Kaukana Vatikaanista – Katolinen kirkko Suomessa 1989–1998

Tutkimuksessa tarkastellaan katolista kirkkoa Suomessa vuosina 1989-1998. Tutkimus alkaa paavi Johannes Paavali II:n Pohjoismaiden-vierailusta kesällä 1989 ja päättyy Suomen katolisen kirkon pitkäaikaisen piispan Paul Verschurenin eroon tehtävästään vuonna 1998. Tutkimuksen kolme pääkysymystä ovat kirkon hallinnon ja rakenteen muutokset, katolisen kirkon identiteetti Suomessa ja ekumeeniset suhteet erityisesti Suomen evankelis-luterilaiseen kirkkoon. Lähteinä olen käyttänyt Helsingin katolisen hiippakunnan lehteä Fidesiä, muuta lehdistömateriaalia ja haastatteluja. Paavin-vierailulla oli merkittävät seuraukset niin Suomen katoliselle paikalliskirkolle kuin luterilaiselle kirkollekin. Vierailun myötä pieni katolinen vähemmistö tuli tunnetummaksi Suomessa. Vierailu muutti Vatikaanin käsityksiä Suomesta, millä oli kauaskantoiset vaikutukset kirkkojen ekumeenisiin suhteisiin. Pyhän Birgitan 600-vuotismuistojuhlien yhteydessä Suomen ja Ruotsin luterilaisten ja katolisten piispojen yhdessä paavin kanssa toimittama jumalanpalvelus, paavin ekumeniaa käsitellyt kiertokirje Ut unum sint ja Pohjoismaiden luterilaisten ja katolisten kirkkojen aloittamat neuvottelut kirkko- ja virkakäsityksistä olivat 1990-luvun merkittäviä ekumeenisia hetkiä, joihin paavin vierailulla oli vaikutusta. Kirkon hallinto ja rakenne olivat monelta osin jo vakiintuneet 1990-luvulle tultaessa, mutta muutamia merkittäviä muutoksia tapahtui. Kirkon jäsenmäärä kasvoi lähinnä maahanmuuton johdosta koko tutkitun ajanjakson ajan. Jäsenmäärän kasvu synnytti uusia seurakuntia ja kappeleita hiippakuntaan. Halu kappelin rakentamiseen ei aina kuitenkaan lähtenyt hiippakunnan tarpeesta vaan yksittäisten ihmisten tai liikkeiden. Esimerkiksi neokatekumenaalinen maallikkoliike rakennutti 1990-luvun alussa Ouluun kappelin, mutta hiippakunta ei ollut täysin hankkeen takana. Ongelmat kappeleiden rakentamisessa ja monet muutkin haasteet, johtuivat pitkälti kirkon taloudellisesta tilanteesta. Kirkolla ei ollut verotusoikeutta eikä jäsenten maksamat avustukset riittäneet kattamaan kuluja. Katolinen kirkko yritti 1990-luvun alkupuolella miettiä keinoja taloudellisen tilanteen parantamiseksi. Piispa Verschuren piti monessa yhteydessä myös esillä vähemmistöjen juridista asemaa koskevia ongelmia ja uskontolainsäädännön epäkohtia. Kolmas merkittävä rakenteellinen muutos kirkossa oli papiston puolalaistuminen. Katolisen kirkon identiteettiä Suomessa on vaikea erottaa omaksi kokonaisuudekseen koskien vain 1990-lukua. Olenkin pyrkinyt tarkastelemaan identiteettiä niistä haasteista käsin, joita kirkko 1990-luvulla kohtasi. Suomessa käytiin keskustelua muun muassa eronneiden tilanteesta ja naisen asemasta. Kirkko kannusti jäseniään keskusteluun ja myös piispa ja papisto olivat usein toivottujen uudistusten kannalla. Suomessa katolinen kirkko eli pienenä vähemmistönä, joten monet kirkon oppiin liittyvät kysymykset olivat haasteellisia. Esimerkiksi perhe- ja seksuaalieettiset kysymykset ja naisen asema olivat vaikeita tilanteessa, jossa suurin osa katolilaisista oli naimisissa ei-katolilaisen kanssa. Vaikka Suomessakin toivottiin muutoksia, joihinkin kirkon oppiin liittyviin kysymyksiin, Keski-Euroopasta alkanut protestiliikehdintä kirkon uudistumiseksi ei näkynyt täällä voimakkaasti. Suomessa kirkon tilanne oli hyvin erilainen kuin niissä Euroopan maissa, joissa liikehdintä sai kannatusta. Suomessa arvostettiin kirkon perinteistä liturgiaa ja pyrittiin rakentamaan yhtenäistä, identiteetiltään suomalaista katolista kirkkoa.

Prisoners of Freedom : A Study on Worldview of Contemporary Finnish Seamen

The aim of this study was to look at the metaphors contemporary merchant seamen use for their ship and for their life at sea. The larger theoretical framework of the study consisted of worldview, which is one of the key concepts of comparative religion. The data for the study consisted of 91 interviews with Finnish professional seafarers that were conducted in 1996, 1999, and 2000, field journals that were written during two periods of fieldwork in 1996 and 1999-2000, and correspondence with some of the Finnish seafarers during 1999-2002. The data was analyzed by using metaphor theory. The study consists of two parts. The first part is ethnography of modern Finnish shipworld. This entails work, organization, hierarchy and gender. The second part discusses the metaphors the seafarers use. The study belongs to the field of anthropology of religions which is part of comparative religion.

Living Poetically in the Modern Age : The Situational Aspects of Kierkegaard's Thought

How did Søren Kierkegaard (1813 1855) situate the human subject into historical and social actuality? How did he take into consideration his own situatedness? As key for understanding these questions the research takes the ideal of living poetically that Kierkegaard outlined in his dissertation. In The Concept of Irony (1841) Kierkegaard took up this ideal of the Romantic ironists and made it into an ethical-religious ideal. For him the ideal of living poetically came to mean 1) becoming brought up by God, while 2) assuming ethical-religiously one s role and place in the historical actuality. Through an exegesis of Kierkegaard s texts from 1843 to 1851 it is shown how this ideal governed Kierkegaard s thought and action throughout his work. The analysis of Kierkegaard s ideal of living poetically not only a) shows how the Kierkegaardian subject is situated in its historical context. It also b) sheds light on Kierkegaard s social and political thought, c) helps to understand Kierkegaard s character as a religious thinker, and d) pits his ethical-religious orientation in life against its scientific and commonsense alternatives. The research evaluates the rationality of the way of life championed by Kierkegaard by comparing it with ways of life dominated by reflection and reasoning. It uses Kierkegaard s ideal of living poetically in trying to understand the tensions between religious and unreligious ways of life.

Normalization and Charter 77 : Violence, Commitment and Resistance in Czechoslovakia

In Czechoslovakia, the occupation of 1968 denoted the beginning of normalization , a political and societal stagnation that lasted two decades. Dissident initiative Charter 77 emerged in 1977, demanding that the leaders of the country respect human rights. The Helsinki process provided a macro-level framework that influenced opposition and dissident activities throughout Eastern Europe. The study contributes a focused empirical analysis of the period of normalization and the dissident movement Charter 77. Dissent in general is seen as an existential attitude; it can be encapsulated as a morally rationalized critical stance as derived from shared experience or interpretation of injustice, which serves as a basis for a shared collective identity comprising oppositional consciousness as one unifying factor. The study suggests that normalization can be understood as a fundamentally violent process and discusses the structural and cultural manifestations of violence with relation to Charter 77. In general, the aim of the system was to passivize the society to such an extent that it would not constitute a potential threat to the hegemonic rule of the regime. Normalization caused societal stagnation and apoliticization, but it also benefited those who accepted the new political reality. The study, however, questions the image of Czechoslovakia s allegedly highly repressive rule by showing that there was also quite considerable tolerance of Charter 77 and consideration before severe repression was brought to bear against dissidents. Furthermore, the study provides understanding of the motives and impetuses behind dissent, the strategic shifts in Charter 77 activities, and the changes in the regime s policies toward Charter 77. The study also adds new perspective on the common image of Charter 77 as a non political initiative and suggests that Charter 77 was, in fact, a political entity, an actively political one in the latter half of the 1980s. Charter 77 was a de facto hybrid of a traditional dissident initiative and an oppositional actor. Charter 77 adopted a two-dimension approach: firstly, it still emphasized its role as a citizens initiative supporting human rights, but, secondly, at the same time, it was a directly political actor supporting and furthering the development of political opposition against the ruling power.

Essays in Philosophical Moral Psychology

The dissertation consists of four essays and a comprehensive introduction that discusses the topics, methods, and most prominent theories of philosophical moral psychology. I distinguish three main questions: What are the essential features of moral thinking? What are the psychological conditions of moral responsibility? And finally, what are the consequences of empirical facts about human nature to normative ethics? Each of the three last articles focuses on one of these issues. The first essay and part of the introduction are dedicated to methodological questions, in particular the relationship between empirical (social) psychology and philosophy. I reject recent attempts to understand the nature of morality on the basis of empirical research. One characteristic feature of moral thinking is its practical clout: if we regard an action as morally wrong, we either refrain from doing it even against our desires and interests, or else feel shame or guilt. Moral views seem to have a conceptual connection to motivation and emotions – roughly speaking, we can’t conceive of someone genuinely disapproving an action, but nonetheless doing it without any inner motivational conflict or regret. This conceptual thesis in moral psychology is called (judgment) internalism. It implies, among other things, that psychopaths cannot make moral judgments to the extent that they are incapable of corresponding motivation and emotion, even if they might say largely the words we would expect. Is internalism true? Recently, there has been an explosion of interest in so-called experimental philosophy, which is a methodological view according to which claims about conceptual truths that appeal to our intuitions should be tested by way of surveys presented to ordinary language users. One experimental result is that the majority of people are willing to grant that psychopaths make moral judgments, which challenges internalism. In the first article, ‘The Rise and Fall of Experimental Philosophy’, I argue that these results pose no real threat to internalism, since experimental philosophy is based on a too simple conception of the relationship between language use and concepts. Only the reactions of competent users in pragmatically neutral and otherwise conducive circumstances yield evidence about conceptual truths, and such robust intuitions remain inaccessible to surveys for reasons of principle. The epistemology of folk concepts must still be based on Socratic dialogue and critical reflection, whose character and authority I discuss at the end of the paper. The internal connection between moral judgment and motivation led many metaethicists in the past century to believe along Humean lines that judgment itself consists in a pro-attitude rather than a belief. This expressivist view, as it is called these days, has far-reaching consequences in metaethics. In the second essay I argue that perhaps the most sophisticated form of contemporary expressivism, Allan Gibbard’s norm-expressivism, according to which moral judgments are decisions or contingency plans, is implausible from the perspective of the theory of action. In certain circumstances it is possible to think that something is morally required of one without deciding to do so. Morality is not a matter of the will. Instead, I sketch on the basis of Robert Brandom’s inferentialist semantics a weak form of judgment internalism, according to which the content of moral judgment is determined by a commitment to a particular kind of practical reasoning. The last two essays in the dissertation emphasize the role of mutual recognition in the development and maintenance of responsible and autonomous moral agency. I defend a compatibilist view of autonomy, according to which agents who are unable to recognize right and wrong or act accordingly are not responsible for their actions – it is not fair to praise or blame them, since they lacked the relevant capacity to do otherwise. Conversely, autonomy demands an ability to recognize reasons and act on them. But as a long tradition in German moral philosophy whose best-known contemporary representative is Axel Honneth has it, both being aware of reasons and acting on them requires also the right sort of higher-order attitudes toward the self. Without self-respect and self-confidence we remain at the mercy of external pressures, even if we have the necessary normative competence. These attitudes toward the self, in turn, are formed through mutual recognition – we value ourselves when those who we value value us. Thus, standing in the right sort of relations of recognition is indirectly necessary for autonomy and moral responsibility. Recognition and valuing are concretely manifest in actions and institutions, whose practices make possible participation on an equal footing. Seeing this opens the way for a kind of normative social criticism that is grounded in the value of freedom and automomy, but is not limited to defending negative rights. It thus offers a new way to bridge the gap between liberalism and communitarianism.

The Restless Love of Thinking : The Concept Liebe in Hegel's Philosophy

The German philosopher G.W.F.Hegel (1770–1831) is best known for his idealistic system philosophy, his concept of spirit [Geist] and for his dictum that the existing and the rational overlap. This thesis offers a new perspective: it examines the working of the concept ‘love’ in Hegel’s philosophy by looking at the contexts and function he puts it to, from his earliest writings to the very last lectures he gave. The starting point of the inquiry is that he applied the concept Liebe to different contexts for different purposes, but each time to provide an answer to a specific philosophical problem. His formulation, reformulation and use of ‘love’ give possible solutions to problems the solving of which was crucial to the development of his thought as a whole. The study is divided into three parts, each analysing the different problems and solutions to which Hegel applied the concept of love. The first part, "Love, morality and ethical life", examines these interconnected themes in Hegel’s early work. The main questions he addressed during this period concerned how to unite Kant’s philosophy and the Greek ideal of the good life. In this context, the concept ‘love’ did three things. First, it served to formulate his grounding idea of the relation between unity and difference, or the manifold. Secondly, it was the key to his attempt to base an ideal folk religion on Christianity interpreted as a religion of love. Finally, it provided the means to criticise Kant’s moral philosophy. The question of the moral value of love helped Hegel to break away from Kant’s thought and develop his own theory about love and ethical life. The second part of the study, "Love and the political realm", considers the way 'Liebe' functions in connection with questions concerning the community and political life in Hegel’s work. In addition to questioning the universal applicability of the concept of recognition as a key to his theory of social relations, the chapters focus on gender politics and the way he conceptualised the gender category ‘woman’ through the concept ‘love’. Another line of inquiry is the way the figure of Antigone was used to conceptualise the differentiated spheres of action for men and women, and the part ‘love’ played in Hegel’s description of Antigone’s motives. Thirdly, Hegel’s analogy of the family and the state and the way ‘love’ functions in an attempt to promote understanding of the relation between citizens and the state are examined. The third and final part of the study, "Love as absolute spirit", focuses on ‘love’ within Hegel’s systemic thought and the way he continued to characterise Geist through the language of Liebe up until and including his very last works. It is shown how Liebe functions in his hierarchical organisation of the domains of art, religion and philosophy, and how both art and religion end up in similar structural positions with regard to philosophy. One recurrent theme in the third part is Hegel’s complex relation to Romantic thought. Another line of investigation is how he reconstructed Christianity as a religion of love in his mature work. In striking contrast to his early thought, in his last works Hegel introduced a new concept of love that incorporated negativity, and that could also function as the root of political action.

Living on voles - plastic life of the Ural owl

Individuals face variable environmental conditions during their life. This may be due to migration, dispersion, environmental changes or, for example, annual variation in weather conditions. Genetic adaptation to a novel environment happens through natural selection. Phenotypic plasticity allows, however, a quick individual response to a new environment. Phenotypic plasticity may also be beneficial for individual if the environment is highly variable. For example, eggs are costly to produce. If the food conditions vary significantly between breeding seasons it is useful to be able to adjust the clutch and egg size according to the food abundance. In this thesis I use Ural owl vole system to study phenotypic plasticity and natural selection using a number of reproduction related traits. The Ural owl (Strix uralensis) is a long-lived and sedentary species. The reproduction and survival of the Ural owl, in fact their whole life, is tied to the dramatically fluctuating vole densities. Ural owls do not cause vole cycles but they have to adjust their behaviour to the rather predictable population fluctuations of these small mammals. Earlier work with this system has shown that Ural owl laying date and clutch size are plastic in relation to vole abundance. Further, individual laying date clutch size reaction norms have been shown to vary in the amount of plasticity. My work extends the knowledge of natural selection and phenotypic plasticity in traits related to reproduction. I show that egg size, timing of the onset of incubation and nest defense aggressiveness are plastic traits with fitness consequences for the Ural owl. Although egg size is in general thought to be a fixed characteristic of an individual, this highly heritable trait in the Ural owl is also remarkably plastic in relation to the changes in vole numbers, Ural owls are laying the largest eggs when their prey is most abundant. Timing of the onset of incubation is an individual-specific property and plastic in relation to clutch size. Timing of incubation is an important underlying cause for asynchronous hatching in birds. Asynchronous hatching is beneficial to offspring survival in Ural owl. Hence, timing of the onset of incubation may also be under natural selection. Ural owl females also adjust their nest defense aggressiveness according to the vole dynamics, being most aggressive in years when they produce the largest broods. Individual females show different levels of nest defense aggressiveness. Aggressiveness is positively correlated with the phenotypic plasticity of aggressiveness. As elevated nest defense aggressiveness is selected for, it may promote the plasticity of aggressive nest defense behaviour. All the studied traits are repeatable or heritable on individual level, and their expression is either directly or indirectly sensitive to changes in vole numbers. My work considers a number of important fitness-related traits showing phenotypic plasticity in all of them. Further, in two chapters I show that there is individual variation in the amount of plasticity exhibited. These findings on plasticity in reproduction related traits suggest that variable environments indeed promote plasticity.

Time to rest : Signals in shoot apex developmental transitions underlying dormancy

Vuodenajat rytmittävät monivuotisten kasvien elämää pohjoisella pallonpuoliskolla, jolla varmin merkki lähestyvästä talvikaudesta on asteittain lyhenevä päivänpituus. Kun päivänpituus on lyhentynyt tiettyyn raja-arvoon saakka, kasvu hiipuu ja kasvin kehityksessä tapahtuu suuria muutoksia. Väitöskirjatyössäni tutkittiin mekanismeja, jotka liittyvät pituuskasvun päättymiseen, silmujen lepotilan kehittymiseen ja kärkisilmun muodostumiseen hybridihaavan ja koivuntaimilla lyhyen päivänpituuden seurauksena kasvihuoneolosuhteissa. Vain lepotilaiset silmut selviytyvät luonnossa ankaran talvikauden yli, joten etenkin lepotilan kehittymisen tutkiminen on keskeistä pyrittäessä selvittämään monivuotisille kasveille tyypillisen kasvutavan mekanismeja. Jo pitkään on tiedetty, että täysikasvuiset lehdet vastaanottavat tiedon päivänpituudesta ja lähettävät signaaleja varren johtojänteissä ylöspäin kohti kasvin kärkiosaa. Sen sijaan varren kärjen ja kärkikasvupisteen roolia lepotilan kehittymisessä on selvitetty vain vähän. Kuitenkin juuri kärkikasvupisteen selviytyminen vuodesta toiseen on tärkeää, koska sen jakautumiskykyiset solukot tuottavat kasvin maanpäälliset osat. Tässä työssä tehdyissä varttamiskokeissa osoitettiin, että varren kärki ei ainoastaan vastaanota signaaleja lehdistä ja ajoita toimintaansa niiden mukaan, vaan myös kärjellä itsellään on aktiivinen rooli lepotilan kehittymisessä. Erityisesti kiinnitettiin huomiota kärkikasvupisteen eri alueiden, ns. apikaalimeristeemin ja rib-meristeemin erilaisiin tehtäviin ja pääteltiin, että molemmat vaikuttavat lepotilan kehittymiseen. Kokeissa käytettiin normaalien hybridihaapojen lisäksi siirtogeenisiä hybridihaapoja, jotka eivät lopeta kasvuaan lyhyt päivä –olosuhteissa. Siirtogeeniset hybridihaavat ilmensivät voimakkaasti fytokromi A -nimistä valon vastaanottajamolekyyliä rib-meristeemin alueella, mikä saattoi osaltaan vaikuttaa poikkeavaan pituuskasvukäyttäytymiseen. Myös useiden lepotilan kehittymiseen liittyvien geenien ilmenemisessä havaittiin poikkeavuuksia verrattuna ei-siirtogeenisiin kontrolleihin, joiden silmuissa kehittyi lepotila lyhyt päivä –altistuksen seurauksena. Väitöskirjatyössäni havaittiin, että myös kaasumainen kasvihormoni etyleeni toimii viestinvälittäjänä silmujen lepotilan kehittymisessä ja vaikuttaa etenkin lepotilan oikeaan ajoittumiseen. Etyleenillä huomattiin olevan määräävä rooli päätesilmun muodostumisessa: siirtogeeniset koivut, jotka eivät aisti etyleeniä, eivät muodostaneet päätesilmua. Silti siirtogeeniset koivut vaipuivat lepotilaan, joskin myöhemmin kuin ei-siirtogeeniset kontrollit. Tämän perusteella todettiin, että lepotilan ja päätesilmun kehittyminen ovat erillisiä kehitystapahtumia, vaikka ne saattavatkin ajoittua osaksi päällekkäin.

Role of cell cycle regulators in development of the inner ear

The inner ear originates from an ectodermal thickening called the otic placode. The otic placode invaginates and closes to an otic vesicle, the otocyst. The otocyst epithelium undergoes morphogenetic changes and cell differentiation, leading to the formation of the labyrinth-like mature inner ear. Epithelial-mesenchymal interactions control inner ear morphogenesis, but the modes and molecules are largely unresolved. The expressions of negative cell cycle regulators in the epithelium of the early-developing inner ear have also not been elucidated. The mature inner ear comprises the hearing (cochlea) and balance (vestibular) organs that contain the nonsensory and sensory cells. In mammals, the inner ear sensory cells, called hair cells, exit the cell cycle during embryogenesis and are mitotically quiescent during late-embryonic differentiation stages and postnatally. The mechanisms that maintain this hair cell quiescense are largely unresolved. In this work I examined 1) the epithelial-mesenchymal interactions involved in inner ear morphogenesis, 2) expression of negative cell cycle regulators in the epithelium of the early developing inner ear and 3) the molecular mechanisms that maintain the postmitotic state of inner ear sensory cells. We observed that during otocyst stages, epithelial fibroblast growth factor 9 (Fgf9) communicates with the surrounding mesenchyme, where its receptors are expressed. Fgf9 inactivation leads to reduced proliferation of the surrounding vestibular mesenchyme and to the absence of semicircular canals. Semicircular canal development is blocked, since fusion plates do not form. These results show that the mesenchyme directs fusion plate formation and give direct evidence for the existence of reciprocal epithelial-mesenchymal interactions in the developing inner ear. Cyclin-dependent kinase inhibitors (CKIs) are negative regulators of proliferation. We show that the members of the Cip/Kip family of CKIs (p21Cip1, p27Kip1 and p57Kip2) are expressed in the early-developing inner ear. Our expression data suggest that CKIs divide the otic epithelium into proliferative and nonproliferative compartments that may underlie shaping of the otocyst. At later stages, CKIs regulate proliferation of the vestibular appendages, and this may regulate their continual growth. In addition to restricting proliferation, CKIs may play a role in regional differentiation of various epithelial cells. Differentiating and adult inner ear hair cells are postmitotic and do not proliferate in response to serum or mitogenic growth factors. In our study, we show that this is the result of the activity of negative cell cycle regulators. Based on expression profiles, we first focused on the retinoblastoma (Rb) gene, which functions downstream of the CKIs. Analysis of the inner ear phenotype of Rb mutant mice show, that the retinoblastoma protein regulates the postmitotic state of hair cells. Rb inactivation leads to hyperplasia of vestibular and cochlear sensory epithelia that is a result of abnormal cell cycle entry of differentiated hair cells and of delayed cell cycle exit of the hair cell precursor cells. In addition, we show that p21Cip1 and p19Ink4d cooperate in maintaining the postmitotic state of postnatal auditory hair cells. Whereas inactivation of p19Ink4d alone leads to low-level S-phase entry (Chen et al., 2003) and p21Cip1 null mutant mice have a normal inner ear phenotype, codeletion of p19Ink4d and p21Cip1 triggers high-level S-phase entry of auditory hair cells during early postnatal life, which leads to supernumerary hair cells. The ectopic hair cells undergo apoptosis in all of the mutant mice studied, DNA damage being the immediate cause of this death. These findings demonstrate that the maintenance of the postmitotic state of hair cells is regulated by Rb and several CKIs, and that these cell cycle regulators are critical for the lifelong survival of hair cells. These data have implications for the future design of therapies to induce hair cell regrowth.

Generation and Characterization of the Cation-Chloride Cotransporter KCC2 Hypomorphic Mouse

The cation-Cl- cotransporter (CCC) family comprises of Na+-Cl- cotransporter (NCC), Na+-K+-2Cl- cotransporters (NKCC1-2), and four K+-Cl- cotransporters (KCC1-4). These proteins are involved in several physiological activities, such as cell volume regulation. In neuronal tissues, NKCC1 and KCC2 are important in determining the intracellular Cl- levels and hence the neuronal responses to inhibitory neurotransmitters GABA and glycine. One aim of the work was to elucidate the roles for CCC isoforms in the control of nervous system development. KCC2 mRNA was shown to be developmentally up-regulated and follow neuronal maturation, whereas NKCC1 and KCC4 transcripts were highly expressed in the proliferative zones of subcortical regions. KCC1 and KCC3 mRNA displayed low expression throughout the embryogenesis. These expression profiles suggest a role for CCC isoforms in maturation of synaptic responses and in the regulation of neuronal proliferation during embryogenesis. The major aim of this work was to study the biological consequences of KCC2-deficiency in the adult CNS, by generating transgenic mice retaining 15-20% of normal KCC2 levels. In addition, by using these mice as a tool for in vivo pharmacological analysis, we investigated the requirements for KCC2 in tonic versus phasic GABAA receptor-mediated inhibition. KCC2-deficient mice displayed normal reproduction and life span, but showed several behavioral abnormalities, including increased anxiety-like behavior, impaired performance in water maze, alterations in nociceptive processing, and increased seizure susceptibility. In contrast, the mice displayed apparently normal spontaneous locomotor activity and motor coordination. Pharmacological analysis of KCC2-deficient mice revealed reduced sensititivity to diazepam, but normal gaboxadol-induced sedation, neurosteroid hypnosis and alcohol-induced motor impairment. Electrophysiological recordings from CA1-CA3 subregions of the hippocampus showed that KCC2 deficiency affected the reversal potentials of both the phasic and tonic GABA currents, and that the tonic conductance was not affected. The results suggest that requirement for KCC2 in GABAergic neurotransmission may differ among several functional systems in the CNS, which is possibly due to the more critical role of KCC2 activity in phasic compared to tonic GABAergic inhibition.

Identification of genetic susceptibility loci for migraine

Migraine is the common cause of chronic episodic headache, affecting 12%-15% of the Caucasian population (41 million Europeans and some half a million Finns), and causes considerable loss of quality of life to its sufferers, as well as being linked to increased risk for a wide range of conditions, from depression to stroke. Migraine is the 19th most severe disease in terms of disability-adjusted life years, and 9th among women. It is characterized by attacks of headache accompanied by sensitivity to external stimuli lasting 4-72 hours, and in a third of cases by neurological aura symptoms, such as loss of vision, speech or muscle function. The underlying pathophysiology, including what triggers migraine attacks and why they occur in the first place, is largely unknown. The aim of this study was to identify genetic factors associated with the hereditary susceptibility to migraine, in order to gain a better understanding of migraine mechanisms. In this thesis, we report the results of genetic linkage and association analyses on a Finnish migraine patient collection as well as migraineurs from Australia, Denmark, Germany, Iceland and the Netherlands. Altogether we studied genetic information of nearly 7,000 migraine patients and over 50,000 population-matched controls. We also developed a new migraine analysis method called the trait component analysis, which is based on individual patient responses instead of the clinical diagnosis. Using this method, we detected a number of new genetic loci for migraine, including on chromosome 17p13 (HLOD 4.65) and 10q22-q23 (female-specific HLOD 7.68) with significant evidence of linkage, along with five other loci (2p12, 8q12, 4q28-q31, 18q12-q22, and Xp22) detected with suggestive evidence of linkage. The 10q22-q23 locus was the first genetic finding in migraine to show linkage to the same locus and markers in multiple populations, with consistent detection in six different scans. Traditionally, ion channels have been thought to play a role in migraine susceptibility, but we were able to exclude any significant role for common variants in a candidate gene study of 155 ion transport genes. This was followed up by the first genome-wide association study in migraine, conducted on 2,748 migraine patients and 10,747 matched controls followed by a replication in 3,209 patients and 40,062 controls. In this study, we found interesting results with genome-wide significance, providing targets for future genetic and functional studies. Overall, we found several promising genetic loci for migraine providing a promising base for future studies in migraine.

Long-term results of operative treatment for Hirschsprung's disease and internal anal sphincter achalasia

The aim of the study was to evaluate long-term results of operative treatment for Hirschsprung's disease(HD) and internal anal sphincter achalasia. Fecal continence and quality of life were evaluated by a questionnaire in 100 adult patients who had undergone surgery for HD, during 1950-75. Fecal continence was evaluated using a numerical scoring described by Holschneider. Fifty-four of the 100 patients underwent clinical examination, rigid sigmoidoscopy and manometric evaluation. In anorectal manometry basal resting pressure(BRP)and maximal squeeze pressure(MSP) were measured and voluntary sphincter force(VSF) was calculated by subtracting the BRP from MSP. The results of operative treatment for adult HD were compared with the results of the patients operated in childhood. In adult HD the symptoms are such mild that the patients attain adolescence or even adulthood. The patients with HD and cartilage-hair-hypoplasia were specifically evaluated. The outcome of the patients with internal anal sphincter achalasia operated on by myectomy was evaluated by a questionnaire and continence was evaluated using a numerical scoring described by Holschneider. Of the 100 patients operated on for HD 38 patients had completely normal bowel habits. A normal or good continence score was found in 91 our of 100 patients. Nine patients had fair continence. One of the patients with fair continence had Down's syndrome and two were mentally retarded for other reasons. Only one patient suffered from constipation. In anorectal manometry the difference in BRP between patients with normal and good continence was statistically significant, whereas the difference between good and fair continence groups was not statistically significant. The differences on MSP and VSF between patient groups with different continence outcome were not statistically significant. The differences between patient groups and normal controls were statistically significant in BRP and MSP. In VSF there was not statistically significant difference between the patients and the normal controls. The VSF reflects the working power of the muscles including external sphincter, levator ani and gluteal muscles. The patients operated at adult age had as good continence as patients operated in childhood. The patients with HD and cartilage-hair-hypoplasia had much more morbidity and mortality than non-cartilage-hair-hypoplasia HD patients. The mortality was as high as 38%. In patients with internal anal sphincter achalasia the constipation was cured or alleviated by myectomy whereas a significant number suffered from soiling-related social problems.

Migraine Comorbidities : A Clinical and Molecular Genetic Study

Migraine is a highly prevalent disease, and despite several important breakthroughs there are still a many questions unanswered in the clinical, genetic and pathophysiological aspects of migraine research. Migraine has been linked to several other diseases such as epilepsy and stroke, but there are still unsolved issues concerning the true nature of these associations. Three genes predisposing to hemiplegic migraine and several loci associated to migraine have been identified, but so far no genes responsible for common forms of migraine have been recognized. Triptans have provided an important step in migraine treatment, but their usefulness in rare forms of migraine have been controversial. The Finnish Migraine Gene Project (FMGP) includes more than 1600 families and 7500 individuals. We evaluated comorbidity from 1000 consecutive subjects in the FMGP. To search for novel loci, we performed a genome-wide linkage scan in 36 families with high prevalences of migraine with visual aura. We collected 76 subjects from the FMGP who suffer from hemiplegic migraine and have used triptans. Finally, to study possible links between stroke and migraine we evaluated the prevalence of migraine in subjects with cervical artery dissection (CAD) and healthy controls. Migraine was associated with increased prevalence of allergy, hypotension and psychiatric diseases. Additionally, men suffering from migraine with aura had increased prevalence of epilepsy and stroke. Further evidence of association between migraine and epilepsy was found in our linkage study. The parametric two-point linkage analysis showed significant evidence of linkage between migraine aura and a locus on 9q21-q22. Interestingly, the same locus has been associated with occipitotemporal epilepsy. CAD seems to be a migraine risk factor, and therefore a link between stroke and migraine. Notably, CAD seems to alleviate migraine activity further indicating the association between these two conditions. Despite the contraindications of triptans, it seems that they are safe and effective in the abortive treatment of hemiplegic migraine.

Bone Stress Injuries of the Foot and Ankle

Bone stress injuries of the foot have been known for more than 150 years. For a century, their primary diagnostic imaging tool has been radiography. However, currently the golden standard for establishing the diagnosis of stress injuries is magnetic resonance imaging (MRI). Although the injury type has been fairly well documented in the earlier literature, little information is available on the healing of stress injuries located in e.g. the talus and calcaneus. The current study retrospectively evaluated the stress injuries of the foot and ankle treated at the Central Military Hospital over a period of eight years in patients who underwent MRI for stress injury of the foot. The imaging studies of the patients were reevaluated to determine the exact nature of the stress injury. Moreover, the hospital records of the patients were reviewed to determine the healing of stress injuries of the talus and calcaneus. Patients with a stress fracture in the talus were recalled for a follow-up examination and MRI scan one to six years after the initial injury to determine if the fracture had completely healed, clinically and radiologically. The bone stress injuries of the foot were found to affect more than one bone in a majority of the cases. The talus and the calcaneus were the bones most commonly affected. In the talus, the most common site for the injuries was the head of the bone, and in the calcaneus, the posterior part of the bone. The injuries in these bones were associated with injuries in the surrounding bones. Stress injuries in the calcaneus seemed to heal well. No complications were seen in the primary healing process. The patients were, however, sometimes compelled to refrain from physical training for up to months. In the talus, minor degenerative findings of the articular surface were seen in half of the patients who participated in a follow-up MRI scan and radiographs taken one to six years after the initial injury. Half of the patients also reported minor exercise related symptoms in the follow-up. The symptoms were, however, not noticeable in everyday life.

CHEK2 in Breast and Colorectal Cancer

Breast and colorectal cancers, are common types of cancer, with over two million newly diagnosed cases annually worldwide. Cancer is a genetic disease and defects in DNA integrity restoring functions make a significant contribution to cancer risk. CHEK2 is a checkpoint kinase functioning as a regulator of cell cycle checkpoints, apoptosis, and DNA repair in response to DNA double-strand breaks. The aim of this study was to evaluate the role of CHEK2 in breast cancer predisposition in Finnish breast cancer families and in breast cancer risk at the population level. We were interested in the clinical and biological characteristics of the breast tumors associated with the CHEK2 germline mutations or aberrant CHEK2 protein expression and the effect on survival of patients with these CHEK2 defects. We also assessed the role of CHEK2 mutations, namely 1100delC and I157T, in colorectal cancer susceptibility in Finland. CHEK2 I157T was found to be a low-penetrance breast cancer susceptibility allele, conferring a 1.4-fold risk for carriers. Reduced or absent CHEK2 protein expression was observed in one-fifth of breast tumors from patients unselected for family history, implying that defective CHEK2 signaling contributes to tumorigenesis. Reduction in CHEK2 expression was more common in tumors with larger diameter and ER expression, but with regard to other tumor characteristics and prognosis of a patient no association was observed. Results from comparison of CHEK2 1100delC carrier tumors with noncarrier tumors were in line with the findings from the CHEK2 expression study. Tumors from CHEK2 1100delC carriers were more often of higher grade than tumors from noncarriers, and they also tended to be ER-positive more often, although generally 1100delC status does not seem to radically affect the tumor characteristics. Our results suggest that CHEK2 1100delC may not be a susceptibility allele for CRC, although a very small effect cannot be excluded. Furthermore, CHEK2 1100delC is equally frequent in HBCC (hereditary breast and colorectal cancer) phenotype families and in breast cancer families. Over 1000 CRC cases were screened for CHEK2 I157T, and a significantly higher frequency of I157T was observed among both familial and sporadic CRC cases. The relation of CHEK2 I157T with familial CRC has not been studied previously. CHEK2 I157T seems to be a susceptibility allele for both familial and sporadic CRC, conferring a 1.5-fold risk for carriers of this variant. CHEK2 I157T has been proposed to have a role as a multiple cancer susceptibility allele, which is supported by our results since we observed a trend towards higher frequency of the variant among cases with multiple primary tumors or those with a family history of cancer. During the last five years CHEK2 has established its role as an important cancer susceptibility gene. It has become apparent that CHEK2 is a low-penetrance susceptibility gene for several cancer types, significantly contributing to familial cancer risk as well as to cancer risk at the population level.