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]-␣, 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-␣, 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.

Rationale: Sleep studies are laborious, expensive, inaccessible, and inconvenient for diagnosing obstructive sleep apnea (OSA) in children. Objectives: To examine whether the urinary proteome uncovers specific clusters that are differentially expressed in the urine of children with OSA. Methods: Two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry proteomics followed by validation with western blot of ELISA. Measurements and Main Results: Morning urine proteins from 60 children with polysomnographically confirmed OSA and from matched children with primary snoring (n 5 30) and control subjects (n 5 30) were assessed. A total of 16 proteins that are differentially expressed in OSA were identified, and 7 were confirmed by either immunoblots or ELISA. Among the latter, receiver-operator curve analyses of urinary concentrations of uromodulin, urocortin-3, orosomucoid-1, and kallikrein assigned favorable predictive properties to these proteins. Furthermore, combinatorial approaches indicated that the presence of values beyond the calculated cutoff concentrations for three or more of the proteins yielded a sensitivity of 95% and a specificity of 100%. Conclusions: Proteomic approaches reveal that pediatric OSA is associated with specific and consistent alterations in urinary concentrations of specific protein clusters. Future studies aiming to validate this approach as a screening method of habitually snoring children appears warranted.

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 Ͻ 0.01), with CD3 ϩ , CD4 ϩ , and CD8 ϩ cell proliferation being higher in OSA (p Ͻ 0.05). Moreover, proinflammatory cytokines, such as TNF-␣, IL-6, and IL-1␣, 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 Ͻ 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. (1). In a series of previous studies from our and other laboratories, it has become apparent that children with OSA are at increased risk for a vast array of morbidities, principally affecting the CNS and cardiovascular systems (2-9). Adenotonsillar hypertrophy has been recognized as the major pathophysiological contributor of OSA in children (10), and it plays an important role as well in recurrent tonsillitis (RI) (11). Consequently, adenotonsillectomy (T&A) is currently the first line of treatment for children with these conditions (12,13). However, the exact mechanisms underlying follicular lymphoid proliferation and hyperplasia remain extremely poorly understood. In adults, there are several lines of evidence, suggesting that both local upper airway and systemic inflammation are implicated in the pathophysiology of this a priori mechanical dysfunction of the upper airway. For example, the number of immune cells is substantially increased in the upper airway mucosa and the muscle of adults with OSA (14). Similar increases in regional and systemic inflammatory markers have also been reported in children with OSA (15-17). In addition, increased expression of mediators of the inflammatory response, such as cysteinyl leukotrienes and glucocorticoid receptors, is consistently found in tonsillar tissues of children with OSA (18 -20). Therefore, we hypothesized that cellular proliferation of tonsillar tissues in children with OSA would differ from that of children with RI, possibly reflecting different pathologic mechanisms and cell type involvement leading to the enlargement of upper airway lymphoid tissue in these two conditions. METHODS Subjects. The study was approved by the University of Louisville HumanRese...

ABSTRACT. Objectives. After resection of hypothalamic/pituitary tumors, children are at risk for development of hormonal deficiencies, obesity, and hypersomnolence. However, the prevalence and pathophysiology of these complications are unclear. The purpose of this study was to assess the prevalence and severity of hypersomnolence in children after resection of pituitary tumors and to study the potential factors that contribute to this sleepiness if present. We further hypothesized that decrements in orexin levels may contribute to the sleepiness.Methods. Six children who underwent hypothalamic/ pituitary surgery were identified. Five of these patients and 5 matched control subjects underwent overnight polysomnography followed by a multiple sleep latency test. Children who had a primary sleep disorder (eg, obstructive sleep apnea) underwent treatment and were restudied subsequently (n ‫؍‬ 2). Blood levels of pituitary hormones were measured. Blood and cerebrospinal fluid (CSF) were drawn from 4 patients and 3 control subjects to measure orexin levels.Results. Endocrine control was appropriate in all children. Although patients had longer sleep duration but similar sleep efficiency than control subjects, relatively severe daytime somnolence was present (mean sleep latency: 10.3 ؎ 5.3 minutes vs 26.2 ؎ 1.1 minute in control subjects). Sleepiness did not correlate with body mass index or age. Furthermore, serum and CSF orexin levels did not differ between patients and control subjects.Conclusions. Severe daytime sleepiness is frequent among children who undergo pituitary/hypothalamic surgery and does not seem to result from inappropriate cortisol or thyroxine replacement, disturbed nocturnal sleep, or low levels of orexin in the serum or CSF. We therefore speculate that other, unidentified neurohormonal mechanisms may mediate the excessive sleepiness of these patients. Pediatrics 2002;110(6). URL: http:// www.pediatrics.org/cgi/content/full/110/6/e74; sleep, excessive daytime sleepiness, adolescents, orexin (hypocretin), brain tumors, craniopharyngioma.