) groups. When stratified by the presence of IOD, log-TSH significantly increased in severe excessive group (β = 0.52, P = 0.014 vs. iodine adequate group) among negative IOD group, but rather decreased in mild excessive group (β = -0.84, P &lt; 0.001 vs. iodine adequate group) among positive IOD group. Meanwhile, when stratified by the presence of DUOX2/DUOXA2 variants, no significant association was found between iodine status and log-TSH levels. Conclusion:DUOX2 mutation was most common in CH patients with eutopic gland. The relationship of iodine status with thyroid function differed by presence of IOD.
Growth Plate Genes Are Key Regulators of Growth: Lessons Learned From Children of Consanguineous Families From Kurdistan, Iraq
Authors: Amaratunga Shenali Anne , Tayeb Tara Hussein , Dusatkova Petra , Elblova Lenka , Pruhova Stepanka , Lebl Jan 
Published: May 2021

Abstract
Introduction: The genetic basis of human growth regulation has only been partly elucidated thus far. Therefore, finding causative genes in patients with short stature help in understanding precise pathophysiological mechanisms, establishing genotype-phenotype relationships and optimizing treatment. In order to extend our knowledge about the genes involved in short stature, we studied a unique cohort of consanguineous families with children with short stature from Sulaymani in Kurdistan, Iraq. Patients and Methods: Fifty-five consanguineous families, with children shorter than -2.3SDS at the time of examination (median height -3.3SDS, range -2.3 to -15SDS), who were examined at the endocrine outpatient clinic of the Department of Pediatrics, Sulaymani University College of Medicine between January 2018 and February 2020, were included in the study. In families with more than one child with short stature, the shorter sibling was selected as the proband (median age 8 years, range 1 - 15 years). Three probands were subsequently excluded due to the diagnosis of Turner’s syndrome and Edward’s syndrome Consent was obtained from all families and probands’ DNA was analyzed by Whole Exome Sequencing (WES) methods. The data were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Selected potentially pathogenic variants were confirmed using Sanger sequencing methods and evaluated by the American College of Medical Genetics (ACMG) standards and guidelines. Results: A monogenic cause of short stature, which explained the patient phenotype, was elucidated in 13 of 26 families who were analyzed thus far. Seven families had multiple affected children making a total of 22 patients with a positive genetic diagnosis. Pathogenic or likely pathogenic variants (according to the ACMG standards) were found in genes involved in the GH-IGF-1 axis (GHR), in the extracellular matrix of the growth plate (COL1A2, MMP13, LTBP3, and ADAMTS17), in the regulation of chondrocytes (NPR2 and CTSK), transporter coding genes (SLC34A3), and other genes (PTCH1, GALNS, DNACJ21, ZSWIM6, GNPTG). Among them, there are 9 novel variants and 10 homozygous variants including variants in genes causing syndromic short stature. Unexpectedly, we successfully identified three cases of autosomal dominant short stature (variants in genes NPR2, COL1A2, PTCH1) as well. The remaining probands from 26 families are still being analyzed. Conclusion: With the help of NGS methods, we have successfully elucidated the genetic cause of short stature in nearly 50% of patients who were analyzed thus far. These results further strength the concept that genes affecting the growth plate (chondrocytes and the extracellular matrix) play a crucial role in growth regulation. Acknowledgements: The study was co-funded by grants AZV 18-07-00283 and GAUK 340420.
11-oxyandrogen Concentrations in Adolescents With Polycystic Ovary Syndrome (PCOS)
Authors: Taylor Anya , Ware Meredith A , Breslow Emily , Pyle Laura , Severn Cameron , Chan Christine L , Kelsey Megan Moriarty , Cree-Green Melanie 
Published: May 2021

Abstract
PCOS is common in adolescents and includes excess testosterone concentrations. The clinical importance of 11-oxyandrogens in PCOS is unclear. We sought to determine if fasted morning 11-oxyandrogens: 1) better identify PCOS diagnosis compared to testosterone, 2) relate to clinical comorbidities of PCOS, 3) are altered with combined oral contraceptive pill (COCP) or metformin therapy. Data from 186 adolescent females aged 12-21 years, mostly obese, enrolled in one of 6 studies in our division were included: 115 untreated PCOS (13 lean, BMI 22.5±2.2 kg/m2; 102 overweight/obese, BMI 35.4±5.3), 9 obese PCOS treated with COCP (BMI 33.7±5.7), 6 obese PCOS treated with metformin (BMI 36.4±5.3) and 70 normally cycling controls (19 lean, BMI 19.9±1.4; 52 overweight/obese BMI 35.5±10.4). Three 11-oxyandrogens (11-hydroxyandrostenedione (11OHA), 11-hydroxytestosterone (11OHT), and 11-ketotestosterone (11KT) and total testosterone were analyzed via liquid chromatography tandem mass spectroscopy (LabCorp/Esoterix, Calabasas, CA). Data between 1) untreated PCOS and controls and 2) untreated PCOS and the 2 treatment groups were compared. ROC analysis was performed to evaluate accuracy of diagnosis of PCOS and Pearson’s correlation coefficient was calculated for 11-oxyandrogens and clinical measures. Untreated PCOS girls had higher 11OHA (129±77 ng/dL PCOS vs 97±52 control, p=0.003) and 11OHT (13.8±7.9 ng/dL PCOS vs 10.5±6.7 control, p=0.005) compared to controls, with no difference in 11KT (30.7±17.3 ng/dL PCOS vs 26.6±16.6 control, p=0.208). Only 11OHA remained significant after controlling for obesity via multiple linear regression. However, neither of these metabolites better predicted PCOS status compared to testosterone (ROC analysis: 11OHA AUC=0.620, p=0.006; 11OHT AUC=0.638, p=0.002; total testosterone AUC=0.840, p&lt;0.001, free androgen index AUC 0.860, p&lt;0.001). Among girls with PCOS, all three 11-oxyandrogens correlated with hirsutism severity as graded by Ferriman Gallwey score. COCP treatment decreased 11KT concentrations compared to untreated PCOS (32±17 untreated vs 17±8 ng/dL COCP; p=0.039) as well as total testosterone (46.9±21 untreated vs 28.1±12.9 ng/dL COCP; p&lt;0.006). However, metformin treatment had no effect 11-oxyandrogens, although total testosterone was lower (46.9±21 untreated vs 26.5±5.9 metformin; p=0.01). Whereas 11-oxyandrogens would not aid in the diagnosis of PCOS, they relate to excess hair growth and 11KT decreases with COCP therapy. Further work is needed to determine the relationship with metabolic outcomes and the clinical utility of measuring these androgens in PCOS.
MRNA Expression of Adipocytokines and Glucose Transporter Type 4 (GLUT4) in Adipose Tissue in Women With and Without Polycystic Ovary Syndrome
Authors: Ozga Katarzyna Maria , Sendrakowska Magdalena Krzyczkowska , Milewicz Tomasz , Sanak Marek , Jach Robert 
Published: May 2021

Abstract
Background: The main feature of polycystic ovary syndrome (PCOS) is hyperandrogenism, adipocytes hypertrophy and chronic low-grade inflammation. It is known that PCOS is closely linked to functional dysfunction in adipose tissue, which in turn are connected with metabolic disturbances such as insulin resistance. However, there is no complete characterization of the adipose tissue in women with PCOS. Aim: To compare the expression of adipocytokines between women with and without PCOS. Materials and Methods: The total number of twenty two participants were enrolled into the study. Study group included ten women with PCOS diagnosed according to the Rotterdam criteria, the control group- twelve women without PCOS. Approximately 3 g of tissue was excised from subcutaneous adipose tissue through a small incision in the suprapubic area. mRNA was isolated and gene expression profiling was performed including following genes: GLUT4, irisin, leptin, omentin, vaspin, adiponectin, visfastin, apelin, serum amyloid A1 and chemerin. Blood samples were taken between 3rd and 5th day of the menstrual cycle to evaluate serum hormonal levels. The oral glucose tolerance test (OGTT) was done simultaneously with the assessment of glucose and insulin plasma levels at 0, 60 and 120 minute. Results: Patients with PCOS presents different mRNA expression of adipocytokines compared with control group. There were statistically significant differences in irisin, leptin, omentin, visfastin, chemerin and serum amyloid A1 expression, that were higher in PCOS. GLUT-4 and adiponectin expression was significantly lower in PCOS patient compared to control. Due to an insufficient measurement of apelin and vaspin gene expression there were not included in following analysis. Conclusions: mRNA expression of adipocytokines in adipose tissue in women with and without polycystic ovary syndrome is different. In women with PCOS, there is a higher expression of genes for most of adipocytokines with lower for adiponectin and GLUT-4.
Obesity Induces Elevated Oxidative Stress in Uteri of Reproductive Age Mice
Authors: Huang Jane , Xiao Emily , Tal Aya , Kelly Kate Corbett , Kim Jung Dae , Whirledge Shannon Deanne , Flannery Clare Ann 
Published: May 2021

Abstract
Obesity is an independent risk factor for endometrial cancer. We hypothesize that obesity changes endometrial physiology, increasing cellular vulnerability to cancer development. We previously found widespread increases in cytochrome P450 (CYP) expression in the uteri of diet-induced obese mice. CYP enzymatic activity is associated with oxidative stress and altered intracellular estrogen metabolism, which increases the potential for oncogenesis. To assess oxidative stress and related DNA damage in uterine tissue, we measured protein carbonyl (PC) and 8-oxo-2’-deoxyguanosine (8-OHdG) levels, respectively, in obese and lean mice.
Post-pubertal C57BL/6 female mice were fed high-fat chow (HF; 45% fat; n=20) or normal chow (NC; 18% calories from fat; n=10) for either 10 or 22 weeks. The mice underwent insulin tolerance testing and MRI for body composition. Vaginal smears were analyzed over 10 days for estrous cycling (n=5 per group). PC and 8-OHdG levels were quantified from uterine tissue lysates and DNA fractions using colorimetric ELISAs and analyzed by 2-tailed t-tests.
The HF mice had 64% higher body fat than NC mice after 10 weeks of diet (24±2% vs. 15±1%; p&lt;0.003) and 176% higher body fat after 22 weeks of diet (35±2% vs. 13±2%; p&lt;0.0001). Additionally, compared to NC mice, insulin levels in HF mice were 1.6-fold higher after 10 weeks (0.89±0.05 vs. 0.55±0.03 ng/mL; p&lt;0.0008) and 2.8-fold higher after 22 weeks (3.56±0.49 vs. 1.28±0.21 ng/mL; p&lt;0.005). Estrous cycle analysis showed obesity-related disruptions by 22 weeks, with HF mice spending 30±3% of their time in the proestrus phase versus 18±2% in NC mice (p&lt;0.03). After 10 weeks of diet, HF and NC mice had similar levels of PC (p=NS). By 22 weeks of diet, however, the HF mice had a 2.3-fold increase in PC compared to the NC mice (1.11±0.2 vs. 0.49±0.09 nmol/mg; p&lt;0.02). While HF and NC mice had similar levels of 8-OHdG for each diet group (p=NS, respectively), 8-OHdG levels increased with age between 10 and 22 weeks of diet in both HF (7.51±1.25 vs. 12.41±1.87 ng/mL; p&lt;0.03) and NC (6.87±1.28 vs. 15.16±2.88 ng/mL; p&lt;0.01) mice.
We show that the uteri of reproductive age mice are altered by chronic diet-induced obesity and hyperinsulinemia. Uterine oxidative stress was higher with increased duration and severity of obesity, and may also be affected by the disrupted HPO axis. In contrast, obesity did not appear to promote DNA damage, suggesting that DNA repair mechanisms remain intact under conditions of increased oxidative stress. The age-dependent increase in 8-OHdG levels demonstrates an expected accumulation of DNA damage over time, which reinforces C57BL/6 mice as an adequate model for human endometrial disease. In sum, this study suggests that chronic high-fat consumption and long-term obesity increase oxidative stress over time and may contribute to the development of a pre-cancerous phenotype in human endometrium.