Väitöskirjat

Recent Submissions

  • Lallukka, Susanna (Helsingin yliopisto, 2018)
    Non-alcoholic fatty liver disease (NAFLD) may result from obesity accompanied by insulin resistance and adipose tissue inflammation or from the common genetic variants in PNPLA3 (rs738409, C>G/I148M), TM6SF2 (rs58542926, C>T/E167K) and MBOAT7 (rs641738, C>T). These variants increase the liver fat content and the severity of NAFLD without features of insulin resistance. This thesis aimed to determine the following: i) whether NAFLD predicts type 2 diabetes independent of obesity and other known risk factors; ii) whether adipose tissue is inflamed in subjects homozygous for the PNPLA3 I148M variant; iii) whether obesity and insulin resistance rather than liver fat content increase coagulation factor activities and expression; and iv) which factors predict NAFLD and liver stiffness during an 11-year follow-up period. The present thesis includes one systematic review, two cross-sectional studies and one longitudinal study. Study subjects comprised Finnish adult men and women. Liver fat content was measured by proton magnetic resonance spectroscopy (studies II–IV). The gene expression of inflammatory markers in adipose tissue and that of coagulation factors in the liver were measured using qPCR (studies II and III). We conducted a systematic review of prospective longitudinal studies to determine if NAFLD predicts type 2 diabetes for aim i). Based on these studies ultrasound-diagnosed NAFLD and liver enzymes predict type 2 diabetes independent of confounders such as age and obesity. We found no studies indicating that NAFLD associated with genetic risk variants predicting future risk of type 2 diabetes. A group of 82 subjects were divided into two groups based on body mass index and PNPLA3 genotype for aim ii). The liver fat content was similarly increased in obese/insulin-resistant subjects and in carriers of the I148M variant compared to non-obese subjects and non-carriers of this variant. In obese subjects, the adipose tissue expression of pro-inflammatory chemokine MCP-1 was increased and anti-inflammatory ADIPOQ and TWIST1 were decreased compared with non-obese subjects, while these were comparable between carriers and non-carriers of the I148M variant. In study III, 92 non-diabetic subjects were divided into two groups based on insulin sensitivity (HOMA-IR) and PNPLA3 genotype. Coagulation factor activities (FVIII, FIX, FXIII, fibrinogen and VWF:RCo) were increased, and the prothrombin time and activated partial thromboplastin time were shortened in insulin-resistant subjects when compared to insulin-sensitive subjects; yet, these factors were similar in carriers and non-carriers of the I148M variant. The hepatic gene expression of FVIII, FIX and fibrinogen gamma-chain were higher in insulin-resistant subjects with NAFLD (n=13) compared with equally obese insulin-sensitive subjects without NAFLD (n=13). In study IV, 97 subjects were examined twice over an interval of 11 years. The baseline liver fat content independently predicted NAFLD and an increased liver stiffness (measured using transient elastography) at 11.3 years more accurately than routinely available clinical and biochemical parameters. Conclusions: Obesity, adipose tissue inflammation and insulin resistance rather than excess hepatic fat per se are related to an increased risk of type 2 diabetes and a pro-coagulant plasma profile observed often in NAFLD. However, the liver fat content emerges as more important predictor of advanced liver fibrosis than the associated metabolic abnormalities. These data support the view that NAFLD is heterogeneous disease.
  • Pihlgren-Eveli, Ann-Kristin (Helsingin yliopisto, 2017)
    Jag har designat en litterär storyline som två lärare i årskurs 7 har genomfört i två klasser i en finlandssvensk skola. Storylinen utgår från boken En ö i havet (1996) av Annika Thor och handlar om två österrikiska judiska syskon som av sina föräldrar sänds till Sverige för att undkomma judeförföljelsen under andra världskriget. Boken, vars överordnade tema är kulturmöten, erbjuder en bearbetning av mångdimensionella existentiella livsfrågor. Fältstudien präglas av en etnografisk metodisk ansats med aktionsinriktning. Min forskarroll i klassrummet är en passiv observatör där jag gör temporära interventioner under pågående projekt. Studien betraktas dels ur ett litteraturpedagogiskt perspektiv, dels ur ett kritiskt mångkulturellt pedagogiskt perspektiv där interkulturell förståelse är centralt. Eleverna har individuellt och kollektivt arbetat inom olika genrer med så kallade nyckelfrågor som rör flyktingar, kulturell tillhörighet och möten i fiktionen och i deras egna liv. Deras produktion analyseras genom receptionsanalys och meningskoncentrering. Studien bidrar till ny kunskap inom tre områden: det kunskapsmässiga, det metodologiska och det didaktiska området. För det första gäller kunskapsbidraget elevers förståelse av en historisk och aktuell samhällsproblematik i en finlandssvensk skolkontext. För det andra är kombinationen av receptionsanalys av litterär storyline och en teoristyrd analys och tolkning av ett digert material ett innovativt metodologiskt bidrag. Till detta fogas dessutom ett litteraturpedagogiskt perspektiv och en presentation av kritisk mångkulturell pedagogisk teori. För det tredje bidrar studien till utveckling av en didaktik där litteraturpedagogiska redskap och interkulturellt pedagogiskt tänkande skapat en gränsöverskridande didaktisk design med stor potential för djuplärande i förhållande till existentiella frågor i unga människors liv. Eleverna visar i olika grad förstärkt medvetande och kritiskt engagemang angående tematiken i Annika Thors bok. Hos merparten framgår en öppen attityd till andra etniciteter och människor som är annorlunda än dem själva. De har dock alltjämt fördomar och etnocentriska och stereotypa uppfattningar. Men de uttrycker också en antydan till förståelse av och empati för krigsbarnen och judarna under andra världskriget både i fiktionen och i verkligheten. I viss mån visar de tendenser till förståelse av och empati för dagens flyktingar. För att optimera litterär storyline som interkulturell pedagogisk metod krävs en utförlig kritisk reflektion och granskning av elevernas värderingar i helklass. Detta förutsätter stor kompetens av läraren, varför utbildning i kritisk mångkulturell pedagogik behövs. Nyckelord: Litteraturpedagogik, kritisk mångkulturell pedagogik, storyline, kulturell mångfald, kulturella minoriteter
  • Magnusson, Roland (Helsingin yliopisto, 2017)
    This thesis consists of three essays on the use of economic instruments in environmental policy. The first essay analyses the case for interstate cooperation in environmental taxation while the second and the third essays study questions specific to the use of economic instruments in climate change mitigation. The first essay analyses the incentives of national governments to cooperate in regulating pollutants that spill over jurisdictional boundaries. A well-established result within the literature that assumes perfect competition is that a country, which is small in the sense that it cannot affect world prices, has no incentive to depart from the cooperative choice of environmental regulation. By generalising the model presented by Oates and Schwab (1987, 1988) it is shown that this result does not hold for pollutants that have regional or global characteristics, as e.g. sulphur dioxide (SO2) and carbon dioxide (CO2) have. The second essay demonstrates a methodology for analysing the progress and failure of projects in the CDM. It models the hazard of first issuance. Integrated over duration, the hazard of first issuance gives the time to market, defined as the duration between the start of the Global Stakeholder Process and the first issuance of Certified Emissions Reductions (CERs). It is shown that 50\% of all projects which have started the Global Stakeholder Process fail to issue CERs, while the remainder has a median time to market of 4 years. The third essay illustrates a paradox in which overlapping climate policy instruments may have the unintended consequence of accelerating rather than decelerating global warming. The insight follows from a dynamic model, where a quota obligation for power generated from renewables is introduced alongside a carbon budget. A dynamic model allows to study how the schedule at which the carbon budget is exhausted is affected by the quota obligation. The exhaustion schedule determines the global temperature response.
  • Saarinen, Jukka (Helsingin yliopisto, 2018)
    This study deals with the poetics of the Finnic tradition of oral poetry known as kalevalaic poetry, concentrating on the interplay between verse structure, syntax and parallelism. The research material consists of all recorded texts of the singer Arhippa Perttunen (1769–1841) from Viena Karelia. This material is approached from two perspectives: folkloristic research on an individual tradition bearer and linguistic analysis elucidating the poetic structures of the texts. The first perspective examines how an individual uses and moulds tradition. The second examines what traits and features in general define and characterise texts in this tradition. These perspectives overlap in the process of composition, which is treated especially by recourse to the theories of the Oral-Formulaic School. The kalevalaic tradition is a poetic register, here addressed through two concepts frequently used in contemporary research on oral poetry: the concept of "register" developed by the systemic-functional approach in linguistics, and the concept of the poetic function of language developed by Roman Jakobson. The study on the syntax of the poems takes as a starting point the theory of enjambement in kalevalaic poetry, as expounded by Matti Kuusi. Kuusi’s theory is advanced by refining his rules for enjambement and rules for combining different syntactic units within a line. Parallelism is a very characteristic feature of kalevalaic poetry. Its most distinctive form, verse parallelism, is studied in detail as a syntactic-semantic phenomenon. It is shown how a set of parallel verses functions to create a poetic picture that is richer in meaning than the verses could convey separately. The research presents and analyses all the information available concerning Arhippa. His narrative poems appear to be quite stable from one sung performance to another, but they usually diverge from the variants of other singers. From this it can be deduced that the shaping of each song for the most part occurred when he acquired it. With respect to lyrical and other non-narrative poems, Arhippa seems to have always been able to create new entities from poems with which he was already familiar or from other traditional materials, especially proverbs.
  • Du, Mian (Helsingin yliopisto, 2017)
    The ongoing information explosion has a particular impact on business areas, involving corporate strategy and business decision-making. Business intelligence tools aim to help users to understand market trends, which is critical for their day-to-day operations. For example, it is a typical business intelligence task to effectively obtain accurate and relevant information about the competitor’s activity in the same industry sector. This thesis presents research on a natural language processing system, which aims to address the problem of information overload in the business domain. It uses document filtering, information extraction, and supervised and semi-supervised learning. Input to the system includes news documents from on-line news websites and company press pages. We first demonstrate that a combination of NLP techniques and frequent sequential pattern mining can be used for finding patterns from unstructured natural-language text, i.e., news articles. The patterns relate to a specific domain of news. Evaluation results show that scenario-based summarization can filter out irrelevant documents and also extract important sentences from relevant documents as summaries for pre-defined scenarios in a specific domain. For document-level filtering, this method achieves very high precision, while keeping quite high recall in our study. Next, we present experiments with supervised learning for labelling business-news documents with multiple industry sectors. The main contribution is that combining a named-entity-based rote classifier with the balanced classifiers yields better results than either classifier alone. This method also improves on the best score previously reported, while using the same amount of training data for the rote classifier, and considerably less for the statistical classifiers. We then explore the interplay between company news, social media visibility, and stock prices. Information extracted from on-line news by means of the deep linguistic analysis is used to construct queries to various social media platforms. The main results presented in the thesis demonstrate the interesting correlations between the mentions of a company in the news and the views of its page in Wikipedia. Based on the above research topics, the thesis also presents the design and architecture of a complete decision-support system. The system is an example of using the above research results to extract, analyze and organize information from plain-text news.
  • Alstola, Tero (Helsingin yliopisto, 2018)
    Judeans in Babylonia: A Study of Deportees in the Sixth and Fifth Centuries BCE The dissertation investigates Judean deportees in Babylonia in the sixth and fifth centuries BCE. These people arrived in Babylonia from Judah in the early sixth century BCE, being but one of numerous ethnic groups deported and resettled by King Nebuchadnezzar II. Naming practices among many deportee groups have been thoroughly analysed, but there has been little interest in writing a socio-historical study of Judeans or other immigrants in Babylonia on the basis of cuneiform sources. The present dissertation fills this gap by conducting a case study of Judean deportees and placing its results in the wider context of Babylonian society. The results from the study of Judeans are evaluated by using a group of Neirabian deportees as a point of comparison. The sources of this study consist of 289 clay tablets written in Akkadian cuneiform. The texts are legal and administrative documents such as promissory notes, leases, receipts, and lists. The texts are rarely isolates and normally they can be connected to larger private and institutional archives. Analysis of the source texts as part of larger archives significantly contributes to our understanding of the socio-economic framework of these texts and the people attested in them. Babylonian sources rarely make the ethnic or geographic origin of people explicit, and naming practices are the most important method to identify immigrants in cuneiform texts. Yahwistic theophoric names – that is, names which refer to the god Yahweh – can be used to identify Judeans in Babylonia. The dissertation shows that most Judeans and other deportees were settled in rural communities according to their geographic origin and integrated into the land-for-service sector of Babylonian agriculture. The deportees were given plots of land to cultivate, and in exchange they were obliged to pay taxes and perform work and military service. Some Judeans were able to profit from the system by working as middlemen between the royal administration and their fellow landholders, while other Judeans worked as minor officials in local administration. Nevertheless, the majority of small farmers lived at a subsistence level. Not all deportees were settled in the countryside, as their labour was also needed in cities. Foreign craftsmen, merchants, and soldiers worked in royal service, and a number of deportees made their way to local and regional administrations in Babylonia. Members of foreign royalty were deported to Babylon, and the Judean king Jehoiachin and his retinue were held hostage there in order to prevent rebellions in the vassal state of Judah. A relatively small number of deportees were turned into slaves or temple dependants. The Babylonian practice of settling deportees in ethnically homogenous rural communities supported the survival of their culture in the countryside. Although the deportees were integrated into the Babylonian economy, there is less evidence of social and cultural integration. Adoption of local culture was faster among those deportees who lived in cities and were in regular contact with the native population. Very little can be said about Judean religious practices, however. The available sources hardly ever touch upon this issue, and naming practices only indicate that the worship of Yahweh probably continued in some form in the late fifth century BCE.
  • Uutela, Marjo (Helsingin yliopisto, 2018)
    The thesis examines with primary sources, how Finland nullified the military articles of the Paris Peace Treaty and the reference to Germany as a potential aggressor in the FCMA-Treaty in September 1990. This project, called later “Operation Pax”, paralleled the restoration of reunified Germany’s full sovereignty in Finland. The study is located in the intersection of Cold War political history and international relations. It utilizes new primary source materials from Finland and Germany and theoretical tools from international relations. The thesis describes first how the Finnish foreign policy leadership interpreted the Paris Peace Treaty during the Cold War years 1962 and 1983. The analysis focuses especially on how the international position of the two German states affected interpreting the Peace Treaty 1987–1990. The main emphasis is on the unilateral move of the Finnish government to reinterpret the military articles of the Peace Treaty in 1990. Easing of tensions between the superpowers and the German states made it possible for President Mauno Koivisto to allow importing a German civilian plane to Finland in 1987 without consulting the Soviet Union and Great Britain, even though acquiring aircraft from Germany was prohibited in the Peace Treaty. Because the decision was made unilateral, it meant differing from usual foreign policy practices and is thus seen as a turning point in the thesis, although importing civilian aircraft was not in itself of great significance. The study concludes that ”Operation Pax” was one of the most important Finnish cases of interpreting the Peace Treaty. Yet, nullifying military articles in 1990 did not change Finland’s international orientation or political goals. Finland’s neutrality policy remained intact. “Operation Pax” was an act of sovereignty, but the leading motive behind it was military-political. In order to acquire weaponry from Germany, the Finnish Ministry of Defence had suggested in November 1989 that the military articles could undergo changes. In June 1990 the Ministry for Foreign Affairs justified in its memorandum to Koivisto the importance of the plan with the interest that the Finnish Defence Forces had in German and Japanese weapons systems.
  • Posti, Mikko (Helsingin yliopisto, 2017)
    This dissertation is a historical and a philosophical study concerning the doctrine of divine providence, as it was understood in Latin academic theology in 13th and 14th centuries. The method of the study is systematic analysis. The aim of the study is to understand the meaning and the doctrinal value of divine providence for some of the most important authors in the era, and analyse philosophical and theological problems that these authors considered important. The dissertation consists of four chapters. In the first chapter, the historical background of the Christian idea of a provident God is traced from Plato and Aristotle and the Hellenistic schools of philosophy to the late ancient Christian authors Augustine and Boethius. Particular attention is paid to the nascent Platonic and Aristotelian traditions of understanding providence. In the second and third chapters, the ideas that a number of medieval authors held on providence are analysed. Some of the most important authors in chapters 2 and 3 include Thomas Aquinas, Siger of Brabant, Matthew of Aquasparta, Peter Auriol, Robert Holkot and Thomas Bradwardine. The fourth chapter focuses on a relatively unknown 13th century work Liber de bona fortuna, attributed to Aristotle. Liber de bona fortuna, consisting of Latin translations of chapters found originally in Aristotle’s Ethica Eudemia and Magna Moralia, asks whether good fortune ought to be attributed to nature, intellect or god. A number of medieval authors, including e.g. Thomas Aquinas, Giles of Rome, Henry of Ghent, John Duns Scotus and Peter Auriol, became highly interested in Liber de bona fortuna. They provided original explanations of the phenomenon of good fortune, ranging from Henry of Ghent’s providential model to Giles of Rome’s naturalistic and Peter Auriol’s psychologizing explanations. This study shows that the central philosophical questions regarding providence, considered important in the ancient era, were inherited and adopted in medieval theology. These questions include most importantly 1. Whether divine providence is reconcilable with freedom of the will and contingency in general; 2. Whether divine providence is concerned with all particular beings, or exclusively with species of beings; and 3. Does divine providence cause its effects immediately or through the mediation of a chain of secondary causes. A special theme regarding the first question is how divine providence may be reconciled with evil and sinful actions committed by rational agents. I argue that two different strategies of treating these questions may be distinguished in the philosophical thought of the 13th and 14th centuries. According to the accidental strategy of reconciling divine providence and evil, evil results accidentally from God’s good providential plan. While evil is not part of divine providence qua evil, it comes under the influence of providence by receiving a just punishment. In contrast, the instrumental strategy of reconciling divine providence and evil treats evil as an instrument used by God for advancing his good plan for the creation. While evil remains evil considered from the created perspective, considered from the divine perspective it has an instrumental function. It is noted that while some authors display a clear preference for one of these strategies, other authors employ them side by side.
  • Spel, Oghogho Christal (Helsingin yliopisto, 2017)
    This study explores why poor African migrants remain in Johannesburg, South Africa’s harsh migration context, to build their lives, and how, in pursuit of a better future, they engage with the various forms of socioeconomic and political constraints that they experience. Popular as a destination for African migrants, South Africa is a country with a very high percentage of asylum seekers, but also a place where they are the targets of violent xenophobia. Yet such migrants are known to live for years in this situation, one which is generally considered socio-economically and politically marginalized and constraining. Their continued presence raises the pertinent sociological query of how and why such large numbers have remained in their host society, continuing to welcome new incoming members, while others have left, been imprisoned or murdered, or died of a range of ailments. Methodologically, resilience theory - conceptualised as a dynamic process of interaction between the individual and his or her environment – is utilised as an explanatory and descriptive framework to examine the subject of this study. Data for the study were collected through life-story interviews with African migrants who are economically active on the streets of Johannesburg, and document analysis was utilised for triangulation purposes. Data were analysed using narrative analysis. Empirical observations called attention to the prominence of aspirations for a better life amongst the informal migrants, an observation that is accompanied by several relevant findings: firstly, that the migrants’ resilience in their constraining environment cannot be attributed to itemized factors. Rather, their resilience takes the form of a dynamic and interactive engagement with the South African context. The interactions are orchestrated by their perceptions of opportunities in their home countries and the South African society, and combined with the application of faith and tactics in dealing with identified adverse conditions. Their resilience is presented as enduring but also transient, as it is subject to individuals’ evaluations and negotiations. In that light, the migrants are shown to be active agents but also victims in their harsh context, calling attention to the duality of the informal migrants’ experience in Johannesburg, irrespective of their violent xenophobic environment. Consequently, considerable challenges are posed to the projects of classifying informal migrants as either passive victims or active agents, and listing or identifying specific factors as means to attaining resilience. Secondly, an observed fallout from the interviewees’ notion of hope – aspiration – is the productive use of ‘waiting time’. The hegemonic control of the interviewees’ time through, for example, official delays or manipulation in the processing of asylum applications, is challenged by the tactical and creative utilization of the period of waiting in which two things stood out: micro-entrepreneurship and development of their social and personal lives but particularly micro-entrepreneurship, as the interviewees focused on achieving a better life through micro businesses. Their engagement in trade and services in a context devoid of institutional support, and under dire personal circumstances, though borne of feelings of ‘no alternatives’, suggests creativity, with potential for growth. Furthermore, my interviewees were also able to make productive social use of the ‘time of waiting’ even as asylum seekers. Living in the city, my interviewees took initiatives to learn new skills, develop new intimate and business relationships, had children, and so on. Their lives reveal that even as asylum seekers, they were slowly building the futures they desired, for instance, through savings and personal projects in the home country. On the basis of empirical observations, the conclusions drawn indicate the limitations of policy in terms of improving the experience of informal migrants, and raises questions concerning the moral or ethical values (or lack thereof) involved in perpetuating their vulnerability – thus calling attention to questions of choice and agency in acts dehumanising informal migrants. Moreover, observations of micro-entrepreneurship beg another question. Could migration management be mutually beneficial if a context conducive to migrants’ entrepreneurial pursuits is promoted? As a contribution to the body of knowledge of Social Policy, the author uses the perspective of the informal migrants as active agents and social victims to argue that political inclusion by the host country cannot be enough to improve the wellbeing of informal migrants. Thus, the author theoretically reflects on the relevance of Social Policy in improving human welfare and emphasizes the informal migrants’ experience of vulnerability as a creative opportunity to engage the development of Social Policy in Africa, for example, from a regional body. Therefore, the thesis postulates that the dilemma of better lives for informal African migrants is a regional political question of belongingness, care, and social responsibility.
  • Tikka, Anna (Helsingin yliopisto, 2018)
    Johdanto: Väitöstyön tarkoituksena oli tutkia ANGPTL3 puutoksen aiheuttamia muutoksia ihmisessä rasva-aineenvaihdunnan osalta kliinisesti, populaatiotasolla sekä solutasolla. ANGPTL3 proteiinin on osoitettu säätelevän lipoproteiinilipaasin (LPL) toimintaa ja siten osallistuvan maksasta sekä ohutsuolesta syntetisoitujen kolmiarvoisten (triglyseridi, TG) rasvojen poistoon verenkierrosta. ANGPTL3 toiminnan estymiseen vaikuttavat mutaatiot (LOF; loss of function) aiheuttavat familiaaliseen hypolipidemian fenotyypin (FHBL2), jonka pääpiirteenä on matalat veren VLDL, LDL ja HDL lipoproteiinien tasot. Päämenetelmät: Solumalleilla tutkittiin ANGPTL3:n kudosspesifistä toimintamekanismia hiljentämällä ANGPTL3 shRNA-lentivirus vektorilla hepatosyyteissä sekä enterosyyteissä. Tutkittavien lipidien ja proteiinien tasoja mitattiin sekä soluista että solumediasta entsymaattisilla menetelmillä sekä ELISA menetelmillä. Leimattujen substraattien avulla selvitettiin solujen metabolian muutoksia. Geenien ilmentymistä soluissa tutkittiin kvantitatiivisella PCR (qPCR)-analyysillä. Koe-henkilöt, joihin kuului ANGPTL3 LOF kantajia sekä kontrollihenkilöitä nauttivat rasvapitoisen aterian, jonka jälkeen kerätyistä plasmanäytteistä mitattiin lipoproteiinien, rasva-aineenvaihdunnan markkereiden sekä TG:ien, kolesterolin ja fosfolipidien pitoisuuksia. Populaatiotutkimuksessa suomalaisten ANGPTL3 varianttien kantajien lipiditasot määritettiin tarkoituksena selvittää ANGPTL3 varianttien osuutta dyslipidemioissa. Verenkierrossa olevan ANGPTL3-proteiinin konsentraatio mitattiin henkilöiltä, joiden lipidiarvot vastasivat hyper- tai hypolipidemiaa, jonka jälkeen tasoja verrattiin lipidiarvoihin sekä muihin lipidimetabolian biomarkkereihin mahdollisten korrelaatioiden löytämiseksi. Johtopäätökset: Tulosten perusteella ANGPTL3:n ilmentymistä soluissa säätelevät insuliini, PPARy-agonisti rosiglitazone sekä LXR-agonistit. ANGPTL3-hiljennys aiheuttaa VLDL-partikkelien lipidaation laskua hepatosyyteissä insuliini stimuloinnin aikana sekä CD36- ja PLTP-geenien ilmentymistason laskua soluissa. ANGPLT3-LOF kantajien kliinisessä tutkimuksessa havaittiin, että ANGPTL3-puutoksen omaavilla homotsygooteilla LOF kantajilla ei esiintynyt postprandiaalista hyperlipidemiaa, toisin kuin heterotsygooteilla kantajilla ja kontrollihenkilöillä, ja tämän fenotyypin voidaan katsoa olevan ateroskleroosia ehkäisevä tekijä. ANGPTL3 puutos aiheuttaa myös veren rasvahappojen määrän vähenemistä verenkierrossa ja siten mahdollisesti vähentää maksaan päätyvien rasvahappojen määrää ja niiden oksidaatiota. Populaatiotutkimuksessa ANGPTL3-varianttien kantajien osuus oli vähäinen, ja dyslipidemiaa oli havaittavissa yhdellä haitallisen variantin kantajalla. Varianttia ei vähäisen kantajien määrän takia pystytä luotettavasti kausaalisesti yhdistämään fenotyyppien aiheuttajaksi. ANGPTL3:n plasma tasot eivät eronneet hypo- tai hyperlipideemisten henkilöiden välillä, ja täten voidaan todeta, että ANGPTL3:n plasmapitoisuudet eivät toimi hyvänä biomarkkerina ennustettaessa veren lipiditasoja.
  • Mikkola, Sini (Helsingin yliopisto, 2017)
    This doctoral dissertation examines Martin Luther’s view of the human being during a decade of ecclesiastical, social, and political turmoil. The vital perspectives in scrutinizing Luther’s anthropology are gender, bodiliness, sexuality, and power. The study first asks how gendered bodiliness was treated in Luther’s discussions on femininity and masculinity, and, consequently, in what way he constructed proper feminine and masculine ways of being and developed the gender system. Under scrutiny are the ideals, norms, and expectations that he framed on the grounds of the gendered body. Thirdly, it is asked whether Luther’s views varied according to historical and textual context, and especially if there are differences between his views of female and male ways of being that are presented in theory, on the one hand, and in practical situations, on the other. The most important contextual factors that set the background for analyzing Luther’s viewpoints are, by and large, the debate on the proper kind of Christian life—whether it should be lived in the cloister or in matrimony—and Luther’s changing personal situation from Augustinian friar to husband and father. The time frame of the study is set from 1520 to 1530—a decade that is less studied in modern research from the viewpoint of gender than, for example, the following one. The structure of the study is thematic, yet it follows a loose chronology. It is thus easier to explore a possible chronological shift in Luther’s language and thinking, and especially whether changes in his personal life or in church and society somehow affected his views concerning the body, gendered ways of being, and the gender system. Many of the key concepts of the study—such as gender and the gender system, power, authority, and otherness—have been adopted from gender studies. Methodologically, the texts are examined through a close critical reading and content analysis of the sources to discuss both the explicit and the implicit dimensions of Luther’s discussion. Texts from the Weimarer Ausgabe (D. Martin Luther’s Werke: Kritische Gesamtausgabe) are used as the source material. The study shows that Luther formulated his views on gender and the gender system firmly on the basis of human bodiliness. The penetrable theoretical idea that Luther deducted from gendered bodiliness was gender hierarchy: the woman’s subordination and otherness, and the man’s normativity and dominion. Luther participated in the reconstruction of femininity and masculinity in close interaction with the past and the present: he was in several ways affected by and bound to his medieval heritage and to the views of his contemporaries. Furthermore, the study proves that overall, Luther’s thinking concerning the gender system did not undergo major changes during the 1520s, but instead involved smaller adjustments. The analyses of real-life situations reveal that Luther could be flexible in his viewpoints concerning the limits that one’s gender constituted—he allowed different rules especially for himself, for instance. However, in many cases regarding his fellow men and women he applied his theoretical views in practice in a very strict sense. Therefore, it is not the difference between theory and practice per se that is pervasive in Luther’s texts. The study proves that the difference between Luther’s practical views and theory is chiefly dictated by subsidiarity. The two core ideas are: (1) the closer to Luther, the more special the case, and (2) the more strategically important for Luther, the more special the case.
  • Laine, Niina (Helsingin yliopisto, 2017)
    BACKGROUND AND OBJECTIVES Rational use of antimicrobials is paramount due to increasing bacterial resistance and a lack of novel antimicrobials. Investigating the clinical use and consumption of antimicrobials aids in the prudent use of these drugs in a tertiary paediatric hospital. The purpose of this study was to obtain detailed information on the use of antimicrobials in a tertiary Children’s Hospital, Helsinki University Hospital, in order to support prudent, safe and efficient use of antimicrobials. The objectives were the following: 1) To evaluate the appropriateness of antimicrobial therapy (AMT) in children with blood culture positive infections (Study I), 2) To investigate the consumption of antimicrobials in the hospital in Defined Daily Doses (Study II), 3) To record the prevalence of off-label use of antimicrobials in neonates (Study III) and last, 4) To analyse the occurrence of antimicrobial medication errors in children (Study IV). MATERIALS AND METHODS The Children’s Hospital, University of Helsinki, is a tertiary hospital in Finland. In Study I, data on 149 children (0–17 years) with blood culture positive hospital infections between 2005 and 2012 were collected. In Study II, the consumption of antimicrobials in Defined Daily Doses (DDDs according to the Anatomical Therapeutic Chemical (ATC)/DDD index) was investigated retrospectively between 2003 and 2013. In Study III, the prevalence of off-label use of antimicrobials was investigated in three different paediatric cohorts. The largest cohort consisted of premature NICU patients (450–2000g) with blood culture positive infections and antimicrobial therapy given between 2005 and 2014 (N=282). In Study IV, the types of documented antimicrobial errors were analysed. The errors were reported by healthcare professionals using a voluntary web-based error reporting system, HaiPro between 2009-2014. Overall, different types of methods were used regarding quantitative and qualitative analysis and retrospective reviews of electronic patient records and registry data. RESULTS The AMT was inappropriate in 17% (26/149) of patients with blood culture positive infections (Study I). Three of these patients received antimicrobials that were totally ineffective according to in vitro data. During 2003 and 2013, the use of many beta-lactam antimicrobials increased. The most notable change was in the use of carbapenems, which increased by 110% during the study period (Study II). A total of 18% (51/282) of premature neonates with blood culture positive infection received at least one off-label antimicrobial (Study III). An increase in birth weight was found to statistically significantly decrease the probability of off-label usage (odds ratio=0.85 for 100g increase in birth weight, p-value < 0.001). In Study IV, there were 157 antimicrobial errors reported in 149 patients from four wards (GEN, NICU, HEM-ONC and INF). Two errors were reported as clinically significant (2/149, 1%). Most of the errors occurred with drugs with high consumption, such as cefuroxime (15/157, 10%) and penicillin G (15/157, 10%). CONCLUSIONS These studies gave a useful overall picture regarding AMT and the use of antimicrobials at the Children’s Hospital. More attention should be paid to appropriate AMT, and training of prescribers should be provided. This thesis provides a window into issues that undermine the quality of care regarding hospital infections in paediatrics and aids the launch of an antimicrobial stewardship program (ASP) in the Children’s Hospital.
  • Paasela, Tanja (Helsingin yliopisto, 2017)
    Conifers dominate the boreal forests of the Northern Hemisphere, and especially members of the family Pinaceae have great economic and ecological significance. Part of their success is thought to arise from the vast array of secondary metabolites they produce. The products of secondary metabolism are essential for plants to survive in the ever-changing environment. In Scots pine (Pinus sylvestris L.), two groups of secondary metabolites, stilbenes and resin acids, are crucial for decay resistance of heartwood timber and for active defense responses against herbivores and fungal pathogens. Several studies have shown that stilbenes improve decay resistance of pine heartwood. Since there is wide variation in the concentration of stilbenes between individuals and the trait has high heritability, it may be possible to breed heartwood that is more decay-resistant. However, breeding for heartwood properties is slow, since the decay resistance characteristics can be estimated at the earliest from 30-year-old trees. Early selection methods utilizing genetic markers or chemical screening are needed, but we do not yet understand which genes control the biosynthesis of stilbenes and what the genetic differences are between individuals that explain the variation in the capacity to produce stilbenes. Importantly, there is genetic correlation between stress-induced stilbene biosynthesis in seedlings and the heartwood stilbene content in their adult mother trees. Here, we examined the pine transcriptional responses under two conditions that were previously known to activate stilbene biosynthesis: heartwood formation in adult trees and ultraviolet (UV)-C treatment of needles in seedlings. We found that these two conditions had very little in common, except for the activation of stilbene pathway genes. For example, the regulators of the two responses seemed not to be shared. The activation of the stilbene pathway in response to UV-C treatment occurred a few hours after the onset of the treatment and was independent of translation. Stilbene biosynthesis seems to be an early defense response in Scots pine. Heartwood formation, an important developmental process in the senescence of secondary xylem, is poorly understood. Based on transcriptomic analysis, stilbene biosynthesis occurs in situ in the transition zone between the sapwood and heartwood, but resin acids were synthesized primarily in the sapwood. Bifunctional nuclease, an enzyme involved in the process of developmentally programmed cell death (dPCD), is a useful marker for heartwood formation and aided us in defining the timing of the process, from spring to late autumn. Expression of this marker, which is strictly confined to dPCD conditions, further clarified that heartwood formation truly is a process that is initiated by intrinsic programming instead of environmental cues. The transcriptomic data revealed that the expression of the previously characterized pinosylvin O-methyltransferase gene, PMT1, was not induced under stilbene-forming conditions. A new PMT-encoding gene, PMT2, was identified by coexpression analysis. The gene showed an inducible expression pattern very similar to that of the stilbene synthase gene under all conditions studied. PMT2 furthermore methylated pinosylvin with high specificity, in contrast to PMT1, which accepted several substrates.
  • Bryk, Saara (Helsingin yliopisto, 2017)
    Adult-type granulosa cell tumors (AGCTs) belong to the sex cord-stromal group of ovarian tumors and account for 3-5% of ovarian neoplasms. Etiological factors of AGCTs remain mostly unknown, although studies have found a somatic missense mutation in the transcription factor FOXL2. AGCTs are usually diagnosed at an early stage and have a favorable prognosis compared with the more common epithelial ovarian cancer. However, tumor recurrence develops in up to 35% of patients, even in early-stage disease - often unpredictably and several years or even decades after the primary diagnosis. The aims of this study were to determine the incidence and epidemiological background of AGCTs in a large, multinational Nordic cohort and to estimate the incidence of other, especially endocrine-related primary malignancies among patients with AGCT. Furthermore, the objective was to describe the clinical characteristics and prognostic factors linked to AGCT–related recurrence and survival, and to introduce an optimal follow-up strategy for these patients. Our epidemiological registry study on AGCT incidence utilized the Finnish, Icelandic, Norwegian, and Swedish Cancer Registry data on AGCTs over several decades. We showed that the age-adjusted incidence rates were quite constant in 1953-2012: about 0.6-0.8 per 100,000 for most of the study period. The age-specific incidence was highest at 50-64 years of age, and there were no occupations with significantly increased risk of AGCT. The conclusions drawn from these results point to AGCT as a primarily sporadic, not exposure-related cancer, typically occurring in peri- or postmenopause. We estimated the incidence of other primary malignancies among AGCT patients using data from the Finnish Cancer Registry in 1968-2013. After AGCT, we found increased risks for cancers of the soft tissue and thyroid as well as leukemia, which likely indicate shared risk factors and therapy-induced side effects. The incidence of AGCT was significantly increased among women with previous breast cancer, suggesting shared hormonal etiology or treatment-induced effects. To evaluate the clinical and prognostic factors, all AGCT patients diagnosed at Helsinki University Hospital during nearly six decades were included in the clinical study cohort (n=240). After a histological review, we analyzed the clinical data for association with both AGCT-related and overall survival and tumor relapse. Of the original study cohort, the diagnosis was histologically confirmed in 78% of patients and molecularly confirmed for the FOXL2 mutation in 68% of patients. In multivariate analysis, stage was the only independent prognostic factor related to AGCT-specific survival. Spontaneous or iatrogenic tumor rupture was independently associated with tumor recurrence. By utilizing the extensive cancer registry data together with the internationally unique, large and carefully validated single-institute patient cohort, these studies reveal the diagnostic challenges of AGCTs, and provide novel epidemiological data and evidence-based tools to develop follow-up strategies for this rare cancer.
  • Tolvanen, Tuomas (Helsingin yliopisto, 2017)
    Background: Type 2 diabetes, characterised by insulin resistance, is an everincreasing problem in the world. Diabetic nephropathy is a renal microvascular complication of diabetes that is a common cause of end-stage renal disease worldwide. Low levels of albumin can be detected in the urine at an early stage of diabetic nephropathy, and more severe albuminuria develops as the disease progresses. Insulin resistance is associated with albuminuria in patients with type 1 or type 2 diabetes. Also, the loss of podocytes plays a major role in the pathogenesis of diabetic nephropathy. The mechanisms underlying the development of insulin resistance and apoptosis in podocytes are still not fully understood. This study aimed to investigate the pathophysiological mechanisms leading to insulin resistance and podocyte apoptosis at the molecular level, and concentrated to the roles of CD2-associated protein (CD2AP) and SH2-domain containing 5’ inositol phosphatase 2 (SHIP2) in these processes. Results: We found that the lack of CD2AP in podocytes led to attenuated glucose uptake, without affecting PI3K-AKT-mediated insulin signalling. This led us to investigate the role of CD2AP in glucose transporter trafficking. Indeed, live-cell imaging revealed that internalized Glucose transporter 4 (GLUT4) was trapped in the perinuclear region of podocytes lacking CD2AP. CD2AP co-fractionated with known components of GLUT4 vesicles and interacted with clathrin and clathrin adaptor GGA2. These results suggest that CD2AP plays a role in GLUT4 vesicle trafficking. We further observed that the level and activity of SHIP2, an interaction partner of CD2AP, was increased in the absence of CD2AP in podocytes. Also, production of reactive oxygen species (ROS) and the rate of apoptosis were increased when CD2AP was lacking from podocytes. We hypothesized that inhibition of SHIP2 would decrease the production of ROS and apoptosis, but even though we detected reduced ROS production, inhibition of SHIP2 increased podocyte apoptosis in the absence of CD2AP. In the search for novel SHIP2 inhibitors we found an old anti-diabetic drug, metformin, to bind to and inhibit the activity of SHIP2 in silico, in vitro and in vivo. By inhibiting the activity of SHIP2, metformin increased glucose uptake and protected podocytes from apoptosis initiated by SHIP2 overexpression. SHIP2 exhibited higher activity in the kidney pieces received from nephrectomy patients with type 2 diabetes receiving non-metformin medication compared to nephrectomy patients without diabetes; in comparison, the activity of SHIP2 did not differ between metformin receiving patients with type 2 diabetes and people without diabetes. Patients with type 2 diabetes with metformin medication also showed reduced podocyte loss. Conclusions: In the light of our results we suggest a novel role for CD2AP in the regulation of sorting of internalized GLUT4 and regeneration of insulin responsive GLUT4 vesicle compartment. We also suggest that SHIP2 inhibitors, including metformin, can be used to reduce the oxidative stress of podocytes and to prevent podocyte loss, except in the case of patients suffering from reduced expression of CD2AP.