Two-Dimensional Differential In-Gel Electrophoresis Proteomic Approaches Reveal Urine Candidate Biomarkers in Pediatric Obstructive Sleep Apnea

Gozal, David; Jortani, Saeed A.; Snow, Ayelet B.; Kheirandish‐Gozal, Leila; Bhattacharjee, Rakesh; Kim, Jinkwan; Capdevila, Óscar Sans

doi:10.1164/rccm.200905-0765oc

Cited by 112 publications

(72 citation statements)

References 64 publications

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“…In a subsequent study using urine samples, we examined the urine proteome in children with OSA, in children with primary snoring, and in control subjects using two-dimensional gel electrophoresis. 19 In this 2009 study, 19 we identifi ed 16 unique proteins that were differentially expressed in the OSA group, and validated four of these proteins (kallikrein-1, urocortin-3, orosomucoid-1, and uromodulin) using enzyme-linked immunosorbent assays. Using a combinatorial-biomarker, discriminative approach similar to the one implemented in the present study, highly predictive ROC were generated.…”

Section: Discussionmentioning

confidence: 99%

Urinary Neurotransmitters Are Selectively Altered in Children With Obstructive Sleep Apnea and Predict Cognitive Morbidity

Kheirandish‐Gozal

McManus²,

Kellermann³

et al. 2013

Chest

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Snoring is a very frequent complaint affecting 10% to 12% of all children 1 and is the primary symptom of obstructive sleep apnea (OSA). OSA is the occurrence of repeated events of partial or complete upper airway obstruction during sleep, leading to disruption of normal ventilation, and to hypoxemia and sleep fragmentation. The pathophysiology of pediatric OSA is multifactorial, but adenotonsillar hypertrophy with or without concurrent obesity constitutes the major pathophysiologic mechanism underlying OSA in children. 2 Pediatric OSA has been extensively associated with an increased risk for behavioral and mood disturbances, as well as with cognitive defi cits. Furthermore, cardiovascular and metabolic morbidities, such as pulmonary hypertension, systemic hypertension, endothelial dysfunction, insulin resistance, and serum lipid alterations, are also frequently observed. 3 However, identifi cation of those children who have developed any such OSAassociated morbidities is diffi cult, and is usually complicated by the need for laborious and onerous test batteries that are not routinely available in most clinical settings. Therefore, such assessments are usually not pursued.Background: Pediatric obstructive sleep apnea (OSA) is associated with cognitive dysfunction, suggesting altered neurotransmitter function. We explored overnight changes in neurotransmitters in the urine of children with and without OSA. Methods: Urine samples were collected from children with OSA and from control subjects before and after sleep studies. A neurocognitive battery assessing general cognitive ability (GCA) was administered to a subset of children with OSA. Samples were subjected to multiple enzyme-linked immunosorbent assays for 12 neurotransmitters, and adjusted for creatinine concentrations. Results: The study comprised 50 children with OSA and 20 control subjects. Of the children with OSA, 20 had normal GCA score (mean Ϯ SD) (101.2 Ϯ 14.5) and 16 had a reduced GCA score (87.3 Ϯ 13.9; P , .001). Overnight increases in epinephrine, norepinephrine, and g -aminobutyric acid (GABA) levels emerged in children with OSA; taurine levels decreased. Using combinatorial approaches and cutoff values for overnight changes of these four neurotransmitters enabled prediction of OSA (area under the curve [AUC]: 0.923; P , .0001). Furthermore, GABA and taurine alterations, as well as overnight reductions in phenylethylamine, were more prominent in children with OSA and low GCA than in children with OSA and normal GCA ( P , .001), and they reliably discriminated GCA status (AUC: 0.977; P , .0001). Conclusions: Pediatric OSA is associated with overnight increases in urinary concentrations of catecholamines indicative of heightened sympathetic outfl ow. Increases in GABA levels and decreases in taurine levels could underlie mechanisms of neuronal excitotoxicity and dysfunction. Combinatorial approaches using defi ned cutoffs in overnight changes in concentrations of selected neurotransmitters in urine may not only predict OSA but also the presence ...

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Section: Discussionmentioning

confidence: 99%

Urinary Neurotransmitters Are Selectively Altered in Children With Obstructive Sleep Apnea and Predict Cognitive Morbidity

Kheirandish‐Gozal

McManus²,

Kellermann³

et al. 2013

Chest

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“…In a level I study of urinary proteinomics, the investigators found that a combination of urinary proteins could predict OSAS with a sensitivity of 95% and a specificity of 100%. 109 Similarly, in a level III study from the same group, the investigators found that a different set of proteins could be used to identify 15 of 20 children who had OSAS and 18 of 20 children who were snorers. 110 The authors note that they studied a highly selected population matched for age, gender, ethnicity, BMI, and inflammatory respiratory disorders, such as allergic rhinitis or asthma.…”

Section: Other Testsmentioning

confidence: 99%

Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome

Marcus¹,

Brooks²,

Ward³

et al. 2012

Pediatrics

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1,504

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OBJECTIVE: This technical report describes the procedures involved in developing recommendations on the management of childhood obstructive sleep apnea syndrome (OSAS). METHODS: The literature from 1999 through 2011 was evaluated. RESULTS AND CONCLUSIONS: A total of 3166 titles were reviewed, of which 350 provided relevant data. Most articles were level II through IV. The prevalence of OSAS ranged from 0% to 5.7%, with obesity being an independent risk factor. OSAS was associated with cardiovascular, growth, and neurobehavioral abnormalities and possibly inflammation. Most diagnostic screening tests had low sensitivity and specificity. Treatment of OSAS resulted in improvements in behavior and attention and likely improvement in cognitive abilities. Primary treatment is adenotonsillectomy (AT). Data were insufficient to recommend specific surgical techniques; however, children undergoing partial tonsillectomy should be monitored for possible recurrence of OSAS. Although OSAS improved postoperatively, the proportion of patients who had residual OSAS ranged from 13% to 29% in low-risk populations to 73% when obese children were included and stricter polysomnographic criteria were used. Nevertheless, OSAS may improve after AT even in obese children, thus supporting surgery as a reasonable initial treatment. A significant number of obese patients required intubation or continuous positive airway pressure (CPAP) postoperatively, which reinforces the need for inpatient observation. CPAP was effective in the treatment of OSAS, but adherence is a major barrier. For this reason, CPAP is not recommended as first-line therapy for OSAS when AT is an option. Intranasal steroids may ameliorate mild OSAS, but follow-up is needed. Data were insufficient to recommend rapid maxillary expansion.

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“…Otherwise, regarding screening, an interesting and promising strategy has been studied in a paediatric population where a proteomic approach revealed that OSA was associated with specific and consistent alterations in urinary concentrations of specific protein clusters [114]. Future studies aimed at validating this approach as a screening method of snoring children and adults are warranted.…”

Section: Osa Diagnosismentioning

confidence: 99%