Orientador: Suzana Erico Tanni / Resumo: O tabagismo é um dos mais importantes problemas de saúde mundial por causar dependência e por atingir todas as faixas etárias e classes sociais. É um dos fatores de risco para infarto agudo do miocárdio, e sua exposição passiva pode elevar o risco para doenças coronarianas. Além do reconhecimento dos efeitos agressores diretos da fumaça do cigarro em doenças coronarianas, o tabagismo pode agredir o miocárdio sendo capaz de colaborar com o processo de remodelação cardíaca. Um dos possíveis mecanismos para esse processo é o acumulo de ácidos graxos no miocárdio, consequente diminuição da β-oxidação, acumulo de triglicérides, aumento da glicólise, disfunção e atrofia mitocondrial que resultam na lipotoxicidade. Objetivos: Avaliar as variações da função, morfologia cardíaca e deposição de ácidos graxos antes e após a cessação do tabagismo e avaliar associações entre a variável dependente e a variação das funções e morfometrias. Métodos: Foram incluídos fumantes entre 30 e 45 anos com carga tabágica de no mínimo 10 anos/maço e consumo tabágico de pelo menos 1 cigarro/dia no último mês. Foi realizada avaliação clínica, estado tabágico, avaliação laboratorial, ecocardiograma, ressonância magnética cardíaca, espectroscopia de prótons; no momento inicial e um mês após a cessação do tabagismo. Para tratamento da cessação tabágica foi utilizado o medicamento bupropiona. Resultados: Foram avaliados 50 tabagistas, 29 foram incluídos, porém apenas 10 participaram de ambas as avaliações sen... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Smoking is one of the most important global health problems to cause addiction and reach all ages and social classes. It is one of the risk factors for acute myocardial infarction, and their passive exposure may increase the risk for coronary heart disease. In addition to the recognition of the direct aggressive effects of cigarette smoke on coronary heart disease, smoking can attack the myocardium and be able to collaborate with the cardiac remodeling process. One of the possible mechanisms for this process is the accumulation of fatty acids in the myocardium, consequent reduction of β-oxidation, accumulation of triglycerides, increased glycolysis, dysfunction and mitochondrial atrophy that result in lipotoxicity. Objectives: To evaluate variations in function, cardiac morphology and deposition of fatty acids before and after cessation of smoking and to evaluate associations between the dependent variable and the variation of functions and morphometrics. METHODS: Smokers aged between 30 and 45 years with a smoking load of at least 10 years / pack and smoking of at least 1 cigarette / day in the last month were included. Clinical evaluation, smoking status, laboratory evaluation, echocardiogram, cardiac magnetic resonance, proton spectroscopy; at the initial time and one month after cessation of smoking. For the treatment of smoking cessation, the drug bupropion was used. Results: Fifty smokers were evaluated, 29 were included, but only 10 participated in both evaluations and... (Complete abstract click electronic access below) / Doutor

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is still a syndrome generating more questions than answers. Today, research focuses mainly on two areas: understanding the pathophysiology – especially how the malfunctioning CSF system affects the brain parenchyma – and finding better methods to select patients benefiting from a shunt operation. This thesis targets the aspect of finding better selection methods by investigating the measurability of intracranial pressure via lumbar space, and determining if intraparenchymal measurement of long-term ICP-oscillations (B-waves) could be replaced by short-term measurements of CSF pulse pressure waves via lumbar space. Furthermore, I look into the interaction between the CSF system and the parenchyma itself by investigating how the cortical activity of the brain changes after long-term CSF drainage, and if there is any regress in the suggested ischemia after this intervention. Finally, I examine if the neuronal integrity in the INPH brain is impaired, and if this feature is relevant for the likeliness of improvement after CSF diversion. METHODS: The comparison of intracranial and lumbar pressure was made over a vast pressure interval using our unique CSF infusion technique, and it included ten INPH patients. Pressure was measured via lumbar space and in brain tissue, and the pressures were compared using a general linear model. Short-term lumbar pressure waves were quantified by determining the slope between CSF pulse pressure and mean pressure, defined as the relative pulse pressure coefficient (RPPC). The correlation between RPPC, B-waves and CSF outflow resistance was investigated. In a prospective study, functional MRI was used to assess brain activity before and after long-term CSF drainage of 400 ml of CSF in eleven INPH patients. The functionalities tested included finger movement, memory, and attention. The results were benchmarked against the activity in ten healthy controls to identify the brain areas improving after drainage. The ischemia (Lactate) and neuronal integrity (NAA and Choline) were measured in a similar manner in 16 patients using proton MR spectroscopy, and the improvement of the patients after CSF drainage was based on assessment of their gait. RESULTS: There was excellent agreement between ICP measured in brain tissue and via lumbar space (regression coefficient = 0.98, absolute difference < 1 mm Hg). Adjusting for the separation distance between the measuring devices slightly worsened the agreement, indicating other factors influencing the measured difference as well. RPPC measured via lumbar space significantly correlated to the presence of B-waves, but not to outflow resistance. In the prospective study, controls outperformed patients on clinical tests as well as tasks related to the experiments. Improved behaviour after CSF drainage was found for motor function only, and it was accompanied by increased activation in the supplementary motor area (SMA). No lactate was detected, either before or after CSF drainage. NAA was decreased in INPH patients compared to controls, and the NAA levels were higher in the patients improving after drainage. CONCLUSIONS: ICP can be accurately measured via lumbar space in patients with communicating CSF systems. The close relation between RPPC and B-waves indicates that B-waves are primarily related to intracranial compliance, and that measurement of RPPC via lumbar space could possibly substitute B-wave assessment as selection method for finding suitable patients for shunt surgery. Improvement in motor function after CSF drainage was associated to enhanced activity in SMA, supporting the involvement of the cortico-basal ganglia-thalamo-cortical loop in the pathophysiology of INPH. There was no evidence indicating a widespread low-graded ischemia in INPH; however, there was a neuronal dysfunction in frontal white matter as indicated by the reduced levels of NAA. In addition, the level of neuronal dysfunction was related to the likeliness of improvement after CSF removal, normal levels of NAA predisposing for recovery.

NMR spectroscopy is a very powerful technique for the characterization of structure and dynamics of a variety of systems starting from small organic molecules to large biological macromolecules. In solids, the study of protons becomes more interesting because they are very sensitive to inter-molecular packing and are directly involved in hydrogen-bonding and aromatic π-π interactions, etc. The present thesis is devoted essentially to utilizing information from proton resonances obtained using multinuclear and multiple-quantum approaches. The thesis has two parts. The first part deals with methodological developments in the area of solid-state NMR, relevant to the study of rigid powder samples as well as partially ordered liquid crystalline materials. Methods have been proposed to investigate the structure of small molecules at moderate spinning frequencies and thermotropic liquid crystals at static conditions. Proton detected heteronuclear experimental methods based on both first and second-order cross polarization at moderate and ultra-fast magic angle spinning rates are also proposed. The second part of the thesis deals with the application of both newly proposed and existing solid state NMR methods to the study of several biologically relevant systems. These include the study of several designed as well as naturally occurring peptides. The use of first-principles calculations based on GIPAW method for supporting the experimentally obtained results has also been made. The thesis is divided into five chapters. In the second chapter, a new pulse sequence to correlate Double Quantum (DQ) proton frequencies to carbon Single Quantum (SQ) chemical shifts in the solid state has been proposed. In this sequence, named as MAS-J-1H (DQ)-13C-HMQC, the correlation between 1H and 13C is achieved through scalar coupling, while the double-quantum coherence among protons is generated through dipolar couplings. This experiment is particularly suited for the study of 13C in natural abundance. The advantages of the technique with applications to alanine, histidine and a model liquid crystalline material have been demonstrated. The assignment of 13C spectra of partially ordered systems has also been considered. In this case the assignment of the spectrum is a major challenge due to the interplay of anisotropic order and chemical shift parameters. The DQ-SQ correlation experiment described in the thesis has been applied to a well known liquid crystal and also to a novel thiophene based liquid crystal and the local order parameters of the liquid-crystal have been obtained. The thesis also presents results on the azelaic acid -isonicotinamide co-crystal as well as the drug ibuprofen obtained by using novel methodologies. In the case of the former, the problem of overlap of resonances was overcome with the use of the REVERSE-CP approach to separate out the carbon attached protons from the rest of the protons. Subsequently, by the use of several combined approaches, the structural features were identified. A new heteronuclear correlation pulse sequence for solids under fast MAS conditions has also been tested. With low r.f powers, a second-order dipolar term mediated transfer of magnetization between I and S spin known as second order cross-polarization (SOCP) was exploited to obtain the entire spin system connectivity. Both carbon detected and proton detected experiments have been carried out and their utility evaluated. Similar approaches to shed light on the structure and conformation of a set of proline and pseudoproline based designed β-turn peptides that are used as templates for understanding protein folding have been made. Results of studies on two biologically important forms of the short-chain peptides namely glutathione reduced (GSH) and oxidized (GSSG) tripeptides are also presented.