Fabienne Nacka

New candidate loci identified by array‐CGH in a cohort of 100 children presenting with syndromic obesity

Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray‐based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).

Pulmonary outcome and its correlates in school-aged children born with a gestational age ≤ 32 weeks.

BACKGROUND There is limited data regarding factors influencing the respiratory outcome at school age of ex-preterms born since the introduction of antenatal steroids, surfactant replacement together with less aggressive ventilation. OBJECTIVES To establish the main antenatal, neonatal and early childhood respiratory correlates of respiratory status in school-aged children born at ≤ 32 weeks of gestation. METHODS Ex-preterm children born at ≤ 32 weeks of gestation between 1997 and 2001 at Bordeaux University Hospital were evaluated at school age, using a respiratory questionnaire and lung function tests (spirometry, plethysmography, exercise challenge test and CO lung diffusing capacity DLCO measurements). Factors associated with lung function were investigated using polynomial regression analyses. RESULTS Of the 151 included children [mean age: 8.6 ± 0.8 years; mean gestational age, 30.1 ± 1.7 weeks; mean birth weight = 1310 ± 380 g; 68.2% ventilated at birth; 46.4% treated with surfactant; 36.4% with prior bronchopulmonary dysplasia (BPD)], 47% presented obstructive lung abnormalities, 11% restrictive or mixed lung abnormalities, 41% exercise-induced bronchoconstriction, and 15.5% reduced DLCO. Surfactant therapy was independently associated with a lower risk of lung abnormalities (p < 0.05). The association between BPD and lung abnormalities at school age was not significant, but prior BPD increased the risk of restrictive or mixed abnormalities (odds ratio: 6.11, confidence interval [1.1; 33.99]). Early childhood respiratory events were not associated with the occurrence of lung abnormalities. CONCLUSION Children born at ≤ 32 weeks of gestation remain at risk for impaired lung function at school age in particular when they did not receive surfactant. Restrictive or mixed lung defects are mainly associated with prior BPD.

Advanced Glycation End Products in Children With Type 1 Diabetes: Family Matters?

Advanced glycation end product (AGE) burden can be indirectly quantified in vivo by measuring skin autofluorescence (SAF) (1). It has been recently published by Felipe et al. (2) that SAF is correlated with glycated hemoglobin (GHb) but not with mean blood glucose (MBG) in type 1 diabetic children. This suggests that factors besides MBG exposure may be influential in skin AGE generation. In the current study, we have compared SAF in type 1 diabetic children and their nondiabetic sibling. We included 52 type 1 diabetic children, 55% boys, aged 12 (6) years [median (interquartile range: 75th percentile − 25th percentile)], and 28 nondiabetic siblings, 46% boys, aged 11 (6) years. Among diabetic children, the duration of diabetes was 71 (45) …

Comparison of Mycoplasma pneumoniae Infections in asthmatic children versus asthmatic adults.

Background: Mycoplasma pneumoniae has been implicated in asthma exacerbations and chronic asthma. A 2-year longitudinal study has been conducted to investigate the role of M. pneumoniae infections in 168 and 20 hospitalized children and adults, respectively, with asthma exacerbation compared with outpatients (88 children and 48 adults) with chronic asthma (without an exacerbation). The prevalence of Chlamydia pneumoniae and respiratory viruses was also assessed in these 2 populations. Methods: Lung function testing, blood sampling and microbiological testing (polymerase chain reaction, culture and serology) were performed for 256 children and 68 adults followed by a 7-week, follow-up visit with repeated blood sampling for serological testing and phone interviews at 6 and 12 months later. Results: M. pneumoniae infection was more prevalent in children with chronic asthma (13.6%) compared with children with exacerbation (7.1%), while the reverse was true in adults (6.3 vs. 10.0%, respectively). However, these differences were not statistically significant. Acute C. pneumoniae infection was identified in 3.9% of children and 7.4% adults. Children seen for chronic asthma were significantly more likely to be infected with C. pneumoniae than children hospitalized for an asthma exacerbation. Viruses were the most prevalent microorganisms detected in children with an asthma exacerbation. No differences in the outcome parameters were identified between M. pneumoniae-infected and noninfected patients. Conclusions: The present study suggests that M. pneumoniae does not play a direct role in the pathogenicity of acute or chronic asthma in most children.

Effects of Maternal Supplementation With Omega-3 Precursors on Human Milk Composition:

Background: Long-chain polyunsaturated fatty acids (LC-PUFAs) are important for newborn neurosensory development. Supplementation of breastfeeding mothers’ diets with omega-3 PUFAs, such as alpha-linolenic acid (ALA), may increase their concentration in human milk. Research aim: This study aimed to assess human milk composition after 15-day supplementation regimens containing either omega-3 PUFAs or olive oil, which does not provide ALA. Methods: A multicenter factorial randomized trial was conducted with four groups of breastfeeding women, with each group containing 19 to 22 women. After a 15-day ALA washout period, three groups received supplementation with omega-3 precursors for 15 days: an enriched margarine (M), a rapeseed oil (R), and a margarine and rapeseed oil (MR). The fourth was unexposed to omega-3 precursors (olive oil control diet, O). After 15 days, blind determination of human milk fatty acid (FA) composition was assessed by gas chromatography, and the FA composition was compared among groups using variance analyses. Results: Alpha-linolenic acid content, expressed as the mean (standard deviation) total human milk FA percentage, was significantly higher after diet supplementation with omega-3 PUFAs, with values of 2.2% (0.7%) (MR), 1.3% (0.5%) (R), 1.1% (0.4%) (M), and 0.8% (0.3%) (O at D30) (p < .003 for each comparison). The lowest LA–ALA ratio (5.5) was found in the MR group (p < .001). Docosahexaenoic acid and trans FA concentrations did not differ among groups. Conclusion: In lactating women, omega-3 supplementation via the combination of enriched margarine and rapeseed oil increased the ALA content of human milk and generated the most favorable LA–ALA ratio for LC-PUFA synthesis.

Nocturnal activity of 11β-hydroxy steroid dehydrogenase type 1 is increased in type 1 diabetic children

AIM The objective of this study was to investigate low-grade inflammation in children with type 1 diabetes (T1D) and its association with cortisol levels as well as its bioavailability through 11β-hydroxy steroid dehydrogenase type 1 (11β-HSD1) activity. METHODS Children with T1D (n=45) and their non-diabetic siblings (n=28) participated in the study. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRPhs) were measured between 1400 and 1800h. Glucocorticoid metabolites were measured in the first morning urine on clinic day and 11β-HSD1 activity was estimated by tetrahydrocortisol/tetrahydrocortisone (THF/THE) ratio. RESULTS Diabetic patients presented with an increased THF/THE ratio compared with controls (median: 0.68 [range: 0.45-1.18] vs 0.45 [0.27-0.98], respectively; P<10(-3)). There was no difference between diabetic patients and controls for IL-6 (0.6ng/mL [0.6-6.8] vs 0.6 [0.6-2.2], respectively; P=0.43) and CRPhs (0.4mg/L [0-7.4] vs 0.3 [0-8.2]; P=0.26, respectively). When adjusted for age, gender and BMI, the THF/THE ratio was significantly associated with CRPhs (β=0.32, P=0.02) in diabetic patients, but not in controls. CONCLUSION Low-grade inflammation assessed by plasma CRPhs and IL-6 concentrations was not detectable in our cohort of T1D children. Nocturnal 11β-HSD1 activity was increased and associated with plasma CRPhs concentration in diabetic patients. These results may be explained by either a direct or inflammation-mediated effect of the relative hepatic lack of insulin due to subcutaneous insulin therapy.

Nasal airway epithelial cell IL-6 and FKBP51 gene expression and steroid sensitivity in asthmatic children

Background Many asthmatic patients exhibit uncontrolled asthma despite high-dose inhaled corticosteroids (ICS). Airway epithelial cells (AEC) have distinct activation profiles that can influence ICS response. Objectives A pilot study to identify gene expression markers of AEC dysfunction and markers of corticosteroid sensitivity in asthmatic and non-asthmatic control children, for comparison with published reports in adults. Methods AEC were obtained by nasal brushings and primary submerged cultures, and incubated in control conditions or in the presence of 10 ng/ml TNFalpha, 10-8M dexamethasone, or both. RT-PCR-based expression of FKBP51 (a steroid hormone receptor signalling regulator), NF-kB, IL-6, LIF (an IL-6 family neurotrophic cytokine), serpinB2 (which inhibits plasminogen activation and promotes fibrin deposition) and porin (a marker of mitochondrial mass) were determined. Results 6 patients without asthma (median age 11yr; min-max: 7–13), 8 with controlled asthma (11yr, 7–13; median daily fluticasone dose = 100 μg), and 4 with uncontrolled asthma (12yr, 7–14; 1000 μg fluticasone daily) were included. Baseline expression of LIF mRNA was significantly increased in uncontrolled vs controlled asthmatic children. TNFalpha significantly increased LIF expression in uncontrolled asthma. A similar trend was observed regarding IL-6. Dexamethasone significantly upregulated FKBP51 expression in all groups but the response was blunted in asthmatic children. No significant upregulation was identified regarding NF-kB, serpinB2 and porin. Conclusion LIF and FKBP51 expression in epithelial cells were the most interesting markers of AEC dysfunction/response to corticosteroid treatment.

P010 - 17-OHP/cortisol à J3 et troubles hémodynamiques sévères chez les grands prématurés

La fonction surrenalienne des prematures de moins de 32 semaines d’amenorrhee (SA) semble presenter une immaturite enzymatique. Nous avons realise une etude de cohorte chez les prematures de moins de 32 SA hospitalises au CHU de Bordeaux. Nous avons couple le depistage de l’hyperplasie congenitale des surrenales au troisieme jour de vie (J3) a un dosage du cortisol sanguin (CS) sur buvard. L’objectif principal de notre etude etait de definir la valeur predictive du rapport 17-OHP/CS a J3 sur la survenue de troubles hemodynamiques severes. Nos objectifs secondaires etaient l’etude de la relation entre les variables 17-OHP, CS ou leur rapport a J3 et la morbidite respiratoire, ainsi que l’analyse des facteurs pouvant influencer ces dosages. Nous n’avons pas pu demontrer, dans notre population de prematures de moins de 32 SA, que le rapport 17-OHP/CS a J3 soit predictif de la morbidite hemodynamique ou respiratoire. En analyse univariee, le dosage de CS a J3 est significativement plus eleve chez les patients requerant un soutien respiratoire. Nos analyses multivariees avec les dosages de 17-OHP et CS a J3 demontrent que seul l’âge gestationnel reste correle de facon negative avec la survenue de troubles hemodynamiques severes, de meme que le poids de naissance avec le rapport 17-OHP/CS.