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  • Koskela, Elina (Helsingin yliopisto, 2015)
    Intracranial aneurysms (IAs) affect 2-3% of the population. In Finland, their rupture rate has been exceptionally high. This study aims to evaluate the prevalence and risk factors affecting neuro-ophthalmic findings in patients undergoing treatment for IAs. We also investigate the utility of conventional head computed tomography (CT) in the diagnosis of Terson´s syndrome (TS, vitreous hemorrhage in association with aneurysmal subarachnoid hemorrhage (aSAH)). Patients treated endovascularly or microsurgically for their IAs at the Department of Neurosurgery, Helsinki University Central Hospital, in 2011 prospectively underwent a neuro-ophthalmic examination preoperatively and at 3 days, 14 days, 2 to 4 months, and 6 months postoperatively. Findings suggestive of TS, as independently reviewed by two radiologists, on conventional CT head scans were compared with dilated fundoscopic findings. Participants comprised 121 patients with a ruptured aneurysm and 142 patients with an unruptured intracranial aneurysm (UIA). TS was present on fundoscopy in 13 patients (11%); the overall observed agreement between the two radiologists was 96% (116/121), with a substantial κ of 0.69 (95% CI 0.56-0.82). On average, CT demonstrated sensitivity of 42% and specificity of 97%. Factors independently predicting TS were female gender (OR 5.34, 95% CI 1.05-27.17) and World Federation of Neurosurgical Societies (WFNS) grade (OR 15.05 for grades IV-V vs. I-III, 95% CI 3.07-73.89). For patients with aSAH, the frequencies of a third, fourth, or sixth nerve palsy were 11 (9%; preoperatively), 16 (13%; immediately postoperatively), and 3 (3%; at the last follow-up), compared with corresponding frequencies of 6 (4%), 15 (11%), and 7 (5%) for patients with UIAs. Significant risk factors for postoperative eye movement disorders (EMDs) among patients with UIAs were aneurysm location in the posterior circulation (OR 142.02, 95% CI 20.13-1002.22) and aneurysm size (OR 1.28, for each 1-mm increase in diameter, 95% CI 1.12-1.47). After a follow-up time of 6 months, patients with aSAH presenting with visual field defects (VFDs) for aneurysm- or operation-related reasons numbered 20 (19%); homonymous VFDs were the most prevalent finding, and in logistic regression analysis, they were significantly associated with the Hunt and Hess (H and H) grade (OR 4.45 for grades IV-V vs. I-III, 95% CI 1.21-16.39) and presence of intracranial hemorrhage (OR 8.93, 95% CI 2.14-37.28). By contrast, seven patients (5%) treated for a UIA had VFDs. Poor-grade aSAH (H and H or WFNS grade IV-V) appears to be a strong predictive factor for TS and VFDs. With a high specificity value, conventional head CT scan might prove a useful tool in the diagnosis of TS. Although a common finding in the acute postoperative stage of ruptured and unruptured IAs, EMDs show marked improvement during follow-up.
  • Ahlqvist, Kati (Helsingin yliopisto, 2015)
    Somatic stem cell (SSC) dysfunction is a common feature of mouse models of premature ageing, most of which are created by disturbing nuclear DNA repair, damage recognition or ROS defence. The SSC dysfunction leads to decline in SSCs ability to maintain tissue homeostasis resulting in degeneration and ageing. The role of mitochondria or mitochondrial DNA (mtDNA) integrity in SSC homeostasis is unknown. Mutator mice, which harbour proof-reading deficient mitochondrial DNA polymerase gamma, accumulate mtDNA point mutations and develop a premature ageing phenotype, whereas Deletor mice, a model for adult-onset mitochondrial myopathy, accumulate mtDNA deletions and have a normal lifespan. Accumulation of mtDNA mutations and respiratory chain (RC) defect are thought to contribute to ageing process, and the Mutator mouse was the first experimental evidence supporting this theory. The aim of this thesis work was to elucidate somatic stem cell function in both Mutator and Deletor models, to investigate whether SSC dysfunction might explain the premature ageing phenotype. Our results show that the Mutator mouse accumulates mtDNA point mutations in SSC compartments, leading to changes in SSC function already during embryonal development. Deletors do not accumulate mtDNA deletions in SSCs and have normal SSC function. This suggests that premature ageing of Mutators is due to disrupted SSC homeostasis. Hematopoietic progenitors are especially sensitive to mtDNA mutagenesis, which may partly explain the high prevalence of anemia without iron deficiency seen in elderly humans. In this thesis, a novel mechanism for mitochondrial anemias is presented. MtDNA mutagenesis in hematopoietic precursors modifies signaling which causes aberrant iron loading and delayed mitochondrial clearance from maturing erythrocytes. In consequence, Mutator mice have abnormal circulating erythrocytes carrying mitochondria, which are prematurely captured and destructed by splenic macrophages, leading to iron accumulation in spleen. Enhanced destruction of newly-born erythrocytes and concurrently depleted iron stores in the bone marrow make compensatory reticulocytosis inefficient. Delayed mitochondrial clearance was also detected in a human patient with Pearson s syndrome, a rare disorder caused by a sporadic single large mtDNA deletion and causing life-threatening anemia. Treatment with N-acetyl-L-cysteine (NAC), a glutathione precursor and a ROS scavenger, was able to rescue the SSC phenotype during embryogenesis and to normalize iron loading in vitro, suggesting that mtDNA mutagenesis affects ROS signaling. However, NAC could not prevent anemia in vivo, nor rescue delayed mitochondrial clearance in vitro. This indicates that signaling in the SSC compartment is different during embryogenesis than in adulthood. This thesis shows that mtDNA integrity is essential for SSC function. Further, a new and essential role is proposed for mitochondria in regulating their own removal from maturing reticulocytes.
  • Itkonen, Juha (Bank of Finland, 2015)
    Climate change is one of the greatest market failures of our time. This thesis consists of three essays in which we study the economics of climate change using networks as a theoretical framework. In the first essay, we discover flaws in the foundations of a recent strand of literature estimating the carbon Kuznets curve (CKC). The CKC hypothesizes that carbon dioxide emissions initially increase with economic growth but that the relationship is eventually reversed. The recent literature attempts to estimate the CKC by adding energy consumption as a control variable. Due to model misspecifications related to the econometric methodology and database definitions, the results are biased to support the existence of a CKC. Consequently, the literature underestimates the need for climate policies. In the second essay, we study how social networks might help to explain why differences of opinion about climate change persist across segments of the lay public despite the scientific consensus. To do this, we programmed a Facebook application that collected survey data on concerns about climate change and network data on friendships. We found that respondents tend to have friends with similar concerns as their own, the unconcerned respondents have fewer friends, and any two respondents who disagreed about the seriousness of global warming were less than half as likely to be friends. The results indicate that the structure of the social network may hinder changes in opinions, explaining why opinions persist despite the scientific consensus. The results suggest that the communication of climate science could be improved by strategies that aim to overcome these network effects. In the third essay, we study permit markets which are connected by a network of links. A link allows participants of one emissions trading system to use permits of other systems. In a linked network of markets, foreign regulators can influence domestic policy outcomes even without a direct link. We apply graph theory to study these dependencies between markets to determine who exactly can affect domestic emissions and prices. We characterize the equilibrium's dependency structure assuming perfect competition and an exogenous trading network. The results help to avoid unexpected foreign interference with domestic policy outcomes and to secure the effectiveness of climate change policies.
  • Kerola, Anne (Helsingin yliopisto, 2015)
    Rheumatoid arthritis (RA) is associated with a substantially increased risk for cardiovascular (CV) morbidity and mortality. Along with their CV burden, RA patients are at increased risk for other comorbidities such as hypothyroidism and depressive symptoms. The aim of this work was to evaluate the prevalence of CV comorbidities and hypothyroidism among RA patients in comparison to those of the general population at the time of RA diagnosis. We also aimed to determine, among patients with early RA, the contribution of psychiatric and CV comorbidities as causes of long-term work disability (WD). Lastly, we assessed CV mortality rates in early RA. Between 2000 and 2007, all patients diagnosed with RA in Finland were possible to identify from a Finnish nationwide register on special reimbursements for medicine expenses. The same register provided information on the presence of comorbidities antedating RA diagnosis. From the pension registers, we retrieved data on permanent or temporary disability pensions. Causes of death were obtainable until the end of 2008. We compared the main outcomes, that is, the prevalence of comorbidities at RA diagnosis, the incidence of comorbidity-related disability pensions, and CV mortality rates to those of the age- and sex-specific Finnish population, and calculated standardized rate, incidence and mortality ratios (SRRs, SIRs, and SMRs). In a population of 7,209 RA patients, the risk of having coronary heart disease (CHD) at RA diagnosis was slightly elevated, the SRR (95% CI) being 1.10 (1.01 1.20). The SRR for levothyroxine-treated hypothyroidism at RA diagnosis was 1.51 (1.35 to 1.67). SRR was highest, almost 2.5, among women with RA aged 20 to 49, the excess prevalence of hypothyroidism decreasing steadily and fading in older age groups. From 2000 to 2008, of 7,831 RA patients, 1,095 were granted a disability pension. The 9-year cumulative incidence of WD resulting from RA was 11.9%, from a psychiatric comorbidity 1.3%, and from a CV disease 0.5%. SIR of WD resulting from CV disease was 1.75 (1.23 to 2.51) and SIR of WD resulting from psychiatric disorders was 0.99 (0.80 to 1.23). By the end of 2008, of 14,878 RA patients, 1,157 had died, 501 (43%) from CV causes. The SMR in the entire RA cohort was 0.57 (0.52 0.62). To conclude, the risks for CHD and hypothyroidism were already higher among RA patients at RA diagnosis, highlighting the importance of CV risk detection and management and of vigilance for hypothyroidism. Psychiatric and CV comorbidities were the primary causes of long-term WD much less frequently than was RA itself; the risk for WD due to CV disease, however, was higher in RA than in the general population. During the era of modern treatment regimens for RA, the risk of CV death during the early years of RA was not elevated. All these findings together stress the importance of recognizing, preventing, and targeting comorbidities in RA, already in the early years of the disease.
  • Paalanen, Tommi (Sexpo-säätiö, 2015)
    The topic of the dissertation is applying of liberal sexual ethics to sexological work with clients, sexual politics and jurisprudential problems. The work consists of an introduction and six articles that look into 1) ethical challenges and tools in therapeutic practice concerning sexuality, 2) the ethical basis of sexuality counselling and utilizing ethics in working with clients, 3) societal and ethical dimensions of women s sexual power, 4) the meaning of objectification to the ethics of pornography, 5) legislative problems and consequent ethical questions caused by child pornography, and 6) the ethical justification of criminalizing sadomasochistic sex and violent pornography. The introduction presents philosophical background for the articles: John Stuart Mill s ethical liberalism and the liberal tradition built on it, including the concepts of liberties and rights, which compose the most central ethos of modern sexual culture. The philosophical basis of liberal sexual ethics is built on egalitarian social philosophy, ethical neutrality of sexual acticity and rejection of paternalism and moralism as liberty-limiting principles. The articles are concerned with questions about supporting freedom and autonomy in helping professions and justifying limiting them in the society. Each article looks into the questions within their own context and thus expands into necessary theoretical backgrounds, arguments, questions and consequences in legal philosophy, criminalization theory, ethical basis of helping professions and sexual politics. The articles share a question about, how liberal sexual ethics support sexual wellbeing of individuals in different contexts. A shared result emerges: prevailing practices should be consistently liberalized in professional ethics and policies concerning equality, sexuality and criminal issues. All of these fields nurture practices that are illiberal, inconsistent and moralist due to their historical and cultural contexts, and thus impede the highest possible realization of sexual rights and well-being.
  • Hirvilammi, Tuuli (Kelan tutkimusosasto, 2015)
    The starting point of this study is a paradoxical situation: the wellbeing of average Finns is very high but simultaneously their environmental impacts threaten the carrying capacity of the earth. The paradox raises the question of what would sustainable wellbeing be and how is it to be studied. This study aims to develop a theory of sustainable wellbeing that recognizes the interaction between people and nature, as well as the goals of sustainability. In this interdisciplinary study the ecological issues are integrated into wellbeing research both in theory and in the empirical research settings. The empirical substudies are based on data that explores the wellbeing, standard of living and natural resource use (material footprints) of minimum income receivers. Material footprints were measured with the MIPS method.The results present a theory of sustainable wellbeing that is based on a relational conception of man. It enables us to see the connections between people and ecosystems, and humans as a part of nature. Sustainable wellbeing is defined as an entity that consists of a sufficient and sustainable standard of living, purposeful and responsible behavior, significant relations and an alert presence. The study develops a dynamic framework that can be used to explain the relations between capabilities, functionings and natural resource use. In order to be sustainable, wellbeing should be eco-efficient, which means satisfying needs with a minimal load on the environment. The results also present an interdisciplinary methodological setting, which can be used to assess the limits of a socially and ecologically sustainable standard of living. The aim of the sustainable standard of living is to secure all people with necessary resources within the carrying capacity of nature.
  • Häkkinen, Margareeta (Helsingin yliopisto, 2015)
    Opioids are the most important drugs causing fatal poisonings. Determining whether an opioid death was poisoning may, however, be difficult even if involving appropriate toxicological laboratory investigation. Apart from heroin, little statistically significant data-analysis is available for interpretation of blood concentrations of opioids from various types of post-mortem cases. Tolerance, route of administration, and delay of death after drug administration all influence postmortem drug concentrations. In this thesis, quantitative blood concentration data extracted from the high-quality Finnish postmortem toxicology database was the investigative tool to overcome this problem. Opioid deaths typically involve drug abuse, and suspected drug-abuser deaths must, by Finnish law, undergo medico-legal examination. Medico-legal autopsy in these cases includes comprehensive drug screening and, based on its results, more specific drug quantification. This thesis combined concentration data stored in the postmortem toxicology database with information from death certificates issued by forensic pathologists to allow statistical comparisons between drug poisonings and other deaths, as well as between drug abusers and other users. Concentration data mainly involved drug concentrations in postmortem femoral blood, but drug concentrations in urine and parent drug/metabolite concentration ratios also allowed assessment of buprenorphine, codeine, and tramadol deaths. Opioid poisonings proved to be mainly unintentional polydrug poisonings, regularly involving benzodiazepines, gabapentinoids, and other psycholeptics. Buprenorphine and methadone blood concentrations in fatal poisonings remained within their therapeutic ranges, and these two opioids involved mostly abuse. Concentrations of the weak opioids tramadol and codeine were above their therapeutic ranges both in abuser cases and in fatal poisonings. Tramadol abuse was common but abuse of oxycodone, fentanyl, and codeine was rather low compared to their therapeutic use. Abuse of the gabapentinoids pregabalin and gabapentin was strongly associated with opioid abuse, and compared to gabapentin abuse, pregabalin abuse was proportionally more frequent. To prevent parenteral buprenorphine abuse, opioid maintenance treatment applied a combination product of buprenorphine-naloxone. This combination product is, however, abused as well, and monitoring its abuse is challenging. In this study, urine samples collected from living patients at different phases of opioid maintenance treatment supplemented the postmortem data. Based on the criteria established with these patients, combined with postmortem data and proper background information, a urine concentration limit was estimated for suspected parenteral abuse of the buprenorphine-naloxone product in postmortem cases. Deaths and fatal poisonings due to parenteral buprenorphine-naloxone abuse occurred frequently, and abuse of the combination product was proportionally even more fatal than was abuse of buprenorphine. The results of this study will assist in medico-legal cause-of-death investigations through providing quantitative reference concentrations for the interpretation of opioid-related deaths. Further, estimating the proportion attributable to prescription opioid abuse compared to that of other opioid use and creating abuser profiles for various opioids can promote public health through proper drug policy. In a clinical context, results may be helpful in evaluating possible drug abuse and compliance among prescription-drug users. Detecting abuse of these important yet addictive medications is vital in promoting welfare and drug safety.
  • Rantanen, Ville (Helsingin yliopisto, 2015)
    Images provide invaluable information to Biomedicine. Especially, microscopy as an information source has been providing knowledge for research and clinical diagnostics. We have moved away from simply looking at the images to quantifiable computerized image analysis. Over the last decades, image analysis developers have prepared algorithms and software to address various scientific enquiries using images. These software are often created for a single purpose. Naturally, not even the most generic software can include all the algorithms ever created. From an image analysis developer point of view, the choice of software creates limitations. It limits the developer to the algorithms included and to the language it was developed in. Even if the software is modular and extendable, a specific language is required and the earlier algorithm implementations would have to be ported. This thesis presents an integration platform for image analysis: Anima. It is capable of using existing software and including them in analysis workflows. Since image analysis is very case specific, custom processing commands are frequently needed. Anima comes with a large number of data and image analysis components developed directly for the platform, as well as components that send custom commands to the integrated software. All of the components can be executed in a single analysis pipeline. Anima itself is built on top of Anduril, another software, inheriting its software architecture. Anduril gives Anima the power of parallel processing and rerun prevention mechanism, speeding up the development cycle of new algorithms. The usability of Anima for method development is shown by implementing new segmentation algorithms and visualization tools. The tools and methods are all suited to large data sets. To display the modularity, the tools are published as separate programs that are then integrated in Anima. The usefulness of the platform is shown by applying it in different biomedical research settings. The settings include different organisms: human, rat and nematode; different sample material: brain tissue, lymphatic nodes and serum; and different medical interests: cerebral ischemia, cancer and allergy. Anima is a versatile open-source image analysis platform, that encourages the use of best practices of programming habits. It makes the development of analysis workflows and individual algorithms more efficient.
  • Nikkonen, Taru (Helsingin yliopisto, 2015)
    In photosynthetic systems, chlorophylls have a vital role in converting the energy of light into chemical energy. The absorption by antenna pigments and subsequent excitation energy transfer to the reaction centre, where charge separation processes take place, result in an electrochemical potential which is utilized in carbohydrate production. The structural properties of the chlorophylls as well as supramolecular interactions, mutual distances and orientations in their natural environment, determine the function of each pigment. The aim of this doctoral thesis was to mimic photosynthetic systems and to develop chlorophyll-based structures and materials for artificial photosynthetic applications. The literature review of this thesis will concentrate on the structural, photophysical, and supramolecular properties of chlorophyll derivatives. Their functions in natural environments and their potential use in artificial light-harvesting assemblies will be thoroughly discussed. The focus of the literature review will be solely on biomimetic systems that are built by the supramolecular approach. In addition to chlorophyll (chlorin) assemblies, supramolecular systems of some important chlorophyll analogues (e.g., porphyrins) are presented. The experimental part of this thesis is based on publications I-IV. Chlorophylls were separated from green algae and modified synthetically to achieve the desired photophysical and structural/supramolecular properties. In the first part of this thesis, the energy transferring antenna structure was designed utilizing a polymer, poly(4-vinylpyridine) (P4VP), to which Zn chlorin pigments were bound noncovalently through metal-ligand axial coordination. The investigation of the assemblies revealed tight coordination both in solution and solid state films. The absorptive and emitting regimes of the solid state Zn chlorin-P4VP assemblies with variable doping levels were determined. In another part of this thesis, a series of covalently linked chlorin dimers were synthesized and their intramolecular folding abilities were investigated using both spectroscopic and theoretical techniques. It was proven that chlorin dimers fold into a C2-symmetric structure via hydrogen bonding when the linker has a suitable length. To be exact, the folding was shown to be favored with 4-10 carbon atom linkers, of which the carbon linker with a 6-atom backbone was the most optimal. As a continuation of the work, the electron donating chlorin dimer was attached to an electron acceptor, fullerene, to give a chlorin dimer−azafulleroid. The experimental spectroscopical studies and theoretical investigations showed that the chlorin dimer−azafulleroid undergoes conformational switching depending on the polarity of the media. In nonpolar media, the hydrogen bonded folded dimer is present, while in polar media the two hydrophopic chlorins wrap around the azafulleroid. The photophysical studies indicated that the lifetime of photoinduced charge separation is longer in the folded conformation having similarities to the natural photosynthetic reaction centre special pair, that is, the self-assembled chlorophyll dimer that performs the primary electron transfer step in photosynthesis. Strong electron donors, such as ferrocene, Fe(η5-C5H5)2, and ruthenocene, Ru(η5-C5H5)2, are often utilized as electron donors in donor-acceptor pairs or conjugated to electron donors to achieve improved charge transfer properties with electron donating moieties. For the first time, metallocene-appended (either [Fe(η5-C5H5)(η5-C5H4)] or [Ru(η5-C5Me5)(η5-C5H4)]) chlorin derivatives were synthesized. The resulting metallocene-chlorins oxidized spontaneously under air to give certain oxidation products depending on the type of metallocene attached to the aromatic chlorin macrocycle. The oxidized metallocene-chlorins were characterized by steady-state and time-resolved absorption and emission spectroscopy.
  • Parviainen, Suvi (Helsingin yliopisto, 2015)
    It has been estimated that up to half of people living in industrial societies will get cancer. Almost all cancer deaths are caused by metastatic disease and only few metastatic solid tumors can be cured with available therapies. Therefore, novel therapeutic modalities are needed. Genetically engineered oncolytic viruses such as adenoviruses and vaccinia viruses are a promising therapeutic approach given their capacity to specifically replicate in and kill tumor cells as well as to reach distant metastasis. Oncolytic viruses have demonstrated good safety, tolerability and promising signs of anti-tumor efficacy in several clinical trials, but the efficacy of the therapy needs improvement to reach its full clinical potential. Adenoviruses are one of the most studied vectors in oncolytic virotherapy. Two major obstacles limiting the efficacy have been insufficient transduction of the tumor cells and the recognition of the virus by the immune system, which rapidly clears the virus from systemic circulation, hampering the overall efficacy. This study shows that novel capsid modifications can increase the transduction efficacy and oncolytic potency of the virus, and that embedding oncolytic virus in a silica implant might help to circumvent the problem of clearance by prompting only modest immune responses against the virus. Recently, arming oncolytic viruses with immunomodulatory molecules has been a major focus in virotherapy. Immunotherapy means inducing the patient´s immune system to recognize and attack the tumor and has been recently linked with oncolytic virotherapy, as the replication of the virus in the tumor can be immunogenic per se and also release cancer epitopes available for antigen-presenting cells. Host immune responses have been shown to be a key player in oncolytic virotherapy as the balance between anti-viral and anti-tumoral immunity determines the efficacy of the therapy. Oncolytic vaccinia virus possesses unique immunogenicity and mechanisms of action that are distinct from other treatment modalities, and its self-perpetuating nature provides an ideal platform for therapeutic transgenic insertion. Therefore we engineered novel oncolytic vaccinia viruses with granulocyte-macrophage colony-stimulating factor (GMCSF) or CD40-ligand and studied their ability to increase the therapeutical outcome and anti-tumor immune responses in preclinical animal models. In the final part of the thesis the life cycle of oncolytic vaccinia virus was studied in more detail as we were able to show that the life cycle was compromised in a feline squamous cell carcinoma cell line. This finding might be important for a deeper understanding of the vaccinia virus-host cell interactions.
  • Rantala, Mari H. (Helsingin yliopisto, 2015)
    Fertility in dairy cows has decreased worldwide, also in Finland. The most common reason for treatments of dairy cattle is various fertility disorders (18 % of all animals in 2013). In practice, decreased fertility warrants use of hormonal estrus synchronization protocols to control follicular waves and luteal regression to achieve acceptable pregnancy rates, without unwanted side effects such as short estrous cycles. In the earlier studies of our research group, short estrous cycles were noted in some cyclic dairy heifers and cows when estrus and ovulation were induced with agonistic analogues of prostaglandin F2α (PGF2α) and GnRH treatments administered 24 h apart. Possible causes for such induced short estrous cycles were further elucidated in the four experiments described in this thesis. Estrus and ovulation were induced with PGF2α and GnRH given 24 h apart during early (Day 7 after ovulation) or late (Day 14 after ovulation) diestrus. Also the effect of gonadorelin doses of 0.1 mg or 0.5 mg given 24 h after PGF2α on the occurrence of short estrous cycles, and on the preovulatory release of LH during 6 h following the gonadorelin administration was investigated. The effect of the time interval between PGF2α and GnRH (0 vs. 24 h) given during early diestrus on the occurrence of short estrous cycles was investigated in cyclic dairy heifers and cows. The expression of endometrial receptors of oxytocin, estrogen-α and progesterone as well as enzymes 20α-hydroxysteroid-dehydrogenase and cyclo-oxygenase-II, on Days 2 and 5 after ovulation was analyzed with real-time quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. The occurrence of induced short estrous cycles was significantly increased with simultaneous administration of PG and GnRH, but was neither related to the size of the preovulatory follicle nor to the GnRH-induced preovulatory release of LH. Also the basal postovulatory release of LH on Days 1, 3 and 5 after ovulation was similar for induced short and normal length estrous cycles. Lower basal LH concentration after ovulation coincided with higher progesterone concentration. The size of the preovulatory follicle was significantly larger when PG and GnRH were given 24 h apart during early diestrus in comparison with late diestrus, but the occurrence of short estrous cycles was similar. The size of the preovulatory follicle in cows did not correlate with the preovulatory secretion of estradiol-17β. The endometrial expressions of receptors and enzymes analyzed were similar for short and normal length estrous cycles. The results described should be taken into account in estrus synchronization protocols utilizing sequential treatments with PG and GnRH.
  • Törnroos, Maria (Helsingin yliopisto, 2015)
    The role of individual differences in perceptions of stress has long been recognized. Despite this, the models that are used to measure stress at the workplace the job strain model and the effort-reward imbalance model were developed to assess strenuous work characteristics and their health effects, regardless of the individual. Because work characteristics are usually measured using self-reports the measures cannot be completely objective. The present study examined the susceptibility of the job strain model and the effort-reward imbalance model to Five-Factor personality traits and cynicism. In addition, this study tested the longitudinal measurement invariance of the effort-reward imbalance scales. This study was part of the ongoing prospective, population-based Young Finns study. The measurements for the present study were carried out in 2001, 2007, and 2012. Five-Factor personality traits were assessed with a questionnaire on the Five-Factor model, and cynicism was assessed with a scale derived from the Minnesota Multiphasic Personality Inventory. Work characteristics were measured with questionnaires on the job strain model and the effort-reward imbalance model. The results showed that high neuroticism was associated with higher job strain and higher effort-reward imbalance and that high agreeableness was associated with lower job strain and lower effort-reward imbalance. High extraversion, high openness, and high conscientiousness were associated with lower job strain. Furthermore, high conscientiousness was related to lower effort-reward imbalance only in men. High job strain prospectively predicted higher cynicism six years later. The effort-reward imbalance scales achieved strict longitudinal measurement invariance and showed adequate criterion validity. Although developed to measure the structural work environment, the job strain model and the effort-reward imbalance model seem to be susceptible to Five-Factor personality traits especially to neuroticism and agreeableness. In addition, high job strain seems to have far reaching consequences on cynical attitudes. Furthermore, the results show that scores on effort-reward imbalance from different time points can reliably be compared with each other. This study shows that organizations and occupational health services should apply a more person-oriented approach to increasing wellbeing at work.
  • Santala, Johanna (Helsingin yliopisto, 2015)
    The spraing symptoms on potato tubers caused by Potato mop-top virus (PMTV) are considered as one of the most important quality problems in potato production in the Nordic countries. PMTV has a tripartite single stranded positive sense RNA genome. RNA-RdRp encodes the viral replicase. PMTV-CP codes for a coat protein (CP) and a read through part of CP associated with the vector transmission. RNA-TGB encodes three movement related triple gene block proteins (TGBp) and an 8 kDa cysteine rich protein (8K) implicated as suppressor of RNA silencing. The aim of this study was to find new host and viral factors affecting PMTV infection and detection. As only few PMTV sequences were available in databanks prior to this study, 28 PMTV isolates obtained from symptomatic and asymptomatic potato tubers were partially sequenced. Two distinguishable types of RNA-CP and RNA-TGB were found, each showing only little genetic variability. Occurrence of tuber symptoms did not correlate with the types of PMTV RNA but seemed to depend on potato cultivar and environmental conditions. Indeed, in some cultivars almost all PMTV infections were asymptomatic. Potato sprouts grown in dark were found to contain high titers of PMTV and can be used to test potatoes for PMTV. However, viral titers decreased rapidly in sprouts exposed to light. Accumulation of PMTV specific small interfering RNAs (siRNA) in both dark grown and light exposed sprouts indicated that RNA silencing was acting against the virus in the sprouts. Moreover, the amount of viral siRNA, as opposed to viral RNA, did not decrease in the light-exposed sprouts indicating that RNA silencing was enhanced in the light exposed sprouts. PMTV TGBp1 was found, and PMTV 8K confirmed, to act as weak suppressor of silencing. PMTV TGBp3 interacts with TGBp2 to target viral ribonucleoprotein complexes to plasmodesmata and further to adjacent cells, but TGBp2 and TGBp3 are recycled through endocytosis. PMTV TGBp3 was found to be phosphorylated on two tyrosine residues, both of which are located within tyrosine based sorting motifs implicated in endocytosis. Mutation of one of the sites led to strengthening of the TGBp2-TGBp3 interaction and restricted the virus to the originally infected cell. Therefore, tyrosine phosphorylation of TGBp3 seemed to affect PMTV infection by regulating the interaction between TGBp2 and TGBp3. According to this study, the current reliance on symptoms in seed potato inspections for PMTV is unreliable and risks spreading the virus to new fields. Light was found to accelerate antiviral silencing in sprouts, which may explain why PMTV and its symptoms are rarely detected in aboveground parts of potato plants. Tyrosine phosphorylation of TGBp3 marked the first evidence that viral proteins can be tyrosine-phosphorylated in plants. This find could offer means for breeding PMTV resistant potato cultivars.  
  • Miettinen, Samuli (2015)
    How is EU criminal legislative competence regulated after the Lisbon Treaty? The European Union has always had powers which affect national criminal law. Classic internal market judgments consider whether national criminal law measures are justified restrictions of freedom of movement. The Union s direct legislative powers in this field have developed more slowly through international agreements, Treaty revision and the case law of the Court of Justice on implied powers. This study asks what powers have been conferred on the Union in the field of substantive criminal law and how the exercise of its powers may be reviewed after the entry into force of the Lisbon Treaty. The questions raise a wide range of issues relevant to EU criminal law, but also to EU constitutional, administrative and institutional law. A state-centric view of European integration holds that EU criminal law powers were framed to preserve core areas of national sovereignty. Scholarship in the field of EU criminal law is often ambivalent or critical of centralized powers in this field. Addressing the Union s competence creep was at the heart of constitutional reforms incorporated by the Lisbon Treaty. This sentiment explains some unusual features of the field after those revisions: the emergency brake , the special position of the UK, Ireland and Denmark, limits to Court of Justice jurisdiction, the unanimity requirement for states participating in the European Public Prosecutor s office, more sensitive ex ante subsidiarity control, and limiting express criminal law powers to directives. Nevertheless, these limits are constructed from the reference point of EU institutional law. The survey of those elements shows that the foundations of these structures are unreliable. If codification was intended to limit creeping competence , the framers have failed. Case law of the Court of Justice of the European Union after December 2009 suggests that Article 83 TFEU, or even the complete set of legal bases in the Union s area of freedom, security and justice , is not an exhaustive codification of the Union s criminal law powers. The central question in the calculus, the Court s rules on choice of legal bases , has been susceptible to creative drafting and suffers from weak judicial oversight. Legislative practice suggests that the new safeguards can be sidelined in this process. Thus, the central, and important debates in EU criminal law on the meaning of specific concepts like minimum rules , what crimes can be included in the 83(1) list, and how the European Public Prosecutor should operate may be gradually sidelined by the incoming tide , or at least creeping competence in other estuaries. At the same time, Member States cling to pre-Lisbon practices that restrict the exercise of competence but which seem disconnected from the post-Lisbon legal framework. A detailed examination of this field finds anomalies in the external relations law of the Union, where pragmatism prevails. Small elements that have criminal law implications may be included within Union powers where express internal competence is doubtful. In others, declarations of competence appear to reserve powers to the Member States that the Union could lawfully exercise. The Court now accepts ancillary provisions with criminal law relevance in mainstream measures that do not offer the safeguards of the express criminal law provisions. This is demonstrated by analogy with the case law on issues in the area of freedom, security and justice . Thus, social security coordination measures can be based on the free movement provisions, criminal law obligations may be part of the common commercial policy, and agreements on the treatment of suspected pirates may properly be concluded as part of an agreement that is exclusively Common Foreign and Security Policy. The Court even allows the EU legislature to predetermine the success of any legal challenge because it relies primarily on textual evidence in recitals to determine the aim of the legislature. Thus, measures establishing information systems and exchange mechanisms concerning road traffic offences are measures of transport policy, not measures concerning cooperation in criminal matters, and data retention is an internal market measure. These judgments have surprised academics, national governments, and even EU institutions legal services. Questions also arise as to the effectiveness of the new safeguards even when they are not circumvented. The emergency brake may lead to consensualism, but it is not pulled when a Member State position that is presented as a red line is ignored. The pleadings of the opt-out states in key cases suggest that national governments are not policing their opt-out. National parliaments rarely raise formal subsidiarity concerns. Intervention is rare even if an EU proposal raises constitutional issues and overrules significant policy choices in national criminal law. National policy choices may be legitimate even if the Union has the technical capacity to overrule them. National criminal law scholars often argue that integration in criminal law will come at a high personal cost to the victims of that policy unless appropriate safeguards are developed. The Court of Justice has struggled to distinguish between criminal and civil rules in the European Union constitutional system. Instead, it has developed institutional safeguards that require, as far as possible, democratic decision-making. It has also begun to use fundamental rights, and in particular the Charter of Fundamental Rights, to test the legality of Union action. Thus, whilst its standard of review has been criticized in the past, the findings suggest the Court may be better placed to cope with the increasing trend to treat de facto penal law as administrative rules than the corpus of EU judicial review literature suggests. This research has used standard legal research methods but combines these with an element of the law in action in the field of EU transparency law. During the research, it became clear that the key research questions required material that had not been published. In order to study the drafting processes, the study sought and obtained series of documents that were not originally released for public use. These include legislative negotiation documents, legal opinions of the legal services, and even the pleadings of Member States and EU institutions in key constitutional law cases. One document was released through litigation; another is pending litigation. Both cases raise novel points in transparency law that may have wide-reaching consequences on the nature of the EU criminal legislative process. To what extent should it be open to public scrutiny? Should the Union consider strictly defined conferral or procedural limits to the enumerated powers? The history of constitutional limits is that they are circumvented at the first opportunity when a crisis presents itself. It is possible to conceive some which are more difficult to ignore than those which appear to have buckled under the strain of post-Lisbon practice. However, when limits are drafted in a strict form, this can later cause constitutional contortions that call into question the rule of law. Instead, the present criminal competence control has been effectively proceduralized: particular steps must be taken, but their review is likely to be unintrusive or sympathetic. More legal research is required in the pre-legislative stage, even to understand the nature of competence control. Debates in poorly studied legislative forums are likely to shed great light on the Union s constitution: what happens .
  • Nordman, Nina (Helsingin yliopisto, 2015)
    Analytical microsystems are attractive in modern bioanalysis where sample amounts often are low and fast analyses are required. Microsystems also provide the prospect of integrating several functional elements on a single platform. The aim of this work was to develop analytical microsystems for fast analysis of bio- and drug molecules. For this, microchips with separation- and injection channels and monolithically integrated electrospray ionization (ESI) emitter were fabricated of epoxy photoresist SU-8 by photolithography and adhesive bonding. For peptide mass fingerprinting and protein sequencing characteristic tryptic peptides were fast and easily separated and detected by microchip capillary electrophoresis (MCE)-ESI/mass spectrometry (MS). Additionally, protein identification based on tandem MS fragmentation data of a single tryptic peptide was achieved. Finally, this rapid (total analysis time below ten minutes) microchip method permitted analysis of human muscle cell lysates. For online coupling of microchip capillary isoelectric focusing (cIEF) to ESI/MS a bilateral sheath flow interface or a two-dimensional separation unit was integrated on-chip. Rapid focusing of peptides by their isoelectric points (pI) was achieved without pretreatment of the SU-8 surface. After focusing the peptides were electrokinetically mobilized toward ESI/MS. The two-dimensional chip design enabled unique separation selectivity for peptides based on both pI values and intrinsic electrophoretic mobilities by multiplex-cIEF-transient-isotachophoresis. Rapid metabolic profiling was demonstrated from urine after intake of tramadol or paracetamol. Both phase I- and II metabolites were separated and detected by MCE-ESI/MS within 35 s. In addition, Michaelis-Menten kinetics was successfully determined for the CYP450-mediated oxidation of bufuralol to 1-hydroxybufuralol. Sample preconcentration (pretreatment) was integrated on-chip by solid-phase extraction (SPE) and liquid-phase microextraction (LPME). For SPE, a monolith zone was firmly anchored at the injection cross of the MCE-ESI/MS microchip by laser induced photopolymerization. The monolith was selective toward hydrophobic and hydrophilic sample molecules and enrichment factors as high as 23-fold was achieved with a loading time as short as 25 s. In addition, LPME was easily downscaled to low volume applications and offered selectivity in the analysis of phase I metabolites compared to SPE. In contrast to previous research in the same field this work offers bioanalysis with several on-chip integrated steps (preconcentration, injection, separation, and analysis) without considerably increasing the short analysis times characteristic of microchip assays.
  • Anastasina, Maria (Helsingin yliopisto, 2015)
    Viruses infect all domains of life. They establish complex interactions with their host cells to subvert and hijack multiple cellular processes and warrant their own replication. Understanding virus-host interactions is critical to control spread of pathogenic viruses, develop vaccines and search for antivirals. Besides that, understanding virus-host interactions allows deciphering complex cellular processes and provides useful tools for biotechnology. My research is dedicated to influenza A virus, an important pathogen that infects humans worldwide, represents a constant health care threat and elicits continuous efforts to control the human spread of the disease. Influenza A expresses a non-structural protein NS1 that is a key regulator of viral interactions with the host cell and an important virulence factor. Versatile functions of NS1 modulate multiple cellular functions to secure viral replication. This work addresses several aspects of NS1-mediated modulation of core cellular processes. We discovered that NS1 binds to dsDNA and inhibits transcription of cellular genes, thus limiting antiviral responses. We found that NS1 secures general protein synthesis and mapped several residues within NS1 that are essential for this function. Further, we showed that the length of C-terminal ``tail'' of NS1 is essential for control of cellular antiviral responses and virus pathogenicity. The presented results increase the understanding of influenza A virus-host interactions and can be further utilized in the search for antivirals and vaccine development. In addition, this work provides a biotechnological application of influenza A NS1 protein for improvement of cell-free translation system.
  • Lehto, Hanna (Helsingin yliopisto, 2015)
    Objective: Aneurysms of the vertebral artery (VA) and its branch posterior inferior cerebellar artery (PICA) are rare, comprising only about 1 to 3% of all intracranial aneurysms. The series published thus far on these lesions are small. We aim to describe the special anatomical and morphological features of these aneurysms compared to aneurysms in other locations, and to describe the variety of symptoms they cause. We describe their treatment and analyze the outcome. Additionally, we describe their anatomy imaged with computed tomography angiography. Patients and methods: We reviewed retrospectively 9 709 consecutive patients with intracranial aneurysms treated in the Department of Neurosurgery at Helsinki University Central Hospital, Finland, between 1934 and 2011. The study population included 268 patients with 284 VA or PICA aneurysms or both. Follow-up data came from the Population Registry Centre (dates of death), Statistics Finland (causes of death), from written questionnaires to patients still alive, medical records of the Department of Neurosurgery, and for those deceased, medical records from all public health services. Results: Among all the aneurysm patients, 5.1% had an aneurysm in the VA or PICA. Most aneurysms, 51%, were located at the VA PICA junction. The proportion of fusiform aneurysms was 28%. Compared to patients with ruptured aneurysms at other locations, patients with a ruptured VA or PICA aneurysm were older and had a higher Fisher grade. Ruptured distal PICA aneurysms also re-bled more regularly. Compared to other ruptured aneurysms, ruptured VA and PICA aneurysms were smaller and more often fusiform. At least one VA or PICA aneurysm was treated in 209 (78%) patients. The most common technique for aneurysm occlusion was clipping, used in 107 aneurysms. Total occlusion of the aneurysm was achieved among saccular aneurysms in 90%, and among fusiform aneurysms in 61%. Within one year of aneurysm diagnosis, 26% of the patients were dead. Among those who survived a minimum one year and in whom the VA or PICA aneurysm received active treatment; those returning to an independent or their previous stage of life amounted to 92%. Conclusion: In treatment of VA and PICA aneurysms, their special anatomical and morphological features are challenge. Despite this, and often severe hemorrhage, most patients surviving the initial stage make a good recovery.
  • Buchholz, Matias (Helsingin yliopisto, 2015)
    The aim of the present work (Roman Law in Greek: Prolegomena to a Linguistic Study of the Composition and Semantics of the Byzantine Vocabulary of Procedural Law) is to study the composition and semantics of Byzantine Greek legal vocabulary, especially that related to procedural law, from the perspective of the Latin influence on Greek. The work is based on a contact-linguistic and semantic analysis of the occurrences of a number of relevant expressions in the primary sources (not only technical terms in the narrowest sense, but also polysemous words). These occurrences have been mainly extracted from the databases TLG (literary sources), PHI (inscriptions) and DDbDP (papyri). The work is not an exhaustive treatment of all relevant words. Instead, by focusing on a selection of examples and on methodological questions, it tries to open a new perspective on Byzantine legal language. The first main chapter (Chapter 4) provides an overview of the ways in which Latin influenced the composition of Byzantine legal vocabulary. Previous research has often focused on lexical borrowings, but, since these are only part of the story, I argue that our understanding of Byzantine legal vocabulary would benefit from an increased attention to semantic borrowings (loan translations/calques and borrowed meanings) and to unchanged Greek words (that is, their continued use vs. their marginalization through Latin influence). I also evaluate the usefulness of different criteria for the distinction between integrated and non-integrated lexical borrowings (Lehnwort vs. Fremdwort). I claim that, i.a., morphological adaptation is not a conclusive criterion, while frequency and distribution over different sub-genres of legal writings are more informative. In addition, I argue that the phenomenon of code-switching, practically neglected in previous studies on Byzantine legal language, was present and would warrant further linguistic research. Chapter 5 is devoted to the semantics of Byzantine legal vocabulary, especially to the ways it differed from that of Latin, and to whether these differences are due to contact-induced change or to language-internal developments. The meanings of individual words often contracted or expanded, and sometimes even shifted. I propose certain systematic effects, e.g., that loanwords are easily affected by a contraction of meaning, and that the lack of contact-induced semantic change is largely restricted to technical terms proper. These developments concerning individual words mean that the semantic structure of Byzantine legal vocabulary as a whole is different from the legal vocabulary of Latin. Even if this has no effects on the legal system itself, it certainly means that we are dealing with another view of that system.
  • Cousminer, Diana (Helsingin yliopisto, 2015)
    Puberty is a highly variable developmental stage marked by the development of secondary sex characteristics and the attainment of reproductive maturity. Variation during childhood developmental phases correlates with altered disease risk in adulthood; variation in pubertal growth and timing, in particular, correlates with adult risk for type 2 diabetes, obesity, adverse cardiovascular heath, and hormone-dependent cancers. While normal variation in age at menarche (AAM) has recently been investigated in large-scale genome-wide association (GWA) studies, the genetic regulation of male puberty remains less understood. Moreover, extreme variation in pubertal timing is a common cause for referral to pediatric specialists, while the underlying genetic factors are largely unknown. This work aimed to identify both common and rare genetic variants influencing pubertal growth and timing in both sexes. Utilizing Finnish population-based samples with frequent height measurements across puberty, we ran GWA of growth during late puberty and uncovered an association for variants near LIN28B, the most robust menarche-associated locus. Investigation of the longitudinal effects of two partly-correlated markers, one tagging a pubertal timing effect and one tagging an effect on adult stature, revealed distinct sex-specific association patterns with height growth from birth until adulthood. Thus, the LIN28B locus tags an important developmental regulator of both growth and maturational development. We then expanded to include European-wide samples within the Early Growth Genetics (EGG) Consortium. Genetic mapping of three pubertal growth traits revealed 9 novel pubertal growth variants in addition to LIN28B, 5 of which also associated with pubertal timing, and one which associated with childhood and adult body mass index (BMI). Longitudinal investigation of these variants showed diverse patterns of association with height growth, some of which contradicted epidemiological correlations between rapid prepubertal growth, advanced puberty, and reduced final adult stature. Given the complex relationships between these traits, tracking individual unique effects across multiple periods of growth may help uncover the pathways linking childhood development with adult health outcomes. Also within the EGG Consortium, GWA meta-analysis of Tanner genital and breast staging data uncovered the first robust male puberty locus on chromosome 16 near MKL2, a locus which also associates with advanced menarche, decreased pubertal growth, and shorter adult stature. Furthermore, part of the genetic architecture underlying the onset of puberty is shared between males and females, evidenced by the high correlation between menarche-advancing alleles and earlier male genital development. However, while BMI-increasing alleles strongly correlate with advanced breast development in girls, our data shows that these variants play a more complex role in male puberty. Finally, we performed targeted sequencing of the pericentromeric region of chromosome 2 previously robustly linked with constitutional delay of growth and puberty (CDGP), an extreme delay in normal pubertal timing, in multiply affected Finnish families. Analysis of shared low-frequency variation in genes and regulatory regions of the best functional candidate genes revealed 6 protein-altering variants in a single gene, DNAH6, in 10 of the families. However, follow-up sequencing in an additional 135 Finnish CDGP cases failed to provide evidence for enrichment of DNAH6 mutations compared to a large, unique set of SISu Finnish population controls. DNAH6 is potentially an appropriate candidate gene that may be involved in the regulation of steroid hormone biosynthesis by the cytoskeleton. This study highlights the difficulties of detecting susceptibility variants under a linkage signal for complex traits. Taken together, these results advance our understanding of the genetics of pubertal timing and development in both sexes. However, more work is needed to understand how each genetic locus functions in the biology of puberty and childhood growth, and further study of the genetic loci highlighted in this work may help pinpoint the mechanisms that link the timing of this important developmental stage with adult health and risk for common diseases. Keywords: puberty, development, growth, genome-wide association studies (GWAS), targeted sequencing, constitutional delay of growth and puberty (CDGP)
  • Andersen, Claus Elholm (University of Helsinki, 2015)
    You have to be on your guard On Literariness in Karl Ove Knausgård s My Struggle This dissertation is a discussion of literariness in Karl Ove Knausgård s novel My Struggle (2009-2011). I argue that My Struggle first and foremost is a novel and should be read accordingly. Though Knausgård might challenge the genre of the novel as we know it, I show how he does so within the framework of one of the strongest traditions in the 20th century. This tradition includes writers such as Proust, Joyce, and Thomas Mann, all of whom, like Knausgård, have sought to challenge the novel as such. Thus, Knausgård is stretching the limits of what a novel can be by taking his point of departure in the challenge that already exists in the genre. Read this way, Knausgård expands the limits of what a novel is and can do, so it becomes impossible to ignore him as a novelist. The dissertation is based on five articles published, or accepted for publication, in peer-reviewed academic journals. Combined, these articles show how Knausgård as a writer belongs to a literary tradition that can be seen as an extension of literary modernism. In each article, I identify what I have named the central paradox of the novel that Knausgård wants to write honestly about his life, but can only do so in the form of a novel and by using the literary devices from the world of fiction. It is through the analysis of this central paradox that I portray the literariness of the novel. Aside from the five articles, the dissertation also consists of a cap or a summarizing report where I place the articles in relation to the existing scholarship on Knausgård and explain my theoretical framework and why I consider it important to read My Struggle as novel. Here, I argue that the dissertation is in clear opposition to the majority of what has previously been written on Knausgård, where the focus has been on how Knausgård plays with reality and fiction instead of striving to understand what the novel is trying to say.