La forme non musculaire de la kinase de la chaine légère de la myosine (MLCKnm) est une kinase principalement exprimée par les cellules endothéliales dont le rôle principal est de phosphoryler la chaine légère de myosine. Cette phosphorylation modifie la conformation des têtes de myosine, augmente l’interaction actine/myosine, et induit une rétraction des cellules endothéliales. Ce processus augmente la perméabilité de la barrière endothéliale. L’activation de MLCKnm permet l’infiltration de cellules inflammatoires en réponse à certains stimuli dont le lipopolysaccharide (LPS) bactérien. Dans ce modèle expérimental de sepsis, la déficience de MLCKnm dans un modèle murin protège les souris injectées avec du LPS, associée à une prévention des stress oxydant et nitrosant ainsi que de l’activation de voies de signalisation inflammatoire. Cependant les mécanismes moléculaires mis en jeu ne sont pas totalement connus. Dans le contexte inflammatoire, le syndrome d’apnées/hypopnées obstructives du sommeil, caractérisé par une obstruction des voies aériennes lors du sommeil menant à une hypoxie intermittente (HI), partage certaines caractéristiques dans l’activation inflammatoire observée lors du sepsis. L’HI modifie le métabolisme des cellules endothéliales en diminuant la biodisponibilité du monoxyde d’azote, augmentant le stress oxydant ainsi que la production de certains facteurs inflammatoires. A long terme, une réponse inflammatoire systémique est observée augmentant les risques d’athérosclérose. L’objectif de ce travail est d’étudier l’implication de MLCKnm dans l’inflammation vasculaire dans deux modèles physiopathologiques, induits par le LPS et l’HI. / Non muscular myosin light chain kinase (nmMLCK) is aprotein mainly expressed by endothelial cells whose roleis to phosphorylate myosin light chain. This phosphorylation modifies the conformation of myosin heads, increasing actin/myosin interaction, and inducing endothelial cells retraction. This process increases endothelial barrier permeability. The activation of nmMLCK increases inflammatory cell infiltration in response to several stimuli such as the bacterial lipopolysaccharide (LPS). In this experimental model of sepsis, nmMLCK deficiency in a murine model protects mice injected with LPS, associated with oxidative and nitrative stresses prevention as well as inflammatory pathway inhibition. However, molecular mechanisms are not fully known. In this inflammatory context, obstructive sleep apnea hypopnea syndrome, characterized by obstruction of upper airway during sleep leading to intermittent hypoxia (IH), share several characteristics in inflammatory activation observed during sepsis. IH modifies the metabolism of endothelial cells decreasing nitric oxide bioavailability, increasing oxidative stress aswell as inflammatory mediators. Long-term, systemic inflammatory response is observed increasing atherosclerosis risk. The objective of this work is to study the implication of nmMLCK in vascular inflammation in two pathophysiological models induced by LPS and IH.

No description available.

Obstructive sleep apnea (OSA) and asthma are potentially linked at several levels. The pathophysiology of these two conditions seems to overlap significantly, as airway obstruction, inflammation, obesity, and several other factors are implicated in the development of both diseases. Gastroesophageal reflux disease (GERD), cardiovascular complications, obesity itself, and the underlying inflammatory processes are all complex contributory factors that provide hypothetical links. Furthermore, a collateral rise in prevalence of both OSA and asthma has been noticed during the past few years, occurring in association with the emerging epidemic of obesity, a common risk factor for both conditions. OSA and asthma share many other risk factors as well. We propose a hypothetical OSA-asthma relationship that has implications on the diagnosis and management of patients presenting with either condition singly. Clinicians should be aware that OSA might complicate asthma management. Based on this hypothesis, we suggest that the treatment of the individual patient who experiences both asthma and OSA needs to be multidisciplinary and comprehensive. This hypothetical association of asthma and OSA, though described anecdotally, has not been systematically studied. In particular, the influence of continuous positive airway pressure therapy (for sleep apnea) on asthma outcomes (such as quality of life, steroid utilization, emergency room visits) and fatality needs to be studied further.

No description available.

Obstructive sleep apnea (OSA) is a disorder that affects a significant portion of middle-aged adult population. Patients exhibit recurring episodes of upper airway obstruction during sleep that decrease blood oxygen concentration (hypoxia) and are terminated by brief arousals. Epidemiologically, OSA has been extensively linked to cardiovascular dysfunction and is an independent risk factor for the development of hypertension. The proposed mechanism of cardiovascular dysfunction in patients is chronic sympathoexcitation and altered vascular tone, with a predominance of the vasoconstrictor endothelin-1 (ET-1) and removal of the vasodilator nitric oxide (NO). Means to reduce the effects of ET-1 and increase synthesis of NO may have beneficial effects on the cardiovascular co-morbidity commonly associated with OSA. OBJECTIVES: The major aim of this study was to assess the relative importance of circulating biomarkers of ET-1 and NO in hemodynamic function in OSA patients. Potential production of ET-1 by circulating mononuclear cells was also measured to assess their contribution to plasma ET-1 levels. Biomarker levels before and after 12 wk of continuous partial airway pressure (CPAP) therapy were used to assess standard treatment. Mild/moderate exercise training was initiated with CPAP therapy in a subgroup of OSA patients to evaluate the potential benefits of physical activity on hemodynamic function and NO and ET-1 levels. METHODS: Overall, 16 newly diagnosed OSA patients (5 female, 11 male; age 45.4 ± 2.7 yr; RDI 24.6 ± 4.0 events/hr) were selected for study. Seven apparently healthy control volunteers (5 female, 2 male; age 39.43 ± 2.6 yr) screened for OSA served as control subjects. Blood pressure was recorded over one complete day and prior to, during, and following maximal exercise testing on a cycle ergometer. Blood samples were taken prior to exercise testing and assessed for nitrate and nitrite by HPLC and for big endothelin-1 and ET-1 by ELISA. Relative gene expression of preproendothelin-1 was measured by real-time RT-PCR. Following initial testing, patients were stratified into either a standard therapy group (nCPAP) or a standard therapy group with a mild/moderate intensity aerobic training regimen (nCPAP+Ex). Baseline testing was repeated following 12 wk of treatment. Statistical significance was set at p < 0.05 a priori. RESULTS: 24 hr ambulatory systolic and diastolic blood pressure were elevated in OSA patients vs. control subjects (systolic: 128.9 ± 3.8 mmHg vs. 108.8 ± 1.3 mmHg, respectively; diastolic: 97.5 ± 2.0 mmHg vs. 82.1 ± 1.9 mmHg, respectively). OSA patients experienced significant elevations in systolic (OSA 209.7 ± 5.7 mmHg; Control 174.5 ± 6.2 mmHg) and mean arterial pressures (OSA 125.8 ± 3.2 mmHg; Control 109.05 ± 4.5 mmHg) at peak exercise. No differences in nitrate, nitrite, or big endothelin-1 were noted. Plasma endothelin-1 concentrations were below assay detection limit. Big endothelin-1 levels were significantly correlated with BMI in both OSA patients (r=0.955; p=0.001) and control subjects (r=0.799; p=0.045). Relative gene expression of preproendothelin-1 was not elevated in OSA patients (0.40 ± 0.20 fold increase over control subjects). Group nCPAP usage was above minimum therapeutic threshold, but was non-uniform in both groups, with an overall range of 182 to 495 min mean usage per night. A mild/moderate exercise training program failed to elicit a training response through standard hemodynamic or cardiopulmonary indices. Plasma nitrite levels rose from 55.3 ± 4.7 μg/ml to 71.0 ± 7.6 μg/ml in the nCPAP group. CONCLUSIONS: Moderate OSA is associated with elevated blood pressure at rest and during exercise stress that bears no relationship to circulating biomarkers of NO and ET-1 or immune preproendothelin production in patients without diagnosed hypertension. nCPAP therapy failed to elicit significant improvements in hemodynamic function, with or without moderate exercise. Plasma nitrite levels rose following nCPAP therapy, indicating a possible increase in basal nitric oxide formation. Higher intensity exercise regimens may be needed to elicit the positive benefits of exercise training in OSA patients without significant cardiovascular dysfunction. / Ph. D.

Snoring is a sleep disruption that can lead to obstructive sleep apnea (OSA), which interrupts breathing by obstructing the airway. Injecting a protein crosslinker, such as genipin, into the soft palate could decrease the severity of snoring and OSA by stiffening the soft palate. Equine soft palates modeled human palates due to a high incidence of awake snoring and apnea. The pilot in vivo study treated six horses with two 100 mM injections of the buffered genipin reagent. The efficacy phase horses underwent respiratory audio recordings to document snoring changes using Matlab and ImageJ in the time and frequency domains. Histological analysis was completed on the safety phase palates post treatment. All horses were successfully treated with the genipin injections. At least one horse showed high frequency amplitude reductions, and all horses had low frequency amplitude reductions, correlating to a reduction in palatal displacement and snoring loudness. One efficacy horse appears to have been completely cured. The histological analysis presented tissue damage, mucosal tissue damage, and mild inflammation due to palate expansion and errant injections. Different injection volumes and techniques should be investigated next. Applying this treatment to human studies for snoring and OSA applications is the ultimate goal.

Le Syndrome d’Apnée Obstructive du Sommeil affecte 4 à 6 % de la population en France soit près de 3 millions de personnes. Toutefois, les techniques de diagnostic usuelles ne permettent pas de déterminer de façon précise les sites d’occlusion ni de décrire les interactions fluide-paroi qui jouent un rôle important dans les processus de fermeture des voies aériennes supérieures. Au cours de ce travail, un ensemble d’outil a été mis en œuvre pour explorer les mécanismes sous-jacents conduisant à une apnée obstructive. La détermination géométrique et la caractérisation mécanique des voies aériennes supérieures, d’une part, la mesure des écoulements dans ces dernières, d’autre part, ont été réalisées par imagerie par résonance magnétique de l’hydrogène, pour les tissus, de l’hélium-3 et du fluor-19 pour les gaz. Les données obtenues ont été exploitées tout d’abord dans un modèle numérique statique pour estimer les lois d’état locales et caractériser la compliance des voies aériennes supérieures, puis, dans un modèle monodimensionnel, prenant en compte l’interaction fluide-structure et la limitation de débit au cours de l’inspiration, pour localiser les sites potentiellement responsables d’un éventuel collapsus. Par ailleurs, les écoulements de gaz d’hélium-3 et d’hexafluorure de soufre ont été simulés afin de déterminer le potentiel de ces deux modalités d’imagerie de gaz pour l’étude des obstructions des voies aériennes. La faisabilité d’une imagerie statique et dynamique par résonance magnétique du fluor a été démontrée. Avec une densité du gaz traceur bien plus importante, cette dernière technique présente une plus grande sensibilité à l’obstruction. Cette thèse ouvre ainsi une nouvelle voie de diagnostic et de guide thérapeutique personnalisé pour ce syndrome. / Obstructive Sleep Apnea (OSA) is a common disorder occurring in almost 3 million French people. However, current diagnosis methods are not sufficient to precisely define obstructing sites and doesn't take into account the fluid structure coupling which plays an important role during upper airway closing. During this thesis, we developed a series of tools exploring upper airway closing process. On the one hand, a screening tool of the structure and the mechanical properties of the upper airway, and on the other hand, a screening tool exploring with dynamic images of inert gases flow into the upper airway, were obtained using conventional hydrogen MRI coupled to magnetic resonance elastography (MRE) and helium-3 or fluor-19 gases MRI, respectively. Geometric and biomechanical data obtained using MRI/MRE are injected into a numerical model given the compliance and the state law of upper airway. Contributions of anatomical restriction on airway collapse are also investigated using a multi-compartmental two-dimensional fluid structure interaction model during a breath inspiration to predicted airway mechanical changes and collapse pressures. Furthermore, helium 3 and sulfur hexafluoride flow was modeled at steady state using commercial finite volume software to evaluate potential feasibility to image upper airway collapsibility during OSA. First dynamic MR imaging using sulfur hexafluoride (SF6) was obtained showing the feasibility of this technique. Using SF6, 6 times denser than air, shows a higher sensibility to upper airway obstruction. This thesis opens a new imaging modality to probe and to diagnose upper airway obstruction.

No description available.

O Projeto Jovem Doutor propicia a transmissão de conhecimentos para jovens do ensino fundamental sobre diversos temas da saúde. A Síndrome da Apneia e Hipopneia Obstrutiva do Sono (SAHOS) deve ser destacada, uma vez que esse quadro clínico implica em consequências impactantes ao indivíduo, e que se estendem para a população em uma escala ampla, tendo como exemplos acidentes de trânsito e de trabalho. Sendo assim, o objetivo foi de implementar um modelo de educação em saúde sobre o tema da SAHOS, fundamentado na dinâmica do Projeto Jovem Doutor. Para isso, realizou-se a parceria com uma escola estadual interessada em participar da dinâmica. A pesquisa foi estruturada em três etapas: organização da estrutura básica e elaboração do material educacional (1ª etapa); aplicação do programa (2ª etapa) e avaliação do modelo de educação em saúde (3ª etapa). Para a elaboração do material educacional (aulas presenciais, cybertutor, banner e folder), realizaram-se buscas em bases de dados, selecionando conteúdos, simplificando e adequando o nível de legibilidade do texto, além de inserir ilustrações (1ª etapa). Na 2ª etapa, houve a participação de 5 alunos nas duas aulas presenciais, acesso ao cybertutor, atividade prática e por fim, executaram a ação social para a disseminação do conhecimento. Foram realizadas orientações sobre o tema por meio do banner, folder, telejornal, teatro de fantoches e jogo de mímica. Ao final da Feira Cultural, houve a multiplicação do conhecimento para 985 pessoas, dentre elas, pais, professores e alunos da escola, que receberam o conhecimento diretamente pelas ações sustentadas dos Jovens Doutores. Em relação à 3ª etapa, observou-se no questionário de investigação do conhecimento o aumento em média de acertos sobre o conteúdo teórico; no acesso ao cybertutor, verificou-se que 100% dos alunos realizaram os materiais complementares e na análise da pesquisa motivacional, foi possível verificar que o curso foi considerado um Curso Impressionante!. Portanto, um modelo de educação em saúde sobre SAHOS, fundamentado na dinâmica do Projeto Jovem Doutor foi implementado, verificandose êxito no seu desenvolvimento, no aspecto motivacional dos alunos e na disseminação do conhecimento. / The Young Doctor Project provides the transmission of new knowledge for elementary school kids about various health topics. The Obstructive Sleep Apnea- Hypopnea Syndrome (OSAHS) should be emphasized, once the disorder implies at impactful consequences for the individual and extends to the population in a large scale, as an example car and work accident. With that been said, this research aims the implementation of a health educational model about OSAHS based on the pattern of the Young Doctor Project. In order to this, a partnership with a public state school interested to participate of dynamic. This research was structured around 3 stages: organization of the basic structure and the educational material elaboration (1st stage); the program application (2nd stage); and an evaluation of the health educational model (3rd stage). To develop the educational material (class attendance, cybertutor, banner and folder), were made searches in databases, selecting content, simplifying and adjusting the text legibility, besides insert illustrations (1st stage). On 2nd stage, were involved 5 students in the two classes, accessed the cybertutor, practical activity, an also executed a social action in order to spread the knowledge. Orientations were made by banner, folder, TV newscast, pupet show and mime game. At the end the Cultural Fair, the dissemination of learning were spread to 985 people, including parents, teachers and students whose knowledge were sustained by the Young Doctors actions. At the 3rd stage, on the learning investigation questionary, were noticed an increase of right answers about the theory; at the cybertutor, 100% of the students realized the complementary material and at the motivational research, was possible to verify that the course was classified as Impressive course!. Therefore, a model of health education about OSAHS based on the Young Doctor Project pattern was implemented and it was verified its success at the motivational aspect such as at the spread of knowledge.

INTRODUÇÃO: Pacientes com síndrome metabólica (SMet) apresentam aumento na atividade nervosa simpática muscular (ANSM) e diminuição no ganho do controle barorreflexo arterial (CBR). E, a apnéia obstrutiva do sono (AOS), uma comorbidade frequentemente encontrada em pacientes com SMet, exacerba essas disfunções autonômicas. Sabe-se que a incidência dos disparos e o padrão oscilatório da ANSM dependem do ganho (sensibilidade) e do tempo de retardo (latência) do CBR da ANSM (CBRANSM). Contudo, o padrão oscilatório da ANSM e o tempo de retardo do CBRANSM em pacientes com SMet associada ou não à AOS são desconhecidos. Além disso, estudos prévios demonstram que o treinamento físico associado à dieta hipocalórica (TF+D) diminui a incidência dos disparos da ANSM e aumenta o ganho do CBR em pacientes com SMet. No entanto, os efeitos de TF+D no padrão oscilatório da ANSM e no ganho e tempo de retardo do CBRANSM em pacientes com SMet associado ou não a AOS permanecem desconhecidos. MÉTODOS: Foram estudados quarenta e quatro pacientes com SMet (critérios do ATP III), sem uso de medicamentos, que foram divididos em dois grupos de acordo com a presença da AOS (SMet-AOS, n=23 e SMet+AOS, n=21). Um grupo controle saudável (n=12) foi, também, incluído no estudo. Para avaliar o efeito da intervenção, os pacientes foram divididos consecutivamente em quatro grupos: 1- Sedentário sem AOS (SMet-AOS Sed, n=10); 2- Sedentário com AOS (SMet+AOS Sed, n=10); 3- TF+D sem AOS (SMet-AOS TF+D, n=13) e; 4- TF+D com AOS (SMet+AOS TF+D, n=11). Os grupos TF+D foram submetidos ao treinamento físico aeróbio (40 min, 3 vezes por semana) associado à dieta hipocalórica (-500 kcal/dia) durante quatro meses e os grupos sedentários não realizaram a intervenção (TF+D) e somente receberam orientações clínicas. A AOS foi determinada através do índice de apneia e hipopneia (IAH) >15 eventos/hora (polissonografia). A ANSM (microneurografia), pressão arterial (batimento a batimento, método oscilométrico), padrão oscilatório da ANSM (relação dos componentes de baixa frequência-BF, e alta frequência-AF da ANSM, BFANSM/AFANSM, análise espectral autorregressivo monovariada) e o CBRANSM espontâneo (ganho e tempo de retardo, análise espectral autorregressivo bivariada) foram avaliados durante o repouso na posição deitada por 10 minutos. RESULTADOS: No período pré-intervenção, os pacientes com SMet-AOS e SMet+AOS apresentaram redução no BFANSM/AFANSM (P=0,01 e P<0,001, respectivamente) e no ganho do CBRANSM (P=0,01 e P<0,001, respectivamente), em comparação com o grupo Controle. E, os pacientes com SMet+AOS apresentaram menor BFANSM/AFANSM (P=0,02) e ganho do CBRANSM (P<0,001) em comparação com SMet-AOS. Ainda, o tempo de retardo do CBRANSM estava aumentado no grupo SMet+AOS em comparação com os grupos SMet-AOS e Controle (P=0,01 e P<0,001, respectivamente). Após a intervenção TF+D, ambos os grupos SMet-AOS e SMet+AOS apresentaram redução do peso corporal, circunferência abdominal e pressão arterial sistólica e aumento consumo de oxigênio no pico do exercício. Nos pacientes com SMet-AOS, o TF+D aumentou o BFANSM/AFANSM (P<0,05) e o ganho do CBRANSM (P<0,01). Nos pacientes com SMet+AOS, o TF+D aumentou o nível de saturação mínima de O2 (P=0,02) durante a polissonografia, o BFANSM/AFANSM (P=0,001) e o ganho do CBRANSM (P<0,01) e, diminuiu o IAH (P<0,01) durante a polissonografia e o tempo de retardo do CBRANSM (P=0,01). Nenhuma alteração foi observada em ambos os grupos sedentários. CONCLUSÕES: O TF+D aumenta o padrão oscilatório da ANSM e o ganho do CBRANSM em pacientes com SMet, independentemente da presença da AOS. No entanto, este efeito é mais pronunciado em pacientes com SMet+AOS, já que após a intervenção o tempo de retardo do CBRANSM foi também diminuído nestes pacientes / INTRODUCTION: Patients with metabolic syndrome (MetS) have increased muscle sympathetic nerve activity (MSNA) and decreased arterial baroreflex control (BRC). Obstructive sleep apnea (OSA), a comorbidity often found in patients with MetS, exacerbates these autonomic dysfunctions. It is known that burst incidence and the oscillatory pattern of MSNA depend on the gain (sensitivity) and the time delay (latency) of BRC of MSNA (BRCMSNA). However, the oscillatory pattern of MSNA and the time delay of BRCMSNA in patients with MetS either with or without OSA are unknown. Moreover, previous studies have shown that exercise training associated with hypocaloric diet (ET+D) decreases the burst incidence of MSNA and increases the gain of BRC in patients with MetS. However, the effects of ET+D on the oscillatory pattern of MSNA and on the gain and time delay of BRCMSNA in patients with MetS with or without OSA remain unknown. METHODS: Forty-four never-treated MetS patients (ATP III criteria) were allocated in two groups according to the presence of OSA (MetS-OSA, n=23 and MetS+OSA, n=21). A healthy control group (n=12) was also included in the study. To evaluate the effect of the intervention, patients were consecutively divided into four groups: 1- Sedentary without OSA (MetS-OSA Sed, n=10); 2- Sedentary with OSA (MetS+OSA Sed, n=10); 3- ET+D without OSA (MetS-OSA TF+D, n=13) and 4- ET+D with OSA (MetS+OSA ET+D, n=11). ET+D groups were submitted to aerobic exercise (40 min, 3 times per week) associated to hypocaloric diet (-500 kcal / day) for four months and sedentary groups did not perform the intervention (ET+D) and only received clinical orientations. OSA was determined by the apnea-hypopnea index (AHI) >15 events/hour (polysomnography). The MSNA (microneurography), blood pressure (beat-to-beat basis, oscillometry method), oscillatory pattern of MSNA (relationship of the components of low frequency - LF, and high frequency - HF of MSNA, LFMSNA/HFMSNA, monovariate autoregressive spectral analysis) and spontaneous BRCMSNA (gain and time delay, bivariate autoregressive spectral analysis) were evaluated during rest at lying position for 10 min. RESULTS: In the pre-intervention period, patients with MetS-OSA and MetS+OSA showed reduced LFMSNA/HFMSNA (P=0.01 and P<0.001, respectively) and gain of BRCMSNA (P=0.01 and P<0.001, respectively) compared to Control group. And, the patients with MetS+OSA had lower LFMSNA/HFMSNA (P=0.02) and gain of BRCMSNA (P<0.001) compared to MetS- OSA. The time delay of BRCMSNA was higher in MetS+OSA group compared to MetS-OSA and Control groups (P=0.01 and P<0.001, respectively). After ET+D, both groups MetS-OSA and MetS+OSA decreased body weight, waist circumference and systolic blood pressure and increased peak oxygen uptake during exercise. In patients with MetS-OSA, the ET+D increased LFMSNA/HFMSNA (P<0.05) and the gain of BRCMSNA (P<0.01). In patients with MetS+OSA, ET+D increased minimum oxygen saturation level (P=0.02) during polysomnography, the LFMSNA/HFMSNA (P=0.001) and the gain of BRCMSNA (P<0.01) and decresed AHI (P<0.01) during polysomnography and the time delay of BRCMSNA (P=0.01). No alterations were observed in both sedentary groups. CONCLUSION: ET+D increase the oscillatory pattern of MSNA and the gain of BRCMSNA in patients with MetS, regardless of the presence of OSA. However, this effect is more pronounced in patients with MetS+OSA, since after intervention the time delay of BRCMSNA was also diminished in these patients