Submitted by Johnny Rodrigues (johnnyrodrigues@ufcg.edu.br) on 2018-08-07T19:46:16Z No. of bitstreams: 1 IANNA DUARTE KOBAYASHI DE SOUZA - DISSERTAÇÃO PPGCC 2012..PDF: 9922437 bytes, checksum: d5cbecd7f839d5802dab4ed420e1665b (MD5) / Made available in DSpace on 2018-08-07T19:46:16Z (GMT). No. of bitstreams: 1 IANNA DUARTE KOBAYASHI DE SOUZA - DISSERTAÇÃO PPGCC 2012..PDF: 9922437 bytes, checksum: d5cbecd7f839d5802dab4ed420e1665b (MD5) Previous issue date: 2012-02-29 / O crescimento da incidência da doença arterial coronariana, que atinge parte da população mundial, tem intensificado avanços na área da medicina nuclear, como forma de prevenção e de diagnóstico dessa doença. A cintilografia do miocárdio com técnica SPECT (Single Photon Emission Computed Tomography), associada ao eletrocardiograma, permite a avaliação tanto da funcionalidade quanto da perfusão do músculo cardíaco. Este estudo tem como objetivo principal aplicar técnicas de processamento digital de imagens para segmentar e reorientar automaticamente as imagens 3D de pacientes doentes, geradas por uma gamma camera. Os resultados obtidos foram comparados com os resultados produzidos pela técnica manual e comprovaram a eficácia do método automático proposto. / The increase in incidence of coronary artery disease, which affects part of the world population, has intensified advances in nuclear medicine as a means of prevention and diagnosis of this disease. The myocardial scintigraphy technique SPECT (Single Photon Emission Computed Tomography), associated with the electrocardiogram, enables evaluating both function and perfusion of the heart muscle. The main objective of this study is to apply techniques of digital image processing to segment and reorient automatically the 3D images of sick patients, generated by a gamma camera. The results obtained were compared to those ones produced by a manual technique and the effectiveness of the proposed automatic method was confirmed.

Introduction: Internal Carotid Stump Syndrome may be one of the possible causes of ischemic stroke (iCMP), as well as retinal infarction (RI). Syndrome of the occluded internal carotid (ACI) (stump syndrome) is a nosological unit, which is characterized by an onset of ipsilateral iCMP or RI of thromboembolic ethiology in patients with occlusion of ACI via the externa carotid or arteria ophthalmica. In my thesis, I have concentrated upon the specification of the stump syndrome, its diagnostics and treatment; furthermore I have assessed the appropriateness of surgical approach in comparison with conservative approach. Material and methods: A total of 621 patients with occlusion were treated in two centres in the course of five years. In a group of 40 patients, the ACI occlusion was detected sonographically, the length of the occluded ACI being >5 mm, with normal vasoreactivity based upon SPECT CO2 and excluded cardiogenic cause of iCMP. The patients were divided in two groups - surgical and conservative. Patients were monitored in 6-month intervals for the total period of four years. Results: No RI or iCMP were detected in the surgical group; one patient died six months after surgery. We observed one case of amaurosis fugax in the conservative group. Conclusion: Ultrasound examination is a fully sufficient...

Les possibilités offertes par les applications en médecine des nanoparticules sont l’un des facteurs essentiels des progrès médicaux attendus pour ce XXIème siècle. Ainsi, le domaine de l’imagerie médicale est aussi touché par cette évolution technologique. Ce présent travail a consisté à élaborer des sondes théranostiques à base de nanoparticules d’oxydes de fer (SPIO) et de nanotubes de titanate (TiONts) pour l’imagerie multimodale (magnétique/nucléaire ou magnétique/optique) et possédant aussi un effet thérapeutique (hyperthermie/PDT ou radiosensibilisation/PDT).Les nanotubes de titanate de cette étude, d’une longueur moyenne d’environ 150 nm, ont été obtenus par synthèse hydrothermale selon la méthode de Kasuga. Ces nanotubes présentent un diamètre extérieur de l’ordre de 10 nm et une cavité interne de 4 nm. Les nanoparticules d’oxydes de fer ont quant à elles été synthétisées par méthode de co-précipitation "Massart". Ces nanoparticules d’oxydes de fer de structure spinelle possèdent des cristallites de 9 nm de diamètre et présentent un comportement superparamagnétique mis en évidence par des mesures FC/ZFC. Pour préparer ces nanoparticules à recevoir des molécules d’intérêt biologique, deux ligands possédant des fonctions organiques plus réactives (APTES : NH2 et PHA : COOH) ont été greffés à la surface de ces deux types de nanoparticules. La présence de l'un ou l'autre a été mise en évidence par différentes techniques d’analyses (XPS, IR, zêtamétrie). La quantité de molécules greffées a été déterminé par ATG, elle est dans tous les cas d’environ 5 molécules/nm2. Dans un premier temps, les nanotubes de titanate ont été fonctionnalisés par un agent macrocyclique (0,2 DOTA/nm2). Après radiomarquage à l’indium 111, les TiONts – DOTA[In] ont été injectés dans des souris Swiss mâle nude pour connaître leur biodistribution en imagerie SPECT/CT. Les images obtenues et le comptage de la radioactivité dans chaque organe ont montré qu’au bout d’une heure, les nanotubes se situent dans les poumons et dans l’urine. Ensuite, les nanotubes sont progressivement éliminés pour n’être plus présents que dans les urines à 24 heures. Ces mêmes agents chélatants ont été greffés à la surface des SPIO pour la création de sondes multimodales IRM/SPECT ou IRM/TEP. En parallèle de cette étude, un fluorophore (phtalocyanine de zinc, ZnPc) a été greffé à la surface des nanoparticules. Le nanohybride SPIO – Pc synthétisé possède les propriétés requises pour être une sonde utilisable en imagerie bimodale IRM/IO grâce à sa longueur d’émission vers 670 nm et sa relaxivité de l’ordre de 70 L.mmolFe3O4-1.s-1. De plus, les nanohybrides ont été fonctionnalisés par du PEG pour les rendre furtifs, biocompatibles et stables. La toxicité de certains de ces nanohybrides a été évaluée avec le modèle in vivo zebrafish. Les nanohybrides étudiés n’ont pas présenté de toxicité, n’ont pas perturbé l’éclosion et n’ont pas provoqué de malformations sur les larves des zebrafish. / The new implementations of nanoparticles in the medical field are one of the essential factors of the medical progress expected at the beginning of this XXIst century. Thus, the domain of the medical imaging is also affected by this technological evolution. This work consisted in developing theranostic probes with iron oxides nanoparticles (SPIO) and titanate nanotubes (TiONts) for multimodal imaging (magnetic/nuclear or magnetic/optical) and also possessing a therapeutic effect (hyperthermia/PDT or radiosensitization/PDT).The titanate nanotubes of this study have an average length of about 150 nm and were obtained by Kasuga's hydrothermal synthesis. These nanotubes present an outside diameter of about 10 nm and an intern cavity of 4 nm. On the other hand, iron oxides nanoparticles were synthesized by soft chemistry ("Massart" method). These spinel-like iron oxides nanoparticles have a crystallite size of 9 nm in diameter and exhibit a superparamagnetic behavior which was highlighted by FC / ZFC measurements.To get these nanoparticles ready to receive molecules of biological interest, two linkers of more reactive organic functions (APTES: NH2 or PHA: COOH) were grafted to the surface of these two types of nanoparticles. Their presence was shown by different techniques (XPS, IR, UV-vis). The amount of grafted linkers was determined by TGA and in all cases this amount is close to 5 molecules/nm2. First, titanate nanotubes were coated by a macrocyclic chelating agent (0.2 DOTA/nm2). After radiolabelling with indium 111, the TiONts – DOTA[In] nanohybrids were injected in Swiss nude mice and observed by SPECT/CT imaging to characterize their biodistribution. The SPECT/CT images and the radioactivity measured in each organ showed that after one hour, nanotubes are located in lungs and in urine. Then, the nanotubes are gradually eliminated and are only found in urines after 24 hours. The same macrocyclic agent was grafted to the SPIO’s surface for the creation of multimodal probes MRI/SPECT or MRI/PET. Alongside this study, a fluorophore (Zinc phthalocyanine) was also grafted to the surface of nanoparticles. The synthesized SPIO – Pc nanohybrid has the required properties of bimodal imaging MRI/OI probe thanks to his emission wavelength around 670 nm and its relaxivity is about 70 L.mmolFe3O4-1.s-1. Furthermore, nanohybrids were coated by PEG to make them stealth, biocompatible and stable.In this study, the toxicity of most nanohybrids was evaluated by the in vivo zebrafish model. The studied nanohybrids did not present any toxicity, hatching disruption or malformation on zebrafish larvae.

Introduction: Internal Carotid Stump Syndrome may be one of the possible causes of ischemic stroke (iCMP), as well as retinal infarction (RI). Syndrome of the occluded internal carotid (ACI) (stump syndrome) is a nosological unit, which is characterized by an onset of ipsilateral iCMP or RI of thromboembolic ethiology in patients with occlusion of ACI via the externa carotid or arteria ophthalmica. In my thesis, I have concentrated upon the specification of the stump syndrome, its diagnostics and treatment; furthermore I have assessed the appropriateness of surgical approach in comparison with conservative approach. Material and methods: A total of 621 patients with occlusion were treated in two centres in the course of five years. In a group of 40 patients, the ACI occlusion was detected sonographically, the length of the occluded ACI being >5 mm, with normal vasoreactivity based upon SPECT CO2 and excluded cardiogenic cause of iCMP. The patients were divided in two groups - surgical and conservative. Patients were monitored in 6-month intervals for the total period of four years. Results: No RI or iCMP were detected in the surgical group; one patient died six months after surgery. We observed one case of amaurosis fugax in the conservative group. Conclusion: Ultrasound examination is a fully sufficient...

The most promising applications for targeted alpha-therapy with astatine-211 (At-211) include treatments of disseminated microscopic disease, the major medical problem for cancer treatment. The primary advantages of targeted alpha-therapy with At-211 are that the alpha-particle radiation is densely ionizing, translating to high relative biological effectiveness (RBE), and short-range, minimizing damage to surrounding healthy tissues. In addition, theranostic imaging with I-123 surrogates has shown promise for developing new therapies with At-211 and translating them to the clinic. Currently, Canada does not have a way of producing At-211 by conventional methods because it lacks alpha-particle accelerators with necessary beam energy and intensity. The work presented here was aimed at studying the Rn-211/At-211 generator system as an alternative production strategy by leveraging TRIUMF's ability to produce rare isotopes. Recognizing that TRIUMF provided production opportunities for a variety of astatine isotopes, this work also originally hypothesized and evaluated the use of At-209 as a novel isotope for preclinical Single Photon Emission Computed Tomography (SPECT) with applications to At-211 therapy research. At TRIUMF's Isotope Separator and Accelerator (ISAC) facility, mass separated ion beams of short­-lived francium isotopes were implanted into NaCl targets where Rn-211 or At-209 were produced by radioactive decay, in situ. This effort required methodological developments for safely relocating the implanted radioactivity to the radiochemistry laboratory for recovery in solution. For multiple production runs, Rn-211 was quantitatively transferred from solid NaCl to solution (dodecane) from which At-211 was efficiently extracted and evaluated for clinical applicability. This validated the use of dodecane for capturing Rn-211 as an elegant approach to storing and shipping Rn-211/At-211 in the future. Po-207 contamination (also produced by Rn-211 decay) was removed using a granular tellurium (Te) column before proceeding with biomolecule labelling. Although the produced quantities were small, the pure At-211 samples demonstrated these efforts to have a clear path of translation to animal studies. For the first time in history, SPECT/CT was evaluated for measuring At-209 radioactivity distributions using high energy collimation. The spectrum detected for At-209 by the SPECT camera presented several photopeaks (energy windows) for reconstruction. The 77-90 Po X­-ray photopeak reconstructions were found to provide the best images overall, in terms of resolution/contrast and uniformity. Collectively, these experiments helped establish guidelines for determining the optimal injected radioactivity, depending on scan parameters. Moreover, At-209-based SPECT demonstrated potential for pursuing image-­based dosimetry in mouse tumour models, in the future. Simultaneous SPECT imaging with At-209 and I-123 was demonstrated to be feasible, supporting the future evaluation of At-209 for studying/validating I-123 surrogates for clinical image-based At-211 dosimetry. This work also pursued a novel strategy for labelling cancer targeting peptides with At-211, using octreotate (TATE, a somatostatin analogue for targeting tumour cells, mostly neuroendocrine tumours) prepared with or without N-terminus PEGylation (PEG2), followed by conjugation with a closo-decaborate linking moiety (B10) for attaching At-211. Binding affinity and in vivo biodistributions for the modified peptides were determined using iodine surrogates. The results indicated that B10-PEG2-TATE retained target binding affinity but that the labelling reaction with iodine degraded this binding affinity significantly, and although having high in vivo stability, no I-123-B10-PEG2-TATE tumour uptake was observed by SPECT in a mouse tumour model positive for the somatostatin receptor (sstr2a). This suggested that further improvements are required for labelling. A new method for producing At-211 at TRIUMF is established, and At-209-­based SPECT imaging is now demonstrated as a new preclinical technology to measure astatine biodistributions in vivo for developing new radiopharmaceuticals with At-211. Combined with the theranostic peptide labelling efforts with iodine, these efforts provide a foundation for future endeavours with At-211-­based alpha-therapy at TRIUMF. All procedures were performed safely and rapidly, suitable for preclinical evaluations. All animal studies received institutional ethics approval from the University of British Columbia (UBC). / Graduate

Ce travail se penche sur les difficultés auxquelles font face les apprenants nigérians de français, précisément ceux de langue maternelle yoruba, quant à ce qui concerne les temps passés du français : l'imparfait et le passé composé. Nous sommes parti des productions des apprenants, deux exercices à trous et un écrit long de type rédaction, pour exposer les erreurs de temps commises. Nous avons découvert, suite à l'analyse des productions, que la plupart de ces erreurs proviennent du système aspectuo-temporel du yoruba, langue ne connaissant pas de conjugaison (désinences verbales) comme le français. Mais, la langue étrangère qu'ils sont en train d'apprendre constitue aussi une source de ces difficultés : il leur est particulièrement difficile de gérer les circonstants et adverbes temporels, les connecteurs syntaxiques et logiques, et l'ensemble des shifters accompagnant les temps verbaux français, surtout un écrit long. D'autre part, l'analyse des deux tests à trous en plus de celle des copies de rédaction montrent que, le manque de connaissance de certaines notions linguistiques est une autre cause des difficultés rencontrées par les apprenants : la notion de discours / récit et celle de premier / arrière-plan.En somme, nous pensons qu'un enseignement / apprentissage des temps basé sur la notion d'aspect grammatical, et prenant en compte les notions précédemment mentionnées, sera certainement plus productif. Nos propositions de pistes pour un meilleur enseignement/apprentissage des temps concernés terminent cette recherche. Nous pensons, par ailleurs, qu'en ajoutant à ce que nous venons de dire, les détails que nous ont révélés les analyses linguistiques des systèmes aspectuo-temporels des deux langues, nous pourrons construire par la suite une méthode d'enseignement et apprentissage des temps verbaux du passé pour l'apprenant nigérian. Ainsi, nous aurons apporté une autre contribution à l'enseignement / apprentissage du français au Nigeria. / Nigerian learners of French as a Foreign Language are generally faced with difficulties while using French Past Tenses in producing written composition. In this thesis, we are particularly interested in the case of the Yoruba learners of French language. The analysis of their written composition copies reveals that most of the errors committed originate from the mother tongue, Yoruba which does not know the tense-markedness of French language with her conjugation and complicated verb endings. This specifically means that there are problems closely related to the French Language herself. Actually, Yoruba learners find it particularly difficult to use French temporal adverbs and shifters in their written composition copies. On the other hand, through our analysis of copies of two objective tests in which students were to produce the missing verb forms, we also found that the learners lack some theoretical linguistic knowledge which is important in understanding French past tenses : for instance, Benveniste's “Discours & récit” and Weinrich's “Premier plan / Arrière-plan”. In addition, our analysis of the tempo-aspectual systems of both languages shows that contrary to French language, Yoruba aspects and tenses do not function separately.We believe that students would better understand the use of French past tenses if they have a good grasp of the “grammatical aspect” notion and if this linguistic notion is taken into account while teaching the topic. We brought the research to a close with different suggestions on how to improve the teaching / learning of the French tenses concerned here. On the whole, placing oneself on the didactic perspective, we are of the opinion that all these information put together can help develop a Methodology for the teaching and learning of French past tenses; and by so doing, advance the more the cause of the teaching and learning of French in Nigeria.

Dor torácica é sintoma frequente em pacientes com cardiomiopatia crônica da doença de Chagas (CCDC). Embora, em muitos casos seja atribuído empiricamente a defeitos transitórios (isquêmicos) encontrados em cintilografia de perfusão miocárdica (CPM), ainda não há evidências científicas que embasem terapêutica adequada para essa condição. Objetivos: Testar a hipótese de que ocorra redução > 50% do déficit perfusional transitório e melhora sintomática e de qualidade de vida após tratamento oral com verapamil e ácido acetilsalicílico (AAS) em pacientes com CCDC e dor torácica. Métodos: Estudo prospectivo, unicêntrico, que incluiu pacientes submetidos a cinecoronariografia por dor torácica, em que não foram identificadas lesões obstrutivas coronarianas significativas (>30%) e não apresentavam disfunção ventricular moderada ou grave. Alterações de mobilidade segmentar na ventriculografia contrastada e epidemiologia sugestiva apontaram para CCDC, que foi confirmada por dois testes sorológicos distintos. Isquemia microvascular foi comprovada por CPM com escore diferencial (Summed Difference Score (SDS) >= 1). Avaliação de dor torácica e qualidade de vida foi realizada por aplicação de Questionário de Angina de Seattle (QAS) e EQ-5D no momento da inclusão e após 3 meses de tratamento com verapamil e AAS, quando a CPM também foi repetida. As comparações pré e pós-tratamento do EQ-5D, QAS e SDS na CPM foi realizada através de teste de Wilcoxon para amostras pareadas e não normalmente distribuídas. Resultados: Vinte e seis pacientes de ambos os gêneros (58% de mulheres), idade média de 64 ±10 anos, apresentaram melhora significativa de 62,5% no SDS após o tratamento (4,5 [4-9] vs 2 [0-4.25], p<0.001). Dos 26 pacientes, 20 apresentaram melhora do SDS, dentre os quais, 10 com SDS igual a zero, ou seja, sem evidência de déficit perfusional transitório após o tratamento. Em 4 pacientes não houve mudança no SDS e apenas 2 apresentaram piora do SDS. Houve melhora significativa no valor indexado do EQ-5D após os 3 meses de tratamento (0,63±0,11 vs 0,77±0,17, p<0.001), assim como nas 5 subáreas que compõem o QAS (p<0,001).Conclusões: O uso combinado de vasodilatador microvascular e antiplaquetário (verapamil + AAS) associou-se a significativa redução dos defeitos perfusionais transitórios sugestivos de isquemia microvascular e a melhora de dor torácica e qualidade de vida em pacientes com CCDC. Este estudo pioneiro embasa investigações futuras no intuito de sedimentar evidências, comparar a placebo por exemplo, com intuito de definir terapêutica em pacientes com CCDC sintomáticos com distúrbios microvasculares. / Chest pain is a common symptom in patients with chronic Chagas disease cardiomyopathy (CCDC). Although this might be explained by myocardial perfusion scintigraphy (MPS) evidence of regional microvascular disturbances in patients with angiographically normal coronary arteries, there is no standard evidence based therapy for this condition. Purpose: Evaluate the impact of verapamil and acetylsalicylic acid (ASA) on symptoms, quality of life and myocardial perfusion defects in CDC patients with chest pain and microvascular ischemia. Methods: 26 patients were evaluated in this clinical trial. CCDC was confirmed by 2 serologic tests. All of them had chest pain and no significant epicardial coronary artery lesions by coronarography or moderate/severe ventricle systolic dysfunction by left ventriculography. Questionnaires to evaluate quality of life (EQ-5D) and chest pain symptoms (Seattle Angina Questionnaire (SAQ)) and SPECT MPS (physical stress preferably) were performed before and three months after treatment with oral verapamil and ASA. Comparison of pre and post EQ-5D/SAQ and SPECT perfusion results were performed using Wilcoxon signed rank test for paired data. Results: Mean age was 64 ± 10 years, 15 (57,7%) men. SDS was significantly reduced by 55,6% after treatment (4,5 [4-9] vs 2 [0-4.25], p<0.001). Decrease in SDS was observed in 20 (77%) participants, of those ten (38,5%) exhibited a post-treatment SDS equals zero, i.e., had no more evidence of stress induced perfusion abnormalities. Four patients (15,3%) maintained SDS values and only 2 (7,7%) increased SDS after 3 months of medications. In the evaluation of quality of life and symptoms, enhancement in EQ-5D values (index value: 0,63±0,11 vs 0,77±0,17, p<0.001) and in all dimensions of QAS post treatment were also significant (improve > 10 points each, p<0,001). Conclusions: The combined use of a microvascular vasodilator and an antiplatelet agent seems to improve quality of life and chest pain symptoms and reduce ischemic perfusion abnormalities in patients with CCDC significantly. This study paved the way for an ongoing investigation aimed at getting more definitive evidence of benefit withthese drugs as compared to placebo in CCDC and idiopathic microvascular derangements.

Dor torácica é sintoma frequente em pacientes com cardiomiopatia crônica da doença de Chagas (CCDC). Embora, em muitos casos seja atribuído empiricamente a defeitos transitórios (isquêmicos) encontrados em cintilografia de perfusão miocárdica (CPM), ainda não há evidências científicas que embasem terapêutica adequada para essa condição. Objetivos: Testar a hipótese de que ocorra redução > 50% do déficit perfusional transitório e melhora sintomática e de qualidade de vida após tratamento oral com verapamil e ácido acetilsalicílico (AAS) em pacientes com CCDC e dor torácica. Métodos: Estudo prospectivo, unicêntrico, que incluiu pacientes submetidos a cinecoronariografia por dor torácica, em que não foram identificadas lesões obstrutivas coronarianas significativas (>30%) e não apresentavam disfunção ventricular moderada ou grave. Alterações de mobilidade segmentar na ventriculografia contrastada e epidemiologia sugestiva apontaram para CCDC, que foi confirmada por dois testes sorológicos distintos. Isquemia microvascular foi comprovada por CPM com escore diferencial (Summed Difference Score (SDS) >= 1). Avaliação de dor torácica e qualidade de vida foi realizada por aplicação de Questionário de Angina de Seattle (QAS) e EQ-5D no momento da inclusão e após 3 meses de tratamento com verapamil e AAS, quando a CPM também foi repetida. As comparações pré e pós-tratamento do EQ-5D, QAS e SDS na CPM foi realizada através de teste de Wilcoxon para amostras pareadas e não normalmente distribuídas. Resultados: Vinte e seis pacientes de ambos os gêneros (58% de mulheres), idade média de 64 ±10 anos, apresentaram melhora significativa de 62,5% no SDS após o tratamento (4,5 [4-9] vs 2 [0-4.25], p<0.001). Dos 26 pacientes, 20 apresentaram melhora do SDS, dentre os quais, 10 com SDS igual a zero, ou seja, sem evidência de déficit perfusional transitório após o tratamento. Em 4 pacientes não houve mudança no SDS e apenas 2 apresentaram piora do SDS. Houve melhora significativa no valor indexado do EQ-5D após os 3 meses de tratamento (0,63±0,11 vs 0,77±0,17, p<0.001), assim como nas 5 subáreas que compõem o QAS (p<0,001).Conclusões: O uso combinado de vasodilatador microvascular e antiplaquetário (verapamil + AAS) associou-se a significativa redução dos defeitos perfusionais transitórios sugestivos de isquemia microvascular e a melhora de dor torácica e qualidade de vida em pacientes com CCDC. Este estudo pioneiro embasa investigações futuras no intuito de sedimentar evidências, comparar a placebo por exemplo, com intuito de definir terapêutica em pacientes com CCDC sintomáticos com distúrbios microvasculares. / Chest pain is a common symptom in patients with chronic Chagas disease cardiomyopathy (CCDC). Although this might be explained by myocardial perfusion scintigraphy (MPS) evidence of regional microvascular disturbances in patients with angiographically normal coronary arteries, there is no standard evidence based therapy for this condition. Purpose: Evaluate the impact of verapamil and acetylsalicylic acid (ASA) on symptoms, quality of life and myocardial perfusion defects in CDC patients with chest pain and microvascular ischemia. Methods: 26 patients were evaluated in this clinical trial. CCDC was confirmed by 2 serologic tests. All of them had chest pain and no significant epicardial coronary artery lesions by coronarography or moderate/severe ventricle systolic dysfunction by left ventriculography. Questionnaires to evaluate quality of life (EQ-5D) and chest pain symptoms (Seattle Angina Questionnaire (SAQ)) and SPECT MPS (physical stress preferably) were performed before and three months after treatment with oral verapamil and ASA. Comparison of pre and post EQ-5D/SAQ and SPECT perfusion results were performed using Wilcoxon signed rank test for paired data. Results: Mean age was 64 ± 10 years, 15 (57,7%) men. SDS was significantly reduced by 55,6% after treatment (4,5 [4-9] vs 2 [0-4.25], p<0.001). Decrease in SDS was observed in 20 (77%) participants, of those ten (38,5%) exhibited a post-treatment SDS equals zero, i.e., had no more evidence of stress induced perfusion abnormalities. Four patients (15,3%) maintained SDS values and only 2 (7,7%) increased SDS after 3 months of medications. In the evaluation of quality of life and symptoms, enhancement in EQ-5D values (index value: 0,63±0,11 vs 0,77±0,17, p<0.001) and in all dimensions of QAS post treatment were also significant (improve > 10 points each, p<0,001). Conclusions: The combined use of a microvascular vasodilator and an antiplatelet agent seems to improve quality of life and chest pain symptoms and reduce ischemic perfusion abnormalities in patients with CCDC significantly. This study paved the way for an ongoing investigation aimed at getting more definitive evidence of benefit withthese drugs as compared to placebo in CCDC and idiopathic microvascular derangements.

Ce travail de thèse réalisé à l'Institut de Chimie Moléculaire de l'Université de Bourgogne porte dans un premier temps sur la synthèse d'agents chélatants bifonctionnels adaptés à la chélation de radiométaux trivalents, notamment l'indium-111. La plus grande partie de ce travail a ensuite consisté à réaliser le greffage d'un agent chélatant bifonctionnel dérivé du DOTA sur différents anticorps ou fragments d'anticorps monoclonaux : le trastuzumab (anti HER2, traitement de cancers du sein), le cétuximab (anti EGFR, traitement de nombreux cancers, dont le cancer colorectal) et l'abciximab (antiagrégant plaquettaire). Une attention particulière a été apportée à la caractérisation des différents immunoconjugués. La dernière étape de ce travail de thèse porte sur le radiomarquage à l'indium-111 de deux immunoconjugués préparés : le trastuzumab et le cétuximab. Ces étapes de radiomarquage nous ont permis de déterminer la fraction immunoréactive et l'affinité de chaque radiotraceur. Nous avons ainsi pu étudier la biodistribution in vivo de ces radiotraceurs chez la souris par imagerie SPECT-CT. Nous avons également développé une méthode de greffage originale pour le marquage d'un fragment d'anticorps de type Fab, l'abciximab, dans le but de suivre la biodistribution de cet antiagrégant plaquettaire. Enfin, nous avons également validé le concept d'imagerie multimodale à travers le greffage et le radiomarquage d'un agent bimodal pour l'imagerie optique et la SPECT sur des lipopolysaccharides bactériens. Les travaux réalisés nous ont permis d'acquérir un savoir faire en matière de greffage d'anticorps et de radiomarquage. Les résultats obtenus permettent d'envisager le greffage d'autres anticorps ou biomolécules, ainsi que l'utilisation d'autres radionucléides pour l'imagerie PET ou la radioimmunothérapie

Les méthodes d'imagerie médicale non invasives, comme la scintigraphie monophotonique (SPECT) ou la tomographie par émission de positons (PET), sont des outils précieux pour le développement et la validation de nouvelles molécules thérapeutiques. Cette approche nécessite la fixation d'une molécule émettrice d'un signal sur un traceur biologique, par exemple par marquage radioisotopique. Parmi les radionucléides largement utilisés en médecine nucléaire, des cations tels que 111In3+ pour la SPECT, 64Cu2+ et 68Ga3+ pour la PET ont été mis en œuvre ces dernières années. Afin de minimiser la distribution de l'élément radioactif par transmétallation ou par transchélation dans l'organisme, il est indispensable de piéger sélectivement le radiométal visé par des ligands adaptés qui forment des complexes stables et inertes vis-à-vis de la démétallation. De nombreux travaux impliquant des ligands polyazotés linéaires ou cycliques ont été entrepris, mais le choix des ligands a rarement été étayé par une caractérisation structurale, thermodynamique et cinétique complète de leurs propriétés de coordination. L'objet de nos travaux est l'étude physico-chimique de ligands modèles N fonctionnalisés en série tétraazamacrocyclique afin d'évaluer l'impact du remplacement d' un groupe acétate par une fonction acétamide lors de la conjugaison du macrocycle au vecteur biologique via un bras de coordination. Les constantes de formation des complexes avec les isotopes naturels du Cu2+, Ga3+ et In3+, ainsi qu'avec les cations métalliques biologiquement importants tels que le Mg2+, Ca2+, Fe3+ et Zn2+ ont été mesurées. Par la suite, nous nous sommes efforcés de synthétiser et d'isoler les complexes métalliques formés avec les ions ciblés (Cu2+, Ga3+, In3+) dans le but de les caractériser par différentes méthodes spectroscopiques (RMN, RPE, UV-visible, IR, MS-ESI) ainsi que par diffraction des rayons X. Par ailleurs, les potentiels redox des complexes de cuivre(II) ont été déterminés dans l'optique d'identifier ceux qui ne sont pas susceptibles d'être réduits par les réducteurs physiologiques.