Circulating serum and plasma levels of micro-RNA in type-1 diabetes in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a complex metabolic disorder characterized by hyperglycaemia, with constantly increasing incidence in paediatric population. The discovery of new molecules, such as microRNAs, and their possible interactions with T1DM create novel aspects in the diagnosis of the disease. METHODS: This systematic review and meta-analysis adhered to PRISMA guidelines. MEDLINE, SCOPUS, Cochrane CENTRAL and Clinicaltrials.gov. were searched up to 20 April 2020. Inclusion criteria for individual studies were quantification of microRNAs in serum/plasma samples and study groups consisting of children and adolescents with T1DM and healthy controls. Primary outcome of the study was the qualitative expression of microRNAs between the two groups. Statistical analysis was performed with Comprehensive Meta-Analysis Software v3.0. Methodological quality of included studies was assessed using Newcastle-Ottawa scale. RESULTS: A total of 484 studies were retrieved from the initial search of the databases. These were subsequently limited to seven included studies. Seven microRNAs demonstrated contrasting expression between the two groups, with two of them showing significant overexpression in T1DM group (miR-181:95% CI: 0.429 to 1.341 P < .001, miR-210:95% CI: 0.381 to 0.852, P < .001) and one micro-RNA being significantly overexpressed in control group (miR-375:95% CI: 0.293 to 1.459, P = .003). CONCLUSION: A total of three micro-RNA molecules appeared to have a significantly different expression in T1DM patients, serving as a possible diagnostic panel of biomarkers. These findings may contribute as reference for future research to further support the use of microRNAs as a novel diagnostic tool in T1DM.

Micro-RNA Implications in Type-1 Diabetes Mellitus: A Review of Literature.

Type-1 diabetes mellitus (T1DM) is one of the most well-defined and complex metabolic disorders, characterized by hyperglycemia, with a constantly increasing incidence in children and adolescents. While current knowledge regarding the molecules related to the pathogenesis and diagnosis of T1DM is vast, the discovery of new molecules, such as micro ribonucleic acids (micro-RNAs, miRNAs), as well as their interactions with T1DM, has spurred novel prospects in the diagnosis of the disease. This review aims at summarizing current knowledge regarding miRNAs' biosynthesis and action pathways and their role as gene expression regulators in T1DM. MiRNAs follow a complex biosynthesis pathway, including cleaving and transport from nucleus to cytoplasm. After assembly of their final form, they inhibit translation or cause messenger RNA (mRNA) degradation, resulting in the obstruction of protein synthesis. Many studies have reported miRNA involvement in T1DM pathogenesis, mainly through interference with pancreatic b-cell function, insulin production and secretion. They are also found to contribute to ß-cell destruction, as they aid in the production of autoreactive agents. Due to their elevated accumulation in various biological specimens, as well as their involvement in T1DM pathogenesis, their role as biomarkers in early preclinical T1DM diagnosis is widely hypothesized, with future studies concerning their diagnostic value deemed a necessity.

Serum Fibroblast Growth Factor 21 Levels in Children and Adolescents with Hashimoto's Thyroiditis before and after l-Thyroxin Medication: A Prospective Study.

Backgrounds and Objectives: Fibroblast growth factor 21 (FGF-21) is a complex hormone, sharing common sites of action with thyroid hormones. We investigated the association among FGF-21 levels, resting metabolic rate (RMR), and l-thyroxin (LT4) treatment in children and adolescents with Hashimoto's thyroiditis. Materials and Methods: A total of 60 youngsters with chronic autoimmune thyroiditis (AIT) (30 with subclinical hypothyroidism, 30 with euthyroidism) and 30 age and sex-matched healthy participants (5-18 years old) were enrolled in the study. Anthropometric, biochemical parameters, and RMR levels were assessed in all participants; serum FGF-21 levels were measured in the control group and the group with subclinical hypothyroidism before and six months after medication with LT4. Results: FGF-21 levels were lower in the treatment group compared with the healthy ones, but this difference was not statistically significant (p > 0.05); despite the increase in FGF-21 levels after six months of LT4 treatment, this difference was not statistically significant (p > 0.05). Free thyroxin (FT4) levels correlated well with FGF-21 levels (r = 0.399, p < 0.01), but further analysis revealed no interaction between these two variables. Both patient groups presented elevated triglyceride (TG) levels compared to controls (p < 0.05). LT4 treatment had no impact on RMR and lipid or liver or glycaemic parameters. An increase in fat mass and fat-free mass were reported, independently of FGF-21 levels. Conclusions: In youngsters with subclinical hypothyroidism due to Hashimoto's thyroiditis, the serum FGF-21 levels are not significantly lower than in healthy individuals and increase after treatment with LT4 without a statistical significance. Further studies with a large number of young patients and severe hypothyroidism are recommended to confirm our results.

DNA methylation analysis within the IL2RA gene promoter in youth with autoimmune thyroid disease.

BACKGROUND: Alpha-subunit of the interleukin-2 receptor (IL2RA) is involved in the regulation of T-cell function and has been related to autoimmune thyroid disease (AITD). Although the exact mechanisms are not fully understood, promoter methylation might account for differences in gene expression. The aim of this study was to investigate whether there are differences in the percentage of DNA methylation within the IL2RA gene promoter in young patients with AITD. MATERIALS AND METHODS: In a cross-sectional design, the presence of DNA methylation in the IL2RA gene promoter was quantified, by real-time PCR and melting curve analysis, in modified genomic DNA isolated from blood samples of a total of 149 children and adolescents with AITD, including patients with Hashimoto thyroiditis (ΗΤ) (n = 60), Graves' disease (GD) (n = 9), concurrent diagnosis of HT and type 1 diabetes (T1DM + HT) (n = 25), and healthy controls (n = 55). RESULTS: The percentage of DNA methylation in the IL2RA gene promoter was significantly decreased in patients with GD (26.0 ± 4.2%) but not in those with HT (36.3 ± 1.4%) in comparison with controls (41.3 ± 1.5%). CONCLUSIONS: The observed DNA hypomethylation in the IL2RA gene promoter in patients with GD might be related to its increased expression, thus contributing to the etiopathogenesis of GD in childhood and adolescence.

l-selenomethionine supplementation in children and adolescents with autoimmune thyroiditis: A randomized double-blind placebo-controlled clinical trial.

WHAT IS KNOWN AND OBJECTIVE: Although a beneficial effect of selenium (Se) administration has been proposed in adults with autoimmune thyroiditis (AT), there is a paucity of similar data in children and adolescents. The purpose of the study was to investigate whether administration of a high dose of organic Se (200 µg daily as l-selenomethionine) has an effect on antithyroid antibody titres in children and adolescents with AT. METHODS: Seventy-one (71) children and adolescents, with a mean age of 11.3 ± 0.3 years (range 4.5-17.8), diagnosed with AT (antibodies against thyroid peroxidase [anti-TPO] and/or thyroglobulin [anti-Tg] ≥60 IU/mL, euthyroidism or treated hypothyroidism and goitre in thyroid gland ultrasonography) were randomized to receive 200 µg l-selenomethionine or placebo daily for 6 months. Blood samples were drawn for measurement of serum fT4, TSH, anti-TPO and anti-Tg levels, and thyroid gland ultrasonography was performed at the entry to the study and after 6 months of treatment. RESULTS AND DISCUSSION: At the end of the study, a statistically significantly higher reduction in anti-Tg levels was observed in the Se group compared to the placebo group (Δ: -70.9 ± 22.1 vs -6.7 ± 60.6 IU/mL, P = 0.021). Although anti-TPO levels were also decreased in the Se group, this change was not statistically different from that of the control group (Δ: -116.2 ± 68.4 vs +262.8 ± 255.5 IU/mL, P = 0.219). No significant difference in thyroid gland volume was observed between the two study groups (P > 0.05). WHAT IS NEW AND CONCLUSION: In this original study, organic Se supplementation appears to reduce anti-Tg levels in children and adolescents with AT.

Osteoprotegerin increases parallel to insulin resistance in obese adolescents.

Purpose/Aim of the Study: Osteoprotegerin (OPG) is an α tumor necrosis factor receptor superfamily glucoprotein that acts as a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL), exerting an antiresoptive bone effect. It was recently shown that OPG/RANKL axis is activated during vascular calcification, contributing to atherosclerotic lesions formation. Additionally, OPG levels are charachterized as an independent risk factor for overall vascular mortality in obese adults. We aimed to investigate OPG levels in children/adolescents with obesity and explore possible relations with obesity-related insulin resistance (IR). MATERIAL AND METHODS: A total of 160 participants (85 obese) were enrolled. Participants with obesity underwent an oral glucose tolerance test. IR was evaluated according to the homeostasis model assessment-insulin resistance index. Serum OPG levels were determined. RESULTS: OPG levels did not differ significantly between obese subjects and controls in the total sample (p = 0.133). However, in the adolescents' subgroup, serum OPG levels were significantly increased in obesity (p = 0.019). After stratifying participants according to their IR status, only subjects with both obesity and IR exhibited increased OPG levels compared to controls (p < 0.001). Factor analysis further associated OPG levels variation to insulin levels variation and to IR. CONCLUSIONS: Obese individuals demonstrate increased serum OPG levels during puberty. Obesity per se is not the potent factor for this increase; indeed, IR accompanying obesity seems to exert a fundamental role in OPG upregulation.

Supplementation with long chain polyunsaturated fatty acids (LCPUFA) to breastfeeding mothers for improving child growth and development.

BACKGROUND: Long chain polyunsaturated fatty acids (LCPUFA), especially docosahexaenoic acid (DHA), are the most abundant fatty acids in the brain and are necessary for growth and maturation of an infant's brain and retina. LCPUFAs are named "essential" because they cannot be synthesised efficiently by the human body and come from maternal diet. It remains controversial whether LCPUFA supplementation to breastfeeding mothers is beneficial for the development of their infants. OBJECTIVES: To assess the effectiveness and safety of supplementation with LCPUFA in breastfeeding mothers in the cognitive and physical development of their infants as well as safety for the mother and infant. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 August 2014), CENTRAL (Cochrane Library 2014, Issue 8), PubMed (1966 to August 2014), EMBASE (1974 to August 2014), LILACS (1982 to August 2014), Google Scholar (August 2014) and reference lists of published narrative and systematic reviews. SELECTION CRITERIA: Randomised controlled trials or cluster-randomised controlled trials evaluating the effects of LCPUFA supplementation on breastfeeding mothers (including the pregnancy period) and their infants. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and trial quality, performed data extraction and evaluated data accuracy. MAIN RESULTS: We included eight randomised controlled trials involving 1567 women. All the studies were performed in high-income countries. The longest follow-up was seven years.We report the results from the longest follow-up time point from included studies. Overall, there was moderate quality evidence as assessed using the GRADE approach from these studies for the following outcomes measured beyond 24 months age of children: language development and child weight. There was low-quality evidence for the outcomes: Intelligence or solving problems ability, psychomotor development, child attention, and child visual acuity.We found no significant difference in children's neurodevelopment at long-term follow-up beyond 24 months: language development (standardised mean difference (SMD) -0.27, 95% confidence interval (CI) -0.56 to 0.02; two trials, 187 participants); intelligence or problem-solving ability (three trials, 238 participants; SMD 0.00, 95% CI -0.36 to 0.36); psychomotor development (SMD -0.11, 95% CI -0.48 to 0.26; one trial, 113 participants); motor development (SMD -0.23, 95% CI -0.60 to 0.14; one trial, 115 participants), or in general movements (risk ratio, RR, 1.12, 95% CI 0.58 to 2.14; one trial, 77 participants; at 12 weeks of life). However, child attention scores were better at five years of age in the group of children whose mothers had received supplementation with fatty acids (mean difference (MD) 4.70, 95% CI 1.30 to 8.10; one study, 110 participants)). In working memory and inhibitory control, we found no significant difference (MD -0.02 95% CI -0.07 to 0.03 one trial, 63 participants); the neurological optimality score did not present any difference (P value: 0.55).For child visual acuity, there was no significant difference (SMD 0.33, 95% CI -0.04 to 0.71; one trial, 111 participants).For growth, there were no significant differences in length (MD -0.39 cm, 95% CI -1.37 to 0.60; four trials, 441 participants), weight (MD 0.13 kg, 95% CI -0.49 to 0.74; four trials, 441 participants), and head circumference (MD 0.15 cm, 95% CI -0.27 to 0.58; three trials, 298 participants). Child fat mass and fat mass distribution did not differ between the intervention and control group (MD 2.10, 95% CI -0.48 to 4.68; one trial, 115 participants, MD -0.50, 95% CI -1.69 to 0.69; one trial, 165 participants, respectively).One study (117 infants) reported a significant difference in infant allergy at short-term follow-up (risk ratio (RR) 0.13, 95% CI 0.02 to 0.95), but not at medium-term follow-up (RR 0.52, 95% CI 0.17 to 1.59).We found no significant difference in two trials evaluating postpartum depression. Data were not possible to be pooled due to differences in the describing of the outcome. One study (89 women) did not find any significant difference between the LCPUFA supplementation and the control group at four weeks postpartum (MD 1.00, 95%CI -1.72 to 3.72).No adverse effects were reported. AUTHORS' CONCLUSIONS: Based on the available evidence, LCPUFA supplementation did not appear to improve children's neurodevelopment, visual acuity or growth. In child attention at five years of age, weak evidence was found (one study) favouring the supplementation. Currently, there is inconclusive evidence to support or refute the practice of giving LCPUFA supplementation to breastfeeding mothers in order to improve neurodevelopment or visual acuity.

Genital Abnormalities and Growth Retardation as Early Signs of Dilated Cardiomyopathy with Ataxia Syndrome.

Dilated cardiomyopathy with ataxia syndrome is a rare mitochondrial disease caused by autosomal recessive mutations in the DNAJC19 gene. The disease has been described in detail in the Canadian Hutterite population, but a few sporadic cases with de novo mutations have been published worldwide. We describe a homozygous pathogenic variant in the DNAJC19 gene, diagnosed in Northern Greece, presenting with genital anomalies, growth failure, cardiomyopathy, and ataxia, but without increased urinary 3-methylglutaconic acid and additional presence of vitamin D disorders, hypercalciuria, and osteopenia. This case not only expands the clinical characteristics of 3-methylglutaconic aciduria type V (MGCA5) but also highlights the power of genetic analysis for detecting a diagnosis when the metabolic screen is negative.

Evaluation of Health-Related Quality of Life in Adolescents With Obesity: A Randomized Qualitative Study Among Healthcare Professionals.

Adolescent obesity constitutes a disorder with physical and psychosocial implications. Childhood and adolescent obesity rates are constantly increasing worldwide. Since adolescent obesity is a chronic disease, which is part of noncommunicative degenerative diseases, its holistic approach decisively includes the assessment of its impact on quality of life. The use of the tools Pediatric Quality of Life Inventory 4.0 (PedsQL4.0) and The Impact of Weight on Quality of Life for Kids (IWQOL-Kids), the familiarity of health professionals with them, their applicability, and relevance in clinical practice, are a cornerstone in the promotion of health services in adolescent obesity. The present randomized qualitative study aimed to highlight the attitudes and preferences of pediatricians on the assessment of health-related quality of life (HRQoL), among obese adolescents. The sample consists of 120 pediatricians, randomly selected from the totality of municipality-registered pediatricians (Municipality of Thessaloniki, Greece) who were interviewed in a semi-structured way, regarding their attitudes in the assessment of health-related quality of life, as measured by the PedsQL4.0 and IWQOL-Kids tools. The interviews revealed that most participants gained insight into the HRQoL assessment process during the present study interview with the researchers. Only eight (n=8/120) participants were familiar with the explored tools, PedsQL4.0 and IWQOL-KIDS. The remaining sample (n=112/120) was unfamiliar with both the two questionnaires and their content as well. Among the referred barriers to the usage of the tools, lack of time was stated as the pivotal factor hindering the implementation of the tools in clinical practice. There was no consensus on the preferred questionnaire among the participating healthcare professionals. All participants stated that the use of one or both questionnaires would have added significant value to the support and care of adolescents with obesity. Tools assessing HRQoL present low familiarity among pediatricians in real-world data. Focus on the engagement of the healthcare providers in the evaluation of obesity-related quality of life is unequivocal, in order to improve health care status in adolescents with obesity.

Earlier Menarche in Greek Girls Born by Caesarean Section: A Case-Control Study.

Objectives: The purpose of this study was to report on the menarcheal age in girls of Greek origin and assess its potential associations with their demographic and perinatal data, as well as their maternal menarcheal age. Methods: In this case-control study, adolescent girls were recruited between September 2021 and September 2022 from two Pediatric Endocrinology Units, Aristotle University of Thessaloniki, Greece. Eligible participants included Greek girls up to the age of 18 years, with menarche and the absence of chronic disease or chronic medication use. Participants were divided into two groups, the early menarche group and the control group (menarche before or after 11 years of age, respectively). Data included participants' maternal menarcheal age, their chronological age, place of residence, anthropometric data (at recruitment) and perinatal data (birth order, gestational age, type of delivery, birth weight/length). Results: A total of 100 girls aged 7-17 years (mean age ± SD 12.51 ± 2.59 years) were included in this study. The mean ± SD menarcheal age of the total sample was 11.47 ± 1.55 years (median 11.20 years; range 7.50-16.25 years); 43% had early menarche (median menarcheal age 10.50 years; range 7.50-10.91 years), and 57% had menarche after age 11 (median menarcheal age 12.08 years; range 11.00-16.25 years). The caesarean section rate was significantly (p < 0.001) higher in girls with early menarche (83.7%) than controls, whereas other variables did not differ significantly between groups. Conclusions: This Greek sample demonstrated a relatively young age at menarche with a significant proportion of girls with early menarche; in the latter group, the rate of caesarian sections was significantly higher than controls.

The efficacy of automated insulin delivery systems in children and adolescents with type 1 diabetes Mellitus: A systematic review and meta-analysis of randomized controlled trials.

AIMS: Insulin administration is the treatment of choice for people with type 1 diabetes mellitus (T1D). Technological advances have led to the development of automated insulin delivery (AID) systems, aiming to optimize the quality of life of patients with T1D. We present a systematic review and meta-analysis of the current literature about the efficacy of AID systems in children and adolescents with T1D. METHODS: We conducted a systematic literature search for randomized controlled trials (RCTs) until August 8th, 2022, investigating the efficacy of AID systems in the management of patients < 21 years of age with T1D. A priori subgroup and sensitivity analyses based on different settings (free-living settings, type of AID system, parallel group or crossover design) were also conducted. RESULTS: In total, 26 RCTs reporting a total of 915 children and adolescents with T1D were included in the meta-analysis. AID systems revealed statistically significant differences in the main outcomes, such as the proportion of time in the target glucose range (3.9-10 mmol/L) (p < 0.00001), in hypoglycemia (<3.9 mmol/L) (p = 0.003) and mean proportion of HbA1C (p = 0.0007) compared to control group. CONCLUSIONS: According to the present meta-analysis, AID systems are superior to insulin pump therapy, sensor-augmented pumps and multiple daily insulin injections. Most of the included studies have a high risk of bias because of allocation, blinding of patients and blinding of assessment. Our sensitivity analyses showed that patients < 21 years of age with T1D can use AID systems, after proper education, following their daily activities. Further RCTs examining the effect of AID systems on nocturnal hypoglycemia, under free-living settings and studies examining the effect of dual-hormone AID systems are pending.

Coexistence of Autoimmune Thyroiditis and Juvenile Idiopathic Arthritis.

PURPOSE: Autoimmune thyroid disease seems to occur more often in children with juvenile idiopathic arthritis (JIA) than in the general pediatric population. We investigated the prevalence of autoimmune thyroiditis (Hashimoto's thyroiditis) in young patients with JIA in Greece, which has not been evaluated previously. METHODS: This descriptive study included patients with JIA followed up at the Pediatric Rheumatology Unit of the Second Department of Pediatrics of a tertiary general hospital in Thessaloniki, Greece. All patients were diagnosed and sorted according to the classification criteria of the International League of Associations for Rheumatology. The presence of thyroid autoantibodies was considered for determining autoimmune thyroiditis. Basic demographic, clinical, and laboratory data were collected from patients' records.  Results: The analyzed sample comprised 130 patients with JIA (mean age 12.22 years; 69.2% female). Most patients (70%) had a family history of at least one autoimmune disease and 30.8% of Hashimoto's thyroiditis. More than half (53.8%) had enthesitis-related arthritis (ERA), 22.3% had oligoarthritis, and 15.4% had psoriatic arthritis. Thyroid autoantibodies were detected in 22/130 patients (16.9%) suggesting autoimmune thyroiditis; most of these patients were euthyroid, whereas 3/22 (13.6%) had overt hypothyroidism determined by elevated levels of thyroid-stimulating hormone, decreased levels of free thyroxine, and typical ultrasound findings for Hashimoto's thyroiditis. The prevalence of clinical cases of Hashimoto's disease was 2.3%. CONCLUSIONS: The prevalence of autoimmune thyroiditis in our JIA cohort is higher compared to the general population and consistent with the previously reported range. Hence, investigation for thyroid autoimmunity should be included in the workup of patients with JIA.

The Prognostic Significance of BRAF Gene Analysis in Children and Adolescents with Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis.

Thyroid cancer represents the prominent endocrine cancer in children. Papillary thyroid cancer (PTC) constitutes its most frequent (>90%) pediatric histological type. Mutations energizing the mitogen-activated-protein kinase (MAPK) pathway are definitely related to PTC. Its most common genetic alteration is in proto-oncogene B-Raf (BRAF). Mutated BRAF is proposed as a prognostic tool in adult PTC. We conducted a systematic review and meta-analysis evaluating the association of mutated BRAF gene and prognostic clinicopathological characteristics of PTC in children/adolescents. Systematic search for relevant studies included PubMed, MEDLINE, Scopus, clinicaltrials.gov and Cochrane Library. Pooled estimates of odds ratios for categorical data and mean difference for continuous outcomes were calculated using random/fixed-effect meta-analytic models. BRAFV600E mutation presents a pooled pediatric/adolescent prevalence of 33.12%. Distant metastasis is significantly associated with mutated BRAF gene (OR = 0.32, 95% CI = 0.16-0.61, p = 0.001). Tumor size (MD = -0.24, 95% CI = -0.62-0.135, p = 0.21), multifocality (OR = 1.13, 95% CI = 0.65-2.34, p = 0.74), vascular invasion (OR = 1.17, 95% CI = 0.67-2.05, p = 0.57), lymph node metastasis (OR = 0.92, 95% CI = 0.63-1.33, p = 0.66), extra-thyroid extension (OR = 0.78, 95% CI = 0.53-1.13, p = 0.19) and tumor recurrence (OR = 1.66, 95% CI = 0.68-4.21, p = 0.376) presented no association or risk with BRAF mutation among pediatric/adolescent PTC. Mutated BRAF gene in children and adolescents is less common than in adults. Mutation in BRAF relates significantly to distant metastasis among children/adolescents with PTC.

The Effect of Saffron Kozanis (Crocus sativus L.) Supplementation on Weight Management, Glycemic Markers and Lipid Profile in Adolescents with Obesity: A Double-Blinded Randomized Placebo-Controlled Trial.

Global rates of adolescent obesity have led the World Health Organization to consider the disease a pandemic that needs focus. In search of new anti-obesity agents, Crocus sativus, popularly known as saffron, is a nutraceutical agent, praised for its beneficial effects. The study aimed to investigate the possible effect of Kozanis saffron administration on weight management of obese prediabetic adolescents. Seventy-four obese prediabetic adolescents participated in a double-blind placebo-controlled trial of three arms, randomly assigned to receive either Kozanis saffron (n = 25, 60 mg/day), metformin (n = 25, 1000 mg/day) or a placebo (n = 24), for twelve weeks. Anthropometry, glycemic markers and lipid profiles were investigated at baseline and post-intervention. Saffron supplementation significantly reduced the weight z-score, BMI, BMI z-score and waist circumference (WC) of obese adolescents; however, this reduction was less significant compared to the effect of metformin. Metformin administration offered a significantly more profound improvement in anthropometry compared to saffron administration. Saffron administration also provided significant improvements in weight, weight z-scores, BMI values, BMI z-scores and WCs compared to the placebo. Saffron supplementation failed to change any glycemic marker, but provided a significant reduction in fasting triglyceride levels and also a significant increase in fasting HDL levels. Saffron Kozanis constitutes a promising nutraceutical option for adolescents and children with obesity and prediabetes in need of weight management.

Methylation haplotypes of the insulin gene promoter in children and adolescents with type 1 diabetes: Can a dimensionality reduction approach predict the disease?

DNA methylation of cytosine-guanine sites (CpGs) is associated with type 1 diabetes (T1D). The sequence of methylated and non-methylated sites in a specific genetic region constitutes its methyl-haplotype. The aim of the present study was to identify insulin gene promoter (IGP) methyl-haplotypes among children and adolescents with T1D and suggest a predictive model for the discrimination of cases and controls according to methyl-haplotypes. A total of 40 individuals (20 T1D) participated. The IGP region from peripheral whole blood DNA of 40 participants (20 T1D) was sequenced using next-generation sequencing, sequences were read using FASTQ files and methylation status was calculated by python-based pipeline for targeted deep bisulfite sequenced amplicons (ampliMethProfiler). Methylation profile at 10 CpG sites proximal to transcription start site of the IGP was recorded and coded as 0 for unmethylation or 1 for methylation. A single read could result in '1111111111' methyl-haplotype (all methylated), '000000000' methyl-haplotype (all unmethylated) or any other combination. Principal component analysis was applied to the generated methyl-haplotypes for dimensionality reduction, and the first three principal components were employed as features with five different classifiers (random forest, decision tree, logistic regression, Naive Bayes, support vector machine). Naive Bayes was the best-performing classifier, with 0.9 accuracy. Predictive models were evaluated using receiver operating characteristics (AUC 0.96). Methyl-haplotypes '1111111111', '1111111011', '1110111111', '1111101111' and '1110101111' were revealed to be the most significantly associated with T1D according to the dimensionality reduction method. Methylation-based biomarkers such as IGP methyl-haplotypes could serve to identify individuals at high risk for T1D.

The Role of the Gut Microbiome in Youth with Polycystic Ovary Syndrome: A Systematic Review.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age and female adolescents. The diagnosis of PCOS is difficult during puberty due to overlapping of the criteria with normal variations of menstruation during this age period. There are insufficient data on the gut microbiome and PCOS and potential mechanisms linking the two. The present systematic review aimed to detect dysbiosis patterns in youth with PCOS, compared with healthy controls. METHODS: One hundred seventy-eight studies were identified by a databases search and sixty-eight by a full-text assessment for eligibility; four were included in the systematic review and underwent quality control. RESULTS: The results of the study were controversial in accordance to findings from the literature. A change in gut microbiome α diversity was found in PCOS adolescents, with no significant alterations in ß diversity. Almost all studies found Firmicutes, Bacteroidetes, and Actinobacteria in abundance in both groups, with changes in family composition and fluctuations at the phylum level. A statistically significant association between these changes and clinical or biochemical features of the syndrome was described. CONCLUSIONS: This systematic review confirmed gut microbiota dysbiosis in youth with PCOS. However, further data are needed to clarify these changes and to build a strategy to prevent the syndrome.

Predictive Factors for Pediatric Craniopharyngioma Recurrence: An Extensive Narrative Review.

Despite being classified as benign tumors, craniopharyngiomas (CPs) are associated with significant morbidity and mortality due to their location, growth pattern, and tendency to recur. Two types can be identified depending on age distribution, morphology, and growth pattern, adamantinomatous and papillary. The adamantinomatous CP is one of the most frequently encountered central nervous system tumors in childhood. Our aim was to review the relevant literature to identify clinical, morphological, and immunohistochemical prognostic factors that have been implicated in childhood-onset CP recurrence. Lack of radical surgical removal of the primary tumor by an experienced neurosurgical team and radiotherapy after a subtotal excision has been proven to significantly increase the recurrence rate of CP. Other risk factors that have been consistently recognized in the literature include younger age at diagnosis (especially <5 years), larger tumor size at presentation, cystic appearance, difficult tumor location, and tight adherence to surrounding structures, as well as the histological presence of whorl-like arrays. In addition, several other risk factors have been studied, albeit with conflicting results, especially in the pediatric population. Identifying risk factors for CP recurrence is of utmost importance for the successful management of these patients in order to ultimately ensure the best prognosis.

Insulin resistance is associated with at least threefold increased risk for prothrombotic state in severely obese youngsters.

UNLABELLED: Obesity in childhood increases the risk for early adult cardiovascular disease. However, the underlying mechanism is not fully known. The aims of this study were to measure levels of prothrombotic factors and examine their possible association with obesity and insulin resistance in obese children and adolescents. A total of 313 obese children and adolescents were recruited. In a cross-sectional design, we measured anthropometric parameters, plasminogen activator inhibitor-1-antigen (PAI-1-Ag), von Willebrand factor-antigen (vWF-Ag), fibrinogen (FB), lipids, fasting glucose, and insulin (FI) levels. Insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA-IR) index. Boys presented significantly higher PAI-1-Ag levels than girls (82.6 vs. 71.3 ng/ml, p = 0.01). Higher levels of PAI-1-Ag (96.8 vs. 69 ng/ml, p < 0.001), vWF-Ag (123.5 vs. 107.6%, p = 0.004) but not FB (353.1 vs. 337.6 mg/dl, p = 0.137) were found in insulin-resistant (IR) participants after adjusted for age, gender, and pubertal stage. IR patients were at 2.98 (CI: 1.084-8.193) and 4.86 (CI: 1.119-15.606) times greater risk for high PAI-1-Ag and vWF-Ag levels, respectively. All three prothrombotic factors were positively correlated with body mass index (BMI) and FI levels (p < 0.05), but only PAI-1-Ag and vWF-Ag were significantly correlated with HOMA-IR index (p ≤ 0.001). After adjustment for confounding factors, both BMI and HOMA-IR indices remained significantly associated with PAI-1-Ag (r2 = 0.225, p < 0.001) and vWF-Ag levels (r2 =0.077, p = 0.003). CONCLUSION: This study shows that obesity in youngsters, when accompanied with insulin resistance, is associated with at least threefold increased risk for elevated levels of prothrombotic factors, contributing to the early development of atherothrombosis. This impaired prothrombotic state may partially explain the increased risk for developing cardiovascular disease later in adulthood.

Diagnosis, treatment and prevention of type 2 diabetes mellitus in children and adolescents.

During the last two decades, there have been several reports of an increasing incidence of type 2 diabetes mellitus (T2DM) in children and adolescents, especially among those belonging to minority ethnic groups. This trend, which parallels the increases in prevalence and degree of pediatric obesity, has caused great concern, even though T2DM remains a relatively rare disease in children. Youth T2DM differs not only from type 1 diabetes in children, from which it is sometimes difficult to differentiate, but also from T2DM in adults, since it appears to be an aggressive disease with rapidly progressive ß-cell decline, high treatment failure rate, and accelerated development of complications. Despite the recent research, many aspects of youth T2DM still remain unknown, regarding both its pathophysiology and risk factor contribution, and its optimal management and prevention. Current management approaches include lifestyle changes, such as improved diet and increased physical activity, together with pharmacological interventions, including metformin, insulin, and the recently approved glucagon-like peptide-1 analog liraglutide. What is more important for everyone to realize though, from patients, families and physicians to schools, health services and policy-makers alike, is that T2DM is a largely preventable disease that will be addressed effectively only if its major contributor (i.e., pediatric obesity) is confronted and prevented at every possible stage of life, from conception until adulthood. Therefore, relevant comprehensive, coordinated, and innovative strategies are urgently needed.

Pseudohypoparathyroidism Type 1A with Normocalcaemia, due to the Novel C.389A>G Variant of Exon 5 of the Guanine Nucleotide-Binding Protein, α-Stimulating Gene.

Pseudohypoparathyroidism type 1A (PHP1A) is a rare disease caused by molecular defects in the maternally-inherited allele of the guanine nucleotide-binding protein, α-stimulating (GNAS) gene. The GNAS gene encodes the stimulatory G-protein α-subunit that regulates production of the second messenger cyclic adenosine monophosphate. Heterozygous inactivating mutations in these specific loci are responsible for a spectrum of phenotypic characteristics of the disease, including clinical features of the Albright's hereditary osteodystrophy, due to resistance to parathyroid hormone (PTH). We report a case of PHP1A and explore the underlying novel point mutation of the GNAS gene that leads to an atypical PHP1A phenotype. A male patient with a round face, short stature, and brachydactyly accompanied by normocalcaemia and mild PTH resistance consulted at our center. The GNAS encoding region from the patient and both of his parents were amplified and sequenced directly in a sample of peripheral blood leukocytes. A novel c.389A>G point mutation in exon 5 of the GNAS gene, resulting in a p.Tyr130Cys peptidic chain change of the Gsα protein, detected in the proband, in heterozygous state. Sequencing of the GNAS gene from his parents did not reveal the c.389A>G mutation, confirming a de novo proband genotype. The maternal origin of the affected GNAS allele, along with mild PTH resistance, confirmed the PHP1A diagnosis. PHP1A, caused by inactivating GNAS mutations, presents a range of complex clinical phenotypes. The novel c.389A>G GNAS mutation presented in this case expands the spectrum of known PHP1A molecular defects and describes the associated phenotype.