Camila Hirotsu

Sleep Loss and Cytokines Levels in an Experimental Model of Psoriasis

Up to 80% of people develop a cutaneous condition closely connected to their exposure to stressful life events. Psoriasis is a chronic recurrent inflammatory skin disorder with multifactorial etiology, including genetic background, environmental factors, and immune system disturbances with a strong cytokine component. Moreover, psoriasis is variably associated with sleep disturbance and sleep deprivation. This study evaluated the influence of sleep loss in the context of an animal model of psoriasis by measuring cytokine and stress-related hormone levels. Male adult Balb/C mice with or without psoriasis were subjected to 48 h of selective paradoxical sleep deprivation (PSD). Sleep deprivation potentiated the activities of kallikrein-5 and kallikrein-7 in the skin of psoriatic groups. Also, mice with psoriasis had significant increases in specific pro-inflammatory cytokines (IL-1β, IL-6 and IL-12) and decreases in the anti-inflammatory cytokine (IL-10) after PSD, which were normalized after 48 h of sleep rebound. Linear regression showed that IL-2, IL-6 and IL-12 levels predicted 66% of corticosterone levels, which were selectively increased in psoriasis mice subject to PSD. Kallikrein-5 was also correlated with pro-inflammatory cytokines, explaining 58% of IL-6 and IL-12 variability. These data suggest that sleep deprivation plays an important role in the exacerbation of psoriasis through modulation of the immune system in the epidermal barrier. Thus, sleep loss should be considered a risk factor for the development of psoriasis.

Interactions between sleep, stress, and metabolism: From physiological to pathological conditions

Poor sleep quality due to sleep disorders and sleep loss is highly prevalent in the modern society. Underlying mechanisms show that stress is involved in the relationship between sleep and metabolism through hypothalamic–pituitary–adrenal (HPA) axis activation. Sleep deprivation and sleep disorders are associated with maladaptive changes in the HPA axis, leading to neuroendocrine dysregulation. Excess of glucocorticoids increase glucose and insulin and decrease adiponectin levels. Thus, this review provides overall view of the relationship between sleep, stress, and metabolism from basic physiology to pathological conditions, highlighting effective treatments for metabolic disturbances.

Single exposure to cocaine or ecstasy induces DNA damage in brain and other organs of mice

We evaluated the overall genetic damage induced by different doses of cocaine and MDMA (3,4‐Methylenedioxymethamphetamine) in several organs. One hour after intraperitoneal drug administration, mice were euthanized; peripheral blood, liver and brain were collected, and the cellular suspensions were used for the single cell gel (comet) assay. We determined that all doses of cocaine and MDMA tested were able to induce DNA damage in blood cells. Extensive genotoxic damage was induced by cocaine or MDMA at the highest doses used in liver cells. Brain cells were affected by all doses administrated. These findings demonstrate that cocaine and MDMA are potent genotoxins.

The NoSAS score for screening of sleep-disordered breathing: a derivation and validation study

BACKGROUND Diagnosis of sleep-disordered breathing requires overnight recordings, such as polygraphy or polysomnography. Considering the cost and low availability of these procedures, preselection of patients at high risk is recommended. We aimed to develop a screening tool allowing identification of individuals at risk of sleep-disordered breathing. METHODS We used the participants from the population-based HypnoLaus cohort in Lausanne, Switzerland, who had a clinical assessment and polysomnography at home, to build a clinical score (the NoSAS score) using multiple factor analysis and logistic regression to identify people likely to have clinically significant sleep-disordered breathing. The NoSAS score was externally validated in an independent sleep cohort (EPISONO). We compared its performance to existing screening scores (STOP-Bang and Berlin scores). FINDINGS We used the 2121 participants from the HypnoLaus cohort who were assessed between Sept 1, 2009, and June 30, 2013. The NoSAS score, which ranges from 0 to 17, allocates 4 points for having a neck circumference of more than 40 cm, 3 points for having a body-mass index of 25 kg/m(2) to less than 30 kg/m(2) or 5 points for having a body-mass index of 30 kg/m(2) or more, 2 points for snoring, 4 points for being older than 55 years of age, and 2 points for being male. Using a threshold of 8 points or more, the NoSAS score identified individuals at risk of clinically significant sleep-disordered breathing, with an area under the curve (AUC) of 0·74 (95% CI 0·72-0·76). It showed an even higher performance in the EPISONO cohort, with an AUC of 0·81 (0·77-0·85). The NoSAS score performed significantly better than did the STOP-Bang (AUC 0·67 [95% CI 0·65-0·69]; p<0·0001) and Berlin (0·63 [0·61-0·66]; p<0·0001) scores. INTERPRETATION The NoSAS score is a simple, efficient, and easy to implement score enabling identification of individuals at risk of sleep-disordered breathing. Because of its high discrimination power, the NoSAS score can help clinicians to decide which patients to further investigate with a nocturnal recording. FUNDING Faculty of Biology and Medicine of the University of Lausanne, Lausanne University Hospital, Swiss National Science Foundation, Leenaards Foundation, GlaxoSmithKline, and Vaud Pulmonary League.

Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats

Cannabidiol (CBD) is one of the main components of Cannabis sativa and has a wide spectrum of action, including effects in the sleep-wake cycle. Objective: The objective of this paper is to assess the effects on sleep of acute systemic administration of CBD. Method: Adult male Wistar rats were randomly distributed into four groups that received intraperitoneal injections of CBD 2.5 mg/kg, CBD 10 mg/kg, CBD 40 mg/kg or vehicle (n=seven animals/group). Sleep recordings were made during light and dark periods for four days: two days of baseline recording, one day of drug administration (test), and one day after drug (post-test). Results: During the light period of the test day, the total percentage of sleep significantly increased in the groups treated with 10 and 40 mg/kg of CBD compared to placebo. REM sleep latency increased in the group injected with CBD 40 mg/kg and was significantly decreased with the dose of 10 mg/kg on the post-test day. There was an increase in the time of SWS in the group treated with CBD 40 mg/kg, although this result did not reach statistical significance. Conclusion: The systemic acute administration of CBD appears to increase total sleep time, in addition to increasing sleep latency in the light period of the day of administration.

Association Between Uric Acid Levels and Obstructive Sleep Apnea Syndrome in a Large Epidemiological Sample

Introduction Recurrent hypoxia, which is associated with obstructive sleep apnea syndrome (OSAS), leads to an increase in the degradation of adenosine triphosphatase into xanthine, which in turn increases uric acid concentrations. Objective The current study aimed to determine whether an association exists between OSAS and uric acid levels in the peripheral blood from a representative population of Sao Paulo (Brazil). Methods A population-based survey adopting a probabilistic 3-stage cluster sample of Sao Paulo was used to represent the population according to gender, age, and socioeconomic class. A total of 1,042 volunteers underwent polysomnography recordings for OSAS diagnosis, blood pressure assessment, and biochemical blood analysis, and answered questionnaires. Results Uric acid levels were correlated with most important risk factors for OSAS, such as AHI, desaturation time and index, minimum oxyhemoglobin saturation (SpO2), blood pressure, cholesterol, BMI, triglycerides and arousal, and with OSAS itself. Also, uric acid was increased in OSAS volunteers even after controlling for all confounders. Hyperuricemic volunteers presented lower mean and minimum SpO2 and increased desaturation index. Importantly, minimum SpO2 was a significant predictor of uric acid levels, which in turn was considered an independent predictor for OSAS in the binary logistic model. However, a ROC curve analysis for establishing cut-off points for uric acid levels as a biomarker of OSAS revealed moderate sensitivity and specificity. Conclusion A strong association was found between uric acid levels and OSAS in a representative sample of the population of Sao Paulo. Although they do not qualify for a biomarker alone, uric acid levels may be involved in OSAS severity and should be considered in sleep apnea management in the future.

Waist circumference and postmenopause stages as the main associated factors for sleep apnea in women: a cross-sectional population-based study.

ObjectiveThe current study aimed to investigate stages of reproductive aging as an associated factor for obstructive sleep apnea syndrome (OSAS) among women in a representative sample of Sao Paulo, Brazil. MethodsFour hundred seven women underwent clinical evaluation, polysomnography, and biochemical analysis. Stages of reproductive aging were defined as premenopause, early postmenopause, and late postmenopause. ResultsOSAS was more frequent in the postmenopausal groups, with 68.4% of women affected by severe OSAS belonging to the late postmenopause group. After adjustment for potential confounding factors, associated factors for OSAS, regardless of its severity, were waist circumference, modified Mallampati score IV, and both postmenopause stages. For moderate to severe OSAS and severe OSAS, we found waist circumference and both postmenopause stages to be the main factors. We carried out a receiver operating characteristic curve analysis, which demonstrated that the cutoff value for waist circumference was 87.5 cm, with a maximum of 75.7% accuracy for the classification of women as OSAS or non-OSAS. ConclusionsOSAS is prevalent in postmenopausal women, especially in late postmenopause. This study highlights the association between waist circumference, early postmenopause and late postmenopause, and severity of OSAS. Our findings suggest that postmenopause stages may potentially exacerbate the presence of sleep disturbance and that reducing waist circumference may be an important strategy for managing OSAS in women.

The effect of menopause on objective sleep parameters: Data from an epidemiologic study in São Paulo, Brazil

OBJECTIVE Our objective was to investigate the influence of menopausal status on sleep patterns in a representative sample of women from São Paulo, Brazil. STUDY DESIGN A population-based survey with a probabilistic three-stage cluster sample of the city of São Paulo was used to represent the local population according to gender, age (20-80 years) and socioeconomic status. MAIN OUTCOME MEASURES The female participants answered a sleep questionnaire, underwent polysomnographic recording and allowed their hormone levels to be measured. They also completed a gynecological questionnaire for classification of the reproductive aging stages: premenopausal or reproductive, perimenopausal or menopausal transition, and postmenopausal, defined as being after 12 months of amenorrhea. Women were allocated into early (the first 5 years after menopause) and late (after the first 5 years) stages. RESULTS A total of 535 women were included in this study: 339 were premenopausal, 53 were early postmenopausal, 118 were late postmenopausal and 25 were using hormone therapy or isoflavone compounds. Our main findings were that women in postmenopause spent more time in N3 sleep, had a higher apnea-hypopnea index (AHI) and lower SaO2 compared with premenopausal women after an analysis adjusted for confounding factors. We found no significant differences between early and late postmenopausal women in the adjusted analysis. CONCLUSION Our results indicate menopause itself exerts a modest, but important influence on objective sleep patterns, independent of age, in particular on AHI and SaO2.

Modafinil ameliorates cognitive deficits induced by maternal separation and sleep deprivation

Animals exposed to an early adverse event may be more susceptible to a second source of stress later in life, and these stressors may have additive deleterious effects. Sleep deprivation is known to be a stressor, affecting multiple body functions such as the cognition. Modafinil enhances working memory and attention in healthy non-sleep deprived subjects and in animal models of sleep deprivation. The first aim of the present study was to investigate the effects of maternal separation (MS) combined with paradoxical sleep deprivation (PSD) in adulthood on recognition memory in rats. Second, we aimed to evaluate whether the administration of modafinil would be able to ameliorate memory deficits induced by MS and PSD. Wistar rat pups were initially distributed into MS and handling (H) groups, with their litters standardized in 4 females and 4 males. In adulthood, the male rats were submitted to PSD or control condition, being redistributed afterwards in modafinil- or vehicle-treatment immediately after the training session of object recognition task. PSD did not potentiate the cognitive deficit due to MS. However, modafinil was able to recover memory impairments associated to PSD and also to MS in the neonatal period. This study demonstrates for the first time that modafinil ameliorates cognitive deficits associated to MS and to PSD in adulthood, independent from MS in the neonatal period.

Sleep loss and acute drug abuse can induce DNA damage in multiple organs of mice

The purpose of the present study was to characterize the genetic damage induced by paradoxical sleep deprivation (PSD) in combination with cocaine or ecstasy (3,4-methylenedioxymethamphetamine; MDMA) in multiple organs of male mice using the single cell gel (comet) assay. C57BL/6J mice were submitted to PSD by the platform technique for 72 hours, followed by drug administration and evaluation of DNA damage in peripheral blood, liver and brain tissues. Cocaine was able to induce genetic damage in the blood, brain and liver cells of sleep-deprived mice at the majority of the doses evaluated. Ecstasy also induced increased DNA migration in peripheral blood cells for all concentrations tested. Analysis of damaged cells by the tail moment data suggests that ecstasy is a genotoxic chemical at the highest concentrations tested, inducing damage in liver or brain cells after sleep deprivation in mice. Taken together, our results suggest that cocaine and ecstasy/MDMA act as potent genotoxins in multiple organs of mice when associated with sleep loss.