Background: Evidence-based medicine (EBM) receives significant attention worldwide. Many studies have used questionnaires to discuss the factors obstructing the practice of EBM. There has however been no large-scale data analysis on who and when to practice EBM. This study aims to fill this gap in research by applying nationally representative data to analyze EBM practice after the provision of new evidence regarding rosiglitazone prescription. Methods: We used the National Health Insurance Database in Taiwan to analyze the changes in the prescription of rosiglitazone after meta-analysis found the drug to increase the risk of myocardial infarction. The study period was 18 months from the second quarter of 2007 to the fourth quarter in 2008. Two models of doctors¡¦ prescription behaviors were analyzed in the study. We conducted univariate analyses to distinguish significant differences in the variable and applied multivariate logistic analyses to predict the probability of physicians ceasing to prescribe rosiglitazone. Results: We found a significant improvement in EBM practice from specialists and experienced physicians. When compared to other specialists, endocrinologists were four times more likely to change rosiglitazone prescription (OR: 4.129, 95% CI: 2.484-6.863). Doctors with more than 10 years of specialist experience performed better in EBM practice than younger doctors. The hospital level that a physician worked at was not a significant factor. Local urbanization and economic status did not affect the practice of EBM by physicians in clinics either. Conclusions: Our study found that the EBM was still not well practiced among doctors in Taiwan. The practice of new evidence depended on the specialty or professional experience. Younger doctors and doctors working in medical centers seemed not to practice EBM well. In clinics, patients did not have enough influence to modify the doctor¡¦s prescription behavior. There was a significant time lag between the EBM emergence and EBM practice. This suggests that setting up an authoritative organization to provide timely EBM recommendations is very important. Further improvements to the practice of EBM are still urgently needed within the medical community.

<p>Successful treatment of myocardial infarction requires anearly and accurate diagnosis. Recent studies have shown thatacute myocardial scintigraphy has a high predictive value forprognosis of myocardial events. Three dimensional (3D)perfusion data obtained with SPECT are however very rare in theemergency department (ED).</p><p>We have developed a mobile tomographic system for myocardialscintigraphy, which can be used in the ED. The objectives ofthe studies presented were:</p><p>    To develop software and hardware for a mobile tomographicgamma camera system: the Cardiotom</p><p>    To demonstrate that a mobile tomographic system can beused in a clinical situation</p><p>    To evaluate the limitations of Ectomography when usingfiltered back projection for reconstruction</p><p>    To develop a method of reconstruction that compensatesfor the incomplete data acquisition associated with theacquisition geometry of Ectomography</p><p>Three prototypes of a mobile tomographic gamma camera systemhave been designed and built at the Division of MedicalEngineering, which all have been used in a clinical setting.The systems are based on Ectomography, a limited view anglemethod, also developed by us. Instead of rotating the entiregamma camera detector around the patient as in SPECT, a slanthole collimator is rotated in front of a stationary detector.Since short imaging times are important in the ED and the heartonly occupies a small area of the detector, system sensitivityhas been increased by dividing the collimator into segmentswith different projection directions. In myocardial imaging, 4segments are used and within 10 minutes from the start ofacquisition, reconstructed short axis view sections areavailable for interpretation.</p><p>Using the Cardiotom in an experimental animal study, weverified that the system could be used to quantify myocardialarea at risk and final infarct size. This conclusion was madefrom a comparison of images obtained from the Cardiotom andpathological staining of the myocardium, analysedpost-mortem.</p><p>Inherent limitations of Ectomography were evaluated withboth phantom studies and computer simulated data, reconstructedusing filtered back-projection Results show that moderatedeviation from optimal position of the detector with respect tothe myocardium will have little or no influence on thediagnostic information when assessed from short axis sectionimages and polar tomograms. However, long axis section imagesappear elongated when reconstructed using filteredback-projection.</p><p>We have shown that this elongation distortion can besuppressed using iterative reconstructions techniques, and wehave implemented such an algorithm, called three-dimensionalTotal Variation Expectation Maximisation (3DTV-EM). Resultswere that elongation distortion was reduced and depthresolution improved. The reconstruction technique was alsoevaluated for SPECT reconstruction and was found to decreasethe noise in reconstructed images, when compared to thetwo-dimensional TV-EM algorithm. Noise pattern were also foundto be more uniform for the 3DTV-EM algorithm compared totwo-dimensional TV-EM.</p><p>In conclusion, we have shown that the Cardiotom may beuseful in a clinical acute setting, providing valuablediagnostic information. Rapid positioning is possible, sincemoderate deviation from optimal positioning will cause few orno artefacts. Image quality can be improved if iterativetechniques are used for image reconstruction instead offiltered back-projection.</p><p><b>Keywords</b>: acute studies, myocardial infarction,scintigraphy, mobile gamma camera, tomography.</p>

Es werden in einer kumulativen Dissertationsschrift zwei wissenschaftliche Arbeiten zusammengefasst. Die erste Arbeit beschreibt die Etablierung der Kontrastmittelechokardiografie zur Charakterisierung des Herzinfarktmodells an der Ratte im zeitlichen Verlauf. Es wird der Ablauf der geometrischen Änderungen am linken Herz nach Herzinfarkt gezeigt. Zusätzlich wird die Methode mit anderen etablierten echokardiografischen Methoden verglichen. Hier wird die Messung der linksventrikulären Querschnittsfläche der Volumenbestimmung nach der modifizierten Simpson-Methode gegenübergestellt. Es wird gezeigt, dass die Flächenmessungen, bei Nichtverfügbarkeit der Kontrastmittelechokardiografie eine valide Methode zur Verlaufsbeobachtung im Modell darstellt. Die zweite Arbeit untersucht im Rattenversuch den Einfluss von mesenchymalen Vorläuferzellen aus Nabelschnurblut auf die Entwicklung des Herzversagens nach Herzinfarkt. Die Injektion der Zellen erfolgt direkt in das Herzmuskelgewebe am Rand des Infarktareals. Zusätzlich zur Phänotypisierung mittels Echokardiografie wurden hämodynamische Messungen, sowie immunhistochemische und molekularbiologische Untersuchungen vorgenommen. Es konnte in einem Multigruppendesign gezeigt werden, dass im vorliegenden Versuch durch die Injektion von Vorläuferzellen kein Einfluss auf die geometrischen und biomechanischen Änderungen nach Herzinfarkt genommen werden konnte. Es konnten jedoch zusätzlich Differenzen zwischen den Versuchsgruppen in der Genexpression von Signalmolekülen der extrazellulären Matrix gezeigt werden, welche Spekulationen über den Einfluss der Zellen auf parakrine Mechanismen im Herzgewebe zulassen.

RNA interference (RNAi) is a conservative post-transcriptional gene silencing mechanism that can be mediated by small interfering RNAs (siRNAs). Given the effectiveness and specificity of RNAi, the administration of siRNA molecules is a promising approach to cure diseases caused by abnormal gene expression. However, as siRNA is susceptible to degradation by nucleases and it can hardly penetrate cell membranes due to its polyanionic nature, a successful translation of the RNAi mechanism for therapeutic purposes is contingent on the development of safe and efficient delivery systems. This dissertation described the development of novel siRNA delivery systems on the basis of polymeric and dendrimeric materials and also demonstrated the application of one optimized delivery system to deliver therapeutic siRNAs in a cardiovascular disease model in vivo. We studied a linear peptide polymer made from cell penetrating peptide monomers and investigated the contribution of the polymeric structure, degradability, and ligand conjugation to the siRNA loading capacity, biocompatibility, and transfection efficiency of polymeric materials. With the obtained knowledge and experience, we invented a neutral crosslinked delivery system aiming to solve the inherent drawbacks of traditional cationic delivery systems that are based on electrostatic interactions. The new concept utilized buffering amines to temporarily bind siRNA and a crosslinking reaction to immobilize the formed particles, and targeting ligands modified on the neutral dendrimer surface further enhanced the interactions between the delivery vehicles and target cells. The obtained delivery system allowed stability, safety, controllability, and targeting ability for siRNA delivery, and the method developed here could be transformed to other polymeric or dendrimeric cationic materials to make them safer and more efficient. To exploit the therapeutic potential of siRNA delivery, we developed a tadpole-shaped dendrimeric material to deliver siRNA against an Angiotensin II receptor in a rat ischemia-reperfusion model. Our results showed that the nonaarginine-conjugated tadpole dendrimer was capable of delivering siRNA effectively to cardiac cells both in vitro and in vivo, and the successful down-regulation of the Angiotensin II receptor preserved the cardiac functions and reduced the infarct size post-myocardial infarction. This dissertation paves a way for transforming multifunctional non-viral siRNA delivery systems into potent therapeutic strategies for the management of cardiovascular diseases.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Heart failure (HF) following myocardial infarction (MI) is the leading cause of mortality and morbidity worldwide. Existing medical and interventional therapies can only reduce the cardiomyocytes (CMs) lost during MI. They are unable to replenish the permanent loss of CMs and this contributes to progressive pathological left ventricular (LV) remodeling and HF. Cell-based therapies using adult stem cells or embryonic stem cells (ESCs) and their cardiac derivatives have frequently been explored as a potential therapeutic approach to restore cardiac function in HF. The objectives of this thesis are to evaluate the efficacy and safety of different approaches of stem cell based therapy to improve cardiac function using small and large animal MI models. In Chapter 3, we studied the functional consequences of direct intramyocardial transplantation of ESCs and ESC-derived cardiomyocytes (ESC-CMs) in a murine model of acute MI. LV ejection fraction (LVEF) and maximal positive or negative pressure derivative (dP/dt) improved 4 weeks after transplantation of either ESCs or ESC-CMs. Nevertheless there was a higher incidence of inducible ventricular tachyarrhythmia (VT) and higher mortality in animals transplanted with ESC-CMs than those with ESCs. At a single cell level, ESC-CMs exhibited immature electrophysiological properties such as depolarized resting membrane potential (RMP), longer action potential duration (APD) and automaticity. In Chapter 4, we tested the hypothesis that genetic modification of these immature electrophysiological properties of ESC-CMs by overexpression of Kir2.1 gene encoding the ion channels for IK1, may alleviate the pro-arrhythmic risk. In this study, Kir2.1 channels expression could be controlled with the administration of doxycycline (DOX). The DOX-treated ESC-CMs were more mature with hyperpolarized RMP and shorter APD than their counterparts without DOX treatment. A similar improvement in LV systolic function was observed 4 weeks after both DOX treated and untreated ESCCMs transplantation, although those animals transplanted with DOX-treated ESC-CMs had a significantly lower incidence of spontaneous and inducible VT. Histological analysis in both studies suggested that the major mechanisms of improvement in cardiac function were related to angiogenesis and low apoptosis rate of native cardiomyocytes mediated via paracrine effects. Importantly, very limited retention of ESC-CMs was observed 4 weeks after transplantation. Cell-based patches that use different bioengineering techniques have been proposed to improve cell retention and survival following transplantation. In Chapter 5, the efficacy of a passive epicardial patch was tested in a chronic large animal MI model with HF created with catheter-based coronary embolization. The implantation of an epicardical patch over the infarcted LV region was performed 8 weeks after MI in pigs with impaired LVEF. At week 20, pigs implanted with epicardical patches had significantly thicker LV wall thickness at the infarction sites, smaller LV dilation and better LV systolic function compared with control animals. The expression of MMP-9 was significant lower in the epicardical patch group at the peri-infarct zones. These findings suggested that a passive epicardial patch can improve LV function in HF and provides important proof-of-principle data to support its use as a platform for delivery of cell-based therapies after MI. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Remifentanil is an ultra-short-acting phenylpiperidine opioid analgesic that is rapidly metabolized by nonspecific blood and tissue esterases. In clinical practice, remifentanil is now more commonly used during both cardiac and non-cardiac surgery than classic opioid agonists such as morphine, since it can be given in higher doses, is more titratable and enables fast recovery of patients in the postoperative period. Remifentanil preconditioning (RPC), achieved by intravenous remifentanil infusion interspersed with infusion-free periods before indexed ischaemia, attenuates cardiac ischaemia-reperfusion injury (IRI). This is experimentally manifested by reduced postischaemic myocardial infarct size (IS) and diminished markers of cardiac failure and apoptosis, and, clinically, by reduced release of biomarkers of myocardial cellular injury after cardiac surgery. However, the underlying mechanisms by which RPC has a cardioprotective effect need to be further explored. It’s generally considered that the Reperfusion Injury Salvage Kinase (RISK) pathway, triggering the expression of phosphatidylinositol 3-kinase (PI3K) as well as Akt, exerts a pivotal role in both classic ischaemic preconditioning (IPC) and pharmacological preconditioning induced cardioprotection. Moreover, recent studies show that the Survivor Activating Factor Enhancement (SAFE) signalling pathway, which involves signal transducers and activators of transcription-3 (STAT3) and janus activated kinase-2 (JAK2), also has an essential role in IPC. Although cross-talk has been found between the RISK and SAFE pathways, the SAFE pathway can function independently of the RISK to confer cardioprotection. However, the roles of JAK/STAT and PI3K/Akt signalling and, in particular, their relative importance in RPC-mediated cardioprotection have not been studied. I explored whether RPC confers cardioprotection via the JAK/STAT or PI3K/Akt pathway and its relationship with GSK3β inhibition. In first part of my study, I explored relative role of the JAK/STAT and PI3K/Akt which were involved in RPC cardioprotection using JAK2 and PI3K inhibition. Male Sprague-Dawley rats were either sham operated or randomly assigned to receive I/R alone or as well as RPC. Pretreatment with the JAK2 inhibitor AG490 or the PI3K inhibitor wortmannin was induced before ischaemia in rats. RPC reduced myocardial infarction and haemodynamic dysfunction induced by IRI accompanied with increased phosphorylation of STAT3 but not Akt or eNOS phosphorylation. AG490 but not wortmannin cancelled RPC’s cardioprotection. In addition, RPC attenuated hypoxia/reoxygenation induced cardiomyocyte apoptosis while STAT3 knock-out abolished the protective effects of RPC. These findings suggest that RPC confers cardioprotection primarily via activation of the JAK/STAT signalling but not the PI3K/Akt signalling pathway. The second study further investigated the role of GSK3β in RPC cardioprotection using the GSK3β inhibitor SB216763. I found that SB restored the ability of RPC to reduce the extent of myocardial infarction and CK-MB release despite the presence of AG490. The phosphorylation of GSK3β was increased by RPC. In addition, GSK3β gene knock-out with siRNA preserved RPC’s cardioprotection regardless of STAT3 abrogation indicating that GSK3β inhibition plays a critical role as a downstream effector in RPC mediated cardioprotection. Taken together with the evidence from this two part study, I conclude that RPC confers cardioprotection by activating the JAK/STAT and, subsequently, inhibiting GSK3β, a critical downstream effector of RPC cardioprotection. / published_or_final_version / Anaesthesiology / Master / Master of Philosophy

In 2015, American Heart Association (AHA) reported that 1 in 9 deaths are attributed to Heart failure (HF), the number one killer in the world. While advancements in interventional cardiology in conjunction with pharmacotherapies have significantly reduced the rate of mortality following MI, there has been a corresponding rise in chronic heart failure (CHF) in surviving patients, largely attributed to the limited regenerative capacity of the heart and the inadequate healing response. Myocardial ischemic injury triggers an exuberant local and systemic inflammation, and the extent and quality of the cardiac wound healing process is intricately tied to the delicate equilibrium of this inflammatory response. While cardiac regeneration is an important goal, it is imperative in the meantime to explore therapeutic strategies that target these inflammatory mediators of early cardiac repair. These interventions to influence and improve cardiac wound healing can represent a new therapeutic window to halt the progression of heart failure between the few hours that may be used to limit infarct size by reperfusion and an irreversible non-contractile cardiac scar. This dissertation examines three therapeutic delivery strategies aimed at modulating the immune response to enhance cardiac repair in rodent models MI: 1) Polyketal nanoparticles as siRNA delivery vehicles for antioxidant therapy; 2) Spherical nucleic acid particles for anti-inflammatory therapy and; 3) Bioactive PEG (polyethyleneglycol)-based hydrogel for immunomodulation. The work presented here applies novel nucleic acid delivery strategies for cardiac gene silencing and has contributed to new knowledge with regard to modulating the immune response following MI.

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