Proefschrift Universiteit Maastricht. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

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Research conducted as part of the MIT World Oil Project and funded by the RANN Division of the National Science Foundation under Grant no. DAR78-19044.

Th.--Sci. phys.--Nancy--I.N.P.L., 1985.

Th.--Sci. phys.--Toulouse--I.N.P., 1977. N°: 22.

Quantitative studies of global radiation damage are presented for two different types of experiments in structural biology: macromolecular crystallography (MX) and small angle X-ray scattering (SAXS) MX is the most common technique to elucidate the atomic resolution structures of biological macromolecules. However, these molecules undergo radiation induced changes during the experiment that undesirably affect the data. Global radiation damage, which is characterised by an overall loss in the diffracted intensity of Bragg reflections, limits the amount of useful data that can be collected from a single crystal in an experiment. Furthermore, for experimental phasing experiments, the radiation induced intensity changes can be so significant that the phasing signal becomes undetectable, thereby hindering successful structure determination. This thesis investigates methods to track and correct the diffraction data that are affected as a result of global radiation damage. First, extensions to the diffraction weighted dose (DWD) metric are investigated for the ability of DWD to track the overall intensity decay of reflections. This metric then is combined with a new mathematical model of intensity decay to perform zero-dose extrapolation. An additional probabilistic extrapolation approach is incorporated into the traditional regression based approach to allow extrapolation of low multiplicity reflections. As an alternative approach, a new hidden Markov model representation of the data collection experiment is developed that allows the time-resolved calculation of structure factor amplitudes, with error estimates calculated explicitly. This method gives comparable refinement statistics to that obtained from data processed with the current data reduction pipeline, and improvements to the algorithm are proposed. SAXS, on the other hand, is a complementary structural technique that results in low resolution information about macromolecules. However it still requires the probing of the macromolecules with ionising radiation, so radiation induced changes are still a problem. Unfortunately the tools for assessing radiation damage in SAXS experiments are not mature enough for them to be used routinely. This thesis presents extensions to RADDOSE-3D to perform dose calculations for SAXS samples. Additionally, a free, open source Python library has been developed to allow the exploration and visualisation of the results of a similarity analysis of frames within a dataset. These tools are then used to determine the efficacy of various radioprotectant compounds at different concentrations to mitigate radiation damage effects.

El trabajo desarrollado tiene por objetivo reducir la dosis absorbida que reciben los pacientes en los exámenes de radiodiagnósticos con rayos X, mediante una evaluación de cada uno de los parámetros que modifican el espectro de rayos X. Por lo tanto, se analiza cómo se modifica el espectro de rayos X con la variación de los siguientes factores: el kilovoltaje en el tubo, la filtración y la corriente multiplicada por el tiempo (mAs), para ello, se determina primero el espectro continuo y discreto del haz de rayos X, empleando una simulación computacional, en donde usamos un programa que calcula la intensidad de los rayos X basados en la teoría de Birch y Marshall a partir de datos de entrada como valores de voltaje de tubo, filtración, corriente de tubo, ángulo del ánodo y factor de paso para la energía, luego, con la respuesta del programa (energía media y fluencia de fotones) y la teoría implicada se analiza la reducción del kerma en las técnicas propuestas. En este trabajo se ha reducido hasta en 56.69 % la dosis absorbida o el kerma para los pacientes en los exámenes radiográficos, Así como también, se propone la factibilidad de implementar, en forma alternativa, el uso de filtros de tantalio. Con la metodología desarrollada en este trabajo se demuestra que es posible optimizar e implementar nuevas técnicas radiológicas, las cuales reducen significativamente la dosis absorbida sobre el paciente, garantizando así la calidad y seguridad en los procedimientos de diagnóstico con rayos X. / --- This research aims to reduce absorbed dose of patients in clinical examinations using diagnostic X-ray, based on the results of the evaluation of each parameters that modify the X-ray spectrum. This study analyzes how to modify the X-ray spectrum with the variation of the following factors: tube potential (kVp), filtration and current multiplied by time (mAs). First, we determine the discrete and continuous X-ray spectrum using a computer simulation, this program that we use to calculate X-ray intensity is founded on the theory of Birch and Marshall. Moreover, from input data as values of tube potential, filtration, tube current, anode angle and a factor for energy, also with the program response (average energy and photon fluence), we analyze kerma reduction in the proposed techniques. We managed to reduce absorbed dose or kerma until 56,69 % in radiographic examinations. Besides this, we are studying the feasibility of implementing alternatively the use of tantalum filters in order to reduce absorbed dose of patients. The advantage of this methodology is that it is possible to optimize as well as implement new radiological techniques, which significantly reduce the absorbed dose. Therefore, guaranteeing the quality and safety in X-ray diagnostic procedures. / Tesis

O diabetes tipo 2 está atingindo proporções epidêmicas em todo o mundo. A Organização Mundial de Saúde estima que 9% dos adultos com mais de 18 anos têm diabetes, sendo a maioria classificada como tendo diabetes tipo 2. A elevada produção de glicose hepática, a redução da secreção de insulina, a resistência à insulina e as alterações do metabolismo da glicose normalmente encontrados em indivíduos com obesidade, são os principais fatores relacionados à patogênese do diabetes tipo 2 e da síndrome metabólica. A adiponectina é um hormônio regulador da homeostase da glicose e dos lipídios ao sensibilizar a ação da insulina. Uma vez que a redução da sensibilidade à insulina está relacionada ao diabetes tipo 2 e à síndrome metabólica, a diminuição dos níveis de adiponectina pode estar relacionada ao desenvolvimento dessas anormalidades metabólicas. Menores concentrações de adiponectina estão relacionadas com maior massa de gordura intraabdominal. Portanto, a adiponectina pode estabelecer um elo entre gordura intra-abdominal, resistência à insulina e desenvolvimento da síndrome metabólica. Dessa forma, o objetivo do primeiro estudo foi investigar a relação entre os níveis de adiponectina e a síndrome metabólica em uma análise transversal com duas populações distintas. Primeiramente, foram analisados indivíduos encaminhados para triagem e avaliação de anormalidades do metabolismo da glicose e síndrome metabólica, submetidos a um teste de tolerância oral à glicose, na unidade de diabetes do Serviço de Endocrinologia do Hospital de Clínicas de Porto Alegre e analisados pela presença da síndrome metabólica. Uma replicação da análise foi realizada em indivíduos submetidos à angiografia cardíaca no Hospital São Paulo da Universidade Federal de São Paulo. Neste estudo, também foi de nosso interesse determinar quais os componentes da síndrome metabólica estavam relacionadas aos níveis de adiponectina. Além disso, analisamos como a resistência e a sensibilidade à insulina e a inflamação subclínica estavam relacionadas com os níveis de adiponectina. Os níveis de adiponectina total e de alto peso molecular estão mais baixos na presença da síndrome metabólica e reduzem com o aumento do número de critérios para síndrome metabólica. Os níveis de adiponectina são, em parte, determinados por sua relação com o colesterol HDL, os triglicerídeos e a adiposidade abdominal. Além disso, a inflamação subclínica e a resistência à insulina podem explicar parcialmente por que os níveis de adiponectina são menores em indivíduos com síndrome metabólica em comparação com indivíduos sem síndrome metabólica. Estratégias terapêuticas de modificação de estilo de vida, que envolvem atividade física de intensidade moderada ou alta e perda de peso, com enfoque na redução da síndrome metabólica e seus componentes, mostraram-se efetivas para aumentar as concentrações de adiponectina. Diferentes intervenções dietéticas também foram identificadas como potenciais modificadores das concentrações de adiponectina e da sensibilidade à insulina, que podem ser moduladas pela ingestão de lipídios. O efeito das dietas que contém baixa ou elevada quantidade de gordura ou de tipos diferentes de gorduras nos níveis de adiponectina foi analisado em diversos estudos que mostraram resultados heterogêneos. De fato, maior adesão à dieta mediterrânea tem sido associada com concentrações mais elevadas de adiponectina, que pode ser explicado pela composição da dieta que é rica em nozes, óleo de oliva e peixes, que são fontes alimentares de ácidos graxos insaturados. Outros lipídios dietéticos, tais como, o ácido linoléico conjugado, o colesterol e o ácido graxo poli-insaturado ômega-3 têm sido associados com diferentes respostas nas concentrações de adiponectina. A fim de esclarecer o efeito dos lipídios da dieta sobre os níveis de adiponectina, o segundo estudo teve como objetivo revisar e analisar sistematicamente ensaios clínicos randomizados que investigaram os efeitos de lipídios da dieta nas concentrações circulantes de adiponectina em adultos. A revisão sistemática com meta-análise mostrou que nos estudos de intervenção que compararam as dietas com baixo e elevado teor de gordura não houve associação entre a quantidade total de gordura com diferenças nos níveis circulantes de adiponectina. Observou-se que a suplementação de ômega-3 aumentou modestamente as concentrações circulantes de adiponectina. Por outro lado, a suplementação de ácido linoléico conjugado reduziu as concentrações de adiponectina quando comparada com a suplementação de ácido graxo insaturado utilizado como placebo ativo. / Type 2 diabetes is reaching worldwide epidemic proportions with the World Health Organization estimating that 9% of adults older than age 18 have diabetes, with the vast majority having type 2 diabetes. Elevated hepatic glucose production, impaired insulin secretion, and insulin resistance, abnormalities of glucose metabolism typically found in subjects with obesity, are major factors underlying the pathogenesis of type 2 diabetes and metabolic syndrome. Adiponectin is a major regulator of glucose and lipid homeostasis by its insulin sensitizer properties. Since decreased insulin sensitivity is linked to type 2 diabetes and metabolic syndrome, decreased adiponectin levels may be related to its development. Lower adiponectin concentrations are related with higher intra-abdominal fat mass. Therefore, adiponectin could link intraabdominal fat with insulin resistance and the development of metabolic syndrome. Therefore, the purpose of the first study was to investigate the relationship between adiponectin levels with metabolic syndrome in two different cohorts. Firstly, screened and evaluated for abnormalities of glucose metabolism and metabolic syndrome were submitted to an oral glucose tolerance test at the diabetes unit of the Endocrine Department of Hospital de Clínicas de Porto Alegre and were cross-sectionally examined according to the presence of metabolic syndrome. A replication analysis was performed in subjects undergoing cardiac angiography at Hospital São Paulo, from Federal University of São Paulo. We were also interested in finding out which metabolic syndrome components are mostly related to adiponectin levels. Additionally, we analyzed how insulin resistance, sensitivity and subchronic inflammation were related to adiponectin levels. Our results have shown that total and highmolecular weight adiponectin levels not only are lower in the presence of metabolic syndrome, but it also decreases by increasing number of metabolic syndrome criteria. These levels are partly determined by their relationship with HDL cholesterol, triglycerides and abdominal adiposity. Furthermore, chronic inflammation and insulin resistance may partially explain why adiponectin levels are lower in subjects with metabolic syndrome compared to subjects without metabolic syndrome. Therapeutic strategies that target the metabolic syndrome and its components have been shown to increase adiponectin concentrations, such as lifestyle modification involving moderate- or high intensity physical activities and weight loss. Different dietary interventions have also been identified as potential modifiers of adiponectin concentrations and insulin sensitivity, and they may be influenced by lipid intake. The relationship of the effect of diets containing either low or high amounts of fat or different type of fat have been analyzed in different studies and has shown heterogeneous results. Indeed, close adherence to a Mediterranean diet has been associated with higher adiponectin concentrations which can be also explained by its composition that is rich in nuts, olive oil and fish, all of which are dietary sources of unsaturated fatty acids. Other dietary lipids such as conjugated linoleic acid, dietary cholesterol and long-chain n-3 polyunsaturated fatty acids have been associated with a variable response to adiponectin concentrations. In order to clarify the effect of dietary lipids on adiponectin levels, the second study aimed to systematically review and analyze randomised controlled trials investigating the effects of dietary lipids on circulating adiponectin concentrations in adults. The meta-analysis has shown that intervention studies that compared diets with low and high fat content were not associated with differences in adiponectin concentrations. However, it was observed that n-3 polyunsaturated fatty acids supplementation modestly increased the circulating concentrations of adiponectin, whereas conjugated linoleic acid supplementation reduced the concentrations when compared with unsaturated fatty acid supplementation used as an active placebo.

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This thesis analyses the cost and profit efficiencies of the GCC banking sector over the period 1995-2000. Efficiencies are estimated using the most recent frontier technique, the Fourier Flexible form. The thesis also uses a logistic regression model to estimate the determinants of GCC banking efficiency. The findings show that the level of inefficiencies in the GCC banking industry ranges between 8 and 10% for costs, and 30 and 32 % for profits. There are no major differences in banks inefficiency levels among GCC countries. Moreover, inefficiencies show almost stable trends over 1995-2000. Comparisons of inefficiency levels across bank ownership type and assets size reveal that national banks are more cost efficient but less profit efficient than foreign banks. In terms of bank size, large banks are found to be more cost efficient but less profit efficient than other sized banks. The results also indicate that foreign banks have on average been operating with higher scale diseconomies than national banks. Moreover, scale diseconomies decline as the assets sizes of both national and foreign banks increase. The main results from our logistic regression are that the strengthening of financial capital is a central element explaining bank efficiency in the GCC region; however, the erosion in loan quality reduces banking sector efficiency. The main policy conclusion from this thesis is that GCC governments need to continue to implement financial reform packages that strengthen banking system soundness, foster banking competition, and also devise incentive schemes to improve managerial efficiency in order that GCC banks are better placed to meet the challenges of greater openness.