RESUMEN
BACKGROUND: Obesity is linked to several health complication, including Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD). Adipose tissue hypoxia has been suggested as an important player in the pathophysiological mechanism leading to chronic inflammation in obesity, and in the progression of MASLD. The study aims to investigate the effect of progressive obesity on adipose and liver tissue hypoxia. METHODS: Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) or control diet (CD) for 4, 8, 12, 16 and 20 weeks. Serum ALT, AST and lipid levels were determined, and glucose and insulin tolerance testing was performed. Liver, gonadal and subcutaneous adipose tissue was assessed histologically. In vivo tissue pO2 measurements were performed in gonadal adipose tissue and liver under anesthesia. A PCR array for hypoxia responsive genes was performed in liver and adipose tissue. The main findings in the liver were validated in another diet-induced MASLD mice model, the choline-deficient L-amino acid defined high-fat diet (CDAHFD). RESULTS: HFHFD feeding induced a progressive obesity, dyslipidaemia, insulin resistance and MASLD. In vivo pO2 was decreased in gonadal adipose tissue after 8 weeks of HFHFD compared to CD, and decreased further until 20 weeks. Liver pO2 was only significantly decreased after 16 and 20 weeks of HFHFD. Gene expression and histology confirmed the presence of hypoxia in liver and adipose tissue. Hypoxia could not be confirmed in mice fed a CDAHFD. CONCLUSION: Diet-induced obesity in mice is associated with hypoxia in liver and adipose tissue. Adipose tissue hypoxia develops early in obesity, while liver hypoxia occurs later in the obesity development but still within the early stages of MASLD. Liver hypoxia could not be directly confirmed in a non-obese liver-only MASLD mice model, indicating that obesity-related processes such as adipose tissue hypoxia are important in the pathophysiology of obesity and MASLD.
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Hígado Graso , Obesidad , Masculino , Ratones , Animales , Ratones Endogámicos C57BL , Obesidad/metabolismo , Hígado/metabolismo , Hígado Graso/metabolismo , Tejido Adiposo/metabolismo , Dieta Alta en Grasa/efectos adversos , Hipoxia/metabolismoRESUMEN
BACKGROUND: Computer Aided Lung Sound Analysis (CALSA) aims to overcome limitations associated with standard lung auscultation by removing the subjective component and allowing quantification of sound characteristics. In this proof-of-concept study, a novel automated approach was evaluated in real patient data by comparing lung sound characteristics to structural and functional imaging biomarkers. METHODS: Patients with cystic fibrosis (CF) aged > 5y were recruited in a prospective cross-sectional study. CT scans were analyzed by the CF-CT scoring method and Functional Respiratory Imaging (FRI). A digital stethoscope was used to record lung sounds at six chest locations. Following sound characteristics were determined: expiration-to-inspiration (E/I) signal power ratios within different frequency ranges, number of crackles per respiratory phase and wheeze parameters. Linear mixed-effects models were computed to relate CALSA parameters to imaging biomarkers on a lobar level. RESULTS: 222 recordings from 25 CF patients were included. Significant associations were found between E/I ratios and structural abnormalities, of which the ratio between 200 and 400 Hz appeared to be most clinically relevant due to its relation with bronchiectasis, mucus plugging, bronchial wall thickening and air trapping on CT. The number of crackles was also associated with multiple structural abnormalities as well as regional airway resistance determined by FRI. Wheeze parameters were not considered in the statistical analysis, since wheezing was detected in only one recording. CONCLUSIONS: The present study is the first to investigate associations between auscultatory findings and imaging biomarkers, which are considered the gold standard to evaluate the respiratory system. Despite the exploratory nature of this study, the results showed various meaningful associations that highlight the potential value of automated CALSA as a novel non-invasive outcome measure in future research and clinical practice.
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Biomarcadores , Fibrosis Quística , Ruidos Respiratorios , Humanos , Estudios Transversales , Masculino , Femenino , Estudios Prospectivos , Adulto , Fibrosis Quística/fisiopatología , Fibrosis Quística/diagnóstico por imagen , Adulto Joven , Adolescente , Auscultación/métodos , Tomografía Computarizada por Rayos X/métodos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Niño , Prueba de Estudio Conceptual , Diagnóstico por Computador/métodos , Persona de Mediana EdadRESUMEN
Hypomagnesemia in patients with type 1 diabetes (T1D) as well as in obesity has been related to insulin resistance in adults, but not yet in pediatric patients. In this observational single-center study, we aimed to investigate the relation between the magnesium homeostasis, insulin resistance, and body composition in children with T1D and in children with obesity. Children with T1D (n = 148) and children with obesity and proven insulin resistance (n = 121) and healthy controls (n = 36) were included in this study. Serum and urine samples were collected to determine magnesium and creatinine. The total daily dose of insulin (for children with T1D), results from the oral glucose tolerance test (OGTT, for children with obesity), and biometric data were extracted from the electronic patient files. Furthermore, body composition was measured via bioimpedance spectroscopy. Serum magnesium levels were decreased in both children with obesity (0.87 ± 0.07 mmol/l) and children with T1D (0.86 ± 0.07 mmol/l) compared to healthy controls (0.91 ± 0.06; p = 0.005). A lower magnesium level was associated with more severe adiposity in children with obesity, while a worse glycemic control was associated with lower magnesium levels in children with T1D. Conclusion: Children with T1D and children with obesity have decreased serum magnesium levels. An increased fat mass is associated with lower magnesium levels in childhood obesity, indicating that the adipose tissue is an important factor in magnesium homeostasis. In contrast, glycemic control was the main determining factor for serum magnesium levels in children with T1D. What is Known: ⢠Hypomagnesaemia has been related to insulin resistance in both adults with T1D and adults with obesity. ⢠There is an increasing prevalence of obesity and T1D in childhood, but little is known about the relationship between magnesium and insulin resistance in these children. What is New: ⢠Both children with T1D and children with obesity have decreased serum magnesium levels. ⢠In childhood obesity an increased fat mass is associated with lower magnesium levels, while glycaemic control is the main determining factor for serum magnesium in children with T1D.
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Diabetes Mellitus Tipo 1 , Resistencia a la Insulina , Obesidad Infantil , Adulto , Humanos , Niño , Magnesio , Obesidad Infantil/complicaciones , Composición Corporal , GlucemiaRESUMEN
RATIONALE: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Lung function and imaging are classically used to assess BPD. Functional respiratory imaging (FRI) combines a structural and functional assessment of the airways and their vasculature. We aimed to assess BPD using FRI and to correlate these findings with the clinical presentation. METHODS: We included 37 adolescents with a history of preterm birth (22 BPD cases and 15 preterm controls). The study protocol included a detailed history, lung function testing and computed tomography (CT) (at total lung capacity (TLC) and functional residual capacity (FRC)) with FRI. CT images were also assessed using the Aukland scoring system. RESULTS: BPD patients had lower forced expiratory volume in 1â s to forced vital capacity ratio (p=0.02) and impaired diffusion capacity (p=0.02). Aukland CT scores were not different between the two groups. FRI analysis showed higher lobar volumes in BPD patients at FRC (p<0.01), but not at TLC. Airway resistance was significantly higher in the BPD group, especially in the distal airways. Additionally, FRI showed more air trapping in BPD patients, in contrast to findings on conventional CT images. CONCLUSION: This study is the first to use FRI in research for BPD. FRI analysis showed higher lobar volumes in BPD patients, indicating air trapping and reduced inspiratory capacity. In contrast to Aukland CT scores, FRI showed more air trapping in the BPD group, suggesting that FRI might be a more sensitive detection method. Importantly, we also showed increased distal airway resistance in BPD patients. By combining structural and functional assessment, FRI may help to better understand the long-term sequelae of BPD.
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Displasia Broncopulmonar , Nacimiento Prematuro , Adolescente , Femenino , Volumen Espiratorio Forzado , Capacidad Residual Funcional , Humanos , Recién Nacido , Pulmón , Embarazo , Capacidad VitalRESUMEN
CONTEXT: Down syndrome (DS) is a prevalent chromosomal disorder associated with a wide range of congenital anomalies and other health problems. OBJECTIVES: To give a scoping overview of encountered lower airway problems (both infectious and non-infectious) in DS children. DATA SOURCES: We systematically searched the MEDLINE and PubMed databases for relevant publications. STUDY SELECTION: Studies were eligible if they were original studies about pediatric airway problems in DS and were evaluated by the PRISMA guidelines. DATA EXTRACTION: Data concerning patient characteristics, study methods and outcomes were critically reviewed. RESULTS: Sixty papers were included. These were reviewed and summarized by topic, i.e. airway anomalies, dysphagia and aspiration, lower respiratory tract infections (and bronchiolitis in particular), pulmonary hypertension and other. Respiratory problems are proven to be a frequent and a major health burden in DS children. Airway anomalies (both single and multiple) are more prevalent and require a specific approach. A large proportion of DS children have (often silent) aspiration, resulting in protracted and difficult-to-treat symptoms. Respiratory tract infections are usually more severe and associated with an increased need for (prolonged) hospitalization. Pulmonary hypertension, wheeze and some other rare conditions are more commonly encountered in DS. LIMITATIONS: Large number of studies and high levels of study heterogeneity. CONCLUSIONS: Several lower airway problems are more frequent and more complex in children with DS. These findings emphasize the need for a multidisciplinary approach by an experienced team allowing for a prompt diagnosis, proper management and improved long term outcome.
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Síndrome de Down , Hipertensión Pulmonar , Trastornos Respiratorios , Infecciones del Sistema Respiratorio , Niño , Síndrome de Down/complicaciones , Síndrome de Down/epidemiología , Humanos , Ruidos RespiratoriosRESUMEN
AIMS: Children with obesity are treated by a lifestyle intervention to obtain weight loss. Nevertheless, weight regain often occurs. This systematic review examines the effect of weight regain on cardiometabolic health and summarizes these results in the metabolic syndrome prevalence as integrated endpoint. DATA SYNTHESIS: A literature search was performed in PubMed and Web of Science. Studies were selected if they included participants aged <18 years with obesity and presented data before and after weight loss and after weight regain hereby reporting minimally 1 cardiovascular risk factor at every assessment. After screening, nine articles remained. Generally, the diastolic BP re-increased after weight regain, whereas for systolic BP a sustained result for 6 months was reported with an increase during longer follow-up. No significant changes in fasting glucose were reported after weight regain compared to baseline. Regarding triglycerides, a complete weight regain re-increased the lowered values to baseline, whereas a partial regain resulted in a sustained decrease in triglycerides in 2 studies and an increase to intermediate levels in 1 paper. HDL-cholesterol only rose several months after initiating treatment. Hs-CRP remained lowered for a longer period than the moment where the weight loss nadir was achieved. CONCLUSION: Research on weight regain and cardiometabolic health in children with obesity is scarce. No convincing evidence was found for a worsening of the cardiometabolic profile after weight regain. Some benefits even persisted despite weight recovery. Subsequently, the metabolic syndrome prevalence seems temporarily lowered after weight loss, despite weight regain.
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Síndrome Metabólico/prevención & control , Obesidad Infantil/terapia , Aumento de Peso , Pérdida de Peso , Adolescente , Factores de Edad , Biomarcadores/sangre , Presión Sanguínea , Proteína C-Reactiva/metabolismo , Factores de Riesgo Cardiometabólico , Niño , Femenino , Estado de Salud , Humanos , Lípidos/sangre , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Síndrome Metabólico/fisiopatología , Obesidad Infantil/diagnóstico , Obesidad Infantil/epidemiología , Obesidad Infantil/fisiopatología , Prevalencia , Medición de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Functional Respiratory Imaging (FRI) combines HRCT scans with computational fluid dynamics to provide objective and quantitative information about lung structure and function. FRI has proven its value in pulmonary diseases such as COPD and asthma, but limited studies have focused on cystic fibrosis (CF). This study aims to investigate the relation of multiple FRI parameters to validated imaging parameters and classical respiratory outcomes in a CF population. METHODS: CF patients aged > 5 years scheduled for a chest CT were recruited in a cross-sectional study. FRI outcomes included regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping and pulmonary blood distribution. Besides FRI, CT scans were independently evaluated by 2 readers using the CF-CT score. Spirometry and the 6-Minute Walk Test (6MWT) were also performed. Statistical tests included linear mixed-effects models, repeated measures correlations, Pearson and Spearman correlations. RESULTS: 39 CT scans of 24 (17M/7F) subjects were analyzed. Patients were 24 ± 9 years old and had a ppFEV1 of 71 ± 25% at the time of the first CT. All FRI parameters showed significant low-to-moderate correlations with the total CF-CT score, except for lobar volume. When considering the relation between FRI parameters and similar CF-CT subscores, significant correlations were found between parameters related to airway volume, air trapping and airway wall thickening. Air trapping, lobar volume after normal expiration and pulmonary blood distribution showed significant associations with all spirometric parameters and oxygen saturation at the end of 6MWT. In addition, air trapping was the only parameter related to the distance covered during 6MWT. A subgroup analysis showed considerably higher correlations in patients with mild lung disease (ppFEV1 ≥ 70%) compared to patients with moderate to severe lung disease (ppFEV1 < 70%) when comparing FRI to CF-CT scores. CONCLUSIONS: Multiple structural characteristics determined by FRI were associated with abnormalities determined by CF-CT score. Air trapping and pulmonary blood distribution appeared to be the most clinically relevant FRI parameters for CF patients due to their associations with classical outcome measures. The FRI methodology could particularly be of interest for patients with mild lung disease, although this should be confirmed in future research.
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Fibrosis Quística/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Modelos Lineales , Masculino , Índice de Severidad de la Enfermedad , Espirometría , Resultado del Tratamiento , Prueba de Paso , Adulto JovenRESUMEN
OBJECTIVE: There is still no consensus regarding the treatment of empyema in children. Intrapleural combination of tissue plasminogen activator and dornase alfa is a promising treatment for empyema in adults. The aim of this pilot study was to determine whether this combination is safe and successful in pediatric empyema. METHODS: Previous well children diagnosed with empyema as classified by the British Thoracic Society. After chest tube insertion, intrapleurally dornase alfa 2.5 mg for 2 days and tissue plasminogen activator 0.15 mg/kg for 3 days was given after which the chest tube was clamped for 4 h. Primary outcome was safety. RESULTS: Ten consecutive children were included (4 boys, aged 3.2 (1.3-15.0) years old). No serious adverse events were seen. One child developed urticaria but additional intervention or cessation of the trial was not needed. There was no bleeding or mortality and no additional procedures were performed. The median hospital stay after intervention was 7.5 days. CONCLUSIONS: The intrapleural treatment of dornase alfa and tissue plasminogen activator as treatment of empyema was safe in ten children with empyema. If confirmed in further studies, this combination of intrapleural therapy may improve the management of pediatric empyema.
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Empiema Pleural , Activador de Tejido Plasminógeno , Adolescente , Niño , Preescolar , Desoxirribonucleasa I , Empiema Pleural/tratamiento farmacológico , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Lactante , Masculino , Proyectos Piloto , Proteínas RecombinantesRESUMEN
BACKGROUND: Airway clearance techniques (ACTs) are an important aspect of the treatment of children with chronic obstructive lung diseases. Unfortunately, a sound evidence base is lacking and airway clearance strategies are largely based on clinical expertise. One of the reasons for the limited evidence is the lack of appropriate outcome measures specifically related to the effectiveness of ACTs. This review discusses all outcome measures applied in previous research in the pediatric population to provide a baseline for future studies. DATA SOURCES: A systematic literature search was performed in PubMed, Web of Science and EMBASE databases. Search terms included chronic obstructive lung diseases and ACTs. STUDY SELECTION: Studies were independently selected by the investigators according to the eligibility criteria. After screening, 49 articles remained for further analysis. RESULTS AND CONCLUSIONS: Data are summarized according to the type of outcome measure. 48 (98%) studies performed pulmonary function tests, 19 (39%) assessed expectorated sputum, 10 (20%) parameters related to disease exacerbation, 8 (16%) oxygenation, 8 (16%) patient-reported outcomes, 5 (10%) exercise capacity and 5 (10%) applied imaging techniques. The synthesis of results showed a high discrepancy between studies due to differences in study design, population and the application of techniques. Since no 'gold standard' method could be identified, a combination of different outcome measures is recommended to gain a better understanding and to identify the potential effects of ACTs. An overview of important considerations has been provided to assist researchers in their choice of outcomes in future studies.
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Enfermedades Pulmonares Obstructivas/terapia , Evaluación de Resultado en la Atención de Salud/métodos , Modalidades de Fisioterapia , Bronquiectasia/diagnóstico , Bronquiectasia/fisiopatología , Bronquiectasia/terapia , Niño , Fibrosis Quística/diagnóstico , Fibrosis Quística/fisiopatología , Fibrosis Quística/terapia , Humanos , Enfermedades Pulmonares Obstructivas/diagnóstico , Enfermedades Pulmonares Obstructivas/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Pruebas de Función Respiratoria/métodosRESUMEN
There is limited knowledge on the occurrence of respiratory manifestations and sleep-disordered breathing in particular in children with the MECP2 duplication syndrome. Although sleep-disordered breathing and nocturnal hypoventilation are currently not cited as an important symptom in these children, we present three cases who all had an abnormal breathing during sleep. In view of the consequences associated with sleep apnea and hypoventilation, we advise to perform a polysomnography in children with MECP2 duplication. Different treatment modalities (ENT surgery, CPAP, and non-invasive ventilation) can be applied to successfully treat these conditions.
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Hipoventilación/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Síndromes de la Apnea del Sueño/genética , Predisposición Genética a la Enfermedad , Humanos , Hipoventilación/diagnóstico por imagen , Hipoventilación/patología , Lactante , Recién Nacido , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico por imagen , Discapacidad Intelectual Ligada al Cromosoma X/patología , Síndromes de la Apnea del Sueño/diagnóstico por imagen , Síndromes de la Apnea del Sueño/patologíaRESUMEN
Respiratory problems have a significant impact on morbidity and mortality in patients with cerebral palsy (CP). In particular, recurrent aspiration, impaired airway clearance, spinal and thoracic deformity, impaired lung function, poor nutritional status, and recurrent respiratory infections negatively affect respiratory status. Bronchopulmonary dysplasia may contribute to pulmonary problems, but asthma is not more common in CP than in the general population. We discuss treatment options for each of these factors. Multiple coexisting and interacting factors that influence the respiratory status of patients with CP should be recognized and effectively addressed to reduce respiratory morbidity and mortality. WHAT THIS PAPER ADDS: Respiratory problems are a significant cause of morbidity in patients with cerebral palsy (CP). Respiratory status in patients with CP is influenced by recurrent aspiration and impaired airway clearance. Spinal and thoracic deformity, impaired lung function, poor nutrition, and respiratory infections also negatively affect respiratory status. These factors should all be addressed to reduce respiratory problems in patients with CP.
MORBILIDAD RESPIRATORIA EN NIÑOS CON PARÁLISIS CEREBRAL: UNA VISIÓN GENERAL: Los problemas respiratorios tienen un impacto significativo sobre la morbilidad y mortalidad en pacientes con parálisis cerebral (PC). En particular, aspiraciones recurrentes, incapacidad para despejar la vía aérea, deformidades de la columna y del tórax, deterioro de la función pulmonar, un pobre estado nutricional e infecciones pulmonares recurrentes, afectan negativamente el estado respiratorio. La displasia broncopulmonar puede contribuir a estos problemas pulmonares, pero el asma no es más común en PC que en la población general. Discutimos las opciones terapéuticas para cada uno de estos factores. La coexistencia e interacción de múltiples factores que influencian el estado respiratorio de las pacientes con PC deben ser reconocidos y tratados efectivamente para reducir la morbilidad respiratoria y la mortalidad.
MORBIDADE RESPIRATÓRIA EM CRIANÇAS COM PARALISIA CEREBRAL: UM PANORAMA: Problemas respiratórios têm impacto significativo na morbidade e mortalidade em pacientes com paralisia cerebral (PC). Em particular, aspiração recorrente, limpeza deficiente das vias aéreas, deformidade espinhal e torácica, função pulmonar deficiente, pobre estado nutricional, e infecções respiratórias recorrentes podem afetar o estado respiratório negativamente. A displasia broncopulmonar pode contribuir para problemas pulmonares, mas a asma não é mais comum em PC do que na população geral. Nós discutimos opções de tratamento para cada um destes fators. Múltiplos fatores coexistentes ou que interagem e que influenciam o estado respiratório de pacientes com PC devem ser reconhecidos e efetivamente abordados para reduzir a morbidade e mortalidade respiratória.
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Parálisis Cerebral/complicaciones , Trastornos Respiratorios/etiología , Trastornos Respiratorios/terapia , Niño , HumanosRESUMEN
AIM: Bronchiolitis is one of the most common lower respiratory tract infections in young children, associated with significant morbidity, but limited therapeutic options. Nebulised hypertonic saline (HS) has been a supportive treatment until current guidelines advised against its routine use. Accordingly, the University Hospital of Antwerp recently changed their policies to stop using it, allowing us to evaluate retrospectively if HS influences the duration of respiratory support. Because, to our knowledge, the effect of HS on children with severe bronchiolitis admitted to a paediatric intensive care unit (PICU) has not been studied yet, we aimed to investigate the effect in this specific patient group. METHODS: Retrospective study including children up to the age of 2, admitted to the PICU with bronchiolitis from October 2013 until March 2016. The primary end point is the duration of respiratory support, including high flow nasal cannula, continuous positive airway pressure and invasive ventilation. RESULTS: A total of 104 children admitted to the PICU with bronchiolitis were included, with an average age of 3.4 months. In respiratory syncytial virus (RSV) positive patients, the use of nebulised HS was correlated with a decrease in the duration of respiratory support and the length of stay by factors 0.72 (P = 0.01) and 0.81 (P = 0.04), respectively. CONCLUSIONS: A significant correlation was found between the use of HS and a decreased duration of respiratory support and admission in the PICU in patients with RSV bronchiolitis. This finding may warrant new prospective studies investigating HS specifically in children with severe bronchiolitis.
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Bronquiolitis/tratamiento farmacológico , Unidades de Cuidado Intensivo Pediátrico , Nebulizadores y Vaporizadores , Solución Salina Hipertónica/administración & dosificación , Bélgica , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Solución Salina Hipertónica/uso terapéuticoRESUMEN
Neuropeptide Y (NPY) and its G protein-coupled NPY Y2 Receptor (NPY2R) are highly expressed in orexigenic NPY/Agouti-related peptide neurons within the arcuate nucleus, a major integrator of appetite control in the hypothalamus. As NPY and NPY2R are interesting candidate genes for obesity, we hypothesized that a genetic variation in these genes might be implicated in the pathogenesis of obesity. In the first part of this study, we performed a mutation analysis of the coding region of NPY and NPY2R with high-resolution melting curve analysis. For the highly conserved NPY gene, an extended population of 436 obese children and adolescents was screened, while for NPY2R, a smaller subset of 306 patients was used. A control population of 300 healthy individuals was screened for NPY2R to determine the general prevalence of the variants found among patients. Direct sequencing was performed for samples with melting patterns deviating from wild-type. In the second part of this study, Multiplex Amplicon Quantification (MAQ) analysis was performed in 308 obese children and adolescents to detect copy number variation (CNV) in the NPY2R region. Mutation analysis of the NPY gene led to the identification of one common missense variant (L7P; MAF 0.04), while the screening of the NPY2R gene resulted in the identification of one rare missense variant F87I in the patient population. In our CNV analysis, we could not identify copy number variation in the NPY2R region among obese children and adolescents. In summary, this study clearly indicates that genetic variation in NPY and NPY2R is at low frequency and thus does not make a major contribution to the obese phenotype in the general population.
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Variaciones en el Número de Copia de ADN , Neuropéptido Y/genética , Obesidad Infantil/genética , Receptores de Neuropéptido Y/genética , Adolescente , Estudios de Casos y Controles , Niño , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , MutaciónRESUMEN
OBJECTIVE: To investigate clinical factors that could predict residual sleep-disordered breathing (SDB) after weight loss. STUDY DESIGN: Obese subjects between 10 and 19 years of age were recruited while entering an in-patient weight loss treatment program. All subjects underwent anthropometry and sleep screening using a portable device at baseline and after 4-6 months of therapy. Sleep and International Study of Asthma and Allergies in Childhood questionnaires were completed at baseline. RESULTS: A total of 339 patients were included. Median age was 15.4 years (10.1-19.1). Body mass index z score at baseline was 2.75 ± 0.42, and 35% of subjects were boys. SDB was present in 32%. After a mean decrease in body mass index z score of 32%, residual SDB was found in 20% of subjects with SDB at baseline. Subjects with more severe SDB (OR 1.18; CI 1.01-1.34; P = .02) and respiratory allergies (OR 7.85; CI 1.20-51.39; P = .03) were at higher risk of developing residual SDB, unlike age, sex, and anthropometric variables. CONCLUSIONS: Weight loss was successful for treating SDB in 80% of patients. More severe SDB and the presence of respiratory allergies at baseline were associated with a higher risk of residual SDB after weight loss.
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Obesidad Infantil/complicaciones , Síndromes de la Apnea del Sueño/diagnóstico , Pérdida de Peso , Adolescente , Antropometría , Índice de Masa Corporal , Niño , Femenino , Humanos , Hipersensibilidad , Masculino , Obesidad Infantil/terapia , Polisomnografía , Sueño , Síndromes de la Apnea del Sueño/complicaciones , Resultado del TratamientoRESUMEN
BACKGROUND: Obesity is a widespread problem that not only leads to medical and psychological diseases in adults, but also in children and adolescents at an early stage in life. Because of its global burden on both the individual and society, it is necessary to develop effective evidence-based treatments. Current "Multidisciplinary Obesity Treatments" (MOT) already provide significant weight loss, but still leave room for more long-lasting improvements. In this protocol paper, we outline the research goals of the WELCOME trial, based on a substantial proof of concept. METHODS: In this Randomized Controlled Trial (RCT) - conducted in both an inpatient and two outpatient treatment settings - existing MOT will be supplemented with an Executive Function (EF) training and compare effects on various parameters in an experimental versus an active control group of obese youngsters (8-18 years old). WELCOME aims to (a) train youngsters' executive functions to facilitate effects on weight loss, psychological and medical comorbidities, (b) to enhance the long-term effects by continuing the training in the daily home context with booster sessions, and (c) to investigate its effects until a 6-month follow-up. In comparison to the active control group, better progress is expected in the experimental group on following variables: weight, psychological comorbidities (unhealthy eating behavior, internalizing symptoms, impaired self-esteem) and medical comorbidities (metabolic syndromes, endothelia dysfunction, tonsillar hypertrophy and sleep obstruction). DISCUSSION: It is stated that this EF-training for enhancing self-control abilities is necessary for a long-lasting effect of childhood obesity treatment interventions. TRIAL REGISTRATION: The Study Procotol was registered on 10/05/2017 (n° ISRCTN14722584 ).
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Función Ejecutiva , Obesidad Infantil/prevención & control , Obesidad Infantil/psicología , Adolescente , Niño , Protocolos Clínicos , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Obesidad Infantil/epidemiología , Autocontrol/psicología , Resultado del Tratamiento , Pérdida de PesoRESUMEN
BACKGROUND: Prader-Willi syndrome (PWS), caused by a paternal defect on 15q11.2-q13, is the most common form of syndromic obesity. However, patients clinically diagnosed with PWS do not always show this defect on chromosome 15q and are therefore molecularly categorized as Prader Willi like (PWL). Deletions at 6q14.1-q16.3 encompassing MRAP2 and SIM1 were reported in some individuals with a PWL phenotype. In addition, a few mutations in SIM1 and MRAP2 were also previously identified in cohorts of obese individuals. Therefore, we decided to perform copy number variation analysis of the 6q14.1-6q16.3 region followed by mutation analysis of SIM1 and MRAP2 in a PWL cohort. METHODS: A genome-wide microarray analysis was performed in a group of 109 PWL patients. Next, we screened 94 PWL patients for mutations in SIM1 and MRAP2 using high-resolution melting curve analysis and Sanger sequencing. Additionally, 363 obese children and adolescents were screened for mutations in MRAP2. RESULTS: No gene harboring deletions were identified at the 6q14.1-q16.3 region in the 109 PWL patients. SIM1 mutation analysis resulted in the identification of one very rare nonsynonymous variant p.P352S (rs3734354). Another rare nonsynonymous variant, p.A40S, was detected in the MRAP2 gene. No variants were identified in the 363 obese individuals. CONCLUSIONS: In contrast to literature reports, no gene harboring deletions were identified in the SIM1 and MRAP2 regions in our PWL cohort. Secondly, taking into account their very low minor allele frequencies in public sequencing databases and the results of in silico prediction programs, further functional analysis of p.P352S found in SIM1 and p.A40S found in MRAP2 is useful. This would provide further support for a possible role of SIM1 and MRAP2 in the pathogenesis of the PWL phenotype albeit in a limited number of patients.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas Portadoras/genética , Variaciones en el Número de Copia de ADN , Eliminación de Gen , Variación Genética , Síndrome de Prader-Willi/genética , Proteínas Represoras/genética , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Niño , Preescolar , Deleción Cromosómica , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Humanos , Masculino , Análisis por Micromatrices , Mutación , Obesidad/genética , Fenotipo , Adulto JovenRESUMEN
Because sFRP5 was shown to be an important extracellular modulator of the Wnt pathway, regulating adipogenesis, we wanted to investigate the role of sFRP5 variants in human, monogenic obesity by performing mutation analysis. We screened the complete sFRP5 coding region in 622 obese children and adolescents and 503 lean control individuals by high-resolution melting curve analysis and direct sequencing. We found a total of 15 sequence variants in sFRP5, 10 of which resulted in a non-synonymous amino acid change. Five of these variants were, to our knowledge, not previously reported. For one of the variants (c.-3G>A), we identified a trend towards association between the variant frequency and the obese phenotype. We argue that, when looking at conservation and location inside known protein domains, several of the identified variants (D103N, A113V, K212N and H317L), may affect sFRP5 protein function. In addition, we found c.-3G>A, residing in the Kozak sequence, with a lower frequency in cases compared to controls. However, functional studies investigating the effect of sFRP5 variants on protein function are necessary to determine the true role of sFRP5 genetic variation in human, monogenic obesity.
Asunto(s)
Proteínas del Ojo/genética , Proteínas de la Membrana/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Niño , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Masculino , Nucleótidos/genéticaRESUMEN
OBJECTIVE: Animal studies, genome-wide association and genomic structural variation studies have identified the SH2B1 gene as a candidate gene for obesity. Therefore, we have designed an extensive mutation and copy number variation (CNV) analysis investigating the prevalence of genetic and structural variations in SH2B1 in the Belgian population. DESIGN AND METHODS: In the first part of this study, we performed a mutation screen for variants in the SH2B1 coding region in 581 obese children and adolescents and 433 healthy, lean individuals with high-resolution melting curve analysis followed by direct sequencing. In the second part of this study, Multiplex Amplicon Quantification (MAQ) analysis was used to identify CNVs in the distal SH2B1-containing chr.16p11.2 region in 421 obese children and adolescents with no developmental delay or behavioral phenotype. RESULTS: Mutation analysis resulted in the identification of fifteen rare non-synonymous heterozygous variants. Several of these were found both in lean and obese subjects, suggesting that these are neutral polymorphisms. However, six private, heterozygous, non-synonymous variations were present in obese children only. Furthermore, we also identified six missense variants solely in lean individuals. CNV analysis could not identify carriers of the distal 16p11.2 deletion in our population. CONCLUSION: Our mutation analysis has demonstrated that variation in the SH2B1 gene is frequent in both lean and obese groups, with distinctive variations being present on either side of the weight spectrum. Although the equal variation frequency does not immediately support disease causality, it cannot be excluded that some variations are weight-increasing or -decreasing. Further functional testing of the variants will be necessary to fully understand the impact of these variants on SH2B1. We were not able to detect carriers of the distal 16p11.2 deletion in our study population. As we excluded patients with developmental or behavioral problems, we suggest that in addition to obesity, the distal deletion might predispose for these traits. Further characterization of the phenotype is therefore necessary to clearly identify the phenotype of the distal 16p11.2 microdeletion syndrome.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Variación Genética , Obesidad/genética , Proteínas Adaptadoras Transductoras de Señales/química , Adolescente , Adulto , Bélgica , Niño , Cromosomas Humanos Par 16 , Femenino , Humanos , Masculino , Sobrepeso/genéticaRESUMEN
PURPOSE: Sleep-disordered breathing (SDB) is common among overweight and obese children. It is a risk factor for several health complications, including cardiovascular disease. Inflammatory processes leading to endothelial dysfunction are a possible mechanism linking SDB and cardiovascular disease. Elevated C-reactive protein (CRP) is a risk factor for cardiovascular disease and is independently correlated with obstructive sleep apnea syndrome (OSAS) in adults. Our goal is to evaluate the relationship between CRP and OSAS in overweight and obese children and adolescents. METHODS: One hundred and twenty children were prospectively studied (85 without OSAS, 20 mild OSAS, 15 moderate-to-severe OSAS). All subjects underwent polysomnography, and a blood sample was taken to determine CRP levels. RESULTS: No significant differences were found in CRP between subjects with or without OSAS, and no correlations were found between CRP and OSAS severity, despite the relationship between CRP and BMI (r = 0.21, p = 0.015) and between CRP and fat mass (r = 0.31, p < 0.001). CONCLUSION: These results suggest that CRP levels are correlated with the level of obesity but are not influenced by SDB in obese children and adolescents; hence, this in contrast to that in adult population.