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1.  Azathioprine in the management of enteropathy in cystic fibrosis 
Journal of the Royal Society of Medicine  2011;104(Suppl 1):S40-S43.
PMCID: PMC3128164  PMID: 21719892
2.  The Th17 Pathway in Cystic Fibrosis Lung Disease 
Cystic fibrosis (CF) is characterized by bronchoalveolar neutrophilia and submucosal lymphocytosis. We hypothesized that Th17 lymphocytes are part of this submucosal infiltrate.
Quantification and phenotyping of the lymphocytic infiltrate in the bronchial submucosa of patients with CF (n=53, of which 20 were newly diagnosed), non-CF bronchiectasis (n = 17), and healthy control subjects (n = 13).
We measured IL-17 levels in bronchoalveolar lavage and CD4+, CD8+, and IL-17+ cell counts in endobronchial biopsies. Correlations were made with infection status and other inflammatory markers. Potential cellular sources of IL-17 were determined by double staining.
Measurements and Main Results
IL-17+ cell counts (median [interquartile range] cells/mm2) were significantly higher in patients with established CF (205 [115–551]) and non-CF bronchiectasis (245 [183–436]) than in control subjects (53 [12–82]) (P<0.01 for both). Patients with newly diagnosed CF had intermediate counts (171 [91–252]). IL-17–positive CD4+ T cells, γδT cells, natural killer T cells, and neutrophils were identified. Bronchoalveolar lavage IL-17 levels (pg/ml) were highest in established CF (14.6 [2.2–38.4]), low in newly diagnosed CF and control subjects (1.7 [1.7–1.74]; 1.7 [1.7–3]), and intermediate in non-CF bronchiectasis (9.1 [1.7–34] pg/ml) (Kruskal-Wallis P = 0.001). There was a significant correlation between IL-17 and neutrophil counts (P < 0.001, R = 0.6) as well as IL-4 (P < 0.001, R = 0.84).
Th17 lymphocytes are present in the airway submucosa in CF, even in a young, newly diagnosed group. Other IL-17+ cells include neutrophils, γδ T cells, and natural killer T cells.
PMCID: PMC3381840  PMID: 21474644
Th17 cells; cystic fibrosis; inflammation
3.  Circulating Adropin Levels in Pediatric Obstructive sleep apnea: Potential Relevance to Endothelial Function 
The Journal of pediatrics  2013;163(4):1122-1126.
To test the hypothesis that levels of adropin, a recently discovered peptide that displays important metabolic and cardiovascular functions, are lower in obstructive sleep apnea (OSA), especially when associated with endothelial dysfunction.
Study design
Age-, sex- and ethnicity-matched children (mean age: 7.2±1.4 years) were included into one of three groups based on the presence of OSA in an overnight sleep study, and on the time to post-occlusive maximal reperfusion (Tmax>45 sec) with a modified hyperemic test. Plasma adropin levels were assayed using a commercial ELISA kit.
Among controls, mean morning adropin levels were 7.4 ng/ml (95% confidence intervals: 5.2–16.3 ng/ml) OSA children with abnormal endothelial function (OSA+/EF+) had significantly lower adropin levels (2.7±1.1 ng/ml, n=35) compared with matched controls (7.6±1.4 ng/ml; n=35; p<0.001), and to children with OSA and normal endothelial function (OSA+/EF−: 5.8±1.5 ng/ml, n=47; p<0.001). Plasma adropin <4.2 ng/ml reliably predicted endothelial functional status, but individual adropin levels were not significantly correlated with age, BMI-z score, obstructive apnea-hypopnea index (AHI) or nadir SpO2. Adropin levels were assessed after adenotonsillectomy in a subset of children with OSA (n=22), and showed increases in OSA+/EF+ (2.5±1.4 ng/ml to 6.4±1.9 ng/ml, n=14; p<0.01) but remained unchanged in OSA+EF− (5.7±1.3 ng/ml to 6.4±1.1 ng/ml, n=8; p>0.05).
Plasma adropin levels are reduced in pediatric OSA when endothelial dysfunction is present, and return to within normal values after adenotonsillectomy. Assessment of adropin circulating levels may provide a reliable indicator of vascular injury in the context of OSA on children.
PMCID: PMC3786030  PMID: 23810721
Obstructive sleep apnea; adropin; Obesity; nitric oxide; Endothelial function
4.  Obstructive sleep apnea in children: a critical update 
Nature and Science of Sleep  2013;5:109-123.
Obstructive sleep apnea (OSA) in children is a highly prevalent disorder caused by a conglomeration of complex pathophysiological processes, leading to recurrent upper airway dysfunction during sleep. The clinical relevance of OSA resides in its association with significant morbidities that affect the cardiovascular, neurocognitive, and metabolic systems. The American Academy of Pediatrics recently reiterated its recommendations that children with symptoms and signs suggestive of OSA should be investigated with polysomnography (PSG), and treated accordingly. However, treatment decisions should not only be guided by PSG results, but should also integrate the magnitude of symptoms and the presence or absence of risk factors and signs of OSA morbidity. The first-line therapy in children with adenotonsillar hypertrophy is adenotonsillectomy, although there is increasing evidence that medical therapy, in the form of intranasal steroids or montelukast, may be considered in mild OSA. In this review, we delineate the major concepts regarding the pathophysiology of OSA, its morbidity, diagnosis, and treatment.
PMCID: PMC3792928  PMID: 24109201
adenotonsillar hypertrophy; polysomnography; pathophysiology; morbidity; treatment; pediatric sleep disordered breathing
5.  T Regulatory Lymphocytes and Endothelial Function in Pediatric Obstructive Sleep Apnea 
PLoS ONE  2013;8(7):e69710.
Obstructive sleep apnea (OSA) is a low-grade inflammatory disease affecting the cardiovascular and metabolic systems. Increasing OSA severity reduces T-regulatory lymphocytes (Tregs) in OSA children. Since Tregs modulate endothelial activation, and attenuate insulin resistance, we hypothesized that Tregs are associated with endothelial and metabolic dysfunction in pediatric OSA.
50 consecutively recruited children (ages 4.8–12 years) underwent overnight polysomnography and fasting homeostatic model (HOMA) of insulin resistance was assessed. Percentage of Tregs using flow cytometry, and endothelial function, expressed as the time to peak occlusive hyperemia (Tmax), were examined. In a subgroup of children (n = 21), in vitro Treg suppression tests were performed.
Circulating Tregs were not significantly associated with either BMI z score or HOMA. However, a significant inverse correlation between percentage of Tregs and Tmax emerged (p<0.0001, r = −0.56). A significant negative correlation between Tregs suppression and the sleep pressure score (SPS), a surrogate measure of sleep fragmentation emerged (p = 0.02, r = −0.51) emerged, but was not present with AHI.
Endothelial function, but not insulin resistance, in OSA children is strongly associated with circulating Tregs and their suppressive function, and appears to correlate with sleep fragmentation. Thus, alterations in T cell lymphocytes may contribute to cardiovascular morbidity in pediatric OSA.
PMCID: PMC3728363  PMID: 23936084

Results 1-5 (5)