Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009. / The human ether-à-go-go-related gene (HERG) encodes the protein underlying the cardiac potassium current IKr. Mutations in HERG may produce defective channels and cause Long QT Syndrome (LQTS), a cardiac disease affecting 1 in 2500 people. The disease is characterised by a prolonged QT interval on a surface electrocardiogram and has a symptomatic variability of sudden cardiac death in childhood to asymptomatic longevity. We hypothesised that genetic variation in the proteins that interact with HERG might modify the clinical expression of LQTS. Yeast two-hybrid methodology was used to screen a human cardiac cDNA library in order to identify putative HERG N-terminus ligands. Successive selection stages reduced the number of putative HERG ligandcontaining colonies (preys) from 268 to 8. Putative prey ligands were sequenced and identified by BLAST-search. False positive ligands were excluded based on their function and subcellular location. Three strong candidate ligands were identified: Rhoassociated coiled-coil containing kinase 1 (ROCK1), γ-sarcoglycan (SGCG) and microtubule-associated protein 1A (MAP1A). In vitro co-immunoprecipitation (Co-IP) and mammalian two-hybrid (M2H) analyses were used to validate these proposed interactions, but failed to do so. This should be further investigated. Analysis of confirmed interactions will shed light on their functional role and might contribute to understanding the symptomatic variability seen in LQTS.

<p>Repolarization inhomogeneity is arrhythmogenic. QT dispersion (QTd) is an easily accessible ECG-variable, related to the repolarization and shown to carry prognostic information. It was originally thought to reflect repolarization inhomogeneity. Lately, arguments have been risen against this hypothesis. Other measures of inhomogeneity are being investigated, such as nondipolar components from principal component analysis (PCA) of the T-wave. In all here described populations, continuous 12-lead ECG was collected during the initial hours of observation and secondary parameters used for description of a large number of ECG-recordings.</p><p>Paper I studied QTd in 548 patients with chest pain with a median number of 985 ECG-recordings per patient. Paper II explored a spatial aspect of QTd in 276 patients with unstable coronary artery disease. QTd and a derived localized ECG-parameter were compared to angiographical measures. QTd, expressed as the mean value during the observation was a powerful marker of risk. It was however not effective in identifying high-risk patients. Variations in QTd contained no additional prognostic information. In unstable coronary artery disease, QTd was increased by a mechanism unrelated to localization of the disease.</p><p>Two relevant conditions for observing repolarization inhomogeneity might occur with conduction disturbances and during initial course of ST-elevation myocardial infarction (STEMI). Paper III compared the PCA-parameters of the T-wave in 135 patients with chest pain and conduction disturbance to 665 patients with normal conduction. Nondipolar components were quantified by medians of the nondipolar residue (TWRabsMedian) and ratio of this residue to the total power of the T-wave (TWRrelMedian). Paper IV described the changes in the nondipolar components of the T-wave in 211 patients with thrombolyzed STEMI. TWRabsMedian increased with increasing conduction disturbance and contained a moderate amount of prognostic information. In thrombolyzed STEMI, TWRabsMedian was elevated and has an increased variability. A greater decrease in absolute TWR during initial observation was seen in patients with early ST-resolution. Nondipolar components do however not reflect identical ECG-properties as the ST-elevation and their change does not occur at the same time.</p>

Repolarization inhomogeneity is arrhythmogenic. QT dispersion (QTd) is an easily accessible ECG-variable, related to the repolarization and shown to carry prognostic information. It was originally thought to reflect repolarization inhomogeneity. Lately, arguments have been risen against this hypothesis. Other measures of inhomogeneity are being investigated, such as nondipolar components from principal component analysis (PCA) of the T-wave. In all here described populations, continuous 12-lead ECG was collected during the initial hours of observation and secondary parameters used for description of a large number of ECG-recordings. Paper I studied QTd in 548 patients with chest pain with a median number of 985 ECG-recordings per patient. Paper II explored a spatial aspect of QTd in 276 patients with unstable coronary artery disease. QTd and a derived localized ECG-parameter were compared to angiographical measures. QTd, expressed as the mean value during the observation was a powerful marker of risk. It was however not effective in identifying high-risk patients. Variations in QTd contained no additional prognostic information. In unstable coronary artery disease, QTd was increased by a mechanism unrelated to localization of the disease. Two relevant conditions for observing repolarization inhomogeneity might occur with conduction disturbances and during initial course of ST-elevation myocardial infarction (STEMI). Paper III compared the PCA-parameters of the T-wave in 135 patients with chest pain and conduction disturbance to 665 patients with normal conduction. Nondipolar components were quantified by medians of the nondipolar residue (TWRabsMedian) and ratio of this residue to the total power of the T-wave (TWRrelMedian). Paper IV described the changes in the nondipolar components of the T-wave in 211 patients with thrombolyzed STEMI. TWRabsMedian increased with increasing conduction disturbance and contained a moderate amount of prognostic information. In thrombolyzed STEMI, TWRabsMedian was elevated and has an increased variability. A greater decrease in absolute TWR during initial observation was seen in patients with early ST-resolution. Nondipolar components do however not reflect identical ECG-properties as the ST-elevation and their change does not occur at the same time.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-09-04T21:36:50Z No. of bitstreams: 1 FlaviaEvelynMedeirosFernandes_DISSERT.pdf: 3743826 bytes, checksum: 26fac5cc089ca895f8a4c3ffee3ecbc4 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-09-12T19:14:16Z (GMT) No. of bitstreams: 1 FlaviaEvelynMedeirosFernandes_DISSERT.pdf: 3743826 bytes, checksum: 26fac5cc089ca895f8a4c3ffee3ecbc4 (MD5) / Made available in DSpace on 2017-09-12T19:14:16Z (GMT). No. of bitstreams: 1 FlaviaEvelynMedeirosFernandes_DISSERT.pdf: 3743826 bytes, checksum: 26fac5cc089ca895f8a4c3ffee3ecbc4 (MD5) Previous issue date: 2017-05-31 / Introdu??o: A s?ndrome do QT longo (SQTL) induzida por medicamentos pode levar ao Torsade de Pointes (TdP), uma taquicardia ventricular polim?rfica rara que pode ser fatal. Objetivos: Investigar o prolongamento do intervalo QTc em pacientes admitidos em Unidade de Terapia Intensiva (UTI) geral quanto a preval?ncia, grau de associa??o com os medicamentos administrados e intera??es medicamentosas, evolu??o no tempo e rela??o com desfechos cl?nicos. M?todos: Aprovado pelo Comit? de ?tica em Pesquisa de acordo com o parecer n? 666.969. Estudo observacional, prospectivo e transversal, realizado entre maio de 2014 a julho de 2016 na UTI do Hospital Universit?rio Onofre Lopes. Os pacientes admitidos foram investigados quanto a presen?a de prolongamento QT na admiss?o atrav?s do eletrocardiograma em um estudo de casos-controle. A corre??o do intervalo QT pela frequ?ncia card?aca (QTc) foi realizada pela f?rmula de Bazzet. Todos os pacientes foram observados at? a alta da UTI (fase de coorte anal?tico prospectivo) para os eventos de parada card?aca ou ?bito, e aqueles com SQTL foram observados por 48 horas e no momento da alta para nova avalia??o do intervalo QTc. A compara??o da diferen?a do QTc para o valor inicial foi analisada por covari?ncia. Para a determina??o do risco de prolongamento do QTc associado a cada medicamento foi utilizada a regress?o log?stica. A compara??o entre pacientes com e sem SQTL do tempo at? parada card?aca ou morte foi analisado com o teste do logrank e por regress?o log?stica. O risco desses eventos foi estimado por Kaplan-Meier. Resultados: Foi identificado uma preval?ncia de 34% (249/734) de SQTL em que 13,3% (33/249) possu?am QTc maior que 500 ms. Amiodarona (OR 2.434, p=0.02) e haloperidol (OR 3.333, p=0.02) foram associados ao SQTL, assim como medicamentos ainda n?o descritos em literatura: sufentanil (OR 3.667, p<0.01), clopidogrel (1.894, p=0.02), midazolam (OR 1.575, p= 0.04), noradrenalina (OR 1.701, p=0.01), nitroglicerina (OR 1.904, p=0.01), cefazolina (OR 1.897, p<0.01), cefepime (OR 0.417, p=0.01) e protamina (OR 5.952, p<0.01). A presen?a de intera??o medicamentosa aumentou o intervalo QTc em 16,8 ms (IC 95% 4.6 a 29.0 ms, p <0.01), sendo que as do tipo farmacodin?micas foram associadas a um aumento de 27.6 ms (IC 95% 2.1 a 53.2 ms, p = 0.03). Nos pacientes em que foram prescritos medicamentos associados ao SQTL, a diferen?a do QTc em 48h para o valor inicial foi de 15,8 ms (IC 95% -9,9 a 41,4 ms) maior do que no grupo que n?o utilizou medicamentos (p=0,22). Dos pacientes com SQTL na admiss?o, 39% o apresentaram ap?s 48 horas e 40% na alta. Foi identificado um risco 3 vezes maior de parada card?aca nos pacientes com SQTL (OR 3,030, p=0,02), enquanto que n?o se observou diferen?a significativa no risco de ?bito (rank p=0,87). Conclus?es: Observou-se preval?ncia elevada de SQTL em pacientes cr?ticos. Medicamentos ainda n?o descritos foram identificados como poss?veis indutores de SQTL. Observou-se que o uso de medicamentos n?o impactou significativamente o intervalo QTc, mas que as intera??es medicamentosas aumentaram o intervalo QTc, destacando-se apenas as do tipo farmacodin?mica. Verificou-se aumento do risco de parada card?aca entre o grupo QTc longo, mas sem diferen?a para a mortalidade. / Introduction: Medication-induced long QT syndrome (LQTS) can lead to Torsade de Pointes (TdP), a rare polymorphic ventricular tachycardia that can be fatal. Objectives: To investigate the QTc interval prolongation in patients admitted to the General Intensive Care Unit (ICU) in terms of prevalence, degree of association with medications administered and drug interactions, time evolution and relation to clinical outcomes. Methods: Approved by the Research Ethics Committee in accordance with opinion No. 666,969. Observational, prospective and cross-sectional study, conducted between May 2014 and July 2016 at the ICU of the University Hospital Onofre Lopes. The admitted patients were investigated for the presence of QT prolongation at admission via the electrocardiogram in a case-control study. Correction of the QT interval by heart rate (QTc) was performed using the Bazzet formula. All patients were observed until discharge from the ICU (prospective analytical cohort phase) for cardiac arrest or death events, and those with LQTS were observed for 48 hours and at discharge for reassessment of the QTc interval. Difference from the QTc to the initial value was analyzed by covariance. For the determination of the risk of QTc prolongation associated with each medication, logistic regression was used. The comparison between patients with and without LQTS from time to cardiac arrest or death was analyzed with the logrank test and logistic regression. The risk of these events was estimated by Kaplan-Meier. Results: A prevalence of 34% (249/734) of LQTS was identified in which 13.3% (33/249) had QTc greater than 500 ms. Amiodarone (OR 2.434, p = 0.02) and haloperidol (OR 3.333, p = 0.02) were associated with LQTS, as well as medicines not yet described in the literature: sufentanil (OR 3.667, p <0.01), clopidogrel (1,894, p = (OR 1.174, p = 0.01), or cephalosporin (OR 1.575, p = 0.04), noradrenaline (OR 1,701, p = 0.01), nitroglycerin (OR 1,904, p = 0.01), cefazolin ) And protamine (OR 5,952, p <0.01). The presence of drug interaction increased the QTc interval by 16.8 ms (95% CI 4.6 to 29.0 ms, p <0.01), and the pharmacodynamic type was associated with an increase of 27.6 ms (95% CI 2.1 to 53.2 ms , P = 0.03). In patients who were prescribed drugs associated with LQTS, the difference in QTc in 48 hours for the initial value was 15.8 ms (95% CI -9.9 to 41.4 ms) higher than in the non-medication group (P = 0.22). Of the patients with LQTS at admission, 39% presented it after 48 hours and 40% at discharge. A 3-fold higher risk of cardiac arrest was observed in patients with LQTS (OR 3.030, p = 0.02), whereas no significant difference in risk of death was observed (rank p = 0.87). Conclusions: There was a high prevalence of LQTS in critically ill patients. Drugs not yet described were identified as possible inducers of LQTS. It was observed that the use of drugs did not significantly affect the QTc interval, but that the drug interactions increased the QTc interval, with only those of the pharmacodynamic type being highlighted. There was an increased risk of cardiac arrest between the long QTc group, but no difference in mortality.

Malignant ventricular arrhythmias are a common cause of sudden cardiac death. Moderate therapeutic hypothermia (MTH) is routinely used in post-resuscitation care for anticipated neuroprotective effects. However, the safety of MTH in terms of the electrical stability of the heart has not been satisfactorily proved yet. Also, the increased sympathetic tone in patients with heart failure contributes to a higher incidence of malignant ventricular arrhythmias. The aim of this work was to verify the safety of MTH as regards the inducibility of ventricular fibrillation (VF) in the pig biomodel, especially in relation to spontaneous changes in the kalemia and QT interval. Furthermore, we assumed that renal denervation (RDN) could reduce the inducibility of VF. In the first part of the thesis, the extracorporeal cooling was introduced in fully anesthetized swine (n = 6) to provide MTH. Inducibility of VF was studied by programmed ventricular stimulation (8 basic stimuli with up to 4 extrastimuli) three times in each biomodel under the following conditions: during normothermia (NT), after reaching the core temperature 32 řC (HT) and after another 60 minutes of stable hypothermia (HT60). VF inducibility, effective ventricular refractory period (ERP), QTc interval, and potassium plasma level were measured. In...

Ecological Economics has not paid sufficient attention to the macroeconomic level both in terms of theory and modelling. Yet, key topics debated in the field of Ecological Economics such as sustainable consumption, reduction in working time, the degrowth debate, the energy-exergy link, and the rebound effect require a wholistic and macro perspective. While this deficiency has been identified before and Keynesian economics has been generally suggested as a potent vehicle to establish economic system's thinking, very little concrete theorizing and practical suggestions have been put forward. We give further credence to this suggestion and demonstrate the value of tackling key concerns of Ecological Economics within a Keynesian growth framework. Contextualized by an application to climate change we suggest that policy relevant recommendations need to be based on a consistent view of the macroeconomy. We end with laying out key building blocks for a Keynesian model framework for an Ecological Macroeconomics. (author's abstract) / Series: SRE - Discussion Papers

Kap. 1 schätzt den Effekt sozial gemischten Wohnens auf Resilienz gegenüber epidemischen Schocks. Anhand von Gesundheitsberichten und Berufsdaten aus Stadtverzeichnissen assoziiere ich die Verbreitung der Cholera während der 1866er Epidemie mit einem Maß für soziale Diversität für ca. 12200 Häuser Berlins. Diversere Häuser erleben mit höherer Wahrscheinlichkeit mindestens einen Fall, sind aber auch erfolgreicher bei der Eindämmung weiterer Fälle. Zur kausalem Interpretation nutze ich exogene Variation, die sich aus den geometrischen Eigenschaften der Gebäude ergibt. Ich zeige, dass Exposition gegenüber Außenkontakten und gemeinsamer Zugang zu Leitungswasser in gemischten Mietergemeinschaften die Inzidenzeffekte teilweise erklären. Kap. 2 evaluiert, ob die Cholera als Katalysator für städtische Was¬ser-infrastrukturreformen fungierte. In einer Fallstudie Berlins im 19. Jahrhundert zeige ich, dass die Interpretation der Cholera durch Miasma- und proto-epidemiologische Theorien der prä-bakteriologischen Ära ineffiziente, kontraproduktive Wasserwirtschaftsreformen inspirierten, was die Sterblichkeit für einige Zeit erhöhte. Das gängige Narrativ eines durch epidemische Schocks „erzwungenen“ sanitären Aufbruchs vermittelt ein irreführendes Bild der westlichen Volksgesundheitsgeschichte. Kap. 3 zeigt, dass Leitungswassernetze ohne Kanalisation geringen gesundheitlichen Nutzen stiften. Mittels Wasserspülung schwemmen Individuen Krankheitserreger in Rinnsteine, Grundwasserleiter, Straßen und offene Gewässer. Entlang dieser Abwasserströme lebende Nachbarn werden zusätzlichen Gesundheitsrisiken ausgesetzt, die durch den Anschluss der Abfallverursacher an eine Kanalisation neutralisiert werden. Mittels eines Flussrichtungsmodells schätze ich die Abwasser-Exposition für alle Gebäude Berlins in 1875/1880. In einer Differenz-in-Differenzen-Regression zeige ich, dass die negativen externen Effekte der Leitungswassernutzung dessen direkte Vorteile im Aggregat teilweise aufheben. / Chapter 1 estimates the causal effect of mixed-income housing on resilience to epidemic shocks. Using detailed health reports and occupational data from town directories, I relate cholera incidence to a social diversity measure at the level of Berlin’s roughly 12,200 buildings during the 1866 pandemic. Mixed tenant communities are more likely to experience an initial case, but also more successful in containing further in-house spread. To establish causality, I exploit exogenous variation from building lots’ geometric properties in an instrumental variable approach. I find that increased exposure to outside contacts and shared tap water access partly explain the effects. Chapter 2 evaluates whether cholera functioned as catalysts for the efficient reform of urban water infrastructure. Studying 19th century Berlin, I find that cholera’s conception through miasmatist frameworks and the proto-epidemiological tools of the pre-bacteriological era inspired inefficient and counterproductive approaches to water management and potentially deepened the mortality penalty for a certain time. This suggests that the popular interpretation of a sanitary awakening enforced by epidemic shocks paints a misleading picture of Western public health history. Chapter 3 tests a mechanism explaining why cities yield little health benefits from tap water if they do not simultaneously construct sewers. Individuals use the pressurized water supply to flush pathogens from their local environment, thus feeding additional waste to gutters, groundwater acquirers, streets and open water bodies. Neighbors living along the resulting waste flows bear indirect costs, only neutralized once waste emitters connect to sewers. Using a flow direction model based on Berlin’s elevation profile, I estimate waste flow trajectories and exposure for all buildings in Berlin in 1875/1880. In a difference-in- differences approach, I find that tap water’s negative external effects partly offset its direct benefits.

This master´s thesis deals with the analysis of experimental telemetrical ECG records with intention to determine the long-term influence of anticancer drug sunitinib on the electrical activity of heart. A laboratory rat was chosen as a model organism for the experimental study carried out at the Department of Physiology at Faculty of Medicine, Masaryk university. The sunitinib was applied to the rats at an early age and the ECG was measured with a 20-week delay using the Stellar telemetry system. To measure the effect of sunitinib on the electrical activity of the heart chambers, an analysis of the duration of the RR and QT interval and the width of the QRS complex was chosen. These parameters were detected by the wavelet transform method. Statistical analysis was performed using nonparametric tests - the Wilcoxon signed rank test, the MannWhitney test and the Friedman Test. The obtained results suggest that the use of sunitinib has no long-term effect on the observed parameters for the chosen animal model. After extension of the study, the results obtained could contribute to assess the effect of drugs on electrical activity of the human heart several decades after sunitinib treatment termination.

Master’s thesis deals with object pose estimation using monocular camera. As an object is considered every rigid, shape fixed entity with strong edges, ideally textureless. Object position in this work is represented by transformation matrix, which describes object translation and rotation towards world coordinate system. First chapter is dedicated to explanation of theory of geometric transformations and intrinsic and extrinsic parameters of camera. This chapter also describes detection algorithm Chamfer Matching, which is used in this work. Second chapter describes all development tools used in this work. Third, fourth and fifth chapter are dedicated to practical realization of this works goal and achieved results. Last chapter describes created application, that realizes known object pose estimation in scene.

This thesis deals with the design and the implementation of a client/server application for the administration of hosting services. Other solutions of hosting services administration are listed as well and they are contrasted and compared with the assigned solution. A description of the particular hosting services and their setting for the Ubuntu Linux distribution are provided. A communication protocol and a data store serving to save all the client accounts and servers were designed. Basic principles of working with C++ framework Qt and its usage for the implementation of both the server and the client application are demonstrated. The basic settings of the server application enabling it to be launched on the server as a service are mentioned as well. In the last part a description is stated of working with the client applications and administration of the client accounts.