Genetic Mechanisms Underlying Autism Spectrum Disorders

Autism is a childhood-onset developmental disorder characterized by deficits in reciprocal social interaction, verbal and non-verbal communication, and dependence on routines and rituals. It belongs to a spectrum of disorders (autism spectrum disorders, ASDs) which share core symptoms but show considerable variation in severity. The whole spectrum affects 0.6-0.7% of children worldwide, inducing a substantial public health burden and causing suffering to the affected families. Despite having a very high heritability, ASDs have shown exceptional genetic heterogeneity, which has complicated the identification of risk variants and left the etiology largely unknown. However, recent studies suggest that rare, family-specific factors contribute significantly to the genetic basis of ASDs. In this study, we investigated the role of DISC1 (Disrupted-in-schizophrenia-1) in ASDs, and identified association with markers and haplotypes previously associated with psychiatric phenotypes. We identified four polymorphic micro-RNA target sites in the 3 UTR of DISC1, and showed that hsa-miR-559 regulates DISC1 expression in vitro in an allele-specific manner. We also analyzed an extended autism pedigree with genealogical roots in Central Finland reaching back to the 17th century. To take advantage of the beneficial characteristics of population isolates to gene mapping and reduced genetic heterogeneity observed in distantly related individuals, we performed a microsatellite-based genome-wide screen for linkage and linkage disequilibrium in this pedigree. We identified a putative autism susceptibility locus on chromosome 19p13.3 and obtained further support for previously reported loci at 1q23 and 15q11-q13. To follow-up these findings, we extended our study sample from the same sub-isolate and initiated a genome-wide analysis of homozygosity and allelic sharing using high-density SNP markers. We identified a small number of haplotypes shared by different subsets of the genealogically connected cases, along with convergent biological pathways from SNP and gene expression data, which highlighted axon guidance molecules in the pathogenesis of ASDs. In conclusion, the results obtained in this thesis show that multiple distinct genetic variants are responsible for the ASD phenotype even within single pedigrees from an isolated population. We suggest that targeted resequencing of the shared haplotypes, linkage regions, and other susceptibility loci is essential to identify the causal variants. We also report a possible micro-RNA mediated regulatory mechanism, which might partially explain the wide-range neurobiological effects of the DISC1 gene.

Managing Project Business Development: an Inter-Organizational and Intra-Organizational Perspective (summary section only)

The driving force behind this study is the gap between the reality of the firms engaged in project business and the available studies covering project management and business process development. Previous studies show that project-based organizations were ‘immature’ in terms of the project-management ‘maturity model’, as few firms were found to be optimizing processes. Even within those, very little attention was paid to combine inter-organizational and intra-organizational perspectives. In this study an effort is made to elaborate some thoughts and views on project management, which interrelate firms’ external and internal activities. In line with the integration, the dissertation uses an approach to the management of project-business interdependencies in the networks of actors, activities and resources. Firstly, the study develops an understanding for inter-organizational perspectives by exploring the complementarities of process activities in the basic development of project business. It presents a framework that is elaborated on the basis of the reciprocal interactions of activities within and outside the organization—thus providing a coherent basis for continuous business-process improvement. In addition, the study presents new tools that can be used to develop project-business processes in each of its functional areas. The research demonstrates how project-business activities can be optimized using the right resources at the right time with the right actors and the right actions. The selected five articles included in this dissertation explain the basic framework for the development of project business. Each paper covers various aspects of inter-organizational and intra-organizational perspectives for project management. The study develops a valuable and procedural model for business-process improvement using the Delphi method that can be used not only in academia but also as a guide for practitioners that takes them through a series of well-defined steps when making informed, consistent and efficient changes to their business processes.

Multidimensionality of Actors in Business Networks: The Influence of Social Action in Pharmacy Networks in Finland

In the markets-as-networks approach business networks are conceived as dynamic actor structures, giving focus to exchange relationships and actors’ capabilities to control and co-ordinate activities and resources. Researchers have shared an understanding that actors’ actions are crucial for the development of business networks and for network dynamics. However, researchers have mainly studied firms as business actors and excluded individuals, although both firms and individuals can be seen as business actors. This focus on firms as business actors has resulted in a paucity of research on human action and the exchange of intangible resources in business networks, e.g. social exchange between individuals in social networks. Consequently, the current conception of business networks fails to appreciate the richness of business actors, the human character of business action and the import of social action in business networks. The central assumption in this study is that business actors are multidimensional and that their specific constitution in any given situation is determined by human interaction in social networks. Multidimensionality is presented as a concept for exploring how business actors act in different situations and how actors simultaneously manage multiple identities: individual, organisational, professional, business and network identities. The study presents a model that describes the multidimensionality of actors in business networks and conceptualises the connection between social exchange and human action in business networks. Empirically the study explores the change that has taken place in pharmaceutical retailing in Finland during recent years. The phenomenon of emerging pharmacy networks is highly contemporary in the Nordic countries, where the traditional license-based pharmacy business is changing. The study analyses the development of two Finnish pharmacy chains, one integrated and one voluntary chain, and the network structures and dynamics in them. Social Network Analysis is applied to explore the social structures within the pharmacy networks. The study shows that emerging pharmacy networks are multifaceted phenomena where political, economic, social, cultural, and historical elements together contribute to the observed changes. Individuals have always been strongly present in the pharmacy business and the development of pharmacy networks provides an interesting example of human actors’ influence in the development of business networks. The dynamics or forces driving the network development can be linked to actors’ own economic and social motives for developing the business. The study highlights the central role of individuals and social networks in the development of the two studied pharmacy networks. The relation between individuals and social networks is reciprocal. The social context of every individual enables multidimensional business actors. The mix of various identities, both individual and collective identities, is an important part of network dynamics. Social networks in pharmacy networks create a platform for exchange and social action, and social networks enable and support business network development.

Moral Education in the Japanese Primary School Curricular Revision at the Turn of the Twenty-first Century: Aiming at a Rich and Beautiful Kokoro

This study examines values education in Japanese schools at the beginning of the millennium. The topic was approached by asking the following three questions concerning the curricular background, the morality conveyed through textbooks and the characterization of moral education from a comparative viewpoint: 1) What role did moral education play in the curriculum revision which was initiated in 1998 and implemented in 2002? 2) What kinds of moral responsibilities and moral autonomy do the moral texts develop? 3) What does Japanese moral education look like in terms of the comparative framework? The research was based on curriculum research. Its primary empirical data consisted of the national curriculum guidelines for primary school, which were taken into use in 2002, and moral texts, Kokoro no nôto, published by the Ministry of Education in the same context. Since moral education was approached in the education reform context, the secondary research material involved some key documents of the revision process from the mid-1990s to 2003. The research material was collected during three fieldwork periods in Japan (in 2002, 2003 and 2005). The text-analysis was conducted as a theory-dependent qualitative content analysis. Japanese moral education was analyzed as a product of its own cultural tradition and societal answer to the current educational challenges. In order to understand better its character, secular moral education was reflected upon from a comparative viewpoint. The theory chosen for the comparative framework, the value realistic theory of education, represented the European rational education tradition as well as the Christian tradition of values education. Moral education, which was the most important school subject at the beginning of modern school, was eliminated from the curriculum for political reasons in a school reform after the Second World War, but has gradually regained a stronger position since then. It was reinforced particularly at the turn of millennium, when a curriculum revision attempted to respond to educational and learning problems by emphasizing qualitative and value aspects. Although the number of moral lessons and their status as a non-official-subject remained unchanged, the Ministry of Education made efforts to improve moral education by new curricular emphases, new teaching material and additional in-service training possibilities for teachers. The content of the moral texts was summarized in terms of moral responsibility in four moral areas (intrapersonal, interpersonal, natural-supranatural and societal) as follows: 1) continuous self-development, 2) caring for others, 3) awe of life and forces beyond human power, and 4) societal contribution. There was a social-societal and emotional emphasis in what was taught. Moral autonomy, which was studied from the perspectives of rational, affective and individuality development, stressed independence in action through self-discipline and responsibility more than rational self-direction. Japanese moral education can be characterized as the education of kokoro (heart) and the development of character, which arises from virtue ethics. It aims to overcome egoistic individualism by reciprocal and interdependent moral responsibility based on responsible interconnectedness.

Designing Creativity Through Clusters - A periodisation of cluster discourse

The thesis focuses on one of the most dominant articulations of the relation between geographical place and development, clusters - internationally competing place-bound economic system of production in related industries. The dominant articulation of cluster discourse represents the subnational region as a system of production, and as a means for competitiveness for Western countries. Its reproduction in theories has become one of the most prolific exports of economic geography to other disciplines and for policymaking. By analysing cluster discourse the thesis traces how the languages and processes of globalization have over time altered the understandings of the relation between geographical place and the economy. It shows how in its latest incarnation of the cluster discourse, the language of mainstream economics is combined with ‘softer’ elements (e.g. community, learning, creativity) in the economic geographic discourse. This is typical for the idea of soft capitalism, wherein it is assumed that economic success emanates from soft characteristics, such as knowledge, learning and creativity, rather than straightforward technological or cost advantages. A reoccurring critique against the dominant understanding of the relationship between competitiveness and regions, as articulated in cluster discourse, has pinpointed the perspective’s inability to reconcile the respective and reciprocal roles of local standard of living with firm competitiveness. The thesis traces how such critique is increasingly appropriated through the fusion of the economic, social and cultural landscape into the language of capitalism. It shows how cluster discourse has appropriated its critique, by focusing on creativity, with its strong associations to arts, individual artists and the cultural sphere in general, while predominantly creating its meaning in relation to competitiveness. The thesis consists of six essays that each outlines the development of the cluster discourse. The essays show how meaning systems and strategies are created, accepted and naturalized in cluster discourse, how this affects individuals, the economic landscape and society at large, as well as showing which understandings are marginalized in the process. The thesis argues that clusters are a) inseparable from ideology and politics and b) they are the result of purposeful social practice. It calls for increased reflexivity within corporate and economic geographic research on clusters, and underlines the importance of placing issues of power at the centre of analysis.

Eläimen tuttuus ja vieraus : Fenomenologisen empatiateorian uudelleentulkinta ja sen sovellus vieraslajisia eläimiä koskevaan kokemukseen

Within the field of philosophy, animals have traditionally been studied from two perspectives: that of self-knowledge and that of ethics. The analysis of the differences between humans and animals has served our desire to understand our own specificity, whereas ethical discussions have ultimately aimed at finding the right way to treat animals. This dissertation proposes a different way of looking at non-human animals: it investigates the question of how non-human animals appear to us humans in our perceptual experience. The analysis focuses on the empathetic, embodied understanding of animals diverse movements and other expressions. The theoretical point of departure for the research is phenomenological philosophy, in particular Maurice Merleau-Ponty s phenomenology of the body. Edmund Husserl s and Edith Stein s analyses of empathy and embodiment are also crucial to the work. In this tradition, empathy means understanding the other s experience through her bodily expressions and seeing the other body as living, as well as motivated and directed towards the surrounding world. The dissertation both explicates and criticizes the earlier phenomenological notions of empathy and human specificity. In order to elucidate the fundamental structures of our experience of non-human animals, it also applies the phenomenological method, which consists of a phenomenological reduction and a free variation of the different aspects of experience. It is shown that our experiences of non-human animals involve a recognition of both similarities and differences. This recognition, however, is not primarily based on intellectual comparisons but is lived as an embodied relationship to another body, and its manifestations vary from one instant to the next. The analysis also reveals that the object of empathy is not the other s experience as such, not even as it is manifested by the other s movements, but rather the other s embodied situation, enriched by elements that remain outside the scope of the other s experience. The dissertation shows that human existence is intertwined with the existence of non-human animals on four levels: those of empathetic sensations, reciprocal communication, experience of the surrounding world and self-definitions. The animals different modes of perception prove to expand our understanding of what is perceivable and how things can be perceived. The presence of non-human animals in our perceptual world is revealed as something that both shows us the limits of our own embodiment and enables us to overcome these limits in empathetic acts. Finally, it is demonstrated that the life of non-human animals is intertwined with ours in a far more complex way than has been presupposed in traditional descriptions of human-animal differences.

Wegener's granulomatosis in Finland in 1981-2000

Objectives: Wegener s granulomatosis (WG) is a vasculitis with a predilection for the airways and kidneys. An increasing incidence and improved prognosis of WG has been shown. The aim of this study was to evaluate the incidence, clinical presentation, diagnostic delay, risk of dialysis-dependent renal insufficiency and mortality of WG in 1981-2000. Patients and methods: Data was retrieved from the Finnish hospital discharge register and hospital case reports. Patients diagnosed with WG in 1981-2000 were included, and their demographic and clinical data recorded. The patients were crossed with the national kidney dialysis register and the national mortality statistics. Results: A total of 492 patients (243 ♂ , 249 ♀) were diagnosed at a mean age of 54 years (SD 18). The incidence increased from 1.9 to 9.3/ million/ year. The median diagnostic delay decreased from 17 to 4 months. Patients presented most often with symptoms of the ear, nose and throat (ENT) (45%), lung (36%), musculoskeletal system (22%) and kidney (11%). Initial lung involvement, constitutional symptoms, high erythrocyte sedimentation rate (ESR) and high ELK scores [(number of simultaneously involved organ groups (ENT, Lung, Kidney)] were associated with a shorter diagnostic delay. Medical treatment of WG patients remained similar in the 1980s and 1990s. Almost 90% of patients received cyclophosphamide (CYC) and more than 90% glucocorticoid medication at some point during the course of the disease. Eighty-four patients (17%) needed dialysis. Initial renal involvement and elevated serum creatinine values were related to an increased risk of dialysis-dependent kidney disease. In two-thirds of the patients, renal impairment was reversible. Dialysis became chronic (>3 months) in 32 patients (6.5%). Nineteen patients (3.9%) received a kidney transplant. Altogether 203 patients (99 men, 104 women) died before 30 June 2005. WG was the underlying cause of death in 37%. The crude one-year and five-year survival rates were 83.3% and 74.2%, respectively. The standardized mortality ratio was 3.43 (95% CI = 2.98 to 3.94). Older age and elevated creatinine level at diagnosis predicted shorter survival. ENT symptoms at presentation and treatment with CYC were associated with better outcome. There was no additional risk associated with male gender or with either of the decades (1981-1990 and 1991-2000) Conclusions: In 1981-2000, the incidence of WG increased ca. 4.5-fold and diagnostic delay decreased to ca. one-fourth, reflecting increased recognition of the disease and improved diagnostic means. WG patients are at great risk of developing dialysis-dependent renal insufficiency and an increased risk of dying. During the study period the treatment of WG did not change markedly, nor did the prognosis improve.

Oral health and kidney disease with emphasis on diabetic nephropathy

Chronic kidney disease (CKD) is a worldwide health problem, with adverse outcomes of cardiovascular disease and premature death. The ageing of populations along with the growing prevalence of chronic diseases such as diabetes and hypertension is leading to worldwide increase in the number of CKD patients. It has become evident that inflammation plays an important role in the pathogenesis of atherosclerosis complications. CKD patients also have an increased risk of atherosclerosis complications (including myocardial infarction, sudden death to cardiac arrhythmia, cerebrovascular accidents, and peripheral vascular disease). In line with this, oral and dental problems can be an important source of systemic inflammation. A decline in oral health may potentially act as an early marker of systemic disease progression. This series of studies examined oral health of CKD patients from predialysis, to dialysis and kidney transplantation in a 10-year follow-up study and in a cross-sectional study of predialysis CKD patients. Patients had clinical and radiographic oral and dental examination, resting and stimulated saliva flow rates were measured, whilst the biochemical and microbiological composition of saliva was analyzed. Lifestyle and oral symptoms were recorded using a questionnaire, and blood parameters were collected from the hospital records. The hypothesis was that the oral health status, symptoms, sensations, salivary flow rates and salivary composition vary in different renal failure stages and depend on the etiology of the kidney disease. No statistically significant difference were seen in the longitudinal study in the clinical parameters. However, some saliva parameters after renal transplantation were significantly improved compared to levels at the predialysis stage. The urea concentration of saliva was high in all stages. The salivary and plasma urea concentrations followed a similar trend, showing the lowest values in kidney transplant patients. Levels of immunoglobulin (Ig) A, G and M all decreased significantly after kidney transplantation. Increased concentrations of IgA, IgG and IgM may reflect disintegration of the oral epithelium and are usually markers of poor general oral condition. In the cross-sectional investigation of predialysis CKD patients we compared oral health findings of diabetic nephropathy patients to those with other kidney disease than diabetes. The results showed eg. more dental caries and lower stimulated salivary flow rates in the diabetic patients. HbA1C values of the diabetic patients were significantly higher than those in the other kidney disease group. A statistically significant difference was observed in the number of drugs used daily in the diabetic nephropathy group than in the other kidney disease group. In the logistic regression analyses, age was the principal explanatory factor for high salivary total protein concentration, and for low unstimulated salivary flow. Poor dental health, severity of periodontal disease seemed to be an explanatory factor for high salivary albumin concentrations. Salivary urea levels were significantly linked with diabetic nephropathy and with serum urea concentrations. Contrary to our expectation, however, diabetic nephropathy did not seem to affect periodontal health more severely than the other kidney diseases. Although diabetes is known to associate with xerostomia and other oral symptoms, it did not seem to increase the prevalence of oral discomfort. In summary, this series of studies has provided new information regarding the oral health of CKD patients. As expected, the commencement of renal disease reflects in oral symptoms and signs. Diabetic nephropathy, in particular, appears to impart a requirement for special attention in the oral health care of patients suffering from this disease.