Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) : Identification of novel TNFRSF1A mutations and intracellular signalling defects

The systemic autoinflammatory disorders are a group of rare diseases characterized by periodically recurring episodes of acute inflammation and a rise in serum acute phase proteins, but with no signs of autoimmunity. At present eight hereditary syndromes are categorized as autoinflammatory, although the definition has also occasionally been extended to other inflammatory disorders, such as Crohn s disease. One of the autoinflammatory disorders is the autosomally dominantly inherited tumour necrosis factor receptor-associated periodic syndrome (TRAPS), which is caused by mutations in the gene encoding the tumour necrosis factor type 1 receptor (TNFRSF1A). In patients of Nordic descent, cases of TRAPS and of three other hereditary fevers, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), chronic infantile neurologic, cutaneous and articular syndrome (CINCA) and familial cold autoinflammatory syndrome (FCAS), have been reported, TRAPS being the most common of the four. Clinical characteristics of TRAPS are recurrent attacks of high spiking fever, associated with inflammation of serosal membranes and joints, myalgia, migratory rash and conjunctivitis or periorbital cellulitis. Systemic AA amyloidosis may occur as a sequel of the systemic inflammation. The aim of this study was to investigate the genetic background of hereditary periodically occurring fever syndromes in Finnish patients, to explore the reliability of determining serum concentrations of soluble TNFRSF1A and metalloproteinase-induced TNFRSF1A shedding as helpful tools in differential diagnostics, as well as to study intracellular NF-κB signalling in an attempt to widen the knowledge of the pathomechanisms underlying TRAPS. Genomic sequencing revealed two novel TNFRSF1A mutations, F112I and C73R, in two Finnish families. F112I was the first TNFRSF1A mutation to be reported in the third extracellular cysteine-rich domain of the gene and C73R was the third novel mutation to be reported in a Finnish family, with only one other TNFRSF1A mutation having been reported in the Nordic countries. We also presented a differential diagnostic problem in a TRAPS patient, emphasizing for the clinician the importance of differential diagnostic vigiliance in dealing with rare hereditary disorders. The underlying genetic disease of the patient both served as a misleading factor, which possibly postponed arrival at the correct diagnosis, but may also have predisposed to the pathologic condition, which led to a critical state of the patient. Using a method of flow cytometric analysis modified for the use on fresh whole blood, we studied intracellular signalling pathways in three Finnish TRAPS families with the F112I, C73R and the previously reported C88Y mutations. Evaluation of TNF-induced phosphorylation of NF-κB and p38, revealed low phosphorylation profiles in nine out of ten TRAPS patients in comparison to healthy control subjects. This study shows that TRAPS is a diagnostic possibility in patients of Nordic descent, with symptoms of periodically recurring fever and inflammation of the serosa and joints. In particular in the case of a family history of febrile episodes, the possibility of TRAPS should be considered, if an etiology of autoimmune or infectious nature is excluded. The discovery of three different mutations in a population as small as the Finnish, reinforces the notion that the extracellular domain of TNFRSF1A is prone to be mutated at the entire stretch of its cysteine-rich domains and not only at a limited number of sites, suggesting the absence of a founder effect in TRAPS. This study also demonstrates the challenges of clinical work in differentiating the symptoms of rare genetic disorders from those of other pathologic conditions and presents the possibility of an autoinflammatory disorder as being the underlying cause of severe clinical complications. Furthermore, functional studies of fresh blood leukocytes show that TRAPS is often associated with a low NF-κB and p38 phosphorylation profile, although low phosphorylation levels are not a requirement for the development of TRAPS. The aberrant signalling would suggest that the hyperinflammatory phenotype of TRAPS is the result of compensatory NF-κB-mediated regulatory mechanisms triggered by a deficiency of the innate immune response.

Auger-emitter radiochemotherapy in squamous cell cancers : in vitro and in vivo experiments with In-111-BLMC

Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer worldwide. Despite advances in combined modality therapy (surgery, radiotherapy, chemotherapy) the 5-year survival rate in stage III and IV disease remains at 40% - 60%. Short-range Auger-electron emitters, such as In-111 and In-114m, tagged with a drug, molecule, peptide, protein or nanoparticles brought in close proximity to nuclear DNA represent a fascinating alternative for treating cancer. In this thesis, we studied the usefulness of Indium-111-bleomycin complex (In-111-BLMC) in the diagnostics and potential therapy of HNSCC using in vitro HNSCC cell lines, in vivo nude mice, and in vivo HNSCC patients. In in vitro experiments with HNSCC cell lines, the sensitivity to external beam radiation, BLM, In-111-BLMC, and In-111-Cl3 was studied using the 96-well plate clonogenic assay. The influence of BLM and In-111-BLMC on the cell cycle was measured with flow cytometry. In in vivo nude mice xenograft studies, the activity ratios of In-111-BLMC were obtained in gamma camera images. The effect of In-111-BLMC in HNSCC xenografts was studied. In in vivo patient studies, we determined the tumor uptake of In-111-BLMC with gamma camera and the radioactivity from tumor samples using In-111-BLMC with specific activity of 75, 175, or 375 MBq/mg BLM. The S values, i.e. absorbed dose in a target organ per cumulated activity in a source organ, were simulated for In-111 and In-114m. In vitro studies showed the variation of sensitivity for external beam radiation, BLM, and In-111-BLMC between HNSCC cell lines. IC50 values for BLM were 1.6-, 1.8-, and 2.1-fold higher than In-111-BLMC (40 MBq/mg BLM) in three HNSCC cell lines. Specific In-111 activity of 40 MBq/mgBLM was more effective in killing cells than specific In-111 activity of 195MBq/mgBLM (p=0.0023). In-111-Cl3 alone had no killing effect. The percentage of cells in the G2/M phase increased after exposure to BLM and especially to In-111-BLMC in the three cell lines studied, indicating a G2/M block. The tumor-seeking behavior was shown in the in vivo imaging study of xenografted mice. BLM and In-111-BLMC were more effective than NaCl in reducing xenografted tumor size in HNSCC. The uptake ratios received from gamma images in the in vivo patient study varied from 1.2 to 2.8 in malignant tumors. However, the uptake of In-111-BLMC was unaffected by increasing the injected activity. A positive correlation existed between In-111-BLMC uptake, Ki-67/MIB activity, and number of mitoses. Regarding the S values, In-114m delivered a 4-fold absorbed radiation dose into the tumor compared with In-111, and thus, In-114m-BLMC might be more effective than In-111-BLMC at the DNA level. Auger-electron emitters, such as In-111 and In-114m, might have potential in the treatment of HNSCC. Further studies are needed to develop a radiopharmaceutical agent with appropriate physical properties of the radionuclide and a suitable carrier to bring it to the targeted tissue.

Matrix proteinases in lung injury in the preterm infant

During inflammation, excess production and release of matrix proteinases, including matrix metalloproteinases (MMPs) and serine proteinases, may result in dysregulated extracellular proteolysis leading to development of tissue damage. Pulmonary inflammation may play an important role in the pathogenesis of lung injury in the preterm infant. The aims of this study were to evaluate involvement of MMPs and serine proteinase trypsin in acute and chronic lung injury in preterm infants and to study the role of these enzymes in acute lung injury by means of an animal model of hyperoxic lung injury. Molecular forms and levels of MMP-2, -8, and -9, and their specific inhibitor, tissue inhibitor of metalloproteinases (TIMP)-2, as well as trypsin were studied in tracheal aspirate fluid (TAF) samples collected from preterm infants with respiratory distress. Expression and distribution of trypsin-2 and proteinase-activated receptor 2 (PAR2) was examined in autopsy lung specimens from fetuses, from preterm infants with respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD), and from newborn infants without lung injury. We detected higher MMP-8 and trypsin-2 and lower TIMP-2 in TAF from preterm infants with more severe acute respiratory distress. Infants subsequently developing BPD had higher levels of MMP-8 and trypsin-2 early postnatally than did those who survived without this chronic lung injury. Immunohistochemically, trypsin-2 was mainly detectable in bronchial epithelium, but also in alveolar epithelium, and its expression was strongest in prolonged RDS. Since trypsin-2 is potent activator of PAR2, a G-protein coupled receptor involved in inflammation, we studied PAR2 expression in the lung. PAR2 co-localized with trypsin-2 in bronchoalveolar epithelium and its expression was significantly higher in bronchoalveolar epithelium in preterm infants with prolonged RDS than in newborn controls. In the experimental study, rats were exposed to >95% oxygen for 24, 48, and 60 hours, or room air. At 48 hours of hyperoxia, MMP-8 and trypsin levels sharply increased in bronchoalveolar lavage fluid, and expression of trypsin appeared in alveolar epithelium, and MMP-8 predominantly in macrophages. In conclusion, high pulmonary MMP-8 and trypsin-2 early postnatally are associated with severity of acute lung injury and subsequent development of BPD in preterm infants. In the injured preterm lung, trypsin-2 co-localizes with PAR2 in bronchoalveolar epithelium, suggesting that PAR2 activated by high levels of trypsin-2 is involved in lung inflammation associated with development of BPD. Marked increase in MMP-8 and trypsin early in the course of experimental hyperoxic lung injury suggests that these enzymes play a role in the pathogenesis of acute lung injury. Further exploration of the roles of trypsin and MMP-8 in lung injury may offer new targets for therapeutic intervention.

Inhibition of CYP1A2-mediated drug metabolism in vitro and in humans : With special emphasis on rofecoxib and other NSAIDs

The cytochrome P450 1A2 (CYP1A2) is one of the major metabolizing enzymes. The muscle relaxant tizanidine is a selective substrate of CYP1A2, and the non-steroidal anti-inflammatory drug (NSAID) rofecoxib was thought to modestly in-hibit it. Cases suggesting an interaction between tizanidine and rofecoxib had been reported, but the mechanism was unknown. Also other NSAIDs are often used in combination with muscle relaxants. The aims of this study were to investigate the effect of rofecoxib, several other NSAIDs and female sex steroids on CYP1A2 ac-tivity in vitro and in vivo, and to evaluate the predictability of in vivo inhibition based on in vitro data. In vitro, the effect of several NSAIDs, female sex steroids and model inhibitors on CYP1A2 activity was studied in human liver microsomes, without and with preincubation. In placebo controlled, cross-over studies healthy volunteers ingested a single dose of tizanidine after a pretreament with the inhibitor (rofecoxib, tolfenamic acid or celecoxib) or placebo. Plasma (and urine) concentrations of tizanidine and its metabolites were measured, and the pharmacodynamic effects were recorded. A caffeine test was also performed. In vitro, fluvoxamine, tolfenamic acid, mefenamic acid and rofecoxib potently in-hibited CYP1A2. Ethinylestradiol, celecoxib, desogestrel and zolmitriptan were moderate, and etodolac, ciprofloxacin, etoricoxib and gestodene were weak inhibi-tors of CYP1A2. At 100 µM, other tested NSAIDs and steroids inhibited CYP1A2 less than 35%. Rofecoxib was found to be a mechanism-based inhibitor of CYP1A2. In vivo, rofecoxib greatly increased the plasma concentrations (over ten-fold) and the pharmacodynamic effects of tizanidine. Also the metabolism of caf-feine was impaired by rofecoxib. Despite the relatively strong in vitro CYP1A2 inhibitory effects, tolfenamic acid and celecoxib did not have a significant effect on tizanidine and caffeine concentrations in humans. Competitive inhibition model and the free plasma concentration of the inhibitor predicted well the effect of fluvoxam-ine and the lack of effect of tolfenamic acid and celecoxib on tizanidine concentra-tions in humans, and mechanism-based inhibition model explained the effects of rofecoxib. However, the effects of ciprofloxacin and oral contraceptives were un-derestimated from the in vitro data. Rofecoxib is a potent mechanism-based inhibitor of CYP1A2 in vitro and in vivo. This mechanism may be involved in the adverse cardiovascular effects of rofecoxib. Tolfenamic acid and celecoxib seem to be safe in combination with tizanidine, but mefenamic acid might have some effect on tizanidine concentrations in vivo. Con-sidering the mechanism of inhibition, and using the free plasma concentration of the inhibitor, many but not all CYP1A2 interactions can be predicted from in vitro data.

Ischemia-reperfusion injury in human liver transplantation : Mechanisms and effects on graft function

Liver transplantation is an established therapy for both acute and chronic liver failure. Despite excellent long-term outcome, graft dysfunction remains a problem affecting up to 15-30% of the recipients. The etiology of dysfunction is multifactorial, with ischemia-reperfusion injury regarded as one of the most important contributors. This thesis focuses on the inflammatory response during graft procurement and reperfusion in liver transplantation in adults. Activation of protein C was examined as a potential endogenous anti-inflammatory mechanism. The effects of inflammatory responses on graft function and outcome were investigated. Seventy adult patients undergoing liver transplantation in Helsinki University Central Hospital, and 50 multiorgan donors, were studied. Blood samples from the portal and the hepatic veins were drawn before graft procurement and at several time points during graft reperfusion to assess changes within the liver. Liver biopsies were taken before graft preservation and after reperfusion. Neutrophil and monocyte CD11b and L-selectin expression were analysed by flow cytometry. Plasma TNF-α, IL-6, IL-8, sICAM-1, and HMGB1 were determined by ELISA and Western-blotting. HMGB1 immunohistochemistry was performed on liver tissue specimens. Plasma protein C and activated protein C were determined by an enzyme-capture assay. Hepatic IL-8 release during graft procurement was associated with subsequent graft dysfunction, biliary in particular, in the recipient. Biliary marker levels increased only 5 7 days after transplantation. Thus, donor inflammatory response appears to influence recipient liver function with relatively long-lasting effects. Hepatic phagocyte activation and sequestration, with concomitant HMGB1 release, occurred during reperfusion. Neither phagocyte activation nor plasma cytokines correlated with postoperative graft function. Thus, activation of the inflammatory responses within the liver during reperfusion may be of minor clinical significance. However, HMGB1 was released from hepatocytes and were also correlated with postoperative transaminase levels. Accordingly, HMGB1 appears to be a marker of hepatocellular injury.

Phase-Field Simulation of Fusion Interface Events during Solidification of Dissimilar Welds: Effect of Composition Inhomogeneity

We investigate the events near the fusion interfaces of dissimilar welds using a phase-field model developed for single-phase solidification of binary alloys. The parameters used here correspond to the dissimilar welding of a Ni/Cu couple. The events at the Ni and the Cu interface are very different, which illustrate the importance of the phase diagram through the slope of the liquidus curves. In the Ni side, where the liquidus temperature decreases with increasing alloying, solutal melting of the base metal takes place; the resolidification, with continuously increasing solid composition, is very sluggish until the interface encounters a homogeneous melt composition. The growth difficulty of the base metal increases with increasing initial melt composition, which is equivalent to a steeper slope of the liquidus curve. In the Cu side, the initial conditions result in a deeply undercooled melt and contributions from both constrained and unconstrained modes of growth are observed. The simulations bring out the possibility of nucleation of a concentrated solid phase from the melt, and a secondary melting of the substrate due to the associated recalescence event. The results for the Ni and Cu interfaces can be used to understand more complex dissimilar weld interfaces involving multiphase solidification.

Applications of Gauge/Gravity Duality to QCD and Heavy Ion Collisions

The description of quarks and gluons, using the theory of quantum chromodynamics (QCD), has been known for a long time. Nevertheless, many fundamental questions in QCD remain unanswered. This is mainly due to problems in solving the theory at low energies, where the theory is strongly interacting. AdS/CFT is a duality between a specific string theory and a conformal field theory. Duality provides new tools to solve the conformal field theory in the strong coupling regime. There is also some evidence that using the duality, one can get at least qualitative understanding of how QCD behaves at strong coupling. In this thesis, we try to address some issues related to QCD and heavy ion collisions, applying the duality in various ways.

Traversing the space between threats and violence: A review of threat assessment guidelines

While the majority of violent threats – defined as an expression of intent to do harm or act out violently against someone or something – do not progress to actual violence, a small proportion of threateners do go on to enact violence. Most researchers argue that violence risk assessments are inadequate for assessing threats of violence, which raises the question: how should a threat assessment (TA) be conducted? To begin to understand available frameworks for assessing threats, a systematic review of TA research literature was conducted. Most TA literature pertains to a specific domain (schools, public figure threats, workplaces) and target audience (clinicians, school personnel, law enforcement). TA guidelines are typically based on literature reviews with some based on empirical measures and others having no strong evidential basis. The most common concepts in TA are exploration of the threatener's mental health, the motivation for the threat and the presence of any plans. Rather than advocating for the development of a protocol for conducting TA, this article outlines the common areas of inquiry in assessing threats and highlights the limitations of current TA guidelines.

Formal Verification of Full-Wave Rectifier: A Case Study

We present a case study of formal verification of full-wave rectifier for analog and mixed signal designs. We have used the Checkmate tool from CMU [1], which is a public domain formal verification tool for hybrid systems. Due to the restriction imposed by Checkmate it necessitates to make the changes in the Checkmate implementation to implement the complex and non-linear system. Full-wave rectifier has been implemented by using the Checkmate custom blocks and the Simulink blocks from MATLAB from Math works. After establishing the required changes in the Checkmate implementation we are able to efficiently verify, the safety properties of the full-wave rectifier.

Synergistic effects of UdgB and Ung in mutation prevention and protection against commonly encountered DNA damaging agents in Mycobacterium smegmatis

The incorporation of dUMP during replication or the deamination of cytosine in DNA results in the occurrence of uracils in genomes. To maintain genomic integrity, uracil DNA glycosylases (UDGs) excise uracil from DNA and initiate the base-excision repair pathway. Here, we cloned, purified and biochemically characterized a family 5 UDG, UdgB, from Mycobacterium smegmatis to allow us to use it as a model organism to investigate the physiological significance of the novel enzyme. Studies with knockout strains showed that compared with the wild-type parent, the mutation rate of the udgB(-) strain was approximately twofold higher, whereas the mutation rate of a strain deficient in the family 1 UDG (ung(-)) was found to be similar to 8.4-fold higher. Interestingly, the mutation rate of the double-knockout (ung(-)ludgB(-)) strain was remarkably high, at similar to 19.6-fold. While CG to TA mutations predominated in the ung(-) and ung(-)/udgb(-) strains, AT to GC mutations were enhanced in the udgB(-) strain. The ung(-)/udgB(-) strain was notably more sensitive to acidified nitrite and hydrogen peroxide stresses compared with the single knockouts (ung(-) or udgB(-)). These observations reveal a synergistic effect of UdgB and Ung in DNA repair, and could have implications for the generation of attenuated strains of Mycobacterium tuberculosis.

Growing Up Vietnamese in Finland - Looking Back 12 Years Later : The Well-Being and Sociocultural Adaptation of Vietnamese as Children or Adolescents and as Young Adults

Varttuminen vietnamilaisena Suomessa: 12 vuoden seurantajakso – Vietnamilaisten hyvinvointi ja sosiokulttuurinen sopeutuminen lapsena/nuorena sekä nuorena aikuisena Tämä tutkimus oli määrällinen pitkittäistutkimus lapsena tai nuorena vuosina 1979-1991 Suomeen saapuneiden vietnamilaisten akkulturaatiosta (kulttuurin muutoksista), psyykkisestä hyvinvoinnista ja sosiokulttuurisesta sopeutumisesta. Tutkimukseen osallistui ensimmäisessä vaiheessa (vuonna 1992) 97 satunnaisesti valittua vietnamilaista peruskoululaista ympäri maata, joita verrattin suomalaisiin luokkatovereihin. Seurantavaiheeseen (vuonna 2004) osallistui 59 ensimmäisessä vaiheessa mukana ollutta vietnamilaista, nyt iältään 20 – 31 -vuotiaita. Tutkimuksen tavoitteena oli selvittää mitkä tekijät ennustivat akkulturaation lopputuloksia, samalla huomioiden iän ja ympäristön (kontekstin) vaikutukset psyykkiseen hyvinvointiin ja sosiokulttuuriseen sopeutumiseen. Yksittäiset akkulturaatiodimensiot (kieli, arvot ja identiteetti) osoittautuivat tärkeämmiksi psyykkiselle hyvinvoinnille ja sosiokulttuuriselle sopeutumiselle kuin etniset, kansalliset tai kaksikulttuuriset profiilit, joissa yhdistyivät ao. kieli, arvot ja identiteetti. Identiteettimuutosta tapahtui (etniseen) vietnamilaiseen suuntaan ajan kuluessa, kun taas arvomuutosta tapahtui (kansalliseen) suomalaiseen suuntaan. Sekä suomen että vietnamin kielen taito lisääntyivät ajan myötä, millä oli myönteisiä vaikutuksia sekä psyykkiseen hyvinvointiin että sosiokulttuuriseen sopeutumiseen. Lähtötilanteen psyykkinen hyvinvointi ennusti hyvinvointia (masennuksen puutetta ja itsetuntoa) aikuisena, mutta sosiokulttuurinen sopeutuminen (koulumenestys) lapsena tai nuorena ei ennustanut kouluttautumista aikuisena. Parempi suomen kielen taito ja vähemmän identifioitumista suomalaiseksi aikuisena sekä masentuneisuuden puute ja vähemmän koettua syrjintää lapsena tai nuorena erottelivat psyykkisesti paremmin voivat aikuiset (ei-masentuneet) heistä, jotka olivat masentuneita. Parempaa kouluttautumista aikuisena ennustivat toisaalta vähemmän koettua syrjintää lapsena tai nuorena ja toisaalta aikuisena parempi suomen kielen taito, suurempi kansallisten (suomalaisten) itsenäisyysarvojen kannattaminen, mutta kuitenkin vähemmän identifioitumista suomalaisiin. Koetun syrjinnän merkitys psyykkiselle hyvinvoinnille, erityisesti lapsena tai nuorena, sekä sen pitkäaikaisvaikutukset psyykkiselle hyvinvoinnille ja sosiokulttuuriselle sopeutumiselle aikuisena osoittavat tarpeen puuttua varhain psyykkisiin ongelmiin sekä parantaa etnisten ryhmien välisiä suhteita. Avainsanat: akkulturaatio, psyykkinen hyvinvointi, sosiokultuurinen sopeutuminen, kieli, arvot, identiteetti, vietnamilainen, Suomi, lapset, nuoret, nuoret aikuiset

A Success Story or a Failure? : Representing the European Integration in the Curricula and Textbooks of Five Countries

The economic, political and social face of Europe has been changing rapidly in the past decades. These changes are unique in the history of Europe, but not without challenges for the nation states. The support for the European integration varies among the countries. In order to understand why certain developments or changes are perceived as threatening or as desired by different member countries, we must consider the social representations of the European integration on the national level: how the EU is represented to its citizens in media and in educational systems, particularly in the curricula and textbooks. The current study is concerned with the social representations of the European integration in the curricula and school textbooks in five European countries: France, Britain, Germany, Finland and Sweden. Besides that, the first volume of the common Franco-German history textbook was analyzed, since it has been seen as a model for a common European history textbook. As the collective representations, values and identities are dominantly mediated and imposed through media and educational systems, the national curricula and textbooks make an interesting starting point for the study of the European integration and of national and European identities. The social representations theory provides a comprehensive framework for the study of the European integration. By analyzing the curricula and history and civics textbooks of major educational publishers, the study aimed to demonstrate what is written on the European integration and how it is portrayed how the European integration is understood, made familiar and concretized in the educational context in the five European countries. To grasp the phenomenon of the European integration in the textbooks in its entirety, it was investigated from various perspectives. The two analysis methods of content analysis, the automatic analysis with ALCESTE and a more qualitative theory-driven content analysis, were carried out to give a more vivid and multifaceted picture of the object of the research. The analysis of the text was complemented with the analysis of visual material. Drawing on quantitative and qualitative methods, the contents, processes, visual images, transformations and structures of the social representations of European integration, as well as the communicative styles of the textbooks were examined. This study showed the divergent social representations of the European integration, anchored in the nation states, in the five member countries of the European Union. The social representations were constructed around different central core elements: French Europe in the French textbooks, Ambivalent Europe in the British textbooks, Influential and Unifying EU in the German textbooks, Enabling and Threatening EU in the Finnish textbooks, Sceptical EU in the Swedish textbooks and EU as a World Model in the Franco-German textbook. Some elements of the representations were shared by all countries such as peace and economic aspects of the European cooperation, whereas other elements of representations were found more frequently in some countries than in others, such as ideological, threatening or social components of the phenomenon European integration. The study also demonstrated the linkage between social representations of the EU and national and European identities. The findings of this study are applicable to the study of the European integration, to the study of education, as well as to the social representation theory.

Biovalta, toiseus ja naisten toimijuus hedelmöityshoidoissa

Biopower, Otherness and Women's Agency in Assisted Reproduction. This sociological study analyses how, why and with what kind of consequences assisted reproductive technologies (ART) have become the primary technology for governing infertility in Finland both on the level of individuals and society. The phenomenon is construed as one the strategies of the Focaultian biopower since ART are political techniques of the beginning of life par excellence, as they are used to prepare the bodies of certain types of women to create certain kind of life, i.e. certain kind of children. Moreover, ART are interpreted to be gendered control techniques with which the pure, and at the same time prevailing, social order symbolised by a female body is maintained by naming and excluding otherness, unsuitable mother candidates and children. Finally, it is considered how the agency, subjectivity, of women experiencing infertility and seeking treatment appears in the prevailing context of ART. The introduction of IVF-based reproductive technologies to Finland and the treatment practices of the early 1990s have been studied on the basis of a clinic questionnaire, medical doctor interviews and articles of the Medical Journal Duodecim from 1969 to 2000. Opinions on the method of the treatment providers were studied by conducting a theme interview with fertilisation doctors in 1993. Experiences of women who have received treatment or experienced infertility were studied by means of a survey in 1994 and by analysing the content of messages in an online discussion forum in 2000. On the basis of the medical doctor interviews, significant criterion for choosing mother candidates turned out to be her vitality and her mental and physical health, which are considered prerequisites for a vitality of the child to be born. The hierarchies concerning children became evident. While people normally make their children on their own, this is what people experiencing infertility are trying to do as well. In the era of ART, the primary child is genetically the parents' own child, a secondary option for Finnish parents is a genetically Finnish child conceived by donated Finnish gametes or embryos and the last option is an adopted child of foreign origin. Women's agency mainly appears in their way of using ART as a technology of the self for self-control on one's own nature, which helps them to prepare their bodies in order to become pregnant in co-operation with a fertilisation doctor. Women's creative free agency exceeding governance appeared as a distinctive use of language with which they created shared meaning for their infertility experience, their own individual and group identity and distinctive reality. ART are very political techniques as they have a possibility to change the methods of having children and to shape life. Therefore, further sociological research on them is important and needed. Key words: practises of assisted reproduction, women's agency, biopower, vital politics of the beginning of life, otherness

Methodological perspectives for register-based health system performance assessment : Developing a hip fracture monitoring system in Finland

The resources of health systems are limited. There is a need for information concerning the performance of the health system for the purposes of decision-making. This study is about utilization of administrative registers in the context of health system performance evaluation. In order to address this issue, a multidisciplinary methodological framework for register-based data analysis is defined. Because the fixed structure of register-based data indirectly determines constraints on the theoretical constructs, it is essential to elaborate the whole analytic process with respect to the data. The fundamental methodological concepts and theories are synthesized into a data sensitive approach which helps to understand and overcome the problems that are likely to be encountered during a register-based data analyzing process. A pragmatically useful health system performance monitoring should produce valid information about the volume of the problems, about the use of services and about the effectiveness of provided services. A conceptual model for hip fracture performance assessment is constructed and the validity of Finnish registers as a data source for the purposes of performance assessment of hip fracture treatment is confirmed. Solutions to several pragmatic problems related to the development of a register-based hip fracture incidence surveillance system are proposed. The monitoring of effectiveness of treatment is shown to be possible in terms of care episodes. Finally, an example on the justification of a more detailed performance indicator to be used in the profiling of providers is given. In conclusion, it is possible to produce useful and valid information on health system performance by using Finnish register-based data. However, that seems to be far more complicated than is typically assumed. The perspectives given in this study introduce a necessary basis for further work and help in the routine implementation of a hip fracture monitoring system in Finland.

Huumeriippuvuudesta toipuminen Nimettömien Narkomaanien toveriseurassa

The subjects of this study are Narcotics Anonymous (NA), a non-profit, peer-support-based fellowship, its recovery programme, and the former drug addicts who consider themselves members of the fellowship. The study data consist of episodic interviews (n=24) and questionnaires (n=212). In the collection of questionnaire data, survey research methods had to be applied judiciously. This study analyses NA members background and their substance abuse and treatment history, as well as factors that have contributed to or hindered their bonding with NA. A recovery model is presented that stems from NA s written and oral tradition, and which has been conceptualised into NA s recovery theory. At its simplest, NA s recovery theory can be described in two sentences: 1) There are drug dependent addicts who have an addiction disease. 2) Through an NA way of life, recovery is possible. In this study, addiction and addiction disease are described through recovery stories shared at NA. It also describes how the way of life offered by NA supports recovery from drug addiction, the way of life which recovering addicts have adopted, and how they have done so. The study also presents results that, based on the study data, emerge from participation in the NA programme, and describes how the NA recovery theory works in practice, i.e. how NA members utilise the tools provided by the fellowship and how the lives of recovering addicts change during their membership. Furthermore, this study also discusses criticism of NA. According to the study, NA affects the lives of recovering drug addicts in a number of ways. People of different ages and with a variety of personal, treatment and drug abuse histories seem to benefit from membership of NA. Viewed from the outside, NA may appear as strictly normative, but in practice each member can adapt the programme in a way that suits him/her best. Indeed, flexibility is one of the strengths of NA, but without more extensive knowledge of the fellowship, it is possible that the norms reflected in NA texts or the fanaticism of individual NA members may drive some people away. Due to the increasing number of NA members, the association is also able to provide more alternatives. This study confirms the view that peer support is important, as well as the fact that an official treatment system is required in parallel with peer support activities. NA can never fully replace professional support, neither should it be left with sole responsibility for recovering addicts. Keywords: Narcotics Anonymous, peer support, recovery study, recovery, substance addiction, drug treatment, drugs, explorative research