231 EFFECTS OF PARADOXICAL SLEEP DEPRIVATION ON IMMUNE CELL DISTRIBUTION IN RESPONSE TO LIPOPOLYSACCHARIDE IN MICE

231 EFFECTS OF PARADOXICAL SLEEP DEPRIVATION ON IMMUNE CELL DISTRIBUTION IN RESPONSE TO LIPOPOLYSACCHARIDE IN MICE

S62 Abstracts of 3rd International Congress of the Association of Sleep Medicine (WASM) / Sleep Medicine 10, Suppl. 2 (2009) S1–S83 Aims: To study t...

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Abstracts of 3rd International Congress of the Association of Sleep Medicine (WASM) / Sleep Medicine 10, Suppl. 2 (2009) S1–S83

Aims: To study the effect of MCH microinjections and MCH immunoneutralization into the DR on sleep parameters as well as on the forced swim test (FST), a behavioral approach commonly used to test antidepressive drugs. Methods: Sleep studies were performed in adult rats (n=12) that were chronically implanted for polysomnographic recordings. A guide cannula directed toward the DR was also implanted for microinjections of MCH and anti-MCH antibodies. Six-hour recordings were performed during the light phase of the light/dark cycle, and analysis of sleep parameters was carried out afterwards. Standard FST and the open field test (OFT) were performed in another group of rats (n=12) that were implanted with only a guide cannula directed toward the DR. Five days after, the behavioral effects of MCH and MCH antibodies microinjected into the DR were analyzed in both paradigms. Results: MCH injection (100 ng) resulted in a moderate increase of slow wave sleep and a marked increase of REM sleep (35.5±2.5 vs. 20.8±3.4 minutes, p<0.01) compared with vehicle microinjections. This effect was due to an increase in the number of REM sleep episodes. Moreover, the immunoneutralization of MCH (anti-MCH antibodies 1:100) decreased the REM sleep time to less than 50% of the control values, as determined by a decrease in the number of REM sleep episodes. In the behavioral tests, while MCH (50 ng) microinjected into the DR increased the immobility time in the FST (p<0.01; depressive-like response), anti-MCH antibodies (1:500) decreased the time to 56% of the control values (p<0.05; antidepressant-like effects). These effects were specific to the FST because these patterns of motor activities were not reproduced in the OFT. Conclusions: These data strongly suggest that the MCHergic system, through the modulation of DR neurons, promotes REM sleep. In addition, the neuropeptide is likely involved in mood regulation. Support: Supported by PDT-Salud 76/36 grant

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AUDITORY INPUT RE-ORGANIZES SLEEP: AN INTRA-COCHLEAR IMPLANTED HUMAN MODEL

R.A. Velluti 1 , M. Pedemonte 2 , H. Suárez 3 , C. Bentancor 2 . 1 Neuro-Otología Experimental, ORL, Hospital de Clínicas, Universidad de la República, Montevideo; 2 Centro de Medicina del Sueño, Facultad de Medicina, CLAEH, Punta del Este; 3 Laboratorio de Otoneurología, British Hospital, Montevideo, Uruguay Introduction: Our aim was to conduct sleep analysis of human patients with profound post-lingual deafness who had been successfully implanted with intra-cochlear devices, in order to find further support for the hypothesis that auditory input has effects on sleep organization. Methods: Nine post-lingual deaf patients (age range 19-65 y.o.) were included in this study. Four of them had been implanted with multichannel cochlear implant devices two years prior to this study, with successful hearing results. Each implanted patient was recorded as their own control, thus allowing assessment of the experimental condition (implant ON) and its control (implant OFF) in the same patient. A standard polysomnographic (PSG) study was carried out considering stages I, II, III-IV and paradoxical sleep (PS). In addition, two temporal leads (T3 and T4) were placed on the scalp for EEG frequency domain analysis using the Fast-Fourier Transform (FFT) during the different sleep stages, with the implant either ON or OFF. The student t-test was used for statistical analysis. Results and Conclusions: (1) The four patients analyzed with the implant ON – allowing night noise listening – showed shifts in sleep percentages, exhibiting a significant decrease in stage II, an increase in stages III-IV and also a significant PS percentage decrease. (2) The FFT analysis of T3 and T4 leads showed power shifts in all patients –implant ON vs. implant OFF – although in a different manner showing great disparities. A possible explanation for the power band diverse behavior may be technical regarding the electrode positioning both over the scalp and in the cochlea. (3) Five deaf subjects, without any implant, did not show differences in sleep stages percentages in comparison with normal hearing persons. A profound post-lingual deaf person suffers changes in the organization of their central auditory networks that could affect other networks determining changes in sleep organization. After a successful intra-cochlear implant, the hearing recovery would produce the reorganization of the networks, introducing changes in sleep architecture. Acknowledgement: We are grateful to PEDECIBA for partial support.

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NEURONAL NETWORK CHANGES ON PASSING TO SLEEP AFTER WAKEFULNESS

R.A. Velluti 1 , M. Pedemonte 2 . 1 Neuro-Otología Experimental, ORL, Hospital de Clínicas, Universidad de la República, Montevideo; 2 Centro de Medicina del Sueño, Facultad de Medicina, Instituto Universitario CLAEH. Punta del Este, Uruguay Introduction: The sleeping brain can process information in a different fashion, which is a function that includes networks shifts. Although still receptive to incoming sensory data, new sets of neuronal networks are reorganized when passing from wakefulness to a different functional state, such as sleep. Sensory data, including auditory, visual, and somesthetic inputs, are present during all stages of sleep, as they continuously come from the environment or from the body. Results and Discussion: Different technological approaches, particularly those related to auditory data, such as auditory evoked potentials, magnetoencephalography evoked activity, and unitary recordings in animal experiments, all lead to the same observation, which is that information may reach every pathway nucleus as well as the corresponding cortical locus. Guinea pig unitary recordings showed neuronal recognition of a stimulus, which was a recording of its own voice, when presented normally or inverted in time during wakefulness (W) as well as during slow wave sleep (SWS). Thus, the neuron may have changed its neuronal network/assembly association as the state changed from W to SWS (Velluti & Pedemonte, 2002; Velluti, 2008). An example in the human involves the dipole localization shift in the primary (A1) cortical human region, which has been visualized via imaging techniques (Kakigi et al. 2003). The concept of neuronal networks/assemblies is defined by the temporal correlation of neuronal firings for the purpose of some functional aim. Neuronal groups that are connected to several other neurons or other neuronal groups can carry out functional cooperation and integration among widely distributed cells, including those with different functional properties, to create or respond to a new state or condition. Furthermore, the neuronal network/cell assembly may enhance the selective synaptic activities, especially with respect to the dynamic and transient efficacy that appears to be correlated with the behavioral and dynamic modulation of the sleep process. Under such a system, a neuron that is actively firing in a particular functionally associated group can then process some new or additional information that may result in its association, at a later time, with other competing and activated neuronal groups that serve different functional purposes. This type of switch could occur, for example, during the transition from a state of wakefulness to one of sleep. Acknowledgement: We are grateful to PEDECIBA for partial support.

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EFFECTS OF PARADOXICAL SLEEP DEPRIVATION ON IMMUNE CELL DISTRIBUTION IN RESPONSE TO LIPOPOLYSACCHARIDE IN MICE

A. Zager, M.L. Andersen, F.S. Ruiz, S. Tufik. UNIFESP Introduction: Sleep is a fundamental biologic phenomenon that is essential for the preservation of human health. Except for the well documented physiologic consequences of sleep deprivation (SD), the interaction sleep has with the immune system as well as the association of SD with specific immunological stimuli remains inconclusive. Objectives: To investigate the effects of paradoxical sleep deprivation (PSD) on the immune cell distribution induced by lipopolysaccharide (LPS) of E. coli, a powerful immune activator. Methods: C57BL/6J mice (n=15/group) were submitted to PSD for 72 hours while controls remained in their home-cages and maintained a normal sleep regimen. At the end of the PSD period, all animals were administered a saline or LPS (doses of 1 or 5 μg/mouse) injection and were returned to their respective cages for an interval of 2 hours before the immunologic analysis were performed. Spleen, lymph nodes and peritoneal wash were collected for staining and analysis of T and B cells, NK cells, macrophages and dendritic cells by flow cytometry. Blood was collected for differential leukocyte count. The results were analyzed by two-way ANOVA, followed by Newman-Keuls post-hoc test. Results: Results demonstrated that PSD was capable of causing a reduction of T (CD4; 5,4±3,1 vs. 45,2±0,8 and CD8; 5,4±3,2 vs. 57,6±10,6) and B lymphocytes (13,6±6,8 vs. 73,6±11,4) and dendritic cells (23,3±2,7 vs. 58,7±20,2) within the spleens of the animals treated with saline. In the bloodstream, the total lymphocytes were also reduced (4,3±0,37 vs. 6,6±0,5). However,

Abstracts of 3rd International Congress of the Association of Sleep Medicine (WASM) / Sleep Medicine 10, Suppl. 2 (2009) S1–S83

other lymphocyte migration sites (peritoneum and lymph nodes) were not affected. No significant difference was encountered between CTRL and PSD in animals administered any dose of LPS. Conclusions: We can thus conclude that sleep acted as an immune response modulator in the saline group, as represented by evidence in the bloodstream and spleen. However, other lymphocyte migration sites were not affected, indicating that such effects of PSD are not due to alterations in cellular migration. Financial Support: This work was supported by grants from AFIP, CNPq and FAPESP (CEPID #98/14303-3 to ST, 06/58275-1 to AZ and 07/55445-6 to FSR).

Sleep Related Breathing Disorders

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USE OF NASAL CANNULA COMPARED TO THERMISTOR IN CHILDREN WITH FACIAL SYNDROMES AND RELEVANCE OF END-TIDAL PCO2 EXPIRED

A.C. Massolo 1 , M.P. Villa 1 , S. Miano 1 , M. Montesano 1 , P. Franco 2 . Department of Paediatrics, Sleep Disorders Center, S.Andrea Hospital, “La Sapienza” University, Rome, Italy; 3 Department of Paediatrics, Sleep Disorders Unit & INSERM U628 Mother and Child Hospital, Lyon, France 1

Introduction: The aim of our study is to compare sleep respiratory events (RE) detected by nasal cannula (NC) to those detected by thermistor (T) in a cohort of children with craniofacial abnormalities with suspected obstructive sleep apnea syndrome (OSAS). We also aimed to measure end-tidal PCO2 (EtPCO2) in the same cohort of children in order to evaluate the relevance of this information to sleep study and diagnosis. Materials and Methods: The study included 23 children with craniofacial abnormalities resulting from Pierre-Robin, Charge, Down’s and Prader Willi syndromes and mucopolysaccharidosis metabolic disorder (mean age 6.26±4.07 years, M=16). All underwent overnight polysomnography (PSG). Airflow was measured using NC and T during the night; RE were scored separately according to signal at NC and at T. Tolerability of the two devices was also measured (number of epochs with signal/total of epochs during sleep). EtPCO2 was measured using a capnometer. Percentage of time during sleep above 45 and 50 mmHg and the  mean EtPCO2 (EtPCO2 at the end of a RE minus last EtPCO2 before the RE) was then calculated. Results: The apnea-hypopnea index (AHI) obtained by recording with NC (6.54±9.9 ev/hr) was higher than that obtained by T (4.61±6.8 ev/hr). Patients were also divided by severity of OSAS; when scored with T, 6 patients had an apnea index (IA) >1, whereas 12 with IA >1 were detected by NC. Moreover, 3 patients showed an AHI >5 when scored with T, compared to 5 subjects when scored with NC. T was well tolerated during sleep (NC = 866.4±254 mean epochs; T = 892.4±258 mean epochs, p=0.00). 3 patients were excluded from the statistical analysis because of complete failure of T channel (in 2) and NC channel (in 1). Mean percentage of sleep time with EtPCO2 >45 and >50 mmHg was, respectively, 8.07±9.7% and 1.14±2.54%. In the group of patients with EtPCO2 >50 mmHg, we found 3 subjects with an AHI <5 (respectively 8.32%, 8.14% and 0.19% of sleep time). There is a significant difference between the mean of EtPCO2 at the end of a RE compared to the mean of EtPCO2 before the RE for obstructive hypopnea (respectively 45.2±4.9 vs. 43.2±4.9; p=0.00; EtPCO2 = 1.9±1 mmHg) and for obstructive apnea (respectively 43.4±4.9 vs. 45.8±4.6 mmHg; p=0.00; EtPCO2 = 2.3±1.6 mmHg). Conclusions: Our study demonstrated that NC detects a higher number of RE than T, while T seems to be better tolerated. Moreover, our data demonstrate the relevance of EtPCO2, especially for patients with craniofacial syndromes.

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DOES GLUCOSE INTOLERANCE AFFECT ENDOTHELIAL DYSFUNCTION IN NON OBESE MEN WITH OSA? PRELIMINARY DATA

D.K. Andaku 1 , V. D’Almeida 2 , S. Tufik 1 , R.M.S. Póvoa 3 , N.F. Novo 4 , S.M. Togeiro 1 . 1 Psychobiology, UNIFESP; 2 Psychobiology, UNIFESP, Biosciences, UNIFESP; 3 Cardiology, UNIFESP; 4 UNISA Introduction: Glucose intolerance (GI) and obstructive sleep apnea (OSA)

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have been associated with cardiovascular morbidities and central obesity. Additionally, GI has proven to be independently associated with OSA. Oxidative stress and inflammation are mechanisms by which OSA impairs the cardiovascular (CV) system, mainly by vascular damage. GI also promotes vascular dysfunction by the same pathways. No studies, however, have controlled GI as a confounder for CV complications that are present in OSA individuals. We hypothesized that GI is an additional factor for the endothelial dysfunction found in OSA. Objective: The aim of this study was to evaluate whether GI affects endothelial dysfunction in male OSA patients after controlling for age, obesity, dyslipidemia and diabetes. Methods: Nineteen patients were distributed into three groups: 1) OSA Group (n=9), with apnea-hypopnea index (AHI) > 15 events/hour, 2) OSA + GI Group (n=5), with AHI > 15 events/hour and a fasting blood glucose level of 100-125 mg/dL and/or a 2-h oral glucose tolerance test of 140-199 mg/dL and/or a HOMA-IR > 2.7) and 3) control group (n=5). Subjects who had a BMI > 30kg/m2 , were >60 years-old, were smokers, or had chronic respiratory failure, heart diseases, diabetes mellitus or severe dyslipidemia were excluded from the study. The endothelial function was evaluated by arterial stiffness through pulse wave velocity (PWV) measurements during both rest and reactive hyperemia. Results: AHI was significantly higher in the OSA and OSA+GI groups when compared to the control group (p<0.005, 25.7±14.1; 31.2±11.3; 2.5±2 events/hour, respectively). Nadir oxygen saturation was not different between the OSA, OSA+GI and Control groups (83.9±7.3; 78.6±10.6; 90.2±3.7%, respectively). The lipid levels were also similar between the OSA, OSA + GI and control groups (total cholesterol: 176±28.5, 176.8±41.3, 164.8±35.8 mg/dL, respectively; triglycerides: 115.7±44.5, 143.2±57.6, 75.8±27.4 mg/dL, respectively). In terms of rest PWV, no significant difference was observed (mean: 11.53±1.37m/s, 12.31±0.74 m/s, 11.77±1.41m/s, respectively). During reactive hyperemia, the OSA+GI group presented a mean of 10.88±1.19 m/s, which was a reduction of 10.8% (p<0.05), the OSA group had a mean of 10.4±1.29 m/s, which was a reduction of 9.45% (p<0.05, and the control group had a mean of 11.02±1.83 m/s, which was a reduction of 6.58% (p=0.08). There was no difference when these parameters where compared among the three groups. Conclusion: Our preliminary data shows that GI does not seem to interfere in the deterioration of endothelial function in non- obese males with OSA.

234

REM SLEEP BEHAVIOR DISORDER IN PATIENTS WITH MOEBIUS SYNDROME

P.S. Bastos. Associação da Pioneiras Sociais Introduction: Moebius syndrome consists of partial or complete congenital paralysis of the VII cranial nerve, usually associated with abducent nerve paralysis and, less frequently, V and XII nerve palsies. Sporadic and familial cases have been reported. The main explanations for the clinical signs are hypoplasia, aplasia or destructive degeneration of the brainstem nuclei. Musculoskeletal abnormalities occur in one third of patients. Sleep disturbance has been reported in this syndrome in association to central and obstructive sleep apnea, but there are few reports of REM sleep behavior disorder (RBD) in this disease. RBD is characterized by the absence of atonia during the REM stage, which is associated with complex movements and/or vigorous and violent behaviors. Objectives: To report two cases of Moebius syndrome associated with an RBD. Methods: Case 1: A 7-year-old girl born with bilateral abducent nerve palsy, complete facial diplegia, club feet malformations, poor sucking and syndactyly, presented with brief crying, episodes of screaming, leg movement, and unintelligible speaking and agitation during nighttime sleep. Case 2: A 17-year-old girl who had congenital bilateral abducent and oculomotor nerve palsies, complete facial diplegia, club feet malformations, syndactyly, palate malformation and retrognathism, who presented with episodes of agitation and vivid nightmares during sleep. Both had no history of snoring, diurnal somnolence, sleepwalking or apnea. They were submitted for a video polysomnography using a standard protocol. Results: Both patients presented a mild sleep obstructive breathing disorder. Their polysomnographic registers showed an excessive augmentation of chin motor activity during REM stages associated with complex motor movements, and in the first case, unintelligible spoken words. Those events were compatibles with RBD.