Proton magnetic resonance spectroscopy of a boron neutron capture therapy 10B-carrier, L-p-boronophenylalanine-fructose complex

Boron neutron capture therapy (BNCT) is a radiotherapy that has mainly been used to treat malignant brain tumours, melanomas, and head and neck cancer. In BNCT, the patient receives an intravenous infusion of a 10B-carrier, which accumulates in the tumour area. The tumour is irradiated with epithermal or thermal neutrons, which result in a boron neutron capture reaction that generates heavy particles to damage tumour cells. In Finland, boronophenylalanine fructose (BPA-F) is used as the 10B-carrier. Currently, the drifting of boron from blood to tumour as well as the spatial and temporal accumulation of boron in the brain, are not precisely known. Proton magnetic resonance spectroscopy (1H MRS) could be used for selective BPA-F detection and quantification as aromatic protons of BPA resonate in the spectrum region, which is clear of brain metabolite signals. This study, which included both phantom and in vivo studies, examined the validity of 1H MRS as a tool for BPA detection. In the phantom study, BPA quantification was studied at 1.5 and 3.0 T with single voxel 1H MRS, and at 1.5 T with magnetic resonance imaging (MRSI). The detection limit of BPA was determined in phantom conditions at 1.5 T and 3.0 T using single voxel 1H MRS, and at 1.5 T using MRSI. In phantom conditions, BPA quantification accuracy of ± 5% and ± 15% were achieved with single voxel MRS using external or internal (internal water signal) concentration references, respectively. For MRSI, a quantification accuracy of <5% was obtained using an internal concentration reference (creatine). The detection limits of BPA in phantom conditions for the PRESS sequence were 0.7 (3.0 T) and 1.4 mM (1.5 T) mM with 20 × 20 × 20 mm3 single voxel MRS, and 1.0 mM with acquisition-weighted MRSI (nominal voxel volume 10(RL) × 10(AP) × 7.5(SI) mm3), respectively. In the in vivo study, an MRSI or single voxel MRS or both was performed for ten patients (patients 1-10) on the day of BNCT. Three patients had glioblastoma multiforme (GBM), and five patients had a recurrent or progressing GBM or anaplastic astrocytoma gradus III, and two patients had head and neck cancer. For nine patients (patients 1-9), MRS/MRSI was performed 70-140 min after the second irradiation field, and for one patient (patient 10), the MRSI study began 11 min before the end of the BPA-F infusion and ended 6 min after the end of the infusion. In comparison, single voxel MRS was performed before BNCT, for two patients (patients 3 and 9), and for one patient (patient 9), MRSI was performed one month after treatment. For one patient (patient 10), MRSI was performed four days before infusion. Signals from the tumour spectrum aromatic region were detected on the day of BNCT in three patients, indicating that in favourable cases, it is possible to detect BPA in vivo in the patient’s brain after BNCT treatment or at the end of BPA-F infusion. However, because the shape and position of the detected signals did not exactly match the BPA spectrum detected in the in vitro conditions, assignment of BPA is difficult. The opportunity to perform MRS immediately after the end of BPA-F infusion for more patients is necessary to evaluate the suitability of 1H MRS for BPA detection or quantification for treatment planning purposes. However, it could be possible to use MRSI as criteria in selecting patients for BNCT.

A Success Story or a Failure? : Representing the European Integration in the Curricula and Textbooks of Five Countries

The economic, political and social face of Europe has been changing rapidly in the past decades. These changes are unique in the history of Europe, but not without challenges for the nation states. The support for the European integration varies among the countries. In order to understand why certain developments or changes are perceived as threatening or as desired by different member countries, we must consider the social representations of the European integration on the national level: how the EU is represented to its citizens in media and in educational systems, particularly in the curricula and textbooks. The current study is concerned with the social representations of the European integration in the curricula and school textbooks in five European countries: France, Britain, Germany, Finland and Sweden. Besides that, the first volume of the common Franco-German history textbook was analyzed, since it has been seen as a model for a common European history textbook. As the collective representations, values and identities are dominantly mediated and imposed through media and educational systems, the national curricula and textbooks make an interesting starting point for the study of the European integration and of national and European identities. The social representations theory provides a comprehensive framework for the study of the European integration. By analyzing the curricula and history and civics textbooks of major educational publishers, the study aimed to demonstrate what is written on the European integration and how it is portrayed how the European integration is understood, made familiar and concretized in the educational context in the five European countries. To grasp the phenomenon of the European integration in the textbooks in its entirety, it was investigated from various perspectives. The two analysis methods of content analysis, the automatic analysis with ALCESTE and a more qualitative theory-driven content analysis, were carried out to give a more vivid and multifaceted picture of the object of the research. The analysis of the text was complemented with the analysis of visual material. Drawing on quantitative and qualitative methods, the contents, processes, visual images, transformations and structures of the social representations of European integration, as well as the communicative styles of the textbooks were examined. This study showed the divergent social representations of the European integration, anchored in the nation states, in the five member countries of the European Union. The social representations were constructed around different central core elements: French Europe in the French textbooks, Ambivalent Europe in the British textbooks, Influential and Unifying EU in the German textbooks, Enabling and Threatening EU in the Finnish textbooks, Sceptical EU in the Swedish textbooks and EU as a World Model in the Franco-German textbook. Some elements of the representations were shared by all countries such as peace and economic aspects of the European cooperation, whereas other elements of representations were found more frequently in some countries than in others, such as ideological, threatening or social components of the phenomenon European integration. The study also demonstrated the linkage between social representations of the EU and national and European identities. The findings of this study are applicable to the study of the European integration, to the study of education, as well as to the social representation theory.

Parathyroid hormone as an outcome indicator in old age

Serum parathyroid hormone (PTH) and vitamin D are the major regulators of extracellular calcium homeostasis. The inverse association between PTH and vitamin D and the common age-related elevation of the PTH concentration are well known phenomena. However, the confounding or modifying factors of this relationship and their impact on the response of PTH levels to vitamin D supplementation need further investigation. Clinical conditions such as primary hyperparathyroidism (PHPT), renal failure and vitamin D deficiency, characterized by an elevation of the PTH concentration, have been associated with impaired long-term health outcomes. Curative treatments for these conditions have also been shown to decreases PTH concentration and attenuate some of the adverse health effects. In PHPT it has also been commonly held that hypercalcaemia, the other hallmark of the disease, is the key mediator of the adverse health outcomes. In chronic kidney disease the systemic vascular disease has been proposed to have the most important impact on general health. Some evidence also indicates that vitamin D may have significant extraskeletal actions. However, the frank elevation of PTH concentration seen in advanced PHPT and in end-stage renal failure have also been suggested to be at least partly causally related to an increased risk of death as well as cognitive dysfunction. However, the exact mechanisms have remained unclear. Furthermore, the predictive value of elevated PTH in unselected older populations has been less well studied. The studies presented in this thesis investigated the impact of age and mobility on the responses of PTH levels to vitamin D deficiency and supplementation. Furthermore, the predictive value of PTH for long-term survival and cognitive decline was addressed in an unselected population of older people. The hypothesis was that age and chronic immobility are related to a persistently blunted elevation of PTH concentration, even in the presence of chronic vitamin D deficiency, and to attenuated responses of PTH to vitamin D supplementation. It was also further hypothesized that a slightly elevated or even high-normal PTH concentration is an independent indicator of an increased risk of death and cognitive decline in the general aged population. The data of this thesis are based on three samples: a meta-analysis of published vitamin D supplementation trials, a randomized placebo controlled six-month vitamin D supplementation trial, and a longitudinal prospective cohort study on a general aged population. Based on a PubMed search, a meta-analysis of 52 clinical trials with 6 290 adult participants was performed to evaluate the impact of age and immobility on the responses of PTH to 25-OHD levels and vitamin D supplementation. A total of 218 chronically immobile, very old inpatients were also enrolled into a vitamin D supplementation trial. Mortality data for these patients was also collected after a two-year follow-up. Finally, data from the Helsinki Aging Study, which followed three random age cohorts (75, 80 and 85 years) until death in almost all subjects, was used to evaluate the predictive value of PTH for long-term survival and cognitive decline. This series of studies demonstrated that in older people without overt renal failure or severe hypercalcaemia, serum 25-OHD and PTH were closely associated, but this relationship was also affected by age and immobility. Furthermore, a substantial proportion of old chronically bedridden patients did not respond to vitamin D deficiency by elevating PTH, and the effect of a high-dose (1200 IU/d) six-month cholecalciferol supplementation on the PTH concentration was minor. This study demonstrated longitudinally for the first time that the blunted PTH also persisted over time. Even a subtle elevation of PTH to high-normal levels predicted impaired long-term health outcomes. Slightly elevated PTH concentrations indicated an increased risk of clinically significant cognitive decline and death during the last years of life in a general aged population. This association was also independent of serum ionized calcium (Ca2+) and the estimated glomerular filtration rate (GFR). A slightly elevated PTH also indicated impaired two-year survival during the terminal years of frail elderly subjects independently of Ca2+, GFR, and of 25-OHD levels. The interplay between PTH and vitamin D in the regulation of calcium homeostasis is more complex than has been generally considered. In addition to muskuloskeletal health parathyroid hormone is also related to the maintenance of other important domains of health in old age. Higher PTH concentrations, even within conventional laboratory reference ranges, seem to be an independent indicator of an increased risk of all-cause and of cardiovascular mortality, independently of established cardiovascular risk factors, disturbances in mineral metabolism, and renal failure. Limited and inconsistent evidence supports the role of vitamin D deficiency-related lack of neuroprotective effects over the causal association between PTH and impaired cognitive functions. However, the causality of these associations remains unclear. The clinical implications of the observed relationships remain to be elucidated by future studies interfering with PTH concentrations, especially by long-term interventions to reduce PTH.

Functional role of the Mso1p-Sec1p complex in membrane fusion regulation

Sec1/Munc18 (SM) protein family members are evolutionary conserved proteins. They perform an essential, albeit poorly understood function in SNARE complex formation in membrane fusion. In addition to the SNARE complex components, only a few SM protein binding proteins are known. Typically, their binding modes to SM proteins and their contribution to the membrane fusion regulation is poorly characterised. We identified Mso1p as a novel Sec1p interacting partner. It was shown that Mso1p and Sec1p interact at sites of polarised secretion and that this localisation is dependent on the Rab GTPase Sec4p and its GEF Sec2p. Using targeted mutagenesis and N- and C-terminal deletants, it was discovered that the interaction between an N-terminal peptide of Mso1p and the putative Syntaxin N-peptide binding area in Sec1p domain 1 is important for membrane fusion regulation. The yeast Syntaxin homologues Sso1p and Sso2p lack the N-terminal peptide. Our results show that in addition to binding to the putative N-peptide binding area in Sec1p, Mso1p can interact with Sso1p and Sso2p. This result suggests that Mso1p can mimic the N-peptide binding to facilitate membrane fusion. In addition to Mso1p, a novel role in membrane fusion regulation was revealed for the Sec1p C-terminal tail, which is missing in its mammalian homologues. Deletion of the Sec1p-tail results in temperature sensitive growth and reduced sporulation. Using in vivo and in vitro experiments, it was shown that the Sec1p-tail mediates SNARE complex binding and assembly. These results propose a regulatory role for the Sec1p-tail in SNARE complex formation. Furthermore, two novel interaction partners for Mso1p, the Rab GTPase Sec4p and plasma membrane phospholipids, were identified. The Sec4p link was identified using Bimolecular Fluorescence Complementation assays with Mso1p and the non-SNARE binding Sec1p(1-657). The assay revealed that Mso1p can target Sec1p(1-657) to sites of secretion. This effect is mediated via the Mso1p C-terminus, which previously has been genetically linked to Sec4p. These results and in vitro binding experiments suggest that Mso1p acts in cooperation with the GTP-bound form of Sec4p on vesicle-like structures prior to membrane fusion. Mso1p shares homology with the PIP2 binding domain of the mammalian Munc18 binding Mint proteins. It was shown both in vivo and in vitro that Mso1p is a phospholipid inserting protein and that this insertion is mediated by the conserved Mso1p amino terminus. In vivo, the Mso1p phospholipid binding is needed for sporulation and Mso1p-Sec1p localisation at the sites of secretion at the plasma membrane. The results reveal a novel layer of membrane fusion regulation in exocytosis and propose a coordinating role for Mso1p in connection with membrane lipids, Sec1p, Sec4p and SNARE complexes in this process.

Espoo shootings: A failure of restraint

Argues that focus on the immigrant status of the Espoo shooter deflects attention from the failure of the relevant authorities to effectively respond to a foreseeable threat to public safety. Response to public discussion of New Year's Day shootings in Espoo shopping mall.

Espoo shootings: A failure of restraint

Argues that focus on the immigrant status of the Espoo shooter deflects attention from the failure of the relevant authorities to effectively respond to a foreseeable threat to public safety. Response to public discussion of New Year's Day shootings in Espoo shopping mall.

Developing Peer-To-Peer Web Applications

As the virtual world grows more complex, finding a standard way for storing data becomes increasingly important. Ideally, each data item would be brought into the computer system only once. References for data items need to be cryptographically verifiable, so the data can maintain its identity while being passed around. This way there will be only one copy of the users family photo album, while the user can use multiple tools to show or manipulate the album. Copies of users data could be stored on some of his family members computer, some of his computers, but also at some online services which he uses. When all actors operate over one replicated copy of the data, the system automatically avoids a single point of failure. Thus the data will not disappear with one computer breaking, or one service provider going out of business. One shared copy also makes it possible to delete a piece of data from all systems at once, on users request. In our research we tried to find a model that would make data manageable to users, and make it possible to have the same data stored at various locations. We studied three systems, Persona, Freenet, and GNUnet, that suggest different models for protecting user data. The main application areas of the systems studied include securing online social networks, providing anonymous web, and preventing censorship in file-sharing. Each of the systems studied store user data on machines belonging to third parties. The systems differ in measures they take to protect their users from data loss, forged information, censorship, and being monitored. All of the systems use cryptography to secure names used for the content, and to protect the data from outsiders. Based on the gained knowledge, we built a prototype platform called Peerscape, which stores user data in a synchronized, protected database. Data items themselves are protected with cryptography against forgery, but not encrypted as the focus has been disseminating the data directly among family and friends instead of letting third parties store the information. We turned the synchronizing database into peer-to-peer web by revealing its contents through an integrated http server. The REST-like http API supports development of applications in javascript. To evaluate the platform’s suitability for application development we wrote some simple applications, including a public chat room, bittorrent site, and a flower growing game. During our early tests we came to the conclusion that using the platform for simple applications works well. As web standards develop further, writing applications for the platform should become easier. Any system this complex will have its problems, and we are not expecting our platform to replace the existing web, but are fairly impressed with the results and consider our work important from the perspective of managing user data.

Developing Peer-To-Peer Web Applications

As the virtual world grows more complex, finding a standard way for storing data becomes increasingly important. Ideally, each data item would be brought into the computer system only once. References for data items need to be cryptographically verifiable, so the data can maintain its identity while being passed around. This way there will be only one copy of the users family photo album, while the user can use multiple tools to show or manipulate the album. Copies of users data could be stored on some of his family members computer, some of his computers, but also at some online services which he uses. When all actors operate over one replicated copy of the data, the system automatically avoids a single point of failure. Thus the data will not disappear with one computer breaking, or one service provider going out of business. One shared copy also makes it possible to delete a piece of data from all systems at once, on users request. In our research we tried to find a model that would make data manageable to users, and make it possible to have the same data stored at various locations. We studied three systems, Persona, Freenet, and GNUnet, that suggest different models for protecting user data. The main application areas of the systems studied include securing online social networks, providing anonymous web, and preventing censorship in file-sharing. Each of the systems studied store user data on machines belonging to third parties. The systems differ in measures they take to protect their users from data loss, forged information, censorship, and being monitored. All of the systems use cryptography to secure names used for the content, and to protect the data from outsiders. Based on the gained knowledge, we built a prototype platform called Peerscape, which stores user data in a synchronized, protected database. Data items themselves are protected with cryptography against forgery, but not encrypted as the focus has been disseminating the data directly among family and friends instead of letting third parties store the information. We turned the synchronizing database into peer-to-peer web by revealing its contents through an integrated http server. The REST-like http API supports development of applications in javascript. To evaluate the platform s suitability for application development we wrote some simple applications, including a public chat room, bittorrent site, and a flower growing game. During our early tests we came to the conclusion that using the platform for simple applications works well. As web standards develop further, writing applications for the platform should become easier. Any system this complex will have its problems, and we are not expecting our platform to replace the existing web, but are fairly impressed with the results and consider our work important from the perspective of managing user data.

On the discursive construction of success/failure in narratives of post-merger integration

This article concentrates on the discursive constmction of success and failure in narratives of post-merger integration. Drawing on extensive interview material from eight Finnish-Swedish mergers and acquisitions, the empirical analysis leads to distinguishing four types of discourse — 'rationalistic', 'cultural', 'role-bound' and 'individualistic' — that narrators employ in recounting their experiences. In particular, the empirical material illustrates how the discursive frameworks enable specific (di.scursive) strategies and moves for (re)framing the success/failure, justification/legitimization of one's own actions, and (re)constniction of responsibility when dealing with socio-psychological pressures associated with success/failtire. The analysis also suggests that, as a result of making use of these discursive strategies and moves, success stories are likely to lead to overly optimistic or, in the case of failure stories, overly pessimistic views on the management's ability to control these change processes. Tliese findings imply that we should take the discursive elements that both constrain our descriptions and explanations seriously, and provide opportunities for more or less intentional (re)interpretations of postmerger integration or other organizational change processes.

Somali State Failure: Players, Incentives and Institutions

In Somalia the central government collapsed in 1991 and since then state failure became a widespread phenomenon and one of the greatest political and humanitarian problems facing the world in this century. Thus, the main objective of this research is to answer the following question: What went wrong? Most of the existing literature on the political economy of conflict starts from the assumption that state in Africa is predatory by nature. Unlike these studies, the present research, although it uses predation theory, starts from the social contract approach of state definition. Therefore, rather than contemplating actions and policies of the rulers alone, this approach allows us to deliberately bring the role of the society – as citizens – and other players into the analyses. In Chapter 1, after introducing the study, a simple principal-agent model will be developed to check the logical consistence of the argument and to make the identification of causal mechanism easier. I also identify three main actors in the process of state failure in Somalia: the Somali state, Somali society and the superpowers. In Chapter 2, so as to understand the incentives, preferences and constraints of each player in the state failure game, I in some depth analyse the evolution and structure of three central informal institutions: identity based patronage system of leadership, political tribalism, and the Cold War. These three institutions are considered as the rules of the game in the Somali state failure. Chapter 3 summarises the successive civilian governments’ achievements and failures (1960-69) concerning the main national goals, national unification and socio-economic development. Chapter 4 shows that the military regime, although it assumed power through extralegal means, served to some extent the developmental interest of the citizens in the first five years of its rule. Chapter 5 shows the process, and the factors involved, of the military regime’s self-transformation from being an agent for the developmental interests of the society to a predatory state that not only undermines the interests of the society but that also destroys the state itself. Chapter 6 addresses the process of disintegration of the post-colonial state of Somalia. The chapter shows how the regime’s merciless reactions to political ventures by power-seeking opposition leaders shattered the entire country and wrecked the state institutions. Chapter 7 concludes the study by summarising the main findings: due to the incentive structures generated by the informal institutions, the formal state institutions fell apart.

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.

Levosimendaanin vaikutusmekanismi ja nykyinen merkitys sydämen vajaatoiminnan hoidossa

Sydämen vajaatoiminta on erilaisista sydän- ja verisuonisairauksista aiheutuva monimuotoinen oireyhtymä, johon sairastuneiden ja kuolleiden potilaiden määrä on yhä suuri. Sen patofysiologiaan voi kuulua muun muassa sympaattisen hermoston ja reniini-angiotensiini-aldosteroni–järjestelmän aktiivisuutta, huonosti supistuva vasen kammio, sydämen uudelleenmuokkautumista, muutoksia [Ca2+]i:n säätelyssä, kardiomyosyyttien apoptoosia sekä systeeminen tulehdustila. Johonkin osaan sairauden patofysiologiasta eivät nykyiset lääkehoidot riittävästi vaikuta. Klassiset inotroopit lisäävät sydämen supistusvireyttä kasvattamalla solunsisäistä Ca2+-pitoisuutta, mutta ne lisäävät rytmihäiriöriskiä, sydämen hapenkulutusta sekä heikentävät ennustetta. Levosimendaani, kalsiumherkistäjä, lisää sydämen supistusvoimaa [Ca2+]i:ta kohottamatta herkistämällä sydänlihaksen kalsiumin vaikutuksille. Lisäksi levosimendaani avaa sarkolemmaalisia ja mitokondriaalisia K+-kanavia, jotka välittävät vasodilataatiota ja kardioprotektiota. Suurilla annoksilla levosimendaani on selektiivinen PDE3-estäjä. Levosimendaania suositellaan äkillisesti pahentuneen sydämen vajaatoiminnan hoitoon, mutta muitakin lupaavia indikaatioita sille on keksitty. Esimerkiksi kroonisesti annosteltu oraalinen levosimendaani on suojannut kardiovaskulaarijärjestelmää ja parantanut selviytymistä in vivo. Erikoistyössä selvitettiin kroonisesti annostellun oraalisen levosimendaanin, valsartaanin ja näiden kombinaatioterapian vaikutuksia selviytymiseen, verenpaineeseen sekä sydämen hypertrofioitumiseen Dahlin suolaherkillä (Dahl/Rapp) rotilla. Levosimendaanin suojavaikutus ilmeni vähäisempänä kuolleisuutena, mutta ero ei ollut tilastollisesti merkitsevä kontrolliryhmään nähden. Kombinaatioterapia suojasi rottia kardiovaskulaarikuolleisuudelta ja vähensi todennäköisesti verenpaineesta riippuvaisesti sydämen hypertofioitumista niin sydän/kehonpaino–suhteen kuin ultraäänitutkimuksenkin perusteella arvioituna paremmin kuin kumpikaan lääke monoterapiana. Lääkekombinaatio alensi additiivisesti hypertensiota kaikissa mittauspisteissä. Sydämen systolista toimintaa levosimendaani kohensi vain vähäisesti. Dahl/Rapp-rotille kehittyikin pääosin hypertension indusoimaa diastolista sydämen vajaatoimintaa kohonneen IVRT-arvon perusteella. Levosimendaani sekä monoterapiana että kombinaatioterapiana valsartaanin kanssa vähensi sydämen diastolista vajaatoimintaa.