Parrhesia and democracy : Truthtelling, WikiLeaks and the Arab Spring

Parrhesia — the practice of truth-telling — was adapted to various ancient legal, political, philosophical and religious contexts. In this essay we focus on parrhesia in politics and its relevance for democracy, concentrating on the account given by Michel Foucault. We suggest that Foucault’s approach to parrhesia and democracy is valuable because of its stress on the analysis of governmental rationalities and the ethical comportment of citizens, rather than on the normative dimensions of democracy, as is more usual (but more sterile) in political thought. We take two modern examples of truth-telling’s role in democracy – the recent WikiLeaks scandal and the political struggles in Tunisia and Egypt – as a way of assessing the value of Foucault’s distinctive approach and the relevance of parrhesia for democracy today.

The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women

Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.03–1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91–1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

"Are there any right or wrong answers in teaching philosophy": ethics, epistemology, and philosophy in the classroom

This article assesses undergraduate teaching students’ assertion that there are no right and wrong answers in teaching philosophy. When asked questions about their experiences of philosophy in the classroom for primary children, their unanimous declaration that teaching philosophy has ‘no right and wrong answers’ is critically examined across the three sub-disciplinary areas to which they were generally referring, namely, pedagogy, ethics, and epistemology. From a pedagogical point of view, it is argued that some teaching approaches may indeed be more effective than others, and some pupils’ opinions less defensible, but pedagogically, in terms of managing the power relations in the classroom, it is counter-productive to continually insist on notions of truth and falsity at every point. From an ethical point of view, it is contended that anti-realist approaches to meta-ethics may represent a viable intellectual position, but from the point of view of normative ethics, notions of right and wrong still retain significant currency. From an epistemological point of view, it is argued using Karl Poppers’ work that while it may be difficult to determine what constitutes a right answer, determining a wrong one is far more straightforward. In conclusion, it is clear that prospective teachers engaging in philosophy in the classroom, and also future teachers in general, require a far more nuanced philosophical understanding of the notions of right and wrong and truth and falsity. In view of this situation, it we wish to promote the effective teaching of philosophical thinking to children, or produce educators who can understand the conceptual limits of the claims they make and their very real and often serious practical and social consequences, it is recommended that philosophy be reinstated to a fundamental, foundational place within the pre-service teaching curriculum.

Research data finder : an institutional metadata repository

QUT’s new metadata repository (data registry), Research Data Finder, has been designed to promote the visibility and discoverability of QUT research datasets. Funded by the Australian National Data Service (ANDS), it will provide a qualitative snapshot of research data outputs created or collected by members of the QUT research community that are available via open or mediated access. As a fully integrated metadata repository Research Data Finder aligns with institutional sources of truth, such as QUT’s research administrative system, ResearchMaster, as well as QUT’s Academic Profiles system to provide high quality data descriptions that increase awareness of, and access to, shareable research data. In addition, the repository and its workflows are designed to foster smoother data management practices, enhance opportunities for collaboration and research, promote cross-disciplinary research and maximize existing research datasets. The metadata schema used in Research Data Finder is the Registry Interchange Format - Collections and Services (RIF-CS), developed by ANDS in 2009. This comprehensive schema is potentially complex for researchers; unlike metadata for publications, which are often made publicly available with the official publication, metadata for datasets are not typically available and need to be created. Research Data Finder uses a hybrid self-deposit and mediated deposit system. In addition to automated ingests from ResearchMaster (research project information) and Academic Profiles system (researcher information), shareable data is identified at a number of key “trigger points” in the research cycle. These include: research grant proposals; ethics applications; Data Management Plans; Liaison Librarian data interviews; and thesis submissions. These ingested records can be supplemented with related metadata including links to related publications, such as those in QUT ePrints. Records deposited in Research Data Finder are harvested by ANDS and made available to a national and international audience via Research Data Australia, ANDS’ discovery service for Australian research data. Researcher and research group metadata records are also harvested by the National Library of Australia (NLA) and these records are then published in Trove (the NLA’s digital information portal). By contributing records to the national infrastructure, QUT data will become more visible. Within Australia and internationally, many funding bodies have already mandated the open access of publications produced from publicly funded research projects, such as those supported by the Australian Research Council (ARC), or the National Health and Medical Research Council (NHMRC). QUT will be well placed to respond to the rapidly evolving climate of research data management. This project is supported by the Australian National Data Service (ANDS). ANDS is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy Program and the Education Investment Fund (EIF) Super Science Initiative.

How much is that data in the window? Advertising your research data with QUT Library

Queensland University of Technology (QUT) Library offers a range of resources and services to researchers as part of their research support portfolio. This poster will present key features of two of the data management services offered by research support staff at QUT Library. The first service is QUT Research Data Finder (RDF), a product of the Australian National Data Service (ANDS) funded Metadata Stores project. RDF is a data registry (metadata repository) that aims to publicise datasets that are research outputs arising from completed QUT research projects. The second is a software and code registry, which is currently under development with the sole purpose of improving discovery of source code and software as QUT research outputs. RESEARCH DATA FINDER As an integrated metadata repository, Research Data Finder aligns with institutional sources of truth, such as QUT’s research administration system, ResearchMaster, as well as QUT’s Academic Profiles system to provide high quality data descriptions that increase awareness of, and access to, shareable research data. The repository and its workflows are designed to foster better data management practices, enhance opportunities for collaboration and research, promote cross-disciplinary research and maximise the impact of existing research data sets. SOFTWARE AND CODE REGISTRY The QUT Library software and code registry project stems from concerns amongst researchers with regards to development activities, storage, accessibility, discoverability and impact, sharing, copyright and IP ownership of software and code. As a result, the Library is developing a registry for code and software research outputs, which will use existing Research Data Finder architecture. The underpinning software for both registries is VIVO, open source software developed by Cornell University. The registry will use the Research Data Finder service instance of VIVO and will include a searchable interface, links to code/software locations and metadata feeds to Research Data Australia. Key benefits of the project include:improving the discoverability and reuse of QUT researchers’ code and software amongst QUT and the QUT research community; increasing the profile of QUT research outputs on a national level by providing a metadata feed to Research Data Australia, and; improving the metrics for access and reuse of code and software in the repository.

Producing and maintaining professional identities in early childhood

This study is an inquiry into early childhood teacher professional identities. In Australia, workforce reforms in early childhood include major shifts in qualification requirements that call for a university four-year degree-qualified teacher to be employed in child care. This marks a shift in the early years workforce, where previously there was no such requirement. At the same time as these reforms to quality measures are being implemented, and requiring a substantive up skilling of the workforce, there is a growing body of evidence through recent studies that suggests these same four-year degree-qualified early childhood teachers have an aversion to working in child care. Their preferred employment option is to work in the early years of more formal schooling, not in before-school contexts. This collision of agendas warrants investigation. This inquiry is designed to investigate the site at which advocacy for higher qualification requirements meets early childhood teachers who are reluctant to choose child care as a possible career pathway. The key research question for this study is: How are early childhood teachers’ professional identities currently produced? The work of this thesis is to problematise the early childhood teacher in child care through a particular method of discourse analysis. There are two sets of data. The first was a key early childhood political document that read as a "moment of arising" (Foucault, 1984a, p. 83). It is a political document which was selected for its current influence on the early childhood field, and in particular, workforce reforms that call for four-year degree-qualified teachers to work in before-school contexts, including child care. The second data set was generated through four focus group discussions conducted with preservice early childhood teachers. The document and transcripts of the focus groups were both analysed as text, as conceptualised by Foucault (1981). Foucault’s work spans a number of years and a range of philosophical matters. This thesis draws particularly on Foucault’s writings on discourse, power/knowledge, regimes of truth and resistance. In order to consider the production of early childhood teachers’ professional identities, the study is also informed by identity theorists, who have worked on gender, performativity and investment (Davies, 2004/2006; McNay, 1992; Osgood, 2012; Walkerdine, 1990; Weedon, 1997). The ways in which discourses intersect, compete and collide produce the subject (Foucault, 1981) and, in the case of this inquiry, there are a number of competing discourses at play, which produce the early childhood teacher. These particular theories turn particular lenses on the question of professional identities in early childhood, and such a study calls for the application of particular methodologies. Discourse analysis was used as the methodological framework, and the analysis was informed by Foucauldian concepts of discourse. While Foucault did not prescribe a form of discourse analysis as a method, his writings nonetheless provide a valuable framework for illuminating discursive practices and, in turn, how people are affected, through the shifts and distribution of power (Foucault, 1980a). The treatment used with both data sets involved redescription. For the policy document, a technique for reading document-as-text applied a genealogical approach (Foucault, 1984a). For the focus groups, the process of redescription (Rorty, 1989) involved reading talk-as-text. As a method, redescription involves describing "lots and lots of things in new ways until you have created a pattern of linguistic behaviour which will tempt the new generation to adopt it" (Rorty, 1989, p. 9). The development and application of categories (Davies, 2004/2006) built on a poststructuralist theoretical framework and the literature review informed the data analysis method of discourse analysis. Irony provided a rhetorical and playful tool (Haraway, 1991; Rorty, 1989), to look to how seemingly opposing discourses are held together. This opens a space to collapse binary thinking and consider seemingly contradictory terms in a way in which both terms are possible and both are true. Irony resists the choice of one or the other being right, and holds the opposites together in tension. The thesis concludes with proposals for new, ironic categories, which work to bring together seemingly opposing terms, located at sites in the field of early childhood where discourses compete, collide and intersect to produce and maintain early childhood teacher professional identities. The process of mapping these discourses goes some way to investigating the complexities about identities and career choices of early childhood teachers. The category of "the cost of loving" captures the collision between care/love, inherent in child care, and new discourses of investment/economics. Investment/economics has not completely replaced care/love, and these apparent opposites were not read as a binary because both are necessary and both are true (Haraway, 1991). They are held together in tension to produce early childhood teacher professional identities. The policy document under scrutiny was New Directions, released in 2007 by the then opposition ALP leader, Kevin Rudd. The claim was made strongly that the "economic prosperity" of Australia relies on investment in early childhood. The arguments to invest are compelling and the neuroscience/brain research/child development together with economic/investment discourses demand that early childhood is funding is increased. The intersection of these discourses produces professional identities of early childhood teachers as a necessary part of the country’s economy, and thus, worthy of high status. The child care sector and work in child care settings are necessary, with children and the early childhood teacher playing key roles in the economy of the nation. Through New Directions it becomes sayable (Foucault, 1972/1989) that the work the early childhood teacher performs is legitimated and valued. The children are produced as "economic units". A focus on what children are able to contribute to the future economy of the nation re-positions children and produces these "smart productive citizens", making future economic contribution. The early childhood teacher is produced through this image of a child and "the cost of loving" is emphasised. A number of these categories were produced through the readings of the document-as text and the talk-as-text. Two ironic categories were read in the analysis of the transcripts of the focus group discussions, when treated as talk-as-text data: the early childhood teacher as a "heroic victim"; and the early childhood teacher as a "glorified babysitter". This thesis raises new questions about professional identities in early childhood. These new questions might go some way to prompt re-thinking of some government policy, as well as some aspects of early childhood teacher education course design. The images of children and images of child care provide provocations to consider preservice teacher education course design. In particular, how child care, as one of the early childhood contexts, is located, conceptualised and spoken throughout the course. Consideration by course designers and teacher educators of what discourses are privileged in course content —what discourses are diminished or silenced—would go some way to reconceptualising child care within preservice teacher education and challenging dominant ways of speaking child care, and work in child care. This inquiry into early childhood teachers’ professional identities has gone some way to exploring the complexities around the early childhood teacher in child care. It is anticipated that the significance of this study will thus have immediate applicably and relevance for the Australian early childhood policy landscape. The early childhood field is in a state of rapid change, and this inquiry has examined some of the disconnects between policy and practice. Awareness of the discourses that are in play in the field will continue to allow space for conversations that challenge dominant assumptions about child care, work in child care and ways of being an early childhood teacher in child care.

Polyalanine repeat polymorphism in RUNX2 is associated with site-specific fracture in post-menopausal females

Runt related transcription factor 2 (RUNX2) is a key regulator of osteoblast differentiation. Several variations within RUNX2 have been found to be associated with significant changes in BMD, which is a major risk factor for fracture. In this study we report that an 18bp deletion within the polyalanine tract (17A>11A) of RUNX2 is significantly associated with fracture. Carriers of the 11A allele were found to be nearly twice as likely to have sustained fracture. Within the fracture category, there was a significant tendency of 11A carriers to present with fractures of bones of intramembranous origin compared to bones of endochondral origin (p=0.005). In a population of random subjects, the 11A allele was associated with decreased levels of serum collagen cross links (CTx, p=0.01), suggesting decreased bone turnover. The transactivation function of the 11A allele was quantitatively decreased. Interestingly, we found no effect of the 11A allele on BMD at multiple skeletal sites, although these were not the sites where a relationship with fracture was most evident. These findings suggest that the 11A allele is a biologically relevant polymorphism that influences serum CTx and confers enhanced fracture risk in a site-selective manner related to intramembranous bone ossification.

The primary school as a logic machine

This paper makes a case for thinking about the primary school as a logic machine (apparatus) as a way of thinking about processes of in-school stratification. Firstly we discuss related literature on in-school stratification in primary schools, particularly as it relates to literacy learning. Secondly we explain how school reform can be thought about in terms of the idea of the machine or apparatus. In which case the processes of in-school stratification can be mapped as more than simply concerns about school organisation (such as students grouping) but also involve a politics of truth, played out in each school, that constitutes school culture and what counts as ‘good’ pedagogy. Thirdly, the chapter will focus specifically on research conducted into primary schools in the Northern Suburbs of Adelaide, one of the most educationally disadvantaged regions in Australia, as a case study of the relationship between in-school stratification and the reproduction of inequality. We will draw from more than 20 years of ethnographic work in primary school in the northern suburbs of Adelaide and provide a snapshot of a recent attempt to improve literacy achievement in a few Northern Suburbs public primary schools (SILA project). The SILA project, through diagnostic reviews, has provided a significant analysis of the challenges facing policy and practice in such challenging school contexts that also maps onto existing (inter)national research. These diagnostic reviews said ‘hard things’ that required attention by SILA schools and these included: · an over reliance on whole class, low level, routine tasks and hence a lack of challenge and rigour in the learning tasks offered to students ; · a focus on the 'code breaking' function of language at the expense of richer conceptualisations of literacy that might guide teachers’ understanding of challenging pedagogies ; · the need for substantial shifts in the culture of schools, especially unsettling deficit views of students and their communities ; · a need to provide a more ‘consistent’ approach to teaching literacy across the school; · a need to focus School Improvement Plans in order to implement a clear focus on literacy learning; and, · a need to sustain professional learning to produce new knowledge and practice . The paper will conclude with suggestions for further research and possible reform projects into the primary school as a logic machine.

Orchids, intersex and the auto/biographical project

Auto/biographical documentaries ask audiences to take a ‘leap of faith’, not being able to offer any real ‘proof’ of the people and events they claim to document, other than that of the film-maker’s saying this is what happened. With only memory and history seen through the distorting lens of time, ‘the authenticity of experience functions as a receding horizon of truth in which memory and testimony are articulated as modes of salvage’. Orchids: My Intersex Adventure follows a salvaging of the film-maker’s life events and experiences, being born with an intersex condition, and, via the filming and editing process, revolving around the core question: who am I? From this transformative creative documentary practice evolves a new way of embodying experience and ‘seeing’, playfully dubbed here as the ‘intersex gaze’.

Slippage: Reclaiming personal family history through contemporary photomedia

This paper addresses the role of photography as a documentary medium and how this forms a basis for my practice-led studio investigations. In it, I will explore how photography is used to create histories and sustain specific notions of ‘legacy’ within the context of the family photo album. Family history is often based on stories to which the photo album provides a visual point of reference. Despite the ostensible ‘objectivity’ of the family photograph though it is nonetheless as subjective as the stories that surround it. In this way, the photo album perpetuates a hegemony of truth that obscures the fragmentary and highly selective nature of these documents and stories. The result is that every photo album implicitly documents the gaps or voids present in understandings of our own histories. Homi Bhabha refers to these kinds of voids as ‘disjunctive historical spaces’ – spaces of slippage that create the opportunity for new narratives and understandings to occur. Using Bhabha’s ideas as a chief point of reference, I will explore how these voids or gaps in information – and the opportunities for re-examination that they open up - can be explored through contemporary photomedia. Digital technologies such as camera phones and scanners generate a space in which photography’s own documentary conventions can be turned in on themselves to create a subterfuge. My current studio-based research involves using the scanner to navigate through my family’s sometimes-‘occulted’ history, in order to explore, document and recover my connection to this narrative. I am primarily interested in the scanner as a tool for capturing not simply surfaces, but objects, moments or movements in time. Objects or moments captured by the scanner can often be simultaneously distorted and consolidated, blurred and sharpened. This paper will propose that this ‘slippage’, literally expressed in the disruption of the pixelated field, can be used to create a space in which alternative readings or understandings of past events can be explored and new narratives produced.

Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults

There is a strong genetic risk for late-onset Alzheimer's disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by ~88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether the CLU risk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset. We scanned 398 healthy young adults (mean age, 23.6 ± 2.2 years) with diffusion tensor imaging, a variation of magnetic resonance imaging sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed-model regression at each point in the brain to map the profile of these associations with white matter integrity. Each C allele copy of the CLUvariant was associated with lower fractional anisotropy-a widely accepted measure of white matter integrity-in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. Young healthy carriers of the CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life.

Constructive Perspectives on Inductive Logic

Constructive (intuitionist, anti-realist) semantics has thus far been lacking an adequate concept of truth in infinity concerning factual (i.e., empirical, non-mathematical) sentences. One consequence of this problem is the difficulty of incorporating inductive reasoning in constructive semantics. It is not possible to formulate a notion for probable truth in infinity if there is no adequate notion of what truth in infinity is. One needs a notion of a constructive possible world based on sensory experience. Moreover, a constructive probability measure must be defined over these constructively possible empirical worlds. This study defines a particular kind of approach to the concept of truth in infinity for Rudolf Carnap's inductive logic. The new approach is based on truth in the consecutive finite domains of individuals. This concept will be given a constructive interpretation. What can be verifiably said about an empirical statement with respect to this concept of truth, will be explained, for which purpose a constructive notion of epistemic probability will be introduced. The aim of this study is also to improve Carnap's inductive logic. The study addresses the problem of justifying the use of an "inductivist" method in Carnap's lambda-continuum. A correction rule for adjusting the inductive method itself in the course of obtaining evidence will be introduced. Together with the constructive interpretation of probability, the correction rule yields positive prior probabilities for universal generalizations in infinite domains.

Early growth and adult health: focus on blood pressure, glucose tolerance status and body composition

Theory of developmental origins of adult health and disease proposes that experiences during critical periods of early development may have consequences on health throughout a lifespan. Thesis studies aimed to characterize associations between early growth and some components of the metabolic syndrome cluster. Participants belong to two epidemiological cohorts with data on birth measurements and, for the younger cohort, on serial recordings of weight and height during childhood. They were born as singletons between 1924-33 and 1934-44 in the Helsinki University Central Hospital, and 500 and 2003 of them, respectively, attended clinical studies at the age of 65-75 and 56-70 years, respectively. In the 65-75 year old men and women, the well-known inverse relationship between birth weight and systolic blood pressure (SBP) was confined to people who had established hypertension. Among them a 1-kg increase in birth weight was associated with a 6.4-mmHg (95% CI: 1.0 to 11.9) decrease in SBP. This relationship was further confined to people with the prevailing Pro12Pro polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPARγ2) gene. People with low birth weight were more likely to receive angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB, p=0.03), and, again, this relationship was confined to the carriers of the Pro12Pro (p=0.01 for interaction). These results suggest that the inverse association between birth weight and systolic BP becomes focused in hypertensive people because pathological features of BP regulation, associated with slow fetal growth, become self-perpetuating in adult life. Insulin resistance of the Pro12Pro carriers with low birth weight may interact with the renin-angiotensin system leading to raised BP levels. Habitual physical activity protected men and women who were small at birth, and thus at increased risk for the development of type 2 diabetes, against glucose intolerance more strongly. Among subjects with birth weight ≤3000 g, the odds ratio (OR) for glucose intolerance was 5.2 (95% CI: 2.1 to 13) in those who exercised less than 3 times per week compared to regular exercisers; in those who scored their exercise light compared with moderate exercisers (defined as comparable to brisk walking) the OR was 3.5 (1.5 to 8.2). In the 56-70 year old men a 1 kg increase in birth weight corresponded to a 4.1 kg (95% CI: 3.1 to 5.1) and in women to a 2.9 kg (2.1 to 3.6) increase in adult lean mass. Rapid gain in body mass index (BMI), i.e. crossing from an original BMI percentile to a higher one, before the age of 2 years increased adult lean mass index (LMI, lean mass/height squared) without excess fat accumulation whereas rapid gain in BMI during later childhood, despite the concurrent rise in LMI, resulted in a relatively higher increase in adult body fat mass. These findings illustrate how genes, the environment and their interactions, early growth patterns, and adult lifestyle modify adult health risks which originate from early life.

Genotyping for genetic association studies: Methods and applications

In this thesis, two separate single nucleotide polymorphism (SNP) genotyping techniques were set up at the Finnish Genome Center, pooled genotyping was evaluated as a screening method for large-scale association studies, and finally, the former approaches were used to identify genetic factors predisposing to two distinct complex diseases by utilizing large epidemiological cohorts and also taking environmental factors into account. The first genotyping platform was based on traditional but improved restriction-fragment-length-polymorphism (RFLP) utilizing 384-microtiter well plates, multiplexing, small reaction volumes (5 µl), and automated genotype calling. We participated in the development of the second genotyping method, based on single nucleotide primer extension (SNuPeTM by Amersham Biosciences), by carrying out the alpha- and beta tests for the chemistry and the allele-calling software. Both techniques proved to be accurate, reliable, and suitable for projects with thousands of samples and tens of markers. Pooled genotyping (genotyping of pooled instead of individual DNA samples) was evaluated with Sequenom s MassArray MALDI-TOF, in addition to SNuPeTM and PCR-RFLP techniques. We used MassArray mainly as a point of comparison, because it is known to be well suited for pooled genotyping. All three methods were shown to be accurate, the standard deviations between measurements being 0.017 for the MassArray, 0.022 for the PCR-RFLP, and 0.026 for the SNuPeTM. The largest source of error in the process of pooled genotyping was shown to be the volumetric error, i.e., the preparation of pools. We also demonstrated that it would have been possible to narrow down the genetic locus underlying congenital chloride diarrhea (CLD), an autosomal recessive disorder, by using the pooling technique instead of genotyping individual samples. Although the approach seems to be well suited for traditional case-control studies, it is difficult to apply if any kind of stratification based on environmental factors is needed. Therefore we chose to continue with individual genotyping in the following association studies. Samples in the two separate large epidemiological cohorts were genotyped with the PCR-RFLP and SNuPeTM techniques. The first of these association studies concerned various pregnancy complications among 100,000 consecutive pregnancies in Finland, of which we genotyped 2292 patients and controls, in addition to a population sample of 644 blood donors, with 7 polymorphisms in the potentially thrombotic genes. In this thesis, the analysis of a sub-study of pregnancy-related venous thromboses was included. We showed that the impact of factor V Leiden polymorphism on pregnancy-related venous thrombosis, but not the other tested polymorphisms, was fairly large (odds ratio 11.6; 95% CI 3.6-33.6), and increased multiplicatively when combined with other risk factors such as obesity or advanced age. Owing to our study design, we were also able to estimate the risks at the population level. The second epidemiological cohort was the Helsinki Birth Cohort of men and women who were born during 1924-1933 in Helsinki. The aim was to identify genetic factors that might modify the well known link between small birth size and adult metabolic diseases, such as type 2 diabetes and impaired glucose tolerance. Among ~500 individuals with detailed birth measurements and current metabolic profile, we found that an insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene was associated with the duration of gestation, and weight and length at birth. Interestingly, the ACE insertion allele was also associated with higher indices of insulin secretion (p=0.0004) in adult life, but only among individuals who were born small (those among the lowest third of birth weight). Likewise, low birth weight was associated with higher indices of insulin secretion (p=0.003), but only among carriers of the ACE insertion allele. The association with birth measurements was also found with a common haplotype of the glucocorticoid receptor (GR) gene. Furthermore, the association between short length at birth and adult impaired glucose tolerance was confined to carriers of this haplotype (p=0.007). These associations exemplify the interaction between environmental factors and genotype, which, possibly due to altered gene expression, predisposes to complex metabolic diseases. Indeed, we showed that the common GR gene haplotype associated with reduced mRNA expression in thymus of three individuals (p=0.0002).

Defects in tricarboxylic acid cycle enzymes Fumarate hydratase and Succinate dehydrogenase in cancer

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a recently characterized cancer syndrome which predisposes to cutaneous and uterine leiomyomas as well as renal cell carcinoma (RCC). Uterine leiomyosarcoma (ULMS) has also been observed in certain Finnish HLRCC families. The predisposing gene for this syndrome, fumarate hydratase (FH), was identified in 2002. The well-known function of FH is in the tricarboxylic acid cycle (TCAC) in the energy metabolism of cells. As FH is a novel cancer gene, the role of FH mutations in tumours is in general unknown. Similarly, the mechanisms through which defective FH is associated with tumourigenesis are unclear. The loss of a wild type allele has been observed in virtually all HLRCC patients tumours and the FH enzyme activities are either totally lost or remarkably reduced in the tissues of mutation carrier patients. Therefore, FH is assumed to function as a tumour suppressor. Mutations in genes encoding subunits of other TCAC enzyme SDH have also been reported recently in tumours: mutations in SDHB, SDHC, and SDHD genes predispose to paraganglioma and pheochromocytoma. In the present study, mutations in the SDHB gene were observed to predispose to RCC. This was the first time that mutations in SDHB have been detected in extra-paraganglial tumours. Two different SDHB mutations were observed in two unrelated families. In the first family, the index patient was diagnosed with RCC at the age of 24 years. Additionally, his mother with a paraganglioma (PGL) of the heart and his maternal uncle with lung cancer were both carriers of the mutation. The RCC of the index patient and the PGL of his mother showed LOH. In the other family, an SDHB mutation was detected in two siblings who were both diagnosed with RCC at the ages of 24 and 26 years. Both of the siblings also suffered PGL. All these tumours showed LOH. Therefore, we concluded that mutations in SDHB predispose also for RCC in certain families. Several tumour types were analysed for FH mutations to define the role of FH mutations in these tumour types. In addition, patients with a putative cancer phenotype were analysed to identify new HLRCC families. Three FH variants were detected, of which two were novel. One of the variants was observed in a patient diagnosed with ULMS at the age of 41 years. However, LOH was not detected in the tumour tissue. The FH enzyme activity of the mutated protein was clearly reduced, being 43% of the activity of the normal protein. Together with the results from an earlier study we calculated that the prevalence of FH mutations in Finnish non-syndromic ULMS is around 2.4%. Therefore, FH mutations seem to have a minor role in the pathogenesis on non-syndromic ULMS. Two other germline variants were detected in a novel tumour type, ovarian mucinous cystadenoma. However, tumour tissues of the patients were not available for LOH studies and therefore LOH status remained unclear. Therefore, it is possible that FH mutations predispose also for ovarian tumours but further studies are needed to verify this result. A novel variant form of the FH gene (FHv) was identified and characterized in more detail. FHv contains an alternative first exon (1b), which appeared to function as 5 UTR sequence. The translation of FHv is initiated in vitro from exons two and three. The localization of FHv is both cytosolic and nuclear, in contrast to the localization of FH in mitochondria. FHv is expressed at low levels in all human tissues. Interestingly, the expression was induced after heat shock treatment and in chronic hypoxia. Therefore, FHv might have a role e.g. in the adaptation to unfavourable growth conditions. However, this remains to be elucidated.