Recurrent copy number variations as risk factors for autism spectrum disorders: analysis of the clinical implications.

Chromosomal microarray analysis (CMA) is currently considered a first-tier diagnostic assay for the investigation of autism spectrum disorders (ASD), developmental delay and intellectual disability of unknown etiology. High-resolution arrays were utilized for the identification of copy number variations (CNVs) in 195 ASD patients of Greek origin (126 males, 69 females). CMA resulted in the detection of 65 CNVs, excluding the known polymorphic copy number polymorphisms also found in the Database of Genomic Variants, for 51/195 patients (26.1%). Parental DNA testing in 20/51 patients revealed that 17 CNVs were de novo, 6 paternal and 3 of maternal origin. The majority of the 65 CNVs were deletions (66.1%), of which 5 on the X-chromosome while the duplications, of which 7 on the X-chromosome, were rarer (22/65, 33.8%). Fifty-one CNVs from a total of 65, reported for our cohort of ASD patients, were of diagnostic significance and well described in the literature while 14 CNVs (8 losses, 6 gains) were characterized as variants of unknown significance and need further investigation. Among the 51 patients, 39 carried one CNV, 10 carried two CNVs and 2 carried three CNVs. The use of CMA, its clinical validity and utility was assessed.

Increased Maternal Serum Interleukin-6 Concentrations at 11 to 14 Weeks of Gestation in Low Risk Pregnancies Complicated with Gestational Diabetes Mellitus: Development of a Prediction Model.

The aim of the study was to examine interleukin-6 (IL-6) maternal serum concentration at 11 to 14 gestational weeks in normal pregnancies and pregnancies complicated by gestational diabetes mellitus (GDM) and to create first trimester prediction models for GDM. Case-control study conducted in a Fetal Medicine Unit. Study population included 40 GDM cases and 94 controls. Maternal characteristics, first trimester ultrasound markers, biochemical indices, and IL-6 levels were used for our analysis. IL-6 was related to maternal weight among the maternal characteristics, (R(2)=0.0679, p=0.01). IL-6 was increased (p=0.001) in the GDM group (median=2 pg/ml) compared to the control group (median=1.5 pg/ml) even after adjustment for maternal weight. IL-6 was inversely related to birth weight adjusted for gestational age at delivery (r=-0.3382, p<0.001) and glucose levels at oral glucose test. Maternal weight and age were the only predictors of GDM among the maternal characteristics [Detection Rate (DR)=59.4%; for 25% False Positive Rate (FPR); Area Under the Curve (AUC)=0.7291; Model R(2)=0.1096, p<0.001]. IL-6 alone was a significant predictor of GDM (DR=51.3%; for 25% FPR; AUC=0.6731; Model R(2)=0.0616, p<0.001). Combination of maternal characteristics with IL-6 yielded an improved prediction (DR=67.5%; for 25% FPR; AUC=0.7586; Model R(2)=0.1521, p<0.001). IL-6 concentrations are increased at 11-14 weeks in pregnancies with GDM. Combination of maternal characteristics and maternal serum IL-6 levels may provide effective first trimester screening for GDM.

Enhanced oxidative stress and platelet activation combined with reduced antioxidant capacity in obese prepubertal and adolescent girls with full or partial metabolic syndrome.

In adults, obesity is a main factor implicated in increased oxidative stress (OS), platelet activation (PA) and impaired antioxidant status (AS), all predisposing factors for cardiovascular disease leading to increased morbidity and mortality. Furthermore, the metabolic syndrome (MetS) is an important cardiovascular risk factor, which progressively develops and may already be present during late childhood or adolescence. However, scarce data exist on oxidative-antioxidant balance and PA in childhood and adolescence in the presence of partial (PMetS) or full MetS. The aim of the study was to evaluate OS, PA, and AS in prepubertal and adolescent obese girls with partial or full MetS. 96 girls with a clinical and metabolic evaluation for obesity and 44 healthy normal-weight sex- and age-matched girls were studied. IDF-adopted criteria were used to define full and partial MetS and the patient population was divided into 4 groups: the first comprised 31 pre-pubertal girls with PMetS (PR-PMetS), the second 37 adolescents with PMetS (AD-PMetS), the third 10 prepubertal girls with full MetS (PR-MetS), and the fourth 18 adolescents with full MetS (AD-MetS). The OS was evaluated by measuring plasma 15-F(2t)-Isoprostane levels (15-F(2t)-IsoP) and protein carbonyls, PA by thromboxane B(2) levels (TXB(2)), and AS by serum vitamin E and plasma total antioxidant capacity (TAC) levels. 15-F(2t)-IsoP, protein carbonyls, and TXB(2) levels were significantly gradually amplified, and vitamin E and TAC reduced, and significantly correlated with obesity from childhood to adolescence and from partial to full MetS. This study demonstrates the loss of the normal homeostatic balance between oxidant-antioxidant state in obese children and adolescents with manifestations of partial and full MetS.

Associations between circulating N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and adiponectin concentrations depend on obesity level in female adolescents: gender dimorphic findings.

N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) is an established biomarker for heart failure in adults, while its plasma concentrations are altered in adult obesity. Plasma adiponectin concentrations are decreased in obesity and low levels are associated with disorders with an increased cardiometabolic risk. A few studies support an association between these two markers in adults with coronary heart disease. Such relations have not been investigated in children with obesity, which is the most prevalent risk factor for cardiovascular disease. Ninety-six children, 24 obese/25 normal BMI boys, and 23 obese/24 normal BMI girls, aged 10-16, were studied. Plasma NT-proBNP was measured using electrochemiluminescence, and adiponectin and other metabolic risk factors, such as glucose, insulin, cholesterol, triglycerides (TG), HDL, and LDL using standard methodology. The findings were gender dimorphic. In overweight and obese females (mean BMI z-score: 2.65+/-1.69), plasma NT-proBNP concentrations correlated significantly with adiponectin levels (r=0.4, r(2)=0.05, p=0.013), while in those with obesity defined as BMI z-score >2.5 (mean BMI z-score: 3.67+/-1.08, n=20) this association was stronger (r=0.6, r(2)=0.22, p=0.005). Adiponectin also correlated significantly with BMI z-scores, TG, HDL, and insulin levels. In boys, there was no correlation between NT-proBNP and adiponectin. NT-proBNP correlated significantly with HDL, while adiponectin correlated with TG, fasting insulin, and the Homeostasis Assessment Model (HOMA) Index. The positive association between NT-proBNP and adiponectin depends on the severity of obesity and is gender dimorphic. This positive correlation in females might be a potential protective mechanism against atherosclerosis in later life.

Bullying victimization: Associated contextual factors in a Greek sample of children and adolescents.

School bullying is increasingly recognized as an important factor affecting both individual's wellbeing and social functioning. Several studies provide evidence for the potential role of contextual factors that relate to bullying victimization such as the socioeconomic status of the parents/ family, the quality of family and home environment, the school climate, structure and ethos, and also various community characteristics. The objectives of this school-based, cross-sectional study were to report the prevalence of the perception of being bullied in a sample of Greek children and adolescents from 6 to 17 years of age and to investigate the relations among the subjective impression of bullying victimization and several sociodemographic and socioeconomic factors. We hypothesized that influences external to individual children and adolescents play a decisive role to their perception of being victimized. Bullying victimization was measured through a simple "yes/no" question, which confirmed or rejected respectively the fact that the child or adolescent has been at some time victimized in the school environment. Also, demographic and socioeconomic data about the families of children and adolescents were collected. A total of 1,588 children (51.8% females, mean age ± SD: 12.9±2.8 years) were assessed. The overall prevalence of victimization was 10.4%. Multiple logistic regression analysis on the probability of being victimized identified that living at a main urban center (Odds Ratio[OR]: 2.63, CI: 1.78-3.87, p<0.001), presence of a person with a chronic illness at home (OR: 1.90, CI: 1.12-3.20, p=0.016), poor family economic status (OR: 1.83, CI: 1.05-3.20, p=0.032),and increased number of adults at home (OR: 2.00, CI: 1.00-3.77, p=0,041) had a positive correlation with the prevalence of reported bullying victimization. Moreover, higher parental educational level related to lower probability of victimization (OR: 0.88, CI: 0.78-0.99, p=0.05). These findings demonstrate that several demographic and socioeconomic factors play a potential role in bullying victimization among schoolchildren. Our results also highlight the need to consider the influence of contextual factors in the design of targeting efforts countering and/or preventing bullying victimization.

The immediate and long-term impact of physical and/or emotional stress from motor vehicle accidents on circulating stress hormones and adipo-cytokines in children and adolescents.

Motor vehicle accidents (MVA) represent a complex physical and emotional stressor. Consequent short- and/or long-term alterations on the circulating concentrations of stress hormones and adipo-cytokines may have potential health implications. Fifty-nine children and adolescents, aged 7-18 years, were evaluated within 24 h after hospitalization for a MVA, and 1 and 6 months later; 40 children served as controls. We examined longitudinally the effects of physical injury-associated (PI) group vs. emotional-only stress (ES) group on circulating cortisol, catecholamine, interleukin (IL)-6, leptin and adiponectin concentrations. Within 24 h after the accident, serum cortisol concentration was greater than the controls in the PI but not the ES group (p = 0.02), while serum IL-6 concentration was greater in both trauma groups than in the controls (p = 0.004 for PI, p = 0.04 for ES). Adiponectin concentration was lower in the PI than the ES (p = 0.031) and the control (p = 0.019) groups and this was mainly attributed to females. The catecholamine and leptin concentrations were similar in the three groups. At the 1 and 6 month evaluations, cortisol and IL-6 concentrations in both trauma groups became normal. Adiponectin concentration in females, however, remained low 1 and 6 months after the accident (p = 0.03 for month six). In conclusion, circulating IL-6 concentration was influenced equally by the physical and emotional stress shortly after the trauma. Physical but not emotional-only stress lowered the circulating adiponectin concentrations in females and this effect persisted for at least 6 months.

Biology of post-traumatic stress disorder in childhood and adolescence.

Diverse patterns of cortisol secretion with consistently high circulating catecholamines have been reported in post-traumatic stress disorder (PTSD), an anxiety state that develops after exposure to traumatic life events. Indeed, peripheral cortisol levels have been reported to be low or normal in the majority of adult chronic PTSD studies, whereas, in most paediatric studies, high cortisol values have been documented. Longitudinal studies on PTSD biology, including the transition from childhood to adulthood, may shed light on these discrepancies. In children, elevated evening salivary cortisol in the aftermath of the trauma was predictive of PTSD development 6 months later, whereas plasma interleukin-6 correlated positively with evening cortisol and was equally predictive of later PTSD. Longitudinal assessment of PTSD children 1 and 6 months later revealed progressive normalisation of cortisol levels, whereas noradrenaline concentrations became gradually higher. We hypothesise that, in adults with chronic PTSD, low cortisol levels, together with high catecholamines, may reflect a late event in the natural history of the disorder, months or years after the trauma. The progressive divergence of cortisol and noradrenaline concentrations over time may be responsible for PTSD maintenance in children and explain the differences between the child and adult PTSD endophenotypes. In adults studied immediately after the trauma, and by contrast to children, low cortisol levels are predictive of later PTSD development. Our hypothesis that low cortisol levels may reflect a previous trauma, earlier in development, is supported by the well established observation that prior trauma is a risk factor for a new PTSD diagnosis. The developmental stage of an individual in relation to previous exposure to trauma and PTSD vulnerability are crucial variables that may determine clinical and biological PTSD phenotypes and explain the discrepancies between adults and children in reported cortisol levels.

Post-traumatic Stress Disorder in children and adolescents: from Sigmund Freud's "trauma" to psychopathology and the (Dys)metabolic syndrome.

Post-traumatic Stress Disorder (PTSD) is an anxiety syndrome that develops after exposure to traumatic life events. Symptoms include re-experience of the initial trauma, avoidance of stimuli associated with the trauma and symptoms of excessive arousal. Neuroendocrine studies in adults with PTSD have demonstrated that basal cerebrospinal fluid (CSF) CRH levels are elevated and urinary cortisol levels are variable--low in the majority of cases--whereas other studies demonstrate no differences in urinary and plasma cortisol concentrations. Urinary catecholamine excretion is higher in PTSD patients than those of control subjects and other psychiatric disorders. Children may differ from adults in their psychologic and physiologic responses to severe stressors. Also, exposure to stress during critical periods of development may have irreversible effects on behavioral maturation and may affect specific vulnerable brain areas, altering CNS development. Similar to findings in adult studies, PTSD in children is characterized by increased sympathetic nervous system (SNS) activity, as indicated by elevated norepinephrine levels in the periphery. High cortisol levels in urine or saliva have been reported in most studies of childhood PTSD, while prospective longitudinal studies concerning the natural history of neuroendocrine changes in pediatric PTSD after an acute stressor are limited. The identification of neurobiologic changes in response to early adverse experiences is of major importance for the prognosis, prevention, management, and treatment of children and adolescents at risk for or suffering from PTSD.