RESUMO
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).
Assuntos
Obesidade/diagnóstico , Obesidade/genética , Fenótipo , Locos de Características Quantitativas , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Lactente , Masculino , SíndromeAssuntos
Síndrome de Down/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antraciclinas/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
AIM: To determine the epidemiology of myeloid leukaemia (ML) in children with Down syndrome (DS) and the efficacy of two approaches, low-dose cytarabine-based regimen (LDC) and standard-dose intensive chemotherapy (SD). PROCEDURE: All children with Down syndrome aged from 2 months to 15 years with ML/myelodysplasia registered in the French registry between January 1990 and December 2003 were included. RESULTS: Forty-four patients were included. The median age was 1.75 years. The French-America-British subtypes were as follows: M7: 24, M0: 6, M2: 5, M6: 2. Forty-three patients were treated with curative prospect, 20 patients with LDC regimen and 22 according to SD protocols, 1 was given the LDC regimen plus autologous stem-cell transplantation. The event-free survival (EFS) and overall survival (OS) at 5 years were 64.4% and 76.8%. At 5 years, OS in LDC and SD groups were 65% and 85.9% (P = 0.08). EFS were 45% and 80.3% respectively (P < 0.01). CONCLUSION: Children with DS can adequately tolerate SD chemotherapy with a significant superiority of EFS relative to LDC. We suggest that higher levels of cure can be obtained in DS-ML with SD chemotherapy including cytarabine and anthracyclines.
Assuntos
Antineoplásicos/uso terapêutico , Síndrome de Down/complicações , Leucemia Mieloide/complicações , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/epidemiologia , Pré-Escolar , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Síndrome de Down/tratamento farmacológico , Feminino , França/epidemiologia , Humanos , Lactente , Masculino , Sistema de Registros , Resultado do TratamentoRESUMO
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.
Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Interleucina-6/genética , Mucosa Nasal/patologia , Proteínas de Ligação a Tacrolimo/genética , Adolescente , Asma/patologia , Criança , Feminino , Humanos , Fator Inibidor de Leucemia/genética , Masculino , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Projetos Piloto , RNA Mensageiro/genéticaRESUMO
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.
Assuntos
Suplementos Nutricionais/análise , Ácidos Graxos Ômega-3/análise , Ácidos Graxos Ômega-3/metabolismo , Comportamento Alimentar , Leite Humano/química , Adulto , Aleitamento Materno , Feminino , França , Humanos , Lactação/metabolismo , Comportamento Materno , Mães , Ácido alfa-Linolênico/análiseRESUMO
Liposomes made from an extract of natural marine lipids and containing a high n-3 PUFA lipid ratio were envisaged as oral route vectors for FA supplements in order to increase PUFA bioavailability. The absorption of FA in thoracic lymph duct-cannulated rats, after intragastric feeding of dietary fats in the form of liposomes or fish oil, was compared. Lipid and FA analyses were also performed on feces. Five mole percent alpha-tocopherol was added to fish oil and incorporated into the liposome membrane. The influence of alpha-tocopherol on FA lymph recovery was also investigated. In vivo, FA absorption in rats was favored by liposomes (98 +/- 1%) compared to fish oil (73 +/- 6%). In the same way, the DHA proportion in lymph was higher after liposome ingestion (78%) than after fish oil ingestion (47%). However, phospholipid (PL) concentration in lymph was not affected by the kind of dietary fat ingested, suggesting a PL regulation due to de novo TAG synthesis. The influence of the intramolecular distribution of n-3 PUFA in dietary lipids (TAG and PL) on the intramolecular FA distribution in TAG of chylomicrons was also investigated. The results obtained showed that the distribution of n-3 PUFA esterified on the sn-2 position of chylomicron TAG depended on the lipid source administered. All these results correlated, at least partly, with in vitro liposome behavior under conditions that mimic those of the gastrointestinal tract. As a whole, this study pointed out that marine PL may constitute an attractive material for the development of liposomes as oral PUFA supplements.
Assuntos
Ácidos Graxos/farmacocinética , Lipossomos/farmacocinética , Animais , Disponibilidade Biológica , Colesterol/análise , Quilomícrons/química , Gorduras Insaturadas na Dieta/administração & dosagem , Gorduras Insaturadas na Dieta/farmacocinética , Nutrição Enteral/métodos , Ácidos Graxos/análise , Ácidos Graxos Monoinsaturados/análise , Ácidos Graxos Insaturados/análise , Fezes/química , Óleos de Peixe/administração & dosagem , Óleos de Peixe/química , Óleos de Peixe/farmacocinética , Absorção Intestinal/fisiologia , Lipossomos/administração & dosagem , Lipossomos/química , Linfa/metabolismo , Masculino , Fosfolipídeos/análise , Ratos , Ratos Wistar , Triglicerídeos/análise , alfa-Tocoferol/farmacologiaRESUMO
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.
Assuntos
Asma , Pneumonia por Mycoplasma/complicações , Pneumonia por Mycoplasma/epidemiologia , Adulto , Asma/complicações , Asma/epidemiologia , Asma/microbiologia , Criança , Infecções por Chlamydophila/complicações , Infecções por Chlamydophila/epidemiologia , Doença Crônica , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mycoplasma pneumoniae , Pneumonia por Mycoplasma/terapia , Prevalência , Viroses/complicações , Viroses/epidemiologiaRESUMO
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.
Assuntos
Recém-Nascido Prematuro/fisiologia , Transtornos Respiratórios/fisiopatologia , Asma Induzida por Exercício/fisiopatologia , Displasia Broncopulmonar/fisiopatologia , Criança , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Pneumopatias Obstrutivas/fisiopatologia , Masculino , Surfactantes Pulmonares/uso terapêutico , Testes de Função Respiratória , Sons Respiratórios/fisiologia , Estudos Retrospectivos , Esteroides/uso terapêuticoRESUMO
BACKGROUND: Due to the improvement in life expectancy in cystic fibrosis (CF), co-morbidities such as renal function impairment may be more frequent. AIM: To determine the prevalence of renal disease in children with CF and to identify associated risk factors. METHODS: A single-center retrospective study analyzing the genetic, clinical and therapeutic characteristics of 112 children. The estimated glomerular filtration rate (GFR), microalbuminuria and lithiasic risk factors were assessed. RESULTS: The median calculated GFR (Schwartz) was 123, 161 and 155ml/min/1.73m(2) in children aged 1, 6 and 15years, respectively. The cumulative dose of aminoglycosides was not correlated to GFR. Microalbuminuria was present in 22/38 patients. Hyperoxaluria was observed in 58/83 patients and was associated with a severe genotype, pancreas insufficiency and liver disease. Hypercalciuria, hyperuricuria and hypocitraturia were identified in 16/87, 15/83 and 57/76 patients, respectively. CONCLUSION: Renal impairment in CF has various presentations. There appears to be low levels of renal impairment in children with CF. However, the risk of oxalocalcic urolithiasis is enhanced, and GFR may be underestimated by the Schwartz formula. Further studies using measured GFR techniques are thus warranted.