The Perfect Storm: A Case of Rapid-Onset Obesity With Hypoventilation, Hypothalamic, Autonomic Dysregulation, Neuroendocrine Tumor (ROHHADNET) With Heart Failure, Narcolepsy, and a Rare Location of a Pelvic Neuroendocrine Tumor.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare disease of concurrent respiratory dysfunction and autonomic dysregulation with endocrine abnormalities. ROHHADNET includes ROHHAD plus coexisting neuroendocrine tumors (NETs). We describe an eight-year-old boy, who originally presented at four years of age with rapid weight gain and hyperhidrosis and who developed mild obstructive sleep apnea (OSA). His clinical course was eventually complicated by hypoxic respiratory failure requiring admission to the pediatric intensive care unit (PICU). Echocardiogram at that time demonstrated dilated cardiomyopathy left ventricular ejection fraction (LVEF) of 28% at time of admission. His respiratory failure persisted despite average volume-assured pressure support (AVAPS) around the clock leading to tracheostomy placement for cardiopulmonary support. He also demonstrated autonomic instability with multiple pituitary hormone deficiencies. Computed tomography (CT) imaging of the abdomen and pelvis demonstrated a presacral soft tissue mass consistent with a tumor of neural crest origin. Daytime somnolence and confusion progressed and a low cerebrospinal fluid hypocretin level revealed a diagnosis of narcolepsy type 1.

Increased incidence of pediatric narcolepsy following the 2009 H1N1 pandemic: a report from the pediatric working group of the sleep research network.

This study was aimed to evaluate the yearly incidence of pediatric narcolepsy prior to and following the 2009 H1N1 pandemic and to evaluate seasonal patterns of narcolepsy onset and associations with H1N1 influenza infection in the United States. This was a multicenter retrospective study with prospective follow-up. Participants were recruited from members of the Pediatric Working Group of the Sleep Research Network including 22 sites across the United States. The main outcomes were monthly and yearly incident cases of childhood narcolepsy in the United States, and its relationship to historical H1N1 influenza data. A total of 950 participants were included in the analysis; 487 participants were male (51.3%). The mean age at onset of excessive daytime sleepiness (EDS) was 9.6  ±â€… 3.9 years. Significant trend changes in pediatric narcolepsy incidence based on EDS onset (p  <  .0001) occurred over the 1998-2016 period, peaking in 2010, reflecting a 1.6-fold increase in narcolepsy incidence. In addition, there was significant seasonal variation in narcolepsy incident cases, with increased cases in spring (p  <  .05). Cross-correlation analysis demonstrated a significant correlation between monthly H1N1 infection and monthly narcolepsy incident cases (p  =  .397, p  <  .0001) with a lag time of 8 months. We conclude that there is a significant increase in pediatric narcolepsy incidence after the 2009 H1N1 pandemic in the United States. However, the magnitude of increase is lower than reported in European countries and in China. The temporal correlation between monthly H1N1 infection and monthly narcolepsy incidence, suggests that H1N1 infection may be a contributing factor to the increased pediatric narcolepsy incidence after the 2009 H1N1 pandemics.

Epilepsy in 22q11.2 Deletion Syndrome: A Case Series and Literature Review.

BACKGROUND: The 22q11.2 deletion syndrome affects multiple organ systems, and the neurological manifestations are an important aspect of this disorder. Many are aware of cardiac anomalies associated with this uncommon genetic disorder. However, the different types of seizures, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) findings seen in this condition are not appreciated. METHODS: Medical records of four patients with epilepsy due to 22q11.2 deletion syndrome were retrospectively reviewed for documentation of seizure types, EEG, and brain MRI findings. In addition, we also did a literature review of previously reported individuals with unprovoked seizures in this condition. RESULTS: A review of all published cases including our patients reveals that focal epilepsy (39 of 88, 44%) is the most common type followed by genetic generalized epilepsy (24 of 88, 27%). Diffuse cerebral atrophy and polymicrogyria were the most frequent MRI findings. CONCLUSIONS: Patients with structural brain abnormalities, especially polymicrogyria and associated epilepsy should have a chromosomal microarray (CMA) performed to screen for the 22q11.2 deletion syndrome. Focal epilepsy and genetic generalized epilepsy are the most frequent epilepsy types reported in this condition.

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.

Stress, coping, and circadian disruption among women awaiting breast cancer surgery.

BACKGROUND: Psychological distress and coping related to a breast cancer diagnosis can profoundly affect psychological adjustment, possibly resulting in the disruption of circadian rest/activity and cortisol rhythms, which are prognostic for early mortality in metastatic colorectal and breast cancers, respectively. PURPOSE: This study aims to explore the relationships of cancer-specific distress and avoidant coping with rest/activity and cortisol rhythm disruption in the period between diagnosis and breast cancer surgery. METHODS: Fifty-seven presurgical breast cancer patients provided daily self-reports of cancer-specific distress and avoidant coping as well as actigraphic and salivary cortisol data. RESULTS: Distress and avoidant coping were related to rest/activity rhythm disruption (daytime sedentariness, inconsistent rhythms). Patients with disrupted rest/activity cycles had flattened diurnal cortisol rhythms. CONCLUSIONS: Maladaptive psychological responses to breast cancer diagnosis were associated with disruption of circadian rest/activity rhythms. Given that circadian cycles regulate tumor growth, we need greater understanding of possible psychosocial effects in cancer-related circadian disruption.

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 assessments in healthy school-aged children using actigraphy: concordance with polysomnography.

Actigraphic (ACT) recordings are used widely in schoolchildren as a less intrusive and more extended approach to evaluation of sleep problems. However, critical assessment of the validity and reliability of ACT against overnight polysomnography (NPSG) are unavailable. Thus, we explored the degree of concordance between NPSG and ACT in school-aged children to delineate potential ACT boundaries when interpreting pediatric sleep. Non-dominant wrist ACT was recorded simultaneously with NPSG in 149 healthy school-aged children (aged 4.1-8.8 years, 41.7% boys, 80.4% Caucasian) recruited from the community. Analyses were limited to the Actiware (MiniMitter-64) calculated parameters originating from 1-min epoch sampling and medium sensitivity threshold value of 40; i.e. sleep period time (SPT), total sleep time (TST) and wake after sleep onset (WASO). SPT was not significantly different between ACT and NPSG. However, ACT underestimated TST significantly by 32.2±33.4 min and overestimated WASO by 26.3±34.4 min. The decreased precision of ACT was also evident from moderate to small concordance correlation coefficients (0.47 for TST and 0.09 for WASO). ACT in school-aged children provides reliable assessment of sleep quantity, but is relatively inaccurate during determination of sleep quality. Thus, caution is advocated in drawing definitive conclusions from ACT during evaluation of the sleep-disturbed child.

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.

Transcriptomic analysis identifies phosphatases as novel targets for adenotonsillar hypertrophy of pediatric obstructive sleep apnea.

RATIONALE: Obstructive sleep apnea (OSA) is a highly prevalent disorder in children, in which enlarged adenotonsillar tissues (AT) play a major pathophysiologic role. Mechanisms leading to the proliferation and hypertrophy of AT in children who subsequently develop OSA remain unknown, and surgical extirpation of AT is associated with potential morbidity and mortality. OBJECTIVES: We hypothesized that a computationally based analysis of gene expression in tonsils from children with OSA and children with recurrent tonsillitis without OSA can identify putative mechanistic pathways associated with tonsillar proliferation and hypertrophy in OSA. METHODS: Palatine tonsils from children with either polysomnographically documented OSA or recurrent infectious tonsillitis were subjected to whole-genome microarray and functional enrichment analyses followed by significance score ranking based on gene interaction networks. The latter enabled identification and confirmation of a candidate list of tonsil-proliferative genes in OSA. MEASUREMENTS AND MAIN RESULTS: In vitro studies using a mixed tonsil cell culture system targeting one of these candidates, phosphoserine phosphatase, revealed that it was more abundantly expressed in tonsils of children with OSA, and that pharmacological inhibition of phosphoserine phosphatase led to marked reductions in T- and B-lymphocyte cell proliferation and increased apoptosis. CONCLUSIONS: A systems biology approach revealed a restricted set of candidate genes potentially underlying the heightened proliferative properties of AT in children with OSA. Furthermore, functional studies confirm a novel role for protein phosphatases in AT hypertrophy, and may provide a promising strategy for discovery of novel, nonsurgical therapeutic targets in pediatric OSA.

Pediatric obstructive sleep apnea: a potential late consequence of respiratory syncitial virus bronchiolitis.

STUDY OBJECTIVES: To examine the hypothesis that children who suffered from severe respiratory syncitial virus (RSV) bronchiolitis during infancy may be at higher risk for obstructive sleep apnea (OSA) later in childhood. METHODS: Survey of Kosair Children's Hospital medical records allowed for identification of potential candidates for the study. Twenty-one randomly selected children (mean age +/- SD: 5.2 +/- 1.5 years) with a history of verified RSV-induced bronchiolitis during their first year of life underwent overnight sleep study (NPSG). Children recruited from the general population with no history of RSV bronchiolitis served as a control group. After matching for age, gender, ethnicity, gestational age at birth, body mass index (BMI) z scores, household cigarette smoking, history of asthma and allergies, 63 control subjects (mean age +/- SD: 5.1 +/- 0.7 years) were also studied. RESULTS: Children who had RSV bronchiolitis as infants had significantly higher obstructive apnea/hypopnea index compared to controls (2.3 +/- 1.9 vs. 0.6 +/- 0.8 /hr total sleep time (TST); P < 0.05). In addition, significantly higher respiratory arousal indices were apparent among children with previous RSV bronchiolitis compared to controls (1.3 +/- 1.0 vs. 0.1 +/- 0.2 /hr TST; P < 0.05). There were no significant differences between the groups in the lowest SpO(2), ETCO(2), and sleep indices. CONCLUSIONS: RSV bronchiolitis may contribute to the pathophysiology of OSA in vulnerable children.

Increased cellular proliferation and inflammatory cytokines in tonsils derived from children with obstructive sleep apnea.

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.

Nocturnal polysomnographic characteristics of habitually snoring children initially referred to pediatric ENT or sleep clinics.

OBJECTIVES: To determine clinical and polysomnographic characteristics of children initially referred by primary care physicians (PCP) to either otolaryngology or sleep clinics for a history of habitual snoring. METHODS: Retrospective review of clinical characteristics and nocturnal polysomnograms (PSG) of snoring children referred initially to otolaryngologists by PCP (i.e., ENT) compared to a cross matched population of snoring children initially referred to a pediatric sleep center (i.e., SLEEP). RESULTS: Sixty-eight ENT referred children were cross-matched to 68 SLEEP children. ENT referred children were found to have significantly larger tonsillar size compared to SLEEP children (tonsil size score 3.1 vs. 2.5, p value <0.01). Despite larger tonsillar size, there were no differences observed in the number of children with clinically significant obstructive sleep apnea syndrome (OSAS) with an obstructive apnea hypopnea index (OAHI)5/h TST (40 ENT vs. 38 SLEEP children). Furthermore, SLEEP children with OSAS exhibited more severe sleep related breathing disturbances compared to ENT children (obstructive apnea index: 5.0 vs. 1.5 /h TST, p value <0.01; mean oxygen saturation nadir [76.3% vs. 87.0%, p<0.01]). Finally, in 28 ENT referred children vs. 30 SLEEP the OAHI was <5/h TST. CONCLUSIONS: Children referred by ENT are not more likely to be diagnosed with OSAS than snoring children directly referred to a pediatric sleep clinic by their pediatricians. The only difference in the referral decision between ENT and SLEEP seems to be tonsil size. Furthermore, PSG revealed a large percentage of children in whom surgical indication for AT is not obvious, thus suggesting that PSG is useful in determining the management of snoring children initially referred to ENT. Finally, SLEEP referred children diagnosed with OSAS exhibited increased indices among selected parameters indicative of sleep-disordered breathing.

A mixed cell culture model for assessment of proliferation in tonsillar tissues from children with obstructive sleep apnea or recurrent tonsillitis.

BACKGROUND: Recurrent infective tonsillitis (RI) and obstructive sleep apnea (OSA) are the major indications for adenotonsillectomy (T&A) in children. However, little is known on the determinants of lymphadenoid tissue proliferation in the pediatric upper airway. OBJECTIVES: To develop an in vitro culture system allowing for assessment of tonsillar or adenoidal proliferation under basal or stimulated conditions. METHODS: Tonsils surgically removed from pediatric patients with obstructive sleep apnea and recurrent tonsillitis during T&A, were dissociated using standard methods. Whole cell tonsillar cultures were either maintained in normal medium or stimulated with lipopolysaccharide (25 microg/mL) and concanavalin A (10 microg/mL) for 24 hours (stimulated conditions [STIM]). Cellular proliferation was evaluated by [3H]thymidine incorporation. In parallel, supernatants were collected after 48 hours, and concentration of cytokines was measured using standard enzyme-linked immunosorbent assay procedures. RESULTS: Basal proliferative rates were increased in the OSA group (305.2 +/- 40.6 cpm; n = 31) compared to RI group (232.8 +/- 31.9 cpm; n = 26; P < .001). No significant differences in proliferative rates emerged after STIM between OSA and RI. Furthermore, basal TNF-alpha, IL-6, and IL-8 concentrations in the supernatant were increased in OSA-derived cultures compared to RI, but IL-8 was higher after STIM in RI, while IL-6 remained increased in OSA. CONCLUSIONS: The proliferative rates and concentrations of inflammatory mediators in tonsillar cell cultures from children with OSA and RI suggest that lymphadenoid tissue proliferation in these two conditions may be regulated by different mechanisms. This novel method may allow for future development of specific therapeutic interventions aimed at curtailing and reversing tonsillar and adenoidal hypertrophy in children in a disease-specific manner.

Obstructive sleep apnea in children: relative contributions of body mass index and adenotonsillar hypertrophy.

BACKGROUND: The obesity epidemic has prompted remarkable changes in the proportion of obese children who are referred for habitual snoring. However, the contribution of obesity to adenotonsillar hypertrophy remains undefined. METHODS: In our study, 206 nonobese habitually snoring children with polysomnographically diagnosed obstructive sleep apnea (OSA) were matched for age, gender, ethnicity, and obstructive apnea-hypopnea index (OAHI) to 206 obese children. Size estimates of tonsils and adenoids, and Mallampati class scores were obtained, and allowed for the assessment of potential relationships between anatomic factors and obesity in pediatric OSA. RESULTS: The mean OAHI for the two groups was approximately 10.0 episodes/h total sleep time. There was a modest association between adenotonsillar size and OAHI in nonobese children (r = 0.22; p < 0.001) but not in obese children. The mean (+/- SEM) adenotonsillar size was larger in nonobese children (3.85 +/- 0.16 vs 3.01 +/- 0.14, respectively; p < 0.0001), and conversely Mallampati class scores were significantly higher in obese children (p < 0.0001). CONCLUSION: The magnitude of adenotonsillar hypertrophy required for any given magnitude of OAHI is more likely to be smaller in obese children compared to nonobese children. Increased Mallampati scores in obese children suggest that soft-tissue changes and potentially fat deposition in the upper airway may play a significant role in the global differences in tonsillar and adenoidal size among obese and nonobese children with OSA.

Leukotriene pathways and in vitro adenotonsillar cell proliferation in children with obstructive sleep apnea.

INTRODUCTION: The abundant expression of leukotrienes (LTs) and their receptors in adenotonsillar tissues of children with obstructive sleep apnea (OSA) suggest that LT antagonists could be useful in treating OSA. METHODS: The effects of LTD4 and of LT receptor antagonists zileuton, montelukast, and BAY u9773 were examined on mixed cell cultures prepared from dissociated tonsils or adenoids harvested intraoperatively from children with polysomnographically diagnosed OSA. Proliferation was assessed by (3)[H]-thymidine incorporation, and inflammatory cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, IL-8, IL-10, and IL-12) was assessed in supernatants using enzyme-linked immunosorbent assay. RESULTS: LTD4 elicited dose-dependent increases in adenotonsillar cell proliferation (p < 0.001; n = 12). All LT antagonists exhibited dose-dependent reductions in adenotonsillar cellular proliferation rates, with montelukast more than BAY u9773 more than zileuton (n = 14/group; p < 0.001). However, BAY u9773 showed partial agonist effects and increased cellular proliferation at higher concentrations (10(-4) mmol/L; p < 0.01; n = 12). LTD4 effects were partially blocked by montelukast and BAY u9773 but not by zileuton. All three antagonists reduced TNF-alpha, IL-6, and IL-12 concentrations, with selective changes in IL-8 and no effects on IL-10 levels. CONCLUSIONS: LT pathways mediate intrinsic proliferative and inflammatory signaling pathways in adenotonsillar tissues from children with OSA, and targeted pharmacologic disruption of these pathways may provide nonsurgical alternatives for prevention and treatment of this disease.