Association of Sleep-Related Hypoxia With Risk of COVID-19 Hospitalizations and Mortality in a Large Integrated Health System.

Importance: The influence of sleep-disordered breathing (SDB) and sleep-related hypoxemia in SARS-CoV-2 viral infection and COVID-19 outcomes remains unknown. Controversy exists regarding whether to continue treatment for SDB with positive airway pressure given concern for aerosolization with limited data to inform professional society recommendations. Objective: To investigate the association of SDB (identified via polysomnogram) and sleep-related hypoxia with (1) SARS-CoV-2 positivity and (2) World Health Organization (WHO)-designated COVID-19 clinical outcomes while accounting for confounding including obesity, underlying cardiopulmonary disease, cancer, and smoking history. Design, Setting, and Participants: This case-control study was conducted within the Cleveland Clinic Health System (Ohio and Florida) and included all patients who were tested for COVID-19 between March 8 and November 30, 2020, and who had an available sleep study record. Sleep indices and SARS-CoV-2 positivity were assessed with overlap propensity score weighting, and COVID-19 clinical outcomes were assessed using the institutional registry. Exposures: Sleep study-identified SDB (defined by frequency of apneas and hypopneas using the Apnea-Hypopnea Index [AHI]) and sleep-related hypoxemia (percentage of total sleep time at <90% oxygen saturation [TST <90]). Main Outcomes and Measures: Outcomes were SARS-CoV-2 infection and WHO-designated COVID-19 clinical outcomes (hospitalization, use of supplemental oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation, and death). Results: Of 350 710 individuals tested for SARS-CoV-2, 5402 (mean [SD] age, 56.4 [14.5] years; 3005 women [55.6%]) had a prior sleep study, of whom 1935 (35.8%) tested positive for SARS-CoV-2. Of the 5402 participants, 1696 were Black (31.4%), 3259 were White (60.3%), and 822 were of other race or ethnicity (15.2%). Patients who were positive vs negative for SARS-CoV-2 had a higher AHI score (median, 16.2 events/h [IQR, 6.1-39.5 events/h] vs 13.6 events/h [IQR, 5.5-33.6 events/h]; P < .001) and increased TST <90 (median, 1.8% sleep time [IQR, 0.10%-12.8% sleep time] vs 1.4% sleep time [IQR, 0.10%-10.8% sleep time]; P = .02). After overlap propensity score-weighted logistic regression, no SDB measures were associated with SARS-CoV-2 positivity. Median TST <90 was associated with the WHO-designated COVID-19 ordinal clinical outcome scale (adjusted odds ratio, 1.39; 95% CI, 1.10-1.74; P = .005). Time-to-event analyses showed sleep-related hypoxia associated with a 31% higher rate of hospitalization and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.08-1.57; P = .005). Conclusions and Relevance: In this case-control study, SDB and sleep-related hypoxia were not associated with increased SARS-CoV-2 positivity; however, once patients were infected with SARS-CoV-2, sleep-related hypoxia was an associated risk factor for detrimental COVID-19 outcomes.

Sleep-disordered breathing and its management in children with rare skeletal dysplasias.

Sleep-disordered breathing (SDB) is common in patients with skeletal dysplasias. The aim of our study was to analyze SDB and respiratory management in children with rare skeletal dysplasias. We performed a retrospective analysis of patients with spondyloepiphyseal dysplasia congenita (SEDC), metatropic dysplasia (MD), spondyloepimetaphyseal dysplasia (SEMD), acrodysostosis (ADO), geleophysic dysplasia (GD), acromicric dysplasia (AD), and spondylocostal dysplasia (SCD) between April 2014 and October 2020. Polygraphic data, clinical management, and patients' outcome were analyzed. Thirty-one patients were included (8 SEDC, 3 MD, 4 SEMD, 1 ADO, 4 GD, 3 AD, and 8 SCD). Sixteen patients had obstructive sleep apnea (OSA): 11 patients (2 with SEDC, 1 with SEMD, 1 with ADO, 1 with GD, 2 with AD, and 4 with SCD) had mild OSA, 2 (1 SEMD and 1 GD) had moderate OSA, and 3 (1 SEDC, 1 MD, 1 SEMD) had severe OSA. Adenotonsillectomy was performed in one patient with SCD and mild OSA, and at a later age in two other patients with ADO and AD. The two patients with moderate OSA were treated with noninvasive ventilation (NIV) because of nocturnal hypoxemia. The three patients with severe OSA were treated with adenotonsillectomy (1 SEDC), adeno-turbinectomy and continuous positive airway pressure (CPAP; 1 MD), and with NIV (1 SEMD) because of nocturnal hypoventilation. OSA and/or alveolar hypoventilation is common in patients with skeletal dysplasias, underlining the importance of systematic screening for SDB. CPAP and NIV are effective treatments for OSA and nocturnal hypoventilation/hypoxemia.

Sleep-disordered breathing and nocturnal hypoventilation in children with the MECP2 duplication syndrome: A case series and review of the literature.

There is limited knowledge on the occurrence of respiratory manifestations and sleep-disordered breathing in particular in children with the MECP2 duplication syndrome. Although sleep-disordered breathing and nocturnal hypoventilation are currently not cited as an important symptom in these children, we present three cases who all had an abnormal breathing during sleep. In view of the consequences associated with sleep apnea and hypoventilation, we advise to perform a polysomnography in children with MECP2 duplication. Different treatment modalities (ENT surgery, CPAP, and non-invasive ventilation) can be applied to successfully treat these conditions.

Increased Platelet Aggregation in Children and Adolescents with Sleep-disordered Breathing.

Rationale: Sleep-disordered breathing (SDB) is associated with increased vascular resistance in children and adults. Persistent increased vascular resistance damages vascular endothelial cells-a marker of which is increased platelet activation.Objectives: This study compared whole-blood impedance platelet aggregation in children with clinically diagnosed SDB warranting adenotonsillectomy and healthy control subjects.Methods: Thirty children who had SDB warranting intervention clinically diagnosed by experienced pediatric otolaryngologists were recruited from adenotonsillectomy waitlists, and 20 healthy children from the community underwent overnight polysomnography to determine SDB severity (obstructive apnea-hypopnea index). Snoring frequency was collected from parents. In the morning, a fasting blood sample was taken, and whole-blood platelet aggregation was measured.Measurements and Main Results: Children with SDB exhibited increased platelet aggregation to TRAP (thrombin receptor-activating peptide) (children with SDB = 114.8 aggregation units [AU] vs. control subjects = 98.0 AU; P < 0.05) and COL antibody (96.7 vs. 82.2 AU; P < 0.05) and an increased trend in ADP antibody (82.3 vs. 69.2 AU; P < 0.07) but not aspirin dialuminate (82.1 vs. 79.5 AU; P > 0.05). No significant association was observed between either the obstructive apnea-hypopnea index and any aggregation parameter, but parental report of snoring was positively associated with TRAP aggregation (Kendall's τ-c = 0.23; P < 0.05).Conclusions: The finding of increased platelet aggregation is consistent with endothelial damage. This suggests that the profile of cardiovascular changes noted in adults with SDB may also occur in children with SDB.

Sleep disordered breathing in children with trisomy 13 and trisomy 18.

PURPOSE: While the prevalence of obstructive sleep apnea (OSA) is well documented in trisomy 21, there has been little published about the incidence in trisomy 13 (T13) and trisomy 18 (T18). Trisomies 13, 18, and 21 have overlapping clinical features that make patients prone to OSA. Because the literature regarding OSA in T13 and T18 children is limited, we performed a retrospective chart review to investigate the characteristics of these patients. METHODS: We reviewed the medical records of children with T13 or T18 seen at seen at a single urban tertiary children's hospital for sleep disordered breathing from 1/1/10 to 5/1/18. Candidates were selected based on ICD-9 diagnosis and procedural codes. RESULTS: We identified 21 T18 patients that had documented symptoms of SDB, of which 3 were diagnosed with OSA, 11 had clinical SDB, and 7 had snoring. Of the T13 patients, 10 had documented symptoms of SDB, of which 1 patient was diagnosed with OSA, 7 with clinical SDB, and 2 with snoring. In both T13 and T18 patients, anatomical features included micrognathia/mandibular hypoplasia, small mouth/small airway, midface hypoplasia, abnormal/difficult airway, glossoptosis, hypotonia, and GERD. Endoscopic findings included laryngomalacia and/or tracheomalacia, adenoid and lingual tonsil hypertrophy, and inferior turbinate hypertrophy. Surgical interventions performed in T13 and T18 patients included adenoidectomy, lingual tonsillectomy, and tracheostomy. Of the 32 T13 and T18 patients, 15 had to be intubated for respiratory insufficiency. CONCLUSION: The results of our study suggest that T13 and T18 patients are at increased risk for OSA due to common features found in this population. These findings indicate a need for otolaryngologist intervention to increase both survival and quality of life in this population.

High-Frequency Ultrasound: A Novel Diagnostic Tool to Measure Pediatric Tonsils in 3 Dimensions.

OBJECTIVE: A wide variety of pathologies can affect the palatine tonsils. Ultrasound is a commonly used modality for assessing head and neck masses in children; however, its use in tonsillar evaluation has not been widely explored. The objective of this study was to measure 3-dimensional tonsillar size with ultrasound, in centimeters, and correlate these measurements with actual ex vivo dimensions on pathology specimens. STUDY DESIGN: We performed a prospective cohort study. SETTING: The study was set in a tertiary care children's hospital. SUBJECTS AND METHODS: Children undergoing tonsillectomy were included in the study. Transcervical high-frequency ultrasonography (HFU) was performed prior to surgery to obtain 3-dimensional measurements of the right and left palatine tonsils. Mean sizes were compared to ex vivo tonsil measurements and correlations were obtained. RESULTS: Seventy-five consecutive children underwent a transcervical HFU, with a total of 150 tonsils analyzed. The mean differences between HFU and pathology measurements were -0.08 cm and -0.24 cm for the right and left craniocaudal axes, -0.19 cm and -0.18 cm for the right and left mediolateral axes, and 0.05 cm and 0.03 cm for the right and left anteroposterior axes. Correlation coefficients between ultrasound and pathology measurements were all above 0.5. CONCLUSION: HFU can accurately measure the size of pediatric tonsils in 3 dimensions.

Biomarker panel in sleep apnea patients after an acute coronary event.

BACKGROUND: Acute coronary syndrome (ACS) is a major cause of death and closely related with obstructive sleep apnea (OSA). Our hypothesis is that several cardiovascular-related biomarkers could have a differential prognostic value for ACS severity in patients with OSA, and could also help (individually or combined) in the detection of OSA in patients after a coronary event. METHODS: Up to 361 consecutive individuals admitted due to ACS were included in the study. All of them were evaluated for ACS severity (Killip score, number of diseased vessels, ejection fraction) and further classified as OSA or non-OSA. Medical records were registered and eleven blood biomarkers were measured, including heart-type fatty acid-binding globulin, N-terminal pro-brain natriuretic peptide, matrix metalloproteinase-9 (MMP9), placental growth factor (PlGF) and high-sensitivity C-reactive protein. Odds ratios of every biomarker for ACS severity-related parameters were calculated and adjusted for age, gender, body-mass index (BMI), hypertension, diabetes, smoking and drinking. The use of clinical measures and biomarkers for the diagnosis of OSA in ACS patients was evaluated both alone and combined using ROC curves. RESULTS: Several biomarkers showed a significant association with ACS severity, which remained after adjusting for OSA and other potentially confounding variables. The mathematical combination of age, BMI, PlGF and MMP9 showed an area under the ROC curve (AUC) for OSA identification of 0.741, which was greater than any individual parameter or combination assessed: AUC(BMI):0.687, AUC(age):0.576, AUC(PlGF):0.584, AUC(MMP9):0.555. CONCLUSIONS: The usefulness of biomarkers in the assessment of ACS severity was independent of OSA and the other variables evaluated. In patients admitted after a coronary event, the combination of clinical measures and biomarkers showed a significant discriminating power for the detection of OSA. CLINICAL TRIAL REGISTRATION: NCT01335087 (clinicaltrials.gov).

Desmin and dystrophin abnormalities in upper airway muscles of snorers and patients with sleep apnea.

BACKGROUND: The pathophysiology of obstruction and swallowing dysfunction in snores and sleep apnea patients remains unclear. Neuropathy and to some extent myopathy have been suggested as contributing causes. Recently we reported an absence and an abnormal isoform of two cytoskeletal proteins, desmin, and dystrophin, in upper airway muscles of healthy humans. These cytoskeletal proteins are considered vital for muscle function. We aimed to investigate for muscle cytoskeletal abnormalities in upper airways and its association with swallowing dysfunction and severity of sleep apnea. METHODS: Cytoskeletal proteins desmin and dystrophin were morphologically evaluated in the uvula muscle of 22 patients undergoing soft palate surgery due to snoring and sleep apnea and in 10 healthy controls. The muscles were analysed with immunohistochemical methods, and swallowing function was assessed using videoradiography. RESULTS: Desmin displayed a disorganized pattern in 21 ± 13% of the muscle fibres in patients, while these fibers were not present in controls. Muscle fibres lacking desmin were present in both patients and controls, but the proportion was higher in patients (25 ± 12% vs. 14 ± 7%, p = 0.009). The overall desmin abnormalities were significantly more frequent in patients than in controls (46 ± 18% vs. 14 ± 7%, p < 0.001). In patients, the C-terminus of the dystrophin molecule was absent in 19 ± 18% of the desmin-abnormal muscle fibres. Patients with swallowing dysfunction had 55 ± 10% desmin-abnormal muscle fibres vs. 22 ± 6% in patients without swallowing dysfunction, p = 0.002. CONCLUSION: Cytoskeletal abnormalities in soft palate muscles most likely contribute to pharyngeal dysfunction in snorers and sleep apnea patients. Plausible causes for the presence of these abnormalities is traumatic snoring vibrations, tissue stretch or muscle overload.

Sleep-disordered breathing in the Cavalier King Charles spaniel: A case series.

OBJECTIVE: To describe sleep-disordered breathing (SDB) in the Cavalier King Charles spaniel (CKCS). STUDY DESIGN: Retrospective case series. ANIMALS: Five client-owned dogs referred for SDB. METHODS: Medical records were reviewed including recheck appointments and routine preoperative and postoperative questionnaires. Whole-body barometric plethysmography was used to categorize SDB. RESULTS: All dogs presented with multiple episodes of stertorous breathing, choking, and apnea during sleep. Severe nasal septal deviation, aberrant nasal turbinates, and soft palate elongation and thickening were noted on computed tomography and rhinoscopy of each dog. Whole-body barometric plethysmography measurements during sleep (in 3 dogs) documented periods of choking, snoring, and apnea. Treatment combined laser turbinectomy, folding flap palatoplasty, tonsillectomy, laryngeal sacculectomy, and cuneiform process resection. All dogs improved in terms of incidence and severity of sleep apnea within 1 week, with 4 of 5 dogs achieving complete resolution. CONCLUSION: The objective measurements used to characterize SDB in this population of CKCS provided some evidence to support an obstructive cause for this condition, which improved with surgical treatment. CLINICAL SIGNIFICANCE: Sleep-disordered breathing in the CKCS is a different clinical presentation of brachycephalic obstructive airway syndrome. Our finding of intranasal abnormalities in these 5 dogs with SDB provides justification for future research into its clinical significance.

Exosome and Macrophage Crosstalk in Sleep-Disordered Breathing-Induced Metabolic Dysfunction.

Obstructive sleep apnea (OSA) is a highly prevalent worldwide public health problem that is characterized by repetitive upper airway collapse leading to intermittent hypoxia, pronounced negative intrathoracic pressures, and recurrent arousals resulting in sleep fragmentation. Obesity is a major risk factor of OSA and both of these two closely intertwined conditions result in increased sympathetic activity, oxidative stress, and chronic low-grade inflammation, which ultimately contribute, among other morbidities, to metabolic dysfunction, as reflected by visceral white adipose tissue (VWAT) insulin resistance (IR). Circulating extracellular vesicles (EVs), including exosomes, are released by most cell types and their cargos vary greatly and reflect underlying changes in cellular homeostasis. Thus, exosomes can provide insights into how cells and systems cope with physiological perturbations by virtue of the identity and abundance of miRNAs, mRNAs, proteins, and lipids that are packaged in the EVs cargo, and are secreted from the cells into bodily fluids under normal as well as diseased states. Accordingly, exosomes represent a novel pathway via which a cohort of biomolecules can travel long distances and result in the modulation of gene expression in selected and targeted recipient cells. For example, exosomes secreted from macrophages play a critical role in innate immunity and also initiate the adaptive immune response within specific metabolic tissues such as VWAT. Under normal conditions, phagocyte-derived exosomes represent a large portion of circulating EVs in blood, and carry a protective signature against IR that is altered when secreting cells are exposed to altered physiological conditions such as those elicited by OSA, leading to emergence of IR within VWAT compartment. Consequently, increased understanding of exosome biogenesis and biology should lead to development of new diagnostic biomarker assays and personalized therapeutic approaches. Here, the evidence on the major biological functions of macrophages and exosomes as pathophysiological effectors of OSA-induced metabolic dysfunction is discussed.

The Curse of Apneic Spells.

A 6-year-old girl had reduced fetal movements, numerous apneic spells, muscle hypotonia, and developmental motor delay. Her muscle biopsy tissue showed variation in myofiber diameters, small minicores by electron microscopy, and near-uniformity of type I fibers. Although no mutations were detected in RYR1, SEPN1, and DMPK genes, the RAPSN gene revealed one known mutation, p.Asn88Lys, from the mother, and one novel mutation, p.Cys366Gly, from the father. Life-saving pyridostigmine treatment suppressed her apneic spells and improved her motor development.

Axon and Schwann Cell Degeneration in Nerves of Upper Airway Relates to Pharyngeal Dysfunction in Snorers and Patients With Sleep Apnea.

BACKGROUND: The pathophysiologic mechanism of nocturnal obstruction and swallowing dysfunction commonly occurring in patients with sleep apnea is unclear. The goal of this study was to investigate whether nerve injuries in the upper airways of snorers and patients with sleep apnea are associated with pharyngeal dysfunction and severity of sleep apnea. METHODS: Twenty-two patients undergoing palatal surgery due to snoring and sleep apnea were investigated for a swallowing dysfunction by using videoradiography. Twelve healthy nonsnoring subjects were included as control subjects. Tissue samples from the soft palate at the base of the uvula were obtained in all patients and control subjects. Nerves and muscle were analyzed with immunohistochemical and morphologic methods, and the findings were correlated with swallowing function and degree of sleep apnea. RESULTS: In the soft palate of patients, nerve fascicles exhibited a significantly lower density of axons (5.4 vs 17.9 × 10-3 axons/µm2; P = .02), a smaller percentage area occupied by Schwann cells (17.5% vs 45.2%; P = .001) and a larger number of circular shaped Schwann cells lacking central axons (43.0% vs 12.7%; P < 0.001) compared with control subjects. The low density of axons was significantly related to degree of swallowing dysfunction (r = 0.5; P = .03) and apnea-hypopnea index > 5 (P = .03). Regenerating axons were frequently observed in patients compared with control subjects (11.3 ± 4.2% vs 4.8 ± 2.4%; P = .02). CONCLUSIONS: Axon degeneration in preterminal nerves of the soft palate is associated with pharyngeal dysfunction in snorers and patients with sleep apnea. The most likely cause for the nerve injuries is traumatic snoring vibrations and tissue stretch, leading to swallowing dysfunction and increased risk for upper airway obstruction during sleep.

Sleep apnea syndrome, inflammation and oxidative stress in hemodialysis patients.

INTRODUCTION: Sleep apnea syndrome (SAS) is an established cardiovascular risk factor in the general population related to inflammation and oxidative stress and is very common among hemodialysis patients. Cardiovascular disease and its complications is the main cause of death among hemodialysis patients. The aim of the present study was to investigate the role of SAS in the promotion of inflammation and oxidative stress and thus in the augmentation of cardiovascular risk in hemodialysis patients. METHODS: Thirty-seven hemodialysis patients underwent an overnight full polysomnography study. The following morning blood samples were obtained and TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), MPO (myeloperoxidase), and oxLDL (oxidized low density lipoprotein) were measured. FINDINGS: We investigated the correlation of patients' markers of inflammation and oxidative stress with their sleep parameters (total sleep time, AHI, apnea/hypopnea index; RDI, respiratory disturbance index; DI, desaturation index, mean and minimum SpO2 and percentage of sleep time with SpO2 < 90%). TNF-α correlated positively with BMI (r = 0.510, P < 0.0001) and total sleep time (r = 0.370, P = 0.027). IL-6 correlated positively with age (r = 0.363, P = 0.027), AHI (r = 0.385, P = 0.018), DI (r = 0.336, P = 0.042) and percentage of sleep time with SpO2 < 90% (r = 0.415, P = 0.012) and negatively with mean SpO2 (r = -0.364, P = 0.027). Myeloperoxidase correlated positively with AHI (r = 0.385, P = 0.018), DI (r = 0.380, P = 0.02) and percentage of sleep time with SpO2 < 90% (r = 0.388, P = 0.019). Finally, oxLDL correlated positively with BMI (r = 0.443, P = 0.007), AHI (r = 0.395, P = 0.015), RDI (r = 0.328, P = 0.048) and total sleep time with SpO2 <90% (r = 0.389, P = 0.019). CONCLUSIONS: These results indicate that, in hemodialysis patients, the severity of SAS and nocturnal hypoxia correlated positively with markers of inflammation and oxidative stress.

Up-regulation of POMC and CART mRNAs by intermittent hypoxia via GATA transcription factors in human neuronal cells.

Sleep apnea syndrome (SAS) is characterized by intermittent hypoxia (IH) during sleep. SAS and obesity are strongly related to each other. Here, we investigated the effect of IH on the expression of major appetite regulatory genes in human neuronal cells. We exposed NB-1, SH-SY5Y, and SK-N-SH human neuronal cells to IH (64 cycles of 5 min hypoxia and 10 min normoxia), normoxia, or sustained hypoxia for 24 h and measured the mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), galanin, galanin-like peptide, ghrelin, pyroglutamylated RFamide peptide, agouti-related peptide, neuropeptide Y, and melanocortin 4 receptor by real-time RT-PCR. IH significantly increased the mRNA levels of POMC and CART in all the neuronal cells. Deletion analysis revealed that the -705 to -686 promoter region of POMC and the -950 to -929 region of CART were essential for the IH-induced promoter activity. As possible GATA factor binding sequences were found in the two regions, we performed real-time RT-PCR to determine which GATA family members were expressed and found that GATA2 and GATA3 mRNAs were predominantly expressed. Therefore, we introduced siRNAs against GATA2 and GATA3 into NB-1 cells and found that GATA2 and GATA3 siRNAs abolished the IH-induced up-regulation of both POMC and CART mRNAs. These results indicate that IH stress up-regulates the mRNA levels of anorexigenic peptides, POMC and CART, in human neuronal cells via GATA2 and GATA3. IH can have an anorexigenic effect on SAS patients through the transcriptional activation of POMC and CART in the central nervous system.

Murine models of sleep apnea: functional implications of altered macrophage polarity and epigenetic modifications in adipose and vascular tissues.

Obstructive sleep apnea (OSA) is a highly prevalent disease across the lifespan, is characterized by chronic intermittent hypoxia and sleep fragmentation, and has been independently associated with substantial cardiometabolic morbidity. However, the reversibility of end-organ morbidity with treatment is not always apparent, suggesting that both tissue remodeling and epigenetic mechanisms may be operationally involved. Here, we review the cumulative evidence focused around murine models of OSA to illustrate the temporal dependencies of cardiometabolic dysfunction and its reversibility, and more particularly to discuss the critical contributions of tissue macrophages to adipose tissue insulin resistance and vascular atherogenesis. In addition, we describe initial findings potentially implicating epigenetic alterations in both the emergence of the cardiometabolic morbidity of OSA, and in its reversibility with treatment. We anticipate that improved understanding of macrophage biology and epigenetics in the context of intermittent hypoxia and sleep fragmentation will lead to discovery of novel therapeutic targets and improved cardiovascular and metabolic outcomes in OSA.

Intermittent hypoxia increases kidney tumor vascularization in a murine model of sleep apnea.

We investigate the effects of intermittent hypoxia (IH), a characteristic feature of obstructive sleep apnea (OSA), on renal cancer progression in an animal and cell model. An in vivo mouse model (Balb/c, n = 50) of kidney cancer was used to assess the effect of IH on tumor growth, metastatic capacity, angiogenesis and tumor immune response. An in vitro model tested the effect of IH on RENCA cells, macrophages and endothelial cells. Tumor growth, metastatic capacity, circulating vascular endothelial growth factor (VEGF) and content of endothelial cells, tumor associated macrophages and their phenotype were assessed in the tumor. In vitro, VEGF cell expression was quantified.Although IH did not boost tumor growth, it significantly increased endothelial cells (p = 0.001) and circulating VEGF (p<0.001) in the in vivo model. Macrophages exposed to IH in vitro increased VEGF expression, whereas RENCA cells and endothelial cells did not. These findings are in keeping with previous clinical data suggesting that OSA has no effect on kidney cancer size and that the association observed between OSA and higher Fuhrman grade of renal cell carcinoma may be mediated though a proangiogenic process, with a key role of macrophages.

Activation of the Integrated Stress Response and Metabolic Dysfunction in a Murine Model of Sleep Apnea.

Intermittent hypoxia (IH) induces activation of the integrated stress response (ISR), but its role in IH-induced visceral white adipose tissue (vWAT) insulin resistance is unknown. CHOP is activated by chronic ISR, whereas GADD34 dephosphorylates the subunit of translation initiation factor 2 (eIF2α), leading to termination of the ISR. We hypothesized that CHOP/Gadd34 null mice would not manifest evidence of insulin resistance after IH exposures. Eight-week-old CHOP/GADD34-/- (double mutant [DM]) and wild-type (WT) littermates were randomly assigned to IH or room air (RA) exposures for 6 weeks. Glucose and insulin tolerance tests were performed, and regulatory T cells (Tregs) and macrophages in vWAT were assessed. Phosphorylated eIF2α:total eIF2α, ATF4, XBP1 expression, and insulin-induced pAKT/AKT expression changes were examined in vWATs. Single GADD34-/- and PERK+/- mice were also evaluated. Body weight and vWAT mass were reduced in DM and WT mice after IH. M1/M2 macrophages and inflammatory macrophages (Ly-6chigh) were significantly increased in WT vWAT but remained unchanged in DM mice. Tregs were significantly decreased in WT vWAT but not in DM mice. Systemic insulin and glucose tolerance tests revealed insulin resistance in IH-WT but not in IH-DM mice. Similarly, decreased pAKT/AKT responses to exogenous insulin emerged in IH-WT compared with RA-WT mice, whereas no significant differences emerged in IH-DM compared with DM-RA. Chronic ISR activation appears to contribute to the insulin resistance and vWAT inflammation that characteristically emerge after long-term IH exposures in a murine model of obstructive sleep apnea.

Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea.

An adverse role for obstructive sleep apnea (OSA) in cancer epidemiology and outcomes has recently emerged from clinical and animal studies. In animals, intermittent hypoxia (IH) mimicking OSA promotes tumor malignancy both directly and via host immune alterations. We hypothesized that IH could potentiate cancer aggressiveness through activation of the cyclooxygenase-2 (COX-2) pathway and the concomitant increases in prostaglandin E2 (PGE2). The contribution of the COX-2 in IH-induced enhanced tumor malignancy was assessed using celecoxib as a COX-2 specific inhibitor in a murine model of OSA bearing Lewis lung carcinoma (LLC1) tumors. Exposures to IH accelerated tumor progression with a tumor associated macrophages (TAMs) shift towards a pro-tumoral M2 phenotype. Treatment with celecoxib prevented IH-induced adverse tumor outcomes by inhibiting IH-induced M2 polarization of TAMs. Furthermore, TAMs isolated from IH-exposed mice treated with celecoxib reduced the proliferation of LLC1 naïve cells, while the opposite occurred with placebo-treated IH-exposed mice. Finally, in vitro IH exposures of murine macrophages and LLC1 cells showed that both cell types increased PGE2 release in response to IH. These results suggest a crucial role for the COX-2 signaling pathway in the IH-exacerbated malignant processes, and designate macrophages and lung adenocarcinoma cells, as potential sources of PGE2.

[Airway inflammation in sleep disordered breathing children: preliminary results].

Objective:To assess the clinical significance of nasal nitric oxide(NNO) levels in children with sleep disordered breathing(SDB).Method:Thirty children with SDB and twenty healthy children were enrolled. The NNO levels were measured non-invasively using a NIOX MINO system. SPSS statistics 20.0 software was used to analyze the data. Result:Compared to healthy children,NNO level was significant higher in children with SDB(Z=-2.215,P<0.05) .Correlation analysis showed that SDB children's NNO level was directly correlated with AHI(r=0.429,P<0.05),and it was inversely correlated with nadir SaO2(r=-0.482,P<0.01).But NNO level was not significantly correlated with other polysomnographic parameters. Conclusion:Our data suggested that NNO levels might be useful for evaluating the disease severity in SDB children.

Oximetry in obese children with sleep-disordered breathing.

BACKGROUND: Obesity is an important risk factor for obstructive sleep apnea syndrome (OSAS), and obese children with OSAS have frequently shown oxygen desaturations when compared with normal-weight children. The aim of our study was to investigate the oximetry characteristics in children with obesity and sleep-disordered breathing (SDB). METHODS: Children referred for suspected OSAS were enrolled in the study. All children underwent sleep clinical record (SCR), pulse oximetry, and polysomnography (PSG). RESULTS: A total of 248 children with SDB were recruited (128 obese and 120 normal-weight children). Obese children showed higher oxygen desaturation index (ODI) and lower nadir oxygen saturation (nadir SaO2) compared to non-obese children (p < 0.05). ODI and nadir SaO2 correlated with obesity (p < 0.05). The SCR evaluation showed that deep bite and overjet were more common among obese children (p < 0.05), whereas habitual nasal obstruction and arched palate were more common among non-obese children (p < 0.05). Furthermore, skeletal malocclusion and tonsillar hypertrophy were significant risk factors in obese children associated with severe desaturation (p < 0.05). CONCLUSION: Obese children with SDB have a more significant oxygen desaturation; adeno-tonsillar hypertrophy is not the only important risk factor for its development but also the presence of malocclusions.