RESUMEN
OBJECTIVES: Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. METHODS: We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. RESULTS: S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78⯵g/L achieved a sensitivity/specificity of 63 and 84â¯%, positive/negative predictive values of 83 and 64â¯%. CONCLUSIONS: The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.
Asunto(s)
Asfixia Neonatal , Hipotermia Inducida , Subunidad beta de la Proteína de Unión al Calcio S100 , Convulsiones , Humanos , Subunidad beta de la Proteína de Unión al Calcio S100/orina , Convulsiones/orina , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Masculino , Recién Nacido , Femenino , Estudios de Casos y Controles , Estudios Prospectivos , Asfixia Neonatal/orina , Asfixia Neonatal/terapia , Asfixia Neonatal/complicaciones , Curva ROC , Hipoxia-Isquemia Encefálica/orina , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/diagnóstico , Fenobarbital/uso terapéutico , Lactante , Biomarcadores/orinaRESUMEN
OBJECTIVES: The early detection and stratification of asphyxiated infants at higher risk for impaired neurodevelopment is challenging. S100B protein is a well-established biomarker of brain damage, but lacks conclusive validation according to the "gold standard" methodology for hypoxic-ischemic encephalopathy (HIE) prognostication, i.e. brain MRI. The aim of the present study was to investigate the predictive role of urinary S100B concentrations, assessed in a cohort of HIE infants receiving therapeutic hypothermia (TH), compared to brain MRI. METHODS: Assessment of urine S100B concentrations was performed by immunoluminometric assay at first void and at 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120-h after birth. Neurologic evaluation, routine laboratory parameters, amplitude-integrated electroencephalography, and cerebral ultrasound were performed according to standard protocols. Brain MRI was performed at 7-10 days of life. RESULTS: Overall, 74 HIE neonates receiving TH were included in the study. S100B correlated, already at first void, with the MRI patterns with higher concentrations in infants with the most severe MRI lesions. CONCLUSIONS: High S100B urine levels soon after birth constitute trustable predictors of brain injury as confirmed by MRI. Results support the reliability of S100B in clinical daily practice and open the way to its inclusion in the panel of parameters used for the selection of cases suitable for TH treatment.
Asunto(s)
Asfixia Neonatal , Hipoxia-Isquemia Encefálica , Subunidad beta de la Proteína de Unión al Calcio S100 , Asfixia Neonatal/diagnóstico por imagen , Asfixia Neonatal/terapia , Biomarcadores/orina , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico por imagen , Recién Nacido , Imagen por Resonancia Magnética , Reproducibilidad de los Resultados , Subunidad beta de la Proteína de Unión al Calcio S100/orinaRESUMEN
Background Perinatal asphyxia is a major cause of mortality and morbidity in neonates: The aim of the present study was to investigate, by means of longitudinal assessment of urinary S100B, the effectiveness of hypothermia, in infants complicated by perinatal asphyxia and hypoxic-ischemic encephalopathy. Methods We performed a retrospective case-control study in 108 asphyxiated infants, admitted to nine tertiary departments for neonatal intensive care from January 2004 to July 2017, of whom 54 underwent hypothermia treatment and 54 did not. The concentrations of S100B protein in urine were measured using an immunoluminometric assay at first urination and 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120 h after birth. The results were correlated with the achievement of S100B levels within normal ranges at 72 h from hypothermia treatment. Routine laboratory parameters, longitudinal cerebral function monitoring, cerebral ultrasound and neurologic patterns were assessed according to standard protocols. Results Higher S100B concentrations were found in hypothermia-treated infants in both moderate (up to 12 h) and severe (up to 24 h) hypoxic-ischemic encephalopathy. S100B levels returned to normal ranges starting from 20 h of hypothermia treatment in moderate and from 36 h in severe hypoxic-ischemic encephalopathy. Conclusions The present results offer additional support to the usefulness of longitudinal neuro-biomarkers monitoring in asphyxiated infants treated by hypothermia. The pattern of S100B concentrations during hypothermia supports the need for further investigations aimed at reconsidering the time-window for patient recruitment and treatment, and the optimal duration of the cooling and rewarming phases of the hypothermia procedure.
Asunto(s)
Asfixia/patología , Hipotermia Inducida , Subunidad beta de la Proteína de Unión al Calcio S100/orina , Biomarcadores/orina , Encéfalo/fisiología , Estudios de Casos y Controles , Electroencefalografía , Femenino , Humanos , Hipoxia-Isquemia Encefálica/patología , Inmunoensayo , Recién Nacido , Masculino , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: S100B is a well-established biomarker of central nervous system (CNS) development and damage in the perinatal period. Because the fetal CNS induces an overproduction of S100B measurable in the maternal bloodstream we evaluated S100B protein in healthy pregnancies in order to provide a reference curve of the protein in the second and third trimesters and to provide information on CNS development when standard monitoring procedures could be silent or unavailable. METHODS: Between July 2012 and December 2014 we conducted a prospective study in 1213 healthy pregnancies delivering healthy newborns. Maternal blood samples were collected for standard monitoring procedures and S100B assessment. S100B correlations with selected outcomes (gestational age at sampling, gender of fetus, gestational age and weight at birth, delivery mode) were calculated using multiple forward stepwise regression analysis. RESULTS: S100B concentrations in the second and third trimesters of pregnancy were found to be gestational age-, gender- and delivery mode-dependent (p<0.05, for all). Multiple forward stepwise regression analysis with S100B as the dependent variable and gestational age at sampling, gender, delivery mode, gestational age and weight at birth as independent variables, showed a significant correlation between S100B and gestational age at sampling (R=0.13; p<0.001). CONCLUSIONS: The present findings offering a S100B protein reference curve in maternal blood suggest that non-invasive fetal CNS monitoring is becoming feasible and open the way to further research in neuro-biomarker assessment in the maternal bloodstream.
Asunto(s)
Edad Gestacional , Inmunoensayo , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Adulto , Biomarcadores/sangre , Peso al Nacer , Femenino , Humanos , Mediciones Luminiscentes , Masculino , Atención Perinatal , Embarazo , Estudios Prospectivos , Análisis de Regresión , Factores Sexuales , Adulto JovenRESUMEN
AIM: To investigate whether S100A1B and BB dimers are predictors of early perinatal death in newborns with perinatal asphyxia (PA). METHODS: The study compared 38 full-term newborns with PA [neonatal death n = 11; hypoxic ischaemic encephalopathy (HIE): n = 27] with a control group of 38 healthy infants. Clinical and laboratory parameters were recorded at eight time points and urine collected for S100B assessment. Multivariate analysis was performed in order to analyse the influence of various clinical parameters on the occurrence of neonatal death. RESULTS: A1B and BB in PA nonsurvivor infants were significantly higher (p < 0.001) than in controls at all monitoring time points. BB at first void (cut-off>42 ng/L) was the best predictor of early neonatal death (p < 0.05) of all the clinical and laboratory parameters studied. CONCLUSION: These results suggest that S100s are valuable predictors of adverse outcome in PA infants. It is also suggested that these biomarkers be used in daily clinical practice, due to their low cost and stress, reproducibility and the possibility of longitudinal monitoring.
Asunto(s)
Asfixia Neonatal/mortalidad , Hipoxia-Isquemia Encefálica/mortalidad , Subunidad beta de la Proteína de Unión al Calcio S100/orina , Asfixia Neonatal/diagnóstico , Asfixia Neonatal/terapia , Asfixia Neonatal/orina , Biomarcadores/química , Biomarcadores/orina , Estudios de Casos y Controles , Técnicas de Apoyo para la Decisión , Femenino , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico , Hipoxia-Isquemia Encefálica/terapia , Hipoxia-Isquemia Encefálica/orina , Recién Nacido , Modelos Logísticos , Masculino , Análisis Multivariante , Evaluación de Resultado en la Atención de Salud , Subunidad beta de la Proteína de Unión al Calcio S100/química , Sensibilidad y EspecificidadRESUMEN
S100B is a calcium-binding protein concentrated in glial cells, although it has also been detected in definite extra-neural cell types. Its biological role is still debated. When secreted, S100B is believed to have paracrine/autocrine trophic effects at physiological concentrations, but toxic effects at higher concentrations. Elevated S100B levels in biological fluids (CSF, blood, urine, saliva, amniotic fluid) are thus regarded as a biomarker of pathological conditions, including perinatal brain distress, acute brain injury, brain tumors, neuroinflammatory/neurodegenerative disorders, psychiatric disorders. In the majority of these conditions, high S100B levels offer an indicator of cell damage when standard diagnostic procedures are still silent. The key question remains as to whether S100B is merely leaked from injured cells or is released in concomitance with both physiological and pathological conditions, participating at high concentrations in the events leading to cell injury. In this respect, S100B levels in biological fluids have been shown to increase in physiological conditions characterized by stressful physical and mental activity, suggesting that it may be physiologically regulated and raised during conditions of stress, with a putatively active role. This possibility makes this protein a candidate not only for a biomarker but also for a potential therapeutic target.
Asunto(s)
Líquidos Corporales/metabolismo , Encefalopatías/patología , Encéfalo/metabolismo , Trastornos Mentales/patología , Factores de Crecimiento Nervioso/metabolismo , Proteínas S100/metabolismo , Biomarcadores/metabolismo , Humanos , Subunidad beta de la Proteína de Unión al Calcio S100RESUMEN
OBJECTIVE: To assess sleepiness, TNF-α plasma levels, and genomic variance in the TNF-α gene in children with obstructive sleep apnea (OSA). STUDY DESIGN: Children being evaluated for OSA (n = 60) and matched control children (n = 80) were assessed with a modified Epworth Sleepiness Scale questionnaire and underwent a blood draw the morning after nocturnal polysomnography. TNF-α plasma concentrations were assayed using ELISA, and genomic DNA was extracted. Genotyping and allelic frequencies were determined for 4 TNF-α single nucleotide polymorphisms using real-time polymerase chain reaction genotyping assays. RESULTS: Morning TNF-α levels and Epworth Sleepiness Scale scores were increased in the presence of OSA, but substantial variability was present. Although TNF-α plasma concentrations were globally increased in OSA, most of the variance was attributable to the presence or absence of TNF-α -308G gene polymorphism. CONCLUSIONS: TNF-α levels are increased in a subset of children with OSA, particularly among those harboring the TNF-α -308G single nucleotide polymorphism. Among the latter, significant increases in excessive daytime sleepiness symptoms are also present. The relatively high variability of excessive daytime sleepiness in pediatric OSA may be related to underlying TNF-α gene polymorphisms, particularly -308G.
Asunto(s)
Polimorfismo Genético , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/genética , Privación de Sueño/etiología , Privación de Sueño/genética , Factor de Necrosis Tumoral alfa/genética , Estudios de Casos y Controles , Niño , Femenino , Variación Genética , Humanos , Masculino , Apnea Obstructiva del Sueño/sangre , Privación de Sueño/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
OBJECTIVE: To assess dietary and physical activity patterns and morning circulating blood levels of the orexigenic hormones ghrelin and visfatin in children with either obesity, obstructive sleep apnea (OSA), or both conditions. STUDY DESIGN: In this cross-sectional design, 5- to 9-year-old participants (n = 245) from the community were identified. After overnight polysomnography, caregivers filled out a food and physical activity questionnaire, and the child underwent a fasting blood draw for ghrelin and visfatin plasma levels. RESULTS: Compared with control subjects, obese children with OSA ate 2.2-times more fast food, ate less healthy food such as fruits and vegetables, and were 4.2-times less frequently involved in organized sports. OSA was positively correlated with plasma ghrelin levels (R(2), 0.73; P < .0001), but not visfatin levels, particularly when obesity was present. CONCLUSION: OSA and obesity in children may adversely impact dietary preferences and may be particularly detrimental to daily physical activity patterns. Furthermore, increased ghrelin levels support the presence of increased appetite and caloric intake in obese patients with OSA, which in turn may further promote the severity of the underlying conditions.
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Dieta , Ejercicio Físico , Apnea Obstructiva del Sueño/fisiopatología , Apetito , Índice de Masa Corporal , Niño , Femenino , Ghrelina/sangre , Humanos , Masculino , Nicotinamida Fosforribosiltransferasa/sangre , Obesidad/sangre , Obesidad/complicaciones , Polisomnografía , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/complicacionesRESUMEN
BACKGROUND: Sleep disordered breathing in children is associated with severity-dependent increases in excessive daytime sleepiness (EDS). TNF-alpha is an inflammatory cytokine that has been implicated in EDS. Since, at any given level of apnea-hypopnea index, there is significant variability in EDS, we hypothesized that morning tumor necrosis factor (TNF)-alpha plasma levels may provide a biologic correlate of EDS. METHODS: Children being evaluated for sleep disordered breathing underwent a blood draw after nocturnal polysomnography, and TNF-alpha plasma concentrations were assayed using ELISA. In a subset of 15 children with sleep disordered breathing and in 15 matched control subjects, whole blood cultures in the presence of lipopolysaccharide and Multiple Sleep Latency Test were conducted. Furthermore, 22 children with obstructive sleep apnea had TNF-alpha levels assayed and underwent nocturnal polysomnography and Multiple Sleep Latency Test before and after adenotonsillectomy. RESULTS: In 298 children, morning TNF-alpha levels were globally increased in the presence of obstructive sleep apnea, particularly in more severe cases, and correlated with obstructive apnea-hypopnea index and sleep pressure score, a measure of respiratory-induced sleep fragmentation, but not with nadir Sa02. A stepwise logistic regression analysis revealed that sleep pressure score and body mass index accounted for 36.2% of the adjusted variance in TNF-alpha levels (P < 0.0001). Furthermore, multiple sleep latencies were correlated with whole blood culture-derived TNF-alpha levels (n = 15), and morning TNF-alpha levels decreased after adenotonsillectomy in 22 children. CONCLUSIONS: TNF-alpha levels are increased in pediatric obstructive sleep apnea, are primarily driven by sleep fragmentation and body mass index, and are closely associated with the degree of sleepiness, as measured by Multiple Sleep Latency Test. Furthermore, surgical treatment of obstructive sleep apnea results in significant reductions in TNF-alpha levels with reciprocal prolongations in sleep latency.
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Ritmo Circadiano/fisiología , Polisomnografía , Apnea Obstructiva del Sueño/inmunología , Factor de Necrosis Tumoral alfa/sangre , Adenoidectomía , Índice de Masa Corporal , Niño , Trastornos de Somnolencia Excesiva/diagnóstico , Trastornos de Somnolencia Excesiva/inmunología , Trastornos de Somnolencia Excesiva/cirugía , Femenino , Humanos , Lipopolisacáridos/sangre , Masculino , Valores de Referencia , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/cirugía , TonsilectomíaRESUMEN
Whole-body hypoxic preconditioning (WHPC) prolongs survival of mice exposed to severe hypoxia by attenuating pulmonary edema and preserving gas exchange. However, the cellular and molecular mechanism(s) of this protection remains unclear. The objective of this study was to identify the cellular target(s) of WHPC in the lung. Conscious mice were exposed to hypoxia (7% O(2)) for 6 hours with or without pretreatment of WHPC ([8% O(2)] x 10 min/[21% O(2)] x 10 min; 6 cycles). Hypoxia caused severe lung injury, as shown by the development of high-permeability-type pulmonary edema and the release of lactate dehydrogenase and creatine kinase into the airspace and the circulation. All these signs of hypoxic lung injury were significantly attenuated by WHPC. Hypoxia also caused a remarkable release of type I cell markers (caveolin-2 and receptor for advanced glycation end products) in lung lavage that was almost completely abolished by WHPC. Conversely, hypoxia-induced release of type II cell markers (surfactant-associated proteins A and D) was only marginal, and was unaffected by WHPC. Electron microscopic analysis demonstrated considerable hypoxic damage in alveolar type I cells and vascular endothelial cells. Notably, WHPC completely eliminated hypoxic damage in the former and alleviated it in the latter. Type II cells appeared normal. Furthermore, WHPC up-regulated protein expression of cytoprotective genes in the lung, such as heat shock proteins and manganese superoxide dismutase. Thus, WHPC attenuates hypoxic lung injury through protection of cells constituting the respiratory membrane, especially hypoxia-vulnerable type I epithelial cells. This beneficial effect may involve up-regulation of cytoprotective genes.
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Células Epiteliales/fisiología , Hipoxia/metabolismo , Lesión Pulmonar/patología , Pulmón/citología , Pulmón/fisiología , Animales , Biomarcadores/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Citoprotección/genética , Células Epiteliales/ultraestructura , Hipoxia/patología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de von Willebrand/inmunología , Factor de von Willebrand/metabolismoRESUMEN
Experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis, is characterized by demyelination, inflammation and neurodegeneration of CNS in which free radicals play a role. Recently, the efficacy of murine mesenchimal stem cells (MSCs) as treatment of EAE induced in mice by the encephalitogenic peptide MOG(35-55) was demonstrated. The present study analyzed some markers of oxidative stress, inflammation/degeneration and apoptosis such as metallothioneins (MTs), antioxidant enzymes (superoxide dismutase, catalase and glutathione-S-transferase), poly(ADP-ribose) polymerase-1 and p53 during EAE progression and following MSC treatment. Expression of the three brain MT isoforms increased significantly in EAE mice compared with healthy controls, but while expression of MT-1 and MT-3 increased along EAE course, MT-2 was up-regulated at the onset, but returned to levels similar to those of controls in chronic phase. The changes in the transcription and activity of the antioxidant enzymes and in expression of poly(ADP-ribose) polymerase-1 and p53 showed the same kinetics observed for MT-1 and MT-3 during EAE. Interestingly, i.v. administration of MSCs reduced the EAE-induced increases in levels/activities of all these proteins. These results support an antioxidant and neuroprotective activity for MSCs that was also confirmed in vitro on neuroblastoma cells exposed to an oxidative insult.
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Antioxidantes/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Animales , Línea Celular Tumoral , Medios de Cultivo Condicionados/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Humanos , Células Madre Mesenquimatosas/citología , Metalotioneína/metabolismo , Metalotioneína 3 , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/fisiologíaRESUMEN
BACKGROUND: Pediatric OSA is associated with substantial morbidity in cognitive function. However, for any given OSA severity level, altered cognitive performance may or may not be present. Since IGF-1 is neuroprotective, we hypothesized that higher systemic IGF-1 levels may identify children at lower susceptibility for cognitive morbidity. METHODS: Consecutive habitually snoring and non-snoring children ages 5-7 years were recruited from the community, and underwent overnight polysomnography, and neurocognitive testing and a blood draw the next morning. Snoring children were divided into OSA or no OSA, and OSA children were further subdivided into those with >=2 abnormal cognitive subtests and into those with normal cognitive scores. Plasma levels of IGF-1 were also measured using ELISA. RESULTS: Among snoring children without OSA, circulating IGF-1 was 910 +/- 110 pg/mL compared with 1070 +/- 240 pg/mL in those with OSA (p<0.01). However, IGF-1 was 540 +/- 70 pg/mL in children with OSA and cognitive deficits, compared to 1370 +/- 170 microg/L in children with OSA and normal cognitive scores (p<0.001). CONCLUSIONS: IGF-1 levels are higher in children with OSA, particularly in those who do not manifest neurocognitive deficits, suggesting that the magnitude of the IGF-1 response elicited by OSA may play a significant protective role against the neurocognitive dysfunction associated with OSA.
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Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/complicaciones , Factor I del Crecimiento Similar a la Insulina/metabolismo , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/psicología , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Polisomnografía , Factores de Riesgo , Apnea Obstructiva del Sueño/complicaciones , Ronquido/sangre , Ronquido/complicaciones , Ronquido/psicologíaRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) is a multi-factorial and highly prevalent disorder in which both genetic and environmental factors may be involved. If left untreated, OSA may lead to significant cardiovascular and neurocognitive and behavioral morbidities. We hypothesized that pediatric OSA would lead to altered gene expression in circulating leukocytes. METHODS AND RESULTS: Oligonucleotide-based microarray technology was used to identify mRNAs that may be differentially regulated in non-obese children with polysomnographically-established OSA compared to matched control children. Total morning blood RNA from 40 children (20 OSA and 20 controls) was extracted, labeled, and hybridized onto independent oligonucleotide-based microarrays. Of the 44,000 transcripts, 1217 transcripts were differentially expressed in OSA (p-value <0.05), with 68 transcripts (38 RefSeq accession numbers, 30 ESTs) fulfilling high stringency criteria. False Discovery rate (FDR) was used to determine the significance-difference of OSA vs. normal samples. Microarray data were further validated using quantitative RT-PCR techniques. Biological pathways pertinent to the differentially expressed genes were explored and revealed prominent involvement of inflammatory pathways. CONCLUSIONS: RNA derived from peripheral leukocytes confirms the presence of altered expression of functionally relevant gene clusters in pediatric OSA. Large-scale genomic approaches may provide further insights into adaptive and end-organ injury related mechanisms in the context of OSA in children.
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Perfilación de la Expresión Génica , Genómica , Apnea Obstructiva del Sueño/genética , Tonsilitis/genética , Tonsila Faríngea/patología , Peso Corporal , Niño , Femenino , Humanos , Hipertrofia , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Tonsila Palatina/patología , Polisomnografía , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Apnea Obstructiva del Sueño/patología , Tonsilitis/patologíaRESUMEN
Adenotonsillar hypertrophy is the major pathophysiological mechanism underlying obstructive sleep apnea (OSA) and recurrent tonsillitis (RI) in children. The increased expression of various mediators of the inflammatory response in tonsils of patients with OSA prompted our hypothesis that the enhanced local and systemic inflammation in children with OSA would promote tonsillar proliferation. Mixed cell cultures from tonsils recovered during adenotonsillectomy in children with OSA and RI were established, and proliferative rates were assessed. Cells were also cultured to determine the levels of proinflammatory cytokines and antioxidant protein levels and mRNA expression. Global cell proliferative rates from OSA tonsils were significantly higher than RI (p < 0.01), with CD3, CD4, and CD8 cell proliferation being higher in OSA (p < 0.05). Moreover, proinflammatory cytokines, such as TNF-alpha, IL-6, and IL-1alpha, were highly expressed in OSA-derived tonsils. Furthermore, thioredoxin (TRX), an antioxidant protein, was also highly expressed in OSA tonsils at the mRNA and protein levels (p < 0.01). Thus, T cells are in a highly proliferative state in the tonsils of children with OSA and are associated with increased production of proinflammatory cytokines and TRX, when compared with children with RI.
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Proliferación Celular , Citocinas/inmunología , Inflamación/inmunología , Tonsila Palatina , Apnea Obstructiva del Sueño/inmunología , Adenoidectomía , Adulto , Linfocitos B/inmunología , Técnicas de Cultivo de Célula , Células Cultivadas , Niño , Preescolar , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas de la Membrana , Tonsila Palatina/citología , Tonsila Palatina/inmunología , Tonsila Palatina/patología , Apnea Obstructiva del Sueño/cirugía , Linfocitos T/inmunología , TonsilectomíaRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) in children is associated with cardiovascular morbidity such as systemic and pulmonary hypertension. However, it remains unclear whether endothelial dysfunction occurs in pediatric OSA and whether it is reversible on effective treatment of OSA. METHODS AND RESULTS: Consecutive nonobese children (aged 6 to 11 years) who were diagnosed with OSA after overnight polysomnography and control children matched on the basis of age, gender, ethnicity, and body mass index underwent blood draw the next morning for soluble CD40 ligand, asymmetric dimethylarginine (ADMA), and nitrotyrosine levels, as well as 2 iterations of 60-second cuff-occlusion tests for assessment of endothelial function. These tests were repeated 4 to 6 months after adenotonsillectomy. OSA children showed blunted reperfusion kinetics after release of occlusion, which completely normalized in 20 of 26 patients after adenotonsillectomy. All 6 children in whom no improvements occurred had a strong family history of cardiovascular disease (versus 2 of the remaining 20 patients; P<0.04). Plasma nitrotyrosine and ADMA levels were similar in OSA and control children; however, soluble CD40 ligand levels were higher in OSA children and were reduced after treatment, particularly in those with normalized hyperemic responses. CONCLUSIONS: Postocclusive hyperemia is consistently blunted in children with OSA, and such altered endothelial function is reversible 4 to 6 months after treatment, particularly if a family history of cardiovascular disease is not present. Although no evidence for either nitric oxide-dependent oxidative/nitrosative stress or for the increased presence of the circulating nitric oxide synthase inhibitor ADMA was found in children with OSA, soluble CD40 ligand levels were increased in OSA and reflected the changes in endothelial function after treatment.
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Adenoidectomía , Endotelio Vascular/fisiología , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/cirugía , Tonsilectomía , Vasculitis/fisiopatología , Arginina/análogos & derivados , Arginina/sangre , Peso Corporal , Ligando de CD40/sangre , Niño , Femenino , Humanos , Hiperemia/fisiopatología , Hipoxia/inmunología , Hipoxia/fisiopatología , Hipoxia/cirugía , Masculino , Óxido Nítrico/metabolismo , Polisomnografía , Apnea Obstructiva del Sueño/inmunología , Tirosina/análogos & derivados , Tirosina/sangreRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) has been associated with increased systemic inflammatory responses that may contribute to an increased risk for end-organ morbidity. The changes in levels of pro-inflammatory cytokine IL-6 , and the anti-inflammatory cytokine IL-10, both of which play a major role in atherogenesis, a major consequence of OSA, have not specifically been assessed in pediatric patients. METHODS: Consecutive non-obese children (aged 4-9years) who were polysomnographically diagnosed with OSA, and age-, gender-, ethnicity-, and BMI-matched control children underwent a blood draw the next morning after a sleep study and plasma samples were assayed for interleukins 6 (IL-6) and 10 (IL-10). These tests were repeated 4-6months after tonsillectomy and adenoidectomy (T&A) in children with OSA. RESULTS: IL-6 levels were higher and IL-10 plasma levels were lower in children with OSA and returned to control levels after T&A. CONCLUSIONS: Systemic inflammation is a constitutive component and consequence of OSA in many children, even in the absence of obesity, and is reversible upon treatment in most patients.
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Mediadores de Inflamación/sangre , Interleucina-10/sangre , Interleucina-6/sangre , Apnea Obstructiva del Sueño/inmunología , Adenoidectomía , Aterosclerosis/inmunología , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Inflamación/diagnóstico , Inflamación/inmunología , Masculino , Polisomnografía , Factores de Riesgo , Apnea Obstructiva del Sueño/cirugía , TonsilectomíaRESUMEN
The aim of the study was to examine the effects of endurance exercise on circulating vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in sickle cell trait (SCT) athletes with or without alpha-thalassemia. Five athletes with SCT, 7 athletes with both SCT and alpha-thalassemia (SCTAT) and 8 control athletes (CONT) performed an incremental test on cycloergometer followed 72 hours later by a 60-min endurance exercise with a workload set at 70% P(peak) (peak power). We assessed levels of sICAM-1, sVCAM-1 and TNF-alpha at rest, immediately after endurance exercise and 1, 2, and 24 hours of recovery. Although, CONT and SCTAT groups exhibited similar basal plasma levels of adhesion molecules and TNF-alpha, SCT group had higher sVCAM-1 basal concentrations. No significant variation in sVCAM-1, sICAM-1 and TNF-alpha was measured following endurance exercise. Consequently, sVCAM-1 remained elevated in the SCT group after exercise and during the recovery period. In conclusion, our findings support the concept that SCT athletes might be at risk for microcirculatory disturbances, but these adhesive processes were not further impaired in response to endurance exercise. In addition, alpha-thalassemia co existing trait may be protective both at rest and after endurance exercise in SCT subjects.
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Ejercicio Físico , Molécula 1 de Adhesión Intercelular/sangre , Resistencia Física , Rasgo Drepanocítico/sangre , Molécula 1 de Adhesión Celular Vascular/sangre , Talasemia alfa/sangre , Adulto , Femenino , Humanos , Masculino , Rasgo Drepanocítico/fisiopatología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangre , Talasemia alfa/fisiopatologíaRESUMEN
STUDY OBJECTIVE: Associations between SDB, the metabolic syndrome, and circulating levels of adipokines have emerged in adults but have not been examined in snoring children, who, in contradistinction to adults, display insulin resistance and lipid abnormalities as a function of adiposity rather than SDB. Therefore, we aimed to examine associations between circulating adipokines levels, insulin resistance, and measures of SDB in children. DESIGN: Prospective study. SETTING: Polysomnographic evaluation and assessment of plasma levels of leptin, adiponectin, resistin, glucose, insulin, and CRP. PARTICIPANTS: 130 children (mean age 8.2 +/- 2.8 years; 39% obese) were studied. MEASUREMENTS AND RESULTS: Log adiponectin levels were lower in obese than nonobese children (3.8 +/- 0.31 vs 4.0 +/- 0.30 corresponding to 8,381.4 +/- 5,841.0 vs 12,853.2 +/- 7,780.2 ng/ml, P < 0.0001) and were inversely correlated with BMI Z scores (r = -0.47, P < 0.0001) but not with log AHI. Log leptin concentrations were higher in the obese group than the nonobese group (4.2 +/- 0.32 vs 3.4 +/- 0.57 corresponding to 19,542.6 +/- 13,643.6 vs 5,875.5 +/- 8,425.7 pg/ml, P < 0.0001), correlated with BMI Z scores (r = 0.64, P < 0.0001), and were significantly lower in children with AHI < or = 1/hr than children with AHI > 1/hr (P = 0.006) and in children with SpO2 nadir > or = 90% than children with SpO2 nadir < 90%, even after controlling for BMI Z score (P < 0.03). No significant differences were found in log resistin levels as a function of obesity or AHI. Significant correlations between log adiponectin levels and log Insulin/Glucose (I/G) ratios (-0.28, P = 0.006) and between log leptin levels and log I/G ratios (r = 0.66, P < 0.0001) emerged. CONCLUSIONS: In close agreement with the absence of a measurable effect of SDB on insulin resistance in children, circulating adipokines levels are primarily attributable to the ponderal index. However, SDB and associated hypoxemia may contribute to the elevation of leptin levels.
Asunto(s)
Hormonas de Insectos/sangre , Oligopéptidos/sangre , Ácido Pirrolidona Carboxílico/análogos & derivados , Apnea Obstructiva del Sueño/sangre , Adolescente , Glucemia/metabolismo , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Niño , Preescolar , Femenino , Humanos , Lactante , Insulina/sangre , Resistencia a la Insulina/fisiología , Leptina/sangre , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/diagnóstico , Obesidad/sangre , Polisomnografía , Ácido Pirrolidona Carboxílico/sangre , Resistina/sangre , Factores de Riesgo , Apnea Obstructiva del Sueño/diagnóstico , Estadística como AsuntoRESUMEN
The aim of the study was to examine the effects of exercise on soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in sickle cell trait (SCT) athletes with or without alpha-thalassemia. Six athletes with SCT, seven athletes with both SCT and alpha-thalassemia (SCTAT), and seven control athletes (Cont) performed an incremental and maximal test on cycloergometer. Levels of sICAM-1 and sVCAM-1 were assessed at rest, immediately after the end of exercise, and 1, 2, and 24 h after exercise. Although Cont and SCTAT groups exhibited similar basal plasma levels of inflammatory and adhesion molecules, the SCT group had higher sVCAM-1 basal concentrations. Incremental exercise resulted in a significant increase of sVCAM-1 in all subjects, which remained elevated only in the SCT group during the recovery period. In conclusion, as sVCAM-1 increased with exercise and during the recovery period, our findings support the concept that SCT athletes might be at risk for microcirculatory disturbances and adhesive phenomena developing at rest and several hours after exercise. alpha-Thalassemia might be considered protective among exercising SCT subjects.
Asunto(s)
Ejercicio Físico/fisiología , Molécula 1 de Adhesión Intercelular/metabolismo , Rasgo Drepanocítico/sangre , Factor de Necrosis Tumoral alfa/sangre , Molécula 1 de Adhesión Celular Vascular/metabolismo , Talasemia alfa/sangre , Adulto , Antropometría , Prueba de Esfuerzo , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Masculino , Esfuerzo Físico/fisiología , Descanso/fisiología , Rasgo Drepanocítico/fisiopatología , Factores de Tiempo , Molécula 1 de Adhesión Celular Vascular/sangre , Talasemia alfa/fisiopatologíaRESUMEN
Perinatal asphyxia and its complication, hypoxic-ischemic encephalopathy, are still among the major causes of perinatal mortality and morbidity. Despite accurate standard postnatal monitoring procedures, the post-insult period is crucial because at a time when radiologic pictures are still silent, brain damage may already be at a subclinical stage. Against this background, the measurement of quantitative parameters, such as constituents of nervous tissue, that are able to detect subclinical lesions at a stage when routine brain monitoring procedures are still silent, could be particularly useful. Therefore, in the present review we report the potentials and limitations of biomarkers in predicting outcome in neonates complicated by perinatal asphyxia.