Essai cinique randomisé / Objectifs : Démontrer la supériorité de l’analgésie périopératoire optimale par rapport aux traitements analgésiques usuels ou conventionnels pour diminuer l'intensité de la douleur aiguë postopératoire (DAPO), la fréquence d'apparition de la douleur chronique post chirurgicale (DCPC) et améliorer la qualité de vie des patients. Méthodes : Un essai clinique randomisé à double insu, sur 57 patients ayant subi une trapéziectomie à l'hôpital Notre-Dame du CHUM. Après avoir reçu une analgésie locorégionale via un cathéter du plexus brachial, le groupe expérimental a reçu une perfusion de bupivacaïne 0,5%, débutée dans la salle de réveil et poursuivie pendant 72 h en ambulatoire, grâce à une pompe à perfusion. Le groupe de contrôle a reçu une solution saline. Les deux groupes ont reçu du célécoxib durant cette même période. L'évolution du profil de la douleur, du fonctionnement de la main et de la qualité de vie des patients ont été saisis à l'aide de questionnaires et de tests fonctionnels en préopératoire et pendant six mois de suivi. Les résultats ont été analysés à l'aide du modèle linéaire général. Une différence de 2 au niveau de l'intensité de la douleur, mesurée par l'échelle visuelle analogique (EVA : 0-10), a été considérée statistiquement significative. Résultats : Notre méthode a abouti à une diminution significative de l'intensité de la DAPO et de la douleur chronique (DC) par rapport à la méthode conventionnelle. Les activités générales, la qualité du sommeil et la concentration des patients étaient significativement meilleures chez le groupe qui a reçu la nouvelle méthode. De plus, dans ce groupe il y avait deux fois moins des patients qui ont continué à souffrir de DC que le groupe de contrôle. Conclusion : Dans la chirurgie de la main, une couverture analgésique périopératoire est essentielle pour réduire l’intensité de la DAPO, la fréquence de la DCPC et pour améliorer la qualité de vie des patients. Mots-clés : essai clinique, douleur chronique, chirurgie, main, analgésie préventive, plexus brachial. / Objectives: Demonstrate the superiority of Optimal Perioperative Analgesia compared to Usual Analgesic Treatment to reduce the intensity of Acute Postoperative Pain (APOP), the frequency of occurrence of Chronic Post Surgical Pain (CPSP) and improve patients’ quality of life. Methods: A double-blinded randomized clinical trial conducted in Notre-Dame Hospital on 57 patients who underwent a trapeziectomy. After locoregional analgesia via a catheter in the brachial plexus, the experimental group received an infusion of bupivacaine 0.5%, which started in the recovery room and continued for 72 h as an outpatient through an infusion pump. Meanwhile, the control group received a saline solution. Both groups took celecoxib during the same period. The evolution of pain profile, hand function and patients’ quality of life have been obtained using questionnaires and functional tests in the preoperative period and through months of follow-up. Results were analyzed using General Linear Model. A difference of 2 in the intensity of pain, measured by Visual Analogue Scale (VAS: 0-10), was considered statistically significant. Results: This method resulted in a significant decrease in the intensity of APOP and Chronic Pain (CP) compared to usual treatment. General activities, quality of sleep and patients’ concentration were better in the experimental group. Moreover, two times less patients continued to suffer from the CP than in the placebo group. Conclusion: In hand surgery, a perioperative analgesic coverage is necessary to reduce the APOP intensity, the CPSP frequency and to improve patients’ quality of life. Keywords: clinical trial, chronic pain, surgery, hand, preemptive analgesia, brachial plexus.

Objectifs : Démontrer la supériorité de l’analgésie périopératoire optimale par rapport aux traitements analgésiques usuels ou conventionnels pour diminuer l'intensité de la douleur aiguë postopératoire (DAPO), la fréquence d'apparition de la douleur chronique post chirurgicale (DCPC) et améliorer la qualité de vie des patients. Méthodes : Un essai clinique randomisé à double insu, sur 57 patients ayant subi une trapéziectomie à l'hôpital Notre-Dame du CHUM. Après avoir reçu une analgésie locorégionale via un cathéter du plexus brachial, le groupe expérimental a reçu une perfusion de bupivacaïne 0,5%, débutée dans la salle de réveil et poursuivie pendant 72 h en ambulatoire, grâce à une pompe à perfusion. Le groupe de contrôle a reçu une solution saline. Les deux groupes ont reçu du célécoxib durant cette même période. L'évolution du profil de la douleur, du fonctionnement de la main et de la qualité de vie des patients ont été saisis à l'aide de questionnaires et de tests fonctionnels en préopératoire et pendant six mois de suivi. Les résultats ont été analysés à l'aide du modèle linéaire général. Une différence de 2 au niveau de l'intensité de la douleur, mesurée par l'échelle visuelle analogique (EVA : 0-10), a été considérée statistiquement significative. Résultats : Notre méthode a abouti à une diminution significative de l'intensité de la DAPO et de la douleur chronique (DC) par rapport à la méthode conventionnelle. Les activités générales, la qualité du sommeil et la concentration des patients étaient significativement meilleures chez le groupe qui a reçu la nouvelle méthode. De plus, dans ce groupe il y avait deux fois moins des patients qui ont continué à souffrir de DC que le groupe de contrôle. Conclusion : Dans la chirurgie de la main, une couverture analgésique périopératoire est essentielle pour réduire l’intensité de la DAPO, la fréquence de la DCPC et pour améliorer la qualité de vie des patients. Mots-clés : essai clinique, douleur chronique, chirurgie, main, analgésie préventive, plexus brachial. / Objectives: Demonstrate the superiority of Optimal Perioperative Analgesia compared to Usual Analgesic Treatment to reduce the intensity of Acute Postoperative Pain (APOP), the frequency of occurrence of Chronic Post Surgical Pain (CPSP) and improve patients’ quality of life. Methods: A double-blinded randomized clinical trial conducted in Notre-Dame Hospital on 57 patients who underwent a trapeziectomy. After locoregional analgesia via a catheter in the brachial plexus, the experimental group received an infusion of bupivacaine 0.5%, which started in the recovery room and continued for 72 h as an outpatient through an infusion pump. Meanwhile, the control group received a saline solution. Both groups took celecoxib during the same period. The evolution of pain profile, hand function and patients’ quality of life have been obtained using questionnaires and functional tests in the preoperative period and through months of follow-up. Results were analyzed using General Linear Model. A difference of 2 in the intensity of pain, measured by Visual Analogue Scale (VAS: 0-10), was considered statistically significant. Results: This method resulted in a significant decrease in the intensity of APOP and Chronic Pain (CP) compared to usual treatment. General activities, quality of sleep and patients’ concentration were better in the experimental group. Moreover, two times less patients continued to suffer from the CP than in the placebo group. Conclusion: In hand surgery, a perioperative analgesic coverage is necessary to reduce the APOP intensity, the CPSP frequency and to improve patients’ quality of life. Keywords: clinical trial, chronic pain, surgery, hand, preemptive analgesia, brachial plexus. / Essai cinique randomisé

La paralysie obstétricale du plexus brachial (POPB) est une paralysie du membre supérieur qui survient à la naissance et peut entraîner une déformation de l'articulation et un fonctionnement anormal de l'épaule. Bien que le traitement de la POPB tente de restaurer la fonction de l'épaule, la pathomécanique sous-jacente n'est pas encore clairement comprise. Les modèles computationnels sont efficaces pour fournir de telles informations, mais il n'existe aucun modèle d'articulation de l'épaule pédiatrique pour comprendre la POPB. Ainsi, ce travail de recherche a pour but de construire un framework combinant les avancées dans les domaines de la modélisation statistique de forme (MSF) et de la modélisation musculo-squelettique multi-corps (MCM). Due à l’insuffisance des données dans la cohorte pédiatrique, ce cadre a été mis en place pour l'articulation de l'épaule adulte. Pour cela, la précision de la MSF a été illustrée en prédisant 1) la forme de l'omoplate pré-morbide, et 2) les régions d'insertion musculaire sur l'omoplate et l'humérus. Cette méthode a ensuite été intégrée aux modèles MCM pour l'épaule adulte pour souligner l’importance des modèles spécifique-patient pour l’usage clinique. Pour le second objectif de cette thèse, j'ai développé un modèle MCM pédiatrique du complexe articulaire de l'épaule en utilisant le logiciel OpenSim. Grâce aux approches de cinématique et dynamique inverse, le modèle a permis de déterminer les différences de dynamique articulaires entre le côté sain et le côté pathologique. Les travaux futurs seront axés sur l’extension du travail réalisé pour la population pédiatrique afin de comprendre la pathomécanique de POPB. / Obstetrician Brachial Plexus Palsy (OBPP) is a common birth injury in children leading to shoulder joint deformity and abnormal function. While the management of OBPP disorder focuses on restoring the shoulder joint function, the underlying pathomechanics is not clearly understood yet. Computational models are effective to provide such insights, however, there is no pediatric shoulder joint model to understand the OBPP disorder. Thus, the global aim of this research work was to build a computational framework combining the advances in statistical shape modeling (SSM) and multi-body musculoskeletal modeling (MSKM) domains. Due to a lack of sufficient data in the pediatric cohort, I first developed the framework for adult shoulder joint. For this, I illustrated the accuracy of SSM in predicting 1) missing part of the scapula, and 2) muscle insertion regions on scapula and humerus bones. This method was then integrated with adult shoulder MSKMs to show the differences between generic and subject specific constructs. For the second aim of this thesis, I developed a pediatric MSKM of the shoulder joint complex using OpenSim software. Pediatric MSKM represented scapulothoracic, sternoclavicular, acromioclavicular, and glenohumeral joints with 13 degrees of freedom, and actuated by 52 musculotendon actuators representing 14 shoulder muscles. Using inverse kinematics and inverse dynamics approaches, the model was used to determine the differences in joint kinematics, and joint dynamics between healthy and unhealthy side of a single OBPP subject. Future work is focused on completing the framework on pediatric population and understanding the pathomechanics of OBPP.

INTRODUÇÃO: A recuperação de sensibilidade protetora na mão deve fazer parte da estratégia na reconstrução cirúrgica das lesões completas do plexo braquial. Existem poucos nervos doadores de fibras sensitivas disponíveis e há poucos trabalhos relacionados na literatura. Um possível doador é o nervo intercostobraquial (NICB), que é o ramo cutâneo lateral do segundo nervo intercostal que inerva a pele da região póstero-medial do braço e da axila. OBJETIVOS: Avaliar a viabilidade anatômica de utilização do NICB como doador de fibras sensitivas para a contribuição do cordão lateral para o nervo mediano (CLNM) e comparar o número de fibras do NICB e da CLNM, para analisar a compatibilidade anatômica entre esses nervos. MÉTODOS: Trinta cadáveres adultos não fixados foram dissecados no Serviço de Verificação de Óbitos da Capital da Universidade de São Paulo, São Paulo, Brasil. Dados de sexo, altura e peso foram registrados. O NICB e o plexo braquial infraclavicular à direita foram expostos e parâmetros anatômicos como número de ramos na origem, diâmetro e divisões no curso do NICB foram mensurados, caracterizados e registrados, assim como o diâmetro da CLNM. As distâncias entre a origem do NICB e seu ponto de divisão e ponto de coaptação com a CLNM também foram medidas e registradas. Fragmentos de nervos foram retirados dos últimos dez espécimes para análise histomorfométrica com contagem do número de fibras de quatro nervos: NICB, nervo supraclavicular (NSC), terceiro nervo intercostal (3ºNIC) e CLNM. RESULTADOS: Oito cadáveres eram do sexo feminino e 22 do masculino. A média de idade, altura e peso foram, respectivamente, 62 anos, 166 cm e 59,5 Kg. O diâmetro médio do NICB na sua origem foi de 2,1 mm e no seu ponto de coaptação de 2,7 mm. O diâmetro médio da CLNM foi de 3,7 mm. Vinte e oito (93,3%) NICBs apresentaram-se como tronco único em sua origem e, em seu trajeto na axila, 22 deles (73,3%) se dividiram em 2 ramos, sete (23,3%) dividiram-se em três ramos e um atingiu o braço como tronco único. As distâncias médias entre a origem do NICB e o seu ponto de ramificação e de coaptação à CLNM foram 23,8 mm e 54 mm, respectivamente. Todos os NICBs dissecados tinham extensão suficiente para alcançar a CLNM. Os números médios de fibras do NICB, NSC, 3ºNIC e CLNM foram 984, 693, 470 e 5273, respectivamente. A análise estatística mostrou diferença significativa entre o NICB e o 3ºNIC, e entre a CLNM (receptor) e os outros potenciais nervos doadores (NICB, NSC e 3ºNIC). CONCLUSÕES: A transferência do NICB como um doador de axônios sensitivos para a CLNM foi anatomicamente viável. O NICB apresenta número de fibras maior do que o 3ºNIC, mas sem diferença significativa em comparação com o NSC. Considerando a importância da recuperação da sensibilidade protetora na mão, esta técnica pode se tornar importante contribuição em doentes com lesões completas do plexo braquial / INTRODUCTION: Restoration of protective sensory function in the hand should be mandatory in the surgical reconstruction of complete brachial plexus lesions. There are few available donors and related papers in the literature are scanty. One possible donor is the intercostobrachial nerve (ICBN), which is the lateral cutaneous branch of the second intercostal nerve that supplies the skin of the medial and posterior parts of the arm and the skin of the axilla. OBJECTIVES: To evaluate the anatomical viability of using the ICBN as a donor of sensitive axons to the lateral cord contribution to the median nerve (LCMN) and to compare the number of fibers of the ICBN, and the LCMN, to analyze the anatomical compatibility between these nerves. METHODS: Thirty non-fixed adult cadavers were dissected at the Serviço de Verificação de Óbitos da Capital of University of São Paulo, São Paulo, Brazil. Data of sex, height and weight were registered. The right ICBN and infraclavicular brachial plexus were exposed and measurements of diameters of the ICBN and of the LCMN were performed. Number of branches at ICBN origin and number of divisions were registered. Distances between the origin of the ICBN and its point of division and point of coaptation to the LCMN were also measured. Histomorphometric analysis of the last ten specimens was performed with fibers counting of four distal nerves: ICBN, supraclavicular nerve (SCN), third intercostal nerve (3rdICN) and LCMN. RESULTS: Eight cadavers were female and 22 male. The mean age, height and weight were, respectively, 62 yo, 166 cm and 59,5 Kg. The mean diameter of the ICBN at its origin was 2,1 mm and at its point of coaptation was 2,7 mm, and the mean diameter of the LCMN was 3,7 mm. Twenty eight (93,3%) ICBNs had only one branch at their origin and, in their axillary course, 22 of them (73,3%) divided in 2 branches, seven (23,3%) divided in 3 branches and one reached the arm as a single nerve. The divisions of the ICBN occurred in a mean distance of 23,8 mm from their origin. The mean distance between the origin of the ICBN and its point of coaptation to the LCMN was 54 mm. All the ICBNs dissected had enough extension to reach the LCMN. The mean numbers of fibers of the ICBN, SCN, 3rdICN and LCMN were 984, 693, 470 and 5273, respectively. Statistical analysis demonstrated significant difference between the ICBN and the 3rdICN, and between the LCMN (recipient) and the other potential donor nerves (ICBN, SCN and 3rdICN). CONCLUSIONS: This study demonstrated the anatomical feasibility of the transfer of the ICBN as a donor of sensitive axons to the LCMN. The ICBN has a number of fibers greater than that of the ICN, but without significant difference in comparison to the SCN. Considering the importance of the recovery of protective sensibility in the hand, this technique may become an important contribution in the treatment of patients with complete lesions of the brachial plexus

O uso de robôs como auxiliares na reabilitação, tanto para ganho de função, como para auxiliar na realização de atividades, é encontrado na literatura em estudos envolvendo acidente vascular encefálico. Diversos dispositivos robóticos têm sido desenvolvidos ao longo da última década para oferecer treinamento sensório-motor direcionado para pacientes com doenças neurológicas, como acidente vascular encefálico, propiciando melhora no desempenho motor dos membros superiores nesta população. Poucos estudos são encontrados sobre o uso de robôs em lesão do plexo braquial ou lesão na medula espinhal. Além disso, há pouca produção nacional relacionada a esse tema. Esse trabalho objetivou-se avaliar o uso de um instrumento robótico, Robô MOREw, que foi desenvolvido pela Escola de Engenharia de São Carlos - EESC - USP com o intuito de facilitação e ganho nos movimentos de flexão e extensão de punho. Dessa forma, pretendia-se a verificação do funcionamento do robô como auxiliar de reabilitação através de testes clínicos e sua aplicabilidade com indivíduos que sofreram lesão do plexo braquial ou lesão na medula espinhal. A metodologia escolhida é de Projeto de Produto que utiliza como proposta a divisão do projeto em quatro fases, sendo estas: projeto informacional, projeto conceitual, projeto preliminar e projeto detalhado. Foi dado enfoque ao projeto detalhado em testes de laboratório e clínicos para verificação do funcionamento e aplicabilidade do robô com voluntários. O estudo foi composto por 2 fases: FASE 1 - Adequação do MOREw: 10 participantes sem comprometimentos nos membros superiores e sem lesões associadas verificaram o funcionamento do robô. Após isso, modificações necessárias foram efetuadas. FASE 2 - Aplicabilidade do MOREw: Teste com 5 participantes que apresentaram diminuição do movimento no Membro Superior, sendo 3 com lesão do plexo braquial e 2 com lesão na medula espinhal que jogaram por 30 minutos uma vez por semana, durante 12 semanas. Nos resultados notou-se que as adequações do robô MOREw foram de extrema importância para o funcionamento adequado do equipamento robótico utilizado por sujeitos com limitação dos movimentos de membros superiores, tanto em relação à ergonomia, funcionamento do jogo e possibilidades de ajustes em programas de reabilitação. Os sujeitos que fizeram uso por 3 meses referiram grande satisfação, motivação e demonstraram maior empenho na reabilitação com o auxílio robótico, que foram corroborados pelos testes funcionais que apresentaram discreta melhora em relação à Amplitude de Movimento e Força Muscular dos membros superiores, além da melhora na pontuação na Escala Específica do Paciente. Assim, MOREw é uma opção a ser utilizada na reabilitação com sujeitos com LM e LPB. / The use of robots as aid in rehabilitation to gain function or to assist in activities performance is found in the literature involving stroke. Several robotic devices have been developed over the last decade to provide sensory-motor training in patients with neurological diseases such as stroke, leading to improvement in motor performance of the upper limbs in this population. Few studies using robot assistance are found in injuries like brachial plexus (BPI) or spinal cord (SCI). In addition, there is little national production related to this topic. The aim of this work was to evaluate the use of a robotic instrument, Robot MOREw, which was developed by the Engineering School of São Carlos - EESC - USP with the purpose to facilitate and/or gain wrist flexion and extension movements. Thus, it was intended to verify the functioning of the robot as a rehabilitation aid through clinical tests, and its applicability with individuals who suffered BPI or SCI. The methodology chosen was the Project Product Design that consists of four phases: informational, conceptual, preliminary and detailed project. This study focuses on the detailed project, which was tested at laboratory as well as with volunteers in clinical trials to verify the robot applicability and operation. The study consisted of 2 phases: Phase 1 - Adequacy: 10 participants with no involvement in the upper limbs and without associated lesions verified the robot functionality. After that, changes were made to the equipment. Phase 2 - Applicability: Tested with 5 participants who had decreased movement in the Upper Limb, 3 with BPI and 2 with SCI, using it 30 min once a week for 12 weeks. It was noticed that the MOREw adjustments were of extreme importance for the correct functionality of the equipment that was used by clients with upper limb deficit movements, regarding ergonomics aspects, game functioning and rehabilitation programs adjustments. The clients who used it for 3 months reported great satisfaction, motivation and demonstrated greater commitment to rehabilitation with robotic assistance, confirmed by functional tests that showed a slight improvement in relation to the range of motion and muscular strength of the upper limbs, besides the improvement on the Patient Specific Scale. MOREw can be an option for BPI and SCI rehabilitation.

No description available.

Until recently, tests of vascular structure, function and compliance have been used predominantly for assessing the efficacy of treatment – for example, aggressive medical therapy may yield improvements in vascular structure and function with a concomitant decrease in cardiac events. However, the role of abnormal vessel function in the development of atherosclerosis, and the relationship of structural changes in peripheral vessels with coronary disease might suggest that these tests could be used as a screening test for patients with subclinical coronary disease. At present, there is insufficient evidence to support the theory that normal vascular structure and function can rule out significant coronary disease, and indeed, such an association may be confounded by the presence of risk factors that alter these test results in the absence of significant coronary artery disease (CAD). The overall hypothesis of the studies undertaken in this thesis was that utilizing contemporary technology during ultrasonic and tonometric assessment of arterial structure, function and compliance, it is possible to non-invasively characterise both early and advanced arterial dysfunction and identify patients both at risk and with cardiovascular disease. The aim of these studies was to determine whether these tests can be used to guide intervention when arterial dysfunction is diagnosed and whether they are robust enough as a follow-up tool. The thesis initially reviews arterial structure, function and compliance and their relationship to cardiovascular risk and in particular, CAD. This review provides a rationale for the studies undertaken here to resolve clinical and technical issues as well as provide an insight into the tests chosen to assess arterial function. The second chapter discusses the methodology used in these studies to assess arterial structure, function and compliance, diagnose coronary artery disease and determine cardiovascular risk. They range from stress echocardiography for the diagnosis of CAD to tests for arterial structure (carotid intima-media thickness [IMT]), endothelial function (brachial artery reactivity [BAR]), local arterial distensibility (distensibility coefficient [DC]) and systemic or total arterial compliance (TAC). In addition, several methods will be discussed for assessing local arterial elasticity with a novel imaging technique. The rationale for using tests for arterial structure, function and compliance in patients with CAD as well as cardiovascular risk is examined in chapter 3. Chapter 3 examines the use of TAC, IMT and BAR in patients undergoing dobutamine stress echocardiography (DSE) in a group of patients with and without disease. TAC was neither an independent predictor of CAD risk or patients having CAD in this study. BAR was a predictor of risk status but not of patients having CAD. Only IMT was an independent predictor of both patients at risk for CAD and those with CAD. In chapter 3 both pulse pressure and total arterial compliance were only univariate predictors of risk for CAD. Chapter 4 examines three different methods of estimating TAC, all based on the two-element Windkessel model in 320 patients with and without cardiovascular risk. The pulse-pressure method (PPM) is based on a combination of pressure, obtained using applanation tonometry of the radial artery, and an estimate of stroke volume obtained by Doppler echocardiography of the left ventricular outflow and by 2D echocardiographic dimension of the left ventricular outflow tract. The area method (AM) is an integral variation of the Windkessel equations and is based on the derived central pressure waveform. The stroke volume-pulse pressure method (SVPP) is a simple ratio of stoke volume and pulse pressure. We conclude that they correlate well and show similar differences between groups with and without risk. The PPM had the smallest difference from the mean and standard deviation in Bland Altman analysis and we therefore used the PPM for most future studies. Chapter 5 discusses the use of tissue Doppler for the derivation of central pressure and determination of distensibility coefficient, a marker of local arterial elasticity. Tissue Doppler can be used to evaluate the low frequency, high amplitude signals which come from tissue by changing filtering settings on an ultrasound machine. Using off-line software, the tissue velocities can be extracted and with a processing algorithm, vessel wall displacement values over time can be generated. These vessel wall displacement values which are in microns (µm) can then be used to calculated distensibility coefficient which is calculated as 2*((net displacement/minD)/PP). We studied a large group of patients with and without cardiovascular risk and conclude that DC using tissue Doppler correlates highly with DC by B-mode and M-mode imaging and is also very reproducible. In a subgroup, the vessel displacement values were “calibrated” using mean and diastolic pressure and with specialised software and a transfer function, central pressure wave forms were reconstructed. In this study we conclude that the central pressure obtained using tissue Doppler displacement of the carotid artery correlates highly with that obtained using applanation tonometry although there are technical challenges involved. With the known prognostic value of pulse pressure, chapter 6 explores whether there is added benefit to measuring total arterial compliance over pulse pressure alone. Once again patients with and without disease were studied and we conclude that brachial pulse pressure correlates well with TAC in men with normal cardiac function. However, in women and in patients at the low and high extremes of function, and in patients with preclinical and overt cardiovascular disease, there appears to be incremental value in measuring TAC. The role of cardiovascular risk factors in association with TAC is examined in chapter 7. Several studies have shown that TAC is lower in certain groups due to age, height, hypertension, hyperlipidaemia or other factors. We studied 720 patients with and without cardiovascular risk factors and did several multiple linear regression models based on anthropomorphic variables. Age was an independent correlate of TAC in most of the regression models and we conclude that TAC is associated with multiple risk factors, but age is a major determinant. The influence of age and other correlates may dwarf the contribution of individual risk factors and therefore their alteration with therapy. Chapter 8 examines the correlates of preclinical cardiovascular disease in both indigenous and non-indigenous Australians with and without diabetes mellitus (DM). DM is a major health problem in the Indigenous population in Australia and CVD occurs earlier in this group than in caucasians and is responsible for 1/3 of all deaths. We studied a large group of indigenous Australians with and without DM and matched them to a caucasian population. There were no differences in BAR between the groups probably due to large standard deviations in the measurements. In assessing DC, both DM groups had significantly lower DC than the non-DM groups. However, in the IMT analysis both of the indigenous groups had significantly higher IMT than their caucasian counterparts and even after IMT was corrected for age, Indigenous patients even at an early age had significantly higher IMT. We conclude that despite a high incidence of risk factors in indigenous Australians both with and without DM, ethnicity (and various other risk factors for which it is a marker) appears to be an independent predictor of preclinical cardiovascular disease. In chapter 3 we determined that TAC was not an independent correlate of patients either at risk of CAD or with CAD. Chapter 9 discusses the results of a study of patients presenting for stress echocardiography for either detection of CAD or risk stratification. Ischaemia was detected in 25% of cases and TAC was similar in those with and without ischaemia. In multiple linear regression models however, in addition to cardiovascular risk factors TAC was independently associated with both the presence of CAD and the extent of ischaemia at stress echocardiography. Several studies have used vascular function as an outcome measure in intervention trials, either lifestyle or pharmacologic. In chapter 10 we undertook a lifestyle and diet intervention study in a large group of healthy patients with type-II DM. The tests for IMT, BAR and TAC were used in addition to biochemical markers and fitness assessment. At follow-up the intervention group had significant changes in weight and BMI and significantly increased fitness but failed to show any changes in any of the vascular parameters. We conclude that while metabolic and fitness parameters respond to treatment in patients with type-II DM, the early changes seen in vascular structure, function and compliance may not change in the long term. Although TAC has been correlated with hypertension, LVH, myocardial ischaemia and heart failure there are few data existing regarding the relationship of TAC to outcome. In the final chapter of this thesis we sought whether TAC was predictive of outcome in a large, primary prevention group of patients with varying degrees of cardiovascular risk. We followed up 719 patients who were studied between 2001 and 2008 in Brisbane, Australia and examined TAC in relation to mortality and a composite endpoint of death or hospital admission. There were significant differences in groups having low and normal TAC for both death and the composite endpoint and in patients with intermediate and high Framingham 10-year risk TAC was an independent predictor of both death and the composite endpoint. We conclude that TAC correlates with outcome in patients with varying degrees of cardiovascular risk and also adds incremental benefit to Framingham risk alone in patients with intermediate risk.

[Formulae and special characters can only be approximated here. Please see the pdf version of the abstract for an accurate reproduction.] Two randomised controlled trials were conducted to explore the relationship between the consumption of alcoholic beverages and cardiovascular disease risk factors. Study 1 was primarily designed to test the hypothesis that the cardio-protective effect of light alcohol could be mediated, in part, via improvements in endothelial function. Study 1 was also designed to explore the effect of alcohol on both traditional risk factors for cardiovascular disease, such as changes in lipid profile, haemostatic factors and blood pressure, and novel risk factors such as homocysteine, markers of inflammation and oxidative stress. The experimental design of this study also allowed us to determine whether reducing alcohol intake in these moderate-to-heavy drinkers could improvement insulin sensitivity, a component of the metabolic syndrome. In this group of sixteen healthy middle-aged men with a history of moderate to heavy alcohol intake of seven standard drinks per day, reducing intake down to approximately one standard drink per day for four weeks had no beneficial effects on conduit vessel endothelial function as assessed by post-ischaemic brachial artery flow-mediated dilatation, nor were there any detectable changes in soluble E-selectin, endothelin-1 and von Willebrand Factor, which are considered biomarkers of endothelial activation. As this study did not investigate the effect of alcohol on endothelial function in resistance vessels, it cannot exclude the possibility that alcohol may affect endothelial cells resident in that vascular bed. This study does show and confirm, however, that the relationship between alcohol and risk factors for cardiovascular disease is an extremely complex one. On the one hand it demonstrated that alcohol was potentially harmful, increasing blood pressure, plasma F2-isoprostane (oxidative stress), and homocysteine. On the other hand it showed that increasing alcohol intake led to significant reductions in two (i.e. fibrinogen and IL-6) of five inflammatory markers, in addition to improving the HDL-cholesterol profile of these subjects. Although the effects of alcohol on blood pressure, fibrinogen and HDL-cholesterol are not in themselves new, they support our choice of study design and strengthen the argument in favour of accepting the more novel findings of this study, specifically, the lack of effect on endothelial function and insulin sensitivity, and the harmful effect of alcohol in increasing oxidative stress and homocysteine. Study 2 was primarily designed to test the hypothesis that the consumption of red wine may confer greater cardio-protection than beer via improvements in endothelial function. Simultaneously, the study was also designed to determine whether drinking red wine for 4-weeks would have different effects than beer on either traditional risk factors for cardiovascular disease (i.e. blood pressure and lipid profile) or the more novel risk factors, homocysteine and oxidative stress. Using a randomised controlled cross-over study design, Study 2 provides evidence that the regular daily consumption of 4 standard drinks of either beer or red wine does not alter endothelial function, as measured by post-ischaemic flow-mediated vasodilatation of the brachial artery in healthy middle-aged men, nor was there evidence of any beneficial effect of de-alcoholised red wine on brachial artery response. As compliance with drinking protocol was confirmed with increased serum γ-GT and HDL during red wine and beer periods, and increased 24-hr urinary excretion of 4OMGA during red wine and de-alcoholised red wine periods, we are confident that there was excellent compliance with the beverage treatments. Study 2 also provides the first evidence from a carefully controlled intervention study that both red wine and beer elevate blood pressure to a similar degree, with no detectable difference in the magnitude of either treatment. As with endothelial function, there was also no evidence of any beneficial effect of de-alcoholised red wine on blood pressure. In addition, although post hoc analysis found evidence that alcohol increased both plasma homocysteine and urinary excretion of F2-isoprostane and endothelin-1, there was no apparent protective effect conferred from either red wine or de-alcoholised red wine on these cardiovascular risk markers. The results from this study cannot disprove the hypothesis that red wine is more beneficial for cardiovascular health; however, they suggest that if red wine has properties beyond those of beer to confer protection, they are not via any interactions with the nitric oxide regulatory function of the endothelium in conduit vessels nor are they via moderation of the vasopressor, homocysteine-raising, and oxidative stress effects of alcohol. The interpretation of the findings from both intervention studies and their place in the context of our current understanding of the role that alcoholic beverages play in the development and/or prevention of cardiovascular disease are explored in this thesis.

Introdução: Tem sido demonstrada uma associação entre a variabilidade da pressão arterial avaliada por diferentes índices e lesão em órgão-alvo, independentemente dos valores de pressão arterial. O índice tornozelo-braquial (ITB) é útil no diagnóstico de doença arterial oclusiva periférica, sendo reconhecido como marcador de aterosclerose sistêmica. Objetivo: Avaliar a associação entre três diferentes métodos de estimar a variabilidade da pressão arterial sistólica (taxa de variação da pressão no tempo - índice "time-rate", coeficiente de variabilidade, desvio padrão das médias da pressão arterial sistólica de 24 horas) e o índice tornozelo-braquial (ITB). Métodos: Em um estudo transversal, pacientes atendidos no ambulatório de hipertensão realizaram medida de ITB e Monitorização Ambulatorial da Pressão Arterial de 24 horas (MAPA). Três parâmetros de variabilidade foram avaliados: o índice "time-rate" definido como a primeira derivada da pressão arterial sistólica em relação ao tempo; desvio padrão (DP) das médias da pressão arterial sistólica (PAS) de 24 horas e coeficiente de variabilidade (CV=DP/média pressóricaX100%). O ITB aferido por doppler foi obtido pela razão entre a maior pressão arterial sistólica do tornozelo ou pediosa e a maior pressão sistólica dos braços. O ponto de corte para o diagnóstico de doença arterial periférica foi ITB <= 0,90 ou>= 1,40. Resultados: A análise incluiu 425 pacientes: 69,2% eram do sexo feminino, com idade média de 57±12 anos, 26,1% eram tabagistas e 22,1% tinham diabetes mellitus. ITB alterado foi detectado em 58 pacientes (13,6%). Para os grupos ITB normal e anormal o índice "time-rate", DP das médias e CV foram: 0,469±0,119 mmHg/min e 0,516± 0,146 mmHg/min (p=0,007); 12,6±3,7 mmHg e 13,2±4,7 mmHg (p=0,26); 9,3±2,9% e 9,3±2,6 % (p=0,91), respectivamente. No modelo de regressão logística, o "time-rate" foi associado com ITB, independentemente da idade (RR=6,9; 95% IC= 1,1-42,1; P=0,04). Em modelo de regressão linear múltipla demonstrou-se uma associação independente da idade, PAS de 24 horas e presença de diabetes mellitus. Conclusão: O índice "time-rate" foi o único parâmetro de variabilidade da pressão arterial sistólica associado com índice tornozelo-braquial e pode ser utilizado na estratificação de risco em hipertensos. Este parâmetro de variabilidade obtido por método não invasivo deve ser melhor investigado em estudos prospectivos. / Introduction: An association between the Blood Pressure Variability, estimated by different indexes, and target-organ damage has been established independently of blood pressure levels. The Ankle-Brachial Index (ABI) is useful in the diagnosis of peripheral arterial disease and it is recognized as a cardiovascular risk marker. Purpose: To evaluate the association between three different methods in estimating the variability of systolic blood pressure (rate of change of pressure over time - time rate index, coefficient of variability, standard deviation of the average 24-hour systolic blood pressure) and the ankle-brachial index (ABI). Methods: In a cross-sectional study, patients of a hypertension clinic underwent ABI measurement and 24-hour Ambulatory Blood Pressure Monitoring (ABPM). Variability was estimated according to three parameters: the time rate index, defined as the first derivative of systolic blood pressure at the time; standard deviation (SD) of 24-hour systolic blood pressure (SBP); and coefficient of variability of 24-hour SBP (CV = SD / mean value X 100%). The ABI was measured by Doppler and obtained by dividing the systolic blood pressure on the ankle or foot (whichever was higher) by the higher of the two systolic blood pressures on the arms. The cutoff point for diagnosis of peripheral arterial disease was ABI<= 0.90 or>= 1.40. Results: The analysis included 425 patients: 69.2% were female, mean age was 57±12 years, 26.1% were current smokers and 22.1% diabetics. Abnormal ABI was detected in 58 patients (13.6%). For the normal and abnormal ABI groups the time rate index, the average SD and CV were 0.469 ± 0.119 mmHg/min and 0.516 ± 0.146 mmHg/min (p = 0.007), 12.6±3.7 mmHg and 13.2±4.7 mmHg (p = 0.26), 9.3±2.9% and 9.3±2.6% (p = 0.91), respectively. In the logistic regression model, time rate was associated with ABI, regardless of age (RR = 6.9, 95% CI = 1.1- 42.1; P = 0.04). The multiple linear regression model showed an association that was independent of age, 24-hour SBP and presence of diabetes. Conclusion: The time rate index was the only measurement of variability of systolic blood pressure associated with ankle-brachial index, and might be used for risk stratification in hypertensive patients. This measurement of variability was obtained by a non-invasive method and should be better investigated in prospective studies.

Introdução: Tem sido demonstrada uma associação entre a variabilidade da pressão arterial avaliada por diferentes índices e lesão em órgão-alvo, independentemente dos valores de pressão arterial. O índice tornozelo-braquial (ITB) é útil no diagnóstico de doença arterial oclusiva periférica, sendo reconhecido como marcador de aterosclerose sistêmica. Objetivo: Avaliar a associação entre três diferentes métodos de estimar a variabilidade da pressão arterial sistólica (taxa de variação da pressão no tempo - índice "time-rate", coeficiente de variabilidade, desvio padrão das médias da pressão arterial sistólica de 24 horas) e o índice tornozelo-braquial (ITB). Métodos: Em um estudo transversal, pacientes atendidos no ambulatório de hipertensão realizaram medida de ITB e Monitorização Ambulatorial da Pressão Arterial de 24 horas (MAPA). Três parâmetros de variabilidade foram avaliados: o índice "time-rate" definido como a primeira derivada da pressão arterial sistólica em relação ao tempo; desvio padrão (DP) das médias da pressão arterial sistólica (PAS) de 24 horas e coeficiente de variabilidade (CV=DP/média pressóricaX100%). O ITB aferido por doppler foi obtido pela razão entre a maior pressão arterial sistólica do tornozelo ou pediosa e a maior pressão sistólica dos braços. O ponto de corte para o diagnóstico de doença arterial periférica foi ITB <= 0,90 ou>= 1,40. Resultados: A análise incluiu 425 pacientes: 69,2% eram do sexo feminino, com idade média de 57±12 anos, 26,1% eram tabagistas e 22,1% tinham diabetes mellitus. ITB alterado foi detectado em 58 pacientes (13,6%). Para os grupos ITB normal e anormal o índice "time-rate", DP das médias e CV foram: 0,469±0,119 mmHg/min e 0,516± 0,146 mmHg/min (p=0,007); 12,6±3,7 mmHg e 13,2±4,7 mmHg (p=0,26); 9,3±2,9% e 9,3±2,6 % (p=0,91), respectivamente. No modelo de regressão logística, o "time-rate" foi associado com ITB, independentemente da idade (RR=6,9; 95% IC= 1,1-42,1; P=0,04). Em modelo de regressão linear múltipla demonstrou-se uma associação independente da idade, PAS de 24 horas e presença de diabetes mellitus. Conclusão: O índice "time-rate" foi o único parâmetro de variabilidade da pressão arterial sistólica associado com índice tornozelo-braquial e pode ser utilizado na estratificação de risco em hipertensos. Este parâmetro de variabilidade obtido por método não invasivo deve ser melhor investigado em estudos prospectivos. / Introduction: An association between the Blood Pressure Variability, estimated by different indexes, and target-organ damage has been established independently of blood pressure levels. The Ankle-Brachial Index (ABI) is useful in the diagnosis of peripheral arterial disease and it is recognized as a cardiovascular risk marker. Purpose: To evaluate the association between three different methods in estimating the variability of systolic blood pressure (rate of change of pressure over time - time rate index, coefficient of variability, standard deviation of the average 24-hour systolic blood pressure) and the ankle-brachial index (ABI). Methods: In a cross-sectional study, patients of a hypertension clinic underwent ABI measurement and 24-hour Ambulatory Blood Pressure Monitoring (ABPM). Variability was estimated according to three parameters: the time rate index, defined as the first derivative of systolic blood pressure at the time; standard deviation (SD) of 24-hour systolic blood pressure (SBP); and coefficient of variability of 24-hour SBP (CV = SD / mean value X 100%). The ABI was measured by Doppler and obtained by dividing the systolic blood pressure on the ankle or foot (whichever was higher) by the higher of the two systolic blood pressures on the arms. The cutoff point for diagnosis of peripheral arterial disease was ABI<= 0.90 or>= 1.40. Results: The analysis included 425 patients: 69.2% were female, mean age was 57±12 years, 26.1% were current smokers and 22.1% diabetics. Abnormal ABI was detected in 58 patients (13.6%). For the normal and abnormal ABI groups the time rate index, the average SD and CV were 0.469 ± 0.119 mmHg/min and 0.516 ± 0.146 mmHg/min (p = 0.007), 12.6±3.7 mmHg and 13.2±4.7 mmHg (p = 0.26), 9.3±2.9% and 9.3±2.6% (p = 0.91), respectively. In the logistic regression model, time rate was associated with ABI, regardless of age (RR = 6.9, 95% CI = 1.1- 42.1; P = 0.04). The multiple linear regression model showed an association that was independent of age, 24-hour SBP and presence of diabetes. Conclusion: The time rate index was the only measurement of variability of systolic blood pressure associated with ankle-brachial index, and might be used for risk stratification in hypertensive patients. This measurement of variability was obtained by a non-invasive method and should be better investigated in prospective studies.