A Síndrome dos Ovários Policísticos (SOP) afeta uma grande parcela da população feminina em idade reprodutiva. Além das alterações morfológicas, hormonais e metabólicas, essas mulheres também apresentam uma alta prevalência de obesidade e alterações no controle autonômico cardiovascular de acordo com a literatura, principalmente modificações na modulação autonômica da variabilidade da frequência cardíaca (VFC). No entanto, pouco sabemos sobre outros parâmetros do controle autonômico, como a variabilidade da pressão arterial (VPA) e a sensibilidade barorreflexa (SBR). Portanto, o principal objetivo do estudo foi investigar em mulheres com a SOP as alterações na modulação autonômica da VPA e na SBR, bem como avaliar se essas alterações são decorrentes da SOP ou do aumento da gordura corporal. Para tanto, foram estudadas 30 mulheres voluntárias eutróficas (IMC ? 25 kg/m2) sem a SOP e 60 mulheres voluntárias com a SOP divididas em dois grupos: eutróficas (IMC ? 25 kg/m2; N=30) e obesas (IMC ? 30 kg/m2; N=30). Todas as mulheres foram submetidas aos seguintes protocolos; coleta de sangue para hemograma completo; avaliação antropométrica e avaliação de parâmetros metabólicos e hormonais em repouso; registro de parâmetros hemodinâmicos e cardiorrespiratórios em repouso e durante o exercício físico; análise da VFC e da VPA; e análise da SBR espontânea. A comparação entre os grupos eutróficos com e sem SOP não apresentou qualquer diferença nos parâmetros autonômicos avaliados. No entanto, a comparação entre os grupos SOP mostrou que o grupo SOP obeso apresentou menores valores de VO2 e testosterona, e maiores valores de triglicerídeos e da pressão arterial em relação ao grupo SOP eutrófico. Quanto aos parâmetros autonômicos, os grupos obeso e eutrófico não diferiram na análise da VPA. Entretanto, o grupo SOP obeso apresentou menores valores da SBR espontânea e das oscilações de baixa frequência (LF) da VFC em unidades absolutas. Por fim, nossos resultados sugerem que a obesidade pouco alterou a VFC em mulheres com SOP, entretanto reduziu sensivelmente a SBR espontânea. Esses achados podem estar associados com diferenças hormonais encontradas nessas mulheres, como os níveis séricos de testosterona mais elevados no grupo eutrófico. / Polycystic Ovarian Syndrome (PCOS) affects a large proportion of the female population at reproductive age. In addition to morphological, hormonal and metabolic alterations, these women also present a high prevalence of obesity and alterations in cardiovascular autonomic control according to the literature. Mainly modifications in the autonomic modulation of heart rate variability (HRV). However, we do not know much about other parameters of autonomic control, such as blood pressure variability (APV) and baroreflex sensitivity (SBR). Therefore, the main objective of the study was to investigate in women with PCOS changes in the autonomic modulation of APV and SBR, as well as to assess whether these alterations are due to PCOS or increased body fat. In order to do, 30 eutrophic non-PCOS voluntary women (BMI ? 25 kg / m2) and 60 voluntary PCOS women who were studied in two groups: PCOS eutrophic (BMI ? 25 kg / m2, N = 30) and PCOS obese women (BMI ? 30 kg / m2, N = 30). All the women were submitted to the following protocols; collection of blood for complete blood count; anthropometric evaluation and evaluation of metabolic and hormonal parameters at rest; recording of hemodynamic and cardiorespiratory parameters at rest and during physical exercise; analysis of HRV, APV and spontaneous SBR analysis. The comparison between the eutrophic PCOS and nonPCOS groups showed no difference in the autonomic parameters evaluated. However, the comparison between the PCOS groups showed that the PCOS obese group presented lower values of VO2 and testosterone, and higher triglyceride values and blood pressure in relation to the PCOS eutrophic group. Regarding the autonomic parameters, the PCOS obese and eutrophic groups did not differ in the APV analysis. However, the PCOS obese group presented lower values of spontaneous SBR and low frequency oscillations (LF) of HRV in absolute units. Finally, our results suggest that obesity did not significantly alter HRV in women with PCOS, but it significantly reduced spontaneous SBR. These findings may be associated with hormonal differences found in these women, such as higher serum testosterone levels in the PCOS eutrophic group.

A asma é uma doença com alta prevalência e leva a importantes danos funcionais à saúde e à qualidade de vida do paciente. A fisiopatologia da doença está centrada na inflamação crônica das vias aéreas que associada a uma disfunção do sistema nervoso autônomo (SNA) favorece a hiper-reatividade e à obstrução brônquica. O treinamento físico pode modular a resposta autonômica e imune em indivíduos saudáveis e a sua prática de maneira regular também é recomendada para os pacientes asmáticos. Porém, permanece pouco compreendido o efeito do treinamento físico sobre a inflamação pulmonar e a modulação autonômica, bem como nos aspectos psicossociais e sintomatologia em pacientes asmáticos. Objetivo: Avaliar o efeito de um programa de treinamento físico aeróbio na inflamação pulmonar, resposta autonômica, fatores relacionados à qualidade de vida (FRQV) e sintomatologia de pacientes adultos com asma persistente moderada ou grave. Casuística e Métodos: Foram estudados 53 adultos asmáticos divididos aleatoriamente nos grupos controle (GC; n=27) e treinado (GT; n=26). Os pacientes do GC (programa educacional + exercícios respiratórios) e GT (similar ao GC + treinamento aeróbio) foram acompanhados durante 3 meses, 2 vezes semanais. A capacidade aeróbia máxima (VO2max), função pulmonar, escarro induzido, fração de óxido nítrico no ar exalado (FeNO), variabilidade da frequência cardíaca (VFC) e 17 FRQV foram analisadas antes e após o treinamento. Os dias com sintomas foram avaliados mensalmente. Resultados: Observamos que os pacientes do GT apresentaram redução da FeNO e do número de eosinófilos no escarro induzido, um aumento do VO2max e a uma melhora dos fatores relacionados à qualidade vida e sintomas de asma (p<0,05). Nenhuma mudança foi observada na função pulmonar e VFC para ambos os grupos após o treinamento. Conclusão: Nossos resultados sugerem que um programa de treinamento físico é capaz de melhorar o condicionamento cardiorrespiratório, a qualidade de vida e reduzir a inflamação pulmonar sem influenciar o comportamento do SNA de pacientes asmáticos. / Asthma is a disease with a high prevalence leading to important impairment on patients functional status and health and quality of life. Asthma pathophysiology is centered on chronic airway inflammation that associated with a dysfunction in the autonomic nervous system (ANS) increases bronchial hyperactivity and obstruction. In healthy subjects, the physical training can modulate autonomic and immune systems and its regular practice is recommended for asthmatic patients. However, it remains poorly known the effect of the physical training on airway inflammation and autonomic modulation as well as on psychosocial factors and clinical management of asthmatic patients. Objective: To evaluate the effects of an aerobic training program on airway inflammation, ANS and health related quality of life (HRQL) in adult patients with moderate or severe asthma. Methods: Fifty-tree asthmatic adult patients were randomly assigned to either control (CG; n=27) or training groups (TG n=26). Patients in CG (educational program + respiratory exercises) and TG (similar to control group + aerobic training) were followed twice a week during a 3-month period. Maximal aerobic capacity (VO2max), pulmonary function, induced sputum, fractional concentration of exhaled nitric oxide (FeNO), heart rate variability (HRV) and HRQL were evaluated before and after treatment. Asthma symptoms were evaluated monthly. Results: Our results show that patients from the TG presented a decrease on FeNO and number of eosinophils in the induced sputum, a increased on 19 VO2max and a improvement of HRQL and asthma symptoms (p<0.05). No change was observed in lung function and HRV in both groups after treatment. Conclusion: Our results suggest that a physical fitness program can improve aerobic capacity, quality of life and reduce airway inflammation, however without any influence on ANS in asthmatic patients.

Nós investigamos os efeitos do modelo de periodização de cargas seletivas (MPCS) sobre a modulação autonômica da variabilidade da freqüência cardíaca (VFC) e marcadores de estresse endógenos, antes e após um período de competição, em jogadores de voleibol (N=32). O protocolo experimental para a avaliação da VFC consistiu do uso da análise espectral das séries temporais compostas dos intervalos R-R derivados do eletrocardiograma obtidos na posição supina e durante o teste de inclinação (tilt test). Os níveis dos marcadores de estresse foram determinados pela quantificação da concentração plasmática de catecolaminas endógenas, cortisol e testosterona livre. Os resultados não demonstraram alterações na VFC antes e após o período de competição. Em contraste, a quantificação da concentração plasmática dos marcadores de estresse endógenos revelou reduções nos níveis de catecolaminas totais, noradrenalina e cortisol. Estas mudanças foram acompanhadas por aumentos na concentração de testosterona livre e na razão testosterona/cortisol. Em conclusão, nossos resultados demonstraram que o MPCS não alterou a modulação autonômica da VFC, mas promoveu adaptações benéficas aos atletas, incluindo mudanças positivas na concentração plasmática dos marcadores de estresse endógenos analisados. A ausência de alterações na VFC indica que não houve relação direta entre modulação autonômica cardíaca e marcadores de estresse endógenos no presente estudo. / We investigated the effects of selective loads of periodization model (SLPM) on autonomic modulation of heart rate variability (HRV) and endogenous stress markers before and after a competition period in volleyball players (N=32). The experimental protocol for the evaluation of HRV consisted of using spectral analysis of time series composed of the R-R intervals derived from electrocardiogram obtained in the supine position and during the tilt test. Stress marker levels were determined by quantifying the plasma concentration of endogenous catecholamines, cortisol and free testosterone. The results showed no changes between the levels of HRV before and after a competition period. In contrast, the quantification of the plasma concentration of endogenous stress markers revealed reductions in the levels of total catecholamines, noradrenaline and cortisol. In conclusion, our results demonstrate that the SLPM did not change the cardiac autonomic modulation of HRV, but promoted beneficial adaptations in athletes, including positive changes in the plasma concentration of the endogenous stress markers. The absence of changes in HRV indicates that there is no direct relationship between cardiac autonomic modulation and endogenous stress markers in the present study.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-14T20:24:58Z No. of bitstreams: 1 fabioantoniodamascenomarques.pdf: 1072493 bytes, checksum: 5c90ebd0061c6a81a5a657aeb312e3bf (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-07-19T15:49:06Z (GMT) No. of bitstreams: 1 fabioantoniodamascenomarques.pdf: 1072493 bytes, checksum: 5c90ebd0061c6a81a5a657aeb312e3bf (MD5) / Made available in DSpace on 2016-07-19T15:49:06Z (GMT). No. of bitstreams: 1 fabioantoniodamascenomarques.pdf: 1072493 bytes, checksum: 5c90ebd0061c6a81a5a657aeb312e3bf (MD5) Previous issue date: 2016-06-15 / Desde o estudo de Robinson, publicado em 1938, em que se utilizou a idade como variável independente, não se conhece outra variável que possa melhorar a predição da freqüência cardíaca máxima (FCMAX). Recentemente, tem se estudado a FC de recuperação (FCREC) após exercício máximo, que tem sido apontada como preditora de mortalidade. Para melhor entender a FCMAX e a FCREC após teste máximo, o presente estudo teve como objetivos: 1)Identificar se a FCMax é influenciada pela variabilidade da freqüência cardíaca (VFC) em repouso, 2) Verificar se a FCREC avaliada por meio de deltas é influenciada pela FCMAX; 3) Sugerir um modelo de avaliação da FCREC relativizado pelos valores de FCMAX. e 4) Propor uma equação que descreva a cinética de recuperação da FCMAX em indivíduos jovens e de meia idade saudáveis. Para alcançar os objetivos propostos, foram realizados dois estudos. Estudo 1 - foram avaliados 63 indivíduos (21 mulheres e 42 homens) de 20 a 30 anos. Foi avaliada a FC e VFC em repouso na posição sentada. Em seguida, os indivíduos realizaram um teste cardiopulmonar máximo em esteira (Protocolo de Bruce). Os indivíduos foram divididos, sexo e pela mediana da FCMAX, em grupo de alta de baixa FCMAX. Os índices de VFC de repouso dos dois grupos foram comparados por teste ―t‖ de Student para grupos independentes (p<0,05). Apenas a banda de baixa freqüência (LF) nas mulheres se mostrou significativamente diferente entre os grupos. Conclui-se que maiores valores de LF nas mulheres em repouso estão associadas à FCMAX mais elevadas. Estudo 2 - foram avaliados 77 indivíduos (24 mulheres e 53 homens) de 18 a 50 anos. Após o teste máximo de Bruce, foi coletada a FC durante 300s após o fim do teste. Foi feita correlação da FCREC em valores absolutos, deltas e percentuais nos tempos 10, 20, 30, 40, 50, 60, 120, 180, 240 e 300 s com a FCMAX atingida no teste. O grupo também foi dividido em grupo e alta e baixa FCMAX pelo valor da mediana do grupo total. As diferenças entre as médias dos grupos foram testadas pelo teste ―t‖ de Student para grupos independentes (p<0,05). Observou-se que os valores absolutos de FCREC se correlacionam com a FCMAX, não sendo assim a melhor estratégia para classificação dessa recuperação. Os deltas de FCREC, na fase rápida (10 a 60 s), não mostraram correlação com a FCMAX. Já, na fase lenta (60 a 300 s), foi evidenciada correlação com a FCMAX. A utilização de valores percentuais da FCMAX se mostrou a única 9 estratégia em que em nenhum momento da FCREC apresentou correlação com a FCMAX. Construíram-se equações de regressão, uma para cada fase da FCREC, para indicar os valores médios de recuperação. / Since Robinson's study, published in 1938, which used age as an independent variable, do not know any other variable that can improve the prediction of maximal heart rate (HRMAX). Recently it has been studied HR recovery (HRR) after maximal exercise, which has been identified as a predictor of mortality. To better understand HRMAX and HRR after maximal test, this study aimed to: 1) Identify if the maximum heart rate is influenced by heart rate variability (HRV) at rest 2) Suggest an assessment model FCREC relativized by the values of HRMAX 3) Test the strategy of the calculation of deltas for the times of 10, 20, 30, 40, 50, 60, 120, 180, 240 and 300 s of recovery, and 4) Propose a strategy for calculating the FCREC by the percentage of recovery, as well as create an equation for predicting% FCREC. To achieve the proposed objectives, two studies were performed. Study 1 - 63 subjects were evaluated (21 women and 42 men) from 20 to 30 years. We evaluated the HR and your variability (HRV) at rest in a sitting position. Then, subjects performed a maximal cardiopulmonary exercise testing on treadmill (Bruce Protocol). The subjects were divided by gender and the median of HRMAX in group high low HRMAX. The indices of (HRV) at rest in both groups were compared by ―t‖ test of Student for independent groups (p <0.05). Only the low frequency band (LF) was significantly different between groups. We conclude that higher values of LF at rest are associated with higher HRMAX. Study 2 - 77 individuals were assessed (24 women and 53 men) from 18 to 50 years. After Bruce protocol, FC was collected for 300s after the test. Correlation of the FCREC in absolute values, deltas and percentages at 10, 20, 30, 40, 50, 60, 120, 180, 240 and 300 s with the HRMAX reached in the test. The group was also divided into groups and high and low HRMAX the median value of total group. The differences between group means were tested by ―t’ test for independent groups (p <0.05). It was observed that the absolute values of FCREC are correlated with HRMAX and thus not the best strategy for classification of that recovery. The deltas of FCREC, the fast phase (10-60 s) showed no correlation with the HRMAX. Already, in the slow phase (60 to 300 s) there was significant correlation with the HRMAX. The use of percentages of HRMAX proved to be the only strategy that at no time was correlated with the HRMAX. We constructed regression equations, one for each phase of the FCREC, to indicate the average values of recovery.

Orientador: Mara Patricia Traina Chacon Mikahil / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Educação Física / Made available in DSpace on 2018-08-26T04:50:01Z (GMT). No. of bitstreams: 1 Bonganha_Valeria_D.pdf: 1034006 bytes, checksum: e2aba82d3926d1b6b0f8303ffe49c706 (MD5) Previous issue date: 2014 / Resumo: Introdução: Modificações do controle cardiovascular autonômico têm sido observadas na obesidade e no processo de envelhecimento, os quais desencadeiam maior risco cardiovascular. Em obesos de meia-idade, ambos, a obesidade e o processo de envelhecimento contribuem para as modificações negativas do controle autonômico do coração. Objetivo: verificar as respostas cardiovasculares e autonômicas, no repouso e durante o exercício, após 24 semanas de treinamento concorrente (TC) em obesos de 40 a 60 anos. Métodos: Vinte e um homens obesos foram divididos aleatoriamente em: grupo controle (GC) e grupo CT, o qual realizava exercícios aeróbios e de força na mesma sessão. O programa de treinamento foi realizado em três sessões semanais. Pressão arterial de repouso, modulação cardíaca autonômica, avaliada pelos índices da variabilidade da frequência cardíaca (VFC), força máxima (teste de 1-RM) e teste cardiorrespiratório foram realizados no momento inicial e após 24 semanas. Resultados: foi encontrado aumento significativo da capacidade aeróbia (VO2 pico, limiar ventilatório e ponto de compensação respiratória: 8,40%; 11,92% e 11,12%, respectivamente), força muscular (leg press e supino reto: 28,12% e 18,7%, respectivamente), diminuição significativa da pressão arterial diastólica (7,1%) e melhora da VFC de repouso (RMSSD e SD2: 79,10% e 29,6%, respectivamente) para o CT, independentemente de modificações na massa corporal total. Houve aumento significante do SD2 (58.3%) durante o exercício em baixa-intensidade e diminuição significante do SD2 durante o exercício em alta intensidade (48.6%) para o CT. Conclusão: o programa de TC proposto nesse estudo (24 semanas) foi capaz de aumentar a aptidão aeróbia, força muscular e melhorar a VFC (índices parassimpáticos) no repouso e em exercício de baixa intensidade, mas não em alta intensidade de exercício em obesos / Abstract: Introduction: autonomic modifications of cardiovascular control have also been observed in the obesity and aging process, which triggers higher cardiometabolic risk. In middle-aged obese men, both obesity and aging contribute to modifications of the autonomic control of the heart. Aim: evaluate the cardiovascular and autonomic responses at rest and during exercise, after concurrent training (CT) in obese men between 40 to 60 years. Methods: twenty-one middle-aged men were randomly assigned in: control group (CG) and CT which performed aerobic and resistance exercises in the same session. Training program was performed in three weekly sessions for 24 weeks. Resting auscultatory blood pressure, cardiac autonomic modulation, assessed using heart rate variability (HRV) indices; maximal dynamic strength (1-RM test) and cardiorespiratory test were measured at baseline and after 24 weeks. Results: we found a significant increase in aerobic fitness (VO2 peak, ventilatory threshold, and respiratory compensation point: 8.40%, 11.92% e 11.12%, respectively), muscle strength (leg and bench press: 28.12% e 18.7%, respectively), significant decrease of resting diastolic blood pressure (7.1%) and improvement in HRV (RMSSD and SD2: 79.10% e 29.6%, respectively) for CT, independently in body weight and body composition changes. There was significant increase in SD2 (58.3%) during low-intensity exercise and significant decrease in SD2 (48.6%) during high-intensity exercise for CT. Conclusion: CT program proposed in this study (24-wk) were able to improve aerobic fitness, muscle strength and improvement in HRV (parasympathetic indices) at rest and during low-intensity exercise, but not in higher intensity in obese men / Doutorado / Atividade Fisica Adaptada / Doutora em Educação Física

Introduction : Le système nerveux autonome (SNA) est le marqueur le plus puissant du vieillissement global de l'organisme, en particulier du vieillissement vasculaire cérébral et cardiaque. Bien que la peau soit richement innervée par les nerfs autonomes et le SNA contrôle de nombreuses fonctions cutanées, la relation entre le SNA et le vieillissement cutané n'a pas été étudiée. Méthodes : Nous avons évalué le vieillissement cutané chez 209 sujets âgés (105 femmes et 104 hommes, âge moyen 77,5 ans) appartenant à la cohorte stéphanoise PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events) qui explore la fonctionnalité du SNA. Le vieillissement cutané a été mesuré par le score clinique SCINEXA (SCore for INtrinsic and EXtrinsic skin Aging), par VISIA, vidéodermatoscopie et cutométrie. L’activité du SNA a été mesurée par la variabilité de la fréquence cardiaque sur enregistrement de l’électrocardiogramme de 24 heures. Résultats : Une relation entre SNA et SCINEXA n’a pas pu être démontrée. Cependant, une relation entre l'activité du SNA et certains items du SCINEXA et certains paramètres du VISIA, de la vidéodermatoscopie et de la cutométrie a été trouvée. En particulier, l'analyse des paramètres VISIA a mis en évidence une relation entre porphyrines élevées et baisse de l’activité sympathique du SNA. Discussion et Conclusion : Quoique nous n’ayons pas trouvé de relation entre le vieillissement cutané global et la fonction du SNA, il est possible que le SNA joue un rôle sur le vieillissement intrinsèque de la peau, mais d’une manière négligeable en comparaison des facteurs externes tels que l’exposition solaire, et que cette partie du vieillissement soit difficile à mettre en évidence. De plus ayant trouvé une relation entre certains paramètres du vieillissement cutané et le SNA, notre étude encourage les futures recherches sur l’influence du SNA sur les différents composants du vieillissement cutané / Background : The autonomic nervous system (ANS) is the most powerful marker of the overall body aging, especially for what concerns the vascular aging of the heart and the brain. Although the skin is richly innervated by ANS nerves and the ANS controls many skin functions, the relation between the ANS and skin aging has not been studied. Methods : We evalusated skin aging of 209 elderly subjects (105 women and 104 men, mean age 77.5 years) belonging to the PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events) cohort of Saint-Etienne which explores the functionality of the ANS. Skin aging was measured by the clinical score SCINEXA (SCore for INtrinsic and EXtrinsic skin Aging), by VISIA, videodermoscopy and cutometry. The ANS status was measuredby the heart rate variability on a 24 hours recording of the electrocardiogram. Results : A relation between ANS and SCINEXA could not be demonstrated. However, a relation between the activity of the ANS and some items of SCINEXA and certain parameters of VISIA, videodermoscopy and cutometry was found. In particular, the analysis of VISIA parameters showed a relation between elevated porphyrins and a decreased sympathetic activity of the ANS. Discussion and conclusion : Although we did not find a relationship between overall skin aging and ANS activity, ANS might play a role in intrinsic skin aging, albeit marginally if compared to external factors such a sun exposure. Moreover, the intrinsic part of the skin aging and the ANS, our study encourages further research on the influence of the ANS on the various components of skin aging.

Cardiovascular disease is the leading cause of mortality in the developed world with up to fifty percent of cases being due to sudden cardiac death. Changes in sympatho-vagal balance underpin many cardiovascular conditions including heart failure and myocardial infarction. Neuraxial modulation of the autonomic nervous system is an emerging therapy to prevent ventricular arrhythmias, the main cause of sudden cardiac death. <b>Chapter One</b> reviews our current understanding of how the cardiac autonomic nervous system influences ventricular arrhythmogenesis. A particular focus was on the controversial role of cholinergic receptors and nitric oxide (NO) in parasympathetic protection from ventricular arrhythmias. Tetrahydrobiopterin (BH₄), a critical cofactor for both tyrosine hydroxylase and NO synthases, and the co-transmitter neuropeptide-Y (NPY) may also influence sympathetic triggering of ventricular arrhythmias. This leads to the specific aims of the thesis which were to determine the mechanisms of the cholinergic antifibrillatory effect, investigate the role of cotransmission in arrhythmogenesis and, the mechanistic role of BH4 in autonomic cardiovascular control. <b>Chapter Two</b> detailed the experimental approach taken to investigate the hypotheses. A novel Langendorff heart preparation was developed with intact autonomic nerves to investigate how the stable analogue of acetylcholine, carbamylcholine (CCh) raises ventricular fibrillation threshold (VFT) and whether exogenous or endogenously released NPY lowers VFT. These actions are further investigated using optical mapping, dye free imaging of ventricular cell monolayers, immunohistochemistry, ELISA assays and measurements of NO metabolite production. To investigate the role of BH4 in the sympathetic control of the heart, an IRES-cre recombinase strategy was used to produce genomic deletion of GCH1 (the gene encoding BH4) in sympathetic neurons. Biopterins and plasma catecholamines were measured using HPLC, and blood pressure and heart rate via tail cuff plethysmography. <b>Chapter 3</b> showed that CCh increased VFT, prolonged action potential duration and flattened the electrical restitution curve. This effect required stimulation of both muscarinic and nicotinic receptors and the generation of nNOS derived NO utilising a cGMP dependent pathway. These observations are in keeping with established evidence demonstrating the obligatory role of the muscarinic receptor and indicate that the role of NO is likely to be via modulation of cholinergic neurotransmission. <b>Chapter 4</b> studied the role of the sympathetic co-transmitter NPY. NPY has been shown to increase ventricular myocyte calcium dynamics. Plasma levels are also increased post myocardial infarction and during heart failure, and correlate with outcomes. Perfusion of NPY decreased VFT via a Y1 receptor dependent mechanism and increased arrhythmic activity in myocyte monolayers. Direct sympathetic stimulation resulted in NPY release and remained pro-arrhythmic despite &beta;-blockade, an effect that could be abolished by combined &beta;-Y₁ receptor blockade. These observations indicated that NPY may be a novel, pro-arrhythmic trigger amenable to therapeutic pharmacological modulation. <b>Chapter 5</b> details the generation and phenotyping of two tissue specific Gch1 knockout mouse models. Whilst one model failed to produce significant lowering of BH₄ in sympatho-adrenal tissue, the other did result in a marked neuro-motor phenotype. A biochemical rescue or alternative genomic modification approach would be required to study the cardiovascular phenotype of sympathetic Gch1 deletion in more detail. <b>Chapter 6</b> is a concluding discussion summarising the main findings of the thesis, placing them in a clinical context and discussing avenues for further research.

Abstract Parkinson's disease (PD) is known to affect both the extrapyramidal system and the autonomic nervous system even in the early phases of the disease. This study was designed to evaluate cardiovascular autonomic regulation in early PD by measuring heart rate (HR) variability from 24-hour ECG recordings. The dynamics of blood pressure (BP), HR and sweating in patients with and without wearing-off were assessed during clinical observations after a morning dose of levodopa. In patients with wearing-off the tests were repeated after selegiline withdrawal. The power spectral components of HR variability and the SD1 value of the Poincaré analysis that quantifies the short-term beat-to-beat variability were suppressed at night in the PD patients. During the daytime only the SD1 of the Poincaré was suppressed. The results indicate impairment of parasympathetic cardiovascular regulation in untreated patients with PD. The dysfunction was more pronounced at night and in patients with more severe PD. The patients with wearing-off had fluctuation of BP during the observation period, BP increasing when the motor performance worsened and vice versa (p &lt; 0.001). The patients without wearing-off did not show fluctuation of BP. Sweating increased during the observation period, and reached its maximum level at the time of the highest UPDRS motor score phase (off-stage) in patients with wearing-off, but in the patients without wearing-off no changes in sweating were observed. Sweating of the hands was significantly higher in PD patients with motor fluctuations than in those without. Selegiline withdrawal decreased systolic BP significantly during the on-stage in a supine position as well as during the orthostatic test. The initial drop of BP in the orthostatic test was significantly smaller after selegiline withdrawal. The HR and sweating remained unaffected. The results show that the autonomic nervous system is affected in the early phases of PD. The dysfunction becomes more pronounced with the disease progression. Wearing-off type motor fluctuations are associated with fluctuation of BP and sweating and these fluctuations may represent autonomic dysfunction caused by PD, the effect of PD medication, or both. Selegiline withdrawal seems to alleviate the orthostatic reaction in patients with advanced PD.

Advances in mobile and pervasive computing, social network technologies and the exponential growth in Internet applications and services will lead to the development of the Internet of Things (IoT). The IoT services will be a key enabling technology to the development of smart infrastructures that will revolutionize the way we do business, manage critical services, and how we secure, protect, and entertain ourselves. Large-scale IoT applications, such as critical infrastructures (e.g., smart grid, smart transportation, smart buildings, etc.) are distributed systems, characterized by interdependence, cooperation, competition, and adaptation. The integration of IoT premises with sensors, actuators, and control devices allows smart infrastructures to achieve reliable and efficient operations, and to significantly reduce operational costs. However, with the use of IoT, we are experiencing grand challenges to secure and protect such advanced information services due to the significant increase in the attack surface. The interconnections between a growing number of devices expose the vulnerability of IoT applications to attackers. Even devices which are intended to operate in isolation are sometimes connected to the Internet due to careless configuration or to satisfy special needs (e.g., they need to be remotely managed). The security challenge consists of identifying accurately IoT devices, promptly detect vulnerabilities and exploitations of IoT devices, and stop or mitigate the impact of cyberattacks. An Intrusion Detection System (IDS) is in charge of monitoring the behavior of protected systems and is looking for malicious activities or policy violations in order to produce reports to a management station or even perform proactive countermeasures against the detected threat. Anomaly behavior detection is a technique that aims at creating models for the normal behavior of the network and detects any significant deviation from normal operations. With the ability to detect new and novel attacks, the anomaly detection is a promising IDS technique that is actively pursued by researchers. Since each IoT application has its own specification, it is hard to develop a single IDS which works properly for all IoT layers. A better approach is to design customized intrusion detection engines for different layers and then aggregate the analysis results from these engines. On the other hand, it would be cumbersome and takes a lot of effort and knowledge to manually extract the specification of each system. So it will be appropriate to formulate our methodology based on machine learning techniques which can be applied to produce efficient detection engines for different IoT applications. In this dissertation we aim at formalizing a general methodology to perform anomaly behavior analysis for IoT. We first introduce our IoT architecture for smart infrastructures that consists of four layers: end nodes (devices), communications, services, and application. Then we show our multilayer IoT security framework and IoT architecture that consists of five planes: function specification or model plane, attack surface plane, impact plane, mitigation plane, and priority plane. We then present a methodology to develop a general threat model in order to recognize the vulnerabilities in each layer and the possible countermeasures that can be deployed to mitigate their exploitation. In this scope, we show how to develop and deploy an anomaly behavior analysis based intrusion detection system (ABA-IDS) to detect anomalies that might be triggered by attacks against devices, protocols, information or services in our IoT framework. We have evaluated our approach by launching several cyberattacks (e.g. Sensor Impersonation, Replay, and Flooding attacks) against our testbeds developed at the University of Arizona Center for Cloud and Autonomic Computing. The results show that our approach can be used to deploy effective security mechanisms to protect the normal operations of smart infrastructures integrated to the IoT. Moreover, our approach can detect known and unknown attacks against IoT with high detection rate and low false alarms.

Abstract Patients with idiopathic Parkinson's disease (PD) may suffer from autonomic nervous system dysfunction even in the early phase of the disease. We assessed the autonomic cardiovascular and sudomotor regulation in de novo PD patients with and without medication. We also measured the dopamine (DAT) and serotonin transporter (SERT) uptake in the PD patients using 2β-carboxymethoxy-3β-(4-iodophenyl)tropane (β-CIT) SPECT and studied the clinical correlates of the uptake. Sixty PD patients were included in the study and randomised to receive levodopa, bromocriptine or selegiline (n=20 in each) as their treatment. Thirty patients were examined with β-CIT SPECT. The results of the patients were compared with those of healthy controls and within the subgroups at different time points. Cardiovascular autonomic regulation was assessed using standard cardiovascular reflex tests at baseline, after six months' medication and following a 6-week washout period. The heart rate (HR) and blood pressure (BP) regulation was impaired in PD patients at baseline, and PD medications modified the responses further. Bromocriptine and selegiline, in contrast to levodopa, increased the orthostatic BP fall and suppressed the BP response to isometric exercise. The long-term cardiovascular autonomic function was evaluated from ambulatory ECG recordings by analysis of traditional spectral and non-spectral components of HR fluctuation together with two-dimensional vector analysis and power-law relationship analysis of the HR dynamics. All spectral measures and the slope of the power-law relationship demonstrated impaired tonic cardiovascular regulation in the PD patients. Sympathetic sudomotor activity was evaluated using the sympathetic skin response (SSR). The major finding was suppression of the SSR amplitudes with an inverse correlation to clinical disability, whereas PD medication seemed to have only minor effects. The changes in amplitude and repetitiveness of the SSRs with normal adaptation suggest deficits at several levels of the SSR reflex arc. DAT uptake, assessed by β-CIT SPECT, was diminished in the striatum and especially the putamen of the PD patients, and correlated with the results of the cardiovascular reflex tests and ambulatory ECG recordings. Simultaneous measurement of SERT binding demonstrated decreased SERT availability in the thalamic and frontal areas. The results demonstrate disturbances of the reflectory and tonic cardiovascular autonomic regulation caused by PD itself. PD medications further modify the reflectory responses. The degenerative process in PD also involves the sympathetic sudomotor pathway. β-CIT SPECT provides a useful method for simultaneous assessment of DAT and SERT binding, demonstrating the deficit of serotonin metabolism in PD.