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STUDY OBJECTIVES: Obstructive sleep apnea and short sleep duration have been separately associated with inadequate serum 25-hydroxyvitamin D [25(OH)D] levels. However, whether these 2 factors may concurrently influence 25(OH)D in the general population is unknown. We hypothesized that both obstructive sleep apnea and short sleep duration would be independently associated with lower concentrations of 25(OH)D in a sex-dependent manner. METHODS: In this cross-sectional study, 712 individuals, part of the prospective EPISONO cohort (Brazil), underwent polysomnography, answered sleep questionnaires, and had their blood collected for serum 25(OH)D quantification. RESULTS: Individuals with a sleep duration of < 6 hours had 2-fold increased odds of 25(OH)D < 20 ng/mL compared with those who reported 6 or more hours of sleep, even after adjusting for confounding factors. Subset sex analysis revealed that men with a sleep duration of < 6 hours had 4-fold increased odds of 25(OH)D < 20 ng/mL. In women, short sleep duration was not associated with lower 25(OH)D levels. The presence of obstructive sleep apnea (as classified according to the individual’s apnea-hypopnea index) was not independently related to 25(OH)D concentrations in men or women. Sleep parameters, including sleep latency and sleep efficiency, had no association with 25(OH)D < 20 ng/mL. CONCLUSIONS: Short sleep, but not apnea-hypopnea index, was an independent factor associated with low 25(OH)D serum levels in men, but not in women. Apnea-hypopnea index scores were not associated with 25(OH)D levels in either sex. These results raise the possibility of investigating sex-specific characteristics, such as gonadal hormone regulation, and re-evaluating obstructive events by classifying them in mild, moderate, and severe obstructive sleep apnea. CITATION: de Oliveira DL, Dokkedal-Silva V, Fernandes GL, Kim LJ, Tufik S, Andersen ML. Sleep duration as an independent factor associated with vitamin D levels in the EPISONO cohort. J Clin Sleep Med. 2021;17(12):2439–2449.

Obesity increases levels of an adipocyte-produced hormone leptin, which activates the sympathetic nervous system leading to hypertension. We have recently reported that acute leptin infusion induces hypertension acting via the TRPM7 (transient receptor potential cation channel subfamily M member 7) cation channel in the carotid bodies. We hypothesize that this mechanism causes hypertension when leptin levels are elevated chronically as observed in diet-induced obesity. We have developed a novel extended release preparation, hydrogel, of a TRPM7 inhibitor FTY720, which was administered to the carotid body area bilaterally and compared with control hydrogel in (1) male lean C57BL/6J mice treated with subcutaneous infusions of leptin; (2) diet-induced obese male C57BL/6J with hyperleptinemia at baseline. In the experiment (3), diet-induced obese C57BL/6J mice, in which Trpm7 was silenced in the carotid body areas by transfection with Ad-Trpm7 shRNA , were compared with control mice transfected with Ad-CON-shRNA . All mice were implanted in the left femoral artery with telemetry before the experiments for continuous blood pressure monitoring. In lean mice, leptin increased 24 hours mean arterial pressure from 101.2±1.2 to 112±1.5 mm Hg; Trpm7 inhibitor abolished leptin-induced hypertension. Obese mice had elevated mean arterial pressure of 115.3±1.7 mm Hg, which was lowered by 8.7±1.0 mm Hg on week 2 after Trpm7 inhibitor treatment ( P Trpm7 shRNA decreased blood pressure from 119.0±2.2 to 109.6±1.4 mm Hg ( P shRNA had no effect. In conclusion, our study has shown that inhibition of TRPM7 in carotid bodies abolished leptin-induced hypertension in obese mice.

Rationale: Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined.Objectives: Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60.Methods: We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep.Measurements and Main Results: Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[18F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep.Conclusions: We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.

Obstructive sleep apnea is associated with insulin resistance, lipid dysregulation, and hepatic steatosis and fibrosis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that hepatocyte HIF-1 (hypoxia-inducible factor-1) mediates the development of liver fibrosis in a mouse model of NAFLD. We hypothesized that intermittent hypoxia (IH) modeling obstructive sleep apnea would worsen hepatic steatosis and fibrosis in murine NAFLD, via HIF-1. Mice with hepatocyte-specific deletion of Hif1a (Hif1a(−/−)hep) and wild-type (Hif1a(F/F)) controls were fed a high trans-fat diet to induce NAFLD with steatohepatitis. Half from each group were exposed to IH, and the other half were exposed to intermittent air. A glucose tolerance test was performed just prior to the end of the experiment. Mitochondrial efficiency was assessed in fresh liver tissue at the time of death. The hepatic malondialdehyde concentration and proinflammatory cytokine levels were assessed, and genes of collagen and fatty acid metabolism were examined. Hif1a(−/−)hep mice gained less weight than wild-type Hif1a mice (−2.3 g, P = 0.029). There was also a genotype-independent effect of IH on body weight, with less weight gain in mice exposed to IH (P = 0.003). Fasting glucose, homeostatic model assessment for insulin resistance, and glucose tolerance test results were all improved in Hif1a(−/−)hep mice. Liver collagen was increased in mice exposed to IH (P = 0.033) and was reduced in Hif1a(−/−)hep mice (P

Study Objectives Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin-deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepRb-deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals. Methods We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepRb or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin. Results Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepRb infection resulted in LepRb expression in the DMH neurons in a similar fashion to wildtype mice. In LepRb-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume, and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals. Conclusion Leptin stimulates breathing and treats obesity hypoventilation acting on LepRb-positive neurons in the DMH.

Obesity can lead to recurrent upper airway obstruction (obstructive sleep apnea, OSA) during sleep as well as alveolar hypoventilation. We have previously shown that leptin stimulates breathing and treats OSA in leptin-deficientob/obmice and leptin-resistant diet-induced obese mice. Our previous data also suggest that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We selectively expressed leptin receptorLepRbin the DMH neurons of obeseLepRb-deficientdb/dbmice (LepRb-DMH mice), which hypoventilate at baseline, and showed that intracerebroventricular injection of leptin in these animals increased inspiratory flow, tidal volume and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2production. Leptin had no effect on upper airway obstruction inLepRb-DMHanimals. We conclude that leptin stimulates breathing and treats obesity related hypoventilation acting on LepRb-positive neurons in the DMH.

The carotid body (CB) is responsible for the peripheral chemoreflex by sensing blood gases and pH. The CB also appears to act as a peripheral sensor of metabolites and hormones, regulating the metabolism. CB malfunction induces aberrant chemosensory responses that culminate in the tonic overactivation of the sympathetic nervous system. The sympatho-excitation evoked by CB may contribute to the pathogenesis of metabolic syndrome, inducing systemic hypertension, insulin resistance and sleep-disordered breathing. Several molecular pathways are involved in the modulation of CB activity, and their pharmacological manipulation may lead to overall benefits for cardiometabolic diseases. In this review, we will discuss the role of the CB in the regulation of metabolism and in the pathogenesis of the metabolic dysfunction induced by CB overactivity. We will also explore the potential pharmacological targets in the CB for the treatment of metabolic syndrome.

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a μ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the μ-opioid receptor agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea, and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in patients with obesity receiving opioids without reducing analgesia.

Objective Sleep apnea has been associated with anxiety, but the mechanisms of the sleep apnea-anxiety relationship are unresolved. Sleep apnea causes oxidative stress, which might enhance anxiety-like behavior in rodents. To clarify the apnea-anxiety connection, we tested the effect of intermittent hypoxia, a model of sleep apnea, on the anxiety behavior of mice. Methods The rodents were exposed daily to 480 one-minute cycles of intermittent hypoxia to a nadir of 7±1% inspiratory oxygen fraction or to a sham procedure with room air. After 7 days, the mice from both groups were placed in an elevated plus maze and were video recorded for 10 min to allow analysis of latency, frequency, and duration in open and closed arms. Glyoxalase-1 (Glo1) and glutathione reductase-1 (GR1) were measured in the cerebral cortex, hippocampus, and striatum by Western blotting. Results Compared to controls, the intermittent hypoxia group displayed less anxiety-like behavior, perceived by a statistically significant increase in the number of entries and total time spent in open arms. A higher expression of GR1 in the cortex was also observed. Conclusion The lack of a clear anxiety response as an outcome of intermittent hypoxia exposure suggests the existence of additional layers in the anxiety mechanism in sleep apnea, possibly represented by sleepiness and irreversible neuronal damage.

Citation:Dokkedal-Silva V, Kim LJ, Morelhao PK, Galduroz JCF, Tufik S, Andersen ML. Use of clonazepam in REM sleep behavior disorder: association with fall-related injuries and alternative treatmen...

[Rationale:] Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified. We previously reported that leptin enhanced activity of the carotid sinus nerve, which transmits chemosensory input from the carotid bodies (CBs) to the medullary centers, and this effect was abolished by nonselective blockers of Trp (transient receptor potential) channels. We searched our mouse CB transcriptome database and found that the Trpm7 (transient receptor potential melastatin 7) channel was the most abundant Trp channel., [Objective] To examine if leptin induces hypertension acting on the CB Trpm7., [Methods and Results] C57BL/6J (n=79), leptin receptor (LepRb) deficient db/db mice (n=22), and LepRb-EGFP (n=4) mice were used. CB Trpm7 and LepRb gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure was recorded continuously in (1) leptin-treated C57BL/6J mice with intact and denervated CB; (2) leptin-treated C57BL/6J mice, which also received a nonselective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with Trpm7 small hairpin RNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprb expression in CB. Leptin receptor and Trpm7 colocalized in the CB glomus cells. Leptin induced a nonselective cation current in these cells, which was inhibited by Trpm7 blockers. Leptin induced hypertension in C57BL/6J mice, which was abolished by CB denervation, Trpm 7 blockers, and Trpm7 small hairpin RNA applied to CBs. Leprb overexpression in CB of Leprb-deficient db/db mice demethylated the Trpm7 promoter, increased Trpm7 gene expression, and induced hypertension., [Conclusions] We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.

The present disclosure generally relates to compositions and methods of treating opioid-induced respiratory depression in a subject in need thereof, the method comprising administering leptin.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic and hypnopompic hallucinations. The onset of the symptoms usually occurs in childhood, and previous studies have reported an association between narcolepsy and other endocrine diseases in the pediatric population, such as obesity and precocious puberty. The incidence of overweight or obesity ranges from 25% to 74% in patients with narcolepsy type I, while precocious puberty is present in 17% of children with narcolepsy with cataplexy. However, the mechanisms involved in the association of narcolepsy with obesity and precocious puberty have not been fully elucidated yet. In this review, we aimed to discuss narcolepsy in pediatric populations, highlighting the diagnostic difficulties and the complexity of the possible mechanisms that can relate narcolepsy to precocious puberty and obesity. We also emphasized the fact that endocrine diseases must be taken into consideration in children diagnosed with narcolepsy.

Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb‐deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/Δurn:x-wiley:00223751:media:tjp13266:tjp13266-math-0001 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non‐rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity., This work was funded by the NIH R01s HL133100 to V.Y.P. and J.S.K.S., R01 HL128970 to V.Y.P. and A.R.S., R01 HL138932 to V.Y.P. V.Y.P. is also supported by NIEHS grant P50 ES018176 and EPA Agreements 83615201 & 83451001. C.C.E. was supported in part by ‘Beca de estancias formativas de la Consejería de Salud de Andalucía 2017. C. Caballero Eraso. Número de expediente: EF‐0128‐2016’.

The association between sleep-disordered breathing and stroke has been a subject of increased interest and research. Obstructive sleep apnea (OSA) is an important risk factor for stroke incidence and mortality. Moreover, OSA is a common clinical outcome after stroke, directly influencing the patient's recovery. The treatment of choice for OSA is positive airway pressure (PAP) support and the PAP appliance is considered the most recommended clinical management for the treatment of patients with cardiovascular complications. However, the implementation of PAP in stroke patients remains a challenge, considering the increased frequency of motor and language impairments associated with the cerebrovascular event. In the present study, we reviewed the main findings describing the association between stroke and OSA treatment with continuous positive airway pressure. We also discussed the types of OSA treatment, the different options and indications of PAP treatment, PAP adherence and the clinical outcomes after treatment.

We investigated the effect of intermittent hypoxia, mimicking sleep apnea, on axonal integrity, blood-brain barrier permeability, and cognitive function of mice. Forty-seven C57BL mice were exposed to intermittent or sham hypoxia, alternating 30s of progressive hypoxia and 30s of reoxigenation, during 8h/day. The axonal integrity in cerebellum was evaluated by transmission electron microscopy. Short- and long-term memories were assessed by novel object recognition test. The levels of endothelin-1 were measured by ELISA. Blood-brain barrier permeability was quantified by Evans Blue dye. After 14 days, animals exposed to intermittent hypoxia showed hypomyelination in cerebellum white matter and higher serum levels of endothelin-1. The short and long-term memories in novel object recognition test was impaired in the group exposed to intermittent hypoxia as compared to controls. Blood-brain barrier permeability was similar between the groups. These results indicated that hypomyelination and impairment of short- and long-term working memories occurred in C57BL mice after 14 days of intermittent hypoxia mimicking sleep apnea.

Introducao: A poluicao do ar e um importante fator ambiental relacionado a doencas cronicas nao transmissiveis, como doencas cardiovasculares e respiratorias. Essa relacao torna-se importante em cidades com alta atividade industrial, como Vitoria/ES. Esta pesquisa utilizou tres revisoes sistematicas (RSs) distintas para avaliar a epidemiologia das doencas cardiovasculares (RS1), a epidemiologia das doencas respiratorias (RS2) e a associacao entre poluicao do ar e doencas cardiorrespiratorias (RS3) na cidade de Vitoria. Metodos: A busca bibliografica considerou tres bases de dados (PubMed, Scopus e LILACS). Foi estabelecida uma quantidade minima de tres estudos para a conducao de metanalises. A heterogeneidade de cada analise foi calculada pelo indice I2 . Resultados: A busca bibliografica resultou em 1.205 registros, dos quais 27 foram incluidos – 17 na RS1, cinco na RS2 e cinco na RS3. Apenas dois desfechos puderam ser avaliados por meio de metanalises: prevalencia de hipertensao e prevalencia de asma em criancas. Estima-se uma prevalencia de 34% (IC95%: 24-45) de hipertensao e de 12% (IC95%: 1-32) de asma em criancas. Os poluentes mais avaliados foram MP10 e SO2 , para os quais nao se pode realizar metanalises. Todas as analises apresentaram baixo numero de registros incluidos e alta heterogeneidade. Conclusao: Ha poucos dados disponiveis sobre a associacao de doencas cardiorrespiratorias e poluicao ambiental em Vitoria. A heterogeneidade, a diversidade de desfechos e a baixa quantidade de estudos impediram a conducao de analises mais profundas e limitaram o poder de sintese e conclusao dessas revisoes, impossibilitando uma avaliacao adequada dos objetivos propostos. Sao necessarios mais estudos epidemiologicos com amostras de grande porte e representativas para que se tenha resultados conclusivos sobre a relacao entre poluicao ambiental e doencas cardiorrespiratorias em Vitoria. Palavras-chave: Doencas cardiovasculares; doencas respiratorias; poluicao do ar; medicina ambiental; revisao sistematica

Chronotype and obstructive sleep apnea (OSA) appear to have a similar lifelong evolution, which could indicate a possible effect of morningness or eveningness in the apnea-hypopnea index (AHI). The present study aimed to examine the prevalence of chronotypes in a representative sample of Sao Paulo city residents and to investigate the effect of chronotypes on the severity of OSA. We performed a cross-sectional analysis using the Sao Paulo Epidemiologic Sleep Study (EPISONO). All participants underwent a full-night polysomnography and completed the Morningness-eveningness, Epworth Sleepiness Scale, and UNIFESP Sleep questionnaires. Chronotypes were classified as morning-type, evening-type, and intermediate. Morning-type individuals represented 52.1 % of the sample, followed by intermediate (39.5 %), and evening-type (8.4 %) individuals. After stratifying the sample by body mass index (BMI) (>26.8 kg/m2) and age (>42 years), we observed increased AHI values in morning- and evening-type individuals. We demonstrated, for the first time, an age- and BMI-related effect of morning- and evening-types in OSA severity, suggesting that the intermediate chronotype might play a role as a protective factor in older and overweight patients.

Obstructive sleep apnea (OSA) is a highly prevalent disease characterized by recurrent closure of the upper airway during sleep. It has a complex pathophysiology involving four main phenotypes. An abnormal upper airway anatomy is the key factor that predisposes to sleep-related collapse of the pharynx, but it may not be sufficient for OSA development. Non-anatomical traits, including (1) a compromised neuromuscular response of the upper airway to obstruction, (2) an unstable respiratory control (high loop gain), and (3) a low arousal threshold, predict the development of OSA in association with anatomical abnormalities. Current therapies for OSA, such as continuous positive airway pressure (CPAP) and oral appliances, have poor adherence or variable efficacy among patients. The search for novel therapeutic approaches for OSA, including pharmacological agents, has been pursued over the past years. New insights into OSA pharmacotherapy have been provided by preclinical studies, which highlight the importance of appropriate use of animal models of OSA, their applicability, and limitations. In the present review, we discuss potential pharmacological targets for OSA discovered using animal models.

Rostral fluid displacement has been proposed as a pathophysiologic mechanism of both central and obstructive sleep apnea. Aquaporins are membrane proteins that regulate water transport across the cell membrane and are involved in brain edema formation and resolution. The present study investigated the effect of intermittent hypoxia (IH), a model of sleep apnea, on brain aquaporins. Mice were exposed to intermittent hypoxia to a nadir of 7% oxygen fraction. Brain water content, Aquaporin-1 and Aquaporin-3 were measured in the cerebellum and hippocampus. Hematoxylin-eosin and immunohistochemistry stainings were performed to evaluate cell damage. Compared to the sham group, the hypoxia group presented higher brain water content, lower levels of Aquaporin-1 and similar levels of Aquaporin-3. Immunoreactivity to GFAP and S100B was stronger in the hypoxia group in areas of extensive gliosis, compatible with cytotoxic edema. These findings, although preliminary, indicate an effect of IH on aquaporins levels. Further investigation about the relevance of these data on the pathophysiology of OSA is warranted.

Objectives Sleep is essential for physical and mental well-being. However, poor sleep is a common complaint among caregivers. The aim of the present study was to determine sleep patterns of caregiver-mothers (CM group) of sons with Duchenne muscular dystrophy (DMD) and also to examine the differences between non-carriers and carriers of the gene related to DMD within the CM group. Methods Observational case–control study. Participants The CM and control (CTRL) groups were matched for age, body mass index and social class. Polysomnography was conducted in a sleep laboratory for one night. The discrete fast Fourier transformation method was used to calculate the electroencephalogram (EEG) power spectrum for the entire night and sleep stages. Results The CM group presented higher sleep latency and N3 sleep stage compared with the CTRL. When carrier and non-carrier CM subgroups were analyzed, increased sleep latency and time awake, as well as reduced sleep efficiency and N2, were observed in the carrier group. Regarding respiratory parameters, carriers demonstrated higher hypopnea index values compared with non-carriers. Spectral analysis showed that carriers compared with non-carrier DMD caregiver-mothers presented lower spectral power in fast waves, mainly beta, during REM sleep in some EEG derivations. Conclusions There was an impairment of sleep pattern in the CM group compared with CTRL mothers; this was possibly associated with difficulty in initiating sleep. Being a DMD gene carrying caregiver further compromised some aspects of sleep microstructure during REM sleep. The data demonstrated the importance of sleep evaluation in caregiver-mothers, and the relationship between sleep and being a carrier of the gene associated with DMD, which was demonstrated as possibly impacting sleep quality.

Cerebral blood flow is associated with the cerebrovascular prognosis. Sleep restriction (SR) may be a limiting factor of the prognosis after a cerebrovascular event, impairing the neurological recovery. We aimed to investigate the effects of SR on mortality rate and on behavioral and histological parameters of animals submitted to permanent cerebral hypoperfusion. Sixty male Wistar rats were distributed in 4 groups, according to the protocol of common carotid artery occlusion (CCAO) and SR: nSR+nCCAO, SR+nCCAO, nSR+CCAO, and SR+CCAO. The groups SR+nCCAO and SR+CCAO were submitted to SR during 10 days. The cerebral hypoperfusion was induced by the permanent CCAO. Neurological function and memory were assessed over 14 days of cerebral hypoperfusion. Analysis of neuropathological alterations were performed in the CA1 region of hippocampus. The mortality rate was 40% in the nSR+CCAO and SR+CCAO groups. SR significantly reduced the survival time of animals submitted to CCAO. After 7 and 14 days of cerebral hypoperfusion, 11% and 33% of the nSR+CCAO and SR+CCAO animals showed severe neurological dysfunction, respectively. A significant association between a high frequency of memory impairments with the group SR+CCAO was observed. The neuropathological alterations in CA1 region of hippocampus were similar among the groups. SR potentiates the negative effects of cerebral hypoperfusion conditions, suggesting that SR could be a factor associated with a worse prognosis after a cerebrovascular event.

Depression (DEP) is one of the main disabling diseases and is considered a contributor factor for erectile dysfunction (ED). Both of these conditions may be associated with hormonal changes and sleep disturbances. We aimed to evaluate the interaction between ED complaints and depression symptoms on sleep parameters, hormone levels and quality of life in men. This was a cross-sectional study of 468 men aged 20-80 years. The participants were classified according to the presence of ED and/or DEP in groups of healthy individuals, ED, DEP and DEP with ED (DEP-ED). All participants completed questionnaires about sleep, clinical history and quality of life, and underwent polysomnography with blood collection the following morning. ED participants showed higher frequency of insomnia symptoms (65.5%), whereas DEP group had more complaints of difficulty in falling asleep and early morning awakening. In the polysomnography, all groups showed similar parameters. No differences were found in cortisol and total testosterone levels; however, free testosterone levels and the physiological domain of quality of life were lower in DEP-ED group. ED and DEP, as independent factors, negatively affected subjective sleep parameters. The interaction between these factors led to a low quality of life and was related to a decrease in free testosterone levels.

Narcolepsy is a disabling disease with a delayed diagnosis. At least 3 years before the disorder identification, several comorbidities can be observed in patients with narcolepsy. The early recognition of narcolepsy symptoms may improve long-term prognosis of the patients. Thus, we aimed to investigate the prevalence of the symptoms associated with narcolepsy and its social and psychological association in a sample of Sao Paulo city inhabitants.We performed a cross-sectional evaluation with 1,008 individuals from the Sao Paulo Epidemiologic Sleep Study (EPISONO). Excessive daytime sleepiness (EDS) was assessed by the Epworth Sleepiness Scale. Volunteers were also asked about the occurrence of cataplectic-like, hypnagogic or hypnopompic hallucinations, and sleep paralysis symptoms. The participants underwent a full-night polysomnography and completed questionnaires about psychological, demographic, and quality of life parameters.We observed a prevalence of 39.2% of EDS, 15.0% of cataplectic-like symptom, 9.2% of hypnagogic or hypnopompic hallucinations, and 14.9% of sleep paralysis in Sao Paulo city inhabitants. A frequency of 6.9% was observed when EDS and cataplectic-like symptoms were grouped. The other associations were EDS + hallucinations (4.7%) and EDS + sleep paralysis (7.5%). Symptomatic participants were predominantly women and younger compared with patients without any narcolepsy symptom (n = 451). Narcolepsy symptomatology was also associated with a poor quality of life and symptoms of depression, anxiety, and fatigue.Narcolepsy-related symptoms are associated with poor quality of life and worse psychological parameters.

Several conditions, comprising obesity, cervical soft tissueaccumulation, nasal obstruction, and craniofacial abnormali-ties, increase the risk for obstructive sleep apnea (OSA). Themaxillomandibularanteroposteriorandverticaldisproportionsare one of the most frequent craniofacial abnormalities andgenerally appear due to an alteration in the mandible growth.Thus, a decrease in oropharyngeal space is often observed[1]which predisposes to OSA. Although transversal alterationsalso play an important role in the OSA development and thetreatment with rapid maxillary expansion shows great results,in the present letter, we discussed only mandibulardeficiencies.In dentistry, the diagnostic classification of these craniofacialabnormalities is still controversial, ranging from the relation-ship between the first permanent molars (Angle’sclassifica-tion) to the cephalometric measurements and subjective anal-ysis of the facial morphology [2]. This absence of an optimi-zation of the diagnostic criteria for craniofacial abnormalitiesimpairsthecomparisonsamongdifferentstudiesandhampersthe evaluation of the maxillomandibular treatmenteffectiveness.In growing patients, one of the craniofacial abnormalitytreatments consists in moving the mandible forward to ananterior position by fixed or removable maxillary orthopedicappliances[3].Althoughcontroversial,thisadvancementlike-ly increases the anterior mandible position in relation to themaxilla and to the skull base by promoting mandible growthand dentoalveolar remodeling. This process also could pro-mote a soft tissue organization and a sagittal malocclusionimprovement which lead to oropharyngeal space increase,facilitating a normal air flow [3]. Hence, maxillomandibularcorrection represents an important and effective treatment tosnoreandOSA duringchildhood,aspreviouslydemonstratedin children with 4 to 10 years treated with removable oralappliances during 6 months [4, 5].Recently, it has been suggested that the therapeutic inter-vention to correct skeletal abnormalities in children and ado-lescents notonly couldtreatthecurrent problems of snore andOSA during childhood and adolescence but also could have along-term effect, preventing these obstructive events even inadulthood [6]. The mechanism of this possible associationwould be the maxillomandibular correction persistence bythe morphological stabilizationofface growth and maturation.This hypothesis, however, still lacks objective evidences. Inthe studies of Villa and colleagues (2002) and Cozza andcolleagues (2004), the authors only observed the short-termeffectoforalappliancestreatingthesnoreandOSAanddidnotinvestigate the skeletal maxillomandibular correction in chil-drenanditsstabilization.Althoughtheimmediateoutcomesofthese treatments performed in the growing face are clinicallysatisfactory for snore and OSA, including significant changesin linear and volumetric dimensions of oropharyngeal spaces[3], the long-term effectiveness of this therapy is still unclear.Another possibility is that the maxillomandibular correctionduring childhood and adolescence could not persist until adult-hood, considering that the craniofacial pattern seems to have apredominant genetic determination (Fig. 1)[7]. In this case,evenpromotingtheadvancementofthemandibleduringchild-hood for treatment of skeletal abnormalities or of OSA andsnore, the genetic determination could contribute to a progres-sive return to the initial maxillomandibular disproportions in

To examine whether in obstructive sleep apnea (OSA) patients the degree of sleepiness, slow-wave sleep (SWS) loss, and hypoxia influence the response of psychological symptoms to continuous positive airway pressure (CPAP) therapy. A prospectively planned cohort was assessed. Participants underwent full overnight polysomnography. All answered the Symptom Checklist-90-Revised (SCL-90) and the Epworth sleepiness scale (ESS). Only cases with an apnea-hypopnea index ≤60 events/h were 24 invited to participate. In an interview by telephone, after a follow-up period between 2 months and 1 year, patients informed whether they were in treatment with CPAP or remained voluntarily untreated. Subjects who accepted to participate answered for the second time the SCL-90 and the ESS. The baseline variables of interest were: (a) score of the ESS, (b) duration of SWS, and (c) time with arterial oxygen saturation below 90 %. The outcomes were the change in SCL-90 scores in all dimensions and indices of the questionnaire. A number of 73 patients, mostly men, were included. In uncontrolled analyses, CPAP-treated patients showed significant improvement at follow-up in 10 of the 13 SCL-90 scores. Comparing with the control group, only six scores were improved. Baseline sleepiness was the best predictor of SCL-90 improvement after CPAP treatment in the univariate analyses, and the only significant predictor of improvement in a multivariate regression model. Sleepiness may supersede other factors that influence psychological improvement in CPAP-treated patients with severe OSA.

We previously published a method for measuring several physiological traits causing obstructive sleep apnea (OSA). The method, however, had a relatively low success rate (76%) and required mathematical modeling, potentially limiting its application. This paper presents a substantial revision of that technique. To make the measurements, continuous positive airway pressure (CPAP) was manipulated during sleep to quantify 1) eupneic ventilatory demand, 2) the level of ventilation at which arousals begin to occur, 3) ventilation off CPAP (nasal pressure = 0 cmH2O) when the pharyngeal muscles are activated during sleep, and 4) ventilation off CPAP when the pharyngeal muscles are relatively passive. These traits could be determined in all 13 participants (100% success rate). There was substantial intersubject variability in the reduction in ventilation that individuals could tolerate before having arousals (difference between ventilations #1 and #2 ranged from 0.7 to 2.9 liters/min) and in the amount of ventilatory compensation that individuals could generate (difference between ventilations #3 and #4 ranged from −0.5 to 5.5 liters/min). Importantly, the measurements accurately reflected clinical metrics; the difference between ventilations #2 and #3, a measure of the gap that must be overcome to achieve stable breathing during sleep, correlated with the apnea-hypopnea index (r = 0.9, P < 0.001). An additional procedure was added to the technique to measure loop gain (sensitivity of the ventilatory control system), which allowed arousal threshold and upper airway gain (response of the upper airway to increasing ventilatory drive) to be quantified as well. Of note, the traits were generally repeatable when measured on a second night in 5 individuals. This technique is a relatively simple way of defining mechanisms underlying OSA and could potentially be used in a clinical setting to individualize therapy.

Background Intermittent hypoxia (IH), a model of sleep apnea, produces weight loss in animals. We hypothesized that changes in brown adipose tissue (BAT) function are involved in such phenomenon. We investigated the effect of IH, during 35 days, on body weight, brown adipose tissue wet weight (BATww) and total protein concentration (TPC) of BAT. Methods We exposed Balb/c mice to 35 days of IH (n = 12) or sham intermittent hypoxia (SIH; n = 12), alternating 30 seconds of progressive hypoxia to a nadir of 6%, followed by 30 seconds of normoxia. During 8 hours, the rodents underwent a total of 480 cycles of hypoxia/reoxygenation, equivalent to an apnea index of 60/hour. BAT was dissected and weighed while wet. Protein was measured using the Lowry protein assay. Results Body weight was significantly reduced in animals exposed to IH, at day 35, from 24.4 ± 3.3 to 20.2 ± 2.2 g (p = 0.0004), while in the SIH group it increased from 23.3 ± 3.81 to 24.1 ± 2.96 g (p = 0.23). BATww was also lower in IH than in SIH group (p = 0.00003). TPC of BAT, however, was similar in IH (204.4 ± 44.3 μg/100 μL) and SIH groups (213.2 ± 78.7 μg/100 μL; p = 0.74) and correlated neither with body weight nor with BATww. TPC appeared to be unaffected by exposure to IH also in multivariate analysis, adjusting for body weight and BATww. The correlation between body weight and BATww is significant (rho= 0.63) for the whole sample. When IH and SIH groups are tested separately, the correlations are no longer significant (rho= 0.48 and 0.05, respectively). Conclusion IH during 35 days in a mice model of sleep apnea causes weight loss, BATww reduction, and no change in TPC of BATww. The mechanisms of weight loss under IH demands further investigation.

Dear Editor, Stroke is the third leading cause of premature death in general population [1]. In childhood, the occurrence of stroke is less frequent than in adulthood; however, the mortality rate reaches 20 % in infants [2]. For instance, sickle cell disease, congenital cardiac disorders, traumatic lesions, and infections contribute to increase the odds for childhood stroke [3]. Recently, iron-deficiency anemia (IDA) has been also suggested as an important risk factor to ischemic cerebrovascular events [4, 5]. In this context, Azab et al. [6] performed a case–control study with 21 stroke children with median age of 36 months. They found a significant effect of IDA predicting stroke. The patients with IDA showed higher median platelet count compared to control and stroke with normal iron parameters groups. Consequently, children with IDA had 2.5-fold greater odds for ischemic stroke. These results suggest that IDA could be a more potent risk factor for perinatal stroke with similar magnitude than the others widely reported. The authors deserve congratulations for this study mainly for two reasons. Firstly, effective stroke treatments must be continuously investigated since the prevention of reversible risk factors is the most indicated therapy to avoid the occurrence and recurrence of stroke. Secondly, these findings may contribute to elucidate the different pathophysiological mechanism involved in the association of stroke and other disorders, such as the periodic limb movements (PLM) [7], for example. PLM is characterized by repeated movements of arms and/ or legs during sleep whose possible etiology comprises an iron deficiency and a consequent dysfunction in dopaminergic transmission [8]. Indeed, children with sickle cell disease showed a higher PLM prevalence than healthy patients [9]. PLM also increase the risk of ischemic stroke. The high prevalence of PLM after stroke may indicate a concomitant pathway of iron deficiency [7]. Indeterminate etiology of stroke can constitute approximately 37 % of all diagnosed patients [10]. Thus, further studies should be performed to analyze underestimated risk factors for stroke. New and common pathophysiological mechanisms of different diseases with stroke must be better understood. The investigations may contribute to elucidate part of the indeterminate stroke.