Genetics of inherited small vessel diseases – in search of a novel small vessel disease and modifiers of the clinical course of CADASIL

The genetic and environmental risk factors of vascular cognitive impairment are still largely unknown. This thesis aimed to assess the genetic background of two clinically similar familial small vessel diseases (SVD), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) and Swedish hMID (hereditary multi-infarct dementia of Swedish type). In the first study, selected genetic modifiers of CADASIL were studied in a homogenous Finnish CADASIL population of 134 patients, all carrying the p.Arg133Cys mutation in NOTCH3. Apolipoprotein E (APOE) genotypes, angiotensinogen (AGT) p.Met268Thr polymorphism and eight NOTCH3 polymorphisms were studied, but no associations between any particular genetic variant and first-ever stroke or migraine were seen. In the second study, smoking, statin medication and physical activity were suggested to be the most profound environmental differences among the monozygotic twins with CADASIL. Swedish hMID was for long misdiagnosed as CADASIL. In the third study, the CADASIL diagnosis in the Swedish hMID family was ruled out on the basis of genetic, radiological and pathological findings, and Swedish hMID was suggested to represent a novel SVD. In the fourth study, the gene defect of Swedish hMID was then sought using whole exome sequencing paired with a linkage analysis. The strongest candidate for the pathogenic mutation was a 3’UTR variant in the COL4A1 gene, but further studies are needed to confirm its functionality. This study provided new information about the genetic background of two inherited SVDs. Profound knowledge about the pathogenic mutations causing familial SVD is also important for correct diagnosis and treatment options.

In Search for the European solidarity: The rule of law within the European Union in the framework of constitutional pluralism

The dissertation examines the rule of law within the European Union in the theoretical framework of constitutional pluralism. The leading lines of constitutional pluralism are examined with relation to the traditional and prevailing, monistic and hierarchical conceptions on how to perceive legal orders in Europe. The theoretical part offers also historical perspective by highlighting some of the turning points for the Union constitutional legal order in the framework of European integration. The concept of rule of law is examined in legal terms and its meaning to the Union constitutional constellation as a constitutional principle and a common value is observed. The realization of the rule of law at supranational and national level is explored with a view to discover that recent developments in some of the Member States give rise to concern about the viability of the rule of law within the European Union. It is recognized that the inobservance of the rule of law at national level causes a threat to the supranational constitutional legal order. The relationship between the supranational and national legal orders is significant in this respect and therefore particularly the interaction between the Court of Justice of the European Union (hereinafter the ECJ) and the Member States’ (constitutional/supreme) courts takes focus. It is observed that functioning dialogue between the supranational and national courts based on mutual respect and judicial deference is an important prerequisite for the realization of the rule of law within Europe. In order to afford a concrete example, a recent case C-62/14 Gauweiler v Deutscher Bundestag is introduced and analysed in relation to the notorious relationship between the Federal Constitutional Court of Germany and the ECJ. The implications of the ECJ’s decision in Gauweiler v Deutscher Bundestag is assessed with reference to some of the pressing issues of constitutionalism within Europe and some institutional aspects are also brought forward. Lastly, the feasibility of constitutional pluralism as a theoretical setting is measured against the legal reality of today’s Europe and its many constitutions. The hierarchical idea of one ultimate source of power, stemming from the traditional approaches to legal systems, is then assessed with relation to the requirement of the realization of the rule of law within the European Union from the supranational and national point of view.

In search of good relationships to music : understanding aspiration and challenge in developing music school teacher practices

This study focuses on teacher practices in publicly funded music schools in Finland. As views on the aims of music education change and broaden, music schools across Europe share the challenge of developing their activities in response. In public and scholarly debate, there have been calls for increased diversity of contents and concepts of teaching. In Finland, the official national curriculum for state-funded music schools builds on the ideal that teaching and learning should create conditions which promote ‘a good relationship to music’. The meaning of this concept has been deliberately left open in order to leave room for dialogue, flexibility, and teacher autonomy. Since what is meant by ‘good’ is not defined in advance, the notion of ‘improving’ practices is also open to discussion. The purpose of the study is to examine these issues from teachers’ point of view by asking what music school teachers aim to accomplish as they develop their practices. Methodologically, the study introduces a suggestion for building empirical research on Alperson’s ‘robust’ praxial approach to music education, a philosophical theory which is strongly committed to practitioner perspectives and musical diversity. A systematic method for analysing music education practices, interpretive practice analysis, is elaborated with support from interpretive research methods originally used in policy analysis. In addition, the research design shows how reflecting conversations (a collaborative approach well-known in Nordic social work) can be fruitfully applied in interpretive research and combined with teacher inquiry. Data have been generated in a collaborative project involving five experienced music school teachers and the researcher. The empirical material includes transcripts from group conversations, data from teacher inquiry conducted within the project, and transcripts from follow-up interviews. The teachers’ aspirations can be understood as strivings to reinforce the connection between musical practices and various forms of human flourishing such that music and flourishing can sustain each other. Examples from their practices show how the word ‘good’ receives its meaning in context. Central among the teachers’ concerns is their hope that students develop a free and sustainable interest in music, often described as inspiration. I propose that ‘good relationships to music’ and ‘inspiration’ can be understood as philosophical mediators which support the transition from an indeterminate ‘interest in music’ towards specific ways in which music can become a (co-)constitutive part of living well in each person’s particular circumstances. Different musical practices emphasise different aspects of what is considered important in music and in human life. Music school teachers consciously balance between a variety of such values. They also make efforts to resist pressure which might threaten the goods they think are most important. Such goods include joy, participation, perseverance, solid musical skills related to specific practices, and a strong sense of vitality. The insights from this study suggest that when teachers are able to create inspiration, they seem to do so by performing complex work which combines musical and educational aims and makes general positive contributions to their students’ lives. Ensuring that teaching and learning in music schools remain as constructive and meaningful as possible for both students and teachers is a demanding task. The study indicates that collaborative, reflective and interdisciplinary work may be helpful as support for development processes on both individual and collective levels of music school teacher practices.

In search of the interrelatedness of innovation and internationalisation processes in entrepreneurial life science companies

This study is motivated by the question how resource scarce innovative entrepreneurial companies seek and leverage global resources. This study takes a resource-seeking perspective a step forward and suggests that resources that enable the entrepreneurial internationalisation are largely accrued from the early stages of entrepreneurial life; that is from the innovation development. Consequently, this study seeks to explain how innovation and internationalisation processes are interrelated in the entrepreneurial internationalisation. This main objective is approached through three research questions, (1) What role do inter-organisational relationships in innovation have in the entrepreneurial internationalisation process? (2) What kind of inward–outward links do inter-organisational relationships create in the resource-seeking-based entrepreneurial internationalisation process? (3) What kind of capability to collaborate forms in the interaction of inter-organisational relationship deployment? The research design is a mixed methods design that consists of quantitative pilot study and qualitative multiple case study of five entrepreneurial life science companies from Finland and Austria. The findings show that innovation and internationalisation processes are tightly interwoven in pre-internationalisation state. The findings also reveal that the more experienced companies are able to take advantage of complexcross-border inter-organisational relationship structures better than the starting companies. However, very minor evidence was found on inward links translating into outward links in the entrepreneurial internationalisation process, despite the expectation to observe more of these links in the data. Combined intangible-tangible resource-seeking was the most preferred to build links between inward–outward internationalisation but also to develop competence to collaborate. By adopting a resource- instead of market-seeking approach, this study illustrated that internationalisation extends to early stages of innovative companies, and that in high-technology companies’ potentially significant cross-border relationships have started to form long before incorporation. Therefore, these observations justified the firmer inclusion of pre-company history in innovative entrepreneurship studies. The study offers a conceptualisation of entrepreneurial internationalisation that is perceived as a process. The main theoretical contributions are in the areas of international entrepreneurship and in the behavioural process studies of entrepreneurial internationalisation and resource-based internationalisation. The inclusion of the innovation-based discussion, namely the innovation process, in the internationalisation process theories has clearly contributed to the understanding of entrepreneurial internationalisation in the context of international entrepreneurship. Innovation development is a central act of entrepreneurial companies, and neglecting innovation process investigation from entrepreneurial internationalisation leaves potentially influential mechanisms unexplored.