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Refractory hypothyroidism (RF) defined as raised serum levels of thyroid stimulating hormone (TSH) above upper limit of the reference range with or without the persistence of hypothyroid symptoms following a 6-week interval after the dosage was last increased to upper limits of dose per age. The most common cause of RH is inadequate compliance. In addition, diet, concomitant medication interactions, and gastrointestinal diseases can all result in l-thyroxine (LT4) malabsorption, which can cause RH. Moreover, weight gain, switching brands of LT4, poor storage of LT4, chronic liver disorders, cystic fibrosis, nephrotic syndrome, consumptive hypothyroidism, Addison's disease are significant contributors to RF in children. RH in children is frequently asymptomatic, when symptoms do occur, they are typically minor and resemble those of hypothyroidism. It is essential to identify RH early and treat its underlying cause in order to avoid overusing LT4, which can lead to cardiac and bone problems. Endocrinologists should handle children who they suspect of having RH methodically after making sure there is enough compliance. Searching for undiagnosed illnesses and/or other factors that can affect LT4 absorption could be part of this. We present this review after an extensive literature search and long-standing clinical experience. This review's objective is to shed light on the causes, clinical manifestations, investigations, and treatment of RH in children., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Idiopathic ketotic hypoglycemia (IKH) is defined as bouts of hypoglycemia with increased blood or urine ketones in certain children after prolonged fasting or during illness. IKH is divided into physiological IKH, which is most frequently observed in normal children with intercurrent acute illness, and pathological IKH, which occurs in children who lack counter-regulatory hormones, have a metabolic disease, or have Silver-Russell syndrome. The typical patient is a young child between the ages of 10 months and 6 years. Episodes nearly always occur in the morning after overnight fasting. Symptoms include those of neuroglycopenia, ketosis, or both. IKH may be diagnosed after ruling out various metabolic and hormonal conditions associated with ketotic hypoglycemia. Sufficient amounts of carbohydrates and protein, avoidance of prolonged fasting, and increased frequency of food ingestion are the main modes of treating IKH. It is crucial to understand the pathogenesis of IKH and to distinguish physiological IKH from pathological IKH. In this mini-review, we present a brief summary of IKH in terms of its definition, types, clinical presentation, diagnosis, and therapeutic approach in children.

Gynecomastia (GM) is a common and continuously evolving condition that commonly occurs during adolescence. It is the source of significant embarrassment and psychological stress in adolescent males. GM is characterized by enlargement of the male breast due to the proliferation of glandular ducts and stromal components. The main cause of GM during adolescence is physiological or pubertal GM, which is primarily attributed to an imbalance between estrogen and androgen activity. Physiological GM is typically transient and resolves within several months, although it may take several years to resolve. GM may also be caused by other pathological conditions and could be indicative of an endocrine disease. It is crucial to understand the pathogenesis of GM to distinguish it from normal developmental variants due to pathological causes. The aim of this review is to highlight the significance of GM during adolescence in terms of potential etiologies, clinical and laboratory diagnoses, and current management.

The most frequent cause of hyperthyroidism in children is Graves' disease (GD). Vascular endothelium is a specific target of thyroid hormone. The purpose of this study is to assess flow-mediated dilatation (FMD)% and serum von Willebrand factor (vWF) levels in children with newly diagnosed GD to reflect the extent of endothelial dysfunction in those children. In this study, 40 children with newly discovered GD and 40 children who were healthy served as the control group. Both patients and controls had anthropometric assessment, as well as measurements of fasting lipids, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), TSH, and free thyroxine (FT4 and FT3), thyrotropin receptor antibodies TRAbs and vWF. Noninvasive ultrasound was utilized to quantify the carotid arteries' intima-media thickness and the brachial artery's FMD. Patients reported significantly reduced FMD response and greater vWF and hs-CRP levels compared to controls (P = 0.001 for each). In multivariate analysis, we reported that vWF was significantly correlated with TSH (OR 2.5, 95% CI 1.32-5.32, P = 0.001), FT3 (OR 3.4, 95% CI 1.45-3.55, P = 0.001), TRAb (OR 2.1, 95% CI 1.16-2.23, P = 0.01), and FMD% (OR 4.2, 95% CI 1.18-8.23, P = 0.001).  Conclusions: Children with newly diagnosed GD have endothelial dysfunction, which is shown by impaired FMD and increased vWF. These findings support the idea that GD may need to be treated as soon as possible. What is Known: • Graves' disease is the most common cause of hyperthyroidism in children. • vWF is a reliable marker for detection of vascular endothelial dysfunction. What is New: • Children with newly diagnosed Graves' disease may have endothelial dysfunction as reflected by impairment of FMD and raised vWF level. • Measurement of vWF level in children with newly diagnosed Graves' disease can be used for early detection of endothelial dysfunction., (© 2023. The Author(s).)

Graves' disease (GD) is the most common cause of hyperthyroidism in children. A common GD symptom is a goiter. The usual biochemical profile in children with GD is a decreased thyroid hormone stimulating hormone (TSH) level and high free thyroxine (FT4) and free triiodothyronine (FT3) concentrations. The presence of thyroid receptor antibodies (TRAb) is the most important specific immunological sign for diagnosing GD. The treatment choices for pediatric GD are anti-thyroid drugs (ATDs), radioiodine, and thyroidectomy, but the risks and benefits of each modality are different. Management recommendations include the first-line use of a prolonged course of ATDs for at least 3 years and potentially 5 years or more. Rituximab and Teprotumumab are new novel alternative medications for the treatment of adult patients with GD and Graves' orbitopathy respectively, but evidence of the efficacy and safety of these drugs in pediatric patients with GD is lacking., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Objective: To assess serum anti-Müllerian hormone (AMH) levels as an ovarian reserve marker in adolescent girls with autoimmune thyroiditis (AIT) and explore the relationship of this marker with autoimmunity and thyroid function biomarkers., Subjects and Methods: This study included 96 adolescent girls with newly diagnosed AIT and 96 healthy, age- and sex-matched controls. All participants were evaluated with detailed history taking and physical examination, thyroid ultrasound, and measurement of levels of thyroid-stimulating hormone (TSH), free thyroxin (FT4), free triiodothyronine (FT3), antithyroid peroxidase antibodies (TPOAb), antithyroglobulin antibody (TGAb), estradiol, total testosterone, and anti-Müllerian hormone (AMH) levels. The LH/FSH ratio was also calculated. Among 96 patients evaluated, 78 were overtly hypothyroid and 18 were euthyroid. AMH levels were significantly lower in participants with overt hypothyroidism and euthyroidism compared with controls., Results: Serum levels of AMH correlated negatively with age, body mass index (BMI) standard deviation score (SDS), and TPOAb, TGAb, and TSH levels but positively with FT4 levels. In multivariate analysis, AMH levels correlated significantly with age (odds ratio [OR] = 1.65, 95% confidence interval [CI] 1.18-2.32, p = 0.05), BMI SDS (OR = 2.3, 95% CI, 2.23-3.50, p = 0.01), TSH (OR = 2.43, 95% CI 1.5-2.8, p = 0.01), and TPOAb (OR = 4.1, 95% CI 3.26-8.75, p = 0.001)., Conclusion: Ovarian reserve of adolescent girls with AIT, as measured by serum AMH levels, is affected by thyroid autoimmunity and hypothyroidism, indicating a possible need for ovarian reserve monitoring in these patients.

Background: Meningitis is one of the most dangerous infection affecting children. The need for rapid and accurate diagnosis is mandatory for improving the outcome., Aim of the Work: To evaluate the role of multiplex polymerase chain reaction (PCR) in diagnosis of meningitis either bacterial or viral and to detect its accuracy., Patients and Methods: A cross-sectional study was carried out in University Children Hospital, Faculty of Medicine, between November 2019 and September 2020. The study was approved by the Ethics Review Board of Faculty of Medicine, Assiut University, and informed written consent was obtained. The committee's reference number is 17200161. Clinicaltrails.gov ID: NCT03387969. Forty-eight children aged 2 to 18 years with meningitis were included. Detailed history and examination, blood glucose level at time of admission prior to lumbar puncture, and multiplex PCR in cerebrospinal fluid (CSF) were evaluated., Results: The mean age of children was 3.27 ± 1.27 years. Thirty-five (72.9%) cases were bacterial meningitis while 13 (27.1%) cases were viral meningitis. Multiplex PCR had 94% sensitivity and 100% specificity for diagnosis of bacterial meningitis., Conclusion: Multiplex PCR may help in diagnosis and differentiation of bacterial and viral meningitis with accurate and rapid results., (© 2022. The Author(s).)

Subclinical hyperthyroidism (SH) is defined as serum thyroid-stimulating hormone (TSH) below the lower limit of the reference range in the presence of normal free T4 and free T3 levels. Depending on the degree of TSH suppression, SH could be defined as mild (TSH, 0.1-0.45 mU/L) or severe (TSH<0.1 mU/L). Patients with SH are often asymptomatic when symptoms are present, they are similar to the symptoms in patients with overt hyperthyroidism, although they are usually milder. The management of the SH is uncertain and should be individualized. We present this review after an extensive literature search and long-standing clinical experience. This review provides the prevalence, causes, clinical presentation, investigation, and therapeutic approach of SH in children., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Meningitis is one of the most dangerous infection affecting children. The need for rapid and accurate diagnosis is mandatory for improving the outcome., Aim of the Work: to evaluate the role of multiplex polymerase chain reaction (PCR), cerebrospinal fluid (CSF)-C-reactive protein (CRP) and serum procalcitonin (PCT) in diagnosis of meningitis and to detect its accuracy., Patients and Methods: A cross-sectional study was carried out in University Children hospital, Faculty of Medicine, between November 2019 and September 2020. The study was approved by the Ethics Review Board of Faculty of Medicine, Assiut University, and informed written consent was obtained. The committee's reference number is 17200161., Clinicaltrials: gov ID: NCT03387969. 48 Children aged 2 to 18 years with meningitis were included. Detailed history and examination. Blood glucose level at time of admission prior to lumbar puncture, serum CRP level, serum PCT, CSF-CRP level and Multiplex PCR were evaluated., Funding: The study was supported by Grant Office of Faculty of Medicine, Assiut University with grant NO. 2018-01-04-006-R2., Results: The mean age of children was 3.27 plus or minus 1.27 years. 35 (72.9%) cases were bacterial meningitis, while 13 (27.1%) cases were viral meningitis. Patients with bacterial meningitis had significantly higher serum CRP, serum PCT and higher CSF-CRP and significantly lower CSF/blood glucose compared to viral meningitis. Multiplex PCR had 94% sensitivity and 100% specificity for diagnosis of bacterial and viral meningitis., Conclusion: CSF-CRP, CSF/blood glucose, PCT and Multiplex-PCR may help in diagnosis and differentiation of bacterial and viral meningitis.

Down syndrome (DS) is the most common genetic disorder in live-born infants. Children with DS are at increased risk of numerous endocrinal comorbidities. The information contained in this article will provide pediatricians with a narrative overview of different presentations, diagnoses, and management recommendations of various endocrinal disorders in children with DS. We systematically searched PubMed, Embase, Google Scholar, MEDLINE, EBSCO, and Science Direct, and potentially relevant articles were identified and retrieved from electronic and print journals.

Background: Healthy vestibular system adjusts balance during static and dynamic conditions. This is important for normal development (standing up and walking). Vestipulopathies (central and peripheral) are common complications of diabetes in adult population. Related studies are scare in children with type 1 diabetes (T1D)., Aim: To assess saccular function of otolith organ in children with T1D and predictors for its dysfunction., Methods: Cervical vestibular evoked myogenic potential (cVEMP) was used for objective evaluation., Results: The study included 40 patients (boys = 15; girls = 25). Patients had mean age of 13.63 ± 1.50 years, duration of diabetes of 5.62 ± 2.80 years, frequent attacks of diabetic ketoacidosis (55%) and hypoglycemia (30%), hyperlipidemia (20%), hypertension (12.5%) and peripheral neuropathy (40%). Dizziness was found in 10%. Compared to healthy children ( n = 25), patients had prolonged cVEMP P1 and N1 latencies and reduced P1-N1 amplitude. Bilateral cVEMP abnormalities were found in 60% ( vs 25% for unilateral abnormalities). Higher frequencies and severe vestibulopathies were found with chronic diabetes of > 5 years, hemoglobin A1c values > 7%, frequent diabetic ketoacidosis and hypoglycemic attacks and presence of dizziness. Regression analyses showed that predictors for prolonged P1 latencies and reduced P1-N1 amplitudes were only chronic diabetes (> 5 years) {odds ratio (OR) = 2.80 [95% confidence interval (CI): 1.80-5.33], P = 0.01; OR = 3.42 (95%CI: 2.82-6.81)} and its severity (hemoglobin A1c > 7%) [OR = 3.05 (95%CI: 2.55-6.82), P = 0.01; OR = 4.20 (95%CI: 3.55-8.50), P = 0.001]., Conclusion: Dysfunction or injury of the saccular macula and its pathways is prevalent in children with T1D. Optimum glycemic control is important to prevent diabetes related vestipulopathies., Competing Interests: Conflict-of-interest statement: The authors declared no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Nonalcoholic fatty liver disease (NAFLD) is the commonest etiology of chronic hepatic problems in children with obesity. This study aimed to assess whether urinary C-peptide creatinine ratio (UCPCR) might be a potential indicator of NAFLD in obese children., Methods: The study included 240 children with simple obesity. Hepatic ultrasonic examination, anthropometric and laboratory measurements including fasting plasma glucose, fasting insulin, fasting C peptide, liver, renal profile, lipid profile, and UCPCR were obtained in all cases. According to the results of the hepatic ultrasonography, cases were classified into two categories, those with NAFLD (n=98) and without NAFLD (n= 142)., Results: In cases with NAFLD, UCPCR was significantly higher than those without NAFLD (P &lt; 0.001). A significant positive correlation between UCPCR and waist circumference (WC SDS), triglyceride, fasting C-peptide, HOMA-IR and alanine aminotransferase (ALT) was found (P &lt; 0.001 for each). Adjusting for other variables, UCPCR was the most significant predictor of NAFLD in children with obesity with higher odds ratio (OR = 3.26) than fasting C peptide (OR = 2.87), triglyceride (OR = 1.89), ALT (OR = 2.20), WC SDS (OR = 1.32) and age (OR=1.27) . UCPCR cut-off value of 0.755 nmol/mmol was able to discriminate cases with NAFLD from those without NAFLD with a sensitivity of 95%, a specificity of 87%., Conclusions: We concluded that UCPCR is a useful, practical and non-invasive predictor of NAFLD in children with obesity with high sensitivity and specificity.

Objective: This study aimed to assess the role of serum midkine (MK) as a biomarker for early detection of diabetic nephropathy in children with type 1 diabetes mellitus (T1DM) before microalbuminuria emerges., Methods: A total of 120 children with T1DM, comprising 60 microalbuminuric patients (Group 1), 60 normoalbuminuric patients (Group 2), and 60 healthy participants as a control group (Group 3) were included. Detailed medical history, clinical examination, and laboratory assessment of high-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c percentage (HbA1c%), lipid profile, urinary albumin to creatinine ratio (ACR), serum MK and estimated glomerular filtration rate based on serum creatinine were performed in all participants., Results: Both Group 1 and Group 2 had significantly higher serum MK compared to controls (p<0.001). Additionally, significantly higher MK concentrations were present in Group 1 compared with Group 2 (p<0.001). Receiver operating characteristic curve analysis revealed that the MK concentration cutoff value of 1512 pg/mL was able to predict microalbuminuria with a sensitivity of 96% and specificity of 92%. Stepwise regression analysis revealed that HbA1c%, hs-CRP, and ACR were independently related to MK levels (p<0.001 for each)., Conclusion: The results of this study suggest that serum MK is a useful, novel, practical marker for the evaluation of renal involvement in children with T1DM, especially in normoalbuminuric children.

Background and Aims: The normal functioning of Kelch-like ECH-associated protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) complex is necessary for the cellular protection against oxidative stress. We investigated the effect of chlorogenic acid (CGA), quercetin (Qt), coenzyme Q10 (Q10) and silymarin on the expression of Keap1/Nrf2 complex and its downstream target; heme oxygenase-1 (HO-1) as well as inflammation and apoptosis in an acute liver toxicity model induced by thioacetamide (TAA)., Main Methods: Wistar rats were divided into 13 groups: Control, silymarin, CGA, Qt, Q10, TAA (single dose 50 mg/kg, i.p.), TAA + silymarin (400 mg/kg, p.o.), TAA + CGA (100 & 200 mg/kg, p.o.), TAA + Qt (200 &300 mg/kg, p.o.) and TAA+ Q10 (30&50 mg/kg, p.o.) and treated for 8 days., Key Findings: The results showed improved liver functions and hepatic tissue integrity in all tested doses of TAA + silymarin, TAA + CGA, TAA + Qt and TAA + Q10 groups compared to the TAA group. Furthermore, these groups showed significantly lower ROS, malondialdehyde and nitric oxide levels but higher glutathione content and superoxide dismutase activity compared to the TAA group, p < 0.05. In these groups, Keap1 expression was significantly decreased while Nrf2 expression and HO-1 activity were increased. In addition, the number of apoptotic cells and the expression level of TNF-α in the liver tissues were significantly decreased compared to the TAA group., Significance: CGA, Qt, Q10 and silymarin protect against TAA-induced acute liver toxicity via antioxidant, anti-inflammatory, anti-apoptotic activities and regulating Keap1-Nrf2/HO-1 expression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

New EGFR inhibitor series of fifteen 5-chloro-3-hydroxymethyl-indole-2-carboxamide derivatives has been designed, synthesized, and tested for antiproliferative activity against a panel of cancer cell lines. The results showed that p-substituted phenethyl derivatives 10, 11, 13, 15 and 17-19 showed superior antiproliferative activity compared to their m-substituted counterparts 12, 14, 16 and 20. Compounds 15, 16, 19 and 20 displayed promising EGFR inhibitory activity as well as an increase in caspase 3 levels. Compounds 15 and 19 increased caspase-8 and 9 levels, as well as inducing Bax and decreasing Bcl-2 protein levels. Compound 19 demonstrated cell cycle arrest at pre-G1 and G2/M phases. The results of the docking study into the active site of EGFR revealed strong fitting of the new compounds with higher binding affinities compared to erlotinib., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: Patients with congenital adrenal hyperplasia (CAH) are at increased risk of cardiometabolic abnormalities. We aimed to evaluate vascular endothelial dysfunction and its association with serum neopterin (NP) levels in CAH patients., Methods: The study included 40 patients, with a mean age of 14.8 ± 2.6 years; 28 (70%) subjects were females. They were compared with 40 healthy controls matched in anthropometric evaluation and measurement of fasting lipids, glucose, insulin, homeostasis model assessment for insulin resistance [HOMA-IR], and serum NP levels (nmol/L). Vascular ultrasound was used to measure brachial artery flow-mediated dilation (FMD%) and carotid intima-media thickness (CA-IMT). According to the degree of control on medical treatment, patients were classified into poor (n = 12) and good (n = 28) control groups., Results: Compared to controls, CAH patients had lower brachial FMD% (4.60 ± 2.13 versus 9.31 ± 2.29, p = 0.001), similar CA-IMT (0.44 ± 0.08 versus 0.44 ± 0.06, p = nonsignificant) and higher NP (42.6 ± 11.6 versus 9.2 ± 3.8, p = 0.001). However, differences between poor and good control CAH patients were significant regarding FMD%, CA-IMT, and NP measurements. FMD% correlated significantly with NP (r = -0.54, p = 0.001), high-sensitivity CRP (r = -0.53, p = 0.001), HOMA-IR (r = -0.31, p = 0.01), CA-IMT (r = -0.22, p < 0.05), diastolic blood pressure (r = 0.32, p = 0.01) and systolic blood pressure (r = -0.022, p < 0.05). NP was the most significant independent predictor of FMD%, as determined by linear regression analysis (p = 0.001)., Conclusions: Our study showed that CAH patients had endothelial dysfunction, which is an early process of vascular affection. This was significantly associated with NP levels, suggesting a crucial role of inflammation in the pathogenesis of vascular damage. Further studies are needed to confirm our findings and to investigate the exact role of NP, as either protective or proatherothrombotic., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Subclinical hypothyroidism (SH) is defined as serum thyroid-stimulating hormone (TSH) above the upper limit of the reference range in the presence of normal free T4 concentrations. Depending on the degree of TSH elevation, SH could be defined as mild (TSH, 4.5-10 mIU/L) or severe (TSH&gt;10 mIU/L). While there is a general consensus to treat children with serum TSH levels above 10 mU/L, the management of the mild form is uncertain and should be individualized. In this mini-review, we present a brief review of SH in children based on extensive literature review and long-standing clinical experience. This review provides the prevalence, causes, clinical presentation, consequences, investigation, and up-to-date therapeutic approach of SH in children. Generally, the purpose of the review is to provide pediatricians with an update of this common and continuously evolving condition.

Objective: Evaluate ferritin levels in children and adolescents with type 1 diabetes mellitus and its relation to diabetic microvascular complications, and metabolic control., Methods: This study included 180 children and adolescents with type 1 diabetes mellitus (T1DM) with a mean age of 14.9 ± 3.1 years and 180 apparently normal children matched for age and sex (control group). All children were evaluated with full history taking, thorough clinical examination, laboratory assessment of high-sensitivity C-reactive protein and hemoglobin A1c (HbA1c), and evaluation of the presence of microvascular complications. Serum ferritin levels were measured using electrochemiluminescence immunoassay. The patients were divided into two groups according to the presence or absence of microvascular complications., Results: Serum ferritin levels were significantly higher in patients with T1DM in both groups compared with healthy controls (p < 0.001). Additionally, patients with microvascular complications had higher serum ferritin concentrations than those without microvascular complications (p < 0.001). Patients with microalbuminuria showed higher ferritin levels compared with patients without microalbuminuria (p < 0.05). Stepwise regression analysis revealed that levels of HbA1c and urinary albumin excretion were independently related to ferritin levels (p < 0.001 for both). On receiver operating characteristic (ROC) curve analysis, a ferritin cutoff value of 163.6 ng/mL differentiated patients with microvascular complications from those without microvascular complications with a sensitivity of 92.1% and specificity of 93.4%., Conclusion: Serum ferritin levels are elevated in T1DM, particularly in patients with microvascular complications.

Colorectal cancer (CRC) is the third highest major cause of morbidity and mortality worldwide. Hence, many strategies and approaches have been widely developed for cancer treatment. This work prepared and evaluated the antitumor activity of 5-Fluorouracil (5-Fu) loaded chromium nanoparticles (5-FuCrNPs). The green biosynthesis approach using Harpullia (H) pendula aqueous extract was used for CrNPs preparation, which was further loaded with 5-Fu. The prepared NPs were characterized for morphology using scanning and transmission electron microscopes (SEM and TEM). The results revealed the formation of uniform, mono-dispersive, and highly stable CrNPs with a mean size of 23 nm. Encapsulation of 5-Fu over CrNPs, with a higher drug loading efficiency, was successful with a mean size of 29 nm being produced. In addition, Fourier transform infrared (FTIR) and X-ray diffraction pattern (XRD) were also used for the investigation. The drug 5-Fu was adsorbed on the surface of biosynthesized CrNPs in order to overcome its clinical resistance and increase its activity against CRC cells. Box-Behnken Design (BBD) and response surface methodology (RSM) were used to characterize and optimize the formulation factors (5-Fu concentration, CrNP weight, and temperature). Furthermore, the antitumor activity of the prepared 5-FuCrNPs was tested against CRC cells (CACO-2). This in vitro antitumor study demonstrated that 5-Fu-loaded CrNPs markedly decreased the IC50 of 5-Fu and exerted more cytotoxicity at nearly all concentrations than 5-Fu alone. In conclusion, 5-FuCrNPs is a promising drug delivery system for the effective treatment of CRC.

Background: Cyanotic breath-holding spells (CBHS) are self-limited conditions among younger children. Frequent spells cause parents' fear and anxiety. Seizures, brain damage and sudden death have been rarely reported with BHS. Some reported spells' frequency reduction with iron or piracetam. We evaluated the effectiveness of valproic acid (VPA) to treat CBHS and predictors of improvement., Methods: Participants were 90 children with CBHS (≥4/week) (age: 1.6±0.4yrs). They were treated with VPA (5 mg/kg/d). Follow-ups occurred after 3-≥6 months. Autonomic nervous system functions were evaluated., Results: The majority (74.4%) had daily spells and 19% had ≥2 spells/d. Crying or anger provoked spells. Postural hypotension was found in 46.7%. They had normal electroencephalography and QT, QTc interval or QTd or QTcd and heart rate. Compared to controls, postural fall in systolic (>20mmHg) and diastolic (>10mmHg) blood pressures and mean arterial pressure (>10mmHg) were observed in 46.7%, 74.4% and 72.2% and miosis observed with 0.125% pilocarpine in 28.9% (P=0.001). Spells' frequency reduction (P=0.001) occurred within 3 months with VPA. The independent prdictors for spell' frequency reduction were reduction of anger and crying [OR=4.52(95%CI=2.35-6.04), P =0.01]., Conclusion: VPA therapy reduces CBHS' frequency. Mood improvement is a suggestive effective mechanism., Clinical Trial Registration: www.clinicaltrials.gov identifier is NCT04482764.

Recent studies have shown additive and synergistic effects associated with the combination of kinase inhibitors. BRAF V600E and EGFR are attractive targets for many diseases treatments and have been studied extensively. In keeping with our interest in developing anticancer targeting EGFR and BRAF V600E , a novel series of 2,3-dihydropyrazino[1,2-a]indole-1,4-dione has been rationally designed, synthesized and evaluated for their antiproliferative activity against a panel of four human cancer cell lines. Compounds 20-23, 28-31, and 33 showed promising antiproliferative activities. These compounds were further tested for their inhibitory potencies against EGFR and BRAF V600E kinases with erlotinib as a reference drug. Compounds 23 and 33 exhibited equipotency to doxorubicin against the four cell lines and efficiently inhibited both EGFR (IC 50  = 0.08 and 0.09 µM, respectively) and BRAF V600E (IC 50  = 0.1 and 0.29 µM, respectively). In cell cycle study of MCF-7 cell line, compounds 23 and 33 induced apoptosis and exhibited cell cycle arrest in both Pre-G1 and G2/M phases. Molecular docking analyses revealed that the new compounds can fit snugly into the active sites of EGFR, and BRAF V600E kinases. Compound 23, 31 and 33 adopted similar binding orientations and interactions to those of erlotinib and vemurafenib., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Wound-healing is a very complex and evolutionary process that involves a great variety of dynamic steps. Although different pharmaceutical agents have been developed to hasten the wound-healing process, the existing agents are still far from optimal. The present work aimed to prepare and evaluate the wound-healing efficacy of phenytoin-loaded copper nanoparticles (PHT-loaded CuNPs). CuNPs were biosynthesized using licorice aqueous extract. The prepared CuNPs were loaded with PHT by adsorption, characterized, and evaluated for wound-healing efficiency. Results showed that both plain and PHT-loaded CuNPs were monodisperse and exhibited a cubic and hexagonal morphology. The mechanism by which PHT was adsorbed on the surface of CuNPs was best fit by the Langmuir model with a maximum loaded monolayer capacity of 181 mg/g. The kinetic study revealed that the adsorption reaction followed the pseudo-second order while the thermodynamic parameters indicated that the adsorption process was physical in nature and endothermic, and occurred spontaneously. Moreover, the in vivo wound-healing activity of PHT-loaded CuNP impregnated hydroxypropylmethyl cellulose (HPMC) gel was carried out using an excisional wound model in rats. Data showed that PHT-loaded CuNPs accelerated epidermal regeneration and stimulated granulation and tissue formation in treated rats compared to controls. Additionally, quantitative real-time polymerase chain reaction (RT-PCR) analysis showed that lesions treated with PHT-loaded CuNPs were associated with a marked increase in the expression of dermal procollagen type I and a decrease in the expression of the inflammatory JAK3 compared to control samples. In conclusion, PHT-loaded CuNPs are a promising platform for effective and rapid wound-healing.

Objective: Soluble CD40 ligand (sCD40L) is elevated in various autoimmune disorders, which may have diagnostic and therapeutic implications. The aims of the current study were to evaluate serum sCD40L concentrations in children with newly diagnosed Graves’ disease (GD) and to correlate its levels with patients’ clinical and laboratory parameters., Methods: This study included 48 children with newly diagnosed GD and 48 healthy children. Serum thyroid-stimulating hormone (TSH) (TSH, fT4 and fT3), TSH receptor antibodies (TRAbs), high sensitivity C-reactive protein (hsCRP) and sCD40L levels and thyroid volume were measured., Results: Compared to control subjects, children with GD had higher thyroid volume standard deviation scores (SDS) (p=0.001), and higher levels of hsCRP (p=0.001), TRAbs (p=0.001) and sCD40L (p=0.001). Significant correlations were found between sCD40L and age (p=0.01), thyroid volume SDS (p=0.001), hsCRP (p=0.01) and TRAbs (p=0.001). In multivariate analysis, sCD40L concentrations were correlated with TRAbs [odds ratio (OR)=3.1, 95% confidence intervals (CI): 2.2-2.7, p=0.001] and thyroid volume SDS (OR=2.1, 95% CI: 1.2-2.7, p=0.001)., Conclusion: This preliminary study has evidence of high concentrations of sCD40L in children with newly diagnosed GD and a correlation between sCD40L and both TRAbs and thyroid volume, which may indicate a biologically active role for sCD40L in the pathogenesis of GD.

This study evaluates the possible protective effects of gallic acid (GaA) and ferulic acid (FeA) against an experimentally induced liver fibrosis by thioacetamide (TAA) in rats. Animals were divided into: Control group, GaA group (20 mg/kg/day, p.o), FeA (20 mg/kg/day, p.o), TAA group (receiving 250 mg/kg twice/week, I.P), TAA + GaA group, TAA + FeA group (received the same previous doses) and TAA+silymarin group (received silymarin at 100 mg/kg/day+TAA as mentioned above). After 6 consecutive weeks, animals were sacrificed and the assessment of liver functions, oxidative stress biomarkers and histopathological examination of the liver tissues were performed. In addition, the effect on TGF-β1/Smad3 signaling and the expression of miR-21, miR-30 and miR-200 were evaluated. The results showed that administration of GaA or FeA with TAA induced a significant reduction in serum ALT, AST and ALP activities and protected the integrity of liver tissues. Furthermore, they increased the activities of the hepatic antioxidant enzymes; superoxide dismutase and catalase while decreased malondialdehyde content to a normal level. The hepatic expression of TGF-β1, phosphorylated and total Smad3 proteins were significantly decreased. In addition, miR-21 expression was downregulated while miR-30 and miR-200 expressions were upregulated by administration of gallic acid or ferulic acid. In conclusion, gallic and ferulic acids exhibit hepatoprotective and antioxidant effects against TAA-induced liver fibrosis in rats. These effects are mediated through inhibition of TGF-β1/Smad3 signaling and differentially regulating the hepatic expression level of miR-21, miR-30 and miR-200., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background : Vitamin D has regulatory effects on different cells of the immune system and low levels are associated with several immune-mediated diseases. Aim : To investigate the association between neonatal 25-hydroxy vitamin D (25-OHD) level and the expression of lymphocyte activation markers (HLA-DR, CD69, CD25, CD45RA) on T-lymphocyte subpopulations and its impact in neonatal infection. Methods : 25-OHD level was measured in the cord blood of 56 neonates and their mothers using an enzyme immune-assay method. Based on the 25-OHD level, infants were categorised into four groups: severe deficiency ( n =  7), moderate deficiency ( n =  21), mild deficiency ( n =  15) and normal 25-OHD level ( n =  13). Mothers were classified into deficient ( n =  18), insufficient ( n =  21) and normal levels ( n =  17). T-lymphocyte subpopulations and lymphocyte activation markers were investigated using flow cytometry. Results : There was a positive correlation between maternal and cord blood 25-OHD levels ( r  = 0.503, p  = 0.001). The group with severe 25-OHD deficiency had the significantly lowest level of total lymphocytes, CD3+ T lymphocytes, CD4+ T-helper and CD8+ T-cytotoxic lymphocytes and CD4+CD45RA+ naïve T-cells compared with the other groups. The frequencies of CD8+CD25+, CD4+CD25+ and CD4+HLA-DR+ activated T-lymphocytes were significantly lower in the severe, moderate and mild deficiency groups than in the normal group. Seven of 43 (16.27%) infants with 25-OHD deficiency were admitted with sepsis to the neonatal intensive care unit and there were no cases of sepsis in the normal 25-OHD group. Conclusion : Vitamin D deficiency is associated with a reduction of lymphocyte subsets and altered T-lymphocyte activation which are considered to be risk factors for neonatal infection.

Objective: Epicardial fat thickness (EFT) is an emerging cardio-metabolic risk factor and has been shown to be related to atherosclerosis. EFT has not been studied in the context of CAH. This study aimed to evaluate EFT in children with CAH and its relation to carotid artery intima-media thickness (CA-IMT) and left ventricular (LV) functions., Methods: Thirty-six children with classical CAH were compared with 36 healthy controls. All patients had confirmed CAH and were receiving steroid substitution therapy. Patients and controls underwent anthropometric evaluation, measurement of fasting lipids, glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR). LV functions and EFT were assessed using conventional echocardiography. Duplex ultrasonography was used to measure CA-IMT., Results: Compared to controls, patients had greater EFT (p=0.001), CA-IMT (p=0.01), LV mass index (LVMI) (p=0.001) and prolonged mitral deceleration time (DcT) (p=0.01). CAH patients also had significantly worse HOMA-IR (p=0.001) than controls. Abnormalities were worse in uncontrolled CAH on treatment. Multivariate analysis in CAH subjects showed EFT correlated positively with waist circumference odds ratio (OR) [OR=1.9; 95% confidence interval (CI): 1.07-1.14; p=0.01], 17-hydroxyprogesterone [OR=1.6; 95% CI: 1.33-2.89; p=0.05], testosterone concentration (OR=1.7; 95% CI: 1.55-2.13; p=0.01), LVMI (OR=1.14; 95% Cl: 1.08-1.13; p=0.01), mitral DcT (OR=2.25; 95% CI: 1.15-2.05; p=0.01) and CA-IMT (OR=1.6; 95% CI: 1.15-2.05; p=0.01)., Conclusion: EFT is elevated in children with classical CAH, particularly in those with poor control, and is correlated with CA-IMT, LV mass and mitral DcT. Measurement of EFT in CAH children may help to identify those at high risk of developing LV dysfunction and subclinical atherosclerosis.

Background/aims: Thyroid hormones (TSH) play a key role in the working of the cardiovascular system, with direct effects on cardiac function, vascular system, and atherosclerotic factors. Epicardial adipose tissue, the visceral fat of the heart, has emerged as a new cardiometabolic risk marker because of its close anatomical proximity to the myocardium and coronary artery. This study aimed to evaluate epicardial fat thickness (EFT) in children with subclinical hypothyroidism (SH) and its relation to early atherosclerotic changes., Methods: The study included 32 children with SH due to autoimmune thyroiditis and 32 healthy children matched for age and gender as control group. Patients and controls underwent anthropometric evaluation and measurement of fasting lipids, glucose, insulin, homeostasis model assessment for insulin resistance and high-sensitivity C-reactive protein (hs-CRP). TSH, free thyroxine (FT4 and FT3) and antithyroid autoantibodies (antithyroid peroxidase and thyroglobulin antibodies) were also measured. Conventional echo-cardiography was used to assess EFT. Noninvasive ultrasound was used to measure carotid intima-media thickness and brachial artery flow-mediated dilation (FMD) responses., Results: Compared to controls, patients had higher atherogenic index (AI) and hs-CRP (p = 0.001 for each). Conventional echocardiography revealed that patients with SH had higher EFT (p = 01) and significantly lower FMD response compared with the control (p = 0.001). In multivariate analysis, EFT values were significantly correlated with TSH (OR 1.2; 95% CI 1.04-1.34; p = 0.01), hs-CRP (OR 1.1; 95% CI 1.09-1.14; p = 0.001, AI (OR 1.6; 95% CI 1.17-2.03; p = 0.001), and FMD response (OR 2.4; 95% CI 1.14-2.53; p = 0.01)., Conclusions: Our study demonstrated that EFT is higher in children with SH compared with controls and associated with FMD responses. Measurement of EFT by echocardiography in children with SH may help to identify those at high risk of developing subclinical atherosclerosis., (© 2019 S. Karger AG, Basel.)

Studies of cognitive function in patients with congenital adrenal hyperplasia (CAH) are few and controversial. This study aimed to investigate general intelligence and specific cognitive functions in children with salt wasting (SW) form of CAH and their relationship to demographic, clinical, and laboratory variables. This study included 36 children with classic 21 hydroxylase deficiency SW type of CAH (males = 12; females = 24; mean age = 15.6 ± 2.3 years). Intelligence quotient (IQ) and cognition were assessed using Wechsler Intelligence Scale for Children 3rd edition (WISC-III) and Stanford Binet Subsets Test version 4 (SBST4). Compared to controls, patients had lower mean full-scale (FS) IQ (P = 0.01) score, particularly performance IQ score (P = 0.001), and comprehension, pattern analysis, quantitation, bead memory, and memory for sentences of SBST4 (P = 0.05, P = 0.014, P = 0.001, P = 0.002, and P = 0.05, respectively). Lower IQ was observed in poorly controlled compared with well-controlled patients on medical treatment. Significant correlations were observed between FSIQ with age (r = - 0.810; P = 0.001), duration of treatment (r = - 0.887; P = 0.01), dose of glucocorticoids (r = - 0.463; P = 0.01), 17-OHP (r = - 0.543; P = 0.01) and testosterone (r = - 0.462; P = - 0.006) levels, and number of hyponatremic episodes (r = - 0.350; P = 0.05). In multivariate analysis, the independent risks of low FSIQ were the dose of glucocorticoids (OR = 1.14; 95% CI = 1.08-1.23, P = 0.0001), 17-OHP levels (OR = 2.25; 95% CI = 1.19-2.85, P = 0.01), and number of hyponatremic episodes (OR = 4.34; 95% CI = 2.05-5.15, P = 0.01).Conclusion: Patients with SW form of CAH may have lower IQ and cognitive deficits which may be related to the dose of glucocorticoids, androgen excess, and number of hyponatremic episodes. What is Known: • Congenital adrenal hyperplasia (CAH) is a group of inherited impairment of cortisol biosynthesis. • Studies of cognitive function in patients with congenital adrenal hyperplasia (CAH) are few and controversial. What is New: • Children with CAH may have lower intelligent quotient (IQ) and cognitive deficits. • Early hyponatremic episodes, overtreatment with glucocorticoids, and high androgen levels may be possible causative factors for the cognitive deficits.

Cardiovascular autonomic neuropathy (CAN) is a major complication of type 1 diabetes (T1D). This study aimed to evaluate cardiac autonomic nervous system (ANS) function in children with T1D and its relation to different demographic, clinical and laboratory variable. This cross-sectional study included 60 children with T1D (mean age = 15.1 ± 3.3 years; duration of diabetes = 7.95 ± 3.83 years). The following 8 non-invasive autonomic testing were used for evaluation: heart rate at rest and in response to active standing (30:15 ratio), deep breathing and Valsalva maneuver (indicating parasympathetic function); blood pressure response to standing (orthostatic hypotension or OH), sustained handgrip and cold; and heart rate response to standing or positional orthostatic tachycardia syndrome or POTs (indicating sympathetic function). None had clinically manifest CAN. Compared to healthy children (5%), 36.67% of children with T1D had ≥ 2 abnormal tests (i.e., CAN) (P = 0.0001) which included significantly abnormal heart rate response to standing (POTs) (P = 0.052), active standing (30:15 ratio) (P = 0.0001) and Valsalva maneuver (P = 0.0001), indicating parasympathetic autonomic dysfunction, and blood pressure response to cold (P = 0.01), indicating sympathetic autonomic dysfunction. 54.55, 27.27 and 18.18% had early, definite and severe dysfunction of ANS. All patients had sensorimotor peripheral neuropathy. The longer duration of diabetes (> 5 years), presence of diabetic complications and worse glycemic control were significantly associated with CAN., Conclusions: The study concluded that both parasympathetic and sympathetic autonomic dysfunctions are common in children with T1D particularly with longer duration of diabetes and presence of microvascular complications. What is Known: • Cardiovascular autonomic neuropathy (CAN) is a major complication of type 1 diabetes (T1D). • Limited studies evaluated CAN in children with T1D. What is New: • CAN is common in children with T1D. • Cardiac autonomic functions should be assessed in children with T1D particularly in presence of microvascular complications.

Background: Obese children are at increased risk for abnormal cardiac structure and function. Little is known about adrenomedullin (AM), a cytokine produced in various organs and tissues, as a biomarker of cardiac hypertrophy in obese children. This study aimed to assess the plasma AM levels in a cohort of obese children and its relationship to left ventricular (LV) functions., Methods: The study included 60 obese children and 60 non-obese children matched for age and gender as control group. Blood pressure, serum lipid profile, fasting glucose, insulin and plasma AM and the homeostatic model assessment of insulin resistance (HOMA-IR) were measured. Cardiac dimensions and LV functions were assessed using conventional echocardiography., Results: Compared to control subjects, obese children had higher blood pressure (P = 0.01), insulin (P = 0.001), HOMA-IR (P = 0.001), and AM (P = 0.001). Moreover, obese children had higher LV mass index (LVMI) (P = 0.001), indicating LV hypertrophy; prolonged isovolumic relaxation times (P = 0.01), prolonged mitral deceleration time (DcT) (P = 0.01) and reduced ratio of mitral E-to-mitral A-wave peak velocity (P = 0.01), indicating LV diastolic dysfunction. Laboratory abnormalities were only present in children with LV hypertrophy. In multivariate analysis in obese children with LV hypertrophy, AM levels were positively correlated with LVMI [odds ratio (OR) 1.14, 95% confidence interval (Cl) 1.08-1.13, P = 0.0001] and mitral DcT (OR 2.25, 95% CI 1.15-2.05, P = 0.01) in the presence of higher blood pressure and HOMA-IR. A cut-off value of AM at 52 pg/mL could differentiate obese children with and without left ventricular hypertrophy at a sensitivity of 94.32% and specificity of 92.45%., Conclusions: Plasma AM levels may be elevated in obese children particularly those with LV hypertrophy and is correlated with higher blood pressure and insulin resistance. Measurement of plasma AM levels in obese children may help to identify those at high risk of developing LV hypertrophy and dysfunction.

This study aimed to evaluate the left ventricular (LV) functions in a cohort of children with Graves' disease (GD). This is a cross-sectional case-control study. It included 36 children with GD and 36 healthy children matched for age and gender. Thyroid hormones (TSH, FT4, and FT3) and anti-thyroid autoantibodies [anti-thyroid peroxidase (anti-TPO), thyrotropin receptor (TRAbs), and thyroglobulin antibodies] were measured. Conventional and tissue Doppler imaging (TDI) echocardiographies were used to assess left ventricular systolic and diastolic functions. LV mass index (LVMI) and myocardial performance index (MPI) were also measured. Compared to healthy children, conventional echocardiography of patients with GD revealed higher LVMI (P = 0.001) indicating LV hypertrophy but normal LV functions while TDI revealed lower Em/Am ratio indicating LV diastolic dysfunction (P = 0.001). Significant correlations were reported between FT4 with LVMI (P = 0.05), Em/Am (P = 0.01), and MPI (P = 0.01). In multivariate analysis, a positive correlation was identified between FT4 with MPI (OR = 1.17; 95% CI = 1.09-1.15; P = 0.001)., Conclusions: Children with newly diagnosed GD may have significant subclinical changes in LV structure and function (diastolic and global). TDI is more sensitive than conventional Doppler in detecting LV dysfunction. These findings highlight the importance of early monitoring of children with GD for left ventricular mass index and diastolic function. What is Known: • There is an increased risk for cardiac abnormalities in children with Graves' disease (GD). • Limited studies assessed left ventricular function in patients with GD. What is New: • Children with newly diagnosed GD may have significant subclinical changes in left ventricular structure and functions. • Children with newly diagnosed GD should be monitored for left ventricular mass index and diastolic function.

Background/aims: Homocysteine is an important and independent risk factor for atherosclerotic diseases. The aim of this study was to evaluate serum levels of homocysteine in children with congenital adrenal hyperplasia (CAH) and their relation to carotid artery intima-media thickness (CA-IMT) and left ventricular (LV) function., Methods: This study included 36 children with classic CAH and 36 healthy children. All underwent anthropometric evaluation. Measurement of serum levels of total homocysteine was carried out. The LV mass (LVM) and function were assessed using conventional echocardiography. Duplex ultrasonography was used to measure CA-IMT., Results: Compared to the controls, the patients had higher homocysteine levels (p = 0.001), a thicker CA-IMT (p = 0.01), a higher LVM index (LVMI) (p = 0.001), and a prolonged mitral deceleration time (DcT) (p = 0.01). Abnormalities were marked in children who were uncontrolled on medical treatment. In multivariate analysis, homocysteine levels were significantly correlated with systolic (OR = 2.2; 95% CI: 1.10-1.18; p = 0.01) and diastolic blood pressures (OR = 2.9; 95% CI: 1.45-2.4; p = 0.01), atherogenic index (OR = 2.6; 95% CI: 1.33-2.89; p = 0.01), HOMA-IR (OR = 1.3; 95% CI: 1.04-1.34; p = 0.001), LVMI (OR = 2.6; 95% CI: 1.1-1.13; p = 0.001), mitral DcT (OR = 2.4; 95% CI: 1.15-2.05; p = 0.01), and CA-IMT (OR = 1.6; 95% CI: 1.16-1.57; p = 0.01)., Conclusions: Serum total homocysteine was elevated in children with classic CAH, particularly in those with poor control on medical treatment, and it was correlated with CA-IMT, LVMI, and mitral DcT. Measurement of homocysteine in children with CAH may help to identify those at high risk of developing LV dysfunction and subclinical atherosclerosis., (© 2018 S. Karger AG, Basel.)

Background: This study aims to assess the levels of visfatin in children and adolescents with autoimmune thyroiditis (AIT) and its relationship with disease-related variables., Methods: The study included 84 children and adolescents with AIT and 84 healthy subjects. Measurements of fasting glucose, insulin, thyroid-stimulating hormone (TSH), free thyroxin (FT4), antithyroid peroxidase antibodies (TPOAb) and antithyroglobulin antibody (TgAb) were completed, with assessment of visfatin levels., Results: Overt hypothyroidism was diagnosed in 58 cases, while subclinical hypothyroidism was diagnosed in 26 of the studied patients. Total studied cases, overt and subclinical subgroups had significantly higher levels of TSH, HOMA-IR, TPOAb, TgAb and visfatin and significantly lower FT4 level compared with the control. Spearman correlation analysis revealed that visfatin was correlated positively with BMI, homeostasis model assessment (HOMA-IR), TSH and TPOAb, while inversely correlation with FT4. In logistic regression analysis, visfatin was correlated only with TPOAb., Conclusions: This preliminary study provides evidence of significantly higher level of visfatin in children and adolescents with AIT. Visfatin might have a potential role in the pathogenesis of AIT, which needs to be validated by measuring immunological responses in children and adolescents with AIT., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Neuron-specific enolase is a sensitive marker of neuronal damage in various neurologic disorders. This study aimed to measure serum neuron-specific enolase levels at different time points and severities of diabetic ketoacidosis. This study included 90 children (age 9.2 ± 3.4 years) with diabetic ketoacidosis. Neuron-specific enolase was measured at 3 time points (baseline and after 12 and 24 hours of starting treatment). Among patients, 74.4% had diagnosis of new diabetes, 60% had Glasgow Coma Scale score <15, and 75.6% had moderate/severe diabetic ketoacidosis. Compared with controls (n = 30), children with diabetic ketoacidosis had higher neuron-specific enolase levels at the 3 time points ( P = .0001). In multiple regression analysis, the factors associated with higher neuron-specific enolase levels were younger age, higher glucose, lower pH, and bicarbonate values. This study indicates that serum neuron-specific enolase is elevated in diabetic ketoacidosis and correlated with the severity of hyperglycemia, ketosis, and acidosis. This study indicates that diabetic ketoacidosis may cause neuronal injury from which the patients recovered partially but not completely.

Oxidative status in autoimmune thyroiditis (AIT) has not been investigated previously in children and adolescents. We investigated oxidant and antioxidant systems in a cohort of Egyptian children and adolescents with AIT to explore these as biomarkers of autoimmunity and thyroid function. Our case control study included 32 children with AIT and 32 healthy subjects with matching age and sex as a control group. After a thorough history and physical examination, a thyroid ultrasound, measurements of thyroid-stimulating hormone (TSH), free thyroxin (FT4), antithyroid peroxidase antibodies (TPOAb), and antithyroglobulin antibody were done with assessment of malondialdehyde (MDA) and total antioxidant capacity (TAC) levels as oxidative stress markers. Overt hypothyroidism was detected in 23/32, while subclinical hypothyroidism was detected in nine of the 32 studied patients. MDA levels were significantly elevated, while TAC levels were significantly decreased in AIT patients compared with healthy controls. The difference was more evident in patients with overt hypothyroidism than those with subclinical hypothyroidism. We also observed significant positive correlations of TPOAb levels with age, TSH, MDA, and thyroid volume, finding a negative correlation with TAC and FT4. In conclusion, the high serum MDA and lower TAC levels in patients with AIT and the correlation of thyroid antibodies with biomarkers of oxidative stress may reflect the role of autoimmunity in the development of oxidative stress. Future studies are needed for evaluation of antioxidant therapy for AIT patients. ClinicalTrials.gov Identifier NCT02318160. https://clinicaltrials.gov/ct2/show/NCT02318160 .

Background: Vitamin D deficiency is a global health problem. Its role as an immune modulator has been recently emphasized. There is increasing evidence for the significant role of vitamin D in reducing the incidence of autoimmune diseases. However, little is known about the status of vitamin D in children and adolescents with autoimmune thyroiditis (AIT)., Objective: The goal of the present study was to assess vitamin D status in Egyptian children and adolescents with AIT and to explore its relation to biomarkers of autoimmunity and thyroid function., Design: A prevalence case-control study that included 56 children with AIT and 56 healthy, age- and sex-matched subjects that served as the control group. The following was done for all participants: thorough history, physical examination, thyroid ultrasound, measurement of thyroid-stimulating hormone (TSH), free thyroxin (FT4), anti-thyroid peroxidase antibodies (TPOAb), anti-thyroglobulin antibody (TgAb) and assessment of serum 25-hydroxy vitamin D (25OHD) level., Results: Overt hypothyroidism was detected in 42/56 while subclinical hypothyroidism was detected in 14/56 of the studied patients. Vitamin D deficiency rate was significantly higher in the AIT group compared to the control subjects (71.4 vs 21.4 %, P < 0.001). In AIT group, the mean level of 25OHD was significantly lower compared to the control group (16.2 ± 8.2 vs 33.9 ± 12.7 nmol/L, P < 0.001). The difference was more evident in patients with overt hypothyroidism than those with subclinical hypothyroidism (P < 0.01). There were significant negative correlations between serum 25OHD and age, duration of the disease, BMI, anti-TPOAb, anti-TGAb and TSH (P < 0.001 each). On the other hand, serum 25OHD correlated positively with FT4 levels. While 25OHD level was an independent risk factor for AIT, it failed to qualify as an independent risk for the progression of AIT to overt hypothyroidism after adjustment for other potential confounding factors; age, sex and BMI., Conclusions: Low serum vitamin D is significantly associated with AIT in Egyptian children. However, vitamin D level is not an independent risk for the progression of AIT to overt hypothyroidism. BMI may have an influence on serum 25OHD levels.

Background: Chemokines have been recently recognized to play a role in chronic pain syndromes' pathophysiology. This study investigated the role of monocyte chemoattractant protein-1 (MCP-1), stromal cell derived factor-1 (SDF-1), and retinoic acid (RA) as targets for the therapeutic approach of neuropathic pain., Methods: A chronic constriction injury (CCI) model of neuropathic pain by unilateral ligation of left sciatic nerve was performed in adult female Wistar rats. The effects of doxycycline (Dox, 50 mg/kg/day i.p. for 7 days), single dose of bicyclam (5 mg/kg i.p.), RA (15 mg/kg/day i.p. for 7 days), and their combination(s) on behavioral tests of nociception (Von Frey filaments; paw pressure test) on days 0, 1, 3, 5, and 7 of operation were studied. Serum concentrations of MCP-1 and SDF-1 were measured by ELISA. Histological examination of the sciatic nerve was investigated., Results: CCI of sciatic nerve significantly induced mechanical allodynia and hyperalgesia and an increase of MCP-1 and SDF-1 serum levels. Dox-treated groups (Dox, Dox+bicyclam, Dox+RA, Dox+bicyclam+RA) and bicyclam-treated groups (bicyclam, Dox+bicyclam, bicyclam+RA, Dox+bicyclam+RA) attenuated CCI-induced behavioral and biochemical changes. RA inhibited CCI-induced mechanical hyperalgesia but produced a time-dependent reversal of allodynia. Histological findings showed degenerative changes of sciatic nerve after CCI that were partially recovered in Dox-treated groups., Conclusions: These findings demonstrate an association between serum MCP-1 and SDF-1 concentrations and behavioral manifestations of neuropathic pain. RA administration decreased neuropathic pain (antihyperalgesic effect) but did not cause any improvement in sciatic nerve tissues, either alone or in combination with chemokine antagonists. Thus, chemokines may serve as potential targets for drug development in neuropathic pain treatment.

Dexmedetomidine (Dex) is a novel Alpha 2-adrenoceptor agonist. It decreases sympathetic tone and attenuates the stress responses to anesthesia and surgery. People exposed to cold suffer unpleasant thermal pain, which is experienced as stress and causes the release of noradrenaline from the sympathetic terminals. The present study investigated the effects of cold stress and dexmedetomidine on chronic constriction injury (CCI) model of the sciatic nerve in rats. Sixty four male Wistar rats were divided into seven groups of eight rats each: repeated cold stress (RCS) group, sham RCS group, CCI group, sham CCI group, Dex-treated group received a single dose of Dex (5 μg/kg), CCI+Dex group, CCI+RCS group. Interleukin-6 (IL-6) and tumor necrosis factor- alpha (TNF-α) levels in the serum were measured by enzyme-linked immunosorbent assay. The mean body weight of CCI, RCS, CCI+RCS, CCI+Dex and RCS+Dex groups decreased significantly compared with pre-values. Dexmedetomidine and CCI caused significant changes of the systolic, diastolic and mean blood pressure. Both RCS and CCI groups showed significant decreased of reaction time in the hot plate test. The RCS and CCI groups demonstrated a significant mechanical hyperalgesia, while pain threshold was increased in the RCS+Dex group. A significant decrease of serum IL-6 and TNF-α was demonstrated in CCI+RCS and CCI+Dex groups. The therapeutic effectiveness of dexmedetomidine in neuropathic pain may be through inhibition of proinflammatory cytokines, primarily IL-6 and TNF-α. Moreover, cold stress may result in increased resistance to neuropathic pain., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: Few studies assessed carotid artery intima-media thickness (CA-IMT) and left ventricular (LV) function in children with congenital adrenal hyperplasia (CAH) as compared to adults. This study aimed to assess carotid artery structural changes and myocardial function with CAH. The study included 32 children with classic CAH and 32 healthy children matched for age, gender, pubertal status, and socioeconomic status. Blood levels of high-sensitivity C-reactive protein (hs-CRP) and circulating endothelial cells (CECs) were measured. LV mass (LVM) and function were assessed using conventional echocardiography. Duplex ultrasonography was used to measure CA-IMT. Compared to controls, patients had higher hs-CRP and CEC concentrations (p < 0.001) and increased CA-IMT (p < 0.001), indicating vascular endothelial injury and subclinical atherosclerosis; higher LVM index (LVMI) (p < 0.001), indicating LV hypertrophy; and lower ratio of E/A wave and prolonged mitral deceleration time (DcT) and isovolumic relaxation times (IVRTs) (p < 0.001), indicating LV dysfunction. Abnormalities were marked in uncontrolled children on medical treatment. Testosterone levels were positively correlated with CA-IMT, LVMI, and DcT values., Conclusion: This study indicates that children with CAH and enhanced androgen levels are at increased risk of vascular endothelial injury, subclinical atherosclerosis, and LV dysfunction. These findings highlight early monitoring of children with CAH for cardiovascular abnormalities.

We hypothesize that the imbalance between oxidant and antioxidant systems might be involved in the pathophysiology of breath-holding spells. The aim of this study is to evaluate the oxidant-antioxidant status in children with breath-holding spells compared to healthy children. In a case control study, 67 children with breath-holding spells were compared with 60 healthy children. Malondialdehyde values of the patients were significantly higher than those in control. Levels of selenium, glutathione peroxidase, and superoxide dismutase of the patient group are significantly lower than those in control. The present study gives helpful data about oxidant-antioxidant systems alterations in breath-holding spells in such a large patient group. These data give support to the hypothesis of the imbalance between oxidant and antioxidant systems, and selenium deficiency might be involved in the pathophysiology of breath-holding spells, suggesting the role of this system dysregulation in breath-holding spells., (© The Author(s) 2014.)

The transcription factor, nuclear factor-κB (NF-κB) is a key inducer of inducible nitric oxide synthase (iNOS) gene expression. The aim of the present study was to investigate the potential protective effect of l-arginine (Arg; nitric oxide precursor) and aminoguanidine (inducible nitric oxide synthase inhibitor) against acetic acid (AA)-induced colitis in rats, and the potential role of NF-κB. Colitis was induced by intrarectal inoculation of rats with 4% acetic acid for three consecutive days. The effect of Arg and aminoguanidine on nitric oxide levels was assessed by Greiss assay and protein expression of NF-κB/p65, and inducible nitric oxide synthase was also investigated by immunohistochemistry. Slides were examined using ImageJ, and results reported as the percent area positive for each marker. Intrarectal AA caused a significant increase in bodyweight loss and colon weights. Arg at 100 mg/day for 7 days before induction of colitis diminished the changes in both bodyweight loss and colon weights. Furthermore, Arg attenuated the colonic tissues macroscopic and microscopic damage induced by acetic acid. In addition, i.p. AG 100 mg/kg given during and after induction of colitis recovered the colonic ulcerative lesion induced by AA. Arg can protect against colonic inflammation; an effect that probably be attributed to its nitric oxide-donating property, resulting in modulatory effects on the expression of NF-κB/p65 in the colon tissues. The results suggested that Arg might reduce the inflammation associated with colitis as confirmed by histopathological investigations. Arg might inhibit AA-induced colitis through the NF-κB/nitric oxide pathway., (© 2014 Wiley Publishing Asia Pty Ltd.)

Background: Only few studies have evaluated the epidemiology and risk factors of hepatitis C virus (HCV) infection in Egyptian children with type 1 diabetes mellitus (T1DM). The present study aimed at measurement of the rates of anti-HCV positivity by Enzyme-Linked Immuno-Sorbent Assay (ELISA) test and of HCV-Ribonucleic acid (RNA) positivity by polymerase chain reaction (PCR) among children with T1DM and to study the possible risk factors of infection., Settings and Design: Cross-sectional controlled study., Materials and Methods: The study included 150 children with T1DM (Group 1) (mean age 14. 76 ± 6.4 years). Fifty children age and sex-matched were included as control group (Group 2) (mean age 13.62 ± 2.11 years). They were screened for HCV antibodies using third generation ELISA and HCV-RNA positivity by PCR., Results: The frequency of anti-HCV positivity by ELISA was significantly higher in children with T1DM (n = 150) in comparison wiith control group (n = 50) (12% vs 6%; P<0.001), while the frequency of HCV-RNA positivity by PCR among the cases testing positive by ELISA was 75% for both diabetic group and control group. There were no significant differences in serum levels of liver biochemical profile in diabetic children with anti-HCV positivity (n = 18) in comparison to those with anti-HCV negativity (n = 132). Residence in rural area, low socioeconomic class and prior hospitalization were significant risk factors for anti-HCV positivity by ELISA., Conclusions: The frequency of HCV infection in children with T1DM in Upper Egypt appears to be high and is mainly related to residence in rural area, low socioeconomic class and prior hospitalization. HCV infection in these children is not associated with significant changes in hepatic biochemical parameters., Recommendations: Implementation of strict infection control measures are highly recommended to reduce the frequency of HCV infection. Furthermore, the silent evolution of HCV infection in children makes periodic screening of HCV in diabetic children mandatory.

Background: Interactions between the sympathetic and somatic nervous system play an essential role in the pathophysiologic mechanisms of neuropathic pain. The α2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Multidrug therapy is potentially valuable to decrease side effects., Objective: The aim of the present study was to investigate the possible antinociceptive effect of dexmedetomidine, an α2-adrenoceptor agonist, and its combination with front-line treatment of neuropathic pain, i.e., amitriptyline or tramadol, in a chronic constriction injury (CCI) model of the sciatic nerve in rats., Study Design: Controlled animal study., Methods: Following unilateral ligation of the left sciatic nerve, the effect of intraperitoneal (i.p.) dexmedetomidine (5 ug/kg), tramadol (5 mg/kg), and amitriptyline (30 mg/kg) on mechanical allodynia (measured by electrical von Frey apparatus) and hyperalgesia (measured by Randall and Selitto test) was studied., Results: The sham-operated rats and un-operated hind paw (right paw) press normally on the floor reproduced by a weighted pain score of 0. Behavioral and mechanical tests confirmed the development of neuropathic pain after CCI. All individual drugs and dexmedetomidine combination with either tramadol or amitriptyline were effective in reducing mechanical allodynia and hyperalgesia. Dexmedetomidine, amitriptyline, tramadol, amitriptyline+dexmedetomidine, and tramadol+dexmedetomidine combination did not produce any sedation/motor impairment (P > 0.05)., Limitations: Although the combination of these drugs improved the CCI model of neuropathic pain in this study, an additional interpretation of the underlying mechanism(s) will be needed to confirm these findings., Conclusion: The combination of these drugs appears to be more effective in increasing the pain threshold after peripheral nerve injury, when compared with the administration of either of amitriptyline or tramadol alone and should be considered as a possible alternative to decrease side effects of individual drug therapy.

Context: Soluble CD40 ligand (sCD40L) is known to be elevated in different clinical situations including hypercholesterolemia, acute coronary syndromes, and type 2 diabetes mellitus (T2DM), Data about the relationship between type 1 diabetes mellitus (T1DM) and sCD40L is limited. In addition, the potential role ofsCD40Lin the pathogenesis of vascular complications in children and adolescents with T1DM is to be clarified. Hence, the study aimed at assessment of sCD40L levels in children and adolescents with T1DM and correlation of these levels with glycemic control and microalbuminuria., Settings and Design: Cross-sectional controlled study., Materials and Methods: The study was performed in the Pediatric Endocrinology and Diabetes Unit, Assuit University Children Hospital, Assiut, Egypt. It included 70 children and adolescents with T1DM (mean age 14. 76 ± 2.21 years). Cases were further subdivided into 43 cases with normoalbuminuria and 27 cases with microalbuminuria according to presence or absence or microalbuminuria in fresh urine samples. Twentyfive healthy subjects, age- and sex-matched were included as control group (mean age = 13.62 ± 2.11 years). Studied cases were subjected to medical history, clinical examination, and laboratory assessment of fasting blood glucose (FBG), lipid profile, glycosylated hemoglobin (HbA1c), and sCD40L were performed., Results: Mean HbA1c and sCD40L were significantly higher in diabetic children (n = 70) compared to control (n = 25) (P < 0.001 for each). Mean HbA1c and sCD40L levels were significantly higher in microalbuminuric cases (n = 27) compared to normoalbuminuric cases (n = 43) (P < 0.05 and <0.01, respectively). We also observed a significant positive correlation between sCD40L levels and the age, diabetes duration, HbA1c, and urinary albumin creatinine ratio., Conclusions: The high serum sCD40L levels in children and adolescents with T1DM particularly in those with microalbminuria and its positive correlation with diabetes duration, urinary albumin excretion, and glycemic control may reflect the role of sCD40L in diabetic vasculopathy in the pediatric age group. Moreover, measurement of serum sCD40L levels in poorly controlled patients would help to identify those at high risk of developing nephropathy.

Background: Growth hormone deficiency (GHD) in adults is associated with a cluster of cardiovascular risk factors that may contribute to an increased mortality for cardiovascular disease. In children, relatively few studies have investigated the effect of GHD and replacement therapy on cardiac performance and metabolic abnormalities that may place them at a higher risk of cardiovascular disease (CVD) at an early age., Aim: This study was aimed to assess the left ventricular function, lipid profile, and degree of insulin resistance in Egyptian children with GHD before and after 1 year of GH replacement therapy., Settings and Design: Prospective case-control study, single-center study., Materials and Methods: Thirty children with short stature due to GHD were studied in comparison to 20 healthy age- and sex-matched children. All subjects were subjected to history, clinical examination, auxological assessment, and echocardiography to assess the left ventricular function. Blood samples were collected for measuring IGF-1, lipid profile (Total, LDL, HDL cholesterol, triglyceride, and atherogenic index (AI), fasting blood sugar, and fasting insulin levels. In addition, basal and stimulated GH levels were measured in children with suspected GHD., Statistical Analysis Used: Student's t-test was used for parametric data, and the Mann-Whitney U-test was used for non-parametric data., Results: Total, LDL cholesterol, triglyceride, AI, and insulin were significantly higher in children with GHD than in healthy controls at baseline. After 12 months of GH replacement therapy, total, LDL cholesterol, triglyceride, AI and insulin were significantly decreased, while homeostatic model assessment for insulin resistance index (HOMA-IR) was significantly increased compared to both pre-treatment and control values. At baseline, the left ventricular mass (LVM) and left ventricular mass index (LVMi) were significantly lower in GHD children than in controls. After 12 months of GH replacement therapy, LVM and LVMi in GHD patients were significantly increased compared to pre-treatment values., Conclusions: GHD in children is associated with a significantly reduced cardiac mass and impairment of lipid profile. GH replacement therapy exerts beneficial effects both on cardiac mass and lipid metabolism by normalizing cardiac size and improving the lipid profile. On the contrary, an increase in insulin resistance is observed after 12 months GH treatment. The study suggests that children with GH deficiency should have echocardiography and lipid profile monitoring before and during treatment with GH.

In this study, the possible role of oxidative stress and nitric oxide (NO) synthase isoforms in the development of morphine tolerance and dependence, and effect of alpha-lipoic acid on these parameters were investigated in mice. The development of morphine tolerance as measured by the hot plate test and dependence, as assessed by naloxone-precipitated withdrawal manifestations, produced an increase in brain glutamate and malondialdehyde (MDA) levels and NO production as well as a decrease in brain intracellular reduced glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity. Also, the development of these syndromes increased inducible but not neuronal NO synthase mRNA and protein expressions in mice brain. Co-administration of alpha-lipoic acid (α-LA) inhibited the development of morphine tolerance and dependence, their associated biochemical alterations, except elevation of brain glutamate level, and their associated increase in brain inducible NO synthase mRNA and protein expressions. The inhibitory effect of α-LA on morphine-induced tolerance and dependence and on naloxone-induced biochemical alterations in morphine-dependent mice was enhanced by concurrent administration of the NMDA receptor antagonist, dizocilpine, the antioxidant, N-acetylcysteine or the selective inducible NO synthase inhibitor, aminoguanidine. On the other hand, this inhibitory effect of α-LA was not changed by concurrent administration of the selective neuronal NO synthase inhibitor, 7-nitroindazole but antagonized by concurrent administration of the NO precursor, L-arginine. These results suggest that α-LA through inhibition of morphine-induced oxidative stress and increase in the expression and activity of inducible NO synthase in the brain can attenuate the development of morphine tolerance and dependence., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Benign neonatal hemangiomatosis is a condition in which multiple cutaneous hemangiomas appear at birth or shortly thereafter; visceral complications are absent. Here, we report a case of a consumption hypothyroidism in an Egyptian baby with benign neonatal hemangiomatosis., Case Presentation: An 8-month-old Egyptian boy with benign neonatal hemangiomatosis was referred to our institution for evaluation of developmental delay. Initial examination revealed a quiet baby who was able to sit only with support. He had hypotonia, a large anterior fontanelle, puffy eyes, cold extremities, hypothermia, bradycardia, and abdominal distension. An examination of his skin revealed more than 100 dome-shaped red-purple cutaneous hemangiomas that varied in size from 5 to 10mm on the back, the abdomen and the extremities without mucus membrane involvement. He had low serum free thyroxine concentration and triiodothyronine levels and high thyroid-stimulating hormone and reverse-triiodothyronine levels. A work-up that involved appropriate imaging ruled out visceral involvement. Based on the above mentioned data, a diagnosis of consumptive hypothyroidism due to benign neonatal hemangiomatosis was made. He was started on oral thyroid medication which was gradually increased to 90μg L-thyroxine daily (15μg/kg/day). After three months of treatment, he was able to sit alone without support and he had normal levels of thyroid-stimulating hormone and serum free thyroxine., Conclusion: Thyroid function should be assessed periodically in babies with benign neonatal hemangiomatosis, especially if symptoms of hypothyroidism appear or the size and number of hemangiomatosis increase rapidly. Moreover, high doses of L-thyroxine may be needed to achieve euthyroidism during the infancy.

Introduction: X-linked congenital adrenal hypoplasia is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the dosage-sensitive sex reversal adrenal hypoplasia congenita critical region of the X chromosome, gene 1 (DAX-1) gene. Most affected children present with failure to thrive, salt wasting and hypoglycemic convulsions in the first months of life. Hypospadias affects approximately one in 250 live male births. Mutations in the mastermind-like domain-containing 1 (MAMLD1) gene have been implicated as one of the causes of hypospadias in children. To the best of our knowledge, an association between congenital adrenal hypoplasia due to a DAX-1 mutation and hypospadias due to mutation of the MAMLD1 gene has not previously been reported in the literature., Case Presentation: A 35-day-old male Egyptian baby was referred to our institution for the evaluation of a two-week history of recurrent vomiting associated with electrolyte imbalance. On examination, our patient was found to have hypotension and dehydration. A genital examination showed distal penile hypospadias with chordee and normal testes. He had hyponatremia, hyperkalemia, hypoglycemia and metabolic acidosis. Endocrinological investigations revealed low levels of cortisol, 17-hydroxyprogesterone and aldosterone, with a high level of adrenocorticotrophic hormone. A provisional diagnosis of congenital adrenal hypoplasia associated with hypospadias was made. A molecular genetics study confirmed the diagnosis of X-linked congenital adrenal hypoplasia due to DAX-1 mutations and hypospadias due to MAMLD1 mutation. He was started on hydrocortisone and fludrocortisone treatment. After three weeks of treatment, his symptoms improved and his blood sugar, sodium, potassium and cortisol levels normalized., Conclusions: We report the case of an Egyptian baby with an association of congenital adrenal hypoplasia due to DAX-1 mutation and hypospadias due to MAMLD1 mutation. Early diagnosis of this association and determining its optimal treatment are vital in helping to avoid its fatal course.