Ion channel gene variants predisposing to severe human ventricular arrhythmias

Congenital long QT syndrome (LQTS) with an estimated prevalence of 1:2000-1:10 000 manifests with prolonged QT interval on electrocardiogram and risk for ventricular arrhythmias and sudden death. Several ion channel genes and hundreds of mutations in these genes have been identified to underlie the disorder. In Finland, four LQTS founder mutations of potassium channel genes account for up to 40-70% of genetic spectrum of LQTS. Acquired LQTS has similar clinical manifestations, but often arises from usage of QT-prolonging medication or electrolyte disturbances. A prolonged QT interval is associated with increased morbidity and mortality not only in clinical LQTS but also in patients with ischemic heart disease and in the general population. The principal aim of this study was to estimate the actual prevalence of LQTS founder mutations in Finland and to calculate their effect on QT interval in the Finnish background population. Using a large population-based sample of over 6000 Finnish individuals from the Health 2000 Survey, we identified LQTS founder mutations KCNQ1 G589D (n=8), KCNQ1 IVS7-2A>G (n=1), KCNH2 L552S (n=2), and KCNH2 R176W (n=16) in 27 study participants. This resulted in a weighted prevalence estimate of 0.4% for LQTS in Finland. Using a linear regression model, the founder mutations resulted in a 22- to 50-ms prolongation of the age-, sex-, and heart rate-adjusted QT interval. Collectively, these data suggest that one of 250 individuals in Finland may be genetically predisposed to ventricular arrhythmias arising from the four LQTS founder mutations. A KCNE1 D85N minor allele with a frequency of 1.4% was associated with a 10-ms prolongation in adjusted QT interval and could thus identify individuals at increased risk of ventricular arrhythmias at the population level. In addition, the previously reported associations of KCNH2 K897T, KCNH2 rs3807375, and NOS1AP rs2880058 with QT interval duration were confirmed in the present study. In a separate study, LQTS founder mutations were identified in a subgroup of acquired LQTS, providing further evidence that congenital LQTS gene mutations may underlie acquired LQTS. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by exercise-induced ventricular arrhythmias in a structurally normal heart and results from defects in the cardiac Ca2+ signaling proteins, mainly ryanodine receptor type 2 (RyR2). In a patient population of typical CPVT, RyR2 mutations were identifiable in 25% (4/16) of patients, implying that noncoding variants or other genes are involved in CPVT pathogenesis. A 1.1 kb RyR2 exon 3 deletion was identified in two patients independently, suggesting that this region may provide a new target for RyR2-related molecular genetic studies. Two novel RyR2 mutations showing a gain-of-function defect in vitro were identified in three victims of sudden cardiac death. Extended pedigree analyses revealed some surviving mutation carriers with mild structural abnormalities of the heart and resting ventricular arrhythmias suggesting that not all RyR2 mutations lead to a typical CPVT phenotype, underscoring the relevance of tailored risk stratification of a RyR2 mutation carrier.

Effects of SLCO1B1 polymorphism on the pharmacokinetics of the oral antidiabetic drugs repaglinide, nateglinide, rosiglitazone, and pioglitazone

Organic anion-transporting polypeptide 1B1 (OATP1B1), encoded by the SLCO1B1 gene, is an influx transporter expressed on the sinusoidal membrane of human hepatocytes. The common c.521T>C (p.Val174Ala) single-nucleotide polymorphism (SNP) of the SLCO1B1 gene has been associated with reduced OATP1B1 transport activity in vitro and increased plasma concentrations of several of its substrate drugs in vivo in humans. Another common SNP of the SLCO1B1 gene, c.388A>G (p.Asn130Asp), defining the SLCO1B1*1B (c.388G-c.521T) haplotype, has been associated with increased OATP1B1 transport activity in vitro. The aim of this thesis was to investigate the role of SLCO1B1 polymorphism in the pharmacokinetics of the oral antidiabetic drugs repaglinide, nateglinide, rosiglitazone, and pioglitazone. Furthermore, the effect of the SLCO1B1 c.521T>C SNP on the extent of interaction between gemfibrozil and repaglinide as well as the role of the SLCO1B1 c.521T>C SNP in the potential interaction between atorvastatin and repaglinide were evaluated. Five crossover studies with 2-4 phases were carried out, with 20-32 healthy volunteers in each study. The effects of the SLCO1B1 c.521T>C SNP on single doses of repaglinide, nateglinide, rosiglitazone, and pioglitazone were investigated in Studies I and V. In Study II, the effects of the c.521T>C SNP on repaglinide pharmacokinetics were investigated in a dose-escalation study, with repaglinide doses ranging from 0.25 to 2 mg. The effects of the SLCO1B1*1B/*1B genotype on repaglinide and nateglinide pharmacokinetics were investigated in Study III. In Study IV, the interactions of gemfibrozil and atorvastatin with repaglinide were evaluated in relation to the c.521T>C SNP. Plasma samples were collected for drug concentration determinations. The pharmacodynamics of repaglinide and nateglinide was assessed by measuring blood glucose concentrations. The mean area under the plasma repaglinide concentration-time curve (AUC) was ~70% larger in SLCO1B1 c.521CC participants than in c.521TT participants (P ≤ 0.001), but no differences existed in the pharmacokinetics of nateglinide, rosiglitazone, and pioglitazone between the two genotype groups. In the dose-escalation study, the AUC of repaglinide was 60-110% (P ≤ 0.001) larger in c.521CC participants than in c.521TT participants after different repaglinide doses. Moreover, the AUC of repaglinide increased linearly with repaglinide dose in both genotype groups (r > 0.88, P 0.001). The AUC of repaglinide was ~30% lower in SLCO1B1*1B/*1B participants than in SLCO1B1*1A/*1A (c.388AA-c.521TT) participants (P = 0.007), but no differences existed in the AUC of nateglinide between the two genotype groups. In the drug-drug interaction study, the mean increase in the repaglinide AUC by gemfibrozil was ~50% (P = 0.002) larger in c.521CC participants than in c.521TT participants, but the relative (7-8-fold) increases in the repaglinide AUC did not differ significantly between the genotype groups. In c.521TT participants, atorvastatin increased repaglinide peak plasma concentration and AUC by ~40% (P = 0.001) and ~20% (P = 0.033), respectively. In each study, after repaglinide administration, there was a tendency towards lower blood glucose concentrations in c.521CC participants than in c.521TT participants. In conclusion, the SLCO1B1 c.521CC genotype is associated with increased and the SLCO1B1*1B/*1B genotype with decreased plasma concentrations of repaglinide, consistent with reduced and enhanced hepatic uptake, respectively. Inhibition of OATP1B1 plays a limited role in the interaction between gemfibrozil and repaglinide. Atorvastatin slightly raises plasma repaglinide concentrations, probably by inhibiting OATP1B1. The findings on the effect of SLCO1B1 polymorphism on the pharmacokinetics of the drugs studied suggest that in vivo in humans OATP1B1 significantly contributes to the hepatic uptake of repaglinide, but not to that of nateglinide, rosiglitazone, or pioglitazone. SLCO1B1 polymorphism may be associated with clinically significant differences in blood glucose-lowering response to repaglinide, but probably has no effect on the response to nateglinide, rosiglitazone, or pioglitazone.

Iodine Brachytherapy for Large Uveal Melanomas

Uveal melanoma is the most common primary intraocular malignancy in adults. Vision in the affected eye is threatened by both the tumor and side-effects from the treatments currently available. Poor prognosis for saving vision increases with tumor size and, consequently, enucleation has been the treatment of choice for large uveal melanomas in most centers. However, increasing evidence suggests that no survival benefit is gained (nor lost) by enucleation as compared to eye-conserving methods. The Helsinki University Eye Hospital has since 1990 offered episcleral iodine-125 plaque brachytherapy (IBT) for all patients unwilling to undergo enucleation for a large uveal melanoma. The primary aim of this study was to assess survival, local tumor recurrence and preservation of the eye and vision after IBT in a population-based series of 97 patients with uveal melanomas classified as large by the Collaborative Ocular Melanoma Study (COMS) criteria. Further aims included reporting the incidence of side-effects and assessing the role of intraocular dose distribution and clinical risk factors in their development. Finally, means to improve the current treatment were investigated by using computer models to compare existing plaques with collimating ones and by comparing the outcome of a subgroup of 54 IBT patients with very thick tumors with 33 patients with similarly-sized tumors managed with transscleral local resection (TSR) in Liverpool, United Kingdom. Kaplan-Meier estimates of all-cause and melanoma-specific survival at 5 years after IBT were 62% and 65%, respectively, and visually comparable with the survival experience of patients reported after enucleation by the COMS. Local recurrence developed in 6% of eyes and 84% of eyes were conserved at 5 years. Visual prognosis was guarded with 11% avoiding loss of 20/70 vision and 26% avoiding loss of 20/400 vision in the tumor eye at 2 years. Large tumor height and short distance from the posterior pole were independently associated with loss of vision. Using cumulative incidence analysis to account for competing risks, such as enucleation and metastatic death, the 5-year incidence of cataract after IBT was 79%, glaucoma 60%, optic neuropathy 46%, maculopathy 52%, persistent or recurring retinal detachment (RD) 25%, and vitreous hemorrhage 36%. In multivariate competing risks regression models, increasing tumor height was associated with cataract, iris neovascularization and RD. Maculopathy and optic neuropathy were associated with distance from the tumor to the respective structure. Median doses to the tumor apex, macula and optic disc were 81 Gy (range, 40-158), 79 Gy (range, 12-632), and 83 Gy (range, 10-377), respectively. Dose to the optic disc was independently associated with optic neuropathy, and both dose to the optic disc and dose to the macula predicted vision loss after IBT. Simulated treatment using collimating plaques resulted in clinically meaningful reduction in both optic disc (median reduction, 30 Gy) and macular (median reduction, 36 Gy) doses as compared to the actual treatment with standard plaques. In the subgroup of patients with uveal melanomas classified as large because of tumor height, cumulative incidence analysis revealed that while long-term preservation of 20/70 vision was rare after both IBT and TSR, preservation of 20/400 vision was better after TSR (32% vs. 5% at 5 years). In multivariate logistic regression models, TSR was independently associated with better preservation of 20/400 vision (OR 0.03 at 2 years, P=0.005) No cases of secondary glaucoma were observed after TSR and optic neuropathy was rare. However, local tumor recurrence was more common after TSR than it was after IBT (Cumulative incidence 41% vs. 7% at 5 years, respectively). In terms of survival, IBT seems to be a safe alternative to enucleation in managing large uveal melanomas. Local tumor control is no worse than with medium-sized tumors and the chances of avoiding secondary enucleation are good. Unfortunately, side-effects from radiotherapy are frequent, especially in thick tumors, and long-term prognosis of saving vision is consequently guarded. Some complications can be limited by using collimating plaques and by managing uveal melanomas that are large because of tumor height with TSR instead of IBT. However, the patient must be willing to accept a substantial risk of local tumor recurrence after TSR and it is best suited for cases in which the preservation of vision in the tumor eye is critical.

Magnetic Resonance Imaging of Atherosclerotic Manifestations in Familial Hypercholesterolemia

Cardiovascular diseases (CVD) are, in developed countries, the leading cause of mortality. The majority of premature deaths and disability caused by CVD are due to atherosclerosis, a degenerating inflammatory disease affecting arterial walls. Early identification of lesions and initiation of treatment is crucial because the first manifestations quite often are major disabling cardiovascular events. Methods of finding individuals at high risk for these events are under development. Because magnetic resonance imaging (MRI) is an excellent non-invasive tool to study the structure and function of vascular system, we sought to discover whether existing MRI methods are able to show any difference in aortic and intracranial atherosclerotic lesions between patients at high risk for atherosclerosis and healthy controls. Our younger group (age 6-48) comprised 39 symptomless familial hypercholesterolemia (FH) patients and 25 healthy controls. Our older group (age 48-64) comprised 19 FH patients and 18 type 2 diabetes mellitus (DM) patients with coronary heart disease (CHD) and 29 healthy controls. Intracranial and aortic MRI was compared with carotid and femoral ultrasound (US). In neither age-group did MRI reveal any difference in the number of ischemic brain lesions or white matter hyperintensities (WMHIs) - possible signs of intracranial atherosclerosis - between patients and controls. Furthermore, MRI showed no difference in the structure or function of the aorta between FH patients and controls in either group. DM patients had lower compliance of the aorta than did controls, while no difference appeared between DM and FH patients. However, ultrasound showed greater plaque burden and increased thickness of carotid arterial walls in FH and DM patients in both age-groups, suggesting a more advanced atherosclerosis. The mortality of FH patients has decreased substantially after the late 1980´s when statin treatment became available. With statins, the progression of atherosclerotic lesions slows. We think that this, in concert with improvements in treatment of other risk factors, is one reason for the lack of differences between FH patients and controls in MRI measurements of the aorta and brain despite the more advanced disease of the carotid arteries assessed with US. Furthermore, whereas atherosclerotic lesions between different vascular territories correlate, differences might still exist in the extent and location of these lesions among different diseases. Small (<5 mm in diameter) WMHIs are more likely a phenomenon related to aging, but the larger ones may be the ones related to CVD and may be intermediate surrogates of stroke. The image quality in aortic imaging, although constantly improving, is not yet optimal and thus is a source of bias.

Macroseismology as a Component of Seismicity Assessments in an Intraplate Region: Studies of Northern Europe with Emphasis on Finland

This work focuses on the role of macroseismology in the assessment of seismicity and probabilistic seismic hazard in Northern Europe. The main type of data under consideration is a set of macroseismic observations available for a given earthquake. The macroseismic questionnaires used to collect earthquake observations from local residents since the late 1800s constitute a special part of the seismological heritage in the region. Information of the earthquakes felt on the coasts of the Gulf of Bothnia between 31 March and 2 April 1883 and on 28 July 1888 was retrieved from the contemporary Finnish and Swedish newspapers, while the earthquake of 4 November 1898 GMT is an example of an early systematic macroseismic survey in the region. A data set of more than 1200 macroseismic questionnaires is available for the earthquake in Central Finland on 16 November 1931. Basic macroseismic investigations including preparation of new intensity data point (IDP) maps were conducted for these earthquakes. Previously disregarded usable observations were found in the press. The improved collection of IDPs of the 1888 earthquake shows that this event was a rare occurrence in the area. In contrast to earlier notions it was felt on both sides of the Gulf of Bothnia. The data on the earthquake of 4 November 1898 GMT were augmented with historical background information discovered in various archives and libraries. This earthquake was of some concern to the authorities, because extra fire inspections were conducted in three towns at least, i.e. Tornio, Haparanda and Piteå, located in the centre of the area of perceptibility. This event posed the indirect hazard of fire, although its magnitude around 4.6 was minor on the global scale. The distribution of slightly damaging intensities was larger than previously outlined. This may have resulted from the amplification of the ground shaking in the soft soil of the coast and river valleys where most of the population was found. The large data set of the 1931 earthquake provided an opportunity to apply statistical methods and assess methodologies that can be used when dealing with macroseismic intensity. It was evaluated using correspondence analysis. Different approaches such as gridding were tested to estimate the macroseismic field from the intensity values distributed irregularly in space. In general, the characteristics of intensity warrant careful consideration. A more pervasive perception of intensity as an ordinal quantity affected by uncertainties is advocated. A parametric earthquake catalogue comprising entries from both the macroseismic and instrumental era was used for probabilistic seismic hazard assessment. The parametric-historic methodology was applied to estimate seismic hazard at a given site in Finland and to prepare a seismic hazard map for Northern Europe. The interpretation of these results is an important issue, because the recurrence times of damaging earthquakes may well exceed thousands of years in an intraplate setting such as Northern Europe. This application may therefore be seen as an example of short-term hazard assessment.

Snow characteristics in Dronning Maud Land, Antarctica

Snow cover is very sensitive to climate change and has a large feedback effect on the climate system due to the high albedo. Snow covers almost all surfaces in Antarctica and small changes in snow properties can mean large changes in absorbed radiation. In the ongoing discussion of climatic change, the mass balance of Antarctica has received increasing focus during recent decades, since its reaction to global warming strongly influences sea-level change. The aim of the present work was to examine the spatial and temporal variations in the physical and chemical characteristics of surface snow and annual accumulation rates in western Dronning Maud Land, Antarctica. The data were collected along a 350-km-long transect from the coast to the plateau during the years 1999-2004 as a part of the Finnish Antarctic Research Programme (FINNARP). The research focused on the most recent annual accumulation in the coastal area. The results show that the distance from the sea, and the moisture source, was the most predominant factor controlling the variations in both physical (conductivity, grain size, oxygen isotope ratio and accumulation) and chemical snow properties. The sea-salt and sulphur-containing components predominated in the coastal region. The local influences of nunataks and topographic highs were also visible on snow. The variations in all measured properties were wide within single sites mostly due to redistribution by winds and sastrugi topography, which reveals the importance of the spatially representative measurements. The mean accumulations occurred on the ice shelf, in the coastal region and on the plateau: 312 ± 28, 215 ± 43 and 92 ± 25 mm w.e., respectively. Depth hoar layers were usually found under the thin ice crust and were associated with a low dielectric constant and high concentrations of nitrate. Taking into account the vast size of the Antarctic ice sheet and its geographic characteristics, it is important to extend investigation of the distribution of surface snow properties and accumulation to provide well-documented data.

Simulations of dimensionally reduced effective theories of high temperature QCD

Quantum chromodynamics (QCD) is the theory describing interaction between quarks and gluons. At low temperatures, quarks are confined forming hadrons, e.g. protons and neutrons. However, at extremely high temperatures the hadrons break apart and the matter transforms into plasma of individual quarks and gluons. In this theses the quark gluon plasma (QGP) phase of QCD is studied using lattice techniques in the framework of dimensionally reduced effective theories EQCD and MQCD. Two quantities are in particular interest: the pressure (or grand potential) and the quark number susceptibility. At high temperatures the pressure admits a generalised coupling constant expansion, where some coefficients are non-perturbative. We determine the first such contribution of order g^6 by performing lattice simulations in MQCD. This requires high precision lattice calculations, which we perform with different number of colors N_c to obtain N_c-dependence on the coefficient. The quark number susceptibility is studied by performing lattice simulations in EQCD. We measure both flavor singlet (diagonal) and non-singlet (off-diagonal) quark number susceptibilities. The finite chemical potential results are optained using analytic continuation. The diagonal susceptibility approaches the perturbative result above 20T_c$, but below that temperature we observe significant deviations. The results agree well with 4d lattice data down to temperatures 2T_c.

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

Communicative and Anticipatory Decision-making Supported by Bayesian Networks

The purpose of this research is to draw up a clear construction of an anticipatory communicative decision-making process and a successful implementation of a Bayesian application that can be used as an anticipatory communicative decision-making support system. This study is a decision-oriented and constructive research project, and it includes examples of simulated situations. As a basis for further methodological discussion about different approaches to management research, in this research, a decision-oriented approach is used, which is based on mathematics and logic, and it is intended to develop problem solving methods. The approach is theoretical and characteristic of normative management science research. Also, the approach of this study is constructive. An essential part of the constructive approach is to tie the problem to its solution with theoretical knowledge. Firstly, the basic definitions and behaviours of an anticipatory management and managerial communication are provided. These descriptions include discussions of the research environment and formed management processes. These issues define and explain the background to further research. Secondly, it is processed to managerial communication and anticipatory decision-making based on preparation, problem solution, and solution search, which are also related to risk management analysis. After that, a solution to the decision-making support application is formed, using four different Bayesian methods, as follows: the Bayesian network, the influence diagram, the qualitative probabilistic network, and the time critical dynamic network. The purpose of the discussion is not to discuss different theories but to explain the theories which are being implemented. Finally, an application of Bayesian networks to the research problem is presented. The usefulness of the prepared model in examining a problem and the represented results of research is shown. The theoretical contribution includes definitions and a model of anticipatory decision-making. The main theoretical contribution of this study has been to develop a process for anticipatory decision-making that includes management with communication, problem-solving, and the improvement of knowledge. The practical contribution includes a Bayesian Decision Support Model, which is based on Bayesian influenced diagrams. The main contributions of this research are two developed processes, one for anticipatory decision-making, and the other to produce a model of a Bayesian network for anticipatory decision-making. In summary, this research contributes to decision-making support by being one of the few publicly available academic descriptions of the anticipatory decision support system, by representing a Bayesian model that is grounded on firm theoretical discussion, by publishing algorithms suitable for decision-making support, and by defining the idea of anticipatory decision-making for a parallel version. Finally, according to the results of research, an analysis of anticipatory management for planned decision-making is presented, which is based on observation of environment, analysis of weak signals, and alternatives to creative problem solving and communication.

Parathyroid hormone as an outcome indicator in old age

Serum parathyroid hormone (PTH) and vitamin D are the major regulators of extracellular calcium homeostasis. The inverse association between PTH and vitamin D and the common age-related elevation of the PTH concentration are well known phenomena. However, the confounding or modifying factors of this relationship and their impact on the response of PTH levels to vitamin D supplementation need further investigation. Clinical conditions such as primary hyperparathyroidism (PHPT), renal failure and vitamin D deficiency, characterized by an elevation of the PTH concentration, have been associated with impaired long-term health outcomes. Curative treatments for these conditions have also been shown to decreases PTH concentration and attenuate some of the adverse health effects. In PHPT it has also been commonly held that hypercalcaemia, the other hallmark of the disease, is the key mediator of the adverse health outcomes. In chronic kidney disease the systemic vascular disease has been proposed to have the most important impact on general health. Some evidence also indicates that vitamin D may have significant extraskeletal actions. However, the frank elevation of PTH concentration seen in advanced PHPT and in end-stage renal failure have also been suggested to be at least partly causally related to an increased risk of death as well as cognitive dysfunction. However, the exact mechanisms have remained unclear. Furthermore, the predictive value of elevated PTH in unselected older populations has been less well studied. The studies presented in this thesis investigated the impact of age and mobility on the responses of PTH levels to vitamin D deficiency and supplementation. Furthermore, the predictive value of PTH for long-term survival and cognitive decline was addressed in an unselected population of older people. The hypothesis was that age and chronic immobility are related to a persistently blunted elevation of PTH concentration, even in the presence of chronic vitamin D deficiency, and to attenuated responses of PTH to vitamin D supplementation. It was also further hypothesized that a slightly elevated or even high-normal PTH concentration is an independent indicator of an increased risk of death and cognitive decline in the general aged population. The data of this thesis are based on three samples: a meta-analysis of published vitamin D supplementation trials, a randomized placebo controlled six-month vitamin D supplementation trial, and a longitudinal prospective cohort study on a general aged population. Based on a PubMed search, a meta-analysis of 52 clinical trials with 6 290 adult participants was performed to evaluate the impact of age and immobility on the responses of PTH to 25-OHD levels and vitamin D supplementation. A total of 218 chronically immobile, very old inpatients were also enrolled into a vitamin D supplementation trial. Mortality data for these patients was also collected after a two-year follow-up. Finally, data from the Helsinki Aging Study, which followed three random age cohorts (75, 80 and 85 years) until death in almost all subjects, was used to evaluate the predictive value of PTH for long-term survival and cognitive decline. This series of studies demonstrated that in older people without overt renal failure or severe hypercalcaemia, serum 25-OHD and PTH were closely associated, but this relationship was also affected by age and immobility. Furthermore, a substantial proportion of old chronically bedridden patients did not respond to vitamin D deficiency by elevating PTH, and the effect of a high-dose (1200 IU/d) six-month cholecalciferol supplementation on the PTH concentration was minor. This study demonstrated longitudinally for the first time that the blunted PTH also persisted over time. Even a subtle elevation of PTH to high-normal levels predicted impaired long-term health outcomes. Slightly elevated PTH concentrations indicated an increased risk of clinically significant cognitive decline and death during the last years of life in a general aged population. This association was also independent of serum ionized calcium (Ca2+) and the estimated glomerular filtration rate (GFR). A slightly elevated PTH also indicated impaired two-year survival during the terminal years of frail elderly subjects independently of Ca2+, GFR, and of 25-OHD levels. The interplay between PTH and vitamin D in the regulation of calcium homeostasis is more complex than has been generally considered. In addition to muskuloskeletal health parathyroid hormone is also related to the maintenance of other important domains of health in old age. Higher PTH concentrations, even within conventional laboratory reference ranges, seem to be an independent indicator of an increased risk of all-cause and of cardiovascular mortality, independently of established cardiovascular risk factors, disturbances in mineral metabolism, and renal failure. Limited and inconsistent evidence supports the role of vitamin D deficiency-related lack of neuroprotective effects over the causal association between PTH and impaired cognitive functions. However, the causality of these associations remains unclear. The clinical implications of the observed relationships remain to be elucidated by future studies interfering with PTH concentrations, especially by long-term interventions to reduce PTH.

Humanitaarisuuden varjossa : Poliittiset tekijät lastensiirroissa Ruotsiin sotiemme aikana ja niiden jälkeen

The evacuation of Finnish children to Sweden during WW II has often been called a small migration . Historical research on this subject is scarce, considering the great number of children involved. The present research has applied, apart from the traditional archive research, the framework of history-culture developed by Rüsen in order to have an all-inclusive approach to the impact of this historical event. The framework has three dimensions: political, aesthetic and cognitive. The collective memory of war children has also been discussed. The research looks for political factors involved in the evacuations during the Winter War and the Continuation War and the post-war period. The approach is wider than a purely humanitarian one. Political factors have had an impact in both Finland and Sweden, beginning from the decision-making process and ending with the discussion of the unexpected consequences of the evacuations in the Finnish Parliament in 1950. The Winter War (30.11.1939 13.3.1940) witnessed the first child transports. These were also the model for future decision making. The transports were begun on the initiative of Swedes Maja Sandler, the wife of the resigned minister of foreign affairs Rickard Sandler, and Hanna Rydh-Munck af Rosenschöld , but this activity was soon accepted by the Swedish government because the humanitarian help in the form of child transports lightened the political burden of Prime Minister Hansson, who was not willing to help Finland militarily. It was help that Finland never asked for and it was rejected at the beginning. The negative response of Minister Juho Koivisto was not taken very seriously. The political forces in Finland supporting child transports were stronger than those rejecting them. The major politicians in support belonged to Finland´s Swedish minority. In addition, close to 1 000 Finnish children remained in Sweden after the Winter War. No analysis was made of the reasons why these children did not return home. A committee set up to help Finland and Norway was established in Sweden in 1941. Its chairman was Torsten Nothin, an influential Swedish politician. In December 1941 he appealed to the Swedish government to provide help to Finnish children under the authority of The International Red Cross. This plea had no results. The delivery of great amounts of food to Finland, which was now at war with Great Britain, had automatically caused reactions among the allies against the Swedish imports through Gothenburg. This included the import of oil, which was essential for the Swedish navy and air force. Oil was later used successfully to force a reduction in commerce between Sweden and Finland. The contradiction between Sweden´s essential political interests and humanitarian help was solved in a way that did not harm the country´s vital political interests. Instead of delivering help to Finland, Finnish children were transported to Sweden through the organisations that had already been created. At the beginning of the Continuation War (25.6.1941 27.4.1945) negative opinion regarding child transports re-emerged in Finland. Karl-August Fagerholm implemented the transports in September 1941. In 1942, members of the conservative parties in the Finnish Parliament expressed their fear of losing the children to the Swedes. They suggested that Finland should withdraw from the inter-Nordic agreement, according to which the adoptions were approved by the court of the country where the child resided. This initiative failed. Paavo Virkkunen, an influential member of the conservative party Kokoomus in Finland, favoured the so-called good-father system, where help was delivered to Finland in the form of money and goods. Virkkunen was concerned about the consequences of a long stay in a Swedish family. The risk of losing the children was clear. The extreme conservative party (IKL, the Patriotic Movement of the Finnish People) wanted to alienate Finland from Sweden and bring Finland closer to Germany. Von Blücher, the German ambassador to Finland, had in his report to Berlin, mentioned the political consequences of the child transports. Among other things, they would bring Finland and Sweden closer to each other. He had also paid attention to the Nordic political orientation in Finland. He did not question or criticize the child transports. His main interest was to increase German political influence in Finland, and the Nordic political orientation was an obstacle. Fagerholm was politically ill-favoured by the Germans, because he had a strong Nordic political disposition and had criticised Germany´s activities in Norway. The criticism of child transports was at the same time criticism of Fagerholm. The official censorship organ of the Finnish government (VTL) denied the criticism of child transports in January 1942. The reasons were political. Statements made by members of the Finnish Parliament were also censored, because it was thought that they would offend the Swedes. In addition, the censorship organ used child transports as a means of active propaganda aimed at improving the relations between the two countries. The Finnish Parliament was informed in 1948 that about 15 000 Finnish children still remained in Sweden. These children would stay there permanently. In 1950 the members of the Agrarian Party in Finland stated that Finland should actively strive to get the children back. The party on the left (SKDL, the Democratic Movement of Finnish People) also focused on the unexpected consequences of the child transports. The Social Democrats, and largely Fagerholm, had been the main force in Finland behind the child transports. Members of the SKDL, controlled by Finland´s Communist Party, stated that the war time authorities were responsible for this war loss. Many of the Finnish parents could not get their children back despite repeated requests. The discussion of the problem became political, for example von Born, a member of the Swedish minority party RKP, related this problem to foreign policy by stating that the request to repatriate the Finnish children would have negative political consequences for the relations between Finland and Sweden. He emphasized expressing feelings of gratitude to the Swedes. After the war a new foreign policy was established by Prime Minister (1944 1946) and later President (1946 1956) Juho Kusti Paasikivi. The main cornerstone of this policy was to establish good relations with the Soviet Union. The other, often forgotten, cornerstone was to simultaneously establish good relations with other Nordic countries, especially Sweden, as a counterbalance. The unexpected results of the child evacuation, a Swedish initiative, had violated the good relations with Sweden. The motives of the Democratic Movement of Finnish People were much the same as those of the Patriotic Movement of Finnish People. Only the ideology was different. The Nordic political orientation was an obstacle to both parties. The position of the Democratic Movement of Finnish People was much better than that of the Patriotic Movement of Finnish People, because now one could clearly see the unexpected results, which included human tragedy for the many families who could not be re-united with their children despite their repeated requests. The Swedes questioned the figure given to the Finnish Parliament regarding the number of children permanently remaining in Sweden. This research agrees with the Swedes. In a calculation based on Swedish population registers, the number of these children is about 7 100. The reliability of this figure is increased by the fact that the child allowance programme began in Sweden in 1948. The prerequisite to have this allowance was that the child be in the Swedish population register. It was not necessary for the child to have Swedish nationality. The Finnish Parliament had false information about the number of Finnish children who remained in Sweden in 1942 and in 1950. There was no parliamentary control in Finland regarding child transports, because the decision was made by one cabinet member and speeches by MPs in the Finnish Parliament were censored, like all criticism regarding child transports to Sweden. In Great Britain parliamentary control worked better throughout the whole war, because the speeches regarding evacuation were not censored. At the beginning of the war certain members of the British Labour Party and the Welsh Nationalists were particularly outspoken about the scheme. Fagerholm does not discuss to any great extent the child transports in his memoirs. He does not evaluate the process and results as a whole. This research provides some possibilities for an evaluation of this sort. The Swedish medical reports give a clear picture of the physical condition of the Finnish children when arriving in Sweden. The transports actually revealed how bad the situation of the poorest children was. According to Titmuss, similar observations were made in Great Britain during the British evacuations. The child transports saved the lives of approximately 2 900 children. Most of these children were removed to Sweden to receive treatment for illnesses, but many among the healthy children were undernourished and some suffered from the effects of tuberculosis. The medical inspection in Finland was not thorough. If you compare the figure of 2 900 children saved and returned with the figure of about 7 100 children who remained permanently in Sweden, you may draw the conclusion that Finland as a country failed to benefit from the child transports, and that the whole operation was a political mistake with far-reaching consequenses. The basic goal of the operation was to save lives and have all the children return to Finland after the war. The difficulties with the repatriation of the children were mainly psychological. The level of child psychology in Finland at that time was low. One may question the report by Professor Martti Kaila regarding the adaptation of children to their families back in Finland. Anna Freud´s warnings concerning the difficulties that arise when child evacuees return are also valid in Finland. Freud viewed the emotional life of children in a way different from Kaila: the physical survival of a small child forces her to create strong emotional ties to the person who is looking after her. This, a characteristic of all small children, occurred with the Finnish children too, and it was something the political decision makers in Finland could not see during and after the war. It is a characteristic of all little children. Yet, such experiences were already evident during the Winter War. The best possible solution had been to limit the child transports only to children in need of medical treatment. Children from large and poor families had been helped by organising meals and by buying food from Denmark with Swedish money. Assisting Finland by all possible means should have been the basic goal of Fagerholm in September 1941, when the offer of child transports came from Sweden. Fagerholm felt gratitude towards the Swedes. The risks became clear to him only in 1943. The war children are today a rather scattered and diffuse group of people. Emotionally, part of these children remained in Sweden after the war. There is no clear collective memory, only individual memories; the collective memory of the war children has partly been shaped later through the activities of the war child associations. The main difference between the children evacuated in Finland (for example from Karelia to safer areas with their families) and the war children, who were sent abroad, is that the war children lack a shared story and experience with their families. They were outsiders . The whole matter is sensitive to many of such mothers and discussing the subject has often been avoided in families. The war-time censorship has continued in families through silence and avoidance and Finnish politicians and Finnish families had to face each other on this issue after the war. The lack of all-inclusive historical research has also prevented the formation of a collective awareness among war children returned to Finland or those remaining permanently abroad.. Knowledge of historical facts will help war-children by providing an opportunity to create an all-inclusive approach to the past. Personal experiences should be regarded as part of a large historical entity shadowed by war and where many political factors were at work in both Finland and Sweden. This means strengthening of the cognitive dimension discussed in Rüsen´s all-inclusive historical approach.

Sense of Coherence : Determinants and consequences

ABSTRACT Sense of coherence (SOC) is a core concept within Antonovsky s salutogenic theory and is argued to be a psychological determinant of health. The present social-epidemiological study explores the associations between a wide range of generalized resistance resources of SOC among Finnish- and Swedish-speaking women and men with a view to gaining deeper insight into its developmental circumstances and determinants. Secondly, a five-year follow-up study was conducted in order to assess the stability of SOC in difficult life events. Finally the role and effect of SOC in the intentions to retire early was investigated in a prospective study. The above studies were based on two data sets: the Finnish 'Survey on Living Conditions' (ELO-94) conducted in 1994 by means of personal face-to-face interviews (N=6506), and a prospective postal survey of the 15-year Health and Social Support (HeSSup) study for which the baseline data was collected in 1998 (N=25 898) and the follow-up in 2003. The present study reveals that the level of SOC in adulthood is strongly dependent on close and successful social relationships during both childhood and adulthood, and that there is a strong association with qualitative work features. Not having a partner as well as being unable to use one s skills at work proved to threaten men s SOC in particular, whereas a lack of social support did the same for women. Otherwise, the association with generalized resistance resources turned out to be quite similar in both genders. Swedish-speaking Finns appear to have a slightly stronger SOC due to the better psycho-emotional circumstances in the childhood home and work circumstances in adulthood, in other words higher levels of generalized resistance resources compared to Finnish speakers. These language group differences did not concern any social-life factors included in the present study. The results of the five-year follow-up study suggest that SOC is not stable, and that the level clearly decreases after a negative life event. Even a strong SOC decreased during the follow-up period and, furthermore, was no more stable than a mediocre or weak SOC. There seems to be a clear and independent association with the intentions to retire early among both men and women following full adjustment. Swedish speakers appear to be less inclined to retire early than Finnish speakers. In the light of the present study, it seems that SOC is determined not only by socio-economic factors but also by close and successful social relationships during both childhood and adulthood. This applied to both genders and language groups. Interventions aimed at promoting the health of the disadvantaged should therefore focus on families with children, and extend later also to other than socio-economic spheres of life. SOC theory could also be applied in efforts to inhibit early retirement: management practices aimed at providing employees with a work environment and tasks that are comprehensible, manageable and meaningful could potentially decrease the intentions to retire early.

Profligate Descent : The Cultural Transformations of Evolutionary Narrative

This dissertation traces a set of historical transformations the Darwinian evolutionary narrative has undergone toward the end of the twentieth century, especially as reflected in Anglo-American popular science books and novels. The study has three objectives. First, it seeks to understand the organizing logic of evolutionary narratives and the role that assumptions about gender and sexuality play in that logic. Second, it asks what kinds of cultural anxieties evolutionary theory raises and how evolutionary narratives negotiate them. Third, it examines the possibilities and limits of narrative transformation both as a historical phenomenon and as a theoretical question. This interdisciplinary dissertation is situated at the intersection of science studies, cultural studies, literary studies, and gender studies. Its understanding of science as a cultural practice that both emerges from and contributes to cultural expectations and institutional structures follows the tradition of science studies. Its focus on the question of popular appeal and the mechanisms of cultural change arises from cultural studies. Its view of narrative as a structural phenomenon is grounded in literary studies in general and feminist narrative theory in particular. Its understanding of gender and sexuality as implicated in discourses of epistemic authority builds on the view of gender and sexuality as contingent cultural categories central to gender studies. The primary material consists of over 25 British and American popular science books and novels, published roughly between 1990 and 2005. In order to highlight historical transformations, these texts are read in the context of Darwin s The Origin of Species and The Descent of Man, on the one hand, and such sociobiological classics as E. O. Wilson s On Human Nature and Richard Dawkins s The Selfish Gene, on the other. The research method combines feminist narrative analysis with cultural and historical contextualization, emphasizing discursive abruptions, recurrent narrative patterns, and underlying continuities. The dissertation demonstrates that the relationship between Darwin s evolutionary narrative and late twentieth-century evolutionary narratives is characterized by reemphasis, omissions, and continuous rewriting. In particular, contemporary evolutionary discourse extends the role assigned to reproduction both sexual and narrative in Darwin s writing, generating a narrative logic that imagines the desire to reproduce as the driving force of evolution and posits the reproductive sex act as the endlessly repeated narrative event that keeps the story going. The study argues that the popular appeal of evolutionary accounts of gender, sexuality, and human nature may arise, to an extent, from this reproductive narrative dynamic. This narrative dynamic, however, is not logically invulnerable. Since the continuation of the evolutionary narrative relies on successful reproduction, the possibility of reproductive failure poses a constant risk to narrative futurity, arousing cultural anxieties that evolutionary narratives need to address. The study argues that evolutionary narratives appease such anxieties by evoking a range of cultural narratives, especially romantic, religious, and national narratives. Furthermore, the study shows that the event-based logic of evolutionary narratives privileges observable acts over emotions, pleasures, identities, and desires, thus engendering a set of conceptual exclusions that limits the imaginative scope of evolution as a cultural narrative.

Maaseutupolitiikan YTR. Itsearviointitutkimus 2010

Maaseutupolitiikan yhteistyöryhmä on pääosin poliittis-hallinnollisessa tilassa toimiva, uusi verkostomainen hallintasommitelma, jossa on mukana myös hallinnon ulkopuolisia toimijoita ja tahoja. Kokonaisuutta nimitetään tässä YTR-verkostoksi. Itsearvioinnin tarkoituksena oli argumentoida esiin YTR-verkoston toiminnan kriittiset kohdat. Arviointitutkimuksesta vastasi Helsingin yliopiston Ruralia-instituutti ja sen toteutti 25.8. – 31.12.2010 välisenä aikana tutkimusjohtaja, dosentti Torsti Hyyryläinen. Itsearviointiin osallistui valtioneuvoston viisivuotiseksi toimikaudeksi (2008-2013) nimeämän maaseutupolitiikan yhteistyöryhmän jäseniä ja varajäseniä. Kokoavana tuloksena esitetään seuraava analyysi: 1. YTR-verkoston tiedollinen kapasiteetti on vahva. 2. YTR-verkostolla on potentiaalisesti laajat suhderesurssit mutta ne ovat alihyödynnettyjä. 3. YTR-verkostolla on mobilisoitikapasiteettia mutta sen omat voimavarat ovat niukat. YTR-verkostolla on ollut keskeinen rooli maaseutupolitiikan muotoutumisessa ja kehittymisessä. Keskustelu maaseudun kehittämistä olisi Suomessa ollut oleellisesti vähäisempää, heikommin jäsenneltyä ja tietopääomaltaan suppeampaa ilman YTR-verkostoa. Verkostossa on monialaista asiantuntemusta, jonka perusteella se on kyennyt vastaamaan laajoihin maaseutupoliittisiin kommunikaatiotarpeisiin. Tästä yhtenä esimerkkinä on maaseutupoliittisen selonteon perusteellinen valmistelu ja monivaiheinen käsittely eduskunnassa vuonna 2010. Verkostosuhteiden hallinnan kehittäminen nousee arvioinnissa tärkeimmäksi YTR-verkoston toimintakyvyn, tuloksellisuuden ja vaikuttavuuden kehittämisen painopisteeksi. Verkosto näyttää saavuttaneen tärkeän kehitysvaiheen, josta ei päästä eteenpäin ilman sen kysymyksen pohdintaa, miten YTR-verkoston suhdekapasiteettia, eli suhteita keskeisiin sidosryhmiin voitaisiin kehittää. Valta on YTR-verkostossa komplisoiduinta ja ongelmallisinta juuri suhderesurssien alueilla. Se kiteytyy kysymykseen poliittisesta valmistelu- ja päätösvallasta, eli kenellä on legitiimi asema toisaalta muotoilla poliittiseen päätöksentekoon etenevät aloitteet ja lopulta tehdä poliittisesti sitovia päätöksiä koskien maaseutua ja sen kehittämistä. Medioiden vaikutusvallan huomioiminen on entistä tärkeämpää. Niiden suuntaan vahvemmin kommunikoimalla YTR-verkosto voi tulevaisuudessa lisätä vaikutusvaltaansa. Toistaiseksi lähes täysin käyttämätön potentiaali on sosiaalisen median verkostoissa, joihin YTR:n säikeet eivät vielä juurikaan ulotu. Suhdepääomassa on siis YTR:n voima ja samalla sen heikkous. Tämä johtopäätös on merkittävä erityisesti valtioneuvoston asettaman yhteistyöryhmän itsensä kannalta. Yhteistyöryhmän tulisi itse vapautua komiteamaisista työtavoista ja kehittää niitä monimuotoisemmiksi. Paikallaan on myös kysyä: mitä yhteistyöryhmän jäsenet ja jäsenyhteisöt ovat valmiita tekemään YTR:n suhderesurssien kehittämiseksi?

The Art of Adaptation : A study on the Europeanization of Finland's foreign and security policy

This study examines how Finnish foreign and security policy has been influenced by the European Union and its Common Foreign and Security Policy. It points to a growing interplay and misfit between the external expectations originating from the European level and the domestic expectations and traditional ways-of-doing-things. It is concluded that the deepening European integration in the sphere of foreign, security and defence policy has played a significant role in a number of transformations in the Finnish policies since 1995. New, more European, meanings have been attached to the key concepts of Finnish foreign and security policy. Neutrality and traditional peacekeeping have been replaced by a minimalist reading of military non-alignment and participation in crisis management operations and EU battle groups. Traditional small state identity has been recast more and more as small member stateness . At the same time Finland has entered an era of post-consensus in national foreign and security policy. A key theoretical argument in the background of the study is that collective understandings attached to European policies, when not resonating well with domestic understandings, cause adaptation pressures on domestic-level processes and may lead to changes in the way interests and identities are constructed. This means that Europeanization is principally seen as identity reconstruction. Consequently, the theoretical framework of the study builds on the Europeanization research literature and constructivist IR theory on state identity. Foreign and security policy is defined as the practice in which state identity is reproduced, and the key foreign and security policy concepts are seen as the vehicles of identity production. It is concluded that for Finland, participation in the EU s foreign, security and defence policies represents not only a tool for responding to the changes in the international security environment but also a new means of self-identification. Concerning the Finnish attempts of projecting national interests on the European security policy agenda, it is concluded that they mainly relate to the compatibility of the potential development of EU s defence dimension with the Finnish military non-alignment. Although neutrality was cast aside in the official security policy when Finland joined the EU, the analysis shows that its impact has continued in the domestic political debate and in the mind-set of the decision-makers. The primary research material includes official Finnish foreign and security policy documentation and the related parliamentary debates from 1994 to 2007. This study serves also as a comprehensive empirical overview on Finland s reactions and contributions to the EU Common Foreign and Security Policy.