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ObjectiveGNRH analog (GNRHa) therapy has not been supported by beneficial effects on adult stature in girls with early puberty. Furthermore, an increased prevalence of polycystic ovary syndrome (PCOS) has been described in girls treated for central precocious puberty. Women with PCOS are at increased risk of cardiometabolic dysfunctions and infertility. Our aim was to assess GNRHa effectiveness on reaching adult stature and the risk of PCOS in girls with early puberty.DesignLongitudinal study of GNRHa-treated and GNRHa-untreated girls at baseline and at final height.MethodsTwenty-five GNRHa-treated girls and 55 controls were compared. Insulin resistance (IR; homeostasis model assessment of IR (HOMA-IR) and glucose-to-insulin ratio (G/I)), the effect of GNRHa on final height, and the prevalence of PCOS were assessed.ResultsIn GNRHa-treated girls, no significant difference was found between predicted final height and final height, whereas a significant difference was detected in untreated girls (P=0.0001). At final height, GNRHa-treated girls showed higher HOMA-IR and lower G/I (P=0.03 for both) as well as higher DHEAS and androstenedione levels (P=0.02 and P=0.01 respectively) than untreated girls. The prevalence of PCOS and hyperandrogenemia was significantly higher in GNRHa-treated adolescents than in untreated adolescents (36 and 14.5% respectively, P=0.04; 56 and 23.6% respectively, P=0.01). Finally, gonadotropin-suppressive therapy was significantly related to PCOS during adolescence (P=0.03).ConclusionsIn girls with early puberty, GNRHa therapy is associated with the achievement of predicted final height; nevertheless, this treatment seems to act as an independent risk factor for the development of PCOS already during adolescence.

Structural traumatic brain injury (TBI) can result in late-occurring health sequelae, consisting mainly of neuroendocrine dysfunctions. Studies have suggested that hypopituitarism is relatively common following TBI in childhood, but recent evidence suggests that the incidence appears to be frequently over-estimated. We recently showed that permanent hypopituitarism is rare after both inflicted and accidental structural TBI in early childhood. This article is protected by copyright. All rights reserved. Language: en

We evaluated the growth patterns of infants born large-for-gestational-age (LGA) from birth to age 1 year compared to those born appropriate-for-gestational-age (AGA). In addition, we investigated possible epigenetic changes associated with being born LGA. Seventy-one newborns were classified by birth weight as AGA (10th–90th percentile; n = 42) or LGA (>90th percentile; n = 29). Post-natal follow-up until age 1 year was performed with clinical assessments at 3, 6 and 12 months. Genome-wide DNA methylation was analysed on umbilical tissue in 19 AGA and 27 LGA infants. At birth, LGA infants had greater weight (p

OBJECTIVE To assess potential alterations in soluble and endogenous secretory receptors for advanced glycation end products (sRAGE and esRAGE) in normal-weight (NW) and obese (Ob) children born small (SGA) and large (LGA) compared with appropriate for gestational age (AGA) subjects and to explore if birth weight (BW), insulin resistance (IR), and obesity represent independent risk factors. RESEARCH DESIGN AND METHODS We categorized 130 prepubertal children into six groups according to BW and obesity and evaluated sRAGE, esRAGE, and homeostasis model assessment of IR. RESULTS sRAGE and esRAGE were lower in Ob SGA and LGA children than Ob AGA subjects (all P < 0.05), and in NW SGA and LGA children than NW AGA subjects (all P < 0.05). Interestingly, BW and IR were significantly and independently related to RAGE. CONCLUSIONS sRAGE and esRAGE are decreased in SGA and LGA children, and BW and IR seem to play an important role in the reduction of RAGE.

Background SHOX alterations have been reported in 67% of patients affected by Léri-Weill dyschondrosteosis (LWD), with a larger prevalence of gene deletions than point mutations. It has been recently demonstrated that these deletions can involve the SHOX enhancer region, rather that the coding region, with variable phenotype of the affected patients. Here, we report a SHOX gene analysis carried out by MLPA in 14 LWD patients from 4 families with variable phenotype. Case presentation All patients presented a SHOX enhancer deletion. In particular, a patient with a severe bilateral Madelung deformity without short stature showed a homozygous alteration identical to the recently described 47.5 kb PAR1 deletion. Moreover, we identified, for the first time, in three related patients with a severe bilateral Madelung deformity, a smaller deletion than the 47.5 kb PAR1 deletion encompassing the same enhancer region (ECR1/CNE7). Conclusions Data reported in this study provide new information about the spectrum of phenotypic alterations showed by LWD patients with different deletions of the SHOX enhancer region.

BACKGROUND:Subjects born small (SGA) and large (LGA) for gestational age have an increased risk of cardio-metabolic alterations already during prepuberty. Nevertheless, the progression of their cardio-metabolic profile from childhood to adolescence has not been fully explored. Our aim was to assess potential changes in the cardio-metabolic profile from childhood to adolescence in subjects born SGA and LGA compared to those born appropriate (AGA) for gestational age. METHODS:This longitudinal study included 35 AGA, 24 SGA and 31 LGA subjects evaluated during childhood (mean age (± SD) 8.4 ± 1.4 yr) and then re-assessed during adolescence (mean age 13.3 ± 1.8 yr). BMI, blood pressure, insulin resistance (fasting insulin, HOMA-IR) and lipids were assessed. A cardio-metabolic risk z-score was applied and this consisted in calculating the sum of sex-specific z-scores for BMI, blood pressure, HOMA-IR, triglycerides and triglycerides:high-density lipoprotein cholesterol ratio. RESULTS:Fasting insulin and HOMA-IR were higher in SGA and LGA than AGA subjects both during childhood (all P

Oxidative stress can be defined as an imbalance between oxidant and antioxidant status, which occurs in physiological conditions. Of note, the alteration of the oxidant–antioxidant system may also influence the pathogenesis of many diseases. Recent data have clearly shown that oxidative stress plays an important role in the onset and progression of several pathologies even during childhood. The aim of this chapter is to summarize the most important and recent findings regarding the role of oxidative stress in growth, puberty, and nutrition. A careful analysis and critical interpretation of the literature data have been made in order to establish the correlation between the special needs of childhood and the impairment of oxidant–antioxidant system. Emerging evidences suggest that children affected by growth, puberty, as well as nutritional disturbances are highly exposed to oxidative stress. New clinical studies need to be performed to establish possible prophylactic actions or treatment protocols limiting the oxidative damage in childhood.

In obese adults with non alcoholic fatty liver disease (NAFLD), treatment with Vitamin E has resulted in an improvement in liver histology, whereas variable and limited results are available in children. Our aim was to assess whether lifestyle combined with supplementation with Vitamin E might reduce oxidative stress and improve cardio-metabolic status in obese children with NAFLD. 24 obese prepubertal children (16M) followed a 6-month lifestyle intervention combined with Vitamin E supplementation (600 mg/day) and they were compared with 21 age and sex-matched obese peers who underwent lifestyle intervention only. At baseline and after 6-month urinary prostaglandin F2α (PGF-2α), endogenous secretory receptor for advanced glycation end products (esRAGE), high sensitivity C-reactive protein (hs-CRP), alanine aminotransferases (ALT), lipid profile, glucose, and insulin were assessed. The two groups were comparable for age (8.3 ± 1.6 vs 8.4 ± 1.3 yr), sex and BMI SDS (2.16 ± 0.29 vs 2.13 ± 0.28). At the beginning of the study, PGF2-α, esRAGE hsCRP, ALT, lipid profile and HOMA-IR levels were similar between the two groups (all p > 0.05). After 6-month treatment, levels of PGF2-α (p < 0.001) significantly decreased and esRAGE significantly increased (p < 0.001) in children treated with Vitamin E. A significant reduction was also found in ALT (p = 0.001), lipid profile and HOMA-IR (p < 0.001). In contrast, no significant change in any of these markers was detected in the lifestyle only group. In conclusion, Vitamin E supplementation was associated with a significant reduction in oxidative stress and improved cardio-metabolic alterations. These data suggest that Vitamin E supplementation could represent a valuable treatment in obese children affected by NAFLD.

Background: Diabetic ketoacidosis (DKA) is a complex metabolic state of hyperglycaemia, ketosis, and acidosis. Diabetes in sub-Saharan Africa is, in many patients a serious disease with a poor prognosis. Most deaths, however, are due to preventable causes. Objective: To improve knowledge on the management of DKA in sub-Saharan Africa. Data sources: Literature review from different published sources. Data synthesis: Health systems in sub-Saharan Africa are currently organised for the treatment of episodes of illness and not long-term conditions like diabetes. Therefore the high rates of DKA is essentially due to lack of training of health professionals, lack of facilities in most hospitals, lack of public awareness as well as lack of health education to individual patients/families. In addition erratic insulin supply coupling with infections, low parental education, poor insulin storage and lack of facilities for self monitoring of blood glucose. Conclusion: A complex unfavourable social and economic environment is the basis of the high prevalence of DKA in sub-Saharan Africa. Several episodes of DKA can be prevented by effective public awareness programmes and education to healthcare providers.

Early development of increased cardiovascular risk in obese children and the possible related cardiovascular diseases into adulthood have been shown; however, the underling pathogenetic mechanisms implicated are not yet completely defined. Receptors for advanced glycation end products (RAGE) pathway play a pivotal role in the genesis of abnormality of arterial wall. However, whether obese prepubertal children present impaired levels of endogenous and soluble secretory receptor for advanced glycation end products (esRAGE/sRAGE) and whether an association exists between RAGE levels and carotid intima media thickness (cIMT) are not yet evaluated in this age group. We note that esRAGE and sRAGE were significantly lower in obese children than controls and were independently related to cIMT. Our findings lead to the hypothesis that RAGE system seems to be related to the development of atherosclerosis even in obese prepubertal children. Antioxid. Redox Signal. 17, 187–191.

Puberty represents a particular period of life characterized by hormonal changes and physical and psychological modifications leading children from childhood to adolescence. During this period, menarche represents the most important event in females. Age of menarche is different among populations and has been recognized as an useful marker of socio-economic status, as well as dietary and environmental patterns (Chumlea et al., 2003; Swenson & Havens, 1987; Thomas et al., 2001). Generally, the first menstrual cycle takes place between 12 and 13 years of age, with 98% of girls having menarche by 15 years of age (Diaz, 2006). The normal range for menstrual cycles is between 21 and 45 days, with flow length varying from 2 to 7 days (Flug et al., 1984; World Health Organization Task Force on Adolescent Reproductive Health, 1986). During the first 2 years after menarche, menses length is often abnormal due to immaturity of the hypothalamic-pituitary-ovarian axis (Diaz, 2006); however, cycles range can be regular also in the first gynecologic year (Flug et al., 1984; World Health Organization Task Force on Adolescent Reproductive Health, 1986). Amenorrhea is defined as the complete absence or anomalous cessation of menstrual cycles in females during reproductive years. Just in three situations amenorrhea is considered physiological: during pregnancy, lactation and menopause. In all other situations, amenorrhea can be due to many pathological conditions and merits a careful assessment. Amenorrhea is classified as primary and secondary according to its occurrence before or after menarche, respectively (The Practice Committee of American Society for Reproductive Medicine, 2008). Amenorrhea is defined primary when menarche does not occur by the age of 16 years in a girl with complete secondary sexual development, or by the age of 14 years in a girl without secondary sexual development. Amenorrhea is defined secondary when menstrual cycles disappear for 6 consecutive months in a girl with irregular menses or for 3 consecutive months in a girl with regular menses (Deligeoroglou et al., 2010). According to the American Society for Reproductive Medicine, currently in literature many causes of amenorrhea have been recognized (The Practice Committee of American Society for Reproductive Medicine, 2008), including: • anatomic defects of the genital tract • hypothalamic/pituitary causes • ovary insufficiency • endocrinopathies • chronic oligoor anovulation

Oxidative stress, occurring as a consequence of imbalance between the production of oxygen free radicals and inactivation of these species by antioxidant defense system, seems to play a pivotal role in the pathophysiology of several diseases. In fact, there are numerous cellular biochemical targets for oxidative stress, all susceptible to long-lasting dangerous effects, especially if they take place early during infancy. Therefore, it is fundamental to obtain data starting in prepuberty to fully explore the intriguing relationship between precocious impairment of the oxidant-antioxidant status and organic alterations, and to preserve prepubertal children to the tracking of disease from infancy to adulthood. Nowadays the identification of children with a highly altered oxidant-antioxidant status is possible through accurate analysis. Much work still needs to be done to offer appropriate treatments aiming to guarantee a good quality of life for the young patients.

Oxidative stress results from a disparity between the generation of reactive oxygen species and the antioxidant ability of the organism. The alteration of the oxidant-antioxidant system brings in adults an effective state of imbalance, which may influence the pathogenesis of many diseases. Oxidative stress also plays a pivotal role in the progression of various pathologies in childhood, through a manipulation of regulatory proteins. In fact, several studies have demonstrated that an unbalanced oxidant-antioxidant status is able to determine toxic effects even during infancy. Therefore, the aim of this review was to summarize current knowledge about the dynamic relationship between oxidative stress and systemic diseases during childhood. In order to better understand these complex mechanisms, a comprehensive review of the literature was done, focusing mainly on pre-pubertal children. In fact, this age-group offers a unique opportunity to exclude confounding factors, especially those related to the metabolic effects induced by puberty. Early identification of these very young patients should be aimed at minimizing the degree of oxidative damage. Only by achieving early diagnosis, will it be possible to identify those children who could benefit from specific therapeutic approaches targeting oxidative stress.

The advanced glycation end products/receptor for advanced glycation end products (AGE–RAGE) pathway is a key mediator of glomerular changes in type 1 diabetes. We evaluated endogenous secretory (es)RAGE and soluble (s)RAGE concentrations in 64 pre-pubertal and pubertal normoalbuminuric patients with type 1 diabetes and compared the values with those of 62 controls matched for age, gender and Tanner pubertal stages. We also explored the possible association of their concentrations with early signs of diabetic nephropathy, defined as changes in kidney volume and estimated glomerular filtration rate (eGFR). Significantly lower concentrations of both esRAGE and sRAGE were documented in pre-pubertal (p = 0.003 and p = 0.001) and pubertal (p = 0.002 and p = 0.001) subjects with type 1 diabetes than in the controls. In both groups of patients with type 1 diabetes, the eGFR (pre-pubertal p = 0.01 and pubertal p = 0.01) and the mean value of kidney volume adjusted for body surface (pre-pubertal p = 0.003 and pubertal p = 0.002) were higher than those of the controls. The regression analysis showed an inverse relationship between esRAGE and body surface-adjusted mean kidney volume (p = 0.0004, r = −0.503). esRAGE and sRAGE concentrations were lower in normoalbuminuric youths with type 1 diabetes than in their healthy peers. The inverse association between esRAGE levels and early kidney alterations suggests a potential role of esRAGE in diabetic nephropathy.

The endogenous secretory receptor for advanced glycation end products (esRAGE) and soluble RAGE (sRAGE) have been shown in human plasma and have emerged as reliable biomarkers of several pathological conditions, including insulin resistance and liver injury. We examined esRAGE and sRAGE levels in obese prepubertal children with and without liver steatosis. esRAGE and sRAGE levels were significantly lower in obese prepubertal children affected by liver steatosis and were independently related to liver steatosis. These findings suggest that AGE-RAGE pathway plays an independent role in the development of liver injury already present in this age group. Antioxid. Redox Signal. 14, 1167–1172.

Although asthma and obesity are among the major chronic disorders their reciprocal or independent influences on lung function testing, airways hyperresponsiveness (AHR) and bronchial inflammation has not been completely elucidated. In 118 pre-pubertal Caucasian children anthropometric measurements functional respiratory parameters (flow/volume curves at baseline and after 6-minute walk test [6MWT]) together with bronchial inflammatory index (FeNO) were assessed. The study population was divided into four groups according to BMI and the presence or absence of asthma: Obese asthmatic (ObA) Normal-weight asthmatic (NwA), Obese non-asthmatic (Ob), non-asthmatic normal-weight children (Nw). Baseline PEF and MEF(75) (%-expected) were significantly different across the four groups with significantly lower values of MEF(75) in ObA and Ob children when compared to Nw children (P = 0.004 and P = .0001, respectively) and this independent role of obesity on upper respiratory flows was confirmed by multiple analysis of covariance. After 6 MWT respiratory parameters decreased only in ObA and NwA children and 12 children presented a positive fall in FEV(1), in contrast no changes of respiratory function testing were detected in Ob and Nw children, and only 2 Ob children presented a significant fall in FEV(1). FeNO analysis demonstrated significantly higher values in ObA and NwA children when compared to Ob (P = 0.008 and P = 0.0002, respectively) and Nw children (P = 0.0001 and P = 0.0003, respectively), although a significant difference was found between Ob and Nw children (P = 0.0004). Multiple analysis of covariance confirmed an independent role of asthma on this parameter. In conclusion while AHR and airway inflammation are clearly associated with an asthmatic status, obesity seems to induce reduction of upper airways flows associated with a certain degree of pro-inflammatory changes.

This study was undertaken in 2 parts to investigate the relationship between body size and insulin resistance during treatment with valproic acid in children. The cross-sectional part revealed differences in terms of body size and homeostasis model assessment of insulin resistance, which were higher in the group on medication. The longitudinal part showed a major increase in body size and insulin resistance during the first year of therapy. There was a subsequent decrease in insulin resistance in association with the rise of body size, however with a trend to level off. These results might be helpful to enhance the knowledge of valproic acid action on both insulin resistance and weight gain, allowing to plan appropriate approach for the prevention of the consequences of the treatment with valproic acid.

Context: Low birth weight is associated with an increased risk of metabolic and cardiovascular diseases in adulthood. The development of insulin resistance (IR) seems to play a pivotal role; no data on the oxidant-antioxidant status are available in this risk group.Objective: This study is an assessment of oxidant-antioxidant status in prepubertal children born small for gestational age (SGA) in comparison to healthy controls and the relationship to IR.Design: This cross-sectional study compares indexes of IR and oxidant-antioxidant status in three different groups (SGA+, SGA−, controls), with analysis by post hoc and Pearson correlation.Setting: The study was conducted in the Academic Department of Pediatrics.Participants: A total of 19 SGA+ and 16 SGA− children were compared with 13 controls.Intervention: No intervention was used.Main Outcome Measures: Indexes of IR (glucose to insulin ratio, homeostasis model assessment of IR) were evaluated, and markers of oxidative stress (lag phase, malonildialdehyde, vitamin E) were measured.Results: Homeostasis model assessment of IR was significantly higher in SGA+ than SGA− children (1.32 ± 0.9 vs. 0.69 ± 0.47; P = 0.03) and controls (0.71 ± 0.37; P = 0.04). Glucose to insulin ratio was significantly lower in SGA+ than SGA− children (12.41 ± 5.01 vs. 26.54 ± 17.18; P = 0.02) and controls (26.96 ± 20.70; P = 0.04). Lag phase was significantly shorter in SGA+ than SGA− children (24.3 ± 4.38 vs. 35.59 ± 11.29 min; P = 0.003) and controls (45.28 ± 7.69 min; P = 0.0001) and in SGA− than controls (P = 0.01). Malonildialdehyde was significantly higher in SGA+ than SGA− children (0.79 ± 0.3 vs. 0.6 ± 0.1 nmol/mg; P = 0.03) and controls (0.36 ± 0.04 nmol/mg; P = 0.0001) and in SGA− children than controls (P = 0.02). Vitamin E was significantly reduced in SGA+ children than controls (27.54 ± 7.9 vs. 43.23 ± 11.32 μmol/liter; P = 0.002).Conclusion: Oxidative stress is present in both SGA+ and SGA− children, with a continuous alteration in relation to IR. Therefore, catch-up growth might exert the greatest influence in the development of future diseases.

Methods Seventy-one singleton infants born at term were classified by birth weight as AGA (10th-90th percentile; n=42) and as LGA (>90th percentile; n=29). Post-natal follow-up until age 1 year was performed with clinical assessments at 3, 6, and 12 months. Assessments included measurement of infants’ weight, length, ponderal index, BMI, as well as head, chest, and abdominal circumference. A subgroup of 38 infants (17 AGA and 21 LGA) was selected for genome-wide DNA methylation analysis. Umbilical cord was collected at birth, and methylation profile on umbilical tissue was analysed using the Illumina Infinium 450K methylation array.

To evaluate epidemiological and clinical data on patients with severe acquired brain injury (sABI) admitted to rehabilitation units in the first 6 years since the inception of a regional register (2005-2010) in the Emilia-Romagna region (Italy).Retrospective multicentre study of a regional cohort using data from an online regional register (Gravi Cerebrolesioni Emilia-Romagna - GRACER). The study included 318 patients who suffered sABI (defined by Glasgow Coma Scale score ≤8 recorded in the initial 24 h following injury), who were admitted to and subsequently discharged from rehabilitation units. Physical and cognitive functions were evaluated at admission and discharge. Other data recorded included aetiology, presence of secondary conditions and need for specific medical support.Three-quarters of patients displayed improvements in physical and/or cognitive function at discharge from rehabilitation units, with 71.4% of patients returning home. Better outcomes at discharge were associated in particular with younger age, traumatic brain injury (versus non-traumatic), or absence of tracheostomy at admission.The GRACER register is a useful tool for the assessment of epidemiological and clinical information on sABI patients. In light of the positive impact on patient outcomes, rehabilitation in specialised units is highly encouraged and should occur as soon as possible. Implications for Rehabilitation There is a need for more epidemiological and clinical data associated with severe acquired brain injury, particular regarding those of non-traumatic origin. In a retrospective multicentre study of a regional cohort using data from an online regional register in Italy (GRACER), more than three-quarters of patients displayed improvements in physical and/or cognitive function at discharge from the rehabilitation units. Better outcomes at discharge were associated in particular with younger age, traumatic brain injury (versus non-traumatic) or absence of tracheostomy at admission. Admission to a specialised rehabilitation unit is highly encouraged for patients with severe acquired brain injury, and should occur as soon as possible. Policy-makers and service planners should continue to develop strategies and allocate adequate resources for rehabilitation services due to their positive impact on patient outcomes. In particular, patients with conditions associated with increased likelihood of poor outcomes may require special attention during rehabilitation to improve outcomes at discharge.

Methods Of the initial 84 women and their offspring who participated in the RCT, follow-up data were available on 46 mothers (26 exercisers, 20 controls) and 46 children. At each follow-up visit (6 months, 1 year, 2 years, 4 years, 6-8 years) clinical assessment included measurement of mothers’ and children’s heights, weights, BMI, and waist circumference, as well as blood pressure. Body composition was assessed in both mothers and children by whole-body dual-energy X-ray absorptiometry (DXA) scans at 4-year and 7-year follow-up visits.