Abstract The repair of thoracoabdominal aortic aneurysms carries a substantial risk of ischaemic perioperative spinal cord injury. Although several protective methods have been developed, the risk of paraplegia has not been eliminated. Moreover, aortic aneurysms, including arch aneurysms, are complex clinical challenges requiring cerebral protection with hypothermic circulatory arrest (HCA). Hypothermia lowers the rate of cerebral metabolism and allows a temporary halt of the systemic circulation. However, there is still a risk for cerebral damage and a need for additional neuroprotective methods. During the last 15 years, our research group has used a porcine model to investigate a variety of neuroprotective tools. In this thesis, an animal model was utilized to study the efficacy of remote ischaemic preconditioning (RIPC) to ameliorate ischaemic damage to the central nervous system, and to shed light on the potential mechanism. Moreover, diazoxide, the pharmacological mimetic of RIPC, was tested in the HCA animal model. In the first Study (I), RIPC showed beneficial effect on the spinal cord against ischaemic insult as recorded with motor-evoked potentials. Strikingly, the beneficial effect of RIPC was observed even before the ischaemia. In the second Study (II), some beneficial effect of RIPC was seen in the immunohistochemical analysis of the spinal cord ischemia but the result remains inconclusive. Similarly, the diazoxide-treated animals had better hemodynamic status postoperatively and mildy better antioxidant activity of the brain in the third Study (III). The fourth study (IV) was a review of the current knowledge of RIPC from the cardiovascular point of view. Our studies indicate that RIPC might be a potential adjunct for preventing neuronal ischaemic injury in the setting of thoracoabdominal aortic surgery. Our result indicates that further preclinical studies with diazoxide are required before studies can be conducted in humans. / Tiivistelmä Torakoabdominaalisen aortan aneurysman kirurginen korjaaminen sisältää riskin iskeemiselle selkäytimen vauriolle. Vaikka useita suojaavia tekniikoita on kehitetty, paraplegian riskiä ei ole saatu poistettua kokonaan. Kirurgisen korjaamisen haasteellisuus moninkertaistuu, jos aneurysma on laajentunut myös aortan kaareen. Tällöin vaaditaan hypotermista verenkierron pysäytystä (HCA). Hypotermia alentaa aivojen metabolista aktiivisuutta merkittävästi ja siten verenkierron väliaikainen pysäytys on mahdollista. Tästä huolimatta hypotermiseen verenkierron pysäytykseen liittyy riski aivokudoksen vauriolle. Meidän tutkimusryhmämme on tutkinut useita keskushermostoa suojaavia tekniikoita ja lääkeaineita viimeisen 15 vuoden aikana. Käytämme sikaa koe-eläin mallina, jota on tämänkin väitöskirjan osajulkaisuissa käytetty. Tämän väitöskirjatyön tarkoituksena on ollut tutkia sekä esialtistavan raajaiskemian (RIPC) että farmakologisen mimeetin, diazoxiden, keskushermostoa suojaavia vaikutuksia sekä niiden mahdollista vaikutusmekanismia. Ensimmäisessä osajulkaisussa esialtistava raajaiskemia paransi selkäytimen iskemian sietokykyä, mikä näkyi alaraajojen motorisissa herätepotentiaaleissa. Merkittävintä tutkimuksessa oli, että esialtistavan raajaiskemian edulliset vaikutuksen selkäytimeen oli nähtävissä jo ennen iskemiaa. Toisessa osajulkaisussa esialtistava raajaiskemialla oli nähtävissä edullisia, mutta ei varauksettomia, vaikutuksia selkäytimen iskemian immunohistokemiallisessa analyysissä. Kolmannessa osatyössä diazoxidin vaikutukset iskemiaa vastaan nähtiin parempana hemodynaamisena tilana ja antioksidatiivisen aktiivisuuden lisääntymisenä aivoissa, mutta tulos on myös tulkinnanvarainen. Neljäs osajulkaisu kokosi tämän hetken tietämyksen esialtistavasta raajaiskemiasta. Tutkimuksissamme osoitimme, että esialtistava raajaiskemiassa on potentiaalia tulla yhdeksi välineeksi keskushermoston iskemiaa vastaan torakoabdominaalisen aortan kirurgiassa. Lisäksi diazoxidin mahdolliset neuroprotektiiviset vaikutukset vaativat lisää koe-eläintutkimuksia ennen ihmiskokeisiin siirtymistä.

A interrupção do fluxo sanguíneo, ou isquemia, representa um dos problemas mais importantes de doenças cardiovasculares e cerebrovasculares enfrentados pelos médicos na sua rotina. Em relação ao miocárdio muitos estudos têm sido realizados nessa área e sabe-se que os anestésicos inalatórios e os opiódes podem protege as células cardíacas contra a lesão de isquemia e reperfusão. O propofol por sua parece não ter efeito de précondicionamento, porém apresenta características similares as ações antioxidantes da vitamina E, neutralizando os efeitos nocivos da produção de radicais livres. A associação de sevoflurano, sufentanil e propofol não está descrita na literatura. O objetivo deste estudo foi examinar a potencialização de cardioproteção entre sevoflurano, propofol e sufentanil por meio de análise do tamanho da área de infarto e inibição de apoptose em células miocárdicas. Ratos foram submetidos a 5 protocolos de pré-condicionamento diferentes e divididos em grupos agudos e crônicos. Os resultados indicaram que a associação destes anestésicos não conferiu proteção maior do que quando administrados isoladamente. Além disso, o sevoflurano conferiu proteção ao miocárdio no pós-infarto agudo e crônico. Já o propofol conferiu cardioproteção no pós-infarto crônico / The interruption of blood flow, or ischemia, represents one of the major problems of cardiovascular and cerebrovascular diseases seen by physicians in their routine. With respect to the myocardium, many studies have been conducted in this area and it is a known fact that inhaled anesthetics and opiates may protect cardiac cells against the ischemia and reperfusion injury. Propofol, in turn, seems to have no preconditioning effect, but it has similar characteristics to the antioxidant actions of vitamin E by neutralizing the harmful effects of free radical production. The combination of sevoflurane, sufentanil and propofol has not been described in literature. The aim of this study was to survey cardioprotection potentiation among sevoflurane, propofol and sufentanil by analyzing the size of infarct area and the inhibition of apoptosis in cardiac cells. Rats were subjected to five different preconditioning protocols and divided into acute and chronic groups. Results indicated that the combination of these anesthetics did not confer greater protection than when they were administered alone. Furthermore, sevoflurane conferred myocardial protection in the postacute and chronic infarction stage. Propofol, in turn, conferred cardioprotection in the chronic post-infarction stage

Call number: LD2668 .T4 1984 N44 / Master of Science

Multiphysics systems with interface coupling are used to model a variety of physical phenomena, such as arterial blood flow, air flow around aeroplane wings, or interactions between surface and ground water flows. Numerical methods enable the practical application of these models through computer simulations. Specifically a high level of detail and accuracy is achieved in finite element methods by discretisations which use extremely large numbers of degrees of freedom, rendering the solution process challenging from the computational perspective. In this thesis we address this challenge by developing a twofold strategy for improving the efficiency of standard finite element coupled solvers. First, we propose to solve a monolithic coupled problem using block-preconditioned GMRES with a new Schur complement approximation. This results in a modular and robust method which significantly reduces the computational cost of solving the system. In particular, numerical tests show mesh-independent convergence of the solver for all the considered problems, suggesting that the method is well-suited to solving large-scale coupled systems. Second, we derive an adjoint-based formula for goal-oriented a posteriori error estimation, which leads to a time-space mesh refinement strategy. The strategy produces a mesh tailored to a given problem and quantity of interest. The monolithic formulation of the coupled problem allows us to obtain expressions for the error in the Lagrange multiplier, which often represents a physically relevant quantity, such as the normal stress on the interface between the problem components. This adaptive refinement technique provides an effective tool for controlling the error in the quantity of interest and/or the size of the discrete system, which may be limited by the available computational resources. The solver and the mesh refinement strategy are both successfully employed to solve a coupled Stokes-Darcy-Stokes problem modelling flow through a cartridge filter.

Symmetric generalized eigenvalue problems arise in many physical applications and frequently only a few of the eigenpairs are of interest. Typically, the problems are large and sparse, and therefore traditional methods such as the QZ algorithm may not be considered. Moreover, it may be impractical to apply shift-and-invert Lanczos, a favored method for problems of this type, due to difficulties in applying the inverse of the shifted matrix. With these difficulties in mind, Golub and Ye developed an inverse free Krylov subspace algorithm for the symmetric generalized eigenvalue problem. This method does not rely on shift-and-invert transformations for convergence acceleration, but rather a preconditioner is used. The algorithm suffers, however, in the presence of multiple or clustered eigenvalues. Also, it is only applicable to the location of extreme eigenvalues. In this work, we extend the method of Golub and Ye by developing a block generalization of their algorithm which enjoys considerably faster convergence than the usual method in the presence of multiplicities and clusters. Preconditioning techniques for the problems are discussed at length, and some insight is given into how these preconditioners accelerate the method. Finally we discuss a transformation which can be applied so that the algorithm extracts interior eigenvalues. A preconditioner based on a QR factorization with respect to the B-1 inner product is developed and applied in locating interior eigenvalues.

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By considering Krylov subspace methods in nonstandard inner products, we develop in this thesis new methods for solving large sparse linear systems and examine the effectiveness of existing preconditioners. We focus on saddle point systems and systems with a nonsymmetric, diagonalizable coefficient matrix. For symmetric saddle point systems, we present a preconditioner that renders the preconditioned saddle point matrix nonsymmetric but self-adjoint with respect to an inner product and for which scaling is not required to apply a short-term recurrence method. The robustness and effectiveness of this preconditioner, when applied to a number of test problems, is demonstrated. We additionally utilize combination preconditioning (Stoll and Wathen. SIAM J. Matrix Anal. Appl. 2008; 30:582-608) to develop three new combination preconditioners. One of these is formed from two preconditioners for which only a MINRES-type method can be applied, and yet a conjugate-gradient type method can be applied to the combination preconditioned system. Numerical experiments show that application of these preconditioners can result in faster convergence. When the coefficient matrix is diagonalizable, but potentially nonsymmetric, we present conditions under which the pseudospectra of a preconditioner and coefficient matrix are identical and characterize the pseudospectra when this condition is not exactly fulfilled. We show that when the preconditioner and coefficient matrix are self-adjoint with respect to nearby symmetric bilinear forms the convergence of a particular minimum residual method is bounded by a term that depends on the spectrum of the preconditioned coefficient matrix and a constant that is small when the symmetric bilinear forms are close. An iteration-dependent bound for GMRES in the Euclidean inner product is presented that shows precisely why a standard bound can be pessimistic. We observe that for certain problems known, effective preconditioners are either self-adjoint with respect to the same symmetric bilinear form as the coefficient matrix or one that is nearby.

Exercise training promotes a beneficial endothelial cell (EC) phenotype and results in conduit vessel adaptation. The specific underlying mechanisms have been proposed (shear stress, circumferential stress, hypoxia, metabolic) but are yet to be fully elucidated. This thesis investigated the predominant stimuli responsible for conduit vessel adaptation with training. Further, it developed a method of in situ EC extraction to allow for determination of the cellular and molecular mechanisms underpinning these adaptations. The methodology utilised two-dimensional (2D) Doppler ultrasound, strain gauge plethysmography, immunocytochemistry and RT-qPCR to provide insight in to vascular characteristics, predominantly of the brachial artery and peripheral EC. Long-term repeated isometric forearm muscle contractions as performed by well-trained rock climbers promoted greater resting, peak (in response to 5 min ischaemia) and maximal (in response to ischaemic exercise) brachial artery diameters compared with controls. This structural response is dependent upon confounders associated with exercise additional to shear stress as evidenced by the lack of brachial artery remodelling in response to 8 weeks of ischaemic preconditioning (IPC). A transient increase in flow-mediated dilation (FMD)% was observed following 6 weeks exposure to IPC, which became significant when controlled for baseline artery diameter, despite an absence of augmentation following long-term (≥ 8 weeks) exposure to a shear stimulus. This is in line with the suggested timeline of conduit vessel adaptation to exercise training of a transient increase in function at 2-4 weeks. Underpinning molecular mechanisms responsible were not determined but may be further investigated given that the endovascular biopsy technique was developed and improved in this thesis. The endovascular biopsy successfully yields approximately 2100 ± 1700 EC per sample, providing sufficient material for determination of expression of both mRNA (RT-qPCR) and protein (immunocytochemistry). Specifically, type 2 diabetics (T2DM) with symptomatic cardiac abnormalities exhibited augmented eNOS mRNA and protein in brachial artery EC as compared with non-diabetic controls with symptomatic cardiac abnormalities. In conclusion, this thesis demonstrates that although shear stress promotes a transient trend for enhancement in function of the peripheral conduit arteries, additional factors are required for long-term structural adaptations. Further, the endovascular biopsy technique offers a novel method of extracting and analysing EC for genes and proteins of interest to vascular health. The use of this technique to decipher the underlying cellular and molecular mechanisms involved in vascular adaptations with exercise requires further investigation.

Passive detrusor smooth muscle exhibits both viscoelastic softening and strain softening. Strain softening is a loss of stiffness following a stretch to a longer length and is reversible upon muscle activation. Because of this behavior, steady state passive force in detrusor is not constant for a given muscle length and can be adjusted by an intracellular mechanism. Thus, passive detrusor exhibits adjustable passive stiffness. Existing three-component mechanical models for muscle, the Kelvin and Voigt, are insufficient to display this characteristic. The goal of this thesis is to develop a new biomechanical model for passive force in detrusor by adding additional elements to the Kelvin or Voigt models. Eight mechanical characteristics of detrusor are identified from the literature and with three new experiments, and a novel adjustable passive stiffness model for smooth muscle is proposed. Simulations are performed to demonstrate that the model qualitatively exhibits each of the eight tissue characteristics.

Cell damage represents a major pathomechanism in many diseases of high clinical interest, such as myocardial infarction (MI), where it plays an important role in ischemia-reperfusion (I/R) injury. Considerable progress has been made towards identifying physiological and pharmacological agents that play a key role in myocardial preconditioning against I/R injury and also elucidating the molecular changes leading to such protection.Second messengers in cellular signaling pathways, such as cGMP have been well implicated as key players in ischemic and pharmacological preconditioning (PC) of the heart. Phosphodiesterase type 5 (PDE-5) is an enzyme that specifically hydrolyzes cGMP thereby decreasing its tissue concentration. Sildenafil is a potent selective inhibitor of PDE-5 and therefore allows the accumulation of cGMP in several tissues shown to express PDE-5, including pulmonary and coronary arteries. We initially hypothesized that vasodilation induced by sildenafil may release several endogenous mediators including adenosine, bradykinin or nitric oxide (NO), that may trigger a signaling cascade leading to protection against I/R injury. Our results show that sildenafil, at a clinically relevant dose, induced powerful acute and delayed cardioprotection against I/R injury in an in vivo rabbit model via opening of mitoKATP channels. The acute cardioprotective effect of sildenafil was dependent on activation of protein kinase C in rabbits. Moreover, we observed that sildenafil induced delayed PC by NO produced through activation of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in the mouse heart. The expression of iNOS/eNOS was regulated by ERK phosphorylation and the delayed protection against I/R was blocked by PD98059, a selective ERK inhibitor. Furthermore, sildenafil-induced delayed protection was abolished in the intact heart as well as adult myocytes derived from adenosine A1 receptor knock-out mice suggesting an essential role of A1 receptor in protection. Taken together, these studies suggest that sildenafil is a powerful tool to reduce I/R injury in the animal models. Future clinical studies with relatively safe and effective PDE-5 inhibitors may have an enourmous impact on the use of these compounds in reducing I/R injury in the heart and other organs.