Candidate gene studies on cardiovascular traits

Cardiovascular diseases (CVD) are a major cause of death and disability in Western countries and a growing health problem in the developing world. The genetic component of both coronary heart disease (CHD) and ischemic stroke events has been established in twin studies, and the traits predisposing to CVD, such as hypertension, dyslipidemias, obesity, diabetes, and smoking behavior, are all partly hereditary. Better understanding of the pathophysiology of CVD-related traits could help to target disease prevention and clinical treatment to individuals at an especially high disease risk and provide novel pharmaceutical interventions. This thesis aimed to clarify the genetic background of CVD at a population level using large Nordic population cohorts and a candidate gene approach. The first study concentrated on the allelic diversity of the thrombomodulin (THBD) gene in two Finnish cohorts, FINRISK-92 and FINRISK-97. The results from this study implied that THBD variants do not substantially contribute to CVD risk. In the second study, three other candidate genes were added to the analyses. The study investigated the epistatic effects of coagulation factor V (F5), intercellular adhesion molecule -1 (ICAM1), protein C (PROC), and THBD in the same FINRISK cohorts. The results were encouraging; we were able to identify several single SNPs and SNP combinations associating with CVD and mortality. Interestingly, THBD variants appeared in the associating SNP combinations despite the negative results from Study I, suggesting that THBD contributes to CVD through gene-gene interactions. In the third study, upstream transcription factor -1 (USF1) was analyzed in a cohort of Swedish men. USF1 was associated with metabolic syndrome, characterized by accumulation of different CVD risk factors. A putative protective and a putative risk variant were identified. A direct association with CVD was not observed. The longitudinal nature of the study also clarified the effect of USF1 variants on CVD risk factors followed in four examinations throughout adulthood. The three studies provided valuable information on the study of complex traits, highlighting the use of large study samples, the importance of replication, and the full coverage of the major allelic variants of the target genes to assure reliable findings. Although the genetic basis of coronary heart disease and ischemic stroke remains unknown, single genetic findings may facilitate the recognition of high-risk subgroups.

Perspectives on prescribing in nursing homes in Helsinki

Prescribing for older patients is challenging. The prevalence of diseases increases with advancing age and causes extensive drug use. Impairments in cognitive, sensory, social and physical functioning, multimorbidity and comorbidities, as well as age-related changes in pharmacokinetics and pharmacodynamics all add to the complexity of prescribing. This study is a cross-sectional assessment of all long-term residents aged ≥ 65 years in all nursing homes in Helsinki, Finland. The residents’ health status was assessed and data on their demographic factors, health and medications were collected from their medical records in February 2003. This study assesses some essential issues in prescribing for older people: psychotropic drugs (Paper I), laxatives (Paper II), vitamin D and calcium supplements (Paper III), potentially inappropriate drugs for older adults (PIDs) and drug-drug interactions (DDIs)(Paper IV), as well as prescribing in public and private nursing homes. A resident was classified as a medication user if his or her medication record indicated a regular sequence for its dosage. Others were classified as non-users. Mini Nutritional Assessment (MNA) was used to assess residents’ nutritional status, Beers 2003 criteria to assess the use of PIDs, and the Swedish, Finnish, INteraction X-referencing database (SFINX) to evaluate their exposure to DDIs. Of all nursing home residents in Helsinki, 82% (n=1987) participated in studies I, II, and IV and 87% (n=2114) participated in the study III. The residents’ mean age was 84 years, 81% were female, and 70% were diagnosed with dementia. The mean number of drugs was 7.9 per resident; 40% of the residents used ≥ 9 drugs per day, and were thus exposed to polypharmacy. Eighty percent of the residents received psychotropics; 43% received antipsychotics, and 45% used antidepressants. Anxiolytics were prescribed to 26%, and hypnotics to 28% of the residents. Of those residents diagnosed with dementia, 11% received antidementia drugs. Fifty five percent of the residents used laxatives regularly. In multivariate analysis, those factors associated with regular laxative use were advanced age, immobility, poor nutritional status, chewing problems, Parkinson’s disease, and a high number of drugs. Eating snacks between meals was associated with lower risk for laxative use. Of all participants, 33% received vitamin D supplementation, 28% received calcium supplementation, and 20% received both vitamin D and calcium. The dosage of vitamin D was rather low: 21% received vitamin D 400 IU (10 µg) or more, and only 4% received 800 IU (20 µg) or more. In multivariate analysis, residents who received vitamin D supplementation enjoyed better nutritional status, ate snacks between meals, suffered no constipation, and received regular weight monitoring. Those residents receiving PIDs (34% of all residents) more often used psychotropic medication and were more often exposed to polypharmacy than residents receiving no PIDs. Residents receiving PIDs were less often diagnosed with dementia than were residents receiving no PIDs. The three most prevalent PIDs were short-acting benzodiazepine in greater dosages than recommended, hydroxyzine, and nitrofurantoin. These three drugs accounted for nearly 77% of all PID use. Of all residents, less than 5% were susceptible to a clinically significant DDI. The most common DDIs were related to the use of potassium-sparing diuretics, carbamazepine, and codeine. Residents exposed to potential DDIs were younger, had more often suffered a previous stroke, more often used psychotropics, and were more often exposed to PIDs and polypharmacy than were residents not exposed to DDIs. Residents in private nursing homes were less often exposed to polypharmacy than were residents in public nursing homes. Long-term residents in nursing homes in Helsinki use, on average, nearly eight drugs daily. The use of psychotropic drugs in our study was notably more common than in international studies. The prevalence of laxatives equaled other prior international studies. Regardless of the known benefit and recommendation of vitamin D supplementation for elderly residing mostly indoors, the proportion of nursing home residents receiving vitamin D and calcium was surprisingly low. The use of PIDs was common among nursing home residents. PIDs increased the likelihood of DDIs. However, DDIs did not seem a major concern among the nursing home population. Monitoring PIDs and potential drug interactions could improve the quality of prescribing.

Molecular Genetics of Lactase Deficiencies

Congenital lactase deficiency (CLD) (MIM 223000) is a rare autosomal recessive gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. The CLD locus was previously assigned by linkage and linkage disequilibrium analyses on 2q21 in 19 Finnish families. In this study, the molecular background of this disorder is reported. The CLD locus was refined in 32 CLD patients in 24 families by using microsatellite and single nucleotide polymorphism (SNP) haplotypes. Mutation analyses were performed by direct sequencing. We identified 5 distinct mutations in the lactase (LCT) gene, encoding the enzyme that hydrolyzes lactose in the intestinal lumen. These findings facilitate genetic testing of CLD in clinical practice and enable genetic counseling. The present data also provide the basis for detailed characterization of the molecular pathogenesis of this disorder. Adult-type hypolactasia (MIM 223100) (lactase non-persistence, lactose intolerance) is an autosomal recessive gastrointestinal condition that is a result of a decline in the activity of lactase in the intestinal lumen after weaning. Adult-type hypolactasia is considered to be a normal phenomenon among mammals and symptoms are remarkably milder than experienced in CLD. Recently, a variant C/T-13910 was shown to associate with the adult-type hypolactasia trait, locating 13.9 kb upstream of the LCT gene. In this study, the functional significance of the C/T-13910 variant was determined by studying the LCT mRNA levels in intestinal biopsy samples in children and adults with different genotypes. RT-PCR followed by solid-phase minisequencing was applied to determine the relative expression levels of the LCT alleles using an informative SNP located in exon 1. In children, the C-13910 allele was observed to be downregulated after five years of age in parallel with lactase enzyme activity. The expression of the LCT mRNA in the intestinal mucosa in individuals with the T-13910 A-22018 alleles was 11.5 times higher than that found in individuals with the C-13910, G-22018 alleles. These findings suggest that the C/T-13910 associated with adult-type hypolactasia is associated with the transcriptional regulation of the LCT gene. The presence of the T-13910 A-22018 allele also showed significant elevation lactase activity. Galactose, the hydrolysing product of the milk sugar lactose, has been hypothesized to be poisonous to ovarian epithelial cells. Hence, consumption of dairy products and lactase persistence has been proposed to be a risk factor for ovarian carcinoma. To investigate whether lactase persistence is related to the risk of ovarian carcinoma the C/T-13910 genotype was determined in a cohort of 782 women with ovarian carcinoma 1331 individuals serving as controls. Lactase persistence did not associate significantly with the risk for ovarian carcinoma in the Finnish, in the Polish or in the Swedish populations. The findings do not support the hypothesis that lactase persistence increases the risk for ovarian carcinoma.

Molecular Genetic Background of Tumours in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a hereditary tumour predisposition syndrome. Its phenotype includes benign cutaneous and uterine leiomyomas (CLM, ULM) with high penetrance and rarer renal cell cancer (RCC), most commonly of papillary type 2 subtype. Over 130 HLRCC families have been identified world-wide but the RCC phenotype seems to concentrate in families from Finland and North America for unknown reasons. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. FH encodes the enzyme fumarase from mitochondrial citric acid cycle. Fumarase enzyme activity or type or site of the FH mutation are unassociated with disease phenotype. The strongest evidence for tumourigenesis mechanism in HLRCC supports a hypoxia inducible factor driven process called pseudohypoxia resulting from accumulation of the fumarase substrate fumarate. In this study, to assess the importance of gene- or exon-level deletions or amplifications of FH in patients with HLRCC-associated phenotypes, multiplex ligation-dependent probe amplification (MLPA) method was used. One novel FH mutation, deletion of exon 1, was found in a Swedish male patient with an evident HLRCC phenotype with CLM, RCC, and a family history of ULM and RCC. Six other patients with CLM and 12 patients with only RCC or uterine leiomyosarcoma (ULMS) remained FH mutation-negative. These results suggest that copy number aberrations of FH or its exons are an infrequent cause of HLRCC and that only co-occurrence of benign tumour types justifies FH-mutation screening in RCC or ULMS patients. Determination of the genomic profile of 11 HLRCC-associated RCCs from Finnish patients was performed by array comparative genomic hybridization. The most common copy number aberrations were gains of 2, 7, and 17 and losses of 13q12.3-q21.1, 14, 18, and X. When compared to aberrations of sporadic papillary RCCs, HLRCC-associated RCCs harboured a distinct DNA copy number profile and lacked many of the changes characterizing the sporadic RCCs. The findings suggest a divergent molecular pathway for tumourigenesis of papillary RCCs in HLRCC. In order to find a genetic modifier of RCC risk in HLRCC, genome-wide linkage and identical by descent (IBD) analysis studies were performed in Finnish HLRCC families with microsatellite marker mapping and SNP-array platforms. The linkage analysis identified only one locus of interest, the FH gene locus in 1q43, but no mutations were found in the genes of the region. IBD analysis yielded no convincing haplotypes shared by RCC patients. Although these results do not exclude the existence of a genetic modifier for RCC risk in HLRCC, they emphasize the role of FH mutations in the malignant tumourigenesis of HLRCC. To study the benign tumours in HLRCC, genome-wide DNA copy number and gene expression profiles of sporadic and HLRCC ULMs were defined with modern SNP- and gene-expression array platforms. The gene expression array suggests novel genes involved in FH-deficient ULM tumourigenesis and novel genes with putative roles in propagation of sporadic ULM. Both the gene expression and copy number profiles of HLRCC ULMs differed from those of sporadic ULMs indicating distinct molecular basis of the FH-deficient HLRCC tumours.

Organic contaminants - occurrence and biological effects in the Baltic Sea

The Baltic Sea was studied with respect to selected organic contaminants and their ecotoxicology. The research consisted of analyses of total hydrocarbons, polycyclic aromatic hydrocarbons, bile metabolites, hepatic ethoxyresorufin-O-deethylase (EROD) activity, polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs). The contaminants were measured from various matrices, such as seawater, sediment and biota. The methods of analysis were evaluated and refined to comparability of the results. Polyaromatic hydrocarbons, originating from petroleum, are known to be among the most harmful substances to the marine environment. In Baltic subsurface water, seasonal dependence of the total hydrocarbon concentrations (THCs) was seen. Although concentrations of parent polycyclic aromatic hydrocarbons (PAHs) in sediment surface varied between 64 and 5161 ug kg-1 (dw), concentrations above 860 ug kg-1 (dw) were found in all the studied sub-basins of the Baltic Sea. Concentrations commonly considered to substantially increase the risk of liver disease and reproductive impairment in fish, as well as potential effects on growth (above 1000 ug kg-1 dw), were found in all the studied sub-basins of the Baltic Sea except Kattegat. Thus, considerable pollution in sediments was indicated. In bivalves, the sums of 12 PAHs varied on a wet weight basis between 44 and 298 ug kg-1 (ww). The predominant PAHs were high molecular weight and the PAH profiles of M. balthica differed from those found in sediment from the same area. The PAHs were both pyrolytic and petrogenic in origin, and a contribution from diesel engines was found, which indicates pollution of the Baltic Sea, most likely caused by the steadily increasing shipping in the area. The HPLC methods developed for hepatic EROD activity and bile metabolite measurements proved to be fast and suitable for the study of biological effects. A mixed function oxygenase enzyme system in Baltic Sea perch collected from the Gulf of Finland was induced slightly: EROD activity in perch varied from 0.30 14 pmol min-1 mg-1 protein. This range can be considered to be comparable to background values. Recent PAH exposure was also indicated by enhanced levels (213 and 1149 ug kg-1) of the bile metabolite 1-hydroxypyrene. No correlation was indicated between hepatic EROD activity and concentration of 1-hydroxypyrene in bile. PCBs and OCPs were observed in Baltic Sea sediment, bivalves and herring. Sums of seven CBs in surface sediment (0 5 cm) ranged from 0.04 to 6.2 ug kg-1 (dw) and sums of three DDTs from 0.13 to 5.0 ug kg-1 (dw). The highest levels of contaminants were found in the most eastern area of the Gulf of Finland where the highest total carbon and nitrogen content was found and where the lowest percentage proportion of p,p -DDT was found. The highest concentrations of CBs and the lowest concentration of DDTs were found in M. balthica from the Gulf of Finland. The highest levels of DDTs were found in M. balthica from the Hanö Bight, which is the outer part of the Bornholm Basin close to the Swedish mainland. In bivalves, the sums of seven CBs were 72 108 ug kg-1 (lw) and the sums of three DDTs were 66 139 ug kg-1 (lw). Results from temporal trend monitoring showed, that during the period 1985 2002, the concentrations of seven CBs in two-year-old female Baltic herring were clearly decreased, from 9 16 to 2 6 ug kg-1 (ww) in the northern Baltic Sea. At the same time, concentrations of three DDTs declined from 8 15 to 1 5 ug kg-1 (ww). The total concentration of the fat-soluble CBs and DDTs in Baltic herring muscle was shown to be age-dependent; the average concentrations in ten-year-old Baltic herring were three to five-fold higher than in two-year-old herring. In Baltic herring and bivalves, as well as in surface sediments, CB 138 and CB153 were predominant among CBs, whereas among DDTs p,p'-DDD predominated in sediment and p,p'-DDE in bivalves and Baltic herring muscle. Baltic Sea sediments are potential sources of contaminants that may become available for bioaccumulation. Based on ecotoxicological assessment criteria, cause for concern regarding CBs in sediments was indicated for the Gulf of Finland and the northern Baltic Proper, and for the northern Baltic Sea regarding CBs in Baltic herring more than two years old. Statistical classification of selected organic contaminants indicated high-level contamination for p,p'-DDT, p,p'-DDD, p,p'-DDE, total DDTs, HCB, CB118 and CB153 in muscle of Baltic herring in age groups two to ten years; in contrast, concentrations of a-HCH and g-HCH were found to be moderate. The concentrations of DDTs and CBs in bivalves is sufficient to cause biological effects, and demonstrates that long-term biological effects are still possible in the case of DDTs in the Hanö Bight.

Computational studies on new chemical species in the gas-phase and the solid-state.

There is intense activity in the area of theoretical chemistry of gold. It is now possible to predict new molecular species, and more recently, solids by combining relativistic methodology with isoelectronic thinking. In this thesis we predict a series of solid sheet-type crystals for Group-11 cyanides, MCN (M=Cu, Ag, Au), and Group-2 and 12 carbides MC2 (M=Be-Ba, Zn-Hg). The idea of sheets is then extended to nanostrips which can be bent to nanorings. The bending energies and deformation frequencies can be systematized by treating these molecules as an elastic bodies. In these species Au atoms act as an 'intermolecular glue'. Further suggested molecular species are the new uncongested aurocarbons, and the neutral Au_nHg_m clusters. Many of the suggested species are expected to be stabilized by aurophilic interactions. We also estimate the MP2 basis-set limit of the aurophilicity for the model compounds [ClAuPH_3]_2 and [P(AuPH_3)_4]^+. Beside investigating the size of the basis-set applied, our research confirms that the 19-VE TZVP+2f level, used a decade ago, already produced 74 % of the present aurophilic attraction energy for the [ClAuPH_3]_2 dimer. Likewise we verify the preferred C4v structure for the [P(AuPH_3)_4]^+ cation at the MP2 level. We also perform the first calculation on model aurophilic systems using the SCS-MP2 method and compare the results to high-accuracy CCSD(T) ones. The recently obtained high-resolution microwave spectra on MCN molecules (M=Cu, Ag, Au) provide an excellent testing ground for quantum chemistry. MP2 or CCSD(T) calculations, correlating all 19 valence electrons of Au and including BSSE and SO corrections, are able to give bond lengths to 0.6 pm, or better. Our calculated vibrational frequencies are expected to be better than the currently available experimental estimates. Qualitative evidence for multiple Au-C bonding in triatomic AuCN is also found.

Quantum Chemical Studies of Intermolecular Interactions

This thesis studies the intermolecular interactions in (i) boron-nitrogen based systems for hydrogen splitting and storage, (ii) endohedral complexes, A@C60, and (iii) aurophilic dimers. We first present an introduction of intermolecular interactions. The theoretical background is then described. The research results are summarized in the following sections. In the boron-nitrogen systems, the electrostatic interaction is found to be the leading contribution, as 'Coulomb Pays for Heitler and London' (CHL). For the endohedral complex, the intermolecular interaction is formulated by a one-center expansion of the Coulomb operator 1/rab. For the aurophilic attraction between two C2v monomers, a London-type formula was derived by fully accounting for the anisotropy and point-group symmetry of the monomers.

Computational Studies on Bimetallic Clusters

The chemical and physical properties of bimetallic clusters have attracted considerable attention due to the potential technological applications of mixed-metal systems. It is of fundamental interests to study clusters because they are the link between atomic surface and bulk properties. More information of metal-metal bond in small clusters can be hence released. The studies in my thesis mainly focus on the two different kinds of bimetallic clusters: the clusters consisting of extraordinary shaped all metal four-membered rings and a series of sodium auride clusters. As described in most general organic chemistry books nowadays, a group of compounds are classified as aromatic compounds because of their remarkable stabilities, particular geometrical and energetic properties and so on. The notation of aromaticity is essentially qualitative. More recently, the connection has been made between aromaticity and energetic and magnetic properties. Also, the discussions of the aromatic nature of molecular rings are no longer limited to organic compounds obeying the Hückel’s rule. In our research, we mainly applied the GIMIC method to several bimetallic clusters at the CCSD level, and compared the results with those obtained by using chemical shift based methods. The magnetically induced ring currents can be generated easily by employing GIMIC method, and the nature of aromaticity for each system can be therefore clarified. We performed intensive quantum chemical calculations to explore the characters of the anionic sodium auride clusters and the corresponding neutral clusters since it has been fascinating in investigating molecules with gold atom involved due to its distinctive physical and chemical properties. As small gold clusters, the sodium auride clusters seem to form planar structures. With the addition of a negative charge, the gold atom in anionic clusters prefers to carry the charge and orients itself away from other gold atoms. As a result, the energetically lowest isomer for an anionic cluster is distinguished from the one for the corresponding neutral cluster. Mostly importantly, we presented a comprehensive strategy of ab initio applications to computationally implement the experimental photoelectron spectra.

Statistical and Information-Theoretic Methods for Data-Analysis

In this Thesis, we develop theory and methods for computational data analysis. The problems in data analysis are approached from three perspectives: statistical learning theory, the Bayesian framework, and the information-theoretic minimum description length (MDL) principle. Contributions in statistical learning theory address the possibility of generalization to unseen cases, and regression analysis with partially observed data with an application to mobile device positioning. In the second part of the Thesis, we discuss so called Bayesian network classifiers, and show that they are closely related to logistic regression models. In the final part, we apply the MDL principle to tracing the history of old manuscripts, and to noise reduction in digital signals.

Power and Authority. Birgitta of Sweden and her Revelations

In the High Middle Ages female saints were customarily noble virgins. Thus, as a wife and a mother of eight children, the Swedish noble lady Birgitta (1302/3 1373) was an atypical candidate for sanctity. However, in 1391 she was canonized only 18 years after her death and became a role model for many late medieval women, who were mothers and widows. The dissertation Power and Authority Birgitta of Sweden and Her Revelations investigates how Birgitta went about establishing her power and authority during the first ten years of her career as a living saint, in 1340 1349. It is written from the perspectives of gender, authority, and power. The sources consist of approximately seven hundred revelations, hagiographical texts and other medieval documents. This work concentrates on the interaction between Birgitta and her audience. During her lifetime Birgitta was already regarded as a holy woman, as a living saint. A living saint could be given no formal papal or other recognition, for one could never be certain about his or her future activities. Thus, the living saint needed an audience for whom to perform signs of sanctity. In this study particular attention is paid to situations within which the power relations between the living saint and her audience can be traced and are open to critical analysis. Situations of conflict that arose in Birgitta s life are especially fruitful for this purpose. During the Middle Ages, institutional power and authority were exclusively in the hands of secular male leaders and churchmen. In this work it is argued, however, that Birgitta used different kinds of power than men. It is evident that she exercized influence on lay people as well as on secular and clerical authorities. The second, third, and fourth chapter of this study examine the beginning of Birgitta s career as a visionary, what factors and influences lay behind it, and what kind of roles they played in establishing her religious authority. The fifth, sixth, and seventh chapter concentrate on Birgitta s exercising of power in specific situations during her time in Sweden until she left on a pilgrimage to Rome in 1349. The central question is how she exercised power with different people. As a result, this book will offer a narrative of Birgitta s social interactions in Sweden seen from the perspectives of power and authority. Along with the concept of power, authority is a key issue. By definition, one who has power also has authority but a person who does not have official power can, nevertheless, have authority. Authority in action is defined here as meaning that a person was listened to. Birgitta acted both in situations of open conflict and where no conflict was evident. Her strategies included, for example, inducement, encouragement and flattery. In order to make people do as she felt was right she also threatened them openly with divine wrath. Sometimes she even used both positive persuasion and threats. Birgitta s power seems very similar to that of priests and ascetics. Common to all of them was that their power demanded interaction with other people and audiences. Because Birgitta did not have power and authority ex officio she had to persuade people to believe in her powers. She did this because she was convinced of her mission and sought to make people change their lives. In so doing, she moved from the domestic field to the public fields of religion and politics.

4QMMT - The Problem of the Epilogue

The main focus of this study is the epilogue of 4QMMT (4QMiqsat Ma aseh ha-Torah), a text of obscure genre containing a halakhic section found in cave 4 at Qumran. In the official edition published in the series Discoveries of the Judaean Desert (DJD X), the extant document was divided by its editors, Elisha Qimron and John Strugnell, into three literary divisions: Section A) the calendar section representing a 364-day solar calendar, Section B) the halakhot, and Section C) an epilogue. The work begins with text critical inspection of the manuscripts containing text from the epilogue (mss 4Q397, 4Q398, and 4Q399). However, since the relationship of the epilogue to the other sections of the whole document 4QMMT is under investigation, the calendrical fragments (4Q327 and 4Q394 3-7, lines 1-3) and the halakhic section also receive some attention, albeit more limited and purpose oriented. In Ch. 2, after a transcription of the fragments of the epilogue, a synopsis is presented in order to evaluate the composite text of the DJD X edition in light of the evidence provided by the individual manuscripts. As a result, several critical comments are offered, and finally, an alternative arrangement of the fragments of the epilogue with an English translation. In the following chapter (Ch. 3), the diversity of the two main literary divisions, the halakhic section and the epilogue, is discussed, and it is demonstrated that the author(s) of 4QMMT adopted and adjusted the covenantal pattern known from biblical law collections, more specifically Deuteronomy. The question of the genre of 4QMMT is investigated in Ch. 4. The final chapter (Ch. 5) contains an analysis of the use of Scripture in the epilogue. In a close reading, both the explicit citations and the more subtle allusions are investigated in an attempt to trace the theology of the epilogue. The main emphases of the epilogue are covenantal faithfulness, repentance and return. The contents of the document reflect a grave concern for the purity of the cult in Jerusalem, and in the epilogue Deuteronomic language and expressions are used to convince the readers of the necessity of a reformation. The large number of late copies found in cave 4 at Qumran witness the significance of 4QMMT and the continuous importance of the Jerusalem Temple for the Qumran community.

The Soviet Union, Finland and the Cold War : The Finnish Card in Soviet Foreign Policy, 1956-1959

From the Soviet point of view the actual substance of Soviet-Finnish relations in the second half of 1950s clearly differed from the contemporary and later public image, based on friendship and confidence rhetoric. As the polarization between the right and the left became more underlined in Finland in the latter half of the 1950s, the criticism towards the Soviet Union became stronger, and the USSR feared that this development would have influence on Finnish foreign policy. From the Soviet point of view, the security commitments of FCMA-treaty needed additional guarantees through control of Finnish domestic politics and economic relations, especially during international crises. In relation to Scandinavia, Finland was, from the Soviet point of view, the model country of friendship or neutrality policy. The influence of the Second Berlin Crisis or the Soviet-Finnish Night Frost Crisis in 1958-1959 to Soviet policy towards Scandinavia needs to be observed from this point of view. The Soviet Union used Finland as a tool, in agreement with Finnish highest political leadership, for weakening of the NATO membership of Norway and Denmark, and for maintaining Swedish non-alliance. The Finnish interest to EFTA membership in the summer of 1959, at the same time with the Scandinavian countries, seems to have caused a panic reaction in the USSR, as the Soviets feared that these economic arrangements would reverse the political advantages the country had received in Finland after the Night Frost Crisis. Together with history of events, this study observes the interaction of practical interests and ideologies, both in individuals and in decision-making organizations. The necessary social and ideological reforms in the Soviet Union after 1956 had influence both on the legitimacy of the regime, and led to contradictions in the argumentation of Soviet foreign policy. This was observed both in the own camp as well as in the West. Also, in Finland a breakthrough took place in the late 1950's: as the so-called counter reaction lost to the K-line, "a special relationship" developed with the Soviet Union. As a consequence of the Night Frost Crisis the Soviet relationship became a factor decisively defining the limits of domestic politics in Finland, a part of Finnish domestic political argumentation. Understood from this basis, finlandization is not, even from the viewpoint of international relations, a special case, but a domestic political culture formed by the relationship between a dominant state, a superpower, and a subordinate state, Finland.

Microeconometric Studies on Unemployment and Business Cycles

Väitöskirja koostuu neljästä esseestä, joissa tutkitaan empiirisen työntaloustieteen kysymyksiä. Ensimmäinen essee tarkastelee työttömyysturvan tason vaikutusta työllistymiseen Suomessa. Vuonna 2003 ansiosidonnaista työttömyysturvaa korotettiin työntekijöille, joilla on pitkä työhistoria. Korotus oli keskimäärin 15 % ja se koski ensimmäistä 150 työttömyyspäivää. Tutkimuksessa arvioidaan korotuksen vaikutus vertailemalla työllistymisen todennäköisyyksiä korotuksen saaneen ryhmän ja vertailuryhmän välillä ennen uudistusta ja sen jälkeen. Tuloksien perusteella työttömyysturvan korotus laski työllistymisen todennäköisyyttä merkittävästi, keskimäärin noin 16 %. Korotuksen vaikutus on suurin työttömyyden alussa ja se katoaa kun oikeus korotettuun ansiosidonnaiseen päättyy. Toinen essee tutkii työttömyyden pitkän aikavälin kustannuksia Suomessa keskittyen vuosien 1991 – 1993 syvään lamaan. Laman aikana toimipaikkojen sulkeminen lisääntyi paljon ja työttömyysaste nousi yli 13 prosenttiyksikköä. Tutkimuksessa verrataan laman aikana toimipaikan sulkemisen vuoksi työttömäksi jääneitä parhaassa työiässä olevia miehiä työllisinä pysyneisiin. Työttömyyden vaikutusta tarkastellaan kuuden vuoden seurantajaksolla. Vuonna 1999 työttömyyttä laman aikana kokeneen ryhmän vuosiansiot olivat keskimäärin 25 % alemmat kuin vertailuryhmässä. Tulojen menetys johtui sekä alhaisemmasta työllisyydestä että palkkatasosta. Kolmannessa esseessä tarkastellaan Suomen 1990-luvun alun laman aiheuttamaa työttömyysongelmaa tutkimalla työttömyyden kestoon vaikuttavia tekijöitä yksilötasolla. Kiinnostuksen kohteena on työttömyyden rakenteen ja työn kysynnän muutoksien vaikutus keskimääräiseen kestoon. Usein oletetaan, että laman seurauksena työttömäksi jää keskimääräistä huonommin työllistyviä henkilöitä, jolloin se itsessään pidentäisi keskimääräistä työttömyyden kestoa. Tuloksien perusteella makrotason kysyntävaikutus oli keskeinen työttömyyden keston kannalta ja rakenteen muutoksilla oli vain pieni kestoa lisäävä vaikutus laman aikana. Viimeisessä esseessä tutkitaan suhdannevaihtelun vaikutusta työpaikkaonnettomuuksien esiintymiseen. Tutkimuksessa käytetään ruotsalaista yksilötason sairaalahoitoaineistoa, joka on yhdistetty populaatiotietokantaan. Aineiston avulla voidaan tutkia vaihtoehtoisia selityksiä onnettomuuksien lisääntymiselle noususuhdanteessa, minkä on esitetty johtuvan esim. stressin tai kiireen vaikutuksesta. Tuloksien perusteella työpaikkaonnettomuudet ovat syklisiä, mutta vain tiettyjen ryhmien kohdalla. Työvoiman rakenteen vaihtelu saattaa selittää osan naisten onnettomuuksien syklisyydestä. Miesten kohdalla vain vähemmän vakavat onnettomuudet ovat syklisiä, mikä saattaa johtua strategisesta käyttäytymisestä.

Itsenäisen Suomen puolesta : Sotilaskomitea 1915-1918

For Independent Finland. The Military Committee 1915–1918 In the course of the First World War, several organizations were founded with the purpose of making Finland independent or, at least, restoring her autonomous status. The Military Committee was the most significant active independence organization in Finland in the First World War, in addition to the activist student movement, i.e., the Jaeger Movement. The Military Committee was an organization founded in 1915 by officers who had attended the Hamina Cadet School, with the goal of creating a national army for a liberation war against the Russian troops. It was believed that the liberation war should succeed only with the help of the German Army. With the situation in society continually tensing up in the autumn 1917, the Military Committee also had to figure on the possibility of a Civil War. The activities of the Military Committee started in the early part of 1915 when they were still small-scale, but they gained significant momentum after the Russian Revolution in March 1917. In January 1918, the Military Committee formed the general staff for the White Army, the Senate’s troops. The independence-related activities of the Hamina cadets in the years of the First World War were more extensive and multifaceted than has been believed heretofore. The work of the Military Committee was divided into preparations for a liberation war in Finland, on one hand, and in Stockholm and Berlin, on the other hand. In Finland, the Military Committee took part in intelligence gathering for Germany and in supporting the recruiting Jaegers, and later in founding the civil guard organization, in solving the law and order authorities issue, and finally in selecting the Commander-in-Chief for the Senate’s troops. The member of the Military Committee, especially Captain Hannes Ignatius of the Cavalry contributed greatly to the drafting of the independence activists’ national action plan in Stockholm in May 1917. This plan preceded the formation of the civil guard organization. The Military Committee’s role in founding the civil guards was initially minor, but in the fall of 1917, the Military Committee started to finance the activities of the civil guards, named several former officers as commanders of the civil guards and finally overtook the entire civil guard movement. In Stockholm and Berlin, the representatives of the Military Committee were in active contact with both the high command of the German Army and with the representatives of the Swedish Army. Colonel Nikolai Mexmontan, who was a representative of the Military Committee, collaborated with Swedish officers and Jaeger officers in Stockholm in coming up with comprehensive and detailed plans for starting the Liberation War. Under Mexmontan’s leadership, there were serious negotiations to enter into a confederation with Germany. Lieutenant Colonel Wilhelm Thesleff, on the other hand, became the commander of the Jaeger Battalion 27. The influence and importance of the Military Committee came to the forefront in independent and conflict-torn Finland. The Military Committee became a Senate committee on the 7th of January 1918, with its chairman, for all practical purposes, as the Commander-in-Chief in an eventual war. Lieutenant General Claes Charpentier was the chairman of the Military Committee from mid-December 1917 onwards, but on the 15th of January 1918 he had to resign in favour of Lieutenant General Gustaf Mannerheim. Soon after that, Mannerheim got an order from the chairman of the Senate P. E. Svinhufvud to organize and assume the leadership of the law and order authorities. The chairman of the Military Committee became the Commander-in-Chief of the Senate troops in January 1918, and the Military Committee became the Commander-in-Chief’s general staff. The Military Committee had turned from a clandestine organization into the first general staff of the independent Finnish Army.

Human genetic variation in the Baltic Sea region: Features of population history and natural selection

In this thesis, the genetic variation of human populations from the Baltic Sea region was studied in order to elucidate population history as well as evolutionary adaptation in this region. The study provided novel understanding of how the complex population level processes of migration, genetic drift, and natural selection have shaped genetic variation in North European populations. Results from genome-wide, mitochondrial DNA and Y-chromosomal analyses suggested that the genetic background of the populations of the Baltic Sea region lies predominantly in Continental Europe, which is consistent with earlier studies and archaeological evidence. The late settlement of Fennoscandia after the Ice Age and the subsequent small population size have led to pronounced genetic drift, especially in Finland and Karelia but also in Sweden, evident especially in genome-wide and Y-chromosomal analyses. Consequently, these populations show striking genetic differentiation, as opposed to much more homogeneous pattern of variation in Central European populations. Additionally, the eastern side of the Baltic Sea was observed to have experienced eastern influence in the genome-wide data as well as in mitochondrial DNA and Y-chromosomal variation – consistent with linguistic connections. However, Slavic influence in the Baltic Sea populations appears minor on genetic level. While the genetic diversity of the Finnish population overall was low, genome-wide and Y-chromosomal results showed pronounced regional differences. The genetic distance between Western and Eastern Finland was larger than for many geographically distant population pairs, and provinces also showed genetic differences. This is probably mainly due to the late settlement of Eastern Finland and local isolation, although differences in ancestral migration waves may contribute to this, too. In contrast, mitochondrial DNA and Y-chromosomal analyses of the contemporary Swedish population revealed a much less pronounced population structure and a fusion of the traces of ancient admixture, genetic drift, and recent immigration. Genome-wide datasets also provide a resource for studying the adaptive evolution of human populations. This study revealed tens of loci with strong signs of recent positive selection in Northern Europe. These results provide interesting targets for future research on evolutionary adaptation, and may be important for understanding the background of disease-causing variants in human populations.