published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

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Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Thesis (Ph.D.)--Aberdeen University, 2009. / Title from web page (viewed on July 1, 2009). Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 92-100). Also available in print.

An increase in heart rate brought about by stimulation of the re centers at the junction of the pulmonary veins and the left atrium in dogs has been reported by Ledsome and Linden, (1964). Although extensive experimentation has shown the afferent pathway for such tachycardia is in the vagus nerve, and efferent impulses appear to travel via the cardiac sympathetics, the location of central synapses, and the degree of central control necessary for its existence are not known. Also unknown is the significance of this cardiovascular control mechanism in the unanaesthetized animal. The series of experiments described in this paper were designed to answer both these questions. A method for decerebrating mongrel dogs (8-18 Kg) by electrocoagulation was devised which avoided traumatic loss of blood, leaving a stable decerebrate preparation. The tachycardia initiated by the inflation of small balloons at the junction of the pulmonary veins with the left atrium was found to be unchanged by such a midcollicular decerebration. Both magnitude and neural characteristics of the increase in heart rate were unaltered. However, careful studies of these characteristics with both drugs and lesions of the spinal cord, revealed a discrepancy with previous reports. The tachycardia produced by balloon inflation could not be totally abolished by the infusion of the sympathetic blocking agent propranolol, either before or after decerebration. In addition small, but significant, increases in heart rate remained upon section of the spinal cord at the level of the first cervical vertebra. These results indicated that the efferent pathway for this reflex, though predominantly relayed by the cardiac sympathetics, may possess a vagal component. Using the same decerebrate preparation, two volatile anaesthetics were used to study the effects of anaesthetics on the response to balloon inflation. Halothane, or a nitrous oxide-sodium pentothal combination were administered prior to decerebration, then discontinued at completion of the section. Throughout the duration of both anaesthetics, cardiovascular reflexes such as the carotid sinus reflex, were depressed. The left atrial reflex was similarly small or absent as compared to dogs under chloralose anaesthesia. Removal of the anaesthetic circuit after successful decerebration coincided with the appearance of small but significant increases in heart rate at balloon inflation, and typical carotid sinus activity at occlusion of the carotid arteries. Neither reflex attained the magnitudes observed in dogs under chloralose anaesthesia, despite prolonged waiting, up to six hours after decerebration. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Obesity is a major risk factor for insulin resistance, type 2 diabetes, cardiovascular disease (CVD), and vascular calcification. Vascular calcification is correlated with advanced CVD and a significant predictor of cardiovascular events. Obese individuals tend to have increased levels of circulating leptin, an adipocytokine that is a significant independent predictor of cardiovascular disease. We have shown that daily intraperitoneal injections of exogenous leptin (125 μg/mouse/d) can promote vascular calcification in an ApoE-/- mouse model of atherosclerosis. This increase in calcification is associated with an increase in the expression of several osteoblast-specific markers and is independent of any affect on atherosclerotic lesion size. Our studies suggest that leptin mediates the osteogenic differentiation of vascular smooth muscle cells (VSMCs) to promote vascular calcification via a pathway involving the inhibition of glycogen synthase kinase (GSK)-3 activity. Other studies have suggested that endoplasmic reticulum (ER) stress-induced GSK-3 activity promotes the development of atherosclerosis. Therefore, we hypothesized that during the progression of vascular disease, GSK-3 functions as a checkpoint for VSMCs at which cells can commit to: i) de-differentiation, thereby contributing to atherosclerosis, or ii) osteogenic differentiation, thereby contributing to vascular calcification. We investigated the effects of modulating GSK-3 activity on the differentiation of VSMCs in vitro. We found that many of the molecular tools that are typically used to modulate ER stress can promote the expression of osteoblast-specific markers and the osteogenic differentiation of MOVAS cells. However, because many of these interventions affect multiple pathways in MOVAS cells, the specific role of the ER stress – GSK-3 pathway is difficult to discern. Future studies are required to determine the effects of direct modulation of GSK-3 on vascular calcification and to delineate the mechanisms/effects of various ER stressors in the osteogenic differentiation of VSMCs. / Thesis / Doctor of Philosophy (Medical Science)

Os shunts vasculares temporários (SVT) são utilizados como uma técnica eficaz para reestabelecer rapidamente o fluxo sanguíneo em casos de lesão vascular com isquemia do membro ou órgão acometido, no qual a revascularização deverá ser postergada. Habitualmente, o SVT é inserido dentro dos cotos proximal e distal do vaso lesado através de uma abertura na pele, visando restaurar a perfusão e interromper a isquemia. O objetivo deste estudo é comparar a pressão arterial média (PAM em mmHg) e o fluxo sanguíneo (em ml/min) em dois modelos de SVT, um habitual e outro implantado por punção, bem como o tempo para a inserção destes dispositivos e suas patências primária e secundária. Realizamos experimentos em 30 suínos, somando 60 intervenções de revascularização arterial temporária dos membros posteriores: trinta SVT habituais e trinta por punção. Analisamos a PAM durante os procedimentos nos membros posteriores e o fluxo através dos dois tipos de SVT. A análise de fluxo mostrou uma diferença significativa entre os SVT testados (p=0,001), sendo menor no grupo SVT por punção. No entanto, o tempo decorrido (min) para inserção do SVT habitual foi maior do que o tempo para inserção do SVT por punção (15,32 ± 3,08 vs. 10,37 ± 1,7, p=0,001). Além disso, observamos uma recuperação da PAM nos membros submetidos aos dois tipos de SVT próxima à PAM sistêmica em 100% dos experimentos. Os resultados revelaram patência primária, secundária, e taxa de complicações similares entre os dois tipos de SVT. Concluímos que o fluxo foi menor no SVT por punção, mas a recuperação da PAM foi semelhante e com menor tempo de inserção do SVT por punção / Temporary vascular shunts (TVS) are used as an effective technique to rapidly restore blood flow in cases of vascular injury with ischemia of the affected limb or organ, in which revascularization shall be postponed. Usually, TVS is positioned within the proximal and distal stumps of the injured vessel, through an opening of the skin, in order to restore perfusion and stop the ischemia. We sought to compare mean blood pressure (MBP in mmHg) and blood flow (ml/min) between two types of TVS, a standard one and a puncture one, as well as the time spent to insert these devices. We performed an experimental study on 30 pigs, including 60 vascular interventions in posterior limbs: thirty standard TVS and thirty puncture TVS. MBP was analyzed during the interventions in both posterior limbs and the flow through both types of TVS. Flow analysis revealed a significant difference between the two types of TVS (p=0,001), being lower in the puncture TVS. However, the time spent during standard TVS insertion was greater than that of the puncture shunt (15,32 ± 3,08 min vs.10,37 ± 1,7 min, p=0,001). In addition, we observed a limb MBP recovery close to systemic MBP in 100% of the experiments. The results show similar primary and secondary patency and complication rate in both TVS types. Therefore, we conclude that the flow was lower in the puncture TVS, but the MBP recovery was similar and it took less time to be inserted

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