Cancer incidence, mortality, and pregnancy outcome among women treated for cervical intraepithelial neoplasia

Cervical cancer develops through precursor lesions, i.e. cervical intraepithelialneoplasms (CIN). These can be detected and treated before progression to invasive cancer. The major risk factor for developing cervical cancer or CIN is persistent or recurrent infection with high-risk human papilloma virus (hrHPV). Other associated risk factors include low socioeconomic status, smoking, sexually transmitted infections, and high number of sexual partners, and these risk factors can predispose to some other cancers, excess mortality, and reproductive health complications as well. The aim was to study long-term cancer incidence, mortality, and reproductive health outcomes among women treated for CIN. Based on the results, we could evaluate the efficacy and safety of CIN treatment practices and estimate the role of the risk factors of CIN patients for cancer incidence, mortality, and reproductive health. We collected a cohort of 7 599 women treated for CIN at Helsinki University Central Hospital from 1974 to 2001. Information about their cancer incidence, cause of death, birth of children and other reproductive endpoints, and socio-economic status were gathered through registerlinkages to the Finnish Cancer Registry, Finnish Population Registry, and Statistics Finland. Depending on the endpoints in question, the women treated were compared to the general population, to themselves, or to an age- and municipality-matched reference cohort. Cervical cancer incidence was increased after treatment of CIN for at least 20 years, regardless of the grade of histology at treatment. Compared to all of the colposcopically guided methods, cold knife conization (CKC) was the least effective method of treatment in terms of later CIN 3 or cervical cancer incidence. In addition to cervical cancer, incidence of other HPV-related anogenital cancers was increased among those treated, as was the incidence of lung cancer and other smoking-related cancers. Mortality from cervical cancer among the women treated was not statistically significantly elevated, and after adjustment for socio-economic status, the hazard ratio (HR) was 1.0. In fact, the excess mortality among those treated was mainly due to increased mortality from other cancers, especially from lung cancer. In terms of post-treatment fertility, the CIN treatments seem to be safe: The women had more deliveries, and their incidence of pregnancy was similar before and after treatment. Incidence of extra-uterine pregnancies and induced abortions was elevated among the treated both before and after treatment. Thus this elevation did not occur because they were treated rather to a great extent was due to the other known risk factors these women had in excess, i.e. sexually transmitted infections. The purpose of any cancer preventive activity is to reduce cancer incidence and mortality. In Finland, cervical cancer is a rare disease and death from it even rarer, mostly due to the effective screening program. Despite this, the women treated are at increased risk for cancer; not just for cervical cancer. They must be followed up carefully and for a long period of time; general health education, especially cessation of smoking, is crucial in the management process, as well as interventions towards proper use of birth control such as condoms.

Hard Custom, Hard Dance : Social Organisation, (Un)Differentiation and Notions of Power in a Tabiteuean Community, Southern Kiribati

Hard Custom, Hard Dance: Social Organisation, (Un)Differentiation and Notions of Power in a Tabiteuean Community, Southern Kiribati is an ethnographic study of a village community. This work analyses social organisation on the island of Tabiteuea in the Micronesian state of Kiribati, examining the intertwining of hierarchical and egalitarian traits, meanwhile bringing a new perspective to scholarly discussions of social differentiation by introducing the concept of undifferentiation to describe non-hierarchical social forms and practices. Particular attention is paid to local ideas concerning symbolic power, abstractly understood as the potency for social reproduction, but also examined in one of its forms; authority understood as the right to speak. The workings of social differentiation and undifferentiation in the village are specifically studied in two contexts connected by local notions of power: the meetinghouse institution (te maneaba) and traditional dancing (te mwaie). This dissertation is based on 11 months of anthropological fieldwork in 1999‒2000 in Kiribati and Fiji, with an emphasis on participant observation and the collection of oral tradition (narratives and songs). The questions are approached through three distinct but interrelated topics: (i) A key narrative of the community ‒ the story of an ancestor without descendants ‒ is presented and discussed, along with other narratives. (ii) The Kiribati meetinghouse institution, te maneaba, is considered in terms of oral tradition as well as present-day practices and customs. (iii) Kiribati dancing (te mwaie) is examined through a discussion of competing dance groups, followed by an extended case study of four dance events. In the course of this work the community of close to four hundred inhabitants is depicted as constructed primarily of clans and households, but also of churches, work co-operatives and dance groups, but also as a significant and valued social unit in itself, and a part of the wider island district. In these partly cross-cutting and overlapping social matrices, people are alternatingly organised by the distinct values and logic of differentiation and undifferentiation. At different levels of social integration and in different modes of social and discursive practice, there are heightened moments of differentiation, followed by active undifferentiation. The central notions concerning power and authority to emerge are, firstly, that in order to be valued and utilised, power needs to be controlled. Secondly, power is not allowed to centralize in the hands of one person or group for any long period of time. Thirdly, out of the permanent reach of people, power/authority is always, on the one hand, left outside the factual community and, on the other, vested in community, the social whole. Several forms of differentiation and undifferentiation emerge, but these appear to be systematically related. Social differentiation building on typically Austronesian complementary differences (such as male:female, elder:younger, autochtonous:allotochtonous) is valued, even if eventually restricted, whereas differentiation based on non-complementary differences (such as monetary wealth or level of education) is generally resisted, and/or is subsumed by the complementary distinctions. The concomitant forms of undifferentiation are likewise hierarchically organised. On the level of the society as a whole, undifferentiation means circumscribing and ultimately withholding social hierarchy. Potential hierarchy is both based on a combination of valued complementary differences between social groups and individuals, but also limited by virtue of the undoing of these differences; for example, in the dissolution of seniority (elder-younger) and gender (male-female) into sameness. Like the suspension of hierarchy, undifferentiation as transformation requires the recognition of pre-existing difference and does not mean devaluing the difference. This form of undifferentiation is ultimately encompassed by the first one, as the processes of the differentiation, whether transformed or not, are always halted. Finally, undifferentiation can mean the prevention of non-complementary differences between social groups or individuals. This form of undifferentiation, like the differentiation it works on, takes place on a lower level of societal ideology, as both the differences and their prevention are always encompassed by the complementary differences and their undoing. It is concluded that Southern Kiribati society be seen as a combination of a severely limited and decentralised hierarchy (differentiation) and of a tightly conditional and contextual (intra-category) equality (undifferentiation), and that it is distinctly characterised by an enduring tension between these contradicting social forms and cultural notions. With reference to the local notion of hardness used to characterise custom on this particular island as well as dance in general, it is argued in this work that in this Tabiteuean community some forms of differentiation are valued though strictly delimited or even undone, whereas other forms of differentiation are a perceived as a threat to community, necessitating pre-emptive imposition of undifferentiation. Power, though sought after and displayed - particularly in dancing - must always remain controlled.

On Musical Self-Similarity : Intersemiosis as Synecdoche and Analogy

Self-similarity, a concept taken from mathematics, is gradually becoming a keyword in musicology. Although a polysemic term, self-similarity often refers to the multi-scalar feature repetition in a set of relationships, and it is commonly valued as an indication for musical coherence and consistency . This investigation provides a theory of musical meaning formation in the context of intersemiosis, that is, the translation of meaning from one cognitive domain to another cognitive domain (e.g. from mathematics to music, or to speech or graphic forms). From this perspective, the degree of coherence of a musical system relies on a synecdochic intersemiosis: a system of related signs within other comparable and correlated systems. This research analyzes the modalities of such correlations, exploring their general and particular traits, and their operational bounds. Looking forward in this direction, the notion of analogy is used as a rich concept through its two definitions quoted by the Classical literature: proportion and paradigm, enormously valuable in establishing measurement, likeness and affinity criteria. Using quantitative qualitative methods, evidence is presented to justify a parallel study of different modalities of musical self-similarity. For this purpose, original arguments by Benoît B. Mandelbrot are revised, alongside a systematic critique of the literature on the subject. Furthermore, connecting Charles S. Peirce s synechism with Mandelbrot s fractality is one of the main developments of the present study. This study provides elements for explaining Bolognesi s (1983) conjecture, that states that the most primitive, intuitive and basic musical device is self-reference, extending its functions and operations to self-similar surfaces. In this sense, this research suggests that, with various modalities of self-similarity, synecdochic intersemiosis acts as system of systems in coordination with greater or lesser development of structural consistency, and with a greater or lesser contextual dependence.

Associations of interleukin-1 (IL-1) gene variation and IL-1 receptor antagonist phenotypes with immunological responses, metabolic dysregulation and type 2 diabetes

The upstream proinflammatory interleukin-1 (IL-1) cytokines, together with a naturally occurring IL-1 receptor antagonist (IL-1Ra), play a significant role in several diseases and physiologic conditions. The IL-1 proteins affect glucose homeostasis at multiple levels contributing to vascular injuries and metabolic dysregulations that precede diabetes. An association between IL-1 gene variations and IL-1Ra levels has been suggested, and genetic studies have reported associations with metabolic dysregulation and altered inflammatory responses. The principal aims of this study were to: 1) examine the associations of IL-1 gene variation and IL-1Ra expression in the development and persistence of thyroid antibodies in subacute thyroiditis; 2) investigate the associations of common variants in the IL-1 gene family with plasma glucose and insulin concentrations, glucose homeostasis measures and prevalent diabetes in a representative population sample; 3) investigate genetic and non-genetic determinants of IL-1Ra phenotypes in a cross-sectional setting in three independent study populations; 4) investigate in a prospective setting (a) whether variants of the IL-1 gene family are predictors for clinically incident diabetes in two population-based observational cohort studies; and (b) whether the IL-1Ra levels predict the progression of metabolic syndrome to overt diabetes during the median follow-up of 10.8 and 7.1 years. Results from on patients with subacte thyroiditis showed that the systemic IL-1Ra levels are elevated during a specific proinflammatory response and they correlated with C-reactive protein (CRP) levels. Genetic variation in the IL-1 family seemed to have an association with the appearance of thyroid peroxidase antibodies and persisting local autoimmune responses during the follow-up. Analysis of patients suffering from diabetes and metabolic traits suggested that genetic IL-1 variation and IL-1Ra play a role in glucose homeostasis and in the development of type 2 diabetes. The coding IL-1 beta SNP rs1143634 was associated with traits related to insulin resistance in cross-sectional analyses. Two haplotype variants of the IL-1 beta gene were associated with prevalent diabetes or incident diabetes in a prospective setting and both of these haplotypes were tagged by rs1143634. Three variants of the IL-1Ra gene and one of the IL-1 beta gene were consistently identified as significant, independent determinants of the IL-1Ra phenotype in two or three populations. The proportion of the phenotypic variation explained by the genetic factors was modest however, while obesity and other metabolic traits explained a larger part. Body mass index was the strongest predictor of systemic IL-1Ra concentration overall. Furthermore, the age-adjusted IL-1Ra concentrations were elevated in individuals with metabolic syndrome or diabetes when compared to those free of metabolic dysregulation. In prospective analyses the systemic IL-1Ra levels were found as independent predictors for the development of diabetes in people with metabolic syndrome even after adjustment for multiple other factors, including plasma glucose and CRP levels. The predictive power of IL-1Ra was better than that of CRP. The prospective results also provided some evidence for a role of common IL-1 alpha promoter SNP rs1800587 in the development of type 2 diabetes among men and suggested that the role may be gender specific. Likewise, common variations in the IL-1 beta coding region may have a gender specific association with diabetes development. Further research on the potential benefits of IL-1Ra measurements in identifying individuals at high risk for diabetes, who then could be targeted for specific treatment interventions, is warranted. It has been reported in the recent literature that IL-1Ra secreted from adipose tissue has beneficial effects on glucose homeostasis. Furthermore, treatment with recombinant human IL-1Ra has been shown to have a substantial therapeutic potential. The genetic results from the prospective analyses performed in this study remain inconclusive, but together with the cross-sectional analyses they suggest gender-specific effects of the IL-1 variants on the risk of diabetes. Larger studies with more extensive genotyping and resequencing may help to pinpoint the exact variants responsible and to further elucidate the biological mechanisms for the observed associations. This would improve our understanding of the pathways linking inflammation and obesity with glucose and insulin metabolism.

Patents, Ethics and Stem Cell Research : The Case of hESC Innovation in Australia, Europe and the United States

Embryonic stem cells offer potentially a ground-breaking insight into health and diseases and are said to offer hope in discovering cures for many ailments unimaginable few years ago. Human embryonic stem cells are undifferentiated, immature cells that possess an amazing ability to develop into almost any body cell such as heart muscle, bone, nerve and blood cells and possibly even organs in due course. This remarkable feature, enabling embryonic stem cells to proliferate indefinitely in vitro (in a test tube), has branded them as a so-called miracle cure . Their potential use in clinical applications provides hope to many sufferers of debilitating and fatal medical conditions. However, the emergence of stem cell research has resulted in intense debates about its promises and dangers. On the one hand, advocates hail its potential, ranging from alleviating and even curing fatal and debilitating diseases such as Parkinson s, diabetes, heart ailments and so forth. On the other hand, opponents decry its dangers, drawing attention to the inherent risks of human embryo destruction, cloning for research purposes and reproductive cloning eventually. Lately, however, the policy battles surrounding human embryonic stem cell innovation have shifted from being a controversial research to scuffles within intellectual property rights. In fact, the ability to obtain patents represents a pivotal factor in the economic success or failure of this new biotechnology. Although, stem cell patents tend to more or less satisfy the standard patentability requirements, they also raise serious ethical and moral questions about the meaning of the exclusions on ethical or moral grounds as found in European and to an extent American and Australian patent laws. At present there is a sort of a calamity over human embryonic stem cell patents in Europe and to an extent in Australia and the United States. This in turn has created a sense of urgency to engage all relevant parties in the discourse on how best to approach patenting of this new form of scientific innovation. In essence, this should become a highly favoured patenting priority. To the contrary, stem cell innovation and its reliance on patent protection risk turmoil, uncertainty, confusion and even a halt on not only stem cell research but also further emerging biotechnology research and development. The patent system is premised upon the fundamental principle of balance which ought to ensure that the temporary monopoly awarded to the inventor equals that of the social benefit provided by the disclosure of the invention. Ensuring and maintaining this balance within the patent system when patenting human embryonic stem cells is of crucial contemporary relevance. Yet, the patenting of human embryonic stem cells raises some fundamental moral, social and legal questions. Overall, the present approach of patenting human embryonic stem cell related inventions is unsatisfactory and ineffective. This draws attention to a specific question which provides for a conceptual framework for this work. That question is the following: how can the investigated patent offices successfully deal with patentability of human embryonic stem cells? This in turn points at the thorny issue of application of the morality clause in this field. In particular, the interpretation of the exclusions on ethical or moral grounds as found in Australian, American and European legislative and judicial precedents. The Thesis seeks to compare laws and legal practices surrounding patentability of human embryonic stem cells in Australia and the United States with that of Europe. By using Europe as the primary case study for lessons and guidance, the central goal of the Thesis then becomes the determination of the type of solutions available to Europe with prospects to apply such to Australia and the United States. The Dissertation purports to define the ethical implications that arise with patenting human embryonic stem cells and intends to offer resolutions to the key ethical dilemmas surrounding patentability of human embryonic stem cells and other morally controversial biotechnology inventions. In particular, the Thesis goal is to propose a functional framework that may be used as a benchmark for an informed discussion on the solution to resolving ethical and legal tensions that come with patentability of human embryonic stem cells in Australian, American and European patent worlds. Key research questions that arise from these objectives and which continuously thread throughout the monograph are: 1. How do common law countries such as Australia and the United States approach and deal with patentability of human embryonic stem cells in their jurisdictions? These practices are then compared to the situation in Europe as represented by the United Kingdom (first two chapters), the Court of Justice of the European Union and the European Patent Office decisions (Chapter 3 onwards) in order to obtain a full picture of the present patenting procedures on the European soil. 2. How are ethical and moral considerations taken into account at patent offices investigated when assessing patentability of human embryonic stem cell related inventions? In order to assess this part, the Thesis evaluates how ethical issues that arise with patent applications are dealt with by: a) Legislative history of the modern patent system from its inception in 15th Century England to present day patent laws. b) Australian, American and European patent offices presently and in the past, including other relevant legal precedents on the subject matter. c) Normative ethical theories. d) The notion of human dignity used as the lowest common denominator for the interpretation of the European morality clause. 3. Given the existence of the morality clause in form of Article 6(1) of the Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions which corresponds to Article 53(a) European Patent Convention, a special emphasis is put on Europe as a guiding principle for Australia and the United States. Any room for improvement of the European morality clause and Europe s current manner of evaluating ethical tensions surrounding human embryonic stem cell inventions is examined. 4. A summary of options (as represented by Australia, the United States and Europe) available as a basis for the optimal examination procedure of human embryonic stem cell inventions is depicted, whereas the best of such alternatives is deduced in order to create a benchmark framework. This framework is then utilised on and promoted as a tool to assist Europe (as represented by the European Patent Office) in examining human embryonic stem cell patent applications. This method suggests a possibility of implementing an institution solution. 5. Ultimately, a question of whether such reformed European patent system can be used as a founding stone for a potential patent reform in Australia and the United States when examining human embryonic stem cells or other morally controversial inventions is surveyed. The author wishes to emphasise that the guiding thought while carrying out this work is to convey the significance of identifying, analysing and clarifying the ethical tensions surrounding patenting human embryonic stem cells and ultimately present a solution that adequately assesses patentability of human embryonic stem cell inventions and related biotechnologies. In answering the key questions above, the Thesis strives to contribute to the broader stem cell debate about how and to which extent ethical and social positions should be integrated into the patenting procedure in pluralistic and morally divided democracies of Europe and subsequently Australia and the United States.