Cardiovascular Disease in Obstructive Sleep Apnea: Putative Contributions of Mineralocorticoid Receptors.

Obstructive sleep apnea (OSA) is a chronic and highly prevalent condition that is associated with oxidative stress, inflammation, and fibrosis, leading to endothelial dysfunction, arterial stiffness, and vascular insulin resistance, resulting in increased cardiovascular disease and overall mortality rates. To date, OSA remains vastly underdiagnosed and undertreated, with conventional treatments yielding relatively discouraging results for improving cardiovascular outcomes in OSA patients. As such, a better mechanistic understanding of OSA-associated cardiovascular disease (CVD) and the development of novel adjuvant therapeutic targets are critically needed. It is well-established that inappropriate mineralocorticoid receptor (MR) activation in cardiovascular tissues plays a causal role in a multitude of CVD states. Clinical studies and experimental models of OSA lead to increased secretion of the MR ligand aldosterone and excessive MR activation. Furthermore, MR activation has been associated with worsened OSA prognosis. Despite these documented relationships, there have been no studies exploring the causal involvement of MR signaling in OSA-associated CVD. Further, scarce clinical studies have exclusively assessed the beneficial role of MR antagonists for the treatment of systemic hypertension commonly associated with OSA. Here, we provide a comprehensive overview of overlapping mechanistic pathways recruited in the context of MR activation- and OSA-induced CVD and propose MR-targeted therapy as a potential avenue to abrogate the deleterious cardiovascular consequences of OSA.

A Low-Cost, Easy-to-Assemble Device to Prevent Infant Hyperthermia under Conditions of High Thermal Stress.

High ambient temperature and humidity greatly increase the risk of hyperthermia and mortality, particularly in infants, who are especially prone to dehydration. World areas at high risk of heat stress include many of the low- and middle-income countries (LMICs) where most of their inhabitants have no access to air conditioning. This study aimed to design, evaluate, and test a novel low-cost and easy-to-assemble device aimed at preventing the risk of infant hyperthermia in LMICs. The device is based on optimizing negative heat transfer from a small amount of ice and transferring it directly to the infant by airflow of refrigerated air. As a proof of concept, a device was assembled mainly using recycled materials, and its performance was assessed under laboratory-controlled conditions in a climatic chamber mimicking realistic stress conditions of high temperature and humidity. The device, which can be assembled by any layperson using easily available materials, provided sufficient refrigerating capacity for several hours from just 1-2 kg of ice obtained from a domestic freezer. Thus, application of this novel device may serve to attenuate the adverse effects of heat stress in infants, particularly in the context of the evolving climatic change trends.

The Critical Nature of Addressing Burnout Prevention: Results From the Critical Care Societies Collaborative's National Summit and Survey on Prevention and Management of Burnout in the ICU.

OBJECTIVES: To summarize the results of expert discussions and recommendations from a National Summit and survey on the promoting wellness and preventing and managing burnout in the ICU. DATA SOURCES: Literature review; Critical Care Societies Collaborative (CCSC) Statement on Burnout Syndrome in Critical Care Healthcare Professionals: A Call for Action; CCSC's National Summit on Prevention and Management of Burnout in the ICU; and a descriptive survey on strategies for addressing burnout using Research Electronic Data Capture (REDCap) (project-redcap.org). DATA SYNTHESIS: Building on the CCSC call for action to address burnout among critical care professionals, the CCSC sponsored the National Summit on Prevention and Management of Burnout in the ICU with 55 invited experts in various fields including psychology, sociology, integrative medicine, psychiatry, suicide prevention, bereavement support, ethics, palliative care, meditation, mindfulness-based stress reduction, among others. Attendees joined breakout groups, to identify factors influencing burnout in ICU professionals and the value of organizational and individual interventions. As a follow-up to the Summit, a descriptive survey assessing strategies for addressing burnout was sent via email or newsletter blast with responses received from 680 CCSC members, including physicians, nurses, pharmacists, therapists, and others. CONCLUSIONS: The Summit attendees identified the importance of raising awareness among critical care clinicians and key stakeholders, advocating for workplace changes to promote healthy work environments, and promoting research to further explore practical strategies to address, mitigate, and prevent burnout. Critical care clinicians reported that a number of initiatives are being implemented both at their hospitals and at the unit level to build resilience and address burnout prevention. However, other respondents reported that no measures were being used within their organizations, and that colleagues were experiencing burnout. Dissemination and application of resiliency building measures and strategies to address burnout in critical care clinicians are needed.

Bispectral Analysis to Enhance Oximetry as a Simplified Alternative for Pediatric Sleep Apnea Diagnosis.

This study aims at assessing the bispectral analysis of blood oxygen saturation (SpO2) from nocturnal oximetry to help in pediatric sleep apnea-hypopnea syndrome (SAHS) diagnosis. Recent studies have found excessive redundancy in the SAHS-related information usually extracted from SpO2, while proposing only two features as a reduced set to be used. On the other hand, it has been suggested that SpO2 bispectral analysis is able to provide complementary information to common anthropometric, spectral, and clinical variables. We address these novel findings to assess whether bispectrum provides new non-redundant information to help in SAHS diagnosis. Thus, we use 981 pediatric SpO2 recordings to extract both the reduced set of features recently proposed as well as 9 bispectral features. Then, a feature selection method based on the fast correlationbased filter and bootstrapping is used to assess redundancy among all the features. Finally, the non-redundant ones are used to train a Bayesian multi-layer perceptron neural network (BYMLP) that estimate the apnea-hypopnea index (AHI), which is the diagnostic reference variable. Bispectral phase entropy was found complementary to the two previously recommended features and a BY-MLP model trained with the three of them reached high agreement with actual AHI (intra-class correlation coefficient = 0.889). Estimated AHI also showed high diagnostic ability, reaching 82.1%, 81.9%, and 90.3% accuracies and 0.814, 0.880, and 0.922 area under the receiver-operating characteristics curve for three common AHI thresholds: 1 e/h, 5 e/h, and 10 e/h, respectively. These results suggest that the information extracted from the bispectrum of SpO2 can improve the diagnostic performance of the oximetry test.

Protein-Tyrosine Phosphatase-1B Mediates Sleep Fragmentation-Induced Insulin Resistance and Visceral Adipose Tissue Inflammation in Mice.

Study Objectives: Sleep fragmentation (SF) is highly prevalent and has emerged as an important contributing factor to obesity and metabolic syndrome. We hypothesized that SF-induced increases in protein tyrosine phosphatase-1B (PTP-1B) expression and activity underlie increased food intake, inflammation, and leptin and insulin resistance. Methods: Wild-type (WT) and ObR-PTP-1b-/- mice (Tg) were exposed to SF and control sleep (SC), and food intake was monitored. WT mice received a PTP-1B inhibitor (RO-7d; Tx) or vehicle (Veh). Upon completion of exposures, systemic insulin and leptin sensitivity tests were performed as well as assessment of visceral white adipose tissue (vWAT) insulin receptor sensitivity and macrophages (ATM) polarity. Results: SF increased food intake in either untreated or Veh-treated WT mice. Leptin-induced hypothalamic STAT3 phosphorylation was decreased, PTP-1B activity was increased, and reduced insulin sensitivity emerged both systemic and in vWAT, with the latter displaying proinflammatory ATM polarity changes. All of the SF-induced effects were abrogated following PTP-1B inhibitor treatment and in Tg mice. Conclusions: SF induces increased food intake, reduced leptin signaling in hypothalamus, systemic insulin resistance, and reduced vWAT insulin sensitivity and inflammation that are mediated by increased PTP-1B activity. Thus, PTP-1B may represent a viable therapeutic target in the context of SF-induced weight gain and metabolic dysfunction.

Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice.

Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

Chronic sleep fragmentation during the sleep period induces hypothalamic endoplasmic reticulum stress and PTP1b-mediated leptin resistance in male mice.

BACKGROUND: Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction. METHODS: Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP-/+ transgenic mice. RESULTS: Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP -/+ mice. CONCLUSIONS: SF induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of ER stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target.

Antiinflammatory therapy outcomes for mild OSA in children.

BACKGROUND: OSA is highly prevalent in children and usually initially treated by adenotonsillectomy. Nonsurgical alternatives for mild OSA primarily consisting of antiinflammatory approaches have emerged, but their efficacy has not been extensively assessed. METHODS: A retrospective review of clinically and polysomnographically diagnosed patients with OSA treated between 2007 and 2012 was performed to identify otherwise healthy children ages 2 to 14 years who fulfilled the criteria for mild OSA and who were treated with a combination of intranasal corticosteroid and oral montelukast (OM) for 12 weeks (ICS + OM). A subset of children continued OM treatment for 6 to 12 months. RESULTS: A total of 3,071 children were diagnosed with OSA, of whom 836 fulfilled mild OSA criteria and 752 received ICS + OM. Overall, beneficial effects occurred in > 80% of the children, with nonadherence being documented in 61 children and adenotonsillectomy being ultimately performed in 12.3%. Follow-up polysomnography in a subset of 445 patients showed normalization of sleep findings in 62%, while 17.1% showed either no improvement or worsening of their OSA. Among the latter, older children (aged > 7 years; OR, 2.3; 95% CI, 1.43-4.13; P < .001) and obese children (BMI z-score > 1.65; OR: 6.3; 95% CI, 4.23-11.18; P < .000001) were significantly more likely to be nonresponders. CONCLUSIONS: A combination of ICS + OM as initial treatment of mild OSA appears to provide an effective alternative to adenotonsillectomy, particularly in younger and nonobese children. These results support implementation of multicenter randomized trials to more definitively establish the role of ICS + OM treatment in pediatric OSA.

A one-hour sleep restriction impacts brain processing in young children across tasks: evidence from event-related potentials.

The effect of mild sleep restriction on cognitive functioning in young children is unclear, yet sleep loss may impact children's abilities to attend to tasks with high processing demands. In a preliminary investigation, six children (6.6-8.3 years of age) with normal sleep patterns performed three tasks: attention ("Oddball"), speech perception (consonant-vowel syllables), and executive function (Directional Stroop). Event-related potentials (ERPs) responses were recorded before (Control) and following 1 week of 1-hour per day of sleep restriction. Brain activity across all tasks following Sleep Restriction differed from activity during Control Sleep, indicating that minor sleep restriction impacts children's neurocognitive functioning.

Sleep-disordered breathing affects auditory processing in 5-7-year-old children: evidence from brain recordings.

Poor sleep in children is associated with lower neurocognitive functioning and increased maladaptive behaviors. The current study examined the impact of snoring (the most common manifestation of sleep-disordered breathing) on cognitive and brain functioning in a sample of 35 asymptomatic children ages 5-7 years identified in the community as having habitual snoring (SDB). All participants completed polysomnographic, neurocognitive (NEPSY), and psychophysiological (event-related potentials [ERPs] to speech sounds) assessments. The results indicated that sub-clinical levels of SDB may not necessarily lead to reduced performance on standardized behavioral measures of attention and memory. However, brain indices of speech perception and discrimination (N1/P2) are sensitive to individual differences in the quality of sleep. We postulate that addition of ERPs to the standard clinical measures of sleep problems could lead to early identification of children who may be more cognitively vulnerable because of chronic sleep disturbances.

Green tea catechin polyphenols attenuate behavioral and oxidative responses to intermittent hypoxia.

RATIONALE: The intermittent hypoxia (IH) that characterizes sleep-disordered breathing impairs spatial learning and increases NADPH oxidase activity and oxidative stress in rodents. We hypothesized that green tea catechin polyphenols (GTPs) may attenuate IH-induced neurobehavioral deficits by reducing IH-induced NADPH oxidase expression, lipid peroxidation, and inflammation. OBJECTIVES: To assess the effects of GTP administered in drinking water on the cognitive, inflammatory, and oxidative responses to long-term (>14 d) IH during sleep in male Sprague-Dawley rats. METHODS: Cognitive assessments were conducted in the Morris water maze. We measured levels and expression of malondialdehyde (MDA), prostaglandin E(2), p47(phox) subunit of NADPH oxidase, receptor for advanced glycation end products (RAGE), and glial fibrillary acidic protein expression in rodent brain tissue. MEASUREMENTS AND MAIN RESULTS: GTP treatment prevented IH-induced decreases in spatial bias for the hidden platform during the Morris water maze probe trails as well as IH-induced increases in p47phox expression within the hippocampal CA1 region. In untreated animals, IH exposure was associated with doubling of cortical MDA levels in comparison to room air control animals, and GTP-treated animals exposed to IH showed a 40% reduction in MDA levels. Increases in brain RAGE and glial fibrillary acidic protein expression were observed in IH-exposed animals, and these increases were attenuated in animals treated with GTP. CONCLUSIONS: Oral GTP attenuates IH-induced spatial learning deficits and mitigates IH-induced oxidative stress through multiple beneficial effects on oxidant pathways. Because oxidative processes underlie neurocognitive deficits associated with IH, the potential therapeutic role of GTP in sleep-disordered breathing deserves further exploration.

Periodic limb movements in sleep and iron status in children.

STUDY OBJECTIVES: To assess potential relationships between serum iron and ferritin levels and the severity of periodic limb movement in sleep (PLMS) in a pediatric population, and to evaluate the response to supplemental iron therapy. DESIGN: A prospective study of all consecutively diagnosed children with PLMS (periodic limb movement index [periodic limb movements per hour of total sleep time, [PLMI] > 5) who underwent overnight polysomnographic evaluation. In all patients, complete blood count and serum iron and ferritin levels were obtained. Patients with serum ferritin concentrations less than 50 microg/L were prescribed iron sulfate at 3 mg/kg of elemental iron per day for 3 months. At the end of treatment, serum iron and ferritin levels and sleep studies were repeated. SETTING: Comprehensive Sleep Medicine Center, Tulane University Health Sciences Center, and Kosair Children's Hospital Sleep Medicine and Apnea Center. PATIENTS: Twenty boys and 19 girls with PLMS with a mean age of 7.5 +/- 3.1 years. INTERVENTION: Iron therapy. RESULTS: Twenty-eight (71.8%) patients had ferritin levels less than 50 microg/L. There was no significant correlation between serum ferritin concentration and PLMS severity as indicated by the PLMI (r = -0.19). The PLMI in patients with serum ferritin levels less than 50 microg/L (29.9 +/- 15.5 PLM/h) was higher than in patients with serum ferritin levels greater than 50 microg/L (21.9 +/- 11.8 PLM/h); however, the difference did not achieve statistical significance (P = 0.09). In contrast, serum iron was significantly correlated with PLMI (r = -0.43, P < 0.01). Indeed, patients with serum iron concentrations less than 50 microg/dL had a higher PLMI compared to patients with serum iron concentrations greater than 50 microg/dL (42.8 +/- 18.3 PLM/h and 23.1 +/- 10.1 PLM/h, respectively; P = 0.02). Twenty-five out of the 28 PLMS patients with serum ferritin levels less than 50 microg/L received treatment with iron sulfate, and 19 (76%) responded favorably. Among the responders to iron therapy, PLMI decreased from 27.6 +/- 14.9 PLM per hour to 12.6 +/- 5.3 PLM per hour after 3 months of iron supplements (P < 0.001) and coincided with increases in serum ferritin levels (pre: 40.8 +/- 27.4 microg/L vs post: 74.1 +/- 13.0 microg/L; P < 0.001). CONCLUSIONS: In children, the presence of PLMS is frequently associated with low serum iron and a tendency toward low serum ferritin levels. In addition, iron therapy is associated with clinical improvement in most of these patients.