Nocturnal Oximetry-based Evaluation of Habitually Snoring Children.

RATIONALE: The vast majority of children around the world undergoing adenotonsillectomy for obstructive sleep apnea-hypopnea syndrome (OSA) are not objectively diagnosed by nocturnal polysomnography because of access availability and cost issues. Automated analysis of nocturnal oximetry (nSpO2), which is readily and globally available, could potentially provide a reliable and convenient diagnostic approach for pediatric OSA. METHODS: Deidentified nSpO2 recordings from a total of 4,191 children originating from 13 pediatric sleep laboratories around the world were prospectively evaluated after developing and validating an automated neural network algorithm using an initial set of single-channel nSpO2 recordings from 589 patients referred for suspected OSA. MEASUREMENTS AND MAIN RESULTS: The automatically estimated apnea-hypopnea index (AHI) showed high agreement with AHI from conventional polysomnography (intraclass correlation coefficient, 0.785) when tested in 3,602 additional subjects. Further assessment on the widely used AHI cutoff points of 1, 5, and 10 events/h revealed an incremental diagnostic ability (75.2, 81.7, and 90.2% accuracy; 0.788, 0.854, and 0.913 area under the receiver operating characteristic curve, respectively). CONCLUSIONS: Neural network-based automated analyses of nSpO2 recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.

Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea.

BACKGROUND: In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Such findings are markedly attenuated in rodents exposed to sustained hypoxia 9SH) of similar magnitude. The hypoxia-sensitive gene erythropoietin (EPO) has emerged as a major endogenous neuroprotectant, and could be involved in IH-induced neuronal dysfunction. METHODS AND RESULTS: IH induced only transiently increased expression of EPO mRNA in hippocampus, which was continued in (SH)-exposed mice. IH, but not SH, adversely affected two forms of spatial learning in the water maze, and increased markers of oxidative stress. However, on a standard place training task, mice treated with exogenously administered EPO displayed normal learning, and were protected from the spatial learning deficits observed in vehicle-treated (C) littermates exposed to IH. Moreover, anxiety levels were increased in IH as compared to normoxia, while no changes in anxiety emerged in EPO-treated mice. Additionally, C mice, but not EPO-treated IH-exposed mice had significantly elevated levels of NADPH oxidase expression, as well as increased MDA and 8-OHDG levels in cortical and hippocampal lysates. CONCLUSIONS: The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by imbalances between EPO expression and increased NADPH oxidase activity, and thus pharmacological agents targeting EPO expression in CNS may provide a therapeutic strategy in sleep-disordered breathing.

Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea.

BACKGROUND: In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Excessive NADPH oxidase activity may play a role in IH-induced CNS dysfunction. METHODS AND FINDINGS: The effect of IH during light period on two forms of spatial learning in the water maze and well as markers of oxidative stress was assessed in mice lacking NADPH oxidase activity (gp91phox(_/Y)) and wild-type littermates. On a standard place training task, gp91phox(_/Y) displayed normal learning, and were protected from the spatial learning deficits observed in wild-type littermates exposed to IH. Moreover, anxiety levels were increased in wild-type mice exposed to IH as compared to room air (RA) controls, while no changes emerged in gp91phox(_/Y) mice. Additionally, wild-type mice, but not gp91phox(_/Y) mice had significantly elevated levels of NADPH oxidase expression and activity, as well as MDA and 8-OHDG in cortical and hippocampal lysates following IH exposures. CONCLUSIONS: The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by excessive NADPH oxidase activity, and thus pharmacological agents targeting NADPH oxidase may provide a therapeutic strategy in sleep-disordered breathing.

Transcriptional landscape of bone marrow-derived very small embryonic-like stem cells during hypoxia.

BACKGROUND: Hypoxia is a ubiquitous feature of many lung diseases and elicits cell-specific responses. While the effects of hypoxia on stem cells have been examined under in vitro conditions, the consequences of in vivo oxygen deprivation have not been studied. METHODS: We investigated the effects of in vivo hypoxia on a recently characterized population of pluripotent stem cells known as very small embryonic-like stem cells (VSELs) by whole-genome expression profiling and measuring peripheral blood stem cell chemokine levels. RESULTS: We found that exposure to hypoxia in mice mobilized VSELs from the bone marrow to peripheral blood, and induced a distinct genome-wide transcriptional signature. Applying a computationally-intensive methodology, we identified a hypoxia-induced gene interaction network that was functionally enriched in a diverse array of programs including organ-specific development, stress response, and wound repair. Topographic analysis of the network highlighted a number of densely connected hubs that may represent key controllers of stem cell response during hypoxia and, therefore, serve as putative targets for altering the pathophysiologic consequences of hypoxic burden. CONCLUSIONS: A brief exposure to hypoxia recruits pluripotent stem cells to the peripheral circulation and actives diverse transcriptional programs that are orchestrated by a selective number of key genes.

Obstructive sleep apnea in poorly controlled asthmatic children: effect of adenotonsillectomy.

BACKGROUND: Asthma and obstructive sleep apnea (OSA) in children share multiple epidemiological risk factors and the prevalence of snoring is higher in asthmatic children, suggesting that the latter may be at increased risk for OSA. Since both asthma and OSA are inflammatory disorders, we hypothesized that polysomnographically demonstrated OSA would be more frequent among poorly controlled asthmatics (PCA), and that treatment of OSA, if present, would ameliorate the frequency of acute asthmatic exacerbations (AAE). METHODS: Children with PCA were referred for an overnight sleep study, and adenotonsillectomy (tonsillectomy and adenoidectomy, T&A) was performed if OSA was present. Frequency of asthma symptoms and exacerbations were compared. RESULTS: Ninety-two PCA children, ages 3-10 years, with a mean frequency of AAE of 3.4 ± 0.4/year were prospectively referred for a sleep study. OSA (i.e., AHI > 5/hrTST) was present in 58 patients (63.0%; OR: 40.9, 12.9-144.1, P < 0.000001 compared to the prevalence of OSA in a non-asthmatic population). Information at 1-year follow-up was available for 35 PCA children after T&A. The annual frequency of AAE, rescue inhaled use, and asthma symptoms in this sub-group decreased compared to no changes in the group without OSA. CONCLUSIONS: The prevalence of OSA is markedly increased among PCA children and treatment of OSA appears to be associated with substantial improvements in the severity of the underlying asthmatic condition.

Sleep estimates in children: parental versus actigraphic assessments.

BACKGROUND: In the context of increasing awareness about the need for assessment of sleep duration in community and clinical settings, the use of questionnaire-based tools may be fraught with reporter bias. Conversely, actigraphy provides objective assessments of sleep patterns. In this study, we aimed to determine the potential discrepancies between parentally-based sleep logs and concurrent actigraphic recordings in children over a one-week period. METHODS: We studied 327 children aged 3-10 years, and included otherwise healthy, nonsnoring children from the community who were reported by their parents to be nonsnorers and had normal polysomnography, habitually-snoring children from the community who completed the same protocol, and children with primary insomnia referred to the sleep clinic for evaluation in the absence of any known psychiatric illness. Actigraphy and parental sleep log were concomitantly recorded during one week. RESULTS: Sleep logs displayed an average error in sleep onset after bedtime of about 30 minutes (P < 0.01) and of a few minutes before risetime in all groups. Furthermore, subjective parental reports were associated with an overestimated misperception of increased sleep duration of roughly one hour per night independent of group (P < 0.001). CONCLUSION: The description of a child's sleep by the parent appears appropriate as far as symptoms are concerned, but does not result in a correct estimate of sleep onset or duration. We advocate combined parental and actigraphic assessments in the evaluation of sleep complaints, particularly to rule out misperceptions and potentially to aid treatment. Actigraphy provides a more reliable tool than parental reports for assessing sleep in healthy children and in children with sleep problems.

Intermittent hypoxia mobilizes bone marrow-derived very small embryonic-like stem cells and activates developmental transcriptional programs in mice.

BACKGROUND: obstructive sleep apnea is a prevalent disorder associated with cognitive dysfunction and cardiovascular and metabolic morbidity and is characterized by recurrent episodes of hypoxia during sleep. Bone marrow-derived very small embryonic-like (VSEL) pluripotent stem cells represent a recruitable pool that may play an important role in organ repair after injury. We hypothesized that exposure to intermittent hypoxia (IH) can mobilize VSELs from the bone marrow (BM) to peripheral blood (PB) in mice and can activate distinct transcriptional programs. METHODS: adult mice were exposed to IH or normoxia for 48 hours. VSELs were sorted from BM and PB using flow cytometry. Plasma levels of stem cell chemokines, stromal cell derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF) were measured. Transcriptional profiling of VSELs was performed, and differentially expressed genes were mapped to enriched functional categories and genetic networks. RESULTS: exposure to IH elicited migration of VSELs from BM to PB and elevations in plasma levels of chemokines. More than 1100 unique genes were differentially expressed in VSELs in response to IH. Gene Ontology and network analysis revealed the activation of organ-specific developmental programs among these genes. CONCLUSIONS: exposure to IH mobilizes VSELs from the BM to PB and activates distinct transcriptional programs in VSELs that are enriched in developmental pathways, including central nervous system development and angiogenesis. Thus, VSELs may serve as a reserve mobile pool of pluripotent stem cells that can be recruited into PB and may play an important role in promoting end-organ repair during IH.