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  • Eränpalo, Tommi (Helsingin yliopisto, 2015)
    Abstract This dissertation deals with young people s civic skills and how these competences can be developed particularly in civics education at school by means of gamification. The dissertation consists of four sub-studies written in article form as well as a summary. The articles examine young people s civic behaviour from the perspective of conceptions of democracy, civic competence and civic identity. The current generation of youth and young adults seems to be shunning the traditional structures of civic participation and political decision making. Young people are re-evaluating their own roles in civic discussion and are often choosing methods that are outside the official channels. To further develop civic activism, this state of affairs should be changed, since our future decision makers will ultimately emerge from this group of people. The role of the school is seen as essential in scientific debate on the subject. The dissertation commences with the question of how deceptive the suggestion is that young people are passive, and how civic education didactics need new ways to recognise students involvement in civic matters. This query is addressed by means of finding new methods for civics education, using, for example, gamification and dialogue education. The intention of the dissertation is to answer the following questions: a) What aspects of young people s civic skills can be detected in the deliberation resulting from game playing? b) How should civics education at school be developed to strengthen young people s inclusion in civic affairs? The Grounded theory method is applied in the study. Each dissertation article introduces a new perspective on the research phenomenon, and the analysis of the research material proceeds in stages revealing new information on young people s civic competence. The theoretical conclusions of the study are presented in the summary. The first article focuses on the public image of young people s civic competence, which has been marked by pessimism in the early 21st century. This negative image has been publicly debated in conjunction with international surveys indicating young people s passive behaviour in civic orientation (CIVED 1999 and ICCS 2009). The article looks for a new perspective by ques-tioning the pessimistic interpretations of these surveys. It also presents new research evidence of a more active youth culture. The second and third articles venture deeper into the world of young people s civic competence. The image of young people being passive is often maintained by the conventional discussion culture in schools, one that avoids open ideological and political debate and does not particularly encourage deliberation on civic matters. The articles raise issues concerning the atmosphere in the classroom as well as the role of the student in education and society as a whole. It also presents the Act now! game, developed by the author and the author s students. The game aims to provide a framework for dealing with civic issues by means of deliberation. The fourth article introduces the concept of dialogue in education, and a comparative Scandinavian example of it. The Act now! game was played in Finland, Sweden and Norway. The article focuses on dialogue education as part of young people s civics education, and examines the features that emerge from analysing civic identity among Scandinavian youth. The summary presents the results in a way that is typical to the Grounded theory method. It then provides a summarizing analysis of them. The results justify claiming that teaching methods involving deliberation in civic education stimulate and strengthen young people s participatory civic orientation as well as their civic competence. The summary also speculates on the possibilities of increasing young people s motivation to participate in civic issues. The competences that arise from young people s deliberation indicate how the young are capable of responding to civic responsibility. The results also high-light the democratic-political need to create a forum in which young people may engage in civic deliberation. The ongoing curricular reform in Finnish primary and secondary schools will emphasise student involvement as well as creating a new and more active role for students. Accordingly, the results of this study can be implemented in civics teaching. They also suggest that deliberation instruments such as the Act Now! game could be used as a solution to didactic needs on a wider scale. A game-like method offers an example of dialogical teaching that enables a path to deliberation. Keywords: Civic competence, deliberation, gamification, inclusion
  • Rajamäki, Kristiina (Helsingin yliopisto, 2015)
    Atherosclerosis is the underlying cause of myocardial infarction and stroke, the leading causes of death worldwide. It is a complex multifactorial disease closely linked with obesity, type II diabetes, and metabolic syndrome and, together, these conditions comprise the global epidemic of metabolic disorders that are becoming more and more prevalent, affecting adults and children alike. Atherosclerosis affects the large arteries that gradully loose their normal structure and function via a degenerative process involving lipid accumulation and chronic inflammation in the arterial wall. The lipid accumulation is driven by high circulating levels of cholesterol-carrying low density lipoproteins that become trapped and modified in the arterial wall. This causes an inflammatory reaction characterized by abundant immune cell infiltrates, mainly monocyte-derived macrophages. The macrophages scavenge large amounts of lipids and become activated to secrete a host of proinflammatory mediators and matrix-degrading enzymes that drive the progression of the disease. These processes result in the focal development of fatty lesions or plaques along the arteries. Over time, more complex lesions develop as a result of inflammatory and fibrotic responses, matrix remodeling, calcification, cholesterol crystallization, neovessel formation, and microhemorrhages. Ultimately, the plaques may rupture, causing thrombosis and acute complications. Although inflammation is recognized as a major driving force in atherosclerotic lesion development, the mechanisms triggering and maintaining the arterial wall inflammation remain incompletely understood. The aim of this thesis was to study the role of a key innate immune signaling pathway, the inflammasome, in atherosclerosis. The inflammasomes are large cytoplasmic signaling complexes that trigger the proteolytic maturation and secretion of two proinflammatory and proatherogenic cytokines, interleukin(IL)-1beta and -18. The inflammasome pathway can be triggered by microbial components or by sterile endogenous danger signals that elicit the activation of cytoplasmic sensor molecules from the NLR (nucleotide-binding domain and leucine-rich repeat containing) or PYHIN (pyrin and HIN domain containing) families. Despite the established roles of IL-1beta and -18 in driving atherosclerotic lesion development, the triggers of inflammasome activation in atherosclerotic plaques remained unknown. Macrophages are the prototypical inflammasome pathway-expressing cells, and thus cultured human macrophages were utilized to identify and characterize atherosclerosis-associated triggers of the inflammasome pathway. Cholesterol crystals and acidic environment were both found to trigger a strong inflammatory response via the activation of NLRP3 inflammasome and secretion of IL-1beta and IL-18. Cholesterol crystals are a hallmark of atherosclerotic lesions, yet they have been considered an inert material that merely acts as a sink for excess free cholesterol in the arterial wall. These new data suggested, however, that cholesterol crystals act as a potent sterile danger signal that may directly link pathological lipid accumulation and inflammation in the lesions. Local extracellular acidosis arises in the growing plaque due to the hindered diffusion of oxygen and the highly active glycolytic metabolism of macrophages. Acidic environment not only triggered the NLRP3 inflammasome, but even a very mild acidification from the physiological pH of 7.4 to 7.0 was sufficient to greatly amplify the IL-1beta response to other NLRP3 activators, including cholesterol crystals. Having showed that the atherosclerotic lesions harbour potent activators of the inflammasome pathway, we further analyzed the expression of this pathway in atherosclerotic human coronary specimens obtained from 10 explanted hearts. For this purpose, we utilized a quantitative PCR array targeting 88 inflammasome pathway-related molecules. Significant upregulation of 12 target genes was found in advanced coronary plaques compared to early lesions from the same coronary trees, including many of the very core components of the inflammasome pathway. Moreover, p38delta mitogen-activated protein kinase (MAPK), a poorly characterized isoform of the stress- and cytokine-activated p38 MAPK family, was consistently upregulated in advanced coronary plaques. Immunohistochemical stainings of human coronary lesions showed strong expression of NLRP3 inflammasome components and p38delta MAPK in macrophages surrounding the cholesterol crystal-rich lipid core. Furthermore, the p38delta MAPK was activated in cultured human macrophages upon NLRP3 inflammasome activation by cholesterol crystals and extracellular ATP, and required for NLRP3-mediated IL-1beta secretion. Taken together, the data presented in this thesis propose novel inflammasome-mediated mechanisms that may trigger sterile inflammation in atherosclerotic lesions and thus drive lesion progression.
  • Oksanen, Tuomas (Suomen Ensihoidon Tiedotus Oy, 2015)
    Aims of the study Intensive care is usually necessary for the good survival of postresuscitation patients. The use of some intensive care methods can make the survival better. The main focus of this thesis was to analyze implementation of therapeutic hypothermia in Finnish intensive care units (ICU) and its impact on survival, impact of strict glucose control on the survival of postresuscitation patients, incidence of postresuscitation myocardial depression during therapeutic hypothermia and usefulness of serum NSE concentration for prognostication. Patients and methods Implementation of therapeutic hypothermia and survival of postresuscitation patients in ICUs in Finland was analyzed retrospectively using data from the Finnish Intensive Care Consortium quality database. Impact of glucose control on survival of postresuscitation patients was studied in a randomized controlled study of patients treated with therapeutic hypothermia (24 hours at 33°C) in HUCH ICUs (n = 90). The study patients were randomized to strict (4 6 mmol/l) or moderate (6 8 mmol/l) glucose control for the first 48 hours. The incidence of myocardial depression was studied in a retrospective analysis of hemodynamic data from clinical information system database of 120 postresuscitation patients treated with therapeutic hypothermia (24 hours at 33°C) in HUCH ICUs. Usefulness of serum NSE and some other factors as prognostic tools were analyzed retrospectively from laboratory database of 90 postresuscitation patients treated with ­therapeutic hypothermia (24 hours at 33°C) in HUCH ICUs. Results Therapeutic hypothermia was implemented widely in Finnish ICUs in a few years after international guidelines were published in 2003. In the same time, mortality of postresuscitation patients treated in ICUs decreased. Mortality or serum NSE concentration did not differ between patients treated with strict or moderate glucose control. However, strict glucose control increased risk of hypoglycemia. Myocardial depression, manifesting as low cardiac output (CI less than 1.5 l/min/m2), was ­observed during the first 12 hours in two thirds of patients monitored with pulmonary artery catheter. Other hemodynamic parametres did not differ. Serum NSE concentration at 48 hours after cardiac arrest and decreasing concentration at that time point correlated with neurologic outcome, but with 100% specificity, sensitivity was low. Conclusions Therapeutic hypothermia was implemented rapidly in Finnish ICUs, compared with other European countries or USA. This was associated with better outcome, but causality is uncertain. Strict normoglycemia during intensive care of postresuscitation patients is not necessary. The optimal goal for blood glucose level is not known. Myocardial depression manifesting as low cardiac output is common in postresuscitation patients, but difficult to detect without monitoring cardiac output. The impact of ­recognition and treatment of myocardial depression on outcome requires further studies. Serum NSE measured at least 48 hours after resuscitation can be used as a prognostic tool together with other methods.
  • Nikula, Karoliina (Helsingin yliopisto, 2015)
    Keywords: goodness, capability, choice, ethics, deaf, sign language, cochlear implant, clinical practice, medicalization. Lapsen hyvää edistämässä. Syntymäkuurojen lasten sisäkorvaistutehoitokäytännön sosiaalieettistä tarkastelua. [Promoting The Good of The Child. A Social-Ethical Analysis of Cochlear Implants in Children Born Deaf]. Karoliina Nikula, University of Helsinki. In 1995, after a long period of lobbying and political action, sign language was granted a legal status in Finland. In 1997, the first cochlear implant surgeries were performed on children in Finland. At present, 90 percent of deaf children undergo cochlear implant surgery. The use of sign language as a first language is diminishing. The majority of deaf children are born to hearing parents, and they are being asked to make the choice whether their children should receive cochlear implants or not. Previous empirical studies have shown that some parents feel that their choices are not always respected. The aim of this research project is to study cochlear implant clinical practices using the concepts of goodness, capability, and choice, as well as to analyse whether the shift in clinical practices from sign language to spoken language is based on careful deliberation and reasonable arguments. This study helps us to better understand the parents process of deciding whether or not to obtain cochlear implants for their children, and the family s journey through treatment options and standard clinical practices. In addition, this study provides tools for parents of deaf children to assist their decision-making and to medical practitioners who advise these parents. The study is focused around the following research questions: (1) What constitutes medical goodness for a child born deaf? (2) In what ways do cochlear implants and sign language promote a deaf child s capabilities? (3) Is it adequate to speak of choice when thinking about the dilemmas of parents of children born deaf? The research methodology is philosophical concept and argumentation analysis along with analysis of the construction of the concept of choice. The research data consists of various sources and literature. The sources can be divided into the following: 1) Avaintietokansio [materials made available to families of the deaf]; 2) publications of the Satakieli seminars; 3) brochures and other information provided by device manufacturers; 4) DVD and video recordings; 5) Internet pages; and 6) legislation. The literature is comprised of (1) previous empirical studies on the parents of deaf children obtaining treatment for their children. Empirical studies on family experience include materials published by the Finnish Association of the Deaf and the Institute for the Languages of Finland, e.g., Suomen viittomakielten kielipoliittinen ohjelma (2010); a publication of the Ombudsman for Children Hei, kato mua! (Johanna Kiili and Kirsi Pollari, eds., 2012); and Riia Celen s documentary Sanoja sormenpäissä (2009) and Minna Luukkainen s Viitotut elämät: Kuurojen nuorten aikuisten kokemuksia viittomakielisestä elämästä Suomessa (2008). These provide information on the experiences of families whose deaf children are being treated. Internationally, Stuart Blum s The Artificial Ear (2010) also provides information on the experiences of families. (2) Ethical and medical discourse on cochlear implants in deaf children. (3) Previous philosophical and ethical work, particularly the following: a) Martha Nussbaum s capability approach; b) Georg Henrik von Wright s The Varieties of Goodness (1963, Finnish translation 2001); and c) rational choice theory, especially in the work of Jon Elster. In addition, (4) methodological handbooks (e.g., literature about the conceptual tools) were used. The study is organized as follows. Chapter two examines deafness from two points of view: audiological and socio-cultural. I also introduce topics often associated with deafness, such as sign language and deaf culture. Here I also discuss the technical aspects of cochlear implants and provide a brief history of the deaf in Finland. In chapters 3 5 I examine the three main concepts goodness, capabilities, and choices with reference to the research questions. These provide essential conceptual tools when analysing the issue, as the processes connected to cochlear implants are centred around the question of what constitutes a good life for the child, the child s ability to develop, and the choices that parents in this situation must make. My research demonstrates the following: (1) The transition from sign language to spoken language is not based on sound arguments. This study did not find a solid rationale for reducing the use of sign language in order to rehabilitate hearing. Giving up sign language cannot be said to promote the child s good, capabilities, or opportunities to make independent choices in the future. On the contrary, it may indeed interfere with them. (2) In conjunction with the cochlear implant treatment process, it sometimes seems that the ideas of promoting choice and increasing capabilities are more of an illusion. We can also speak of language as an illusion in the sense that in the literature I surveyed (as well as in this discourse), language is often used synonymously with spoken language. The rhetoric used directs choice and creates impressions. We cannot speak of a family s autonomous, rational choices if the situation does not meet the criteria for choice. (3) Occasionally, the process seems to be about audism, i.e., valuing spoken language over signed language, medicalization, technological imperatives, and the treatment of cochlear implants as an ideological issue. All of these can have an effect on the decision-making processes of parents. (4) Cochlear implant clinical practices differ from general health care practices in the sense that implant practices are not always based on evidence (e.g., there is no evidence of the advantages of choosing not to learn sign language; there is as yet no knowledge of the long-term effects of cochlear implants). Furthermore, health care usually focuses only on areas within the medical field, but a language is not only a medical issue. Health care practices are usually based on research results, limited to areas in which medical authorities have competence and designed to maximize the patient s capabilities. (5) Legislation, different schools of thought, and treatment practices create different ways of understanding deafness. Legislation treats the deaf in terms of language and handicap. Different schools of thought lead to polarized discourse about deafness. Finally, according to the reports of parents, current clinical practices require them to choose one language for their child, although it would be possible to choose both sign language and spoken language. These divisions in the discourse may affect the decision-making of parents. (6) The idea of choice is not the best way to promote the well-being of deaf children. Focusing instead on capabilities would free parents and health care practitioners from the burden of predicting outcomes which will only come with time: that is, if all capabilities are promoted, it is not necessary to know how hearing or speech will develop, what the child would like to do or be when s/he grows up, or what sort of future the child will have. A discourse of choice creates an either/or, rather than a both/and situation. Both/and is a better platform from which to develop a child s full capabilities. (7) The concepts of goodness, capabilities, and choice provide useful tools to examine cochlear implant clinical practices and the dilemma of families with deaf children. These concepts can also be used more generally in thinking about ethical considerations in medical practice, as they represent fundamental issues in terms of both ethics and health care practice. (8) Cochlear implant clinical practices need to be developed. This study shows that written materials supporting parental decisions need to be improved, and care needs to be taken that space is given to different alternatives. In addition, more multi- and cross-disciplinary co-operation needs to be developed to improve the prospects for deaf children. Based on this study, I suggest that in the future we need to focus on four issues. First, we must pay attention to the rhetoric used in legislation, in information packets for families of the deaf, and in the research literature. Second, instead of talking about choice, we must take into consideration the child s strengths and skills on many levels. Third, we should consider the possibilities offered by multiculturalism, which includes different types of language choices, as well as multi- and cross-disciplinary clinical teams. If advice is being given on language, the treatment team should include a language specialist as well as a member who knows sign language. This study affirms the need for further multi- and cross-disciplinary co-operation. Fourth, deaf children should be treated as a whole person, not simply through their hearing or lack thereof.
  • Pérez Vera, Cristina (Helsingin yliopisto, 2015)
    The incidence of arthropod-borne infections is increasing worldwide and Fennoscandia is no exception. In the last decades, infections transmitted by ticks are being diagnosed more frequently in people living in the Nordic countries. Ixodes ricinus, the sheep or castor bean tick, which is the most common tick in North-Western Europe, is widely distributed in Finland. Ixodes ticks are vectors of a broad spectrum of pathogens of medical and veterinary importance, such as Babesia spp., Borrelia spp., Anaplasma phagocytophilum (Ap), Bartonella spp., tick-borne encephalitis virus (TBEV), and Francisella tularensis. To date, there is limited information regarding the prevalence of many vector borne diseases in companion animals in Finland, and therefore the majority of available data come from human medicine studies. Infections caused by Bartonella species are considered an emerging zoonosis. One peculiarity of this genus of bacteria is its ability to cause long lasting bacteremia in reservoir hosts. Also, it appears that no other infectious agent is transmitted by more vectors. The deer ked, Lipoptena cervi, is an ectoparasite of moose (Alces alces), which carries Bartonella DNA. Deer keds, which are a nuisance for people, can occasionally bite humans and cause deer ked dermatitis. Whether or not the deer ked can successfully transmit bartonellae to ruminants or humans has not been determined. Because many of the arthropod-borne infections that affect dogs can cause serious disease in people, dogs are considered to be effective sentinel animals to assess the risk of human infection. Also, pets represent a large reservoir for human Bartonella infection because most of the species that infect them are zoonotic. The objective of the present research project was threefold: first, to establish the serological and molecular prevalence of selected tick borne diseases in a large group of dogs in Finland; second, to retrospectively compare different diagnostic approaches and clinicopathologic findings in dogs infected with Bartonella spp.; and third, to explore the role of the deer ked in the transmission of Bartonella spp. to Finnish moose. The serological results from dogs in this study indicate that Finnish dogs are exposed to at least one of four tested arthropod borne pathogens. Dogs were most frequently exposed to Ap (5.3%) followed by Bb (2.9%). Exposure rates were significantly higher in dogs living in Åland. No Finnish dog in this study was infected with Bartonella spp, based on PCR. Bartonella-infected dogs from the USA were most often infected with B. henselae, based on BAPGM enrichment PCR. Interestingly, for most of these dogs, no positive antibodies against Bartonella spp were detected. Clinicopathologic abnormalities in dogs with Bartonella infection were similar to those dogs suspected to have other vector-borne infection. The presence of Bartonella DNA (B. schoenbuchensis and B.bovis) was demonstrated in deer ked pupae samples and in one winged adult, which indicates transstadial transmission of this bacterium in the deer ked. The same Bartonella species were identified in blood samples from free ranging moose in Finland. Furthermore, a high prevalence of Bartonella infection was found in moose, which was significantly lowest in northern Lapland, a region considered deer-ked free. These findings further support the potential of L.cervi as vector of Bartonella.
  • Aivelo, Tuomas (Helsingin yliopisto, 2015)
    Parasite community dynamics is one of the central themes in contemporary parasitology. While between-host dynamics has been studied for a long time, within-host dynamics is less well studied. My aim was to identify which factors affect the parasite community during the lifetime of individual hosts by following longitudinally several individuals from a long-living species. Specifically, I was interested in how the dynamics of infra- and component communities differ from one another and which traits explain the variation in infracommunities. I studied rufous mouse lemur (Microcebus rufus), which is a primate living in the eastern montane rainforests of Madagascar. Mouse lemur is a well-suited study species as it can live for up to ten years in the wild. Due to its small size, the population density is high and trapping straightforward. Nematodes are the most common helminths found in mouse lemurs, but their identification is difficult. Typically, the nematodes are identified from adult specimens, but for longitudinal studies, this is not possible, as we cannot dissect the host individuals. In addition, morphological differences between species are small and we expected to encounter previously undescribed species. These difficulties led to the development of a new method, based on metabarcoding, to identify parasitic nematodes from fecal samples. The method I developed encompasses all steps from fieldwork to sequence analysis. Despite numerous confounding factors, the method managed to amplify and analyze half of the samples collected. Whilst there is room for further improvements, the main advantage is that the method works well for different host species, for example mouse lemurs and gastropods. In principle, this method works for all species of nematode, including free-living soil nematodes. Nevertheless, the resolution of identification do not allow for species-level identification. The variation in the parasite community inside individual hosts was extensive, but at the population level remained stable. Most of the parasites belonged to the putative species thought to be Strongyloides sp. The reason for this species success might be its lifecycle, the parasite can live in the intestine or as a free-living form in the soil. Due to the limited number of samples, the factors affecting the dynamics in individual mouse lemurs are difficult to analyze. It appears that sex and age do not have an effect on either parasite load or variation in parasite dynamics. Nevertheless, body condition appears to bear a consequence with the individuals in better condition having more parasite species in addition to higher fecal egg loads. The reason may be that those individuals are able to sustain larger populations of parasites, or that they are more tolerant to parasites. Hibernation could lead to the extinction of the nematode community, whereas higher precipitation appeared to lead to higher prevalences. This work gives insights into the dynamics of parasite communities both at the host individual and population level. It highlights the need for longitudinal studies as parasite community dynamics in host individual-level cannot be inferred from the host population-level The method I have developed can be used to perform more efficient and faster surveys of previously unknown parasite communities, though further development is necessary for better reliability.
  • Yli-Hemminki, Pirjo (Helsingin yliopisto, 2015)
    Mineral concretions or nodules are found from the Oceans, lakes and in soils. Their element content has been studied well due to possible commercial use, but interest in their bacterial communities has risen due to environmental implications. Iron manganese (Fe Mn) concretions cover vast bottom areas in the Gulf of Bothnia and the Gulf of Finland (GoF). These mineral precipitates sequester several times higher amounts of Fe, Mn, phosphorus (P) and arsenic (As) than the surrounding sediment. Despite their large occurrence, the environmental significance of the concretion bottoms has been a somewhat understudied issue. The aim of the present study was to investigate the bacterial community structure, and possible microbial contributions to the formation and decay of concretions in the Baltic Sea. The further aim was to study how concretions respond to different environmental stresses, such as anoxia and crude oil contamination, which the concretions may encounter in GoF bottoms. The methods used were determination of solid and dissolved Fe, Mn, P and As during microcosm incubations under oxidising or reducing conditions, also with crude oil and 14C naphthalene added. Bacterial community structure was studied by cloning and sequencing taxonomic marker gene (partial 16S rRNA gene), and quantification of polycyclic aromatic hydrocarbon degradation (PAH RHDα) gene copy number. Morphologically and taxonomically diverse bacteria colonise both the pitted surface and the porous interior of spherical concretions. Half of the population was affiliated to uncultured Proteobacteria, and one third was unclassified bacteria. Concretion bacteria populations appeared typical for this habitat. Bacteria may significantly affect the formation of the concretions in the GoF, because known Mn oxidising bacteria were enriched in Mn2+ containing liquid and semi solid media. The Fe2+ oxygen gradient favoured the enrichment of species which are known to reduce Fe and to degrade petroleum hydrocarbons. Concretions released Fe and Mn during anoxic conditions only if they were supplied with labile carbon source, indicating bacterial metal reduction. The dissolution of Mn was the highest, but the release of P and As followed Fe. The release rates (µmol m-2 d-1) from the concretions were within the range of the previously estimated fluxes out of the GoF sediment. Still, the concretions released only minor proportions (0.1 0.4%) of their total Fe, Mn, P and As content during a prolonged anoxic period. Concretions and sediment had a very similar capacity to remove petroleum compounds and mineralise naphthalene under oxic as well as anoxic conditions, and over one half of the added crude oil disappeared from the microcosms. Copy numbers of PAH degradation genes increased, indicating biological degradation potential of PAHs by the concretion bacterial community. Both concretions and sediment had rich and clearly different bacterial communities prior to and also past the exposure to crude oil. Only 9% of the OTUs were shared between the initial concretions and the sediment. Concretion bacterial sequences were affiliated to bacterial groups previously found from concretions and metal rich environments (ecotypes) even after the crude oil exposure, whereas sediment bacterial sequences were similar to those originating from sediments and oil contaminated sites.
  • Rissanen, Päivi (Kuntoutussäätiö, 2015)
    Päivi Rissanen, A Hopeless Case? An Autoethnography of Getting Mentally Ill and Re-habilitation of It The starting point of this doctoral thesis is my personal experience of falling mentally ill, being rehabilitated and getting treatment. I have analyzed my story through and with the help of the considerations used in social work, mental health nursing, psy-chotherapy and rehabilitation. My research setting is multi-layered. I am studying, firstly, the experience of falling ill and being rehabilitated and the changing identity in the process. The second viewpoint has been shaped from the client-worker rela-tionship, co-operation and the meaning of working habits. The third position enlight-ens the meaning of peer support and being an expert by experiment. For the fourth, I consider the changes in the Finnish service system. My research also includes a meta level reflection of the meaning of studying one s own experience. This study is aimed to clarify in narrative description my own experiences as a pa-tient, a service user, a peer counsellor, and an expert by experiment. Thus, the re-search method can be called an autoethnographic service user research. Autoethnog-raphy is a form of research that seeks to describe and analyse systematically personal experience in order to understand cultural experience. Also, the service user research is linked to research methodology, which strives for the participation and empower-ment of the service user. It concerns the close relationship between knowledge and the firsthand experience, which it may be based on. Data in this research has been collected from different kinds of texts. I have mainly used dialogical evaluation with the other researcher, Ms. Susanna Hyväri. The second source of data is the autoeth-nographic material of my diaries in addition to letters to friends, nurses, and my psy-chotherapist. The research opens up new viewpoints into mental illness, and provides new insights into analysis and interpretation. This research provides new knowledge regarding the rehabilitation process as an identity issue. Key words: mental illness, rehabilitation, service user involvement, expert of exper-tise, identity
  • Lahtinen, Susanna (Helsingin yliopisto, 2015)
    The study is concerned with the interaction between Robert Boyle s experimentalism and medicine. Boyle made an attempt to establish his kind of experimental philosophy as the basis of of medicine. At the same time, however, medicine offered him a model of a discipline which, unlike other learned disciplines, embodied several notions of experiment and ways of writing about experiment. Boyle s involvement in medicine was a complicated exchange of ideas and practices. On the one hand, medical literature and the medical notions of experiment had an impact on his experimental philosophy. On the other hand, however, he also applied his own ideas about experiment and its function to his medical work. In this study, Boyle s medical writings of various kinds, such as recipe books, natural historical works and treatises discussing medical practice, theory and medical reform are explored. I examine these works to find out what kind of activities were called experiment on the one hand, and to explicate the functions of experimental texts in Boyle s medical writings, on the other. To do this, I approach Boyle s medical works from several viewpoints. First of all, I examine Boyle s role as a medical author and place his medical writings in the immediate context formed by contemporary medical literature. Secondly, I explore the different kinds of texts Boyle wrote on the basis of medical experiments and the functions these texts have in his published works. Finally, I examine what these texts tell us about the nature of his experimental activities. My dissertation advances an argument about Boyle s experimentalism and method. I seek to show that contrary to what has often been presumed, Boyle applied no single experimental method in his experimental activities but, instead, that his experimentalism embodied experimental methods of various kinds. His writings do not define experimentalism as a method but rather as a particular kind of approach to natural knowledge. Moreover, the manner in which Boyle s medical works describe his experimental activities shows that there hardly was much method in his manner of working. Hence, this study presents his medical experimentalism as a somewhat disorderly effort and suggests that Boyle s experimental philosophy embodied no single and consistent methodological doctrine.
  • Torppa, Ritva (Helsingin yliopisto, 2015)
    The cochlear implant (CI) provides a sensation of hearing for deaf-born children. However, many CI children show poor language outcomes, which may be related to the deficiency of CIs in delivering pitch. This thesis studies the development of those neural processes and behavioural skills linked to the perception of pitch which may play a role in language acquisition. We measured with event-related brain potentials (ERPs) the neural discrimination of and attention shift to changes in music, the perception of word and sentence stress and related acoustic cues, and the auditory working memory (forward digit span) in 4̶ 13-year-old normally hearing (NH) and early-implanted children. We studied how the development of these aspects is related to musical activities known to advance brain development and perceptual skills in the NH population, and whether the perception of music is connected to word stress or visuospatial perception in NH adults. With regard to the development of neural responses, we found for the CI children usually well-formed ERP waveforms resembling those found for the NH children. However, some brain responses implied impoverished processing for the CI children, especially for timbre and pitch. The CI children who sang regularly at home were advantaged over the other CI children for the development of attention shift, which was linked to improved auditory working memory, implying better neural discrimination, an advantaged development of neural networks for attention and better updating of auditory working memory for the CI singers. For the CI children perception of word and sentence stress improved with improving discrimination of pitch (f0) and intensity and auditory working memory. Only the CI children participating in supervised musical activities performed and developed similarly to the NH children in these skills. The perception of musical rhythm improved with improving word stress and visuospatial perception for the NH adults. The results indicate that (i) perception of music and speech are connected not only via pitch and timbre, but also via rhythm, and (ii) the combination of singing at home and taking part in supervised musical activities, using also rhythmic exercises and visual cues, might be the best way to optimize pitch-related abilities, underlying cognitive functions, spoken language skills and quality of life for early-implanted children.
  • Kriikku, Pirkko (Helsingin yliopisto, 2015)
    Driving under the influence of drugs (DUID) can adversely affect driving skills in numerous ways and put lives at risk. Legal approaches to DUID vary considerably from country to country, even within Europe, and, in the last decades the emergence of new psychoactive substances (NPS) has further complicated the scene. DUID is an unlawful act if the substance taken is banned or impairs driving. The latter is hard to define and prove, putting pressure on governments to ban NPS as quickly as possible in order to protect the public by facilitating enforcement of DUID laws. However, banning requires knowledge on several aspects of NPS such as prevalence, pharmacology, abuse potential and toxicity. Up-to-date, evidence-based information on NPS is needed by legislators, toxicologists, clinicians, and other health care professionals. Such information would enable potential drug users and the public to be more aware of the risks associated with illicit use of NPS. This study aimed to add to the knowledge of the NPS most relevant in Finland. In this thesis, the prevalence, blood concentrations in drivers and in post-mortem cases, and demographic details of 3,4-methylenedioxypyrovalerone (MDPV) and desoxypipradrol (2-DPMP), were investigated. Changes in prevalence and other characteristics of MDPV were monitored over a time span covering a period before its banning as well as a few years after banning. Phenazepam, a Russian therapeutic benzodiazepine now illegal in Finland, was studied by examining both DUID and post-mortem cases. The use by apprehended drivers of pregabalin, a prescription anticonvulsant with therapeutic indications for neuropathic pain, partial seizures and generalised anxiety disorder, was also studied. The results of this study showed that DUID cases provide a valuable source of information on NPS prevalence and user profiles. However, little specific information could be gained about the impact on driving performance and health risks of NPS mainly due to the fact that NPS were usually used together with a spectrum of other psychoactive substances. It could, however, be concluded that all of the studied NPS were frequently detected in the samples collected from apprehended drivers and, in the case of MDPV, the prevalence changed with time. The number of MDPV-positive cases among apprehended drivers decreased by 51.1% after the drug was banned. The concentrations of NPS found in DUID cases were within the range anticipated to produce significant adverse effects on driving performance, or, in some cases, in the range found in post-mortem cases where the drug may have contributed to the fatality. The presence of the medicinal drug, pregabalin, was found to be connected to abuse rather than appropriate medical use since it was in most cases found in concentrations higher than those recommended for therapeutic use and together with illegal drugs such as amphetamine or cannabis. In post-mortem cases positive for MDPV, the prevalence of suicide was much greater than in fatalities related to other drugs. Three independent registries, namely the DUID toxicology data, the post-mortem toxicology database, and court documents, were examined to gain novel information on the characteristics of NPS use and those abusing them. The large number of cases studied produced information on concentration ranges associated with abuse of the studied substances.
  • Luostarinen, Teemu (Helsingin yliopisto, 2015)
    The main goals of neuroanesthesia are to maintain adequate cerebral perfusion pressure (CPP) and, consequently, cerebral blood flow (CBF) to guarantee sufficient oxygenation of the brain and to provide good surgical conditions for the neurosurgeon. This thesis aimed to examine critical aspects of neuroanesthesia with regard to CBF, CPP, blood coagulation, and transfusion of blood products. In our material the requirement of intraoperative blood product transfusion was low during surgery for ruptured arterial aneurysm. Intraoperative red blood cell transfusion (RBCT) seems to be preemptive in nature according to the hemoglobin levels prior to transfusion. RBCT is associated with intraoperative rupture of an aneurysm. Intraoperative RBCT may itself worsen SAH patients neurological outcome. In the event of sudden intraoperative rupture of an aneurysm, adenosine-induced asystole can be used to stop the bleeding and facilitate clipping of the aneurysm. Early infusion of fresh frozen plasma instead of crystalloids should be considered to compensate for expected excess bleeding in neurosurgery to preserve normal coagulation capacity. The potentially less harmful effect of hypertonic saline (HS), relative to mannitol, on blood coagulation may shift the decision towards HS when choosing an optimal solution for treatment of elevated ICP or brain swelling, at least when excess bleeding occurs. However, the clinical relevance of this finding remains unclear and warrants further study. Reliability of end-tidal concentration of carbon dioxide (EtCO2) as an estimate of arterial carbon dioxide partial pressure (PaCO2) after anesthesia induction is not adequate, as seen in the correlation between a decrease in mean arterial pressure and EtCO2-PaCO2 difference in our study. Optimal ventilation after induction of anesthesia should be confirmed by arterial blood gas analysis in patients undergoing neurosurgery to prevent a potentially harmful increase in PaCO2, and consequently, in CBF. Anesthesia in both sitting and prone positions is associated with changes in blood pressure and cardiac function. However, preemptive goal-directed therapy with either Ringer s acetate or hydroxyethyl starch (HES) solutions before positioning enables a stable hemodynamic state during neurosurgery in both positions. The fluid requirement did not differ between the two positions. Slightly less HES is needed to achieve comparable hemodynamics, but is it questionable whether this advantage outweighs the recent concerns regarding colloid safety.
  • Polinati, Padmini (Unigrafia, 2015)
    Mitochondrial diseases are generally caused by genetic variants that may affect cell function during the process of energy generation: right from the start of protein translocation to the fatty acid degradation by beta-oxidation (β-oxidation). The main objective of this PhD thesis is to study genetic variants that cause mitochondrial diseases and also to understand the disease pathogenesis of a known disease using the induced pluripotent stem cell (iPSC) method, a revolutionary approach in regenerative medicine. In the first study, we carried out a long-term follow up of six metabolic diseased patients and subsequently we performed a carrier frequency study of the identified carnitine palmitoyl transferase 1A (CPT1A) gene variant in the Finnish population. We identified a novel homozygous variant c.1364A>C (p.Lys455Thr) in exon 12 of the CPT1A gene. No carriers of the variant c.1364A>C were detected upon minisequencing of 150 control samples but the allele frequency of CPT1A variant in global population is 0.0002142 (ExAC Browser) whereas in the Finnish population (6614 allele number) the frequency is 0.001966. The identified variant was predicted to cause improper folding of the CPT1A protein, which leads to its degradation. All patients were treated with a high-carbohydrate and a low fat diet. In the second study, we focused on the human DnaJ (Hsp40 homolog) subfamily C, member 19 (DNAJC19) deficiency. Our studies showed that it causes early onset dilated cardiomyopathy syndrome (DCMA). This is the first report of a genetic defect in the mitochondrial protein, DNAJC19, outside of the Canadian Dariusleut Hutterite population. This defect is characterized by an unusual aetiology for an early onset recessively inherited dilated cardiomyopathy that is associated with ataxia and male genital anomalies. Sequencing of the human DNAJC19 gene revealed a homozygous single nucleotide (A) deletion in exon 6 that cause a frameshift and lead to the premature termination of the protein. In the third study, the pathogenesis of retinopathy in long-chain acyl-CoA dehydrogenase deficiency (LCHADD) was studied using iPSC technology. Retinopathy is an unusual manifestation of LCHADD, as mitochondrial fatty acid β-oxidation (FAβO) has not been considered to play a major role in the metabolism of the retina. Among all defects of mitochondrial FAβO, only long-chain acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (TFP) deficiencies have developed pigmentary retinopathy and peripheral neuropathy. We elucidated how a genetic variant in the FAβO cycle can disrupt the retinal pigment epithelium (RPE) that can eventually lead to blindness. In addition, we developed a new in vitro cell model; iPSC clones were generated from LCHADD patient fibroblasts and further differentiated into RPE cells. Several changes were observed in patient RPE cells such as decreased cell size, lower pigmentation and irregular pattern of morphology. Electron microscopy analysis showed an accumulation of a few melanosomes, more melanolysosomes, and large sized lipid droplets in patient RPE cells. Furthermore, increased levels of triglycerides in patient RPE cells were observed upon mass spectrometric analysis. We concluded that all these changes had contributed to the disruption of the RPE layer that leads to blindness in LCHAD deficiency patients. Finally, the research done for this thesis succeeded in identifying novel variants in CPT1A and DNAJC19 genes in Finnish patients. Our long-term follow up studies on CPT1A deficiency can help patients in better diagnosis, which further helps clinicians to identify the genetic cause. We also found a novel phenotype with DNAJC19 deficiency. Further we established the groundwork to understand the pathogenesis of retinopathy in LCHADD patients using an advanced method that helps to study in depth pathogenesis mechanism.
  • Gao, Yuan (Helsingin yliopisto, 2015)
    This study presents a general overview of Augustine s insights into passions as well as his approach to the therapy of emotions and their sanctification. Attending to various phases of his writings, this work explores the systematic structure of Augustine s tenets on passions and on the freedom from passions in the context of his philosophical and theological convictions on the issue of amor sui and amor Dei. The analysis begins by examining Augustine s language of passions and the doctrinal connections between Augustine and his predecessors. I provide a survey of Augustine s usage of emotional terms and criticise the position that Augustine suggested a dichotomy between passio and affectus as well as the claim that none of Augustine s Latin terms can be justifiably translated by the modern term emotion . On the basis of terminological and doctrinal observations, I clarify the general features of Augustine s psychology of passions in Chapter 2. In addressing the issue of how Augustine transformed his predecessors therapy of passions and their ideal of freedom from emotion into his theological framework in Chapter 3, I examine a series of related concepts, such as propatheia, metriopatheia, apatheia and eupatheia, to determine how he understood them in various stages of his philosophical and theological thinking. On this basis, I draw an outline of Augustine s interpretation of emotions in his theological anthropology. During his early period, Augustine adopted the Stoic and Platonic therapy of passions and the Stoic ideal of freedom from emotion (apatheia), but he changed his position later, re-evaluating the received terminologies and values of emotions (love, will, justice, virtue, etc.) from the perspective of the doctrines of sin and grace. He developed a theological vision and evaluation of the human condition of emotions and he expressed a pessimistic attitude towards the human condition without the help of supernatural grace. Chapter 4 addresses Augustine s position on the criticism and renewal of passions in social life: the household, city, and the world. In Chapter 5, I argue that Augustine s ideal of freedom from passions was participation in the inner Trinitarian spiritual life by the bond of the Holy Spirit as a hallmark of deification. This is wholly dependent on the divine kenosis and the transaction in the person of Christ. By virtue of the gift of grace (the salvific real presence of the Holy Spirit in faith), the pilgrimaging citizens of the City of God will be elevated to the divine realm and become transformed into a better substance in the union with God in Heaven. Contrary to arguments by some Orthodox theologians, Augustine s theory of deification is not simply a matter of fulfilment of humanity without a genuine transformation. While grace improves the control of sinful impulses in the emotional life of believers who suffer the consequences of the damage of the soul through original sin, Augustine maintained that the new life in Heaven denotes freedom from this emotional condition as well as the non-apathetic peaceful love and joy of resurrected persons in their participation in the divine spiritual nature.
  • Hirvonen, Sami-Pekka (Helsingin yliopisto, 2015)
    Poly(benzimidazobenzophenanthroline) (BBL), which may be doped into a p- and n-type semiconductor, has been chemically modified to enhance its processability. In its pristine form BBL is processable only in some concentrated acids and nitromethane/Lewis acid solutions. The corrosiveness of these solvents and moisture sensitivity of the solutions severely limits the possibilities for the use of BBL as an electroactive material in organoelectronic devices and limit the possibilities for its post synthetic chemical modification. In this work processable BBL derivatives have been prepared using two different approaches i) preparation of block-copolymers by attachment of water soluble polymers on BBL functional chain ends ii) attaching bulky side groups on one of the monomers and using that as a starting material in the polymerization reaction. Short BBLs of DP 10 or 20 were prepared with functional chain ends and monofunctional poly(ethylene oxide) (PEO) or poly(N-isopropylacrylamide) of several different molecular weights were attached at the chain ends. Elemental analysis showed that the extent of chain end substitution varied quite a lot when PEO was used. It was also shown that thermogravimetric analysis (TGA) was not suitable to determine the fraction of PEO in BBL-PEO block-copolymers. However, the extent of chain end substitution using PNIPAM was evaluated using TGA. BBL-PEOs could be processed into aqueous dispersions at concentrations ≥ 1.5 mg/ml by means of ultrasonication, and these dispersions were proven to be colloidally very stable. The dispersions could be used to spin- or drop cast films. At higher concentrations BBL-PEO dispersions were shown to form gels. The reason for the gelling is the packing of the polymer into nano-wire structures which then aggregate into 3D-network. SEM- and cryo-TEM imaging confirmed the existence of wire-type structures. Wire structures and gelation were also observed for aqueous dispersions of pristine BBL. BBL-PNIPAM block-copolymers were found to be indispersible in water with PNIPAM fractions lower than 35 mass %. However, they gelled upon ultrasonication. With higher PNIPAM fractions the polymers were dispersible and did not form gels in any of the studied concentrations. Dispersibility in water and the colloidal stability of BBL-PEOs and BBL-PNIPAMs was attributed to electrostatic stabilization as the particles showed negative zeta-potentials. Dispersible BBL-PNIPAMs were more stable due the high amount of dissociative groups originating from the partial degradation of the amide moieties during the coupling to BBL. One of the monomers used to prepare BBL, 1,4,5,8-naphthalenetetracarboxylic acid 1,8-monoanhydride, was successfully mono- and dibrominated. The bromine was then used as a functional group and replaced either directly with 2-ethyl-1-hexylamine or substituted with azide and reacted with 1-hexyne. The modified monomers were used in preparation of BBL. BBLs bearing either 2-ethyl-1-hexylamine or 4-butyl-1,2,3-triazole groups were found to be sparingly soluble in dimethylsulphoxide and N-methyl-2-pyrrolidone.
  • Laitakari, Elina (Helsingin yliopisto, 2015)
    Background: In recent decades, the total number of burn injuries has decreased globally, while the number of childhood burns has been increasing. Infant burn victims are a specific group because they are highly dependent on parents or caregivers. Aim of the study: The aim of this study was to clarify special characteristics and clinical outcome of infant burns. The purpose of this study was to determine the incidence and trends of inpatient and outpatient treatments for burn-injured infants. Patients and methods: Burn victims younger than 1 year born 1990 2010 were identified from the National Institute of Health and Welfare (THL) and the Statistics Finland registers. The analysis consisted of the incidence of burn injury, trends of treatment, and risk factors for burns. Between 2005 and 2009 126 burn victims aged less than 1 year were treated in the Children s Hospital, Helsinki, Finland. Hospital electronic databases were searched to clarify detailed information and patients treated as inpatients and outpatients were analyzed separately. The HRQoL of the 126 burn-injured children was evaluated with a validated, standardized 17D questionnaire 5 to 9 years after the burn injury. Results: Between 1990 and 2011, 1842 infant burn victims were treated at Finnish hospitals. The annual overall incidence per 1000 persons rose from 0.77 to 2.04, and the incidence of outpatient-treated burns increased from 1.11 to 1.67. Based on the analysis, the risk factors for infant burn injuries are male gender, being firstborn, the mother s young age, and low socioeconomic status. During the 5-year study period 20 burn injured infants were treated as inpatients and 106 as outpatients in the Children s Hospital. Girls outnumbered boys in the inpatient-treated group, and 45% were younger than 6 months. The final mean TBSA was 8.5% (from 0.5 to 40%). In the outpatient group, 52% were boys, and 57% were aged 9 to 12 months. The final mean TBSA burned was 1.4% (range from 0.5 to 7%). Caregiver eyewitnessed the accident in 66% of the cases, and 44% of the burns were on the hands. Most burns occurred at home, and two thirds of the burns were scalds caused by hot liquids. The respondents (n=44, 35%) appeared not to suffer from long-term consequences of the burn injury, and the respondents and non-respondents proved to be similar in terms of age, injury severity, and treatment given. Conclusions: The number of infant burns increased in Finland during the study period. Two thirds of infant burns were scalds caused by hot liquids, and most of these were preventable. Firstborn boys aged 9 to 12 months of young mothers with low socioeconomic status are at greater risk for burn injuries. The long-term HRQoL of burn-injured children was comparable to that of the controls.
  • Helenius, Mikko (Helsingin yliopisto, 2015)
    Irreversible vascular remodeling has a central role in a variety of pathophysiological conditions including pulmonary arterial hypertension (PAH). Hypoxia and inflammation are prominent features in PAH, along with hyperplasia and hypertrophy of vessel wall layers. Although, endothelial cell (EC) dysfunction is thought to drive the multiple forms of vascular remodeling, the origins of this phenomenon are poorly understood. Extracellular ATP and its metabolites are important regulators of vascular tone, permeability, and homeostasis. Yet little is known about their role in pathological vascular remodeling. By using chronic hypoxia and PAH animal models as well as human PAH patient samples, this study was undertaken to evaluate the catalytic activities and expression levels of nucleoside triphosphate diphosphohydrolase-1 (NTPDase1, otherwise known as CD39) and other purine-converting ectoenzymes with a primary focus on vascular EC. For this purpose we employed thin-layer chromatographic enzyme assays with 3H-labelled nucleotide substrates, in combination with various immunoassays and qPCR. In addition we have developed a highly sensitive assay for simultaneous sensing of extracellular ATP and its metabolites and also a novel method for measuring CD39 activity in modeled to in vivo conditions. In functional assays, cells or animals were stimulated through purine signaling pathways and proliferation, apoptosis, permeability, and DNA damage were assayed. Our results clearly demonstrated that the activity of CD39 was downregulated in chronic hypoxia, monocrotaline induced animal models of PAH and in human PAH patients. Attenuated enzyme activities could create a niche in the vasculature where ATP levels were increased and adenosine levels were decreased. Even a small increase in ATP concentration was enough to induce an apoptosis-resistant, hyper-proliferative, and DNA-damageresistant phenotype in ECs of pulmonary origin. The observed effects were at least partly dependent on P2Y11 receptor activation. In addition, we found that low ATP concentrations could induce pulmonary smooth muscle cell proliferation and migration. Interestingly, we found that small apelin peptide could directly restore the downregulated CD39 activity. This study implies that purinergic signaling, ATP mediated cell activation in particular, plays a truly significant role in pathological vascular remodeling, and that it could be used as a therapeutic target. Moreover, purinergic signaling pathways could be used before vascular injury to precondition EC against irradiation or chemotherapy induced DNA damage.
  • Savolainen, Mari (Helsingin yliopisto, 2015)
    Parkinson's disease (PD) is characterized by a slow and gradual loss of neurons and subsequent loss of neurotransmitter dopamine in the movement-related nigrostriatal brain tracts. This causes symptoms of PD, which are resting tremor, rigidity and slowness of movement. Genetic and environmental factors are linked to PD, but its etiology is still largely unknown. Current drug therapies can only relieve the symptoms of PD but treatment to stop or delay the disease progression does not exist at the moment. The main findings in neuropathological characterization of the brain regions that are influenced in PD, are abnormal intraneuronal protein inclusions, called Lewy bodies. Insoluble, aggregated α-synuclein (aSyn) protein is the most abundant component of Lewy bodies. Pathological aggregation and accumulation of aSyn is associated with neuronal death in PD. Therefore, approaches to target aSyn as a potential disease-modifying treatment for PD have been under investigation. The aim of this study was to examine the role of prolyl oligopeptidase (PREP) and pharmacological inhibition of its enzymatic activity by KYP-2047 in aSyn aggregation. Using purified proteins and cell culture model, we showed that PREP forms direct protein-protein interaction with aSyn, thus enhancing its aggregation. KYP-2047 reduced the PREP-mediated aSyn aggregation in cell culture. Then the effects of PREP inhibition on aSyn aggregation were examined in vivo. The purpose was to first characterize a genetic mouse model, carrying mouse A30P mutated aSyn, which is linked to early-onset PD in humans, in order to find out if the mutated mouse aSyn is more prone to aggregate; and to cause PD-like phenotype. The effects of KYP-2047 treatments were assessed in the model. The main findings were that the A30P mutation in mouse aSyn protein caused minor hyperactive behaviour but did not change the brain dopamine levels, and A30P aSyn accumulated in the brain more than wildtype aSyn by age. KYP-2047 treatment reduced the amount of A30P aSyn in immunohistochemical analysis, and the reduction was more specific for high-molecular weight aSyn oligomers in Western blot analysis. We also observed increased autophagy markers in brain tissue. Therefore, PREP inhibition was further studied in cell culture, where it was shown to enhance macroautophagic protein clearance pathway, which is an important pathway in the degradation of high-molecular weight aSyn forms. In the last study, the effects of KYP-2047 were examined in a mouse model of PD that was based on lactacystin-induced inhibition of ubiquitin-proteasome protein degradation pathway. Proteasome inhibition was shown to induce rapid PD-like neurodegeneration recapitulating the cardinal features of PD. KYP-2047 treatment partially protected dopaminergic neurons in the brain and had beneficial effect on motor behaviour, but did not have an effect on aSyn amount. Taken together, this study has provided new insights into the role of PREP in aSyn aggregation and suggest that PREP inhibition has beneficial effects on reducing the aggregation process via two mechanisms. PREP inhibition could be promising and further assessed in the treatment of PD, other α-synucleinopathies and possibly other protein accumulation diseases.
  • Hellsten, Kati Susanna (Helsingin yliopisto, 2015)
    GABAergic inhibition is crucial for regulation of neuronal excitability and hence for optimal function of the nervous system. The GABAA receptor forms a pentameric ligand-gated anion channel. The subunit combinations of the receptors define their pharmacological and electrophysiological properties. The individual subunits display a distinct but often widespread distribution throughout the nervous system. GABAA receptor-mediated inhibition can be divided to fast and transient synaptic inhibition and to background (tonic) inhibition that is mediated by extrasynaptic GABAA receptors. The synaptic inhibition regulates the rhythmic activities in neuronal networks. Benzodiazepines, interacting with an allosteric binding site of GABAA receptors typically concentrated at synaptic locations, are anxiolytic drugs, but their long-term use evokes severe side-effects. The functional role of extrasynaptic GABAA receptor-mediated inhibition is not yet well understood. Expanding the understanding of local role of GABAA receptors and neuronal circuits mediating anxiolysis is relevant for the development of more selective and safe treatment for anxiety disorders. Studying the properties of extrasynaptic GABAA receptors may help to understand their physiological relevance and role in psychiatric and neurological disorders. The main objectives of this thesis were to study the local expression of benzodiazepine-sensitive GABAA receptors in human locus coeruleus (LC), the pharmacology of extrasynaptic GABAA receptors in vivo (in mice) and in vitro and the brain structures mediating acute anxiolytic responses in a transgenic mouse model as a consequence of enhanced tonic inhibition in specific forebrain structures. Firstly, the present in situ hybridization and receptor autoradiography studies in human LC revealed benzodiazepine binding sites indicating that LC may directly mediate the sedative and/or anxiolytic effects of benzodiazepines in humans. Previously, contradictory reports had been published in regard to the benzodiazepine binding sites in the rodent LC suggesting a potential species difference in the direct sites of action of benzodiazepines. Secondly, the behavioral tests showed that gaboxadol, a GABA site agonist, acts preferentially via extrasynaptic α6β/γ2 receptors in vivo as the transgenic mice overexpressing these receptors were significantly more sensitive to the anxiolytic and hypnotic effects of gaboxadol than the wild-type mice. Electrophysiological recordings on recombinant receptors revealed that GABA is a partial agonist as compared to gaboxadol at α6β3, α6β3δ and α4β3δ receptors but not at α6β3γ2 receptors. Gaboxadol and GABA displayed also different receptor desensitization and deactivation kinetics on these receptors. Thirdly, by increasing tonic inhibition in specific forebrain structures, the anxiolytic dose of gaboxadol increased c-Fos expression in the transgenic mouse model especially in the limbic areas, such as the cingulate cortex, septal nuclei, central extended amygdala and basolateral nucleus of amygdala. In addition to demonstrating how neuronal excitability can be altered in different brain regions as a consequence of enhanced tonic inhibition, this result suggests that a widespread neuronal inhibition, as typically associated with benzodiazepines, may not be the exclusive mechanism of acute anxiolysis.
  • Sheehy, Jatta (Helsingin yliopisto, 2015)
    Soils comprise more carbon (C) than any other terrestrial source and hence even a small change in the C content can be significant in regards to atmospheric CO2 concentration. Cultivated soils have lost soil organic carbon (SOC) during the latest decades in Finland. New cereal crop management practices, like no-till (NT) and reduced tillage (RT), can affect not only soil organic carbon (SOC) stocks and stabilization, but also nitrous oxide (N2O) emissions. The aim of this study was to gain better understanding about the changes in soil C dynamics and N2O emissions as a result of management practice changes in the boreal region, and the implications of these changes to climate change mitigation. Changes in SOC stocks and stabilization rates under different tillage (NT, RT, CT (conventional tillage with a moldboard plow)) and straw management (straw retention, straw removal, straw burning) practices, were studied at different sites with clayey and coarse textured soil across southern Finland. This was done by soil fractionation method (wet sieving and microaggregate isolation) to elucidate the composition of different soil fractions, namely large and small macroaggregates, microaggregates, silt and clay and macroaggregate-occluded soil fractions, and where the C is stored within them. The effects of Lumbricus terrestris on SOC were studied using the same method. Nitrous oxide fluxes were monitored biweekly for 2 years under CT, NT and RT practices using closed chambers. Measurements of several environmental and soil parameters were taken to study the underlying factors controlling the observed changes in soil C stocks and N2O emissions under the different management practices. Climate change mitigation potential through the studied cereal crop management practices seems small in the humid boreal region based on the results of this study. The minimum tillage treatments did not sequester SOC at any of the study sites which had been under NT or RT for a decade and the total C stocks were lower in the 0 15 cm topsoil layer at one clayey site under RT compared to CT after implementing RT for 30 years. All clayey sites had a fairly high SOC content originally and all sites had higher decomposition rate of crop residues in NT compared to CT, possibly hindering C sequestration. However, the aggregate stability was enhanced in NT cropping systems compared to CT, and NT increased the amount of SOC in large macroaggregates at several sites and in microaggregates within macroaggregates in the coarse textured site. L. terrestris mediated the formation of soil aggregates and the increase of SOC in the topsoil but possibly enhanced the decomposition rate in the soils. Cumulative N2O emissions were higher under NT compared to both CT and RT at the clayey sites and lower at the coarse textured site. However, the coarse textured site under NT received slightly less N fertilizer compared to CT. Increased N2O emissions under NT on clayey soils were likely due to denser soil structure with consistently higher soil moisture content and poor aeration. Therefore, mitigating N2O emissions requires special attention to soil structure and drainage. This study suggests that RT is a notable option to control N2O emissions. In the future, climate change could increase precipitation and freeze-thaw cycles in boreal agroecosystems possibly enhancing N2O fluxes and C losses of cultivated soils which puts pressure on finding new mitigation measures.