Exploring the molecular pathways linking sleep phenotypes and POGZ-associated neurodevelopmental disorder.

Pogo transposable element-derived protein with ZNF domain (POGZ) gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these patients, yet the biological pathways which link sleep traits to the POGZ-associated syndrome remain unclear. We screened for sleep implications among individuals with causative POGZ variants previously described. Sleep disturbances were observed in 52% of patients, and being obese was not observed as a risk factor for sleep problems. Next, we identified genes associated with sleep-associated traits among the POGZ regulatory targets, aiming to uncover the molecular pathways that, when disrupted by POGZ loss of function, contribute to the aetiology of sleep phenotypes in these patients. The intersect between POGZ targets and sleep-related genes was used in a pathway enrichment analysis. Relevant pathways among these overlapping genes are involved in the regulation of circadian rhythm, tau protein binding, ATPase activator activity. This study may represent the beginning for novel functional investigations on shared molecular mechanisms between sleep disturbances and rare developmental syndromes related to POGZ and its regulatory targets.

Sleep is associated with telomere shortening: A population-based longitudinal study.

As the chronological age increases, there is a decrease in the telomere length (TL). Associations between TL and age-related diseases have been described. Since the major pathophysiological factors related to inadequate sleep (including sleep complaints and sleep disorders) contribute to the exacerbation of inflammation and oxidative stress, an association of sleep and TL has been proposed. The aim of this study was to evaluate the association between sleep-related variables with TL in a longitudinal framework. We used data derived from the EPISONO cohort, which was followed over 8 years. All individuals answered sleep-related questionnaires, underwent a full-night polysomnography (PSG), and had their blood collected for DNA extraction. The TL was measured through a quantitative real time polymerase chain reaction. Age, sex, body mass index (BMI), smoking, physical activity status, and the 10 principal components (ancestry estimate) were considered covariables. Of the 1042 individuals in the EPISONO cohort, 68.3% agreed to participate in the follow-up study (n = 712). Baseline SpO2 (ß = 0.008, p = 0.007), medium SpO2 (ß = 0.013, p = 0.013), and total sleep time <90% (ß = -0.122, p = 0.012) had an effect on TL from the follow-up. The 8 year TL attrition was inversely associated with total sleep time, sleep efficiency, sleep architecture variables, wake after sleep onset, arousal index, oxygen-related variables baseline, and the presence of obstructive sleep apnea (OSA). We conclude that individuals with worse sleep quality, alterations in sleep architecture, and OSA had greater TL attrition over the 8 years. Using a longitudinal approach, these findings confirm previous cross-sectional evidence linking sleep with accelerated biological ageing.

The effects of social jetlag and sleep variability on sleepiness in a population-based study: The mediating role of sleep debt.

Sleepiness is a multicausal condition, and previous research has highlighted associations between this symptom and the circadian timing system, specifically concerning social jetlag and sleep variability. Recent inquiries have shown that the effects of social jetlag on sleepiness can be confounded with the consequences of sleep debt. In light of the current evidence, we aimed to assess the effects of social jetlag and sleep variability on sleepiness and the potential mediating role of sleep debt. We used data from the EPISONO study, a cross-sectional population-based study with a sample size of 1042 participants, representative of the city of Sao Paulo, Brazil. Participants completed the UNIFESP Sleep Questionnaire (self-reported bedtime and get-up time) and the Epworth Sleepiness Scale (subjective daytime sleepiness). Subsequently, sleep-corrected mid-sleep time (chronotype), total sleep time, social jetlag (absolute difference between the mid-sleep time on workdays and mid-sleep time on free days), sleep variability (standard deviation of mid-sleep time), and sleep debt (difference between total sleep time on workdays and free days) were calculated. Generalised linear models were used to test whether social jetlag and sleep variability affected sleepiness. Mediation models were used to determine if any observed significant effects were mediated by sleep debt. The prevalence of social jetlag was 23% for >1 h and 12% for >2 h. The mean sleep variability was 41 ± 30 min. Social jetlag had a significant effect on the Epworth Sleepiness Scale scores. This association was no longer statistically significant after controlling for age, sex, body mass index, work schedule, and chronotype. A significant indirect effect of social jetlag on sleep debt and subsequently on the Epworth Sleepiness Scale scores was found. No effect of sleep variability on sleepiness could be identified. In conclusion, the association between social jetlag and sleepiness was mediated by sleep debt but was not independent of demographic, work, and chronotype variables. This study provides new evidence on the importance of circadian misalignment and sleep debt for sleep health on a population level.

The role of upper airway and facial skeleton anatomy in the evolution of obstructive sleep apnea: an 8-year follow-up.

PURPOSE: To evaluate the role of anatomic alterations of the upper airway and facial skeleton in the evolution of obstructive sleep apnea (OSA) in a prospective population-based study with an 8-year follow-up. METHODS: This was a population-based, longitudinal, prospective study, which took place from 2007 to 2015 at the Instituto do Sono, Sao Paulo, Brazil. In 2007, type I polysomnography (PSG), otorhinolaryngological examination, and collection of anthropometric measurements of all volunteers were performed. Volunteers were classified according to their anatomical features of the upper airway and facial skeleton. After 8 years, volunteers were invited for reevaluation. The relationship between anatomical characteristics and polysomnographic evolution was evaluated. RESULTS: The study included 554 patients. After 8 years of follow-up, there was an increase in neck circumference and body mass index of the participants. There was a worsening in all polysomnographic parameters analyzed, with an increase in the apnea-hypopnea index, a decrease in minimum saturation values, and an increase in the percentage of sleep time with peripheral oxyhemoglobin saturation <90%. There was no statistical relationship between the anatomical findings considered unfavorable and the worsening of polysomnographic parameters. CONCLUSIONS: In a sample of the general population, after 8 years, we did not find any relationship between upper airway and facial skeleton characteristics and the progression of OSA.

The effects of hormonal contraceptive use on sleep in women: A systematic review and meta-analysis.

Hormonal contraceptives are some of the most widely used medications worldwide, but studies on their effects on sleep are contradictory, with some reporting a sleep-promoting effect, while others a sleep-inhibiting effect. Our objective was, therefore, to undertake a systematic review and meta-analysis of the literature on this subject to try to clarify their effects. A search was conducted in three databases (PubMed, Scopus and Web of Science). Only studies evaluating hormonal contraception use were considered eligible, and both objective and subjective sleep-related outcomes were considered. Individual effect size was calculated for each article, and meta-analyses were performed using a DerSimonian and Laird random effects method. The initial search identified 2076 articles, of which 13 met the criteria for the study after full text evaluation. A total of 33 meta-analyses were performed, three of them related to subjective measures and 30 considering data from polysomnography. The only statistically significant result between contraceptive users and non-contraceptive users was observed in respect of wake after sleep onset, which was 7 min shorter among contraceptive users (-7.12 [-12.80; -1.44]; I2  = 65%; p = 0.01). In conclusion, hormonal contraceptives are not associated with clinically relevant changes in sleep patterns in women.

The effects of sleep deprivation and obstructive sleep apnea syndrome on male reproductive function: a multi-arm randomised trial.

Sleep is essential for the maintenance of health and systemic homeostasis. Decreased sleep time and sleep quality have been associated with a wide range of diseases. To evaluate the effects of obstructive sleep apnea (OSA) and total or selective rapid eye movement (REM) sleep deprivation on male reproductive function, we performed a three-arm parallel study with one pre-defined OSA group and a group of healthy volunteers who were then randomised into total or REM sleep deprivation groups. Questionnaires were completed and overnight polysomnography was undertaken, and blood and sperm samples were collected at the Sleep Institute, São Paulo, Brazil. OSA was diagnosed using questionnaires and polysomnography. Male sexual function was assessed through the questionnaires, blood tests, and semen samples. Data showed an association between OSA and lower circulating levels of total and free testosterone and high-density lipoproteins, as well as a lower proportion of healthy sperm cells and decreased sperm concentration, in comparison to volunteers. Volunteers subjected to either total or REM sleep deprivation had increased circulating levels of thyroid-stimulating hormone, insulin, and higher homeostatic model assessment of insulin resistance (HOMA-IR) values. Both sleep-deprived groups also shown decreased cholesterol, and low-density lipoproteins when compared to their baseline levels, but had no alterations in their spermograms. We observed a reduction in total testosterone following total sleep deprivation, but no effect after REM sleep deprivation. OSA was associated with a hormonal imbalance, which is probably linked with impaired reproductive function and associated comorbidities, such as sleep fragmentation/loss and obesity.

Oxygen saturation as a predictor of inflammation in obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) is a chronic sleep disorder, and its prevalence is increasing worldwide. This disorder has been consistently associated with several comorbidities. Although it is clear that obstructive sleep apnea severity is associated with inflammation, the trigger for this phenomenon continues to puzzle scientists. Here, we investigated the relationship between obstructive sleep apnea severity and immune parameters. METHODS: In this cross-sectional epidemiological research, we analyzed the immune profile of 461 adults according to OSA severity (mild, moderate, and severe) and oxygen saturation. RESULTS: The hallmark of OSA severity - the apnea-hypopnea index (AHI) - weakly correlated with an inflammatory profile. However, individuals who experienced lower oxygen saturation were more likely to exhibit higher total leukocyte and neutrophil counts, a higher neutrophil-lymphocyte ratio (NLR), and an increased concentration of C-reactive protein. CONCLUSION: Our findings indicated that oxygen saturation is a predictor of inflammation during OSA and should be considered crucial in disease diagnostic and treatment strategies.

Depression and obesity, but not mild obstructive sleep apnea, are associated factors for female sexual dysfunction.

PURPOSE: Mild obstructive sleep apnea (OSA) is more prevalent than moderate and severe OSA and is more frequent in men than women. The association between OSA and female sexual dysfunction (FSD) is still poorly explored in published studies. Our aim was to investigate the prevalence of FSD in women with mild OSA and assess the impact of OSA on FSD, as well as to determine the predictors for FSD risk. METHODS: The sample comprised 70 women aged 26-65 years: a control group (N = 28) with no sleep complaints, and a group with mild OSA (an apnea-hypopnea index of 5 or more and less than 15 events/hour, N = 42), who had been diagnosed using polysomnography performed in the sleep laboratory of a sleep research institute. All participants volunteered to take part in the study and completed the female sexual function index (FSFI), the Beck depression index (BDI), the Kupperman menopausal index (KMI), and the Epworth sleepiness scale (ESS). Their socioeconomic group was assessed using the Brazilian Economic Classification Criterion. Polysomnography and serum levels of free testosterone and total testosterone were analyzed. RESULTS: We found low FSFI scores (< 26.55) in the mild OSA (18.1) and control (21.7) groups (p = 0.97). There was no statistically significant difference between the mild OSA group and the control group. However, a higher BMI (p = 0.04), a higher BDI (p = 0.02), and being sexuality inactive (p = 0.001) were risk factors for FSD. CONCLUSION: There was a high prevalence of FSD in the entire sample. The presence of mild OSA did not affect sexual function in this sample. Depressive symptoms and a high BMI were associated risk factors for FSD. Being sexually active may protect female sexual function.

The reproducibility of clinical OSA subtypes: a population-based longitudinal study.

PURPOSE: The identification of subgroups of obstructive sleep apnea (OSA) is critical to understand disease outcome and treatment response and ultimately develop optimal care strategies customized for each subgroup. In this sense, we aimed to perform a cluster analysis to identify subgroups of individuals with OSA based on clinical parameters in the Epidemiological Sleep Study of São Paulo city (EPISONO). We aimed to analyze whether or not subgroups remain after 8 years, since there is not any evidence showing if these subtypes of clinical presentation of OSA in the same population can change overtime. METHODS: We used data derived from EPISONO cohort, which was followed over 8 years after baseline evaluation. All individuals underwent polysomnography, answered questionnaires, and had their blood collected for biochemical examinations. OSA was defined according to AHI ≥ 15 events/h. Cluster analysis was performed using latent class analysis (LCA). RESULTS: Of the 1042 individuals in the EPISONO cohort, 68% agreed to participate in the follow-up study (n = 712), and 704 were included in the analysis. We were able to replicate the OSA 3-cluster solution observed in previous studies: disturbed sleep, minimally symptomatic and excessively sleepy in both baseline (36%, 45% and 19%, respectively) and follow-up studies (42%, 43%, and 15%, respectively). The optimal cluster solution for our sample based on Bayesian information criterion (BIC) was 2 cluster for baseline (disturbed sleep and excessively sleepy) and 3 clusters for follow-up (disturbed sleep, minimally symptomatic, and excessively sleepy). A total of 45% of the participants migrated clusters between the two evaluations (and the factor associated with this was a greater delta-AHI (B = - 0.033, df = 1, p = 0.003). CONCLUSIONS: The results replicate and confirm previously identified clinical clusters in OSA which remain in the longitudinal analysis, with some percentage of migration between clusters.

Effects of sleep modulation during pregnancy in the mother and offspring: Evidences from preclinical research.

Disturbed sleep during gestation may lead to adverse outcomes for both mother and child. Animal research plays an important role in providing insights into this research field by enabling ethical and methodological requirements that are not possible in humans. Here, we present an overview and discuss the main research findings related to the effects of prenatal sleep deprivation in animal models. Using systematic review approaches, we retrieved 42 articles dealing with some type of sleep alteration. The most frequent research topics in this context were maternal sleep deprivation, maternal behaviour, offspring behaviour, development of sleep-wake cycles in the offspring, hippocampal neurodevelopment, pregnancy viability, renal physiology, hypertension and metabolism. This overview indicates that the number of basic studies in this field is growing, and provides biological plausibility to suggest that sleep disturbances might be detrimental to both mother and offspring by promoting increased risk at the behavioural, hormonal, electrophysiological, metabolic and epigenetic levels. More studies on the effects of maternal sleep deprivation are needed, in light of their major translational perspective.

Oxygen saturation during sleep as a predictor of inflammation in anovulatory women.

PURPOSE: To evaluate the inflammatory profile of premenopausal women with anovulatory cycles, regular menstrual cycles, or using contraceptives, and the associations with sleep and health-related parameters. METHODS: Subjects completed questionnaires including the Pittsburgh Sleep Quality Index and the Epworth sleepiness scale, underwent whole-night polysomnography, and had blood collected for analysis of inflammatory, cardiovascular, and hormonal parameters. Women of reproductive age were categorized into three groups for comparisons: anovulatory menstrual cycles, regular menstrual cycles, and hormonal contraceptive use. RESULTS: Women with anovulatory menstrual cycles (n = 20) had higher circulating levels of the proinflammatory cytokine IL-6 compared with women who had regular menstrual cycles (n = 191) and those on hormonal contraception (n = 72). No other classical marker of low-grade inflammation was significantly different. Subjective and objective sleep data were similar among groups. However, the mean peripheral oxygen saturation (SpO2) during sleep was reduced in anovulatory women. The analysis of associated variables of the inflammatory profile demonstrated that mean SpO2 during sleep was a predictive factor of IL-6 levels. CONCLUSIONS: Our data suggest that in premenopausal women with anovulation, a proinflammatory condition mediated by IL-6 is associated with lower oxygen levels during sleep. These findings reflect the balance between gynecological status, the immune system, and sleep, pointing to the need to control for these factors in clinical practice and research contexts.

The Potential of Black Cohosh in the Treatment of Depression and Anxiety Due to Menopause: An Effective and More Natural Solution?

No Abstract Available.

Waist-to-height ratio and waist circumference as the main measures to evaluate obstructive sleep apnea in the woman's reproductive life stages.

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder. In women, the frequency of OSA increases substantially during and after the menopause, as does the prevalence of obesity in this reproductive life stage. This cross-sectional study uses data from the Sao Paulo Epidemiologic Sleep Study (EPISONO, 2007), and comprises a sample of 500 women aged 20-80 years. Multiple logistic regression analysis was used to assess the factors associated with OSA in premenopausal and postmenopausal women. All participants underwent polysomnography, and obesity was assessed using the waist-to-height ratio (WHtR), body mass index, neck and waist circumference, measured using standard methods. WHtR was the factor most associated with a significant increase in risk of OSA in premenopausal women. Waist circumference was the factor most associated with OSA in postmenopausal women, for all severities of the disease. Anthropometric factors presented a high rate of accuracy in the classification of women with OSA. The study found that different obesity-related anthropometric measures should be considered in the diagnosis of OSA, according to the woman's reproductive stage.

Hormonal contraceptive use and subjective sleep reports in women: An online survey.

Female sexual hormones have known hypnogenic effects and the use of hormonal replacement therapy in postmenopausal women leads to improvement in sleep quality. However, the effects of hormonal contraceptives in women of reproductive age are still scarcely understood. This study sought to evaluate the impact of hormonal contraceptive use on subjective self-reports of sleep through a web-based cross-sectional survey. A total of 2,055 women between 18 and 40 years old participated by answering an online questionnaire evaluating hormonal contraceptive use, sleep-related characteristics and related features. Sleep assessment tools comprised the Epworth Sleepiness Scale (ESS) and the Insomnia Severity Index (ISI). Statistical comparisons were performed between hormonal contraceptive users and those who reported no current use. Analyses were repeated to compare users of combined contraceptives with users of progestagens only, as well as to compare users of different generations of contraceptives. Among the total sample, 1,286 participants met the inclusion criteria (918 of them were currently taking a hormonal contraceptive). Contraceptive users reported more frequent sleep complaints and had higher scores on ESS and ISI, which means increased excessive daytime sleepiness and more insomnia symptoms. Women using progestagen-only therapies reported lower total sleep duration compared with combined therapy. Users of third-generation contraceptives showed lower total sleep time and higher ISI score when compared with non-users. In conclusion, contraceptive users have more insomnia symptoms and increased excessive daytime sleepiness when compared with women who do not use any hormonal contraceptive method, and progestagen-only therapy was associated with lower sleep duration.

Sleep influences the immune response and the rejection process alters sleep pattern: Evidence from a skin allograft model in mice.

INTRODUCTION: Sleep generally regulates immune functions in a supportive manner and can affect parameters that are directly involved in the rejection process. STUDY OBJECTIVES: The first objective was to assess whether sleep deprivation (SD) or sleep restriction (SR) affects the allograft rejection process in mice. The second objective was to investigate whether the rejection process itself modulates the sleep pattern of allografted mice. DESIGN: Adult BALB/c and C57BL/6J male mice were used as the donors and recipients, respectively, except for the syngeneic group (ISOTX), which received skin from mice of the same strain (C57BL/6J). The recipients were randomly assigned to either one of two control groups - TX (allogenic) or ISOTX (syngeneic) - which underwent stereotaxic surgery to enable sleep recording prior to the allograft but were not sleep deprived; one of two paradoxical sleep deprived groups - SDTX and TXSD - which underwent 72h of continuous SD either before or after the allograft respectively, and one of two sleep restricted groups - SRTX and TXSR - which underwent 21h of SD and 3h of sleep for 15days either before or after the allograft respectively. INTERVENTIONS: The skin allograft was inspected daily to determine the survival time, expected as 8.0±0.4days in this transplant model under no treatment. The sleep pattern was controlled throughout the rejection process in the SD and SR groups. Draining lymph nodes, spleen, blood and skin grafts were harvested on the 5th day after transplantation for evaluation of the immune parameters related to allograft rejection. MEASUREMENTS AND RESULTS: In the control groups, we observed a reduction in paradoxical sleep throughout the entire allograft rejection process. Acute and chronic experimental sleep loss in the SD and SR groups produced marked alterations in the immune response. Both SD and SR prolonged allograft survival compared to the non-sleep-deprived group. There were reductions in the following parameters involved in the allograft rejection under sleep loss: CD4+ and CD8+ T cell subpopulations in the peripheral lymph organs and spleen, circulating sIL-2R levels, graft-infiltrating CD4+ T cells and skin allograft global gene expression. CONCLUSIONS: We provide, as far as we are aware, the first evidence in vivo that the immune response can alter the normal sleep pattern, and that sleep loss can conversely affect the immune response related to graft rejection.

Effects of Bach Flower Remedies on Menopausal Symptoms and Sleep Pattern: A Case Report.

Context • During the postmenopausal stage, women go through many remarkable changes, including physical, emotional, and hormonal. They also experience some unwanted effects, such as vasomotor symptoms, anxiety, and insomnia. The use of Bach flower remedies has been described as a supporting therapy for those symptoms. Objectives • The investigation aimed to evaluate the effects of the supplement on sleep pattern (ie, sleep perception and objective sleep) and on menopausal symptoms. Design • The research team created a case report. Setting • The study was conducted at the Menopause Transition and Postmenopause Sleep Disorder Clinic at the Department of Gynecology of the Federal University of São Paulo in São Paulo, Brazil. Participant • The participant was a 53-y-old, single woman, at the postmenopausal stage, who had been diagnosed with insomnia according to the criteria of the American Academy of Sleep Medicine and complained of climacteric symptoms. Intervention • The patient underwent treatment with a blend of the supplement for 4 mo. Outcome Measures • Sleep questionnaires were given and polysomnography was performed before and after treatment. Results • Both sleep perception and objective sleep were improved. The patient's anxiety and menopausal symptoms were reduced after the treatment with the supplement. Conclusion • The use of Bach flower remedies as a therapeutic strategy to relieve menopausal symptoms, such as anxiety, mood changes, and insomnia, seems worthy of further investigation.

Ocimum gratissimum Essential Oil and Its Isolated Compounds (Eugenol and Myrcene) Reduce Neuropathic Pain in Mice.

Ocimum gratissimum is used in popular medicine to treat painful diseases. The antihypernociceptive properties of O. gratissimum essential oil and two of its active components (eugenol and myrcene) were tested in a model of neuropathic pain induced by a chronic constriction injury of the sciatic nerve. In tests to determine chronic antinociception, adult male C57BL/6 J mice were treated orally with corn oil (control group), O. gratissimum essential oil at doses of 10, 20, or 40 mg/kg or eugenol or myrcene at doses of 1, 5, or 10 mg/kg for 14 days after surgery. Pregabalin (20 mg/kg) was used as a standard in this study. The treatment with 20 and 40 mg/kg of O. gratissimum essential oil and at doses of 5 and 10 mg/kg of the active components were able to promote antihypernociception in both mechanical (von Frey) and thermal (hot plate) tests. The treatment with the essential oil of the plant or eugenol was effective in reducing the levels of interleukin-1ß in the sciatic nerve. Our findings demonstrate that O. gratissimum essential oil and its isolated active components possess antihypernociceptive activity in neuropathic pain models.

Scientific research in obstructive sleep apnea syndrome: bibliometric analysis in SCOPUS, 1991-2012.

PURPOSE: The research in obstructive sleep apnea (OSA) may be beneficial from the collaboration between countries and researchers. In this study, we aimed to analyze the scientific research on OSA from 1991 to 2012 and to evaluate the collaboration networks between countries. METHODS: We conducted a bibliometric study in the SCOPUS database. The systematic search was limited to "articles" published from 1991 to 2012. Articles are results of original research; we evaluated the following criteria: number of countries represented, number of authors, number of citations, and journal names. We determined which countries were the most productive (more articles published) and the number of collaborations between these countries. The probability of citation was evaluated using adjusted odds ratios in a logistic regression analysis. RESULTS: We found a total of 6,896 OSA-related articles that had been published in 1,422 journals, 50 % of these articles were concentrated in 41 journals. Of the 74 different countries associated with these articles, the USA had the highest involvement with 23.8 % of all articles published. The probability of citation increased by 1.23 times for each additional author, and by 2.23 times for each additional country represented; these findings were independent of time since publication, journal, or the country of the author. CONCLUSIONS: Scientific production on OSA is increasing with limited international collaboration. The country with the greatest production in this period (1991-2012) was the USA, which concentrated the international collaboration network on OSA. We recommended that articles should be produced with international collaboration to improve the quantity of scientific publications and their chances of publication in high impact journals.