Effects of oral calcium sensitizers on experimental heart failure

Suun kautta annosteltava kalsiumherkistäjä parantaa sydämen vajaatoimintaan liittyvää pumppausvajetta kokeellisissa sydämen vajaatoimintamalleissa Huolimatta viime vuosikymmenien lääketieteellisestä kehityksestä krooninen sydämen vajaatoiminta on silti edelleen vakava, elämänlaatua voimakkaasti rajoittava sairaus. Kalsiumherkistäjät ovat uusi, sydämen pumppausvoimaa lisäävä lääkeryhmä. Levosimendaani, kotimaista alkuperää oleva kalsiumherkistäjä, on kliinisessä käytössä akuutin vajaatoiminnan hoitoon suonensisäisesti ja lyhytaikaisesti annosteltavana valmisteena. Levosimendaanilla on aktiivinen metaboliitti, OR-1896, jonka oletetaan olevan vuorokauden mittaisen levosimendaani-infuusion jälkeen havaittujen useita päiviä kestävien hyödyllisisten vaikutuksisten takana. Levosimendaanin kroonisen, suun kautta tapahtuvan annostelun vaikutuksista tieto on vähäisempää, mutta sillä näyttää olevan positiivisia vaikutuksia potilaiden raportoimana. FM Marjut Louhelainen on selvittänyt väitöskirjassaan suun kautta annosteltavan levosimendaanin ja sen pitkäkestoisen aktiivisen metaboliitin vaikutuksia kroonisen vajaatoiminnan hoidossa käyttämällä sekä hypertensiivisen sydäntaudin että 2 tyypin diabeteksen komplisoimaan sydäninfarktin kokeellisia malleja. Tutkimuksessa selvitettiin lisäksi vajaatoimintaan johtavia molekyylitason tapahtumia sydänlihaksessa. Tutkimuksessa osoitettiin, että krooninen suun kautta annosteltu hoito sekä kalsiumherkistäjä levosimendaanilla että sen aktiivisella metaboliitilla estää hypertensiiviseen sydämen vajaatoiminnan aikaasaamaa sydämen uudelleenmuovaantumista ja siihen liittyvää kuolleisuutta. Nämä vaikutukset välittyivät vähentyneen sydänlihassoluhypertrofian, solukuolleisuuden ja neurohumaraalisen aktivaation kautta. Levosimendaanin ja OR-1896:n osoitettiin myös parantavan sydämen pumppausfunktiota tyyppi 2 diabeteksen komplisoimassa sydäninfarktissa. Ei-diabeettiseen tilanteeseen verrattuna diabetekseen liittyvä infarktin jälkeinen vajaatoiminnan kehitys oli yhteydessä lisääntyneeseen tulehdukseen, fibroosiin, solukuolemaan, neurohumoraaliseen aktivaatioon ja ennenaikaiseen kudoksen vanhenemiseen. Sekä levosimendaani, että OR-1869 vähensivät tulehduksen, fibroosin ja solukuoleman merkkejä ja vaimensi neurohumoraalista aktivaatiota. OR-1896 myös vähensi solujen vanhenemiseen liittyvien merkkiaineiden ilmentymistä. Väitöskirjassa todettiin, että suun kautta annosteltuna sekä levosimendaani, että sen aktiivinen metaboliitti OR-1896, omaavat terapeuttista potentiaalia sekä hypertensiivisen sydäntaudin hoitoon että sydäninfarktin jälkeisen vajaatoiminnan estoon. FM Marjut Louhelaisen farmakologian alaan kuuluva väitöskirja Effects of oral calcium sensitizers on experimental heart failure tarkastetaan Helsingin yliopiston Lääketieteellisessä tiedekunnassa perjantaina 29.01.2010 klo 12 (Biomedicum Helsinki, luentosali 2, Haartmaninkatu 8, Helsinki). Vastaväittäjänä toimii professori Raimo Tuominen, Helsingin yliopiston Farmasian tiedekunnasta ja kustoksena professori Eero Mervaala Helsingin yliopiston Lääketieteellisestä tiedekunnasta.

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.

Cystatin C, a measure of renal function, as prognostic risk marker in acute heart failure : Studies on the cardiorenal syndrome

Acute heart failure (AHF) is a complex syndrome associated with exceptionally high mortality. Still, characteristics and prognostic factors of contemporary AHF patients have been inadequately studied. Kidney function has emerged as a very powerful prognostic risk factor in cardiovascular disease. This is believed to be the consequence of an interaction between the heart and kidneys, also termed the cardiorenal syndrome, the mechanisms of which are not fully understood. Renal insufficiency is common in heart failure and of particular interest for predicting outcome in AHF. Cystatin C (CysC) is a marker of glomerular filtration rate with properties making it a prospective alternative to the currently used measure creatinine for assessment of renal function. The aim of this thesis is to characterize a representative cohort of patients hospitalized for AHF and to identify risk factors for poor outcome in AHF. In particular, the role of CysC as a marker of renal function is evaluated, including examination of the value of CysC as a predictor of mortality in AHF. The FINN-AKVA (Finnish Acute Heart Failure) study is a national prospective multicenter study conducted to investigate the clinical presentation, aetiology and treatment of, as well as concomitant diseases and outcome in, AHF. Patients hospitalized for AHF were enrolled in the FINN-AKVA study, and mortality was followed for 12 months. The mean age of patients with AHF is 75 years and they frequently have both cardiovascular and non-cardiovascular co-morbidities. The mortality after hospitalization for AHF is high, rising to 27% by 12 months. The present study shows that renal dysfunction is very common in AHF. CysC detects impaired renal function in forty percent of patients. Renal function, measured by CysC, is one of the strongest predictors of mortality independently of other prognostic risk markers, such as age, gender, co-morbidities and systolic blood pressure on admission. Moreover, in patients with normal creatinine values, elevated CysC is associated with a marked increase in mortality. Acute kidney injury, defined as an increase in CysC within 48 hours of hospital admission, occurs in a significant proportion of patients and is associated with increased short- and mid-term mortality. The results suggest that CysC can be used for risk stratification in AHF. Markers of inflammation are elevated both in heart failure and in chronic kidney disease, and inflammation is one of the mechanisms thought to mediate heart-kidney interactions in the cardiorenal syndrome. Inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) correlate very differently to markers of cardiac stress and renal function. In particular, TNF-α showed a robust correlation to CysC, but was not associated with levels of NT-proBNP, a marker of hemodynamic cardiac stress. Compared to CysC, the inflammatory markers were not strongly related to mortality in AHF. In conclusion, patients with AHF are elderly with multiple co-morbidities, and renal dysfunction is very common. CysC demonstrates good diagnostic properties both in identifying impaired renal function and acute kidney injury in patients with AHF. CysC, as a measure of renal function, is also a powerful prognostic marker in AHF. CysC shows promise as a marker for assessment of kidney function and risk stratification in patients hospitalized for AHF.

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.

Myoblast Sheet Transplantation for Treatment of Heart Failure after Myocardial Infarction

Heart failure is a common, severe, and progressive condition associated with high mortality and morbidity. Because of population-aging in the coming decades, heart failure is estimated to reach epidemic proportions. Current medical and surgical treatments have reduced mortality, but the prognosis for patients has remained poor. Transplantation of skeletal myoblasts has raised hope of regenerating the failing heart and compensating for lost cardiac contractile tissue. In the present work, we studied epicardial transplantation of tissue-engineered myoblast sheets for treatment of heart failure. We employed a rat model of myocardial infarction-induced acute and chronic heart failure by left anterior descending coronary artery ligation. We then transplanted myoblast sheets genetically modified to resist cell death after transplantation by expressing antiapoptotic gene bcl2. In addition, we evaluated the regenerative capacity of myoblast sheets expressing the cardioprotective cytokine hepatocyte growth factor in a rat chronic heart failure model. Furthermore, we utilized in vitro cardiomyocyte and endothelial cell culture models as well as microarray gene expression analysis to elucidate molecular mechanisms mediating the therapeutic effects of myoblast sheet transplantation. Our results demonstrate that Bcl2-expression prolonged myoblast sheet survival in rat hearts after transplantation and induced secretion of cardioprotective, proangiogenic cytokines. After acute myocardial infarction, these sheets attenuated left ventricular dysfunction and myocardial damage, and they induced therapeutic angiogenesis. In the chronic heart failure model, inhibition of graft apoptosis by Bcl-2 improved cardiac function, supported survival of cardiomyocytes in the infarcted area, and induced angiogenesis in a vascular endothelial growth factor receptor 1- and 2-dependent mechanism. Hepatocyte growth factor-secreting myoblast sheets further enhanced the angiogenic efficacy of myoblast sheet therapy. Moreover, myoblast-secreted paracrine factors protected cardiomyocytes against oxidative stress in an epidermal growth factor receptor- and c-Met dependent manner. This protection was associated with induction of antioxidative genes and activation of the unfolded protein response. Our results provide evidence that inhibiting myoblast sheet apoptosis can enhance the sheets efficacy for treating heart failure after acute and chronic myocardial infarction. Furthermore, we show that myoblast sheets can serve as vehicles for delivery of growth factors, and induce therapeutic angiogenesis in the chronically ischemic heart. Finally, myoblasts induce, in a paracine manner, a cardiomyocyte-protective response against oxidative stress. Our study elucidates novel mechanisms of myoblast transplantation therapy, and suggests effective means to improve this therapy for the benefit of the heart failure patient.

Tyhjä taivas : Georges Bataille ja uskonnon kysymys

Empty Heavens. Georges Bataille and the Question of Religion. The dissertation explores the question of religion in the texts of Georges Bataille (1897 1962), the controversial French avant-garde writer and philosopher. Passionate about religion throughout his life, Bataille devoted to it both critical analyses and personal meditations. In this study, Bataille s multifaceted relationship to religion is interpreted as expressing a passion for radical otherness. Bataille is approached as a characteristically modern thinker who, nevertheless, questions some landmarks of modernity insofar as modernity is interpreted as a triumph of secularization. The dissertation is situated at the intersection of comparative religion and philosophy of religion. Methodologically, the study resorts to theoretical contextualization and concept analysis. Acknowledging that Bataille s writings challenge the assumptions about coherent meaning taken for granted in traditional philosophical analysis, the study also pays attention to the literary means and, in general, the performative level of Bataille s texts. The study constructs three theoretical contexts for Bataille s question of religion first of all, the interpretation of Hegel in the mid-20th century French philosophy. In the first section of the study, Bataille s uneasy relationship with Hegel as mediated by Alexandre Kojève is explored. The motivation of his question of radical otherness is argued to arise from his struggle with the Hegelian Kojèvean notion of negativity. The second context is the dialogue with the Christian mystical tradition. Starting from the analysis of two Bataillean notions, dramatization and contestation , it is argued that, firstly, Bataille s approach to radical otherness is analogous to certain procedures of mystical texts while, secondly, the function of otherness providing no firm foundation in Bataille s texts differs from its function in mystical texts. In the third section of the study, Bataille s quest for otherness is concretized by analyzing his views on otherness of other person, on violence, and on death themes that are brought together in Bataille s lasting interest in sacrifice. Bataille s understanding of sacrifice is proportioned to social scientific and philosophical discussions on sacrifice. It is argued that the commitment to the idea of sacrifice accounts for a partial failure in the Bataillean approach to otherness, the otherness of other person remaining its (at least half) blind spot. The study presents an overview of Bataille s thought on religion. It brings out Bataille s view of the paradoxical fundamental yet impossible role of otherness in the construction of human world, as well as his understanding of religious representations as both covering over and indicating this otherness. It describes Bataille s atheological mysticism as a peculiar modern form of religiosity, as an ambivalent mourning for and exaltation of fundamental loss.

Talousmetafysiikan kritiikkiä

Jakke Holvas: A Critique of the Metaphysics of Economy The research problem of this dissertation is the commonly held opinion according to which everything has become a question of economy in the present day. Economy legitimates and justifies. In this study, the pattern of thinking and conceptualizing in which economy figures as the ultimate reason is called the metaphysics of economy. The defining characteristic of the metaphysics of economy is its failure to recognize non-economic rules, ethics, or ways of existence. The sources included in the study cover certain classics of philosophy (Plato, Aristotle, Friedrich Nietzsche) and sociology (Karl Marx, Max Weber, Marcel Mauss), as well as the more recent French social theory (Jean Baudrillard, Michel Foucault). The research methods used are textual analysis and evaluation of concepts by means of historical comparison. The background to the study is given by the views of historians and sociologists according to whom traditional forms have ceased to exist and the market economy become established as the western system of values. The study identifies points of transition from the traditional forms to economic values. In addition, the dissertation focuses on the modern non-economic forms. The study examines the economic and ethical meanings of gift in antiquity in Homer, Plato, and Aristotle. Following Marcel Mauss, the study analyzes the forms and principles of gift exchange. The study also applies Nietzsche’s philosophy to evaluate under what conditions giving a gift becomes an act of exercising power that puts its receiver into debt. The conclusion of the study is that the classics of philosophy and sociology can rightly be interpreted in terms of the metaphysics of economy, but they also offer grounds for criticizing this metaphysics, even alternatives. One such alternative is non-economic archaic ethic. The study delineates a duality between economy and non-economy as well as creating concepts which could be used in the future to critically analyze economy from a position external to the economic system of concepts.

Psychological resources, their social antecedents, and association with well-being and health behaviour in early adulthood

The success of entering work life, young people s psychological resources and self-reported well-being were studied in a longitudinal setting from a life-span developmental-contextual perspective in early adulthood. The aim was to analyse how psychosocial characteristics in early childhood and adolescence predict successful entrance into work life, how this is associated with well-being, and to assess the level of psychological resources such as dispositional optimism, personal meaning of work and coping in early adulthood. The role of these and social support, in the relationship between regional factors (such as place of residence and migration), self-reported health and life satisfaction was studied. The association between a specific coping strategy, i.e. eating and drinking in a stressful situation and eating habits, was studied to demonstrate how coping is associated with health behaviour. Multivariate methods, including binary logistic regression analyses and ANOVA, were used for statistical analyses. The subjects were members of the Northern Finland 1966 Birth Cohort, which consists of all women and men born in 1966 in the two northernmost provinces of Finland (n= 12,058). The most recent follow-up, at the age of 31 years when 11,637 subjects were alive, took place in 1997-1998. The results show, first, that social resources in the childhood family and adolescence school achievement predict entrance into the labour market. Secondly, psychosocial resources were found to mediate the relationship between migration from rural to urban areas, and subjective well-being. Thirdly, psychological resources at entrance into the labour market were found to develop from early infancy on. They are, however, influenced later by work history. Fourthly, stress-related eating and drinking, as a way of coping, was found to be directly associated with unhealthy eating habits and alcohol use. Gender differences were found in psychosocial resources predicting, and being associated with success in entering the labour market. For men, the role of attitudinal and psychological factors seems to be especially important in entrance into work life and in the development of psychological resources. For women, academic attainment was more important for successfully entering work life, and lack of emotional social support was a risk factor for stress-related eating only among women. Stress-related eating and drinking habits were predicted by a long history of unemployment as well as a low level of education among both genders, but not excluding an academic degree among men. The results emphasize the role of childhood psychosocial factors in preventing long-term unemployment and in enhancing psychological well-being in early adulthood. Success in entering work life, in terms of continuous work history, plays a crucial role for well-being and the amount of psychological resources in early adulthood. The results emphasize the crucial role of enhancing psychological resources for promoting positive health behaviour and diminishing regional differences in subjective well-being.

Feeling Better, Performing Better? Holistically-Oriented Top Performance and Well-Being (HOPE) : Performance Enhancement and Its Perceived Impacts on Musicians

Most musicians choose a career in music based on their love of the art and a desire to share it with others. However, being a performing musician is highly demanding. Despite considerable evidence of the great frequency of performance-related problems (e.g. debilitating performance anxiety) among professional musicians or aspiring musicians in the current Western classical music tradition these problems are seldom discussed openly. The existing system offers musicians very little help in learning how to build sustainable performance success into their musical career. This study it is first of its kind in Finland which addresses the issue on larger scale in a systematic way. I devised the HOPE intervention (Holistically-Oriented Top Performance and Well-Being Enhancement), in order to learn how to integrate professional peak performance and a sense of personal well-being into the lives and careers of musicians. Unlike most interventions in previous research, the HOPE intervention is explicitly holistic and aims at enhancing the whole musician, not just alleviating performance anxiety. Earlier research has not in principle focused on musicians´ psychological well-being or on their subjective perceptions. The main purpose of the study is to understand the perceived impacts of the specially devised HOPE intervention on the participants and particularly in four key areas: performing, playing or singing well-being, and overall (performing, playing or singing and well-being combined). Furthermore, it is hoped that a deeper understanding of performers´ development will be gained. The research method is interdisciplinary and mainly qualitative. The primary data consist of a series of linked questionnaires (before and after the intervention) and semi-structured follow-up interviews collected during action research-oriented HOPE intervention courses for music majors in the Sibelius Academy. With the longitudinal group called Hope 1, the core data were collected during a nine month HOPE intervention course and from follow-up interviews conducted six months later in 2003-2004. The core data of Hope 1 (nine participants) are compared with the perceived impacts on fifty-three other participants in the HOPE courses during the period since their inception, 2001-2006. The focus is particularly on participants´ subjective perceptions. Results of the study suggest that the HOPE intervention is beneficial in enhancing overall performance capacity, including music performance, and a personal sense of well-being in a music university setting. The findings indicate that within all key areas significant positive changes take place between the beginning and the end of a HOPE intervention course. The longitudinal data imply that the perceived positive changes are still ongoing six months after the HOPE intervention course is finished. The biggest change takes place within the area of performing and the smallest, in participants´ perception of their playing or singing. The main impacts include reduced feelings of stress and anxiety (an enhanced sense of well-being) as well as increased sense of direction and control in one's life. Since the results of the present research gave no other reason to believe otherwise, it is to be expected that the HOPE intervention and the results of the study can be exploited in other areas of human activity as well, especially where continuous professional top performance is a prerequisite such as in business or sports. Keywords: performance enhancement, professional top performance, subjective well-being, subjective perceptions, holism, coaching, music performance anxiety, studying music, music.

Lukemisen vaikeuden kuntoutus ensiluokkalaisilla : Kolme pedagogista interventiota

Remediation of Reading Difficulties in Grade 1. Three Pedagogical Interventions Keywords: initial teaching, learning to read, reading difficulties, intervention, dyslexia, remediation of dyslexia, home reading, computerized training In this study three different reading interventions were tested for first-graders at risk of reading difficulties at school commencement. The intervention groups were compared together and with a control group receiving special education provided by the school. First intervention was a new approach called syllable rhythmics in which syllabic rhythm, phonological knowledge and letter-phoneme correspondence are emphasized. Syllable rhythmics is based on multi-sensory training elements aimed at finding the most functional modality for every child. The second intervention was computerized training of letter-sound correspondence with the Ekapeli learning game. The third intervention was home-based shared book reading, where every family was given a story book, and dialogic reading style reading and writing exercises were prepared for each chapter of the book. The participants were 80 first-graders in 19 classes in nine schools. The children were matched in four groups according to pre-test results: three intervention and one control. The interventions took ten weeks starting from September in grade 1. The first post-test including several measures of reading abilities was administered in December. The first delayed post-test was administered in March, the second in September in grade 2, and the third, “ALLU” test (reading test for primary school) was administered in March in grade 2. The intervention and control groups differed only slightly from each other in grade 1. However, girls progressed significantly more than boys in both word reading and reading comprehension in December and this difference remained in March. The children who had been cited as inattentive by their teachers also lagged behind the others in the post-tests in December and March. When participants were divided into two groups according to their initial letter knowledge at school entry, the weaker group (maximum 17 correctly named letters in pre-test) progressed more slowly in both word reading and reading comprehension in grade 1. Intervention group and gender had no interaction effect in grade 1. Instead, intervention group and attentiveness had an interaction effect on most test measures the inattentive students in the syllable rhythmic group doing worst and attentive students in the control group doing best in grade 1. The smallest difference between results of attentive and inattentive students was in the Ekapeli group. In grade 2 still only minor differences were found between the intervention groups and control group. The only significant difference was in non-word reading, with the syllable rhythmics group outperforming the other groups in the fall. The difference between girls’ and boys’ performances in both technical reading and text comprehension disappeared in grade 2. The difference between the inattentive and attentive students cold no longer be found in technical reading, and the difference became smaller in text comprehension as well. The difference between two groups divided according to their initial letter knowledge disappeared in technical reading but remained significant in text comprehension measures in the ALLU test in the spring of grade 2. In all, the children in the study did better in the ALLU test than expected according to ALLU test norms. Being the weakest readers in their classes in the pre-test, 52.3 % reached the normal reading ability level. In the norm group 72.3 % of all students attained normal reading ability. The results of this study indicate that different types of remediation programs can be effective, and that special education has been apparently useful. The results suggest careful consideration of first-graders’ initial reading abilities (especially letter knowledge) and possible failure of attention; remediation should be individually targeted while flexibly using different methods.

Is a Majority Enough? Psychological Well-being and Its Relation to Academic and Prosocial Motivation, Self-regulation and Achievement at school

This cross-sectional study analyzed psychological well-being at school using the Self-Determination theory as a theoretical frame-work. The study explored basic psychological needs fulfillment (BPNS), academic (SRQ-A), prosocial self-regulation (SRQ-P) and motivation, and their relationship with achievement in general, special and selective education (N=786, 444 boys, 345 girls, mean age 12 yrs 8 mths). Motivation starts behavior which becomes guided by self-regulation. The perceived locus of control (PLOC) affects how self-determined this behavior will be; in other words, to what extent it is autonomously regulated. In order learn and thus to be able to accept external goals, a student has to feel emotionally safe and have sufficient ego-flexibility—all of which builds on satisfied psychological needs. In this study those conditions were explored. In addition to traditional methods Self-organizing maps (SOM), was used in order to cluster the students according to their well-being, self-regulation, motivation and achievement scores. The main impacts of this research were: a presentation of the theory based alternative of studying psychological well-being at school and usage of both the variable and person-oriented approach. In this Finnish sample the results showed that the majority of students felt well, but the well-being varied by group. Overall about for 11–15% the basic needs were deprived depending on the educational group. Age and educational group were the most effective factors; gender was important in relation to prosocial identified behavior. Although the person-oriented SOM-approach, was in a large extent confirming what was no-ticed by using comparison of the variables: the SEN groups had lower levels of basic needs fulfillment and less autonomous self-regulation, interesting deviations of that rule appeared. Some of the SEL- and GEN-group members ended up in the more unfavorable SOM-clusters, and not all SEN-group members belonged to the poorest clusters (although not to the best either). This evidence refines the well-being and self-regulation picture, and may re-direct intervention plans, and turn our focus also on students who might otherwise remain unnoticed. On the other hand, these results imply simultaneously that in special education groups the average is not the whole truth. On the basis of theoretical and empirical considerations an intervention model was sug-gested. The aim of the model was to shift amotivation or external motivation in a more intrinsic direction. According to the theoretical and empirical evidence this can be achieved first by studying the self-concept a student has, and then trying to affect both inner and environmental factors—including a consideration of the basic psychological needs. Keywords: academic self-regulation, prosocial self-regulation, basic psychological needs, moti-vation, achievement

Levosimendan: Studies on its mechanisms of action and beyond

Acute heart failure syndrome represents a prominent and growing health problem all around the world. Ideally, medical treatment for patients admitted to hospital because of this syndrome, in addition to alleviating the acute symptoms, should also prevent myocardial damage, modulate neurohumoral and inflammatory activation, and preserve or even improve renal function. Levosimendan is a cardiac enhancer having both inotropic and vasodilatory effects. It is approved for the short-term treatment of acutely decompensated chronic heart failure, but it has been shown to have beneficial clinical effects also in ischemic heart disease and septic shock as well as in perioperative cardiac support. In the present study, the mechanisms of action of levosimendan were studied in isolated guinea-pig heart preparations: Langendorff-perfused heart, papillary muscle and permeabilized cardiomyocytes as well as in purified phosphodiesterase isoenzyme preparations. Levosimendan was shown to be a potent inotropic agent in isolated Langendorff-perfused heart and right ventricle papillary muscle. In permeabilized cardiomyocytes, it was demonstrated to be a potent calcium sensitizer in contrast to its enantiomer, dextrosimendan. It was additionally shown to be a very selective phosphodiesterase (PDE) type-3 inhibitor, the selectivity factor for PDE3 over PDE4 being 10000 for levosimendan. Irrespective of this very selective PDE3 inhibitory property in purified enzyme preparations, the inotropic effect of levosimendan was demonstrated to be mediated mainly through calcium sensitization in the isolated heart as well as the papillary muscle preparations at clinically relevant concentrations. In the isolated Lagendorff-perfused heart, glibenclamide antagonized the levosimendan-induced increase in coronary flow (CF). Therefore, the main vasodilatory mechanism in coronary veins is believed to be the opening of the ATP-sensitive potassium (KATP) channels. In the paced hearts, CF did not increase in parallel with oxygen consumption (MVO2), thus indicating that levosimendan had a direct vasodilatory effect on coronary veins. The pharmacology of levosimendan was clearly different from that of milrinone, which induced an increase in CF in parallel with MVO2. In conclusion, levosimendan was demonstrated to increase cardiac contractility by binding to cardiac troponin C and sensitizing the myofilament contractile proteins to calcium, and further to induce coronary vasodilatation by opening KATP channels in vascular smooth muscle. In addition, the efficiency of the cardiac contraction was shown to be more advantageous when the heart was perfused with levosimendan in comparison to milrinone perfusion.

Expression and function of angiotensins in the regulation of intraocular pressure - an experimental study

Glaucoma is a multifactorial long-term ocular neuropathy associated with progressive loss of the visual field, retinal nerve fiber structural abnormalities and optic disc changes. Like arterial hypertension it is usually a symptomless disease, but if left untreated leads to visual disability and eventual blindness. All therapies currently used aim to lower intraocular pressure (IOP) in order to minimize cell death. Drugs with new mechanisms of action could protect glaucomatous eyes against blindness. Renin-angiotensin system (RAS) is known to regulate systemic blood pressure and compounds acting on it are in wide clinical use in the treatment of hypertension and heart failure but not yet in ophthalmological use. There are only few previous studies concerning intraocular RAS, though evidence is accumulating that drugs antagonizing RAS can also lower IOP, the only treatable risk factor in glaucoma. The main aim of this experimental study was to clarify the expression of the renin-angiotensin system in the eye tissues and to test its potential oculohypotensive effects and mechanisms. In addition, the possible relationship between the development of hypertension and IOP was evaluated in animal models. In conclusion, a novel angiotensin receptor type (Mas), as well as ACE2 enzyme- producing agonists for Mas, were described for the first time in the eye structures participating in the regulation of IOP. In addition, a Mas receptor agonist significantly reduced even normal IOP. The effect was abolished by a specific receptor antagonist. Intraocular, local RAS would thus to be involved in the regulation of IOP, probably even more in pathological conditions such as glaucoma though there was no unambiguous relationship between arterial and ocular hypertension. The findings suggest the potential as antiglaucomatous drugs of agents which increase ACE2 activity and the formation of angiotensin (1-7), or activate Mas receptors.

Oral Immune Defense against Chronic Hyperplastic Candidosis

Candida yeast species are widespread opportunistic microbes, which are usually innocent opportunists unless the systemic or local defense system of the host becomes compromised. When they adhere on a fertile substrate such as moist and warm, protein-rich human mucosal membrane or biomaterial surface, they become activated and start to grow pseudo and real hyphae. Their growth is intricately guided by their ability to detect surface defects (providing secure hiding , thigmotropism) and nutrients (source of energy, chemotropism). The hypothesis of this work was that body mobilizes both non-specific and specific host defense against invading candidal cells and that these interactions involve resident epithelial cells, rapidly responding non-specific protector neutrophils and mast cells as well as the antigen presenting and responding den-dritic cell lymphocyte plasma cell system. It is supposed that Candida albicans, as a result of dar-winistic pressure, has developed or is utilizing strategies to evade these host defense reactions by e.g. adhering to biomaterial surfaces and biofilms. The aim of the study was to assess the host defense by taking such key molecules of the anti-candidal defense into focus, which are also more or less characteristic for the main cellular players in candida-host cell interactions. As a model for candidal-host interaction, sections of chronic hyperplastic candidosis were used and compared with sections of non-infected leukoplakia and healthy tissue. In this thesis work, neutrophil-derived anti-candidal α-defensin was found in the epithelium, not only diffusely all over in the epithelium, but as a strong α-defensin-rich superficial front probably able to slow down or prevent penetration of candida into the epithelium. Neutrophil represents the main host defence cell in the epithelium, to which it can rapidly transmigrate from the circulation and where it forms organized multicellular units known as microabscesses (study I). Neutrophil chemotactic inter-leukin-8 (IL-8) and its receptor (IL-8R) were studied and were surprisingly also found in the candidal cells, probably helping the candida to keep away from IL-8- and neutrophil-rich danger zones (study IV). Both leukocytes and resident epithelial cells contained TLR2, TLR4 and TLR6 receptors able to recognize candidal structures via utilization of receptors similar to the Toll of the banana fly. It seems that candida can avoid host defence via stimulation of the candida permissive TLR2 instead of the can-dida injurious TLR4 (study V). TLR also provides the danger signal to the immune system without which it will not be activated to specifically respond against candidal antigens. Indeed, diseased sites contained receptor activator of nuclear factor kappa B ligand (RANKL; II study), which is important for the antigen capturing, processing and presenting dendritic cells and for the T lymphocyte activation (study III). Chronic hyperplastic candidosis provides a disease model that is very useful to study local and sys-temic host factors, which under normal circumstances restrain C. albicans to a harmless commensal state, but failure of which in e.g. HIV infection, cancer and aging may lead to chronic infection.