No description available.

<p> Experimental carbon-13 nuclear magnetic resonance chemical shifts are given for substituted 1,3-dioxanes, tetrahydrofurans, dihydro-2-furanones and succinic anhydrides. The experimental data are used to improve and extend the carbon-13 chemical shift prediction parameters which allow one to estimate with considerable accuracy unknown chemical shift values.</p> / Thesis / Master of Science (MSc)

A variable temperature 13C and 6Li NMR study has been conducted for 6Li-enriched ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, t-butyl--, isopentyl-, 2-ethylbutyl-, and n-hexyllithium in cyclopentane. Significant differences in the 13C NMR parameters are observed as a function of the alkyl group and temperature. These changes are compared to the 6Li spectra and explained in terms of the aggregates present. 13C-6Li coupling is readily observed in both the 13 6 C and Li spectra of compounds which contain branching at either the alpha or beta carbons of the alkyl group. This coupling has been used to identify the aggregates present in solution and to identify the fluxional behavior of these aggregates.

Heart failure is a complex clinical syndrome in which the heart cannot pump sufficient blood and nutrients to the organs in the body. Increasingly, alterations in cardiac energetics are being implicated as playing an important role in the pathogenesis of heart failure. An understanding of specific metabolic switches which occur during the development of heart failure in patients would be greatly beneficial as a new diagnostic method and for the development of new therapies for patients with failing hearts. This thesis deals with the non-invasive assessment of metabolism in the heart. New magnetic resonance imaging (MRI) methods for metabolic characterization of the heart using hyperpolarized carbon-13 MRI are presented. Spatially resolved images of hyperpolarized 13C substrates and their downstream products can provide insight into real-time metabolic processes occurring in vivo, within minutes of injection of a pre-polarized 13C-labeled substrate. Conventional 3D spectroscopic acquisitions require in excess of 100 excitations, making it challenging to acquire full cardiac and respiratory-gated, whole-heart metabolic volumes. Each of the developments described in this thesis is intended to advance cardiac hyperpolarized 13C metabolic imaging towards a routine, clinical exam which can be used for prognosis and treatment optimization in patients with cardiovascular disease. The major technical development is a new interleaved-frequency, time-resolved MRI pulse sequence that can provide robust and reliable measurements of cardiac metabolic signals. The technique was applied to several realistic pre-clinical models of cardiac disease and the work presented will hopefully lead towards significant improvement in the management of patients with heart failure.

Heart failure is a complex clinical syndrome in which the heart cannot pump sufficient blood and nutrients to the organs in the body. Increasingly, alterations in cardiac energetics are being implicated as playing an important role in the pathogenesis of heart failure. An understanding of specific metabolic switches which occur during the development of heart failure in patients would be greatly beneficial as a new diagnostic method and for the development of new therapies for patients with failing hearts. This thesis deals with the non-invasive assessment of metabolism in the heart. New magnetic resonance imaging (MRI) methods for metabolic characterization of the heart using hyperpolarized carbon-13 MRI are presented. Spatially resolved images of hyperpolarized 13C substrates and their downstream products can provide insight into real-time metabolic processes occurring in vivo, within minutes of injection of a pre-polarized 13C-labeled substrate. Conventional 3D spectroscopic acquisitions require in excess of 100 excitations, making it challenging to acquire full cardiac and respiratory-gated, whole-heart metabolic volumes. Each of the developments described in this thesis is intended to advance cardiac hyperpolarized 13C metabolic imaging towards a routine, clinical exam which can be used for prognosis and treatment optimization in patients with cardiovascular disease. The major technical development is a new interleaved-frequency, time-resolved MRI pulse sequence that can provide robust and reliable measurements of cardiac metabolic signals. The technique was applied to several realistic pre-clinical models of cardiac disease and the work presented will hopefully lead towards significant improvement in the management of patients with heart failure.

The study consists of three major areas of research. First, the dihedral angle dependence of vicinal carbon-carbon coupling constants is determined for aliphatic and alicyclic carboxylic acids wherein the formal hybridization and substituents are held constant. Second, the magnitudes and relative signs of long-range carbon-carbon coupling constants in a. triple- 13 C-labeled system are determined and compared with carbon-proton and/or proton-proton coupling constants in geometrically similar compounds. Third, the effect of changes in hybridization on long-range carbon-carbon coupling constants is determined for the following three groups of molecules: olefins and saturated hydrocarbons, aliphatic carboxylic acids, and aromatic compounds. In all cases only closely related systems are compared in order to identify the effect of individual molecular parameters. Most importantly, the results indicate that carbon-carbon couplings do correlate in magnitude and sign with carbon-proton and proton-proton couplings in analogous molecular. frameworks. Thus, the coupling mechanisms are similar in all three types of coupling. In addition, the observed trends in long-range carbon-carbon couplings provide an unambiguous method for assigning carbon chemical shifts.

No description available.

Es gliomes sont des tumeurs cérébrales associées à une mortalité élevée. Le glioblastome multiforme (GBM) est la forme la plus fréquente des tumeurs cérébrales primaires. Malgré une prise en charge thérapeutique optimale constituée d'une chirurgie, d'une radiochimiothérapie concomitante et d'une chimiothérapie adjuvante, la survie médiane est de 15 mois. Ceci s'explique surtout par le potentiel infiltratif de ces tumeurs. Il est donc difficile de réaliser une exérèse chirurgicale totale, ce qui entraine une récidive quasi-systématique avec l'apparition de chimiorésistance. Ces phénomènes de résistances associés à une importante toxicité des molécules cytotoxiques mettent en évidence l'importance de rechercher de nouvelles stratégies thérapeutiques. Parmi ces dernières, les anticorps monoclonaux thérapeutiques sont très prometteurs, leurs actions ciblées limitent la toxicité au niveau du tissu sain. Cependant ces nouvelles thérapies manquent cruellement de suivi. L'apparition d'effets secondaires graves remet en cause leur intérêt. C'est pourquoi ces nouvelles thérapies, bien qu'efficaces, doivent être contrôlées par l'intermédiaire de biomarqueurs compagnons ce qui permettrait une meilleure efficience de la molécule. Le bevacizumab en est un bon exemple, de par une pharmacocinétique interindividuelle variable (de 11 à 50 jours) et une absence d'adaptation de la posologie on constate l'apparition d'effets secondaires (phlébite, hémorragie) qui entrainent l'arrêt du traitement. Or, ces effets secondaires pourraient être limités par un simple suivi de la concentration sérique de bevacizumab. De plus, dans le cas particulier des GBM, la présence de la barrière hémato-encéphalique (BHE) nécessite de développer de nouvelles stratégies pour favoriser une meilleure biodistrubution de molécules au niveau de la tumeur cérébrale. De ce fait, nous avons étudié l'efficacité d'un contournement de la BHE mécanique par une administration localisée directement dans la tumeur. Et dans cette étude préclinique, une amélioration significative de la médiane de survie des animaux ayant eu un traitement par CED (Convection Enhanced Delivery) par rapport à une administration intrapéritonéale. Enfin, dans le but de proposer une technique innovante de criblage de biomarqueurs compagnons, nous avons mis en place une stratégie innovante de marquage isotopique in vivo afin d'étudier la dynamique du protéome tumoral en réponse au traitement. Cette stratégie, déjà validée, est en cours de transfert chez l'homme dans l'étude du métabolisme des GBM. / Gliomas are brain tumors associated with important mortality. Glioblastoma multiforme (GBM) is the most frequent of primary brain tumors. Despite an optimal therapeutic management consists that includes surgery, radiotherapy plus concomitant and adjuvant chemotherapy, the median survival is 15 months. This, is mainly due to the presence of infiltrative tumor cells that hamper total surgical excision, and leads to relapse with the emergence of drug resistance. This highlights the importance of seeking new therapeutic strategies.Of these, therapeutic monoclonal antibodies are very promising. Their targeted actions limit the toxicity to healthy tissue. However, these new therapies are desperately short of monitoring. The appearance of serious side effects is a present challenge to their use. In consequences, these targeted therapies, even effective, have to be controlled via companion’s biomarkers that would provide better monitoring of the molecule. Bevacizumab is a good illustration for the existence of interindividual pharmacokinetic variability (11 to 50 days). In addition to its effect on the therapy efficiency, this inte variability must be also considered for side effects (phlebitis, hemorrhage) that lead to failure of treatment. However, these side effects could be limited by a simple monitoring of serum concentration of bevacizumab.Moreover, in the specific case of GBM, the action to the blood-brain barrier (BBB) requires the development of new strategies to promote a better bio-distribution of molecules in the brain tumor. Therefore, we investigated the effectiveness of a mechanical bypass of BBB in experimental brain tumors by a localized administration directly in the tumor. In this preclinical study, a significant improvement in median survival of animals treated with convection-enhanced delivery (CED) versus intraperitoneal administration was demonstrated.Finally, in order to offer an innovative technique of companion’s biomarkers screening, we have implemented an isotope labeling in vivo in order to study the dynamics of the proteome in tumor response to treatment. This strategy has already been released and is being transferred in humans in the study of the metabolism of GBM.

Orientador: Roberto de Oliveira Roça / Resumo: O objetivo este estudo foi avaliar o turnover isotópico de δ13C e δ15N no leite, sangue e fezes, ocasionados pela inclusão da cama de aviário na dieta de vacas leiteiras, a fim de determinar o tempo de incorporação do valor isotópico da dieta. Foram utilizadas 12 vacas mestiças, distribuídas em delineamento inteiramente casualizado com seis repetições e dois tratamentos. Os tratamentos foram: T1 – dieta estritamente vegetal durante todo o período experimental; T2 – 50% cama de aviário e 50% vegetal durante o primeiro período experimental e depois dieta vegetal. Foram colhidas amostras diariamente e analisadas com espectrômetro de massas de razão isotópica. Para mensurar o turnover de δ13C e δ15N em determinado intervalo de tempo, foi utilizada a função exponencial de primeira ordem. Os dados isotópicos foram submetidos ao teste t-Student. Os valores isotópicos das fezes e do leite atingiram o patamar de equilíbrio. O sangue não conseguiu atingir o patamar de equilíbrio nos períodos avaliados indicando ser um tecido para detecção de dietas de períodos mais longos. O resultado do teste de t Student (p<0,05) foi semelhante ao encontrado pela análise dos isótopos estáveis mostrando que no primeiro período os valores isotópicos das fezes do T1 diferiram do T2, e para o leite não houve diferença entre os tratamentos. No segundo período, os valores isotópicos das fezes e do leite do T1 não diferiram do T2. Os valores isotópicos de δ 15N no leite para o 1°período diferiram entre o T1... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Made available in DSpace on 2014-06-11T19:27:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-03-31Bitstream added on 2014-06-13T19:56:23Z : No. of bitstreams: 1 sernagiotto_er_me_botfmvz.pdf: 1359784 bytes, checksum: 84f17ebed4c4e393a3cb6edca2994970 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / O presente trabalho teve por objetivo avaliar a capacidade da técnica dos isótopos estáveis em rastrear a farinha de vísceras de aves (FVA), na alimentação de codornas de corte criadas por longo período, após a substituição da dieta com 8% de FVA por dieta vegetal. Foram utilizadas 320 codornas, distribuídas aleatoriamente em oito tratamentos: dieta vegetal (T1) e sete tratamentos com inclusão de 8% de FVA na dieta, um mantendo a dieta até o final do período experimental (T2), e nos demais a dieta foi substituída aos 42; 56; 70; 84; 98; 112 dias; respectivamente, por dieta vegetal. Para coleta das amostras de músculo peitoral foram sacrificadas ao acaso, quatro aves (n = 4) por tratamento, a cada 14 dias, sendo que no T1 e T2 tiveram início aos 42 dias e nos demais a partir da troca das dietas. Os resultados isotópicos obtidos foram submetidos à análise multivariada de variância (MANOVA) com auxílio do procedimento GLM do programa estatístico SAS. Os tratamentos diferiram do vegetal quando as aves foram sacrificadas duas semanas após a troca da dieta; após esse período os tratamentos experimentais tiveram comportamento semelhante ao vegetal, exceto o T3, que se mostrou semelhante ao T1 no abate 14 dias após a troca da dieta; e do T2 que em todos os períodos de comparação diferiu do T1. Conclui-se que a aplicação da técnica dos isótopos estáveis de carbono e nitrogênio na rastreabilidade da FVA, na alimentação de codornas de corte criadas por longo período é possível nas aves abatidas 14 dias após a troca de dieta, com exceção das aves sacrificadas aos 56 dias de idade. / The present work aimed to evaluate the capability of the stable isotope technique to trace poultry visceral meal (PVM) in the diet of meat quails raised for a long period after substitution of an 8% PVM diet for a vegetable diet. Three hundred and twenty poultries (320) were randomly distributed into eight treatments: vegetable diet (T1) and seven treatments containing 8% PVM in the diet: in one treatment, the same diet was kept until the end of the experimental period (T2), and in the remaining treatments, the diet was substituted at 42, 56, 70, 84, 98, and 112 days, respectively, for a vegetable diet. To collect chest muscle samples, four poultries (n = 4) per treatment were randomly sacrificed at every 14 days, starting at 42 days in T1 and T2 and from diet substitution in the remaining treatments. The obtained isotopic results were subjected to multivariate analysis of variance (MANOVA) using the GLM procedure of SAS statistical software. Treatments differed from the vegetable diet when poultries were sacrificed at two weeks following the diet substitution; after such period, the behavior of experimental treatments was similar to that of the vegetable diet, except for T3, which was similar to T1 at slaughtering at 14 days after the diet substitution, and T2 which, in all comparison periods, differed from T1. In conclusion, the technique of stable isotopes of carbon and nitrogen can be used to trace PVM in the diet of meat quails slaughtered at 14 days after diet substitution, except for poultries sacrificed at 56 days.