O exercício resistido dinâmico é recomendado, em complemento ao aeróbico, para indivíduos hipertensos. O aumento da pressão arterial durante sua execução se faz, primordialmente, pelo aumento da resistência vascular periférica, porém o aumento do débito cardíaco também parece estar envolvido. A elevação da pressão arterial parece ser exacerbada em hipertensos não medicados. Entretanto, grande parte dos hipertensos está sob terapêutica medicamentosa e vários fazem uso de -bloqueadores, que reduzem o débito cardíaco pela diminuição da resposta taquicárdica e inotrópica à estimulação simpática. Assim, é possível supor que o uso de -bloqueadores reduza o aumento da pressão arterial nos exercícios resistidos. Porém, pelo nosso conhecimento, este efeito ainda não foi estudado. Assim, esta investigação teve por objetivo investigar o efeito do atenolol sobre a resposta da pressão arterial durante o exercício resistido de diferentes intensidades. Foram estudados 10 hipertensos essenciais com pressão arterial sistólica/diastólica sob placebo entre 140 e 160/90 e 105 mmHg. Os pacientes foram estudados após 6 semanas de uso de placebo e de atenolol, sendo que os indivíduos estavam cegos para a medicação. Em cada fase, os voluntários fizeram o exercício de extensão de joelhos na cadeira extensora até a exaustão, seguindo 3 protocolos realizados em ordem aleatória: a) uma série em 100% de 1RM (repetição máxima), b) três séries em 40% de 1RM e; c) três séries em 80% de 1RM. Antes, durante e após os exercícios, a pressão arterial foi medida diretamente na artéria radial. Os dados foram comparados pelo teste t student ou pela ANOVA de dois fatores para amostras repetidas. Quando necessário, foi utilizado o post-hoc de Newman-Keuls e aceito como significante o índice de P≤0,05. Verificou-se que o atenolol reduziu os valores absolutos atingidos pela pressão arterial sistólica durante a execução do exercício nas três intensidades (valores máximos: 100% = 186±4 vs. 215±7, 80% = 224±7 vs. 247±9 e 40% = 223±7 vs. 252±16, mmHg, P≤0,05). Além disso, ele reduziu o aumento desta pressão arterial na 1ª série do exercício nas 3 intensidades (100% = +38±5 vs. +54±9; 80% = +68±11 vs. +84±13 e 40% = +69±7 vs. +84±14, mmHg, P≤0,05). Em relação à pressão arterial diastólica, o atenolol diminuiu os valores máximos absolutos e o aumento desta pressão arterial (126±6 vs. 145±6 e +41±6 vs. +52±6, mmHg, P≤0,05) no exercício em 100% de 1RM, mas não a alterou nas demais intensidades. Dessa forma, é possível concluir que o atenolol foi eficaz em atenuar tanto o valor absoluto quanto a resposta da pressão arterial sistólica durante o exercício resistido de diferentes intensidades em hipertensos, conferindo-lhes uma certa proteção cardiovascular. Este achado reforça o conceito de que o aumento do débito cardíaco é um mecanismo importante para o aumento da pressão arterial sistólica durante este tipo de exercício / Dynamic resistance exercise is recommended in association to aerobic exercise for hypertensive patients. Blood pressure increase during this kind of exercise is mainly due to an increase in peripheral vascular resistance, however, an increase in cardiac output might also be involved. This blood pressure increase seems to be exacerbated in non-medicated hypertensives. Nevertheless, most of the hypertensives are taking medications, and some of them are receiving -blockers, which decreases cardiac output by the inhibition of sympathetic-induced increase on heart rate and cardiac contractility. Thus, -blockers might decrease blood pressure rise during resistance exercise which, to our knowledge, has not been studied yet. Hence, the aim of this study was to verify the effects of the selective -blocker atenolol on blood pressure increase during dynamic resistance exercise of different intensities. Ten essential hypertensives with systolic/diastolic blood pressures under placebo condition maintained among 140 and 160/90 and 105 mmHg were recruited. These volunteers were studied after 6 weeks of placebo and atenolol treatment, and they were blinded for the medication used. In each phase, the volunteers executed, in a random order, 3 protocols of knee extension exercise until fatigue: a) 1 set at 100% of 1 repetition maximum (1RM); b) 3 sets at 40% of 1RM; c) 3 sets at 80% of 1RM. Before, during and after the exercises, intra-arterial radial blood pressure was measured. Data were compared by paired student t-test and by two-way ANOVA for repeated measures. Newman-Keuls post-hoc test was applied when necessary. P≤0.05 was considered as significant. Atenolol decreased the absolute value achieved by systolic blood pressure during the exercise performed at the 3 intensities (maximum values: 100% = 186±4 vs. 215±7, 80%= 224±7 vs. 247±9 e 40% = 223±7 vs. 252±16, mmHg, P≤0.05). Moreover, atenolol also reduced systolic blood pressure increase in the first set of exercise at the 3 intensities (100% = +38±5 vs. +54±9; 80% = +68±11 vs. +84±13 e 40% = +69±7 vs. +84±14, mmHg, P≤0.05). In regard to diastolic blood pressure, atenolol decreased its absolute values and its increase during exercise performed at 100% of 1RM (126±6 vs. 145±6 e +41±6 vs. +52±6, mmHg, P≤0.05), but it did not change diastolic blood pressure at the other exercise intensities. In Conclusion, atenolol therapy was effective in reducing both, systolic blood pressure absolute values and increase during resistance exercise of different intensities in hypertensive subjects; given them some cardiovascular protection. This result enhances the belief that cardiac output increase is important for blood pressure enhancement during this kind of exercise

<p>Intra-Arterial Chemotherapy (IAC) is a preferred treatment for the primary liver cancer, despite its adverse side-effects. During IAC, a mixture of chemotherapeutic drugs, e.g. Doxorubicin, is injected into an artery supplying the tumor. A fraction of Doxorubicin is absorbed by the tumor, but the remaining drug passes into systemic circulation, causing irreversible heart failure. The efficiency and safety of the IAC can be improved by chemical filtration of the excessive drugs with a catheter-based Chemofilter device, as proposed by a team of neuroradilogists. </p> <p>The objective of my work was to optimize the hemodynamic and drug binding performance of the Chemofilter device, using Computational Fluid Dynamics (CFD) modeling. For this, I investigated the performance of two distinct Chemofilter configurations: 1) a porous “Chemofilter basket” formed by a lattice of micro-cells and 2) a non-porous “honeycomb Chemofilter” consisting of parallel hexagonal channels. A multiscale modeling approach was developed to resolve the flow through a representative section of the porous membrane and subsequently characterize the overall performance of the device. A heat and mass transfer analogy was utilized to facilitate the comparison of alternative honeycomb configurations. </p> A multiphysics approach was developed for modeling the electrochemical binding of Doxorubicin to the anionic surface of the Chemofilter. An effective diffusion coefficient was derived based on dilute and concentrated solution theory, to account for the induced migration of ions. Computational predictions were supported by results of <i>in-vivo</i> studies performed by collaborators. CFD models showed that the honeycomb Chemofilter is the most advantageous configuration with 66.8% drug elimination and 2.9 mm-Hg pressure drop across the device. Another facet of the Chemofilter project was its surface design with shark-skin inspired texturing, which improves the binding performance by up to 3.5%. Computational modeling enables optimization of the chemofiltration device, thus allowing the increase of drug dose while reducing systemic toxicity of IAC.

PhD Aims: The aim of our study was to evaluate an efficacy and safety of intra-arterial injection of bone marrow mononuclear cells (BMMCs) in patients with chronic critical limb ischemia (CLI) Methods.In average 400ml bone marrow blood was harvested from posterior iliac crests in 24 CLI patients. BMMCs were obtained from the blood by standard procedure used for bone marrow transplantation. After digital subtraction angiography was performed in each patient, BMMCs were injected into arteries of 28 limbs. Primary outcome was the efficacy of BMMCs injection measured as a successfull healing of limb defects, a change of Fontain ischemia grade and a rate of high limb amputations. Secondary outcomes were a safety of the BMMCs injections, changes in angiographic findings after BMMCs injections and changes in quality of life (questionnaire SF-36). Results: After one year follow-up all patients were alive and 2 patients have undergone high limb amputation. Out of 14 limb defects, eleven have been healed completely and the average Fontain ischemia grade has changed from baseline value of 3.5 to 2.0 after one year (P<0.0001). Angiographic findings have improved in all examined segments of limb vessels. One year after the procedure patients have reported significant improvement. Conclusion: The intra-arterial...

<p>The duodenal epithelium secretes bicarbonate ions and this is regarded as the primary defence mechanism against the acid discharged from the stomach. For an efficient protection, the duodenum must also function as a sensory organ identifying luminal factors. Enteroendocrine cells are well-established intestinal “taste” cells that express signaling peptides such as orexins and guanylins. Luminal factors affect the release of these peptides, which may modulate the activity of nearby epithelial and neural cells.</p><p>The present thesis considers the effects of orexins and guanylins on duodenal bicarbonate secretion. The duodenal secretory response to the peptides was examined in anaesthetised rats <i>in situ</i> and the effects of orexin-A on intracellular calcium signaling by human as well as rat duodenal enterocytes were studied <i>in vitro</i>.</p><p>Orexin-A, guanylin and uroguanylin were all stimulants of bicarbonate secretion. The stimulatory effect of orexin-A was inhibited by the OX₁-receptor selective antagonist SB-334867. The muscarinic antagonist atropine on the other hand, did not affect the orexin-A-induced secretion, excluding involvement of muscarinic receptors. Orexin-A induced calcium signaling in isolated duodenocytes suggesting a direct effect at these cells. Interestingly, orexin-induced secretion and calcium signaling as well as mucosal orexin-receptor mRNA and OX₁-receptor protein levels were all substantially downregulated in overnight fasted rats compared with animals with continuous access to food. Further, secretion induced by Orexin-A was shown to be dependent on an extended period of glucose priming.</p><p>The uroguanylin-induced bicarbonate secretion was reduced by atropine suggesting involvement of muscarinic receptors. The melatonin receptor antagonist luzindole attenuated the secretory response to intra-arterially administered guanylins but had no effect on secretion when the guanylins were given luminally. </p><p>In conclusion, the results suggest that orexin-A as well as guanylins may participate in the regulation of duodenal bicarbonate secretion. Further, the duodenal orexin system is dependent on the feeding status of the animals.</p>

The duodenal epithelium secretes bicarbonate ions and this is regarded as the primary defence mechanism against the acid discharged from the stomach. For an efficient protection, the duodenum must also function as a sensory organ identifying luminal factors. Enteroendocrine cells are well-established intestinal “taste” cells that express signaling peptides such as orexins and guanylins. Luminal factors affect the release of these peptides, which may modulate the activity of nearby epithelial and neural cells. The present thesis considers the effects of orexins and guanylins on duodenal bicarbonate secretion. The duodenal secretory response to the peptides was examined in anaesthetised rats in situ and the effects of orexin-A on intracellular calcium signaling by human as well as rat duodenal enterocytes were studied in vitro. Orexin-A, guanylin and uroguanylin were all stimulants of bicarbonate secretion. The stimulatory effect of orexin-A was inhibited by the OX1-receptor selective antagonist SB-334867. The muscarinic antagonist atropine on the other hand, did not affect the orexin-A-induced secretion, excluding involvement of muscarinic receptors. Orexin-A induced calcium signaling in isolated duodenocytes suggesting a direct effect at these cells. Interestingly, orexin-induced secretion and calcium signaling as well as mucosal orexin-receptor mRNA and OX1-receptor protein levels were all substantially downregulated in overnight fasted rats compared with animals with continuous access to food. Further, secretion induced by Orexin-A was shown to be dependent on an extended period of glucose priming. The uroguanylin-induced bicarbonate secretion was reduced by atropine suggesting involvement of muscarinic receptors. The melatonin receptor antagonist luzindole attenuated the secretory response to intra-arterially administered guanylins but had no effect on secretion when the guanylins were given luminally. In conclusion, the results suggest that orexin-A as well as guanylins may participate in the regulation of duodenal bicarbonate secretion. Further, the duodenal orexin system is dependent on the feeding status of the animals.

Le glioblastome (GBM) est la tumeur cérébrale primaire la plus fréquente et agressive chez l’adulte. Son traitement, une exérèse chirurgicale maximale suivi d’un traitement adjuvant (radiothérapie et témozolomide [TMZ]), n’offre qu’un bénéfice modeste de survie médiane (14.6 mois vs. 12.1 mois pour radiothérapie post-chirurgie seule) (STUPP et al., 2005). Le TMZ demeure l’agent de choix pour le traitement du GBM. Malgré sa biodisponibilité approchant 100% suivant son administration per os (PO) (Diez et al., 2009), sa pénétration dans le liquide céphalorachidien n’est que de 20% (Ostermann et al., 2004). Ainsi, il se peut que les limites thérapeutiques du TMZ soient reliées aux barrières hémato-encéphalique (BHE) et hémato-tumorale (BHT). Plusieurs stratégies alternatives tentent de contourner ces barrières comme l’administration intra-artérielle (IA) avec une ouverture osmotique de la BHE (OBHE). Cette technique permet une plus grande distribution d’agent thérapeutique au système nerveux central (SNC). L’utilisation de cette stratégie avec le témozolomide n’a jamais été étudiée à ce jour. Nous avons émis l’hypothèse que son utilisation permettra d’augmenter la concentration de TMZ dans le SNC et que, lorsque combiné avec la radiothérapie, permettra de rehausser son activité anti-tumorale. Les objectifs du projet sont : (1) l’évaluation de la sensibilité des cellules F98 au TMZ in vitro; (2) la caractérisation de la neuropharmacocinétique du TMZ in vivo, selon différents modes d’administration; et (3) l’évaluation de l’effet anti-tumoral du TMZ in vivo, selon différents modes d’administration. Les expérimentations in vivo ont été exécutées dans le modèle syngénique Fischer-F98, porteur de tumeur gliale. L’expérimentation in vitro a démontré une résistance importante des cellules F98 au TMZ. La méthodologie développée a permis de démontrer que l’infusion IA avec et sans OBHE augmente la concentration maximale et l’aire sous la courbe du TMZ dans la tumeur cérébrale et dans le parenchyme cérébral ipsilatéral du rat Fischer-F98. Par contre, aucun bénéfice de survie n’a été observé en utilisant ces stratégies alternatives. Au contraire, l’acheminement augmenté du TMZ au SNC semble toxique. Un bénéfice de survie a été mesuré suite à l’ajout d’un traitement de radiothérapie, mais de façon indépendante au mode de livraison de TMZ ou de solution saline normale (groupe contrôle). Enfin, nos résultats témoignent de l’impact du mode d’acheminement sur la distribution d’un agent thérapeutique au SNC. En détournant la BHE, l’utilisation judicieuse d’approches alternatives combinée à un agent thérapeutique approprié a un grand potentiel clinique dans le traitement des GBM. / Abstract : Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. Its’ standard treatment, maximal surgical resection followed by an adjuvant treatment (radiotherapy and temozolomide [TMZ]) offers only a modest median survival benefit of 14.6 months (vs. 12.1 months with post-surgery radiotherapy alone) (Stupp et al., 2005). TMZ remains the therapeutic agent of choice for the treatment of GBM. Despite its bioavailability approaching 100% after a per os administration (Diez et al., 2009), its cerebrospinal fluid penetration is only of 20% (Ostermann et al., 2004). Thus, TMZ’s therapeutic limitations could be due to the blood-brain barrier (BBB) and blood-tumor barrier (BTB). Alternative routes of drug delivery attempt to bypass these barriers. For example, intra-arterial (IA) administration with an osmotic blood-brain barrier disruption (OBBBD) allows greater drug distribution to the central nervous system (CNS). Its use with TMZ, with or without radiotherapy, has never been studied. We hypothesized that it will increase TMZ concentration in the CNS and that, when combined to radiotherapy, it will intensify its anti-neoplastic activity. The project was divided in three parts: (1) the evaluation of F98 cells’ in vitro sensitivity to TMZ; (2) the in vivo caracterization of TMZ’s neuropharmacokinetics, following different routes of administration; and (3) the in vivo evaluation of TMZ’s anti-tumoral effect, following different routes of administration. The syngenic glioma Fischer-F98 model was used in all in vivo experiments. Our results showed the F98 cells to be resistant to TMZ in vitro. The methodology developed showed that an IA infusion with and without OBBBD increased TMZ’s peak concentration and area under the curve in the brain tumor and ipsilateral brain parenchyma in the Fischer-F98 rat. All the while limiting systemic exposure. However, no survival benefit was observed with the use of these alternative strategies. More so, TMZ’s enhanced delivery to the CNS seemed toxic. A survival benefit was measured following the addition of radiotherapy. This was independent of the route of delivery of TMZ or normal saline. In summary, our results provide evidence that the method of TMZ administration does impact its CNS delivery. By bypassing the BBB, the judicious use of local delivery approaches combined with the appropriate therapeutic agent can have a great clinical potential in the treatment of glioblastomas.

No description available.