Obstructive Sleep Apnea and Mental Health Disorders in the Pediatric Population: A Retrospective Population-based Cohort Study.

RATIONALE: Information is limited about the association between obstructive sleep apnea (OSA) and mental disorders in children. OBJECTIVES: In children, (1) to evaluate the association between OSA and new mental healthcare encounters; (2) to compare mental healthcare encounters two years post- to pre-OSA treatment initiation. METHODS: We conducted a retrospective longitudinal cohort study using Ontario health administrative data (Canada). Children (0-18 years) who underwent diagnostic polysomnography (PSG) 2009-2016 and met criteria for definition of moderate-severe OSA (PSG-OSA) were propensity score weighted by baseline characteristics and compared to children who underwent a PSG in the same period but did not meet the OSA definition (PSG-No-OSA). Children were followed until March 2021. Weighted cause-specific Cox Proportional Hazards and Modified Poisson regression models were used to compare time from PSG to first mental healthcare encounter and frequency of new mental healthcare encounters per person time, respectively. Among those who underwent adenotonsillectomy (AT) or were prescribed and claimed positive airway pressure therapy (PAP), we used age-adjusted conditional logistic regression models to compare two years post- to pre-treatment odds of mental healthcare encounters. RESULTS: Of 32,791 children analyzed, 7,724 (23.6%) children met criteria for moderate-severe OSA. In PSG-OSA group, 7,080 (91.7%) were treated (AT or PAP). Compared to PSG-No-OSA, the PSG-OSA group had a shorter time from PSG to first mental healthcare encounter (HR: 1.08; 95%CI: 1.05-1.12), but less frequent mental healthcare encounters in follow-up (RR: 0.92; 95% CI: 0.87-0.97). OSA treatment (AT or PAP) was associated with lower odds of mental healthcare encounters two years post-treatment initiation compared to two years prior (OR: 0.69; 95% CI: 0.65-0.74). CONCLUSION: In this large population-based study of children who underwent PSG for sleep disorder assessment, OSA diagnosis/treatment was associated with an improvement in some mental health indicators, such as fewer new mental healthcare encounters compared to no OSA, and lower odds of mental healthcare encounters compared to pre-OSA treatment.

Aripiprazole, a Novel Option in the Management of Restless Legs Syndrome (RLS) Patients with Augmentation and/or Severe RLS Symptoms: A Report of 4 Cases.

Purpose: Restless Legs Syndrome (RLS) is a sensorimotor disorder associated with an unpleasant urge to move the limbs, relieved with movement, occurring in the evenings and with prolonged rest/inactivity. Treatment with dopamine agonists is effective for up to 60-90% of affected individuals. However, augmentation, ie, the paradoxical worsening of RLS symptoms after prolonged RLS treatment, is frequently reported, typically after 3-10 years of treatment. Here, we present 4 patients with RLS who were successfully treated with dopamine agonists but later developed augmentation. A trial of aripiprazole, a dopamine receptor partial agonist (DRPA), was initiated for treatment of augmentation symptoms. Patients and Methods: Four patients treated for RLS with dopamine agonists developed augmentation. In each instance, augmentation symptoms did not respond adequately to a variety of medications including α2δ drugs, opioids or other agents. A trial of aripiprazole was initiated for each patient, and effects were evaluated. Results: All four patients with severe RLS and augmentation with dopamine agonists achieved symptom control with aripiprazole. Patients endorsed 90-100% efficacy with aripiprazole by subjective self-report after failures with other agents. Further evaluation with the International Restless Legs Syndrome Study Group RLS Rating Scale (IRLS-SGRS) showed that benefits (from moderate to very severe, to mild to moderate severity) were largely maintained for 1-2 years. Aripiprazole doses to control augmentation symptoms were low (1-4 mg). No significant side effects were reported. Conclusion: Aripiprazole may have utility for augmentation in RLS. We speculate that the partial agonist and antagonist properties of aripiprazole may limit potential for dopamine hyposensitization to progress to cause augmentation. Further research is needed to see if aripiprazole and/or other DRPAs are a viable long-term treatment option for patients experiencing augmentation and/or severe RLS with dopamine agonist therapy.

Vestibular symptoms are related to the proportion of REM sleep in people with sleep complaints: A preliminary report.

OBJECTIVE/BACKGROUND: Though sleep problems (apnea, insomnia) and related daytime symptoms (fatigue, anxiety, depression) have been associated with vestibular problems (falls, dizziness), it is not well known which particular sleep features relate to vestibular problems. We thus assessed symptoms of vestibular problems in patients visiting a sleep clinic and evaluated how they were associated with objective sleep parameters derived from polysomnography and relevant daytime symptoms. PATIENTS/METHODS: The polysomnography data of thirty-one patients (61% female, between 20 and 79 years of age) who were referred for clinical sleep assessment was collated with subjective measures of symptoms linked to vestibular problems (rated on the Situational Characteristics Questionnaire), as well as fatigue, anxiety and depression symptoms. Multiple linear regression was used to identify factors associated with vestibular symptoms, including analyses adjusted for age, sex, medication use and total sleep time. RESULTS: A higher percentage of REM sleep and more severe anxiety symptoms were independently associated with more severe vestibular symptoms, which survived adjusted analyses. Other sleep stages, as well as as sleep efficiency, apnea-hypopnea index and oxygen saturation were not significantly related to vestibular symptoms. CONCLUSIONS: These results point at vestibular symptoms as possible important and overlooked correlates of variations in sleep architecture in individuals with sleep complaints. Though replication is needed to confirm findings from this limited sample, the results highlight the importance of assessing vestibular symptoms in people with sleep complaints. In particular, further investigations will need to address the potential implication of REM sleep for vestibular functions and the directionality of this relation.

Association between obstructive sleep apnea and persistent postural-perceptual dizziness.

BACKGROUND: Obstructive sleep apnea (OSA) has been linked to vestibular dysfunction, but no prior studies have investigated the relationship between Persistent Postural-Perceptual Dizziness (PPPD), a common cause of chronic dizziness, and OSA. OBJECTIVE AND METHODS: We determined the frequency of OSA in an uncontrolled group of PPPD patients from a tertiary dizziness clinic based on polysomnogram (PSG). We then assessed the sensitivity and specificity of common OSA questionnaires in this population. RESULTS: Twenty-five patients with PPPD underwent PSG (mean age 47, 60% female, mean BMI 29.5). A majority, or 56%, of patients were diagnosed with OSA, and in most, the OSA was severe. OSA patients were older (56 years versus 40 years, p = 0.0006) and had higher BMI (32 versus 26, p = 0.0078), but there was no clear gender bias (56% versus 64% female, p = 1.00). The mean sensitivity and specificity of the STOP BANG questionnaire for detecting OSA was 86% and 55%, respectively. Sensitivity and specificity of the Berlin Questionnaire was 79% and 45%, respectively. CONCLUSIONS: The prevalence of OSA was much higher in our small PPPD group than in the general population. Screening questionnaires appear to demonstrate good sensitivity to detect PPPD patients at risk of OSA in this small study. Future studies should confirm these findings and determine whether treatment of OSA improves symptoms in PPPD.

Selective serotonin reuptake inhibitor use is associated with worse sleep-related breathing disturbances in individuals with depressive disorders and sleep complaints: a retrospective study.

STUDY OBJECTIVES: The effects of serotonergic agents on respiration neuromodulation may vary according to differences in the serotonin system, such as those linked to depression. This study investigated how sleep-related respiratory disturbances relate to depression and the use of medications commonly prescribed for depression. METHODS: Retrospective polysomnography was collated for all 363 individuals who met selection criteria out of 2,528 consecutive individuals referred to a specialized sleep clinic (Ottawa, Canada) between 2006 and 2016. The apnea-hypopnea index (AHI), oxygen saturation nadir, and oxygen desaturation index during REM and NREM sleep were analyzed using mixed analyses of covariance comparing 3 main groups: (1) medicated individuals with depressive disorders (antidepressant group; subdivided into the selective serotonin reuptake inhibitor and norepinephrine-dopamine reuptake inhibitor subgroups), (2) non-medicated individuals with depressive disorders (non-medicated group), and (3) mentally healthy control patients (control group). RESULTS: Individuals with depressive disorders (on antidepressants or not) had significantly higher AHIs compared to control patients (both P ≤ .007). The antidepressant group had a lower NREM sleep oxygen saturation nadir and a higher NREM sleep oxygen desaturation index than the control and non-medicated groups (all P ≤ .009). Within individuals with depressive disorders, independent of depression severity, the selective serotonin reuptake inhibitor group had a lower oxygen saturation nadir and a higher oxygen desaturation index during NREM sleep than the norepinephrine-dopamine reuptake inhibitor (both P ≤ .045) and non-medicated groups (both P < .001) and a higher NREM sleep AHI than the non-medicated group (P = .014). CONCLUSIONS: These findings suggest that the use of selective serotonin reuptake inhibitors may be associated with impaired breathing and worse nocturnal oxygen saturation in individuals with depressive disorders and sleep complaints, but this needs to be confirmed by prospective studies.

Obstructive sleep apnea and hypertension in pediatric chronic kidney disease.

BACKGROUND: Children with chronic kidney disease (CKD) are at risk for obstructive sleep apnea (OSA) and hypertension. The objectives of this study were to explore associations between OSA severity using the apnea-hypopnea-index(AHI) and obstructive apnea-hypopnea-index(OAHI) on polysomnography (PSG), OSA symptoms, and measures of hypertension in children with CKD. METHODS: One-night in-laboratory PSGs and 24-h ambulatory blood pressure monitoring (ABPM) were performed on children with CKD stages 2-5 (non-dialysis dependent). Sleep questionnaires, including the modified Epworth Sleepiness Scale (ESS) and the Pediatric Sleep Questionnaire (PSQ), were administered during the sleep study. RESULTS: Nineteen children and adolescents completed a PSG and questionnaires and thirteen completed ABPMs. Mean (standard deviation) age at the time of the sleep study was 14.1 (3.2) years. Eleven (58%) participants had CKD stage two, and eight (42%) had stage 3-4. None of the participants were found to have OSA on PSG. One participant had a positive ESS score (≥ 11) and five participants had positive PSQ scores (≥  eight). Night systolic and diastolic pressures were strongly correlated with the OAHI (r = 0.67 and r = 0.69, respectively, p < 0.05), while the AHI was not correlated with any blood pressure measures. CONCLUSIONS: Our study did not find OSA on PSG in children with predominantly mild to moderate CKD. The OAHI was found to be strongly correlated with nighttime blood pressures. Future prospective studies with a larger sample size are needed to monitor for potential progression of symptoms and findings on PSG in pediatric patients as they evolve across the spectrum of CKD.

PPAR ligands decrease human airway smooth muscle cell migration and extracellular matrix synthesis.

Airway smooth muscle cells produce extracellular matrix proteins, which in turn can promote smooth muscle survival, proliferation and migration. Currently available therapies have little effect on airway smooth muscle matrix production and migration. Peroxisome proliferator-activated receptor (PPAR) ligands are reported to decrease migration and matrix production in various cell lines. In this study, we examined the effect of PPAR ligands on human airway smooth muscle (HASM) matrix production and migration. PPAR expression was examined by RT-PCR and Western blotting. Endogenous PPAR activity was examined by transfecting cells with a PPAR response element-luciferase reporter plasmid. We observed that HASM cells express PPARα, ß and γ. A six-fold induction of luciferase activity was observed by stimulating cells with a pan-agonist, indicating endogenous PPAR activity. The PPAR ligands ciglitazone, 15-deoxy-Δ12,14-prostaglandin J(2) and WY-14643 decreased migration towards platelet-derived growth factor receptor. This was not mediated by inhibiting Akt phosphorylation or promoting PTEN activity, but partly through cyclooxygenase-2 induction and prostaglandin E(2) production that increased cyclic AMP levels in the cells. All three ligands also caused an inhibition of collagen and fibronectin secretion by cultured smooth muscle cells. We conclude that PPAR ligands decrease HASM migration and matrix production and are, therefore, potentially useful for modulating airway remodelling.

Cystic fibrosis transmembrane conductance regulator gene abnormalities in patients with asthma and recurrent neutrophilic bronchitis.

The present case series describes four patients with asthma, airway hyperresponsiveness and neutrophilic bronchitis who harboured abnormal cystic fibrosis transmembrance conductance regulator (CFTR) gene mutations. It serves both to alert clinicians to consider CFTR-related disease in both young and elderly patients with persistent neutrophilic bronchitis, and to highlight the potential utility of future genetic testing for CFTR abnormalities in patients with asthma and recurrent bronchitis or pansinusitis, and the role of nebulized hypertonic saline as a therapeutic option in these patients.

Update on exhaled nitric oxide in pulmonary disease.

The ability to assess the inflammatory status of a patient's airway using a noninvasive method is the ideal situation for clinicians. Owing in part to the relationship between the levels of exhaled nitric oxide to inflammation and the ease of the technique, the measurement of the fraction of exhaled nitric oxide (F(E)NO) has achieved considerable attention, particularly with respect to asthma. A multitude of studies have shown that when measured in exhaled air, this unique molecule has the potential to have both diagnostic and therapeutic roles in the clinical setting for many pulmonary diseases. The incorporation of F(E)NO into asthma management and treatment algorithms may help shed further insight on the current control and future risk of patients. Research is ongoing to determine the biology and the benefits of the use of F(E)NO in respiratory conditions in addition to asthma. This review will briefly outline the pathophysiology of nitric oxide, the measurement of F(E)NO and the potential clinical uses of F(E)NO in asthma and a number of other respiratory diseases. Despite its promise, until further research is conducted, the use of F(E)NO cannot be recommended for routine clinical management of respiratory diseases at present, but should be considered as an adjuvant to help guide therapy in certain patients with asthma and in those with eosinophilic bronchitis.

Identification of metal-binding proteins in human hepatoma lines by immobilized metal affinity chromatography and mass spectrometry.

The metalloproteome is defined as the set of proteins that have metal-binding capacity by being metalloproteins or having metal-binding sites. A different metalloproteome may exist for each metal. Mass spectrometric characterization of metalloproteomes provides valuable information relating to cellular disposition of metals physiologically and in metal-associated diseases. We examined the Cu and Zn metalloproteomes in three human hepatoma lines: Hep G2 and Mz-Hep-1, which retain many functional characteristics of normal human hepatocytes, and SK-Hep-1, which is poorly differentiated. Additionally we studied a single specimen of normal human liver and Hep G2 cells depleted in vitro of cellular copper. We used matrix-assisted laser desorption ionization and electrospray ionization quadrupole time-of-flight mass spectrometry to analyze peptide sequences of tryptic digests obtained by either in-gel digestion of metal-binding proteins or peptides on an immobilized metal affinity chromatography column loaded with either Cu or Zn. Mainly high abundance proteins were identified. Cu-binding proteins identified included enolase, albumin, transferrin, and alcohol dehydrogenase as well as certain intracellular chaperone proteins. The Cu metalloproteome was not identical to the Zn metalloproteome. Peptide binding experiments demonstrated that Cu coordination prefers the order of residues histidine > methionine > cysteine. Although the Cu metalloproteome was similar from line to line, subtle differences were apparent. Gel profiling showed more extensive variation in expression of annexin II in SK-Hep-1 and Mz-Hep-1 than in Hep G2 and normal liver tissue. Glycerylphosphorylethanolamine was identified as a post-translational modification at residue Glu-301 of elongation factor 1-alpha in Hep G2. Intracellular copper depletion was associated with loss of the glycerylphosphoryl side group. These findings suggest that post-translational modification could be affected by intracellular actions of copper. Comparison of the Cu and Zn metalloproteomes in Hep G2 with a published general proteome of Hep G2 disclosed little overlap (Seow, T. K., et al. (2001) Proteomics 1, 1249-1263). Proteins in the metalloproteomes of human hepatocytes can be identified by these methods. Variations in these metalloproteomes may have important physiological relevance.