INTRODUÇÃO: A diabetes mellitus tipo 2 (DM) é uma doença metabólica caracterizada pela presença de hiperglicemia crônica. Estudos prévios demonstraram que pacientes com pré-diabetes (PDM) têm uma história natural de progressão para DM. A neuropatia diabética é a complicação mais comum da DM e avanços recentes na neurofisiologia clínica trouxeram um refinamento das técnicas de avaliação. Entre estas estão à resposta cutânea simpática (SSR) e o teste sensorial quantitativo (QST). Biomarcadores como Enolase Neurônio-Específica (NSE) e a Proteína S100-Beta (S100B) vem sendo descritos por muitos autores como associados a danos em células do sistema nervoso. OBJETIVO: O objetivo deste estudo é avaliar parâmetros neurofisiológicos e compará-los com achados clínicos e bioquímicos (S100B e NSE) em pacientes com DM, PDM e controles saudáveis. MÉTODOS: Pacientes dos ambulatórios de Neurologia e Endocrinologia foram randomizados em um estudo transversal. Os participantes foram submetidos a uma bateria de testes clínicos e neurofisiológicos que englobaram condução nervosa, Onda-F, SSR e QST. Níveis séricos de NSE e S100B foram quantificados através de ensaio ELISA (Enzyme-linked immunosorbent assay). RESULTADOS: A avaliação clínica e os estudos de condução nervosa e Onda-F foram similares nos grupos estudados. Já os limiares QST calor (QSTc) e QST dor (QSTd) foram significativamente elevados nos pacientes PDM e DM com relação aos controles (P<0.05 para todas as comparações). No entanto, estes parâmetros não foram capazes de distinguir pacientes DM vs. PDM (P >0.1 para todas as comparações). O SSR foi capaz de diferenciar o grupo DM do controle (P <0,01) embora não tenha mostrado diferença entre os grupos PDM e controle (P = 0,6). Não houve diferença entre os níveis de S100B (P = 0.6) e NSE (P = 0.2) entre os grupos DM, PDM e controles. CONCLUSÃO: O QST e SSR são testes úteis para a avaliação de pacientes com diferentes graus de tolerância a glicose. Este estudo não encontrou diferenças entre os biomarcadores NSE e S100B em indivíduos com DM e PDM. / BACKGROUND: Type 2 diabetes mellitus (DM) is a metabolic disease characterized by the presence of chronic hyperglycemia. Previous studies demonstrated that patients with prediabetes states (PDM) have a natural history of progression to DM. Neuropathy is the most common and disabling complication of diabetes and recent advances in neurophysiology have enabled a refinement of neurophysiological diagnostic techniques such as sympathetic skin response (SSR) and quantitative sensory testing (QST). Biomarkers like Neuron-specific Enolase (NSE) and S100- Beta Protein (S100B) has been described for many authors as associated with damage at nervous system cells and are related with severity of injury as well as clinical outcomes. OBJECTIVE: The aim of this study is to evaluate neurophysiological findings and compare them with clinical and biochemical findings (S100B and NSE) in patients with DM, PDM and healthy controls. METHODS: Patients at the outpatient Neurology and Endocrinology service were randomized in a cross-sectional study. Participants underwent a battery of clinical and neurophysiological tests that encompassed nerve conduction studies, F-wave, SSR and QST. ELISA (enzyme-linked immunosorbent assay) were perform to quantify serum levels of NSE and S100B. RESULTS: There were no difference regarding clinical evaluation, nerve conduction studies and F-wave were between groups. The QST thresholds of warm (QSTw) and QST pain (QSTp) were significantly elevated in patients with PDM and DM compared to controls (P <0.05 for all comparisons). However, these parameters were not able to distinguish among DM and PDM (P > 0.1 for all comparisons). The SSR was able to differentiate DM from control group (P <0.01) but did not show difference between PDM and control groups (P = 0.6). There was no difference on levels of S100B (P = 0.6) and NSE (P = 0.2) between the DM, PDM and control groups. CONCLUSION: The QST and SSR are useful tests to evaluating patients with different degrees of glucose tolerance. This study found no differences between biomarkers NSE and S100B in subjects with DM and PDM.

INTRODUÇÃO: A diabetes mellitus tipo 2 (DM) é uma doença metabólica caracterizada pela presença de hiperglicemia crônica. Estudos prévios demonstraram que pacientes com pré-diabetes (PDM) têm uma história natural de progressão para DM. A neuropatia diabética é a complicação mais comum da DM e avanços recentes na neurofisiologia clínica trouxeram um refinamento das técnicas de avaliação. Entre estas estão à resposta cutânea simpática (SSR) e o teste sensorial quantitativo (QST). Biomarcadores como Enolase Neurônio-Específica (NSE) e a Proteína S100-Beta (S100B) vem sendo descritos por muitos autores como associados a danos em células do sistema nervoso. OBJETIVO: O objetivo deste estudo é avaliar parâmetros neurofisiológicos e compará-los com achados clínicos e bioquímicos (S100B e NSE) em pacientes com DM, PDM e controles saudáveis. MÉTODOS: Pacientes dos ambulatórios de Neurologia e Endocrinologia foram randomizados em um estudo transversal. Os participantes foram submetidos a uma bateria de testes clínicos e neurofisiológicos que englobaram condução nervosa, Onda-F, SSR e QST. Níveis séricos de NSE e S100B foram quantificados através de ensaio ELISA (Enzyme-linked immunosorbent assay). RESULTADOS: A avaliação clínica e os estudos de condução nervosa e Onda-F foram similares nos grupos estudados. Já os limiares QST calor (QSTc) e QST dor (QSTd) foram significativamente elevados nos pacientes PDM e DM com relação aos controles (P<0.05 para todas as comparações). No entanto, estes parâmetros não foram capazes de distinguir pacientes DM vs. PDM (P >0.1 para todas as comparações). O SSR foi capaz de diferenciar o grupo DM do controle (P <0,01) embora não tenha mostrado diferença entre os grupos PDM e controle (P = 0,6). Não houve diferença entre os níveis de S100B (P = 0.6) e NSE (P = 0.2) entre os grupos DM, PDM e controles. CONCLUSÃO: O QST e SSR são testes úteis para a avaliação de pacientes com diferentes graus de tolerância a glicose. Este estudo não encontrou diferenças entre os biomarcadores NSE e S100B em indivíduos com DM e PDM. / BACKGROUND: Type 2 diabetes mellitus (DM) is a metabolic disease characterized by the presence of chronic hyperglycemia. Previous studies demonstrated that patients with prediabetes states (PDM) have a natural history of progression to DM. Neuropathy is the most common and disabling complication of diabetes and recent advances in neurophysiology have enabled a refinement of neurophysiological diagnostic techniques such as sympathetic skin response (SSR) and quantitative sensory testing (QST). Biomarkers like Neuron-specific Enolase (NSE) and S100- Beta Protein (S100B) has been described for many authors as associated with damage at nervous system cells and are related with severity of injury as well as clinical outcomes. OBJECTIVE: The aim of this study is to evaluate neurophysiological findings and compare them with clinical and biochemical findings (S100B and NSE) in patients with DM, PDM and healthy controls. METHODS: Patients at the outpatient Neurology and Endocrinology service were randomized in a cross-sectional study. Participants underwent a battery of clinical and neurophysiological tests that encompassed nerve conduction studies, F-wave, SSR and QST. ELISA (enzyme-linked immunosorbent assay) were perform to quantify serum levels of NSE and S100B. RESULTS: There were no difference regarding clinical evaluation, nerve conduction studies and F-wave were between groups. The QST thresholds of warm (QSTw) and QST pain (QSTp) were significantly elevated in patients with PDM and DM compared to controls (P <0.05 for all comparisons). However, these parameters were not able to distinguish among DM and PDM (P > 0.1 for all comparisons). The SSR was able to differentiate DM from control group (P <0.01) but did not show difference between PDM and control groups (P = 0.6). There was no difference on levels of S100B (P = 0.6) and NSE (P = 0.2) between the DM, PDM and control groups. CONCLUSION: The QST and SSR are useful tests to evaluating patients with different degrees of glucose tolerance. This study found no differences between biomarkers NSE and S100B in subjects with DM and PDM.

We study some aspects of liquidity of stocks traded through the National Stock Exchange (NSE) of India. Initially we examine the multi-dimensional nature of liquidity by conducting day-wise factor analysis of eleven liquidity proxies across a cross-section of stocks, using data from two periods reflecting different market conditions. Five factors emerge consistently, interpretable as depth, spread, volume, price elasticity and relative activity. Subsequently, we study execution of limit orders in the NSE from three angles. First we consider order execution probability, using 106 stock-specific logistic models. Important predictors of order execution probability are price premium followed by volatility, relative activity, bid ask spread and order imbalance. Some differences are noted when comparing companies of different sizes and between buy and sell orders. Second, we study order execution times using survival analysis. Several diagnostic tests indicate that parametric Accelerated Failure Time models using the log-logistic distribution for the survival time S(t) are suitable for current data. 100 stock-specific models are built; results are consistent with the logistic models. Additionally depth is also found to be important. Finally we build 4 combined models across stocks for both execution probabilities as well as times. These models perform well on out of sample data, suggesting their predictive utility.

El presente proyecto de plan de negocio tiene como objetivo implementar un colegio en Villa el Salvador, el cual nos muestra que, según el análisis de mercado, nuestra decisión estratégica permitirá explotar las actuales y recientes necesidades educativas de las nuevas familias emergentes con mayor capacidad adquisitiva y mayores factores aspiracionales de crecimiento socioeconómico. Por lo que existe una conveniente oportunidad de negocio, la misma que se ve fortalecida por la cercanía de nuestra sede a los nuevos centros de desarrollo urbano y a los polos productivos de la zona. El nombre elegido para el colegio es Terra Nova, el cual ofrecerá una moderna infraestructura, equipamiento vanguardista, con convenios para segundo idioma e informática, áreas multifuncionales, talleres, formación técnica extracurricular para secundaria y capacidad para 680 alumnos, ofreciendo una educación de alta calidad con una metodología basada en el aprendizaje por proyectos (ABP), todo ello concreta una sinergia diferenciadora y altamente apreciada en el nivel socioeconómico C – D. Para la ejecución del presente proyecto se requerirá una inversión de S/ 8,168,595, financiado por los accionistas y de una entidad financiera. Los valores positivos obtenidos mediante el análisis financiero nos permiten asegurar que el proyecto es viable y atractivo, pues supera las expectativas de los accionistas y se muestra sostenible más allá del período analizado de 10 años. / This business plan project aims at implementing a school in Villa El Salvador. According to the market analysis, our strategic decision will exploit the current and recent educational needs of new emerging families with greater monetary capacity, and greater aspirational factors of socioeconomic growth. Therefore, it is a business opportunity, which is strengthened by the proximity of our headquarters to the new urban development centers and the productive poles of the area. The name chosen for the school is Terra Nova, which will offer a modern infrastructure, avant-garde equipment, with conventions for second language and computer labs, multifunctional areas, workshops, extracurricular technical training for secondary students, and a capacity for 680 students. Offering a high quality education with a methodology based on Project based learning (PBL), all these form a differentiating synergy, which is highly appreciated in the socioeconomic levels C and D. For the execution of this project, an investment of S / 8,168,595 will be required, financed by the shareholders and a financial entity. The positive values obtained through financial analysis allow us to ensure that the project is viable and attractive, since it exceeds the expectations of shareholders and is sustainable beyond the analyzed period of 10 years. / Trabajo de investigación

The doctoral dissertation: Searching for pathomechanisms of late-life minor depression – a combined MRI, biomarker and meta-analytic study was one of the first studies investigating the underlying pathophysiology of minor depression. The dissertation comprises a systematic review of the prevalence rates of minor depression, two meta-analyses of peripheral BDNF changes in major depressive disorder, as well as two original studies investigating serum BDNF, S100B and NSE levels and gray matter changes in minor depression. The limitations of studies and proposed improvements to the study design are discussed extensively.:1. INTRODUCTION 1.1 Motivation 1.1.1 Minor depression in the spectrum of psychiatric disorders 1.1.2 Minor depression is prevalent but unrecognized. 1.2 Theoretical background 1.2.1 Overview of depression hypotheses 1.2.2 Neurotrophic hypothesis of depressive disorders 1.2.3 Glial hypothesis of depressive disorders 1.2.4 Structural neuroimaging changes in major depression 1.3. Rationale and hypotheses of the empirical studies 1.3.1 Research questions 1.3.2 Research hypotheses 2. EMPIRICAL STUDIES 2.1 The prevalence of minor depression in the late life 2.2 The meta-analysis of BDNF changes in mood disorders 2.3 The meta-analysis of BDNF changes following ECT in depression 2.4 Serum biomarkers in minor depression 2.5 Structural brain imaging in minor depression 3. GENERAL DISCUSSION 3.1 Summary of results 3.2 Implications for research 3.3 Implications for clinical studies SUMMARY REFERENCES APPENDIX A: DECLARATION OF CONTRIBUTION APPENDIX B: STATEMENT OF AUTHORSHIP APPENDIX C: CURRICULUM VITAEAPPENDIX D: ACADEMIC CONTRIBUTIONS APPENDIX E: ACKNOWLEDGMENT

Yes / Small-angle neutron scattering (SANS) and neutron spin-echo (NSE) have been used to investigate the temperature-dependent solution behaviour of highly-branched poly(N-isopropylacrylamide) (HB-PNIPAM). SANS experiments have shown that water is a good solvent for both HB-PNIPAM and a linear PNIPAM control at low temperatures where the small angle scattering is described by a single correlation length model. Increasing the temperature leads to a gradual collapse of HB-PNIPAM until above the lower critical solution temperature (LCST), at which point aggregation occurs, forming disperse spherical particles of up to 60 nm in diameter, independent of the degree of branching. However, SANS from linear PNIPAM above the LCST is described by a model that combines particulate structure and a contribution from solvated chains. NSE was used to study the internal and translational solution dynamics of HB-PNIPAM chains below the LCST. Internal HB-PNIPAM dynamics is described well by the Rouse model for non-entangled chains.

Mesmo a isquemia sendo a terceira causa de morte em países industrializados, os mecanismos relacionados a esta doença ainda continuam polêmicos e obscuros. Utilizou-se a técnica de privação de oxigênio e glicose (OGD) em fatias do hipocampo de rato para investigar parâmetros mitocondriais, neurais, astrogliais e metabólicos no período de isquemia e durante o período de reoxigenação. Os resultados mostraram uma diminuição na atividade mitocondrial durante o período isquêmico que foi mantido durante todo o período de reoxigenação. Analisando o sobrenadante destas fatias submetidas à OGD, foi observado que os níveis de LDH, NSE e GFAP se elevaram. Com relação aos níveis de lactato, verificou-se sua diminuição durante todos os períodos. Os níveis de S100B estavam elevados somente durante o período de reoxigenação. Este aumento pode ser tanto um mecanismo de neuroproteção desta proteína frente ao insulto ou ainda uma liberação por dano celular astrocitário. Além disso, foi observado um grande aumento nos níveis de glutamato durante a isquemia e este aumento retornou no período de reoxigenação. Por fim, houve uma diminuição na captação de glutamato somente no período de reoxigenação. Todos estes resultados podem ser conseqüência de uma hiper-estimulação dos receptores glutamatérgicos devido ao insulto isquêmico. Em resumo, nosso estudo mostrou alterações em diversos parâmetros neuroquímicos específicos tanto no período isquêmico quanto na reoxigenação, mostrando que cada tipo celular, reage diferentemente frente ao insulto isquêmico na técnica de OGD in vitro. / Stroke is the third cause of mortality in industrialized countries, and the mechanisms related to this disease are polemic and unclear. Oxygen and glucose deprivation (OGD) in acute rat hippocampal slices was performed to investigate mitochondrial, neural, astroglial and metabolic neurochemical parameters at different ischemic and reoxygenation periods. Results showed the mitochondrial activity decrease due energy failure during ischemic insult and reoxygenation time. In the supernatant medium, LDH, NSE and glutamate levels were increased and the lactate decrease by the lack of energy observed in the ischemic period. Parameters such as GFAP, S100B and glutamate uptake suffered alterations only at the reoxygenation period. These results have shown the vulnerability of neurons facing ischemic insult. Meanwhile, it was also observed a delayed injure of astrocytes only at reoxygenation time, which demonstrate the difference between cell types at OGD. In summary, our finding has shown altered at specific neurochemical parameters in OGD in vitro which features the ischemic episodes and reoxygenation periods.

Financial Derivatives are one of the most popular and emerging innovations in the field of financial engineering. Since their inception, there has been a phenomenal growth in the volumes of derivatives traded all over the world. Financial markets are known to be extremely volatile and derivatives provide a way of eliminating or reducing the risks involved in these markets. Since these instruments derive their value from some underlying asset, trading in these instruments is bound to affect the underlying assets. Thus it becomes important to examine what these effects are and whether they have been favourable or detrimental to the underlying stock markets specially when there has been an explosive growth of these financial derivatives all over the world. This issue gains more importance in the case of emerging markets like India as they try to be more competitive and efficient as the developed Western markets. This thesis mainly deals with looking at this impact on the Indian stock markets. The Indian markets still being very new in this area, not many studies have been reported here related to this issue. The main focus of this thesis is to provide some more evidence on the impact of one kind of derivative instrument, namely options on different characteristics of underlying stocks in the Indian stock market. The thesis has the following objectives: • To examine the impact of option introduction on the price of underlying stocks in National Stock Exchange (NSE). • To examine the impact of option introduction on the volatility of underlying stocks in NSE • To examine the impact of option introduction on liquidity of underlying stocks in NSE NSE introduced derivatives beginning with index futures on June 12, 2000, followed by index options on June 4, 2001, options on individual securities on July 2, 2001 and finally futures on individual securities on November 9, 2001. Due to the temporal proximity of the introduction of index options and individual options, there exists a possibility of an interaction of these two effects. This problem is solved by a judiciously chosen sampling design. In particular, three groups of stocks are considered. The first group consists of stocks on which options were first introduced on 2nd July 2001 and thus would exhibit a combined effect of the two events if any. The second group consists of stocks on which options were introduced much later and therefore would show effects of individual option introduction if any. The third group comprises of nonoptioned stocks whose returns are considered around the date of index option introduction and thus would show effects of index option alone if any. To separate the two effects an ANOVA/ Logistic Regression model is used. An objective selection of the event and estimation windows is done using a Bayesian Change Point Analysis. The first part of the thesis looks at the effect of option introduction on the price of underlying stocks. A standard event study methodology as has been used in the literature is employed for this purpose. The study does not find any significant effect of option introduction on the prices. The second part of the thesis deals with the effect on volatility. Volatility is measured as the risk of a stock and as is done in the literature, three kinds of risk are looked at: total risk, systematic risk and the unsystematic risk. In case of the total risk, an F-test and an Ansari Bradley test is used to check for changes in the variance and scale parameters of market-adjusted continuously compounded returns of the stocks before and after option introduction. The results of these tests are recorded as a categorical variable taking on the value 0 for no change and 1 for a change and a Binomial Logistic Regression is used to separate the effects of the two events. Furthermore, after recording the results of the above mentioned tests as a categorical variable with three categories (0, 1, -1), a Multinomial Logistic Regression is also used in order to estimate the direction of the change (increase, decrease or no change). The ratios of after to before total risks are also analyzed using an ANOVA model. The systematic risk is measured using three kinds of betas – OLS betas, Scholes-Williams betas and Fowler-Rorke betas. The differences in the before and after betas of every stock are modelled using an ANOVA model in order to separate the two effects as well as the interaction effect. The unsystematic risk is estimated by the conditional variances and the unconditional variances of ARMA and ARMA-GARCH models fitted to market model excess returns. The ANOVA model is used here as well. In addition to this, the before and after ARCH and GARCH coefficients of GARCH (1, 1) models fitted to the excess returns are also compared using the ANOVA model. The results indicate that individual options are leading to a decline in total risk however index options are causing an increase in total risk. The interaction effect is significant in this case thereby causing an increase in total risk in the Group I stocks. The OLS betas indicate that individual option introduction seems to have increased the systematic risk. The Scholes-Williams betas indicate that index option introduction seems to have increased the systematic risk. The Fowler Rorke betas on the other hand, do not show any significant impact of individual option or index option introduction. For all the three betas index options introduction seems to have no effect on the systematic risk. Though the interaction effect seems to be significant in all the three cases, it however does not significantly affect the systematic risk in Group I stocks. As regards the unsystematic risk, both the conditional and unconditional variances of ARMA models show a significant reduction for individual option introduction but index options do not have any significant impact on either one of these measures. In case of unconditional variances of ARMA-GARCH models, none of the effects come out as significant. While comparing the news and persistence coefficients of GARCH (1, 1) models, the news coefficients indicate that the due to index option introduction, stocks are becoming more efficient in terms of absorbing the news more rapidly. No significant effect of either event is found on the persistence coefficients. The last part of the thesis deals with the liquidity issue. Liquidity has been measured using two measures – relative volume (based on daily data) and implicit bid-ask spread given by Roll (1984) (calculated from intra-day data). In case of the liquidity measures, the Logistic Regression models are used i.e. a categorical variable with two or three categories obtained from the results of a Wilcoxon Rank Sum test for comparing the median volume and spread before and after option introduction, is used. It is found that for the relative volume, individual option introduction has led to a favourable effect in terms of increasing the volume post introduction of options; however index options seem to have had a negative effect. As for the spread, index options seem to have had a stabilizing influence on the underlying stocks than the individual options.

Esta tese de doutorado aborda o assunto apneia do sono, especialmente a síndrome de apneia e hipopneia obstrutiva do sono (SAHOS) como principal motivo de investigação. Nosso estudo teve como objetivo estudar o mecanismo fisiológico de funcionamento da válvula expiratória nasal (nEPAP) denominada Provent. Trata-se de um dispositivo descartável utilizado em ambas as narinas e que permite a inspiração normal, porém oferece resistência à expiração, fazendo com que o próprio paciente gere uma determinada pressão expiratória nasal. Este mecanismo de atuação da válvula determina algum grau de modificação na via aérea superior e no pulmão. Embora já se saiba que este dispositivo é efetivo no tratamento de pacientes com SAHOS leve e moderada3 o seu mecanismo fisiológico de funcionamento ainda não está completamente entendido. Utilizamos um método de ressonância magnética para avaliar a via aérea superior e o pulmão de pacientes em utilização do Provent nasal. Estudamos dez pacientes, 7 homens e 3 mulheres, entre 30 e 62 anos, com diagnóstico clínico de SAHOS e confirmado pela polissonografia (IAH>5 ev/h). Realizamos então, em diferentes momentos, polissonografia diagnóstica, polissonografia em uso da válvula nasal e exame de imagem (ressonância magnética). A faringe e o pulmão foram inspecionados e medidos durante alguns ciclos respiratórios, com e sem a válvula nasal. Neste estudo, validamos o exame de Ressonância Magnética para a avaliação da área transversal da via aérea superior e da capacidade residual funcional durante a respiração através da válvula nasal. Com os nossos resultados reforçamos os achados anteriores da literatura referentes aos três possíveis mecanismos de funcionamento desta válvula nasal: hiperinflação pulmonar importante aumentando a tração na traqueia, uma tendência à dilatação da faringe durante a expiração que se mantém no início da inspiração reduzindo a colapsabilidade da faringe e, finalmente, hipoventilação e aumento de PCO2. Considerando estes resultados, podemos dizer que a pressão expiratória positiva nasal pode ser uma alternativa de tratamento da SAHOS. Os resultados deste estudo são apresentados sob a forma de artigo já publicado em revista internacional de alto impacto científico (Journal of Applied Physiology). Adicionalmente, na forma de apêndice, realizamos outro estudo objetivando estudar o comportamento da SAHOS na Doença de Parkinson e as alterações ocasionadas em marcadores periféricos de lesão neuronal, especificamente a proteína S100B e a Enolase. Os transtornos do sono, incluindo os distúrbios respiratórios, são frequentes nos pacientes com Doença de Parkinson (DP), e, estudos já realizados mostram que a proteína S100B pode estar aumentada tanto em pacientes com SAHOS1 como naqueles com Doença de Parkinson2, sugerindo a possibilidade de algum grau de dano neuronal nestes pacientes quando comparados com indivíduos normais. Estes achados serviram de motivação para o estudo das variáveis neurofisiológicas do sono e do comportamento de biomarcadores em pacientes com Parkinson e, supostamente, SAHOS concomitantemente. / The issue of this doctoral thesis is Obstructive Sleep Apnea (OSA). Our study intended to clarify the mechanism of action of nEPAP (Nasal Expiratory Positive Airway Pressure), delivered with a disposable device (Provent, Ventus Medical). It has been shown to improve sleep disordered breathing (SDB) in some subjects3, but how it works is still not completely understood. We studied 10 patients, 7 males and 3 females, age between 30 and 62 years old, with clinic OSA and confirmed by sleep study (IHA>5). Sleep studies were performed in different nights, a night for diagnostic of OSA and other night under nasal valve. We did use MRI (Magnetic Resonance Imaging) to see upper airway and lung in patients wearing Provent. The present study demonstrate that significant hyperinflation (an increase in end expiratory lung volume) occurs during breathing through the device. In addition, there may be some trend to dilate the UA during expiration, and this may carry over into inspiration, providing a second mechanism to reduce the tendency of the UA to collapse in patients with SDB. Finally, we were able to show significant hypoventilation and a rise in PCO2 during breathing through the nEPAP during wakefulness, which may persist into sleep. Results are presented in the format of a paper published in a international journal with high scientific impact (Journal of Applied Physiology). In addition, as appendix, we did perform other protocol intended to study OSA in the Parkinson Disease (PD) and correlation with detectable levels of S100B and NSE, biochemical markers of neuronal damage. Sleep breathing disorders are frequent in Parkinson Disease and there are some studies showing that S100B, a known biochemical marker of astrocyte damage, is increased in both SAOS and PD1 2, suggesting a possible neuronal damage while compared to controls. These findings were motivation to investigate biochemical markers and sleep in patients with Parkinson. Our results suggest that sleep disturbance in PD causes a worse sleep quality and leads to S100B elevation during the night. Probably PD patients are suffering some degree of brain damage during the night that trigger a S100B response.

Esta tese de doutorado aborda o assunto apneia do sono, especialmente a síndrome de apneia e hipopneia obstrutiva do sono (SAHOS) como principal motivo de investigação. Nosso estudo teve como objetivo estudar o mecanismo fisiológico de funcionamento da válvula expiratória nasal (nEPAP) denominada Provent. Trata-se de um dispositivo descartável utilizado em ambas as narinas e que permite a inspiração normal, porém oferece resistência à expiração, fazendo com que o próprio paciente gere uma determinada pressão expiratória nasal. Este mecanismo de atuação da válvula determina algum grau de modificação na via aérea superior e no pulmão. Embora já se saiba que este dispositivo é efetivo no tratamento de pacientes com SAHOS leve e moderada3 o seu mecanismo fisiológico de funcionamento ainda não está completamente entendido. Utilizamos um método de ressonância magnética para avaliar a via aérea superior e o pulmão de pacientes em utilização do Provent nasal. Estudamos dez pacientes, 7 homens e 3 mulheres, entre 30 e 62 anos, com diagnóstico clínico de SAHOS e confirmado pela polissonografia (IAH>5 ev/h). Realizamos então, em diferentes momentos, polissonografia diagnóstica, polissonografia em uso da válvula nasal e exame de imagem (ressonância magnética). A faringe e o pulmão foram inspecionados e medidos durante alguns ciclos respiratórios, com e sem a válvula nasal. Neste estudo, validamos o exame de Ressonância Magnética para a avaliação da área transversal da via aérea superior e da capacidade residual funcional durante a respiração através da válvula nasal. Com os nossos resultados reforçamos os achados anteriores da literatura referentes aos três possíveis mecanismos de funcionamento desta válvula nasal: hiperinflação pulmonar importante aumentando a tração na traqueia, uma tendência à dilatação da faringe durante a expiração que se mantém no início da inspiração reduzindo a colapsabilidade da faringe e, finalmente, hipoventilação e aumento de PCO2. Considerando estes resultados, podemos dizer que a pressão expiratória positiva nasal pode ser uma alternativa de tratamento da SAHOS. Os resultados deste estudo são apresentados sob a forma de artigo já publicado em revista internacional de alto impacto científico (Journal of Applied Physiology). Adicionalmente, na forma de apêndice, realizamos outro estudo objetivando estudar o comportamento da SAHOS na Doença de Parkinson e as alterações ocasionadas em marcadores periféricos de lesão neuronal, especificamente a proteína S100B e a Enolase. Os transtornos do sono, incluindo os distúrbios respiratórios, são frequentes nos pacientes com Doença de Parkinson (DP), e, estudos já realizados mostram que a proteína S100B pode estar aumentada tanto em pacientes com SAHOS1 como naqueles com Doença de Parkinson2, sugerindo a possibilidade de algum grau de dano neuronal nestes pacientes quando comparados com indivíduos normais. Estes achados serviram de motivação para o estudo das variáveis neurofisiológicas do sono e do comportamento de biomarcadores em pacientes com Parkinson e, supostamente, SAHOS concomitantemente. / The issue of this doctoral thesis is Obstructive Sleep Apnea (OSA). Our study intended to clarify the mechanism of action of nEPAP (Nasal Expiratory Positive Airway Pressure), delivered with a disposable device (Provent, Ventus Medical). It has been shown to improve sleep disordered breathing (SDB) in some subjects3, but how it works is still not completely understood. We studied 10 patients, 7 males and 3 females, age between 30 and 62 years old, with clinic OSA and confirmed by sleep study (IHA>5). Sleep studies were performed in different nights, a night for diagnostic of OSA and other night under nasal valve. We did use MRI (Magnetic Resonance Imaging) to see upper airway and lung in patients wearing Provent. The present study demonstrate that significant hyperinflation (an increase in end expiratory lung volume) occurs during breathing through the device. In addition, there may be some trend to dilate the UA during expiration, and this may carry over into inspiration, providing a second mechanism to reduce the tendency of the UA to collapse in patients with SDB. Finally, we were able to show significant hypoventilation and a rise in PCO2 during breathing through the nEPAP during wakefulness, which may persist into sleep. Results are presented in the format of a paper published in a international journal with high scientific impact (Journal of Applied Physiology). In addition, as appendix, we did perform other protocol intended to study OSA in the Parkinson Disease (PD) and correlation with detectable levels of S100B and NSE, biochemical markers of neuronal damage. Sleep breathing disorders are frequent in Parkinson Disease and there are some studies showing that S100B, a known biochemical marker of astrocyte damage, is increased in both SAOS and PD1 2, suggesting a possible neuronal damage while compared to controls. These findings were motivation to investigate biochemical markers and sleep in patients with Parkinson. Our results suggest that sleep disturbance in PD causes a worse sleep quality and leads to S100B elevation during the night. Probably PD patients are suffering some degree of brain damage during the night that trigger a S100B response.