La música orquestal peruana de 1945 a 2005 : Identidades en la diversidad

Peruvian orchestral music 1945–2005. Identities in diversity Peruvian music for orchestra has not been studied as a whole before, and is hardly known by Peruvian musicians and public. The aim of the thesis is to give a panoramic view of Peruvian orchestral music after 1945, study the particular historical context in which these works were created and how they reflect the search for a musical identity of its own, be it individual, local, national or Latin American. Identity is a construction that changes permanently, and individuals can share many identities at the same time. This is a central issue in multicultural societies as the Peruvian, and music is an important mean for constructing cultural identity. The hypothesis of this research is that orchestral work is a medium for Peruvian composers to express their relationship with traditional and popular musics of the country in different ways, from quotation of melodies to a more abstract appropiation of concepts or suggestive title references. Representative works by selected composers, of different techniques, styles or special reception are chosen and analyzed. Research methodology includes analysis of works with various methods according to their stylistic and technical features, in order to find the particular ways in which composers have approached or expressed diverse identities. The investigation shows that Peruvian orchestral music includes works in the main stylistic trends and using the main compositional techniques of the modernist and postmodern periods. It also shows that the construction and expression of particular identities through the study and use of other Peruvian musical traditions is a constant interest shared by composers of different age and esthetic. In a multicultural society as the Peruvian, characterized by its diversity, different forms of transcultural composition are an important mean of dealing with identity issues in music. This thesis also includes for the first time a list of all orchestral works composed in the country or by Peruvian composers in the period, their composers and genres. KEYWORDS: Peruvian music, contemporary music for orchestra, identity

Vuorovaikutus ääniterapiassa : Keskustelunanalyyttinen tutkimus harjoittelun rakenteesta, terapeutin antamasta palautteesta ja oppimisesta

This conversation analytical study analyses the interactional practices adopted by speech therapists and their clients during their training in voice therapy. This study also describes how learning takes place during the therapy process. In contrast to traditional voice therapy studies, change is examined here by using qualitative research methodology, namely conversation analysis. This study describes the structures of interaction in voice therapy, shows how the shortcomings in the client s performance are evaluated and corrected and finally, how the voice training sequence and the participation changes during therapy. The database consists of 51 videotaped voice therapy sessions from six clients with voice disorders. The analytic focus is on the practices in one voice training exercise of the trilled /r/. All the sequences of this exercise (in total 36) and all adjacency pairs within (N = 627) were transcribed and analysed in detail. This study shows that voice training consists of successive model imitation adjacency pairs. This adjacency pair works as a resource in voice training. Furthermore, the use of this particular adjacency pair is an institutional practice in all therapies in this study. The structure of interaction in voice training sequences resembles the practices found in aphasia therapy and in speech therapy of children, as well as the practices of educational and counselling interaction and physiotherapy. More than half of the adjacency pairs were expanded to three (or more) part structures as client s responses were typically followed by therapist s feedback. With their feedback turns, therapists: 1) maintain training practice, 2) evaluate the problem of client s performance, 3) deliver information, 4) activate the client to observe the performance and 5) assist her in correcting the performance. This study describes the four different ways that therapists help their clients to improve the performance after encountering a problem. The longitudinal data shows that learning in therapy is manifested in the changing participation. As clients learn to identify their voice features, they can participate in evaluating or correcting their performances by themselves. This study describes the recurrent professional practices of voice therapists and shows how the institutional commitments of voice therapy are managed in and through talk and interaction. The study also provides detailed description of the management of help in voice training. By describing the interaction in training sequences, this study expands the conception of voice rehabilitation and how it can be researched. The results demonstrate that the learning process and therapy outcomes can be assessed by analysing interaction in therapy. Moreover, this analysis lays the foundation for a novel understanding of the practices in speech therapy and for the development of speech therapy theory. By revealing the activities of interaction, it also makes it possible to discuss them explicitly with speech therapy students. Key words: voice therapy, conversation analysis, institutional interaction, learning, change in participation, feedback, evaluation, error correction, self-repair

Oppimisen kohteen ja oppijan vastavuoroinen kehitys : Teleyrityksen asiakaspalvelun työyhteisöjen oppimiskäytäntöjen uudistaminen osana teknologis-taloudellista kumousta

Reciprocal development of the object and subject of learning. The renewal of the learning practices of front-line communities in a telecommunications company as part of the techno-economical paradigm change. Current changes in production have been seen as an indication of a shift from the techno-economical paradigm of a mass-production era to a new paradigm of the information and communication technological era. The rise of knowledge management in the late 1990s can be seen as one aspect of this paradigm shift, as knowledge creation and customer responsiveness were recognized as the prime factors in business competition. However, paradoxical conceptions concerning learning and agency have been presented in the discussion of knowledge management. One prevalent notion in the literature is that learning is based on individuals’ voluntary actions and this has now become incompatible with the growing interest in knowledge-management systems. Furthermore, commonly held view of learning as a general process that is independent of the object of learning contradicts the observation that the current need for new knowledge and new competences are caused by ongoing techno-economic changes. Even though the current view acknowledges that individuals and communities have key roles in knowledge creation, this conception defies the idea of the individuals’ and communities’ agency in developing the practices through which they learn. This research therefore presents a new theoretical interpretation of learning and agency based on Cultural-Historical Activity Theory. This approach overcomes the paradoxes in knowledge-management theory and offers means for understanding and analyzing changes in the ways of learning within work communities. This research is also an evaluation of the Competence-Laboratory method which was developed as part of the study as a special application of Developmental Work Research methodology. The research data comprises the videotaped competence-laboratory processes of four front-line work communities in a telecommunications company. The findings reported in the five articles included in this thesis are based on the analyses of this data. The new theoretical interpretation offered here is based on the assessment that the findings reported in the articles represent one of the front lines of the ongoing historical transformation of work-related learning since the research site represents one of the key industries of the new “knowledge society”. The research can be characterized as elaboration of a hypothesis concerning the development of work related learning. According to the new theoretical interpretation, the object of activity is also the object of distributed learning in work communities. The historical socialization of production has increased the number of actors involved in an activity, which has also increased the number of mutual interdependencies as well as the need for communication. Learning practices and organizational systems of learning are historically developed forms of distributed learning mediated by specific forms of division of labor, specific tools, and specific rules. However, the learning practices of the mass production era become increasingly inadequate to accommodate the conditions in the new economy. This was manifested in the front-line work communities in the research site as an aggravating contradiction between the new objects of learning and the prevailing learning practices. The constituent element of this new theoretical interpretation is the idea of a work community’s learning as part of its collaborative mastery of the developing business activity. The development of the business activity is at the same time a practical and an epistemic object for the community. This kind of changing object cannot be mastered by using learning practices designed for the stable conditions of mass production, because learning has to change along the changes in business. According to the model introduced in this thesis, the transformation of learning proceeds through specific stages: predefined learning tasks are first transformed into learning through re-conceptualizing the object of the activity and of the joint learning and then, as the new object becomes stabilized, into the creation of new kinds of learning practices to master the re-defined object of the activity. This transformation of the form of learning is realized through a stepwise expansion of the work community’s agency. To summarize, the conceptual model developed in this study sets the tool-mediated co-development of the subject and the object of learning as the theoretical starting point for developing new, second-generation knowledge management methods. Key words: knowledge management, learning practice, organizational system of learning, agency

Kehittämisen kompastuskivet - myytit kehittämishankkeen keskusteluissa

I studied discussions during development project. Aim of the study was to analyse, what way workers represented their work: how normalized way of interpretation myths appeared in discourse and what consequences these utterances caused to drift of discussion. Change laboratory, which is a development method, is based to developmental work research methodology. Development is designed to be successful by learning activity and learning acts. Preventing factors of learning have been studied widely. Research has leaned to concept of resistance to change. Phenomenon of learning has been interpreted to be successful only if everybody has an agreement about the situation. There is also a new kind of concept of resistance. Resistance can be seen as a part of learning, normal processing of the learning activity. Another preventing factor can be seen as disorders of discourse, which are verbal ways of telling something that aren t real. Theoretically I consider these verbal ways as myth interpretations, which can be used as argumentative tools. I used analysis of discourse as an analytical method. Results of analysis revealed four different myth interpretations in workers discussions. Character of work was been described with myths unforeseen situations and disturbances are normal . Work was also described to be functional with myths system works and workers cause disturbances . Change laboratory discussions can be described as different social languages, which caused diverse perspectives to workers and researchers representations. Social languages also affected the way people analysed disturbances and system. Critical phase of change laboratory method seems to be analysis of disturbances and planning new mode of action. Myth utterances were used to reject ways of developing, analysis of system level and need of development. Myth utterances worked three different ways: ineffective, active or passive.

Matkalla suomalaiseksi ja hoiva-alan ammattilaiseksi? : Venäläis- ja virolaistaustaisten naisten ja suomalaisuuden kohtaamiset kuulumista rakentamassa

The research examines the process by which a sense of belonging to Finnish society is constructed among women of Russian and Estonian background who are multiply marginalised in Finnish society. It does so by analysing the encounters between their nationality and 'being Finnis'. Attention is focused on the question of what kind of "journey" they take after moving to Finland, how a sense of belonging is constructed especially along the paths followed in education and at work, and what kind of agency is available to them. The thesis is connected with post-colonial research and also draws from studies on citizenship and nationality as well as the social structures of interaction, when analysing careers. As the educational system forms the most central context of the research, the work is also focused on educational sociology. The research methodology includes life history and a narrative approach. The raw data is from thematic interviews concerning the life experiences of women of immigrant backgrounds. They were studying in Finland to be practical nurses or to complete Bachelor of Social Service degree. According to the study, the women had been encountered as alien, strange, and carrying a shade of "otherness". The experience of inclusion in Finnish communities and society turned out to be conditional, an inclusion based on the notion of a citizen worker, which is defined by national needs. The person from abroad is placed in the position of someone who fills gaps in the services of the welfare state. The choice of education in the care sector and the overall necessity of obtaining Finnish education turned out to be socially directed. Gendered structures of education and working life were found to act as a frame in which the decisions of the immigrant women were made. Although national education policy emphasis as an orientation to global labour markets, the immigrant student is placed above all in the position of an object to be made suitable for the Finnish labour market. Citizenship, a goal of education, requires consent to being "socialised" into Finnish society as well as learning to be Finnish. One s only option to negotiate appearing suitable as a member is to construct oneself into someone who adopts Finnish and Western cultural values, values which favour individuality. However, Finnish education is a resource to Finnishness. Finnish education enables a sense of being Finnish, and empowers the job applicant for example, and in addition to providing cultural, human and social capital strengthen inclusion as well. The study confirms the view that the encounter of an immigrant is still characterised by its colonial nature. It shows that encounters with Finns and Finnish society place the person of immigrant background, even one receiving a Finnish education, in the position of "the other". The journey as an immigrant continues. The immigrant has access only to certain predefined subject positions, which limits agency. When categorised as an immigrant, one becomes a per-son who is different and "other", while the sense of belonging as a member of Finnish society without conditions appears to be somewhat unreachable. Yet, new arrivals are capable of acting change. An immigrant woman can challenge the positions offered to her and present herself as strong. Her life story has often included struggle, and she has the fortitude strength to change her circumstances. Key words: life story, post-colonial encounter, nationality, citizenship, the career of immi-grant, position, agency

Digestion capasity, nutrient digestibilities and physico-chemical conditions in the intestine influenced by the age of growing turkeys

Six experiments have been conducted to examine digestibility and feeding value of domestic Finnish fibre-rich cereals (barley and oats as compared to maize and wheat) and protein sources (rapeseed meal and cake, peas, faba beans, lupin seeds) for growing turkeys and to investigate effects of age of the birds (from 3 to 12 weeks of age) on digestion process and estimated nutrient digestibility and energy values. Besides, an objective of the study was to test applications of digestibility research methodology for turkeys. Total tract digestibility and apparent metabolizable energy (AME) was assayed in experimental cages using excreta collection, and a slaughter method was applied to sample small intestinal digesta for determination of apparent ileal crude protein digestibility (AICPD), jejuno-duodenal digesta viscosity and caecal volatile fatty acid (VFA) concentration. Digesta viscosity decreased and caecal VFA production increased with age of growing turkeys. Digesta retention times in the small intestine were generally longer in the older birds than in the younger ones. Crude fat digestibility and AME increased with age of growing turkeys, especially with viscous diets. AICPD seemed to decrease with age in most cases. Supplementation with β-gucanase-xylanase decreased viscosity, improved crude fat digestibility and metabolizable energy value and increased VFA production especially in barley-fed turkeys and especially in the young birds. Poor protein digestibility and low energy value of rapeseed meal and rapeseed cake decreased their feeding value for turkeys. In addition, a typical goitrogenic effect of rapeseed feeding was detected. Use of legume seeds as feed for growing turkeys is limited mostly by the low energy value in lupin seeds and the low ileal protein and amino acid digestibility in faba beans. Digestibility of fibre-rich protein sources was not improved with age of the turkeys. Euthanizing the turkeys for AICPD determination by carbon dioxide and bleeding led to lower digestibility values than mechanical stunning and cervical dislocation, suggesting inferiority of carbon dioxide stunning in experimental use. Comparison of AICPD and AME results obtained using different markers showed that considerable differences may occur, especially on total tract level, when acid-insoluble ash gave considerably lower AME values than titanium dioxide and chromic oxide.

Adipose tissue inflammation, liver fat and insulin resistance in humans

BACKGROUND: Obesity is closely associated with insulin resistance, which is a pathophysiologic condition contributing to the important co-morbidities of obesity, such as the metabolic syndrome and type 2 diabetes mellitus. In obese subjects, adipose tissue is characterized by inflammation (macrophage infiltration, increased expression insulin resistance genes and decreased expression of insulin sensitivity genes). Increased liver fat, without excessive alcohol consumption, is defined as non-alcoholic fatty liver disease (NAFLD) and also associated with obesity and insulin resistance. It is unknown whether and how insulin resistance is associated with altered expression of adipocytokines (adipose tissue-derived signaling molecules), and whether adipose tissue inflammation and NAFLD coexist independent of obesity. Genetic factors could explain variation in liver fat independent of obesity but the heritability of NAFLD is unknown. AIMS: To determine whether acute regulation of adipocytokine expression by insulin in adipose tissue is altered in obesity. To investigate the relationship between adipose tissue inflammation and liver fat content independent of obesity. To assess the heritability of serum alanine aminotransferase (ALT) activity, a surrogate marker of liver fat. METHODS: 55 healthy normal-weight and obese volunteers were recruited. Subcutaneous adipose tissue biopsies were obtained for measurement of gene expression before and during 6 hours of euglycemic hyperinsulinemia. Liver fat content was measured by proton magnetic resonance spectroscopy, and adipose tissue inflammation was assessed by gene expression, immunohistochemistry and lipidomics analysis. Genetic factors contributing to serum ALT activity were determined in 313 twins by statistical heritability modeling. RESULTS: During insulin infusion the expression of insulin sensitivity genes remains unchanged, while the expression of insulin resistance genes increases in obese/insulin-resistant subjects compared to insulin-sensitive subjects. Adipose tissue inflammation is associated with liver fat content independent of obesity. Adipose tissue of subjects with high liver fat content is characterized infiltrated macrophages and increased expression of inflammatory genes, as well as by increased concentrations of ceramides compared to equally obese subjects with normal liver fat. A significant heritability for serum ALT activity was verified. CONCLUSIONS: Effects of insulin infusion on adipose tissue gene expression in obese/insulin-resistant subjects are not only characterized by hyporesponse of insulin sensitivity genes but also by hyperresponse of insulin resistance and inflammatory genes. This suggests that in obesity, the impaired insulin action contributes or self-perpetuates alterations in adipocytokine expression in adipose tissue. Adipose tissue inflammation is increased in subjects with high liver fat compared to equally obese subjects with normal liver fat content. Concentrations of ceramides, the putative mediators of insulin resistance, are increased in adipose tissue in subjects with high liver fat. Genetic factors contribute significantly to variation in serum ALT activity, a surrogate marker of liver fat. These data imply that adipose tissue inflammation and increased liver fat content are closely interrelated, and determine insulin resistance even independent of obesity.

Social Responsibility in Developing New Biotechnology : Interpretations of Responsibility in the Governance of Finnish Biotechnology

The object of the dissertation is to analyse the concept of social responsibility in relation to research and development of new biotechnology. This is done by examining the relevant actors – researchers, administrators, decision-makers, experts, industry, and the public – involved in the Finnish governance of biotechnology through their roles and responsibilities. Existing practises of responsibility in biotechnology governance, as well as the discourses of responsibility – the actors’ conceptions of their own and others responsibilities – are analysed. Three types of responsibility that the actors have assumed are formulated, and the implications of these conceptions to the governance of new biotechnology are analysed. From these different types of responsibility adopted and used by the actors, theoretical models called responsibility chains are constructed. The notion of responsibility is under-theorised in sociology and this research is an attempt to create a mid-range theory of responsibility in the context of biotechnology governance. The research aims to increase understanding of the governance system from a holistic viewpoint by contributing to academic debates on science and technology policy, public understanding of science, commercialisation of research, and corporate social responsibility. With a thorough analysis of the concept of responsibility that is derived from empirical data, the research brings new perspectives into these debates by challenging many normative ideas embedded in discourses. For example, multiple roles of the public are analysed to highlight the problems of consumerism and citizen participation in practise, as well as in relation to different policy strategies. The research examines also the contradictory responsibilities faced by biotechnology researchers, who balance between academic autonomy, commercialisation of research, and reflecting social consequences of their work. Industries responsibilities are also examined from the viewpoint of biotechnology. The research methodology addresses the contradictions between empirical findings, theories of biotechnology governance, and policies in a novel way, as the study concentrates on several actors and investigates both the discourses and the practises of the actors. Thus, the qualitative method of analysis is a combination of discourse and content analysis. The empirical material is comprised of 29 personal interviews as well as documents by Finnish and multinational organizations on biotechnology governance.

Asiakassuunnitelma asiakaslähtöistä auttamista tavoitteellistamassa : Kohteen rakentumisen moniääninen menetelmä

The research focuses on client plan in the field of health care and social work on families with children. The purpose of the plan is to create objectives for helping the client and to assist in coordinating the ever-increasing multi-professional work. In general, the plan is understood in terms of assignments and as a contract specifying what to do in client cases. Taking this into consideration, the plan is outsourced into a written document. Instead of understanding the plan as a tool that stabilizes the objectives of action, documents it and facilitates evaluation, the client plan is conceptualized in this study as a practice. This kind of practice mediates client work as being itself also a process of action that focuses on an object whose gradual emergence and definition is the central question in multi-professional collaboration with a client. The plan is examined empirically in a non-stabilized state which leads to the research methodology being based on the dynamics between stabilization and emerging, non-stabilized entities the co-creation and formulation of practice and context. The theoretical approach of the research is the micro analytic approach of activity theory (Engeström R. 1999b). Grounding on this, the research develops a method of qualitative analysis which follows an emerging object with multiple voices. The research data is composed of the videotaped sessions from client meetings with three families, the interviews with the client and the workers as well as client documents that are used to follow up on client processes for at least one year. The research questions are as follows: 1) How is the client plan constructed between the client and different professional agents? 2) How are meanings constructed in a client-centred plan? 3) What are the elements of client-employee relationships that support the co-configuration necessitated by the changes in the client s everyday life? The study shows that the setting of objectives were limited by the palette of institutional services, which caused that the clients interpretations and acts of giving meaning to the kinds of help that was required were left out of the plan. Conceptually, the distinctions between client-centred and client-specific ways of working as well as an action-based working method are addressed. Central to this action-based approach is construing the everyday life of the client, recognizing different meanings and analyzing them together with the client as well as focusing attention on developing the prerequisites for social agency of the clients. The research portrays the elements for creating an action-based client plan. Key words: client plan, user perspective, multi-voiced meaning, multi-professional social work with children and families, agency

Perspectives on knowledge creating inquiry in higher education

Higher education is faced with the challenge of strengthening students competencies for the constantly evolving technology-mediated practices of knowledge work. The knowledge creation approach to learning (Paavola et al., 2004; Hakkarainen et al., 2004) provides a theoretical tool to address learning and teaching organized around complex problems and the development of shared knowledge objects, such as reports, products, and new practices. As in professional work practices, it appears necessary to design sufficient open-endedness and complexity for students teamwork in order to generate unpredictable and both practically and epistemologically challenging situations. The studies of the thesis examine what kinds of practices are observed when student teams engage in knowledge creating inquiry processes, how the students themselves perceive the process, and how to facilitate inquiry with technology-mediation, tutoring, and pedagogical models. Overall, 20 student teams collaboration processes and productions were investigated in detail. This collaboration took place in teams or small groups of 3-6 students from multiple domain backgrounds. Two pedagogical models were employed to provide heuristic guidance for the inquiry processes: the progressive inquiry model and the distributed project model. Design-based research methodology was employed in combination with case study as the research design. Database materials from the courses virtual learning environment constituted the main body of data, with additional data from students self-reflections and student and teacher interviews. Study I examined the role of technology mediation and tutoring in directing students knowledge production in a progressive inquiry process. The research investigated how the scale of scaffolding related to the nature of knowledge produced and the deepening of the question explanation process. In Study II, the metaskills of knowledge-creating inquiry were explored as a challenge for higher education: metaskills refers to the individual, collective, and object-centered aspects of monitoring collaborative inquiry. Study III examined the design of two courses and how the elaboration of shared objects unfolded based on the two pedagogical models. Study IV examined how the arranged concept-development project for external customers promoted practices of distributed, partially virtual, project work, and how the students coped with the knowledge creation challenge. Overall, important indicators of knowledge creating inquiry were the following: new versions of knowledge objects and artifacts demonstrated a deepening inquiry process; and the various productions were co-created through iterations of negotiations, drafting, and versioning by the team members. Students faced challenges of establishing a collective commitment, devising practices to co-author and advance their reports, dealing with confusion, and managing culturally diverse teams. The progressive inquiry model, together with tutoring and technology, facilitated asking questions, generating explanations, and refocusing lines of inquiry. The involvement of the customers was observed to provide a strong motivation for the teams. On the evidence, providing team-specific guidance, exposing students to models of scientific argumentation and expert work practices, and furnishing templates for the intended products appear to be fruitful ways to enhance inquiry processes. At the institutional level, educators do well to explore ways of developing collaboration with external customers, public organizations or companies, and between educational units in order to enhance educational practices of knowledge creating inquiry.

Exploring Marketing in Micro Firms

Purpose - The purpose of the paper is to explore the practice of marketing in micro firms. Which are the challenges micro firms encounter and how do they handle them? Methodology - The research methodology is based on the theory-in-use approach (Zaltman, Heffring & LeMasters 1982) in order to inductively explore the practice of marketing in micro firms. The empirical findings rest on ten case studies, where data has been generated through repeated interactions with each case. Findings - The empirical findings show that micro firms handle their marketing challenges in a distinctive manner, by creatively using available resources and network relations. Marketing in micro firms is largely about a long-term, gradual development of a position on the market. This process we label germinal marketing. Two key dimensions of germinal marketing were identified: “earning your position” and “being your brand”. Research limitations and implications - The findings rest on an explorative study consisting of ten cases and the general applicability of the results need to be validated by further studies. These cases are however sufficient to illuminate the need for further research into the area. Value of the paper - The value of the paper is twofold. First, it expands the theory-in-use approach, and presents a research method for successful inductive empirical studies of small firm phenomena. Secondly, the paper widens our understanding of the marketing reality and practice of micro firms, identifying new dimensions of marketing and revealing the strategic implications of ordinary business activities.

Towards Optimal Testing of Auditory Memory : Methodological development of recording of the mismatch negativity (MMN) of the auditory event-related potential (ERP)

The overlapping sound pressure waves that enter our brain via the ears and auditory nerves must be organized into a coherent percept. Modelling the regularities of the auditory environment and detecting unexpected changes in these regularities, even in the absence of attention, is a necessary prerequisite for orientating towards significant information as well as speech perception and communication, for instance. The processing of auditory information, in particular the detection of changes in the regularities of the auditory input, gives rise to neural activity in the brain that is seen as a mismatch negativity (MMN) response of the event-related potential (ERP) recorded by electroencephalography (EEG). --- As the recording of MMN requires neither a subject s behavioural response nor attention towards the sounds, it can be done even with subjects with problems in communicating or difficulties in performing a discrimination task, for example, from aphasic and comatose patients, newborns, and even fetuses. Thus with MMN one can follow the evolution of central auditory processing from the very early, often critical stages of development, and also in subjects who cannot be examined with the more traditional behavioural measures of auditory discrimination. Indeed, recent studies show that central auditory processing, as indicated by MMN, is affected in different clinical populations, such as schizophrenics, as well as during normal aging and abnormal childhood development. Moreover, the processing of auditory information can be selectively impaired for certain auditory attributes (e.g., sound duration, frequency) and can also depend on the context of the sound changes (e.g., speech or non-speech). Although its advantages over behavioral measures are undeniable, a major obstacle to the larger-scale routine use of the MMN method, especially in clinical settings, is the relatively long duration of its measurement. Typically, approximately 15 minutes of recording time is needed for measuring the MMN for a single auditory attribute. Recording a complete central auditory processing profile consisting of several auditory attributes would thus require from one hour to several hours. In this research, I have contributed to the development of new fast multi-attribute MMN recording paradigms in which several types and magnitudes of sound changes are presented in both speech and non-speech contexts in order to obtain a comprehensive profile of auditory sensory memory and discrimination accuracy in a short measurement time (altogether approximately 15 min for 5 auditory attributes). The speed of the paradigms makes them highly attractive for clinical research, their reliability brings fidelity to longitudinal studies, and the language context is especially suitable for studies on language impairments such as dyslexia and aphasia. In addition I have presented an even more ecological paradigm, and more importantly, an interesting result in view of the theory of MMN where the MMN responses are recorded entirely without a repetitive standard tone. All in all, these paradigms contribute to the development of the theory of auditory perception, and increase the feasibility of MMN recordings in both basic and clinical research. Moreover, they have already proven useful in studying for instance dyslexia, Asperger syndrome and schizophrenia.

Nikotiinireseptoreiden kautta vaikuttavat lääkeaineet nikotiiniriippuvuuden ja neurologisten sairauksien hoidossa

Neuronaaliset nikotiinireseptorit liittyvät tupakkariippuvuuden lisäksi moniin neurologisiin sairauksiin, kuten Alzheimerin tautiin, skitsofreniaan, masennukseen ja tarkkaavaisuus- ja ylivilkkaushäiriöön. Nikotiinireseptorien stimulaation on tutkimuksissa havaittu parantavan kognitiota. Useat lääkeyritykset tutkivat nikotiinireseptoriagonisteja ja -antagonisteja eri neurologisten sairauksien hoidossa. Ongelmana nikotiinireseptori-agonisteja käytettäessä on reseptorissa tapahtuva desensitisaatio. Tällöin reseptori sulkeutuu, eikä aktivoidu vaikka agonistia olisi tarjolla tai sitoutuneena reseptoriin. Varsinkin alfa7-reseptori desensitoituu hyvin nopeasti agonistialtistuksen seurauksena. Reseptorien desensitoituminen voi kliinisessä käytössä aiheuttaa lääkeaineen tehon menetyksen. Perinteisen agonistin sitoutumiskohdan lisäksi nikotiinireseptorissa sijaitsee myös muita sitoutumiskohtia, joita kutsutaan allosteerisiksi sitoutumispaikoiksi. Tutkimuksissa on havaittu, että eräät allosteerisesti sitoutuvat aineet, kuten PNU-120596, voivat vahvistaa agonistin aikaansaamaa vastetta ja/tai estää reseptorin desensitoitumista. Näitä aineita kutsutaan positiivisiksi allosteerisiksi modulaattoreiksi ja niiden ajatellaan olevan vaihtoehto desensitoitumisen aiheuttamaan tehon menetyksen ongelmaan. Nikotiinireseptorien positiivisten allosteeristen modulaattorien tarkkaa vaikutusta ja sitoutumiskohtaa reseptoriin ei vielä tarkkaan tiedetä. Tutkimuksen aiheena oli karakterisoida positiivisten allosteeristen modulaattoreiden vaikutuksia alfa7-nikotiinireseptoriin. Tutkimuksessa tarkoituksena oli käyttää hyväksi laboratoriossa aiemmin tehtyä havaintoa, jonka mukaan alfa7-nikotiinireseptorin transmembraaniosan aminohappoon tehdyn mutaation L247T seurauksena positiiviset allosteeriset modulaattorit muuttuvat agonisteiksi. Haluttiin selvittää, kuinka agonistin sitoutumiskohtaan kohdennettua mutageneesiä käyttäen tehty mutaatio W149M tai W149F vaikuttavat PNU-120596:n kykyyn toimia agonistina alfa7L247T reseptoriin. Asetyylikoliini toimi konventionaalisen agonistin mallina tutkimuksessa. Tutkimuksen toinen tavoite oli tehdä mutaatio M253Lalfa7-reseptorin transmembraaniosaan. Mutaation on todettu estävän allosteeristen potentiaattoreiden kykyä voimistaa agonistin aikaansaamaa vastetta. Tarkoitus oli tutkia millaisia vaikutuksia M253L-mutaatiolla on allosteerisen potentiaattorin kykyyn toimia agonistina L247T-mutaation sisältävään reseptoriin. Mutatoidun reseptorin mRNA mikroinjektoitiin oosyyttiin ja elektrofysiologian avulla tutkittiin ilmennettyjen reseptorien toimintaa käyttäen kahden elektrodin jännitelukitus -menetelmää. Kaikki suunnitellut mutaatiot saatiin tehtyä onnistuneesti alfa7- ja alfa7L247T-reseptoreihin. Ortosteerisen sitoutumiskohdan mutaatio villin tyypin Į7-reseptorissa vaikutti hyvin voimakkaasti joko asetyylikoliinin sitoutumiseen reseptoriin tai reseptorin toimintaan, sillä asetyylikoliinilla ei reseptorista saatu mitattua vasteita. Myöskään PNU-120596 yksinään ei saanut aikaan vasteita alfa7W149M-reseptorissa. Kaksoismutatoidussa alfa7W149M/L247T-reseptorissa puolestaan havaittiin, että asetyylikoliinin annos-vaste -kuvaaja siirtyi huomattavasti enemmän oikealle kuin PNU-120596:n, kun verrattiin annos-vaste –kuvaajia alfa7L247T ja alfa7W149M/L247T–reseptoreiden välillä. Transmembraaniosan mutaatio M253L ei vaikuttanut PNU-120596:n kykyyn toimia agonistina alfa7L247T-reseptoriin, eikä sillä ollut vaikutusta asetyylikoliinin annosvaste-kuvaajiin. Tutkimus tukee aiempia havaintoja siitä, että positiivisten allosteeristen modulaattoreiden sitoutumiskohta nikotiinireseptorissa sijaitsisi transmembraaniosassa. M253L-mutaation osalta tulokset ovat hieman ristiriidassa aiempien tulosten kanssa. L247T-mutaatio vaikuttaa hyvin voimakkaasti nikotiinireseptorin toimintaan sekä sijaitsee aminohapon M253 läheisyydessä. On mahdollista, että se peittää M253L-mutaation vaikutuksen. Toisaalta voi olla, että M253 on aminohappo, joka vaikuttaa vain reseptorivasteiden voimistumiseen eikä allosteeristen potentiaattoreiden sitoutumiseen.