Tübingen, Univ., Diss., 2008.

Thesis (Ph.D.) - James Cook University, 2003. / Typescript (photocopy) Bibliography: leaves 170-238.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 172-238) Also available in print.

Thesis (Ph. D.)--Auburn University. / Abstract. Vita. Includes bibliographical references (p. 148-174).

Thesis (M. Med. Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 53-61).

Thesis (M.Med.Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 53-61). Also available in print.

Thesis (Ph. D.)--University of Louisville, 2005. / Department of Physiology and Biophysics. Vita. "May 2005." Includes bibliographical references (leaves 114-131).

München, Techn. Univ., Diss., 2004.

Made available in DSpace on 2014-06-11T19:30:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-08-24Bitstream added on 2014-06-13T18:40:40Z : No. of bitstreams: 1 caetano_amm_dr_botfm.pdf: 904781 bytes, checksum: 71fb65bf25040c2baff3cda7362c5ead (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A isquemia e reperfusão (I/R) é a principal causa de lesão renal aguda após transplante renal. Hiperglicemia está associada a diminuição da tolerância à isquemia e aumento da gravidade da lesão renal da I/R. Eritropoetina administrada antes da isquemia/reperfusão renal (pré-condicionamento da eritropoetina) exerce efeito renoprotetor em animais normoglicêmicos, mas, este efeito, ainda não foi estudado em animais com hiperglicemia transitória. O objetivo desta pesquisa foi investigar o efeito da eritropoetina na lesão de isquemia/reperfusão renal em ratos com hiperglicemia transitória. Vinte e oito ratos Wistar machos (>300g) foram anestesiados com isoflurano a 3%, intubados e submetidos à ventilação mecânica com isoflurano a 1,5%. Artéria carótida e veia jugular foram cateterizadas. Dióxido de carbono em final de expiração, concentração inspirada e expirada de gás anestésico, pressão arterial invasiva e temperatura retal foram continuamente monitorizados (Datex, AS3). A temperatura retal foi mantida entre 36oC-38oC. Os animais foram divididos aleatoriamente em quatro grupos e todos receberam glicose 2,5 g.kg-1 por via intraperitoneal, sendo submetidos a laparotomia mediana e nefrectomia direita (Grupo S – sham - n=6). Os demais animais foram submetidos a 25 minutos de isquemia renal esquerda por clampeamento da artéria renal esquerda (Grupos ISO, EA e EM). 30 minutos antes da isquemia renal esquerda o Grupo ISO (n=6) recebeu soro fisiológico, o Grupo EA (n=8) eritropoetina 5000 UI.kg- 1 e o Grupo EM (n=8) eritropoetina 600 UI.kg-1por via intravenosa. A pressão arterial média (PAM) e a temperatura foram avaliadas a cada 10 minutos. Os valores plasmáticos da glicose e da creatinina foram determinados no inicio (M1) e no final do experimento (M2). Vinte e quatro horas após o final do experimento (M3) os animais retornaram ao laboratório e foram anestesiados... / Ischemia and reperfusion (I/R) injury is the leading cause of acute renal injury following renal transplantation. Hyperglycemia is associated with decreased tolerance to ischemia and increases the severity of renal I/R injury. Erythropoietin administered before renal ischemia/reperfusion (erythropoietin preconditioning) may exert some renoprotective effect in normoglycemic animals. However, such effect has not been studied in transiently hyperglycemic animals. This study aimed to examine the effect of erythropoietin preconditioning on renal ischemia /reperfusion injury in transiently hyperglycemic rats. Twenty- eight male Wistar rats weighting more than 300g were anesthetized with 3% isoflurane. After tracheal intubation, the animals were mechanically ventilated with air and 1.5 % isoflurane. Carotid artery and jugular vein were cannulated. End-tidal carbon dioxide partial pressure, inspired and expired anesthetic gas concentrations, direct arterial pressure and rectal temperature were continuously measured. Glucose 2,5 g.kg-1 was administered intraperitoneally to induce hyperglycemia. Rectal temperature was kept between 360C-380C. Animals were submitted a midline laparotomy and right nephrectomy. Animals were randomly allocated into four groups: S, sham, (n=6) underwent only right nephrectomy, no left kidney ischemia/reperfusion. Group ISO (n=6), underwent a 25-minute period of left renal artery clamping, not preceded by erythropoietin preconditioning dose, Group EH (n = 8), received high-dose erythropoietin (5000 UI.kg-1 i.v.), 30 minutes before a 25 minutes period of left renal artery clamping; Group EL (n = 8) received low-dose erythropoietin (600 UI.kg-1, i.v.) 30 minutes before a 25-minute period of left renal artery clamping. Creatinine and glucose serum levels were determined at the start (M1), at the end (M2), and 24 hours after the experiment (M3). Rats were then anesthetized... (Complete abstract click electronic access below)

La reperfusion complète et précoce est le moyen le plus efficace pour limiter l'extension de l'infarctus cérébral et les séquelles neurologiques. Le traitement de l'infarctus cérébral a été révolutionné par la thrombectomie mécanique intra-artérielle en permettant une recanalisation dans plus de 70% des cas et une réduction significative de la morbidité comparativement à la thrombolyse seule pour le territoire carotidien. Le pronostic des occlusions basilaires reste dramatique et aucun essai n'a démontré le bénéfice de l'approche intra-artérielle à l'heure actuelle. Dans la première partie du travail, nous avons réalisé une méta-analyse sur la thrombectomie par «stent-retriever» des occlusions basilaires, à partir des résultats publiés dans MEDLINE entre novembre 2010 et avril 2014: recanalisation angiographique (TICI≥2b)=81% (IC 95%: 73-87); hémorragie cérébrale symptomatique à 24 heures=4% (IC 95%: 2-8); évolution neurologique favorable (mRS≤2 à 3 mois)=42% (IC 95%: 36-48); mortalité=30% (IC 95%: 25-36). L'approche intra-artérielle ouvre une nouvelle ère thérapeutique, cependant un modèle animal adapté et pertinent est nécessaire pour l'évaluation pré-clinique. Dans la deuxième partie du travail, nous avons caractérisé l'évolution spatio-temporelle précoce de l'infarctus par IRM multimodale dans un modèle d'ischémie cérébrale focale transitoire réalisé par occlusion sélective intra-artérielle de l'artère cérébrale moyenne chez le rat adulte. Une occlusion complète de l'artère cérébrale moyenne proximale était observée dans 75% des 16 rats opérés, et un mismatch diffusion/perfusion dans 77% des cas. Le volume ischémique durant l'occlusion artérielle, définie sur la séquence de diffusion, était de 90±64 mm3 et de 57±67 mm3 à 24 heures sur la séquence T2. La recanalisation artérielle s'associe à une reperfusion tissulaire dans 36% des cas. L'hypoperfusion persistait chez la majorité des animaux 3 heures après recanalisation. L'infarctus était de localisation cortical dans 31%, striatale dans 25%, et cortico-striatale dans 44%. Tous les animaux étaient en vie à 24 heures confirmant le caractère mini-invasif de ce modèle. Bien que la reperfusion sauve incontestablement une partie du parenchyme ischémique, elle s'accompagne également de lésions irréversibles spécifiques, dites de reperfusion, s'ajoutant aux lésions initiales. Limiter l'importance des lésions de reperfusion représente un objectif thérapeutique majeur. Dans la troisième partie, nous avons testé l'effet neuroprotecteur de la Cyclosporine A sur la réduction du volume de l'infarctus cérébral et sur le pronostic clinique. Une procédure d'ischémie reperfusion cérébrale de 60 minutes a été réalisée chez 48 animaux, puis ont été randomisés en quatre groupes (groupe témoin, pré-conditionnement, postconditionnement intraveineux et intra-artériel avec la Cyclosporine A à la dose de 10 mg/kg dans les 30 secondes suivant la reperfusion). Sur les 43 animaux inclus dans l'analyse, il n'a pas été observé de réduction du volume ischémique ni une amélioration du pronostic après injection intraveineuse ou intra-artérielle de Cyclosporine A. La Cyclosporine A ne permet pas non plus de limiter l'extension des lésions de reperfusion au sein de la zone à risque à 24 heures de la reperfusion cérébrale / Early and complete reperfusion is the most effective therapy to limit the extent of brain infarction. The treatment of acute anterior ischemic stroke has been revolutionized by the intra-arterial mechanical thrombectomy allowing a 70% recanalization rate and a significant reduction of morbidity compared with thrombolysis alone. The prognosis of basilar artery occlusion remains catastrophic, and to date any trial has demonstrated the benefit of intra-arterial approach. In the first part of the work, we conducted a systematic review and meta-analysis of all previous studies of stent retriever thrombectomy in basilar artery occlusion patients between November 2010 and April 2014: recanalization (TICI≥2b)=81% (95% CI: 73-87); symptomatic intracranial haemorrhage at 24 hours=4% (95% CI 2-8); favorable neurological outcome (mRS≤2 at 3 months)=42% (95% CI: 36-48); mortality=30%(95% CI 25-36). Intra-arterial approach opens new avenues for the developement of treatments for brain infarction, but a relevant animal model of acute ischemic stroke is required for preclinical evaluation. In the second part of the work, we evaluated the spatiotemporal evolution of cerebral ischemia by sequential multimodal MRI in a new minimally invasive model of transient focal ischemia by selective intra-arterial occlusion of the middle cerebral artery in rat. A complete occlusion of the proximal portion of the middle cerebral artery was observed in 75% of 16 operated rats, and a mismatch diffusion/perfusion in 77% of cases. Acute stroke volume during arterial occlusion was 90±64 mm3 on diffusion-weighted imaging, and 57±67 mm3 at 24 hours on T2-weighted imaging. Recanalization is associated with tissue reperfusion in 36% of cases. The hypoperfusion persisted in the majority of animals 3 hours after recanalization. Brain infarction was cortical in 31%, striatal in 25%, and corticalstriatal in 44% of cases. All animals were alive at 24 hours, confirming the minimally invasive nature of the model. Although reperfusion saves a portion of ischemic tissue, it also carries specific irreversible damage, called reperfusion injury, in addition to initial damage caused by ischemia. Limiting the size of infarction is a major objective. In the third part, we tested the neuroprotective effect of Cyclosporine A in reducing the lesion volume and functional outcome. A total of 48 adult rats underwent the intra-arterial ischemia reperfusion procedure, and were randomly assigned to four treatment groups (control, preconditioning, intravenous and intra-arterial postconditioning with Cyclosporine A). Intravenous or intra arterial injection of Cyclosporine A at reperfusion does not either reduce the volume of stroke or improve the neurological outcome. Administation of Cyclosporin A at reperfusion does not limit the extension of reperfusion injuries within the ischemic risk area at 24 hours