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  • Vatanen, Anu (Helsingin yliopisto, 2016)
    Long-term ovarian function was retrospectively evaluated after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood and adolescence. Cardiovascular risk factors, arterial morphology and stiffness, left ventricular (LV) mass and function, physical fitness and frailty were investigated in adult and adolescent survivors of high-risk neuroblastoma (HR NBL) after autologous HSCT in childhood. The first study population included a cohort of 92 female long-term survivors who were less than 20 years of age when treated at the Children s Hospital, Helsinki University Hospital, or Karolinska University Hospital, Huddinge, between 1978 and 2000. The follow-up data included signs of spontaneous puberty, age at menarche, the use of hormone replacement therapy, pregnancies, and information about pubertal or postpubertal serum FSH levels. The second study population included the Finnish national cohort of 19 long-term HR NBL survivors treated between 1980 and 2000, and 20 age- and sex-matched controls. Clinical examinations included 24h ambulatory blood pressure (BP), very-high-resolution vascular ultrasound, 3D echocardiography and Tissue Doppler Imaging ultrasounds, body composition, physical performance tests and interview. Older age at HSCT and total body irradiation and busulfan-based conditionings were risk factors for early ovarian aging. Leukemia survivors with previous cranial radiotherapy or transplanted after disease relapse were at high risk of premature ovarian failure. The HR NBL survivors showed increased carotid intima-media thickness, plaque formation and stiffness, increased radial artery intima thickness, and increased cardiovascular risk profile when compared to the controls. They had increased LV mass, decreased systolic and diastolic LV function when compared to the controls. Poor LV function associated with cardiac biomarkers, poor physical performance and increased BP. The survivors showed shorter telomere length and increased frequency of frailty phenotype when compared to the controls. The frailty phenotype associated with cardiovascular health and chronic inflammation. In conclusion, our study shows that the adult survivors after HSCT in young age are at risk of early reproductive and vascular aging and frailty. The survivors of pediatric HSCT require regular follow-up in adulthood and interventions for declining ovarian function, cardiovascular risk factors, high BP, subclinical signs of atherosclerosis and decreased cardiac function. Since lifestyle choices can influence cardiovascular health and frailty status, a healthy non-smoking lifestyle and physical activity should be advocated among all survivors who have received HSCT in childhood.
  • Lassenius, Mariann (Helsingin yliopisto, 2016)
    Around one-third of patients with type 1 diabetes develop diabetic nephropathy. Even though the pathogenesis of diabetic nephropathy is not fully understood, the process involves several environmental factors. Low grade inflammation has been linked to many metabolic diseases and is also evident in patients with type 1 diabetes, especially in the presence of nephropathy. Bacterial lipopolysaccharides (LPS) are powerful triggers of inflammation, but whether low grade inflammation is caused by these components is an open question. The aim of this thesis was to examine the relationship between LPS and the development of diabetic nephropathy, inflammation, vascular function, lipid metabolism, and intestinal homeostasis in patients with type 1 diabetes. The studies are part of the ongoing Finnish Diabetic Nephropathy Study (FinnDiane), a nationwide, multicenter study that aims to identify genetic and environmental risk factors for the development of diabetic complications in patients with type 1 diabetes. Study I was a follow-up study, and Studies II IV were cross-sectional in their design. Renal status was verified at follow-up by laboratory data and a review of all available medical files (Study I). Study II included, in addition to patients with type 1 diabetes, patients with IgA glomerulonephritis and non-diabetic control subjects. The participants in Studies III and IV had three consecutive high-fat meals and were followed for 10 hours postprandially. Factors associated with endotoxemia, vascular function, inflammation, and lipid metabolism were investigated. For all studies, LPS was measured by the limulus amebocyte lysate (LAL) assay from serum samples. In the patients with type 1 diabetes, high serum LPS activity at baseline was associated with the development of microalbuminuria during the follow-up. High serum LPS was also associated with features of the metabolic syndrome in both the patients with type 1 diabetes and the overweight non-diabetic controls. Of note, no accumulation of LPS in the circulation was evident in response to three high-fat meals. However, the patients with type 1 diabetes showed altered postprandial lipid metabolism and vascular response. Moreover, factors associated with gut homeostasis were altered in the patients with type 1 diabetes compared to the non-diabetic controls. We show that high serum LPS is associated with the development of diabetic nephropathy and features of the metabolic syndrome. The metabolic syndrome is associated with insulin resistance, and it is a risk factor for both diabetic nephropathy and cardiovascular disease. Endotoxins may affect the development of diabetic nephropathy through the direct disruption of the filtration barrier, but also through insulin resistance at both the tissue and systemic levels. In response to acute high-fat feeding, no evidence for LPS accumulation was seen. However, unfavorable changes in lipid metabolism and vascular response in patients with type 1 diabetes may render them at higher cardio-metabolic risk. This risk may be further enhanced by adverse changes in both inflammatory and protective factors in the gut, leading to a possibly higher gut permeability and an increase in circulating endotoxins.
  • Backlund, Michael (Helsingin yliopisto, 2016)
    The renin-angiotensin system is a key regulator of blood pressure and electrolyte homeostasis. Most hemodynamic responses to angiotensin II are mediated via angiotensin II type 1 receptor (AT1R). The 3 -untranslated region (3 UTR) of AT1R mRNA is important in posttranscriptional regulation of AT1R expression. It contains multiple adenylate-uridylate-rich elements that are recognized by various RNA-binding proteins (RNBP) affecting the stability, conformation, subcellular localization, and translation of their target mRNAs. The aim of this study was to identify novel AT1R 3 UTR-binding RNBPs and understand their physiological role in AT1R function. AT1R 3 UTR-associated RNBPs were isolated from human vascular smooth muscle cells by protein affinity purification using AT1R 3 UTR as a probe. Mass spectrometric identification of the isolated proteins led to identification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Hu antigen R (HuR) and TIA1 cytotoxic granule-associated RNA-binding protein (TIA-1). GAPDH was identified as a novel AT1R mRNA-binding protein that suppresses AT1R translation. GAPDH binds to a hairpin-structure rich in adenosine and uridine in the proximal region of AT1R 3 UTR. Hydrogen peroxide-induced oxidative stress increased AT1R expression by dissociating GAPDH from AT1R 3 UTR and relieving it from the GAPDH-mediated suppression. Insulin-induced increase in AT1R expression was shown to be posttranscriptionally mediated by HuR. Insulin stabilized AT1R mRNA in a 3 UTR-dependent manner and HuR was shown to bind AT1R 3 UTR. Insulin induced nucleocytoplasmic translocation of HuR to cytoplasm and increased HuR binding to AT1R 3 UTR. This increased AT1R expression via stabilization of AT1R mRNA. AT1R avoids the endoplasmic reticulum (ER) stress-mediated translational suppression. Binding of TIA-1 to AT1R 3 UTR was shown to suppress AT1R expression. TIA-1 normally colocalized with AT1R mRNA in the cytoplasm. However, during ER stress TIA-1 was dissociated and directed to translationally silenced stress granules, while AT1R mRNA remained excluded from them. Thus, AT1R mRNA avoids aggregation to SGs and TIA-1-mediated translational suppression during ER stress. In conclusion, oxidative stress, insulin, and ER stress regulates AT1R expression posttranscriptionally by affecting the binding of GAPDH, HuR, and TIA-1 to its mRNA 3 UTR.
  • Leppilahti, Jussi (Helsingin yliopisto, 2016)
    Matrix metalloproteinases (MMP) and especially MMP-8 is one of the most widely reported oral fluid biomarkers and a promising target candidate for periodontal point-of-care (POC) diagnostics. Periodontitis is associated with increased oral fluid MMP-8 levels, which typically decrease after conventional periodontal treatments. Employing the measurement of oral fluid MMP-8 levels diagnostically, however, is complicated due to high variability. Chronic periodontal inflammation can induce MMP-8 expression in a wide array of cell types, although a great extent of the MMP-8 detected from the gingival crevicular fluid (GCF) originates from polynuclear neutrophil granulocytes (neutrophils). MMP-8 mediates periodontal tissue breakdown by processing extracellular matrix (ECM) proteins with a wide substrate specificity. There is also increasing evidence that MMP-8 contributes to inflammatory signaling cascades and has a protective role in periodontitis and cancer. Thus, it is important to define and differentiate a (statistical) range of physiological fluctuations in the oral fluid MMP-8 POC diagnostics, from the pathologically high MMP-8 levels. The aim of this study was to study methodological and biological reasons for the large variability of GCF MMP-8 and further to evaluate the utility of GCF MMP-8 for POC diagnostics and its ability to predict the treatment outcome after the conventional scaling and root plaining (SRP) treatment and during the supportive maintenance period. Different laboratory and POC MMP-8 detecting methods were compared to study methodological reasons of variability in the GCF MMP-8 levels. In addition, correlations between different inflammatory GCF biomarkers and MMP-8 were compared. The MMP-8 levels measured with laboratory methods or POC tests/devices based on the same monoclonal antibody were clearly in agreement and correlated significantly. There was surprisingly large variability in MMP-8 levels, however, when measured with different assays based on different antibodies. The comparison of different GCF biomarkers revealed highly discriminating properties, especially for myeloperoxidase (MPO) and MMP-8, to differentiate both healthy and gingivitis sites from moderate to advanced chronic periodontitis sites. The longitudinal variability in GCF MMP-8 response patterns was explored and the prognostic utility of GCF MMP-8 was studied. Distinct response patterns during the maintenance period could be found via cluster analysis, especially among smoking patients. High MMP-8 levels at baseline and especially the high-responding pattern among smokers during the maintenance period predicted the compromised treatment outcome. The utility of the GCF MMP-8 levels in the prognostic POC diagnostics was further studied within a heterogenic population by combining different independent datasets. Continuously high MMP-8 levels, at baseline and during the maintenance period, predicted an increased risk for compromised treatment outcome for both non- smoking and smoking patients. Low MMP-8 levels decreased the risk respectively. Overall, the different MMP-8 antibodies can have a quite large difference in affinities to different MMP-8 isoforms, causing variability to the measured levels. If researchers fail to use the same detection methods in different studies, result comparisons may be complicated. GCF MMP-8, however, is a promising candidate as a prognostic biomarker to identify sites with an increased risk for compromised treatment outcome. This study also strongly supports the evidence that MMP-8 can diagnostically differentiate between periodontitis and healthy or gingivitis sites and can also be used for the quantitative, therapeutic monitoring of treatment outcome. Different GCF MMP-8 cutoff levels should be applied for smokers and non-smokers in the MMP-8 based POC diagnostics, however.
  • Schatz, Monika (Helsingin yliopisto, 2016)
    This doctoral dissertation is a multi-faceted case study producing qualitative insights into Finland s education export policies. Drawing on education, anthropology, and critical intercultural studies, the dissertation is embedded in an interdisciplinary theoretical framework. The major contribution of this research is a critical approach that enhances understanding of Finland s newly emerging education export sector. The dissertation consists of a research summary and three original refereed studies (Schatz, 2015 and Schatz, et al., 2015, and Schatz, 2016). Conceptually and empirically, the research responds to the following research questions: RQ1: What is the context for the emergence of Finnish education export? RQ2: What are the motives and objectives of Finnish education export policies? RQ3: What is the Finnish education export product? RQ4: How do Finnish higher education institutions perceive their role as education exporters? RQ5: What kinds of ideologies underpin Finnish education export policies? The scope of the research concentrates on the Finnish education export context. In focus are two Finnish education export policy documents, published by the Finnish Ministry of Education and Culture in 2010 and 2013. The Finnish national education brand and empirical data gathered through questionnaires serve as supporting research data. The applied data analysis methods include Anderson s associative network memory model and Mayring s qualitative content analysis. Research literature on education export in other contexts is used to conceptually grasp the developments in Finland and to highlight differences and similarities between Finland and the international education export sector. Taken together, the findings suggest that Finland s education export ambitions are embedded in international tendencies towards the commodification of education. It is demonstrated that current Finnish education export policies are closely intertwined with public discourses on PISA rankings, Finland s national education brand, and structural changes in the Finnish higher education landscape. The data reveals a large gap between the education export policy goals and their implementation. Based on the findings, several challenges relating to the Finnish education export product and the role of Finnish higher education institutions as education exporters are highlighted. The dissertation problematizes the sustainability of Finland s education export sector and emphasizes the need for a critical debate on education export policy and practice. ________________________________________ Keywords: Education export, Finnish education, education policy dynamics, education branding, commodification of education
  • Sandberg, Erja (Helsingin yliopisto, 2016)
    ADHD in the family - The support provided by the educational, social and health sectors, and the experienced impact The aim of this study was to collect and describe the experiences of families with family members who have ADHD and are in need of support from different bodies such as educational, social and health services. The study also collected and described the co-operation between such bodies over the last six decades. With the assistance of netnography, the research data was collected in 2012 to 2014 from a social network group a nationwide ADHD peer support group. The material includes both questionnaires and interviews. The interviews were used to complement the results of the questionnaires. The main unit of analysis was the family (N = 208), and in each family, one or more members had been diagnosed with or showed symptoms of ADHD. The entire family was included in the study because ADHD affects more than just the individual him/herself. ADHD is often familial, and therefore some of the families in this study had over sixty years experience of ADHD, even though the definitions have changed over the years. Despite the increase in and specification of supportive services, the participants saw the different bodies as too bureaucratic, splintered and regionally differentiated. People showing symptoms of ADHD who had notable functional impairments were not able to find the supportive measures they needed and were not able to endure long wait times due to their worsening situation. Co-operation between the different bodies was seen as a necessity. In the research material, three out of five families described such co-operation as not being realised as it is meant to be according to the law. The difficult situations of the families were demonstrated in the research material in that every third family participating in this study included a socially excluded person or someone at risk of social exclusion. In general, a lack of education, fewer chances of finding a job and associated symptoms of ADHD all contributed to social exclusion. Becoming socially excluded is a long process and not a conscious choice. The participants stated that social exclusion is a vicious circle from which escape is difficult when no support is available. After examining the family types, it can be stated that socio-demographic background variables, particularly educational capital, and the latest information on ADHD, along with support found within the family, were seen as protective factors allowing highly educated families with ADHD a greater chance to better function in Finnish society. Keywords: ADHD, family, netnography, support services, service system, social exclusion
  • Tarkiainen, Lasse (Helsingin yliopisto, 2016)
    Disparity in longevity by income level has been reported in numerous studies. However, few studies have focused on the possible changes over time in the association between income and mortality. The main aim in this thesis was to describe mortality trends in Finland by income quintiles, and to investigate the age- and cause-of-death structure of any changes among these groups in 1988-2012. A further aim was to investigate the income-mortality association independently of the individual socio-demographic factors that are present in childhood and adulthood, and how this association has changed over time in all-cause and cause-specific mortality. The data originated from administrative registers containing individual-level annual information on socio-demographic characteristics linked to cause-specific mortality records in 1971-2012, and also included data linking these registers to 1950 census. Disparities in mortality among those aged over 35 were analysed by calculating life expectancies and their decomposition, and fitting survival regression models to the data. Life expectancy among the highest four income quintiles increased substantially in 1988-2007, but stagnation among men and minor increase among women caused the disparity with other quintiles to increase markedly in the lowest quintile. Mortality relative to the highest quintile among 35-64-year-olds increased between 1988-91 and 2004-07 in all other quintiles even following adjustment for individual socio-demographic characteristics including education, occupation, economic activity, and living alone. Changes in the socio-demographic composition of the income quintiles did not explain the increasing or stagnating mortality level in the lowest quintile among men and women. The disparity in mortality by income in 1971-2007 also persisted following adjustment for observed and unobserved factors of childhood family background shared by siblings. The disparity in mortality remained even when adult socio-demographic factors were controlled for. This observation was consistent over cause-of-death groups. Alcohol-related causes of death were the main drivers of the adverse mortality trend in the lowest quintile because of substantial rise in mortality to these causes among those with low income. Disparities in cancer mortality and ischaemic heart diseases among men also widened the gap in life expectancy. Socio-demographic characteristics explained 50-60 per cent of the excess alcohol-related mortality in the lowest quintile among men. Among women the proportion explained by these factors declined over the study period, from roughly 70 to 30 per cent. The change in the cause-of-death composition of the disparity in mortality towards alcohol-related causes emphasizes addressing mental and behavioural problems such as alcohol abuse in tackling increasing disparity in mortality.
  • Alves Antunes Soares, Joana Soares (2016)
    Atmospheric aerosols are subject to extensive research, due to their effect on air quality, human health and ecosystems, and hold a pivotal role in the Earth s climate. The first focus of this study is to improve the modelling of aerosol emissions and its dispersion in the atmosphere in both spatial and temporal scales and secondly, to integrate the dispersion modelling with population activity data that leads to exposure metrics. The mathematical models used in this study are fully or partially developed by the Finnish Meteorological Institute: a global-to -mesoscale chemical transport model, SILAM; a local-scale point/line-source dispersion model, UDM/CAR-FMI; and a human exposure and intake fraction assessment model, EXPAND. One of the outcomes of this work was the refinement of the emissions modelling for global-to-mesoscale dispersion model. Firstly, a new parameterisation for bubble-mediated sea salt emissions has been developed by combining and re-assessing widely used formulations and datasets. This parameterisation takes into account the effects of wind speed and seawater salinity and temperature, and can be applicable to particles with dry diameters raging between 0.01 and 10 µm. The parameterization is valid for low-to-moderate wind speed, seawater salinity ranging between 0 and 33 and seawater temperature ranging between -2 and 25 °C. Secondly, the near-real time fire estimation system, IS4FIRES, based on Fire Radiative Power (FRP) data from MODIS, was refined to reduce the overestimation of particulate matter (PM) emissions by including more vegetation types, improving the diurnal variation, removing highly-energetic sources and recalibrating the emission factors. Applying dynamic emission modelling brought more insight to the spatial distribution of these emissions, their contribution to the atmospheric budget, and possible impact on air quality and climate. The modelling shows that sea salt aerosol (SSA) can be transported far over land and contribute up to 6 µg m-3 to PM10 (at annual level), and indicate that the Mediterranean has sharp gradients of concentrations, becoming an interesting area to analyse for climate considerations. For fire, the simulations show the importance of meteorology and vegetation type for the intensity of the emissions. The simulations also show that MODIS FRP is accounting for highly energetic sources as a wildland fire, bringing up to an 80% overestimation in AOD, close to the misattributed sources. The second outcome is related to urban-scale modelling. The emissions for Helsinki Metropolitan Area (HMA) were revised to bring up-to-date the emissions for traffic and energy sectors in use for urban-scale modelling. The EXPAND model was revised to combine concentrations and activity data in order to compute parameters such as population exposure or intake fraction. EXPAND includes improvements of the associated urban emission and dispersion modelling system, time use of population, and infiltration coefficients from outdoor to indoor air. This refinement showed that PM2.5 in HMA is mainly originated from long-range transport, with the largest local contributors being vehicular emissions and shipping (at harbours and its vicinity). At annual level, the population living mostly indoors (home and work) is mainly exposed to PM2.5 with an acutely increased exposure while commuting.
  • Ilander, Mette (Helsingin yliopisto, 2016)
    Chronic myeloid leukaemia (CML) is caused by a translocation between chromosomes 9 and 22. As a result of the translocation Philadelphia chromosome that contains a malignant oncogene is formed. Tyrosine kinase inhibitors (TKIs) target the malignant oncokinase that is produced from the oncogene and drives the development of CML. The prognosis of CML patients has improved significantly after the emergence of the TKI therapy. Some patients can even stop the treatment without imminent disease relapse. However, it has been shown that patients who stay in remission without any treatment still have leukemic cells left. We hypothesised that the immune system is able to keep these cells under control and studied the mechanisms behind immune surveillance by analysing the immune cell phenotype and function in CML patients. The results of this thesis show that the immune system plays a role in the successful discontinuation of the treatment. The results from 3 separate studies suggested that natural killer cells are important in successful treatment discontinuation in CML, and that they might be capable of activating T cells and adaptive immunity to keep leukaemia under control. We further studied the effects of 2nd generation TKI dasatinib, known to have immunomodulatory effects. We observed that dasatinib treatment increased the number of Granzyme B expressing memory CD4+ helper and CD8+ cytotoxic T-cells, which were highly active by secreting interferon  (IFN-. We hypothesise that these cells may have a role in the anti-leukaemia immune activity, as IFN- is known to be important in tumour control. The dasatinib induced antitumour immune effects were confirmed in a B16.OVA mouse melanoma model. We were able to demonstrate that dasatinib treatment increases the amount of tumour-infiltrating CD8+ cytotoxic T cells and induces a tumour size reduction dependent on the presence of functional T cells. Taken together, this thesis work illustrates the significance of an active immune system in successful treatment discontinuation in CML. Based on our results it would be important to combine immune activating agents in the future treatment strategies of CML in order to increase the number of patients who are able to successfully discontinue the treatment and be cured.
  • Hansen, Petteri (Helsingin yliopisto, 2016)
    Over the past 30 years, the political steering of the Finnish education system has gradually shifted from being under the direct supervision of the state to adopting a development and evaluation policy based on networks and projects. Development projects, often funded by ministries, and based on governmental programmes, have also become a more common form of steering in the Finnish teacher education system. In this case study, I examine the opportunities and limits of project-based steering in the light of two development projects based on a Finnish governmental programmes. The theoretical framework of my research is grounded in Niklas Luhmann`s systems theory and especially in its application within organisational research. In order to characterise the research problem, I have applied the concepts and research methodology particularly developed by Niels Åkerstøm-Andersen. I describe projects as second-order organisations, which are placed in the overlapping area of various function and organisation systems and the purpose of which is to change the ways that organisations related to teacher education regard themselves and their environment. As the main conclusion, I argue that, instead of the realisation of predefined objectives, teacher development projects appear to respond to changing expectations. Projects as second-order organisations are constantly seeking opportunities for inter-organisational collaboration and they also render the opportunities and limits for change in teacher education more visible. Indeed, owing to the temporary nature of projects, organisations are able to use them as a means of demonstrating their responsiveness to different audiences. The projects examined in this study can also be said to play a diagnostic, cautionary, and confessional role for social education, the status of which inside teacher education has, in contrast to its psychological and didactical contents, been somewhat marginalised. Nevertheless, as a form of political steering, development projects within teacher education are associated with several serious problems with them. First and foremost, project-based steering transfers some political and administrative services to temporary organisations and, in doing so, the opportunities and limits for steering are only observable insofar as the project(s) in question continues to exist. Furthermore, projects can be seen to blur the role definition of various actors, as well as the delineations between the areas in which scientific, economic, and educational data is applied.
  • Kuhlefelt, Marina (Helsingin yliopisto, 2016)
    Smoking cessation and surgical planning decrease complications and compromised healing in patients undergoing orthognatic surgery Orthognatic surgery is surgery for the correction of discrepancies in the facial skeleton. The main aim of the thesis was to identify factors that increase complications and compromised healing in these patients. Medical records of orthognatic patients treated at the Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland were retrieved retrospectively for the first two studies. For the last two studies patients planned for bilateral sagittal split osteotomy (BSSO) were recruited at the Department before surgery and followed up for one year. The outcome variable in the first study was the removal of one symptomatic titanium miniplate, whereas in the second study it was a surgical site infection. The predictor variables were age, gender, smoking status, duration of operation, general diseases, dimensions of mandibular movement and osteosynthesis supporting material. The main outcome variable in the third study was neurosensory disturbance, whereas in the last study it was temporomandibular disorders at one year post-operative. The main predictor variable in the third study was the degree of manipulation of the mandibular nerve and in the last study TMD before surgery, evaluated by the Helkimo Dysfunction index. Explanatory variables age, gender, smoking status, mandibular advancement and duration of operation were also recorded for the statistical analyses. 19.0% of the inserted miniplates were removed in 153 BSSO patients. Plate-related reasons for removal were infection and screw-loosening. 9.1% of the patients (n= 286) in the second study had a surgical site infection. Smoking was the only significant predictor for infections or removal of osteosynthesis material. 90.2% BSSO patients (n= 41) reported altered sensations in the lower lip one year after surgery. The disturbance tended to increase the more the mandibular nerve was manipulated during surgery. Four patients had a visible nerve laceration and all of them experienced a major burden of the altered sensation. Two of these patients (4.9%) had neuropathic pain. Most patients were satisfied with the treatment, but the four patients with visible nerve lacerations were not. A substantial proportion (42.5%) of the patients in the last study had TMD as one of the reasons for seeking treatment. The TMD did not change after treatment in the majority of patients (60%), 30% improved and for 10% the situation impaired. The main finding was that smoking cessation will reduce infections and the need for removal of osteosynthesis material. Regarding neurosensory complications, the surgical technique does matter, and nerve manipulation and lacerations should be avoided at all costs. TMD symptoms improved for only 30% of patients undergoing BSSO. Thus BSSO is not a predictable treatment for TMD patients.
  • Vaahersalo, Jukka (Helsingin yliopisto, 2016)
    Aims The objectives of this study were to evaluate the incidence and neurological outcomes of out-of-hospital cardiac arrest (OHCA) patients in Finnish intensive care units (ICU). This study also investigated the use of therapeutic hypothermia (TH), arterial blood gas (ABG) pressures and different biomarkers association with one-year neurological outcome after OHCA. Materials and methods The FINNRESUSCI study was conducted in 21 out of 22 ICUs in Finland during a one-year study period. All adult patients after OHCA who were treated in ICU were included. Blood samples for biomarker evaluation were collected and neurological outcomes were determined 12 months after CA. All patients were included when evaluated the incidence, the implementation of TH and outcomes. In Study II, all ABG samples obtained from mechanically ventilated patients during the first 24h from ICU admission. In Study III and IV, biomarkers were measured from patients resuscitated from VF/VT. Main results FINNRESUSCI study included 548 patients, of whom 311 (56.8%) had shockable (VF/VT) and 237 (43.2%) non-shockable (PEA or asystole) as an initial rhythm. TH was induced totally in 311 unconscious patients 85.8% in VF/VT and 31.4% in PEA or asystole group. Good neurologic outcome was achieved in 58.0% patients with shockable rhythms and in 19.4% with non-shockable rhythms after TH treatment. The mean PaCO2 tension during the first 24-hour in ICU was an independent predictor of a good outcome with an odds ratio (OR) of 1.054, but the mean PaO2 tension was not. The time spent above PaCO2 45 mmHg was associated with good neurologic outcome and patients with the highest mean PaCO2 and PaO2 values had better neurologic outcome than predicted with an OR of 3.2 (95% CI 1.1-9.2). IL-6 and S-100B was associated with time to ROSC and poor neurological outcome (p less than 0.001). Admission IL-6 was associated with extra-cerebral organ dysfunction (p less than 0.001) and was an independent predictor of poor neurological outcome with an OR of 1.006 (95% CI 1.000-1.011). Hs-TnT levels were elevated in all of the patients, higher in patients with poor vs. good neurological outcome 739 vs. 334 ng/l (p=0.028), but there was no statistical difference in mortality. Conclusions TH is well implemented in clinical practice in Finnish ICUs. The majority of OHCA patients with shockable rhythms survive with good neurology, while the outcome of patients with non-shockable rhythms is poorer despite the TH treatment. There was no harmful association between hyperoxia and outcome, but instead mild hypercapnia combined with mild hyperoxia might be beneficial during the first 24 hours. IL-6 was associated with extra-cerebral organ dysfunction and predicted neurological outcome after OHCA-VF/VT, while hs-TnT does not give any additional prognostic information.
  • Hyvönen, Maija (2016)
    Gliomas, malignant brain tumors, are among the most aggressive cancers in adults. Due to their invasive growth, resistance mechanisms and tendency to relapse, the prognosis of high-grade glioma patients is very poor. Therefore, to improve therapeutic strategies it is essential to study molecular mechanisms underlying the progression of gliomas and identify novel, glioma-specific proteins that could be therapeutically targeted. In this study we first mapped vascular markers of malignant gliomas to find potential candidates for tumor targeting. By using in vivo phage display method we identified a peptide, CooP, which, after systemic delivery, specifically homed to brain tumor satellites and their vasculature in mice. Coop was successfully used in tumor imaging and targeted drug delivery. We also identified mammary-derived growth inhibitor (MDGI) as an interacting partner for CooP in the brain tumor tissue and tumor-associated vasculature. Homing peptide-conjugated nanocarriers have shown great potential in targeting various tumors, including gliomas. Therefore, we estimated the potential of CooP peptide in the surface functionalization and targeted delivery of porous silica nanoparticles in vitro and in vivo. CooP-functionalized particles were shown to be stable, non-toxic and suitable for targeting MDGI expressing subcutanous xenografts. In the last part of this study we characterized the expression and function of MDGI in gliomas. Our immunohistochemical analyses revealed abundant MDGI expression in clinical brain tumor specimens and patient-derived gliospheres. In lower-grade glioma patients MDGI expression correlated with poorer overall survival. Importantly, also endothelium-associated expression of MDGI in the clinical samples was observed. Functional in vitro and ex vivo assays demonstrated that MDGI overexpression enhanced the aggressive growth of glioma cells, whereas even more striking changes occurred when MDGI was genetically silenced. MDGI silencing compromised the growth of human gliospheres, altered the expression of stress-related proteins, disrupted mitochondrial function and eventually caused apoptotic cell death. In addition, mass spectrometric analyses revealed significant changes in the intracellular metabolites after MDGI silencing. Together our results show that the glioma-specific CooP peptide can be utilized both in glioma imaging and targeted drug delivery as well as in biofunctionalization and targeting of nanoparticles in vivo. In addition, MDGI, the interacting partner of CooP, is abundantly expressed in malignant gliomas and essential for glioma cell survival. Since MDGI is reachable via intravenously injected agents, it could be a potential candidate for the targeted treatment of gliomas.
  • Yukin, Alexey (Helsingin yliopisto, 2016)
    This Thesis addresses fundamental mechanisms of brain disorders that occur in preterm infants or during early childhood. To this end, we have developed animal models to mimic disorder-specific pathological conditions in the brain. During critical periods of development of the mammalian brain, cell migration and synapse formation are crucially important to set up newly developed neuronal circuits that will support complex network activity. A particular set of cells, the subplate neurons, is the first to mature during the earliest stages of cortical development. These neurons act as transient relay and processing station for signals coming from subcortical structures to the cortex. Their high dependence on oxygen supply makes them vulnerable to injuries that take place during pregnancy. In the present work, conditions of this kind were mimicked by specific toxin-based ablation of subplate neurons. At a more advanced stage of brain development, a very common type of brain disorder is febrile seizures (FS). They represent convulsive events in humans that are promoted by respiratory alkalosis during febrile illness. The global incidence of FS is estimated from 2 to 14 % (depending on ethnicity) of all children in the age of 6 months to 5 years. Using an animal based on 13-14 day old rats exposed to hyperthermia, we show that a pro-excitatory action of GABA based on the neuron-specific carbonic anhydrase (CA) isoform VII is crucially involved in the generation of these seizures. Finally, while it is widely assumed that FS are limbic in origin, this Thesis provides new evidence that the brainstem can have an independent and prominent role in the generation of FS, and also of convulsions induced by kainic acid, which so far, have been considered prototypical in studies of limbic seizures. As a whole, this work demonstrates the high utility and heuristic value of custom-designed animal models in studies of basic mechanisms and consequences of disorders in the developing brain.
  • Godenhjelm, Sebastian (Helsingin yliopisto, 2016)
    Over the past few decades, contemporary public policy and governance systems have been transformed in response to both local and supra-national societal problems and demands. Clear-cut means of tackling these problems and demands are rare. Public policy problems seldom fall neatly within specific jurisdictions or agencies. The state has become increasingly dependent on a wide range of policies and arrangements that produce public services, provide rapid results and facilitate timely interventions. As a response, the choice of governance mechanisms and organizational forms that enable collaborative, dynamic and flexible arrangements in the implementation of public policy becomes highly relevant. This study analyses the increasing use of temporary project organisations as new governance mechanisms in contemporary policy implementation and the prospects for action that this entails. The main argument is that project organisations could yield significant benefits and can play a vital role as horizontal as well as vertical interlinking mechanisms between various administrative levels. They could also include challenges that have not yet been fully understood. The overarching aim of the study is to conceptualise and understand the benefits and challenges related to the increasing number of temporary governance mechanisms in the form of project organisations in the public sector context. The study analyses the potential consequences and advantages of public sector projectification in four research articles and this summary article, focusing on how projectification is driven forward, as well as what the consequences of projectification are in the European Union (EU) context and the public sector in general. It considers the long-term effects of project organisations and the extent to which the added value they produce can be utilized. Who are the beneficial social partners and what types of collaborative procedures and actions are needed to achieve innovation in EU structural fund projects? The multifaceted and ambiguous nature of public sector project research, the uniqueness associated with the various actor objectives, interests and participatory procedures regarding projects, as well as their management requires a broad theoretical view and a variety of methods. Three interrelated strands of research in this respect are particularly relevant: the New Public Management (NPM) discourse, theories of Governance, and project management ideals and Governance of Projects (GoP). They represent a mixture of old and new, which is necessary in order to understand the functioning of projects and projectification as well as their embeddedness in the public sector environment. The study follows an empirically informed interpretive approach, which emphasises the intentionality of actions, practices, and social life. It uses a mixed-methods approach and advocates multi-perspectivism and paradigm interplay. It also combines different interpretations of the existing governance frameworks and public sector projects, thus acknowledging that alternative views might exist. The methods used in the individual articles represent metaevaluation, qualitative content analysis, logistic regression analysis and social network analysis (SNA). The findings highlight the lack of conceptualizations concerning the relationship between temporary and permanent structures, and suggest that an increasing temporality in public decision-making may challenge fundamental administrative values such as transparency and democratic accountability. The findings question the often over-emphasised value of using projects as opposed to other more permanent mechanisms in the public sector environment and suggest that there is a potential mismatch between the operational logic of projects and the prevailing project and program evaluation system in the public sector. Projects can act as hubs where valuable information is produced, and project stakeholder networks and various collaborative efforts can play a role in predicting project innovations. There is, however, an overly optimistic view of collaborative efforts in achieving project innovations, calling collaboration in projects into question as a direct remedy for a lack of innovation. The study concludes that an increasing use of project organisations in the public sector may have significant consequences, as well as showing that the expected advantages of project organisations are related to the rationalistic ideals, but also that temporality as such poses challenges to permanent administrative structures. Although projects might be superior to permanent structures in producing quick outputs, too much focus on the rational logic of project organisations means that their added value remains underutilized in a public sector context. The study contributes to a theoretical understanding of projectification, what the key drivers of projectification are, as well as specific public sector features that need to be accounted for in a projectified public sector. The study concludes that contextually sensitive interlinking mechanisms between temporary and permanent organizations are vital in explaining the outcome of temporary organizations in a politico-administrative context.
  • Tapiola, Olli (Helsingin yliopisto, 2016)
    Different dyadic techniques are an inseparable part of modern-day harmonic analysis both in the Euclidean space and in metric spaces. In this dissertation, we improve adjacent and random dyadic techniques in metric spaces and apply these and previously known techniques for questions related to metric, Euclidean and vector-valued analysis. The dissertation consists of an introductory part and four research articles. In the first article, we present a general randomization procedure for dyadic systems in metric spaces which can be used for constructing both random and adjacent dyadic systems. As an application of the new random systems, we improve the continuity properties of metric wavelets of P. Auscher and T. Hytönen by exploiting the improved ``smallness of boundary'' property of our random cubes. In the third article, we prove some additional properties for our adjacent dyadic systems to prove a decomposition result for dyadic systems in metric spaces. With its help, we give an alternative proof for the quantitative bound of the Lp norm of shift operators acting on vector-valued functions in metric spaces. In the second article, we explore certain properties of the Muckenhoupt weight classes, the class of Reverse Hölder weights and their weakened versions in spaces of homogeneous type. In the Euclidean setting, the Muckenhoupt weight classes have numerous different equivalent definitions but in spaces of homogeneous type some of those equivalences break down. We show that although certain definitions are no longer equivalent in this context, their weakened versions still define the same weight classes. We also show that every weak Reverse Hölder weight has a self-improving property. In the literature, these types of weak weights appear especially in the theory of partial differential equations. In the fourth article, we prove quantitative weighted bounds for so called rough homogeneous singular integrals by combining older techniques with a quantitative version of M. Lacey's recent extension of the A2 theorem. The proof of this extension is based on a domination technique which provides a way to dominate Calderón-Zygmund operators pointwise with the help of a finite number of simple sparse operators associated with adjacent dyadic systems.
  • Bofah, Emmanuel Adu-tutu (Helsingin yliopisto, 2016)
    The aim of the present set of studies in this dissertation was to examine the psychometric properties of measures of mathematics-related affect developed and normalized in one culture for use in another, how these properties transcend cross-culturally in an African context, and the methodological challenges associated with the process. Further aims were to examine the relationships between these constructs on a cross-cultural level, and to explore any associations be-tween students background variables and mathematics achievement. With these aims in mind, we conducted four original empirical studies based on different types of structural equation modeling. Studies I and II explored the problems of importing an instrument from one culture into another, and the associated methodological challenges. More specifically, Study I gives a detailed account of the processes involved in applying structural equation modeling to validate mathematics-related affective measures developed in one culture (Finland) for use in another (Ghana). Reliability estimates and confirmatory factor analyses indicated that the Ghanaian data set did not fit the original hypothesized model (seven-factor structure). A series of factor and confirmatory factor analyses indicated a four-factor structure for the Ghanaian sample. Study II examined the possible causes of the differences in the factor structures from a cross-cultural perspective. The results indicate that measurement artifacts, cultural differences, and construct validity and adaptability were possible causes of the observed differences in factor structure between the Ghanaian and the theoretical model. In conclusion, it is suggested that re-searchers should be aware of construct importation and adaptation, and of the fact that measurement errors, question order, negatively worded item, translation, and content overlap may influence the reliability and validity of survey measures. Moreover, it is necessary to consider cultural variation and the methodological approaches involved in the theoretical settings in order to make any meaningful comparative assessment. Researchers focusing on cross-cultural mathematics-related affect are recommended to acquire the theoretical and practical knowledge necessary to address these issues using appropriate tools such as structural equation modeling. Study III investigated the psychometric properties (factor structure, reliabilities, method effect, and measurement invariance country and gender) of the mathematics-related affective constructs used in the 2011 Trends in International Mathematics and Science Study (TIMSS 2011) across the five participating African countries. It also examined the relationship between these mathematically related affective constructs, as well as the associations amongst the constructs, and between the students background variables and mathematics achievement cross-culturally. The results empirically support the multidimensionality of the construct, and the measures were largely invariant across the five educational systems and gender. There was also some evidence to suggest that negatively worded items in a construct can attenuate the reliability and validity of the measures: a series of confirmatory factor analyses (CFAs) revealed the need to control for the method effects associated with such items. It seems that responses to negatively worded items differ systematically across countries and are systematically linked to students achievement. The analyses also covered the relationships between the student affect, achievement, and background variables such as parental education, gender and students educational aspirations. Lower mathematics achievement was associated with students from countries reporting higher motivational belief. On the association between students mathematics-related affect, achievement, parental education, educational aspirations and gender, it seems that there are culture-specific as well as cross-cultural universal outcomes. For instance, the relationship linking parental involvement, teacher responsiveness and mathematics achievement turned out to be culture-specific whereas, boys rated their mathematics competence more highly than girls did. Parental education, gender and long-term educational aspirations also influenced student achievement and motivation, but to different extents in different countries. Study IV, based on non-recursive structural equation models, tested theoretical and methodological models of the reciprocal relationship between mathematics-related affect (e.g., self-concept) and achievement using the TIMSS 2011 cross-sectional data set. The results in different countries support the existence of a unidirectional influence of affect on achievement and of achievement on affect, and a direct feedback-loop relationship between affect and achievement. According to the evidence, the reciprocal determinism between affect and achievement is dependent on the national context. Moreover, there was a cross-cultural universal pattern among males: reporting a stronger mathematics self-concept and higher long-term educational aspirations significantly predicted higher mathematics achievement. The effects of socioeconomic status on mathematics achievement and self-concept among the students were dependent on the national context.
  • Koivisto, Juhani (Helsingin yliopisto, 2016)
    The dissertation Amenability of metric measure spaces and fixed point properties of groups consists of three articles revolving around amenability and property (T) in different contexts, and a summary. In the first article, (non-)amenability of hyperbolic metric spaces is considered. In it, we prove that a uniformly coarsely proper hyperbolic cone of a connected bounded metric space containing at least two points is non-amenable. In particular, this implies that any uniformly coarsely proper visual Gromov hyperbolic space with connected boundary containing at least two points is non-amenable. In the second article, the degree of amenability of metric measure spaces is considered in general. Here, we prove a homological characterisation of global weighted Sobolev inequalities for quasiconvex uniform metric measure spaces that support a local weak (1,1)-Poincaré inequality using methods from large scale algebraic topology. Returning to the topic of the first article, we show that a quasiconvex visual Gromov hyperbolic uniform metric measure space that supports a local weak (1,1)-Poincaré inequality with a connected boundary containing at least two points satisfies a global Sobolev inequality. In the third article, fixed point conditions for uniformly bounded group actions on Hilbert spaces are considered. In the article, we establish a spectral condition for the vanishing of the first cohomology group of the complex of square integrable cochains twisted by a uniformly bounded representation of an automorphism group of a 2-dimensional simplicial complex. In particular, if the automorphism group acts properly discontinuously and cocompactly on the complex this implies that every affine action of the automorphism group on the Hilbert space with linear part given by the representation has a fixed point. In the summary, the results of the articles are further explained and placed in a larger context: mathematically as well as historically.
  • Mäkelä, Johanna (Helsingin yliopisto, 2016)
    Neurodegenerative diseases are characterized by the progressive loss of structure and function of neurons, but the underlying mechanisms for this are largely unknown. Disturbed cell signaling and protein metabolism as well as mitochondrial dysfunctions are thought to be involved in several neurodegenerative diseases. Mitochondria are the major source of energy in the cell, and they also regulate cell death. In brain, neurons are highly dependent on oxidative energy metabolism. Mitochondrial dysfunctions cause oxidative stress with an excess production of reactive oxygen species (ROS). In neurodegenerative diseases such as Parkinson s disease (PD), ROS are thought to contribute to the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), which leads to dopamine depletion in striatum. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a transcriptional co-activator that regulates mitochondrial biogenesis, ROS defense and respiration. The lack of PGC-1α has been shown to increase the sensitivity of neurons to oxidative stress and brain injuries. In this study we show that increasing the expression of PGC-1α protects against toxin-induced oxidative stress in dopaminergic neurons. We show that PGC-1α expression in dopaminergic neurons can be modulated by resveratrol (RSV), fibroblast growth factor 21 (FGF21) and peroxisome proliferator-activated receptor γ (PPARγ) that are known to regulate metabolism in other tissues. The increase in PGC-1α expression and activation was linked to metabolic changes mimicing low energy levels in the cell, and an increase in SIRT1, a metabolic regulator sensing changes in energy levels. PGC-1α activation was further associated with an increase in mitochondrial respiration and antioxidant levels suggesting that the neuroprotective effect of PGC-1α was due to an improved capacity to combat oxidative stress. These results show that regulation of metabolism by PGC-1α activators could be a useful tool to prevent neurodegeneration in PD. In addition to modulating PGC-1α, RSV was also found to increase the expression of dopamine transporter (DAT) in dopaminergic neurons of female mice. The increase in the level of DAT increases the uptake of dopamine, further indicating that RSV has beneficial effects in dopaminergic neurons. By affecting DAT, RSV also contributes to maintaining functional neurons, as a decline in DAT has been associated with degeneration of dopaminergic neurons. This effect on DAT expression was mediated by estrogen receptors, indicating that the effect of RSV differs between genders that should be considered if RSV is used as therapy for patients with PD.
  • Anyan, James (Helsingin yliopisto, 2016)
    This study explores how opportunities for higher education (HE) are distributed in Ghana's public universities to students; and particularly, how those from the disadvantaged sections of the Ghanaian society fare in that regard. It was approached as a multi-level (integrating elements of micro, meso and macro) and multi-perspective dual transformative case study. Drawing mainly upon data collected from semi-structured interviews with students, graduates, university officials and policy-makers, as well as secondary data archived by the relevant institutions; it examines the processes and patterns in the distribution of admission slots to students. It engages with the tensions and dilemmas confronting the universities in such allocations, and debates same, in the context of procedural justice and meritocracy on the one hand, and distributive justice and affirmative action on the other. The interactions and intersections of socio-economic and other significant variables parental education, family income, geographical location, gender and disability are discussed, principally, in the framework of effectively maintained inequality (EMI), to understand the factors influencing the patterns of distribution observed. The data were thematically analysed using both sensitising concepts from the literature review, the conceptual frameworks as well as the indigenous concepts that emerged from the data. The findings indicate that the distribution of HE seats in the two public universities selected for the study is highly inequitable with students who graduated from the few urban-based and elite upper secondary schools overrepresented while graduates from the majority rural-based and resource-poor schools are underrepresented. Although there was unanimity among the different groups of participants about the existence and persistence of the problem, their approaches to dealing with the problem proved dichotomous. While students from the rural schools, for instance, exposed their status frustration and assumed a reformist stance on the issue of remodelling the current grade-based admission system to one cognisant of the difficult circumstances under which rural students pursue their upper secondary education, their counterparts from the elite schools essentially defended the maintenance of the status quo. The majority of female participants, contrary to the views of policy-makers, strongly objected to affirmative action for the admission of females; arguing that the policy reinforces the notion that they are inferior to their male counterparts. The results further reveal a multi-layered social stratification in access to, and equity in HE in Ghana. Almost all the students and graduates who were admitted into the universities on affirmative action basis identified themselves as rural people from low-income families, with little or no parental education, and poor parental occupations. Such students, though in dire financial straits, were contrary to expectations, found to be very resilient and highly motivated to complete their studies; posting excellent academic performance. Students with disabilities were also found to be internally excluded, facing life and academic threatening challenges, whereas female students reported entrenched socio-cultural norms impeding the education and aspirations of women in the Ghanaian society. Against these backdrops, the study calls for a rethink of the current overly meritocratic admission procedures in Ghana's public universities that do harm to access and equity for the majority rural students. It further recommends financial support from government to support the affirmative action initiatives of the public universities; an improvement in the conditions of students with disability, and multi-sectoral interventions to ameliorate the barriers impeding the education of females. The successful completion of HE holding all things constant by these disadvantaged groups, with its attendant better educated citizenry, enhanced civic consciousness, empowerment and participation, in addition to other socio-economic benefits, make such investments worthwhile. Keywords: distributive justice, procedural justice, affirmative action, gender, disability, stratification.