Molecular mechanisms of hypertension-induced heart failure : Experimental studies with special emphasis on local renin-angiotensin system, cardiac metabolism and levosimendan

Hypertension is a major risk factor for stroke, ischaemic heart disease, and the development of heart failure. Hypertension-induced heart failure is usually preceded by the development of left ventricular hypertrophy (LVH), which represents an adaptive and compensatory response to the increased cardiac workload. Biomechanical stress and neurohumoral activation are the most important triggers of pathologic hypertrophy and the transition of cardiac hypertrophy to heart failure. Non-clinical and clinical studies have also revealed derangements of energy metabolism in hypertensive heart failure. The goal of this study was to investigate in experimental models the molecular mechanisms and signalling pathways involved in hypertension-induced heart failure with special emphasis on local renin-angiotensin-aldosterone system (RAAS), cardiac metabolism, and calcium sensitizers, a novel class of inotropic agents used currently in the treatment of acute decompensated heart failure. Two different animal models of hypertensive heart failure were used in the present study, i.e. hypertensive and salt-sensitive Dahl/Rapp rats on a high salt diet (a salt-sensitive model of hypertensive heart failure) and double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes (a transgenic model of hypertensive heart failure with increased local RAAS activity). The influence of angiotensin II (Ang II) on cardiac substrate utilization and cardiac metabolomic profile was investigated by using gas chromatography coupled to time-of-flight mass spectrometry to detect 247 intermediary metabolites. It was found that Ang II could alter cardiac metabolomics both in normotensive and hypertensive rats in an Ang II receptor type 1 (AT1)-dependent manner. A distinct substrate use from fatty acid oxidation towards glycolysis was found in dTGR. Altered cardiac substrate utilization in dTGR was associated with mitochondrial dysfunction. Cardiac expression of the redox-sensitive metabolic sensor sirtuin1 (SIRT1) was increased in dTGR. Resveratrol supplementation prevented cardiovascular mortality and ameliorated Ang II-induced cardiac remodeling in dTGR via blood pressure-dependent pathways and mechanisms linked to increased mitochondrial biogenesis. Resveratrol dose-dependently increased SIRT1 activity in vitro. Oral levosimendan treatment was also found to improve survival and systolic function in dTGR via blood pressure-independent mechanisms, and ameliorate Ang II-induced coronary and cardiomyocyte damage. Finally, using Dahl/Rapp rats it was demonstrated that oral levosimendan as well as the AT1 receptor antagonist valsartan improved survival and prevented cardiac remodeling. The beneficial effects of levosimendan were associated with improved diastolic function without significantly improved systolic changes. These positive effects were potentiated when the drug combination was administered. In conclusion, the present study points to an important role for local RAAS in the pathophysiology of hypertension-induced heart failure as well as its involvement as a regulator of cardiac substrate utilization and mitochondrial function. Our findings suggest a therapeutic role for natural polyphenol resveratrol and calcium sensitizer, levosimendan, and the novel drug combination of valsartan and levosimendan, in prevention of hypertension-induced heart failure. The present study also provides a better understanding of the pathophysiology of hypertension-induced heart failure, and may help identify potential targets for novel therapeutic interventions.

Applications of Treatment Effects Models and Semiparametric Estimation

This thesis is composed of an introductory chapter and four applications each of them constituting an own chapter. The common element underlying each of the chapters is the econometric methodology. The applications rely mostly on the leading econometric techniques related to estimation of causal effects. The first chapter introduces the econometric techniques that are employed in the remaining chapters. Chapter 2 studies the effects of shocking news on student performance. It exploits the fact that the school shooting in Kauhajoki in 2008 coincided with the matriculation examination period of that fall. It shows that the performance of men declined due to the news of the school shooting. For women the similar pattern remains unobserved. Chapter 3 studies the effects of minimum wage on employment by employing the original Card and Krueger (1994; CK) and Neumark and Wascher (2000; NW) data together with the changes-in-changes (CIC) estimator. As the main result it shows that the employment effect of an increase in the minimum wage is positive for small fast-food restaurants and negative for big fast-food restaurants. Therefore, it shows that the controversial positive employment effect reported by CK is overturned for big fast-food restaurants and that the NW data are shown, in contrast to their original results, to provide support for the positive employment effect. Chapter 4 employs the state-specific U.S. data (collected by Cohen and Einav [2003; CE]) on traffic fatalities to re-evaluate the effects of seat belt laws on the traffic fatalities by using the CIC estimator. It confirms the CE results that on the average an implementation of a mandatory seat belt law results in an increase in the seat belt usage rate and a decrease in the total fatality rate. In contrast to CE, it also finds evidence on compensating-behavior theory, which is observed especially in the states by the border of the U.S. Chapter 5 studies the life cycle consumption in Finland, with the special interest laid on the baby boomers and the older households. It shows that the baby boomers smooth their consumption over the life cycle more than other generations. It also shows that the old households smoothed their life cycle consumption more as a result of the recession in the 1990s, compared to young households.

Late Pleistocene and Holocene environmental evolution of the Murchisonfjorden area, Nordaustlandet, Svalbard

The purpose of this study was to establish the palaeoenvironmental conditions during the late Quaternary in Murchisonfjorden, Nordaustlandet, based on foraminiferal assemblage compositions, and to determine the onset and termination of the Weichselian glaciations. The foraminiferal assemblage compositions were studied in marine sediments from three different archives, from sections next to the present shoreline in the Bay of Isvika, from a core in the Bay of Isvika and from a core from Lake Einstaken. OSL and AMS 14C age determinations were performed on samples from the three archives, and the results show deposition of marine sediments during ice-free periods of the Early Weichselian, the Middle Weichselian and the Late Weichselian, as well as during the Holocene in the investigated area. Marine sediments from the Early and Middle Weichselian were sampled from isostatically uplifted sections along the present shoreline.Sediments from the transition from the Late Weichselian to early Holocene time intervals were found in the bottom of the core from Lake Einstaken. Holocene sediments were investigated in the sections and in the core from the Bay of Isvika. The marine sediments from the sections are comprised of five benthic foraminiferal assemblages. The Early Weichselian is represented by two foraminiferal assemblages, the Middle Weichselian, the early and the late Holocene each by one. All five foraminiferal assemblages were deposited in glacier-distal shallow-water environments, which had a connection to the open ocean. Changes in the composition of the assemblages can be ascribed to differences in the bottom-water currents and changes in the salinity. The Middle Weichselian assemblage is of special importance, because it is the first foraminiferal assemblage to be described from this time interval from Svalbard. Four benthic foraminiferal assemblages were deposited shortly before the marine to lacustrine transition at the boundary between the Late Weichselian and Holocene in Lake Einstaken. The foraminiferal assemblages show a change from a high-arctic, normal marine shallow-water environment to an even shallower environment with highly fluctuating salinity. The analyses of the core from 100 m water depth in the Bay of Isvika resulted in the determination of four foraminiferal assemblages. These indicated changes from a glacier-proximal environment during deglaciation, to a more glacier-distal environment during the Early Holocene. This was followed by a period with a marked change to a considerably cooler environment and finally to a closed fjord environment in the middle and late Holocene times. Additional sedimentological analyses of the marine and glacially derived sediments from the uplifted sections, as well as observations of multiple striae on the bedrock, observations of deeply weathered bedrock and findings of tills interlayered with marine sediments complete the investigations in the study area. They indicate weak glacial erosion in the study area. It can be concluded that marine deposition occurred in the investigated area during three time intervals in the Weichselian and during most of the Holocene. The foraminiferal assemblages in the Holocene are characterized by a transition from glacier-proximal to glacier-distal faunas. The palaeogeographical change from an open fjord to a closed fjord environment is a result of the isostatic uplift of the area after the LGM and is clearly reflected in the foraminiferal assemblages. Another influencing factor on the foraminiferal assemblage composition are changes in the inflow of warmer Atlantic waters to the study area.

Production process of Scots pine.

The accompanying collective research report is the result of the research project in 1986­90 between The Finnish Academy and the former Soviet Academy of Sciences. The project was organized around common field work in Finland and in the former Soviet Union and theoretical analyses of tree growth determining processes. Based on theoretical analyses, dynamic stand growth models were made and their parameters were determined utilizing the field results. Annual cycle affects the tree growth. Our theoretical approach was based on adaptation to local climate conditions from Lapland to South Russia. The initiation of growth was described as a simple low and high temperature accumulation driven model. Linking the theoretical model with long term temperature data allowed us to analyze what type of temperature response produced favorable outcome in different climates. Initiation of growth consumes the carbohydrate reserves in plants. We measured the dynamics of insoluble and soluble sugars in the very northern and Karelian conditions. Clear cyclical pattern was observed but the differences between locations were surprisingly small. Analysis of field measurements of CO2 exchange showed that irradiance is the dominating factor causing variation in photosynthetic rate in natural conditions during summer. The effect of other factors is so small that they can be omitted without any considerable loss of accuracy. A special experiment carried out in Hyytiälä showed that the needle living space, defined as the ratio between the shoot cylindric volume and needle surface area, correlates with the shoot photosynthesis. The penetration of irradiance into Scots pine canopy is a complicated phenomenon because of the movement of the sun on the sky and the complicated structure of branches and needles. A moderately simple but balanced forest radiation regime submodel was constructed. It consists of the tree crown and forest structure, the gap probability calculation and the consideration of spatial and temporal variation of radiation inside the forest. The common field excursions in different geographical regions resulted in a lot of experimental data of regularities of woody structures. The water transport seems to be a good common factor to analyse these properties of tree structure. There are evident regressions between cross-sectional areas measured at different locations along the water pathway from fine roots to needles. The observed regressions have clear geographical trends. For example, the same cross-sectional area can support three times higher needle mass in South Russia than in Lapland. Geographical trends can also be seen in shoot and needle structure. Analysis of data published by several Russian authors show, that one ton of needles transpire 42 ton of water a year. This annual amount of transpiration seems to be independent of geographical location, year and site conditions. The produced theoretical and experimental material is utilised in the development of stand growth model that describes the growth and development of Scots pine stands in Finland and the former Soviet Union. The core of the model is carbon and nutrient balances. This means that carbon obtained in photosynthesis is consumed for growth and maintenance and nutrients are taken according to the metabolic needs. The annual photosynthetic production by trees in the stand is determined as a function of irradiance and shading during the active period. The utilisation of the annual photosynthetic production to the growth of different components of trees is based on structural regularities. Since the fundamental metabolic processes are the same in all locations the same growth model structure can be applied in the large range of Scots pine. The annual photosynthetic production and structural regularities determining the allocation of resources have geographical features. The common field measurements enable the application of the model to the analysis of growth and development of stands growing on the five locations of experiments. The model enables the analysis of geographical differences in the growth of Scots pine. For example, the annual photosynthetic production of a 100-year-old stand at Voronez is 3.5 times higher than in Lapland. The share consumed to needle growth (30 %) and to growth of branches (5 %) seems to be the same in all locations. In contrast, the share of fine roots is decreasing when moving from north to south. It is 20 % in Lapland, 15 % in Hyytiälä Central Finland and Kentjärvi Karelia and 15 % in Voronez South Russia. The stem masses (115­113 ton/ha) are rather similar in Hyytiälä, Kentjärvi and Voronez, but rather low (50 ton/ha) in Lapland. In Voronez the height of the trees reach 29 m being in Hyytiälä and Kentjärvi 22 m and in Lapland only 14 m. The present approach enables utilization of structural and functional knowledge, gained in places of intensive research, in the analysis of growth and development of any stand. This opens new possibilities for growth research and also for applications in forestry practice.

Peeking through the Iron Curtain: Memories of Watching Finnish Television in Estonia during Soviet Occupation

The present study analyses the memories of watching Finnish television in Estonia during the last decades of the Soviet occupation from the late 1960s until the beginning of 1990s. The study stems from a culturalist approach, perceiving television as a relevant aspect in the audiences’ everyday lives. It explores the significance of Finnish television on the society of occupied Estonia from the point of view of its historical audiences. The literature review concentrates on concepts such as the power of television, transnational media, historical audience reception and memory as an object of research. It also explains the concept of spillover, which refers to the unintentional bilateral flow of television signals from one country to another. Despite the numerous efforts of the Soviet authorities to prevent the viewing of the "bourgeois television", there still remained a small gap in the Iron Curtain. The study describes the phenomenon of watching Finnish television in Estonia. It provides understanding about the significance of watching Finnish television in Soviet Estonia through the experiences of its former audience. In addition, it explores what do people remember about watching Finnish television, and why. The empirical data was acquired from peoples’ personal memories through the analysis of private interviews and written responses during the period from February 2010 to February 2011. A total of 85 responses (5 interviews and 83 written responses) were analysed. The research employed the methods of oral history and memory studies. The main theoretical sources of the study include the works of Mati Graf and Heikki Roiko-Jokela, Hagi Šein, Sonia Livingstone, Janet Staiger and Emily Keightley. The study concludes that besides fulfilling the role of an entertainer and an informer, Finnish television enabled its Estonian audiences to gain entry into the imaginary world. Access to this imaginary world was so important, that the viewers engaged in illegal activities and gained special skills, whereby a phenomenon of "television tourism" developed. Most of the memories about Finnish television are vivid and similar. The latter indicates both the reliability and the collectiveness of such memories, which in return give shape to collective identities. Thus, for the Estonian viewers, the experience of watching Finnish television during the Soviet occupation has became part of their identity.

Biomarkers in acute respiratory failure

Acute respiratory failure (ARF) is the most common type of organ failure leading to the need for intensive care. It is often secondary to acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). ARF, and especially ALI and ARDS, cause increased morbidity, and mortality rates remain high (up to 40%). These disorders are characterised by inflammatory reaction and tissue damage. In some cases, inflammation continues and leads to an overwhelming repair process with ongoing fibrosis, accompanied by organ dysfunction and eventually a loss of function. Measuring the magnitude of the inflammation, and the repair process, would theoretically offer information concerning outcome. Early identification of patients whose disease process is likely to proceed unfavourably, would help clinicians to optimise their treatment. The aim of this study was to evaluate the epidemiology of ARF, its treatment, and outcome in Finland, with special interest in biomarkers, and their value in the prediction of mortality. Altogether, 958 adult patients treated with ventilatory support were prospectively included in this study during an eight week period in 2007 in 25 intensive care units. Plasma aminoterminal pro-brain natriuretic peptide (NT-pro-BNP) was assessed in 602 patients, and plasma cell-free DNA in 580 patients, to evaluate their prognostic value in ARF. Markers of collagen metabolism were studied in longitudinal serum samples in 68 patients in order to evaluate their evolution in ARF and the association to multiple organ dysfunction (MOD). Ventilatory support was used in 39% of all ICU patients. The estimated incidence of ARF was 149.5/100 000 per year. Median tidal volumes used were higher than recommended. Overall mortality at 90 days was 31%. Plasma NT-pro-BNP and cell-free DNA were highly increased in the majority of patients. Both markers were independent predictors of 90-day mortality, but their discriminative power was at most moderate when used separately. The mortality was highest in those patients, in whom both biomarkers were over their separate cut-off values. Thus, combined use of these biomarkers may increase their clinical value in the mortality prediction. The markers of collagen metabolism changed significantly over time in surviving patients. None of these markers did associate with MOD in these patients.